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  Caution needed in using oral polio vaccine beyond the cold chain: Vaccine vial monitors may be unreliable at high temperatures

  Indian J Med Res 135, April 2012, pp 36-38
  Ashutosh Shrivastava, Neeraj Gupta, Pramod Upadhyay & Jacob Puliyel
  Background & objectives: Stabilized live attenuated oral polio vaccine (OPV) is used to immunize children up to the age of five years to prevent poliomyelitis. It is strongly advised that the cold-chain should be maintained until the vaccine is administered. It is assumed, that vaccine vial monitors (VVMs) are reliable at all temperatures. VVMs are tested at 37°C and it is assumed that the labels reach discard point before vaccine potency drops to >0.6 log10. This study was undertaken to see Show More...Background & objectives: Stabilized live attenuated oral polio vaccine (OPV) is used to immunize children up to the age of five years to prevent poliomyelitis. It is strongly advised that the cold-chain should be maintained until the vaccine is administered. It is assumed, that vaccine vial monitors (VVMs) are reliable at all temperatures. VVMs are tested at 37°C and it is assumed that the labels reach discard point before vaccine potency drops to >0.6 log10. This study was undertaken to see if VVMs were reliable when exposed to high temperatures as can occur in field conditions in India. Methods: Vaccine vials with VVMs were incubated (10 vials for each temperature) in an incubator at different temperatures at 37, 41, 45 and 49.5°C. Time-lapse photographs of the VVMs on vials were taken hourly to look for their discard-point. Results: At 37 and 41°C the VVMs worked well. At 45°C, vaccine potency is known to drop to the discard level within 14 h whereas the VVM discard point was reached at 16 h. At 49.5°C the VVMs reached discard point at 9 h when these should have reached it at 3 h. Conclusion: Absolute reliance cannot be placed on VVM in situation where environmental temperatures are high. Caution is needed when using ‘outside the cold chain’ (OCC) protocols. Key words Cold chain - oral polio vaccine - vaccine potency- vaccine vial monitors Poliomyelitis is a disease caused by poliovirus. Stabilized live attenuated oral polio vaccine (OPV) is used to immunize children up to the age of five years. The vaccine being highly thermo-labile needs a stringently monitored cold-chain. All the vials of OPV have a temperature sensitive label, the vaccine vial monitor (VVM), attached at the time of manufacture, to prominently display the cumulative exposure to heat. It is a standard practice to discard vials when VVM colour changes to grey from white suggesting that the potency of the vaccine has dropped to >0.6 log101. It is strongly advised that the cold-chain should be maintained until the vaccine is administered. In a recent study2 reliance on VVMs was recommended to achieve less wastage. There was greater user-preference for carrying vaccines without cold packs on national immunization days (NIDs). It is assumed, that VVMs are completely reliable at all temperatures. Routinely, VVMs are tested in an accelerated degradation test at 37°C3,4. The heat sensitive polymers in the label change colour and it represents the cumulative exposure to heat. When vaccine potency has dropped to >0.6 log10 (vaccine unlikely to provide protection), the VVM inner square becomes darker than the outer reference ring (vial discard-point)4. It has been proven repeatedly that the monitors work well at 37°C and the labels reach discard point well before vaccine potency drops to >0.6 log101. However, it is not necessarily true that because vaccine virus degeneration matches colour changes on the VVM at 37°C, this will hold true at other temperatures. At higher temperatures virus may degenerate faster than the heat sensitive polymer. We carried out this study based on the known degradation rate of vaccine virus; to see if VVMs were reliable when exposed to higher temperatures as can occur in field conditions in India. In India, in the northern States of Uttar Pradesh, Bihar and Rajasthan, summer temperatures rise to 45°C routinely and sometimes go as high as 50°C5,6. The half life of polio vaccine virus is 48 to 72 h at 37°C, 24 h at 41°C, 14 h at 45°C and 3 h at 50°C7. Material & Methods The study was conducted in National Institute of Immunology, New Delhi in January 2010. For this study the VVMs on OPV bottles used for routine immunization in India were used. The bottles were kept in the deep freezer at -20°C. The vials were incubated in a lighted dry-incubator (Galaxy 48S made by New Brunswick, UK) at different temperatures. The tests were performed at 37, 41, 45 and 49.5°C. Ten vials were used for each test-run for convenience in calculations, in terms of percentages. Time-lapse photographs of the VVMs were taken hourly, using a Nikon D70s camera (Nikon D70s, Thailand) controlled by a PC through the Camera Control Pro 2 software (version 2.5.0, Japan). The digital images were examined to look for the time at which VVMs reached their discard-point. Two investigators (AS and NG) independently examined the digital images for the discard point and the difference of opinion (<5% cases) was resolved with the help of another investigator (JP). Results & Discussion At 37°C all 10 vials reached discard point within 43 h (well before 48 h when the vaccine potency deteriorates to a level that the vaccine is useless). At 41°C the vials reached discard point within 24 h. Here again the VVMs worked well. However at 45°C, only three vials reached discard point at 14 h. At 49.5°C no bottle reached discard point at 3 h which was the half life point of vaccine. Only 40 per cent vials reached discard point at 6 h, all 10 vials reached discard point only after 9 h (Table). The Fig. shows the disparity between virus viability and the discard point of the VVMs. Conventionally, VVMs were used within the cold chain where the vaccine is stored at temperatures below 8°C. Field workers are trained to place reliance on VVMs8. Experiments using the VVMs outside the cold chain were done by Halm and colleagues2. They used 20 dose vials, and at the end of the day, unopened vials were returned to cold storage for use on the following day, and so on, till the VVM reached discard point. They found that no vials reached discard point and needed to be thrown away unused, when this protocol was utilized. On the other hand, in the control group, three vials carried in ice-lined vaccine-carriers had to be disposed of, because the labels got wet and detached from their bottles. The ambient temperatures went up to 40°C during the study. Over 90 per cent supervisors and vaccinators preferred NIDs without ice packs and this will soon become the standard practice2. There is support for this form of innovation9. This study was done in the context of the temperatures in the states of Uttar Pradesh and Bihar in India where polio has been difficult to control and where summer temperatures rise to 45°C routinely and sometimes go as high as 50°C5. Our findings suggest that the VVMs are not reliable when exposed to high environmental temperatures. Previous studies have shown deterioration in virus levels resulting from thawfreeze cycles which are not indicated by the VVMs1. This makes the practice of returning vials exposed to ambient temperatures, to the freezer for storage at night and reuse later, particularly risky. The main shortcoming of our study was that we did not test for vaccine potency but depended on literature for determining the half life of the virus strain at different temperatures. It was not considered crucial because VVMs are not specific to any one strain of polio virus but generic to all polio viruses. Studies recommend looking at total virus load although specific virus, with differing heat labiality, may have different rates of degradation4. Under such circumstances, immunization against one strain may be ineffective although the total number of virus would be higher than the number required for passing the test of potency. The WHO recommends VVMs to be sealed in a plastic cover and tested in a water bath at 37°C8. In the present study incubator was used as this was more likely to mimic conditions in the field. In conclusion, absolute reliance cannot be placed on VVM in situation where environmental temperatures are high. Caution is recommended when using ‘outside the cold chain’ (OCC) protocols. References 1. Chand T, Sahu AK, Saha K, Singh V, Meena J, Singh S. Stability of oral polio vaccine at different temperatures and its correlation with vaccine vial monitors. Curr Sci 2008; 94 : 172-5. 2. Halm A, Yalcouye I, Kamissoko M, Keita T, Modjirom N, Zipursky S, et al. Using oral polio vaccine beyond the cold chain: a feasibility study conducted during the national immunization campaign in Mali. Vaccine 2010; 28 : 3467-72. 3. WHO. Manual of Laboratory methods for testing of vaccines used in the WHO Expanded Programme on Immunization (WHO/VSQ/97.04). WHO [WHO/VSQ/97.04]. 1997. WHO. Geneva Ref Type: Electronic Citation, http://whqlibdoc. who.int/hq/1997/WHO_VSQ_97.04_%28parts1-2%29.pdf, accessed on March 20, 2012. 4. WHO. Testing the correlation between vaccine vial monitor and vaccine potency (WHO/V&B/99.11). WHO . 1999. WHO. Geneva Ref Type: Electronic Citation, http://whqlibdoc.who. int/hq/1999/WHO_V&B_99.11.pdf, accessed on March 20, 2012. 5. SAARC. SAARC disaster management center New Delhi South Asia Disaster Report 2007. SAARC. 2010. 7-7-2010. New Delhi Ref Type: Electronic Citation, http://saarcsdmc. nic.in/pdf/publications/sdr/chapter-7.pdf, accessed on March 20, 2012. 6. Wikipedia. Geography of Uttar Pradesh. Wikipedia. 2010. Florida Ref Type: Electronic Citation, http://en.wikipedia.org/ wiki/Geography_of_Uttar_Pradesh, accessed on March 20, 2012. 7. WHO. Temperature sensitivity of vaccines (WHO/IVB/06.10). WHO Geneva . 2006. WHO. Ref Type: Electronic Citation, http://whqlibdoc.who.int/hq/2006/WHO_IVB_06.10_eng.pdf, accessed on March 20, 2012. 8. WHO. World Health Organization Vaccine vial monitor Training guidelines (WHO/EPI/LHIS/96.04). WHO. 1996. WHO. Geneva Ref Type: Electronic Citation, http:// whqlibdoc.who.int/hq/1996/WHO_EPI_LHIS_96.04_eng.pdf, accessed on March 20, 2012. 9. WHO. Making use of Vaccine Vial Monitors Flexible vaccine management for polio (WHO/V&B/00.14). WHO. 2004. WHO. Geneva Ref Type: Electronic Citation, http:// whqlibdoc.who.int/hq/2000/WHO_V&B_00.14.pdf, accessed on March 20, 2012.
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  Introducing Pentavalent Vaccine in India: How Public Interest Litigation Forced a Re-evaluation of the Evidence ENGLISH VERSION of article published in Turkish language

  Turkish Medical Association's journal
  Puliyel Jacob
  Introducing Pentavalent Vaccine in India: How Public Interest Litigation Forced a Re-evaluation of the Evidence The Istanbul Experience – Natural Immunity In the year 2000 researchers from Turkey contradicted conventional wisdom about Haemophilus influenzae type b (Hib) infection when they suggested that infants in Istanbul had high concentrations of maternally transferred anti-polyribosylribitol phosphate antibodies (anti-PRP) and they acquired natural active immunity at an early age.  Show More...Introducing Pentavalent Vaccine in India: How Public Interest Litigation Forced a Re-evaluation of the Evidence The Istanbul Experience – Natural Immunity In the year 2000 researchers from Turkey contradicted conventional wisdom about Haemophilus influenzae type b (Hib) infection when they suggested that infants in Istanbul had high concentrations of maternally transferred anti-polyribosylribitol phosphate antibodies (anti-PRP) and they acquired natural active immunity at an early age. Tastan and colleagues investigated naturally acquired anti-PRP in healthy children during the first year of life in a prospective longitudinal study repeatedly testing anti-Hib titres in a cohort of 64 to arrive at this conclusion. Prior to this, it was said that children under 2 years have poor immune response to capsular polysaccharide of Hib and that under 18 months, even children who develop invasive Hib infections such as meningitis, do not develop a substantial concentration of serum antibodies. In India, studies looking at antibody response to Hib vaccination showed that the babies had protective levels of antibodies even before vaccination was started. This was seen even at ages where passively acquitted immunity should have waned Also it was noted that post vaccination antibody titers raised some 10 fold higher in these children , than they did in the West. The incidence of Hib diseases is 6 per 100,000 in Asia compared to 109 per 100,000 in the Western Pacific and Oceanic countries An editorial in the Bulletin of the WHO also highlights this difference. The longitudinal study from Turkey provided insights into why the incidence of invasive disease with Hib is low in Asia and also why post-vaccination titers were so high here. In Asians the vaccine was acting like a booster immunization dose, in children who were already immune. Natural Immunity: Mechanisms The author and colleagues tried to find reasons for this difference in immune response in the different regions and it led them to studies from the early 1970s showing that many bacteria having cross-reactive antigens to the Hib capsular polysaccharide. Bradshaw et al. demonstrated the development of serologically specific precipitate antibodies to Hib, after immunisation of the animals (burros) with Staphylococcus aureus and Bacillus subtillis. They demonstrated that strains of Staplylcocci, Group D Streptococci, Diphtheroids and Escherichia colil have cross-reactive antigens to Hib. Robbins et al. studied infants and noticed enhanced immune response to H. influenzae capsular polysaccharide when they have concurrent crossreacting E. coli infection of the gut. Such infants had a rapid and sustained rise in antibody to Hib. E. coli infection is common in developing countries like India and this may explain why infants in such countries developed antibodies and natural immunity to Hib Research to Promote Vaccines Many studies have been done to provide evidence of the need to introduce Hib in India but they failed to yield suitable data. The best and perhaps the most expensive such study, done over 2 years by Minz and colleagues found a Hib meningitis incidence of only 7.1/100,000 children under 5. In India’s population of 125 million children under 5, there would be about 8750 cases of Hib meningitis. As these studies did not provide evidence of disease burden sufficient to warrant inclusion of immunization ‘Probe studies’ were introduced. Hib vaccine has been used as a ‘probe’ to evaluate the vaccine-preventable disease burden. According to Santosham, vaccine probe studies are randomized clinical trials of Hib vaccine in which non-specific endpoints such as purulent meningitis and radiographically confirmed pneumonia are used. The difference in the incidence of disease between vaccinated and unvaccinated children represents the vaccine-preventable disease burden. Probe studies were initiated in India also. However the probe study in Indonesia found more pneumonia (although not statistically significant) in the group vaccinated. The trial in Bangladesh found no significant reduction in either meningitis or pneumonia in those vaccinated with 3 doses of vaccine. We have published in the Indian Journal of Medical Research and the BMJ how a misleading press release suggesting benefits from the vaccine during the trial was released by WHO, GAVI and Johns Hopkins and others. WHO Changes Its Position on Evidence By happy coincidence, around this time the WHO changed its position on the need for evidence before including Hib in the routine immunization programmes of countries. The 1998 position paper states that countries should consider Hib burden before introducing the vaccine. The 2006 modification, instead recommends the inclusion of Hib vaccine in all routine immunization programs, regardless of national burden. According to information obtained under India’s Right to Information after the Bangladesh study (June 2000 to Sept 2003) showed the vaccine was not useful, the Accelerated Development and Introduction Plans (ADIP) of GAVI stopped further funding of the probe study in India (November 2006) quoting the changed WHO position paper. However by the time the Indian probe study was stopped, data from the first part of the study on incidence and mortality from pneumonia and meningitis had already been collected. Mortality in the three centers for meningitis ranged between 0 to 4.7%. Projecting this mortality data on the figures for meningitis obtained from the Minz study, one would expect 440 deaths among the 8750 cases of meningitis all over India. The vaccination of this population with Pentavalent vaccine (DPT + Hib + Hepatitis B) being recommended by the WHO ($10 for 3 doses/child) would cost $ 1250 million for vaccine alone. Without adding costs of administering the vaccine, if the vaccine is 100% efficacious, it would mean the cost is $3 million per life saved - in a country where per capita income is $1000 The DPT vaccine costs less than $0.30 per child. India at present manages to give this inexpensive DPT vaccine to only 50% of the population. This was to be replaced by a Pentavalent vaccine that costs $10 per child. In a desperate move to push the vaccine in India, GAVI has offered the vaccine free of charge for 3 years something it has not done before – not even in the poorest of poor countries in Africa. Death by Vaccine The cost is just one aspect of the problem. The other alarming aspect is deaths due to the Pentavalent vaccine. Deaths have been reported from Sri Lanka, Bhutan and Pakistan. These were investigated by expert committees and ‘no alternate cause of death’ was found. Using the Brighton Classification of adverse events following immunization (AEFI) this meant the vaccine was probably responsible for these deaths. However the expert committee looking into the deaths, removed the categories ‘probably related’ and ‘possibly related’ from the Brighton Classification, and reported the deaths were unrelated to vaccine. Public Interest Lawsuit (PIL) in the Delhi High Court A group of persons led by Professor K B Sexana (former Health Secretary to the Union of India) and including this author, filed a public interest lawsuit (PIL) in the Delhi High Court asking for the recommendation to introduce the Pentavalent vaccine be reconsidered given the high costs, low utility and risk of deaths. The Government of India then set up an ‘experts group’ to look into the matter and it was brought before a reconstituted National Technical Advisory Group on Immunization (NTAGI). The author was inducted into this NTAGI. The NTAGI suggested that the vaccine be introduced in only 2 states (Kerala and Tamil Nadu) to look for side effects and benefits if any. The programme was initiated in the two states around the 3rd week of December 2011. Pentavalent Deaths in Kerala and PIL in the Kerala High Court On the first day of starting the programme in Kerala one 2 month old baby died following immunization. The post mortem report suggested death was due to a hypersensitivity reaction. The Human Rights Legal Network (HRLN) filed an affidavit in the Kerala High Court on behalf of the mother of this girl who died, asking for the programme to be stopped. The Kerala High Court ordered the Government to submit its report. In its counter-affidavit the Government admitted that 4 children died from adverse events following immunization (AEFI) with the new vaccine within about a month of its introduction. No other clear ‘alternate cause’ of death was found as defined by WHO Brighton classification. One of the babies was under weight and the other had a heart murmur but the Government affidavit does not say these were considered the cause of the children’s death. At the time of writing the courts are yet to give their verdicts. Judicial oversight however has already had a salutary and moderating influence on the NTAGI and the Government, as it has had to look for evidence to justify the decisions made. Conclusion The purpose of the PIL endeavor has not been to thwart an immunization programme. The petitioners insist that they are pro-science, actively pro-vaccine and want to see the practice of ethical and evidence-based-medicine. The exercise has been undertaken to bring in an evidence-based-vaccine policy that mandates universally available free vaccines when they are cost effective and retards the entry of harmful vaccines and those being introduced purely for private profits. The Right to Information Act of 2005 in India and an independent judiciary have been useful in demanding accountability from government and asking for the evidence-of-efficacy from entities that are looking for easy profits and a share in the huge India market. Jacob Puliyel St Stephens Hospital Delhi India puliyel@gmail.com Puliyel is member of the National Technical Advisory Group on Immunization of the Government of India
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  Of Micro-organisms and Men: Immunity and Vaccines Malayalam article

  Chandrika 14 -20 April 2012
  Puliyel Jacob
  Of Micro-organisms and Men: Immunity and Vaccines The best laid schemes of mice and men- Often go awry John Steinbeck. 1937 There are billions of micro-organisms in our environment. Some have a symbiotic relationship with us, meaning that the relationship between man and the micro-organism are mutually beneficial. Thus there are bacteria resident in our gut, that eats some of the food we have eaten, but in return they make useful vitamins for us to absorb and use. If we kill these harmless Show More...Of Micro-organisms and Men: Immunity and Vaccines The best laid schemes of mice and men- Often go awry John Steinbeck. 1937 There are billions of micro-organisms in our environment. Some have a symbiotic relationship with us, meaning that the relationship between man and the micro-organism are mutually beneficial. Thus there are bacteria resident in our gut, that eats some of the food we have eaten, but in return they make useful vitamins for us to absorb and use. If we kill these harmless or good bacteria, two consequences follow. The first relates to losing out on the benefits provided by the bacteria like the vitamins produced. The other more dangerous, relates to the replacement bacteria. If we kill the bacteria in our gut with a powerful antibiotic, then other bacteria will replace them and these may be harmful bacteria and they will certainly be antibiotic resistant. This replacement phenomenon occurs sometimes even if we use vaccines to eliminate resident micro-organisms. Not all micro-organisms are good for man. Some produce disease and death. Some harmless bacteria may themselves become harmful to us when our resistance is lowered. Thus Staphylococcus epidermidis is part of human skin flora but in people with catheters (like patients undergoing dialysis) this can produce lethal disease. It is important to hold this complexity at the back of our minds when we consider vaccines and immunity. How vaccines work If a child gets a disease like chicken-pox he will get a little fever and a couple of boils and after a few days he will recover. The reason for his recovery is that the body recognizes this new viral invasion and produces antibodies against the virus. Once produced, the antibodies eliminate the chicken pox virus. And after this the person will never ever get chicken pox, because he is now immune. Not only that, women who have had chicken pox pass on some of these antibodies to their babies and their babies are protected by this immunity got from mothers (called passive immunity) for 3 to 9 months. During this period, if the child comes across infection, they may get a very mild type of infection that goes unnoticed. With this mild infection, the child develops active immunity that lasts a life time. If we kill the virus and inject its protein into the skin, the dead virus cannot produce infection. However the body may take up the viral protein and make antibodies as if this were a real infection. This is the principle behind vaccines. It has been a major advancement in our battle against disease. Evaluating Costs and Benefits Vaccines against deadly diseases like small pox that spread easily in the community are a good idea but there is no meaning in making vaccines against every mild disease. This can do harm in a number of ways. 1. The vaccine may be associated with side effects more harmful than the disease. The Pentavalent vaccine seems to fall in this category but this has been discussed else where in this magazine. 2. The replacement organisms that take the place of the eliminated bacteria or virus may in fact be more lethal than the original organism. An example of this is seen when they used the 7 valent pneumococcal vaccine in the West. The new strains (that replaced the old vaccine strains) were more harmful and more antibiotic resistant. 3. The cost: benefit ratio of the vaccine. This is a crucial factor especially when considering vaccines for minor diseases, because the vaccine has to be given to everyone in the community to prevent a disease which may have affected only one or two persons. The cost of treating the mild disease in these two must be compared to the cost of giving the vaccine to every one in the community. Often investing in other programmes will save many more lives than spending money on vaccine against minor diseases. Hypersensitivity and the Pentavalent Vaccine In this context it is pertinent to discuss the Pentavalent vaccine being pushed by vaccine manufacturers and some international organisations. The vaccine is known to have caused deaths in Sri Lanka, Bhutan and Pakistan. No other cause for the deaths were found on investigation, and according to the WHO’s Brighton criteria, this makes vaccine the probable cause of death. Many persons have received the vaccine with no harmful effects. The reactions appear to be a hypersensitivity reaction in some persons. This is why the National Technical Advisory Group on Immunization (NTAAGI) insisted that before it is introduced in the country we must look for side effects and deaths in a limited area. An example of a drug that causes hypersensitivity reaction and deaths is Penicillin injections. This is why doctors test for sensitivity to penicillin every time before giving it. There is however no test for sensitivity to Pentavalent vaccine and so if Pentavalent vaccine cause hypersensitivity in some – it cannot be used in the national immunization programme because every child is at risk of death from undetected hypersensitivity. Jacob Puliyel Puliyel@gmail.com Puliyel is member of the Government of India’s National Technical Advisory Group on Immunization --------------------------------------- The Mathematics Of Pentavalent Vaccine The vaccine costs Rs 525 per child and this is the final price we will be paying, although it is being provided free for a short time (like sales men push introductory offers). The DPT vaccine costs less than Rs 15/child is to be replaced with this expensive vaccine. India at present manages to give this cheap (Rs 15) DPT vaccine to only 50% of the population. The new vaccine adds protection against Hib and Hepatitis B which are not known to be a major problem in the country. For the majority Hepatitis B carriers, it is a harmless virus that does little harm. Hib rarely (7 cases per every 100,000 children under 5) produces meningitis. The mortality from meningitis in the multi-center study done by the government was 0 to 4.7%. This means that there are 8850 cases of Hib meningitis in the whole country with (1250 lac children under 5), and some 440 deaths. If we assume 10% meningitis die (double the highest mortality seen in the study) that makes 880 deaths. The cost of vaccinating 1250 lac children and the cost per life saved are now easy to calculate. In an affidavit filed by the Government of Kerala, within about a month of starting the programme in Kerala, 4 children died after vaccination. No other clear ‘alternate cause’ of death was found under the WHO Brighton classification (although one baby was a little under weight and the other had a heart murmur) the Government affidavit does not say this was the cause of the children’s death. If 4 children died in a month, it means that some 40 to 48 children will die in Kerala from the vaccine each year and if we project this on India’s population (which is 50 times the Kerala population) 2000 children will die from the vaccine ( which is given to protect 440 children who would otherwise die from the disease). The remedy is worse than the malady – the vaccine is worse than the disease. Dr P G Hari Dr Hari is the petitioner in the PIL in the Kerala High Court in response to whose petition the Government had admitted to the deaths from Pentavalent vaccine
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  Polio programme: let us declare victory and move on

  Indian Journal of Medical Ethics Vol IX No 2 April - June 2012 Page 114-7. http://www.issuesinmedicalethics.org/pdfs/202co114.html.pdf
  Neetu Vashisht, Jacob Puliyel
  TITLE: Polio programme: let us declare victory and move on AUTHORS: Neetu Vashisht1, Jacob Puliyel1 AFFILIATION: Department of Paediatrics, St Stephens Hospital, Delhi 110054 INDIA Author for correspondence: Jacob Puliyel: e-mail puliyel@gmail.com Abstract It was hoped that following polio eradication, immunization could be stopped. However the synthetesis of polio virus in 2002, made eradication impossible. It is argued that getting poor countries to expend their scarce resources on a Show More...TITLE: Polio programme: let us declare victory and move on AUTHORS: Neetu Vashisht1, Jacob Puliyel1 AFFILIATION: Department of Paediatrics, St Stephens Hospital, Delhi 110054 INDIA Author for correspondence: Jacob Puliyel: e-mail puliyel@gmail.com Abstract It was hoped that following polio eradication, immunization could be stopped. However the synthetesis of polio virus in 2002, made eradication impossible. It is argued that getting poor countries to expend their scarce resources on an impossible dream over the last 10 years was unethical. Furthermore, while India is polio-free for a year, there has been a huge increase in non-polio acute flaccid paralysis (NPAFP). In 2011 there were an extra 47500 new cases of NPAFP. Clinically indistinguishable from polio paralysis but twice as deadly, the incidence of NPAFP was directly proportional to doses of oral polio received. Through this data was collected within the polio surveillance system, it was not investigated. The principle of primum-non-nocere was violated. The authors suggest that the huge bill of US$ 8 billion spent on the programme, is a small sum to pay if the world learns to be wary of such verticle programmes in the future. “For of all sad words of tongue or pen, the saddest are these: 'It might have been!” John Greenleaf Whittier (1807-1892) January 12, 2012, marked a significant milestone for India. It was the first anniversary of the last reported wild polio case from India. Keeping the country free of polio for a whole year was a feat that is a tribute to the Government of India and its 2.3 million vaccinators, who visited over 200 million households to ensure that the nearly 170 million children (under five years in age) were repeatedly immunised with oral polio vaccine (OPV) (1). India’s programme has largely been self financed. The country has thus far spent more than Rs 120 billion (US$2.5 billion US$ 1 = Rs 50) on polio eradication after the programme started here in 1994 (2). The $2.5 billion spent by India must be seen against $2 billion spent by the United States of America on world-wide polio eradication (3), the $1.3 billion expended by Bill Gates (4), and the $0.8 billion raised by the loudest voice for polio eradication - Rotary International - over the last 20 years (5). The celebrations of January 12, 2012 would have been accompanied by a collective, massive sigh of relief because a new ‘name and shame’ policy has been adopted by the World Health Organisation (WHO), apparently without approval (6), to boost the eradication effort. In this vein, the acronym PAIN has been used, while referring to the polio-endemic countries of Pakistan, Afghanistan, India and Nigeria. While the exact origin of this oft-repeated acronym is unclear (7,8), India will be happy to be rid of the opprobrium. Internationally, supporters of eradication desperately needed a victory in India to drum up enthusiasm, at a time when commitment to the programme had been flagging, and funding was rapidly drying up. With a $410 million shortfall in the funds available, this gap threatens to undermine eradication efforts (9). While India chalked up a year of being polio free, four other countries, Angola, Chad, The Democratic Republic of Congo and Sudan, have had year-long outbreaks. Another 13 countries have had recent infections - eight in Africa, along with Nepal, Kazakhstan, Tajikistan, Turkmenistan and Russia (10). The ethics of spending so much on polio eradication has been challenged by Richard Horton, editor of the Lancet (11), and Arthur L Caplan, director of the University of Pennsylvania’s bioethics centre (12). Besides, former supporters of the programme are now questioning its feasibility (13-16). History and origin Professor William Muraskin, the noted historian who specialises in problems of international health policy and infectious disease, has written in his book Polio Eradication and its Discontents that the polio programme was primarily designed to prove the fundamental usefulness of eradication as a public health tool by the Pan American Health Organisation (PAHO) - the incubator of eradication campaigns (17). It is noteworthy that the Pulse Plus programme was begun in India with a $ 0.02 billion grant from overseas in 1995 (18), at a time when experts in India felt that polio eradication was not the top priority for the country. Four years into the programme of eradication, in 1998, Dr T Jacob John wrote, “Today poliomyelitis is not the number one priority of public health in India. However, we must eradicate it for the sake of the rest of the world.” (19) Having accepted the grant of $ 0.02 billion, India has spent a hundred times as much. This is a startling reminder of how initial funding and grants from abroad distort local priorities. Terminology: eradication versus elimination versus control The first step in understanding the issue is to clarify what the term eradication implies as distinct from elimination and control of disease. The different concepts have been described by Dowdle (20) • Control is the reduction of disease to a locally acceptable level as a result of deliberate efforts; continued intervention is required to maintain the reduction. • Elimination is reduction of the incidence of a disease to zero in a defined geographical area as a result of deliberate efforts. Even after elimination, continued intervention is needed to maintain the incidence at zero. • Eradication is the permanent reduction to zero of the worldwide incidence of infection as a result of deliberate efforts such that intervention is no longer needed. • Extinction is said to have occurred when the specific infectious agent no longer exists in nature or in the laboratory. Eradication spares future generations the risk of infection and renders further vaccination unnecessary. Eradication is thus considered an investment with resultant huge savings from not having to vaccinate any more (6, 21). Caplan, in his essay entitled ‘Is disease eradication ethical?’, has noted that eradication may be public health’s greatest rhetorical weapon and unmatched in its ability to command funding, popular support, the attention of politicians and positive media coverage (12). The stakes involved portend relief forever as well as the ability to relax humanity’s guard against the disease (12). Synthetic polio makes eradication impossible The charade about polio eradication and the great savings it will bring has persisted to date. It is a paradox that while the director general of WHO, Margret Chan, and Bill Gates are trying to muster support for polio eradication (22) it has been known to the scientific community, for over 10 years, that eradication of polio is impossible. This is because in 2002 scientists had synthesised a chemical called poliovirus in a test-tube with the empirical formula C332,652H492,388N98,245O131,196P7,501S2,340. It has been demonstrated that by positioning the atoms in sequence, a particle can emerge with all the properties required for its proliferation and survival in nature (23, 24). Wimmer writes that the test-tube synthesis of poliovirus has wiped out any possibility of eradicating poliovirus in the future. Poliovirus cannot be declared extinct because the sequence of its genome is known and modern biotechnology allows it to be resurrected at any time in vitro. Man can thus never let down his guard against poliovirus. Indeed the 18-year-old global eradication campaign for polioviruses will have to be continued in some format forever. The long promised “infinite” monetary benefits from ceasing to vaccinate against poliovirus will never be achieved (24). The attraction that ‘eradication’ has for policy makers will vanish once this truth is widely known. The elephant in the room: the problem of non-polio Acute Flaccid Paralysis (AFP) It has been reported in the Lancet that the incidence of AFP, especially non-polio AFP has increased exponentially in India after a high potency polio vaccine was introduced (25). Grassly and colleagues suggested, at that time, that the increase in AFP was the result of a deliberate effort to intensify surveillance and reporting in India (26). The National Polio Surveillance Programme maintained that the increased numbers were due to reporting of mild weakness, presumably weakness of little consequence (27). However in 2005, a fifth of the cases of non-polio AFP in the Indian state of Uttar Pradesh (UP) were followed up after 60 days. 35.2% were found to have residual paralysis and 8.5% had died (making the total of residual paralysis or death - 43.7%) (28). Sathyamala examined data from the following year and showed that children who were identified with non-polio AFP were at more than twice the risk of dying than those with wild polio infection (27). Data from India on polio control over 10 years, available from the National Polio Surveillance Project, has now been compiled and made available online for it to be scrutinised by epidemiologists and statisticians (29). This shows that the non-polio AFP rate increases in proportion to the number of polio vaccines doses received in each area. Nationally, the non-polio AFP rate is now 12 times higher than expected. In the states of Uttar Pradesh (UP) and Bihar, which have pulse polio rounds nearly every month, the non-polio AFP rate is 25- and 35-fold higher than the international norms. The relationship of the non-polio AFP rate is curvilinear with a more steep increase beyond six doses of OPV in one year. The non-polio AFP rate during the year best correlates to the cumulative doses received in the previous three years. Association (R2) of the non-polio AFP rate with OPV doses received in 2009 was 41.9%. Adding up doses received from 2007 increased the association (R2 = 55.6% p < 0.001) (30). Population density did not show any association with the non-polio AFP rate, although others have suggested that it is related to polio AFP (31). The international incidence of non-polio AFP is said to be 1 to 2/100,000 in the populations under 15 (32, 33). The benchmark of good surveillance is the ability to detect one case of AFP per 100,000 children even in the absence of polio (34). In 2011, an additional 47,500 children were newly paralysed in the year, over and above the standard 2/100,000 non-polio AFP that is generally accepted as the norm. (32-33). It is sad that, even after meticulous surveillance, this large excess in the incidence of paralysis was not investigated as a possible signal, nor was any effort made to try and study the mechanism for this spurt in non-polio AFP. These findings point to the need for a critical appraisal to find the factors contributing to the increase in non-polio AFP with increase in OPV doses – perhaps looking at the influence of strain shifts of entero-pathogens induced by the vaccine given practically once every month. From India’s perspective the exercise has been extremely costly both in terms of human suffering and in monetary terms. It is tempting to speculate what could have been achieved if the $2.5 billion spent on attempting to eradicate polio were spent on water and sanitation and routine immunisation. Perhaps control of polio, to the level of elimination, may well have been achieved as it has been in more developed countries. When the US was badly mired in Iraq in 2005, Joe Galloway suggested that the US must simply declare victory, and then exit (35). Perhaps the time is right for such an honourable strategy with regard to polio eradication. Strategy for the future Eckard Wimmer has noted the WHO's current policy calls for cessation of OPV vaccination three years after the last case of poliovirus-caused poliomyelitis. Injectable polio vaccine (IPV) will replace OPV in countries which can afford it. The risks inherent in this strategy are immense. Herd immunity against poliomyelitis will rapidly decline as new children are born who have not been infected with wild-type viruses or were not vaccinated, a situation that has never existed in human history. Thus, any outbreak of poliomyelitis will be disastrous, whether it is caused by residual samples of virus stored in laboratories, by vaccine-derived polioviruses, or by poliovirus that is chemically synthesised with malignant intent (24). The huge costs of repeated rounds of OPV in terms of money and non-polio AFP shows that monthly administration of OPV must cease. The low incidence of non-polio AFP in places given less than six doses, suggests that routine immunisation is relatively safe. Our resources are perhaps better spent on controlling poliomyelitis rather than trying to eradicate the disease. Routine immunisation must be strengthened and perhaps one or two rounds of pulse polio may be needed. The problem however is that the manufacturers of OPV may cease to produce the vaccine - a scenario that was predicted for India eight years ago (36). The Government of India is in a quandary, having given up its capacity to manufacture OPV indigenously, on misguided advice from overseas (37). It is now dependent on international manufacturers for its supplies. India needs to urgently ensure that adequate supplies of the vaccines that it requires are available for our children, so that this eradication adventure does not transform itself into an epidemic disaster. Conclusion The ethics of polio eradication and other vertical programmes The polio eradication programme epitomises nearly everything that is wrong with donor funded ‘disease specific’ vertical projects, at the cost of investments in community-oriented primary health care (horizontal programmes)(38). Gilliam has described how vertical programmes undermine broader health services through duplication of effort (each single disease control programme requires its own bureaucracy), distort national health plans and budgets and, because salaries of donor-funded vertical programmes are often more than double those of equally trained government workers, lead to a diversion of skilled local health personnel from primary healthcare, causing an ‘internal brain drain’ (39). We have seen how polio, that was not a priority for public health in India, was made the target for attempted eradication with a token donation of $ 0.02 billion. The Government of India finally had to fund this hugely expensive programme, which cost the country 100 times more than the value of the initial grant. De Maeseneer and colleagues suggest that vertical programmes have unwittingly increased the incidence of other diseases and broken the first rule of medicine – primum non nocere – first do no harm. They cite the example of HIV and hepatitis caused by WHO-endorsed immunisation programmes against other diseases. With polio eradication there was a huge increase in non-polio AFP, in direct proportion to the number of doses of the vaccine used. Through all the data was collected within an excellent surveillance system, the increase was not investigated openly. Another question ethicists will ask, is why champions of the programme continued to exhort poor countries to spend scarce resources on a programme they should have known, in 2002, was never going to succeed. In the final analysis, if the right lessons have been learnt and the world does not repeat these mistakes, the costs may yet be justified. References 1. Bancroft-Hinchey T. India Free of Polio. Pravda Ru[Internet]. 2012 Jan[cited 2012 Jan 30]. Available at http://english.pravda.ru/health/15-01-2012/120233-polio_india-0/ 2. Press Information Bureau, Government of India Ministry of Health and Family Welfare. One year of polio free India 2012 Jan 12[cited 2012 Jan 30]. Press release ID:79524 Available at http://pib.nic.in/newsite/erelease.aspx?relid=79524 3. United States Embassy Bangui. U.S. Assistance to Eradicate Polio. Press release March 30, 2010.[cited 2012 Jan 30] Available at http://bangui.usembassy.gov/pr_20100330.html 4. McNeil DG. Gates Calls for a Final Push to Eradicate Polio. The New York Times. January 31, 2011 [Cited 2012 Jan 30]Available at http://www.nytimes.com/2011/02/01/health/01polio.html 5. Bill and Melinda Gates Foundation. Rotary International: A Hands-On Effort to Eradicate Polio [cited 2012 Jan 30] Available at http://www.gatesfoundation.org/grantee-profiles/Pages/rotary-international.aspx 6. Barrett S. Eradication versus control: the economics of global infectious disease policies. Bull World Health Organ 2004;82:683-688 7. Choudhury U. India celebrates polio victory, but braces for US funding cuts. First Post India 14/1/12 [cited 2012 Jan 30].Available at http://www.firstpost.com/india/india-celebrates-polio-victory-but-braces-for-us-funding-cuts-181851.html 8. Rotary Club of Englewood Rotary District 6960 Webpage [cited 2012 Jan 30].Available at http://www.englewoodrotary.org/page3.php. 9. Narayan A, Anis K. Gates push for polio-free world gets boost as India foils virus. Bloomberg 18/1/ 2012. [cited 2012 Jan 30]. Available at http://www.businessweek.com/news/2012-01-18/gates-push-for-polio-free-world-gets-boost-as-india-foils-virus.html 10. Rahi A. Critics Say Gates’s Anti-Polio Push Is Misdirected. Health 30/1/11 [cited 2012 Jan 30].Available at http://health-dwi.blogspot.com/2011/01/health-critics-say-gatess-anti-polio.html#1 11. Kenny C Polio eradication is worth $1 billion The Record 21/1/ 2012 [cited 2012 Jan 30].Available at http://www.therecord.com/opinion/columns/article/658159--polio-eradication-is-worth-1-billion 12. Caplan AL. Is disease eradication ethical? Lancet 2009;373:2192-3 13. Arita I, Nakane M, Fenner F. Is polio eradication realistic? Science 2006; 312 : 852-4. 14. Roberts L, Polio eradication: Is it time to give up? Science 2006; 312 : 832-5. 15. Pallansch MA, Sandhu HS. The eradication of polio - progress and challenges. N Engl J Med 2006; 355 : 2508-11. 16. Kimman TG, Boot H. The polio eradication effort has been a great success- let us finish it and replace it with something better. Lancet Infect Dis 2006: 6 : 675-8. 17. Muraskin W. Polio Eradication and its Discontents: An Historian’s Journey Through an International Public Health (Un)Civil War. Prepublication copy Orient Blackswan Hyderabad August 2012 18. Sathyamala C, Mittal O, Dasgupta R, Priya R. Polio eradication initiative in India: Deconstructing the GPEI. Int J Health Serv 2005; 35 : 361-83. 19. John TJ. India’s polio eradication efforts at the crossroads. Indian Pediatr 1998; 35 : 307-10. 20. Dowdle WR. The Principles of Disease Elimination and Eradication. MMWR 1999;48(Suppl). 23-27 21. Centers for Disease Control and Prevention. Recommendations of the International Task Force for Disease Eradication. Morbidity and mortality weekly report, 1993, 42(RR-16):1–38. 22. Global Polio Eradication Initiative. What people are saying. [cited 2012 Jan 30]. Available at http://www.polioeradication.org/Aboutus/Peoplearesaying.aspx 23. Cello J, Paul AV, Wimmer E. Chemical synthesis of poliovirus cDNA: generation of infectious virus in the absence of natural template. Science 2002;297: 1016–1018. 24. Wimmer E. The test-tube synthesis of a chemical called poliovirus: The simple synthesis of a virus has far-reaching societal implications. EMBO Rep. 2006; 7(SI): S3–S9. 25. Puliyel J, Sathyamala C, Banerji D. Protective efficacy of a monovalent oral type 1 poliovirus vaccine. Lancet 2007;370:129-30 26. Grassly NC, Wenger J, Bahl S, Sutter RW, Aylward RB. Protective efficacy of a monovalent oral type 1 poliovirus vaccine. Lancet 2007;370: 129-30 27. Sathyamala C. Polio eradication programme in India. Indian J Med Res. 2007;125:695-6. 28. Puliyel JM, Gupta MA, Mathew JL. Polio eradication & the future for other programmes: Situation analysis for strategic planning in India. Indian J Med Res 2007;125:1-4 29. Puliyel J, Vashisht N, Sreenivas V. National Polio Surveillance India data 2000 -2010: NPSP Polio surveillance data on Acute Flaccid Paralysis (AFP) and non-polio AFP and Demographic data. [cited 2012 Jan 30]. Available at http://bit.ly/polio-afp 30. Puliyel JM, Vashisht N, Sreenivas V. Non-Polio AFP Rate in Different States of India: A Regression Model. Under journal review 31. Grassly NC, Fraser C, Wenger J, Deshpande JM, Sutter RW, Heymann DL, Aylward RB. New strategies for the elimination of polio from India. Science 2006 17;314:1150-3. 32. Kennedy RH, Danielson MA, Mulder DW, Kurland LT. Guillain-Barré syndrome: a 42-year epidemiologic and clinical study. Mayo Clin Proc 1978;53:93-99. 33. Marx A, Glass JD, Sutter RW. Differential diagnosis of acute flaccid paralysis and its role in poliomyelitis surveillance. Epidemiol Rev 2000;22:298-316. 34. Ibrahim N, Karim IA, Abbas M. Acute Flaccid Paralysis: Field Manual. World Health Organization. Available at http://www.emro.who.int/iraq/pdf/polio_manual_2010.pdf Accessed on 30/1/12 35. Greg M. Declare victory in Iraq, and then exit. Editor & Publisher;Feb 2005;138 (2):p18 36. Sathyamala C, Puliyel JM. Polio vaccine and Gresham’s Law. Indian J Pediatr. 2004;71:1141 37. Madhavi Y. Liberalization and the cost-benefit aspects of vaccines: The case of Hepatitis B. Working Paper Series 1, CHS/WP/01/01 2001, Bombay Centre for Health Studies. Tata Institute of Social Sciences 38. De Maeseneer J, VanWeel C, Egilman D, Mfenyana K, Kaufman A, Sewankambo N, Flinkenflogel M. Funding for primary health care in developing countries. BMJ 2008;336(7643):518-9 39. Gillam S. Is the declaration of Alma Ata still relevant to primary health care? BMJ 2008;336(7643):536-8. 40. De Maeseneer J, van Weel C, Egilman D, Mfenyana K, Kaufman A, Sewankambo N. Fifteen by 2015: Strengthening primary health care in developing countries. WONCA, World Conference Singapore, 25.07.07 Power point (a) and presentation(b) available at: http://www.jpowerpoint.com/Fifteen-by-2015-strengthening-primary-health-care-in-developing------PPT.html https://docs.google.com/viewer?a=v&q=cache:ymoswKST7i8J:www.15by15.org/wp-content/uploads/2008/01/background-15-by-2015-2.doc+At+the+same+time.+selective+health+care,+or+verticle+programs+that+target&hl=en&gl=in&pid=bl&srcid=ADGEESjeR0IV4X0Yrf-T2XtUWPXLSiy_IyOo3Oz1PrUudFbXN8Wppxtx2y1WZXsRX838b7zwgraKZ1uXNeMHG2n9twnyoq45pNaa6aI4Ekz1E0rUgQsnjMOIeFuGz0ZRZRiFw2-OYoxn&sig=AHIEtbT72Qru9KVWq8tUbP6KJP70_jXKrQ Accessed on 22/2/12
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  Of Micro-organisms and Men: Immunity and Vaccines English version of Malayalam article

  Chandrika 14 -20 April 2012. English version of Malayalam article
  Jacob Puliyel
  Of Micro-organisms and Men: Immunity and Vaccines The best laid schemes of mice and men- Often go awry John Steinbeck. 1937 There are billions of micro-organisms in our environment. Some have a symbiotic relationship with us, meaning that the relationship between man and the micro-organism are mutually beneficial. Thus there are bacteria resident in our gut, that eats some of the food we have eaten, but in return they make useful vitamins for us to absorb and use. If we kill these harmless Show More...Of Micro-organisms and Men: Immunity and Vaccines The best laid schemes of mice and men- Often go awry John Steinbeck. 1937 There are billions of micro-organisms in our environment. Some have a symbiotic relationship with us, meaning that the relationship between man and the micro-organism are mutually beneficial. Thus there are bacteria resident in our gut, that eats some of the food we have eaten, but in return they make useful vitamins for us to absorb and use. If we kill these harmless or good bacteria, two consequences follow. The first relates to losing out on the benefits provided by the bacteria like the vitamins produced. The other more dangerous, relates to the replacement bacteria. If we kill the bacteria in our gut with a powerful antibiotic, then other bacteria will replace them and these may be harmful bacteria and they will certainly be antibiotic resistant. This replacement phenomenon occurs sometimes even if we use vaccines to eliminate resident micro-organisms. Not all micro-organisms are good for man. Some produce disease and death. Some harmless bacteria may themselves become harmful to us when our resistance is lowered. Thus Staphylococcus epidermidis is part of human skin flora but in people with catheters (like patients undergoing dialysis) this can produce lethal disease. It is important to hold this complexity at the back of our minds when we consider vaccines and immunity. How vaccines work If a child gets a disease like chicken-pox he will get a little fever and a couple of boils and after a few days he will recover. The reason for his recovery is that the body recognizes this new viral invasion and produces antibodies against the virus. Once produced, the antibodies eliminate the chicken pox virus. And after this the person will never ever get chicken pox, because he is now immune. Not only that, women who have had chicken pox pass on some of these antibodies to their babies and their babies are protected by this immunity got from mothers (called passive immunity) for 3 to 9 months. During this period, if the child comes across infection, they may get a very mild type of infection that goes unnoticed. With this mild infection, the child develops active immunity that lasts a life time. If we kill the virus and inject its protein into the skin, the dead virus cannot produce infection. However the body may take up the viral protein and make antibodies as if this were a real infection. This is the principle behind vaccines. It has been a major advancement in our battle against disease. Evaluating Costs and Benefits Vaccines against deadly diseases like small pox that spread easily in the community are a good idea but there is no meaning in making vaccines against every mild disease. This can do harm in a number of ways. 1. The vaccine may be associated with side effects more harmful than the disease. The Pentavalent vaccine seems to fall in this category but this has been discussed else where in this magazine. 2. The replacement organisms that take the place of the eliminated bacteria or virus may in fact be more lethal than the original organism. An example of this is seen when they used the 7 valent pneumococcal vaccine in the West. The new strains (that replaced the old vaccine strains) were more harmful and more antibiotic resistant. 3. The cost: benefit ratio of the vaccine. This is a crucial factor especially when considering vaccines for minor diseases, because the vaccine has to be given to everyone in the community to prevent a disease which may have affected only one or two persons. The cost of treating the mild disease in these two must be compared to the cost of giving the vaccine to every one in the community. Often investing in other programmes will save many more lives than spending money on vaccine against minor diseases. Hypersensitivity and the Pentavalent Vaccine In this context it is pertinent to discuss the Pentavalent vaccine being pushed by vaccine manufacturers and some international organisations. The vaccine is known to have caused deaths in Sri Lanka, Bhutan and Pakistan. No other cause for the deaths were found on investigation, and according to the WHO’s Brighton criteria, this makes vaccine the probable cause of death. Many persons have received the vaccine with no harmful effects. The reactions appear to be a hypersensitivity reaction in some persons. This is why the National Technical Advisory Group on Immunization (NTAAGI) insisted that before it is introduced in the country we must look for side effects and deaths in a limited area. An example of a drug that causes hypersensitivity reaction and deaths is Penicillin injections. This is why doctors test for sensitivity to penicillin every time before giving it. There is however no test for sensitivity to Pentavalent vaccine and so if Pentavalent vaccine cause hypersensitivity in some – it cannot be used in the national immunization programme because every child is at risk of death from undetected hypersensitivity. Jacob Puliyel Puliyel@gmail.com Puliyel is member of the Government of India’s National Technical Advisory Group on Immunization
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  Public Interest Petition (PIL) Vaccine case 7th affidavit 14/02/12

  Prashant Bhushan on behalf of the petitioners
  IN THE HIGH COURT OF DELHI AT NEW DELHI (CIVIL ORIGINAL JURISDICTION) C.M. No. 18416 of 2011 IN Writ Petition (Civil) No. 13698 Of 2009 PUBLIC INTEREST LITIGATION IN THE MATTER OF: DR. K. B. SAXENA & ORS. …PETITIONERS VERSUS UNION OF INDIA & ORS. …RESPONDENTS BRIEF REJOINDER AFFIDAVIT ON BEHALF OF THE PETITIONERS TO THE AFFIDAVIT FILED BY THE UNION OF INDIA I, Dr. Jacob M Puliyel S/o Late Shri P. M. Mammen, Head, Dept. of Pediatrics, St. Stephens Hospital, Tis Haz Show More...IN THE HIGH COURT OF DELHI AT NEW DELHI (CIVIL ORIGINAL JURISDICTION) C.M. No. 18416 of 2011 IN Writ Petition (Civil) No. 13698 Of 2009 PUBLIC INTEREST LITIGATION IN THE MATTER OF: DR. K. B. SAXENA & ORS. …PETITIONERS VERSUS UNION OF INDIA & ORS. …RESPONDENTS BRIEF REJOINDER AFFIDAVIT ON BEHALF OF THE PETITIONERS TO THE AFFIDAVIT FILED BY THE UNION OF INDIA I, Dr. Jacob M Puliyel S/o Late Shri P. M. Mammen, Head, Dept. of Pediatrics, St. Stephens Hospital, Tis Hazari, New Delhi-110054, do hereby solemnly state and affirm as under: 1. That I am the Petitioner No. 8 in the above writ petition and being conversant with the facts and circumstances of the case, am competent to swear this Affidavit. I have also been authorized by other petitioners to file this affidavit on their behalf. 2. Petitioners had filed the above writ petition highlighting how in the absence of a rational evidence-based vaccine policy, newer and newer vaccines are being pushed into the public health system at the behest of pharmaceutical industry and international bodies like World Health Organization (WHO). Petitioners had specifically challenged the proposed introduction of Pneumococcal, Hepatitis B, Hib and Pentavalent vaccines into the country’s Universal Immunization Programme. 3. Petitioners have filed the above application putting on record the recent disturbing developments and seeking specific direction pursuant to the earlier orders of this Hon’ble Court passed in the above proceedings. This Hon’ble Court was pleased to issue notice on the above application. Now the Government of India has filed its response to the above application. Petitioners have gone through the same and submit their reply as given below. Petitioners crave liberty not to file a para-wise reply. 4. The vaccine policy framed by the Government is totally contrary to letter and spirit of the orders passed by this Hon’ble Court. This Hon’ble Court had vide order 07.04.2010 had stated the following: “A vaccine policy has been framed by some experts (it appears on page 211 of the paper book). The Respondents may examine the policy for framing similar or other guidelines, whenever it becomes necessary at some stage.” 5. On 15.09.2010, this Hon’ble Court inter-alia recorded in the order: “At this juncture, Mr. Prashant Bhushan submitted that the committee has to keep in view the four vital aspects:- (i) Incidents of disease in India and its effect potentially, (ii) The efficacy of the vaccine to prevent the disease as prevention is better than cure, (iii) The side effects of the vaccine, the nature of adverse side effects and the approximate statistics of the persons who are likely to be effected by such side effects and (iv) The costs factor.” 6. This Hon’ble Court on 08.12.2010 stated: “Let the policy be finalized within two months from today.” Thereafter, on 23.02.2011, this Hon’ble Court stated: “Petitioner No. 8 can file additional comments including all the objections that have been raised in the writ petition within three weeks hence, if not yet filed. It is submitted by the learned counsel for the respondent- Union of India that the policy shall be finalized within two months.” 7. Therefore, respondents had to comply with certain direction given from time to time by this Hon’ble Court. The same has not been done as detailed in the application. 8. The Government has vouched for the safety and efficacy of the Pentavalent vaccine without the “study” underway in 2 states is even complete. This shows that Government has prejudged the issue and is also not interested in monitoring the after-effects of the administration of vaccine on children in 2 states at huge cost to the public exchequer. 9. It is surprising that Government has completely ignored serious reports of deaths and adverse side-effects of Pentavalent in countries like Japan and Pakistan. Reports from the above two countries are annexed as Annexure A25 and Annexure A26 respectively. 10. Government has launched a cover-up after a child died due to administration of Pentavalent in Kerala. News report on this is annexed as Annexure A27. The post-mortem report of the girl infant who died clearly stated that she died due to reaction to the injection. The said report is annexed as Annexure A28. 11. After these developments petitioner no. 8 Dr. Jacob Puliyel (Member, NTAGI) had written to the Health Secretary apprising him of the recent disturbing developments. The Health Secretary was also requested to intervene in the above matter and call for a full meeting of NTAGI. A copy of the said letter is annexed as Annexure A29. 12. NTAGI has itself stated: “As the vaccine has not been introduced there is not enough data on vaccine safety therefore the vaccine should be initially used in the states with better AEFI management and surveillance system to monitor the vaccine safety… The Core committee recommendation on Pentavalent vaccine were discussed and based on the recommendation the committee members felt that the vaccine should be introduced in selected few well performing states and further roll out should be based on the impact assessment of the vaccine including safety aspects… Pentavalent vaccine to be introduced in Immunization programme in the states of Tamil Nadu and Kerala. Thereafter data may be reviewed after 1 year of introduction before expanding the vaccine to other states.” 13. Hence, AEFI (Adverse Effects Following Immunization) was a serious concern for even NTAGI, and therefore the need was to monitor the AEFI in the above 2 states. Not only the said effects are not being monitored, even the death of a child is being ignored. Government has not only publically said that the death is not related to the vaccine, but has also in its affidavit has said that the study is being conducted “to dispel the fear of increased AEFI due to Pentavalent vaccine unnecessarily created, perpetuated by petitioner 8.” This shows that Government has prejudged the issue. The Government through its affidavit has made clear that it has no intention of following the NTAGI recommendation to monitor the side-effects of the vaccine. Therefore, this Hon’ble Court should direct the Government to do the same. 14. Since the Government appoints NTAGI members without any fair process or transparency, most of them toe the Government’s line. With the Government being adamant in pushing for newer expensive vaccines that would only benefit big pharmaceutical companies, there is no way that NTAGI would come to a different conclusion, as its past history shows. Government has made personal allegations against petitioner no. 8 who is a Member of NTAGI. This shows how dissenting voices are dealt with. Government has also opposed any videographing of the NTAGI meetings. DEPONENT VERIFICATION I, the deponent above-named, do hereby verify that the contents of the above affidavit are true to my knowledge, no part of it is false and nothing material has been concealed therefrom. Verified at New Delhi on day of February 2012. DEPONENT Annexures 1. http://www.japantimes.co.jp/text/nn20110305x3.html 2. http://tribune.com.pk/story/293191/vaccine-nation-globally-supported-company-is-funding-fatal-polio-shots/ 3. http://articles.timesofindia.indiatimes.com/2011-12-17/thiruvananthapuram/30528346_1_pentavalent-vaccine-infant-kerala 4. Post Mortem report death in Kerala Hypersensitivity to injection (see below) 5. Letter to Health Secretary To Mr P K Pradhan The Health Secretary New Delhi Dear Sir, I congratulate you on your appointment as Union Health Secretary and also wish you greetings for the New Year. I write as a member of the National Technical Advisory group on Immunization. There has not been a meeting of the NTAGI for over a year and a half - since 26 August 2010. Two meeting that were scheduled last year were cancelled at short notice. There are a number of issues that need to be discussed and I hope you will address these expeditiously. 1. Reform in NTAGI Selection and Functioning The constitution of this NTAGI needs urgent reform. The Government has set this up as it needs independent scientific advice. As of now, the Government appoints members to the NTAGI. It is therefore possible for the government to select persons whose viewpoint it is comfortable with, and thereby defeat the very purpose of setting up the independent scientific NTAGI. Also there is a tendency not to record dissenting voices. Taking a vote on the views of the majority as no meaning as the committee is not representative in any way. 2. We need a three member team to regularly recruit experts from qualified applicants to this NTAGI for a fixed term. Term appointment will ensure fresh ideas are introduced regularly. Overlap of tenures can ensure institutional memory and continuity. In this way the Government will get the best advice. Some suggestions for reform were made in the last NTAGI meeting but this needs to be followed up and elaborated. 3. Deaths in Japan and Report of the Pakistan Prime Ministers Inspection Commission I bring to your attention the recent events related to adverse events with Hib associated combination vaccines in neighboring countries. The deaths in Bhutan, Pakistan and Sri Lanka have been noted in the minutes of the last NTAGI meeting. The effort to gloss over the deaths in Sri Lanka as being ‘unlikely to be related to vaccine’ after changing the vary classification system used for such AEFI where using the standard protocol of the Brighton Collaboration would have led to the conclusion that the vaccine was possibly related to the deaths has been pointed out before. 4. Recently the Prime Ministers Prime Minister’s Inspection Commission (PMIC) on the working of the Expanded Programme on Immunisation (EPI), headed by Dr Malik Amjad Noon, has recommended that Prime Minister Yousaf Raza Gilani immediately suspend the administration of all types of vaccines funded by the GAVI because of deaths and side effects of - among others – the pentavalent vaccine. 5. The commission also drew attention to five deaths have been reported in Japan this year soon after the vaccination was administered while 25 serious adverse reactions, after a Hib combination with DPT. 6. It is ironic that Pakistan, which is more dependent on foreign funding than is India, feels empowered to take an independent stance in the interest of their children, where as we are do not feel able to resist these international pressures. 7. I must point out that according to press reports; GAVI has agreed to fund the full vaccine costs for introduction of Pentavalent vaccine in India for 3 years. Those who have studied GAVI functioning, will know that part payment is a basic guiding principle underlying all its funding – even to the poorest of poor countries. The fact that full funding is on offer for India, is indicative of the serious crisis of confidence internationally with the Pentavalent vaccine and the desperation of GAVI to get it introduced in India. Discernment and prudence would mandate looking with suspicion on this GAVI offer which is completely alien to its standard operating practices. 8. Need for Active Surveillance of Adverse Effects At the last NTAGI meeting, concerns were raised regarding the safety and efficacy of the Pentavalent Vaccine which was sought to be introduced in India. In view of the adverse events following immunization (AEFI), including deaths, with use of this vaccine in Sri Lanka, Bhutan, and Pakistan, it was decided to introduce the vaccine in two states with better AEFI management and surveillance systems to monitor vaccine safety (Minutes meeting 26/8/10 Agenda item 1). The recommendations state: “Since AEFI is a concern hence same will be monitored and also system(s) will be strengthened so as to ensure immediate management of AEFIs; NCDC (is) to lead this activity.” 9. Accordingly Pentavalent vaccine was introduced in Kerala and Tamil Nadu in the on the 14th and 17th of December 2011 respectively. On the next day, the vernacular press reported a death in a 2 month old health child on the day after vaccination. Initially after the first symptoms of AEFI the parents went with the child to a hospital and were seen and sent home but the child died by next morning. The matter came to public notice only because of the press report. 10. This is a very unsatisfactory situation. We have no system in place to record adverse events and this case would not have been noticed had it not come in the press. The press cannot be expected to report isolated cases of deaths. Vaccine reactions don’t take place routinely. Isolated deaths don’t make it to news papers. We certainly need a better system to actively enquire about side effects. Every child who is vaccinated must be followed up after a week. Even in the USA where there is a well publicized Vaccine Adverse Event Reporting System (VAERS) jointly maintained by the US CDC and the US FDA, according to the FDA-Commissioner David Kessler “only about one percent of serious events ... are reported”. (1) Given that the NTAGI has asked for introduction of the vaccine to look for side effects, every child needs to be followed up actively. 11. You will remember that the Final Report of the Committee appointed by the Govt. of India (vide notification No. V.25011/160/2010-HR dated 15th April, 2010) to enquire into “Alleged irregularities in the conduct of studies using Human Papilloma Virus (HPV) vaccine” by PATH in India (February 15, 2011) noted as follows: “It may be highlighted that 4 of the 5 primary outcome measures proposed in the study related to evaluation of the safety of the vaccine in population setting… There is no dairy card based information record for assessing minor or major AEFI in the study protocol which seems unusual with such a large observational study.” 12. Not to have a system in place an active surveillance of AEFI, for the Pentavalent vaccine in Kerala and Tamil Nadu and to rely on press reports will be inexcusable. Small cluster samples will not provide information on relatively uncommon side effects. Unless we capture all cases, it will not be possible to evaluate harms and benefits. 13. In response to a PIL filed in the Kerala High Court the Government of Kerala has told the court that 40,000 doses of Pentavalent vaccine have been administered in the first month of starting the programme and there were no side effects (as if no child even had fever with the vaccine - leave alone the death already reported in the papers about which the Government's final report is awaited). Such blatant denials, in an affidavit to the court, seriously erode the credibility of the government's stand. 14. I hope you will call a full meeting of the NTAGI to discuss these and related matters Sincerely Jacob Puliyel 1. Kessler, DA, the Working Group, Natanblut S, Kennedy D, Lazar E, Rheinstein P, et al. Introducing MEDWatch: a new approach to reporting medication and device adverse effects and product problems. JAMA 1993; 269(21): 2765. 6.
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  Congenital Dengue and Myocarditis: A Case Report and Systematic Review of Literature

  Infectious Diseases in Clinical Practice, 2012
  Sharma, Richa DCH; Parwal, Natwar DCH; Kumar, Nirmal MD; Puliyel, Jacob M. MD
  Abstract We report a newborn with congenital dengue infection and cardiomyopathy. Congenital dengue is known to occur owing to vertical transmission of the virus from an infected mother to her baby through the placenta. Dengue-related cardiomyopathy has been reported previously. This is arguably the first time cardiomyopathy is being reported in the context of congenital dengue. A systematic review of literature on congenital dengue as cited in Pubmed is also presented. (C) 2012 Lippincott W Show More...Abstract We report a newborn with congenital dengue infection and cardiomyopathy. Congenital dengue is known to occur owing to vertical transmission of the virus from an infected mother to her baby through the placenta. Dengue-related cardiomyopathy has been reported previously. This is arguably the first time cardiomyopathy is being reported in the context of congenital dengue. A systematic review of literature on congenital dengue as cited in Pubmed is also presented. (C) 2012 Lippincott Williams & Wilkins, Inc. Copyright @ 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Congenital Dengue and Myocarditis A Case Report and Systematic Review of Literature Richa Sharma, DCH, Natwar Parwal, DCH, Nirmal Kumar, MD, and Jacob M. Puliyel, MD Abstract: We report a newborn with congenital dengue infection and cardiomyopathy. Congenital dengue is known to occur owing to vertical transmission of the virus from an infected mother to her baby through the placenta. Dengue-related cardiomyopathy has been reported previously. This is arguably the first time cardiomyopathy is being reported in the context of congenital dengue. A systematic review of literature on congenital dengue as cited in Pubmed is also presented. Key Words: congenital dengue, cardiomyopathy (Infect Dis Clin Pract 2011;00: 00Y00) Dengue infection is caused by arbovirus pathogens (Flavivirus). Serologically, there are 4 types of dengue virus. Infection with one serotype does not confer immunity against infection with other serotypes. On the other hand, previous dengue infection (primary dengue) and the developed antibodies predispose the patient to more severe illness when infected with other serotypes subsequently (secondary dengue).1 Congenital infection occurs when the virus is directly transmitted to the baby through the placenta, and there is insufficient time for protective antibodies developed in the mother to be transferred to the baby.2 However ‘‘infection-enhancing antibodies’’ acquired by the mother from previous Flavivirus infections are passively transmitted to the baby, and this results in serious manifestations in the newborn.3 It is reported that although hemorrhagic manifestations are mainly a feature of secondary dengue infection, it also manifests in congenital dengue owing to these infectionenhancing antibodies.4 Cardiomyopathy has been described in adults with dengue infection.5Y7 Cardiomyopathy, however, has not been previously reported in congenital dengue to the best of our knowledge. A systematic review of congenital dengue in PubMed is also presented. CASE REPORT A term 3.2-kg male baby was delivered by AQ1 cesarean birth with Apgar scores 2, 4, and 4 at 1, 5, and 10 minutes, respectively. His mother had a history of fever with thrombocytopenia for 2 days before delivery. Result of her dengue nonstructural antigen 1 (NS1) test was positive. The mother’s serological test reAQ2 sults were negative for human immunodeficiency virus, HBsAg, AQ2 and VDRL. The baby developed severe respiratory distress and bradycardia soon after birth. His peripheral pulses were feeble, and his blood oxygen saturation fluctuated between 70% and 80% on pulse oximetry. He was centrally cyanosed; had massive hepatomegaly (liver 4 cm in the right midclavicular line), decreased air entry in right basal region of the lung, and a systolic murmur in mitral and tricuspid areas. His dengue nonstructural antigen 1 test was positive. The first blood sample taken soon after delivery showed C-reactive protein of 0.45 (positive, 90.5), and platelet count was 21,000/mL of blood; blood culture was sterile. A chest x-ray showed cardiomegaly with bilateral pulmonary infiltrations. An echocardiogram (ECG) done on the unit AQ4 by a pediatrician with special interest in pediatric cardiology showed massive right atrial and ventricular dilatation with severe tricuspid regurgitation. Twenty-four hours after birth, the ECG repeated by a pediatric cardiologist showed cardiomyopa- thy with dilated left atrium and right ventricle, patent foramen ovale, small pericardial effusion with right systolic dysfunction, and moderate tricuspid regurgitation with a pressure gradient of 4 mm Hg. He was given ventilatory assistance, IV fluids, antibiotics, and blood transfusions. This shock was refractory to ino- tropes and hydrocortisone. He went on to develop multiple organ failure (MODS) and died on day 7 of life. DISCUSSION Our child, born during the peak of the dengue season in Delhi India, probably had congenital dengue as evidenced by symptoms in the mother 2 days before delivery as well as the dengue antigen positivity in both the mother and the child. Echocardiography in the newborn with refractory shock suggested cardiomyopathy. Dengue virus is known to cause cardiac complication in children. Salgado et al8 has reported 11 pediatric patients with myocarditis due to dengue. Sinus node dysfunction with sinus bradycardia or tachycardia and T-wave inversions on ECG, pericardial effusion, and diastolic dysfunctions have all been reported. Promphan et al9 described sinus node dysfunction leading to bradycardia and hypotension a day after recovery from DHF in a 13-year-old boy. Obeyesekere and Hermon10 have listed the diagnostics criteria for dengue myocarditis: 1. Clinical evidence of myocarditis; 2. Presence of electrocardiographic evidence of myocarditis, ST segment and T wave changes, and disturbances in conduction and rhythm; 3. Recent history of denguelike fever; 4. Serological evidence of past dengue infection as revealed by the presence of antibody in high titer.10 Our neonate with congenital dengue had clinical and echocardiographic evidence of myocarditis. The pathogenesis of myocarditis is not clear. It could be that the virus invades the myocardium and directly damages the muscle fibers or it may give rise to a hypersensitivity or autoimmune reaction causing myocardial damage. The altered state of myocardium may persist long after the initial viral infection and make it prone to recurrent damage from other agents.10 Salgado et al8 have demonstrated infection of heart tissue in vivo Copyright @ 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. and striated cells in vitro with dengue. It has been proposed that derangements of calcium storage in infected cells may directly contribute to presentations of myocarditis. A systematic review of the literature looking for reported cases of congenital dengue in Pubmed was performed using the search criteria: ((‘‘congenital’’[Subheading] OR ‘‘congenital’’ [All Fields]) AND (‘‘dengue’’[MeSH Terms] OR ‘‘dengue’’[All Fields])) AND (Case Reports[ptyp] AND ‘‘infant, newborn’’ [MeSH Terms]). Four case reports were found. The papers were retrieved and reviewed. The symptoms in the mothers and the newborn and tests used for diagnosis AQ7T1 are tabulated in Table 1. CLINICAL MANIFESTATIONS OF NEONATAL DENGUE INFECTION In all the cases of neonatal dengue caused by vertical transmission, fever was detected. All the neonates manifested a rash. Other manifestations include hepatomegaly,11,13 respiratory distress, 4 pleural infiltrates,13 and pleural effusion.13 The laboratory manifestations consisted of thrombocytopenia and raised AQ8 liver enzymes.12 Diagnosis of 2 patients was based on PCR, and both were of serotype 2.11,12 The diagnosis of 2 other patients was based on 4-fold rise in antibody IgM titers.4,13 All 4 patients recovered from their illness. None of the cases of congenital dengue had evidence of myocarditis. In our case, there were features suggestive of myocarditis and shock, which was refractory to inotropes. Cardiomyopathy seems to be a novel complication of congenital dengue fever. One must have a high index of suspicion and be vigilant for this potentially serious complication. REFERENCES 1. Gubler DJ. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev. 1988;11:480. 2. Perret C, Chanthavanich P, Pengsaa K. Dengue infection during pregnancy and transplacental antibody transfer in Thai mothers. J Infect. 2005;51:287Y293. 3. Kilkis SC, Nimmannitya S, Nisaliak A, et al. Evidence that maternal dengue antibodies are important in the development of dengue hemorrhagic fever in infants. Am J Trop Med Hyg. 1988;411Y419. AQ9 4. Fatimil LE, Mollah AH, Ahmed S, et al. Vertical transmission of dengue: first case report from Bangladesh. Southeast Asian J Trop Med Public Health. 2003;34:800Y803. Review. Erratum in: Southeast Asian J Trop Med Public Health. 2004;35:494. 5. Lee IK, Lee WH, Liu JW, et al. Acute myocarditis in dengue hemorrhagic fever: a case report and review of cardiac complications in dengue-affected patients. Int J Infect Dis. 2010;14:e919Ye220. 6. Lee CH, Teo C, Low AF. Fulminant dengue myocarditis masquerading as acute myocardial infarction. Int J Cardiol. 2009;136:e69Ye71. 7. Kularatne SA, Pathirage MM, Kumarasiri PV, et al. Cardiac complications of a dengue fever outbreak in Srilanka, 2005. Trans R Soc Trop Med Hyg. 2007;101:804Y808. 8. Salgado DM, Eltit JM, Mansfield K, et al. Heart and skeletal muscles are targets of dengue virus infection. Pediatr Infect Dis J. 2010;29:238Y242. 9. Promphan W, Sopontammarak S, Pruekprasert P, et al. Dengue myocarditis. Southeast Asian J Trop Med Public Health. 2004;35:61. 10. Obeyesekere I, Hermon Y. Arbovirus heart disease: myocarditis and cardiomyopathy following dengue and chikungunya feverVa follow-up study. Am Heart J. 1973:186Y194. AQ9 11. Witayathawornwong P. Parturient and perinatal dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health. 2003;34:797Y799. 12. Janjindamai W, Pruekprasert P. Perinatal dengue infection: a case report and review of literature. Southeast Asian J Trop Med Public Health. 2003;34:793Y796. Res 1997;23:445Y448. 13. Bugna J, Moreno J, Sanchez S, et al. Fever and bleeding in a newborn baby. Pediatr Infect Dis J. 2010;29:1153Y1158. TABLE 1. Symptoms in Mothers and Newborns and Tests Used Citation Pregnant Women’s Symptoms Newborn Symptoms Outcome Diagnostic Test 1 Witayathawornwong11 (Thailand) 2003 Fever, 5 days; thrombocytopenia and pleural effusion; postpartum anemia Fever, 2 days (48 h of life); thrombocytopenia; pleural effusion; hepatomegaly Recovered Dengue virus type 2 by PCR 2 Fatimil et al,4 (Bangladesh) 2003 Fever, intense body ache, tourniquet test +, bilateral mild pleural effusions with hepatomegaly Fever, respiratory distress Recovered IgM and IgG for dengue with 4-fold rise of IgM 3 Janjindamai and Pruekprasert,12 (Thailand) 2003 Acute dengue Fever, convalescent rash, elevated SGOT and SGPT Recovered Dengue virus type 2 by PCR 4 Bugna et al13 (Poland) 2010 Fever, thrombocytopenia, rashes Fever, thrombocytopenia, erythematous rashes, hepatomegaly, bilateral pleural infiltrates, mild pleural effusion Recovered Dengue IgM and IgG Sharma et al Infectious Diseases in Clinical Practice & Volume 00, Number 00, Month 2011 2 www.infectdis.com * 2011 Lippincott Williams & Wilkins REVIEW ARTICLE Infectious Diseases in Clinical Practice & Volume 00, Number 00, Month 2011 www.infectdis.com 1 Copyeditor: Wilma Q. Sabueto From the Department of Pediatrics, St Stephen’s Hospital, Tis Hazari, New Delhi, India. Correspondence to: Richa Sharma, St Stephen’s Hospital, Tis Hazari, Delhi 110054 India. E-mail: Richa.dr.sharma@gmail.com.
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  National Polio Surveillance India data 2000 -2010 NPSP Polio surveillance data on Acute Flaccid Paralysis (AFP) and non-polio AFP and Demographic data

  http://bit.ly/polio-afp
  J. Puliyel, N.Vashisht, V. Sreenivas
  The data on acute flaccid paralysis (AFP), polio and non-polio AFP and number of polio rounds in each state in each year from 2000 to 2009 were from the National Polio Surveillance web site (http://www.npspindia.org/bulletin.pdf). a) Data on numbers of polio rounds during the year 2003 was incomplete. b) When different areas within a state received different number of doses, the arithmetic mean number of doses was taken as the representative dose for that state. 2. Per capita income w Show More...The data on acute flaccid paralysis (AFP), polio and non-polio AFP and number of polio rounds in each state in each year from 2000 to 2009 were from the National Polio Surveillance web site (http://www.npspindia.org/bulletin.pdf). a) Data on numbers of polio rounds during the year 2003 was incomplete. b) When different areas within a state received different number of doses, the arithmetic mean number of doses was taken as the representative dose for that state. 2. Per capita income was obtained from Swati Gupta. States Performance in Per capita Income Growth ASSOCHAM ECO PULSE January 2008 www.assocham.org/arb/aep/states-per-capita-income.doc 3. Population density of each state and union territory was obtained from Census of India. "Area and Population". Government of India (2001). http://www.censusindia.gov.in/Census_And_You/area_and_population.aspx. Quoted in Wikipedia: List of states and union territories of India by population. http://en.wikipedia.org/wiki/List_of_states_and_union_territories_of_India_by_population 4. Data on female literacy and overall literacy was obtained from the Census of India. Census of India 2001-- State wise population totals
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  Occupy Medicine: Vaccines for 99% versus profits for the 1%

  http://www.youtube.com/watch?v=AWE_L5-mGWE&feature=bf_prev&list=ULPIxogXq35bk&lf=mfu_in_order
  Jacob Puliyel
  Available on youtube at address in referenceIn acknowledgement of the world wide “Occupy Wall Street’ movement this talk is on ‘Occupy Medicine’ Specifically it is about vaccines for 99% versus profits for the 1% There is the story of a sales person who went to a villager and asked to buy a donkey. The villager said. I have a donkey. I need the money. You can have my donkey. It will cost $100. The salesman paid the money and the villager promised to deliver the donkey on the following day.  Show More...Available on youtube at address in referenceIn acknowledgement of the world wide “Occupy Wall Street’ movement this talk is on ‘Occupy Medicine’ Specifically it is about vaccines for 99% versus profits for the 1% There is the story of a sales person who went to a villager and asked to buy a donkey. The villager said. I have a donkey. I need the money. You can have my donkey. It will cost $100. The salesman paid the money and the villager promised to deliver the donkey on the following day. However the donkey did not arrive on the next day. The salesperson went to the villager and asked why the donkey was not delivered. “I am very sorry” said the villager, “ but the donkey died’ “ The donkey died?” said the salesperson – “Give me back the money” “ I am sorry” said the villager, “I told you I needed the money desperately. I am afraid your money is spent’ “The give me the dead donkey” said the sales person. “You want the dead donkey?” asked the villager – “What can you do with a dead donkey?” “That is none of your business”, said the salesperson. “Just get me the donkey” The next day the villager got a cart and delivered the dead donkey. The villager was curious. 2 weeks later he went to the salesperson and asked him just what he did with the dead donkey. “ I sold him for a profit of $898 said the salesperson” “Well not sold him. I raffles him for $2 a ticket. I sold 500 tickets” “You raffled a dead donkey’ asked the villager incredulously, “ and no one complained?’ “Well” said the salesperson “one chap did complain. The guy who won the lottery. I gave him back his 2 dollars” I am reminded of this clever salesman when I think of how vaccines are sold today We were told that 250,000 die of hepatocellular carcinoma due to Hepatitis B in India each year. This was published in the journal Health Economics by Mark Miller who gives his affiliation variously as CDC Atlanta and WHO Geneva. Data from well maintained, population based cancer registries at that time, suggested the figure was around 5000 deaths. So I wrote to the journal and asked to see the model Miller had used to arrive at his figures. Miller wrote back that a model ‘stratified by income group and geographic region’ was used and it was available on the CDC web site. There was no model on the web site. So how would the number 250,000 deaths have been arrived at? I figured that they may be projecting the mortality rates of Taiwan male hepatitis B carriers on the population in India – both male and female. 1 in 4 male carrier in Taiwan die of hepatic cancer. This is a world record. It is 3 times the mortality rates among Taiwan females. It is 17 times the mortality in Canada. We now know that this is due to a strain of the virus in Taiwan. India and this is what you get. About 4% of Indians are carriers. If 1 in 4 of the 4% is to die of hepatic cancer then 1% of all our deaths must be due to Hepatitis B cancer. 1% of deaths in a population of 1 billion is 200,000. We wrote this up and sent it to the Lancet saying Miller’s model is not available but this appears to be how to arrive at that figure. The Lancet published it. I then wrote to the journal Health Economicsasking that in the light of the Lancet publication, Miller must either publish his model or otherwise retract his paper. Prof Miller wrote – and this published in Health Economics – that the model was ‘lost’. The paper has not been retracted as yet. H influenza b (Hib ) disease. The incidence of Hib in Asia we know is about a tenth of what it is in the West. An editorial in the Bull of the WHO wonders if the vaccine is really needed in Asia Pre-vaccination titers were consistently high in Asia. This study from Turkey showed that antibody levels rise with age – If it were all due to passive immunity the antibody levels should fall with age. There is another phenomenon. Post vaccination, the antibody titers rise to levels some 10 times higher than that seen in the West. Such levels are not seen with primary immunization - only with booster immunization. This suggests the children were already having active immunity before being vaccinated. There are animal models to explain why Asian were naturally immune to Hib. Many bacteria like the E.coli have cross reacting antigens and infection with one protects against the other. E coli is so common in Asia and is a commensal in most children and this could be protecting against invasive Hib disease. However vaccine manufacturers are not easy to persuade. They are convinced that the poor culture rates of Hib invasive disease in India relates to the fact that we don’t know how to culture the organism. The culture medium needs Isovitalex they say. So the Invasive Bacterial Infection Surveillance Group (IBIS) decided to do the cultures themselves using the best culture media, in 6 of the biggest hospital in India. They did this continuously over 4 years and all they got was 125 cases. The numbers were so abysmally low that it was necessary to provide an explanation in the journal article reporting the study. They suggested the reason for the low numbers may be related to poor access to these large hospitals and Hib patients may all be dying quietly at home. They suggested a community based study to look at the real picture. Community studies are exorbitantly expensive but the WHO funded the study The community study found an incidence of Hib meningitis of only 7/100,000. This papers now suggests other reasons for the low numbers. Among them they admit that there may be natural immunity to Hib in The vaccine manufacturers are not happy with that explanation. Now culture media cannot be blamed, poor access to hospitals is not the cause – a new reason for the poor culture rates needs to be found. Well can it not be that India is a country of quacks and doctors who are all prescribing antibiotics left right and center. Under such circumstances culture rates will be low. The only way to know would be to do Probe Studies Probe studies identify reduction in clinical disease after immunization. All the disease the unvaccinated have over and above the vaccinated must be due to Hib. No culture proof is needed. Lambok Study was done in Indonesia. It was an excellent study. 55000 children were randomized to receive Hib or act as controls. This was a double-blind study. There was active case surveillance. Reported in 2005 Unfortunately in this study there was more Pneumonia among the vaccinated – not statistically significant, but more pneumonia in those vaccinated There were more children with pneumonia in the vaccinated group than in the control group. It did not however reach the level of statistical significance. This was published in 2005 Then we have the Bangladesh probe published in 2007 This study was not as rigorous as the Indonesia study. There was no blinding – no randomization. There was no active surveillance. It was an incident case-control study. 35% had received the vaccine. There were 475 cases of pneumonia from this population of 68,000. There was no significant difference in either of the end points – not for meningitis or pneumonia. This was published in the journal Pediatric Infectious Disease but who among the public reads medical journals? Let us see what the press release after this study, says. Believe it or not: this is what the press release said: Study shows Hib vaccine could prevent about 1/3 of life-threatening cases of bacterial pneumonia in Asia. The press release was signed jointly among others by the WHO, GAVI, USAID and Johns Hopkins. This was exposed in both the BMJ and the Indian Journal of Medical Research. None of the organizations have refuted this allegation of deliberately misleading the public in this press release. There is no hidden agenda. The cost of the vaccine in the USA is $5.60. Price can come down only if Hib is part of EPI internationally. This was published in Nature Medicine and the Lancet. By inference, poor countries must include this vaccine in the EPI that they do not need, so the price of the vaccine can come down in the West. Studies in Canada have shown that the vaccine has eliminated Hib in the country but there is proportional increase in non-B H. influenza strains causing invasive H influenza disease in the post-Hib vaccine era. The pneumococcal vaccine. The vaccine costs Rs 12,000 per child for 3 doses. According to what has been published in the WHO Bulletin it reduces 3.6 cases of pneumonia per 1000 children vaccinated. The vaccine doubles the chance the child will get asthma, according to this article in the New England Journal of Medicine. According to this Lancet article, in India the vaccine costs Rs 12,000 per child and Vaccinating 1000 children costs Rs 12 million. On the other hand treating 4 cases of pneumonia will cost Rs 40 if WHO recommended Septran is used. So we spend Rs 12 million to save Rs 40. Assuming the prices come down to a tenth of the present market rate. It will cost Rs 1.2 million to save Rs 40. Good value for money? Treating 4 cases of pneumonia will cost Rs 40 if WHO recommended Septran is used Where the 7 valent vaccine was used, those strains have come down but it has been replaced by 19A. Previously the pneumococci were nearly all Pencilline sensitive. The new strain is often Pencilline resistant. So now a 13 valent vaccine that includes 19A. We await results on what new strains will emerge. There are about 100 known strains of pneumococci. Briefly, on the rotavirus vaccine. Studies have shown that there is continuous re-assortment between bovine and human rotavirus strains in India; that the strain is different in different places and at different times in the same area. There is not one study to show that the vaccine reduces diarrhea in the country. Yet it is promoted in the country. There are so many wonderful programs of disease control. How does one decide what programmes to chose. Take this hypothetical case study. You have Rota virus control that costs Rs 200 crores for implementation nationwide. It saves 1 life year per Rs 20,000 spent. There is polio control costs Rs 350 crores and saves 1 life year per Rs 10,000 spent. TB control costs Rs 700 crores and it saves 1 life year per Rs 5000. Assume you have a budgetary constraint of Rs 1000 crores. What programmes will you chose and why? I am using heath economic terms here in a non-technical manner, for easy understanding. We need to rank the programmes in the incremental order of cost-utility ratios. TB is most cost effective as it saves a life per Rs 5000 spent. That will be the first priority. That will use up Rs 700 crores from the budget. We are left with only Rs 300 crores. We must spend it on polio control. Rota vius control will not feature in our plans although the whole programme costs only Rs 200 crores. If we spend on Rota virus programme we have Rs 200 crores less for TB control. For ever life we save from Rota virus, we will be losing 3 extra lives to TB. This is why it will be unethical and even criminal to divert money for a less cost effective scheme when there are more cost beneficial uses for the resources. In India 50% of the population don’t receive the basic EPI vaccines costing Rs 30/ child. Vaccinating with the HPV vaccine costs Rs 9000, Rota virus cost Rs 2000 and the Pneumococcal vaccine costs Rs 12,000 per child. From the community perspective will use of these newer vaccines be ethical? Let us look at it from an individual perspective. We have a vaccine that costs Rs 12,000 but the marked price on the vials, paid by the patient, includes a kickback of Rs 3000 for the doctor who administers the vaccine. The vaccine does little good (only 3.6 cases of pneumonia reduced per 1000 vaccinated); it doubles the risk of asthma (1.4 extra cases of asthma for every 3.6 cases of pneumonia prevented); and the community risks the emergence of antibiotic resistant strains. Can it be prescribed ethically to those who have the money and can afford to pay? If these vaccine are so bad, then how come the WHO is promoting it? How come anyone uses it? How can it be promoted? Half truths areused to sell the vaccines. The following are statements from the SAGE report of the WHO recommending pneumococcal vaccine. 10.6 million children under five years of age die each year. Pneumonia, leading cause of mortality among children in developing countries. Pneumonia is a vaccine preventable disease. The unsaid part of this truth is that the vaccine is against only one bacterial pathogen among the numerous agents that cause pneumonia, and that against only a limited number of strains of that bacteria. It is dishonest to pretend the vaccine can prevent all pneumonia Another half-truth is that Pneumococcal vaccine protects against 80% vaccine-strain invasive-disease (VS-IPD). That is straight from the Cochrane meta analysis. The other half of the truth in the Cochrane report is that there is no reduction in all-cause mortality with the vaccine, but this is not highlighted. The incidence of vaccine-strain invasive-disease was so low - the absolute risk difference (ARR) is only -0.002 and the number needed to vaccinate to prevent one case of pneumonia was 500 in this analysis. Misleading statistics are what we need to understand. A risk reduction (RR) of 50% sounds good for a vaccine. Patients and doctors are easily convinced with this figure. This article in Clinical Oncology shows how it can be misleading. Suppose risk comes down from 4% to 2% the RR is 50%. Another accurate way to describe the benefits would be to say that the intervention affords 2% reduction in absolute risk. Only this is less likely to convince patients to take the treatment. Take the instance of yellow fever vaccine. Assuming it has 100% efficacy against yellow fever. We in India would not use the vaccine in a national immunization programme because the disease is non-existent here and the absolute risk reduction is zero. Let me elaborate on this statistical concept because it is crucial. Relative risk (RR) is the ratio of the two risks. If the risk of disease comes down from 2/1000 to 1/1000 the RR is 50% and it can be said to halve the risk. To calculate the absolute risk reduction (ARR) you do not need any new data to be collected. Here instead of a ratio, one risk is subtracted from the other. The ARR in this case is 0.001. ARR is very useful because the reciprocal of ARR is the numbers needed to treat (NNT) to prevent one case. In the example above the ARR is 0.0001 and we can easily calculate the NNT as 1000 children vaccinated to prevent one case. Thus using the same raw data if ARR is reported it allows one to calculate the total cost to prevent one case. This is very useful. RR is quite useless without data on the frequency of the problem in the community The BMJ has been pleading for this change for some time. A chief editor Godlee has written in an editorial entitled ‘Absolute Risk Please’ where she says that impressive sounding reductions in relative risk can mask much smaller reductions in absolute risk. Clinical decisions must be based on absolute risk (AR) rather than relative risk (RR). So what can we do to avoid buying a dead donkey? We need a resolution in the World Health Assembly along the lines recommended by the BMJ. For all intervention being recommended to enhance child survival, the WHO and other agencies must always report efficacy in terms of 'absolute risk reduction' (NOT Relative risk (RR)) so that member states can calculate cost benefits easily. There can be no logical objection to deny this demand. 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  Public Interest Petition (PIL) Vaccine case 6th affidavit 14/11/11

  Prashant Bhushan on behalf of the petitioners
  IN THE HIGH COURT OF DELHI AT NEW DELHI (CIVIL ORIGINAL JURISDICTION) C.M. No. OF 2011 IN WRIT PETITION (CIVIL) No. 13698 OF 2009 PUBLIC INTEREST LITIGATION IN THE MATTER OF: DR. K. B. SAXENA & ORS. …PETITIONERS VERSUS UNION OF INDIA & ORS. …RESPONDENTS APPLICATION FOR DIRECTION ON BEHALF OF THE PETITIONERS UNDER SECTION 151 CPC To, The Hon’ble Chief Justice of Delhi And His Hon’ble Companion Justices of the Hon’ble Hig Show More...IN THE HIGH COURT OF DELHI AT NEW DELHI (CIVIL ORIGINAL JURISDICTION) C.M. No. OF 2011 IN WRIT PETITION (CIVIL) No. 13698 OF 2009 PUBLIC INTEREST LITIGATION IN THE MATTER OF: DR. K. B. SAXENA & ORS. …PETITIONERS VERSUS UNION OF INDIA & ORS. …RESPONDENTS APPLICATION FOR DIRECTION ON BEHALF OF THE PETITIONERS UNDER SECTION 151 CPC To, The Hon’ble Chief Justice of Delhi And His Hon’ble Companion Justices of the Hon’ble High Court of Delhi The humble application of the petitioners above named: 1. The Petitioners had filed the instant writ petition in public interest highlighting how irrational vaccines were being introduced in the public health system by the Government, under the influence of vaccine manufacturers and international agencies like World Health Organization (WHO), without proper epidemiological and medical studies. Petitioners (who are generally pro-vaccine and pro-modern medicine) were appalled at how in the absence of a rational vaccine policy, newer and newer vaccines were being pushed by the Government into the national immunization programme. Vaccines which are either of little utility or which are not required at all were being introduced and promoted by the Government at the behest of these vested interests and, at the same time, basic vaccines that are the right of every child are not being made available under the Universal Immunization Programme (UIP) to 53% of the population – mostly poor living in rural areas who should be the priority for any immunization program as the poor cannot afford the consequences of disease. 2. Though this petition caused a temporary halt to Government’s ill-conceived plans, yet now the Government is again pushing for the introduction of new vaccines, especially Pentavalent (5-in-one) vaccine. Pentavalent combines the essential EPI vaccines of DPT with non-EPI non-essential and expensive vaccines of Hib and Hepatitis B. Thus the new vaccines for which there is low demand and which are expensive, would piggy-bank on the essential DPT vaccine (which is of extremely low price). This will make the plain DPT vaccine unavailable and every child would have to take Pentavalent to get access to DPT. Introducing Pentavalent in the UIP would mean that UIP would have extremely low coverage and would cost tens of thousands of crores of public money. This is a giant scam in the making. 3. This is happening at a time when the Government has shut down virtually all public sector units that were supplying the essential vaccines at a cost that is a fraction of the cost at which same vaccines are produced by the private sector. There were no complaints against these units and the general view was that these units were doing exemplary work. No question was ever raised regarding the quality of vaccines produced in these centres. Yet, without any provocation they were closed down on the pretext that they were not following “good manufacturing practices” which related to their building set-up. Even if they required upgrade, government should have sanctioned some funds for the purpose. More and more information has come in the public domain to highlight how this was a systematic attempt to benefit private companies. Now, response under RTI has clearly shown that after the above public sector facilities were shut down, there has been a huge increase in the number of deaths of children due to vaccination side effects. RTI reply and reports on this are annexed as Annexure A1 (Colly). This shows how the Government played with the health of children just to benefit private companies. After the closure of public sector units became a big public scandal and this fact was highlighted in the instant petition, Government announced its decision to reopen the 3 vaccine manufacturing facilities. But the 3 units have still not been opened. A news report on this is annexed as Annexure A2. 4. National Technical Advisory Group on Immunization (NTAGI) is the apex advisory group on vaccination and immunization for Universal Immunization Programme (UIP). Petitioner No. 8 was inducted as a Member of the said group during the pendency of the instant petition. The proceedings and the minutes of NTAGI meeting exemplifies clearly the reasons for which the petitioners came to court – how irrational expensive vaccines are being introduced in the public health system by the Government, without proper epidemiological and medical studies in a country where needed inexpensive vaccines are being denied to 50% of the population. Decisions are made before-hand based on extraneous considerations. Data is provided only to give it a veneer of objectivity. When such data is shown to be wrong, other equally fanciful data is provided but the determination to introduce the vaccine persists. The NTAGI had previously recommended universal immunization with the Pentavalent vaccine. But then it was pointed out to this court that the data from a multi-center study done by the Government of India was deliberately left out because it did not support the need for the vaccine. After this, the Government set up an ‘Experts Group’ to look at this and followed it with a ‘Core Committee’ recommendation After all this, the NTAGI met on 26 August 2010. The NTAGI again recommended introduction of Hib and Hepatitis B vaccine in 2 states but now gave different reasons and quoted other data. The new ‘evidence’ is as fallacious as before and this has been clearly pointed out to the Government in a presentation to the Planning Commission. A copy of the presentation made to the Planning Commission is annexed as Annexure A3. 5. The numbers benefiting (deaths avoided by vaccination) from Hepatitis B was based on ‘personal communication’ from Prof Acharaya of AIIMS Dept of Gastroenterology. He claimed to have done liver biopsies on all Hepatitis B carrier patients going to AIIMS over one and a half years. Such an invasive and potentially lethal investigation on all patients would be gravely unethical and inconceivable. One can surmise that Dr Acharaya wanted to project the data of patients going to him in the Gastroenterology Unit on the whole population of India. It must be for this reason that he stated that liver biopsy was done in all patients (consecutive patients) going to AIIMS. The figure of 3 lakh cases of cirrhosis a year in the country is based on this fiction. Other than this, the only other data on deaths averted nationally by Hepatitis vaccination that is presented is ‘22238 cases of Hepatocellular Carcinoma from the ICMR cancer registry’. Here again the figure has been exaggerated by over 200%. The correct figure from the ICMR cancer registry is about 10,000. 6. In the same way the recommendation for Hib vaccine was made on the projection that 52000 cases of Hib meningitis occur in the country each year. The projection for the whole country is made from 9 cases of ‘presumed Hib meningitis’ in one year, in one district in Kerala. The same paper that reported 9 ‘presumed Hib’ also reported there were only 3 cases of presumed Hib in that district, in the next year. No explanation is given of why this figure of 3 cases was not used for making national predictions. Selective use of data flies in the face of the basic tenets of ‘Evidence Based Medicine’. The numbers needed to vaccinate to prevent one death is crucial to make informed decisions on the cost benefit of introducing a new vaccine. The fanciful figures that were used in the ‘expert committees recommendation’ and the NTAGI recommendation, supports the contention of the petitioners that the vaccine is being introduced at the behest of various vested interests without clear evidence that it will be useful or that it is needed. 7. The petitioners had drawn attention of this Hon’ble court to the deaths from Pentavalent vaccine in Sri Lanka. The Government provided the Court with a report about these deaths to say that deaths were investigated and were found not to be related to the vaccine. Petitioners had highlighted how the standard classifications of adverse effects were changed so that reactions which should have been classified as ‘probably related’ were classified as ‘unlikely’. To enable them to do it the ‘experts’ temporarily deleted the category ‘probably related’ from the classification itself for use in this report. WHO has now stated that it still stands by its full standard classification and does not use the mutilated format for reporting adverse effects. A report on this is annexed as Annexure A4. The draft policy, that was submitted to this Hon’ble Court by the Government, on the other hand uses the watered down, mutilated version; as if serious side effects and deaths from the vaccine are not of any importance to this government. Concerns were raised on the above issues in a special mention in the Rajya Sabha on 12.08.2011. A copy of the special mention made in Rajya Sabha on Pentavalent vaccine is annexed as Annexure A5. 8. The National Technical Advisory Group on Immunization (NTAGI) noted that the utility of the two new components of the Pentavalent vaccine (Hib and Hepatitis B) is not known in India. Furthermore there have been deaths with the use of this combination vaccine in neighboring countries Sri Lanka, Bhutan and Pakistan. The cost of the standard DPT vaccine will go up 10 fold with this vaccine. 50% of India’s children already do not receive the inexpensive DPT. However, NTAGI inexplicably still recommended that the vaccine be tried in 2 states – in Kerala and Tamil Nadu to evaluate the impact and side effects before introduction in other states. There is considerable disquiet in the 2 states at being selected as guinea pigs for this experiment. Special mention was made of this in the Rajya Sabha. Tremendous international pressure is being brought to bear on India to introduce the expensive Pentavalent vaccine in India. This was also the agenda of a meeting of WHO, pharmaceutical companies and Bill Gates Fund in Delhi on 2 August 2011. Although the NTAGI recommended introducing the vaccine in 2 states to study its adverse effects and benefits, and the programme is said to be on the verge of being rolled out, no mechanism has been put in place check with recipients of the vaccine after a week about the side effects or to study objectively if there is any benefits. 9. The entire exercise is reminiscent of the HPV study by PATH where the Expert committee found that 4 of the 5 objectives were to study safety of the vaccine but no diary or log of adverse effects was maintained. The Government cannot be allowed a repetition of that situation. Wherever study of efficacy, adverse affects and general safety of a drug or vaccine is conducted, it is always done in a small district and the after-effects of that drug or vaccine are surveyed, house to house. Studying the after-effects of a vaccine would require frequent follow-up visits of all the children, which is impossible if the vaccine is introduced in the whole state. By introducing the Pentavalent in the entire states of Tamil Nadu and Kerala, the Government is not only allowing the pharma companies to make huge profits, but also leaving no scope for study of affects of the vaccine. Thus, only if newspapers break news of serious adverse effects and it becomes a public scandal, then and only then, would the Government reluctantly state that trial did not prove efficacy and safety of the vaccine. There have been protests in the above states by people stating that they are being used a guinea pigs. This unethical trial of Pentavalent in the 2 states without any monitoring of its aftereffects has met stiff resistance from the local populations. Reports on this are annexed as Annexure A6 (Colly). 10. The procedure of selection to NTAGI and the processes followed at the meeting was witnessed by Dr. Puliyel (Petitioner No. 8) who was inducted into the NTAGI without any examination of his credentials - perhaps on the basis of the fact that he is a petitioner in this case. A request by Dr. Puliyel to have the proceedings recorded, so that members can be held accountable for what they say, was denied on the grounds that members would not voice their views freely, if it were recorded. No explanation was given why members on a vaccine advisory group may need secrecy for the recommendations they make. The wisdom of denying the request of recording was plain when the minutes of the meeting were circulated. The minutes are manipulated to selectively quote members statements as consensus statements. 11. This Hon’ble Court had asked the Government to frame an appropriate policy for vaccination and immunization. Pursuant to the orders of this Hon’ble Court, NTAGI resolved that Dr. Puliyel would help Dr N K Ganguly to draft the Vaccine Policy. This was recorded as such in the first draft of the minutes circulated to members and attached. The name of Dr. Puliyel was removed in the final version of the minutes in blatant violation of the expressed wishes of the NTAGI. A copy of the letter written by Dr. Puliyel protesting against the removal of his name is annexed as Annexure A7. 12. After this manipulation, a draft policy was prepared by Dr. Ganguly that was submitted to this Hon’ble Court by the Government. A copy of his response of the Dr. Puliyel to the above draft policy is annexed as Annexure A8. According to a story published in CSE’s Down to Earth the draft policy backed new expensive vaccines without study. A copy of the said article is annexed as Annexure A9. This shows that right from the very beginning there were systematic attempts to push newer expensive vaccines under corporate pressures. 13. Now Dr. Ganguly has on his own drafted a vaccine policy. There are serious issues that the petitioners have with this policy which defeats the objective with which petitioners had approached this Hon’ble Court. The policy document states it will be “mandatory for the government to support advance market commitments and honor the commitments”. Advance market commitments (AMC) are made even before the prototype of the vaccine is produced. The commitments are made before the vaccine is tested for its efficacy/effectiveness in the local population. A copy of the said policy drafted on the directions of this Hon’ble Court is annexed as Annexure A10. 14. The policy goes further to suggests the government use ‘innovative finance mechanisms’ (GAVI terminology that means the Government must take loans by the issue of bonds) to pay the World Bank in advance. By including the line making AMC mandatory on all future Governments, the authors of this policy propose to bind the hands of all future governments. 15. In an interview to Centre for Science and Environment (CSE)’s fortnightly magazine Down to Earth, author of the policy, Dr. Ganguly says “The government will commit to the manufacturers so that they invest in vaccine production. If governments do not commit, the company which will set up the plant exclusively for the need of the country, may sink because no one else would want that vaccine and the company would be producing it exclusively for the country which demanded it…” This statement is self-explanatory. In the same article he also says that, “…One contract will last for a year for one programme. Once the programme is over, the government will revise the programme and select new companies. If the government wants to discontinue a particular vaccine after a year, it can easily do that…” The above statements contradict each other. While in the first he is worried about the vaccine companies, in the second he withdraws from this, knowing that the former position cannot be defended even to a press reporter. This clearly shows that the policy is made in the interest of and at the behest of private pharmaceutical companies. A copy of the said story titled ‘Experts contest new vaccine policy document’ is annexed as Annexure A11. National daily ‘Mail Today’ has done a story highlighting how the vaccine policy has come under criticism for favouring manufacturers and not the general public. A copy of the said story is annexed as Annexure A12. 16. According to the above article in Down to Earth, this policy was approved by UN agencies. On the other hand there was no open consultation with experts in India nor was the Indian public taken into confidence. A recent publication authored by 8 international experts on behalf of 140 organizations of the world has drawn attention to the fact that UN is playing into the hands of all kinds of industry with huge conflicts of interests. A copy of the said article published in ‘The Lancet’ is annexed as Annexure A13. The swine-flu vaccine scam is too well known where swine-flu was declared as a pandemic by the WHO which turned out to be a false-alarm that only benefited vaccine manufacturers. Reports on this are annexed as Annexure A14 (Colly). A letter written by prominent political leader Ms. Brinda Karat who has been closely monitoring the HPV vaccine trials, to the Health Minister highlights the unethical practices by WHO in developing countries. A copy of the said letter dated 27.10.2011 is annexed as Annexure A15. An editorial published in The Hindu called the said trial as “shockingly unethical”. A copy of the said editorial is annexed as Annexure A16. Newspaper The Tribune has also written a detailed report highlighting the serious lapses in the HPV vaccine trial. A copy of the report published in The Tribune dated 09.05.2011 is annexed as Annexure A17. There have been several other reports on the way trials are conducted in India and the way vaccines are being pushed onto Indian children. The said reports are annexed as Annexure A18 (Colly). The Government of India has now admitted lapses in the HPV vaccine trial. A copy of the report on this is annexed as Annexure A19. This has also exposed the dubious designs of international donor organizations as stated above. 17. Dr. Puliyel, Member NTAGI has registered his strong protest at the final version of the policy. In a latter to the Health Secretary who is also the Chairperson NTAGI he has stated: “The vaccine policy ideally would state how the government proposes to universalize the benefits of immunization to the large sections who don’t receive the basic vaccinations. It would also describe how new vaccines are to be selected for introduction in the programme for universal immunization. Ideally it would lay down the process of selection of members to the NTAGI and how the procedures of this committee are to be recorded and made open to the public. Methods of estimating disease burden, vaccine efficacy, and assessment of costs, benefits and adverse effects of newer vaccines; and the process of how new vaccines are to be introduced, should have found a place in the policy. Unfortunately the draft is non committal on almost all of these issues.” A copy of his letter is annexed as Annexure A20. EPW has also published a detailed article against the new vaccine policy stating that it puts the interest of industry over the public health. A copy of the said article dated 05.11.2011 is annexed as Annexure A21. 18. Earlier, in response to our petition Government has stated that it would conduct trials in 2 states of India: Tamil Nadu and Kerala, to determine the efficacy and the need of Pentavalent vaccine. It is now clear that this push was made for eventual introduction of Pentavalent in the country’s UIP at the behest of international agencies like UN and Bill Gates Fund. There is now ample evidence to show that vaccination policies and funding is being driven on the basis of industrial pressures and misplaced priorities. Studies and reports on this are annexed as Annexure A22 (Colly). Now there is clear evidence that cost of pneumococcal vaccine was underestimated by 10 times. A published letter of Dr. Puliyel is annexed as Annexure A23. Now, even the WHO has been forced to accede to concerns of doctors that there is not adequate data to push for Hepatitis B vaccine. A report on this is annexed as Annexure A24. 19. In the face of the above facts, the vaccine policy prepared on the directions of this Hon’ble Court does not address the concerns of millions of children who have been left out from receiving even basic essential vaccination and instead tries to protect the vested interest of vaccine manufacturers, it violates Article 14 and Article 21 of the Constitution and therefore deserves to be set-aside by this Hon’ble Court. The said policy has been made without any transparency, without even the pretence of public consultations, has not been approved by NTAGI, does not have approval of Union Cabinet or of the Parliament, and yet it tries to steer the country’s immunization programme in the wrong direction, tries to make commitments of thousands of crores of rupees binding future governments, into purchase of newer expensive vaccines whose prototype has not even been modeled alone tested, from foreign private companies. Such a policy is therefore void ab initio. 20. There is no transparent method to select members to the NTAGI. As such, the government does not get independent advice but it merely hears what it wants according to the persons that they have appointed to the committee. It is clear that there needs to be an open and transparent selection process for appointing members to this advisory body. The Government may appoint an expert committee to select the best persons from among applicants for the job in a transparent manner. The duration of the appointment must be fixed, and to ensure organizational memory, only a part of the committee must retire each year. The discussions in the NTAGI meetings must be open to the public so that each member is accountable for the advice they proffer. Only this can ensure that public health policies are not hijacked by vested interests in the future. 21. That the present Application is being made bona fide and in the interest of justice. PRAYERS In these circumstances the Petitioners pray that your Lordships may be pleased to pass following ad-interim directions: (i) Set aside the vaccine policy (Annexure A10) and direct the Government to set up a committee to transparently select members of NTAGI for a fixed term from credible public health experts and pediatricians with no conflict of interest, to formulate new vaccine policy and study the effects of introduction of Pentavalent in the 2 states (ii) Pass further orders as may be deemed fit and proper. AND FOR THIS ACT OF KINDNESS THE APPLICANTS AS IN DUTY BOUND SHALL EVER PRAY Petitioners Through: PRASHANT BHUSHAN Counsel for the Petitioners Filed on: November 2011 New Delhi IN THE HIGH COURT OF DELHI AT NEW DELHI (CIVIL ORIGINAL JURISDICTION) C.M. No. OF 2011 IN WRIT PETITION (CIVIL) No. 13698 OF 2009 PUBLIC INTEREST LITIGATION IN THE MATTER OF: DR. K. B. SAXENA & ORS. …PETITIONERS VERSUS UNION OF INDIA & ORS. …RESPONDENTS INDEX S. NO PARTICULARS PAGE NO. C.FEE 1 Urgent Application 2 Application for Direction on behalf of the Petitioners under section 151 CPC with Affidavit 3 Annexure A1 (Colly): RTI response and reports on number of deaths due to vaccination side-effects 4 Annexure A2: News report showing that 3 public sector units are still shut 5 Annexure A3: Copy of presentation made to Planning Commission on immunization 6 Annexure A4: Report on WHO standing by its classification on vaccine deaths/adverse affects http://blogs.timesofindia.indiatimes.com/staying-alive/entry/26-measles-vaccine-deaths-in-3-years-no-investigative-report-yet1 http://blogs.timesofindia.indiatimes.com/News-sick/entry/investigating-vaccine-deaths-to-be-managed-primarily-by-national-government-who 7 Annexure A5: Special mention in Rajya Sabha on Pentavalent on 12.08.2011 8 Annexure A6 (Colly): Reports on the trial of Pentavalent in Tamil Nadu and Kerala 9 Annexure A7: Copy of letter written by Dr. Jacob Puliyel, Member NTAGI See below 10 Annexure A8: Copy of the response of Dr. Puliyel to draft vaccine policy See below 11 Annexure A9: CSE’s report on draft policy pushing for new expensive vaccines http://www.downtoearth.org.in/content/policy-draft-backs-new-vaccines 12 Annexure A10: Copy of vaccine policy made pursuant to the directions of this Hon’ble Court 13 Annexure A11: Copy of CSE’s report on experts contesting the new policy http://www.downtoearth.org.in/content/experts-contest-new-vaccine-policy-document 14 Annexure A12: Copy of report published in Mail Today showing how policy supports manufacturers http://indiatoday.intoday.in/story/draft-national-vaccine-policy-favouring-industry/1/158925.html 15 Annexure A13: Copy of Lancet article on UN’s conflict of interest 16 Annexure A14 (Colly): Reports on how vaccine industry benefitted from WHO’s alarmist declarations on swine flu 17 Annexure A15: Letter of Ms. Brinda Karat on HPV vaccine trial 18 Annexure A16: Editorial in The Hindu on HPV vaccine trial http://www.thehindu.com/opinion/editorial/article2021657.ece 19 Annexure A17: Report on the serious lapses in the HPV vaccine trial 20 Annexure A18 (Colly): Reports on the way vaccines are pushed onto Indian children 21 Annexure A19: Government admits to lapses in HPV vaccine trial 22 Annexure A20: Copy of letter of Dr. Puliyel to the Health Secretary criticizing the new vaccine policy See below 23 Annexure A21: Article published in EPW on the vaccine policy http://jacob.puliyel.com/download.php?id=244 24 Annexure A22 (Colly): Studies and reports on how vaccination policies are being led by industry 25 Annexure A23: Published letter showing how the cost of pneumococcal vaccine was underestimated by 10 times http://jacob.puliyel.com/download.php?id=239 25 Annexure A24: Report on WHO acceding to concerns of doctors on Hepatitis B vaccine (PRASHANT BHUSHAN) COUNSEL FOR THE PETITIONERS 301, NEW LAWYERS CHAMBERS SUPREME COURT OF INDIA NEW DELHI-110 001 NEW DELHI CODE NO. P195 DATED: ENROLLMENT Letter to NTAGI To Mr. K Chandramouli The Secretary Health and Family Welfare Nirman Bhawan New Delhi Dear Mr. K Chandramouli Thank you for the invitation dated 6 June 2011 to the NTAGI meeting on 13 June 2011. I would like to raise the following points at the meeting and the agenda may please be modified suitably. 1. Discussion of Minutes of meeting of 26 August 2011 Agenda Item 5- National Vaccine Policy The original minutes had recorded that: ‘Dr. NK Ganguly, Ex-DG, ICMR would draft a National Vaccine policy; Dr. Jacob Puliyel, will also provide his inputs in facilitating the drafting the policy document. Thereafter the policy document will be circulated to all members for their inputs before the final draft is discussed in the NTAGI meeting.’ The minutes were then altered to delete the name of Jacob Puliyel. I must request the chair to tell the house at whose behest this alteration was made and who colluded? How can we prevent repetition of this in the future? I had earlier suggested recording of the proceedings. Regarding the draft policy: What has been done with the inputs from members on this draft? When will the draft be discussed in the NTAGI? 2. This NTAGI meeting has been called to ‘discuss the proposal for expansion of Pentavalent vaccine to some other States’ Whose proposal is this? Is it a proposal of the Government of India? Is it proposed by some other agency? This needs to be explicitly stated. I request that we be informed about this at the meeting. 3. Concerns about Pentavalent Vaccine Safety and its Utility The stated rationale for introducing the vaccine in India were recently called into question at the Planning Commission. I have attached that document but more ominous is the safety record of the vaccine. There have been several deaths immediately following vaccination. As such, if the vaccine is to be introduced a vote must be taken, and I request that my dissent must be recorded stating the following reasons: There have been many death in neighboring countries immediately following use of Pentavalent vaccine. Sri Lanka Deaths The ICMR has given the Delhi High Court a report of the WHO expert group investigating Sri Lanka deaths, saying the vaccine ‘was unlikely to be the cause for the deaths’. However this report states clearly that no other cause was found to explain the deaths which happened soon after vaccination. Using the Brighton Classification of the WHO, this would be classified as ‘Probably related to Vaccine’. The report given to the Delhi High Court says that the Experts of this investigation removed the categories ‘Probably related’ and ‘Possibly related to the vaccine’ from the Brighton Classification and made their own improvised classification. This is how the deaths came to be classified by these ‘experts’ as ‘unlikely to be related to vaccine’ Pakistan Deaths Professor SK Mittal writing in the BMJ has recorded the following “According to an expert on the committee investigating the Pakistan deaths, one child died within half an hour of receiving the vaccine and 2 others died within 12 to 14 hours. No alternate cause of death was found for any of the deaths but the experts misleadingly suggest that ‘two cases were diagnosed as Sudden Infant Death Syndrome (SIDS) but we (the experts) were not sure of the third case’. Sudden Infant Death Syndrome (SIDS) is a diagnosis of exclusion when no cause can be found and to call sudden death following a vaccine as SIDS suggests a lack of understanding of the term or worse, it points to an attempt to obfuscate. Bhutan Deaths Professor Mittal also points out: “The 'expert report' on the 8 deaths in Bhutan is not available in the public domain as far as we can ascertain. A WHO spokesperson is reported to have said the cause of death in Bhutan was not vaccination, but they were due to a three other causes namely ‘sudden death, convulsions and meningitis’”. (Professor S. K. Mittal 'Sudden Deaths' after Pentavalent vaccination: Is the vaccine really safe? BMJ http://www.bmj.com/content/340/bmj.c3508/reply#bmj_el_239257?sid=0d933918-9cbf-4fc3-a023-d6705097271f) India Deaths 4 children died in Lucknow in August 2010. Although Measles vaccine was sought to be blamed The Hindu and some other news channels (http://ipsnews.net/news.asp?idnews=52638) noted that some of those who died were only 3 months old (well below the age to receive measles vaccine). The Hindu reported the deaths could have been due to pentavalent vaccine. This has not been denied by the Government. The Health Minister said that experts were investigating the deaths and their report will show which vaccine was used. 10 months later, the vaccine involved has not been revealed and the Government has refused to respond to an RTI about it, saying the matter was ‘subjudice’. The Hindu report is below http://hindu.com/2010/08/24/stories/2010082457281300.htm Initially, it was said that three deaths had occurred due to the anti-measles vaccine and one death due to the BCG shot. Then it was said the children were given BCG vaccine instead of anti-measles, and it was also said that the shots were pentavalent vaccine given during a pilot project under the universal immunization programme. All these questions will be answered once the enquiry was complete, the Minister said, adding there was an internationally prescribed procedure to be followed during vaccination. With these facts known about sudden deaths following this vaccine, I would consider myself foolhardy and reckless to agree to introduce the vaccine in more states without proper study. Even in the States of Tamil Nadu and Kerala it must be introduced very cautiously, in limited areas where both the side effects and benefits can be monitored. My dissent may please be recorded. Jacob Puliyel Letter to Health Secretary about Draft Policy Sub: National Vaccine Policy and Advance Market Commitments Dear Sir, I write to you as a member of the National Technical Advisory Group on Immunization (NTAGI) and put on record some of my concerns in making of a ‘National Vaccine Policy’– a document seemingly drafted a by few persons without much needed consultations or even a modicum of public debate. What is worrying, is the process as it has not been discussed or sanctioned by this expert body of which I am member. The NTAGI had resolved (meeting of 26 August 2010) that the policy was to be drafted by Dr Ganguli with help from Jacob Puliyel and this was stated in the first version of the minutes circulated after the meeting. But it did not happen this way; one wonders at whose behest, the collective decision of the NTAGI was overruled. I believe that a section of Ministry of Health cannot unilaterally make a policy that is binding on all future governments, to honor advance-marketing-commitment it has entered into, to favor some vaccine manufacturer. What the policy prescribes There are serious issues that this policy raises on pages 10, 11 and 16. The policy document states it will be “mandatory for the government to support advance market commitments and honor the commitments”[1]. Advance market commitments (AMC) are made even before the prototype of the vaccine is produced. The commitments are made before the vaccine is tested for its efficacy/effectiveness in the local population. Advance commitments are made with a front end loading (meaning a very high price to start with) and a tail price (a little lower price after some 5 years), all of which are negotiated well before the vaccine is made - leave alone tested!! The first manufacturer past the goal post (who makes a vaccine) gets the contract. It is for many years - usually at least 5 years. Ordinarily the World Bank holds the money for the AMCs for several years in advance. Page 16 of the policy goes further to suggests the government use ‘innovative finance mechanisms’ (GAVI terminology that means the Government must take loans by the issue of bonds) to pay the World Bank in advance. By including the line making AMC mandatory on all future Governments, the authors of this policy propose to bind the hands of all future governments. Such a decision can only be made if there is widespread consensus for the proposal in Parliament. There has been recent press coverage of this issue of AMC in the policy.[2] In the magazine Down to Earth, the author of the policy says , “The government will commit to the manufacturers so that they invest in vaccine production. If governments do not commit, the company which will set up the plant exclusively for the need of the country, may sink because no one else would want that vaccine and the company would be producing it exclusively for the country which demanded it,…”. This statement is self explanatory. In the same article he also says that, “..One contract will last for a year for one programme. Once the programme is over, the government will revise the programme and select new companies. If the government wants to discontinue a particular vaccine after a year, it can easily do that…” The above statements contradict each other, while in the first he is worried about the vaccine companies, in the second he withdraws from this. This tacit admission of the fact that long term advance market commitment is not defensible and it may not be in the national interest but merely in the interest of private vaccine manufacturers, is reassuring. According to the article in Down to Earth, this policy was approved by UN agencies but failed to consult Indian experts or take the Indian public into confidence. A recent publication authored by 8 international experts on behalf of 140 organisations of the world has drawn attention to the fact that UN is playing into the hands of all kinds of industry with huge conflicts of interests.[3] Current global mechanisms established around vaccination are under scanner because of conflicts of interests. “The extent and range of relationships between tax-exempt foundations and for-profit corporations suggest that transparency or grant-making recusal of employees alone may not be preventing potential conflicts of interests between global health programs and their financing”. This is because of the Gates Foundation-supported project-- Advance Market Commitment (AMC)-- a market expansion strategy for increasing profits for vaccine manufacturers masquerading as an innovative method for developing vaccines for neglected disease to save the lives of millions of poor children…”[4] The Missing Point The vaccine policy ideally would state how the government proposes to universalize the benefits of immunization to the large sections who don’t receive the basic vaccinations. It would also describe how new vaccines are to be selected for introduction in the programme for universal immunization. Ideally it would lay down the process of selection of members to the NTAGI and how the procedures of this committee are to be recorded and made open to the public. Methods of estimating disease burden, vaccine efficacy, and assessment of costs, benefits and adverse effects of newer vaccines; and the process of how new vaccines are to be introduced, should have found a place in the policy. Unfortunately the draft is non committal on almost all of these issues. Notwithstanding all this I would have welcomed a draft policy that was in the interest of public health. Unfortunately the policy as published ignores the interest of millions of children who are left out from the routine vaccination. I would like to place my concerns on record and include as agenda items in the next NTAGI meting. I look forward to your kind response to my request. With best regards, Sincerely yours Jacob Puliyel MD MRCP M Phil Pediatrician Member of the National Technical Advisory Group on Immunization (NTAGI) and of the Working Group on Food and Drug Regulation in the 12th Five Year Plan. puliyel@gmail.com ________________________________________ [1] http://www.slideshare.net/prabirkc/national-vaccine-policy-2011 [2] http://www.downtoearth.org.in/content/experts-contest-new-vaccine-policy-document [3] http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61463-3/fulltext [4] http://www.ahrp.org/cms/content/view/799/55/
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  Vaccine Policy and Advance Market Commitments

  November 5, 2011 vol xlvI nos 44 & 45 EPW Economic & Political Weekly Pages 18-9
  Jacob M. Puliyel
  COMMENTARY november 5, 2011 vol xlvI nos 44 & 45 EPW Economic & Political Weekly 18 Vaccine Policy and Advance Market Commitments Jacob Puliyel The new National Vaccine Policy Draft 2011 by the Union Ministry of Health and Family Welfare comes out openly in favour of public-private partnerships and suggests flexible governing and funding mechanisms to support vaccine development in the PPP mode. This article argues that our vaccine policy must look into the health of the children in the cou Show More...COMMENTARY november 5, 2011 vol xlvI nos 44 & 45 EPW Economic & Political Weekly 18 Vaccine Policy and Advance Market Commitments Jacob Puliyel The new National Vaccine Policy Draft 2011 by the Union Ministry of Health and Family Welfare comes out openly in favour of public-private partnerships and suggests flexible governing and funding mechanisms to support vaccine development in the PPP mode. This article argues that our vaccine policy must look into the health of the children in the country and it should not be overly concerned solely with the viability of the vaccine industry COMMENTARY november 5, 2011 vol xlvI nos 44 & 45 EPW Economic & Political Weekly 18 Vaccine Policy and Advance Market Commitments Jacob Puliyel The new National Vaccine Policy Draft 2011 by the Union Ministry of Health and Family Welfare comes out openly in favour of public-private partnerships and suggests flexible governing and funding mechanisms to support vaccine development in the PPP mode. This article argues that our vaccine policy must look into the health of the children in the country and it should not be overly concerned solely with the viability of the vaccine industry support vaccine development in the PPP mode, because “the private sector has the discipline and culture for business development and marketing”. The policy draft states that industry (the private partner) will in future be allowed to influence policy. It states that “industry must be provided a channel to voice opinion to be utilised in framing policy”. The fact that this would invite conflicts of interest because of the tension between the profit motives of industry and the promotion of public health is ignored. Furthermore, the policy states that if industry has a “genuine concern that a decision is made to its detriment”, there must be a speedy redressal by an independent (of government) mechanism. The funding mechanisms will ensure that costs are borne by the government and profits are reserved for the private partner for their “entrepreneurial skills and marketing abilities”. The document even suggests that repositories in public sector institutes and platforms in the Indian Institute of Technology must support the vaccine industry (private partner) as they manufacture “risky vaccines”. The policy prescribes the “risk of manufacturing vaccines must be cushioned by assistance from government”. The boldest suggestion is that it should be “mandatory for government to support developments with Advance Market Commitments and honour the commitments”. It further says that a vaccine fund, through “innovative financing mechanisms” must be considered, for introducing new vaccines. Advance Market CommitmentsThe concepts of advance market commitment (AMC) and the implications of the term “innovative financing” as used by the Global Alliance for Vaccines and Immunisation (GAVI) – an organisation of vaccine manufacturers, the Bill and Melinda Gates Foundation and the World Health Organisation (WHO), among others need to be stated explicitly. AMCs are aimed at providing incentives for new vaccines through guaranteeing the market for the product even before it is tested – the government promising it will buy a certain amount of vaccines at a given price. It is to be binding even if the vaccine produced has poor efficacy orsupport vaccine development in the PPP mode, because “the private sector has the discipline and culture for business development and marketing”. The policy draft states that industry (the private partner) will in future be allowed to influence policy. It states that “industry must be provided a channel to voice opinion to be utilised in framing policy”. The fact that this would invite conflicts of interest because of the tension between the profit motives of industry and the promotion of public health is ignored. Furthermore, the policy states that if industry has a “genuine concern that a decision is made to its detriment”, there must be a speedy redressal by an independent (of government) mechanism. The funding mechanisms will ensure that costs are borne by the government and profits are reserved for the private partner for their “entrepreneurial skills and marketing abilities”. The document even suggests that repositories in public sector institutes and platforms in the Indian Institute of Technology must support the vaccine industry (private partner) as they manufacture “risky vaccines”. The policy prescribes the “risk of manufacturing vaccines must be cushioned by assistance from government”. The boldest suggestion is that it should be “mandatory for government to support developments with Advance Market Commitments and honour the commitments”. It further says that a vaccine fund, through “innovative financing mechanisms” must be considered, for introducing new vaccines. Advance Market CommitmentsThe concepts of advance market commitment (AMC) and the implications of the term “innovative financing” as used by the Global Alliance for Vaccines and Immunisation (GAVI) – an organisation of vaccine manufacturers, the Bill and Melinda Gates Foundation and the World Health Organisation (WHO), among others need to be stated explicitly. AMCs are aimed at providing incentives for new vaccines through guaranteeing the market for the product even before it is tested – the government promising it will buy a certain amount of vaccines at a given price. It is to be binding even if the vaccine produced has poor efficacy or support vaccine development in the PPP mode, because “the private sector has the discipline and culture for business development and marketing”. The policy draft states that industry (the private partner) will in future be allowed to influence policy. It states that “industry must be provided a channel to voice opinion to be utilised in framing policy”. The fact that this would invite conflicts of interest because of the tension between the profit motives of industry and the promotion of public health is ignored. Furthermore, the policy states that if industry has a “genuine concern that a decision is made to its detriment”, there must be a speedy redressal by an independent (of government) mechanism. The funding mechanisms will ensure that costs are borne by the government and profits are reserved for the private partner for their “entrepreneurial skills and marketing abilities”. The document even suggests that repositories in public sector institutes and platforms in the Indian Institute of Technology must support the vaccine industry (private partner) as they manufacture “risky vaccines”. The policy prescribes the “risk of manufacturing vaccines must be cushioned by assistance from government”. The boldest suggestion is that it should be “mandatory for government to support developments with Advance Market Commitments and honour the commitments”. It further says that a vaccine fund, through “innovative financing mechanisms” must be considered, for introducing new vaccines. Advance Market CommitmentsThe concepts of advance market commitment (AMC) and the implications of the term “innovative financing” as used by the Global Alliance for Vaccines and Immunisation (GAVI) – an organisation of vaccine manufacturers, the Bill and Melinda Gates Foundation and the World Health Organisation (WHO), among others need to be stated explicitly. AMCs are aimed at providing incentives for new vaccines through guaranteeing the market for the product even before it is tested – the government promising it will buy a certain amount of vaccines at a given price. It is to be binding even if the vaccine produced has poor efficacy oreven if the market price of the vaccine is a fraction of the AMC price. AMC was first used for pneumococcal vaccine research. The vaccine that resulted from this effort prevents  just four cases of cough and cold for every 1,000 babies vaccinated and the vaccine costs Rs 1,200 per child at the United Nations International Children’s Emergency Fund (UNICEF) prices. The cost of vaccinating 1,000 children to prevent four cases of pneumonia is Rs 12 lakh. Instead, on an average, treating the pneumonia in four children with the drugs recommended by the WHO would cost only Rs 40. The money for the vaccine in the AMC must be deposited with the World Bank even before the delivery of vaccine, so the directors of the pharmaceutical do not have to lose sleep about marketing the drug or about withdrawal of orders on account of the low efficacy of the product. The policy drafters understand the government will not be able to foot the hefty bill. The draft, therefore, helpfully suggests “innovative financing” to be able to make the money available to the World Bank upfront. The term “innovative fifi nancing” is GAVI speak and must be understood as such. The Government of India is being urged to issue sovereign bonds in the capital markets so that investors and speculators can put up the money. This is a win-win situation for the pharmaceutical industry and the bond investors – for all, except perhaps the taxpayer. These innovations need careful consideration before this is accepted as a national policy. Moving ForwardVaccines have eradicated small pox and it is one of the greatest successes of modern medicine. Characteristics of vaccines in the past have been their low costs and their remarkable cost-effectiveness. The diphtheria, tetanus, pertussis vaccine (DPT) costs less than Rs 15 for all the doses needed to immunise a child. According to the National Family Health Survey, we are not been able to provide this vaccine to half our population. The production of these essential vaccines, inexpensively in our public sector undertakings, was a source of security for the country, at a time when private manufacturers were dropping out of the market because of the low profitability of these products. The public sector should be what the national vaccine policy supports. It is no one’s case that more expensive vaccines sold by private manufacturers must not be introduced in the public health system in India. However, there must be a transparent evaluation of the need for the vaccine and it must have demonstrable cost-effectiveness. Vaccine policy must enunciate these guiding principles and describe how the evaluation is to be done. Our vaccine policy must look into the health of the children in the country and it should not be overly concerned solely with the viability of the vaccine industry. This looks like a policy not to have a policy, but to utilise vaccines indiscriminatingly. If we are being asked to make long-term advance market commitments before evaluating the utility or even the market value of a vaccine, this policy needs a careful scrutiny. Note 1 http://www.slideshare.net/prabirkc/national-vaccine-policy-2011
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  Nebulized Hypertonic-Saline vs Epinephrine for Bronchiolitis: Proof of Concept Study by Cumulative Sum (CUSUM) Analysis

  INDIAN PEDIATRICS 2011, SEPTEMBER 30. [E-PUB AHEAD OF PRINT] PII: S097475591100270-1.
  NEERAJ GUPTA, *ASHISH PULIYEL, AYUSH MANCHANDA AND JACOB PULIYEL
  Nebulised Hypertonic-Saline against Epinephrine for Bronchiolitis: Proof-of-Concept Study by Cumulative Sum (CUSUM) Analysis NEERAJ GUPTA, *ASHISH PULIYEL, AYUSH MANCHANDA AND JACOB PULIYEL From the Department of Pediatrics and Neonatology, St Stephen’s Hospital, Delhi, India; and * Tech Guru gonzoBuzz, Singapore. Correspondence to: Dr Neeraj Gupta, Registrar, Department of Pediatrics, St Stephen’s Hospital, Tis Hazari, Delhi 110 054, India. drneeraj79@yahoo.co.in Received: March 29, 2 Show More...Nebulised Hypertonic-Saline against Epinephrine for Bronchiolitis: Proof-of-Concept Study by Cumulative Sum (CUSUM) Analysis NEERAJ GUPTA, *ASHISH PULIYEL, AYUSH MANCHANDA AND JACOB PULIYEL From the Department of Pediatrics and Neonatology, St Stephen’s Hospital, Delhi, India; and * Tech Guru gonzoBuzz, Singapore. Correspondence to: Dr Neeraj Gupta, Registrar, Department of Pediatrics, St Stephen’s Hospital, Tis Hazari, Delhi 110 054, India. drneeraj79@yahoo.co.in Received: March 29, 2011; Initial review: April 26, 2011; Accepted: August 11, 2011. PII: S097475591100270-1 Objective: To apply cumulative sum (CUSUM) to monitor a drug trial of nebulised hypertonic-saline in bronchiolitis. To test if monitoring with CUSUM control lines is practical and useful as a prompt to stop the drug trial early, if the study drug performs significantly worse than the comparator drug. Design: Prospective, open label, controlled trial using standard therapy (epinephrine) and study drug (hypertonic-saline) sequentially in two groups of patients. Setting: Hospital offering tertiary-level pediatric care. Patients: Children, 2 months to 2 years, with first episode of bronchiolitis, excluding those with cardiac disease, immunodeficiency and critical illness at presentation. Interventions: Nebulised epinephrine in first half of the bronchiolitis season (n = 35) and hypertonic saline subsequently (n = 29). Continuous monitoring of response to hypertonic-saline using CUSUM control-chart developed with epinephrine-response data. Main outcome measures: Clinical score, tachycardia and total duration of hospital stay. Results: In the epinephrine group, the maximum CUSUM was +2.25 (SD 1.34) and minimum CUSUM was -2.26 (SD 1.34). CUSUM score with hypertonic-saline group stayed above the zero line throughout the study. There was no statistical difference in the post-treatment clinical score at 24 hours between the treatment groups {Mean (SD) 3.516 (2.816): 3.552 (2.686); 95% CI: -1.416 to + 1.356}, heart rate {Mean (SD) 136 (44): 137(12); 95% CI: -17.849 to +15.849) or duration of hospital stay (Mean (SD) 96.029 (111.41): 82.914 (65.940); 95% CI: -33.888 to +60.128}. Conclusions: The software we developed allows for drawing of control lines to monitor study drug performance. Hypertonic-saline performed as well or better than nebulised epinephrine in bronchiolitis. Key words: Bronchiolitis, Control limit lines, CUSUM, Randomized Control Trials, Stopping rule. Clinical Trial Registration No.: CTRI/2008/091/000233. Nebulised epinephrine is commonly used for treatment of bronchiolitis in children having significant respiratory distress. Nebulised hypertonic saline is another modality of treatment [1,2]. It has previously been studied in the context of cystic fibrosis (CF) [3]. The various mechanisms of action of hypertonic saline have been reviewed by Mandelberg and Amirav [4]. Nebulised hypertonic saline with or without bronchodilators has been demonstrated to reduce hospital stay and improved clinical severity [5,6]. The studies directly comparing nebulised hypertonic saline with nebulised epinephrine are lacking. The best answer to this question, of which of the two alternative interventions is better, can be studied in a double blind Randomized Control Trial (RCT) comparing the new drug (nebulised hypertonic saline) against standard therapy (nebulised epinephrine). However, RCT’s have inherent problems, especially in the context of trials in children. According to Mc Culloch and colleagues, RCTs involve difficult blinding, require large samples, long duration, and are very expensive [7]. Others have noted that it is difficult to recruit cases [8]. Drug trials often include a provision of interim analysis and stopping of the trial if large differences between treatment groups are detected. We did this study to see if instead of such interim analyses, Cumulative Sum (CUSUM) can be used for continuous monitoring of the use of the study drug. Cumulative Sum (CUSUM) is a statistical technique used in industry for quality control. Positive weights are given for successes and negative weights for failures such that, as the process continues, the cumulative score stays close to the zero line. Control lines are drawn so that if there are more failures or success than would be expected by chance, the lines would be crossed. These lines can be drawn using boot-strapping methods, as the sequence of failures and success depends on chance. By repeatedly reordering the same data randomly in say 10,000 iterations, the limits of the CUSUM that can occur by chance can be defined [9]. The highest CUSUM and the lowest CUSUM is noted for each iteration. The upper limit of CUSUM is considered the mean upper CUSUM + 2 SD and the lower limit is considered as the mean lower CUSUM-2SD. CUSUM has been used to study antimicrobial treatment in neutropenic patients [10] and in the qualitative assessment of clinical competence [11]. Watkins and colleagues used CUSUM for the detecting Ross River Virus disease [12]. We have used this novel statistical tool to test if hypertonic saline was better or worse than the standard therapy with epinephrine. In this communication we report the procedure, the software we developed and the results of the study. METHODS The study was conducted from November 2008 to April 2009. Children aged between two months and two years, presenting with first episode of acute bronchiolitis and respiratory distress to our hospital emergency room were enrolled in the study after obtaining written informed consent from parents. Children with history suggestive of chronic cardiopulmonary disease, immunodeficiency, past history of respiratory disease requiring nebulisation and critical illness at presentation were excluded. Children with a history of use of systemic or nebulised bronchodilators or nebulised hypertonic saline in last 24 hours were also excluded from study. The clinical scoring system described by Uyan, et al. [13] was used to clarify severity of respiratory distress (Web Table I). As per protocol, children with a clinical score of 4 or more, and those with oxygen saturation less than 94% in room air, were advised admission and they were eligible for enrolment in the study. Enrolled children were treated as usual with standard drug; nebulised epinephrine (non racemic solution, 1:1000 concentration,1 mL diluted in 2 mL normal saline) [14] every 6 hours, for first 24 hours. Children whose clinical score increased by 2 points or more (using admission score as baseline), or whose heart rate went above 200/minute were considered treatment failures. If the child improved or did not deteriorate using the above criteria, the treatment was considered useful, for the purpose of our study. In case of failure, the drug was stopped and alternative measures were instituted which could be escalated up to ventilation. Nebulised epinephrine was given during the first 3 months of study. CUSUM data were analyzed to look for failures in standard therapy, to draw control limit lines. In CUSUM, the data were arranged as either treatment success (S) or failure (F) with standard drug (epinephrine). The weightage of each success and failure was calculated such that the cumulative sum of original data, comes to zero. Using boot-strapping technique and by random rearrangement of the sequence we looked at the CUSUM scores in 10,000 iterations. This helped to examine the limits that occur purely on account of chance changes in the sequence of successes. CUSUM scores using the boot-strapping method provided the upper and lower control lines. The mean upper CUSUM score + 2SD provided the upper limit and the mean lower CUSUM score -2SD provided the lower limit. Children enrolled in the second half of the bronchiolitis season (the next 3 months after the initial 35 patients were recruited to receive standard therapy) received nebulised hypertonic (3%) saline, 3 mL every 6 hours. Clinical score and heart rate were monitored. Success and failures were measured by the same criteria as with epinephrine. The CUSUM score with nebulised hypertonic saline was plotted. Apriory, it was decided that if failure rate crossed the lower CUSUM control line, the trial would be stopped immediately. If however, successes were more and it crossed the upper control line, the study would be continued till the end of bronchiolitis season and it would be clear that new drug is superior to standard therapy. In the absence of suitable software, we developed custom-built open source software [15] which allows inputting of any initial series data (epinephrine in the study). The software does the boot-strapping and calculates the limits for the control line and the stopping rule. Conventional statistical methods were employed to examine differences between groups. To compare means and the confidence intervals, we used statistical software (Confidence Interval Analysis) (CIA) [16]. This study was approved by the Hospital Ethics Committee. RESULTS 64 patients were enrolled in the study; 35 received nebulised epinephrine and subsequently, 29 received nebulised hypertonic saline. Details of children in the two groups are given in Table I. There was no statistically significant difference in the age, sex distribution, clinical score and heart rate at admission. There was no significant difference in the duration of stay between the groups. With the initial trial with epinephrine, there were 5 children with ‘treatment failure’ (2 with worsening of clinical score and 3 with tachycardia). The resultant weightage for each success and failure were +0.286 and –1.714, respectively. The highest CUSUM during the trial using epinephrine was +5.429 and the lowest CUSUM was –0.571. Bootstrapping was done with 10,000 iterations. Increasing iterations beyond this number did not significantly alter the CUSUM maximum and minimum values. The maximum CUSUM was +2.253 (SD 1.342) and minimum was –2.259 (SD 1.337). 2 SD (standard deviation) was added to the maximum CUSUM, and 2 SD was subtracted from the minimum CUSUM values, to draw the control lines as shown in Fig. 1. The CUSUM score while using hypertonic saline stayed above the zero. DISCUSSION Many clinical trials include some strategy for interim analysis and early stopping, if large differences between treatment groups are detected. This design feature can reduce the study participants’ exposure to inferior treatment in addition to saving time and resources. Interim analyses are done at different predetermined points during the study. Instead of using the traditional form of interim analysis, we used the CUSUM to continuously monitor the new drug (nebulised hypertonic saline). In this ‘proof-of-concept study’ we monitored the new drug with a view to terminate the study if the drug was less useful than standard therapy with epinephrine in preventing deterioration in bronchiolitis. Other than using CUSUM for this stopping rule, we employed conventional statistical methods to compare the two treatment groups. We found that CUSUM monitoring is possible in the context of clinical trials. The software we have developed allows CUSUM to be deployed easily in a number of clinical contexts besides drug trials. The use of this software in evaluating the competence of ophthalmic surgeons for cataract surgery has been published [17]. In this study, we found that nebulised hypertonic saline was at least as good as nebulised epinephrine in the treatment of acute bronchiolitis. Deterioration after hospitalization was no more frequent with hypertonic saline than with epinephrine. Previous studies using hypertonic saline have also found it more useful than placebo (normal saline) [1,5,18] or salbutamol alone [19]. This is the first study directly comparing nebulised hypertonic saline with nebulised epinephrine. It must be emphasized that epinephrine is not used as standard therapy, in the treatment of bronchiolitis universally. In our proof-of-concept study we used epinephrine as ‘standard therapy’ for the first 3 months to act as controls, and study drug in the second half of the bronchiolitis season. We did not determine the sample size for this study as we felt that the stopping rule would govern numbers of patients recruited for the trial drug. However, we should have used conventional methods to calculate sample size to determine the number of children receiving standard therapy. The study drug trial recruitment could also be continued till the required sample is reached, unless the study has to be curtailed early for breaching the stopping rule. Another major limitation of the study was the comparison of two interventions at different time periods in a sequence. Changes other than the drug might have influenced the results during two different time periods. This novel technique of using CUSUM helps to stop trials early, if the study drug performs worse than the comparator. This will help limit the risks to study subjects. The parameters to be monitored using CUSUM could be side effects or therapeutic benefits. It can be used for comparisons against placebo or against standard therapy. The new tool can be used within open label RCT to allow for continuous monitoring of the trial. The idea for a clinical CUSUM calculator was taken from industry (quality control mechanism) to provide a simple method to monitor a drug trial. Paradoxically, industry itself may find the simple software we developed, handy for quality control. Compared to RCT this tool, however, does not allow blinding and randomization easily. Though use of CUSUM provides the advantage of continuous monitoring of the trial, it cannot replace the standard double blind RCTs. We believe that the software we developed for the study allows easy boot-strapping and drawing of control lines and thus has potential for use in many clinical situations. WHAT IS ALREADY KNOWN? • Nebulised hypertonic saline is better than placebo in bronchiolitis. WHAT THIS STUDY ADDS? • Nebulised hypertonic saline is at least as good as treatment with nebulised epinephrine in bronchiolitis. • A software for easy calculations of CUSUM has been developed that can help monitor new therapies in real time. Contributors credit: NG, AP, AM and JP conceived the project, NG conducted the clinical trial. AP helped NG and JP in the statistical analysis and development of software.NG, AM and JP were responsible for the write up. JP will act as guarantor. Funding: None. Competing interests: None stated. Note: The software used in this study was custom built for the study. It can be downloaded free from the internet. REFERENCES 1. Mandelberg A, Tal G, Witzling M, Someck E, Houri S, Balin A, et al. Nebulized 3% hypertonic saline solution treatment in hospitalized infants with viral bronchiolitis. Chest. 2003;123:481-7. 2. Tal G, Cesar K, Oron A, Houri S, Ballin A, Mandelberg A. Hypertonic saline/epinephrine treatment in hospitalized infants with viral bronchiolitis reduces hospitalization stay: 2 years experience. Isr Med Assoc J. 2006;8:169-73. 3. Wark PA, McDonald V. Nebulized hypertonic saline for cystic fibrosis. Cochrane Database Syst Rev. 2000;2:CD001506. 4. Mandelberg A, Amirav I. Hypertonic saline or high volume normal saline for viral bronchiolitis: mechanisms and rationale. Pediatr Pulmonol. 2010;451:36-40. 5. Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Nebulized hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev. 2008;4:CD006458. 6. Mathew JL. What works in bronchiolitis? Indian Pediatr. 2009;46:154-8. 7. McCulloch P, Taylor I, Sasako M, Lovett B, Griffin D. Randomised trials in surgery: problems and possible solutions. BMJ. 2002;324:1448-51. 8. Yeung V. Clinical trials in children. In: Pediatric drug handling Available from http://www.pharmpress.com/ shop/samples/paeditaric_sample_chapter.pdf. Accessed October 12, 2009. 9. Taylor WA. Change-Point Analysis: A Powerful New Tool for Detecting Changes. Available from: URL http:// www.variation.com/cpa/tech/changepoint.html. Accessed October 11, 2009. 10. Kinsey SE, Giles FJ, Holton J. Cusum plotting of temperature charts for assessing antimicrobial treatment in neutropenic patients. BMJ. 1989;299:775-6. 11. Ravn LI, Sprehn M, Pedersen CB. The Cusum score. A tool for evaluation of clinical competence. Ugeskr Laeger. 2001;163:3644-8. 12. Watkins RE, Eagleson S, Veenendaal B, Wright G, Plant AJ. Applying cusum-based methods for the detection of outbreaks of Ross River virus disease in Western Australia. BMC Med Inform Decis Mak. 2008;8:37. 13. Uyan AP, Ozyurek H, Keskin M, Afsar Y, Yilmaz E. Comparison of two different bronchodilators in the treatment of acute bronchiolitis. Internet Journal of Pediatrics and Neonatology. 2003;3;1. 14. Beck R, Elias N, Shoval S, Tov N, Talmon G, Godfrey S, et al. Computerized acoustic assessment of treatment efficacy of nebulized epinephrine and albuterol in RSV bronchiolitis. BMC Pediatr. 2007;7:22. 15. Foresee: CUSUM Calculator for Clinical Control (4-C Software). Available from http://jacob.puliyel.com/ calculator/. Accessed August 7, 2011. 16. Confidence Interval Analysis (CIA) Software. Available from http://www.som.soton.ac.uk/research/sites/cia/. Accessed August 7, 2011. 17. Puliyel A, Puliyel J. CUSUM for monitoring competency: computer software is useful for bootstrapping and real time CUSUM plotting. Br J Ophthalmol. 2011;95:295-6. 18. Kuzik BA, Al-Qadhi SA, Kent S, Flavin MP, Hopman W, Hotte S, et al. Nebulized hypertonic saline in the treatment of viral bronchiolitis in infants. J Pediatr. 2007;151:266-70. 19. Luo Z, Liu E, Luo J, Li S, Zeng F, Yang X, et al. Nebulized hypertonic saline/salbutamol solution treatment in hospitalized children with mild to moderate bronchiolitis. Pediatr Int. 2010;52:199-202. TABLE I POPULATION CHARACTERISTICS* Patient characteristic 95% CI for P Nebulised Nebulised Epinephrine hypertonic difference between value group(n=35) saline group(n=29) means Male: Female 25:10 23:6 Mean age mo (SD) 7.157 (6.582) 5.276 (3.827) -0.886 to + 4.646 >0.05 Mean Clinical score at admission (SD) 8.229 (2.576) 7.552 (2.283) -0.549 to + 1.909 >0.05 Mean Heart Rate at admission (/min.) (SD) 149 (41) 143 (16) -10.168 to + 22.168 >0.05 Mean Clinical score at 24 hours (SD) 3.516 (2.816) 3.552 (2.686) -1.416 to + 1.356 >0.05 Mean Heart rate at 24 hours (/min.) (SD) 136 (44) 137 (12) -17.849 to + 15.849 >0.05 Mean Duration of stay in hours (SD) 96.029 (111.41) 82.914 (65.940) -33.888 to + 60.128 >0.05 *All values in mean (sd); Serial number of patients enrolled in hypertonic saline group FIG. 1 Real time CUSUM plot with nebulised Hypertonic Saline with CUSUM control lines. WEB TABLE I CLINICAL SCORING SYSTEM [13] Score 0 1 2 3 Breath Rate(/min.) < 30 30 – 45 46 – 60 > 60 Retractions No Only intercostals Intercostals, subcostal & Abdominal respiration supraclavicular accompanying Nasal flaring No Mild & rarely Moderate to Severe & Severe & continuously during inspiration intermittently Wheezing No Heard only with Heard in both phases of Heard in both phases of Stethoscope respiration with respiration without Stethoscope Stethoscope General Status Normal Moderately Very uneasy, crying Lethargic uneasy & continuously occasionally crying Score 4-8 = moderately ill; 9 or more = severely ill; [13]
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  Case Report: Trypanosoma lewisi or T. lewisi -like Infection in a 37-Day-Old Indian Infant

  Am. J. Trop. Med. Hyg., 85(2), 2011, pp. 221–224 doi:10.4269/ajtmh.2011.11-0002
  Archana Verma , Samiksha Manchanda , Nirmal Kumar , Archna Sharma , Masha Goel , Partha Sarathi Banerjee , Rajat Garg , Brahma Pal Singh , Fatima Balharbi , Veerle Lejon , Stijn Deborggraeve , Udai Veer Singh Rana , and Jacob Puliyel *
  221 Am. J. Trop. Med. Hyg., 85(2), 2011, pp. 221–224 doi:10.4269/ajtmh.2011.11-0002 Copyright © 2011 by The American Society of Tropical Medicine and Hygiene INTRODUCTION Trypanosomes are flagellated protozoan parasites infecting a wide range of animals and man. Human infection with Trypanosoma brucei ( T.b.) gambiense or T.b. rhodesiense causes African sleeping sickness (African trypanosomiasis) and Trypanosoma cruzi causes Chagas disease (American trypanosomiasis). These infections h Show More...221 Am. J. Trop. Med. Hyg., 85(2), 2011, pp. 221–224 doi:10.4269/ajtmh.2011.11-0002 Copyright © 2011 by The American Society of Tropical Medicine and Hygiene INTRODUCTION Trypanosomes are flagellated protozoan parasites infecting a wide range of animals and man. Human infection with Trypanosoma brucei ( T.b.) gambiense or T.b. rhodesiense causes African sleeping sickness (African trypanosomiasis) and Trypanosoma cruzi causes Chagas disease (American trypanosomiasis). These infections have not been reported from the Indian subcontinent. Other species of trypanosomes are known to affect animals in different parts of the world but human infection with them is rare. Trypanosoma lewisi is an infection of rats and there have been seven previous reports of human infection with the organism. Here, we report a case of a T. lewisi infection in a 37-day-old child from Bagpat, Uttar Pradesh in India. This infant is arguably the youngest case to be reported. The symptoms and treatment of the infant are discussed and the literature is reviewed. We also discuss the morphological identification of the parasite and its confirmation by molecular analysis. CASE REPORT A 37-day-old infant, resident of Bagpat, Uttar Pradesh, India, with no history of travel outside Uttar Pradesh was admitted at St. Stephens Hospital, Delhi, India, in August 2010, with pyrexia (going up to 39°C), poor feeding (anorexia), and lethargy for 1 day. On the day before admission, the child got up from his sleep in the afternoon, screaming. His mother went into the room and noticed three red spots on the leg. The area became indurated and inflamed, about 2 cm around the marks. The induration subsided in a couple of hours. The sting marks remained to form a scab ( Figure 1 ). At that time his mother attributed the crying and sting marks to wasps. The child was cuddled and was consolable. The next day he developed fever, seemed listless, and went off feeds. He then had several episodes of generalized tonic seizures for which he was brought to the hospital. Initially lorazepam at 0.1 mg/kg/dose, and later phenobarbitone (20 mg/kg/dose over 20 minutes, and repeated at 10 mg/kg over 10 minutes) followed by phenytoin (20 mg/kg/dose over 20 minutes) were administered in succession before the seizures were controlled. On examination, the infant had no hepatosplenomegaly or lymphadenopathy. Investigations on admission were essentially normal ( Table 1 ). The infant had hemoglobin 10.6 gm/dL, white blood cell counts 7,400/mm 3 , and platelet counts 102,000/mm 3 . Blood smear showed trypomastigote forms of Trypanosoma with the distinct subterminal kinetoplast, nucleus located toward the anterior half, and a flagellum arising from near the kinetoplast forming an undulating membrane before emerging free from the anterior end ( Figure 2 ). Wet smear preparation showed many motile trypanosomes. Biochemical tests were unremarkable. Cerebrospinal fluid (CSF) was partially traumatic and showed normal cell counts and biochemistry but trypanosomes were seen in the specimen . The CSF examination was repeated after 24 hours. This sample was not contaminated by blood and did not show the parasite. Specimens of blood on filter paper and blood thin smears were sent to two laboratories for confirmation of trypanosomiasis infection (Division of Parasitology, Indian Veterinary Research Institute (IVRI), Izatnagar, U.P. and Institute of Tropical Medicine, Antwerp, Belgium). On the basis of detailed morphologic characters as described previously and micrometry (average length 30.8 μm and width 1.9 μm) the eukaryote was tentatively identified as a member of the subgenus Herpetosoma, resembling Trypanosoma lewisi . At IVRI, Izatnagar, DNA was extracted from 200 μL of the blood sample using the GENEAID Genomic DNA Mini Kit (Taipei, Taiwan) . Polymerase chain reaction (PCR) was performed for amplification of the internal transcribed spacer 1 (ITS1) region, which is flanked by the 18S and 5.8S ribosomal genes, and this yielded an amplicon of 623 bp. This corresponds to the size of this region for T. lewisi . 1 Furthermore, the organism was experimentally inoculated intraperitoneally in laboratory-bred Swiss mice. The mice were negative for trypanosome up to the 28th day post-inoculation. Trypanosoma lewisi is host specific and fails to develop in mice. 1 A follow-up investigation was conducted at Bagpat by the National Center for Disease Control (formerly NICD), Delhi. Ten rats ( Rattus rattus ) were trapped from the surroundings of the patient’s house and blood was examined both microscopically and by PCR at IVRI. Two of the 10 rats were also found to be infected with the same hemoflagellate. At the Institute of Tropical Medicine Antwerp (Belgium), the World Health Organization (WHO) reference laboratory, DNA was extracted from the blood on filter paper using the QIAamp DNA micro kit (Qiagen, Valencia, CA). To check if DNA was successfully extracted from the blood specimens, Case Report: Trypanosoma lewisi or T. lewisi -like Infection in a 37-Day-Old Indian Infant Archana Verma , Samiksha Manchanda , Nirmal Kumar , Archna Sharma , Masha Goel , Partha Sarathi Banerjee , Rajat Garg , Brahma Pal Singh , Fatima Balharbi , Veerle Lejon , Stijn Deborggraeve , Udai Veer Singh Rana , and Jacob Puliyel * Department of Paediatrics, St. Stephens Hospital, Delhi, India; Department of Pathology, St. Stephens Hospital, Delhi, India; Division of Parasitology, Indian Veterinary Research Institute, U.P., India; Institute of Tropical Medicine Antwerp, Belgium; National Centre for Disease Control, Delhi, India Abstract. Trypanosomes were observed in the peripheral blood smear of a 37-day-old Indian infant admitted off feeds, with fever and convulsions. Trypanosoma ( Herpetosoma ) lewisi was identified in the blood. The species identification was confirmed by morphometry, polymerase chain reaction, and sequencing. Human infection with this organism is rare. Only seven cases of this infection have been reported previously in humans. The cases reported are reviewed to develop a composite picture of this disease. * Address correspondence to Jacob Puliyel, St. Stephens Hospital, Tis Hazari, Delhi, India 110054. E-mail: puliyel@gmail.com 222 VERMA AND OTHERS a control PCR targeting the human beta-globin gene was performed. To identify the trypanosome, PCRs specific for the Trypanosomatidae, 2 Trypanozoon , 3 T. evansi , 4 and T.lewisi 1 were performed. The PCR for T. evansi and Trypanozoon were negative but it was positive for in the Trypanosomatidae . The length of the amplified ITS1 DNA sequence corresponded with that of T. lewisi described by Desquesnes and colleagues. 1 The ITS1 DNA sequence differentiates T. lewisi (amplicon of 623 bp) from T. brucei and T. evansi (amplicon of 520 bp). The ITS1 PCR product was sequenced at the University of Antwerp, Belgium. The DNA sequence was analyzed with the Bioedit software (Ibis Therapeutics, Carlsbad, CA) and aligned with the T. lewisi DNA sequence reported by Desquesnes and others using Multalin 5 (see Box 1 ). Sequencing results. The upper ends of the ITS1 PCR product could not be sequenced because sequencing was done directly on the PCR product. Sequencing similarity of 90% was observed. Human trypanosomiasis is rare in India and the anti- Trypanosoma medication for this child (Pentamidine and Suramine) had to be sent from WHO, Geneva; this took 5 days. Pending availability of definitive treatment, the infant was started empirically on Liposomal Amphotericin B along with Ceftriaxone as given in infants with clinical signs and symptoms of sepsis. Amphotericin B is an antifungal medication used also in Leishmania infections, which is endemic in India. The infant became asymptomatic after 3 days. The serial blood reports are shown in Table 1 . Injection of Pentamidine was started on Day 5 of admission with cardiac monitoring. Blood sugar and blood pressure were also monitored. Ceftriaxone and Phenytoin were stopped on Day 10 of admission. Pen tamidine was continued for a total of 10 days. The numbers of trypanosomes progressively decreased. On the seventh day of admission, peripheral smear did not show the parasite. The child was discharged on 17/08/2010. At the followup examination on 4/10/10, the chile child was asymptomatic and showed no parasites on peripheral blood smear and had normal blood counts. His high-density lipoprotein (HDL) levels were estimated at this time and found to be normal. DISCUSSION We describe here a case of T. lewisi infection in a 37-dayold infant. There are only seven previously reported cases of T. lewisi -like infection in humans ( Table 2 ). Infants seem to be Figure 1. Sting marks seen on child’s leg. Table 1 Investigation reports Day 1 Day 2 Day 3 Day 5 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 Day 15 Hemoglobin (g/dL) 9.7 7.7 9.8 7.9 8.0 8.6 5.8 7.4 9.2 8.2 9.1 8.0 8.6 Total leukocyte counts (×10 3 /μL) 8.7 8.0 9.4 5.9 6.2 8.3 6.7 6.8 11.7 7.5 7.8 8.5 8.9 Platelet counts (×10 3 /μL) 27 41 51 68 317 151 542 467 416 591 477 601 570 Peripheral smear remark Tryp seen Tryp seen Tryp seen Tryp seen Tryp not seen Tryp not seen Tryp not seen Tryp not seen Tryp not seen Tryp not seen Tryp not seen Tryp not seen Tryp not seen Blood urea nitrogen (mg/dL) 17.4 3.9 12.7 6.7 4.5 5.2 5.2 6.1 6.3 8.9 Creatinine (mg/dL) 0.3 0.3 0.1 0.3 0.2 0.3 0.3 0.2 0.3 0.3 Sodium (mmol/L) 132 145 133 133 134 145 146 143 146 134 Potassium (mmol/L) 4.6 4.91 5.6 4.6 5.0 6.31 5.7 5.68 5.53 5.1 Calcium (mg/dL) 9.9 9.1 10.1 9.8 Cerebrospinal fluid (CSF) analysis: Day 1 – Trypanosomes seen in blood stained CSF. Day 2 – No trypanosomes seen in CSF. No biochemical abnormality. Tryp – Trypanosoma . Figure 2. Magnification 100×. TRYPANOSOMA LEWISI INFECTION 223 Table 2 Blood smear showing Trypomastigotes * Author year (reference) Place Age of patient Presenting complaints Method of identification Treatment given Outcome Johnson, 1933 12 Malaysia 4 months Anorexia, lassitude, fever Morphology in blood None Recovered Shrivastava and others 1974 13 Madhya Pradesh, India 35 years Fever, lassitude Morphology in blood Immune fluorescence antibody test Formol-gel test None described Recovered Shrivastava and others 1974 13 Madhya Pradesh, India 40 year Fever, lassitude Morphology in blood Immune fluorescence antibody test Formol-gel test None described Recovered Howie and others, 2003 15 Gambia 2 months Fever, generalized edema Morphology in blood and CSF PCR analysis Melarso- Prol Recovered Kaur and others, 2006 14 Bombay India 2 months Fever Morphology in blood None described Recovered Sarataphan and others, 2007 11 Thailand 45 days Fever, cough, anorexia, depression Morphology on blood smear dissimilar to T. lewisi . ITS1 sequence analysis and amplicon size similar to T. lewisi -like Herpetosoma Injection gentamycin Recovered Banerjee and others, 2008 6 Pune, Maharashtra 55 years Intermittent fever, anorexia, pedal oedema, lethargy, splenomegaly, and hepatomegaly Morphology similar to T. lewisi . ITS1 amplicon size similar to T. lewisi Injection suramin Died * CSF = cerebrospinal fluid; PCR = polymerase chain reaction; ITS1 = internal transcribed spacer. more vulnerable to this infection. Five of the eight infections so far have been in infants. This might be attributed to immunologically naive status of this group of patients. 6 Our infant is arguably the youngest case to be reported until now. The first case of human trypanosomiasis reported from India was a case of T. evansi in a herdsman of village Seoni in Chandrapur district of Maharashtra in 2004. 7– 9 Trypanosoma evansi is also the most commonly occurring hemoflagellate of domestic animals in India. Trypanosoma evansi can be cultured easily in mice within 3 to 5 days. Failure of development in mice is a good indicator that the organism, in all probability, is not T. evansi . Trypanosoma evansi can also be cultured in rats, but it takes more time to develop. Trypanosoma lewisi is more host specific and fails to develop in mice but often can be cultured in rats. Parasitemia is intermittent and rate of development depends upon the strain of rats used. It was postulated earlier that a trypanolytic factor in human plasma prevents infection with zoonotic trypanosomes. Lack Box 1 Alignment sequence of the internal transcribed spacer 1 (ITS1) polymerase chain reaction (PCR) product from the child’s blood and T. lewisi ITS1 product, Desquesnes and others. 1 224 VERMA AND OTHERS of this trypanolytic factor is seen in persons with low HDL levels and this can make a person vulnerable to trypanosomiasis. 10 Our infant had normal HDL levels. Fever and lassitude were the chief presenting complaints in all the cases reported previously. Four of the seven cases reported previously were identified only by morphology. The ITS1 PCR has been used for identification of human infection with T. lewisi in two cases so far. In one infant from Thailand, ITS1 PCR identified T. lewisi infection but the morphology of the organism was different, 11 and this suggests that the identification based on ITS1 PCR is not specific. The ITS1 PCR tallied with the morphology in our case. We further confirmed species by DNA sequencing. In four cases no specific treatment was administered 12– 14 ; these cases recovered clinically and showed disappearance of trypanosomes from blood films. Follow-up did not show any relapses. However, a 55 year old, with the infection, died in spite of receiving Suramine. 6 One case reported use of Gentamycin injections for treatment. 11 The Gambian infant was treated with Melarsoprol. 15 Our infant responded symptomatically within 3 days of admission, while being administered Liposomal Amphotericin B and Ceftriaxone. The parasitemia however persisted albeit in reduced numbers up to Day 7. Pentamidine was started on Day 5, but in retrospect, it is difficult to say that it was needed for clearing the parasites. Specific treatment with anti-trypanosomal drugs (Melarsoprol and Suramine) was given in only two of the seven previously reported cases. It appears to be a self-limiting infection in humans. However, given the present evidence it will be prudent to prescribe antibiotics in an infant with clinical evidence of sepsis, even if T. lewisi is detected in the blood film. Aggressive anti-trypanosomal treatment is perhaps not indicated. In rats, T. lewisi is an infection transmitted by the excreta of fleas through contamination of rat food or ingestion of fleas by the rats. The route of transmission to humans is unclear. Our child had bite marks over the left leg. We cannot say with certainty if these were flea bites transmitting infection to our child . Received January 1, 2011. Accepted for publication April 30, 2011. Acknowledgment: We acknowledge WHO (Dr. P. Simarro, World Health Organization, Control of Neglected Tropical Diseases, Innovative and Intensified Disease Management, Geneva, Switzerland) for technical assistance. The American Society of Tropical Medicine and Hygiene (ASTMH) assisted with publication expenses. Authors’ addresses: Archana Verma, Samiksha Manchanda, and Nirmal Kumar, Department of Pediatrics, St. Stephens Hospital, Delhi, India, E-mails: dr_archanaverma@yahoo.com , manchanda sami@yahoo.com , and nsk9_2000@yahoo.com . Archna Sharma and Masha Goel, Department of Pathology, St. Stephens Hospital, Delhi, India, E-mails: drarchna_sharma@yahoo.com and Mashagoel86@ gmail.com . Partha Sarathi Banerjee, Rajat Garg, and Brahma Pal Singh, Division of Parasitology, Indian Veterinary Research Institute, U.P., India, E-mails: banerjeeparth62@gmail.com , rajatgarg_2000@ yahoo.com , and bpsingh_para@yahoo.co.in . Fatima Balharbi, Veerle Lejon, and Stijn Deborggraeve, Department of Parasitology, Institute of Tropical Medicine, Antwerp, Belgium, E-mails: fbalharbi@itg.be , vlejon@itg.be , and sdeborggraeve@itg.be . Udai Veer Singh Rana, National Centre for Disease Control, Delhi, India, E-mail: druvsrana@ gmail.com . Jacob Puliyel, St. Stephens Hospital, Delhi, India, E-mail: puliyel@gmail.com . REFERENCES 1. Desquesnes M , Ravel S , Cuny G , 2002 . PCR identification of Trypanosoma lewisi , a common parasite of laboratory rats . Kinetoplastid Biol Dis 1: 2 – 8 . 2. Deborggraeve S , Koffi M , Jamonneau V , Bonsu FA , Queyson R , Simarro P , Herderwijn P , Büscher P , 2008 . Molecular analysis of archived blood slides reveals an atypical human Trypanosoma infection . Diagn Microbiol Infect Dis 61: 428 – 433 . 3. Deborggraeve S , Lejon V , Ali Ekangu R , Mumba Ngoyi D , Pyana P , Ilunga M , Mulunda JP , Büscher P , 2011 . Diagnostic accuracy of PCR in gambiense sleeping sickness diagnosis, staging and post-treatment follow-up: a 2-year longitudinal study . PLoS Negl Trop Dis 5: e972 . 4. Claes F , Radwanska M , Urakawa T , Majiwa P , Goddeeris B , Buscher P , 2004 . Variable surface glycoprotein RoTat 1.2 PCR as a specific diagnostic tool for the detection of Trypanosoma evansi infections . Kinetoplastid Biol Dis 3: 1 – 6 . 5. Corpet F , 1988 . Multiple sequence alignment with hierarchical clustering . Nucleic Acids Res 16: 10881 – 10890 . 6. Banerjee PS , Basavaraj A , Kaur R , Rana UVS , Tewari AK , Baidya S , Rao JR , Raina OK , 2008 . Fatal case of Trypanosoma lewisi in a human patient in India . 40th Asia Pacific Academic Consortium for Public Health Conference, Hanoi , Vietnam , November 4 – 6 , 2008 . 7. Joshi PP , Shegokar VR , Powar RM , Herder S , Katti R , Salkar HR , Dani VS , Bhargava A , Jannin J , Truc P , 2005. Human trypanosomiasis caused by Trypanosoma evansi in India: the first case report . Am J Trop Med Hyg 73: 491 – 495 . 8. Shegokar VR , Powar RM , Joshi PP , Bhargava A , Dani VS , Katti R , Zare VR , Khanande VD , Jannin J , Truc P , 2006 . Short report: human trypanosomiasis caused by Trypanosoma evansi in a village in India: preliminary serologic survey of the local population . Am J Trop Med Hyg 75: 869 – 870 . 9. Truc P , Gibson W , Herder S , 2007 . Genetic characterization of Trypanosoma evansi isolated from a human patient in India . Inf Gen Evol 7: 305 – 307 . 10. Brun R , 2005 . Human Asian trypanosomiasis, a new threat to human health . Am J Trop Med Hyg 73: 484 . 11. Sarataphan N , Vongpakorn M , Nuansrichay B , Autarkool N , Keowkarnkah T , Rodtian P , Stich RW , Jittapalapong S , 2007 . Diagnosis of a Trypanosoma lewisi -like (Herpetosoma) infection in a sick infant from Thailand . J Med Microbiol 56: 1118 – 1121 . 12. Johnson PD , 1933 . A case of infection by Trypanosoma lewisi in a child . Trans R Soc Trop Med Hyg 26: 467 – 468 . 13. Shrivastava KK , Shrivastava GP , 1974 . Two cases of Trypanosoma ( Herpetosoma ) species infection of man in India . Trans R Soc Trop Med Hyg 68: 3 – 4 . 14. Kaur R , Gupta VK , Dhariwak AC , Jain DC , Shiv L , 2007 . A rare case of trypanosomiasis in a two month old infant in Mumbai, India . J Commun Dis 39: 71 – 74 . 15. Howie S , Guy M , Fleming L , Bailey W , Noyes H , Faye JA , Pepin J , Greenwood B , Whittle H , Molyneux D , Corrah T , 2006 . A Gambian infant with fever and an unexpected blood film. PLoS Med 3: 1508 – 1512 .
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  Sex Ratio at Birth in India, Its Relation to Birth Order, Sex of Previous Children and Use of Indigenous Medicine

  PLoS ONE | www.plosone.org June 2011 | Volume 6 | Issue 6 | e20097 http://dx.plos.org/10.1371/journal.pone.0020097.
  Samiksha Manchanda*, Bedangshu Saikia, Neeraj Gupta, Sona Chowdhary, Jacob M. Puliyel
  Sex Ratio at Birth in India, Its Relation to Birth Order, Sex of Previous Children and Use of Indigenous Medicine Samiksha Manchanda*, Bedangshu Saikia, Neeraj Gupta, Sona Chowdhary, Jacob M. Puliyel Department of Neonatology and Pediatrics, St Stephen Hospital, Delhi, India Abstract Objective: Sex-ratio at birth in families with previous girls is worse than those with a boy. Our aim was to prospectively study in a large maternal and child unit sex-ratio against previous birth sex and use  Show More...Sex Ratio at Birth in India, Its Relation to Birth Order, Sex of Previous Children and Use of Indigenous Medicine Samiksha Manchanda*, Bedangshu Saikia, Neeraj Gupta, Sona Chowdhary, Jacob M. Puliyel Department of Neonatology and Pediatrics, St Stephen Hospital, Delhi, India Abstract Objective: Sex-ratio at birth in families with previous girls is worse than those with a boy. Our aim was to prospectively study in a large maternal and child unit sex-ratio against previous birth sex and use of traditional medicines for sex selection. Main Outcome Measures: Sex-ratio among mothers in families with a previous girl and in those with a previous boy, prevalence of indigenous medicine use and sex-ratio in those using medicines for sex selection. Results: Overall there were 806 girls to 1000 boys. The sex-ratio was 720:1000 if there was one previous girl and 178:1000 if there were two previous girls. In second children of families with a previous boy 1017 girls were born per 1000 boys. Sexratio in those with one previous girl, who were taking traditional medicines for sex selection, was 928:1000. Conclusion: Evidence from the second children clearly shows the sex-ratio is being manipulated by human interventions. More mothers with previous girls tend to use traditional medicines for sex selection, in their subsequent pregnancies. Those taking such medication do not seem to be helped according to expectations. They seem to rely on this method and so are less likely use more definitive methods like sex selective abortions. This is the first such prospective investigation of sex ratio in second children looked at against the sex of previous children. More studies are needed to confirm the findings. Citation: Manchanda S, Saikia B, Gupta N, Chowdhary S, Puliyel JM (2011) Sex Ratio at Birth in India, Its Relation to Birth Order, Sex of Previous Children and Use of Indigenous Medicine. PLoS ONE 6(6): e20097. doi:10.1371/journal.pone.0020097 Editor: Qamaruddin Nizami, Aga Khan University, Pakistan Received January 13, 2011; Accepted April 22, 2011; Published June 15, 2011 Copyright:  2011 Manchanda et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist. * E-mail: manchandasami@yahoo.com Introduction According to the last census, there are only 933 women for every 1000 men in India [1]. Gender bias favoring males is largely responsible for this [2]. Neglect of girls and women resulting in early death [3,4,5], female infanticide [6,7] and more recently, antenatal sex determination and female feticide [8], all contribute to it. Several reports suggest that sex selective abortion became more common in the 1990s [9,10] after ultrasound machines became available widely in the 1980s [11,12]. While the Nobel laureate Amratya Sen believes that the pattern of gender inequality shifted from ‘mortality inequality’ to what he calls ‘natality inequality’ due to female feticide after the facility for antenatal sex determination became available [11,13], others suggest that parents are not substituting pre-natal for post-natal discrimination against girls, but combining the two strategies [14]. The relative contribution of these modes of discrimination, to the unbalanced sex ratio in India, is still unresolved [15]. It is important to resolve this issue so as to target remedies appropriately, before they threaten the stability and security of society [16]. The sex ratio in newborns as registered in the birth register (Registration of Births and Deaths Act 1969), is an indicator of the magnitude of the problem of female feticide as it does not include deaths due to neglect of girl children. However infanticides, in the first few days, are often reported as still-births [15] or not reported at all, within the incomplete birth registration system [7]. Data on sex ratio at birth in hospital records are therefore crucial, to estimate the influence of female feticide on the sex ratio, and which is not affected by other factors like infanticide and neglect of girl children. A study of hospital birth records over 110 years published by us previously has showed that there was an excess of boys born, if the previous child was a girl. If the first child was girl the sex ratio was 716 girls to 1000 boys and if the first child was boy it was 1140 girls to 1000 boys [17]. This finding apparently runs counter to the normal tendency of biological heterogeneity which results in families having a predilection to have children of the same sex. Biggar et al in Denmark found the probability of having another boy increases to 51.5, 51.6, 52.4 and 54.2 percent for families with previous one, two, three, or four prior boys, respectively [18]. The findings in second children in our previous study points to antenatal interventions and suggest that sex selective abortions are practiced quite commonly to overcompensate for the slight penchant in families to have babies of the same sex. However, we also found this excess of boys in families with a previous girl in a cohort of babies born in 1970s when ultrasound machines were uncommon and the only method of sex determination was amniocentesis and which was not available widely [17]. The methods used by parents to overcome the tendency to have second children of the same sex as the first are not fully understood. The sex of second children born to parents with a previous girl (or boy) has not previously been studied prospectively in India, to the best of our knowledge. This study was performed to look at the PLoS ONE | www.plosone.org 1 June 2011 | Volume 6 | Issue 6 | e20097 sex ratio in second children depending on the sex of the first child. By studying this prospectively and interviewing mothers it was hoped to gain insights into the practices for sex selection that are in vogue. A priori, it was known that because antenatal sex determination and sex selective abortions are proscribed by law, parents would not admit to these practices, but it was felt they would be more forthcoming about other ‘legal’ methods like use of traditional medicines, to promote birth of babies of the desired sex. The study hypothesis was that families with previous girls are more likely to use traditional medicines for sex selection and that mother taking these medicines are more likely to have a boy child. Methods This prospective study was done from 19 November 2008 to 18 November 2009 in a large hospital known for its maternal and child care services in Delhi. The hospital is century old charitable hospital in the heart of old Delhi catering to the poor and middle class people of the city. All mothers of live born babies delivering in hospital were eligible for inclusion. Informed consent for participation in the study was obtained from the mothers prior to inclusion. The primary focus of interest was mothers delivering their second and third babies. The sex of the child at birth, the sex of previous children was recorded. Mothers were interviewed after they had recovered from the strain of the delivery process – usually 12 hours after delivery. The lady researcher (SM) built up a rapport with the mothers and enquired from her if they knew of any methods or drugs used to get babies of a particular sex. They were also asked if they had utilized any of these methods. The data were recorded on an Excel spreadsheet. Sample Size Calculation The previous data [17] from 2005 in our hospital showed the sex ratio was 629 girls to 1000 boys if the first child was a girl. This gives an odd ratio of 0.49 for second child being female, if the first is female. To detect this odds ratio, in a case control design (case is a girl been born as a second child, control being boy born as a second child if the first is a girl child) with 5% alpha error and 90% power, we needed to study 182 cases and 182 controls. With 80% power this would be 136 cases and 136 controls. We assumed for simplicity, that the prevalence of exposure – first child being female is 50%. As the remaining 50% first children are presumed to be males, we would need 182+182 cases and 182+182 controls, making a total of 728 babies born as second children, to look at significance in the two sexes separately. About 800 babies are born as second children in our hospital in a year, and therefore we planned to study this over a 1 year period. Statistical Methods Sex ratio was analyzed separately for primigravidas, and in multigravidas according to sex of their previous babies. We looked at the sex of the newborn against the methods they admitted to using for having babies of any particular sex, to see if any method influenced the sex of the baby. 95% confidence intervals (CI) for the sex ratios were calculated. Differences in proportions of the sex ratios were estimated. To look for proportions and their CI, and the difference in proportions with confidence intervals, we used the software ‘Statistics with Confidence’ (www.som.soton.ac.uk). Approval of the study protocol was obtained separately from the Hospital Research Committee and the Hospital Research Ethic Committee. Results A total of 3795 mothers delivered in the hospital that year. 48 had multiple pregnancies and were not included in the study. 2773 mother who gave birth to singleton babies, participated in the study. In the remaining, data could not be recorded on the account of early discharge from the hospital, before the researcher could interview the mother. A preliminary analysis was done looking at the sex ratio in the group that were not studied and this was no different from the sex ratio in the children studied (difference in proportion 0.009; 95% CI 20.015 to 0.033), suggesting that the drop-out of 974 babies did not bias the study. Further analysis was done on the sample of 2773 mothers who agreed to participate in the study and who signed the consent form. The results are tabulated in Table 1. The sex ratio in the study sample as a whole was 806 girls to 1000 boys. In primigravida mothers 866 girls were born to every 1000 boys. The sex ratio was 850:1000 in mothers with one previous child. However, there were only 255 girls to 1000 boys among mothers delivering their third child. This was significantly different from the overall sex ratio (difference in proportion 0.243; 95% CI 0.175 to 0.229). When looking at the sex ratio in the second babies, taking into account the sex of the first baby, we found that for every 1000 boys there were only 720 girls if the first was a girl and this rose to 1017 girls if the first was a boy. The difference was statistically significant (difference in proportion 20.086; 95% CI 20.148 to 20.022). There were 184 mothers with two previous children, 106 mother had two previous girls, 21 had two previous boys and 57 had each one girl and one boy. If the two previous children were girls, the sex ratio in the present pregnancy was 178 girls to 1000 boys. Those with two previous boys had a sex ratio of 615 girls for 1000 boys. Among the 1685 primiparous mothers, only 9 (0.5%) said that they had taken traditional medicine to help them get the baby of a desired sex. However among 978 mothers with 1 previous child, 58 (5.9%) of the mothers had taken these medicines and 54 out of 58 were from 510 mothers with a previous girl (10.6%) and 4 were from 486 mothers with a previous boy (0.8%). Among the 54 with a previous girl child, who had taken medication, there were 26 girls and 28 boys making the sex ratio 928 girls to 1000 boys. Among 184 mothers with previous two children, 106 had two previous girls and 42 of them had taken medication (39.6%); 21 had 2 previous boys and of them 1 had taken medication (4.8%); 57 had one girl and one boy previously, and of them 3 had taken medication (5.3%). Discussion Some researchers have suggested that the problem of sex selection and the status of women can be expected to be self correcting: as men begin to dramatically outnumber women, women’s relative rarity will increase their value; their social status will rise and female offspring will become more desirable [19]. However, studies of societies with high sex ratio and a high proportion of males fail to support this prediction and there is evidence that such societies are disproportionately violent societies [19]. When there is a shortage of women in the marriage market the women can ‘marry up’ inevitably leaving the least desirable men with no marriage prospects [20]. It is a consistent finding across cultures that an overwhelming percentage of violent crime is perpetrated by young unmarried low status males [16]. The need for avoiding this situation is self evident. Sex Ratio at Birth and Its Relation to Birth Order PLoS ONE | www.plosone.org 2 June 2011 | Volume 6 | Issue 6 | e20097 We found that the overall sex ratio for deliveries at our hospital was 806 girls to 1000 boys. This is even lower than the sex ratio 865:1000 we reported from our hospital in the year 2005 [17]. We found that the sex ratio in the second babies, if the first was a girl, was even lower at 720. The sex ratio was 1017 girls to 1000 boys if the first was a boy. The previous retrospective study showed a similar trend where sex ratio was 716 (CI=672 to 762) if the first child was girl and 1140 (CI=1072 to 1212) if the first was a boy. The prospectively collected data in this study validated the finding of previous retrospective study and suggest that parents tend to manipulate sex of their offspring. 184 mothers had had two previous children and of these 106 had two previous girls and 21 had two previous two boys. The remaining 57 had had one boy and one girl. Sex ratio for newborns in families with two previous girls was as low as 178 girls to 1000 boys and this empathically underlines the inference of human interference. There were only 21 mothers with 2 previous boys who went on to have a third child compared to 106 who had 2 previous girls. The fact that there were more mothers with two previous girls than there were mothers with two previous boys suggests a tendency among mothers with girls to have more children in the hope of having a boy, while mothers with boy children tend to stop having more babies. In the natural course of events where sex ratio is not manipulated by human intervention, if there is a preference for males, the overall sex ratio will favor girls [18]. This is because of biological heterogeneity which results in families tending to have children of same sex. This phenomenon is not evidenced in India which suggests there is more direct manipulation of the sex ratio in India. Sex ratio in mothers with 2 previous boys was 615 compared to 1017 in those with 1 previous boy. The small sample size of mothers with 2 previous boys can be the reason for an artifactually low sex ratio here. Our findings are similar to the findings of Jha et al who looked at sex in second children in a household survey. They found the adjusted sex ratio for the second birth when the preceding child was a girl was 759 per 1000 males. By contrast, adjusted sex ratio for second births if the previous child was a boy was 1102:1000 [21]. One of the objectives of our prospective study was to enquire into themethods parents may be using to get babies of the desired sex. We were aware that parents are unlikely to incriminate themselves by telling the investigator about antenatal sex determination. However the use of other methods have not been proscribed by law, so we felt it was reasonable to enquire about them in this study. A study by Bandyopadhyay and Singh found that up to 46% mothers use sex selection drugs. They tested 7 samples of such medicines and found 3 contained testosterone one contained progesterone and one a natural steroid [22]. Our study found that more parents who have girls tend to take traditional medicine in the next pregnancy. Overall, some 0.5% mothers took such medication and this percentage increased to 10% if the first child was a girl. 40% of mothers with two girls took such medication. We found mothers with a previous girl child are more likely to take indigenous medication for sex selection, than mothers with previous a previous boy. Mothers with previous girls were also more likely to have a boy in the next pregnancy. On the face of it may appear that these traditional medicines help mothers to have more boys. However the sex ratio of newborns of mothers taking traditional medicines was 928 girls to 1000 boys. This was much higher compared to the overall ratio of 720 girls to 1000 boys in Table 1. Sex Ratio in different Groups. Serial Number (Row Number) Groups [Numbers Girls:Boys] Sex Ratio (Number of Girls To 1000 Boys) Observed Proportion (95% CI) Difference in proportions between groups (Rows) [95% CI] 1 Study Sample [1238:1535] 806 0.446 (CI 0.428–0.465) Row 1:2 0.018 [CI 20.048 to 0.013] Row 1:3 0.013 [CI 20.050 to 0.023] 2 Primiparous Mothers [754:870] 866 0.464 (CI 0.440–0.489) Row 2:3 0.005 [CI 20.035 to 0.044] Row 2:6 0.261 [CI 0.191 to 0.319]* 3 One Previous Child [438:515] 850 0.460 (CI 0.428–0.491) Row 3:4 0.041 [CI 20.013 to 0.094] 4 Previous Child: Girl [209:290] 720 0.419 (CI 0.376–0.463) Row 4:5 0.086 [CI 20.148 to 20.022]* 5 Previous Child: Boy [229:225] 1017 0.504 (CI 0.459–0.550) Row3:5 20.045 [CI 20.100 to 0.011] 6 Two Previous Children [36:141] 255 0.203 (CI 0.151–0.269) Row 1:6 0.243 [CI 0.175 to 0.229]* Row 3:6 0.256 [CI 0.184 to 0.318] 7 Two Previous Girls [15:84] 178 0.152 (CI 0.094–0.235) Row7:9 20.229 [CI 20.447 to 20.037]* 8 One Girl And Boy Previously [13:44] 295 0.229 (CI 0.138–0.352) Row 7:8 20.077 [CI 20.213 to 0.046] 9 Two Previous Boys [8:13] 615 0.381 (CI 0.209–0.591) Row 8:9 20.153 [CI 20.381 to 0.060] *Statistically significant difference in proportion. doi:10.1371/journal.pone.0020097.t001 Sex Ratio at Birth and Its Relation to Birth Order PLoS ONE | www.plosone.org 3 June 2011 | Volume 6 | Issue 6 | e20097 mothers with one previous girl child. It was also higher than the overall sex ratio of 806:1000. This suggests that the subset of mother who took these medicines perhaps relied on them and it prevented them from resorting to techniques like antenatal sex determination and sex selective abortions. Our study has one notable weakness. It relates to sex ratio of children born in a hospital. According to the National Family Health Survey 3 (2005–2006), 60% of all deliveries in India take place at home and outside of the medical institutions. Our data cannot therefore be said to be representative of India. It may be argued that if the sex of the child is known antenatally, there is a greater chance that male fetuses will be brought to the hospital for delivery and this could alter the ratio. This may be seen as an antenatal extension of the practice wherein boys are presented earlier in their illness and more frequently to the hospital [4]. However the data from second children delivered at this hospital shows that the majority of children are girls if the previous child was a boy, and this militates against the suggestion that boy fetuses are selectively bought to hospital for delivery. In summary our study suggests that in spite of Pre-natal Diagnostic Techniques (Regulation and Prevention of Misuse) Act 1994, the sex ratio at birth continues to fall. Evidence from the second children clearly suggests this is the result of human interventions. The use of traditional medicines in mother with previous girl children does not influence the sex ratio and mother who use traditional medicine perhaps do not employ other means to manipulate the sex ratio. The exact method used by some parents to influence the sex of their children is yet not clear. The impulse is to blame it all on ultrasound machines but our previous work on sex ratio in second babies has shown that the skewed sex ratio in second children was common even in the 1970s before ultrasound machines were freely available. More research is needed to elucidate this. Author Contributions Conceived and designed the experiments: JMP SM. Performed the experiments: SM. Analyzed the data: JMP SM. Wrote the paper: SM SC BS NG JMP. References 1. Census of India (2001) Provisional population totals http://www.censusindia.net (accessed on 25/6/10). 2. Sudha S, Rajan SI (1999) Female demographic disadvantage in India 1981– 1991: Sex selective abortions and female infanticide. In Development and Change Volume 30 Oxford: Blackwell publishers Ltd. pp 585–618. 3. Ghosh S (1987) The female child in India: a struggle for survival. Bull Nutr Found India 8: 4. 4. Chatterjee M (1990) A report on Indian women from birth to twenty. New Delhi: National Institute of Public Cooperation and Child Development. 5. Khanna R, Kumar A, Vaghela JF, Sreenivas V, Puliyel JM (2003) Community based retrospective study of sex in infant mortality in India. Br Med J 327: 126–130. 6. George S (1997) Female infanticide in Tamil Nadu, India: From recognition back to denial? Available: www.hsph.harvard.edu/grhf-asia/suchana/0224/ george.html. Accessed 2010 June 26. 7. Leidl P (2005) Silent springs: The tragedy of India’s never-born girls. The State of World Population 2005, The promise of equality: Gender equity, reproductive health and the millennium development goals United Nations Population Fund. Available: http://www.unfpa.org/swp/2005/presskit/docs/ india.doc. Accessed 2010 June 26. 8. George S (2002) Sex selection/discrimination in India: contemporary developments. Reprod Health Matters 10: 190–2. 9. Gangadharan S (1991) Second sex or subordinate sex? The Economic Times April 18. 10. Visaria PM (1991) Overall stability in growth not demographic inertia. The Economic Times April 18,1991. 11. Sen A (2003) Missing women revisited. Br Med 327: 1297–1298. 12. Grover A, Vijayvergiya R (2006) Sex ratio in India. Lancet 367: 1726. 13. Sen AK (2001) Many faces of gender inequality. Frontline 19 November 18: 4–14. Available at www.hindonnet.com/fl1822/1820040.htm. 14. Gupta MD, Bhat PNM (1997) Fertility decline and increased manifestation of sex bias in India. Population Studies 51: 307–315. 15. George S, Rajaratnam A, Miller BD (1998) Female infanticide in rural India. Search Bull 12: 18–26. 16. Hesketh T, Xing ZW (2006) Abnormal sex ratio in human population. Available: http://www.pnas.org/content/103/36/13271.full. Accessed 2010 June 23. 17. Sahni M, Verma N, Puliyel J (2008) Missing girls in India: infanticide, feticide, and made-to-order pregnancies? Insight from hospital based sex ratio at birth over the last century. PLoS One 3(5): e2224. 18. Biggar RJ, Melbye M (1999) Sex ratio, Family size and Birth order. Amer J Epi 150: 957–61. 19. Levy N (2007) Against Sex Selection. Southern Med J 100(1): 107–9. 20. Zeng Y, Tu P, Gu B, Xu Y, Li B, et al. (1999) Population Development Review 19: 283–302. 21. Jha P, Kumar R, Vasa P, Dhingra N, Thiruchelvam D, et al. (2006) Low maleto- female sex ratio of children born in India : national survey of 1.1 million household. Lancet 367: 211–18. 22. Bandyopadhyay S, Singh AJ (2007) Sex selection through traditional drugs in rural north India. Indian J Community Med 32: 32–4. Sex Ratio at Birth and Its Relation to Birth Order PLoS ONE | www.plosone.org 4 June 2011 | Volume 6 | Issue 6 | e20097
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  Introducing pentavalent vaccine in EPI in India: A counsel for prudence in interpreting scientific literature Author's response

  Indian J Med Res 133, May 2011, pp 560-563
  Lone Z, Puliyel J
  Sir, We thank Gupta et al1 for responding to our editorial. Perhaps they have written the letter before the correspondences of Drs Madhavi & Raghuram2, Drs John & Muliyil3 and our response appeared in print. All their questions have been answered in response to the letters above and we will be hard pressed to answer these questions without simply repeating ourselves. The points they make are: 1. We should not have used under-2 morbidly statistics on the under 5 population.   The answer is a Show More...Sir, We thank Gupta et al1 for responding to our editorial. Perhaps they have written the letter before the correspondences of Drs Madhavi & Raghuram2, Drs John & Muliyil3 and our response appeared in print. All their questions have been answered in response to the letters above and we will be hard pressed to answer these questions without simply repeating ourselves. The points they make are: 1. We should not have used under-2 morbidly statistics on the under 5 population.   The answer is available in Reference 3. In brief, we did this to show that even after the figures were exaggerated in this manner it still did not come up to the projections of the UNICEF. 2. The Vellore study4 cannot reflect community morbidity as parents’ exercised choice of taking or not taking treatment (notwithstanding the 2-weekly visits by the study teams).    Some patients may have died before coming to hospital. We have addresses this question in Reference 3. Verbal autopsies were done of all deaths at home precisely to overcome the problem of missing deaths at home. 3. The correspondents1 make their own estimates from other studies like the Million Death Study. As these were not referred to in our editorial and they do not pertinent, we will not discuss the merits of their assumptions in this letter. 4. With regard the Bangladesh ‘probe like’  study5, the correspondents   think that  although the end-point for study was to be measured after 3 doses of vaccine (and there was no benefit), it is appropriate to present effectiveness with 2 doses  without using appropriate statistical tests for multiple testing. We respect their right to have their opinion, although it is at variance with standard teachings of statistics. 5. They write that the Cochrane review only concluded “we could not conclude that the immune response elicited by the combined vaccine was different from or equivalent to the separate vaccines”. We refer to the next sentence in the authors’ conclusions of the Cochrane review for an explanation. They say “The data showed significantly less immunological response for H influenza and hepatitis B, and more local reactions to the injections”. 6. The equity argument was addressed in our responses earlier3. If the vaccine provides no protection as seen from the Bangladesh study, then it is important that resources are not squandered on the programme. The poor need equity in a number of areas but they do not seek equity in terms of being injected with worthless vaccines. References Gupta M, Prinja S, Kumar D, Kumar R. Introducing pentavalent 1. vaccine in EPI in India: A counsel for prudence in interpreting scientific literature. Indian J Med Res 2011; 133 : 560-3. Madhavi Yy, Raghuram N. Pentavalent & other new combination 2. vaccines: solutions in search of problems. Indian J Med Res 2010; 132 : 456-7. John TJ, Muliyil J. Introducing pentavalent vaccine in EPI in 3. India: Issues involved. Indian J Med Res 2010; 132 : 450-5. Minz S, Balraj V, Lalitha MK, Murali N, Cherian T, 4. Manoharan G, et al. Incidence of Haemophilus influenzae type B meningitis in India. Indian J Med Res 2008; 128 : 57-64. Baqui AH, El Arifeen S, Saha SK, Persson L, Zaman K, 5. Gessner BD, et al. Effectiveness of Haemophilus influenzae type B conjugate vaccine on presention of pneumonia and meningitis in Bangladesh children: a use control study. Pediatr Infect Dis J 2007; 26 : 565-71.
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  Cost of pneumococcal vaccine underestimated ten-fold.

  Hum Vaccin. 2011 May 1;7(5). [Epub ahead of print]
  Puliyel Jacob
  Cost of pneumococcal vaccine underestimated ten-fold I commend Professor Light1 for his article on the pneumococcal AMC. His excellent article was however marred by a typographic error that overestimates the benefit from the vaccine at least ten-fold. I hope you will permit it to be corrected so the scientific record is accurate. The author quotes a paper by Madhi et al to suggest that 360 lives are saved per 100,000 vaccinated.2 This is a mistake. Madhi et al., in fact suggests only 360 “case Show More...Cost of pneumococcal vaccine underestimated ten-fold I commend Professor Light1 for his article on the pneumococcal AMC. His excellent article was however marred by a typographic error that overestimates the benefit from the vaccine at least ten-fold. I hope you will permit it to be corrected so the scientific record is accurate. The author quotes a paper by Madhi et al to suggest that 360 lives are saved per 100,000 vaccinated.2 This is a mistake. Madhi et al., in fact suggests only 360 “cases of pneumonia” are prevented by vaccinating 100,000 children (3.6 cases per 1000 vaccinated is the figure they use). Not all children with pneumonia die. The Unicef suggests that in areas with inadequate medical services, up to 10 % die.3 Even assuming this high death rate, deaths averted by pneumococcal vaccine will be 36/100,000 vaccinated—not 360. The cost per life saved is ten-fold higher than calculated and this will be $47,220. The pneumococcal vaccine cannot be considered cost effective in developing countries. It is probably unethical to promote a vaccine with such low utility here. It is of note that GAVI in their response, make no effort to draw attention to this error in the original article by Light. Jacob Puliyel, St Stephens Hospital; Delhi, India Jacob Puliyel St Stephens Hospital; Delhi, India *Correspondence to: Jacob Puliyel; Email: puliyel@gmail.com Submitted: 4/02/11; Accepted: 4/18/11 DOI: 10.4161/hv.7.5.16276 References 1. Light DW. Human Vaccines2011; 7: 138-141. 2. Madhi SA, et al. Bulletin of the World Health Organization. 2008; 86: A. 3 http://www.unicef.org/publications/files/ Pneumonia_The_Forgotten_Killer_of_Children. pdf
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  Effectiveness versus efficacy of conjugated pneumococcal vaccine: a systematic review of randomised, controlled trials with meta-analysis examining absolute risk reduction and relative risk

  Word Text: Clinical Microbiology and Infection (CMI) and the International Journal of Antimicrobial Agents (IJAA), the official journals of ESCMID and ISC . (Abstract accepted for presentation 9/5/2011 and publication
  J. Puliyel (1), J. Mathew (2), N. Vashisht (1), V. Sreenivas (3) : 1 Department of Pediatrics St Stephens Hospital Delhi, 2 Department of Pediatrics Post Graduate Institute of Medical Science, (PGI) Chandigarh, 3 Department of Biostatistics All India Institute of Medical Science (AIIMS) Delhi
  Numbers Needed to Treat (NNT) is a measure of the effectiveness. In the context of newer vaccines it is good to ask how many children need to be vaccinated so that one life is saved - the NNT of the vaccine. This is sometimes called the Numbers Needed to Vaccinate (NNV) The next question is related to the cost: How much does it cost to vaccinate one child with this new vaccine. Once we have these 2 figures we can easily calculate the cost per life saved. We did a meta analysis (a study  Show More...Numbers Needed to Treat (NNT) is a measure of the effectiveness. In the context of newer vaccines it is good to ask how many children need to be vaccinated so that one life is saved - the NNT of the vaccine. This is sometimes called the Numbers Needed to Vaccinate (NNV) The next question is related to the cost: How much does it cost to vaccinate one child with this new vaccine. Once we have these 2 figures we can easily calculate the cost per life saved. We did a meta analysis (a study of all the studies available) to look at Pneumococcal vaccine. The vaccine has very poor efficacy that the NNT to save one life could not be calculated. Instead we calculated the NNT to prevent one case of clinical pneumonia - (a condition that is usually easily treated with very inexpensive medicines). This allows the cost of prevention with vaccine to be compared to the cost of treatment with simple antibiotics. There was a small but statistically significant benefit of vaccination on clinical pneumonia (OR=0.927, 95%CI 0.885-0.971, NNT=200), radiological pneumonia (OR=0.749; 95%CI 0.682-0.822, NNT=143) and invasive disease caused by vaccine serotypes (OR=0.215, 95%CI 0.149-0.311, NNV=500). The small benefit in terms of reduction of clinical pneumonia is also offset by an increase in Asthma (0.001, 95% CI 0.000 to 0.002, p=0.007, NNT=1000). ------------------------------------------- Effectiveness versus efficacy of conjugated pneumococcal vaccine: a systematic review of randomized controlled trials with meta-analysis examining absolute risk reduction and relative risk. Objectives Use of the 7-valent pneumococcal conjugate vaccine (PCV7) resulted in reduction in vaccine serotypes invasive pneumococcal disease (IPD). However, IPD due to serotypes not included in the PCV7 increased in frequency. This prompted the introduction of a 13 valent vaccine. Previous systematic reviews have examined vaccine efficacy (odds ratio and relative risk). However, effectiveness of PCV in reducing childhood morbidity and mortality (in terms of absolute risk reduction (ARR) and numbers needed to treat (NNT)) has not been published. At the threshold of introducing the PCV13, such an assessment of the old vaccine is useful for comparison. The objective here was to evaluate the effectiveness of PCV through a systematic review of literature. Methods Systematic literature search for randomized controlled trials reporting on measures of vaccine effectiveness (invasive Pneumococcal disease, pneumonia, meningitis, all-cause mortality, Pneumococcal disease specific mortality, and systemic adverse events/effects) was undertaken and data extracted based on a priori criteria. Data were analysed to calculate odds ratio, relative risk and absolute risk reduction (ARR); and pooled through meta-analysis. Number needed to treat (vaccinate) was calculated for effectiveness. Results There were five methodologically good trials presenting data through 11 publications. There was a small but statistically significant benefit of vaccination on clinical pneumonia (OR=0.927, 95%CI 0.885-0.971, NNT=200), radiological pneumonia (OR=0.749; 95%CI 0.682-0.822, NNT=143) and invasive disease caused by vaccine serotypes (OR=0.215, 95%CI 0.149-0.311, NNV=500). The effect on all-cause mortality was OR and RR=0.88, 95%CI 0.78 to 0.99, and RD 0.00, 95%CI -0.01 to 0.00 (NNT cannot be calculated). There was no difference in invasive Pneumococcal disease caused by vaccine-related and vaccine-unrelated serotypes. There was no data on meningitis and Pneumococcal disease-specific mortality. Examination of multiple adverse events did not show a difference in risk compared to control, except for a small but statistically significant increase in risk of asthma. Conclusion PCV7 appears to have limited effectiveness against pneumonia; but does not reduce all-cause mortality. There is significant reduction in vaccine serotype IPD. There is no data to draw conclusions for other clinical problems of public health significance such as meningitis, and Pneumococcal disease-specific mortality.
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  Effectiveness versus efficacy of conjugated pneumococcal vaccine: a systematic review of randomised, controlled trials with meta-analysis examining absolute risk reduction and relative risk

  21st European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 27th International Congress of Chemotherapy (ICC) 07.05.2011 - 10.05.2011
  J. Puliyel (1), J. Mathew (2), N. Vashisht (1), V. Sreenivas (3) : 1 Department of Pediatrics St Stephens Hospital Delhi, 2 Department of Pediatrics Post Graduate Institute of Medical Science, (PGI) Chandigarh, 3 Department of Biostatistics All India Institute of Medical Science (AIIMS) Delhi
  Numbers Needed to Treat (NNT) is a measure of the effectiveness. In the context of newer vaccines it is good to ask how many children need to be vaccinated so that one life is saved - the NNT of the vaccine. This is sometimes called the Numbers Needed to Vaccinate (NNV) The next question is related to the cost: How much does it cost to vaccinate one child with this new vaccine. Once we have these 2 figures we can easily calculate the cost per life saved. We did a meta analysis (a study of all th Show More...Numbers Needed to Treat (NNT) is a measure of the effectiveness. In the context of newer vaccines it is good to ask how many children need to be vaccinated so that one life is saved - the NNT of the vaccine. This is sometimes called the Numbers Needed to Vaccinate (NNV) The next question is related to the cost: How much does it cost to vaccinate one child with this new vaccine. Once we have these 2 figures we can easily calculate the cost per life saved. We did a meta analysis (a study of all the studies available) to look at Pneumococcal vaccine. The vaccine has very poor efficacy that the NNT to save one life could not be calculated. Instead we calculated the NNT to prevent one case of clinical pneumonia - (a condition that is usually easily treated with very inexpensive medicines). This allows the cost of prevention with vaccine to be compared to the cost of treatment with simple antibiotics. There was a small but statistically significant benefit of vaccination on clinical pneumonia (OR=0.927, 95%CI 0.885-0.971, NNT=200), radiological pneumonia (OR=0.749; 95%CI 0.682-0.822, NNT=143) and invasive disease caused by vaccine serotypes (OR=0.215, 95%CI 0.149-0.311, NNV=500). The small benefit in terms of reduction of clinical pneumonia is also offset by an increase in Asthma (0.001, 95% CI 0.000 to 0.002, p=0.007, NNT=1000) ------------------------ Effectiveness versus efficacy of conjugated pneumococcal vaccine: a systematic review of randomised, controlled trials with meta-analysis examining absolute risk reduction and relative risk Joseph L. Mathew1, V. Sreenivas2, N. Vashisht3, Jacob M. Puliyel3 1Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India 160012. 2Department of Biostatistics, All India Institute of medical Education and Research, New Delhi, India 110029 3Department of Pediatrics, St. Stepehen’s Hospital, Delhi, India 110054. Address for correspondence: Dr. Joseph L. Mathew Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India 160012. Tel: +91-172-2755357 Fax: +91-172-2744401 Email: joseph.l.mathew@gmail.com Abstract Objectives Use of the 7-valent pneumococcal conjugate vaccine (PCV7) resulted in reduction in vaccine serotypes invasive pneumococcal disease (IPD). However, IPD due to serotypes not included in the PCV7 increased in frequency. This prompted the introduction of a 13 valent vaccine. Previous systematic reviews have examined vaccine efficacy (odds ratio and relative risk). However, effectiveness of PCV in reducing childhood morbidity and mortality (in terms of absolute risk reduction (ARR) and numbers needed to treat (NNT)) has not been published. At the threshold of introducing the PCV13, such an assessment of the old vaccine is useful for comparison. The objective here was to evaluate the effectiveness of PCV through a systematic review of literature. Methods Systematic literature search for randomized controlled trials reporting on measures of vaccine effectiveness (invasive Pneumococcal disease, pneumonia, meningitis, allcause mortality, Pneumococcal disease specific mortality, and systemic adverse events/effects) was undertaken and data extracted based on a priori criteria. Data were analysed to calculate odds ratio, relative risk and absolute risk reduction (ARR); and pooled through meta-analysis. Number needed to treat (vaccinate) was calculated for effectiveness. Results There were five methodologically good trials presenting data through 11 publications. There was a small but statistically significant benefit of vaccination on clinical pneumonia (OR=0.927, 95%CI 0.885-0.971, NNT=200), radiological pneumonia (OR=0.749; 95%CI 0.682-0.822, NNT=143) and invasive disease caused by vaccine serotypes (OR=0.215, 95%CI 0.149-0.311, NNV=500). The effect on all-cause mortality was OR and RR=0.88, 95%CI 0.78 to 0.99, and RD 0.00, 95%CI -0.01 to 0.00 (NNT cannot be calculated). There was no difference in invasive Pneumococcal disease caused by vaccine-related and vaccine-unrelated serotypes. There was no data on meningitis and Pneumococcal disease-specific mortality. Examination of multiple adverse events did not show a difference in risk compared to control, except for a small but statistically significant increase in risk of asthma. Conclusion PCV7 appears to have limited effectiveness against pneumonia; but does not reduce all-cause mortality. There is significant reduction in vaccine serotype IPD. There is no 3 data to draw conclusions for other clinical problems of public health significance such as meningitis, and Pneumococcal disease-specific mortality. Introduction Pneumococcal conjugate vaccine (PCV) has been recommended by the World Health Organization for consideration in the routine immunization programme of developing countries (1,2) based on the impression that it is highly efficacious and thereby effective in reducing childhood morbidity and mortality attributable to pneumonia. However, recent correspondence suggests that the efficacy of PCV for clinically important outcomes may have been over-estimated (3). Most of the currently available data reflect vaccine efficacy in terms of sero-efficacy (immunogenicity), and to some extent protective efficacy against Pneumococcal serotypes contained in the vaccine. Previous systematic reviews have not examined the absolute reduction in risk (ARR) attributable to PCV, restricting the findings to efficacy expressed by relative risk reduction. ARR is an important outcome for policy-makers and health-care stakeholders to base decisions on (4, 5). This issue gains particular importance because when the baseline risk of an outcome is small (as appears to be the case with invasive pneumococcal disease, based on the control group event rate in trials on PCV), impressive vaccine efficacy (reduction in RR) may not directly translate to equivalent effectiveness (absolute risk reduction). In such a setting, the number needed to treat (vaccinate) would be very large, hence the cost considerations alone could constrain poorer economies from deciding in favour of an otherwise efficacious intervention. In other words, while OR and RR reflect efficacy in a research setting, ARR reflects the public health benefit (effectiveness) in a real-world setting. A Cochrane systematic review published in 2004 examined efficacy of PCV (6), but the review was outdated at the time of initiating this review. The authors of the review presented outcomes as relative risk (RR), but not ‘absolute risk reduction’ (ARR). The Cochrane Review was recently updated (7), however since it appeared during the completion of this systematic review, we did not access it, in order to avoid bias. Upon competition of this review, we have studied the review and noted the same limitations as in the older version. During the completion of this systematic review, yet another systematic review appeared in the literature again reporting efficacy measures (relative risk reduction for invasive Pneumococcal disease, otitis media, and pneumonia) (8). However, number needed to treat and effectiveness were not explored. These facts necessitate critical appraisal of available literature to derive best evidence on the effectiveness (or otherwise) of PCV, especially in the context of developing countries. We therefore undertook a systematic review of literature examining randomized controlled trials reporting the effect of Pneumococcal conjugate vaccine (PCV) on clinically relevant outcomes (mortality, invasive pneumococcal disease, pneumonia, meningitis and systemic adverse effects/ events). We did not include otitis media since the burden of disease (incidence, morbidity and mortality) is currently not of public health significance to merit a prevention programme in most countries. We calculated ARR and NNT (numbers needed to harm for adverse events), to enable decision-making stakeholders to estimate the likely impact of PCV in their real-world scenario. Since reliable national data on the burden of Pneumococcal disease is lacking in most developing countries, we also tried to estimate the burden of disease by examining the event rates among control groups in the various RCTs. Methods: We undertook a systematic review of literature with the following characteristics: Types of studies: Randomised clinical trials (RCT) comparing PCV versus placebo/another vaccine, irrespective of blinding, publication status, or language. Types of participants: Participants of any age, gender, and socio-economic status who were either confirmed to be HIV negative or not tested for the same. RCT recruiting only HIV positive participants were excluded because testing is not usually performed prior to routine vaccination. Types of interventions: We analysed PCV (intervention) versus placebo, or no intervention, or another vaccine (control). We considered PCV with any valency, any type of protein conjugate, any number of serotypes, administered by any route, using any schedule, with or without simultaneous administration of other vaccines, administered singly or as a combination vaccine. Trials that only compared different doses, schedules or types of PCV, without a comparator group who received placebo or another vaccine or no vaccination were excluded. As Pneumococcal polysaccharide vaccine is not recommended for use in young infants, it was not included in this systematic review. Types of outcome measures: Primary outcome: Incidence of pneumonia (defined by any standard definition). Secondary outcomes: Incidence of invasive Pneumococcal disease (IPD), meningitis, all-cause mortality, Pneumococcal disease specific mortality and systemic adverse events/effects. Baseline Pneumococcal disease morbidity was evaluated through calculation of event rate among control group in RCTs for clinical pneumonia (of unspecified etiology), radiological pneumonia (consolidation of unspecified etiology) and invasive pneumococcal disease defined as Pneumococcus cultured from blood or cerebro-spinal fluid (CSF). Invasive pneumococcal disease event rate was grouped as follows: all serotypes, vaccine serotypes, vaccine-related serotypes and non-vaccine-related serotypes. Adverse events studied were (i) serious adverse events (reported by authors in their studies), (ii) death in the first week after administering the vaccine or placebo, (iii) evidence of serotype replacement (increase in incidence of Pneumococcal disease with strains not included in the vaccine) and (iv) incidence of other events reported by authors of individual trials. Non serious events including post-vaccination fever, pain and erythema were not considered. NNH was calculated for adverse events where data was available. Search strategy: We searched the Cochrane Library using the term “Pneumococcal vaccine” in “Record Title”, on 15 March 2009, and updated it on 15 May 2009. Simultaneous Medline search for Randomized Controlled Trials, was conducted using the same term, without using any other filters. We also examined the lists of included and excluded trials in the Cochrane review and identified those meeting the inclusion and exclusion criteria of our systematic review. Data extraction: Two reviewers (JLM and JP) independently extracted data from eligible trials. Disagreement was resolved through mutual discussion. Data on trial characteristics, design, participant characteristics, interventions, primary and secondary outcome measures, assessment of methodological quality (risk of bias), and sub-groups into which the trial could be included, were extracted. Assessment of bias risk: The methodological quality (and hence risk of bias due to the methodology) of the trials was done using the Cochrane Risk of Bias Tool (9) by assessment of each trial for adequacy of allocation sequence generation, allocation concealment, blinding, addressing incomplete outcome data, freedom from selective outcome reporting and other sources of bias. Each trial was assessed against these parameters for each outcome and the risk of bias graded as Low or High within each study and across all studies. Data analysis: Odds ratio (OR) was used as the primary reporting modality as it is the most robust statistical reporting format (10). However, it is reportedly difficult for clinicians and other decision-makers to understand its significance; hence Relative Risk and Absolute Risk Reduction are also reported here. NNT was calculated from the OR. Per protocol analysis was used and meta-analysis performed using Stata 9.1 (StataCorp 4905 Lakeway Drive, Special Edition College Station, Texas 77845 USA). Random effects model was used and heterogeneity explored when I2 >50%. For testing the difference between groups the Chi square test was performed. Results: Search results: The Cochrane Library search yielded 7 Cochrane reviews, 7 other systematic reviews and 255 methodologically appraised trials. Only one outdated Cochrane review (5) was relevant to this systematic review and was examined in detail to identify RCT relevant to this review. Medline search yielded 289 citations. Initial screening of titles and abstracts short-listed 45 papers, of which 34 were excluded for the following reasons: (i) not RCT comparing pneumococcal conjugate vaccine versus control (n=21), (ii) outcomes not relevant to this review (n=7), (iii) trials comparing alternate schedules/routes/doses (n=3), and (iv) effect of booster doses studied (n=3). A total of 5 RCT reported through 11 publications were eligible for inclusion in this systematic review (11-21). Two trials were conducted in developing countries viz South Africa (17-19) and Gambia (20,21), and three in developed countries - one in USA (11-13), one in Finnish children (14,15) and one in American Indian children (16). All included healthy infants within a few weeks of birth. Three trials used a seven-valent PCV (11,14,16) while two used a 9-valent PCV (17,20). Two trials used Meningococcal conjugate vaccine as control (11,16), one used hepatitis-B vaccine (14) and two used placebo (17,20). Various outcomes relevant to this review were reported in the included RCT, however none of the trials reported meningitis, or Pneumococcal disease mortality as outcomes. Four trials were described as double-blind (14,16,17,20) and one was a cluster-randomized trial. A summary of the characteristics of these five trials is shown in Table 1. The five trials fulfilled the criteria for high methodological quality (low risk of bias) as shown in Table 2. The South African trial (17-19) included infants from the population without pre-selection based on HIV status. However, the authors reported results separately in HIV positive and negative children by extrapolating pre-existing population prevalence to the recruited population. Thus the exact number of HIV positive and negative children is not known; however the authors provided an estimated number through personal communication to the authors of the 2004 Cochrane review (5). However, this “estimated number” is different from that in subsequent publications (18,19), suggesting that the data included in the 2004 Cochrane review may be erroneous. Therefore, given that HIV testing in not done routinely prior to immunization with PCV, in this review, the combined data of HIV positive and negative children has been used for analysis. The Finland trial (14,15) was a three-arm trial with two arms comparing two different 7-valent PCV with a control (hepatitis B vaccine). The two PCV differed in the nature of the protein conjugate; but were otherwise similar in terms of antigen content and composition. For this review, the data of both PCV arms were added together and compared against the control. The US (NCKP) trial reported the results in two separate publications (11,12) and these had to be considered separately as the denominator for different outcomes was different. Hansen et al (13) presented results of the same trial by retrospectively using WHO criteria for defining pneumonia radiologically. However they did not provide data that could be used in the meta-analysis. There was near total agreement between the data extraction of both reviewers; the single discordance was in the trial reporting different numbers in the text and tables of the publication (16). This was resolved through discussion and it was decided to use the data presented in the tables. Table 3 presents the meta-analysis of primary and other outcomes. Meta-analysis shows that both the odds and risk of developing clinical pneumonia are marginally reduced with Pneumococcal vaccination; number needed to treat is 200. The vaccine appears to be more beneficial in preventing radiological pneumonia, judged by lower odds and risk; NNT is 143. As expected the odds and risk of invasive Pneumococcal disease (any serotype) were dramatically lower with vaccination; however the absolute risk difference was very small, yielding a NNT of 500. This was similar to the NNT for IPD caused by vaccine-serotypes. Vaccination did not have any effect on invasive Pneumococcal disease caused by vaccine related or unrelated serotypes. Three trials included all-cause mortality as an outcome, however one did not report data (11). Meta-analysis showed that the odds and risk were similar with PCV (0.88, 95% CI 0.78 to 0.99), but RD was 0.00 (95%CI -0.00 to 0.00), making it impossible to calculate NNT. The There is no data available on meningitis, or Pneumococcal disease specific mortality. In terms of adverse effects, odds of post-vaccination mortality was lower with vaccination, although the risk was similar; likewise the risk difference was not statistically significant. A similar trend was observed for post-vaccination hospitalization. Serious adverse events and seizures appeared to be evenly distributed among those who did and did not receive PCV. An interesting but potentially disturbing finding was that asthma was more common following vaccination, although data is limited in terms of quality and quantity to definitely prove or disprove this issue. Discussion This is the first systematic review on PCV reporting measures of vaccine effectiveness. It shows that despite reduction in the odds and risk of developing pneumonia, invasive pneumococcal disease by vaccine serotypes and all-cause mortality (efficacy), vaccine effectiveness represented by absolute risk reduction is much lower. At first glance, the results of this systematic review are surprising, in the sense that effectiveness of PCV appears to be much lower than that anticipated. This result is robust through all outcome reporting formats. Intention-to-treat analysis is likely to show even less benefit as compared to the per protocol analysis used here. The poor effectiveness calls for explanation. It could be related to two phenomena viz over-estimation of the burden of childhood pneumonia (owing to non-specific definition) and over-estimation of the burden of Pneumococcal disease in particular (owing to extrapolation from limited data and/or assumptions when organisms are not isolated). The former tends to inflate the baseline risk; while the latter provides a large multiplication factor that could erroneously suggest greater benefit. A recent publication (22) cautioned against both tendencies. It is important to recognize this because trials calculate vaccine efficacy on the basis of a relatively specific definition of Pneumococcal disease, and try to derive population estimates of benefit using less specific definitions. For example, while this review shows nearly 25% reduced risk of pneumonia defined radiologically using stringent WHO criteria, it cannot be taken to mean that pneumonia is reduced by the same factor in the population. These findings again highlight the dichotomy between efficacy and effectiveness. In the context of PCV, the former is measured either as seroefficacy (antibody levels after vaccination) or protective-efficacy (reduction in disease caused by vaccine serotypes), whereas effectiveness ought to be evaluated (by measuring reduction in disease burden, mortality etc) to facilitate informed decision-making by stakeholders (4). This is why measures of effectiveness were chosen in this systematic review. On the brighter side, barring asthma, no major safety concerns are evident with PCV. If the prevalence of asthma is really higher, then it would raise serious concerns. This issue can be resolved through a larger trial, especially when newer PCV become available. Therefore, the importance of this systematic review cannot be over-emphasized, as pneumococcal vaccine has become available in many developing countries with resultant pressure on health-care professionals, policy-makers and people in general; to prescribe/recommend/use the vaccine liberally. For these reasons, despite the demonstration of vaccine efficacy (albeit limited) through randomized controlled trials and recent systematic reviews (7,8); it was felt necessary to undertake a fresh systematic review to estimate the effectiveness of PCV. It must be noted that the difficult issue of serotype replacement following vaccination has not been addressed here; this phenomenon is increasingly noted in many developed countries in recent years (23,24). This gains importance when vaccine effectiveness is high and large scale immunization programme are instituted. It is also recognized that no trials examining the recently licensed 13-valent PCV were available for inclusion in this systematic review, hence the findings are not directly applicable to this newer vaccine. Conclusions: PCV has limited effectiveness against pneumonia; but is not effective in reducing all-cause mortality. There is significant reduction in invasive Pneumococcal disease caused by vaccine serotypes. There is no data to draw conclusions for other clinical problems of public health significance such as meningitis, and Pneumococcal disease specific mortality. Thus this systematic review shows that although currently available PCV have fair efficacy, they have limited effectiveness, for clinically relevant outcomes of importance. Examination of multiple adverse events did not show a difference in risk compared to control, except for a small but statistically significant increase in risk of asthma. Acknowledgements: The authors record their special gratitude to Dr. Georgia Salanti for her assistance and advice with statistical calculations. Authors’ Contributions: JLM and NV undertook the literature search. JLM was responsible for data extraction, data anaylsis and manuscript preparation. VS undertook the statistical analysis and confirmation of results. JMP conceptualized the review, extracted data, assisted with analysis, and finalized the manuscript. Conflicts of interest: None of the authors has any conflict of interest. Funding: None References 1 Madhi SA, Levine OS, Hajjeh R, Mansoor OD, Cherian T. Vaccines to prevent pneumonia and improve child survival. Bull World Health Organ. 2008;86:365-72 2 Madhi SA, Levine OS, Cherian T. Pneumococcal conjugate vaccine is efficacious and effective in reducing the burden of disease. Bull World Health Organ 2008;86: available on line http://www.who.int/bulletin/publish ahead of print/en/index.html 3 Chowdhary S, Puliyel J. Incidence of pneumonia is not reduced by pneumococcal conjugate vaccine. Bull World Health Organ 2008; 86. Accessed at: http://www.who.int/bulletin/publish ahead of print/en/index.html. 4 Alonso-Coello P, Garcia-Franco AL, Guyatt G, Moynihan R. Drugs for pre-osteoporosis: prevention or disease mongering. BMJ 2008;336:126-129 5 Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures of the consequences of treatment. New England Journal of Medicine 1988; 318: 1728-1733. 6 Lucero MG, Dulalia VE, Parreno RN, Lim-Quianzon DM, Nohynek H, Makela H, Williams G. Pneumococcal conjugate vaccines for preventing vaccine-type invasive pneumococcal disease and pneumonia with consolidation on x-ray in children under two years of age. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD004977. DOI: 10.1002/14651858.CD004977. 7 Lucero MG, Dulalia VE, Nillos LT, Williams G, Parreño RA, Nohynek H, Riley ID, Makela H. Pneumococcal conjugate vaccines for preventing vaccine-type invasive pneumococcal disease and X-ray defined pneumonia in children less than two years of age. Cochrane Database Syst Rev 2009; 4: CD004977. 8 Pavia M, Bianco A, Nobile CGA, Marinelli P, Angelillo IF. Efficacy of pneumococcal vaccination in children younger than 24 months: a meta-analysis. Pediatrics 2009; 123: e1103-e 1110. 9 Higgins JPT, Altman DG eds. Assessing risk of bias in included studies. In Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org. 10 Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 9: Analysing data and undertaking meta-analyses. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org. 11 Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen J, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatric Infectious Disease Journal 2000;19:187-95. 12 Black S, Shinefield H, Ling S, Hansen J, Fireman B, Spring D, et al. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatric Infectious Disease Journal 2002;21(9):810-5. 13 Hansen J, Black S, Shinefield H, Cherian T, Benson J, Fireman B, Lewis E, Ray P, Lee J. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than 5 years of age for prevention of pneumonia: updated analysis using World Health Organization standardized interpretation of chest radiographs. Pediatr Infect Dis J 2006; 5: 779-781. 14 Eskola J, Kilpi T, Palmu A, Jokinen J, Haapakoski J, Herva E, et al.Efficacy of a pneumococcal conjugate vaccine against acute otitis media. New England Journal of Medicine 2001;344:403-9. 15 Kilpi T, Ahman H, Jokinen J, Lankinen KS, Palmu A, Savolainen H, et al.Protective efficacy of a second pneumococcal conjugate vaccine against pneumococcal acute otitis media in infants and children: randomized, controlled trial of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine in 1666 children. Clinical Infectious Diseases 2003;37:1155-64. 16 O'Brien K, Moulton L, Reid R, Weatherholtz R, Oski J, Brown L, et al. Efficacy and safety of seven-valent conjugate pneumococcal vaccine in American Indian children: group randomised trial. The Lancet 2003;362(9381):355-61 17 Klugman K, Madhi S, Huebner R, Kohberger R, Mbelle N, Pierce N for the Vaccine Trialists Group. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. New England Journal of Medicine 2003 Oct 2;349:1341-8. 18 Madhi SA, Kuwanda L, Cutland C, Holm A, Käyhty H, Klugman KP. Quantitative and qualitative antibody response to pneumococcal conjugate vaccine among African human immunodeficiency virus-infected and uninfected children. Pediatr Infect Dis J 2005; 24: 10-41. 19 Madhi SA, Adrian P, Kuwanda L, Jassat W, Jones S, Little T, Soininen A, Cutland C, Klugman KP. Long-term immunogenicity and efficacy of a 9-valent conjugate pneumococcal vaccine in human immunodeficient virus infected and non-infected children in the absence of a booster dose of vaccine. Vaccine 2007; 25: 2451-2457. 20 Cutts FT, Zaman SM, Enwere G, Jaffar S, Levine OS, Okoko JB, et al.; Gambian Pneumococcal Vaccine Trial Group. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial. Lancet 2005; 365: 1139-1146 21 Saaka M, Okoko BJ, Kohberger RC, Jaffar S, Enwere G, Biney EE, Oluwalana C, Vaughan A, Zaman SM, Asthon L, Goldblatt D, Greenwood BM, Cutts FT, Adegbola RA. Immunogenicity and serotype-specific efficacy of a 9-valent pneumococcal conjugate vaccine (PCV-9) determined during an efficacy trial in The Gambia. Vaccine 2008; 26: 3719-3726. 22 Mathew JL. Pneumococcal vaccination in developing countries: Where does science end and commerce begin? Vaccine 2009; 27: 4247-4251. 23 Kellner JD, Vanderkooi OG, acDonald J, Church DL, Tyrrell GJ, Scheifele DW. Changing epidemiology of invasive pneumococcal disease in Canada, 1998-2007: update from the Calgary-area Streptococcus pneumoniae research (CASPER) study. Clin Infect Dis 2009; 49: 205-212. 24 Sá-Leão R, Nunes S, Brito-Avô A, Frazão N, Simões AS, Crisóstomo MI, Paulo AC, Saldanha J, Santos-Sanches I, de Lencastre H. Changes in pneumococcal serotypes and antibiotypes carried by vaccinated and unvaccinated day-care centre attendees in Portugal, a country with widespread use of the seven-valent pneumococcal conjugate vaccine. Clin Microbiol Infect 2009; 15: 1002-1007. Table 1: Characteristics of included trials Trial US (NCKP) trial Finland trial US (American Indian) trial South African trial Gambian trial Setting 23 medical centres in Northern California Kaiser Permanente Communities of Tampere, Kangasala and Nokia in Finland. Navajo and White Mountain Apache tribes in USA Soweto, South Africa Upper and Central River Division of the Gambia. Participants Healthy infants Healthy infants Healthy infants Healthy infants Healthy infants Intervention PCV-7* (n=18927) PCV-7* (n=831), PCV-7**(n=835) PCV-7* (n=4165) PCV-9 *** (n=19914) PCV-9*** (n=8718) Control Meningococcus C conjugate vaccine (n=18941) Hepatitis B vaccine (n=831) Meningococcus C conjugate vaccine (n=3926) Placebo (n=19922) Placebo (n=8719) Outcomes IPD by vaccine serotypes, otitis media, pneumonia, mortality mortality, IPD**** , adverse events mortality, IPD**** , adverse events mortality, IPD****, pneumonia, adverse events mortality, pneumonia (various definitions), IPD, adverse events Schedule 2,4,6, 12-15 months. 2,4,6, 12 months 2,4,6, 12-15 months 6,10,14 weeks, Longest follow-up: 6.1 years Schedule: not specified (3 doses given) References 11-13 14,15 16 17-19 20,21 *Composition: 2mcg of saccharides of serotypes 4, 9V, 14, 18C, 19F, 23F and 4 mcg of 6B conjugated to CRM197 ** Composition: 2mcg of saccharides of serotypes 4, 9V, 14, 18C, 19F, 23F and 4 mcg of 6B conjugated to meningococcal outer membrane protein complex. *** Composition: 2mcg of capsular polysaccharide (serotypes 1,4,5,9V,14,19F,23F), 4mcg of 6B, 2mcg of oligosaccharide 18C, conjugated to CRM197. **** Invasive pneumococcal disease by vaccine serotypes, non-vaccine serotypes ad vaccine related serotypes Table 2: Assessment of methodological quality and risk of bias Criteria US (NCKP) trial Finland trial US (American Indian) trial South African trial Gambian trial Adequacy of allocation sequence generation Unclear Yes Yes Unclear Yes Adequacy of allocation concealment Unclear Yes Yes Unclear Yes Adequacy of blinding Unclear Yes Yes Yes Yes Adequacy of addressing incomplete outcome data Yes Yes Yes Yes Yes Freedom from selective outcome reporting Yes Yes Yes Yes Yes Freedom from other sources of bias Yes Yes Yes Yes Yes Overall bias Low Low Low Low Low Table 3: Meta-analysis showing efficacy and safety data of Pneumococcal conjugate vaccine Outcome RCT Vaccinated (n) Control (n) OR (95% CI), I2 RR (95% CI), I2 RD (95% CI), I2 NNT (95% CI) Clinical Pneumonia 3 43335 43284 0.927 (0.885, 0.971), 0% 0.940 (0.905, 0.977), 0% -0.005 (-0.010, 0.001), 41.1% 200 (100, 1000) Radiological Pneumonia 3 43335 43284 0.749 (0.682, 0.822), 64.7% 0.744 (0.636, 0.870), 64.4% -0.007 (-0.012, 0.002), 84.9% 143 (83, 500) IPD (vaccine serotypes) 5 46998 45886 0.215 (0.149, 0.311), 0% 0.158 (0.075, 0.333), 24.0% -0.002 (-0.004, -0.000), 90.6% 500 (250, ~) IPD (all serotypes) 5 46998 45886 0.395 (0.297, 0.526), 57.7% 0.341 (0.180, 0.645), 62.2% -0.002 (-0.004, -0.000), 85.7% 500 (250, ~) IPD (Vaccine related serotype) 4 45407 45092 0.838 (0.376, 1.866), 35.8% 0.931 (0.286, 3.027), 25.8% -0.000 (-0.001, 0.001), 59.1% ** IPD (Vaccine unrelated serotype) 5 46998 45886 1.199 (0.667, 2.155), 10.3% 1.151 (0.599, 2.210), 5.2% 0.000 (-0.000, +0.000), 100.0% ** Meningitis 0 All cause mortality 3 27411 28065 0.88 (0.78-0.99), 0% 0.88 (0.78-0.99), 0% 0.00 (-0.00, 0.00) ** Pneumococcal disease specific mortality 0 ADVERSE EVENTS Mortality 4 28753 27618 1.02 (0.53, 1.96), 28.5% 1.02 (0.53, 1.96), 28.4% 0.00 (-0.002, 0.002), 14.8% Hospitalization 3 27162 26824 0.910 (0.857, 0.965), 72.3% 0.925 (0.831, 1.031), 77.8% -0.008 (-0.020, 0.005), 76.2% 125 (50, 200) Serious adverse events as defined by authors 4 31745 30632 0.987 (0.785, 1.242), 69.9% 1.500 (0.748, 3.006), 67.8% 0.000 (-0.002, 0.003), 73.6% *** Seizures 2 33810 33804 1.095 (0.721, 1.664), 88.7% 0.957 (90.255, 3.598), 88.2% 0.000 (-0.002, 0.002), 89.2% *** ** NNT cannot be calculated *** NNT result suggests that vaccination could benefit as well as harm
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  Effectiveness versus efficacy of conjugated pneumococcal vaccine: a systematic review of randomised, controlled trials with meta-analysis examining absolute risk reduction and relative risk

  You have free access to this content Clinical Microbiology and InfectionVolume 17, Issue Supplement s4, Article first published online: 4 MAY 2011 http://onlinelibrary.wiley.com/doi/10.1111/j.1469-0691.2011.03558.x/pdf Page 299 P1442
  J. Puliyel (1), J. Mathew (2), N. Vashisht (1), V. Sreenivas (3)
  Effectiveness versus efficacy of conjugated pneumococcal vaccine: a systematic review of randomised, controlled trials with meta-analysis examining absolute risk reduction and relative risk Objectives: Use of the 7-valent pneumococcal conjugate vaccine (PCV7) resulted in reduction in vaccine serotypes invasive pneumococcal disease (IPD). However, IPD due to serotypes not included in the PCV7 increased in frequency. This prompted the introduction of a 13 valent vaccine. Previous systematic rev Show More...Effectiveness versus efficacy of conjugated pneumococcal vaccine: a systematic review of randomised, controlled trials with meta-analysis examining absolute risk reduction and relative risk Objectives: Use of the 7-valent pneumococcal conjugate vaccine (PCV7) resulted in reduction in vaccine serotypes invasive pneumococcal disease (IPD). However, IPD due to serotypes not included in the PCV7 increased in frequency. This prompted the introduction of a 13 valent vaccine. Previous systematic reviews have examined vaccine efficacy (odds ratio and relative risk). However, effectiveness of PCV in reducing childhood morbidity and mortality (in terms of absolute risk reduction (ARR) and numbers needed to treat (NNT)) has not been published. At the threshold of introducing the PCV13, such an assessment of the old vaccine is useful for comparison. The objective here was to evaluate the effectiveness of PCV through a systematic review of literature. Methods: Systematic literature search for randomized controlled trials reporting on measures of vaccine effectiveness (invasive Pneumococcal disease, pneumonia, meningitis, all-cause mortality, Pneumococcal disease specific mortality, and systemic adverse events/effects) was undertaken and data extracted based on a priori criteria. Data were analysed to calculate odds ratio, relative risk and absolute risk reduction (ARR); and pooled through meta-analysis. Number needed to treat (vaccinate) was calculated for effectiveness. Results : There were five methodologically good trials presenting data through 11 publications. There was a small but statistically significant benefit of vaccination on clinical pneumonia (OR=0.927, 95%CI 0.885-0.971, NNT=200), radiological pneumonia (OR=0.749; 95%CI 0.682-0.822, NNT=143) and invasive disease caused by vaccine serotypes (OR=0.215, 95%CI 0.149-0.311, NNV=500). The effect on all-cause mortality was OR and RR=0.88, 95%CI 0.78 to 0.99, and RD 0.00, 95%CI -0.01 to 0.00 (NNT cannot be calculated). There was no difference in invasive Pneumococcal disease caused by vaccine-related and vaccine-unrelated serotypes. There was no data on meningitis and Pneumococcal disease-specific mortality. Examination of multiple adverse events did not show a difference in risk compared to control, except for a small but statistically significant increase in risk of asthma. Conclusion: PCV7 appears to have limited effectiveness against pneumonia; but does not reduce all-cause mortality. There is significant reduction in vaccine serotype IPD. There is no data to draw conclusions for other clinical problems of public health significance such as meningitis, and Pneumococcal disease-specific mortality.
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  Public Interest Petition (PIL) Vaccine case 5th affidavit 5/5/11

  Prashant Bhushan on behalf of petitioners
  IN THE HIGH COURT OF DELHI AT NEW DELHI (CIVIL ORIGINAL JURISDICTION) Writ Petition (Civil) No. 13698 Of 2009 PUBLIC INTEREST LITIGATION IN THE MATTER OF: DR. K. B. SAXENA & ORS. …PETITIONERS VERSUS UNION OF INDIA & ORS. …RESPONDENTS SUPPLEMENTARY AFFIDAVIT ON BEHALF OF THE PETITIONERS I, Dr. Jacob M Puliyel S/o Late Shri P. M. Mammen Head, Dept. of Pediatrics, St. Stephens Hospital, Tis Hazari, New Delhi-110054, do hereby solemnly state and affirm as under:  Show More...IN THE HIGH COURT OF DELHI AT NEW DELHI (CIVIL ORIGINAL JURISDICTION) Writ Petition (Civil) No. 13698 Of 2009 PUBLIC INTEREST LITIGATION IN THE MATTER OF: DR. K. B. SAXENA & ORS. …PETITIONERS VERSUS UNION OF INDIA & ORS. …RESPONDENTS SUPPLEMENTARY AFFIDAVIT ON BEHALF OF THE PETITIONERS I, Dr. Jacob M Puliyel S/o Late Shri P. M. Mammen Head, Dept. of Pediatrics, St. Stephens Hospital, Tis Hazari, New Delhi-110054, do hereby solemnly state and affirm as under: 1. That I am the Petitioner No. 8 in the above writ petition and being conversant with the facts and circumstances of the case, am competent to swear this Affidavit. I have also been authorized by other petitioners to file this affidavit on their behalf. 2. Petitioners have filed the above writ petition highlighting how in the absence of a rational evidence-based vaccine policy, newer and newer vaccines are being pushed into the public health system at the behest of pharmaceutical industry and international bodies like World Health Organization (WHO). Petitioners have specifically challenged the proposed introduction of Pneumococcal, Hepatitis B, Hib and Pentavalent vaccines into the country’s Universal Immunization Programme. 3. National Technical Advisory Group on Immunization (NTAGI) is the apex advisory group on vaccination and immunization for Universal Immunization Programme (UIP). Petitioner No. 8 was inducted as a Member of the said group during the pendency of the instant petition. The proceedings and the minutes of NTAGI meeting exemplifies clearly the reasons for which the petitioners came to court – how irrational expensive vaccines are being introduced in the public health system by the Government, without proper epidemiological and medical studies in a country where needed inexpensive vaccines are being denied to 50% of the population. Decisions are made before-hand based on extraneous considerations. Data is provided only to give it a veneer of objectivity. When such data if shown to be wrong, other equally fanciful data is provided but the determination to introduce the vaccine persists. The NTAGI had previously recommended universal immunization with the Pentavalent vaccine. But then it was pointed out to this court that the data from a multi-center study done by the Government of India was deliberately left out because it did not support the need for the vaccine. After this the Government set up an ‘Experts Group’ to look at this and followed it with a ‘Core Committee’ recommendation After all this, the NTAGI met on 26 August 2010. The NTAGI again recommended introduction of Hib and Hepatitis B vaccine in 2 states but now gave different reasons and quoted other data. The new ‘evidence’ is as fallacious as before and this has been clearly pointed out to the Government in a presentation to the Planning Commission. A copy of the presentation made to the Planning Commission is annexed as Annexure A. 4. The numbers benefiting (deaths avoided by vaccination) from Hepatitis B was based on ‘personal communication’ from Prof Acharaya of AIIMS Dept of Gastroenterology. Professor Acharaya is now being investigated by the Society for Scientific Values. He claimied to have done liver biopsies on all Hepatitis B carrier patients going to AIIMS over one and a half years. Such an invasive and potentially lethal investigation on all patients would be gravely unethical. One can surmise that Dr Acharaya wanted to project the data of patients going to him in the Gastroenterology Unit on the whole population of India. It must be for this reason, he stated that liver biopsy was done in all patients (consecutive patients) going to AIIMS. The figure of 3 lakh cases of cirrhosis a year in the country is based on this fiction. 5. Other than this the only other data on deaths averted nationally by Hepaptitis vaccination that is presented is ‘22238 cases of Hepatocellular Carcinoma from the ICMR cancer registry. Here again the figure has been exaggerated by over 200%. The correct figure from the ICMR cancer registry is 10,000. 6. In the same way the recommendation for Hib vaccine was made on the projection that 52000 cases of Hib meningitis occur in the country each year. The projection for the whole country is made from 9 cases of ‘presumed Hib meningitis’ in one year in one district in Kerala! The same paper which reported 9 ‘presumed Hib’ also reported 3 presumed Hib in the same district in the next year. No explanation is given of why this figure was not used for making national predictions. Selective use of data flies in the face of the basic tenets of ‘Evidence Based Medicine’. The numbers needed to vaccinate to prevent one death is crucial to make informed decisions on the cost benefit of introducing a new vaccine. The fanciful figures that were used in the ‘expert committees recommendation’ and the NTAGI recommendation, supports the contention of the petitioners that the vaccine is being introduced at the behest of various vested interests without clear evidence that it will be useful or that it is needed. 7. The procedure of selection to NTAGI and the processes followed at the meeting was witnessed by Petitioner No. 8 who was inducted into the NTAGI without any examination of his credentials - based perhaps on the basis of the fact that he is a petitioner in this case. A request by the petitioner to have the proceedings recorded, so that members can be held accountable for what they say, was denied on the grounds that members would not voice their views freely if it were recorded. No explanation was given why members on a vaccine advisory group may need secrecy for the recommendations they make. 8. The wisdom of denying the request of recording was plain when the minutes of the meeting were circulated. The minutes are manipulated to selectively quote members statements as consensus statements. 9. The NTAGI resolved that Petitioner No. 8 must help Dr N K Ganguly to draft the Vaccine Policy. This was recorded as such in the first draft of the minutes circulated to members and attached. A copy of the draft minutes is annexed as Annexure B. The name of Petitioner No. 8 was removed in the final version of the minutes in blatant violation of the expressed wishes of the NTAGI. A copy of final version of the minutes is annexed as Annexure C. 10. The objections to the policy have been raised and it shows why the author of the minutes was keen to exclude the Petitioner no. 8 from the drafting. The NTAGI according to the original minutes was due to meet in 1 month (in September). The final minutes had to be passed at this meeting. A call for such a meeting has not been made even till date (May 2011). Similarly member’s suggestions on the draft Vaccine Policy were to be incorporated before it was brought to the NTAGI. It is improper on part of the Government to present “draft policy” to this Hon’ble court without incorporating suggestions of NTAGI as promised. 11. The petitioner has pointed out numerous flaws with the draft policy which was presented to this Hon’ble court. The main objection to the said policy is that while it maintains that decisions on vaccination and immunization should be guided by disease burden, surveillance, date etc. but contradicts itself elsewhere by recommending specific vaccines without any such qualifying data. A copy of the response made by Petitioner No. 8 to the policy drafted by Dr. Ganguly is annexed as Annexure D. 12. The petitioners had drawn attention of this Hon’ble court to the deaths from Pentavalent vaccine in Sri Lanka. The Government provided the Court with a report about these deaths to say that deaths were investigated and were found not to be related to the vaccine. Petitioners had highlighted how the standard classifications of adverse effects were changed so that reactions which should have been classified as ‘probably related’ were classified as ‘unlikely’ as ‘probably related’ was deleted as a classification itself. WHO has now stated that it still stands by its full standard classification. An interview given by WHO representative to Times of India is annexed as Annexure E. The draft policy on the other hand uses the watered down version as if side effects and deaths from the vaccine are not of any importance. The same ToI correspondent draws attention to numerous deaths from vaccines and that many expert committees has been set-up to investigate them. None of these expert committees have ever submitted a report. 13. It must be mentioned that there were 4 deaths in Lucknow on 22.08.2010. Some newspapers suggested that Pentavalent vaccine was used there. A copy of the report published in The Hindu is annexed as Annexure F. The petitioner asked the Government under RTI of the vaccines used in the children who died but this information was denied on the ground that an FIR has been registered and the matter is under investigation. A copy of the RTI reply is annexed as Annexure G. DEPONENT VERIFICATION I, the deponent above-named, do hereby verify that the contents of the above affidavit are true to my knowledge, no part of it is false and nothing material has been concealed therefrom. Verified at New Delhi on day of May 2011. DEPONENT Beguiling Half Truths and Vaccine Policy A number of new vaccines have been introduced in the international market. Many of these are being recommended for the immunization schedule in the country. Notable among them are: 1. Pentavalent vaccine (DPT + Hepatitis B + Hib), 2. Pneumococcal conjugate vaccine 3. Rotavirus vaccine Half truths are being deployed to convince policy makers. Below are 4 examples of the half truths that are used by vaccine manufacturers and persons lobbying on their behalf. According to the Marrian Webster definition, a half truth is a deceptive statement that includes some element of truth. The statements are partly true, or the statement may be totally true but only part of the whole truth and they are used with intend to deceive or to misrepresent the truth. 1. The Million Death Study by Prabath Jha suggest that pneumonia and diarrhoea are responsible for 24.5% of the death of children 1-59 months in India. “Addition of vaccines against pneumonia (pneumococcal conjugate , Haemophilus influenza type B) and diarrhoeal diseases (rotavirus) to outreach home-based immunization programmes would reduce child deaths,” says the study published in the Lancet (Lancet 2010;376:1853-60) 2. “Even though a safe efficacious and cheap Hepatitis B vaccine is available and in spite of the carrier rate of around 4% in the country, the vaccine is still not part of the universal immunization programme.” Even if most carriers are asymptomatic and only 10,000 of these cases go on to develop hepatocellular carcinoma nationally, each year (ICMR data), “the cost of treating chronic hepatitis B cases will come to Rs 12 to 14 billion” (Core Committee on Vaccines: http://www.icmr.nic.in/minutes/Minutes%20Core%20Committee%20on%20Vaccines.pdf) (Treatment probably includes cost of liver transplantation for some of these patients). This huge cost justifies the cost of prevention by immunization with Hepatitis B vaccine. 3. The vaccine reduces the number of injections from 9 injections to 3 injections and reduces need for additional cold chain requirements. 4. GAVI is willing to give funds to allow the introduction of Pentavalent vaccine in India. What is left unsaid Diarrhoea and pneumonia are caused by a number of etiological agents and there is no vaccine against all causes of diarrhea or pneumonia that has been manufactured nor is there one anywhere in the pipeline. It is fraudulent to give the figures for diarrhea deaths and pneumonia deaths from all these causes and project pneumococcal, Hib and rotaviral vaccines (that too covering only few strains of three pathogens) as if the vaccines can prevent all cases of pneumonia and diarrhea. The Planning Commission needs to know how many deaths can be prevented by each of these vaccines Numbers Needed to Treat (NNT) is statistical measure of the effectiveness that can be used here. How many children need to be vaccinated so that one life is saved - the NNT of the vaccine. How much does it cost to vaccinate one child with this new vaccine? From this the Planning Commission can evaluate the cost per life saved and look at it against other life saving measures competing for resources. Hepatitis B In the past it used to be said that 250,000 people die in India each year from Hepatocellular carcinoma related to Hepatitis B. This was a good figure from which to calculate benefits from vaccination. This was the figure used by the Indian Association for study of the Liver (INSAL Ind J Gastroenterol 2000;19 (Suppl3):C54-74)) to suggest the vaccine was cost effective. The author of the ‘250,000 deaths’ figure said they had used a model ‘stratified by income group and geographic region’. However when challenged to produce the model or to retract the paper, the author wrote that his model was lost! (Miller MA Health Economics 2004;13:1147-8). The figure 250,000 deaths are now no longer used. Instead it is said that 4% of the population is carriers and that some develop Hepatocellular carcinoma. This figure of 4% carriers is not useful to estimate NNT. Most carriers are merely asymptomatic carriers. The situation is akin to H pylori infection. 84% of the population is H pylori carriers in India. ( Joshi. J of Ind Acad Clin Med 2000;5:149-57). H pylori infection can cause acid peptic disease in some and this can sometimes lead to cancer. The fact is that the vast majority are asymptomatic carriers. No one suggests that all carriers must be treated. The 84% carrier rate with H pylori is not persuasive reasons for universal eradication of the pathogen. Neither is the 4% carrier rate with Hepatitis B a compelling reason for universal immunization with Hepatitis B vaccine. Yet based on the carrier rate (without data on NNT) this vaccination program is being pushed, saying the vaccine is not expensive. A country that is expected to be able to vaccinate the birth cohort of 25 million babies each year, 3 times with the Hepatitis B vaccine, can easily afford to collect concrete data on NNT of the vaccine before embarking on this programme. It is not entirely true that there are no figures on the risks of chronic liver disease among Hepatitis B carriers in India besides the ICMR Cancer Registry data. The ‘Expert group on Hepatitis’ refers to a personal communication from Dr SK Acharya of AIIMS about an unpublished study where liver biopsies were allegedly performed on all Hepatitis B carriers, who visited AIIMS between January 2008 and June 2009. (http://www.icmr.nic.in/minutes/Minutes%20Expert%20Group%20%20Hepatitis%20B%20and%20Hib%20vaccines.pdf). As such a study would have been gravely unethical to perform, one must assume there is some error in the records of this ‘Expert’s group meeting’. However it is quoted again uncritically in the Core Committee’s recommendation for Hepatitis B. (http://www.icmr.nic.in/minutes/Minutes%20Core%20Committee%20on%20Vaccines.pdf). Data from the study has not been taken into consideration in this discussion. H influenza b (Hib) These are a number of studies from India and also from other countries in Asia that are of relevance to India. a) The Invasive Bacterial Infection Surveillance Group (IBIS) Study, for example, cultured only 125 cases of Hib over 4 years (in 6 large hospitals in the country). (IBIS Group Clinical Infect. Dis 2002;34:949-57). b) The WHO sponsored prospective community study found incidence of Hib meningitis in Tamil Nadu was as low as 0.007%. (Minz Indian J Med Res 2008; 128 : 57-64). This works out to less than 8750 cases in all children under 5, nationwide. This figure of 8750 cases of Hib meningitis. Yet the Core Committee on Vaccines projects this figure as 52,000 cases of Hib meningitis. (http://www.icmr.nic.in/minutes/Minutes%20Core%20Committee%20on%20Vaccines.pdf). c) Finally ‘Probe studies’ where Hib vaccine was given to one population and others acted as controls, showed that Hib did not reduce pneumonia in Indonesia or Bangladesh. (Indonesia: Gessner et al Lancet 2005;365:43-52. Bangladesh: Baqui Ped Infect Dis 2007;26:565-71). Gessner has categorically stated after his study, “Hib vaccine will not have a major role in efforts to reduce the overall burden of respiratory illness…..” If the vaccine will not reduce the incidence of pneumonia (or meningitis according to the Bangladesh study) there is no justification for the cost of including the vaccine in the programme of universal immunization. ‘Core Committee on Vaccines’ makes its recommendation for inclusion of Hib, saying that Hib vaccine can prevent 52,000 cases of Hib meningitis. (http://www.icmr.nic.in/minutes/Minutes%20Core%20Committee%20on%20Vaccines.pdf). It is instructive to look at how the nationwide projection of 52,000 cases was arrived at, by the Core Committee. The figure 52,000 is based on just 9 cases of ‘presumed Hib meningitis’ seen in one district in Kerala in 1999. The same district had only 3 cases of ‘presumed Hib’ in the following year, and it was reported in the same paper, but this was not used for making nation-wide projections. (John IJMR 2004;120:86-93) No justification is given for this selective use of data. This is against the basic principles of evidence based medicine. It again reflects on the quality of the recommendations of the Core Committee. Pentavalent Vaccine: 3 injections instead of 9 50% of the population does not receive the basic EPI vaccines against 6 diseases that together cost Rs 30. The Pentavalent combination vaccine costs Rs 525/child. It increases the price of DPT 20 fold and adds vaccines with little utility. There is a GAVI subsidy of Rs 145 so the price comes down to Rs 380/child as long as the subsidy lasts for 5 years. The full cost of Rs 525/childwill have to be paid after that. The details of how combination vaccines piggy-back new and relatively useless vaccines, on the standard vaccines like DPT has been discussed by Madhavi in Current Science (Madhavi, 2006, Current Science). It used to be said that when more countries begin using a vaccine the prices will come down, (by the time GAVI subsidy is withdrawn in 5 years). A study by GAVI actually found the opposite. Vaccine prices went up in the five years after GAVI subsidy was started. (Kamara L. Vaccine 2008; 26: 6717–26) According what the ICMR has published on the Cochrane Collaboration web site, DPT vaccine in the combination vaccine (DPT + Hib + Hepatitis B) is less effective than the components given separately and the side effects are also more. (http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD008658/frame.html) Pneumococcal vaccine With regard pneumococcal vaccine, there is data on NNT provided in the WHO Bulletin (Madhi et al WHO Bull 2008;86). Pneumococcal vaccine reduces 4 cases of pneumonia for every 1000 children vaccinated. The vaccine costs Rs 12,000 per child and so vaccinating 1000 children costs Rs 120 lacs and this prevent 4 cases of pneumonia which can be treated with WHO recommended Co trimoxazole for Rs 40 (Dabade Lancet 2009;373:2195-6 ). Assuming the prices come down to one tenth of the present prices, it will still cost Rs 12 lacs to save Rs 40. Rotavirus vaccine Studies done before introduction of the vaccine in India, showed the strains prevalent in India are different from that in the vaccine and further that the strain is different in different parts of the country and there is constant re-assortment of bovine and human strains that it will be impossible to provide a vaccine for the strain in different places at different times. (Ramani IJMR 2007;125:619-32). There is not one study from India to show that vaccine reduces incidence of diarrhea in this country. Costs in context 50% of the population doesn’t receive the basic EPI vaccines all of which together costs Rs 30/child. • HPV costs Rs 9000/child • Rotavirus costs Rs 2000/child • Pneumococcal vaccine Rs 12000/child • Pentavalent vaccine Rs 525/child We are told that investment in new vaccine will automatically improve uptake of the basic vaccines. This is of course reminiscent of what was told about investment in polio eradication – that it will magically improve overall immunization rates but what happened actually was that universal immunization fell from over 60 - 70% to less than 50% in the ensuing 10 years. There is a surge in the incidence of deaths due to diphtheria which is prevented by DPT vaccine. There are no real advocates asking to make sure the basic vaccines are available to the un-reached 50% of the population. Many of the challenges for the 12th plan for better health can be met by provision of clean water, sanitation and nutrition. There are no short cuts or magic bullets and vertical single disease vaccination programs are not the way forward. Other Asian countries like Japan and China that have an independent method to evaluate costs and benefits of vaccines have all rejected introduction of these Hib and Hepatitis B vaccines in their country. Half Truths The rest of the facts 24.5% U5MR due to pneumonia and diarrhea so pneumococcal, Hib and rotavirus vaccines must be introduced. There is no vaccine against all causes of diarrhea or pneumonia (and the available vaccines have not been shown to reduce pneumonia or diarrhea) 4% of the population is Hepatitis B carriers and a relatively inexpensive vaccine is available so Hepatitis B vaccine must be used. 1. Asymptomatic carriers come to no harm usually. 2. We need to know NNT for lives saved by vaccine. The Cancer Registry data is the best we have. 3. The AIIMS study reported by the ‘Expert group on Hepatitis’ seems seriously flawed ethically, as not to merit consideration. Pentavalent (5-in-one) vaccine must be introduced for its programmatic convenience: 3 injections instead of 9 1. Combination vaccine jacks up cost of DPT 20 fold. The additional vaccines have little utility. 2. The combined vaccine is less effective according to the ICMR. GAVI will pay 1. Cost of vaccination goes up from Rs 30 per child to over Rs 525/child. 2. Of this, GAVI pays only Rs 145, and that for 5 years only. 3. 50% of India don’t receive the currently mandated vaccines that all together costs only Rs 30/child. 1. We are concerned that these new vaccines will swallow up funds so crucial for real achievements of the 12th Challenge. 2. We would like to plead that the EPI vaccine coverage be increased to near 100% 3. No new vaccines be introduced without proper cost benefit assessment or scientific rationale justifying the costs. 4. We would welcome universal introduction of newer vaccines that are efficacious and cost effective and request funding for research in this area. 5. Adequate resources need to be provided so the public sector could supply good quality, life saving vaccines, adequate for the countries needs, to insure against the vagaries of supply and costs (as when the programme is entirely dependent on private players). 6. From a governance standpoint, it will be worthwhile to investigate how misleading errors have crept into the recommendations of the Core Committee on Vaccines. Jacob Puliyel MD MPhil Head of Pediatrics St Stephens Hospital Delhi 110054 puliyel@gmail.com Professor S. K. Mittal MD Director of Pediatrics at Pushpanjali Crosslay Hospital. Former Head of Pediatrics Department Maulana Azad Medical College, Delhi. Formerly Member of Medical Council of India skmittal44@yahoo.com. Phone 9818372811 Dr Mira Shiva MD Founder Coordinater All India Drug Action Network Member, Central Social Welfare Board, Government of India A-60 Hauz Khas New Delhi 110016 mirashiva@gmail.com Phone 9810582028 Professor K B Saxena Former Union Health Secretary Council for Social Development 53 Lodhi Estate New Delhi saxenakb2@gmail.com Phone 246926655, 24693065 (Council for Social Development). Professor N J Kurian Former Advisor to Finance Ministry & Planning Commission Council for Social Development 53 Lodhi Estate New Delhi njkurian@yahoo.com Phone 9871595816 Meeting of National Technical Advisory Group on Immunization 26th August 2010, R. No. 155A, Nirman Bhawan Minutes of Meeting The meeting of National Technical Advisory Group on Immunization was held on 26th August 2010 chaired by Secretary (H&FW) and co-chaired by Secretary (DHR) & DG (ICMR). The list of participants is annexed. The meeting started with a welcome note by Secretary (H&FW) who highlighted the fact that NTAGI has been reconstituted with representation from the specialist from Paediatrics, Public Health, Researchers, program division etc to encourage healthy technical discussions in an open and transparent manner. On suggestion for audio-recording of the proceedings, the house felt that NTAGI should be a forum where the technical experts can provide inputs in an open and free manner; and such recording might preclude such open discussions. Further it was agreed to circulate the detailed minutes of the proceedings at the earliest. Secretary (H&FW) also expressed concern at the recent incident of Adverse Event Following Immunization (AEFIs) in UP and its significance in view of the introduction of newer vaccines and therefore urged the NTAGI to consider such issues while recommending new vaccines under the National Program. The key recommendations of last NTAGI meeting held on 3rd Aug’09 and action taken note was presented. Thereafter the meeting deliberated on the agenda items. Agenda Item1- Introduction of Pentavalent vaccine The house was informed that Hib vaccine has been introduced in 137 countries of the world and out of these the vaccine is part of the programme as Pentavalent vaccine in 56 countries and remaining countries use Hib vaccine in different combination. There are multiple studies providing data in support of Hib vaccination. The studies like Million Death Study by Dr Prabhat K Jha et al and on status of Millennium Development Goal (MDG) by Prof V. K. Paul et al have raised the concern on continued burden of lower respiratory illness as one of the major cause of child mortality and morbidity, thereby precluding achievement of the MDG goals. Dr. Ganguly mentioned that there have been various studies from Lambok (Indonesia), Bangladesh, Sri Lanka, Myanmar and Pakistan on efficacy of Hib vaccine. Further Cochrane review also strengthens the fact that vaccine is efficacious in reducing morbidity and mortality burden due to Hib pneumonia and meningitis. Dr. Jacob Puliyel pointed out that this contradicts what has been published in BMJ & IJMR which showed that there was no statistical difference between those vaccinated and the non- vaccinated. The house also deliberated upon as to why some of the developed countries are not using Hib combination vaccine as Pentavalent vaccine while it is being used in developing countries. In response, various experts cited that the different situation in immunization delivery system in developed and developing countries as one of the reasons for adopting Pentavalent vaccine. As introduction of newer vaccine in developing countries is always a challenge to cold chain with weaker immunization delivery systems therefore Pentavalent vaccine is preferred which provides operational advantages - one vaccine conferring protection against five diseases, with no change in immunization schedule thus no needs for beneficiary to approach health facility at different time interval , saves cold-chain space and logistics. While in developed countries, the vaccine schedule is different based on local epidemiology, market dynamics and also influenced by Advisory Committees on Immunization. Also these developed countries are using DTaP, (having acellular Pertussis vaccine which is costlier as compared to DTP containing whole cell pertussis vaccine), where combination vaccine has reduced seroconversion. In addition these developed countries are using Hib and Hep-B vaccine. The pentavalent vaccine used in the developing countries are combination of Hepatitis B, Hib and DPT (having whole cell Pertussis vaccine). In the ensuing discussion, concern was raised regarding the safety and efficacy of the Pentavalent vaccine in view of the AEFIs reported following usage of this vaccine in Sri Lanka, Bhutan and Pakistan. The vaccination in Sri Lanka and Bhutan was stopped following these incidents of AEFI, however, after investigation; Srilanka has resumed vaccination in 2010 and Bhutan have decided to resume the Pentavalent vaccination. The available reports published by WHO have concluded that these events are unlikely due to Pentavalent vaccine, some of the members felt that the complete report of these incidents should be accessed for analysis. Keeping in view the number of children vaccinated in these countries, the background rate of these AEFI may not be significant and the benefit gain may not have raised alarm to stop vaccination. As the vaccine has not been introduced in India, there is not enough data on vaccine safety therefore; vaccine should be initially used in the states with better AEFI management and surveillance systems to monitor the vaccine safety. The house was of unanimous opinion on the use of Hib vaccine, but few members had reservations about using the formulation combination vaccine of Pentavalent vaccine. The house considered that lives saved by the Pentavalent vaccine far outnumber the few AEFI deaths reported in the neighbouring countries and therefore has favourable risk-benefit ratio. However Dr. Puliyel said that if Hib vaccine was to be introduced to look for utility, it may be introduced as a standalone vaccine. The house also deliberated upon the immunogenicity of combination vaccines and it was felt that the available evidence based on Cochrane review reveals that although there is reduced immunogenicity of some of the components of vaccine when compared to given separately, this reduction in sero-conversion is not significant enough to affect protective levels of antibodies. The Core Committee recommendations on Pentavelant Vaccines were discussed and based on the recommendations the committee members felt that vaccine should be introduced in selected few well performing states and further roll-out should be based on an impact assessment of vaccination including safety aspects. The house also discussed the selection of states for studying the impact of Pentavalent vaccine introduction. Though some of the northern states are having high burden of Hib disease, the introduction in these states with poor coverage would not be able to demonstrate significant impact and also these states have poor monitoring of AEFI. Further, the introduction of newer vaccine requires good delivery systems and some of the states with high vaccination coverage like Tamil Nadu and Kerala may be selected. The house also considered the options of limited introduction of the vaccine in the hospitals (rather than in outreach sessions) or in selected districts; however it was felt that this would not provide the sufficient sample size to study the impact of the vaccine. It was stressed that clinical trials for impact assessment is difficult in view of the large sample size that would be required and high cost that would be incurred for such study. It was pointed out that data from Hib probe study by ICMR is available for some of the areas in Tamil Nadu which can be taken as baseline data and will facilitate the study of post-vaccination impact. In the ensuing discussion the house was informed that vaccine is already available in private sector in many parts of the country and has brought about decline in cases of Hib disease over a period as observed in PGI Chandigarh, though the private vaccination does not contribute much in the National scenario. Recommendations: • Pentavalent vaccine to be introduced in Immunization programme in the states of Tamil Nadu and Kerala. • Thereafter, data may be reviewed after 1 year of introduction before expanding the vaccine into other states. • A protocol will be prepared by the ICMR for surveillance of Hib meningitis in selected hospitals to understand the trend over time. This will be circulated to NCDC and NTAGI members through email; once the protocol is finalized, the surveillance will be carried out by ICMR. • Since AEFI is a concern hence same will be monitored and also system will be strengthened so as to ensure immediate management of AEFIs; NCDC to lead this activity. Agenda Item 2- Introduction of Hepatitis B vaccination The house discussed expansion of Hepatitis B vaccine in the entire country under immunization programme. It was pointed out that even though safe, efficacious and cheap Hepatitis B vaccine is available and in spite of carrier rate of around 4% in India the vaccine is still not part of Universal Immunization programme although all the countries have been using this vaccine under the national programme. This vaccine is manufactured in the country and exported to many countries. There have been enough data showing impact of Hepatitis B vaccination on disease burden due to hepatitis B infection like acute hepatitis, as well as its long term sequel like chronic hepatitis, cirrhosis and liver cancer. Therefore it is high time that this vaccine is introduced all over the country at the earliest. Over the period the cost of the Hepatitis B vaccine has dropped and is one of the cheaper vaccine available in the market. As the vaccinated cohort is only protected, any change in morbidity and mortality would take 10-15 years to be detected. However, the impact assessment on carrier rate may be carried out and the house was informed that ICMR has already initiated a study for the same. It was also brought to notice that there may be possibility of escape mutation of hepatitis B virus and this may also be monitored. The experts also stressed that it is critical to give the vaccine at birth to cut down the vertical transmission and to impact the carrier rate. The house was informed that under the immunization programme of Hepatitis B in the selected States/Districts/Cities the Hepatitis B vaccine is given at birth (in institutional deliveries) and thereafter at 6th, 10th and 14th week of age of the child. The Janani Suraksha Yojana (JSY) has been launched to improve institutional delivery and this may further boost the coverage of Hepatitis B vaccination at birth. Recommendation • In view of the disease burden and availability of safe and efficacious vaccine, the expansion of Hepatitis B vaccine should be carried out all over the country as part of Universal Immunization Programme. Before rolling out in newer areas there should be a plan for trainings, microplanning etc. • Simultaneously, multi-centric impact study on carrier rate of hepatitis B will be conducted by ICMR. Agenda Item 3- Introduction of Rubella vaccination The house deliberated upon the risks and benefits of introduction of rubella vaccine in the immunization programme. If the vaccine is introduced in form of MR and targeting to vaccinate children at 16-24 months of age, then it is critical to ensure coverage above 80% failing which the rubella will shift to older age group of susceptible cohort and this may lead to paradoxical increase in congenital rubella syndrome (CRS). The manufacturing capacity and availability of MR and rubella vaccines are need to be considered before introducing the Rubella vaccination in the National programme. In view of the above, the house felt that Rubella vaccine may be introduced in adolescent girls of 10-15 year old so that those who have not acquired the natural immunity due to infection are also protected. This would reduce the risk of getting this infection during the pregnancy and thereby reduce CRS cases. Recommendation • The NTAGI recommended the introduction of rubella vaccination for 10-15 year old adolescent girls under the Universal Immunization Programme in the entire country. Agenda Item 4- Draft Multi Year Strategic Plan 2010-17 for UIP The house was unanimous that there is need for a Multi-year strategic Plan 2010-17 for UIP. The document does not comprehensively address Vaccine preventable disease surveillance; some of the points at page 58 in the document for setting up a new body with development partner to review, utilized information for deciding introduction of new and under-utilized vaccine were objected and house felt that this draft needs editorial corrections before any further discussion. Recommendation: • The draft MYP is to be revised for further discussion. Agenda Item 5- National Vaccine Policy Secretary (H&FW) raised the need for a national vaccine policy and NTAGI unanimously agreed to the suggestion. There have been some attempts in drafting vaccine policy earlier, also a regional vaccine policy has been developed by WHO recently which may be used for developing this draft. The need for a National Immunization Authority was also felt as the current technical structure of only 3 technical officers managing the immunization programme in the entire country like India is a daunting task. In this regard, the house was informed that IIM-Ahmedabad is conducting a study on the HR structure required for immunization programme in the country; it was felt that this study should be expedited. Recommendation • Dr. NK Ganguly, Ex-DG, ICMR agreed to draft a National Vaccine policy. Thereafter the policy document will be circulated to all members for their inputs before the final draft is discussed in the NTAGI meeting. Secretary (H&FW) also suggested members to suggest names of more experts to prepare broad contours of composition of NTAGI so that the terms of reference for NTAGI may be suitable amended including memberships. Dr. Jacob Puliyel suggested that appointment of members may be for two years and it must be specified that no person can serve more than three terms (except for Ex-officio appointments). For institutional memory, one third of the members must be replaced every two years. It was also suggested that the committee should also have experts from the background of statistics, economist and public health nurse The meeting was concluded with vote of thanks. The NTAGI is to meet again after 1 – 2 months. Annexure Meeting of National Technical Advisory Group on Immunization 26th August 2010, R. No. 155A, Nirman Bhawan 1. Chairperson : Ms. Sujatha Rao, Secretary, Health & Family Welfare, Govt. of India 2. Co-Chairperson : Dr. V.M Katoch, secretary, (Department of Health research), Govt. of India & director general, ICMR, List of Participants 1. Prof. (Dr.) M. K. Bhan, Secretary (Department Bio-technology) 2. Dr. R. K. Srivastava, Director General Health Services 3. Mr. P. K. Pradhan, Additional Secretary & Mission Director, NRHM 4. Mr. Amit Mohan Prasad, Joint Secretary, RCH programme 5. Dr. N.K. Ganguly - Ex DG, ICMR 6. Prof. (Dr.) V. K. Paul, Prof.& Head, Dept. of Pediatrics, AIIMS, New Delhi 7. Dr. N. K. Arora, Paediatrician, & ED, INCLEN 8. Prof. (Dr.) A. P. Dubey, Head, Dept of Pediatrics, MAMC 9. Prof. (Dr.) Rajesh Kumar, Prof. & Head School of Public Health, PGIMER, Chandigarh 10. Dr. J. Pulliyel, Head, Deptt. of Pediatrics, St. Stephen's Hospital, Delhi 11. Dr. Shahid Jameel, Prof. of Virology, ICGEB, New Delhi 12. Dr. Sudhanshu Vrati, Dean, THSTI, Faridabad. 13. Dr. R. L. Icchpujani, Director, National Centre for Disease Control, Delhi 14. Dr V. G. Somani, Dy. Drugs Controller (India), CDSCO 15. Dr. A. C. Bannerjea, Staff Scientist, National Institute of Immunology 16. Dr Shyam Kukreja, Executive Director, Indian Academy of Paediatrics 17. Dr Henri van den Hombergh, Chief, Health, UNICEF, India office 18. Dr. Satish Gupta, Health Specialist(Immunization), UNICEF 19. Dr. Sangey Thinley, WHO Representative (Act), India office 20. Dr. Hamid Jafari, Project Manager, WHO-NPSP 21. Dr. Pradeep Haldar, Assistant Commissioner, (UIP) 22. Dr. N. K. Dhamija Assistant Commissioner,(I) 23. Dr. V. K. Mishra, SMO(Immunization) 24. Dr. Siddhartha Saha, Consultant, Immunization 25. Dr. Ajay Khera, Deputy Commissioner, member secretary Annexure Meeting of National Technical Advisory Group on Immunization 26th August 2010, R. No. 155A, Nirman Bhawan 3. Chairperson : Ms. Sujatha Rao, Secretary, Health & Family Welfare, Govt. of India 4. Co-Chairperson : Dr. V.M Katoch, secretary, (Department of Health research), Govt. of India & director general, ICMR, List of Participants 26. Prof. (Dr.) M. K. Bhan, Secretary (Department Bio-technology) 27. Dr. R. K. Srivastava, Director General Health Services 28. Mr. P. K. Pradhan, Additional Secretary & Mission Director, NRHM 29. Mr. Amit Mohan Prasad, Joint Secretary, RCH programme 30. Dr. N.K. Ganguly - Ex DG, ICMR 31. Prof. (Dr.) V. K. Paul, Prof.& Head, Dept. of Pediatrics, AIIMS, New Delhi 32. Dr. N. K. Arora, Paediatrician, & ED, INCLEN 33. Prof. (Dr.) A. P. Dubey, Head, Dept of Pediatrics, MAMC 34. Prof. (Dr.) Rajesh Kumar, Prof. & Head School of Public Health, PGIMER, Chandigarh 35. Dr. J. Pulliyel, Head, Deptt. of Pediatrics, St. Stephen's Hospital, Delhi 36. Dr. Shahid Jameel, Prof. of Virology, ICGEB, New Delhi 37. Dr. Sudhanshu Vrati, Dean, THSTI, Faridabad. 38. Dr. R. L. Icchpujani, Director, National Centre for Disease Control, Delhi 39. Dr V. G. Somani, Dy. Drugs Controller (India), CDSCO 40. Dr. A. C. Bannerjea, Staff Scientist, National Institute of Immunology 41. Dr Shyam Kukreja, Executive Director, Indian Academy of Paediatrics 42. Dr Henri van den Hombergh, Chief, Health, UNICEF, India office 43. Dr. Satish Gupta, Health Specialist(Immunization), UNICEF 44. Dr. Sangey Thinley, WHO Representative (Act), India office 45. Dr. Hamid Jafari, Project Manager, WHO-NPSP 46. Dr. Pradeep Haldar, Assistant Commissioner, (UIP) 47. Dr. N. K. Dhamija Assistant Commissioner,(I) 48. Dr. V. K. Mishra, SMO(Immunization) 49. Dr. Siddhartha Saha, Consultant, Immunization 50. Dr. Ajay Khera, Deputy Commissioner, member secretary Meeting of National Technical Advisory Group on Immunization 26th August 2010, R. No. 155A, Nirman Bhawan Minutes of Meeting The meeting of National Technical Advisory Group on Immunization was held on 26th August 2010 chaired by Secretary (H&FW) and co-chaired by Secretary (DHR) & DG (ICMR). The list of participants is annexed. The meeting started with welcome note by Secretary (H&FW) and highlighted the fact that NTAGI has been reconstituted with representation from the specialist from Paediatrics, Public Health, Researchers, program division etc to encourage healthy technical discussions in an open and transparent manner. On suggestion for audio-recording of the proceedings, the house felt that NTAGI should be forum where the technical experts can provide inputs in an open and free manner; and such recording might preclude such open discussions. Secretary (H&FW) also expressed concern at the recent incident of Adverse Event Following Immunization (AEFIs) in UP and its significance in view of the introduction of newer vaccines and therefore urged the NTAGI to consider such issues while recommending new vaccines under the National Program. The key recommendations of last NTAGI meeting held on 3rd Aug’09 and action taken note was presented. Thereafter the meeting deliberated on the agenda items. Agenda Item1- Introduction of Pentavalent vaccine The house was informed that Hib vaccine has been introduced in 137 countries of the world and out of these the vaccine is part of the programme as Pentavalent vaccine in 56 countries and remaining countries use Hib vaccine in different combination. There are multiple studies providing data in support of Hib vaccination. The studies like Million Death Study by Dr Prabhat K Jha et al and on status of Millennium Development Goal (MDG) by Prof V. K. Paul et al have raised the concern on continued burden of lower respiratory illness as one of the major cause of child mortality and morbidity, thereby precluding achievement of the MDG goals. There have been various studies in Lambok (Indonesia), Bangladesh, Sri Lanka, Myanmar and Pakistan on efficacy of Hib vaccine. Further Cochrane review also strengthens the fact that vaccine is efficacious in reducing morbidity and mortality burden due to Hib pneumonia and meningitis. Although, there was a difference of opinion in interpretation of findings of Lambok study, citing that the difference between those vaccinated and non-vaccinated is not significant. The house also deliberated upon as to why some of the developed countries are not using Hib combination vaccine as Pentavalent vaccine while it is being used in developing countries. In response, various experts cited that the different situation in immunization delivery system in developed and developing countries as one of the reasons for adopting Pentavalent vaccine. As introduction of newer vaccine in developing countries is always a challenge to cold chain with weaker immunization delivery systems therefore Pentavalent vaccine is preferred which provides operational advantages - one vaccine conferring protection against five diseases, with no change in immunization schedule thus no needs for beneficiary to approach health facility at different time interval , saves cold-chain space and logistics. While in developed countries, the vaccine schedule is different based on local epidemiology, market dynamics and also influenced by Advisory Committees on Immunization. Also these developed countries are using DTaP, (having acellular Pertussis vaccine which is costlier as compared to DTP containing whole cell pertussis vaccine), where combination vaccine has reduced seroconversion. In addition these developed countries are using Hib and Hep-B vaccine. The pentavalent vaccine used in the developing countries are combination of Hepatitis B, Hib and DPT (having whole cell Pertussis vaccine). In the ensuing discussion, concern was raised regarding the safety and efficacy of the Pentavalent vaccine in view of the AEFIs reported following usage of this vaccine in Sri Lanka, Bhutan and Pakistan. The vaccination in Sri Lanka and Bhutan was stopped following these incidents of AEFI, however, after investigation; Srilanka has resumed vaccination in 2010 and Bhutan have decided to resume the Pentavalent vaccination. The available reports published by WHO have concluded that these events are unlikely due to Pentavalent vaccine, some of the members felt that the complete report of these incidents should be accessed for analysis. Keeping in view the number of children vaccinated in these countries, the background rate of these AEFI may not significant and the benefit gain may not to raise alarm to stop vaccination. As the vaccine has not been introduced in India, there is not enough data on vaccine safety therefore; vaccine should be initially used in the states with better AEFI management and surveillance systems to monitor the vaccine safety. It was pointed out that there may be some co-incidental deaths and morbidity in this age-group during the implementation of the Pentavalent vaccination which might be wrongly get implicated to vaccine. However, the house was of unanimous opinion on the use of Hib vaccine, but few members had reservations about using the formulation combination vaccine of Pentavalent vaccine. The house considered that lives saved by the Pentavalent vaccine far outnumber the few AEFI deaths reported in the neighbouring countries and therefore has favourable risk-benefit ratio. The house also deliberated upon the immunogenicity of combination vaccines and it was felt that the available evidence based on Cochrane review reveals that although there is reduced immunogenicity of some of the components of vaccine when compared to given separately, this reduction in sero-conversion is not significant enough for protective levels of antibodies. The Core Committee recommendations on Pentavelant Vaccines was discussed and base on the recommendations the committee members felt that vaccine should be introduced in selected few well performing states and further roll-out should be based on an impact assessment of vaccination. The house also discussed the selection of states for studying the impact of Pentavalent vaccine introduction. Some of the northern states are having high burden of Hib disease however, introduction in these states with poor coverage would not be able to demonstrate significant impact. Further, the introduction of newer vaccine requires good delivery systems and some of the states with high vaccination coverage like Tamil Nadu and Kerala may be selected. The house also considered the options of limited introduction of the vaccine in the hospitals (rather than in outreach sessions) or in selected districts; however it was felt that this would not provide the sufficient sample size to study the impact of the vaccine. It was stressed that clinical trials for impact assessment is difficult in view of the large sample size that would be required and high cost that would be incurred for such study. It was pointed out that data from Hib probe study by ICMR is available for some of the areas in Tamil Nadu which can be taken as baseline data and will facilitate the study of post-vaccination impact. In the ensuing discussion the house was informed that vaccine is already available in private sector in many parts of the country and has brought about decline in cases of Hib disease over a period as observed in PGI Chandigarh, though the private vaccination does not contribute much in the National scenario. Recommendations: • Pentavalent vaccine to be introduced in Immunization programme in the states of Tamil Nadu and Kerala. • Thereafter, data may be reviewed after 1 year of introduction before expanding the vaccine into other states. • A protocol will be prepared by the ICMR for impact study; this will be circulated to NCDC and others through email; once the protocol is finalized, the study would be carried out by ICMR. • Since AEFI is a concern hence same will be monitored and also system will be strengthened so as to ensure immediate management of AEFIs; NCDC to lead this activity. • There may be an insurance scheme for the beneficiaries against the AEFIs. Agenda Item 2- Introduction of Hepatitis B vaccination The house was unanimous on expansion of Hepatitis B vaccine in the entire country under immunization programme. It was pointed out that even though safe, efficacious and cheap Hepatitis B vaccine is available and in spite of carrier rate of around 4% in India the vaccine is still not part of Universal Immunization programme although all the countries have been using this vaccine under the national programme. This vaccine is manufactured in the country and exported to many countries. There have been enough data showing impact of Hepatitis B vaccination on disease burden due to hepatitis B infection like acute hepatitis, as well as its long term sequel like chronic hepatitis, cirrhosis and liver cancer. Therefore it is high time that this vaccine is introduced all over the country at the earliest. Over the period the cost of the Hepatitis B vaccine has dropped and is one of the cheaper vaccine available in the market. As the vaccinated cohort is only protected, any change in morbidity and mortality would take 10-15 years to be detected. However, the impact assessment on carrier rate may be carried out and the house was informed that ICMR has already initiated a study for the same. It was also brought to notice that there may be possibility of escape mutation of hepatitis B virus and this may also be monitored. The experts also stressed that it is critical to give the vaccine at birth to cut down the vertical transmission and to impact the carrier rate. The house was informed that under the immunization programme of Hepatitis B in the selected States/Districts/Cities the Hepatitis B vaccine is given at birth (in institutional deliveries) and thereafter at 6th, 10th and 14th week of age of the child. The Janani Suraksha Yojana (JSY) has been launched to improve institutional delivery and this may further boost the coverage of Hepatitis B vaccination at birth. Recommendation • In view of the disease burden and availability of safe and efficacious vaccine, the expansion of Hepatitis B vaccine should be carried out all over the country as part of Universal Immunization Programme. Before rolling out in newer areas there should be a plan for trainings, microplanning etc. • Simultaneously, multi-centric impact study on carrier rate of hepatitis B will be conducted by ICMR. Agenda Item 3- Introduction of Rubella vaccination The house deliberated upon the risks and benefits of introduction of rubella vaccine in the immunization programme. If the vaccine is introduced in form of MR and targeting to vaccinate children at 16-24 months of age, then it is critical to ensure coverage above 80% failing which the rubella will shift to older age group of susceptible cohort and this may lead to paradoxical increase in congenital rubella syndrome (CRS). The manufacturing capacity and availability of MR and rubella vaccines are need to be considered before introducing the Rubella vaccination in the National programme. In view of the above, the house felt that Rubella vaccine may be introduced in adolescent girls of 10-15 year old so that those who have not acquired the natural immunity due to infection are also protected. This would reduce the risk of getting this infection during the pregnancy and thereby reduce CRS cases. Recommendation • The NTAGI recommended the introduction of rubella vaccination for 10-15 year old adolescent girls under the Universal Immunization Programme in the entire country. Agenda Item 4- Draft Multi Year Strategic Plan 2010-17 for UIP The house was unanimous that there is need for a Multi-year strategic Plan 2010-17 for UIP. The document does not comprehensively address Vaccine preventable disease surveillance; some of the points at page 58 in the document for setting up a new body with development partner to review, utilized information for deciding introduction of new and under-utilized vaccine were found to be objectionable and house felt that this draft needs editorial corrections before any further discussion. Recommendation: • The draft MYP is to be revised for further discussion. Agenda Item 5- National Vaccine Policy Secretary (H&FW) raised the need for a national vaccine policy and NTAGI unanimously agreed to the suggestion. There have been some attempts in drafting vaccine policy earlier, also a regional vaccine policy has been developed by WHO recently which may be used for developing this draft. The need for a National Immunization Authority was also felt as the current technical structure of only 3 technical officers managing the immunization programme in the entire country like India is a daunting task. In this regard, the house was informed that IIM-Ahmedabad is conducting a study on the HR structure required for immunization programme in the country; it was felt that this study should be expedited. Recommendation • Dr. NK Ganguly, Ex-DG, ICMR would draft a National Vaccine policy; Dr. Jacob Puliyel, will also provide his inputs in facilitating the drafting the policy document. Thereafter the policy document will be circulated to all members for their inputs before the final draft is discussed in the NTAGI meeting. • The policy would also suggest suitable structure for National Immunization Authority. Secretary (H&FW) also suggested members to prepare broad contours of composition of NTAGI so that the terms of reference for NTAGI may be suitable amended including memberships. The meeting was concluded with vote of thanks and the NTAGI is to meet again after 1 month. Annexure Meeting of National Technical Advisory Group on Immunization 26th August 2010, R. No. 155A, Nirman Bhawan List of Participants 51. Prof. (Dr.) M. K. Bhan, Secretary (Department Bio-technology) 52. Dr. R. K. Srivastava, Director General Health Services 53. Mr. P. K. Pradhan, Additional Secretary & Mission Director, NRHM 54. Mr. Amit Mohan Prasad, Joint Secretary, RCH programme 55. Dr. N.K. Ganguly - Ex DG, ICMR 56. Dr. Ajay Khera, Deputy Commissioner 57. Prof. (Dr.) V. K. Paul, Prof.& Head, Dept. of Pediatrics, AIIMS, New Delhi 58. Dr. N. K. Arora, Paediatrician, & ED, INCLEN 59. Prof. (Dr.) A. P. Dubey, Head, Dept of Pediatrics, MAMC 60. Prof. (Dr.) Rajesh Kumar, Head of Community Medicine, PGIMER, Chandigarh 61. Dr. J. Pulliyel, Head, Deptt. of Pediatrics, St. Stephen's Hospital, Delhi 62. Dr. Shahid Jameel, Prof. of Virology, ICGEB, New Delhi 63. Dr. Sudhanshu Vrati, Dean, THSTI, Faridabad. 64. Dr. R. L. Icchpujani, Director, National Centre for Disease Control, Delhi 65. Dr V. G. Somani, Dy. Drugs Controller (India), CDSCO 66. Dr. A. C. Bannerjea, Staff Scientist, National Institute of Immunology 67. Dr Shyam Kukreja, Executive Director, Indian Academy of Pediatrics 68. Dr Henri van den Hombergh, Chief, Health, UNICEF, India office 69. Dr. Satish Gupta, Health Specialist(Immunization), UNICEF 70. Dr. Sangey Thinley, WHO Representative (Act), India office 71. Dr. Hamid Jafari, Project Manager, WHO-NPSP 72. Dr. Pradeep Haldar, Assistant Commissioner, (UIP) 73. Dr. N. K. Dhamija Assistant Commissioner,(I) 74. Dr. V. K. Mishra, SMO(Immunization) 75. Dr. Siddhartha Saha, Consultant, Immunization Response to the Draft Vaccine Policy of Dr. Ganguly A ‘Policy’ is a "Statement of Intent" or a "Commitment". Policy is the principle(s) that guide(s) decision and actions that are most likely to achieve a desired outcome. Policy guides all subsequent decisions that are made. Policies are adopted by the governance body within an organisation. This must not be confused with manuals of procedures and protocols. Procedures and protocols are developed and adopted by senior executive officers based on the policy. Organizations can be held accountable for its ‘Policy’. Executives are held responsible if the deviate from policy in their protocols. The compromised process (of drafting a policy) NTAGI at its last meeting had resolved that Dr Jacob Puliyel with Dr NK Ganguly shall facilitate the drafting of the policy document. The Health Secretary who chaired the meeting will bear witness to it and it is mentioned in the first draft-minutes circulated for approval to the members. (Subsequent changes to the minutes can only be approved at the next full NTAGI meeting). I wish to state categorically that I had no role in preparing this draft policy, as I was not consulted for this purpose at all. It needs to be established at whose behest the collective decision of the NTAGI was overruled in the letter of the Ministry of Health and Family Welfare (MoH&FW) dated 23rd September 2010. The compromised product (Draft Policy) Regardless of my role, I would have welcomed a policy document of unmistakable clarity of purpose and unquestionable focus on principles. However, this “draft policy” is a good example of a compromised product that emerges out of a compromised process and therefore I am constrained to denounce it. The present document cannot be construed as a ’Policy document’ by any stretch of imagination. It does not even read like a manual of procedures or protocols. Instead it appears merely to be recommendations by the author in favor of some vaccines like the Pneumococcal vaccine, rotaviral vaccine and some combination vaccines, without stating rationale and without any cost benefit analysis (despite the lip service paid to such criteria elsewhere in the ‘policy’). It makes a passionate plea to allow international agencies to influence the immunization agenda of the country, and seeks abundant funding for ‘foreign trips’ of ‘would-be experts’. It also suggests numerous steps to make private vaccine manufacturers feel secure and insulated from the rough and tumble of market forces, while being lackadaisical about the role of the public sector. I have highlighted a few specific instances that illustrate my general comments above, after the following paragraphs. The section on ‘Adverse Events follows Immunization’ looks like a policy statement, but it is seriously misguided policy. It states that ‘establishing / dissociating a causal link between the event and immunization should be established based on laboratory findings and baseline demography data from the region’. By analogy, using these criteria, deaths due to Penicillin-reactions have never occurred anywhere in the world, because the vials have not been shown to be contaminated and the death of that one person has not altered the baseline demographics of the region! This flies straight in the face of the recommendations of the Brighton Collaboration – to which the document makes a passing reference. This is policy that cannot be allowed to pass Regarding the National Technical Advisory Group on Immunization (NTAGI) the author has said that there must be epidemiologists and public health persons etc on the committee but has not suggested how they are to be selected. It does not suggest advertising vacancies like in the USA. Further it says the term of the member must be 2 years but in the same sentence says they can be reappointed indefinitely, defeating the very purpose of having a fixed term. The way forward The policy needs to be redrafted. I am willing to participate in the process as desired by the NTAGI. The draft policy must take into account all available policy literature, relevant developments and government documents. It must then be open to other experts, intellectuals, think tanks, civil society organizations and even corporations and lobbyists for their inputs. The draft policy can then be finalized for approval after considering all their inputs. Public Health policy is the domain of the public and their participation is crucial for its successful passage through the parliament and subsequent implementation. Specific comments illustrating some of the points made above 1. The moot policy question is not whether a vaccine works, but whether that vaccine is necessary for all in India, and how many cases/deaths can be prevented by vaccinating how many people and at what cost. This basic logic is missing throughout this policy document. Is this deliberate? (See section 4.3) A hundred years ago George Bernard Shaw had written ‘Suppose it were ascertained that every child in the world could be rendered absolutely immune from all disease during its entire life by taking half an ounce of radium to every pint of its milk. The world would be none the healthier, because not even a Crown Prince – no, not even the son of a Chicago Meat King – could afford the treatment. Yet it is doubtful whether doctors would refrain from prescribing it on that ground. The recklessness with which they now recommend wintering in Egypt or at Davos to people who cannot afford to go to Cornwall, and the orders given for champagne jelly and old port in households where such luxuries must obviously be acquired at the cost of stinting necessaries, often make one wonder whether it is possible for a man to go through a medical training and retain a spark of common sense’ Shaw GB. The Doctors Dilemma. Penguin Books, London, UK, 33 (1957) (First published 1911). 2. Executive summary (Page 7 first para): It is fraudulent to project pneumococcal and rotaviral vaccines (that too covering only few strains) as vaccines against pneumonia and diarrhea, as these diseases are caused by many more etiological agents and there are no vaccines against all causes of these two diseases. This is a common and deliberate mischief played by people who push some vaccines. The policy should have specified how to avoid such mischief in public interest. Instead, it plays into the hands of such mischief mongers. 3. Product development (Page 8 first para): Why should product development be only in PPP mode? Why should a policy limit its options to one such mode? Why can’t government learn from the dubious PPP deals in the vaccine park, and the MOUs between PII and Green Signal Biopharma and Vatsan Biopharma? 4. (Page 8, last para): The opening line “Vaccine Policy is a guiding document for maximizing the use of vaccines available globally” is a patently wrong and objectionable objective. The policy should encourage development, production, adoption and administration of NECESSARY vaccines, rather than maximize the use of all vaccines available globally. One wonders if this is a Freudian slip where the author of this policy has revealed his true intentions in making this document. 5. (Section 4.1.) The policy mentions how vaccine decisions should be gui
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  Evidence Based Medicine: Making It Better

  Economic & Political Weekly EPW april 2, 2011 vol xlvi no 14. Page 23-26 http://epw.in/epw/uploads/articles/15901.pdf
  Jacob M. Puliyel
  Evidence Based Medicine: Making It Better Jacob M Puliyel MD MPhil Head of Pediatrics St Stephens Hospital Delhi 110054 Puliyel@gmail.com Phone 09868035091 Abstract Evidence Based Medicine (EBM) began as a 'bottom-up' paradigm that taught residents to search the literature for the best available evidence and to critically appraise it for making patient care decisions. As its popularity increased, there evolved a huge market for readymade EBM summaries and reviews and th Show More...Evidence Based Medicine: Making It Better Jacob M Puliyel MD MPhil Head of Pediatrics St Stephens Hospital Delhi 110054 Puliyel@gmail.com Phone 09868035091 Abstract Evidence Based Medicine (EBM) began as a 'bottom-up' paradigm that taught residents to search the literature for the best available evidence and to critically appraise it for making patient care decisions. As its popularity increased, there evolved a huge market for readymade EBM summaries and reviews and there is a now a scramble to provide this service. Those who provide the service come to wield tremendous influence and power. This article describes the evolution of this important tool and describes the pitfalls in how it is practiced. People in the health care field need to understand all these aspects of EBM if they are to exploit its potential for public health. Evidence Based Medicine: Making It Better Evidence Based Medicine (EBM) is today a buzzword - it is used in the wider society outside of its originally narrow technical context, often pretentiously and inappropriately to impress and to make discourse appear esoteric, and technically sound. EBM has an enchanting image that reaches out to researchers and scholars (Holmes et al 2006). Also it has a ring of scientific authority that mesmerizes decision-makers and government officials, that health planners value and purchasers and payers feel reassured by. This paper looks at the evolution of EBM and describes the pitfalls in how it is practiced. People in the health care field need to understand all these aspects of EBM if they are to exploit its potential for public health. How it started EBM was originally developed as a method for teaching medical residents (Druss 2000). Keeping up to date with knowledge has become more difficult in the internet age. Coiera has shown how the exponential growth of information creates a poverty of attention (Coiera 2000). The low cost of production of poor quality information results in high quality information being drowned out, increasing the cost of finding specific information. It was estimated in 1992 that a dedicated doctor would have to study at least 17 papers every day of the year to keep abreast (Davidoff et al 1995). Alongside this glut in information and data, the cost of medical care also increased with introduction of newer technology - many of them of doubtful utility. These developments resulted in enormous variation in the standard of care and costs of care. It is in this milieu that the term EBM was coined at McMaster Medical School in Canada in the 1980s to ‘make use of explicit search criteria to find the best available evidence’ (Rosenberg & Donald 1995). EBM has been described by one of its leading lights, Dr David Sackett, as the conscientious, explicit and judicious use of current best research evidence in making decisions about care of individual patients (Sackett et al 1996). It was expected that this would result in better care of patients. Costs would be curtailed by the avoidance of less useful technologies. Thus it began as a 'bottom-up' paradigm that taught residents to ask answerable and focused questions, search the literature in a transparent and reproducible way to find the best evidence and to critically appraise it in an explicit and structured manner, often using mathematical analyses to give a clear idea of the strength, statistical significance and possible clinical significance of the results. This article describes also some of the risks attendant on its spectacular success in capturing the public imagination. It will touch on how vested interests have exploited its vulnerabilities. The basic principles underlying the ‘evidence-based’ practice movement are that there is a hierarchy of evidence and that modern informatics can make the evidence available to practitioners at the point of care. Clinicians should seek evidence from as high in the appropriate hierarchy of evidence as possible (Guyatt et al 2000). This was seen as a major shift away from traditional medicine that emphasized the expertise of the medical profession. The ‘freestyle’ nature of ‘expert’ critical appraisal was sought to be reined in (Malone et al 2002). It undercut the autonomy and authority of the doctor and the resultant variability in care breaking the lockhold the profession had over how medicine is practiced and compensated (Healy 2006). It was tremendously appealing for those who sought to impose uniform standards to assess performance and cost effectiveness. However EBM has had its critics. It was noted that the team that coined the term EBM considered using the phase ‘scientific medicine’ but rejected it because it implied that other approaches were by definition unscientific (Guyatt 2002). They ignored the fact that the term ‘evidence based medicine’ carries a similar moral valence and linguistic slipperiness (Sehon & Stanley 2003). Holmes and colleagues have castigated EBM because it excluded alternate forms of knowledge (Holmes et al 2006). Newer definitions of EBM now acknowledge that research evidence alone is not adequate to guide action. It emphasizes that clinicians must use their expertise to assess the patient’s problem and incorporate patient’s preferences or values to research evidence before making management recommendations (Haynes et al 2002). It appears as if we have come a full circle, giving the clinician preeminence again, so much so that Druss has lamented the overly inclusive definition threatening to deprive the term of meaning (Druss 2005) Sehon and Stanley have argued that the new definition merely says that EBM is the wise use of the best evidence available (Sehon & Stanley 2003). They write that EBM defined in this manner cannot be thought of as revolutionary or even useful. After all who could possibly be opposed to using best evidence wisely (Sehon & Stanley 2003)? They suggest that the debate between EBM and alternate approaches can change medical practice only if EBM ceases to be described in this ‘all embracing and vacuous’ manner. The heart of EBM is the use of evidence hierarchies including randomized controlled trials (RCTs), systematic reviews and meta-analysis of RCTs. Alternative approaches to medical practice also take into account the patient’s condition and values hence this is not what separates EBM from the other approaches. What separates it is how it gives priority to certain forms of evidence (Sonnabend 2008). This essay will look primarily at the aspects that make EBM distinctive and revolutionary. Systematic Reviews and Meta-analysis Versus Traditional Reviews Traditionally review articles were written for journals by ‘experts’. Sonnabend writes that experts are often elevated to this rank by marketing department of drug manufacturers. It is not beyond conjecture, he says, that an expert has been created expressly to justify their claims (Sonnabend 2008). In the review ‘experts’ state their opinion about the proper evaluation and management of a condition, supporting key conclusions with selected references, and they have been shown to be both non-reproducible and as a scientific exercise, of low mean scientific quality (Sackett & Rosenberg 1995). Oxman and Guyatt found that adherence to simple scientific principles in reviews were inversely proportional to self self-professed expertise of the experts (Oxman & Guyatt 1993). EBM provided the framework for systematic reviews and the popularity of EBM has been helped by journals seeking explicit and transparent methods in reviews with bias-free list of citations. The hierarchy of evidence meant that the best evidence (that with the least chance of bias) was considered. Meta-analysis combines the results of several studies. In its simplest form, output of meta-analyses is the effect size where the weighting might be related to sample sizes of the individual studies. This aggregation of different studies helps overcome the problem of reduced statistical power in studies with small sample sizes. Minor Flaws in EBM Concepts For a meta analysis to be meaningful all studies need to be included – both those that showed benefit and those that did not. It is usually hard to publish studies that show no significant results. Studies that fail to show benefit don’t get sent for publication and if they do, they are seldom published by editors. This ‘file drawer problem’ where non-significant study results are hidden away from general view in someone’s file drawer creates a serious base rate fallacy, biased or skewed distribution of effect-sizes and the overestimation of the significance of the published studies (Rosenthal 1979). An attempt is being made to overcome this file-drawer problem by making registration of clinical trials mandatory. But the benefits of such a registry in meta-analyses have not been tested as yet. Also it has been suggested that the practice of using weights in a meta analysis according to the sample size, rather than the size of the population they represent, may be misleading (Puliyel & Sreenivas 2005; Batham et al 2009). This is best illustrated with the block buster pain killer (anti-inflammatory drug) Rofecoxib (brand name Vioxx), which has now been withdrawn from the market. Initially, according to an Editorial in the New England Journal of Medicine, peer-reviewed-literature was flooded by papers and RCTs from the employees of Merck and their consultants. There were epidemiological studies showing concerns about myocardial infarction and stroke with Vioxx but Merck claimed that only RCTs were suitable for determining whether there was any risk. There was an excess of 16 cases of myocardial infarction or stroke per 1000 patients on the drug. 80 million people had received the drug before it was withdrawn (Topol 2004). The appellation ‘evidence based recommendations’ does not necessarily mean that the recommendations are based on firm empirical data. It only means that the level of evidence is indicated along side each recommendation. (See Box for ‘quality of evidence’ and ‘probability of harm over good’ and how reviewers ‘judgment’ relates to the ‘recommendations’ made. It shows how recommendations based on opinion, not substantiated by any study data can be provided as evidence-based consensus-statements/recommendations) Do-it-yourself EBM Evolves in Complexity Along with the popularity of EBM the complexity for evaluating evidence has increased. No longer was it an amateurs’ enterprise. Multiple data bases are explored, the references in the papers are further hand searched for new references, Clinical Trials Registers and conference proceedings are scrutinized and pharmaceutical companies and individual researchers are contacted for unpublished data and ongoing trials. It has now been felt that most practitioners are not able to keep up to date by learning evidence based strategies but are willing to seek out EBM produced by others. Busy clinicians are provided a detailed report and through a process of dumbing down EBM, also a one line answer called ‘clinical bottom lines’ (Puliyel et al 2004). Thus there evolved a huge market for EBM summaries and reviews and a scramble to provide this service. Those who provide the service come to wield tremendous influence and power and have introduced methodological refinements making the process more and more complicated to minimize the competition from copycat startups. Funding and Bias in Conclusions of RCT Theoretically, well blinded RCTs provide incontrovertible evidence. However empirical evidence has shown repeatedly that randomised trials are more positive if funded by for-profit organizations (Davidson 1986;Kjaergard et al 2002; Djulbegovic et al 2000; Bekelman et al 2003; Lexchin et al 2003). Als-Nielsen and colleagues have shown that association with for profit organizations had little effect on treatment effect but the conclusions were more positive due to biased interpretation of trial results (Als-Neilsen et al 2003). Lundh and colleagues have shown that publication of industry-supported trials was associated with an increase in journal impact factors and revenue (Lundh et al 2010). Richard Smith – the former Editor of the BMJ, has suggested that publishing one drug company sponsored RCT could yield a million dollars in the sales of reprints alone (Smith R 2010). According to Marcovitch – another BMJ Editor, potential conflicts arise when the journal or publisher receives a substantial proportion of its income from reprints (23%, Massachusetts Medical Society –publishers of the New England Journal of Medicine; 41%, The Lancet; 53%, American Medical Association publishers of the JAMA) (Marcovitch 2010). There is therefore an obvious publication bias favoring drug trials sponsored by the pharmaceutical industry. Funding of Systematic Reviews and Meta-analyses Yank and colleagues found that not just RCTs are biased by industry funding - even meta-analysis done by persons with financial ties to drug companies are likely to come to more favorable conclusions although not with more favorable results (Yank et al 2007). It is therefore important that meta-analyses are done by not-for-profit organizations. The Cochrane Collaboration is a rapidly growing international group of researchers who form an unselfish collaboration to provide evidence from systematic searches (Sackett & Rosenberg 1995). However as the group becomes bigger it becomes easy for those with vested interests to infiltrate the organisation. The Cochrane review on surfactant illustrates the point clearly. Surfactact is a substance put into the airways of premature babies to help them breath easier. The drug is expensive and meta analysis showed that it’s use did not improve survival. However the Cochrane review says the drug reduces ‘neonatal mortality’ (Soll 2000). The author who has declared conflicts of interests (payments in the past from many surfactant manufacturers) did a further analysis and found there were more children surviving the first 30 days of life (neonatal age group) and although there were no differences in mortality prior to discharge from the hospital he was able to write in the Abstract that it reduces neonatal mortality and in the Conclusion that it reduces mortality. Although this anomaly has been publicized in the BMJ (Tiwari et al 2004), this misleading statement has not been revised in the updated meta-analysis (Soll & Ozek 2010). Dangers of agenda-driven bias Wikipedia suggests the most severe weakness and abuse of meta-analysis often occurs when the person or persons doing the meta-analysis have an economic, social or political agenda such as the passage or defeat of legislation. “If a meta-analysis is conducted by an individual or organization with a bias or predetermined desired outcome, it should be treated as highly suspect or having a high likelihood of being junk science. From an integrity perspective, researchers with a bias should avoid meta-analysis and use a less abuse-prone (or independent) form of research” (Wikipedia 2011). However reviews often ignore this warning. In the Indian context the Cochrane Database of Systematic Reviews recently published a protocol that illustrates the point poignantly (Kapoor et al 2010). The protocol states that the rationale for the systematic review is a public interest petition in the Delhi High Court questioning the introduction of newer vaccines and vaccine combination (DPT vaccine combined with Hepatitis B vaccine and H Influenza B vaccine) in the public health system by the Government, under the influence of vaccine manufacturers and international agencies like World Health Organization (WHO), without proper epidemiological and clinical studies (Delhi 2009). The ICMR and the National Technical Advisory Group on Immunization (India) are named as respondents. Yet the new review to be done by the South Asian Cochrane Network is to be performed by the very persons who were party to the impugned recommendation (Subcommittee 2009). Conclusion Holms has written that EBM groups like the Cochrane Collaboration have a profound sense of entitlement, what they take as a universal right to control the scientific agenda. In a polarised world it is as if you either embrace them or else be condemned as recklessly non-scientific (Holmes et al 2006). The picture may appear hopeless. Marcia Angell, editor of the NEJM for 20 years writes, “It is simply no longer possible to believe much of the clinical research that is published or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion which I reached slowly and reluctantly over my two decades as an editor of the New England Journal of Medicine” (Angell 2009). All is however not so bleak. Shakespeare has pointed out: ‘Though all things foul would wear the brows of grace, yet grace must still look so’ (Shakespeare Macbeth). Although a lot of junk science purports to be EBM, we must not discredit everything that carries the name. A healthy skepticism and more widespread appreciation of the misuses of the label will make EBM better. One hopes EBM will somehow reincarnate itself to live by its original bottom-up paradigm. References Als-Nielsen B, Chen W, Gluud C, Kjaergard LL. (2003) Association of funding and conclusion in randomised drug trials JAMA:290:921-928 Angell M (2009) Drug companies and doctors: A story of corruption. The New York Review of Books 56. Available: http://www.nybooks.com/articles/archives/2009/jan/15/drug-companies-doctorsa-story-of-corruption/ Batham A, Gupta MA, Rastogi P, Garg S, Sreenivas V, Puliyel JM. (2009) Calculating prevalence of hepatitis B in India:Using population weights to look for publication bias in conventional meta analysis. Indian J of Pediatrics;76 1247-57. Bekelman JE, Li Y, Gross CP. (2003) Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA;289:454-465. Coiera E. (2000) Information economics and the internet. J Am Med Inform Assoc;7:215-21. Davidoff F, Haynes B, Sackett D, Smith R. (1995) BMJ ;310:1085-1112 Davidson RA.(1986) Source of funding and outcome of clinical trials. J Gen Intern Med;1:155-158. Delhi High Court. (2009) Writ Petition (Civil) No. 13698 of 2009. Public Interest Litigation. Available at http://delhihighcourt.nic.in/index.html 2009 Djulbegovic B, Lacevic M, Cantor A, et al. (2000) The uncertainty principle and industry-sponsored research. Lancet. 356:635-638. Druss B. (2005) Evidencebasd medicine: does it make a difference. Use wisely BMJ 2005;330:92. Guyatt GH, Haynes RB, Jaeschke RZ, et al., (2000) Users' Guides to the Medical Literature: XXV. Evidence-based medicine: principles for applying the Users' Guides to patient care. Evidence- Based Medicine Working Group. JAMA; 284 (10):1290-1296. Guyatt G. (2002) Preface in Users' Guides to the Medical Literature: Essentials of Evidence-Based Clinical Practice Guyatt G, Rennie D, eds. Chicago, IL 60610, AMA Press. Haynes RB, Devereaux PJ, Guyatt GH. (2002) Clinical expertise in the era of evidence-based medicine and patient choice. Evid Based Med;7:36-38 doi:10.1136/ebm.7.2.36 Healy B. (2006) Who says what is best. http://health.usnews.com/usnews/health/articles/060903/11healy.htm Holmes D, Murray SJ, Perron A, Rail G. (2006) Deconstructing the evidence-based discourse in health sciences: truth, power and fascism. Int J Evid Based Health.;4:180-6. Kapoor AN, Tharyan P, Kant L, Balraj V, Shemilt I. (2010) Combined DTP-HBV vaccine versus separately administered DTP and HBV vaccines for primary prevention of diphtheria, tetanus, pertussis, and hepatitis B (Protocol). Cochrane Database of Systematic Reviews 2010, Issue 9. Art. No.: CD008658. DOI: 10.1002/14651858.CD008658. http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD008658/frame.html Kjaergard LL, Als-Nielsen B. (2002) Association between competing interests and authors' conclusions: epidemiological study of randomised clinical trials published in BMJ. BMJ.;325:249-252. Lexchin J, Bero LA, Djulbegovic B, Clark O. (2003) Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ.;326:1167-1170. Lundh A, Barbateskovic M, Hrobjartsson A, Gotzsche PC. (2010) Conflict of interest at medical journals: The influence of industry-supported randomised trials on journal impact factors and revenue – Cohort study. PLoS Medicine:7:e1000354 doi:10.1371/journal.pmed.1000354 Malone DE, Skehan SJ, MacEneaney PM, Staunton M, Schranz M (2002) Evidence based radiology.net http://www.evidencebasedradiology.net/ebr_overview/ebr_overview_notes.html Marcovitch H (2010) Editors, Publishers, Impact Factors, and Reprint Income. PLoS Med 7(10): e1000355. doi:10.1371/journal.pmed.1000355 Oxman A, Guyatt GH. (1993) The science of reviewing research. Ann NY Acad Sci;703:125-34. Puliyel J, Noopur Baijal, Dherain Narula (2004) Evidence-Based Investigation into the Relation Between Sexual Intercourse and Pregnancy http://adc.bmj.com/content/88/12/1135/reply#archdischild_el_742?sid=0ef6f4a3-575a-422c-8699-95871d4bef9d. Puliyel J, Sreenivas V. (2005) Meta-analysis can be statistically misleading. EBM; 10:130. Rosenthal R (1979). "The "File Drawer Problem" and the Tolerance for Null Results". Psychological Bulletin. 86 (3): 638–641. doi:10.1037/0033-2909.86.3.638 Rosenberg W, Donald A. (1995) Evidence based medicine: an approach to clinical problem solving. BMJ ;310:1122-6. Sackett DL, Rosenberg WMC, Grey JAM, Haynes RB, Richardson WS. (1996) Evidence based medicine: what it is and what it isn’t. BMJ 1996;312:71. Sackett DL, Rosenberg WMC. (1995) The need for evidence-based medicine J R Soc Med;88:620-24. Sehon SR, Stanley DE. (2003) A philosophical analysis of the evidence-based medicine debate. BMC Health Serv Res;3:14. Shakespeare W. Macbeth, Act IV scene iii. Smith R (2010) On editors’ conflict of interests BMJ Blog 2 Nov 2010. http://blogs.bmj.com/bmj/2010/11/02/richard-smith-on-editors-conflicts-of-interest/#more-5395 Soll RF. (2000) Prophylactic natural surfactant extract for preventing morbidity and mortality in preterm infants (Cochrane Review). In: Cochrane Library. Issue 3. Chichester: John Wiley, 2004. (Cochrane Database Syst Rev 2000(2):CD000511. Soll R, Özek E. (2010) Prophylactic animal derived surfactant extract for preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 1997, Issue 4. Art. No.: CD000511. DOI: 10.1002/14651858.CD000511. Sonnabend JA. (2008) What constitutes expert opinion. http://www.bmj.com/content/312/7023/71.full/reply#bmj_el_242222 Subcommittee on introduction of Hib vaccine in the universal immunization programme, National Technical Advisory Group on Immunization, India, Kant L. (2009) NTAGI Subcommittee Recommendation on Himophilus influenza Type b (Hib) Vaccine Introduction in India. Indian Pediatr;46:945-54 . Tiwari L, Puliyel JM, Upadhyay P. (2004) Truth and evidence based medicine: spin is everything. BMJ;329:1043. Topol EJ. (2004) Failing the public health -- Rofecoxib, Merck, and the FDA. N Engl J Med; 351:1707-9. Wikipedia (2011) Meta-analysis http://en.wikipedia.org/wiki/Meta-analysis Yank V, Rennie D, Bero LA. (2007) Financial ties and concordance between results and conclusions in meta-analyses: retrospective cohort study. BMJ doi:10.1136/bmj39376.447211BE. 1. The ‘file drawer problem’ and bias of meta analysis 2. Harm from Hierarchy of Evidence 3. ‘Best Available Evidence’ Confers EBM Status to Dodgy Science Delhi 110054 Phone 09868035091

• Ethical use of newer vaccines

  Indian Medical Association National Conference Jaipur 27 December 2010
  Jacob Puliyel
  http://www.youtube.com/watch?v=vGvu1sQfxAw http://www.youtube.com/watch?v=elHP06rJvp8 http://www.youtube.com/watch?v=ib-Z9iPRI9s
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  CUSUM for monitoring competency: Computer software is useful for bootstrapping and real time CUSUM plotting.

  Br J Ophthalmol 2011;95:295e296. doi:10.1136/bjo.2010.188805. http://bjo.bmj.com/content/94/4/445/reply#bjophthalmol_el_9709
  Ashish Puliyel, Jacob Puliyel
  CUSUM for monitoring competency: Computer software is useful for bootstrapping and real time CUSUM plotting. We congratulate Salowi and colleagues on their study of the use of CUSUM to monitor competency in cataract extraction (1). However there are two modifications that could make their system more responsive and reliable. Firstly the authors use a CUSUM chart that fluctuates on only one side of the zero line. Traditionally CUSUM charts fluctuate on both sides of the zero line (2,3). Show More...CUSUM for monitoring competency: Computer software is useful for bootstrapping and real time CUSUM plotting. We congratulate Salowi and colleagues on their study of the use of CUSUM to monitor competency in cataract extraction (1). However there are two modifications that could make their system more responsive and reliable. Firstly the authors use a CUSUM chart that fluctuates on only one side of the zero line. Traditionally CUSUM charts fluctuate on both sides of the zero line (2,3). The consultant in their Figure 1 performed 48 procedures and 43 were successful while 5 were failures. The weight for a failure would be -1.791666 and for a success it would be + 0.208333. Figure 1 depicts the traditional CUSUM graph with this data. Against this, the data from his trainee is also drawn. The trainee CUSUM score keeps going further and further away from the zero line, suggesting that he has not reached the bottom of his learning curve. Once his learning is over, his mean CUSUM line will run parallel to the zero line. The second modification relates to the decision interval. The authors discuss in detail the arbitrary decision intervals (control lines) that they have employed, based on a trade-off between the need to detect poor performance quickly and that to avoid a large number of false alarms. Decision lines need not be arbitrary. With the help of computers, bootstrapping techniques can be employed, so that these lines are placed where they are statistically meaningful. As an illustration, in Figure 1 with the consultant performance, there were 5 failures and 43 successes. The 5 failures need not be evenly interspersed among the successes. The sequence of failures is purely a matter of chance and 2 or even 3 failures may be clustered together. Bootstrapping allows random reordering of the failures and successes in a way that the overall numbers of success and failures are the same for each iteration. The computer can calculate the maximum and minimum score for each iteration. If a 1000 iterations are performed it is possible to calculate the mean of the highest scores (maximum score in the iteration) and the mean of the lowest scores (minimum score in the iteration) and also the standard deviation around the means. The upper decision line is the limit drawn with the mean upper score plus 2SD. The lower decision line is the mean lower score minus 2SD. If surgery is performed by a person of comparable competence as the consultant, his CUSUM score will lie within the two decision lines, 95% of the time. We have recently used CUSUM for a clinical trial and for this we developed software that allows for easy bootstrapping, drawing of control lines and plotting of CUSUM score. This software is available free on the internet. (http://jacob.puliyel.com/foresee/). Figure 2 can also be redrawn using the acceptable rate for posterior capsule rupture (PCR) of 5%. Here the acceptable standard is 1 failure for 19 successes. For Figure 3 using the acceptable rate for impaired vision as 10% (using data reported by the authors from the Malaysian National Cataract Surgery Registry) there can be 1 failure for 9 successes. The software is interactive and allows CUSUM plotting in real time (meaning that it allows one to see how the CUSUM graph evolves, with each new success or failure). We hope that the free software available on the net will encourage more widespread use of CUSUM in various clinical situations. Figure 1 Standard reference cumulative sum (CUSUM) showing performance by a trainee and a consultant can be viewed at http://jacob.puliyel.com/#paper_199 Reference 1. Salowi MA, Choong YF, Goh PP, Ismail M, Lim TO. CUSUM: a dynamic tool for monitoring competency in cataract surgery performance. Br J Ophthalmol. 2010;94:445-9. 2. Van Rij AM, McDonald JR, Pettigrew RA, Putterill MJ, Reddy CK, Wright JJ. Cusum as an aid to early assessment of the surgical trainee. Br J Surg. 1995;82:1500-3. 3. Sibanda T, Sibanda N. The CUSUM chart method as a tool for continuous monitoring of clinical outcomes using routinely collected data. BMC Med Res Methodol. 2007;7:46. The CUSUM software available free on the internet, was developed by the authors in the context of a clinical trial. Ashish Puliyel, Tech Guru gonzoBuzz, Singapore ashishpuliyel@gmail.com Jacob Puliyel, Consultant Pediatrician, St Stephens Hospital, Delhi, India puliyel@gmail.com
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  An Index of 'Arm-twistability' of Governments Will be Useful

  http://www.plosone.org/annotation/listThread.action?inReplyTo=info:doi/10.1371/annotation/bae6b668-a8fc-4b28-9964-bcac42a473dd&root=info:doi/10.1371/annotation/bae6b668-a8fc-4b28-9964-bcac42a473dd
  Puliyel J
  Response to Glatman-Freedman A, Cohen M-L, Nichols KA, Porges RF, Saludes IR, et al. (2010) Factors Affecting the Introduction of New Vaccines to Poor Nations: A Comparative Study of the Haemophilus influenzae Type B and Hepatitis B Vaccines. PLoS ONE 5(11): e13802. doi:10.1371/journal.pone.0013802 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013802 Response at http://www.plosone.org/annotation/listThread.action?inReplyTo=info:doi/10.1371/annotation/bae6b668-a8fc-4b Show More...Response to Glatman-Freedman A, Cohen M-L, Nichols KA, Porges RF, Saludes IR, et al. (2010) Factors Affecting the Introduction of New Vaccines to Poor Nations: A Comparative Study of the Haemophilus influenzae Type B and Hepatitis B Vaccines. PLoS ONE 5(11): e13802. doi:10.1371/journal.pone.0013802 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013802 Response at http://www.plosone.org/annotation/listThread.action?inReplyTo=info:doi/10.1371/annotation/bae6b668-a8fc-4b28-9964-bcac42a473dd&root=info:doi/10.1371/annotation/bae6b668-a8fc-4b28-9964-bcac42a473dd An Index of 'Arm-twistability' of Governments Will be Useful The authors assume that all vaccines are equally useful and cost effective in all countries. This is far from established. The 1998 position paper of the WHO stated that countries should consider Hib burden before introducing the vaccine (1). After the Bangladesh and Indonesia probe studies showed little benefit from Hib vaccine in these countries (2), inexplicably, the WHO modified its recommendation to say Hib vaccine must be introduced in all routine immunization programs, regardless of national burden (3). Vaccines against pneumonia (Hib and pneumococcal vaccine) only address two of the many causes of pneumonia (and causes of deaths from pneumonia). Even vaccines that are very efficacious against strain-specific-disease may have very little utility in the community, because the strain-specific-disease is a rare, compared to all the other causes of pneumonia (-low utility in terms of absolute risk reduction). For example, the pneumococcal vaccine reduces only 3.6 cases of pneumonia per 1000 children vaccinated according to Madhi et al. The abysmal cost-benefit equation of this vaccine was discussed by us in the Lancet not long ago - ( $250,00 will need to be spent to prevent 4 cases of pneumonia. Treatment of 4 cases of pneumonia with Septan- as recommended by the WHO - would instead cost $1) (4). And this was before strain shifts made these vaccines even less useful (5-13). The uptake of expensive vaccines of doubtful utility in poor countries thus requires a huge push. International organizations like the WHO and GAVI have all played their part. A previous study has shown that countries without democracy take up vaccines more easily (14). I wonder if one can develop an index of arm twistability of these poor countries. Factors like corrupt dictatorships, greater dependence on foreign aid, absence of expertise within the country to allow it to make an independent evaluation of the costs and benefits, will all contribute to this index of arm-twistability. Excellent correlation to vaccine uptake with this index is likely to be found. Jacob Puliyel puliyel@gmail.com Reference 1. Anonymous (1998) Global programme for vaccines and immunization (GPV). the WHO position paper on Haemophilus influenzae type b conjugate vaccines. Wkly Epidemiol Rec 73: 64–68. Find this article online 2. Puliyel J. GAVI and WHO: Demanding accountability. BMJ 2010;341:c4081 Pg 266 3. World Health Organization (2006) WHO Position Paper on Haemophilus influenzae type b conjugate vaccines. Wkly Epidemiol Rec 81: 445–452. 4. Dabade G, Puliyel J. Global health and the Bill and Melinda Gates Foundation. Lancet 2009;373:2195-6 5. Sheldon L. Kaplan, William J. Barson, Philana L. Lin, Stephanie H. Stovall, John S. Bradley, Tina Q. Tan, Jill A. Hoffman, Laurence B. Givner, Edward O. Mason, Jr. Serotype 19A Is the Most Common Serotype Causing Invasive Pneumococcal Infections in Children. PEDIATRICS Vol. 125 No. 3 March 2010, pp. 429-436 (doi:10.1542/peds.2008-1702) 6. Brown VM, Madden S, Kelly L, Jamieson FB, Tsang RS, Ulanova M. Invasive Haemophilus influenzae disease caused by non-type b strains in Northwestern Ontario, Canada, 2002-2008. Clin Infect Dis. 2009 Oct 15;49(8):1240-3. 7. Tsang RS, Sill ML, Skinner SJ, Law DK, Zhou J, Wylie J. Characterization of invasive Haemophilus influenzae disease in Manitoba, Canada, 2000-2006: invasive disease due to non-type b strains. Clin Infect Dis. 2007 Jun 15;44(12):1611-4. 8. Urwin G, Krohn JA, Deaver-Robinson K, Wenger JD, Farley MM. Invasive disease due to Haemophilus influenzae serotype f: clinical and epidemiologic characteristics in the H. influenzae serotype b vaccine era. The Haemophilus influenzae Study Group. Clin Infect Dis. 1996 Jun;22(6):1069-76. 9. Perdue DG, Bulkow LR, Gellin BG, Davidson M, Petersen KM, Singleton RJ, Parkinson AJ. Invasive Haemophilus influenzae disease in Alaskan residents aged 10 years and older before and after infant vaccination programs. JAMA. 2000 Jun 21;283(23):3089-94. 10. McConnell A, Tan B, Scheifele D, Halperin S, Vaudry W, Law B, Embree J; of The Canadian Immunization Monitoring Program, ACTive (IMPACT). Invasive infections caused by haemophilus influenzae serotypes in twelve Canadian IMPACT centers, 1996-2001. Pediatr Infect Dis J. 2007 Nov;26(11):1025-31. 11. Adderson EE, Byington CL, Spencer L, Kimball A, Hindiyeh M, Carroll K, Mottice S, Korgenski EK, Christenson JC, Pavia AT. Invasive serotype a Haemophilus influenzae infections with a virulence genotype resembling Haemophilus influenzae type b: emerging pathogen in the vaccine era? Pediatrics. 2001 Jul;108(1):E18. 12. [No authors listed] Invasive Haemophilus influenzae disease in Manitoba in the post-vaccination era suggests a changing epidemiology. Can Commun Dis Rep. 2006 Jun 1;32(11):125-30. 13. Kalies H, Siedler A, Gröndahl B, Grote V, Milde-Busch A, von Kries R. Invasive Haemophilus influenzae infections in Germany: impact of non-type b serotypes in the post-vaccine era. BMC Infect Dis. 2009 Apr 20;9:45. 14. Jessica C. Shearer, Meghan L. Stack, Marcie R. Richmond Allyson P. Bear, Rana A. Hajjeh, David M. Bishai. Accelerating Policy Decisions to Adopt Haemophilus influenzae Type b Vaccine: A Global, Multivariable Analysis. http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000249
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  Ondansetron-Induced Dystonia, Hypoglycemia, and Seizures in a Child

  Ann Pharmacother 2011;45:xxxx. Published Online, 28 Dec 2011, theannals.com, DOI 10.1345/aph.1P332
  Aneet Patel, Shweta Mittal, Samiksha Manchanda, and Jacob Mammen Puliyel
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  Public Interest Petition (PIL) Vaccine case 4rd affidavit
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  Adverse events following Immunization (AEFI) Causality Assessment WHO 2005 Brighton Classification

  http://www.rho.org/files/rb3/AEFI_Causality_Assessment_WHO_2005.pdf
  https://brightoncollaboration.org/public/who-we-are/our-story.html Page not found! WHO Aide-Mémoire on AEFI causality assessment - http://www.who.int/vaccines-documents/DocsPDF05/815.pdf Page not found The WHO Has removed the Brighton Classification from it's web site it appears. The classification is available still at http://www.rho.org/files/rb3/AEFI_Causality_Assessment_WHO_2005.pdf In case this page is removed it is available on this website
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  “If they don’t have bread let them take vaccines” - The contemporary Marie Antionette. Unedited response to 'Why fear of vaccination is spelling disaster in the developing world'. Published as; 'India cannot afford to use vaccines that are not cost-effective. Developing countries must spend their budgets wisely to save as many lives as possible'

  http://www.guardian.co.uk/commentisfree/2010/oct/27/india-vaccines-not-cost-effective. Unedited version of Response to http://www.guardian.co.uk/lifeandstyle/2010/oct/11/vaccination-fears-developing-world-deaths.
  Jacob M Puliyel
  Published title: India cannot afford to use vaccines that are not cost-effective. Developing countries must spend their budgets wisely to save as many lives as possible. http://www.guardian.co.uk/commentisfree/2010/oct/27/india-vaccines-not-cost-effective
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  India cannot afford to use vaccines that are not cost-effective Developing countries must spend their budgets wisely to save as many lives as possible

  # The Guardian, Wednesday 27 October 2010. http://www.guardian.co.uk/commentisfree/2010/oct/27/india-vaccines-not-cost-effective
  Jacob Puliyel
  Unabridged version of the article is entitled “If they don’t have bread let them take vaccines” - The contemporary Marie Antionette. It is available at http://jacob.puliyel.com/#paper_224
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  Misrepresenting data : Deception or dogma? (Response to IJMR Editorial on Pentavalent Vaccine: Counsel for Caution)

  Indian J Med Res 132, October 2010, pp 463-465
  Responses By J Puliyel and Z Lone to Correspondence from Jacob John*, Anuradha Bose & Vinohar Balraj
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  Introducing pentavalent vaccine in EPI in India: issues involved. (Response to Editorial Counsel for Caution on Pentavalent Vaccine.)

  Indian J Med Res 132, October 2010, pp 450-455
  Response by J Puliyel and Z Lone to correspondence from T. Jacob John & Jayaprakash Muliyil
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  CPAP Technology: Where Affordability meets Utility

  Recent Advances in Pediatrics - Special Volume 21 Neonatology and Intensive Care, Editor Suraj Gupte, Japee Medical publishers Delhi 2011
  Jacob M.Puliyel, Neeraj Gupta
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  Public Interest Petition (PIL) Vaccine case 3rd affidavit and Delhi High Court order of 15/9/10

  Prashant Bhushan on behalf of petitioners
  IN THE HIGH COURT OF DELHI AT NEW DELHI (CIVIL ORIGINAL JURISDICTION) Writ Petition (Civil) No. 13698 Of 2009 PUBLIC INTEREST LITIGATION IN THE MATTER OF: DR. K. B. SAXENA & ORS. …PETITIONERS VERSUS UNION OF INDIA & ORS. …RESPONDENTS SUPPLEMENTARY AFFIDAVIT ON BEHALF OF THE PETITIONERS I, Dr. Jacob M Puliyel S/o Late Shri P. M. Mammen Head, Dept. of Pediatrics, St. Stephans Hospital, Tis Hazari, New Delhi-110054, do hereby solemnly state and affirm as under:  Show More...IN THE HIGH COURT OF DELHI AT NEW DELHI (CIVIL ORIGINAL JURISDICTION) Writ Petition (Civil) No. 13698 Of 2009 PUBLIC INTEREST LITIGATION IN THE MATTER OF: DR. K. B. SAXENA & ORS. …PETITIONERS VERSUS UNION OF INDIA & ORS. …RESPONDENTS SUPPLEMENTARY AFFIDAVIT ON BEHALF OF THE PETITIONERS I, Dr. Jacob M Puliyel S/o Late Shri P. M. Mammen Head, Dept. of Pediatrics, St. Stephans Hospital, Tis Hazari, New Delhi-110054, do hereby solemnly state and affirm as under: 1. That I am the Petitioner No. 8 in the above writ petition and being conversant with the facts and circumstances of the case, am competent to swear this Affidavit. 2. Petitioners (who are generally pro-vaccines and pro-vaccination/immunization) have filed the above writ petition highlighting how in the absence of a rational evidence-based vaccine policy, newer and newer vaccines of questionable efficacy and of huge costs are being pushed into the public health system at the behest of pharmaceutical industry and international bodies like World Health Organization (WHO). Petitioners have specifically challenged the proposed introduction of Pneumococcal, Hepatitis B, Hib and Pentavalent vaccines into the country’s Universal Immunization Programme (UIP). The above writ petition has highlighted the serious short-comings in the present regulatory system wherein, for instance, a vaccine was recommended for introduction in the UIP which was not even available and was recommended without any tests or epidemiological study. 3. Government’s own draft Multi-Year Strategic Plan 2010-2017 states the following as regards to the principles to guide the addition of new vaccines: a) There should be sufficient disease burden to warrant introduction of the vaccine into the national programme. b) The vaccine available should be effective. c) The vaccine available should be safe. d) The cost of the vaccine should be judged reasonable and suitable for absorption into the budget provision, even if the initial introduction is funded. Copies of the relevant pages of the said plan are annexed as Annexure P1. But this is still a draft and so far no policy has been formulated by the Government on immunization and vaccines. 4. Yet the Government plans to introduce the Hib vaccine in the form of the Pentavalent vaccine (DPT + Hepatitis B + Hib) violating each one of the above basic principles as is shown in the petition, petitioner’s interim application, petitioner’s rejoinder and is shown below. 5. Numerous studies have been done to prove the vaccine is needed in Asia and India and each has proved the opposite. The studies have been summarized in an Editorial in the Indian Journal of Medical Research (IJMR). The said editorial is annexed as Annexure P2. 6. The vaccine recipients were no better off than those who received the placebo. This was discussed in the British Medical Journal and in the IJMR. The relevant page of BMJ is annexed as Annexure P3. 7. More importantly the same Pentavalent vaccine was used in Sri Lanka in 2008 and was withdrawn after 5 deaths. It was used in Bhutan in July 2009 and withdrawn after 8 deaths. It was used in Pakistan and it killed 3 children – one healthy infant within 30 minutes of getting the vaccine. Under pressure from the WHO the vaccine has been reintroduced in Pakistan and Sri Lanka but not in Bhutan. 8. Government produced a document to the Court to say the vaccine was unrelated to the Sri Lankan deaths. Now, after a farce of a re-examination, a core committee has again recommended the vaccine. The document that was produced to the court (to show the vaccine was not related to the deaths) actually shows the deaths were probably related to the vaccine but the WHO changed its classification of adverse effects and removed the category "probably related to vaccine". The story came out in the British Medical Journal (Annexure P4), Down to Earth (Annexure P5) and Tehelka (Annexure P6). The DG ICMR has told Down to Earth that they did not know the classification was changed by WHO when they made the recommendation to introduce the vaccine. Thus the Core committee recommended the vaccine even without reading the WHO committee report carefully. This issue also came up in Parliament that the Core Committee did not exercise due diligence when it recommended the vaccine. Relevant pages of the Parliamentary Debate are annexed as Annexure P7. 9. Recently the Advisory body (National Technical Advisory Group on Immunization or NTAGI) met again and recommended the introduction of Pentavalent in 2 states in spite of the call by some members (including Petitioner No. 8) that it would be negligent on the part of NTAGI to recommend the vaccine without even looking at the full report on the adverse effects of the vaccine and deaths. 10. At present 50% of our population do not get the basic vaccines which cost Rs 30 altogether. Yet the NTAGI under the clear influence of international agencies and other vested interests have recommended a Pentavalent vaccine (combining the DPT that costs Rs 5/per dose with Hib and Hepatitis B vaccine) be introduced in India, that by itself costs Rs 350 per child. In effect the cost of DPT will jump from Rs 15 (three doses) to Rs 350. 11. The Government has not drafted a policy on immunization in spite of the Courts directive. If there is such a policy, it may become impossible to introduce the expensive and irrational vaccines on the prompting of vested interests. The Government says it will study impact of the vaccine components Hib and Hepatitis B. If it wants to do such an impact study it may study the vaccines given separately. The Government must be restrained from introducing the Pentavalent vaccine till the reports of the deaths in Pakistan and Bhutan can be examined by the court. The NTAGI minutes talk about starting an insurance scheme for vaccine deaths. This is no substitute. Lives cannot adequately be compensated with money. The Government must report the results of the impact studies to the court before roll out to the country. Only the separate vaccines Hib and Hep B may be allowed to be used (without combining it with essential EPI vaccines of DPT) till vaccine side effects reports from Pakistan and Bhutan are available. DEPONENT VERIFICATION I, the deponent above-named, do hereby verify that the contents of the above affidavit are true to my knowledge, no part of it is false and nothing material has been concealed therefrom. Verified at New Delhi on 13th day of September 2010. DEPONENT Annexure 1 Multiyear Plan https://www.google.com/accounts/ServiceLogin?service=mail&passive=true&rm=false&continue=https%3A%2F%2Fmail.google.com%2Fmail%2F%3Fview%3Datt%26th%3D12a8f80a216c6dac%26attid%3D0.4%26disp%3Dattd%26realattid%3Df_gd30p6dp3%26zw%26ui%3Dhtml%26zy%3Dl&bsv=llya694le36z&scc=1<mpl=default<mplcache=2 Strategic Area 5: Accelerated introduction of licensed new and underutilized vaccines against diseases with the significant mortality and morbidity in the country The last two decades have seen a number of new vaccines becoming available in the global market. These vaccines have also been introduced in the National Immunization Programs of almost all developed and majority of the developing nations. As part of cMYP, the choice of newer vaccines to be included in the UIP will be determined and periodically reviewed by the MoHFW, taking guidance from the NTAGI. The institutional mechanism for clinical and operational studies for newer vaccines will be encouraged to provide inputs for NTAGI. These studies will provide evidence for decisions on the timing and selection of new vaccine introduction and provide guidelines for the use of these new vaccines. Such analysis will include the major mortality-causing diseases of children in India, namely acute diarrhoeal diseases and acute respiratory diseases etc. The disease burden and health economic analyses will help assess the cost–benefit ratios of new vaccine introduction. Specific recommendations of the NTAGI on the introduction of new vaccines have been taken into account to develop this goal. Principles to guide the addition of new vaccines: 1. There should be sufficient disease burden to warrant introduction of the vaccine into the national programme. 2. The vaccine available should be safe and effective. 3. The cost of the vaccine should be judged reasonable and suitable for absorption into the budget provision, even if the initial introduction is funded. 4. Financial sustainability should be built into the plan of new vaccine introduction. OBJECTIVE 1 To ensure that institutional mechanisms are in place to adequately obtain, review and utilize information for deciding on the introduction of new and underutilized vaccines INDICATORS: • Number of burden of disease studies ongoing or completed on newer vaccines • Number of states having established and expanded the surveillance facilities for the potentially new vaccines • Availability of clear policy guidelines for new vaccine introduction M I L E S T O N E S • A technical group for new vaccine review is established with functional links with the GoI and research institutes. • The NTAGI has subcommittees on new vaccine being considered for UIP in India. • A research sub-committee on newer vaccines is formed. • A new vaccine focal point is established at the national level. • National Immunization Policy is in place and available. STRATEGIES: 1. Enabling institutional mechanisms: The introduction of new vaccines involves reviewing all licensed vaccines in different global regions and identifying those that would be relevant to India in the context of the country’s disease profile. There are vaccines that are popular in the private market, and those that are recommended by the Indian Academy of Pediatrics. Accurate information on which to base the decision of introducing a new vaccine to the UIP requires periodic review by all agencies concerned. This process requires strong coordination and collaboration. There are three main agencies, concerned with the introduction of new vaccines in India: o National Technical Advisory Group on Immunization (NTAGI) o Indian Council of Medical Research (ICMR) o Central drug Standard Control organization (erstwhile, called office of the Drug Controller General of India) The development partners (WHO, WHO/NPSP, UNICEF, USAID) technically support these agencies in carrying out the responsibilities assigned. A technical group for new vaccine review will be established with members from three agencies and development partners. This technical group will have the mandate to advise the GoI on: o Designing and drafting the National Immunization Policy for the GoI o Defining policies on vaccine use against typhoid, Varicella, Japanese encephalitis, Hepatitis A, Human Papilloma Virus Vaccine; both within and outside the UIP o Coordination of studies on disease burden, vaccine efficacy trials and health economic issues of new vaccine introduction (with special focus on the Hib and Pneumococcal vaccine). o Together with academic institutes review new immunization technologies and research as appropriate to the Indian context. 2. Strengthening the country capacity to assess the disease burden and analyze cost effectiveness: An appropriate mechanism will be devised to assess the burden of diseases, for which the vaccines are becoming available and/or are expected to be available in the near future. The capacity will also be built to assess the cost effectiveness of new vaccines and technologies by the standard tools available. 3. Assisting the country decision making: build upon an evidence base of country experiences and methodology, the partners will assist the government in informed decision making for the introduction of new vaccines. The exiting global tools and information on the decision making process for the introduction of new vaccine will be utilized, as appropriate. 4. Integrate the introduction of new vaccines: The efforts will be made to integrate the introduction of new vaccines in UIP, by addressing this issue in cMYP and by providing financial analysis for the same. 5. Better coordination and collaboration: The need for a formal mechanism of coordination and collaboration between governmental agencies and development partners was urgently required to establish closer links, pool resources more efficiently, plan research more effectively and share results of studies more freely. The IHSCC, which has a representation from different government organizations, ministries and development partners, will plays this role in India. Annexure 2 Indian J Med Res. 2010 Jul;132:1-3. Introducing pentavalent vaccine in the EPI in India: a counsel for caution. Lone Z, Puliyel JM. http://icmr.nic.in/ijmr/2010/july/editorial.pdf Annexure 3 GAVI (Global Alliance for Vaccines and Immunisation) and WHO. Demanding accountability. Puliyel JM. BMJ. 2010 Aug 4;341:c4081. doi: 10.1136/bmj.c4081. http://jacob.puliyel.com/#paper_217 Incomplete reporting of research in press releases: et tu, WHO? Puliyel J, Mathew JL, Priya R. Indian J Med Res. 2010 Apr;131:588-9. http://www.icmr.nic.in/ijmr/2010/april/0418.pdf Annexure 4 Probably related to vaccine Report submitted by ICMR on Pentavalent deaths http://jacob.puliyel.com/download.php?id=213 Down To Earth • July 16-31, 2010 Officials push five-in-one vaccine Pentavalent vaccine linked to child deaths in Sri Lanka, Bhutan; ball in high court http://xa.yimg.com/kq/groups/18156219/1478359652/name/pentavalent.pdf From Tehelka Magazine, Vol 7, Issue 24, Dated June 19, 2010 More Than A Pinprick THE RISK TO INDIA’S NEWBORNS A SLY FUDGING OF FACTS IS PUSHING INDIA INTO BUYING VACCINES BACKED BY THE WHO THAT MAY HAVE KILLED CHILDREN IN OTHER COUNTRIES http://www.tehelka.com/story_main45.asp?filename=Ne190610coverstory.asp Annexure 5 NEED FOR CAUTION ON VACCINE INTRODUCTION SHRIMATI BRINDA KARAT (WEST BENGAL): Sir, even as the Javed Choudhury Report on the closure of the three P.S.U. vaccine producing units exposes the deeply compromised process behind the closures, comes a fresh warning on the vaccine issue. Fifty per cent of India's children do not receive the three doses of the triple vaccine against diphtheria, whooping cough and tetanus that costs Rs.7.50 per child, leading to many deaths. An Expert Committee has now suggested that a new vaccine produced by MNC pharma companies that costs Rs.525 per child replace DPT vaccine. Other experts have argued that the incidence of the two additional diseases to be covered, namely, HIB and Hepatitis- B, is not high enough to warrant change of vaccine. Cost is not the only factor. The vaccine meant to save lives has been associated with infant deaths in neighbouring countries of Sri Lanka, Pakistan and Bhutan. The investigation being done on the deaths by the prestigious British Medical Journal also implicates W.H.O. officials in the cover-up. W.H.O., it is alleged, may have changed classifications of safety of vaccines to suit the interests of companies. Why did the Indian Expert Committee, which has admitted that it did not know that the deaths in the neighbouring countries were probably related to the vaccine, not exercise due diligence in understanding the reasons for the deaths before recommending this vaccine? Their flawed report must be withdrawn. The Government must exercise caution on introduction of vaccines and prevent manipulation of our immunization system by powerful pharma lobbies. http://164.100.47.5/newsynopsis1/Englishsessionno/220/Synopsis%20English%20Dated%2002.08.2010.pdf IN THE HIGH COURT OF DELHI AT NEW DELHI W.P.(C) 13698/2009 and CM APPL. 1663/2010 DR. K. B SAXENA and ORS ..... Petitioners Through: Mr. Prashant Bhushan, Advocate with Mr.Pranav Sachdeva, Ms. Poulami Putatunda and Ms. Pyoli Swatija, Advocates. versus UNION OF INDIA and ORS ..... Respondents Through: Mr. A.S. Chandhiok, ASG with Ms. Maneesha Dhir, Ms. Preeti Dalal, Mr. Sandeep Bajaj and Mr. K.P.S. Kohli, Advocates for respondents No.1 and 2. Mr. V.K. Rao, Senior Advocate with Ms. Neha Bhatnagar, Advocate for R-3. CORAM: HON'BLE THE CHIEF JUSTICE HON'BLE MR. JUSTICE MANMOHAN O R D E R 15.09.2010 Heard Mr. Prashant Bhushan, learned counsel for the appellant and Mr. A.S. Chandhiok, learned ASG for the Union of India. In the course of hearing of this petition, it was submitted by Mr. A.S. Chandhiok, learned ASG that a high level committee has been constituted to formulate a comprehensive vaccination policy. W.P.(C) 13698/2009 page 1 of 2. At this juncture, Mr. Prashant Bhushan submitted that the committee has to keep in view the four vital aspects namely:- (i) Incidents of disease in India and its effect potentiality, (ii) the efficacy of the vaccine to prevent the disease as prevention is better than cure, (iii) the side effects of the vaccine, the nature of adverse side effects and the approximate statistics of the persons who are likely to be effected by such side effects and (iv) the costs factor. Quite apart from the above, it is submitted by Mr. Prashant Bhushan that there is a universal immunization programme under which certain new vaccines are likely to be introduced without doing the relevant scientific studies thereof. The said aspect shall be adverted to and deliberated upon as per law on the next date of hearing. List the matter on 08th December, 2010. CHIEF JUSTICE MANMOHAN, J SEPTEMBER 15, 2010 js W.P.(C) 13698/2009 page 2
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  Issue raised about incomplete reporting of research in press release: Response to response

  Indian J Med Res 2010;132: 230-233
  Joseph L. Mathew, J. Puliyel
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  GAVI and WHO: Demanding accountability

  BMJ 2010;341:c4081 Pg 266
  Jacob M Puliyel
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  “Antivaccine Lobby” replies to the BMJ

  BMJ 2010;341 c4001 Page 218
  K B Saxena, Debabar Banerji, Imrana Qadeer, N J Kurian, Ritu Priya, Mira Shiva, Jacob Puliyel, and Gopal Dabade
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  Sri Lankan deaths following Pentavalent vaccine: Acceptable collateral damage?

  http://www.bmj.com/cgi/eletters/340/jun29_4/c3508
  Jacob Puliyel, KB Saxena, Debabar Banerji, Imrana Qadeer, NJ Kurian, Ritu Priya , Mira Shiva and Gopal Dabade.
  Sri Lankan deaths following Pentavalent vaccine: Acceptable collateral damage? As a group of pediatricians, health care activists, teachers in Public Health and bureaucrats who have championed the cause of universal immunization in India all our working lives, we were taken aback at being described as ‘anti-vaccine’, in the print version of the BMJ (1). We plead for the right to respond in our defense, in the print version. India is a country where 50% of the population, (mostly poor liv Show More...Sri Lankan deaths following Pentavalent vaccine: Acceptable collateral damage? As a group of pediatricians, health care activists, teachers in Public Health and bureaucrats who have championed the cause of universal immunization in India all our working lives, we were taken aback at being described as ‘anti-vaccine’, in the print version of the BMJ (1). We plead for the right to respond in our defense, in the print version. India is a country where 50% of the population, (mostly poor living in remote rural areas) do not receive the 6 basic vaccines in the EPI, namely BCG, DPT, OPV and measles vaccine. The incremental cost of complete immunization is less than US $1 (Rupees 30) per child. Every Rupee we can mobilize, we need to invest to ensure that all babies in India get this basic right. The push to include newer vaccines into the routine immunization schedule must be viewed in this context. The ‘pentavalent vaccine’ that is being canvassed, on its own, will increase cost of DPT immunization twenty-fold. It stands to reason that these new vaccines will be taken up mostly by the urban privileged and there will be even less available for the rural poor. The thrust for including Hib vaccine in India is based on 2 arguments. The first is that there is anecdotal evidence of the existence of Hib disease and Hib meningitis in India and that Hib meningitis may lead to long term morbidity. The second argument is that the well-to-do parents sometimes buy Hib vaccine in the open market to vaccinate their children. The Government of India must therefore provide it free for the poor, on the grounds of equity and fair play (2). The problem with the anecdotal reports is that they do not specify the size of the universe from which the samples are drawn and public health policies cannot be based on these figures without a denominator. The many systematic surveys done to look at the magnitude of the problem of Hib disease in India have nearly always shown that the incidence of Hib disease is much lower than what was projected for India. Most of these studies have been funded by the WHO and these have been reviewed recently in an open access journal (3). Over and above this, is the fact that ‘probe studies’ and ‘probe-like studies’ done in Asia have all shown the vaccine does not result in significant reduction in disease burden compared to placebo (4). The poor need a modicum of equity in terms of food for survival, potable water and basic sanitation but they are certainly not hankering after the useless vaccines the rich may be taking. In this situation, to foist this vaccine program on them in the name of equity is at once insensitive and cruel. It merely siphons-off the limited funds available for the poor, and in its place provides them a service they do not need and which does them no good. Crucially, there is another reason why the authors decided to approach the Law Courts in India to block introduction of the Pentavalent vaccine and this is the safety issue. The pentavalent vaccine combines DPT, Hib and Hepatitis B. A Cochrane meta-analysis has found that the combination vaccine is not as effective as the vaccines administered separately (5). As such, the combined vaccine is not used widely in the West – in areas which have a good system for reporting adverse events. Vaccines are generally given to healthy children and therefore the tolerance in the public for vaccine-related adverse-reactions is low. If a vaccine results in death it is a very serious concern. A vaccine may have been used successfully in millions and with no adverse effects, yet in the next patient it may cause a fatal anaphylaxis reaction. The adverse effect following immunization (AEFI) investigation is set up to study if the reaction in the given child was related to the vaccine or is unrelated. The AEFI report does not comment on the likelihood of reaction if the vaccine is given to other children in the future. If the same reaction occurs twice it is defined as a cluster. Pentavalent vaccine was introduced in the national immunization programme in Sri Lanka in January 2008 but after several thousand doses were administered, it was withdrawn in April 2008 because of 25 serious adverse reactions that included 5 deaths. A WHO expert panel investigated the adverse effects and deaths and in its report classified 3 deaths (identified as cases D1, D3, and D6) as ‘Unlikely’ (to have been caused by the vaccine). Pentavalent vaccine was then introduced in national immunization programme of Bhutan in July 2009. Within 2 months, after 8 deaths, the vaccine was withdrawn in that country (6). At the behest of the WHO, the vaccination programme was restarted in Sri Lanka some 4 months ago and it is claimed that there is no change in the death rate in Sri Lanka – as if deaths in 3 infants from AEFI will alter the countries mortality statistics. In response to our petition in the High Court in Delhi, the detailed AEFI report on the deaths in Sri Lanka was made available to the Court and thereby, in the public domain. As only a summary of this report is available on the internet (7), we have scanned the report and put it on the net and it can be accessed freely (8). The report quotes an aide-memoire on the standard WHO classification on AEFI (9). The standard WHO classification of AEFI is best understood in the form of an algorithm. The first question is whether the adverse events have a plausible time relationship to vaccine administration. All such reactions are classified in one of three categories: ‘Very likely/Certain’, ‘Probable’ or ‘Possible’. If the time of the adverse event and the time of vaccine administration make a causal connection improbable, it is classified as ‘Unlikely to be related’. If the time of the event and the time of vaccine administration make a causal connection incompatible, it is to be classified as ‘Unrelated’ For adverse events that have a plausible time relationship to vaccine administration, the next level of the algorithm is used to distinguish Probable from Possible. If the death cannot conclusively be attributable to another cause, it is classified as ‘Probable related’. If the death can be attributable to another cause then the association with vaccine is said to be ‘Possible’ The report presented to the Delhi High Court shows that the experts on AEFI in Sri Lanka deleted the categories Probable and Possible from the standard classification. All adverse events which could not be classified as Very likely/Certain were classified as Unlikely. Using this new classification, they declared that 3 of the Sri Lanka reactions were ‘unlikely’ to be related to vaccine ‘although it could not be conclusively attributable to another cause’. It is evident from the discussion above that the three deaths (D1, D3, D6) would have been classified as ‘Very likely/certain AEFI’ or ‘Probable AEFI’ using the standard WHO classification. When the news of this change in classification caught the attention of the press, a WHO spokesperson defended the change saying that the WHO used ‘independent experts’ and they were free to make up their own classification. Furthermore the WHO spokesperson clarified that even if the standard classification were used; the three deaths would not be classed as probable or possible as there was ‘non-conclusive evidence of other potentially attributable causes for the adverse events’. The potentially attributable conditions unearthed by the experts were the following: one had malnutrition (a condition which defines a large proportion of the population in rural areas), the second case had autopsy findings of milk aspiration (often seen as a terminal event in many cases of sudden death from any cause) and the third case had ‘autopsy findings suggestive of Reye’s syndrome’. The expert body did not suggest that these findings qualified as plausible explanations for the deaths and the temporal relation of the deaths to vaccination has not been disputed. Interestingly the experts say that they discussed the possibility that the vaccine may have unmasked an underlying condition. One is left wondering whether they considered malnutrition, milk in the trachea, or Reye ’s syndrome as conditions that would have remained ‘masked’ had it not been for the vaccine. For a document produced to a court of law, the document is not even complete. The names of the experts and their declaration of conflict of interests were left out. We have learnt that at least one of experts has previously been accused of not declaring his conflict of interest arising from research funded by pharmaceutical companies including GlaxoSmithKline. Classification of AEFI as ‘Certain/ Very likely’, often needs de-challenge or re-challenge evidence. This is not possible when the initial reaction results in death. The question the larger public (outside of India and Asia) needs to answer is whether they will permit this new classification to replace the standard WHO classification of AEFI. If this is allowed, deaths which occur as reaction to vaccine will nearly always be classified as ‘unlikely’ because de-challenge and re-challenge will not be possible post-mortem. The opprobrium of the BMJ stems from our raising these issues. Using the same yard-stick the Editor of the BMJ can be castigated as being ‘anti-vaccine’ for exposing the N1H1 vaccine scam (10). Dr KB Saxena Former Union Health Secretary, Government of India. Dr Debabar Banerji Professor Emeritus, Centre of Social Medicine and Community Health, Jawaharlal Nehru University Delhi. Dr Imrana Qadeer Professor (Retired) Centre of Social Medicine and Community Health, Jawaharlal Nehru University Delhi. Dr NJ Kurian Former advisor, Union Ministry of Finance, Government of India. Dr Ritu Priya Professor of Community Health, Jawaharlal Nehru University Delhi. Dr Mira Shiva Coordinator Initiative for Health and Equity in Society/ Member, Third World Network/ Co Convener All India Drug Action Network (AIDAN). Dr Jacob Puliyel Head of Paediatrics, St Stephens Hospital, Delhi. Dr Gopal Dabade President, Drug Action Forum- Karnataka/ Co-convener, All India Drug Action Network. References 1. Ganapati Mudur. Antivaccine lobby resists introduction of Hib vaccine in India, BMJ 2010;340:c3508 2. ICMR Expert Group. Minutes of the Expert group meeting on Hepatitis B and Hib vaccines. http://www.icmr.nic.in/minutes/Minutes%20Expert%20Group%20%20Hepatitis%20B%20and%20Hib%20vaccines.pdf accessed on 4/7/10 3. Lone Z, Puliyel JP. Introducing pentavalent vaccine in the EPI in India: A counsel for caution. Indian J Med Res 2010; 132:1-3 4. Puliyel JM, Mathew JL, Priya R. Incomplete reporting of research in press releases: Et tu, WHO? Indian J Med Res 2010;131:588-9 5. Bar-On ES, Goldberg E, Fraser A, Vidal L, Hellmann S, Leibovici L. Combined DTP-HBV-HIB vaccine versus separately administered DTP-HBV and HIB vaccines for primary prevention of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae B (HIB). Cochrane Database Systematic Rev 2009, Issue 3. Art. No.: CD005530. 6. Pelden S. Pentavalent vaccine suspended. Kuensel Online 27. 28 October 2009. Available at : http://www.kuenselonline.com/modules.php?name=News&file=article&sid=13826 accessed on 4/7/2010. 7. WHO Investigation of adverse events following immunization with liquid pentavalent vaccine in Sri Lanka. http://www.who.int/immunization_safety/aefi/investigation_pentavalent_Sri_Lanka/en/index1.html accessed on 4/7/10 8. WHO. Report of an ad-hoc WHO expert panel to review reports of serious AEFI following administration of pentavalent and other vaccines in Sri Lanka 2008 available at: http://jacob.puliyel.com/#paper_213. 9. WHO. Adverse events following immunization (AEFI): causality assessment. http://www.who.int/vaccines-documents/DocsPDF05/815.pdf accessed on 4/7/2010 10. Godlee F. Conflicts of interest and pandemic flu. BMJ 2010;340:c2047
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  Introducing pentavalent vaccine in the EPI in India: A counsel for caution

  Indian J Med Res 132, July 2010, pp 1-3
  Zubair Lone & Jacob M. Puliyel
  The story of how pharmaceutical companies influenced scientists and official agencies like the World Health Organization (WHO) in the recent swine flu scare1 and the saga of the undeclared conflicts of interests of members of the WHO’s Strategic Advisory Group of Experts2 has set off alarm bells around the world. When trusted advisors are less than honest, the potential for harm is great, and the feeling of betrayal is poignant. A similar feeling of sadness and betrayal was evoked by the report  Show More...The story of how pharmaceutical companies influenced scientists and official agencies like the World Health Organization (WHO) in the recent swine flu scare1 and the saga of the undeclared conflicts of interests of members of the WHO’s Strategic Advisory Group of Experts2 has set off alarm bells around the world. When trusted advisors are less than honest, the potential for harm is great, and the feeling of betrayal is poignant. A similar feeling of sadness and betrayal was evoked by the report of National Technical Advisory Group on Immunization (NTAGI) sub-committee on Haemophilus influenzae B (Hib) published recently3. On December 14, 2009, the Health Secretary chaired a meeting to discuss the policy framework for vaccine preventable disease in the country. Invited to this meeting were the chairperson, vice-chairperson and Indian Academy of Pediatrics representative to the NTAGI Hib sub-committee. Data from an ICMR study in Anaicut block of Vellore, obtained under the Right to Information Act were presented. The study showed that the incidence of all-cause pneumonia was 30 per 1000 children under-five, and mortality was 0.3 per 1000 children under-five. Thus mortality is 50 times lower than 14 per 1000 projected by the UNICEF for India4. It was additionally pointed out that even if mortality was assumed to be as high as 10 per cent (instead of 0.7% observed in the study), there would be 3 deaths per 1000 children under-five. This study data undercut one of the main points in the sales pitch for introducing 2 vaccines - the pneumococal conjugate vaccine and the Hib vaccine in India. Members of the NTAGI were asked why the data on pneumonia were not included in the NATGI report when it had selectively quoted nasopharyngeal-carrier data from the same study. The Chairperson of NTAGI admitted that the results from Anaicut and also that from Kolkata and Chandigarh Indian J Med Res 132, July 2010, pp 1-31EditorialIntroducing pentavalent vaccine in the EPI in India: A counsel for cautionin this multi-center study were reviewed by the sub-committee, but it was left out from the report. WHO directive on Hib The latest WHO position paper on Hib says ‘Hib vaccine should be included in all routine immunization programmes’5. This suggests that Hib vaccine should be included in the immunization programme universally, irrespective of an individual country’s disease burden, not withstanding of natural immunity attained within the country against the disease, and not taking into account the rights of sovereign States to decide how they use their limited resources. The mandate and wisdom of issuing such a directive, for a disease that has little potential of becoming a pandemic, needs to be questioned. The directive has come after a number of failed attempts to convince the scientific community of the need for this vaccine in Asia6,7. We present this as a case study on the visible and invisible pressures brought to bear on governments to deploy expensive new vaccines. Invasive Hib in pre-vaccination era There is a clear distinction between invasive Hib disease (resulting in pneumonia and meningitis) on the one hand and harmless nasopharyngeal colonization on the other. The incidence of invasive disease was 500-1000 per 100,000 children under-2 in the Apache reservation and this came down to 22 per 100,000 after immunization8. In Dallas county, Texas, it was 109 per 100,000 children under-59. In Gambia, incidence of Hib meningitis was 200 per 100,000 infants and it fell to 21 with immunization8. On the other hand, the incidence of invasive disease in Asia, even without immunization was reported as 3 to 9 per 100,000 children-under-510,11. IBIS (Invasive Bacterial Infections Surveillance) study (India) It has been suggested that the low incidence of invasive disease in Asia may be due to early exposure to other bacteria with cross reactive antigens12,13. Others deny the incidence of Hib in Asia is low and suggest that this is a wrong impression resulting from the use of inappropriate culture plates14. However, the IBIS Group using appropriate culture techniques, working in 6 large referral hospitals over 4 yr (1993-1997), came up with only 125 positive cultures15. To explain this low culture yield the IBIS group speculated that all cases of meningitis may not had access to the hospitals. They recommended that community based studies must be done15. Community study of Hib meningitis (India) A community based study looking for Hib meningitis followed (1997-1999). It showed the Hib meningitis incidence of 0.007 per cent12. In 2002, Dr Thomas Cherian, who is now the WHO Co-ordinator of EPI, wrote that based on the available data, Hib vaccine could not be recommended for routine use in India16. Prior antibiotic use and problems with transport of CSF specimens were then blamed for the poor yield in cultures12. This led investigators to undertake ‘probe studies’ to identify reduction in disease burden after immunization17. Asian probe studies The probe trial in Indonesia from December 1998 to December 2002 found more cases of pneumonia admitted to hospital among those vaccinated and meningitis admissions were not reduced significantly either18. A case-control study on the effectiveness of Hib vaccine in Bangladesh (June 2000 to September 2003) found no significant vaccine effectiveness after 3 doses of vaccine when either radiologically confirmed pneumonia or meningitis were compared with matched community controls19. Data dredging and post-hoc analysis found statistical significance in vaccine effectiveness against pneumonia after two doses of vaccine. It is recommended that the results of post-hoc analysis should be explicitly labelled to avoid misleading readers and unadjusted P values must be interpreted in light of the fact that these are a small and selected subset of a potentially large group of P values20. This was not done in the original report nor has this been explained in the various discourses on this paper.Strain replacement with invasive nonserotypable H. influenzae disease The wisdom of having introduced Hib in the West is now being questioned. The vaccine has effectively reduced the incidence of Hib disease. However, there has been a proportionate increase in non-Hib strains, of H. influenzae, including non-serotypeable strains, causing invasive disease in the post-Hib vaccine era21,22. Vaccine efficacy of pentavalent formulation The NTAGI has recommended that Hib vaccine be introduced in India as pentavalent vaccine combined with DPT and hepatitis B. A Cochrane meta-analysis has however, shown that the combination is less effective than the vaccines given separately23. It is not used for primary immunization in many countries and the experience with this is therefore limited24. Coincidental side-effects: cause and effect relation not proven yetDeaths as side effect: Pentavalent vaccine was introduced in the national immunization programme in Sri Lanka in January 2008 but after several thousand doses were administered, it was withdrawn in April 2008 because of 25 serious adverse reactions that included 5 deaths. A WHO expert panel investigated the adverse effects and deaths and in its report said that the vaccine was ‘unlikely’ to have caused the adverse events. It states that although it was not certain if the vaccine was responsible, the committee could not declare categorically that the pattern of adverse events was unrelated to the vaccine and conclusive evidence regarding an alternate cause of the events and outcome was lacking25. This nuanced WHO report was misleadingly summarized to suggest that ‘investigations conducted by WHO did not reveal any causal association between the events and the Hib containing vaccine’26. Pentavalent vaccine was then introduced in national immunization programme of Bhutan in July 2009. Within 2 months, after 8 deaths, the vaccine was withdrawn in that country27. The NTAGI has not yet withdrawn its recommendation, nor has the Drug Controller of India sent out advisory asking doctors to look out for these rare adverse events. The jury is still out on the evidence about side effects but parents may like to know the odds of benefits and harms.2 INDIAN J MED RES, JULY 2010 Justification for introducing Hib in the National Immunization Programme The equity argument is often brought up. It is said the vaccine is given by private practitioners to their well-to-do clientele and it is the responsibility of government to make it available to the poor. Introduction of this vaccine in the national programme in the face of proven low incidence of invasive disease, absence of benefit from Hib vaccination demonstrated in the probe studies from Asia and the evidence of strain replacement in the West, appears to be a profligate exercise in futility.Zubair Lone & Jacob M. Puliyel*Department of PaediatricsSt Stephens HospitalDelhi 110 054, India*For correspondence:puliyel@gmail.comReferencesDelamothe T.1. H1N1: now entering the recrimination phase. BMJ 2010; 340 : c225.Watson R.2. Politician accuses drug companies of overplaying dangers of H1N1. BMJ 2010; 340 : c198.Kant L. NTAGI subcommittee recommendations on 3. Haemophilus influenzae type B (Hib) vaccine introduction in India. Indian Pediatr 2009; 46 : 945-54.UnicefNICEF4. . Pneumonia the forgotten killer of children. Available at: http://www.unicef.org/publications/files/Pneumonia_The_Forgotten_Killer_of_Children.pdf, accessed on January 24, 2010. World Health Organization. WHO position paper on 5. Haemophilus influenzae type b conjugate vaccines. Wkly Epidemiol Rec 2006; 81 : 445-52.Lau YL. 6. Haemophilus influenzae type b disease in Asia. Bull World Health Organ 1999; 77 : 867-8.Puliyel JM, Mathew JL, Priya R. Incomplete reporting of 7. research in press releases: Ettu, WHO. Indian J Med Res 2010; 131 : 588-9.Watt JP, Levine OS, Santosham M. Global reduction of Hib 8. disease: What are the next steps? Proceedings of the meeting Scottsdale, Arizona. J Pediatr 2003; 143 : S163-87.Murphy TV, Osterholm MT, Pierson LM, White KE, 9. Breedlove JA, Seibert GB, et al. Prospective surveillance of Haemophilus influenzae type b disease in Dallas County, Texas, and in Minnesota. Pediatrics 1987; 79 : 173-80.Levine OS, Benjamin S, Nathanial P, Mark K. Development, 10. evaluation and implementation of Haemophilus influenza type b vaccines for young children in developing countries: current status and priority actions. Pediatr Infect Dis J 1998; 17 (9 Suppl): S95-113.Lau YL, Yung R, Low L, Sung R, Leung CW, Lee WH. 11. Haemophilus influenzae type b infections in Hong Kong. Pediatr Infect Dis J 1998; 17 (Suppl. 9) : S165-9.Puliyel JM, Agarwal KS, Abed Abass F. Natural immunity 12. to Haemophilus influenzae b in infancy in Indian children. Vaccine 2001; 19 : 4592-4.Minz S, Balraj V, Lalitha MK, Murali N, Cherian T, Manoharan 13. G, et al. Incidence of Haemophilus influenzae type b meningitis in India. Indian J Med Res 2008; 128 : 57-64.Gellert GA, Wenger JD, Brilla A. 14. Haemophilus influenzae type b disease in Latvia. Lancet 1994; 344 : 959.Invasive Bacterial Infections Surveillance (IBIS) Group 15. of the International Clinical Epidemiology Network. Are Haemophilus influenzae infections a significant problem in India? A prospective study and review. Clin Infect Dis 2002; 34 : 949-57.Cherian T, Thomas N, Raghupathy P, Durot I, Dutta A. Safety 16. and immunogenicity of Haemophilus influenzae type B vaccine given in combination with DTwP at 6, 10 and 14 weeks of age: author reply. Indian Pediatr 2002; 39 : 1070-71. The Hib initiative. Hib initiative research and surveillance 17. activities. Available at: http://www.hibaction.org/research.php#vaccine_probe, accessed on January 23, 2010.Gessner BD, Sutanto A, Linehan M, Djelantik IG, Fletcher 18. T, Gerudug IK, et al. Incidences of vaccine-preventable Haemophilus influenzae type b pneumonia and meningitis in Indonesian children: hamlet-randomised vaccine-probe trial. Lancet 2005; 365 : 43-52.Baqui AH, EI Arifeen S, Saha SK, Persson L, Zaman 19. K, Gessner BD, Moulton LH, Black RE, Santosham M. Effectiveness of Haemophilus influenzae type B conjugate vaccine on prevention of pneumonia and meningitis in Bangladesh children: a case control study. Pediatr Infect Dis J 2007; 26 : 565-71.Wikipedia. Post-hoc analysis. Available at: 20. http://en.wikipedia.org/wiki/Post-hoc_analysis, accessed on January 25, 2010.Tsang RS, Sill ML, Skinner SJ, Law DK, Zhou J, Wylie J. 21. Characterization of invasive Haemophilus influenzae disease in Manitoba, Canada, 2000-2006: invasive disease due to non-type b strains. Clin Infect Dis 2007; 44 : 1611-4.Brown VM, Madden S, Kelly L, Jamieson FB, Tsang RSW, 22. Ulanova M. Invasive Haemophilus influenzae disease caused by non–type b strains in Northwestern Ontario, Canada, 2002-2008. Clin Infect Dis 2009; 49 : 1240-3.Bar-On ES, Goldberg E, Fraser A, Vidal L, Hellmann S, 23. Leibovici L. Combined DTP-HBV-HIB vaccine versus separately administered DTP-HBV and HIB vaccines for primary prevention of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae B (HIB). Cochrane Database Systematic Rev 2009, Issue 3. Art. No.: CD005530. Adult A. Combination DPT/Hib vaccine fails FDA test. 24. Lancet 1997; 349 : 1752. WHO. Expert Panel Report. Report of a WHO ad hoc 25. expert panel to review reports of serious AEFI following administration of pentavalent and other vaccines-Sri Lanka, 23 December 2008.Chaturvedi S. Vaccines as tools to reduce ARI burden: Merits 26. and some inherent verticality in the debate. Indian Pediatr 2010; 47 : 34-7.Pelden S. Pentavalent vaccine suspended. Kuensel Online 27. 28 October 2009. Available at : http://www.kuenselonline.com/modules.php?name=news&file=article&sid=138 26, accessed on January 24, 2010. LoneONE & PuliyelULIYEL: IntroducingNTRODUCING pentavalentPENTAVALENT vaccineVACCINE inIN theTHE EPI IndiaNDIA 3
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  NTAGI Recommendations Overlooked Crucial ICMR Data

  Ind Pediatrics 2010:47:542-3
  Pompa Dutta and Jacob M Puliyel
  We thank the NTAGI for publishing its recommendation on Hib vaccine in Indian Pediatrics(1) as this journal allows ‘extended peer review’ in its correspondence columns. We are concerned that the technical advisory body has overlooked crucial evidence gathered in studies done by the ICMR while making its recommendations.
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  Evidence-based National Vaccine Policy

  Indian J Med Res 2010;131: 617-628
  Y. Madhavi, Jacob M. Puliyel, Joseph L. Mathew, N. Raghuram, Anant Phadke, Mira Shiva, S. Srinivasan, Yash Paul, R.N. Srivastava, A. Parthasarathy, Sunil Gupta, Udaykumar Ranga, V. Vijaya Lakshmi, Nayana Joshi, Indira Nath, C.M. Gulhati, Prabir Chatterjee, Anuradha Jain, Ritu Priya, Rajib Dasgupta, S. Sridhar, Gopal Dabade, K.M. Gopakumar, Dinesh Abrol, M.R. Santhosh, Sadhana Srivastava, S. Visalakshi, Anurag Bhargava, N.B. Sarojini, Devinder Sehgal, Sakthivel Selvaraj & D. Banerji
  India has over a century old tradition of development and production of vaccines. The Government rightly adopted self-sufficiency in vaccine production and self-reliance in vaccine technology as its policy objectives in 1986. However, in the absence of a full-fledged vaccine policy, there have been concerns related to demand and supply, manufacture vs. import, role of public and private sectors, choice of vaccines, new and combination vaccines, universal vs. selective vaccination, routine immuni Show More...India has over a century old tradition of development and production of vaccines. The Government rightly adopted self-sufficiency in vaccine production and self-reliance in vaccine technology as its policy objectives in 1986. However, in the absence of a full-fledged vaccine policy, there have been concerns related to demand and supply, manufacture vs. import, role of public and private sectors, choice of vaccines, new and combination vaccines, universal vs. selective vaccination, routine immunization vs. special drives, cost-benefit aspects, regulatory issues, logistics etc. The need for a comprehensive and evidence based vaccine policy that enables informed decisions on all these aspects from the public health point of view brought together doctors, scientists, policy analysts, lawyers and civil society representatives to formulate this policy paper for the consideration of the Government. This paper evolved out of the first ever ICMR-NISTADS national brainstorming workshop on vaccine policy held during 4-5 June, 2009 in New Delhi, and subsequent discussions over email for several weeks, before being adopted unanimously in the present form.
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  Validation of 'Signs of Inflammation in Children that Kill' (SICK) score for immediate non-invasive assessment of severity of illness

  Ital J Pediatr. 2010 Apr 26;36(1):35. [Epub ahead of print]
  Gupta MA, Chakrabarty A, Halstead R, Sahni M, Rangasami J, Puliyel A, Sreenivas V, Green DA, Puliyel JM.
  To validate the SICK scoring system's ability to differentiate between individuals with higher and lower probabilities of death Method We performed a one year two-centre prospective evaluation of all children aged between one month and 12 years referred to the Paediatric team at St Stephens Hospital in Delhi and admitted to the Paediatric Department at West Middlesex University Hospital in London. We calculated SICK scores at presentation and correlated them with subsequent in-hospital morta Show More...To validate the SICK scoring system's ability to differentiate between individuals with higher and lower probabilities of death Method We performed a one year two-centre prospective evaluation of all children aged between one month and 12 years referred to the Paediatric team at St Stephens Hospital in Delhi and admitted to the Paediatric Department at West Middlesex University Hospital in London. We calculated SICK scores at presentation and correlated them with subsequent in-hospital mortality. We used discrimination by areas under receiver operating characteristic (ROC) curves to measure performance. Results We prospectively evaluated 3895 children in Delhi and 1473 children in London. The areas under the ROC curves were 84.8% in Delhi, 81.0% in London and 84.1% (95% CI 77.4 - 90.8%) for combined data. Hosmer-Lemeshow goodness of fit for the combined data was good (Hosmer-Lemeshow Chi-square = 2.13 (p = 0.3450). Conclusions We propose the SICK score as a useful triage tool at initial presentation and highlight its particular suitability for resource poor settings.
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  Demanding Accountability from GAVI and WHO

  http://www.bmj.com/cgi/eletters/340/apr20_2/c2004#234904
  Puliyel J
  Lee and Harmer have highlighted the achievements of GAVI but they have also cited the criticisms leveled against it (1). Their article however would have gone to press before the recent controversy over WHO and GAVI functioning, started in India. This week, the Indian Journal of Medical Research published an article entitled: "Incomplete reporting of research in press releases: Et tu, WHO" (2). The article relates to a press release issued by WHO jointly with GAVI, USAID, and Johns Hopkins a Show More... Lee and Harmer have highlighted the achievements of GAVI but they have also cited the criticisms leveled against it (1). Their article however would have gone to press before the recent controversy over WHO and GAVI functioning, started in India. This week, the Indian Journal of Medical Research published an article entitled: "Incomplete reporting of research in press releases: Et tu, WHO" (2). The article relates to a press release issued by WHO jointly with GAVI, USAID, and Johns Hopkins among others (3,4), after the Bangladesh case-control study on effectiveness of Hib vaccination (5). The press release suggested that the vaccine is useful, whereas the study itself showed no benefit. No statistical difference was seen in the vaccination status of those with pneumonia or meningitis compared to controls. A post-hoc analysis presented without proper multiple testing was used to bolster the erroneous claim. Contrary to the subtle suggestion in the press release, analysis of data from an earlier Indonesian probe study also found no benefit (6). This misleading press release is seen as the smoking gun. After the Bangladesh study (2006) the WHO issued a position paper recommending the inclusion of Hib vaccine in all routine immunization programs, regardless of national burden (7) replacing the earlier 1998 position paper which suggested countries should consider Hib burden before introducing the vaccine (8). GAVI (which includes representatives of vaccine manufacturers on its Board,) "encouraged" developing countries in Asia to avail of the vaccine at a highly subsidized rate. The subsidy of course came from money given by donor countries and the Bill and Melinda Gates foundation, for achievement of the MDGs. Given that the probe studies in Asia had failed to confirm benefit from the vaccine, it would appear that millions of dollars from the MGD Fund were spent wastefully. A possible argument that the vaccine was/is/maybe highly efficacious in other parts of the world hence should be used in Asia, is unscientific because the very basis of the research studies was that the situation in Asia was/is different. A collective of civil society organizations have written to the Director General of the WHO to investigate how the misleading press release came to be put out and the events surrounding the Bangladesh study. It is hoped that widespread reporting of these events, will bring about changes in the way decisions are taken for/in developing countries. Jacob M Puliyel MD puliyel@gmail.com References 1. Lee K, Harmer A. Ten years of the Global Alliance for Vaccines and Immunization BMJ 2010;340:c2004. 2. Puliyel JM, Mathew JL, Priya R. Incomplete reporting of research in press releases: Et tu, WHO. Indian J Med Res 2010;131:588-589. http://www.icmr.nic.in/ijmr/2010/april/0418.pdf accessed 23/4/2010. 3. The Hib Initiative. Hib vaccine: A critical ally in Asia's effort to reduce child deaths. (Press release) http://www.hibaction.org/news/2007/20070627.pdf accessed on 23/4/2010. 4. WHO. Hib vaccine: A critical ally in Asia’s effort to reduce child deaths. http://www.who.int/immunization/newsroom/Hib_vaccine/en/ accessed on 23/4/2010. 5. Baqui AH, El Arifeen S, Saha SK, Persson L, Zaman K, Gessner BD, Moulton LH, Black RE, Santosham M. Effectiveness of Haemophilus influenzae type B conjugate vaccine on prevention of pneumonia and meningitis in Bangladesh children: a case control study. Pedaitr Infect Dis J. 2007;26: 565-571. 6. Gessner BD, Sutanto A, Linehan M, Djelantik IG, Fletcher T, Gerudug IK, Ingerani, Mercer D, Moniaga V, Moulton LH, Moulton LH, Mulholland K, Nelson C, Soemohardjo S, Steinhoff M, Widjaya A, Stoeckel P, Maynard J, Arjoso S. Incidences of vaccine-preventable Haemophilus influenzae type b pneumonia and meningitis in Indonesian children: hamlet- randomised vaccine-probe trial. Lancet 2005; 365: 43-52. 7. World Health Organization. WHO Position Paper on Haemophilus influenzae type b conjugate vaccines. Wkly Epidemiol Rec 2006;81: 445-452. 8. [Anonymous] Global programme for vaccines and immunization (GPV). The WHO position paper on Haemophilus influenzae type b conjugate vaccines. Wkly Epidemiol Rec 1998;73: 64-68.
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  Incomplete reporting of research in press releases: Et tu, WHO?

  Indian J Med Res 2010;131:588-9
  Puliyel JM, Mathew JL, Priya R.
  Incomplete reporting of research in press releases: Et tu, WHO? Jacob Puliyel Head of Department of Pediatrics, St Stephens Hospital, Delhi, India JL Mathew Assistant Professor of Pediatrics, Advanced Pediatrics Centre, PGIMER, Chandigarh, India Ritu Priya Associate Professor Centre of Social Medicine and Community Health Jawaharlal Nehru University, New Delhi, India Address for correspondence Jacob Puliyel St Stephens Hospital Tis Hazari, Delhi. 110054 India puliy Show More...Incomplete reporting of research in press releases: Et tu, WHO? Jacob Puliyel Head of Department of Pediatrics, St Stephens Hospital, Delhi, India JL Mathew Assistant Professor of Pediatrics, Advanced Pediatrics Centre, PGIMER, Chandigarh, India Ritu Priya Associate Professor Centre of Social Medicine and Community Health Jawaharlal Nehru University, New Delhi, India Address for correspondence Jacob Puliyel St Stephens Hospital Tis Hazari, Delhi. 110054 India puliyel@gmail.com Press releases reporting research findings and interpretations have recently been the subject of research and editorials (1,2). Woloshin et al pointed out that press releases from academic medical centers often do not provide key facts or acknowledge important limitations (1). Press releases represent the public face of science and research. Tight control on research methods and reporting in scientific journals can be negated by loose misrepresentation of those facts to the public in the press releases. We were made aware of this recently in the context of the debate about introducing Hib vaccination in India, when a press release (3,4) reporting the internationally funded Bangladesh Hib Probe Study (5) was quoted rather than the study itself. On the face of it, this press release issued by a number of international agencies sponsoring the research, seems to selectively report the study findings. We are concerned because such statements are taken very seriously globally. By publishing this comment we hope to raise the standards to which such organizations are held, while providing them an opportunity to explain any aspects we may have overlooked. Press Release Referring to the research (5), the press release stated: 1. “Results showed that routine immunization of infants with a Hib conjugate vaccine prevented over one-third of life-threatening pneumonia cases and approximately 90% of Hib meningitis cases.” 2. “This vaccine study builds on the evidence of the real burden of Hib pneumonia … shown in …Indonesia.” Both these statements that appear to argue in favor of Hib vaccination in developing countries actually reflect selective interpretation/presentation of the research findings. Bangladesh study details The Bangladesh study compared Hib vaccination status among children with confirmed pneumonia or meningitis (cases), against those without these diseases (controls). Two groups of children constituted controls viz community based controls (matched for age, sex, season and distance from the hospital) and hospital-based controls with no matching. 93.4% children received all 3 doses of Hib-DPT or DPT vaccine as per protocol. The numbers that received fewer than 3 doses was relatively small. Study Findings Bangladesh Study The major findings of the Bangladesh study were as follows: 1. There was no difference in the Hib vaccination status of children with pneumonia compared to community controls, irrespective of how radiological pneumonia was defined. The authors reported differences in the vaccination status of children attending the hospital for other diseases, compared to those referred to the hospital with pneumonia for the purposes of this study [Vaccine effectiveness 39% (CI 14 to 56) per protocol]. The fact that there was no difference in the matched community controls was omitted in the press release. 2. The study found only 15 cases of confirmed Hib meningitis and 41 ‘probable meningitis’. Among those who received all 3 doses of vaccine there was no statistically significant protective effect against either confirmed meningitis or probable meningitis, irrespective of comparison with hospital or community controls. The authors observed statistical significance in the sub-group that received only two dose of vaccine [Vaccine effectiveness 93% (CI 53 to 100)]. This point was highlighted in the press release in a manner suggesting benefit of the vaccine, without mentioning that no significant difference was found with three doses of vaccine. Indonesia study The press statement that the study ‘builds on’ evidence of the burden of Hib pneumonia from Indonesia, is another misrepresentation. The Indonesia study (6) actually reported more pneumonia (though not statistically significant) in the Hib vaccinated group than controls. In fact the Indonesia study paper concludes by saying “Hib vaccine will not have a major role in efforts to reduce the overall burden of respiratory illness….. as improvements in nutritional status, maternal education and socioeconomic status” (can have). (5). Paradoxically the press release, that the Bangladesh study ‘builds on’ the evidence of the Indonesian study, is true. They both actually argue against the vaccine. Conclusion Table 1 summarizes the key findings of both studies (5,6). Health-care stakeholders and decision-makers in developing countries need to be cognizant of these issues when confronted with such information. References 1. Woloshin S, Schwartz LM, Casella SL, Kennedy AT, Larson RJ. Press releases by academic medical centers: not so academic? Ann Intern Med. 2009;150:613-8 2. Editorial. Incomplete reporting of research in academic press releases. Lancet 2009; 373: 1920. 3. The Hib Initiative. Hib vaccine: A critical ally in Asia’s effort to reduce child deaths. (Press release) http://www.hibaction.org/news/2007/20070627.pdf accessed on 18/9/09 4. WHO. Hib vaccine: A critical ally in Asia’s effort to reduce child deaths http://www.who.int/immunization/newsroom/Hib_vaccine/en/ accessed 18/9/09 5. Baqui AH, El Arifeen S, Saha SK, Persson L, Zaman K, Gessner BD, Moulton LH, Black RE, Santosham M. Effectiveness of Haemophilus influenzae type B conjugate vaccine on prevention of pneumonia and meningitis in Bangladesh children: a case control study. Pedaitr Infect Dis J. 2007;26: 565-571 6. Gessner BD, Sutanto A, Linehan M, Djelantik IG, Fletcher T, Gerudug IK, Ingerani, Mercer D, Moniaga V, Moulton LH, Moulton LH, Mulholland K, Nelson C, Soemohardjo S, Steinhoff M, Widjaya A, Stoeckel P, Maynard J, Arjoso S. Incidences of vaccine-preventable Haemophilus influenzae type b pneumonia and meningitis in Indonesian children: hamlet-randomised vaccine-probe trial. Lancet 2005; 365: 43-52.
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  Hyperimmunoglobulin E syndrome with juvenile dermatomyositis and calcinosis. Clin Rheumatol. 2010 Apr 8

  Clin Rheumatol. 2010 Apr 8
  Saikia B, Aneja H, Jain J, Puliyel JM.
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  Demolishing democratic institutions to promote biotechnology

  http://www.plosmedicine.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2F76eddb74-d498-4996-a22c-ac2e5a5f9ab8&root=info%3Adoi%2F10.1371%2Fannotation%2F76eddb74-d498-4996-a22c-ac2e5a5f9ab8
  Jacob Puliyel
  Demolishing democratic institutions to promote biotechnology In our previous comment we had noted that the authors had found that democratic institutions retard introduction of vaccines. We had also written about how data from a local multi-center study was obtained through the ‘Right to Information Act’ (RTI) in India. This data showed the problem of Hib was much lower than what was being projected, to justify introduction of the vaccine in the national programme of immunization. This ‘RTI  Show More...Demolishing democratic institutions to promote biotechnology In our previous comment we had noted that the authors had found that democratic institutions retard introduction of vaccines. We had also written about how data from a local multi-center study was obtained through the ‘Right to Information Act’ (RTI) in India. This data showed the problem of Hib was much lower than what was being projected, to justify introduction of the vaccine in the national programme of immunization. This ‘RTI data’ was used for a ‘public interest litigation’ against introduction of Hib. The argument was that invasive Hib disease was rare in India and so the vaccine costs could not be justified considering the benefits from alternate use of those resources. We stated in our comment that it was hoped that vaccine manufacturers would not take the cue from the article by Shearer and colleagues, and attack democratic institutions as a means of promoting their vaccines. Such a comment seemed excessively alarmist and paranoid. However it seems the fear is not completely unfounded. Already a draft bill to form a new biotechnology regulatory authority (BRAI), that they say stifles opposition to genetically modified (GM) products, is planned to be introduced in the Parliament in India. It contains a clause to the effect that people who criticize a GM product ‘without sufficient scientific proof’ could face penalties including a fine and jail. Another clause causing concern, article 27, suggests that the BRAI could override India's Right to Information Act, which mandates citizens' right to obtain information from the government. Readers are referred to a recent issue of SciDev Net for details (1). Thomas Jefferson has said “The price of freedom is eternal vigilance.” Dare I say, even paranoid vigilance! Jacob Puliyel MD MRCP M Phil Head of Pediatrics St Stephens Hospital Delhi puliyel@gmail.com Reference 1) Padma T. V. Furore over silencing clause in Indian biotech bill http://www.scidev.net/en/news/furore-over-silencing-clause-in-indian-biotech-bill.html accessed 7/4/10
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  Respiratory viruses in acute bronchiolitis in Delhi

  Indian Pediatrics 2010;47:342-5. http://indianpediatrics.net/apr2010/342.pdf
  Kaur C, Chohan S, Khare S, Puliyel J.
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  Pediatric Protocols St Stephens Hospital Delhi

  Department of Pediatric St Stephens Hospital, Delhi
  Pediatrics Protocols Pediatric Handbook 3rd Edition Department of Pediatrics and Neonatology St Stephens Hospital Tis Hazari Delhi 110054 Preface This protocol was prepared by Dr Neetu Vashisht, building on the work of previous editions and the work of Dr R S Beri, Dr Nirmal Kumar, Dr Vineet Tyagi and Dr Jyotsna James. The First Edition was published in 2003 and the Second Edition in 2004. This third edition has been a long time coming. The 3rd edition i Show More...Pediatrics Protocols Pediatric Handbook 3rd Edition Department of Pediatrics and Neonatology St Stephens Hospital Tis Hazari Delhi 110054 Preface This protocol was prepared by Dr Neetu Vashisht, building on the work of previous editions and the work of Dr R S Beri, Dr Nirmal Kumar, Dr Vineet Tyagi and Dr Jyotsna James. The First Edition was published in 2003 and the Second Edition in 2004. This third edition has been a long time coming. The 3rd edition is in the format of a web-based-protocol that allows up-dating and ever-greening. We will appreciate comments and suggestion for corrections at all times. You can send these to Puliyel@gmail.com This book of protocols adapts some standard protocols laid out by others, but elsewhere it merely accepts them without change. Acknowledgement in each instance would by unwieldy. References are quoted mostly for controversial recommendations only. We changed the title for this edition. It is hardly a book of protocols. It is more a handbook – a ready reckoner. We used the ‘dummy yardstick’ to decide what goes into the book and what goes out. Instructions were simplified that we could understand them ourselves. The new book of protocols is called – Pediatric Handbook Jacob Puliyel Feburary 2011 Contents Drug Infusions 3 Status Epilepticus 6 Status Asthamaticus/Ventlation 7 Ventilation and ARDS Management 9 Peritoneal dialysis 11 Septic Shock 12 Hypokalemia ( <3.5 mEq/l ) 13 Hyperkalemia (>6 mEq/l) 14 Hyponatremia (Sodium <130 mEq/l) 15 Hypernatremia 16 Hypocalcemia 17 Rapid Sequence Intubation 18 Neonatal Hypoglycemia 19 TPN 20 Miscellaneous 21 Drugs And Infusions DRUG DOSE CONCENTRATION IN VIAL DILUTION INFUSION RATE DOPAMINE 5-20 microgms/kg/min 40mg/ml (Wt × 6× 3) mg dilute in 30 ml NS 1ml/hr =10mcg/kg/min DOBUTAMINE 5-20 microgms/kg/min 25mg/ml (Wt × 6× 3) mg dilute to 30 ml NS 1ml/hr =10mcg/kg/min ADRENALINE 0.1-1 microgms/kg/min 1mg/ml (Wt × 0.6) mg dilute in 10 ml NS 1ml/hr =1mcg/kg/min FENTANYL 1-4 microgms/kg/hr 50 micrograms/ml (Wt × 40) mcg dilute in 40 ml NS 1ml/hr =1mcg/kg/hr MORPHINE 10-20 microgm/kg/hr 15 micrograms/ml (Wt × 0.5) mg dilute in 50 ml 5% Dextrose 1ml/hr =10mcg/kg/hr MIDAZOLAM 1-24 microgms/kg/min 5 mg/ml (Wt × 0.6×5) mg dilute in 50 ml NS 1ml/hr =1mcg/kg/min VECURONIUM 1.5-2.5mic/kg/min or o.09-0.12mg/kg/hr As powder, 10 and 20 mg, dilute 10 mg vial in 2 ml NS (i.e 5mg/ml) (Wt X0.6 X 5 ) mg dilute in 50 ml NS 1ml/hr = 1 mcg/kg/min NOREPINEPHRINE 0.1-1 microgms/kg/min 1mg/ml (Wt × 0.6) mg dilute in 10 ml NS 1ml/hr =1mcg/kg/min VASOPRESSIN 0.02 to 0.06 unit/kg/hour 20 units / ml 1 unit/kg in 50 ml 5% dextrose 1-3 ml/hour MILRINONE 0.5 to 0.75mcg/kg/min 1mg/ml Wt X 0.6 mg dilute in 10 ml NS 1ml/hr = 1 mcg/kg/min PROSTAGLANDIN 0.05-0.1 microgms/kg/min May need to go up to 0.4 microgram/kg/min 0.25mg/ml or 250mcg/ml or 500mcg/ampoule ( 1 ampoule = 2ml = 0.5mg ) (Wt × 0.6 × 0.3) mg dilute in 30 ml NS Works well for babies less than 2.5 kg. --------------- For 5 kg child add to 15 ml NS (Wt × 0.6 × 0.15) ---------------- For 4 kg child add to 20 ml (Wt × 0.6 × 0.2) ------------------ For 3 kg child add to 25 ml (Wt × 0.6 × 0.25) 1ml/hr =0.1mcg/kg/min NITROGLYCERINE 0.5mcg/kg/minute - 5mcg/kg/minute Increase every 5 minutes 5mg/ml (10 ml vial = 50 mg) (Wt × 0.6) mg dilute in 10 ml dextrose 1ml/hr =1mcg/kg/min Start at 0.5ml/hour. Increase every 5 minutes by 0.5ml/hour NITROPRUSSIDE 0.3mcg/kg/minute to 4mcg/kg/minute 25mg/ml (Wt X 0.6 X 3) mg dilute in 30 ml 5%D 1ml/hour =1mic /kg/min KETAMINE 5-20 mic/kg/min 50mg/ml Wt X 3 X 3 mg dil in 30 ml NS 1 ml/hr= 5 mic/kg/min SILDENAFIL 5-8mg/kg/day given 8 hourly Available as tablets , suspension to be made from pharmacy , as desired Adenosine 0.1mg/kg (max 6 mg as first dose). Repeat with 0.2mg/kg if needed - in absence of response (max 12 mg as repeat dose) 3mg/ml(2ml ampoule) To be administered as rapid IV push followed by NS flush. Dilute 1ml adenosine in 2 ml normal saline as stock solution. (1mg/ml) Take 1 ml stock solution and add to 9 ml saline. This Solution has 0.1 mg/ml. Give 1 ml per Kg. Stock solution can be used with less dilution in bigger babies. Use 1ml stock solution without dilution in 10 kg child Amiodarone 5mg/kg IV in 10-30 minutes. Repeat if needed. Followed by continuous infusion of 5 mic/kg/min upto a max of 10mic/kg/min 50mg/ml For infusion: Wt X 3 X 3 mg dilute in 30 ml NS 1 ml/hr= 5 mic/kg/min Lignocaine Loading dose:1mg/kg followed by continuous infusion of 20-50mic/kg/min 100mg/5 ml or 20mg/ml For infusion Wt X 3 X 12 mg dilute in 30 ml NS 1 ml/hr= 20 mic/kg/min Procainamide Loading dose :10-15mg/kg max of 1g followed by continuous infusion of 30-80mic/kg/min 100mg/ml or 500mg/ml For infusion Wt X 4.5 X 12 mg dilute in 30 ml NS 1 ml/hr= 30 mic/kg/min Aropine 0.02mg/kg (min 0.1mg, max 0.5 mg in smaller children and 1mg in adolescents) 0.1mg/ml Digoxin LOADING DOSES Preterm neonate IV: 15-30 mic/kg, Oral:20-30mic/kg Term neonate IV: 20-30mic/kg, Oral: 25-35mic/kg 1-2 Years IV: 30-50 mic/kg, Oral:40-50mic/kg 2-5 Years IV: 25-35mic/kg, oral:30-40mic/kg 5-10 Years IV: 5-30 mic/kg, Oral: 20-35mic/kg Give half dose stat followed by ¼ dose twice in 8-12 hrs MAINTAINENCE DOSES Preterm neonate IV: 4-9- mic/kg/day Oral: 4-12mic/kg/day Term neonate IV: 6-8mic/kg/day Oral: 6-10mic/kg/day 1-2 Years IV: 8-10 mic/kg/day Oral: 10-15mic/kg/day 2-5 Years IV: 6-8mic/kg/day, Oral: 8-10mic/kg/day 5-10 Years IV: 4-8 mic/kg/day, Oral:5-10mic/kg/day Divide oral maintenance doses in 2 doses to 4 doses Available as Inj:100,250mic/ml Elixir: 50mic/ml Carnitine 50 mg/kg as loading dose followed by 50mg/kg/day as maintenance in 4 or 6 divided doses 100mg/ml solution for oral use or 200mg/ml for IV use Baclofen 2-7 years age oral route: 10-15 mg/day, titrate to effect and increase every 3 days by 5-15mg/day 8 years age: Titrate to effect, max dose of 60mg/day Available as tablets in strengths of 10,20 mg Enoxaparin (Low molecular weight Heparin) Prophylaxis in > 2 months age for DVT or pulmonary embolism: 0.5mg/kg SC in 2 divided doses Treatment of the same: 1mg/kg SC in 2 doses. Titrate to desired anti factor Xa level (0.1-1u/ml) Do not administer IV or IM 100mg/ml only for Sub Cutaneous administration only Levothyroxine 0-6 months:8-10mic/kg/day 6-12months:6-8mic/kg/day 1-5yrs:5-6mic/kg/day 6-12yrs:4-5mic/kg/day >12yrs:2-3mic/kg/day Tablets strengths: 25, 50, 75, 100, 125, 150, 175, 200, 300 mcg Enalapril Start with oral dose of 0.1mg/kg/day in 2 divided doses (max 5mg) Titrate upto 0.5mg/kg/day in 2 divided doses (max 40mg/day) Available as tablets in strengths of 2.5, 5, 10, 20 mg. Nifedipine 0.6-0.9mg/kg/day PO in 2 or 4 div doses Hypertensive emergency: 0.25-0.5 mg/kg/dose PO/Sublingual (max 10 mg) can repeat in 4-6 hrs Available as capsules 10, 20 mg Read “add in 30 ml NS” to mean: Add drug to normal saline (NS) to reach desired volume of 30 ml. Similarly for Dextrose (D). Status Epilepticus • Oxygen • Dextrose infusion 0-5 Minutes IV Lorazepam in doses of 0.1 mg/kg/dose 5-10 Minutes Repeat above dose of IV Lorazepam 10-30 Minutes IV Phenytoin in dose of 20mg/kg (1g max) (over 20 minutes) @ 1mg/kg/min OR Inj Fosphenytoin dose 20 mg/kg of Phenytoin equivalents. (Can be infused three times faster @ 3 mg/kg/min) 35 Minutes Loading dose of Inj Valproate 30 mg/kg (1:1 dilution in NS over 10 minutes) OR Inj Phenobarbitone @ 20 mg/kg ( @1mg/kg/min) OR Inj Leveteriacetam @20-30 mg/kg (@ 5 mg/kg/min ) If Responds 45 Minutes If response is seen to Valproate: Follow the loading dose by continuous infusion @ 5 mg/kg / hour (till 6 hours seizure free period) and taper by 1 mg/kg/hr every 2 hrs. Start maintenance dose of Valproate @ 10 mg/kg/dose 8 hourly when tapering Valproate. No response 45 Minutes Consider elective intubation at this juncture. Propofol infusion 2-5 mg/kg IV bolus followed by 1-4 mg/kg/hr OR Midazolam Infusion 2-24 mcg/kg/min (after 24 hr seizure free period taper by 1 mic/kg/min every 3 hours) OR Thiopentone infusion Of 2-4 mg/kg bolus followed by 2-4 mg/kg/hr infusion (Titrate with EEG, increments of 1 mg/kg/hr every 30 minutes upto max of 6 mg/kg/hr or till burst suppression pattern attained) • Reduce Intra cranial tension  Mannitol  Hypertonic saline  Diuretics  Hyperventilate Status Asthamaticus Oxygen + Nebulised beta agonists + IV Steroids + inhaled Ipratropium bromide IV Hydrocort @10mg/kg loading dose followed by maintenance dose of 5mg/kg/dose Q 6 hourly OR IV Methylprednisolone @ 2mg/kg as loading dose followed by maintenance dose of 0.5 – 1 mg/kg Q 6 hourly Reassess in 1 hour Good response No response PICU Transfer IV Terbutaline in bolus dose of 10 mcg/kg in 30 minutes followed by IV infusion of 0.1-4 mcg/kg/min OR SC Terbutaline 0.005mg/kg 6 hourly (max 0.3 mg) (It is to be noted that the sc and iv preparations of terbutaline are separate and cannot be interchanged for administration ) OR IV Salbutamol 15mcg/kg IV bolus over 10 minutes (Reference: Ped Critical Care Med 2002) OR IV Magnesium Sulphate 25-75 mg/kg as infusion over 20 Minutes Dilute to 30 ml (D5 OR N/5 ) (max dose is 2 – 2.5 g/dose ) OR IV Aminophylline (with O2 on flow) at loading dose of 5-6 mg/kg followed by infusion @ following rates: 2 – 6 months: 0.4 mg/kg/hr 6 – 11 months: 0.7 mg/kg/hr 1 – 9 year: 1 mg/kg/hr 9 – 12 year: 0.9 mg/kg/hr 12 year & above: 0.5 mg/kg/hr Not to exceed continuous infusion rate > 25 mg/minutes OR SC Adrenaline 0.01 mg/kg -0.3 mg (max dose) (every 20 minutes for 3 doses) Neutralize Metabolic Acidosis (Base Excess if more than 10) with NaHCO3 MgSO4 50 mg/kg (0.1ml/kg) over 30 minutes Methylprednisolone 2 -3 mg/kg/day Turbutaline 5-10 ug/kg loading over 10 minutes Follow by 0.4 ug/kg/minutes Increase by 0.2 ug/kg/minute every 10-15 minutes Maximum 10ug/kg/min Asthma Ventilation Ventilation indications • Exhaustion • Lethargic • Silent chest • Worsening SpO2 Strategy  Use ketamine  Low PIP (low volume)  Slow rate  Low PEEP  Allow permissive hypercarbia. Ventilation and ARDS Management Definition ARDS = PaO2 / FiO2 < 200. (ALI = PaO2 / FiO2 < 300) ARDS = Saturation less than 100% (PaO2 less than 100) in 50% O2 ----------------------------------------- • Acute onset respiratory distress • Radiographic infiltrates (bilateral patchy, diffuse or homogenous consistent with pulmonary edema like in CCF) • Normal heart size suggesting absence of CCF o . Reference NIH NHLBI ARDS Clinical Network Volume ventilation Broad target guidelines Start with 8 ml / kg Safe volume is 6 ml / kg Minute Ventilation is 200 ml/kg/minute in newborns Going down to 100 ml/kg in adults Peritoneal dialysis Monitor Vitals Sedate with Benzodiazepines Empty bladder, prepare abdomen Pre-warm PD fluid to body temperature Add Heparin (1000 u/l) to PD fluid Inject PD fluid through 14 g needle into peritoneal cavity initial infusion is 20 ml/kg Pass stylet through needle and remove needle, to thread 14 gauge canula over stylet Initial infusion volume of 15-30 ml/kg, Increase upto 50-70 ml/kg as tolerated. (usual amount is 40-50 ml/kg ) Stop Heparin after 2 cycles if returns are clear No Potassium to be added to PD fluid unless Serum k < 5 meq/l Dwell time of 30-45 mins Outflow time of 15-20 mins 1 Cycle/hr Remove PD Catheter after 20 Cycles Monitoring: • Monitor Vitals • Monitor Urine output • Renal function and electrolytes at the end of 3 rd , 10 th and 20 th cycles • Blood Gas at the end of 3rd, 10th and 20th cycles • 4 Hourly Blood Glucose • Blood Counts, Gram staining, Cultures of drained PD fluid once or twice a day • Blood cultures at the end of PD • PD catheter tip for fungal smear and culture Septic Shock The following should be achieved in the first hour of management: 1. Airway 2. Breathing (Oxygen) 3. Circulation Fluid Bolus 20 ml/kg with Isotonic Crystalloids, going up to 60 ml/kg (may use Colloids instead of Crystalloids) 4. Correct Hypoglycemia and Hypocalcemia 5. Start Antibiotics 6 Stress dose hydrocortisone @ 2mg/kg iv stat, followed by 2 mg/kg/day for 48 hours, as continuous infusion Fluid Responsive: (responding to 2-3 fluid boluses) • Capillary filling time improves to< 2 seconds • Peripheral core temperature difference becomes < 3 degrees C Heart rate normalizes • Urine output improves to > 1 ml/kg/hr • Consciousness improves • Serum lactates decrease • Base deficit decreases • B P normalises NON FLUID RESPONSIVE NORMOTENSIVE ScVO2 <70% HYPOTENSIVE VASODILATED ScVO2>70% Warm Shock Sepsis (High pulse volume) HYPOTENSIVE VASOCONSTRICTED ScVO2 <70% Cold Shock (Low pulse volume) DOPAMINE 5- 20mcg/kg/min DOBUTAMINE 5- 20mcg/kg/min DOPAMINE 5- 20mcg/kg/min DOBUTAMINE 5- 20mcg/kg/min DOPAMINE 5- 20mcg/kg/min DOBUTAMINE 5- 20mcg/kg/min HYDROCORTISONE Replacement 2mg/kg Stress dose may be 50 mg/kg Max dose 300 mg HYDROCORTISONE Replacement 2mg/kg Stress dose may be 50 mg/kg Max dose 300mg HYDROCORTISONE Replacement 2mg/kg Stress dose may be 50 mg/kg Max dose 300 mg NOREPINEPHRINE 0.05 to 1.5 mcg/kg/min EPINEPHRINE 0.1 to 3 mcg/kg/min MILRINONE 50 mcg/kg (0.05mg/kg)] Preparation: 1mg/ml (Sufficient for 20 kg) Follow by 0.5 to 1mcg/kg/minute (Wt X 0.6)mg dilute in 20ml NS Run at 1ml/hr= 0.5mcg/kg/min NITROPRUSSIDE 0.5 to 4 mcg/kg/min (can be used only in normotensive cold shock and not in hypotensive VASOPRESSIN 0.02 to 0.06 u/kg/hour Prepare 20 units / ml Add 1 unit per kg in 50 ml of 5% dextrose Dose 1-3 ml/hour Hypokalemia ( <3.5 mEq/l ) ECG changes in severe Hypokalemia: Prominent u waves, diphasic T waves, ST segment depression, apparent QTC prolongation, PR interval prolongation, sino-atrial block. Serum Potassium Infusion Rates 2.5-3.5 Add IV Potassium 40 mEq/l to 60 mEq/l 1 ml KCl provides 2O mEq/L if added to 100 ml of Potassium free fluid. < 2.5 OR Severe Symptomatic Hypokalemia Speak to Consultant Rapid correction 0.3-0.5 mEq/kg Run in 1 hour and STOP. Remember this is nearly 200mEq/L (Central vein) Wt × 0.5/2 ml KCl dilute in 5%Dextrose Add this to 50 ml in child less than 10 kg Add to 100 ml in 10 to 20 kg child Add to 150 ml in 20-30 kg child Add to 200 ml if more than 30 kg Run in 1 hour Hyperkalemia (>6 mEq/l) Normal ECG ( Potassium = 6 - 7 mEq/l) Abnormal ECG ( Potassium >7 mEq/l ) (peaked T waves, loss of p waves, widened QRS complex, sine waves, AV blocks, bradycardia, ventricular arrhythmias ) 1. Stop all Enteral AND Parenteral Potassium 2. Sodium polysterene resin 0.25 to 1gm/kg orally or rectally one to 4 times daily 1. IV Calcium Gluconate in dose of 1 ml/kg/dose over 3-5 minutes. Repeat the second dose after 10 minutes if required. 2. IV Sodium Bicarbonate 1-2 mEq/kg over 5- 10 minutes 3. Subcut Crystalline Insulin in doses of 0.1 u/kg WITH 2 ml/kg of 25% Dextrose (0.5 g/kg ) in 30 minutes. Repeat dose in 30-60 minutes OR begin a continuous infusion of Insulin at 0.1u/kg/hr + 1-2 ml/kg/hr of 25 % dextrose 4. Salbutamol inhaled OR IV Salbutamol of 4 Microgram/kg in 20 minutes 5. Sodium polysterene resin 1gm/kg orally or rectally 6. Dialysis Hyponatremia (Serum Sodium <130 mEq/l) GI loss And Dehydration Water Intoxication SIADH Renal Salt Wasting High BUN High Urine Osmolarity Oliguria • Fe Na >1 % • Low Urine Osmolarity • Polyuria • Fe Na >1% • High Urine Osmolarity > 100 mOsm/l • Oliguria • Fe Na >1% • High Urine Osmolarity • Polyuria Replace deficit with 0.9% NaCl over 48 Hours Restrict Water + Replace Urine Sodium Losses Restrict Water to 2/3 Maintenance using 0.9% NaCl Replace Urine Sodium Losses + Replace Water Deficit as 0.9% NaCl Treatment of Hyponatraemia SYMPTOMATIC (seizures, deeply comatose, depressed respiration) Consider intubation and ventilation 3% NS through central vein (don’t delay while administering anticonvulsants simultaneously): to be given as 2 ml/kg over 15-30 minutes (1ml/kg of 3% NS raises serum sodium by 1 mEq/l). Repeat infusion if symptoms persists up to 3 times. Aim is to raise the plasma sodium till CNS symptoms resolve and/or change in plasma sodium <12 mmol/l/24hrs or plasma sodium becomes 125 mmol/l. • Risk of Central Pontine Myelinolysis if rapidly corrected especially in long standing hyponatraemia. • Acute hyponatraemia is more symptomatic and is also safer to treat with hypertonic saline. ASYMPTOMATIC Treatment with half normal saline is often all that is needed. • Restrict fluids to 60% of maintenance ( IVF or enteral feeds ) • 3% NS to achieve change in plasma sodium by 1-2 meq/l/over 30 minutes • Lasix if edematous Hypernatremia Free water deficit estimation (FWD) = 0.6 × Wt × (1 – 145/current sodium) (As total body water is 60% of the body weight) STRATEGY Use Maintenance fluid +additional 30% of maintenance (for correction of hypernatraemic dehydration slowly) Choice of fluids In Hypernatremia: • Replacement fluid in absence of complicating factors: Half Normal Saline • If with shock: NS OR 5% Albumin • If due to Sodium overload: add Sodium free fluid like 5% dextrose in addition to loop diuretic • If associated with Hyperglycemia: use 2.5 % dextrose. • Do not use Insulin for hyperglycemia as that can cause precipitous fall in Plasma Glucose/Osmolarity with subsequent cerebral edema.  Monitor Serum Sodium 4 hourly  Correct concomitant Hypocalcemia  Add 40mEq/l of KCl if patient passes urine well.  If Sodium > 200mEq/l: Peritoneal Dialysis  If associated with Diabetes Insipidus: use DDAVP, Diuretics, VASOPRESSIN. Hypocalcemia ECG changes in Hypocalcemia: prolonged QTc interval Asymptomatic Symptomatic No Bolus. 10% Ca Gluconate 8ml/Kg/Day OR 80 mg/Kg/Day Elemental Calcium PO for 2 Days 10% Cal Gluconate as Bolus of 2ml/kg diluted in 1:1 dilution using 5%DEXTROSE Repeat Serum Calcium Repeat Bolus if no response occurs If normal,taper to 4ml/kg/day of IV Calcium OR 40 mg/kg/day elemental Calcium PO for 1 Day Follow it with IV infusion of 8ml/kg/day for 48 hrs of Ca Gluconate Taper to 4ml/Kg/day of Cal Gluconate OR 40 mg/kg/day of elemental Calcium for 1 Day Hypocalcaemia in an Older Child • 1-2 ml/kg of 10% calcium gluconate (100-200 mg/kg) IV stat in 15-20 minutes under cardiac monitoring • Followed by 20-50mg/kg/hr (0.2-0.5 ml/kg/hr ) Run this for 4 hours only. Check serum levels before starting infusion for next 4 hours. Stop infusion when calcium levels reach 8mg% May need to supplement with magnesium also Rapid Sequence Intubation Neonatal Hypoglycemia Glucose Delivery Rate (GDR) (mg/kg/min) = % dextrose X Volume (ml/kg/day) ------------------------------------------- 144 ASYMPTOMATIC SYMPTOMATIC TPN Made Simple Glucose 10% or 12.5% Isolyte P for maintainance electrolytes Heparin 1 unit/ml of above MVI add 1 ml to days fluid Aminoacid Add 15 ml to 85 ml AA to Isolyte P Day 3 add 20 ml AA to 80 ml Isolyte P Day 5 add 25 ml AA to 75 ml Isolyte P Day 7 add 30 ml AA to 70 ml Isolyte P Run through long line Don’t break the line for another infusion After 7 days lipids may be added Infuse 2.5ml/kg of 20% Intralipid Day 9 run 5 ml/kg (0.2ml/kg/hour) Day 11 run 7.5 ml/kg (0.3ml/kg/hour) Day 13 run 10 ml/kg (0.4 ml/kg/hour) Day 15 run 12.5 ml /kg (0.5ml/kg/hour) Day 17 onwards run 15 ml/kg (0.6 ml/kg/hour) This is the maximum of 3 gm/kg/day Run lipid through a peripheral line Miscellaneous PEF (5 Height in cm) - 400(+/-50) Systolic BP 70 + (Age X 2) Diastolic BP 55 + Age Endotracheal tube size (Age [Y] divided by 4 ) + 4 Preterm 2.5 Term 3 1 year 4 Endotracheal tube length (Age[Y] divided by 2) + 12 ET size X 3 Cricothyroid needle 14 gauge needle with 3 mm ET adapter Drug infusion calculation (Weight 0.6 mg) Add to 10 ml Run 1 ml/hour = 1 microgram/kg/minute Empyema Streptokinase 2.5 to 3 lakh units in 100 ml saline. Retain 4 hours (Cost Rs 1500) SaO2 between 90 and 60% SaO2 – 30 = PaO2 Weight in <12 months of age Age(in months) +9/2 Weight ( 1-6 yr age) (Age X2)+ 8 Weight(> 6 yrs age) (Age X 7)-5/2 Height( >2 yrs) (Age X 6) +77 pAo2 (760-47) X FiO2 - paCO2/0.8
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  Civil Society Activism Hinders Vaccine-introduction in India: Vote for autocracy?

  http://www.plosmedicine.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2Ff75e65f0-2b4c-40f7-9c10-93f92d150b35&root=info%3Adoi%2F10.1371%2Fannotation%2Ff75e65f0-2b4c-40f7-9c10-93f92d150b35
  Prashant Tyagi, Mira Shiva, Jacob Puliyel
  Civil Society Activism Hinders Vaccine-introduction in India: Vote for autocracy? Posted by Puliyel on 18 Mar 2010 at 11:18 GMT Shearer and colleagues use sophisticated modeling techniques to try and explain why some countries take longer to adopt Haemophilus influenza type b (Hib) vaccine in their national immunization programs (1). A primary premise they make is that the vaccine is beneficial to society. Published evidence of strain shifts and side effects however contradict this ass Show More...Civil Society Activism Hinders Vaccine-introduction in India: Vote for autocracy? Posted by Puliyel on 18 Mar 2010 at 11:18 GMT Shearer and colleagues use sophisticated modeling techniques to try and explain why some countries take longer to adopt Haemophilus influenza type b (Hib) vaccine in their national immunization programs (1). A primary premise they make is that the vaccine is beneficial to society. Published evidence of strain shifts and side effects however contradict this assumption. Data from Canada and elsewhere suggests that Hib vaccine has nearly eliminated Haemophilus influenza type b but there has been a proportional increase in non-Hib strains including non-serotypable strains causing invasive H influenza disease in the post Hib vaccine era (2-10). Studies from Finland have shown an increase in type 1 diabetes after introduction of the vaccine. The increase in incidence was 58/100000 (p=0.029) (11,12) where the pre-Hib vaccine incidence of Hib in Europe was 12 to 54/ 100000 (13) We note that research by Shearer and colleagues did not model the results of local studies – only their existence (1). The authors state that knowing a study exists is not equivalent to knowing the implication of their findings or their dissemination to decision makers. Such patronization of decision makers does not serve the cause of objective discourse. In India as also in other countries, evidence of natural immunity to Hib, developed in infancy because of infection with other bacteria (with cross-reactive antigens) (14-17) have been quoted as the rationale negating need to vaccinate with Hib. The low incidence of Hib disease has had a direct bearing on the non-introduction of the vaccine in India. A large multi-center study in India, funded by GAVI (18) found that the incidence of all-cause pneumonia deaths was fifty times less than what was projected previously (19, 20). The incidence of pneumonia was so low that even with 10% mortality; the deaths would not match the figures projected to make the vaccine appear cost-effective. This study argues against the need for both the Hib vaccine and the pneumococcal vaccine in India. Rather conveniently the data from this study was not included in the National Technical Advisory Group on Immunization (NTAGI) report recommending Hib (21). The data from the study was obtained under the Right to Information Act. The omission of this data from the recommendation of the NTAGI (to decision makers) became the focus of a public interest petition in the Delhi High Court and it has resulted in reevaluation of the NTAGI report by the Government of India (22). This suggests that attempts ‘not to disseminate findings to decision maker’ may not always serve the purpose. Another premise the authors start with (1), is that ‘democracy’ results in early introduction of vaccines. A previous study (23) and their own results (not included in the abstract) (1) have actually proved the opposite - that autocracy favors vaccine introduction. The experience from India also suggests that a well informed and active civil-society movement sometimes stands in the way of the introduction of vaccines. It is not such bad news either. One is left to speculate what lessons the GAVI will take from this finding. One hopes accelerated introduction of the other vaccines like human papillomavirus, pneumococcal and rotavirus vaccines will not be accompanied by an assault on democratic rights, institutions and systems like the Right to Information Act in India. Prashant Tyagi MBBS Department of Pediatrics St Stephens Hospital Delhi 110054 India prash119@yahoo.com Mira Shiva MD Initiative for Health , Equity and Society/Third World Network All India Drug Action Network A-60, Hauz Khas New Delhi - 110 016 Tel: 91-11-26512385, Mob:91 9810582028 mirashiva@gmail.com Jacob Puliyel MD MPhil Department of Pediatrics St Stephens Hospital Delhi 110054 India Puliyel@gmail.com References 1. Shearer JC, Stack ML, Richmond MR, Bear AP, Hajjeh RA, et al. (2010) Accelerating Policy Decisions to Adopt Haemophilus influenzae Type b Vaccine: A Global, Multivariable Analysis. PLoS Med 7(3): e1000249. doi:10.1371/journal.pmed.1000249 2. Brown VM, Madden S, Kelly L, Jamieson FB, Tsang RS, Ulanova M. Invasive Haemophilus influenzae disease caused by non-type b strains in Northwestern Ontario, Canada, 2002-2008. Clin Infect Dis. 2009 15;49:1240-3. 3. Tsang RS, Sill ML, Skinner SJ, Law DK, Zhou J, Wylie J. Characterization of invasive Haemophilus influenzae disease in Manitoba, Canada, 2000-2006: invasive disease due to non-type b strains. Clin Infect Dis. 2007 15;44:1611-4. 4. Urwin G, Krohn JA, Deaver-Robinson K, Wenger JD, Farley MM. Invasive disease due to Haemophilus influenzae serotype f: clinical and epidemiologic characteristics in the H. influenzae serotype b vaccine era. The Haemophilus influenzae Study Group. Clin Infect Dis. 1996;22:1069-76. 5. Perdue DG, Bulkow LR, Gellin BG, Davidson M, Petersen KM, Singleton RJ, Parkinson AJ. Invasive Haemophilus influenzae disease in Alaskan residents aged 10 years and older before and after infant vaccination programs. JAMA. 2000;283:3089-94. 6. McConnell A, Tan B, Scheifele D, Halperin S, Vaudry W, Law B, Embree J; of The Canadian Immunization Monitoring Program, ACTive (IMPACT). Invasive infections caused by haemophilus influenzae serotypes in twelve Canadian IMPACT centers, 1996-2001. Pediatr Infect Dis J. 2007;26:1025-31. 7. Adderson EE, Byington CL, Spencer L, Kimball A, Hindiyeh M, Carroll K, Mottice S, Korgenski EK, Christenson JC, Pavia AT. Invasive serotype a Haemophilus influenzae infections with a virulence genotype resembling Haemophilus influenzae type b: emerging pathogen in the vaccine era? Pediatrics. 2001;108:E18. 9. [No authors listed] Invasive Haemophilus influenzae disease in Manitoba in the post-vaccination era suggests a changing epidemiology. Can Commun Dis Rep. 2006;32):125-30. 10. Kalies H, Siedler A, Gröndahl B, Grote V, Milde-Busch A, von Kries R. Invasive Haemophilus influenzae infections in Germany: impact of non-type b serotypes in the post-vaccine era. BMC Infect Dis. 2009;9:45. 11. Classen JB, Classen DC. Clustering of cases of insulin dependent diabetes (IDDM) occurring three years after hemophilus influenza B (HiB) immunization support causal relationship between immunization and IDDM. Autoimmunity. 2002 ;35:247-53. 12. J. B. Classen, D. C. Classen. Vaccines and the risk of insulin-dependent diabetes (IDDM): potential mechanism of action. Medical Hypotheses 2001;57, 532-538. 13. Watt JP, Levine OS, Santosham M. Global reduction of Hib disease: what are the next steps? Proceedings of the meeting: Scottsdale, Arizona, September 22-25, 2002. The Journal of Pediatrics 2003;143, S163-S187. 14. Puliyel JM, Agarwal KS, Abed Abass F. Natural immunity to Haemophilus influenza b in infancy in Indian children. Vaccine. 2001;19:4592-4. 15. Minz S, Balraj V, Lalitha MK, Murali N, Cherian T, Manoharan G, Kadirvan S, Joseph A, Steinhoff MC. Incidence of Haemophilus influenzae type b meningitis in India. Indian J Med Res. 2008;128:57-64 16. Tastan Y, Alikasifoglu M, Ílter O, Erginöz E, Arvas A, Yüksel D, Türkcü F, Badur S. Natural Immunity to Haemophilus influenzae Type b Among Healthy Children in Istanbul, Turkey. Indian Pediatrics 2000;37: 414-417 17. Toraño Peraza G, Hernández Vadell I, Toledo Romaní ME, Baly Gil A, Tamargo Martínez I, Carmenate García A. Naturally acquired immunity to Haemophilus influenzae type B in healthy Cuban children. Mem Inst Oswaldo Cruz. 2004;99:687-9. 18. Final Report. India Hib vaccine probe study: Part A. http://pdf.usaid.gov/pdf_... accessed 17/3/10 19. WHO Estimating the local burden of Heamophilus influenza type b(Hib)disease preventable by vaccination http://www.who.int/vaccin... accessed 17/1/10 20. Unicef. Pneumonia the forgotten killer of children. http://www.unicef.org/pub... accessed 24/1/10 21. Kant L. NTAGI subcommittee recommendations on Haemophilus influenzae type B (Hib) vaccine introduction in India. Indian Pediatr. 2009;46:945-54 NTAGI. 22. Sexana KB and others in the High Court of Delhi. Writ Petition (Civil) No. 51 Of 2009 Public Interest Litigation. Delhi High Court New Delhi. 23. Gauri V, Khaleghian P. Immunization in developing countries: its political and organizational determinants. World Development 2002;30: 2109-2130.
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  PIL about Vaccine: Rejoinder to reply by ICMR

  Petitioners on PIL by Professor K B Saxena. Filed by Prashant Bhushan
  IN THE HIGH COURT OF DELHI AT NEW DELHI (CIVIL ORIGINAL JURISDICTION) Writ Petition (Civil) No. 13698 Of 2009 PUBLIC INTEREST LITIGATION IN THE MATTER OF: DR. K. B. SAXENA & ORS. …PETITIONERS VERSUS UNION OF INDIA & ORS. …RESPONDENTS REJOINDER AFFIDAVIT ON BEHALF OF THE PETITIONERS TO THE COUNTER-AFFIDAVIT OF RESPONDENT NO. 3 (ICMR) I, Dr. Jacob M Puliyel S/o Late Shri P. M. Mammen Head, Dept. of Pediatrics, St. Stephans Hospital, Tis Hazari, New Delhi-110054, d Show More...IN THE HIGH COURT OF DELHI AT NEW DELHI (CIVIL ORIGINAL JURISDICTION) Writ Petition (Civil) No. 13698 Of 2009 PUBLIC INTEREST LITIGATION IN THE MATTER OF: DR. K. B. SAXENA & ORS. …PETITIONERS VERSUS UNION OF INDIA & ORS. …RESPONDENTS REJOINDER AFFIDAVIT ON BEHALF OF THE PETITIONERS TO THE COUNTER-AFFIDAVIT OF RESPONDENT NO. 3 (ICMR) I, Dr. Jacob M Puliyel S/o Late Shri P. M. Mammen Head, Dept. of Pediatrics, St. Stephans Hospital, Tis Hazari, New Delhi-110054, do hereby solemnly state and affirm as under: 1. That I am the Petitioner No. 8 in the above writ petition and I have also been authorized by other Petitioners to file this affidavit on their behalf. I, being conversant with the facts and circumstances of the above writ petition, am competent to swear this affidavit. 2. That I have gone through the Counter Affidavit of Indian Council of Medical Research/Respondent No. 3 (hereinafter the ICMR) and submit my reply as given below. Petitioners crave leave of this Hon’ble court to not to give a para-wise reply. 3. It is at the outset humbly submitted that ICMR has filed a vague 5 page affidavit which does not contain any scientific data or any annexures. It is not well drafted either, perhaps deliberately so. 4. The Petitioners had filed the above writ petition highlighting how irrational vaccines are sought to be introduced into the national immunization programme without proper epidemiological studies. The Petitioners showed that how vaccines which are of questionable utility, expensive and also carry possible side-effects are sought to be introduced at the cost of public exchequer at the behest of WHO and vaccine manufacturers. It was shown that all this is happening because India does not have a policy for vaccine evaluation and that is why the petition had sought a direction from this Hon’ble court to the Government to formulate a rule-based vaccine policy incorporating the principles of scientific assessment and transparency, as has been done by other countries. 5. ICMR has now filed its reply. In their counter-affidavit, ICMR has stated that it was aware of the multicenter study done by ICMR itself on the need for Hib vaccine in India. This begs the question of why the data from the study on pneumonia incidence and deaths was not included in the NTAGI report. Selective quoting of the literature is an antithetical to the principles of evidence based medicine and cannot be accepted from an “expert” advisory body to the Government. 6. Furthermore at the meeting held under the chairmanship of the health secretary the chairperson of the NTAGI sub-committee was asked in the presence of the health secretary why this data was not included. J P Muliyil, CMC Vellore - Chairperson; Jacob John, Vellore – Co-Chair NTAGI; and Dr Naveen Thacker, Indian Academy of Pediatircs representative to NTAGI; were present at this meeting and they admitted that this data was available to the committee. 7. The Petitioners had alleged that a pneumococcal vaccine covering 70% strains, that was not even manufactured, leave alone tested, had been recommended to be introduced in 2010 by NTAGI. These shocking facts have been confirmed by the ICMR affidavit. 8. ICMR states that the letter quoted in the petition was a letter by one of the petitioners published in an indexed medical journal and it was published after the NTAGI meeting. The letter does not pertain to any new facts but is data taken from the article by Minz. It is surprising that the expert body could not make the simple deduction made in the letter from the article by Minz. The data on diabetes and Hib strain replacement were all available well before the HTAGI but are not referred to in the section on safety. 9. ICMR correctly states that Cochrane review (a comprehensive analysis) came after the NTAGI sub-committee meeting. But it came much before the NTAGI recommendation was submitted and NTAGI made no effort to review its recommendation. 10. In Canada, Hib vaccine has nearly eliminated H influenza B bacteria but it has replaced it with another H influenza strain which is even more difficult to treat. Studies on this are annexed and are marked as Annexure A (colly). 11. In the case of Pneumococcal vaccine, strain shifts are also there. The replaced bacteria are far more serious and cause 70% in pus infection of chest. A study on the same is annexed and is marked as Annexure B. 12. Two more studies have been accessed by the Petitioners which clearly show that Hib vaccine is causing Diabetes. The said studies are annexed and are marked as Annexure C and Annexure D. 13. In fact, Global Alliance for Vaccines and Immunization (GAVI), on whose partial funding Government has proposed to introduce Pentavalent vaccine has itself come under criticism that its policies are promoting inequality and are at the behest of vaccine manufacturers. Their recommendations are ill-suited for a developing country like India with very low immunization coverage which by Government’s own statistics is less than 50%. Two reports regarding GAVI on this issue are annexed and are marked as Annexure E (colly). 14. The intervention of the court and the work of public health specialists have induced the Government to reexamine the basis on which the National Technical Advisory Group on Immunization (NTAGI) made its recommendation to introduce Pentavalent vaccine. It has constituted an experts body that excludes outside influence of bodies like the World Health Organization (WHO). A copy of the letter of invite to a meeting for such review is annexed and is marked as Annexure F. News reports that introduction of Pentavalent vaccine has been stayed by the Government till the review are annexed and are marked as Annexure G (colly). 15. However again there is no transparency on how this body has been constituted and many credible experts have not been invited while many old NTAGI members have found a place in this committee also. This means that NTAGI members would not sit on review of their own recommendation. This also smacks of ad-hocism. 16. Thus the Government has conceded the demand to exclude outside agencies like the WHO, but the Petitioners fear it may only be window dressing to reassure the court. The major demand that such a body must be made up only of persons without conflict of interests and that the recommendation of the committee must be open to the public and scientific scrutiny have not yet been conceded. 17. Under these circumstances, Petitioners pray to this Hon’ble Court to stay the introduction of new vaccines till a scientific system of vaccine evaluation is evolved and a professional body of public health experts created for the purpose. 18. The Petitioner craves leave of this Hon’ble Court to add/amend to this rejoinder affidavit if required. DEPONENT VERIFICATION I, the deponent above-named, do hereby verify that the contents of the above affidavit are true to my knowledge, no part of it is false and nothing material has been concealed therefrom. Verified at New Delhi on 24th day of February 2010. DEPONENT Annexure 1 Mail Today The 'false' pandemic: Drug firms cashed in on scare over swine flu, claims Euro health chief Fiona Macrae http://www.dailymail.co.uk/news/article-1242147/The-false-pandemic-Drug-firms-cashed-scare-swine-flu-claims-Euro-health-chief.html Annexure 2 India asks WHO to explain swine flu alarm Indo-Asian News Service http://www.hindustantimes.com/India-asks-WHO-to-explain-swine-flu-alarm/Article1-499880.aspx Annexure 3 Meeting of National Technical Advisory Group on Immunization 26th August 2010, R. No. 155A, Nirman Bhawan Minutes of Meeting Annexure 4 Inaccuracies in minutes Jacob Puliyel Head of Pediatrics St Stephens Hospital Tis Hazari Delhi 110054 puliyel@gmail.com Phone 9868035091 To Ms Saumitra Sahar Section Officer Health and Family Welfare Nirman Bhawan New Delhi Subject: Inaccuracies in Minutes circulated of the Technical Consultative meeting on Immunization on 14.12.2009 Dear Ms Sahar Ref T-13011/47/2009-CC&V I notice some inadvertent inaccuracies have crept into the minutes of this meeting. If these are not corrected they may be used to discredit all the contents of the minutes. 1. Para 5 Dr SK Mittal is described as a ‘former President –IAP’ Correction needed Professor Mittal was Director Head of Pediatrics Maulana Azad Medical College and Chairperson of the IMA sub committee on Immunization. He was never IAP President 2. Para 5 referring to my presentation it says: Dr J Puliyel raising concerns about the technical basis of estimating the burden of disease for introduction of vaccines against Hepatitis B, Haemophilus influenza type b (Hib) and pneumococcal infective diseases---- Dr Naveen Thaker ex IAP President stated that there exists burden of above mentioned disease and that vaccines are the most cost effective way of reducing this burden questioning some of the assumptions drawn by J Puliyel. Correction needed I raised no concerns about the technical basis of estimating burden of disease. I presented data from an ICMR study in Anaicut block obtained through a series of RTI. I asked why the data was not included in the data reviewed by NTAGI sub committee recommending Hib. I showed how the study found incidence of ‘all-cause pneumonia needing admission’ was 30/1000 and deaths were 0.3/1000. The only assumption I made was to say that even if 10% cases of pneumonia were to die in ‘out of study’ circumstances (the observed mortality in the study was only 0.7% of cases), the mortality would be 3/1000 and this was much lower than the 14/1000 death from pneumonia projected for India. In one stroke the study undercut one of the main planks for the demand for 2 vaccines – the Hib and the pneumococcal vaccines. Prof Mulayalil Chairman of NTAGI sub committee admitted the data from this study had been reviewed by the sub-committee but it was kept out of the report. Dr Thacker stated anecdotal evidence for the existence of Hib disease. The Health Secretary asked him if he had published studies to support his stand but he provided no further evidence. Please arrange to show this letter to the Health Secretary Ms Sujatha Rao, and issue a corrected minutes if needed. In any case these objections may please be recorded. Sincerely Jacob Puliyel Copy Dr V M Katoch Secretary Dept of Health Research ICMR New Delhi Annexure 5 GOVERNMENT OF INDIA MINISTRY OF HEALTH AND FAMILY WELFARE LOK SABHA UNSTARRED QUESTION NO 2548 ANSWERED ON 22.07.2009 INCLUSION OF NEW VACCINE UNDER NATIONAL IMMUNISATION PROGRAMME 2548 . SUPRIYA SULE Will the Minister of HEALTH AND FAMILY WELFARE be pleased to state:- (a) whether the Government has any plan to introduce Pentavalent Vaccine in the National Immunisation Programme; (b) if so, whether this plan has already been cleared by the Ministry of Finance; (c) if so, the details thereof; (d) whether the Government is also negotiating with the World Bank to get some funds for the scheme; and (e) if so, the time by when a final decision in this regard is likely to be taken and the aid likely to be received from the World Bank? ANSWER THE MINISTER OF HEALTH AND FAMILY WELFARE (SHRI GHULAM NABI AZAD) (a): Yes. Based on the recommendation of the National Technical Advisory Group on Immunization (NTAGI) , a decision has been taken to introduce Pentavalent combination vaccine of DPT-Hepatitis B-Hib (Haemophilus influenzae b) in five states, namely, Himachal Pradesh, Jammu and Kashmir, Karnataka, Kerala and Tamilnadu during 2009-10 to 2011-12 (b) & (c): Expenditure Finance Committee in its meeting on 9th June, 2009, has recommended the proposal with few observations; reply to these will be incorporated in the final ‘Note for Cabinet Committee on Economic Affairs’. (d) & (e): Yes. A letter seeking funds from the World Bank was sent to the Department of Economic Affairs, Ministry of Finance, in June, 2008. ________________________________________ Top This Site is designed and hosted by National Informatics Centre. Contents are provided and updated by Lok Sabha Secretariat. Best viewed with IE 7.0 and above 800x600 resolution GOVERNMENT OF INDIA MINISTRY OF HEALTH AND FAMILY WELFARE LOK SABHA UNSTARRED QUESTION NO 440 ANSWERED ON 20.11.2009 IMMUNISATION OF CHILDREN 440 . SUPRIYA SULE UDAY PRATAP SINGH Will the Minister of HEALTH AND FAMILY WELFARE be pleased to state:- (a) whether most of the children in the country are not immunised; (b) if so, whether in the absence of basic immunization of children, most of them run risk of disease even in the period of basic immunization schedule; (c) if so, the facts thereof; (d) whether the Union Government in consultation with the State Governments proposes to evolve policy to ensure that each and every child is immunized in the scheduled period itself; and (e) if so, the details thereof? ANSWER THE MINISTER OF HEALTH AND FAMILY WELFARE(SHRI GHULAM NABI AZAD) (a) to (c): As per the latest DLHS-3 survey in 2007-08, 54.1 % children (12-23 months) had received full immunization and only 11.3% children (12-23 months) were found to have had ‘No Immunization’. The details of Vaccine Preventable Diseases (VPDs) as reported by the Central Bureau of Health Intelligence (CBHI) and the World Health Organization- National Polio Surveillance Project (WHO-NPSP) during 2006, 2007 and 2008 are at Annexure. (d) & (e): Under the Universal Immunization Programme (UIP) of National Rural Health Mission (NRHM), immunization cards are issued to individual beneficiary at the time of birth/at first immunization and is monitored by the Health Worker during Village Health and Nutrition Days and during home visits, so as to ensure timely immunization. Annexure 6 Clin Infect Dis. 2007 Jun 15;44(12):1611-4. Epub 2007 May 2. Characterization of invasive Haemophilus influenzae disease in Manitoba, Canada, 2000-2006: invasive disease due to non-type b strains. Tsang RS, Sill ML, Skinner SJ, Law DK, Zhou J, Wylie J. Annexure 7 Child sacrifice for Bio-medical research in Bhutan and other countries Govinda Rizal 2010-01-17, Kyoto http://www.redroom.com/articlestory/child-sacrifice-bio-medical-research Annexure 8 Invasive Haemophilus influenzae disease in Manitoba in the post-vaccination era suggests a changing epidemiology. Can Commun Dis Rep. 2006 Jun 1;32(11):125-30. Invasive Haemophilus influenzae disease caused by non-type b strains in Northwestern Ontario, Canada, 2002-2008. Brown VM, Madden S, Kelly L, Jamieson FB, Tsang RS, Ulanova M. Clin Infect Dis. 2009 Oct 15;49(8):1240-3. Empyema hospitalizations increased in US children despite pneumococcal conjugate vaccine. Li ST, Tancredi DJ. Pediatrics. 2010 Jan;125(1):26-33. Epub 2009 Nov 30 Vaccines and the risk of insulin-dependent diabetes (IDDM): potential mechanism of action. Classen JB, Classen DC. Med Hypotheses. 2001 Nov;57(5):532-8. Clustering of cases of insulin dependent diabetes (IDDM) occurring three years after hemophilus influenza B (HiB) immunization support causal relationship between immunization and IDDM. Classen JB, Classen DC. Autoimmunity. 2002 Jul;35(4):247-53. BMJ 322 : 754 doi: 10.1136/bmj.322.7289.754/c (Published 31 March 2001) News roundup [abridged versions appear in the paper journal] Global vaccine initiative creates inequity, analysis concludes Gavin Yamey HAI Europe, 2001, Vol.6, No. 1 Immunisation for All? A critical look at the first GAVI partners meeting by Anita Hardon http://www.haiweb.org/pubs/hailights/mar2001/index.html Concerns raised, five-in-one vaccine will have to wait Teena Thacker http://www.indianexpress.com/news/concerns-raised-fiveinone-vaccine-will-ha/578781/ Life-saving’ vaccine project on hold Namita Kohli, Hindustan Times New Delhi, February 14, 2010 http://www.hindustantimes.com/Life-saving-vaccine-project-on-hold/Article1-508638.aspx
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  Calculating prevalence of hepatitis B in India: Using population weights to look for publication bias in conventional meta-analysis

  Ind J Pediatr 2009;76:1247-1257
  Batham A, Gupta MA, Rastogi P, Garg S, Sreenivas V, Puliyel JM
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  Nasopharyngeal teratoma as a cause of neonatal stridor

  Indian Pediatr. 2009 Dec;46(12):1097-8.
  Tiwari L, Baijal N, Puliyel JM.
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  Public Interest Petition (PIL) in Delhi High Court on Vaccines

  Delhi High Court. (2009) Writ Petition (Civil) No. 13698 of 2009. Public Interest Litigation. Available at http://delhihighcourt.nic.in/index.html 2009
  Prashant Bhushan Advocate, Petitioners: Saxena KB, Mittal SK, Banerji D, Imrana Qadeer, Kurien NJ, Priya R, Mira Shiva, Puliyel JM, Dabade G.
  IN THE HIGH COURT OF DELHI AT NEW DELHI (CIVIL ORIGINAL JURISDICTION) Writ Petition (Civil) No. 13698 Of 2009 PUBLIC INTEREST LITIGATION A WRIT PETITION IN PUBLIC INTEREST UNDER ARTICLE 226 OF THE CONSTITUTION OF INDIA HIGHLIGHTING HOW IRRATIONAL VACCINES ARE BEING ARBITRARILY INTRODUCED AND PROMOTED BY THE GOVERNMENT AT THE BEHEST OF VACCINE MANUFACTURERS AND OTHER VESTED INTERESTS. Memo of Parties IN THE MATTER OF: DR. K. B. SAXENA (PH.D) FORMER HEALTH SECRETARY, GOVERNME Show More...IN THE HIGH COURT OF DELHI AT NEW DELHI (CIVIL ORIGINAL JURISDICTION) Writ Petition (Civil) No. 13698 Of 2009 PUBLIC INTEREST LITIGATION A WRIT PETITION IN PUBLIC INTEREST UNDER ARTICLE 226 OF THE CONSTITUTION OF INDIA HIGHLIGHTING HOW IRRATIONAL VACCINES ARE BEING ARBITRARILY INTRODUCED AND PROMOTED BY THE GOVERNMENT AT THE BEHEST OF VACCINE MANUFACTURERS AND OTHER VESTED INTERESTS. Memo of Parties IN THE MATTER OF: DR. K. B. SAXENA (PH.D) FORMER HEALTH SECRETARY, GOVERNMENT OF INDIA VISITING PROFESSOR, CENTRE FOR SOCIAL DEVELOPMENT 53 LODI ESTATE, NEW DELHI-110003 …PETITIONER NO. 1 PROF. S. K. MITTAL (MD) FORMER HEAD OF PEDIATRICS, MAULANA AZAD MEDICAL COLLEGE DIRECTOR, PEDIATRICS, PUSHPANJALI CROSSLAY HOSPITAL VAISHALI, GHAZAIABAD …PETITIONER NO. 2 PROF. DEBABAR BANERJI (MD) PROFESSOR EMERITUS CENTRE OF SOCIAL MEDICINE & COMMUNITY HEALTH JAWAHARLAL NEHRU UNIVERSITY, DELHI …PETITIONER NO. 3 PROF. IMRANA QADEER (MD) MEMBER, NATIONAL RURAL HEALTH MISSION R/O C-4/111, SAFDARJUNG DEVELOPMENT AREA NEW DELHI-110016 …PETITIONER NO. 4 DR. N. J. KURIAN (PH.D) S/O CHAKO JOHN FORMER ADVISOR TO FINANCE MINISTRY & PLANNING COMMISSION VISITING PROFESSOR, COUNCIL FOR SOCIAL DEVELOPMENT SANGHA RACHANA, 53 LODI ESTATE, NEW DELHI-110003 …PETITIONER NO. 5 DR. RITU PRIYA (MD) PUBLIC HEALTH ADVISOR, NRHM MINISTRY OF HEALTH & FAMILY WELFARE NIRMAN BHAWAN, NEW DELHI-110001 …PETITIONER NO. 6 DR. MIRA SHIVA (MD) FOUNDER COORDINATOR, ALL INDIA DRUG ACTION NETWORK D/O LATE MAJOR D S SHIVA R/O A-60, HAUZ KHAS, NEW DELHI-110016 …PETITIONER NO. 7 DR. JACOB M PULIYEL (MD MRCP MPHIL) HEAD, DEPT. OF PEDIATRICS ST. STEPHANS HOSPITAL, TIS HAZARI NEW DELHI- 110054 …PETITIONER NO. 8 DR. GOPAL DABADE (MBBS, DLO) PRESIDENT, DRUG ACTION FORUM (KARNTAKA) 57, TEJASWINAGAR DHARWAD-580002 (KARNATAKA) …PETITIONER NO. 9 VERSUS THE UNION OF INDIA THROUGH ITS SECRETARY MINISTRY OF HEALTH & FAMILY WELFARE NIRMAN BHAWAN, NEW DELHI-110001 …RESPONDENT NO. 1 NATIONAL TECHNICAL ADVISORY GROUP OF IMMUNIZATION THROUGH ITS CHAIRPERSON MINISTRY OF HEALTH & FAMILY WELFARE NIRMAN BHAWAN, NEW DELHI-110001 …RESPONDENT NO. 2 INDIAN COUNCIL OF MEDICAL RESEARCH THROUGH ITS DIRECTOR GENERAL V. RAMALINGASWAMI BHAWAN, ANSARI NAGAR NEW DELHI-110029 …RESPONDENT NO. 3 NEW DELHI DATED: (PRASHANT BHUSHAN) ADVOCATE FOR THE PETITIONER 301, NEW LAWYERS CHAMBERS SUPREME COURT OF INDIA NEW DELHI-110001 IN THE HIGH COURT OF DELHI AT NEW DELHI (CIVIL ORIGINAL JURISDICTION) Writ Petition (Civil) No. .................... Of 2009 PUBLIC INTEREST LITIGATION IN THE MATTER OF: DR. K. B. SAXENA (PH.D) FORMER HEALTH SECRETARY, GOVERNMENT OF INDIA VISITING PROFESSOR, CENTRE FOR SOCIAL DEVELOPMENT 53 LODI ESTATE, NEW DELHI-110003 …PETITIONER NO. 1 PROF. S. K. MITTAL (MD) FORMER HEAD OF PEDIATRICS, MAULANA AZAD MEDICAL COLLEGE DIRECTOR, PEDIATRICS, PUSHPANJALI CROSSLAY HOSPITAL VAISHALI, GHAZAIABAD …PETITIONER NO. 2 PROF. DEBABAR BANERJI (MD) PROFESSOR EMERITUS CENTRE OF SOCIAL MEDICINE & COMMUNITY HEALTH JAWAHARLAL NEHRU UNIVERSITY, DELHI …PETITIONER NO. 3 PROF. IMRANA QADEER (MD) MEMBER, NATIONAL RURAL HEALTH MISSION R/O C-4/111, SAFDARJUNG DEVELOPMENT AREA NEW DELHI-110016 …PETITIONER NO. 4 DR. N. J. KURIAN (PH.D) S/O CHAKO JOHN FORMER ADVISOR TO FINANCE MINISTRY & PLANNING COMMISSION VISITING PROFESSOR, COUNCIL FOR SOCIAL DEVELOPMENT SANGHA RACHANA, 53 LODI ESTATE, NEW DELHI-110003 …PETITIONER NO. 5 DR. RITU PRIYA (MD) PUBLIC HEALTH ADVISOR, NRHM MINISTRY OF HEALTH & FAMILY WELFARE NIRMAN BHAWAN, NEW DELHI-110001 …PETITIONER NO. 6 DR. MIRA SHIVA (MD) FOUNDER COORDINATOR, ALL INDIA DRUG ACTION NETWORK D/O LATE MAJOR D S SHIVA R/O A-60, HAUZ KHAS, NEW DELHI-110016 …PETITIONER NO. 7 DR. JACOB M PULIYEL (MD MRCP MPHIL) HEAD, DEPT. OF PEDIATRICS ST. STEPHANS HOSPITAL, TIS HAZARI NEW DELHI- 110054 …PETITIONER NO. 8 DR. GOPAL DABADE (MBBS, DLO) PRESIDENT, DRUG ACTION FORUM (KARNTAKA) 57, TEJASWINAGAR DHARWAD-580002 (KARNATAKA) …PETITIONER NO. 9 VERSUS THE UNION OF INDIA THROUGH ITS SECRETARY MINISTRY OF HEALTH & FAMILY WELFARE NIRMAN BHAWAN, NEW DELHI-110001 …RESPONDENT NO. 1 NATIONAL TECHNICAL ADVISORY GROUP OF IMMUNIZATION THROUGH ITS CHAIRPERSON MINISTRY OF HEALTH & FAMILY WELFARE NIRMAN BHAWAN, NEW DELHI-110001 …RESPONDENT NO. 2 INDIAN COUNCIL OF MEDICAL RESEARCH THROUGH ITS DIRECTOR GENERAL V. RAMALINGASWAMI BHAWAN, ANSARI NAGAR NEW DELHI-110029 …RESPONDENT NO. 3 A WRIT PETITION IN PUBLIC INTEREST UNDER ARTICLE 226 OF THE CONSTITUTION OF INDIA HIGHLIGHTING HOW IRRATIONAL VACCINES ARE BEING ARBITRARILY INTRODUCED AND PROMOTED BY THE GOVERNMENT AT THE BEHEST OF VACCINE MANUFACTURERS AND OTHER VESTED INTERESTS. To, THE HON’BLE CHIEF JUSTICE OF DELHI AND HIS COMPANION JUDGES OF THE HON’BLE HIGH COURT OF DELHI, AT NEW DELHI The Humble Petition of the Petitioners above-named MOST RESPECTFULLY SHOWETH: - 1) That the Petitioners are filing the instant writ petition in public interest highlighting how irrational vaccines are being introduced in the public health system by the Government, under the influence of vaccine manufacturers and international agencies like World Health Organization (WHO), without proper epidemiological and medical studies. Petitioners (who are generally pro-vaccine and pro-modern medicine) are appalled at how in the absence of a rational vaccine policy, newer and newer vaccines are being pushed by the Government into the national immunization programme. Vaccines which are either of little utility or which are not required at all are being introduced and promoted by the Government at the behest of these vested interests and, at the same time, basic vaccines that are the right of every child are not being made available under the Universal Immunization Programme (UIP) to 53% of the population – mostly poor living in rural areas who should be the priority for any immunization program as the poor cannot afford the consequences of disease. 2) Under the Expanded Programme of Immunization (EPI), 6 primary vaccines are covered: BCG, DPT, DT, TT, Measles and Polio. At a time when the Government has utterly failed to ensure that every child receives these vaccines and the country is facing a shortage of these vaccines, new vaccines of questionable utility and efficacy are sought to being introduced in an arbitrary and irrational manner, and at huge cost. These expensive vaccines, after being introduced, are very likely to be cornered by the urban elite at the expense of the exchequer. The only beneficiaries of this are the vaccine manufacturers. Government has shown little interest to make the EPI vaccines available to the large number of children who are either poor or are in remote rural areas and thereby violating their Fundamental Rights guaranteed under Article 14 and 21 of the Constitution. 3) The Petitioners is highlighting the Government’s arbitrary policy on vaccines by using, as case studies, the proposed introduction of Hepatitis B, Haemophilus influenzae Type B (Hib), Pneumococcal and the Pentavalent vaccines which are of doubtful utility, unproven efficacy, expensive and are not required. World over, before a vaccine is introduced in the public health system, a number of studies are carried out with proper methodology and expertise, taking into account a number of factors, and also conflict of interest is strictly guarded against. In India, not only these tests are not being done, adverse studies against these new vaccines are deliberately being ignored. It is of note that the very studies that were done by the WHO to demonstrate the need for the vaccines in India showed that there was very low incidence of the disease and as such there was little sense in introducing the vaccine and these very studies were ignored in the recommendation made to GOI to introduce the vaccine. This practice of selectively ignoring studies (even those done by the ICMR with funding from the WHO) which are inconvenient, goes against the basic tenets of Evidence Based Medicine and results in promoting irrational medicine. This Petition seeks a direction to the Government to formulate a rule-based rational vaccine policy by which vaccines are scientifically evaluated in a transparent manner before they become part of country’s UIP. This Petition also seeks an immediate stay against the introduction of Hepatitis B, Haemophilus influenzae Type B (Hib), Pneumococcal and the Pentavalent vaccines till the requisite studies are carried out. THE PETITIONERS 1) Petitioner No. 1 is Dr. K. B. Saxena (Ph.D). He is the former Secretary in the Ministry of Health & Family Welfare. He is also former Secretary in the Department of Rural Development. He is also former Principal Advisor to the Planning Commission. He is currently a Visiting Professor at Centre for Social Development. 2) Petitioner No. 2 is Prof. S. K. Mittal (MD). He is the former Head of Pediatrics Department in Maulana Azad Medical College, Delhi. He has been a Member of Medical Council of India and President of Delhi Medical Association. He has authored seven books in Pediatrics including two books on immunization. He is a recipient of many awards and is currently Director of Pediatrics at Pushpanjali Crosslay Hospital. 3) Petitioner No. 3 is Prof. Debabar Banerji (MD). He is the Professor Emeritus at the Centre of Social Medicine and Community Health at Jawaharlal Nehru University. 4) Petitioner No. 4 is Prof. Imrana Qadeer (MD), former Professor and Head at Centre of Social Medicine and Community Health at Jawaharlal Nehru University. Prof. Qadeer is Member, PM Advisory Committee and Member, National Rural Health Mission. She is also Member of the Population Council. 5) Petitioner No. 5 is Prof. N. J. Kurian (Ph.D). He is the former advisor to Ministry of Finance and Planning Commission. He has been Director of Public Report on Health and Director of Council for Social Development (CSD). He is currently a Visiting Professor of CSD. 6) Petitioner No. 6 is Dr. Ritu Priya (MD). She is currently an Advisor (Public Health Planning) under the National Rural Health Mission, Government of India. She has researched extensively on epidemiology, communicable diseases and public health systems. 7) Petitioner No. 7 is Dr. Mira Shiva (MD). For the last 30 years, she has been extensively involved in issues of primary health care, medicine technologies and health safety. She was Chairperson, Consumer Education of Task Force on Safety of Food and Medicine, Government of India. She is Member, Central Social Welfare Board, Government of India and Member, Central Ethics Committee on Human Research, Government of India. She is the Founder Coordinator of All India Drug Action Network, Director- Rational Drug Policy, Director- Initiative for Health Equity & Society. She has won many awards internationally and also by Government of India for her contribution in prevention of misuse of medicines and medical technology. 8) Petitioner No. 8 is Dr. Jacob M Puliyel (MD, MRCP & M.Phil). He is the head of the Pediatrics Department at St. Stephens Hospital in New Delhi. He was vice-Chairperson of the Indian Medical Association’s sub-committee on Immunization. He is a well-known expert on the role of vaccines in the public health system and has over 100 publications in indexed national & international medical journals. 9) Petitioner No. 9 is Dr Gopal Dabade (MBBS, DLO). He is the President of Drug Action Forum - Karnataka, which is campaigning for rational drug and vaccines policies. He is also the Co-convener of All India Drug Action Network (AIDAN), which is a national network of civil society members actively involved in promoting the concept of rational drug and vaccines policies. THE RESPONDENTS 1) Respondent No. 1 is the Union Ministry of Health and Family Welfare which is responsible for the maintenance and promotion of public health standards in the country. It is the nodal ministry responsible for the evaluation and introduction of vaccines. 2) Respondent No. 2 is National Technical Advisory Group on Immunization (NTAGI) which is the body responsible for advising the Government on policies and practices for the implementation of the National Immunization Programme. This body is directly under the supervision of the Health Ministry. 3) Respondent No. 3 is the Indian Council of Medical Research (ICMR) which is the apex body in the country for formulation and coordination of biomedical research. It is funded by the Government and its governing body is presided over by the Union Health Minister. The Director General ICMR is also Secretary Health Research under Ministry of Health & Family Welfare. THE CASE IN BRIEF 1) Vaccines are vital to avoid unnecessary suffering, disability, and death. Immunization is a proven tool for controlling and even eradicating disease. Just as essential and life saving medicines are needed for medical care, certain vaccines, based on proven utility, are considered essential and they have an important role in health care promotion. India is one of the biggest consumers of vaccines in the world. Under the EPI, six basic vaccines are provided to the children in the country: BCG, DPT, DT, TT, Measles and Polio. These vaccines cost as little as Rs. 30 per child to the exchequer. Yet they are still not made universally available and many children are denied their basic right to immunization. The survey by the Government of India has shown that 53% of the population does not receive these basic vaccines. 2) The Government has in recent times closed down virtually all public sector units that were supplying the essential vaccines at a cost which is a fraction of the cost at which same vaccines are produced by the private sector. There were no complaints against these units and the general view was that these units were doing exemplary work. No question was ever raised regarding the quality of vaccines produced in these centres. Yet, without any provocation they were closed down on the pretext that they were not following “good manufacturing practices” which related to their building set-up. Even if they required upgrade, government should have sanctioned some funds for the purpose. One of India’s most credible research institution, Centre for Science and Environment (CSE) did a detailed study of vaccine shortage due to the closure of these public sector units which clearly shows how the closure is irrational, unreasonable and malafide. The said study published in their publication is annexed and is marked as Annexure P1. Closure of Vaccine Public Sector Units No. Current Name & location Year Estd. Current status 1 Pasteur Institute of India, Coonor 1907 Suspended in 2008 2 Central Research Institute 1905 Suspended in 2008 3 BCG Vaccine Laboratory (BCGVL), Chennai 1951 Suspended in 2008 4 King Institute of Preventive Medicine 1898 Suspended in 2003 5 Haffkine Institute, Mumbai 1898 Running 6 Institute of Preventive Medicine, Hyderabad 1870 Closed in 2005 7 Pasteur Institute, Shillong 1917 Closed in 2006 8 Vaccine Lymph Department, Belgaum 1904 Closed in 1980 9 Vaccine Institute, Ranchi 1900 Closed in 2003 10 State Vaccine Institute, Patwadanagar 1900’s Closed in 2005 The said malafide closures in recent times, clearly to benefit private sector manufacturers, are currently under challenge in the Hon’ble Supreme Court of India where the Hon’ble Court has issued notice to the Government. A news report on this case is annexed and is marked as Annexure P2. Recently, CSE has published the findings of a RTI application which show the shortage of the basic vaccines, caused due to the closure of government’s vaccine manufacturing facilities. The said report is annexed and is marked as Annexure P3. 3) Within a few months of the said closure, the Government has gone full steam ahead and is on the verge of introducing newer vaccines in the country’s Universal Immunization Programme (UIP). These vaccines are of doubtful efficacy, little utility, costly, manufactured only by private sector, have unknown side effects and are being introduced without any proper study. It is to be noted that unlike curative drugs which are given to the few who fall ill, vaccines are given to the entire population. Hence they need a strong economic logic and clear cost-benefit analysis that uses, inter alia, epidemiological data about the disease being sought to be prevented. Clearly, there is a trade off in the number of vaccines one can introduce in a community, depending on costs, number of people affected, the seriousness of the condition, and the consequences - if untreated - for the entire community. A number of research papers have been published showing how the vaccine policy in India is faltering. The said studies are annexed and are marked as Annexure P4 (colly). Frontline, India’s most respected fortnightly publication, did a research which warned that vaccines which are not necessary may become a part of nation’s immunisation programme as there is a push by global pharmaceutical companies for their introduction. The said research, as published on 29.03.2008, is annexed and marked as Annexure P5. Now, the said warning is on the verge of coming true and therefore Petitioners seek urgent intervention of this Hon’ble Court. 4) World over, about 6 factors are seriously studied and researched before a vaccine is introduced: a) Incidence of the disease: How many people are affected by the disease for a given population in the country or a particular region? b) Severity of the disease: Whether the disease causes serious discomfort, disability or death? Or is it just a minor ailment in the majority of cases and it results in complication in a very small number? c) Public Health significance: Which is the population vulnerable to the disease? How is the disease transmitted? What are the health care and economic consequences of the disease? d) Treatment options: Is the disease untreatable? Does it require expensive or prolonged medication? Is it curable with inexpensive and easily available drugs? Is it naturally curable? e) Efficacy of the vaccine: If a said number of persons are vaccinated, then what fraction/percentage of them acquire immunity from the disease? f) Cost of the vaccine: How much will it cost to vaccinate the entire population as against giving medical care to the few who fall ill? g) Side effects: What are the health side effects of the vaccine that is sought to being given to every child? 5) Clearly, these factors are being ignored and no proper epidemiological and other studies are being carried out, and Government is trying to introduce newer and newer irrational vaccines. The Petitioners are using the proposed introduction of Pentavalent, Hepatitis B, Haemophilus influenzae Type B (Hib) and Pneumococcal as case studies to highlight the totally arbitrary and irrational system of recommendation for introduction of new vaccines. This is being done at the behest of vaccine manufacturers who conduct and promote doubtful studies, and the WHO which, of late, has come under the influence of pharmaceutical industry. It is of note that in the latest recommendation of the NTAGI, important data available from studies done by the ICMR have been conveniently ignored. Pneumococcal vaccine: 6) NTAGI (Respondent No. 2) has recommended that Pneumococcal vaccine be introduced in a phased manner from 2010. This is the Government body responsible for conducting the relevant studies before recommending introduction of any vaccine. The said recommendation is annexed and is marked as Annexure P6. The document given to the Petitioner No. 1 under RTI clearly shows that the vaccine would be developed only by 2010. Thus, NTAGI has recommended the introduction of a vaccine in the public health system without any trial. The said recommendation states that results of immunogenicity studies of the Pneumococcal vaccine in Indian children “will be available soon.” 7) Pneumococcal vaccine has been proposed for introduction on the recommendation of WHO which states that this vaccine be included in national immunization programmes in countries where mortality among children aged less than 5 years is more than 50 per 1000 live births or where more than 50,000 children die annually. The latter figure has no reference to the birth rate or number of children. In a large country like India, more than 50,000 children die but that figure has little relation to the disease which this vaccine claims to prevent. The first criterion of mortality of more than 50 per 1000 live births is met by 70 countries and the total population to be vaccinated is 316 million. By including the irrational criterion of where more than 50,000 children die annually only 7 additional countries are added but it adds another 161 million to the numbers eligible for vaccination. The WHO recommendations seem dictated by needs of increasing demand for vaccines and profits for manufacturers rather than the needs of public health. This WHO recommendation shows how it is becoming a tool in the hands of pharmaceutical companies who are eyeing major developing countries like India to further their commercial interests. In fact, we would be spending Rs. 1.5 lakh for preventing 1 case of pneumonia which can be treated by spending Rs. 100. This is shown in Petitioners’ letter published in The Lancet. The said letter is annexed and is marked as Annexure P7. 8) Also, Pneumococcus is one of the many organisms which cause Pneumonia. And even in the case of Pneumococcus, there are over 90 strains and the Pneumococcal vaccine covers only 1/10th of them. Attacking some strains of one or two bacteria, do not make much of an overall impact on bacteria. Even in countries where the disease strains match the prevalent vaccine, it only prevents 3.6 cases of pneumonia per 1000 children vaccinated. It is commonly known medically that if one vaccinates against one strain then other less common strains take its place. ICMR study which was received by the Petitioner under RTI which shows low incidence of meningitis and pneumonia was ignored by NTAGI. The said ICMR study is annexed and is marked as Annexure P8. Pneumonia is easily treatable by adequate use of antibiotics and the use of the new vaccines is still unproven. Also, Pneumonia is easily treatable at low cost with use of antibiotics which does not justify that an expensive vaccine be given to all children, especially a vaccine of very little efficacy. Dr. Anuradha Bose (Christian Medical College)’s piece published in The Hindu in this regard is annexed and is marked as Annexure P9. Pneumococcus also causes potential side-effects of doubling the incidence of asthma in children. Hence, the actual costs of this vaccine far outweigh its claimed benefits. Research analysis as published in bulletin of WHO are annexed and is marked as Annexure P10. A research paper published in prestigious journal of International Society for Vaccines shows how Pneumococcal vaccination is more about commerce and less about science. The said paper is annexed and is marked as Annexure P11. Hib vaccine: 9) NTAGI has now shockingly recommended the introduction of the Hib vaccine in the UIP. The recommendation of NTAGI, as published in the journal Indian Pediatrics, is annexed and is marked as Annexure P12. It clearly shows that they have selectively quoted from studies favorable to the recommendation and have ignored all studies and material which shows that the vaccine is not required in the country. Also, ICMR (Respondent No. 3) study in Vellore district which was available through RTI has been completely ignored by NTAGI. That ICMR study showed incidence of all cause pneumonia requiring attention in hospital was only 3/100 and all cause meningitis was only 2/100. Some of the studies that were conveniently ignored are annexed and are marked as Annexure P13 (colly). The evidence available was not favorable for the introduction of the Hib vaccine, and in a totally biased manner it was ignored, reflecting the unscientific nature of the Government’s system of vaccine evaluation. Hib vaccine is also known to increase the incidence of Diabetes and hence its costs far outweigh the claimed benefits. A piece in this regard is annexed and is marked as Annexure P14. 10) In fact, even without vaccination, the incidence of Hib disease in India is about a tenth of that in the West. The incidence in Asia is 9 per 100,000 compared to 109 per 100,000 in Western countries. A study funded by the WHO published in the Indian Journal of Medical Research suggests that the incidence of Hib meningitis is as low as 0.007% and it speculates that the low incidence may be due to natural immunity in the population or due to low virulence of the organism. The same person (Dr. Thomas Cherian) who was the author of the study is also the author of the NTAGI report. He has also admitted previously in an article that incidence is too low to use Hib vaccine in EPI. The probe studies (Bangladesh) showed that there was no statistical difference between vaccinated and unvaccinated children when properly matched. The said study is annexed and is marked as Annexure P15. WHO is pushing the governments to introduce Hib vaccine into the immunization programme irrespective of an individual country’s disease burden, irrespective of natural immunity attained within the country against the disease, and not taking into account the rights of sovereign states to decide the use of their resources. Sadly, Indian government has not been able to put forth an internal mechanism which evaluates the need for such vaccines like Hib in the country. Hepatitis B vaccine: 11) Hepatitis B vaccine is a stark example of what is wrong with the current system. It was first wrongly claimed that 250,000 people die of Hepatitis B disease in India, while real figure is somewhat close to 5000. Though the vaccine was not formally introduced in the UIP, but it was given on a large scale for “pilot studies” or “trials” in selected areas which included the city of Delhi. This was done at a huge cost. Also after the Government’s promotion of the vaccine, it was sold and bought in open market on a large scale. Nothing was evaluated in the “trial” and nobody bothered to check as to how many people benefited from the vaccine. A study done by National Institute of Science, Technology and Development Studies in 2002 showed that Hepatitis B vaccination is not cost-effective in India due to low incidence of the disease and the high cost of the vaccine. This was reported in the media, a copy of which is annexed and marked as Annexure P16. Yet, the Health Minister said that experiment was a “success” and it must now be introduced nationwide. 12) A number of studies have been done and research papers have been published which clearly show that Hepatitis B vaccine was totally not required in India and the claims of high incidence of the disease in the country were highly exaggerated. A study on Hepatitis B vaccine experience in India published in Economic & Political weekly is annexed and is marked as Annexure P17. Even the Indian Medical Association (IMA) was highly critical of the Government’s proposal to put Hepatitis B in UIP calling it “wasteful expenditure” on low priority health issue. IMA also said that rate of chronic carriage is 1.6% and not 4% as originally claimed vaccinating babies is totally a wasteful expenditure. A news report on the IMA report is annexed and is marked as Annexure P18. Apparently, the only people who benefited out of this exercise are the vaccine manufacturers. Pentavalent vaccine: 13) The government is now on the verge of introducing a new five-in-one (Pentavalent) vaccine which would be a combination of DPT (diphtheria, pertussis, tetanus) with Hepatitis B and Hib. Copy of a news report on this Government’s move is annexed and is marked as Annexure P19. Pentavalent combines the basic DPT vaccine dose which costs Rs. 5 per child with, as is shown above, two unnecessary and expensive vaccines, Hib and Hepatitis B. This would make the Pentavalent cost about Rs. 525 per child. An inexpensive DPT, which is already in short supply after closure of public sector manufacturing facilities, would soon become unavailable. The reason for this is not far to seek. The market for Hepatitis B vaccine in India was in a bad shape since 2005 owing to tepid demand and falling prices. Many manufacturers were in dilemma whether to remain in the business or not. That is when they managed to convince the Health Ministry to come to their rescue which announced that the Hepatitis B vaccine would be included in the UIP. This is expected to increase the demand for the vaccine by more than 300% in the first year and an annual growth of at least 25-30% in the following years. This has been noted by India’s most respected business daily Business Standard in a news report. The said report is annexed and is marked as Annexure P20. Thus the health ministry decision which came to the rescue of drug manufacturers gives an indication of the financial stakes involved in making such decisions. A basic vaccine for Diphtheria, which is highly contagious and fatal disease, which is already unavailable to 53% of our children, would soon become expensive and hence unavailable. This is also despite the fact that DPT combined with Hepatitis B and Hib vaccine is less effective than vaccines given separately. This has been shown in a comprehensive assessment of various research papers (meta-analysis) published in prestigious Cochrane Library. The said assessment is annexed and is marked as Annexure P21. The tendency to combine EPI vaccine with non-EPI vaccines creates an artificial scarcity of affordable EPI vaccines and creates a backdoor method for entry of expensive and unnecessary non-EPI vaccines into the universal immunization programme, riding piggyback on the EPI vaccines. 14) The health ministry’s decision to shut down public sector units manufacturing vaccines for the UIP appears to be driven by similar considerations. The ministry has been accused of closing public sector facilities to help provide a huge market of millions of doses of vaccines for private drug companies which they had no access to as long as the government undertakings were manufacturing low cost vaccines. Thus, by switching to the Pentavalent vaccine the ministry would not only ensure permanent closure of the public sector undertakings (which cannot manufacture Pentavalent) but will also lead the country to being totally dependent on the private manufacturers who can then dictate terms. A paper by Y. Madhavi of National Institute of Science, Technology & Development shows how new combination vaccines are providing a backdoor entry to expensive and unnecessary vaccines into the nation’s UIP. The said paper is annexed and is marked as Annexure P22. Role of WHO and other agencies: 15) WHO is financed by contributions from member states and from donors. Its funding from member countries is only 20% and the rest of the funds come from various sources chief of them being the pharmaceutical industry. In recent years, the WHO's work has involved more collaboration and there are currently around 80 such partnerships with the pharmaceutical industry and NGOs, as well as with foundations such as the Bill Gates Foundation and the Rockefeller Foundation. WHO’s role has been criticized in recent times as it has, under the influence of its corporate partners, tried to push newer and newer drugs and vaccines on the developing countries. It has often been stated that to reduce the price of non-EPI vaccines in developed countries (like US) such vaccines should be introduced in the UIP of the developing countries. Countries with huge populations like India are seen as a market for these expensive vaccines. WHO has also in the past tried to increase the market for drug against Osteoporosis by what has now been popularly been termed as ‘disease mongering.’ A paper on this, published in prestigious bio-medical journal BMJ, is annexed and is marked as Annexure P23. WHO’s perverse recommendations on Pneumococcal, Hepatitis B, Hib and Pentavalent, as highlighted in this Petition, are enough reason for the Government to formulate a stringent mechanism for evaluation of the newer vaccines and not take advice of WHO and other such bodies as gospel. 16) Now, Global Alliance for Vaccines and Immunization (GAVI) has agreed to provide subsidy for introduction of Pentavalent vaccine in India. After GAVI subsidy, its price would drop from Rs. 525/child to Rs. 380/child which is still too high. According to its usual practice, GAVI would withdraw its subsidy after 5 years leaving the Government to foot the entire bill. A recent article published in Lancet has also shown that price of combination vaccines has gone up after funding was provided by GAVI. Thus, the developing countries where Pentavalent vaccine has been introduced will have to continue the programme at a much higher cost. ‘Save the Children’, a noted international organization, has shown that GAVI has managers of pharmaceutical companies on its board. A news report on this is annexed and is marked as Annexure P24. Hence, it is important for us to beware of ulterior designs and do our own cost-benefit analysis before a vaccine is sought to be introduced. Conflict of interest in decision making in matters of public policy is becoming a major public health concern. Indian system of vaccine evaluation 17) Since vaccines, unlike medicines, are given to all, they need a clear cost-benefit rationale. It must be noted that ‘costs’ does not only include the cost of the vaccine but also includes the financial and administrative burden of installing the requisite infrastructure (hospitals, clinics, refrigerators, storage), hiring and maintaining staff (doctors, nurses), expenditure on consumables (vaccine containers, syringes), and administrative costs and other overheads. Cost of procuring vaccines is only a small fraction of the total cost of imminuzation. Also, these new vaccines have potential side effects. Unfortunately, India has in recent times accepted the advice of WHO, on the basis of doubtful studies sponsored by vaccine manufacturers. This has happened because we have not yet put in place a strong scientific system of vaccine evaluation where requisite studies including epidemiological probes are carried out before a vaccine is recommended for introduction. 18) A long standing demand of public health experts was fulfilled when Government in August 2001 established NTAGI, an advisory committee, for immunization policies. This move was strongly welcomed in the editorial of the noted journal Indian Pediatrics. The said editorial is annexed and is marked as Annexure P25. The Secretary to the Government, Department of Family Welfare, is the chairman of this committee, and the Assistant Commissioner, Immunization Program is its Member Secretary. Although not formal members, representatives of UNICEF, the World Health Organization, and the World Bank have a presence in the committee as special invitees. The sub-committees which have made perverse recommendations for introduction of newer vaccines are heavily loaded with persons from WHO and other agencies. 19) There has been little or no transparency in the system of evaluation of vaccines. NTAGI neither calls for civil society participation in its deliberations not does it put its analysis for public scrutiny and objections. Crucial decisions have huge ramifications on the public health system are taken behind closed doors raising serious eyebrows whether secret deals are being worked out in our top health policymaking bodies. As is shown above NTAGI’s bias is evident as it has ignored evidence available, not done proper epidemiological studies, have not quoted from research papers which argued against the introduction and have not done any cost-benefit analysis. Contrast this with the UK system (NICE model), where any intervention that is sought to be made in immunization is first publically announced. Then the requisite clinical and economic evidence is stringently and critically evaluated and then a draft is drawn for circulation among the stakeholders (public health experts, patients, WHO, industry). After that the draft is revised based on the said reviews and put up before an independent review panel for final assessment. We in India can follow a similar model keeping in mind our needs as a developing country with a huge population. 20) The Petitioners submit that the Government has acted totally arbitrarily and unreasonably by promoting and seeking to introduce irrational vaccines in the UIP and thereby caused serious harm to public interest. Petitioners have used the proposed introduction of Pneumococcal, Hib, Hepatitis B and Pentavalent as case studies to show how the current system of evaluation of vaccines has failed. Government has acted under the influence of vaccine companies, international agencies like WHO and other vested interests, and not on the basis of scientific rationale or the public health needs of the country. Hence, the said proposals for introduction of these vaccines in nation’s UIP are arbitrary, perverse and mala fide, and deserve to be stayed. 21) The recent actions of the Government are contrary to National Health Policy, 2002 which inter-alia states: 4.11 USE OF GENERIC DRUGS AND VACCINES 4.11.1.2 The National programme for Universal Immunization against Preventable Diseases requires to be assured of an uninterrupted supply of vaccines at an affordable price. To minimize the danger arising from the volatility of the global market, and thereby to ensure long-term national health security, NHP-2002 envisages that not less than 50% of the requirement of vaccines/sera be sourced from public sector institutions. 22) A rational, scientific and evidence-based draft National Vaccine Policy was made under the auspices of National Institute of Science Technology and Development Studies (NISTADS), CSIR New Delhi in consultation with ICMR. Eminent public health experts participated in the process and drafted a policy framework which was put up for consideration of the Government. The said draft policy is annexed and is marked as Annexure 26. In the recent times, Government has violated every basic principle of this draft policy. Therefore, the Petitioners seek urgent intervention of this Hon’ble court. 23) The Petitioners have not filed any other writ, complaint, suit or claim in any manner regarding the matter of dispute. The Petitioners have no other better remedy available. 24) The Petitioners seek liberty from this Hon’ble Court to produce other documents and records as and when required in the course of the proceedings. GROUNDS A. Government is on the verge of introducing newer and newer vaccines which are irrational, of low efficacy, expensive and are of no real utility. Government’s move to introduce new vaccines without first doing proper epidemiological studies is unreasonable, arbitrary and deserves to be quashed. Government’s move to introduce non-EPI vaccines of Hepatitis B, Pneumococcal, Hib and Pentavalent into the national immunization programme is arbitrary and mala fide. B. The current system of vaccine evaluation is arbitrary and promotes the interests of vaccine manufacturers at the expense of health needs of the country and at huge cost to the exchequer. It is also in conflict with the National Health Policy. Government is duty-bound to create a rule-based rational and scientific system of evaluating vaccines and doing epidemiological studies before a vaccine is proposed for introduction in the Universal Immunization Programme. A requisite body of experts without any conflict of interest which should then work in a transparent manner and put up its draft recommendation for scientific and public scrutiny before finalizing them. The said vaccine policy should be based on the fundamental principles of the draft vaccine policy (annexed as Annexure 26). PRAYER In view of the facts & circumstances stated above, it is most respectfully prayed that this Hon’ble Court in public interest may be pleased to: - a. Quash the introduction of Hepatitis B, Pneumococcal, Hib and Pentavalent vaccines in the Universal Immunization Programme until proper trials, epidemiological studies are carried out and a clear cost-benefit analysis is done in a transparent manner by an expert technical body which does not suffer any conflict of interest. b. Issue a writ of mandamus or any other appropriate writ to the Government to formulate a rule-based rational vaccine policy which would prescribe mandatory analysis and epidemiological studies which need to be carried out before a vaccine is sought to be introduced into the public health system and will do so in a transparent manner and allow for public and scientific scrutiny. c. Issue a writ of mandamus to the Government to ensure that basic EPI vaccines which are the fundamental right of every child are provided to each and every children without discrimination or any constraint of funds. d. Issue or pass any writ, direction or order, which this Hon’ble court may deem fit and proper under the facts and circumstances of the case. Petitioners Through New Delhi Prashant Bhushan Dated: December , 2009 (Advocate for the Petitioners) Annexure 1 Down to Earth. 15 July 2009 Get your own Vaccine http://www.downtoearth.org.in/node/3557 Annexure 2 Ganapati Mudur, British Medical Journal, March 7, 2009 Activists file petition against suspension of vaccine production http://infochangeindia.org/200903137654/Health/News/Activists-file-petition-against-suspension-of-vaccine-production.html Annexure 3 Down to Earth 30 Nov 2009. Vaccine shortage to continue http://www.downtoearth.org.in/node/2657 Annexure 4 1.Vaccines: Policy for public good or private profit? Indian J Med Res 127, January 2008, pp 1-3 http://jacob.puliyel.com/download.php?id=150 2. Vaccine Policy in India Yennapu Madhavi PLoS Med. 2005 May; 2(5): e127. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1140944/ 3. Regulating Vaccines: Can Health- Economics Tools be used Profitably? INDIAN PEDIATRICS VOLUME 44__JANUARY 17, 2007 http://jacob.puliyel.com/download.php?id=130 4. Polio eradication & the future for other programmes: Situation analysis for strategic planning in India Indian J Med Res 125, January 2007, pp 1-4 http://www.icmr.nic.in/ijmr/2007/january/editorial1.pdf 5. Economic evaluation tailored to promote vaccine uptake: how third world consumers can respond. Arora Expert Rev. Pharmacoeconomics Outcomes Res. 5(5), 515–516 (2005) http://jacob.puliyel.com/download.php?id=126 6. The Hindu Nov 19, 2006 Lessons from the polio campaign http://www.hindu.com/mag/2006/11/19/stories/2006111900100400.htm Annexure 5 Frontline March 29-11 April 2008 http://www.hinduonnet.com/fline/fl2507/fl250700.htm http://www.hinduonnet.com/fline/fl2507/stories/20080411250700400.htm http://www.hinduonnet.com/fline/fl2507/stories/20080411250700900.htm http://www.hinduonnet.com/fline/fl2507/stories/20080411250701100.htm http://www.hinduonnet.com/fline/fl2507/stories/20080411250701600.htm http://www.hinduonnet.com/fline/fl2507/stories/20080411250702000.htm http://www.hinduonnet.com/fline/fl2507/stories/20080411250702500.htm Annexure 6 NTAGI Subcommittee on pneumococcal vaccine http://mohfw.nic.in/NTAGI.pdf Annexure 7 Global health and the Bill and Melinda Gates Foundation Dabade G, Puliyel J. Lancet 2009;373:2195-6 http://jacob.puliyel.com/#paper_175 Annexure 8 ICMR reply to RTI on Anicut Hib probe study Annexure 9 Anuradha Bose Hindu 1/11/09 http://www.thehindu.com/health/article41824.ece Annexure 10 Bulletin of the World Health Organization | October 2008, 86 (10) doi: 10.2471/BLT.08.054692 . http://www.who.int/bulletin/volumes/86/10/08-056572.pdf Annexure 11 Pneumococcal vaccination in developing countries: where does science end and commerce begin? Mathew JL Vaccine. 2009;27:4247-51 Annexure 12 NTAGI Subcommittee Recommendations on Haemophilus influenzae Type b (Hib) Vaccine Introduction in India SUBCOMMITTEE ON INTRODUCTION OF HIB VACCINE IN UNIVERSAL IMMUNIZATION PROGRAM, NATIONAL TECHNICAL ADVISORY GROUP ON IMMUNIZATION, INDIA http://www.indianpediatrics.net/nov2009/945.pdf Annexure 13 1. Are Haemophilus influenzae Infections a Significant Problem in India? A Prospective Study and Review IBIS http://cid.oxfordjournals.org/content/34/7/949.full 2. Indian J Med Res 129, February 2009, pp 205-207 WHO study suggests low incidence of Hib in india is due to natural immunity http://www.icmr.nic.in/ijmr/2009/february/0216.pdf 3. Incidence of Haemophilus influenzae type b meningitis in India Indian J Med Res 128, July 2008, pp 57-64 Minz S et al http://www.icmr.nic.in/ijmr/2008/july/0711.pdf 4. Vaccine introduction where incidence of Hib meningitis is 0.007%: Decision-making based on health economic or ideology? Indian J Med Res 129, March 2009, pp 339-340 http://www.icmr.nic.in/ijmr/2009/march/0323.pdf 5. Journal of Clinical Epidemiology 62 (2009) 677e686 Inactivated influenza vaccines: Methods, policies, and politics T. Jefferson*, C. Di Pietrantonj, M.G. Debalini, A. Rivetti, V. Demicheli http://download.thelancet.com/flatcontentassets/H1N1-flu/vaccination/vaccination-48.pdf Final Report India Hib Vaccine Probe Study: Part A http://pdf.usaid.gov/pdf_docs/PNADM961.pdf Annexure 14 Association between type 1 diabetes and Hib vaccine http://www.bmj.com/content/319/7217/1133.1.extract Annexure 15 Pediatr Infect Dis J. 2007 Jul;26(7):565-71. Effectiveness of Haemophilus influenzae type B conjugate vaccine on prevention of pneumonia and meningitis in Bangladeshi children: a case-control study. Baqui AH, El Arifeen S, Saha SK, Persson L, Zaman K, Gessner BD, Moulton LH, Black RE, Santosham M. Annexure 16 Universal Hepatitis B vaccination is not cost effective Annexure 17 Manufacture of consent Hepatitis B Vaccination Y Madhavi http://www.jstor.org/pss/4413684 Annexure 18 Indian J Med Res 127, May 2008, pp 494-497 Hepatitis B in India: Systematic review & report of the ‘IMA sub-committee on immunization’ http://www.icmr.nic.in/ijmr/2008/may/0513.pdf Annexure 19 Health minister seeks cabinet nod for pentavalent combination vaccine. Joseph Alexander Pharmabiz. Annexure 20 15 Sep 2005 C H Unnikrishnan. Hepatitis B firms get shot in the arm Annexure 21 Cochrane Review: Combined DTP-HBV-HIB vaccine versus separately administered DTP-HBV and HIB vaccines for primary prevention of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae B (HIB) 1. Edna S Bar-On1,*, 2. Elad Goldberg1, 3. Abigail Fraser2, 4. Liat Vidal1, 5. Sarah Hellmann1, 6. Leonard Leibovici1 http://onlinelibrary.wiley.com/doi/10.1002/ebch.637/full Annexure 23 New combination vaccines: backdoor entry into India’s universal immunization programme? Current Science. Y. Madhavi http://www.ias.ac.in/currsci/jun102006/1465.pdf Annexure 24 Fiona Fleck. Children's charity criticises global immunisation initiative BMJ 2002;324:129 (Published 19 January 2002) http://www.bmj.com/content/324/7330/129.1.full Children's charity criticises global immunisation initiative BMJ 2002;324:129 (Published 19 January 2002) Annexure 25 Indian Pediatrics 2002; 39:327-330 Jacob John http://www.indianpediatrics.net/april2002/april-327-330.htm Annexure 26 Evidence-based National Vaccine Policy Indian J Med Res 131, May 2010, pp 617-628 http://www.centad.org/evidence_based_national_vaccine_policy.pdf
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  Selling vaccines: Deciding on who can afford HPV

  Indian Pediatrics 2009:46;647
  Aneja H, Puliyel J.
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  Pneumococcal vaccination in developing countries: where does science end and commerce begin?

  Vaccine. 2009;27:4247-51
  Mathew JL
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  Global health and the Bill and Melinda Gates Foundation

  Lancet 2009;373:2195-6
  Dabade G, Puliyel J.
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  Vaccine introduction where incidence of Hib meningitis is 0.007%: Decision-making based on health economic or ideology?

  Indian J Med Res. 2009;129;339-340
  Gupta N, Puliyel J.
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  Setting the Scene to Blame the GOI for Failure of Polio Eradication

  INDIAN PEDIATRICS 2009; 46:184-5
  Siddharth and Jacob Puliyel
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  WHO study suggests low incidence of Hib in india is due to natural immunity

  Indian J Med Res 2009;129: 205-207
  Neeraj Gupta & Jacob Puliyel
  Sir, We congratulate the authors of this meticulous study1. The authors found the incidence of Hib meningitis only 0.007 per cent and they speculate that the population may have ‘natural immunity’ to invasive Hib disease. This paper is published 10 years after the data were obtained. Three years ago an editorial published in the ‘Expert Review Pharmacoeconomics Outcomes Research’, cited this study as an instance of selective non-publication of research2. To understand the interest in t Show More...Sir, We congratulate the authors of this meticulous study1. The authors found the incidence of Hib meningitis only 0.007 per cent and they speculate that the population may have ‘natural immunity’ to invasive Hib disease. This paper is published 10 years after the data were obtained. Three years ago an editorial published in the ‘Expert Review Pharmacoeconomics Outcomes Research’, cited this study as an instance of selective non-publication of research2. To understand the interest in this paper it is useful to remember the context in which the study was done. Hib disease in Asia is very low – six in 100,000 compared with 109 in 100,000 in the Western Pacific3. The thrust of Hib research in Asia is to convince health planners that Hib was a major problem that had gone unrecognized due to poor microbiologic facilities and the technical inability to culture the organism. An Invasive Bacterial Infections Surveillance Group (IBIS) study performed over 4 years, in six large referral hospitals in India, employed sophisticated culture techniques to isolate the organism4. This study also revealed a remarkably low incidence of Hib disease4,5. Not convinced, the World Health Organization (WHO) undertook this large population-based study in Tamil Nadu, assuming that hospital-based study like the IBIS study would miss cases of meningitis that die in the community, before they reach the hospital. The very low incidence in this community based study, is therefore of great interest to epidemiologists and health planners. Unfortunately, because of this delay in publication, the data could not inform the debate prior to decision of the WHO to recommend Hib vaccine to all infants. We have previously suggested that ‘natural immunity’ (due to infections with bacteria with cross-reacting antigens) was the WHO study suggests low incidence of Hib in india is due to natural immunity reason for the low incidence of invasive Hib disease in India, and the reason why this population does not need vaccination with Hib6. It is gratifying that this is now borne out in a study supported by the WHO. We hope the government and public health planners will take note of this latest evidence against the need for Hib vaccine in India. Neeraj Gupta & Jacob Puliyel Department of Pediatrics St. Stephens Hospital Delhi 110 054, India puliyel@gmail.com References 1. Minz S, Balraj V, Lalitha MK, Murali N, Cherian T, Manoharan G, et al. Incidence of Haemophilus influenzae type b meningitis in India. Indian J Med Res 2008; 128 : 57- 64. 2. Arora R, Puliyel JM. Economic evaluation tailored to promote vaccine uptake: how third world consumers can respond. Expert Rev Pharmacoeconomics Outcomes Res 2005; 5 : 515-6. 3. Levine OS, Schwartz B, Pierce N, Kane M. Development, evaluation and implementation of Haemophilus influenzae type b vaccines for young children in developing countries: current status and priority actions. Pediatr Infect Dis J 1998; 17 (9 Suppl) : S95-113. 4. Invasive Bacterial Infections Surveillance (IBIS) Group of the International Clinical Epidemiology Network. Are Haemophilus influenzae infections a significant problem in India? A prospective study and review. Clin Infect Dis 2002; 34 : 949-57. 5. Watt JP, Levine O, Santosham M. Global reduction of Hib disease: what are the next steps? Proceedings of the meeting Scottsdale, Arizona, September 22–25, 2002. J Pediatr 2003; 143 (6 Suppl) : S163-87. 6. Puliyel JM, Agarwal KS, Abass FA. Natural immunity to Haemophilus influenzae in infancy in Indian children. Vaccine 2001; 19 : 4592-4.
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  Antenatal Diagnosis of Downs Syndrome: How Good is State of the Art

  Journal Indian Medical Association 2009;107:36-40
  Mittal R, Varghese RM, Puliyel JM.
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  Report of an ad-hoc WHO expert panel to review reports of serious AEFI following administration of pentavalent and other vaccines in Sri Lanka 2008

  Papers presented to Delhi High Court by the Government of India on Vaccine Petition of Dr KS Sexana et al
  WHO experts
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  Incidence of pneumonia is not reduced by pneumococcal conjugate vaccine

  Bulletin of the World Health Organization | October 2008, 86 (10) doi: 10.2471/BLT.08.054692 . http://www.who.int/bulletin/volumes/86/10/08-056572.pdf
  Sona Chowdhary & Jacob Puliyel
  http://www.who.int/bulletin/volumes/86/10/08-056572.pdf Incidence of pneumonia is not reduced by pneumococcal conjugate vaccine Sona Chowdharya & Jacob Puliyela a Department of Pediatrics, St Stephens Hospital, Tis Hazari, Delhi 110054, India. Correspondence to Jacob Puliyel (e-mail: puliyel@gmail.com). Madhi et al.1 write that the pneumococcal conjugate vaccine (PCV) is an effective instrument for pneumonia prevention in children. This is not strictly true. WHO data2 suggest that the Show More... http://www.who.int/bulletin/volumes/86/10/08-056572.pdf Incidence of pneumonia is not reduced by pneumococcal conjugate vaccine Sona Chowdharya & Jacob Puliyela a Department of Pediatrics, St Stephens Hospital, Tis Hazari, Delhi 110054, India. Correspondence to Jacob Puliyel (e-mail: puliyel@gmail.com). Madhi et al.1 write that the pneumococcal conjugate vaccine (PCV) is an effective instrument for pneumonia prevention in children. This is not strictly true. WHO data2 suggest that there are 450 million cases of pneumonia each year and that it causes 3.9 million deaths. In the sub-Saharan region of Africa, 1 022 000 die and 702 000 die in south Asia.1 The pneumonia referred to is “clinical pneumonia” – a diagnostic syndrome within the Integrated Management of Childhood Illness – WHO and United Nations Children’s Fund (UNICEF) system for triage and clinical management in developing countries.3 The Cochrane database4 states that PCV does not reduce the incidence of clinical pneumonia, although it has been shown to reduce vaccine-serotype bacteraemic pneumonia and radiological pneumonia. The benefit of reducing bacteraemic pneumonia and radiological pneumonia is so minimal that it has no effect on “clinical pneumonia”. Poor nations will need to assess its cost utility carefully. A study from the Gambia showed that mortality was 16% lower in a PCV immunized group compared to placebo recipients (25.2/1000 children years versus 30.1/1000 children years).5 Data are also provided on adverse effects and deaths within 1 week of receiving any dose of the vaccine or placebo. The mortality benefit was seen in the first week after injection, well before vaccine efficacy could have been established. There were 12 deaths in the vaccine group and 15 among controls (23.8/1000 children years versus 29.8/1000 children years). This suggests that factors other than vaccine efficacy are responsible for the difference in mortality between the groups compared. There is also another issue that we hope to raise here. The paper states that the vaccine programme would exceed the WHO threshold in 69 eligible countries. The authors assert that these findings are conservative in the sense that they did not assume any herd protection and did not assume protection beyond the age of 2.5 years. Beutels6 has cautioned against this trend of noting the “positive” uncertainties (herd immunity, protection beyond 2.5 years) without reporting the “negative” ones (serotype replacement,7 increased incidence of asthma),8 which could dampen enthusiasm for the intervention. References 1. Madhi SA, Levine OS, Hajjeh R, Mansoor OD, Cherian T. Vaccines to prevent pneumonia and improve child survival. Bull World Health Organ 2008;86:365-372. PMID:18545739 doi:10.2471/BLT.07.044503 2. Revised global burden of disease 2002 estimates. Geneva: WHO. Available from: http://www.who.int/healthinfo/bodgbd2002revised/en/index.html [accessed 5 August 2008]. 3. Integrated Management of Childhood Illness. Geneva: WHO; 2000. 4. Lucero MG, Dulalia VE, Parreno RN, Lim-Quianzon DM, Nohynek H, Makela H, et al. Pneumococcal conjugate vaccines for preventing vaccine-type invasive pneumococcal disease and pneumonia with consolidation on x-ray in children under two years of age. Cochrane Database Syst Rev 2004;CD004977. PMID:15495133 5. Cutts FT, Zaman SM, Enwere G, Jaffar S, Levine OS, Okoko JB, et al.; Gambian Pneumococcal Vaccine Trial Group. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial. Lancet 2005;365:1139-46. PMID:15794968 doi:10.1016/S0140-6736(05)71876-6 6. Beutels P. Potential conflicts of interest in vaccine economics research: a commentary with a case study of pneumococcal conjugate vaccination. Vaccine 2004;22:3312-22. PMID:15308354 doi:10.1016/j.vaccine.2004.03.001 7. Eskola J, Kilpi T, Palmu A, Jokinen J, Haapakoski J, Herva E, et al.; Finnish Otitis Media Study Group. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001;344:403-9. PMID:11172176 doi:10.1056/NEJM200102083440602 8. Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N; Vaccine Trialists Group. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003;349:1341-8. PMID:14523142 doi:10.1056/NEJMoa035060 Pneumococcal conjugate vaccine is efficacious and effective in reducing the burden of pneumonia Shabir A Madhi,a Orin S Levineb & Thomas Cherianc a Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, Chris Hani Baragwanth Hospital, Bertsham 2013, South Africa. b Health Section, United Nations Children’s Fund (UNICEF), New York, NY, USA. c Department of Immunization, Vaccines and Biologicals, World Health Organization, Geneva, Switzerland. Correspondence to Shabir A Madhi (e-mail: madhis@hivsa.com). While Chowdhary & Puliyel1 are correct that there has been a non-significant reduction in clinically diagnosed pneumonia in the vaccine-efficacy trials conducted to date, their assertion that pneumococcal conjugate vaccine (PCV) does not reduce severe pneumonia or reduce mortality in the Gambia is fundamentally flawed. Updated estimates indicate that there are 155.8 million clinical episodes of pneumonia globally, which contribute to approximately 1.9 million deaths, 70% of which occur in Africa and south-east Asia.2 The major drawback in evaluating the efficacy of PCV against “clinical pneumonia” is the lack of specificity of this clinical outcome measure that was designed for case management of pneumonia. It is therefore biased in favour of higher sensitivity, at the expense of specificity, rather than for vaccine efficacy trials. Indeed, a large proportion of the cases that meet the case definitions for clinical pneumonia have a low positive predictive value and are, therefore, not pneumonia.3 In the case management strategy, one accepts a level of over-treatment because of the important mortality reduction benefits. Nevertheless, that pneumococci contribute to significant pneumonia-related mortality is evident in the success of the WHO case-management strategy of pneumonia, which is premised upon early antibiotic therapy especially targeting S. pneumoniae and is associated with a 36% reduction in pneumonia-mortality.4 On the other hand, radiologically-confirmed pneumonia is a relatively more specific measure of bacterial pneumonia and so efficacy of vaccine on this outcome measure a better indicator of effect on pneumonia mortality. This outcome was indeed the primary outcome measure for determining efficacy of the vaccine against pneumonia, rather than the less specific measure of clinical pneumonia. The vaccine trials were thus not powered to measure efficacy against clinical pneumonia and it is not surprising that the efficacy estimate did not reach statistical significance. Furthermore, low specificity of the outcome measure leads to misclassification and a substantial underestimation of vaccine efficacy.5 The case fatality ratio in the Gambia trial was significantly greater in children with radiologically-confirmed pneumonia (3%) compared with clinical pneumonia cases that do not fulfil the criteria of radiologically-confirmed pneumonia (0.8–1.2%) even with access to antibiotic therapy.6 In the absence of antibiotics, this difference may have been even greater. Radiologically-confirmed pneumonia accounts for as much as 16.7–34% of cases of clinical pneumonia,6–8 The higher case fatality rate of radiologically-confirmed pneumonia and the higher impact of vaccine on this clinical outcome suggests that the impact of vaccine is more than a “minimal” contribution. Additionally, PCV is able to reduce pneumonia with an abnormal chest x-ray, but not defined as “radiologically-confirmed”, from 1.2–7% to 30–32% when the specificity of this outcome is improved for bacterial pneumonia by using a C-reactive protein of ≥ 40 mg/l as an adjunctive marker.9,10 Thus, the impact of vaccine on true pneumonia and pneumonia mortality are substantially greater than is indicated by the efficacy against “clinical pneumonia”. Additionally, vaccine-efficacy trials may underestimate the public health benefit of vaccines, as indicated by the indirect herd-protection observed following introduction of PCV into the United States of America11 and, more recently, the 39% reduction in the burden of clinical pneumonia hospitalization after PCV-introduction,12 compared to a non-significant 7% reduction in northern California during the vaccine-efficacy trial.13 It is only through the phased introduction of PCV, which has been shown to be safe and efficacious in children from diverse settings, that the true public health benefit of PCV would be realized in developing countries. This would however need to be coupled with robust surveillance systems to evaluate changes in the epidemiology of pneumonia before and after its introduction in representative populations of different regions of the world. The mortality benefit in the Gambian study was not evident only within 1 week of vaccination, but in fact mainly from 12 months onward when 238 of (72.1%) of the 330 PCV-recipients’ deaths and 289 (73.5%) of the placebo recipients’ deaths occurred.14 The rate of mortality within 7 days of any dose of study vaccine (n = 12; 0.15%) and placebo (n = 15; 0.18%; P = 0.55) did not differ between the two groups, and their calculated reported incidence calculations are incorrect. The higher rate of reactive airway disease observed in the South African study was not evident upon subsequent analysis following extended follow up of the cohort until an average of 6.3 years of age (S Madhi, personal communication). Additionally, the higher initially reported risk (1.3 per 1000 children) needs to be weighed against the net reduction of disease prevented, which was 3.6 per 1000 child years against radiologically-confirmed pneumonia alone.15 In conclusion, while we agree with the assertion that the use of PCV in developing countries needs to be weighed in relation to its cost and benefit, we believe that the potential benefit of PCV in developing countries is beyond question, as indicated by the WHO recommendation on PCV.16 Nevertheless, it is essential that the introduction of PCV be coupled with adequate surveillance at least in representative communities of regions in which it is introduced to fully establish the potential to public health of the vaccine. Reference 1. Chowdharya S, Puliyela J. Incidence of pneumonia is not reduced by pneumococcal conjugate vaccine. Bull World Health Organ 2008;86:XXX. 2. Rudan I, Tomaskovic L, Boschi-Pinto C, Campbell H. Global estimate of the incidence of clinical pneumonia among children under five years of age. Bull World Health Organ 2004;82:895-903. PMID:15654403 3. Cherian T, John TJ, Simoes E, Steinhoff MC, John M. Evaluation of simple clinical signs for the diagnosis of acute lower respiratory tract infection. Lancet 1988;2:125-8. PMID:2899187 doi:10.1016/S0140-6736(88)90683-6 4. Sazawal S, Black RE. Effect of pneumonia case management on mortality in neonates, infants, and preschool children: a meta-analysis of community-based trials. Lancet Infect Dis 2003;3:547-56. PMID:12954560 doi:10.1016/S1473-3099(03)00737-0 5. Jaffar S, Leach A, Smith PG, Cutts F, Greenwood B. Effects of misclassification of causes of death on the power of a trial to assess the efficacy of a pneumococcal conjugate vaccine in The Gambia. Int J Epidemiol 2003;32:430-6. PMID:12777432 doi:10.1093/ije/dyg082 6. Enwere G, Cheung YB, Zaman SM, Akano A, Oluwalana C, Brown O, et al. Epidemiology and clinical features of pneumonia according to radiographic findings in Gambian children. Trop Med Int Health 2007;12:1377-85. PMID:18045264 7. Madhi SA, Kuwanda L, Cutland C, Klugman KP. The impact of a 9-valent pneumococcal conjugate vaccine on the public health burden of pneumonia in HIV-infected and -uninfected children. Clin Infect Dis 2005;40:1511-8. PMID:15844075 doi:10.1086/429828 8. Magree HC, Russell FM, Sa'aga R, Greenwood P, Tikoduadua L, Pryor J, et al. Chest X-ray-confirmed pneumonia in children in Fiji. Bull World Health Organ 2005;83:427-33. PMID:15976893 9. Madhi SA, Klugman KP. World Health Organisation definition of “radiologically-confirmed pneumonia” may under-estimate the true public health value of conjugate pneumococcal vaccines. Vaccine 2007;25:2413-9. PMID:17005301 doi:10.1016/j.vaccine.2006.09.010 10. Cheung YB, Zaman SM, Ruopuro ML, Enwere G, Adegbola RA, Greenwood B, et al. C-reactive protein and procalcitonin in the evaluation of the efficacy of a pneumococcal conjugate vaccine in Gambian children. Trop Med Int Health 2008;13:603-11. PMID:18331385 11. Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease — United States, 1998-2003. MMWR Morb Mortal Wkly Rep 2005;54:893-7. PMID:16163262 12. Grijalva CG, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, Griffin MR. Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis. Lancet 2007;369:1179-86. PMID:17416262 doi:10.1016/S0140-6736(07)60564-9 13. Black SB, Shinefield HR, Ling S, Hansen J, Fireman B, Spring D, et al. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr Infect Dis J 2002;21:810-5. PMID:12352800 doi:10.1097/00006454-200209000-00005 14. Cutts FT, Zaman SM, Enwere G, Jaffar S, Levine OS, Okoko JB, et al. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial. Lancet 2005;365:1139-46. PMID:15794968 doi:10.1016/S0140-6736(05)71876-6 15. Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003;349:1341-8. PMID:14523142 doi:10.1056/NEJMoa035060 16. Pneumococcal conjugate vaccine for childhood immunization – WHO position paper. Wkly Epidemiol Rec 2007;82:93-104. PMID:17380597
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  Bubbling CPAP Reply in Indian Pediatrics.

  Indian Pediatrics 2008;45:942-3
  Kaur C, Puliyel J
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  A Simple Circuit to Deliver Bubbling CPAP Power point Slide Show

  http://www.slideworld.org/check1.aspx?q=A+Simple+Circuit+to+Deliver+Bubbling+CPAP&cx=006439031743921743230%3Awco__orfxxs&cof=FORID%3A11&as_filetype=ppt&newwindow=1#392
  Charanjit Kaur, Akatoli Sema, Rajbir S. Beri and Jacob M. Puliyel
  New Humidifier design
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  Diabetic ketoacidosis and cerebral edema: The story so far

  Abstract sent 20th International Congress of Pediatrics Teheran
  J Puliyel
  1. The Enigma of Death in DKA Death among children being treated for diabetic ketoacidosis (DKA) is something of an enigma: The deaths occur during treatment and has not declined in spite of the use of better human insulins and continuous infusions with accurate syringe pumps. 2. Overestimation of dehydration in DKA At an annual meeting of the British Pediatric Association an elegant paper was presented that suggested that iatrogenic over-hydration was perhaps responsible. The author Show More... 1. The Enigma of Death in DKA Death among children being treated for diabetic ketoacidosis (DKA) is something of an enigma: The deaths occur during treatment and has not declined in spite of the use of better human insulins and continuous infusions with accurate syringe pumps. 2. Overestimation of dehydration in DKA At an annual meeting of the British Pediatric Association an elegant paper was presented that suggested that iatrogenic over-hydration was perhaps responsible. The authors retrospectively studied the patients admitted with DKA in their hospital. They looked at the admission weight and the weight of children after rehydration - a couple of days later. From this they calculated the quantum of dehydration. They looked at this against the treating doctors assessment of dehydration at admission. The doctors had consistently overestimated the dehydration. Those with mild dehydration were classified as moderate dehydration and those with moderate dehydration were considered as having severe dehydration. Fluids were prescribed accordingly and it was speculated that this over-hydration could result in cerebral edema and death in this manner. Grove LM, Noble-Jamieson CM, Barnes ND, Challenger J. Assessment of dehydration, fluid balance and insulin requirements in diabetic ketoacidocis. Proceeding of the British Pediatric Association 7th annual meeting Abstracts 1995;67:27(pg 10) 3. Hypertonic dehyration the cause of overestimation of dehydration? I was present at this presentation and asked myself the question: Why would experienced pediatric doctors who estimated dehydration all the time in the context of gastroenteritis, consistently make this error when estimating dehydration in DKA? I developed a hypothesis that it was probable that children with DKA had hypertonic dehydration and that was the reason doctors were misled. Hypertonicity caused children to have parched dry tongues and associated with the acidosis of DKA they were judged to have severe dehydration when their fluid deficits were not so bad. I decided to test the hypothesis. We studied prospectively the serum osmolality (using the depression of freezing point method ) of children with DKA and found that the mean osmolality was indeed 318mOsm/kg (SD12.9 Range 297-337). This could result in over estimation of dehydration. The paper was presented at the 2nd European Pediatric Congress in Berlin Puliyel JM, Puliyel MM, Hincliffe R. Hypertonicity may contribute to overestimation of dehydration in diabetic ketoacidosis. 2nd European Pediatric Congress Berlin Germany. Abstract Book 1996 Endocrine and Metabolism 2 4. Hyperosmolity in DKA due to unmeasured substances like ketone bodies Having proved that DKA is associated with hypertonicity, we did a follow-up study to understand what caused the hypertonicity. We found the calculate osmolality [2 (Na + K) + Urea + Glucose] was within the normal range (275-295) but the measured osmolality (freezing point method) was above 300 in 22 of the children (55% cases). In 3 children measured osmolality was greater than 310mOsm/kg. We found that the main cause of increase osmolality was the presence in DKA of unmeasured substances like ketone bodies. This finding was presented at the International Symposium on Diabetes in Chaing Mai. Puliyel J, Puliyel M, Hincliffe R. Hypertonicity in diabetic ketoacidosis: Unexpected biochemical correlates and clinical implications. Prioceedings of International Symposium on Diabetes. Chaing Mai Thailand, 1997; 26-29 5. Lancet suggests that ketone bodies add to osmolality but not to osmotonicity of serum and so it cannot cause fluid shifts and cannot be responsible for hypertonic dehydration and thereby it cannot explain the overestimation of dehydration by doctors. Van der Meulen JA, KlipA, Grinstein S: Possible mechanism for cerebral oedema in diabetic ketoacidosis. Lancet, 1987; ii: 306-8 Paradoxically our study of increased osmolality due to unmeasured compounds contradicted our ‘hypertonicity causes overestimation’ theory. If hypertosmolality was due to ketone bodies it could not cause hypertonicity because according to an article in the Lancet ketone bodies are like urea and it moves across cell membranes freely and it cannot to produce fluid shifts. 6. A simple study that proves the assertion in the Lancet wrong Although the article in the Lancet asserted that ketone bodies do not exert osmotonicity no empirical evidence of this was provided. We there for devised a simple test to see if ketone bodies were osmotonic. A modified erythrocyte fragility test was used to check the osmotonic and osmoprotective effects of the ketone body. Red blood cells were suspended in different test tubes containing distilled water, normal saline, glucose, urea and acetoacetic acid (lithium salt C4H5O3Li). All solutions (except the tube with distilled water) were made to match the osmolality of plasma. We hypothesized that solutions in which red cell hemolysis does not take place have greater tonicity than the tonicity of 0.45% saline. Results: Spectrophotometry showed that there was no hemolysis in the solutions of normal saline or solutions containing glucose or acetoacetate. Complete hemolysis was demonstrated in the tube with plain distilled water and also in the solutions containing urea. Conclusion: This study shows that acetoacetate is functionally similar to glucose in that it contributes to increased osmotonicity. The drop in ketone body levels can produce a drop in the osmolar tonicity of plasma and precipitate cerebral edema. Puliyel JM. Osmotonicity of acetoacetate: possible implications for cerebral edema in diabetic ketoacidosis. Med Sci Monit 2003;9:BR130-3. 7. We recommended estimation of ketone bodies (or measured osmolality) and its gradual reduction in treating DKA We recommended that we measure real osmolality by the freezing point depression technique rather than calculated osmolality as this left out unmeasured substances like ketoacids that could cause fluid shifts. Puliyel JM, Bhambhani V. Ketoacid levels may alter osmotonicity in diabetic ketoacidosis and precipitate cerebral edema [letter]. Arch Dis Child 2003;88:366. This is impractical, as most centers do not have the equipment to measure osmolality. 8. Cerebral odema if serum sodium at admisson is less than 135mMol/L Excess ketones may drive down serum sodium making low sodium the marker of risk. Hoorn et al suggest that blood glucose must be brought down slowly. Hoorn E, Carlotti A, Costa L, et al. Preventing a drop in effective plasmaosmolality to minimize the likelihood of cerebral edema during treatment of children with diabetic ketoacidosis. J Pediatr 2007;150:467-73. A study of their data suggests a simple way to avoid cerebral odema. No child with a serum sodium greater than 135mMol/L at admission developed cerebral edema. We speculate that ketoacids drive the serum sodium levels down. The message now is to be careful if the child has serum sodium less than 135mmol/L. They are the ones that perhaps have high ketone levels and so susceptible to cerebral edema when the ketone levels come down with treatment. Akatoli Sema, Jacob M. Puliyel Cerebral edema in diabetic ketoacidosis with serum sodium <135 mEq/L Pediatr. 2008 Jan;152(1):145-6
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  Missing Girls in India: Infanticide, Feticide and Made-to-Order Pregnancies? Insights from Hospital-Based Sex-Ratio-at-Birth over the Last Century

  http://www.plosone.org/doi/pone.0002224. PLoS ONE 3(5): e2224. doi:10.1371/journal.pone.0002224.
  Mohit Sahni, Neeraj Verma, D. Narula, Raji Mathew Varghese, V. Sreenivas, Jacob M. Puliyel
  Introduction Data from the census of 2001 suggests that there are only 933 women for every1000 men in India [1]. In 1992 Amartya Sen calculated that 37 million women were ‘missing’ in India [2]. The UN in 2001 estimated that there were 44 million missing women in India [3]. Societal bias favoring males is responsible for the situation [4]. This bias manifests as neglect of girls and women resulting in their early death [5], [6], [7], female infanticide [8], [9] and more recently, antenatal se Show More...Introduction Data from the census of 2001 suggests that there are only 933 women for every1000 men in India [1]. In 1992 Amartya Sen calculated that 37 million women were ‘missing’ in India [2]. The UN in 2001 estimated that there were 44 million missing women in India [3]. Societal bias favoring males is responsible for the situation [4]. This bias manifests as neglect of girls and women resulting in their early death [5], [6], [7], female infanticide [8], [9] and more recently, antenatal sex determination and female feticide [10]. In India, ultra sound machines that permit non-invasive antenatal sex determination first became available in select centers in the late 1970s and became more widespread in the 1980s [11], [12]. Soon thereafter abortion of female fetuses were reported from many major cities of India [13], [14]. Several reports suggest that sex selective abortion became more common in the 1990s [15], [16]. Amartya Sen believes that the pattern of gender inequality shifted from ‘mortality inequality’ to what he calls ‘natality inequality’ due to female feticide after the facility for antenatal sex determination became available [11], [17]. Others suggest that parents are not substituting prenatal for post-natal discrimination against girls but combining the two strategies [18]. The relative contribution of these modes of discrimination, to the unbalanced sex ratio in India, is still unresolved [19]. The age specific sex ratio is used to determine the age at which women go ‘missing’. However infanticides, in the first few days, are often reported as still-births [19] or not reported at all within the incomplete birth registration system [9]. It is therefore difficult to assess the number of girl children ‘missing’ from the census data on account of sex selective abortion and the number lost due to early infanticide. Data on sex ratio at birth in hospital records can be crucial to estimate the influence of female feticide on the sex ratio as this is not affected by other factors like infanticide and neglect of girl children. This study was done to look at secular trends in the sex ratio at birth of babies born in a hospital over the last 110 years. We hypothesized that if female feticide is a factor affecting the sex ratio, there would be a fall in the newborn female to male sex ratio after the technology for antenatal sex determination became widespread in the1980s. Materials and Methods Records of 321991 babies delivered at the hospital (St Stephens Hospital, Tis Hazari, Delhi India) from 1900 to 2006 were available with the hospital records office. Data pertaining to an additional, approximately 700 deliveries, for the period 1907 to 1910 could not be accessed. We used data from the middle year of each decade to represent the sex ratio during that decade and as such we studied records from 1 July 1904 to 30 June 1905 for the first decade in the century and so on for each of the subsequent 10 decades. Some pages in the records for 1914 and 1934 were damaged due to improper storing and so, for those two decades, data from 1915–16 and 1935–36 respectively were collected. Data from 33,524 deliveries was taken as representative of the 321,991 deliveries at the hospital and these were the subjects of the present study. Of these, 197 deliveries were excluded due to incomplete recordings, or because ambiguous genitalia made gender assignment uncertain. Still births and abortions were excluded. For multiple pregnancies, each live born baby was recorded as a separate delivery. Mother's age, religion, maternal education and details of previous pregnancies were noted. Sex ratio was studied for each decade as number of girl babies born for every 1000 boys. We looked for statistical significance comparing the sex ratio for each decade with the overall average sex ratio. Data for each decade was combined with that of previous decades and compared to the data of subsequent decades to look for any change in the trend. For example in the analysis for changes after the fourth decade the century (1940–1949) we compared the sex ratio of babies born 1900–1949 with the sex ratio in babies born after that (1950–2005). Data on previous pregnancies and sex of previous children were available in the records only after 1970. Sex ratio in the second children born to mothers was also studied. This sex ratio was examined in mothers whose first child was a boy and separately in those whose first child was a girl. Data on the education status of mothers was available only from 1985. Approval of the hospital research committee was obtained for this retrospective study of hospital records and recording of the data in an anonymized manner with serial numbers. Formal ethics approval was therefore not obtained. Confidence interval (CI) for the sex ratios at different reference time periods were calculated and Chi-square test was used for assessing the statistical significance. Analyses of these were done using Stata version 9.1. To look for the difference in proportions of the sex ratios and their CI we used the software ‘Statistics with Confidence’ (www.som.soton.ac.uk). Results Figure 1 shows the data from the census of India on sex ratio declining gradually over the century. The hospital based sex ratio in each decade is depicted alongside. Data for the period prior to 1930 comes from a relatively small sample so detailed analysis is done only for the period after 1930. Table 1 shows the sex ratio at birth in each decade and also the analyses comparing sex ratio in the period after the reference decade with the sex ratio till that point. Overall, there were 910 girls to 1000 boys (95% CI; 891 to 930). The sex ratio in 1995 was 855 (CI: 816 to 895) and this was significantly lower than the overall average sex ratio of 910. The sex ratio was 782 (CI: 675 to 905) up to 1929 compared to 913 (CI: 893 to 933) (P = 0.04) in the decades that followed. The next big change in the evaluation of trends (columns d e f) was seen in 1979. The sex ratio for the decades up to 1979 was 935 (CI: 905 to 967) and it was 892 (868 to 918) for the decades after 1980 (P = 0.04). thumbnail Figure 1. Sex Ratio by Decade. doi:10.1371/journal.pone.0002224.g001 thumbnail Table 1. Sex ratio at birth in every decade from 1905 to 2005. doi:10.1371/journal.pone.0002224.t001 Table 2 looks at sex ratio in accordance with religion and Table 3 looks at sex ratio according to maternal education. There was no significant difference between groups. Table 4 looks at sex ratios in second children depending on the sex of the first child. The sex ratio in the second child if the first was a girl fell to 716 (CI: 672 to 762) girls per 1000 boys. The difference from the overall sex ratio of 910 girls was statistically significant (P<0.001). In contrast to this, there was an excess of girls, if the previous child were a boy. The sex ratio was 1140 girls per 1000 boys (CI: 1072 to 1212) (P<0.001). thumbnail Table 2. Sex ratio according to the religion (1905–2005). doi:10.1371/journal.pone.0002224.t002 thumbnail Table 3. Sex ratio according to the mother's education (1985–2005). doi:10.1371/journal.pone.0002224.t003 thumbnail Table 4. Sex ratio among the second order babies, depending on gender of first born. doi:10.1371/journal.pone.0002224.t004 Discussion Our study shows that the sex ratio at birth fell significantly in 1995 to 855 (girls per 1000 boys) when comparisons were made to the overall average sex ratio of 910 seen over the eleven decades. While looking for trends we found that the sex ratio for the period ‘1979 and earlier’ was significantly higher [935 (CI 905 to 967)] than the period ‘1980 and after’ [892 (CI 868 to 918) P = 0.04]. This fall in sex ratio coincided with the availability of ultra sound for antenatal sex determination [4], [12]. The Pre-natal Diagnostic Techniques (Regulation and Prevention of Misuse) (PNDT) Act that made antenatal sex determination and sex selective abortion illegal, was passed in 1994. It came into effect in 1996 [20]. Our data shows the sex ratio in 2005 (865 CI: 814 to 918) was not very different from that in the decade before the PNDT act came into effect (855 CI: 816 to 895). This suggests that the Act has had little impact on the problem. This is similar to the findings of others [21], [22], [23]. The sex ratio for the period prior to 1929 was 782 (CI: 675 to 905) compared to 913 (CI: 893 to 933) (P = 0.04) in the decades that followed. However the sample size for the period prior to 1929 was small and the CI for the difference in proportion between sex ratios was not significant at the 95% level of confidence. Our data showed no relation between the sex ratio and religion or years of education of the mother. This is in agreement with the findings of others who have shown that gender bias exists regardless of religion, caste and socio-economic class, although it seems that it is more prevalent among the middle classes compared to the poor [3], [7]. In our study we made no comparison between income groups. The concept of ‘missing women’ was highlighted by the Nobel laureate Amartya Sen to focus scholarly and public attention on this social problem [2]. He had said at that time that there were 100 million missing women world-wide of whom 37 million were missing in India. Using more sophisticated methodology, Klasen estimated in 1994 that the correct figure was 90 million missing women worldwide and that it would be 100 million by the year 2000 [24]. Ordinarily females have greater resistance to disease and overall greater longevity, so in circumstances where they have the same nutrition and healthcare (as males), females have lower mortality across all age groups [2]. The bleak situation for men is compounded by a greater tendency to engage in risk behaviour and violence which increases their risk of premature mortality [25]. This leads to there being more women than men. Sen in his original computation had used the female: male ratio of 1.022 observed in sub-Saharan Africa as the standard for comparison [2]. A decade after he made his original observation on missing women, Sen wrote in 2003 that female disadvantage in mortality had reduced substantially but this was counterbalanced by a new female disadvantage–that of natality through sex specific abortions against female fetus [11]. Compared to normal ratio of about 950 girls being born per 1000 boys as observed in Europe and North America, the ratio was 920 in Singapore and Taiwan, 880 in Korea and 860 in China. Data in this study suggests that the sex ratio in India after 1995 was similar to that in China (approximately 860) [11]. Biological explanations for some of the missing women have been offered. Nobel Laureate BS Blumberg has proposed that Hepatitis B can influence sex ratio. Carriers of hepatitis B have offspring sex ratio around 1.5 boys for each girl[26], [27], [28], [29]. Emily Oster [30] used this information alongside the Hepatitis B carrier rate in India to suggest that Hepatitis B can explain 20% of the missing women in India. The model however ignores the suggestion by Blumberg that while hepatitis B infection leads to an excess of boys, immunity to Hepatitis B moves the sex ratio in the opposite direction such that persons with anti-HBsAg tend to have more girls. The numbers of people with naturally acquired anti-HbsAg are much higher than the HbsAg carriers in India. In one study HbsAg carrier rate ranged from 0.9 to 4.1% but anti-HbsAg ranged from 12.9% to 18.4% [31]. This high prevalence of anti-HbsAg should have caused an excess of girls. Hepatitis B is therefore an unlikely explanation for the missing girls. Sex ratio at birth is also influenced by a host of other factors including infections like toxoplasma infection [32], smoking [33], maternal nutrition [34], and hormonal factors during pregnancy [35], [36]. There may be differences in the prevalence of these factors in different populations and this may be responsible for the differentials in sex ratio seen world wide. Jha et al found the adjusted sex ratio in India, if the first child was a girl was 759 per 1000 males and in contrast to this, it was 1102 females per 1000 males if the first were a boy [37]. This was evidence of sex selective feticide but could also result from non-reporting of infanticides or misclassification of infanticides as still births. Our study done on hospital deliveries was expected to obviate the misclassification problem. The study by Jha and the correspondence that followed showed up an interesting paradox. The research looking for ‘missing girls’, discovered also ‘missing boys’ (among families who have already had a boy). George in his comments on the paper by Jha et al has written that it would appear from the paper that 200,000 male feticides take place in India annually among those who have had a previous boy child [38]. As a researcher and activist, George writes that he has traveled to many parts of India looking for sex-selection practices but he has not come across selective male feticide reported even anecdotally. His conclusion was that the only plausible reason for Jha and colleagues' unusual birth order distribution was systematic undercounting of live-born girls. Our study also showed the same trend as shown by Jha et al.–that more girls are born as second children, if the first child was a boy [1140 girls (CI: 1072 to 1212) if the first child was a boy compared to 716 girls (CI: 672 762) born as second children when the first child was a girl. This trend was seen even in the data prior to 1980 (during an era when facility for antenatal sex determination was not widely available) [12]. This excess of girls born to families with previous boys is unlike data from other countries like China where the sex ratio in second children ‘normalized’ after the birth of the first boy. In China, Yi et al found that women whose first child was a daughter had a much greater chance of having a boy the next time (sex ratio 670 girls to 1000 boys) but the chance of having a girl if the first child was a boy was not significantly higher than the natural sex ratio at birth (sex ratio 987 girls to 1000 boys) [39]. The phenomenon wherein there is an excessive number of girls (even higher than the natural sex ratio at birth considered as 950–1000 girls to 1000 boys) born as the second children to families with a previous boy thus seems peculiar to India and dates back to a period when antenatal sex determination was not feasible. Further qualitative research is needed to elucidate the methods used in this form of sex selection. We have looked at sex ratio at birth over 110 years. We used hospital delivery data and so we can be confident the figures are not corrupted by infanticides. Our study however has one notable weakness. It relates to sex ratio of children born in a hospital. According to the National Family Health Survey 2 (1998–1999), two thirds of deliveries in India take place at home and outside of medical institutions. Our data cannot therefore be said to be representative of India. Further it may also be argued that if the sex of the child is known antenatally, there is a greater chance that male fetuses will be brought to the hospital for delivery and this could alter the ratio. This may be seen as an antenatal extension of the practice wherein boys are presented earlier in their illness and more frequently to the hospital [6]. However the data from second children delivered at this hospital shows that the majority of children are girls if the previous child was a boy, and this militates against the suggestion that boy fetuses are selectively bought to hospital for delivery. In conclusion, our data shows there was a fall in the sex-ratio at birth, temporally coinciding with the widespread availability of the technology for antenatal sex determination. The PNDT act has not improved the situation. There is therefore reason to further invigorate the campaign against this unethical practice. Furthermore and more notably our study of second children born before 1980 suggests that sex selection practices must have been in vogue prior to the advent of antenatal sex screening. This form of sex selection has mostly preferred boy children but has also manifested itself as a preference for girl children in some families with a previous boy. It is reasonable to assume that these traditional methods of sex selection have not been abandoned in the face of the availability of the more definitive technique of antenatal sex determination and selective abortion. More research is needed to understand these traditional methods. It is evident that mere legislation and the prosecution of a few high profile cases under the PNDT act cannot solve this social evil. Moves to address all forms of gender inequality with equal social and economic rights for males and females including the rights of inheritance are needed to strike at the causes for distortion of the sex ratio [40]. Author Contributions Conceived and designed the experiments: JP NV RV. Performed the experiments: MS NV DN RV. Analyzed the data: JP VS MS NV DN. Wrote the paper: JP VS MS NV DN RV. References 1. Census of India 2001 Provisional population totals http://www.censusindia.net (accessed 27/1/07). Find this article online 2. Sen A (1992) Missing women. Br Med J 304: 586–587. Find this article online 3. United Nations World population prospects: The 2000 revision: Highlights. New York: Population Division, Department of Economics and Social Affairs. 4. Sudha S, Rajan SI (1999) Female demographic disadvantage in India 1981–1991: Sex selective abortions and female infanticide. Development and Change Vol 30 Oxford Blackwell publishers ltd. pp. 585–618. 5. Ghosh S (1987) The female child in India: a struggle for survival. Bull Nutr Found India 8: 4. Find this article online 6. Chatterjee M (1990) A report on Indian women from birth to twenty. New Delhi: National Institute of Public Cooperation and Child Development. 7. Khanna R, Kumar A, Vaghela JF, Sreenivas V, Puliyel JM (2003) Community based retrospective study of sex in infant mortality in India. Br Med J 327: 126–130. Find this article online 8. George SFemale infanticide in Tamil Nadu, India: From recognition back to denial? Available at www.hsph.harvard.edu/grhf-asia/suchana /0224/george.html (accessed 27/1/07). Find this article online 9. Leidl PSilent springs: The tragedy of India's never-born girls. The State of World Population 2005, The promise of equality: Gender equity, reproductive health and the millennium development goals United Nations Population Fund. Available at http://www.unfpa.org/swp/2005/presskit/docs/india.doc (accessed 27/1/07). Find this article online 10. George S (2002) Sex selection/discrimination in India: contemporary developments. Reprod Health Matters 10: 190–2. Find this article online 11. Sen A (2003) Missing women revisited. Br Med J 327: 1297–1298. Find this article online 12. Grover A, Vijayvergiya R (2006) Sex ratio in India. Lancet 367: 1726. Find this article online 13. Ramanamma A, Bambawale U (1980) The mania for sons: an analysis of social values in South Asia. Social Science and Medicine 14B: 107. Find this article online 14. Patel V (1989) Sex determination and sex preselection tests in India: modern technique for femicide. Bulletin of Concerned Asian Scholars 21: 2. Find this article online 15. Gangadharan S (1991) Second sex or subordinate sex? The Economic Times April 18: Find this article online 16. Visaria PM (1991) Overall stability in growth not demographic inertia. The Economic Times April 18: Find this article online 17. Sen AK (2001) Many faces of gender inequality. Frontline 19 November 18: 4–14. Available at www.hindonnet.com/fl1822/1820040.htm (accessed on 27/1/07). Find this article online 18. Gupta MD, Bhat PNM (1997) Fertility decline and increased manifestation of sex bias in India. Population Studies 51: 307–315. Find this article online 19. George S, Rajaratnam A, Miller BD (1998) Female infanticide in rural India. Search Bull 12: 18–26. Find this article online 20. Gupta MD (2005) Explaining Asia's “Missing Women”: A New Look at the Data. Population and Development Review 31: 529–535. http://www.popcouncil.org/publications/pdr/vol31_3.html (accessed 27/1/07). Find this article online 21. Jaising I (2004) Preconception and Pre-natal diagnostic techniques act. A user's guide to the law. New Delhi: Universal Law Publishing Co. Pvt Ltd. 22. Arnold F, Kishore S, Roy TK (2002) Sex-selective abortions in India. Population and Development Review 28: 759–785. Available at http://www.popcouncil.org/publications/pdr/vol28_4.html (accessed 27/1/07). Find this article online 23. Bagga C (2005) Delhi is also capital of female foeticide. The Times of India 14 July: http://timesofindia.indiatimes.com/articleshow/1171449cms (accessed on 1/2/07). Find this article online 24. UNFPA (2001) Sex selective abortion and fertility decline: the case of Haryana and Punjab. New Delhi: United Nations Population Fund. 25. Kalsen S (1994) “Missing women” reconsidered. World Development 22: 1061–1071. http://ideas.repec.org/a/eee/wdevel/v22y1994i7p1061-1071.html (accessed 27/1/07). Find this article online 26. Waldron L (1993) Recent trends in sex mortality ratios for adults in developed countries. Soc Sci Med 36: 451–462. Find this article online 27. Chalnazarian A, Blumberg BS, London WT (1988) Hepatitis B and the sex ratio at birth: a comparative analysis of four populations. J Biosoc Sci 20: 357–370. Find this article online 28. Drew JS, London WT, Lustbader ED, Hesser JE, Bumberg BS (1978) Hepatitis B virus and sex ratio of offspring. Science 201: 687–692. Find this article online 29. Hesser JE, Economidou J, Blumberg BS (1975) Hepatitis B surface antigen (Australia antigen) in parents and sex ratio of offspring in a Greek population. Hum Biol 47: 415–425. Find this article online 30. Drew JS, Blumberg BS, Robert-Lambblin J (1986) Hepatitis B virus and sex ratio of offspring in East Greenland. Hum Biol 58: 115–20. Find this article online 31. Emily Oster (2005) Hepatitis B and the Case of the Missing Women. Journal of Political Economy 113: 1163–1216. Find this article online 32. Tandon BN, Irtshad M, Raju M, Mathur GP, Rao MN (1991) Prevalence of HBsAg & anti-HBs in children & strategy suggested for immunisation in India. Indian J Med Res 93: 337–339. Find this article online 33. Kankova S, Sulc J, Nouzova K, Frynata D, Flegr J (2007) Naturwissenschaften 94: 122–127. Find this article online 34. Fukuda K, Fukuda T, Shimizu T, Andersen CY, Byskov AG (2002) Parental periconceptional smoking and male: female ratio of newborn infants. Lancet 359: 1407–1408. Find this article online 35. Williams RJ, Gloster SP (1992) Human sex ratio as it relates to caloric availability. Soc Biol 39: 285–291. Find this article online 36. James WH (1996) Evidence that mammalian sex ratios at birth are partially controlled by parental hormone levels at the time of conception. J Theor Biol 180: 271–286. Find this article online 37. Jha P, Kumar R, Vasa P, Dhingra N, Thiruchelvam D, Moinedddin R (2006) Low male-to-female sex ratio of children born in India: national survey of 1.1 million households. Lancet 367: 211–218. Find this article online 38. George SM (2006) Sex ratio in India. Lancet 367: 1725. Find this article online 39. Yi Z, Ping T, Baochang G, Yi X, Bohma L, Yongping L (1993) Causes and implicactions of the recent increase in the reported sex ratio at birth in China. Population Development Review 19: 283–302. Find this article online 40. Hesketh T, Xing ZW (2006) Abnormal sex ratios in human populations: causes and consequences. Proc Natl Acad Sci U S A 103: 13271–13275. Find this article online
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  Poor nations are being lured into a debt trap

  BMJ, May 2008; 336: 974 - 975
  Jacob M Puliyel and Ashutosh Shrivastava
  Unmasking GAVI and Big Pharma: Rethinking Vaccine Access 9 April 2008 Previous Rapid Response Next Rapid Response Top Jacob M. Puliyel, Consultant Pediatrician and Head of Department St Stephens Hospital, Tis Hazari, Delhi 110054 India., Ashutosh Shrivastava Send response to journal: Re: Unmasking GAVI and Big Pharma: Rethinking Vaccine Access We are dismayed that the article �Rethinking global access to vaccines� has been published as an �Analysis� Show More...Unmasking GAVI and Big Pharma: Rethinking Vaccine Access 9 April 2008 Previous Rapid Response Next Rapid Response Top Jacob M. Puliyel, Consultant Pediatrician and Head of Department St Stephens Hospital, Tis Hazari, Delhi 110054 India., Ashutosh Shrivastava Send response to journal: Re: Unmasking GAVI and Big Pharma: Rethinking Vaccine Access We are dismayed that the article �Rethinking global access to vaccines� has been published as an �Analysis� article in the BMJ (1). The article has the hallmarks and specious logic of a story planted by the vaccine industry and we hope that in fairness to developing countries, you will provide comparable space to present the counter point and dispute the implications of the paper. HPV vaccine: The authors write, �Our difficulty in disseminating well established vaccines cast doubts on our ability to promote wide spread use of new ones such as for diarrhea associated with rotavirus infection and for human papillomavirus (HPV). Currently - -93% of 260,000 annual deaths from cervical cancer occur outside the 60 wealthiest countries� For a start, we would like to put these figures in its perspective. For the analysis let us assume that Gardasil, the vaccine against HPV related cervical cancer, covers all strains causing the cancer. (Actually Gardasil protects against 4 of the over-100 different strains of HPV and it protects against 70% of the strains presently associated with cervical cancer. It is not known if the infective strains will shift with time, with widespread use of the vaccine.) What will it cost to buy vaccines to avoid these 260,000 deaths? 21 million girls will have to be vaccinated each year, as they approach the age of 10 (2). The vaccine costs $400 per person. The total cost will be $8400 million. This program has to be sustained for over 20 years. Even if it prevents all cervical cancers, this would result in a mere 2% reduction of the mortality related to infective diseases. (The total deaths due to infective diseases is 10.9 million (2)) Let us assume that through very innovative pricing mechanisms, the cost of the vaccine comes down to $1 per dose. It will still cost $63 million for the vaccine alone, without including the cost of implementing the program and for injecting all these children. Rotavirus vaccine: The case for Gardasil has always been a little insecure because cervical cancers are not so common and the vaccine is exorbitantly expensive. Let us therefore examine the case for rotavirus vaccine � the other vaccine that the authors discuss in their introductory paragraph. The authors lament the fact that it causes 440,000 deaths each year. Let us assume that we have a vaccine that covers all the human strains (A CDC sponsored study by Ramani and Kang has shown bovine-human strain reassortment and emergence of several new strains (not covered by vaccines) in India (3)). 126 million children around 2 months of age will need to be vaccinated three times (378 million doses) (2). At the present public sector cost of $7/dose (4) the cost of the vaccine will be $7938 million. This expenditure will bring down the deaths due to infections by 4%. Vaccines and Market Forces: Clearly, vaccines are not invariably a public good. We need to lay to rest, the concept that immunizations are always cost-effective (5). In an ideal market with perfect information, if a vaccine is not cost-effective and not capable of yielding better returns than other uses of the resource (6), there will be no demand for that vaccine. The compulsion to increase demand for these vaccines is felt by the manufacturers not the consumer. That is why organizations like GAVI have to enter the picture and give grants-in-aid to poor countries to offload those vaccines. It is hoped that poor countries can be persuaded to continue to use the vaccine after the aid is withdrawn. Willy-nilly poor nations are lured into a debt trap by such schemes. All the time, these organizations (like GAVI) masquerade as philanthropic organizations. Drug trials among vulnerable populations: Traditionally vaccines are tested by multinational manufacturers in the USA and Europe and only later in developing countries, as supplies and competition increase, and the cost of vaccine come down. This is in accordance with the Helsinki Declaration that trials be done in populations who are directly to use the drug. Vaccine manufacturers want the rules changed. Chokshi and Kesselheim point out that Gardasil (the vaccine that costs over $400 for three doses needed to immunize one person) produced in the USA and Australia was tested in Brazil, India and Costa Rica (1). The cost of research is halved by conducting it in developing countries (7). The compensation needed to pay for adverse events is much lower. In an upside down world where profits are paramount, the authors write that this arrangement �could help meet international demand for low cost products� (1). The fates of human guinea pigs in developing countries don�t count for much. �Competing interests: None declared�: A casual reader of the article will notice it is written by a medical student and his teacher. However the BMJ demands to know more than just the names of the authors and it is published in small print. The article was written as the result of a �dialogue� with the former President of Merck Vaccines (1,8) and a few others. To some of us, that explains a lot. Email: puliyel@gmail.com References 1. Chokshi DA, Kesselheim AS. Rethinking global access to vaccines BMJ 2008;336:750-3 2. WHO Revised global burden of disease 2002 estimates http://www.who.int/healthinfo/bodgbd2002revised/en/index.html accessed on 8/4/08 3. Ramani S, Kang G. Burden of disease of group A rotavirus infection in India. Indian J of Med Res 2007;125:619-32 4. PATH Rotavirus. http://www.rotavirusvaccine.org/documents/RotaQA_Jan06.pdf accessed 8/4/07. 5. Jean-Pierre Le Clavez. GAVI funding and assessment of vaccine cost -effectiveness. Lancet 2007;369:189. 6. Dhanasiri SK, Puliyel JM. Regulating vaccines: Can health- economics tools be used profitably? Indian Pediatrics 2007;44:11-14 7. Sharma D. India pressed to relax rules on clinical trials. Lancet 2004;363:1528-9. 8. Global HIV Vaccine Enterprise. Adel Mahmoud http://www.hivvaccineenterprise.org/_dwn/news/mahmoud_bio.pdf accessed 8/4/08 Competing interests: None, except that we live in a developing country � India.
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  Ask The Doctor

  file:///C:/Documents%20and%20Settings/prem/Desktop/Ask.htm
  Jacob M. Puliyel
  Asthma, Seroflo under four, Poor eating, Slow child.
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  A Simple Circuit to Deliver Bubbling CPAP.

  Indian Pediatr. 2008 Apr;45(4):312-4.
  Kaur C, Sema A, Beri RS, Puliyel JM.
  Indian Pediatrics 2008; 45:-312-314 A Simple Circuit to Deliver Bubbling CPAP Charanjit Kaur, Akatoli Sema, Rajbir S Beri and Jacob M Puliyel From the Department of Pediatrics, St Stephens Hospital, Tis Hazari, Delhi 110 054, India. Correspondence to: J M Puliyel, Department of Pediatrics, St Stephens Hospital, Tis Hazari, Delhi 110 054, India. E-mail: puliyel@gmail.com Manuscript received: June 4, 2007; Initial review completed: September 15,  Show More...Indian Pediatrics 2008; 45:-312-314 A Simple Circuit to Deliver Bubbling CPAP Charanjit Kaur, Akatoli Sema, Rajbir S Beri and Jacob M Puliyel From the Department of Pediatrics, St Stephens Hospital, Tis Hazari, Delhi 110 054, India. Correspondence to: J M Puliyel, Department of Pediatrics, St Stephens Hospital, Tis Hazari, Delhi 110 054, India. E-mail: puliyel@gmail.com Manuscript received: June 4, 2007; Initial review completed: September 15, 2007; Revision accepted: November 19, 2007. Abstract Nasal continuous positive airway pressure (CPAP), especially ‘bubbling CPAP’, is known to reduce the need for more invasive ventilation. We here describe a circuit that can deliver bubbling CPAP in resource poor settings. We describe how the oxygen concentration can be altered from 98% to 21% oxygen using this system. Addition of a humidifier in the circuit has the effect of reducing the oxygen concentration by 1 to 5%. The cost of putting together the system is approximately Rs 5000. Key words: CPAP, Nasal, Newborn. Introduction In the quest to bring down the neonatal mortality rate, the challenge is to develop low cost technology that can be used in remote settings(1,2). It is known that early use of continuous positive airway pressure (CPAP) reduces the incidence of chronic lung disease(3) and it may be used as an alternative to intubation and ventilation is some cases(4-7). Recent literature suggests that ‘bubbling CPAP’ is better than conventional CPAP. The bubbling CPAP is a form of oscillatory pressure delivery in which mechanical vibrations are transmitted to the chest secondary to non-uniform flow of gas bubbles across the downstream of a water seal(8) and this system results in waveforms similar to those produced by high-frequency ventilation when recorded by a transducer attached to the infant’s airway. The chest vibrations produced contribute to gas exchange by facilitated diffusion(9). We describe a circuit which delivers bubbling CPAP, is easy to assemble and can be adapted for use in any health facility where oxygen and compressed air are available. Methods In its most basic form, pressurized oxygen from an oxygen cylinder is delivered to the nasopharynx of the baby. An under water ‘T tube’ that acts as a blow off valve is interposed between the oxygen source and the baby. Adjusting the height of the water column above the exit of the ‘T tube’ can regulate the pressure in the system and the amount of CPAP delivered to the baby. The constant bubbling of gas through the blow off mechanism delivers the bubbling CPAP effect. Oxygen may be delivered by nasal prongs or more cheaply by a shortened endotrachel tube or a nasopharyngeal catheter (8F) inserted into the nose to a depth equal to the distance from the side of the nose to the front of the ear so the tip of the catheter is just visible in the pharynx below the soft palate when the mouth of the infant is open(10). This system however delivers 100% oxygen and can harm premature babies. The system can be modified by having a Y tube deliver a mixture of air and oxygen from 2 separate cylinders. Flow meters indicate the flow rate of the gases and the relative concentration of oxygen. A humidifier can also be added so the gas mixture is not dry and it does not irritate the airway. This humidifier consists of a heating element that keeps the water at 37degrees centigrade and the air that passes over it is saturated with moisture at body temperature (Fig. 1). Fig. 1. Circuit for bubbling CPAP with blow-off valve 4 cm under water and autoclavable-glass humidifier unit. In centers where it is available, a saturation monitor can be used to adjust the air: oxygen mix to maintain saturations of 92 to 98% in the baby, and minimize the risk of oxygen toxicity. We have used different flow rates of oxygen and air and measured the resultant oxygen concentration using a MiniOX 111 oxygen meter. The readings were taken three times and the mean values are reported. The resultant table can help guide adjustment of flow rates to deliver the desired oxygen concentration. This is similar to the theoretical values achieved which are also shown in the table. For the theoretical calculations we assumed partial pressure of humidity saturated at 37ºC is 47 mm of Hg or approximately 5% of the total atmospheric pressure at sea level. The oxygen concentration is given by the formula: Final O2 concentration = n–n×5/100 where n is the oxygen concentration before saturation with humidity. Results Table I shows the oxygen mix when the total flow rate is 8 liters /minute and the ratio of air and oxygen is varied. The use of a humidifier reduces the oxygen concentration from 1% to 5% as shown in the Table. Table I Saturations of Oxygen Achieved with Different Flow Rates for Oxygen and Air Flow rate of Oxygen (L) Flow rate of air (L) Theoretical O2 concentration (%) (without humidity) Theoretical O2 concentration (%) (humidity saturated at 37ºC ) Mean saturation achieved in three tests (%) 8 0 100 95.0 98.7 7 1 90 86.5 84.5 6 2 80 76.0 72.5 5 3 70 66.5 61.3 4 4 60 57.0 53.6 3 5 50 47.5 38.8 2 6 40 38.0 23.5 1 7 30 28.5 21.2 0 8 20 19.0 21.2 Discussion CPAP helps maintain the functional residual capacity (FRC) of infants, prevents atelectasis, augments surfactant production, reduces fatigue in ventilatory muscles, provides respiratory stimulation against apnea and allows gas exchange(11). Oxygen is ideally used only in neonates who are continuously monitored. The flow mix of oxygen and air can be adjusted to keep the saturation around 96%. However in areas where saturation monitors are not available, bubbling air for CPAP would be safe. Bubbling CPAP has been found safe to be used by nurses(2). Use of the table provided in this study will help users to determine the quantities of oxygen being delivered to the child. A single prong CPAP, using a cut down endotracheal tube, or a large bore suction tube may be used. This has shown to be as comfortable for the baby as the more expensive nasal prongs(12). This is a cheaper alternative to nasal prongs. Mouth closure is not considered essential although it can raise pharyngeal pressure(13). The authors have utilized this system within their neonatal unit for the last 10 years both for neonates with respiratory distress prior to ventilation (with a view to reduce the need for mechanical positive pressure ventilation) and also for weaning from the ventilator. A commercial version of the CPAP system is available in the market for Rs 155,000. All elements of the system described here can be bought for Rs 500 ($10) except the humidifier which is available for Rs 4500 ($100). Widespread use of this system has the potential for saving lives in small hospitals where there is no facility for mechanical ventilation of babies. Contributors: RSB and JP conceived the project, CK and AS did the measurements. All authors contributed to the manuscript preparation. JP will be guarantor. Funding: None. Competing interests: None stated. What This Study Adds? • We describe a simple circuit to deliver bubbling CPAP in newborn infants. References 1. Bhargava SK. The challenge of neonatal mortality in India. Indian Pediatr 2004; 41: 657-662. 2. Koyamaibole L, Kado J, Qovu JD, Colquhoun S, Duke T. An evaluation of bubble-CPAP in a neonatal unit in a developing country: Effective respiratory support that can be applied by nurses. Trop Pediatr 2006; 52: 249-253. 3. Avery ME, Tooley WH, Keller JB, Hurd SS, Bryan MH, Cotton RB, et al. Is chronic lung disease in low birth weight infants preventable? A survey of eight centres. Pediatrics 1987; 79: 26-30. 4. Jacobsen T, Grønvall J, Petersen S, Andersen GE. "Minitouch" treatment of very low-birth-weight infants. Acta Paediatr 1993; 82: 934-938. 5. Gittermann MK, Fusch C, Gittermann AR, Regazzoni BM, Moessinger AC. Early nasal continous positive airway pressure treatment reduces the need for intubation in very low birth weight infants. Eur J Pediatr 1997; 156: 384-388. 6. Lindner W, Vossbeck S, Hummler H, Pohlandt F. Delivery room management of extremely low birth weight infants: spontaneous breathing or intubation? Pediatrics 1999; 103: 961-967. 7. Thomson MA. Early nasal CPAP + prophylactic surfactant for neonates at risk of RDS. The IFDAS trial. Pediatr Res 2001; 50: 304A. 8. Narendran V, Donovan EF, Hoath SB, Akinbi HT, Stteichen JJ, Jobe AH. Early CPAP and outcomes in ELBW preterm infants. J Perinatol 2003; 23: 195-199. 9. Kyong-Soon Lee, Dunn MS, Fenwick M, Shennan AT. A comparison of underwater bubble CPAP with ventilator derived CPAP in premature neonates ready for extubation. Biol Neonate 1998; 73: 69-75 10. Frey B, Shann F. Oxygen administration in infants. Arch Dis Child Fetal Neonatal Ed 2003; 88: F84-F88. 11. Millar D, Kirpalani H. Benefits of non-invasive ventilation. Indian Pediatr 2004; 41: 1008-1017. 12. Ahluwalia JS, White DK, Morley CJ. Infant flow driver or single prong nasal continuous positive airway pressure: short-term physiological effects. Acta Paediatr 1998; 87: 325-327. 13. De Paoli AG, Morley C, Davis PG. Nasal CPAP for neonates: what do we know in 2003? Arch Dis Child Fetal Neonatal Ed 2003; 88: F168- F172.
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  Cerebral edema in diabetic ketoacidosis with serum sodium below 135 mEq/L

  J Pediatr. 2008 Jan;152(1):145-6;
  Sema A, Puliyel JM.
  Cerebral edema in diabetic ketoacidosis with serum sodium below 135 mEq/L Hooran et al1 have studied a group of patients with diabetic ketoacidosis (DKA) and cerebral edema (CE) against 2 control groups without CE, one with and the other without hypernatraemia. They suggest that a gradual decrease in plasma glucose and a concomitant increase in serum sodium, decrease the likelihood of CE. This finding takes us a little closer to understanding CE in DKA. However our analysis of their data s Show More...Cerebral edema in diabetic ketoacidosis with serum sodium below 135 mEq/L Hooran et al1 have studied a group of patients with diabetic ketoacidosis (DKA) and cerebral edema (CE) against 2 control groups without CE, one with and the other without hypernatraemia. They suggest that a gradual decrease in plasma glucose and a concomitant increase in serum sodium, decrease the likelihood of CE. This finding takes us a little closer to understanding CE in DKA. However our analysis of their data shows that there is a characteristic of the CE group that has not been highlighted by the authors which may be crucial. The CE group had significantly lower levels of serum sodium at the start of therapy, than even the ‘low sodium control group’ (LSCG). The 95% confidence intervals (CI) lies below the normal serum sodium threshold (135 mEqL), while the CI in the LSCG lies above this threshold. We have previously shown that DKA patients have raised osmolality (measured osmolality evaluated by depression of freezing point) and that they have a large osmolar gap (Osmolar gap = Measured osmolality (-) Calculated osmolality); (Calculated osmolality = 2 ×PNa + P Glucose (in mmol/l)2. Unmeasured substances like ketoacids are responsible for the osmolar gap. Using a modified red-blood-cell saline fragility test, we have previously shown that ketoacids are osmotonic in nature, and that they cause fluid shifts across cell membranes3. Ketoacids are also responsible for the effective osmolality like glucose in DKA. The finding of significant hyponatraemia before the onset of treatment, in patients with CE by Hooran and colleagues, ties in with our observations. Patients with DKA and a high serum osmolality [due to high levels of glucose (a measured substance) and high ketoacid levels (unmeasured)], will respond with reduced serum sodium levels in an effort to maintain serum osmolality as close to normal as possible. Treatment of DKA results in a fall in glucose and ketoacid levels. Physicians know to be careful to bring down levels of glucose gradually but they are not aware how quickly ketoacid levels are changing. We believe that Hoorn et al have shown that a serum sodium level below 135mEq/L before treatment, is a risk factor for development of CE and this may be a pointer to the high levels of unmeasured osmotic substances in the blood. Further we reiterate that patients with DKA should have serum osmolality measured objectively by techniques like the depression of freezing point as this provides a clearer index of the changes being brought about during the treatment of DKA 4. Akatoli Sema DCH Jacob M Puliyel MD MRCP M Phil Department of Pediatrics St Stephens Hospital, Delhi 110054 India puliyel@gmail.com References 1. Hoorn EJ, Carlotti AP, Costa LA, MacMohan B, Bohn G, Zietse R, Halperin ML, Bohn D. Preventing a drop in effective plasma osmolality to minimize the likelihood of cerebral edema during treatment of children with diabetic ketoacidosis. J Pediatr. 2007;150:467-73. 2. Puliyel J, Puliyel M, Hincliff R. Hypertonicity in diabetic ketoacidosis: Unexpected biochemical correlates and clinical implications. Joint Meeting of International Symposium on Diabetes and Endocrine disorders of the young and 4th Asian Symposium of Childhood and Juvenile Diabetes: Chaing Mai Thailand Jan 26-9 1997 3. Puliyel JM. Osmotonicity of acetoacetate: possible implications for cerebral edema in diabetic ketoacidosis. Med Sci Monit. 2003;9:BR130-3. 4. Puliyel JM, Bhambhani V. Ketoacid levels may alter osmotonicity in diabetic ketoacidosis and precipitate cerebral edema. (Letter) Arch Dis Child. 2003; 88:366.
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  Authors reply Cerebral edema in diabetic ketoacidosis with serum sodium below 135 mEq/L

  J Pediatr 2008 Jan;152(1):147-9
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  Estimation of true incidence of polio: Some metodological issues.

  Ind Pediatrics 2008;45:158-9
  Rajib Dasgupta, Sanjay Chaturvedi,
  Estimation of "True Incidence" of Polio: Some Methodological Issues A recent report(1) has claimed that the true incidence of polio (due to wild polio virus) in India was 1625 in 2006 and not 674 as officially notified. The authors’ notions of "true incidence" and "misclassification" call for careful examination as they challenge the sensitivity of Acute Flaccid Paralysis (AFP) surveillance. Our methodological objections are as follows: 1. Computation of probability needs to be based on  Show More...Estimation of "True Incidence" of Polio: Some Methodological Issues A recent report(1) has claimed that the true incidence of polio (due to wild polio virus) in India was 1625 in 2006 and not 674 as officially notified. The authors’ notions of "true incidence" and "misclassification" call for careful examination as they challenge the sensitivity of Acute Flaccid Paralysis (AFP) surveillance. Our methodological objections are as follows: 1. Computation of probability needs to be based on the assumption that the trials (denominator) are independent of each other and the outcomes (numerator) are independent of each other. In this case two stool samples taken from a child is incorrectly considered as independent samples. Therefore, number in the denominator i.e., 1286 which comes from 643 children (i.e., two samples per subject) are not independent; and the outcomes (growth of virus) on two samples from a subject are also not independent. If a child is truly a case of polio then the chances of getting virus grown on both the samples is more, though not always. The authors have considered that "both sample results are independent of each other". For the 148 cases that had one sample negative for WPV, a sample testing positive for pild polio virus (WPV) in Round I implies that the sample from the same AFP case was negative in Round II and vice versa. Therefore, it is incorrect to consider two stool samples taken from the same child as independent samples(2). 2. For those 148 children where one of the two samples was negative, labelling these 148 samples as ‘false negative’ is incorrect. While labelling a sample as false negative there is always a reference. These 148 samples can be labelled as false negative only when there is a superior method than the method in question to show that these 148 samples actually had the virus that was not grown by the candidate method. It is incorrect to label one of the stool samples as ‘false negative’ by retrospectively considering the virological status of child (which is based on any of the stool samples being positive). For any analysis of the performance of a diagnostic test the units of study/analysis must remain the same i.e. both the test result and the disease status have to be on the same unit of study. In this case, there are two units (child and the stool sample) and the authors have used these two units interchangeably. While labelling a stool sample as false negative they have compared the growth of virus at the stool level in the second sample and the true disease status at the child level. Two stool samples are sent for the culture of polio virus to increase the sensitivity of the test. Other examples of similar approach are: sputum testing in RNTCP and stool examinations to diagnose worm infestation. In the two-by-two analysis, for sensitivity and specificity all four cells, including the one which includes disease negative and test negative subjects/samples, should be consi-dered(3). The authors have not included ‘both negatives’ (24,771 cases); the probability estimates would therefore be biased upwards with compromised validity. 3. The authors have retrospectively computed ‘two’ sensitivity figures–one, if a single sample was received and another, if two samples are received. However, it is not feasible to estimate the sensitivity of the yield of polio virus from the stool collected during AFP surveillance in its current form because no gold standard is used for the purpose. Proxy markers like enterovirus isolation rates indicate well functioning surveillance system. ‘Insensitivity’ is not an appropriate jargon in this context. While all efforts that can enhance our understanding of virological classification are welcome, careful attention needs to be paid to methodological details. The assertions made in the report need careful re-examination. Rajib Dasgupta, Assistant Professor, Center of Social Medicine & Community Health, Jawaharlal Nehru University, New Delhi. Email: dasgupta_jnu@yahoo.com and Sanjay Chaturvedi, Professor of Community Medicine, University College of Medical Sciences, Delhi, India. References 1. Sreenivas V, Puliyel JM. Estimation of true incidence of polio: Overcoming misclassification errors due to stool culture insensitivity. Indian Pediatr 2007; 44: 596-597. 2. Mahajan BK. Methods in Biostatistics. New Delhi: Jaypee Brothers; 2006. 3. Hennekens CH, Buring JE. Epidemiology in Medicine. Boston/Toronto: Little Brown and Company; 1987; p. 331-335.
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  Estimation of true incidence of polio: Some metodological issues. REPLY

  Indian Pediatrics 2008; 45:158-159
  Puliyel J, Sreenivas V.
  Reply 1. We explicitly stated in our paper that we have assumed that the chance of one of the two stool samples being negative is independent of the result in the other while calculating the ‘false negatives’. Cases of polio may be misclassified as ‘non-polio AFP’ because culture techniques are not perfect, methods used for collection, storage and transport of stool samples are sub-optimal, and viral shedding is not continuous. The fact that the excretion of virus in the stool is intermi Show More...Reply 1. We explicitly stated in our paper that we have assumed that the chance of one of the two stool samples being negative is independent of the result in the other while calculating the ‘false negatives’. Cases of polio may be misclassified as ‘non-polio AFP’ because culture techniques are not perfect, methods used for collection, storage and transport of stool samples are sub-optimal, and viral shedding is not continuous. The fact that the excretion of virus in the stool is intermittent adds credence to our assumption of the independence between two stool specimens. However, we agree with the correspondents that ‘if a child is truly a case of polio, then the chances of getting virus grown on both the samples is more’. Our assumption of independence of the two samples is, therefore, likely to underestimate (rather than overestimate) the number of polio cases misclassified as non-polio AFP. Dasgupta and Chaturvedi are concerned that our estimates put the number of polio higher than the ‘officially notified’ figure. Their methodology would in fact, erode the credibility of the official figure even more! 2. We agree that where two stool samples are sent for the culture of polio virus it increases the sensitivity of the test. We were concerned that many children had only sent in one sample for testing and in these children the sensitivity of the test is decreased. Inclusion of the ‘24,771 cases when both tests were negative’ in a two by two analysis is necessary if one is interested in calculating the sensitivity, specificity etc., which was not our aim. We tried to derive the true number of polio cases in the community, by estimating the ‘missed’ cases. 3. We agree that it is not feasible to estimate the sensitivity of the yield of polio virus from the stool collected during AFP surveillance in its current form because no gold standard is used for the purpose. However we have our reservations about the proxy markers and here too there is no gold standard estimates for the correspondent to make this claim! We are as concerned as the correspondents, to ensure that polio is eradicated from our country at the earliest. However, effective program planning needs accurate data and not ‘feel good figures’. We undertook the present exercise only to allow a more realistic post intervention figure to emerge. It is not perfect, but is a conservative estimate. The method suggested by the correspondents would have yielded higher estimates. V Sreenivas, Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India. and Jacob Puliyel, St Stephens Hospital, Tis Hazari,
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  Vaccines: Policy for Public Good or Private Profit?

  Indian Journal of Medical Research 2008;127:1-3
  Puliyel JM, Madhavi Y
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  Retinopathy of prematurity in South Africa: an assessment of needs, resources and requirements for screening programmes

  Br. J. Ophthalmol.2008;92:879-882
  S Varughese, C Gilbert, C Pieper, C Cook.
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  RCPCH Spring Meeting, York, 15th April 2008. Abstract : . International collaboration validating SICK score: a non-invasive severity-of-illness assessment.

  Archives of Disease in Childhood 2008; 93 Suppl 1: A10 [paper].
  Gupta MA, Sahni M, Puliyel JM, Rangasami J, Chakrabarti A, Halstead R*, Green DA, Puliyel A, Sreenivas V.
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  Hepatitis B in India: Systematic review & report of the ‘IMA sub-committee on immunization’

  Indian J Med Res. 2008;127:494-497
  Jacob M. Puliyel, Pallav Rastogi & Joseph L. Mathew
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  Swan-neck sign of the big toe - association with hypocalcaemia.

  Trop Doct. 2007 Oct;37(4):238-9.
  Agarwal KS, Baijal N, Tiwari L, Verma N, Sahni M, Puliyel JM.
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  Protective efficacy of a monovalent oral type 1 poliovirus vaccine

  www.thelancet.com Vol 370 July 14, 2007 Pages 129-30
  Jacob Puliyel, C Sathyamala, D Banerji.
  Protective efficacy of a monovalent oral type 1 poliovirus vaccine We the undersigned are shocked and dismayed that the Lancet should have published the paper on the protective efficacy of monovalent oral type 1 poliovirus vaccine by Grassly et al (April 21, p1356)1, having overlooked the serious ethical issues involved. The article describes how the international oversight body on polio eradication recommended the rapid development licensing and introduction of a new monovalent type 1 ora Show More... Protective efficacy of a monovalent oral type 1 poliovirus vaccine We the undersigned are shocked and dismayed that the Lancet should have published the paper on the protective efficacy of monovalent oral type 1 poliovirus vaccine by Grassly et al (April 21, p1356)1, having overlooked the serious ethical issues involved. The article describes how the international oversight body on polio eradication recommended the rapid development licensing and introduction of a new monovalent type 1 oral vaccine for India. The WHO (and its organ, The National Polio Surveillance Project (NPSP), from where some of the authorship of this article was drawn) was party to this accelerated introduction of the new vaccine in the country. What was introduced, according to this article, was a new vaccine that was five times more potent than previous vaccines, presumably also with increased likelihood of adverse effects. No informed consent was taken nor was the public told that the vaccine was experimental. In fact the truth was carefully hidden from the public and the doctors in India. Efforts were made to give the impression that the monovalent vaccine was not new but just the monovalent vaccine used in the 1960s, before the introduction of the trivalent vaccine2. This was exactly what was stated and propagated to the public through an article published in the journal of the Indian Medical Association and circulated to 178,000 doctors in the country2. The oversight body which introduced this vaccine should have monitored adverse effects also. Now the oversight body, who set up this massive experiment on human subjects without informed consent, have published a paper without ethics approval, saying it was not a prospective intervention study. In the absence of proper post-vaccination surveillance of adverse effects we have to rely on indirect evidence of possible adverse effects available from the NPSP3. Data from Uttar Pradesh (where Grassly and colleagues show improved vaccine efficacy) shows an increase in the incidence of non-polio acute flaccid paralysis since the introduction of the monovalent vaccine3. Jacob Puliyel, C Sathyamala, D Banerji. puliyel@vsnl.com St Stephens Hospital, Delhi 110054, India (JP); Public Report on Health, Council for Social Development, 53 Lodhi Estate New Delhi (CS) and Centre for Social Medicine and Community Health, Jawaharlal Nehru University, New Delhi, India (DB)
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  Point prevalence of hepatitis B in mother-child dyads in a stratified random sample in an urban resettlement community in Delhi

  Ind J Gastroentrology 2007;26:July 193-4
  Toteja Tanmay, Satyamala C, Chowdhary Sona, Lata Suman, Puliyel Jacob
  Point prevalence of hepatitis B in mother-child dyads in a stratified random sample in an urban resettlement community in Delhi Toteja Tanmay1, Satyamala C2, Chowdhary Sona1, Lata Suman1, Puliyel Jacob1 1 Department of Pediatrics St Stephens Hospital, Delhi 110 054, India 2 Public Report on Health, Department of Social Welfare, 53 Lodhi Estates, New Delhi, India Correspondence Address: Puliyel Jacob Department of Pediatrics St Stephens Hospital, Delhi 110 054 India puliyel@vsnl.com  Show More...Point prevalence of hepatitis B in mother-child dyads in a stratified random sample in an urban resettlement community in Delhi Toteja Tanmay1, Satyamala C2, Chowdhary Sona1, Lata Suman1, Puliyel Jacob1 1 Department of Pediatrics St Stephens Hospital, Delhi 110 054, India 2 Public Report on Health, Department of Social Welfare, 53 Lodhi Estates, New Delhi, India Correspondence Address: Puliyel Jacob Department of Pediatrics St Stephens Hospital, Delhi 110 054 India puliyel@vsnl.com How to cite this article: Toteja T, Satyamala C, Chowdhary S, Lata S, Puliyel J. Point prevalence of hepatitis B in mother-child dyads in a stratified random sample in an urban resettlement community in Delhi. Indian J Gastroenterol 2007;26:193-4 How to cite this URL: Toteja T, Satyamala C, Chowdhary S, Lata S, Puliyel J. Point prevalence of hepatitis B in mother-child dyads in a stratified random sample in an urban resettlement community in Delhi. Indian J Gastroenterol [serial online] 2007 [cited 2007 Nov 5];26:193-4. Available from: http://www.indianjgastro.com/text.asp?2007/26/4/193/36925 There have been no community studies, employing epidemiologically valid sampling techniques, looking at prevalence of hepatitis B in India [1] . We did this study to see how many mothers and children were HBsAg positive, and to estimate the number of children who can be protected by selective immunization of HBsAg positive mothers. [2] A cluster of approximately 20,000 households with a population of about 100,000 persons in a resettlement colony in East Delhi was selected. 600 households were chosen by stratified random method. All 302 households with children-under-5 years were approached. Written informed consent was obtained. Mother and their children were considered as dyads for analysis. Blood was tested using HEPACARD HBsAg spot test. (Hepaacard; J Mitra, New Delhi: Test sensitivity 99%, specificity 100%) Every posi­tive sample was tested a second time for confirma­tion. The study had the approval of the hospital research committee. 156 households with 242 children consented to participate and provided blood samples; 17 samples were lost so 148 mothers and 231 children were tested. The group that participated in the study was similar to the non-participators in economic and religious groupings. Five mothers were HBsAg positive (point preva­lence 3.38% [proportion 0.034; 95% CI 0.015-0.077]. [2] 3 children were positive (point prevalence 1.30% [proportion 0.013; CI: 0.004-0.037]). The 5 moth­ers who tested positive had 9 children, of whom 3 were positive. All these 3 were children of the 5 HBsAg-positive mothers. Three of 9 children of HBsAg-positive mothers presumably got infection vertically. The anti-HBs status of children was not tested; so it is not clear how many others acquired the infection and cleared it subsequently. A study by Nayak et al, [3] like our study, sug­gested that 33% of chronic carriers in India get the infection from their mothers. Immunization at birth targeted at babies of HBsAg-positive mothers will reduce this 33% of infection and also horizontal spread from this group. Another study also looking at mother­child dyads but not utilizing random sampling tech­niques, recruiting 400 children and their mothers, found that 2.25% of children below five were HBsAg positive. [4] The authors concluded that vertical trans­mission is responsible for the majority of chronic carriers. Cost constraints in India stand in the way of universal immunization at birth. Other alternatives are universal immunization starting at 6 weeks or selective immunization at birth to babies of HBsAg­positive mothers. [5],[6] Immunization at 6 weeks will not protect against vertical transmission. Also, cov­erage with immunization is unlikely to be complete; those who are not immunized are at risk from the pool of children who get the infection vertically. A systematic review of world literature found that was no study has demonstrated that the carrier rate can come down with immunization starting af­ter 6 weeks. [7] Further community-based studies are needed before a final answer is available. Acknowledgements: Funding for the test kits was made available from research fund, St. Stephen's Hospital. We gratefully acknowledge help from Dr. Y Singh, Dr. Kirti Sharma, Mr Pawan Wadhwa, Ms. Meetu Gupta of the Institute of Genomics and Integrative Biology, Delhi in testing the samples. The assistance received from the Community Health Project, Seemapuri, especially from Mrs. Chaya Sharma and Mrs. Chaya Devi, is also acknowledged. » References Top 1. Batham A, Narula D, Toteja T, Sreenivas V, Puliyel JM. Systematic review and meta-analysis of data on point prevalence of hepatitis B in India. Indian Pediatr (In press). Back to cited text no. 1 2. Altman DG, Machin D, Bryant TN, Martin J, Gardner MJ. CIA software Statistics with confidence BMJ Books, London. Back to cited text no. 2 3. Nayak NC, Panda SK, Zuckerman AJ, Bhan MK, Guha DK. Dynamics and impact of perinatal transmission of hepatitis B virus in north India. J Med Virol 1987;21:137­-45. Back to cited text no. 3 [PUBMED] 4. Chakravati A, Rawat D, Jai NM. A study on perinatal transmission of hepatitis B virus. Indian J Med Microbiol 2005;23:128-30. Back to cited text no. 4 5. Mittal SK, Rao S, Rastogi A, Aggarwal V, Kumari S. Hepatitis B potential of perinatal transmission in India. Trop Gastroenterol 1996;17:190-2. Back to cited text no. 5 [PUBMED] 6. Lodha R, Jain Y, Anand K, Kabra SK, Pandav CS. Hepatitus B in India: a review of disease epidemology. Indian Pediatr 2001:38;349-71. Back to cited text no. 6 7. IMA position paper on hepatitis B immunization: issues related to hepatitis B vaccination: systematic review of literature. http://www.imanational.com/ (Accessed on April 20, 2007). Back to cited text no. 7
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  Research on Hib vaccine 'dubious'

  http://www.scidev.net/EditorLetters/index.cfm?fuseaction=readeditorletter&itemid=119&language=1
  Jacob Puliyel
  Research on Hib vaccine 'dubious' * Author: Jacob M Puliyel, M.D. Affiliation: Head of Paediatrics St Stephens Hospital Delhi, India Date: 10 July 2007 I was quoted in the Hib vaccine news story from 4 July (see Hib vaccine could save thousands in Asia), but perhaps due to constraints of column space, I feel justice was not done to what I said. My main argument against the research findings from Bangladesh is not that it does not make economic sense, but that the study is seriou Show More...Research on Hib vaccine 'dubious' * Author: Jacob M Puliyel, M.D. Affiliation: Head of Paediatrics St Stephens Hospital Delhi, India Date: 10 July 2007 I was quoted in the Hib vaccine news story from 4 July (see Hib vaccine could save thousands in Asia), but perhaps due to constraints of column space, I feel justice was not done to what I said. My main argument against the research findings from Bangladesh is not that it does not make economic sense, but that the study is seriously flawed. The visible enthusiasm of the sponsors of the study must not be allowed to cloud scientific objectivity. In the study, cases of pneumonia were compared with a control group without pneumonia. Because more children in the control group received the Hib vaccine, the researchers considered the vaccine to prevent pneumonia. But closer reading of the paper suggests that the Hib vaccination status in the control children was only coincidental. The control children were significantly richer, lived in better houses and their mothers were better educated. With their greater affluence, more children in the control group probably wore branded T-shirts, but we would not expect Nike or Reebok to suggest that wearing their apparel is protective against pneumonia. Where starvation and cholera kill thousands of children each year, international agencies such as the GAVI Alliance, USAID and the WHO are busy spending millions on dubious research to emphasise the harm from a disease that local doctors hardly ever come across. All this so that vaccine manufacturers can fill their coffers. This situation can only be described as scandalous. It is unfortunate that five resource poor countries ― Afghanistan, Bangladesh, Bhutan, Pakistan and Sri Lanka ― have been persuaded to undertake the expensive intervention on the basis of flawed research. Lois Privor-Dumm says in your report that Bangladesh is eligible for funding for the Hib vaccine from the GAVI Alliance, so they will only have to pay 20 US cents per dose instead of US$5.60 per dose. He failed to mention that there is no long-term assurance of continued GAVI funding, or that funding will be withdrawn soon after universal vaccination becomes government policy.
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  Outbreak of Coxsackie B4 arthritis among newborns and staff of a neonatal unit.

  Trop Doct. 2007 Jul;37(3):188-9.
  Bhambhani V, Abraham J, Sahni M, Harit AK, Khare S, Puliyel JM.
  We investigated an outbreak of Coxsackie B4 arthritis in a neonatal unit involving 20 neonates and 12 staff members, over an eight-month period. Laboratory investigations, serology tests, indicate that the outbreak was caused by Coxsackie B4 virus. Contamination of one of the overhead water reservoirs, supplying the nursery, was responsible. After the water tanks were cleaned out, no new cases were reported over five years.
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  Sick score
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  Press release after Bangladesh Hib study

  Hib initiative
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  WHO press release after Bangladesh Hib study

  http://www.who.int/immunization/newsroom/Hib_vaccine/en/
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  Regulating vaccines: Can health-economics tools be used profitably?

  Indian Pediatrics 2007;44:11-14
  Dhanasiri SK, Puliyel JM.
  Editorial Indian Pediatrics 2007; 44:11-14 Regulating Vaccines: Can Health-Economics Tools be used Profitably? Direct-to-consumer vaccine advertisements are a recent phenomenon. In India a newborn can make up to 27 visits to the doctor for immunizations before his fifth birthday(1) (Table I). The vaccines cost approximately Rs 11,000. There is a built-in incentive for doctors to prescribe the vaccines. After a market presence is established, in the next stage the equity argume Show More... Editorial Indian Pediatrics 2007; 44:11-14 Regulating Vaccines: Can Health-Economics Tools be used Profitably? Direct-to-consumer vaccine advertisements are a recent phenomenon. In India a newborn can make up to 27 visits to the doctor for immunizations before his fifth birthday(1) (Table I). The vaccines cost approximately Rs 11,000. There is a built-in incentive for doctors to prescribe the vaccines. After a market presence is established, in the next stage the equity argument is brought up. Pressure is brought to bear on Government, to bring the vaccine under the Universal Immunization Program (UIP) saying that the well-to-do are protected and it is not equitable that the poor go unprotected(2). The Government of India recently had to take out advertisements in leading newspapers cautioning the public to ‘evaluate carefully the commercial claims’ of various vaccines beyond the 6 UIP vaccines(3). TABLE I Vaccines on the Indian Market for Children Under Five Vaccine Supplier/Brand* needed Doses needed Marked maximum retail price (MRP) Price to supply Price from multi-dose vial Alternative to government supply MRP for alternate BCG Govt Supply 1 Aventis Pasteur 25 OPV Govt Supply 6 Aventis Pasteur 73 Hep B Engerix B (SKB) 3 181 152 70 Hib Biomed 3 350 235 168 DPT Govt Supply 4 DT Govt Supply 1 Measles Govt Supply 1 M-VAC Sii Serum Institute 33 MMR Trimovax Merieux Serum Institute 1 71 57 Hep A HAVRIX (GSK) 3 712 598 Meningo coccus Quadrimeningo (Biomed) 2 650 550 510 Pneumococcal disease PNU IMMUNE 23 (Wyeth) 1 745 625 Influenza virus VAXIGRIP (Aventis Pasture) 6 525 453 Chicken Pox VARILIX(GSK) 1 1345 1120 Typhoid Typhim Vi (Newgen) 2 290 243 *In this illustration, where several brands are available, the ones that are profitable for doctors are mentioned. *UIP vaccines are supplied by government, free-of-charge and this is often used even in private clinics. Pressure is also put by international organizations like the World Health Organization (WHO) and Global Alliance for Vaccines and Immunization (GAVI). Resolution 45.17 of the World Health Assembly mandates that member countries integrate cost effective 'newer vaccines' into the national immunization programs. Regardless of cost-effectiveness, organizations like GAVI persuade developing countries to use new vaccines by providing donor-grants (effectively driving costs to zero in the initial stages). The full cost implications are only realized once funding is withdrawn, after the vaccine has been included in the UIP. As more vaccines come on to the market, the government needs a reliable strategy to evaluate vaccines for the UIP. The question is whether Health Economics tools can provide the answer. Risk-Benefit Analysis The first step is to assess efficacy and side effects in the context of the disease burden. Sound epidemiological research and good clinical trials are needed to provide the data. Suppose the lifetime risk of an individual getting a disease is 1 in 1000 and 1 in 10 of those with the disease, develop undesirable consequences. Then 1 in every 10, 000 vaccinated persons, is a potential beneficiary. If the vaccine protects 50% of those vaccinated, the vaccine benefits 1 in 20,000 of those vaccinated. If this vaccine has serious adverse effects in 1 in 10,000 doses, the vaccine has more risks than benefits and should not be used(4). The lifetime risk is different for different populations and changes with time. The chance of contracting hepatitis A is much lower in Europe than it is in Asia. Hepatitis A vaccine risks may be too high for Europe but it may be acceptable in Asia. Small pox risk is an example of how time alters the risk benefit ratio. As long as small pox was epidemic, the risks of the disease were more than the risks from vaccination. However, after the eradication of small pox, the risk of continuing with vaccination is unacceptably high, compared to the risk from the disease. Economic evaluation: Cost calculations If the perspective of the government (as health care provider) is adopted, capital costs (infrastructure and equipment), staffing costs (physician and nursing time), cost of consumables (vaccines syringes, etc.), and administration and overhead costs need to be calculated. Cost of treating side-effects of the vaccine is also to be included. Economic evaluation: Calculation of benefits The term 'benefit' is used here in a generic sense and implies ‘advantages’. Benefits may be estimated in natural units like ‘life-years gained’ (cost-effectiveness analyses) monetary units (cost-benefit analyses), or in terms of utility units (cost-utility analyses) The calculation of benefits often generates controversy. It is possible to inflate benefits to justify nearly any intervention. The cost of interferon treatment and liver transplants may be considered as cost savings from Hepatitis B vaccination, and immunization may be justified although these treatments are not options for the majority of the population. In the same way to justify chicken pox vaccine, wages lost by the parent to stay at home with the sick child, were added as benefit(5). Cost in terms of deaths averted and cost-utility analyses are more objective. ‘Utility gained’ may be in terms of quality adjusted life years saved (QALY) or disability adjusted life years saved (DALY). Economists have various methods to adjust for quality of life and disability. Let us assume polio does not affect life expectancy (60 years) but it produces paralysis of one limb. Quality of life without disability is taken as one. Assume the quality of life with one limb paralyzed is 0.8. The QALYs of a patient who is afflicted with polio around birth, is 60 × 0.8, which works out to be 48 years (12 QALYs are lost to polio). The ‘time trade-off’ and the ‘standard gamble’ are methods used to arrive at the quality of life associated with disability or illness(6). Discounting If benefits accrue more that 2 years after the costs were incurred, it is good practice to discount benefits for the opportunity cost of money. Discounting is done at various rates, (3%, 6%, etc.) depending on the rate of inflation and interest rate that is anticipated(7). Comparing costs with benefits: Defining what is cost-effective; Defining what is affordable After the discounted cost-effectiveness is known, the next step is to decide if it is acceptable and affordable. Cost-effectiveness is compared to that of other interventions already in place. This is not an absolute value and policy makers may desire more clear guidelines. Defining if the intervention is affordable may help. A general guideline is those interventions that cost less than the per capita gross national product (GNP), per QALY saved are considered cost-effective(8). This can be used as the measure to see if the program is affordable to the country. A corollary to this, is that if benefits of a program are clearly defined in terms of life-years gained, using the GNP we can calculate what is the ‘acceptable cost’ for a vaccine and utilize this to negotiate prices with producers(9) However, in the cost-benefit analysis discussed above, intangible benefits for entities like pain and suffering have not been reckoned. These non-monetary benefits may sometimes become crucial in public debate about interventions(10) and a methodology that judges ‘willingness-to-pay’ can be used to obtain values for intangible costs and benefits. According to the WHO Commission on Macro-economics and Health, any intervention that costs less than three times GDP per capita for saving a ‘healthy life-year equivalent’ should be considered worthwhile and good value for money(11). Allocative efficiency Evaluations up to this point are mathematical. Interventions that have poor risk-benefit ratio, those that are not cost-effective or affordable are not to be introduced under any circumstance. If it is both cost-effective and affordable, there is also the need to evaluate efficiency of the program – whether it is capable of providing better returns than other uses of this resource. If a cost-utility assessment has been done, the ‘optimum decision rule’ involves ranking the incremental cost-utility ratios of different interventions and selecting those with the lowest ratio ("best value") until the budget is depleted(12). A hypothetical example may be used to clarify this. Assume polio control costs Rs. 350 crores and saves 1 QALY per Rs 10,000 spent, rotavirus control costs Rs 200 crores and saves one QALY per Rs. 20,000 spent, and tuberculosis control costs Rs 700 crores and saves one QALY per Rs. 5000 spent. Assume also a budgetary constraint of Rs. 1000 crores. The first program to be accepted would be TB control as it provides the best utility (one QALY / Rs. 5000). Once this is accepted there is only Rs. 300 crores left in the budget. The next program to be accepted must be polio control. Rota virus control costs only Rs. 200 crores which is less than the cost of polio control (Rs. 350 crores) but polio control takes precedence as it provides more utility. NICE Model Given contrary pulls and pressures it is not easy for government to synthesize all the above objectively, to arrive at a truly rational decision on the introduction of vaccines. The authors believe that the solution lies in setting up an independent body similar to the National Institute of Clinical Excellence (NICE) in the UK, to decide these matters(13). The NICE equivalent can be referred to as ‘NICE India’. It should be a statutory body made up of health professionals, epidemiologists and health economists. To start the process the government must publish the vaccine under consideration. Stake holders – (patient groups, health professionals, academic institutions, industry producing the vaccine, trade unions and international organizations like the WHO and GAVI) then register their interest. In the next stage, ‘NICE India’ must assess the clinical evidence and the economic data on benefits. Based on the evidence, draft guidelines are drawn up for assessment by the registered stakeholders values that underpin the work of group). 'NICE India' revises the guidelines if more evidence is provided by the stake holders. An ‘independent-review-panel’ then reviews the guidelines to decide if all stake holder comments are taken into account. The final guidelines are then issued and government has clear and unbiased advice on which to base decisions. Conflict of interest: None. Funding: Nil. Sujith Kumar Dhanasiri, Research Officer, Personal and Social Services Research Unit, London School of Economics, London, United Kingdom. Jacob M. Puliyel,* Department of Pediatrics, St. Stephens Hospital, Tis Hazari, Delhi 110 054, India. E-mail: puliyel@vsnl.com *corresponding author Key Messages 1. In the face of pressures from vaccine manufacturers and international organizations, developing countries need a reliable tool with which to decide about what vaccines to include in the EPI. Health-economics tools may be used for this. 2. Cost-utility data helps prioritize the conflicting demands of various interventions on the limited health budget. 3. An independent body like NICE in the UK could weigh the evidence, incorporate opinions of stake-holders and make recommendations. References 1. Mishra L. Vaccines in Drugs Today. Delhi; Lorina Publication (India) Inc. July-September 2006 pp 1078-1087. 2. Hardon A, Blume S. Shifts in global immunization goals (1984-2004): Unfinished agendas and mixed results. Soc Sci Med 2005; 60: 345-356. 3. Madhavi Y. New combination vaccine: backdoor entry into India’s universal immunization programme? Curr Sci 2006; 90: 1464-1469. 4. Puliyel J. The dummies’ guide to risk-benefit analysis of vaccines. Pediatrics 2002; 110: 193. 5. Thiry N, Beutels P, Van Damme P, Van Doorsiaer F. Economic evaluations of varicella vaccination programs: A review of the literature. Pharmaco-economics 2003; 21: 13-38. 6. Puliyel JM, Thomas AJ, Jindal K. A primer on health economics for pediatricians. In: Suraj Gupte ed. Recent Advances in Pediatrics Vol 13. New Delhi: Jaypee Brothers, 2003: 231-236. 7. Parsonage M, Neuburger H. Discounting and health benefits. Health Econom 1992; 1: 71-79. 8. Miller MA, McCann L. Policy analysis of Hepatitis B, Hemophilus influenza type B, Streptococcus pneumoniae–conjugate and rotavirus vaccines in national immunization schedule. Health Econ 2000; 9: 19-35. 9. Tyagi V, Singh SK, Sawhney A, Taneja V, Puliyel JM. Using gross national product to calculate acceptable immunization costs. Deploying cost-effectiveness calculations in reverse. Pharmacoeconomics 2003; 21: 497-499. 10. Meltzer IM. Introduction to health economics for physicians. Lancet 2001;358:993-998. 11. World Health Organization (WHO). The World Health Report 2002. Reducing risks, promoting healthy life. Geneva: WHO, 2002. 12. Palmer S, Byford S, Raftery J. Economics Notes: Types of economic evaluation. BMJ 1999;318:1349. 13. Martin B. Implications of the appraisal function of the National Institute of Clinical Excellence. Value Health 2001;4:212-216.
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  Discordant twins with the smaller baby appropriate for gestational age – unusual manifestation of superfoetation: A case report

  BMC Pediatrics 2007, 7:2
  Noopur Baijal* 1 , Mohit Sahni* 1 , Neeraj Verma* 1 , Amit Kumar* 1 , Nittin Parkhe* 2 and Jacob M Puliyel* 1
  Case report . Discordant twins with the smaller baby appropriate for gestational age – unusual manifestation of superfoetation: A case report Noopur Baijal* 1 , Mohit Sahni* 1 , Neeraj Verma* 1 , Amit Kumar* 1 , Nittin Parkhe* 2 and Jacob M Puliyel* 1 1Department of Pediatrics and Neonatology St Stephens Hospital, Tis Hazari, Delhi 110054, India 2Department of Radiology, St Stephens Hospital, Tis Hazari, Delhi 110054, India BMC Pediatrics 2007, 7:2 doi:10.1186/1471-2431-7-2  Show More...Case report . Discordant twins with the smaller baby appropriate for gestational age – unusual manifestation of superfoetation: A case report Noopur Baijal* 1 , Mohit Sahni* 1 , Neeraj Verma* 1 , Amit Kumar* 1 , Nittin Parkhe* 2 and Jacob M Puliyel* 1 1Department of Pediatrics and Neonatology St Stephens Hospital, Tis Hazari, Delhi 110054, India 2Department of Radiology, St Stephens Hospital, Tis Hazari, Delhi 110054, India BMC Pediatrics 2007, 7:2 doi:10.1186/1471-2431-7-2 The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2431/7/2 Received 19 May 2006 Accepted 19 January 2007 Published 19 January 2007 © 2007 Baijal et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background Documentation of superfoetation is extremely rare in humans., The younger foetus has invariably been small for gestational age (estimated from the date of the last menstrual bleed) in all the cases reported in the literature. We report a case where the younger twin was of appropriate size for gestation. Case Presentation The first of twins was of 32 weeks gestation and the baby was of appropriate size and development for the gestational age. The second twin was of 36 weeks gestation. Gestational age was estimated with the New Ballard score, x-ray of the lower limbs, dental age on x-ray, and ophthalmic examination. Conclusion Bleeding on implantation of the first foetus probably helped demarcate the two pregnancies. Dental age and the New Ballard score can be used to diagnose superfoetation in discordant twins, when detailed first trimester ultra-sound data is not available. Background Superfoetation implies fertilization and subsequent development of an ovum when a foetus is already present in the uterus. Growth discordance in multiple pregnancies due to placental insufficiency, twin to twin transfusion or aneuploidy need to be differentiated from superfoetation. In most instances the larger twin is nearer appropriate size for gestational age calculated from the last menstrual period (LMP). We report a case where superfoetation was likely superfoetationbecause the smaller of the twin was of appropriate maturity, weight and length for gestational age. These circumstances argued against intrauterine growth retardation in the smaller twin. Outline Case Presentation Abstract Background Case Presentation Conclusion Competing interests Authors' contributions Acknowledgements References Pre-publication history Figures Figure 1 Radiological examination for bone showing absence of epiphysis at the lower end of femur and upper end of tibia in Twin A Figure 2 Radiological examination for bone showing epiphysis at the lower end of femur and upper end of tibia in Twin B Figure 3 X-ray chest with mandible showed absence of calcified crowns of the first and second deciduous molar in Twin A Figure 4 X-ray chest with mandible showed calcified crowns of the first and second deciduous molar in Twin B Tables Table 1 Ante-natal ultrasonography findings at 26 weeks after LMP Table 2 Differences between the twins at birth A 21-year-old mother of two had an ante-natal ultrasound examination done 26 weeks after her last menstrual period (LMP). This showed twins, one was of appropriate size for duration of amenorrhoea while the other was approximately four weeks too large. The ultrasound findings are described in Table 1. Six weeks later, after 32 weeks of amenorrhoea, live twins were delivered. They had not received ante-natal steroids. The first of the twins (Twin A) weighed 980 grams and the next baby (Twin B) weighed 2160 grams. Detailed neurological assessment using the New Ballard Scoring [1], was done on the second day. The score for Twin A was 15, pointing to a gestational age of 30 weeks (+/- 2 weeks) and the score for Twin B was 32, appropriate for 36 weeks (+/- 2 weeks). Table 2 lists the differences between the twins. Radiological examination for bone age done on the second day of life revealed the absence of epiphysis at the lower end of femur and upper end of tibia in Twin A while they were present in Twin B (Figure 1, 2). The epiphysis at the lower end of femur appears normally between 31 and 40 weeks and for the upper end of tibia between 34 weeks and 5 postnatal weeks [2]. Thus, Twin A had a bone age of less than 31 weeks and Twin B had a bone age of at least 34 weeks. X-ray chest with mandible showed absence of calcified crowns of the first and second deciduous molar in Twin A and both crowns calcified in Twin B (Figure 3, 4). The crowns of the first and second molars are never seen prior to 33 and 36 weeks respectively and are invariably seen after that [3]. This suggests that twin A was at less 33 weeks and twin B was at least 36 weeks old. Retinal vessels normally reach nasal ora serrata by 36 weeks and periphery on the temporal side by 40 weeks. Ophthalmological examination of Twin Ashowed a hazy cornea and the underlying papillary membrane was not visualised. The retinal vessels had not reached the nasal ora serrata. In Twin B the cornea was clear, there was no papillary membrane and the retinal vessels migration was complete on the nasal side and near complete on the temporal side. Outline Conclusion Abstract Background Case Presentation Conclusion Competing interests Authors' contributions Acknowledgements References Pre-publication history Intrauterine growth retardation (IUGR) is the usual cause of discordance in multiple pregnancies. We did not find anyreport in the literature of discordance due to one baby being large-for-date. In this case the smaller twin was of appropriate size and maturity for gestation assessed from LMP. The second twin was approximately a month too large and mature. Superfoetation was considered as a possible explanation for the observation. Bleeding one month after conception occurs in about 8% pregnancies and represents a physiological response to implantation or slight bleed from the endometrium in early pregnancy [4]. We therefore also considered the possibility that both twins were conceived simultaneously a month prior to the presumed date of the LMP, and the smaller Twin A was small-for-date. Detailed neurological and physical assessment is considered the most reliable method of estimation of gestational age, in circumstances where IUGR is suspected and there is uncertainty in using LMP [2]. Using the New Ballard Score [1] the first of the twin was 30 weeks and the second was 36 weeks (+/- 2 weeks). This evidence of disparity in the gestational ages of the 'twins', was corroborated by the estimation of age based on anthropometric measurements, weight, length and head circumference, ophthalmic examination, bone age and dental age estimates. The twins had not received ante-natal steroids which, which had they been given, may have influenced some of the markers of foetal maturity. The evidence taken together, suggests that there was a real difference of approximately 4 weeks in the gestational ages of the twins and this was in keeping with the findings of the ante-natal ultrasound examination. Among the evidence listed above, anthropometric measurements and bone maturation are delayed in first-trimester-malnutrition and results in symmetric growth retardation [2,5]. However the work of Kuhns et al [3] suggest that the age of calcification of the crowns of the molars is not affected by IUGR and we use this criterion along with the New Ballard Score and the ophthalmic examination to confirm the disparity in gestational ages of the neonates. Harrison et al [6] have recently reported a case of superfoetation and suggested that in growth-discrepant multiple deliveries, skilled neurosonography and ophthalmic examination may be used to support the diagnosis of superfoetation when detailed first trimester data is lacking. We would like to add the role of the New Ballard Scoring and, as they may help clinch the diagnosis, even where suggestive fortuitous circumstances as in this case (distinct marker separating the two fertilizations in the form of bleeding on implantation of first ovum) are not available. Competing interests The author(s) declare that they have no competing interests. Authors' contributions NB, SM, NV and AK investigated the case, searched the literature and helped with the write up, NP helped with the radiological input, and JMP conceived of the study and helped with its write up. All authors read and approved the final manuscript. Acknowledgements Written consent was obtained from the guardian of these twins for publication. References 1. Ballard JL, Khoury JC, Wedig K, Wang L, Ellers-Walsman BL, Lipp R: New Ballard Score, expanded to include extremely premature infants. J Pediatr 1991, 119:417-23. [PubMed Abstract] [Publisher Full Text] OpenURL Return to citation in text: [1] [2] 2. Kuhns LR, Finnstrom O: New standards of ossification of the newborn. Radiology 1976, 119:655-660. [PubMed Abstract] OpenURL Return to citation in text: [1] [2] [3] 3. Kuhns LR, Sherman MP, Poznanski AK: Determination of neonatal maturation on the chest radiograph. Radiology 1972, 102:597-603. [PubMed Abstract] OpenURL Return to citation in text: [1] [2] 4. Guttmacher SH: Frequency and significance of bleeding in early pregnancy. J Am Med Assoc 1954, 19;155:712-5. OpenURL Return to citation in text: [1] 5. Vik T, Vatten L, Jacobsen G, Bakketeig LS: Prenatal growth in symmetric and asymmetric small-for-gestational-age infants. Early Human Development 1997, 48:167-76. [PubMed Abstract] [Publisher Full Text] OpenURL Return to citation in text: [1] 6. Harrison A, Valenzuela A, Gardiner J, Sargent M, Chessex P: Superfetation a cause of growth discordance in multiple pregnancy. J Ped 2005, 147:254-5. [Publisher Full Text] OpenURL Return to citation in text: [1]
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  Polio Eradication and the Future for Other Programs:

  Indian J Med Res 2007;125:1-4.
  Puliyel JM, Gupta MA, Mathew JL
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  Vitamin A deficiency in children under 6 months

  Tropical Doctor 2007;37;59-60
  Sara Varughese
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  Ask The Doctor

  http://www.hindu.com/mag/2007/07/01/stories/2007070150200600.htm
  Puliyel J
  Asthma, inhaled steroids, Bronciolitis, Seroflo
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  Systematic Review and Meta-analysis of Prevalence of Hepatitis B in India

  Indian Pediatrics 2007;44:663-74
  Ashish Batham, Dherian Narula, Tanmay Toteja, V Sreenivas*, Jacob M Puliyel.
  Abstract Objective: To evaluate the point prevalence of Hepatitis B in India. Design: Meta-analysis of data on point prevalence from different parts of the country. Data sources: Searches were made in Medline, Cochrane Library and Best bets and previous reviews. A limited hand search of cross references was also done. Finally a consultation with experts was held to enlarge the references base. Review methods: Studies reporting prevalence of HBsAg were selected. Data from high risk groups were e Show More...Abstract Objective: To evaluate the point prevalence of Hepatitis B in India. Design: Meta-analysis of data on point prevalence from different parts of the country. Data sources: Searches were made in Medline, Cochrane Library and Best bets and previous reviews. A limited hand search of cross references was also done. Finally a consultation with experts was held to enlarge the references base. Review methods: Studies reporting prevalence of HBsAg were selected. Data from high risk groups were excluded. Main Results: 54 papers reporting data on 61 populations were identified. The true prevalence for each study was calculated from the reported prevalence using the specificity and sensitivity of the test employed. The true prevalence in non-tribal populations is 2.4% (95% CI: 2.2% - 2.7%). True prevalence among tribal populations is 15.9 % (CI: 11.4% -20.4%). Conclusion: These figures may be useful in estimation of the burden of the disease in the country and for projecting the cost-benefits of immunization. What is Known The prevalence of hepatitis B in India is different in different regions; it is higher among tribal populations. It is often said that the chronic carrier rate in India is 4.7%. What this Paper Adds This meta-analysis reveals that the prevalence of Hepatitis B in tribal and non-tribal populations of India is 15.9 % (CI: 11.4% - 20.4%), and 2.4% (95% CI: 2.2 - 2.7%), respectively The carrier rate of Hepatitis B in India is different in the different regions of the country. The overall carrier rate is often quoted as being 4.7% (1). This is the weighted means of various studies and includes high risk populations (2). Lodha et al. (3) did a systematic review of literature and concluded that the true prevalence of Hepatitis B in India was 1 to 2%. No statistical tool was used in the systematic review to synthesise the results of the different studies. There is therefore need to calculate the prevalence of Hepatitis B using appropriate meta-analytic tools. This study was undertaken under the auspices of the Indian Medical Association’s ‘Subcommittee on Immunization’ to evaluate the true prevalence of Hepatitis B in India. Material and Methods Lodha et al. (3) published a systematic review of Hepatitis B in India having accessed 128 papers. This analysis included 18 papers on prevalence (4-21). A limited hand search within these articles was performed to identify new references. We also used relevant papers that were referenced in the correspondence regarding the systematic review. This exercises identified 7 new papers (22-28). The 25 papers included data from 29 population studies. To update the review, we did a search for papers published subsequently. Assuming publication delays of 18 to 24 months, we searched the literature from January 1999 onwards up to January 2006, and incorporated these studies into the analysis. Search strategy and outcome: Search terms included “hepatitis b” [MeSH Terms] OR Hepatitis B [Text Word]) AND (“india” [MeSH Terms] OR India [Text Word])) AND (“1999”[PDAT] : “3000”[PDAT]. (Search date 19/1/06). Titles and abstracts identified by electronic searches were examined independently by 2 researchers on-screen, to select potentially relevant studies. All studies looking at the point prevalence of hepatitis B were considered prima facie relevant. Criteria for inclusion are given below. Differences were resolved by consensus. The full text paper was obtained wherever possible. Inclusion & Exclusion criteria: We included studies of voluntary blood donors (VBD) (altruistic donations) and replacement donors (RBD) (blood donated to replace blood utilized in specific patients – often friends or blood relations of the donor) and studies involving antenatal women and community studies. We excluded studies from the following special groups who were assumed to be at high risk for hepatitis B: patients from sexually-transmitted-disease clinics, thalassaemia-clinics, hospitalised patients, professional blood donors, sex workers, drug abusers, dialysis patients, and hospital staff. Best bet: Best bet search (http;//www.bestbets.org/cgi-bin/browse.pl) Search term: ‘Hepatitis’: All years. Cochrane collaboration (http://www.cochrane.de/cc_bin/) Search term: ‘Hepatitis B’: All years. Experts’ consultation: A draft of this meta-analysis was sent to experts in the field who were invited to enlarge the review by contributing references which may have been missed using the search strategy adopted. Researchers in the field and stakeholder from various organizations namely; The India Advisory Expert Group, Indian Academy of Pediatrics, WHO, Ministry of Health ,were invited to an experts consultation in Delhi. The draft paper was then modified using inputs from reviewers. Two new papers [16, 22] were added and one study originally included in the non-tribal group [34], was identified as a study among tribals. These corrections were made and the meta-analysis was done again. Overall this new systematic review includes data from a total 61 populations identified in 54 papers (Table 1). Data extraction and data analysis a) Quality assessment. Lodha et al. (3) have pointed out that there is need to compensate for ‘misclassification errors’ caused by the false positives and false negatives (due to less than 100% specificity and sensitivity of the test used) where the estimated prevalence of a disease is low. The true prevalence can be calculated using the formula of Tu et al 1992.(58). The specificity and sensitivity of the test as described in the paper was used. If this was not mentioned, enzyme immunoelectrophoresis (ELISA) was considered 99.8% sensitive and 99.8% specific (59) reverse passive haemagglutinatin (RPHA) as 75% sensitive and 98% specific (60) and dipstick immunobinding enzyme-linked immunosorbent assay (DIA) 98% specific and sensitive (18). If two tests were done on one sample sequentially the test was considered true positive. True prevalence = [Estimated prevalence – (1 – specificity)]/[Sensitivity – (1 – specificity)] We disregarded studies where the test used was not specified and where the specificity and sensitivity of the test used was not known. b) Sensitivity testing. Sensitivity analysis was performed with all studies included, as if the specificity and sensitivity of all the tests used were 100%/100%. This analysis included 12 papers which did not specify the specificity and sensitivity of the tests employed c) Forest plot and evidence of heterogeneity. In the first stage, the prevalence with its 95% confidence intervals was calculated for each individual study. In the second stage of meta-analysis, an overall prevalence was calculated as a weighted average of individual summary statistics. The results were displayed as a forest plot (Figure 1). The prevalence of Hepatitis B among tribal peoples was distinctly different from that of others. Meta-analysis has therefore to be done separately in the two groups. Presentation of Graphs and Tables of the Meta analysis: Where a large number of studies are included in the forest plots, the weights and confidence intervals of individual studies are listed in a table separate form the graph, in order to reduce the clutter and to improve readability. Meta analysis of data according to the population group studied. In the State of Delhi from where a large number of studies on prevalence have been published, we looked at the summary prevalence among voluntary blood donors, replacement donors and antenatal mothers separately. We did a similar analysis after pooling the studies from Punjab, Haryana and Chandigarh. All analyses were implemented on Stata 9.0. (Stata Corporation, 4905 Lakeway Drive, College Station, TX 77845, USA) Results The Medline search resulted in 272 hits, yielded 29 papers and 32 population studies after applying the inclusion criteria (29-57). Best Bet and the Cochrane collaboration yielded 2 and 96 papers respectively, but none were not relevant Figure 2 shows the results of the meta-analysis of true prevalence data of hepatitis B among non tribal populations in India. The true prevalence in the non-tribal population is 2.4 (95% CI: 2.2%-2.7 %). True prevalence among tribal populations is 15.9%. (95% CI: 11.4 % -20.4 %) [Figure 3] Sensitivity testing: Assuming 100% specificity and sensitivity the prevalence among non-tribal people was 2.7% (CI: 2.4% - 2.9%) The prevalence among tribal populations was 15.9% (CI: 11.4% - 20.4%) Prevalence in the sub-groups. Figure 4 shows the table and graph of the meta-analysis of studies from Delhi classified according to the population group studied. It appears that voluntary blood donors have a higher prevalence than replacement donors. A similar pattern was seen in the Punjab, Haryana and Chandigarh (Figure 5). Here replacement donors had prevalence even lower than the overall mean. Discussion This is the first meta-analysis of hepatitis B prevalence studies in India. In our analysis, the results showed significant heterogeneity and we had to study the tribal populations separately from that of non-tribal populations (61). Even after analyzing the non-tribal and tribal populations separately, there was significant heterogeneity among the studies. (Heterogeneity Chi-square significant (P < 0.01) in both groups and the I2 being 85% in tribal populations and > 90% in non-tribal populations). This is not unexpected in view of the different populations studied and the nature of variations associated with the different methods, kits, antigens etc used in estimating the prevalence. However, a meta-analysis of such studies might still be useful in providing an idea of the overall prevalence. Nearly all the studies we have analysed are cross-sectional studies and are therefore indicative of the point prevalence of the disease. A chronic carrier is one with persistence of infection for more than 6 months (62). Studies that have followed up initial HBsAg positive cases for 6 months have found 75% to 80% chronic carriers. Assuming that the chronic carrier rate is 80% of the point prevalence, the chronic carrier rate in the country among non-tribal populations is 1.9% John and Abraham (63) have questioned the inclusion of voluntary blood donors in the systematic review by Lodha et al. (2). They refer to a study among voluntary donors at Vellore where the carrier rate was 0.7%. This, they suggest, is artificially low because voluntary donors are a self-selected group and persons who are found hepatitis b positive, do not come for repeat blood donation. They suggest using data from replacement donors. Lodha et al. in their rejoinder have justified the use of voluntary donors and suggested that replacement donors on the other hand, are likely contaminated by professional donors masquerading as replacement donors. To test these contrary viewpoints, we conducted subgroups analysis of patients tested in Delhi. The carrier rate among voluntary donors was in fact higher than that of replacement donors and if we had taken the suggestion of John et al to exclude voluntary donors, the true prevalence would come out to be lower than 2.4%. On examining at the forest plots from the Delhi studies; voluntary donors, replacement donors and ante-natal mothers have prevalence close to the overall mean and it seems appropriate that all these groups are included in the systematic review and meta-analysis. The analysis of data from Haryana and Punjab also support this conclusion. It is possible that despite of the extensive search done by the authors, the specific search terms used, may not have captured all good quality papers published in peer-reviewed indexed journals. The electronic search was therefore supplemented by a limited hand search of references. Further, a consultation with experts was conducted specifically to enlarge the systematic review by including additional references. In these studies that we have retrieved and analysed, there was little attempt to get a sample representative of population in India. Most studies published data from ‘convenience samples’ – women coming for antenatal check-up or people coming to make blood donations and mostly from urban areas. This constitutes a further limitation to the inference drawn. It is understood that only a large national epidemiological study can give the final answer as to the overall prevalence of Hepatitis B in India. In the absence of such a national sample survey, a meta-analysis of all the studies from India provides the best evidence. Blood donors constituted 85% of the total sample and blood donors are frequently male. Pregnant women constituted 4.2% of the sample and children 0.25%. Internationally males have a higher prevalence of hepatitis B (64) and the large representation of males in this analysis may overestimate the true prevalence in a society made up of equal numbers of males and females. Conclusion We found that the point prevalence among non-tribal populations is 2.4% (corresponding to a chronic carrier rate of 1.9%) and the point prevalence among tribal populations is 15.8%. These figures may be useful in estimation of the burden of the disease in the country and for projecting the cost-benefits of immunization. Acknowledgements The authors acknowledge with thanks the help received from the Indian Medical Association (IMA) ‘Subcommittee on Immunization’ and the experts who came for the consultation. We also acknowledge the finacial support provided by ‘Plan International (India)’ to the IMA that helped to conduct the experts consultation. Contributors: The project was conceived by JP as member of the ‘IMA Sub committee on Immunization’. AB, DN, TT did the systematic review.AB and VS did the meta-analysis. AB, DN, TT and JP did the write up. All authors have approved of the manuscript. JP stands guarantor for the study. Funding : None Competing interests: None stated.
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  Author's Reply Polio eradication and the future of other programmes

  Ind J of Med Res 2007; 125:696-8
  Gupta MA, Puliyel J
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  Estimation of True Incidence of Polio: Overcoming Misclassification Errors due to Stool Culture Insensitivity

  Indian Pediatrics 2007;44:596-7
  Sreenivas V, Puliyel JM
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  Full Report on Meeting of Experts to discuss White Papers presented by the IMA Subcommittee on Immunization

  http://www.imanational.com/Hepatitis/PositionPaper.htm
  Prof SK Mittal Dr Dharam Prakash, Dr Onkar Mittal, Dr C Sathyamala, Dr Jacob Puliyel, Dr T Gera Dr Joseph L Mathew
  Hepatitis B,
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  Lessons from the polio campaign

  http://www.hindu.com/mag/2006/11/19/stories/2006111900100400.htm The Hindu Magazine 19/11/06 Page 4
  Jacob M Puliyel
  IT is now being acknowledged that the National Polio Eradication Programme did not work according to plan. The failure of this magic bullet approach (repeated doses of oral polio vaccine) to solve what is essentially a water and sanitation problem was predictable. Yet, that did not mitigate the sadness its failure caused among many of us who have worked tirelessly to make it succeed. The Indian Medical Association (IMA) Sub-Committee on Immunisation debated on whether to go public with its find Show More... IT is now being acknowledged that the National Polio Eradication Programme did not work according to plan. The failure of this magic bullet approach (repeated doses of oral polio vaccine) to solve what is essentially a water and sanitation problem was predictable. Yet, that did not mitigate the sadness its failure caused among many of us who have worked tirelessly to make it succeed. The Indian Medical Association (IMA) Sub-Committee on Immunisation debated on whether to go public with its findings about the failure of this initiative. In August 2006, it concluded that it was its duty to do so. The need to publicise dissent Dr. Pushpa Bhargava, who is presently the Vice-Chairperson of the National Knowledge Commission, had written an article, "Fighting the polio virus", published on December 12, 1999 in The Hindu. In 1988, he had attended a meeting where it was decided to use injectable polio vaccine (IPV) in India because of the poor efficacy of the alternate vaccine, oral polio vaccine (OPV). A factory to manufacture IPV was set up in Gurgaon. Four years later, in 1992, on advice from the WHO, these plans were shelved and it was decided to use OPV. Dr. Bhargava wrote letters to the then Prime Minister (Mr. Narasimha Rao), the Health Minister and to the Health Secretary at different stages. Having been party to the earlier meeting that suggested the OPV was unsuitable for India, he asked for the evidence on which the government decided to switch in favour of OPV. He also demanded to know how the Rs. 50 crores spent by Indian Vaccine Corporation Ltd. to produce IPV would be justified. His letters were not answered. In the end he wrote this article to the press. He concluded the article saying, "No one will be more delighted and satisfied than me if it can be shown indisputably that OPV has worked in this country. Unfortunately all the evidence available today goes against that view. It is therefore not unlikely that polio will meet the same fate as BCG with valuable time and money lost." Events have proved the prophetic nature of that statement. Pubic accountability Thanks to this publication, we now have some form of a paper trail. There is a need for public accountability and this applies to faceless mandarins in the WHO as also to officials of the Government of India who have been named in the article. Decisions based on judgment can go wrong but unless this is acknowledged, we are bound to repeat these mistakes over and over again. The IMA Sub-Committee was also placed in a somewhat similar predicament as Dr. Bhargava. It was alarmed by the number of vaccine induced polio cases (1,600 last year) that repeated doses of OPV were producing. More alarming were the 27,000 cases of polio-like paralysis in children in whom the polio virus was not cultured in the stools. The government was not willing to even enquire how many were left with residual paralysis in this group. There was also clear evidence that many who were already vaccinated, were getting polio paralysis, suggesting the vaccine was not efficacious. In the face of a bureaucracy that would not even acknowledge the problem, the IMA Sub-Committee was left with the unpleasant task of exposing this farce. It is to the credit of the maturity of this Government that they have not set out to castigate the messenger and discredit the IMA. Unfortunately the knee-jerk reaction of the government has been to start another programme which will aggravate rather than remedy this situation. This essay will conclude with suggesting a mechanism to avoid these innumerable cycles of folly. Before we go into the bigger issues, readers need to understand the disease which started all this fuss. Polio is a virus that can cause paralysis. The virus multiplies in the gut and is spread by contaminated water. Improvements in water and sanitation can control the disease. Routine immunisation would help hasten the eradication of polio. The polio control programme was working well with routine immunisation before the stepped up polio eradication programme was started. The incidence of polio fell from 24,000 in 1988 to 4,800 in 1994, well before pulse-polio started. However in 1998, the WHO and other international bodies started this grand plan to eliminate the disease worldwide through repeated use of vaccines. Initial funding, to the tune of Rs. 400 crores a year, came from international agencies (including Rotary International). Inevitably, a couple of years after the programme started, these agencies claimed donor fatigue and withdrew funding. The Government of India spent Rs. 1,000 crores on this programme last year. Expenditure on all other immunisation (five diseases) was Rs. 300 crores. A pattern with external funding — countries are lured into a debt trap. With international funding initiatives the government is made to look foolish, refusing to accept a donation made for the benefit of its people. Once the programme is introduced on the basis of the external funding, overseas support is withdrawn. Poor countries fall for this ploy and vaccines are introduced without the mandatory cost-effectiveness study. We have no way of knowing what influence the offer of overseas funding had on this decision, but the fact is that, in the end, the GOI was landed with unprecedented bills for a programme that was destined to fail . No lessons learnt But unfortunately we haven't learnt from our mistakes. In the aftermath of the failure of OPV polio eradication programme, the government has accepted an overseas offer of "free" injectable polio vaccine (IPV) to be given in the high endemic areas. The imported injectable vaccine is 25 times more costly than the oral vaccine. One lot of near-expiry injectable vaccines is being provided free, but we cannot base a national immunisation programme on this. Furthermore, the costs of delivery of this injectable vaccine from door to door will be staggering. If this money were spent on improving water and sanitation in these areas, we will have a permanent solution to the problem. Injectable vaccine must be given to every child, and if we have not succeeded in getting OPV to 100 per cent of the population, the uptake will be much less with the injectable vaccine. So failure is guaranteed once again! The IMA Sub-Committee had in fact suggested that that the government cool down this entire campaign and get back to strengthening routine immunisation along with concerted efforts to improve the water and sanitation in affected areas. We need a permanent mechanism to make such intricate decisions related to introduction of vaccines. A solution could be the setting up of an independent body similar to the "National Institute of Clinical Excellence" (NICE) in the U.K., to decide these matters. A professional body of health professionals, technical experts, health economists and public representatives should be formed. The government must publicise the vaccine under consideration. All stake holders, such as patient groups, health professionals, academic institutions, industry producing the vaccine, trade unions and international organisations like the WHO and GAVI must register their interest. The body should assess the clinical evidence and the economic data of benefits. They should put up draft guidelines, to be assessed by the registered stakeholders, and a citizen's council (which provide the social values that underpin the work of group). Based on their input, the panel should then revise the guidelines. Finally an independent panel should review the guidelines, to decide if all stakeholder comments have been taken into account. The final guidelines should then be issued so that the government has clear and unbiased advice on which to base decisions. The writer is Vice Chairman, the IMA Sub-Committee on Immunisation. The opinions expressed here are his own. Email: puliyel@vsnl.com
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  Development of an indigenous paediatric crash cart based on the ABC of resuscitation.

  Trop Doct. 2006 Oct;36(4):216-7.
  Green DA, Chowdhary S, Tiwari L, Lata S.
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  Audit of nurse-led-training for epipen in a District General Hospital.

  Allergy. 2006 Aug;61(8):1019-20.
  Ratnaweera D, von Trilsbach J, Rangasami J, Green DA, Puliyel JM
  Department of Paediatrics, West Middlesex University Hospital, Twickenham Road, Isleworth, Middlesex, UK. A community-based study in the London Borough of Hounslow, which included patients in our District General Hospital (DGH) Paediatric Department, found that most families who had been prescribed adrenaline auto-injectors could not use them properly. This prompted the establishment of a new protocol for doctors and an Allergy Clinic where one nurse was responsible for training all patients. Show More...Department of Paediatrics, West Middlesex University Hospital, Twickenham Road, Isleworth, Middlesex, UK. A community-based study in the London Borough of Hounslow, which included patients in our District General Hospital (DGH) Paediatric Department, found that most families who had been prescribed adrenaline auto-injectors could not use them properly. This prompted the establishment of a new protocol for doctors and an Allergy Clinic where one nurse was responsible for training all patients. This audit was done to reassess this service 3 years after the changes were made. 68 of the 81 (83%) patients followed up in our District General Hospital Nurse led Allergy Clinic agreed to participate. They were compared with the District General Hospital sub-group of the previous study. We found that most patients now reported they were trained to use the devise, had written instructions, were able to demonstrate competence on a dummy and would appropriately call an ambulance. This was significantly better than the previous situation. The study shows that training can be improved in a DGH setting with the strategy of protocolised prescribing and a Nurse led Allergy Clinic.
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  Who's WHO; Hepatitis B Controversy: Debate in Pediascene

  http://tinyurl.co.uk/0eyc accessed 9/7/06
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  Down's Syndrome: Antenatal Diagnosis

  Recent Advances in Pediatrics 13. Jaypee Brothers New Delhi 2003. Editor Suraj Gupte Page 436 - 441
  Puliyel J., Riju Mittal
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  Brief Report: IMA Subcommittee on Immunization Report on Meeting of Experts 14 May 2006 Hotel Imperial Janpath

  http://www.imanational.com/Hepatitis/Report.htm
  Prof SK Mittal Dr Dharam Prakash, Dr Onkar Mittal, Dr C Sathyamala, Dr Jacob Puliyel, Dr T Gera Dr Joseph L Mathew
  This is a brief report of the meeting of Experts held at Hotel Imperial on 14/5/06. The meeting was sponsored jointly by the IMA and PLAN international (India) Indian Medical Association Subcommittee on Immunization Report on Hepatitis B and Poliomyelitis in India Chairperson Professor S K Mittal Indian Medical Association New Delhi 2006 Contents Section 1 Brief Report  Show More...This is a brief report of the meeting of Experts held at Hotel Imperial on 14/5/06. The meeting was sponsored jointly by the IMA and PLAN international (India) Indian Medical Association Subcommittee on Immunization Report on Hepatitis B and Poliomyelitis in India Chairperson Professor S K Mittal Indian Medical Association New Delhi 2006 Contents Section 1 Brief Report 3 Section 2 Systematic Review of Hepatitis B in India 24 Section 3 Position paper on Polio Eradication Initiative in India 82 Section 4 Discussions and recommendations of Expert Committee 125 On Hepatitis B and Polio Brief Summary Preface The issue related to introducing Hepatitis B immunisation and controversies regarding the polio eradication program have been causing concern among medical professionals in the country. The National President of the Indian Medical Association, Dr Sundipo Roy set up a subcommittee under the chairmanship of Prof S K Mittal with Dr. Dharam Prakash as Convener, to look at the issues involved. The committee first met on 19 October 2005 . It was decided to hold a national level consultation on 14 May 2006 to discuss the issues related to Hepatitis B immunization and polio eradication in India. It was resolved that prior to this, the sub committee must draft a White Paper to act as a position document. The background papers were circulated to a host of eminent experts in the country, spanning several specialties including Pediatrics, Gastroenterology, Public Health, Biostatistics and Social Sciences. The experts studied the documents and met together for a workshop on May 14, 2006 at New Delhi. Besides researchers, Dr. P. M. Bhargav, Vice Chairman of the National Knowledge Commission, Dr. Jay Wenger, Project Manager of the WHO National Poliomyelitis Surveillance Project, representatives of the Indian Academy of Pediatrics (IAP) and India Expert Advisory Group on Polio Eradication were invited. The background papers were presented and each member present was asked to respond. The comments of all members were tape recorded. The final conclusions were drawn by consensus at the end of the day. Thereafter the summary of the proceedings was circulated by e-mail to all participants who were again invited to suggest further modifications. These responses along with the proceedings of the work-shop used to develop a set of conclusions and recommendations. The full text of the two White papers presented and the discussion at the consultation is available on line on the IMA website imanational.com. This booklet contains a short summary of the proceedings of the day and the recommendations of the IMA Subcommittee on Immunization on the issues of Hepatitis B vaccination and Oral Polio Vaccine in India. Full report is available on the IMA website: imanational.com Brief Summary Report on meeting of experts IMA National Consultation of Experts on Immunization A national consultation of experts was held on 14 May 2006 co-sponsored by Plan International (India). Plan International (India) was represented by the India Health Advisor Dr Nalini Abraham. The President of the IMA Dr Sanjiv Malik, and Honorary General Secretary General, Dr Vinay Aggarwal were dignitaries present from the IMA. The program was inaugurated with a welcome address by Dr Vinay Aggarwal. The inaugural address was given by the IMA President Dr Sanjiv Malik. Professor S K Mittal as Chairperson of the Subcommittee on Immunization spoke of the objectives of the workshop. Workshop on Hepatitis B in India The first session was on Hepatitis B. Professor SK Mittal was the Moderator and Dr Joseph Mathew was rapporteur. Dr Jacob M Puliyel presented the draft White Paper. The White Paper was based on a systematic review of literature and a meta-analysis of the point prevalence data on hepatitis B and data on resultant deaths from Hepatocellular carcinoma. Also a search of literature using broad and inclusive search terms was performed for studies evaluating the pilot project in India. Systematic search of international literature for efficacy of the 6, 10, 14 week schedule was also presented. The experts were invited to add references which were missed in the systematic review. Each expert was invited to respond. The entire white paper and discussions are available on the IMA website imanational.com. A summary of the systematic review and the final recommendations is presented in this brief report. Workshop on the Global Polio Eradication Initiative in India This second session was held after lunch. The moderator of the session was Professor S K Mittal. Dr Tarun Gera was rapporteur. Dr J Wenger National Polio Surveillance Project spoke first on the current status of polio eradication in India. He also responded in writing to the position document. His written response is being published unedited on the web site. Dr Onkar Mittal and Dr C Sathyamala presented the position document. They discussed the strides made in control of the disease and the costs both monitory and to other public health initiatives. They highlighted the problems of vaccine induced poliomyelitis and the unexplained, unprecedented increase in non-polio acute flaccid paralysis. The issue of the use of monovalent polio vaccine as part of a Phase 4 trial without following established national guidelines evoked expressions of concern. Conclusion Immediately after a tea break a draft of recommendations was formulated having incorporated the opinions of all the experts and presented to the group. A formal set of recommendations was then emailed to the experts. This booklet summarizes the position papers and the final recommendations. Vote of Thanks Dr A Gambhir General Secretary IMA Academy of Medical Specialities HQs, gave the vote of thanks to the sponsors, and participants. Brief Summary Systematic Review and Meta-analysis of Papers Related to Hepatitis B in India Executive Summary Objectives • To assess the prevalence of Hepatitis B in the country, and collect available data on deaths from hepatocellular carcinoma. • To evaluate what the immunization program will cost the country. • To look for evidence of the success of the pilot project. • To collect evidence from world wide literature on the results of Hepatitis B vaccination starting at 6 weeks Search strategy Searches were made in Medline, Cochrane Library and Best bets and previous reviews, including cross references. Data analysis Done using standard Meta analysis software Main results 1. The true prevalence of Hepatitis B, in non-tribal populations in India is 2.1 (95% CI 1.8-2.5). This corresponds to a chronic carrier rate of approximately 1.6%. Among tribal populations it is 19.4 (95% CI 15.3–23.5) 2. The death rate from Hepatocellular carcinoma is very low in the country and constitutes 1.6% of all cancer deaths. 3. The pilot project has not been evaluated properly. 4. The proposed schedule of immunization starting at 6 weeks has not been shown to be efficacious (in reducing prevalence) in any country in the world. 5. The cost outlay for universal immunization in India is Rs 500 crores each year. Author’s conclusions An evaluation of the pilot project is required before the Government of India decides to incorporate Hepatitis B immunization in the EPI. The data required are: 1. Coverage (with 3 doses of Hepatitis B vaccine) in the pilot area. 2. The fall in carrier rate in the pilot study area 3. Carrier rate among those immunized at 6 weeks compared to those immunized at birth This is essential because the proposed schedule of immunization starting at 6 weeks, has not been shown to be efficacious (in reducing prevalence) in any country in the world. Professors SK Mittal on the importance of preventing vertical transmission Vertically acquired hepatitis B results in chronic carrier state in 90% compared to only 5% when infection acquired after 6 year of age. It is therefore responsible for most cases of HCC due to Hepatitis B infection. It is important to know the extent of vertical transmission before formulating Public Health Policies for Universal Infant Immunization In China, horizontal transmission important. Qu ZY report that the number of chronic carriers increases from infancy to childhood. Prevalence of HBsAg +ve in China: 0-1 yr 3.2 % 1-4 yr 8.9% 5-9 yr 10% In India however there is no significant difference in prevalence of Hepatitis B markers among infants 0-6 months old and children 4-5 years old (Jain V. et al, Tandon BN et al.) Thus there is little evidence to support hypothesis of the acquisition of Hepatitis B infection in infancy/early childhood by horizontal transmission in India. Most children are carriers by 5 years of age in India. 2/3rd of all carriers probably occur due to vertical transmission Synopsis of comments of the experts Dr Anand Phadke pointed out that point prevalence must be multiplied by 0.67 to get the carrier rate. He said the meta-analysis showed India was a low endemicity country. Dr Ashok Gupta cited a thesis where no vertical transmission was recorded Dr Ashok Kale said the previous estimate of 4.7% carrier rate was an arithmetic mean and hence methodologically incorrect. Dr C Sathyamala said that the forest plots in the white paper showed very narrow CI suggesting the data is well powered to interpret it reliably. Dr CP Bansil also wanted vaccines to cover both vertical and horizontal transmission. Dr Joseph L Mathew said that the HBV program must be looked at against other pressing health care needs. Dr Naveen Thaker said that the major route of transmission was horizontal but the most important was vertical transmission. Dr Panna Choudhury said deaths from cirrhosis due to HBV must be studied. He also favored a study in the pilot areas of Delhi and Andhra Pradesh. He said the present evidence was insufficient to decide on a vaccination policy. Professor R Agarwal suggested that horizontal transmission was the major problem in India. Dr Raju Shah suggested that cost efficacy be compared with other vaccines. He said one third carriers were due to vertical transmission. He felt the program may cost only Rs 135 crores. Dr Ritu Priya said 1% of all deaths were due to chronic liver disease. She wanted clarity on what proportion of this was due to HBV. Dr Tarun Gera said that there was indeed no study in world literature where the 6,10,14 week schedule was found efficacious. Dr V Sreenivas said that the ICMR cancer registry was reliable and accepted the world over. He also said evidence based medicine was the best approach although traditional wisdom has its own place. Dr V N Tripathi strongly supported the birth dose Prof B N Tandon felt that academic discussions need to be abandoned and we need to get on with immunization but it must be decided whether to vaccinate universally or selectively. He too thought the cirrhosis deaths due to HBV need to be studied. He opined that we had become slaves to evidence based medicine. Prof Parthasarthy suggested routine testing of pregnant mothers and birth dose to babies born to HBsAg positive mothers. Prof U Jhamb said 0.5% admissions in children were due to Chronic liver disease and 20% of this was due to HBV. Professor Nirmal Kumar felt Evidence Based Medicine was not the appropriate approach to arrive at right answers. He felt that vertical transmission needs to be prevented and suggested that if costs of vaccine came down, people would buy their own vaccine. None of the experts cited papers that had been missed out from the systematic review. Plain Language Summary The pilot project areas can provide useful data on feasibility, cost and efficacy of the Hepatitis B vaccination program starting at six weeks. It is difficult to defend the incorporation of Hepatitis B vaccine in the EPI without evaluating experience from the pilot project. More research is needed, especially as there is no data in literature that vaccination starting at 6 weeks is efficacious. Costs must be looked at against competing priorities Recommendation on Hepatitis B vaccination in India Conclusions and Recommendations from the National Consultative Meeting on Hepatitis B Vaccination Indian Medical Association May 14, 2006 at New Delhi Conclusion 1 On meta-analysis the true prevalence of Hepatitis B in India among non-tribals is 2.1% (95% CI 1.8 - 2.5). This is the meta analysis of data of point prevalence not carrier rate. It was pointed out that chronic carriers by definition have to be positive on repeat testing at least 6 months later. The carrier rate is approximately 80% of the point prevalence rate. This corresponds to a chronic carrier rate of 1.6% for India Conclusion 2 “Hepatocellular carcinoma constitutes only 1.6% of all cancers in India, hence is very rare.” However, it is not clear how many of these are related to Hepatitis B. The estimated annual deaths attributable to hepatocellular carcinoma due to hepatitis B are only 5000. A better marker of burden of Hepatitis B may be obtained by a registry counting cases of cirrhosis as about a third of cases of cirrhosis in adults is related to Hepatitis B. Reliable data on this is not available. Recommendation In view of these estimates, the cost efficacy of universal immunization with Hepatitis B needs to be re-evaluated. Conclusion 3 Vertical transmission of infection from mother to child is an important mode of acquiring Hepatitis B infection, especially in establishing chronic Hepatitis B carriers. The exact incidence of vertical transmission is not known in our country but it may be contributing at least 30% to 40% of the pool of chronic Hepatitis B carrier rate. Recommendation Before launching any national program it would be vital to assess the contribution of vertical transmission to the overall Hepatitis B carrier pool. If universal hepatitis B vaccination is to be carried out, currently available data, though inadequate, would strongly favour initiation of Hepatitis B vaccination starting at birth. Conclusion 4 There is no scientific data from anywhere in the world that the schedule of 6,10 and 14 weeks has been found to be effective in reducing the carrier rates of Hepatitis B. The pilot project carried out in Andhra Pradesh and Delhi with 6, 10 and 14 weeks has not been evaluated for its efficacy. We need to know the effect on carrier rates among the children who received the vaccine at 6, 10 and 14 weeks compared to the unvaccinated children. Recommendation It will not be advisable to initiate a National/ Sub-national immunization program without proper evaluation of the pilot project. Conclusion 5 The overall prevalence of chronic carrier rate among the tribal population is very high (19.4%) (95% CI 15.3 – 23.5) which is comparable to those living in the East Asian Countries Recommendation A well designed epidemiological study is needed in this population to study the natural history of the disease. If necessary, a vaccination program, with first dose being given at birth, could be considered in these population groups. Brief Summary Global Polio Eradication Initiative in India-1995- 2006 Prepared for IMA Conference by Dr. Onkar Mittal. Dr. C. Sathyamala Summary Main Points 1. Circulation of Wild Polio Virus (WPV) continues despite 12 years of intensive efforts. 2. There has been a dramatic increase in the number of AFP cases in the last 2-3 years, with a national average rate of 6.3/1,00,000 and even higher incidence of 12-13 /1,00,000 in endemic states of UP and Bihar, against an international average of 1/1, 00, 000. 3. There is an urgent need for a complete epidemiologic investigation into the cases of AFP with a view to find out the reason for the rising incidence, to know the exact cases and nature of these AFP cases, and to provide appropriate treatment and rehabilitation. 4. Strategy of increasing the number of pulse polio rounds each year ( the NIDs and SNIDs) to meet the challenge of continuing transmission of WPV does not seem to be meeting the desired objective of stopping the transmission of WPV and needs to be reviewed. 5. The monovalent Oral Polio Vaccine-1 (mOPV1) has been introduced in India since last year, through the polio eradication programme. More than 5-6 pulse polio rounds have been undertaken in the selected districts of UP and Bihar with mOPV1, contrary to the recommended 1-2 doses. Impact of these multiple rounds of mOPV1 needs to be assessed. 6. Inactivated Polio Vaccine (IPV) has been introduced in many developed countries, to tackle the problem of Vaccine Associated Polio Paralysis (VAPP) due to OPV, while maintaining the immunity against wild polio virus. Desirability, feasibility and cost efficacy of this strategy needs to be discussed in the national context. 7. Strategies that need to be adopted, if we fail to stop the transmission of WPV, need to be discussed as much as the ‘post- eradication- strategies’ which would be required if we are somehow able make the achievement of stopping the wild polio virus transmission. One Way Forward 1. The year 2006 should be the year of the phased withdrawal and closure of the National Pulse Polio Program. 2. Urgent investigation should be carried out on the actual incidence of Post Polio Residual Paralysis (PPRP) in the cases of reported AFP in the last 10 years. 3. The activities of the polio-immunization should be re-integrated into the Universal Immunization Program. 4. An expert committee should review the present evidence base on efficacy of the IPV and cost –benefit- ratio of substituting IPV for OPV and other issues related to the relative merits of these programs in the prevention of the transmission of WPV. 5. The improvement of sanitation and hygiene should be taken up as the highest priority, specially, in those urban and rural pockets of UP and Bihar, which have been reporting the cases of WPV in the last three years. Adequate funds are available under the ‘Rajiv Gandhi Drinking Water and Sanitation Mission’ for this purpose and more can be provided by the Central and State Governments. The public health professionals should put their time and energy for the effective implementation of this program. 6. An independent commission should be appointed to review all aspects of National Pulse Polio Program in the last ten years and appropriate lessons should be drawn for the health policy formulation, program implementation and health governance in this country. 7. A comprehensive policy and program for the rehabilitation of the children who have been paralyzed during the period of the polio eradication initiative should be worked out. Synopsis of comments of the experts Dr A D Tiwari said that his personal experience was that there was a lot of under reporting from Bihar. Dr A Kale spoke of the threat of bioterrorism with polio virus. Dr A Phadke thought that polio was not eradicable Dr Ajay Gambhir said doctors were developing apathy to PEI He said there was no attention being paid to water supply and sanitation. Dr Ashok gupta said water and sanitation need to be looked at and the possibility of using IPV. Dr CP Bansal felt workers at the grass root level were poorly paid and not motivated. Dr Jay Wenger’s response was that great progress was already made with polio eradication. He felt that the 1/100,000 rate of non polio AFP was only a minimum target not the international average. He felt that once OPV is stopped VDPV and iVPDV will disappear after some time. He felt that the authors must tone down the “experimental drug rhetoric.” The full text of his response is published on the web site: imanational.com. Dr Joseph Mathew felt evaluation of surveillance must be by an external agency independent of the NPSP/ WHO. As long as OPV is used, VAPP will occur hence poliomyelitis cannot be eradicated with the current strategy. Since elimination of wild virus circulation (with the current strategy) is not the same as eradication of poliomyelitis by definition, the emphasis must shift from surveillance of poliomyelitis to surveillance for poliovirus. Dr Mahesh thought there was fatigue among PEI workers. Dr Naveen Thacker said WPV was localized to a few pockets. He said the IEAG had recommended IPV in these areas. Dr P M Bhargava spoke of the plan in 1980 to manufacture IPV in India and how the plan was shelved for no explicit reason. He spoke of his experience of the poor condition of the cold chain in district hospitals. Dr Panna Choudhuryfelt that dissemination of information by the NPSP was selective leading to confusion and concern. Dr Parthasarthy felt that looking at the numbers we might be looking at a resurgence of WPV. He felt IPV must be used. Dr R N Srivastava said the problem in western UP was lack of political will. He said that 45 – 49% of non polio AFP were not in fact AFP. Dr Rajeev Tandon said we should aim at eradication not control. Dr Raju Shah felt that IPV was not affordable and that eradication was still possible. He said VAPP was not a big issue. Dr Ritu Priya said that by epidemiological classification the agencies were not aiming for eradication. Dr Verma (NPSP) felt polio eradication was the only option available. He said that mOPV was being used as phase 4 trial. Professor Mittal wondered why consent from parents as for a phase 4 trial was not being obtained. Dr Yash Paul wondered if the population in North India was resistant in its response to OPV or genetically predisposed to WPV Recommendations on Polio Conclusions and Recommendations from the National Consultative Meeting on Polio Eradication Initiative Indian Medical Association May 14, 2006 at New Delhi Gains achieved by the program: • Confirmed wild polio cases down significantly. • Number of ‘infected’ states has decreased. • Very focal transmission now. • P3 almost absent. • Less genetic bio-diversity now. • Coverage during pulse polio rounds is ‘improving’. • “Excellent” surveillance system in place. • Large scale social mobilization operation in India that cut across several barriers (during pulse polio rounds). The costs: • Financial cost involved is upwards of Rs 4000 crores. • Higher priority health problems have receded to the background. • Even routine immunization has suffered, as evidenced by higher number of cases of traditional VPDs. • No mention of VAPP at all in the grand reports of covering 170 million per NID and 67 million per SNID. • Fatigue at all levels. • Confidence of public and professionals shaken. • A close look shows that with the current strategy “polio cannot be eradicated”. (Please see point made to Dr. Wenger’s comments) • Now the WHO plans to label the absence of WPV cases for three years as certification of eradication and leave countries in the lurch as to future plans to maintain this status. Conclusion 1 Continuing circulation of the wild polio virus in a few states, despite intensified pulse polio activities, with multiple changes in strategies and interventions, is a matter of serious concern. At the same time a large number of states which have been free of WPV for last several years are being unnecessarily being exposed to hazards of VAPP due to OPV Recommendation Strategies need to be reviewed by setting up a National Expert group. Possible use of IPV (alone or in combination with OPV) needs to be considered strongly. (See also Conclusion /recommendation 4) Conclusion 2 There is an alarming increase in the number of clinical AFP cases, particularly in the states of UP and Bihar. Such high incidence of non-polio AFP has not been reported from anywhere else in the world. Recommendation These reported cases need thorough evaluation, including clinical follow-up, to assess the possible causes, and sequelae thereof. There is also an urgent need of establishing an independent agency (separate from NPSP) for carrying out surveillance activities. Conclusion 3 Administration of multiple doses of mOPV1 in a pulse manner to a very large number of children in different states of the country is unprecedented. It is alarming that the same is being done as phase IV clinical trial without following the established national guidelines for such trials. Recommendation There is a need to immediately evaluate the impact and side effects, if any, of the use of multiple doses of mOPV1. Conclusion 4 At present, there does not appear to be a coherent policy for the future keeping in mind the possibilities of a) Pockets of continuing circulation of WPV; or b) Ultimate cessation of circulation of WPV Recommendation There is a need for an independent National Expert Group to consider future strategies, which would be best, suited to our country within the overall objectives of the Global Polio Eradication Initiative. The feasibility and desirability of introducing IPV and the suitable timing for the same also needs to be examined by this expert group. There is urgency for deciding on these issues with a view to establish and achieve self sufficiency in manufacturing of IPV in the country, if it is considered desirable to introduce IPV in the immunization program. Conclusion 5 The number of cases of VAPP is not available in the public domain. It is not even known whether there is a definition of VAPP or compatible VAPP. Recommendation District wise and state wise data on VAPP should be made available on a regular basis. Efforts must also be made to asses VAPP among contacts of those vaccinated. It is also important that the state initiates a comprehensive program of rehabilitation and possibly compensation for the victims of VAPP List of experts invited to the expert consultation and to whom the draft White Papers circulated for comments 1. Dr.J.C.Vij S-477 Greater Kailash-I New Delhi 48 jcvij@hotmail.com 2. Dr. Moon Shrestha Prof of Paed Kathmandu Medical College Sinamangal, POB 21266 Nepal moonshrestha@htmail.com 3. Dr Anant Phadke 8, Ameya Ashish Society Kakan Express Hotel Lane Kothrud Pune-38 Maharashtra cehatpun@vsnl.com 4. Dr Rakesh Lodha A-5 Type # 5 Iari Pusa New Delhi rakeshlodha@hotmail.com 5. Dr Sushil Kumar Kabra Additional Professor Dept Of Pediatrics All India Institute Of Medical Sciences New Delhi skkabra@hotmail.com 6. Dr Rakesh Agarwal Assoc. Prof of Pead G.E. Sanjay Gandhi Post Graduate Institute Raebareli Road Lucknow-226014 UP 7. Dr Jacob Puliyel Dept. of Pead St.Stephen Hospital Tis Hazari New Delhi puilyel@gmail.com 8. Dr. S.K Sareen HOD Dept. of Gastroentrology GB Pant Hospital New Delhi 9. Dr.Ashok P. Kale Associate Professor, Dept of Community Medicine, Padamshree Dr.D.Y.Patel Medical College, Pimpri, Pune Maharashtra Ashokpkale2003@yahoo.com 10. Dr. Rajib Dasgupta Asst.Professor Centre of Social Medicine & Community Health School of Social Sciences-II Jawaharlal Nehru University New Delhi rdasgupta@mail.jnu.ac.in, dasgupta_jnu@yahoo.com 11. (Prof.) Sanjay Chaturvedi UCMS & GTB Hospital Complex Dilshad Garden Delhi 12. Dr. Ritu Priya Professor Centre for Social Medicine, Jawahar Lal Nehru University New Delhi ritupriya@vsnl.com 13. Dr.C.S.Pandav C/o Dr. Sathyamala cpandav@iqplusin.org 14. Dr.Y.Madhvi Yannapu y_madhavi01@hotmail.com 15. Dr.Sangeeta Yadav Prof of Pead Dept. of Pead Maulana Azad Medical College New Delhi 16. Mr. Rama Murthy Secretary Ministry of Health & Family Welfare Nirman Bhawan New Delhi 17. Dr Naveen Thacker D-70 Shaktinagar Gandhidham Kutch 370201 Gujarat drnaveenthacker@gmail.com, presidentiap2007@iapindia.org 18. Dr Vipin M Vashishtha Consultant , Pediatrician & Neonatologist Mangla Nursing Home, Station Road, Bijnor 246701 Uttar Pradesh 19. Dr Onkar Mittal E-43 South Extn., Part I New Delhi o-mittal@rediffmail.com 20. Dr Sathyamala 121, Pocket-B, SFS Flats Sukhdev Vihar New Delhi c_sathyamala@rediffmail.com 21. Dr RN Srivastava 487 Mandakini Enclave Alaknanda New Delhi rnsri@vsnl.net 22. Dr.C.M.Khanijo OSD Pulse Polio Dept of F.W. Govt. of NCT of Delhi Old SDA Build, Malka Ganj, New Delhi 23. Dr.Harish Kumar Consultant IMNCI WHO Nirman Bhawan New Delhi 24. Dr T Jacob John Thekkekara, 439 Civil Supplies, Godown Lane Kamalakshipuram, Vellore, North Arcot 632002 Tamil Nadu vlr_tjjohn@sancharnet.in 25. Dr Nitin K Shah 186-A Vaswani Villa 1st Floor Block # 3 Jain Society, Near Jain Temple, Sion (West), Mumbai 400022 Maharashtra drnitinshah@hotmail.com 26. Dr Yash Paul A-D-7, Devi Marg Bani Park Jaipur 302016 Rajasthan Dryashpaul2003@yahoo.com 27. Dr SK Mittal 3 Lucknow Road New Delhi skmittal44@yahoo.com 28. Dr Panna Choudhury R-3 Hauz Khas New Delhi drpchoudhury@gmail.com 29. Dr AK Dutta Flat # 8 Lady Hardinge Medical College Campus New Delhi duttaak@vsnl.net, drdutta@gmail.com 30. Dr AP Dubey 6E Ms Flats Minto Road New Delhi apdubey52@rediffmail.com 31. Dr A Parthasarathy 'Brindavan', 166 Park Road Anna Nagar, Western Extension Chennai 600101 Tamil Nadu apartha2000@yahoo.com 32. Dr Raju C Shah Ankur Children Hospital Behind City Gold Cinema Ashram Road Navarangpura Ahmedabad 380009 Gujarat rajucshah@rediffmail.com, rajucshah@lycos.com 33. Dr Lalit Kant Sr. Deputy Director (ECD) Indian Council of Medical Research New Delhi lalitkant@icmr.org.in 34. Dr Joseph Mathew Assistant Professor Department Of Pediatrics Advanced Pediatrics Centre, PGI Chandigarh jlmathew@rediffmail.com, joseph.l.mathew@gmail.com 35. Dr. Urmila Jhamb Asst. Prof, Deptt. Of Pead Maulana Azad Medical College & LNJP Hospital New Delhi ujhamb@hotmail.com 36. Dr. Gopal Dabade President Drug Action Forum 57, Tejasvani Nnagar Dharwad-580002 (Karnataka) drdabade@gmail.com 37. Dr.A.J. Chitkara 118, Vaishali Pitam Pura New Delhi chitkara@liveindia.com 38. Dr.(Prof) J Muliyel Prof /Pricipal PSM CMC Vellore 39. Dr. Rajiv Tandon Tandon Clinic C-55 Anand Niketan New Delhi rtandon@eth.net 40. Dr.Shyam Kukreja 10, Hargobind Enclave New Delhi drshyamkukreja@hotmail.com 41. Prof. Imrana Qader Centre of Social Medicine & Community Health School of Social Sciences Jawahar Lal Nehru University New Delhi-110067 qadeeroy@vsnl.com 42. Dr.Anoop Saraia Assoc. Prof Dept. of Gastroentrologist All India Institute of Medical Sciences New Delhi 43. Dr. Avinash Kaur Mehta Director Family Welfare Malka Ganj New Delhi 44. Dr.Ajay Gambhir Hony. Secretary, IMA AMS T-721, Saraswati Vihar New Delhi ajaygambhir@rediffmail.com 45. Dr.V.Sreenivas Associate professor of Biostatistics AIIMS, Ansari Nagar New Delhi sreevishnubhatla@gmail.com 46. Dr.Nalani Abraham Health Advisor PLAN International B-4/161, Gulmohar House , 5th Floor, Gautam Nagar New Delhi nalini.abraham@plan-international.org 47. Mr. Pravin Jha Plan International B-4/161, Gulmohar House, 5th Floor, Gautam Nagar New Delhi 48. Dr.Marzio Babillee UNICEF New Delhi mbabillee@unicef.org 49. Dr.M.Galway UNICEF New Delhi mgalway@unicef.org 50. Salim J. Hebayeb WHO-India New Delhi wrindia@searo.who.int 51. Dr. Paul Francis WHO-India New Delhi pfrancis@gmail.com 52. Shri. M.S. Jalaja Addl. Secretary Govt. of india Ministry of Health and Family Welfare Nirman Bhawan New Delhi 53. Dr. P.Haldar Asstt. Commissioner, UIP 106B, Nirman Bhawan New Delhi pradeephaldar@yahoo.com 54. Dr. P.Biswal Asst. Commissioner-Immunization 106-B, Nirman Bhawan New Delhi polivindia@yahoo.com 55. Dr. Ashok Dayalchand Director- IHMP, Pachod Aurangabad 56. Dr. Roma Solomon CORE 57. Dr. Kumuda Aruldas Population Foundation of India B-28, Qutab Institutional Area New Delhi kumudha@popfound.org 58. Dr. Vinohar Balraj Christian Medical College Vellore 59. Dr.Philip Abraham Prof. Of Gestroentrology KEM Hospital, Parel Mumbai Maharashtra 60. Dr. Murhekar MV Regional Medical Centre ICMR Port Blair Andamon-Nicobar mmurhekar@yahoo.com 61. Dr S.Sehgal pbcicmr@sancharnet.in 62. Dr. Tarun Gera B-256 Derawal Nagar New Delhi Tarun.256@yahoo.com 63. Dr.J.Wenger Head of Dept Natinal Polio Survellence Project WHO Gate No.3, 2nd Floor Jawahar Lal Nahru Stadium, New Delhi wengerj@npsu.org 64. Dr.S.K.Acharya HOD Dept. of Gestroentrology Subratacharya2004@yahoo.com, gastroaiims@yahoo.com 65. Prof. Nirmal Kumar Head , Dept of Gastroentrology & Hepatology Sri Balaji Action Medical Institute Paschim Vihar New Delhi Prof_nirmal@yahoo.co 66. Dr.B.N.Tandan Metro Hospital L-94, Sector-11 Noida UP drvivektandan@revioomail.com 67. Dr C P Bansal (EBM) 1/5, Shahbad Pratap 1 Ashram Lashkar Gwalior, 4 Madhya Pardesh dansaicp@sancharnet.in, cpbansal@hotmail.com 68. Dr Sunil Gomber (EBM) F-4 (A) Vijay Nagar New Delhi sunilgomber@hotmai.com 69. Dr Ashok Gupta (EBM) 25, Chetak Marg Near JK Lon Hospital Jaipur-302004 Rajeshthan dr_ashok@sancharnet.in 70. Dr Vinit K Saxena (EBM) B-3, PWD Collony Parbhat Nagar Merrut -250001 . UP drvineetpeds@yahoo.com, drvineetkilkari@hotmail.com 71. Dr V N Tripathi (EBM) HOD Kanpur P-5, Medical College Campas Kanpur-208002 UP vntripathi@rediffmail.com 72. Dr. Mahesh Kr Goel (EBM) Toolika Nursing Home Near Church Mission Compound Saharan Pur-247001, UP drmaheshgoel@yahoo.com 73. Dr Verender N Mehendiratta (EBM) 50-L, Model Town Panipat-132103, Haryana mvirender@yahoo.com 74. DR B D Bhatia HOD, Dept of Paediatric Banaras Hindu University Institute of Medical Sciences VARANASI UP baldev_bhatia@rediffmail.com 75. Dr Ashok Rai (EBM) Banaras Hindu University Institute of Medical Sciences VARANASI UP drashokrai@rify.com 76. Dr Atul Aggarwal, Atul Latika Hospital Barelly 77. Dr. .M. M. Faridi President IAP New Delhi iapdelhi@rediffmail.com 78. Dr. Tamaria, Secretary IAP New Delhi iapdelhi@rediffmail.com 79. Dr. A.D. Tiwari HOD Medical College Rohtak dradtiwari@yahoo.com 80. Dr. Joana M. Raid Senior Health Advisor DFID India B-28, Taso Crescent Qutab Institutional Area New Delhi jm-reid@dfid.gov.uk. 81. Dr. Narendra Arora Editor Journal of Indian Pediatrics nkmanan@yahoo.com narendrakumararora@hotmail.com 82. Dr.Pushpa Bhargava Anveshna `For Qan’, Cottage, 12-13-100, LANE # 1, Street # 3 Taranaka Hyderabad-500017 Bhargava.pm@gmail.com 83. Dr. Parbir Chatterjee Consultant UNICEF 219/2, AJC Bose Road Kolkata-700017 W.Bengal prabirkc@yahoo.com 84. Dr.R.K.Aggarwal State President Rajasthan State Branch 39, Ravindra nagar Airport Road Udaipur (Rajasthan) rk_hospital@hotmail.com 85. Dr. Kulbhushan Sharda 412, Master Tara Singh Nagar Jalandhar-144001 (Punjab) drkbsharda@vsnl.met 86. Dr. Mira Shiva Convener, All India Drug Action A-60, Hauz Khas New Delhi-110016 mirashiva@yahoo.com 87. Dr.I.C.Tiwari 204, Lake View Complex Near Ayushman Hospital, Shahapura, Sector-C Bhopal MP ictiwari@yahoo.com 88. Dr. M.C.Gupta G-17/9, Malviya nagar New Delhi-110017 mcgupta44@rediffmail.com 89. Dr.P.S.Sahni B-30-A Kailash Colony New Delhi 90. Dr.D.K.Taneja Prof. Of PSM Maulana Azad Medical College New Delhi-110002 91. Dr.G.R.Sethi Prof of Paediatrics Maulana Azad Medical College New Delhi-110002 92. Dr.Varinder Singh Prof. Of Peadiatrics Kalawati Saran Hospital New Delhi 93. Dr. Mathew Verghese Director St.Stephan Hospital Tis Hazari Delhi 94. Dr.Rajiv Nayan New Delhi 95. Dr.Puneet Bedi New Delhi drpuneetbedi@gmail.com 96. Mr.Jatinder Singh I.V.D. WHO Ring Road New Delhi singhj@whosea.org 97. Dr.Sudhansh Malhotra malhotras@whosea.org
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  Gradenigo's syndrome.

  Indian Pediatr. 2006 May;43(5):456-7
  Rangasami JJ, Puliyel J.
  West Middleswx University Hospital London
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  Evaluation of pulse-oximetry oxygen saturation taken through skin protective covering.

  BMC Pediatr. 2006 May 6;6(1):14
  James J, Tiwari L, Upadhyay PK, Sreenivas V, Bhambhani V, Puliyel J.
  ABSTRACT: BACKGROUND: The hard edges of adult finger clip probes of the pulse oximetry oxygen saturation (POOS) monitor can cause skin damage if used for prolonged periods in a neonate. Covering the skin under the probe with Micropore surgical tape or a gauze piece might prevent such injury. The study was done to see if the protective covering would affect the accuracy of the readings. METHODS: POOS was studied in 50 full-term neonates in the first week of life. After obtaining consent from thei Show More...ABSTRACT: BACKGROUND: The hard edges of adult finger clip probes of the pulse oximetry oxygen saturation (POOS) monitor can cause skin damage if used for prolonged periods in a neonate. Covering the skin under the probe with Micropore surgical tape or a gauze piece might prevent such injury. The study was done to see if the protective covering would affect the accuracy of the readings. METHODS: POOS was studied in 50 full-term neonates in the first week of life. After obtaining consent from their parents the neonates had POOS readings taken directly (standard technique) and through the protective covering. Bland-Altman plots were used to compare the new method with the standard technique. A test of repeatability for each method was also performed. RESULTS: The Bland-Altman plots suggest that there is no significant loss of accuracy when readings are taken through the protective covering. The mean difference was 0.06 ( SD of 1.39) and 0.04 (SD 1.3) with Micropore and gauze respectively compared to the standard method. The mean difference was 0.22 (SD 0.23) on testing repeatability with the standard method. CONCLUSION: Interposing Micropore or gauze does not significantly affect the accuracy of the POOS reading. The difference between the standard method and the new method was less than the difference seen on testing repeatability of the standard method.
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  Universal immunization with Hepatitis B: Keeping up with the Joneses

  http://www.bmj.com/cgi/eletters/332/7545/804#131729
  Puliyel J, Amit Kumar
  Universal vaccination of all in the UK with Hepatitis B vaccine will reduce the yearly incidence of new cases of chronic carriers by a mere 4%. 96% of the burden of disease results from disease in immigrants who will not be helped by universal immunisation in the UK. Although these stark facts are widely known (1), in the space of a little more than a year, we have had two editorials in the BMJ, (authored by individuals with declared conflict of interests) suggesting that the UK government must Show More... Universal vaccination of all in the UK with Hepatitis B vaccine will reduce the yearly incidence of new cases of chronic carriers by a mere 4%. 96% of the burden of disease results from disease in immigrants who will not be helped by universal immunisation in the UK. Although these stark facts are widely known (1), in the space of a little more than a year, we have had two editorials in the BMJ, (authored by individuals with declared conflict of interests) suggesting that the UK government must adopt a policy of universal immunisation (2, 3). The latest editorial (3) says that 168 countries worldwide and 44 of 52 countries in WHO's European region have already implemented this policy. It will be interesting to see at what critical mass of editorial badgering, the government will be persuaded against its better judgement, to undertake this wasteful programme � just to keep up with the Joneses References 1. Foundation for Liver Research. Hepatitis B: out of the shadows. London, Foundation for Liver Research, 2004. www.ucl.ac.uk/liver- research/hepatitis-report.pdf 2. Beeching NJ Hepatitis B infections BMJ 2004; 329: 1059-1060 3. Banatvala J, Damme PV, Emiroglu N. Hepatitis B immunisation in Britain: time to change? BMJ 2006;332:804-805 Competing interests: None declared
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  Ask the Doc: The Hindu

  2/4/06 Sunday Magazine The Hindu
  Puliyel J
  Tourette Syndrome, Asthma, Constipation
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  Signs of inflammation in children that can kill (SICK score): Preliminary prospective validation of a new non-invasive measure of severity-of-illness.

  J Postgrad Med. 2006 Apr-Jun;52(2):102-5.
  Bhal S, Tygai V, Kumar N, Sreenivas V, Puliyel JM
  Triage score Sick score calculator. BACKGROUND: Signs of Inflammation in Children that can Kill (SICK score) is a new severity-of-illness score. It uses the physical signs of the Systemic Inflammatory Response Syndrome (SIRS) and its continuum - the Multiple Organ Dysfunction Syndrome (MODS). The development of the score used multiple logistic regression model coefficients converted to integer scores that have been published earlier. AIMS: The present study was done to validate the scoring syst Show More...Triage score Sick score calculator. BACKGROUND: Signs of Inflammation in Children that can Kill (SICK score) is a new severity-of-illness score. It uses the physical signs of the Systemic Inflammatory Response Syndrome (SIRS) and its continuum - the Multiple Organ Dysfunction Syndrome (MODS). The development of the score used multiple logistic regression model coefficients converted to integer scores that have been published earlier. AIMS: The present study was done to validate the scoring system by predicting outcomes in a fresh data set. SETTING: Intensive care unit in a tertiary referral hospital. DESIGN: Prospective. MATERIALS AND METHODS: 125 admissions to the intensive care unit were evaluated so that the SICK score and the PRISM score could be calculated. In-hospital mortality was noted. STATISTICAL ANALYSIS: Calibration (Hosmer-Lemeshow goodness of fit) and discrimination (area under the ROC curve) were used to measure performance. RESULTS: Of the 125 patients studied 23 died. The area under the ROC curve was 0.76 compared to 0.80 in the development sample. Using PRISM in the validation group, the ROC was 0.78. Calibration was excellent. CONCLUSION: The SICK score can predict severity of illness with nearly the same accuracy as the PRISM score. The SICK score can be calculated immediately on admission and can help to prioritize care for the more sick children who need urgent aggressive management. Larger studies, that includes all admissions to the hospital, will now need to be done.
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  Lactate: Creatinine ratio in babies with thin meconium staining of amniotic fluid.

  BMC Pediatr. 2006 Apr 20;6(1):13
  Ojha RK, Singh SK, Batra S, Sreenivas V, Puliyel JM.
  ABSTRACT: BACKGROUND: ACOG states meconium stained amniotic fluid (MSAF) as one of the historical indicators of perinatal asphyxia. Thick meconium along with other indicators is used to identify babies with severe intrapartum asphyxia. Lactate creatinine ratio (L: C ratio) of 0.64 or higher in first passed urine of babies suffering severe intrapartum asphyxia has been shown to predict Hypoxic Ischaemic Encephalopathy (HIE). Literature review shows that meconium is passed in distress and thin mec Show More...ABSTRACT: BACKGROUND: ACOG states meconium stained amniotic fluid (MSAF) as one of the historical indicators of perinatal asphyxia. Thick meconium along with other indicators is used to identify babies with severe intrapartum asphyxia. Lactate creatinine ratio (L: C ratio) of 0.64 or higher in first passed urine of babies suffering severe intrapartum asphyxia has been shown to predict Hypoxic Ischaemic Encephalopathy (HIE). Literature review shows that meconium is passed in distress and thin meconium results from mixing and dilution over time, which may be hours to days. Thin meconium may thus be used as an indicator of antepartum asphyxia. We tested L: C ratios in a group of babies born through thin and thick meconium, and for comparison, in a group of babies without meconium at birth. METHODS: 86 consecutive newborns, 36 to 42 weeks of gestation, with meconium staining of liquor, were recruited for the study. 52 voided urine within 6 hours of birth; of these 27 had thick meconium and 25 had thin meconium at birth. 42 others, who did not have meconium or any other signs of asphyxia at birth provided controls. Lactate and creatinine levels in urine were tested by standard enzymatic methods in the three groups. RESULTS: Lactate values are highest in the thin MSAF group followed by the thick MSAF and controls. Creatinine was lowest in the thin MSAF, followed by thick MSAF and controls. Normal babies had an average L: C ratio of 0.13 (+/- 0.09). L: C ratio was more among thin MSAF babies (4.3 +/- 11.94) than thick MSAF babies (0.35 +/- 0.35). Median L: C ratio was also higher in the thin MSAF group. Variation in the values of these parameters is observed to be high in the thin MSAF group as compared to other groups. L: C ratio was above the cutoff of 0.64 of Huang et al in 40% of those with thin meconium. 2 of these developed signs of HIE with convulsions (HIE Sarnat and Sarnat Stage II) during hospital stay. One had L: C Ratio of 93 and the other of 58.6. A smaller proportion (20%) of those with thick meconium had levels above the cutoff and 2 developed HIE and convulsions with L: C ratio of 1.25 and 1.1 respectively. CONCLUSION: In evolving a cutoff of L: C ratios that would be highly sensitive and specific (0.64), Huang et al studied it in a series of babies with severe intrapartum asphyxia. Our study shows that the specificity may not be as good if babies born through thin meconium are also included. L: C ratios are much higher in babies with thin meconium. It may be that meconium alone is not a good indicator of asphyxia and the risk of HIE. However, if the presence of meconium implies asphyxia then perhaps a higher cut-off than 0.64 is needed. L: C ratios should be tested in a larger sample that includes babies with thin meconium, before L: C ratios can be applied universally.
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  Understanding the Absolute Risk Reduction from HPV Screening is Crucial

  http://www.bmj.com/cgi/eletters/338/apr06_2/b1423#214238
  Jacob M. Puliyel, Himanshu Aneja, Sona Chowdhary.
  By happenstance, the week after the BMJ �Short cuts� (1) summarized the paper by Sankaranarayanan et al that HPV testing can reduce cervical- cancer mortality (RR 0.52) (2) the Lancet published its editorial on harms from screening (3). However none of the many reviews of the study on �HPV- testing� questioned the wisdom of author�s suggestion that screening for HPV would be an efficient way to reduce cervical cancer. We hope our letter will redress that situa Show More... By happenstance, the week after the BMJ �Short cuts� (1) summarized the paper by Sankaranarayanan et al that HPV testing can reduce cervical- cancer mortality (RR 0.52) (2) the Lancet published its editorial on harms from screening (3). However none of the many reviews of the study on �HPV- testing� questioned the wisdom of author�s suggestion that screening for HPV would be an efficient way to reduce cervical cancer. We hope our letter will redress that situation. The problem of quoting relative risk without giving the absolute risk has been highlighted repeatedly in the BMJ (4,5). The cervical-cancer death-rate in the control group of the study can be used to calculate the risk in the population without any screening program. There were 64 deaths in 8 years in the population of 31,488 making for an absolute risk of 2.5/10,000/year. The absolute risk reduction in this case works out to be 0. 00013. The cost of the HPV testing strategy is much higher than �$20 for each woman over 30�, suggested by the authors. 10% women showed up positive on HPV testing and they needed further investigations including repeated PAP smear examinations and biopsies to effect this lowering of mortality. The costs for all these procedures needs to be added up and weighed against the ARR of 0.00013. The intangible costs of the anxiety to 10% of the population of women, who need these repeated examinations, also need consideration. References 1. BMJ Short Cuts HPV test is best for a single round of cervical cancer screening in India. BMJ 2009;338:b1423 2. Sankaranarayanan R, Nene BM, Shastri SS, Jayant K, Muwonge R, Budukh AM, Hingmire S, Malvi SG, Thorat R, Kothari A, Chinoy R, Kelkar R, Kane S, Desai S, Keskar VR, Rajeshwarkar R, Panse N, Dinshaw KA. HPV screening for cervical cancer in rural India. N Engl J Med. 2009;360:1385- 94. 3. Editorial. The trouble with screening Lancet 2009;373:1223 4. Campbell MJ. Resting heart rate as predictor. What about absolute risks? BMJ. 2009;338:b1197 5. Alonso-Coello P, Garc�a-Franco AL, Guyatt G, Moynihan R. Drugs for pre-osteoporosis: prevention or disease mongering? BMJ. 2008;336:126-9.
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  Issues Related to Hepatitis B Vaccination in India:

  Ashish Batham, Dherian Narula, Tanmay Toteja, V Sreenivas and Jacob M Puliyel
  Meeting of Experts on Draft White Paper presented by Jacob Puliyel. Systematic Review and Meta analysis
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  Prone versus supine position in mechanically ventilated babies

  J Pediatrics and Child Health. 2006;42: A8
  Baijal N, Puliyel J, Beri R, Sreenivas V.
  Royal Australasian College of Physicians. Pediatrics and Child Health Division Annual Conference Queensland 2006
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  Smuggling contraband drugs using paediatric

  Arch Dis Child. 2006 Jan;91(1):51.
  Chakrabarty A, Hydros S, Puliyel JM.
  See last page 51
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  Indian association questions plan for hepatitis B immunisation

  BMJ 2006;333:621, doi:10.1136/bmj.333.7569.621-c
  Ganapati Mudur
  Indian Medical Association report on Hepatitis B Indian association questions plan for hepatitis B immunisation New Delhi Ganapati Mudur The Indian Medical Association has criticised a government proposal to expand universal immunisation against the hepatitis B virus throughout India, saying that it would be “wasteful spending” on a low priority health problem. In a report sent to the health ministry, the association said that a systematic review of studies indicates that the rate of ch Show More...Indian Medical Association report on Hepatitis B Indian association questions plan for hepatitis B immunisation New Delhi Ganapati Mudur The Indian Medical Association has criticised a government proposal to expand universal immunisation against the hepatitis B virus throughout India, saying that it would be “wasteful spending” on a low priority health problem. In a report sent to the health ministry, the association said that a systematic review of studies indicates that the rate of chronic carriage of hepatitis B in India is 1.6% and not 4% as projected. It has also cautioned that the proposal to immunise infants at 6, 10, and 14 weeks would not significantly change rates of chronic carriers because most cases result from vertical transmission (directly from mother to baby during and after pregnancy). The report, made public by the association last week, has evoked sharp reactions from some doctors who have said that the lower estimate of rates of chronic carriers should not deter universal immunisation. “When an effective, inexpensive vaccine is available, it would be unethical to deny it to the population,” said Subrat Acharya, a gastroenterologist at the All India Institute of Medical Sciences in New Delhi. After a pilot project to immunise infants against hepatitis B in 15 cities and 32 districts, the health ministry has proposed to scale up the programme nationwide at an estimated annual cost of 5bn rupees (£58m; €86m; $110m). The lower estimate of chronic carrier rate translates into only 16 million cases instead of 40 million, the association said in its report, which follows a 10 month long consultative process. It has also cited national cancer registry data that show that the number of deaths from liver cancer from hepatitis B is only 5000 instead of previous estimates of more than 180 000. “The decision to introduce the hepatitis B vaccine into universal immunisation appears to have been taken without thought to either the disease burden or the efficacy of the 6, 10 and 14 week schedule,” said Jacob Puliyel, a paediatrician at the St Stephen’s Hospital in New Delhi and author of the report released by the association. “Nowhere in the world is there any study that has demonstrated the efficacy of the 6, 10, and 14 week schedule to reduce chronic carrier rates,” Dr Puliyel said. “The results of India’s pilot project also remained unevaluated.” The association has said that studies from India show that vertical transmission contributes to a significant proportion of chronic carriers in the community and favours introducing hepatitis B vaccination at birth. “The health ministry knows it can’t reach all children at birth, so it’s designed this alternative schedule,” Dr Puliyel said. However, several doctors have expressed surprise at the association’s report and have said that its recommendations spring from “mistaken notions of the true disease burden from hepatitis B.” “Neither the association nor paediatricians are in any position to appreciate the true disease burden caused by this virus,” said Vivek Saraswat, a gastroenterologist at the Sanjay Gandhi Postgraduate Institute of Medical Sciences in Lucknow. Doctors have argued that the primary source of hepatitis B infection in children is horizontal transfer in and before early school. “We have no explanation yet for the mode of transmission, but it could be injuries,” Dr Sarawat said. But even doctors who favour universal immunisation concede that large community studies will be needed to resolve the true prevalence of hepatitis B in India. “There will always be sceptics,” Dr Acharya said. “But instead of arguing against universal immunisation, they should try to suggest ways to reduce the cost of immunisation.”
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  An initial inquiry into cost-effectiveness of surfactant in India: a pilot randomised controlled trial

  Medical Varitas 2006;3: Proof pages
  Tiwari L, Baijal N, Kumar N, Puliyel JM
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  Comment: Death of twins after intravenous varicella zoster immunoglobulin.

  * Ann Pharmacother. 2005 Dec;39(12):2140; author reply 2140-1.
  Bhambhani V, Kumar N, Puliyel JM.
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  Not by bread alone project: a 2-year follow-up report

  Child: Care, Health and Development Volume 31 Page 703 - 6. November 2005
  V. Taneja, R. Aggarwal, R. S. Beri and J. M. Puliyel
  BACKGROUND: We have previously reported the developmental gains achieved, after introducing a simple programme of structured play to stimulate children in an orphanage. It was envisaged that the caregivers could continue the programme. However, the enthusiasm of the caregivers waned over the year the programme was entrusted to them. After 1 year, a full time play therapist was recruited to rejuvenate the play programme. METHODS: Children's development was assessed using the Indian adaptation of  Show More...BACKGROUND: We have previously reported the developmental gains achieved, after introducing a simple programme of structured play to stimulate children in an orphanage. It was envisaged that the caregivers could continue the programme. However, the enthusiasm of the caregivers waned over the year the programme was entrusted to them. After 1 year, a full time play therapist was recruited to rejuvenate the play programme. METHODS: Children's development was assessed using the Indian adaptation of the Bayley Scales of Infant Development. The first assessment was done when the play therapist joined. Subsequently, three-monthly assessments were done and the scores achieved were recorded. RESULTS: The initial mean motor and mental scores, when the play therapist joined, were 66.14 and 56.95, respectively (similar to the pre-intervention scores of the pilot study reported in an earlier paper). The scores improved to 81.84 and 78.25 within 3 months of restarting the play programme. CONCLUSION: The schedule of the 'Not by Bread Alone' project can accelerate the motor and mental development of children in orphanages. However, it requires a highly motivated and dedicated person to sustain this programme over long periods.
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  Ask the Doc The Hindu

  Sunday Magazine The Hindu 30/10/05
  Puliyel J
  Erb's Palsy, Rubella vaccine, Nocturnal enuresis, Primary complex, Hair on the upper lip in girls, Eating problems
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  If OSCE is not a valid test of Clinical Skills- What Next?

  The News of the National Board of Examination Volume 1 Number 3 Oct-December, 2005 Page 4. http://www.natboard.edu.in/news_latters/NBE%20BulletinVol.I%20No.3,%20October-Dec%202005.pdf
  Puliyel J
  http://www.natboard.edu.in/news_latters/NBE%20BulletinVol.I%20No.3,%20October-Dec%202005.pdf
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  Prone to survive.

  Crit Care Med. 2005 Oct;33(10):2448; author reply 2448-9.
  Sawhney A, Puliyel JM.
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  Inadvertent overdosing of neonates as a result of the dead space of the syringe hub and needle.

  Arch Dis Child Fetal Neonatal Ed. 2005 Sep;90(5):F444-5.
  Bhambhani V, Beri RS, Puliyel JM.
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  Refractive error at birth and its relation to gestational age.

  Curr Eye Res. 2005 Jun;30(6):423-8.
  Varughese S, Varghese RM, Gupta N, Ojha R, Sreenivas V, Puliyel JM.
  PURPOSE: The refractive status of premature infants is not well studied. This study was done to find the norms of refractive error in newborns at different gestational ages. METHODS: One thousand two hundred three (1203) eyes were examined for refractive error by streak retinoscopy within the first week of life between June 2001 and September 2002. Tropicamide eye drops (0.8%) with phenylephrine 0.5% were used to achieve cycloplegia and mydriasis. The refractive error was measured in the vertica Show More...PURPOSE: The refractive status of premature infants is not well studied. This study was done to find the norms of refractive error in newborns at different gestational ages. METHODS: One thousand two hundred three (1203) eyes were examined for refractive error by streak retinoscopy within the first week of life between June 2001 and September 2002. Tropicamide eye drops (0.8%) with phenylephrine 0.5% were used to achieve cycloplegia and mydriasis. The refractive error was measured in the vertical and horizontal meridia in both eyes and was recorded to the nearest dioptre (D). The neonates were grouped in five gestational age groups ranging from 24 weeks to 43 weeks. RESULTS: Extremely preterm babies were found to be myopic with a mean MSE (mean spherical equivalent) of -4.86 D. The MSE was found to progressively decrease (become less myopic) with increasing gestation and was +2.4 D at term. Astigmatism of more than 1 D spherical equivalent was seen in 67.8% of the eyes examined. Among newborns with > 1 D of astigmatism, the astigmatism was with-the-rule (vertical meridian having greater refractive power than horizontal) in 85% and against-the-rule in 15%. Anisometropia of more than 1 D spherical equivalent was seen in 31% babies. CONCLUSIONS: Term babies are known to be hypermetropic, and preterm babies with retinopathy of prematurity (ROP) are known to have myopia. This study provides data on the mean spherical equivalent, the degree of astigmatism, and incidence of anisometropia at different gestational ages. This is the largest study in world literature looking at refractive errors at birth against gestational age. It should help understand the norms of refractive errors in preterm babies.
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  Prone versus supine position in mechanically ventila

  Med Sci Monit. 2005 May;11(5):CR235-240. Epub 2005 Apr 28.
  Sawhney A, Kumar N, Sreenivas V, Gupta S, Tyagi V, Puliyel JM.
  BACKGROUND: It is known that mechanically ventilated patients in the prone position have improved oxygenation compared with those supine. We did a prospective, randomized, controlled trial to evaluate the effect of prone position during mechanical ventilation, on survival in critically ill children. MATERIAL/METHODS: Forty-two children needing mechanical ventilation for various illnesses were randomized to receive initial ventilation for four hours prone or supine by drawing lots. Initial severi Show More...BACKGROUND: It is known that mechanically ventilated patients in the prone position have improved oxygenation compared with those supine. We did a prospective, randomized, controlled trial to evaluate the effect of prone position during mechanical ventilation, on survival in critically ill children. MATERIAL/METHODS: Forty-two children needing mechanical ventilation for various illnesses were randomized to receive initial ventilation for four hours prone or supine by drawing lots. Initial severity of illness and blood gases in all children were noted. In a crossover design, after the initial four hours the children were turned over and ventilated in the alternate posture for an hour. Oxygenation parameters and mean airway pressures were noted at one hour, four hours, and five hours. Mortality, duration of ventilation, and the above parameters were compared in the two groups. RESULTS: Initial PRISM scores were similar in the two groups. Mortality in the prone group was less than in the supine group. The odds ratio of mortality was 0.20 (95% CI 0.05-0.75). Duration of ventilation was similar in the two groups. The oxygenation index was significantly lower in the prone group at one, four, and five hours after onset of ventilation. CONCLUSIONS: Prone position in the first few hours of ventilation significantly improves gas exchange and oxygenation, reduces the mean airway pressures required to ventilate children, and may cause significant improvement in survival. Our study protocol allowed ventilator settings to be changed as needed during ventilation.
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  Death of twins after intravenous varicella zoster immunoglobulin.

  Ann Pharmacother. 2005 Jan;39(1):198-9.
  Bhambhani V, Kumar N, Puliyel JM.
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  Meta-analysis can be statistically misleading

  Evidence-Based Medicine 2005;10:130; doi:10.1136/ebm.10.5.130-a
  Jacob M Puliyel, MRCP, MPHIL, MD1 and Vishnubhatla Sreenivas, PhD2
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  Economic Evaluation Tailored to Promote Vaccine Uptake: How Third World Consumers Can Respond

  Expert Rev. Pharmacoeconomics Outcomes Res.2005;5:515-6
  Arora R, Puliyel JM.
  “Suppose it were ascertained that every child in the world could be rendered absolutely immune from all disease during its entire life by taking half an ounce of radium to every pint of its milk. The world would be none the healthier, because not even a Crown Prince - no, not even the son of a Chicago Meat King, could afford the treatment. Yet it is doubtful whether doctors would refrain from prescribing it on that ground. The recklessness with which they now recommend wintering in Egypt or at D Show More...“Suppose it were ascertained that every child in the world could be rendered absolutely immune from all disease during its entire life by taking half an ounce of radium to every pint of its milk. The world would be none the healthier, because not even a Crown Prince - no, not even the son of a Chicago Meat King, could afford the treatment. Yet it is doubtful whether doctors would refrain from prescribing it on that ground. The recklessness with which they now recommend wintering in Egypt or at Davos to people who cannot afford to go to Cornwall, and the orders given for champagne jelly and old port in households where such luxuries must obviously be acquired at the cost of stinting necessaries, often make one wonder whether it is possible for a man to go through a medical training and retain a spark of common sense.” George Bernard Shaw1 This issue of ‘Expert Review’ carries a review of the economic evaluations of Rotavirus vaccines2. Common sense suggests that if a vaccine is safe and efficacious and it has been shown to be cost-beneficial (saves lives and saves money), it should be included in the program for universal immunization. The authors of the Rotavirus review note that this does not happen routinely – that the experience with introducing Hepatitis B and Hib vaccines in developing countries (countries that have the largest markets) has not been encouraging2. The twin issues of biased cost-effectiveness evaluations and the question of affordability are discussed in this annotation. Rotavirus vaccine was withdrawn in 1999 due to unacceptable side effects – one intusussception in 5000 vaccine recipients3. Given this background, reintroducing Rotavirus vaccine in resource poor countries is going to be particularly difficult. Economic evaluation, need to include costs of side effects, to be comprehensive. However the reviewers point out that none of the papers studied by them computed the cost of vaccine side effects2. As the data is not available, it is impossible to draw conclusions about cost-benefits of the vaccine. Cost-benefit equations can be biased in other ways . Underplaying the costs and enlarging the perspective in which the benefits are evaluated can justify any vaccine, no matter how expensive. Economic evaluations done on chicken pox and Hepatitis B vaccines illustrate various aspects of this problem. The recent call for the retraction of an economic evaluation that exaggerated the number of deaths from Hepatitis B in India from 5000 to 250,000 per year shows how data is manipulated4. A national vaccination program would have been difficult to justify preventing only 5000 deaths and so the mortality was inflated to 250,000. The authors could not provide the model used to project the figure of 250,000 deaths5. Chicken pox is a relatively mild disease in childhood. When chicken pox vaccine was first introduced in the USA the cost of vaccination worked out at US$ 98 million. The cost of Chickenpox disease, if no vaccine was used, is US$ 90 million. The vaccine was not cost-effective. The perspective was therefore enlarged, to add loss in wages of a parent staying at home with the child with chicken pox, to show the vaccine as cost effective6. Loss in wages was estimated at US$ 390 million6, allowing for justifying a considerable hike in the price of chicken pox vaccine The saga of Hib research in India demonstrates how international research funding is used to promote the interest of vaccine manufacturers - to demonstrate a need that does not in fact exist. The incidence of Hib disease in Asia is very low - 6/100.000 compared to 109/100,000 in the Western Pacific7. The thrust of Hib research was to convince health planners that Hib was a major problem that had gone unrecognized because of poor microbiological facilities and the technical inability to culture the organism. IBIS study done over 4 years, in 6 large referral hospitals in India, employed sophisticated culture techniques to isolate the organism, also found a remarkably low incidence of Hib disease 8, 9. Not convinced, the WHO undertook a large population based study following this. The study found the incidence of Hib disease of 9 per 100 00010. It merely confirmed the low incidence of Hib being similar to 1998 figures of Levine et al7. The WHO study was completed in 2002 and presented at a conference but it is yet to be published a paper. Research designed to promote the interest of vaccine manufacturers, and its selective publication, make health planners look at health economic evaluations with skepticism Even if a vaccine is cost effective there is the question of affordability. The reviewers of the Rotavirus evaluation point out that many countries cannot afford more than US $ 8 per child for vaccination2. One method to judge if an intervention is affordable is to look at costs against the GNP of the country. It can be assumed that interventions that cost more than the per-capita-GNP of the country, per QALY saved, are not affordable11.. It is up to vaccine manufacturers to lower prices and comply with the affordability criteria in developing countries. Public funding for vaccine research has all but dried up. In a market economy, it is open to vaccine manufacturers to produce biased cost-effectiveness evaluations and even determine what vaccines are produced to boost dividends for shareholders. Yet, in the market economy, it is for the consumer (health care provider) to decide whether the vaccine needs to be used at all for the benefit of the target population. Decreased demand will drive prices down. National health planners, and those advising vaccination need to play their part as consumer advocates. Unbiased critical reviews of economic analyses, as done by the authors of the review of Rotavirus can help2. Rajiv Arora MD Senior Registrar Jacob M Puliyel MD MRCP M Phil Consultant Pediatrician St Stephens Hospital Delhi 110054 India puliyel@vsnl.com
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  Severe anaemia owing to hookworm in a 12-day-old Nepalese infant.

  Ann Trop Paediatr. 2004 Dec;24(4):361-3.
  Tiwari L, James J, Chowdhary S, Sharma A, Puliyel JM.
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  Polio vaccine and Gresham's law

  Indian J Pediatr. 2004 Dec;71(12):1141;
  Sathyamala C, Puliyel JM.
  If the polio eradication program fails, oral polio vaccine will be withdrawn from the market. User fee will be introduced for the injectable polio vaccine. The poor will be unprotected and then we will have a catastrophic epidemic.
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  Universal immunisation with hepatitis B in the UK is not cost beneficial

  http://www.bmj.com/cgi/eletters/329/7474/1059#87378
  S. Hydros, V Sreenivas Puliyel J
  Nicholas J Beeching has succinctly summarized the situation with regards hepatitis B in the UK (1). It is however unclear how he arrived at the conclusion that universal immunization should be preferred in Britain. We have serious concerns about this. An assessment of the data provided, shows an unfavourable cost: benefit ratio. The annotation has drawn heavily on one reference (2). In this paper we will also rely on the same source for most of our calculations, so it is not just a matter of us Show More... Nicholas J Beeching has succinctly summarized the situation with regards hepatitis B in the UK (1). It is however unclear how he arrived at the conclusion that universal immunization should be preferred in Britain. We have serious concerns about this. An assessment of the data provided, shows an unfavourable cost: benefit ratio. The annotation has drawn heavily on one reference (2). In this paper we will also rely on the same source for most of our calculations, so it is not just a matter of using one reference against another, to arrive at slightly different conclusions. We are told that 430 persons develop hepatitis B related carcinoma in the UK each year and that Hepatitis B costs the NHS �26m-�375m per year (UK � = US $ 1.8).(1) The reference quoted by the author (2) elaborates how this wide range of costs has been arrived at. The lower-limit figure was based on an eight year study in Tayside, Scotland. It projects the resources consumed each year, by the 45,700 people, with diagnosed chronic hepatitis B in all of the UK. The costs for treating patient with chronic hepatitis B in Germany or the USA are very different. The upper-limit figure �375m, is the cost of treating all the hepatitis B cases in the UK, at the German rate! Obviously the figure of �26 m is a more realistic estimate of costs in the UK and will be used in this letter. In his rapid response, Peter MB English calculates that using a hexavalent vaccine that includes hepatitis B (at a marginal programme cost of �5/dose of hepatitis B) to immunise the UK birth cohort of 695,500 each year, would result in an additional bill of only �10m. Does this prove that universal immunization is more cost beneficial? To evaluate this, it is important to look at the proportion of �hepatitis B related problems� that can be prevented by universal immunization in the UK. There 7500 new cases of chronic infection with hepatitis B virus in the UK who are consuming these resources but only 4% of these are from among persons born in the UK(2). The remainder are immigrants who have been infected overseas and cannot be helped by the programme of universal immunization in the UK. Thus universal immunization can bring about only a cost reduction of 4% of the total expenditure of �26m. This works out to be a saving of �1m per year. Most hepatitis B infection in the UK occurs in adolescence and it is several years afterwards, that they develop cirrhosis and hepatocellular carcinoma. With a neonatal immunization programme the benefit may be seen more than 40 years later.(3) Using a conservative discounting rate of 3% (4) the discounting factor for 40 years is 0.2. If the benefit is discounted, this works out to savings of � 0.2m per year . The cost savings through universal immunization with Hepatitis B vaccine is there for not � 375m nor even � 26m but � 0.2m per year and it is against this, that the cost of immunization must be compared. This is of course only an economic argument. The decision to go for universal immunisation need not be based on economic arguments. Italy undertook universal immunization although a cost effectiveness assessment performed by Demicheli and Jefferson showed an unfavourable cost-benefit ratio.(5) We also know from literature that the phenomenon of ignoring cost benefit analysis is not of recent origin. George Bernard Shaw in the preface of The Doctor�s Dilemma (6) under the subheading The Perils of Inoculation wrote a follows: �Suppose it were ascertained that every child in the world could be rendered absolutely immune from all disease during its entire life by taking half an ounce of radium to every pint of its milk. The world would be none the healthier, because not even a Crown Prince - no, not even the son of a Chicago Meat King, could afford the treatment. Yet it is doubtful whether doctors would refrain from prescribing it on that ground. The recklessness with which they now recommend wintering in Egypt or at Davos to people who cannot afford to go to Cornwall, and the orders given for champagne jelly and old port in households where such luxuries must obviously be acquired at the cost of stinting necessaries, often make one wonder whether it is possible for a man to go through a medical training and retain a spark of common sense� References 1. Beeching NJ Hepatitis B infections BMJ 2004; 329: 1059-1060 2. Foundation for Liver Research. Hepatitis B: out of the shadows. London, Foundation for Liver Research, 2004. www.ucl.ac.uk/liver- research/hepatitis-report.pdf (accessed 18 November 2004) 3. Acharya AK, Murray CJL. Rethinking discounting of health benefits in cost effectiveness analysis. http://www.sussex.ac.uk/Units/economics/dp/arnab1.pdf accessed on 18/11/2004) 4. Evans D Hurley B. The application of economic evaluation in the Health Sector. The state of art. The Journal of International Development 1995;7:503-24 5. Demicheli V, Jefferson TO. Cost-benefit analysis of the introduction of mass vaccination against hepatitis B in Italy. J Public Health Med. 1992;14:367-75. 6. Shaw GB. The Doctor�s Dilemma. London Penguin Books 1957 pp33 puliyel@vsnl.com
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  Selling scare

  The Telegraph
  G.S.Mudur
  Miller Call for retraction in Health Economics
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  Policy analysis of the use of Hepatitis B, Hemophilius influenzae type B, Steptococcus pneuomniae-conjugate and Rotavirus vaccines in the national immunization schedules.

  Health Econ. 2004 Nov;13(11):1147; author reply 1147-8.
  Puliyel JM.
  Mark Miller, Call for retraction of paper, Exaggeration of deaths caused by Hepatitis B in India
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  Natural immunity to haemophilus influenza B in India; Implications for a pricing policy for the vaccine .

  http://books.google.com/books?hl=en&lr=&id=Z222-Oul_VgC&oi=fnd&pg=PA117&ots=8ZpQ4Bra5p&sig=ExPzsrXM1EOVFl5509wLvi9smkM#PPA117,M1 In Focus on Meningitis Research. Editor Phyllis V. Strong Chapter 7, Nova Biomedical Books New York 2004. Pg 117-129.
  Samridh Nagar, Jacob M. Puliyel
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  Truth and evidence based medicine: spin is everything.

  BMJ. 2004 Oct 30;329(7473):1043
  Tiwari L, Puliyel JM, Upadhyay P.
  Surfactant, Cochrane meta-analysis
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  Vitamin d level in slum children of Delhi

  Indian Pediatr. 2004 Oct;41(10):1076-7.
  Tiwari L, Puliyel JM.
  Sundernagri
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  Rotavirus vaccines

  Lancet. 2004 Jul 17-23;364(9430):245-6.
  Narula D, Tiwari L, Puliyel JM.
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  Non-Academic Science : An Oxymoron

  http://www.bmj.com/cgi/eletters/328/7440/597#58014
  Puliyel J
  I have been following the discussion on academic medicine, and have been impressed by your global approach. Thus you seem, not to be attempting to revitalize academic medicine in the UK but internationally, and such an approach is most likely to promote the science and health in general. In India research is an essential component of post-graduate training. For the MD, or MS and the DNB (Diplomate of the National Board) it is mandatory to submit a research dissertation or thesis, besides app Show More... I have been following the discussion on academic medicine, and have been impressed by your global approach. Thus you seem, not to be attempting to revitalize academic medicine in the UK but internationally, and such an approach is most likely to promote the science and health in general. In India research is an essential component of post-graduate training. For the MD, or MS and the DNB (Diplomate of the National Board) it is mandatory to submit a research dissertation or thesis, besides appearing for written and clinical examinations. This research need not be PhD level seminal work, but it is in place to familiarize the candidate with research methodology, and the process of analysis and presentation of research. I find that specialists-in-training are keen researchers, but they need mentoring and also the confidence that their mentor has the tenacity to carry the project through, up to publication. Research funding is not such a big issue, if research-data-collection and computation is done by volunteer-junior-doctors, who are keen on the experience and the glory of publication. This is not part of the MRCP requirements in the UK and I feel you forgo a unique opportunity to impart training in research skills. We have of late become overly concerned about applying research to practice. The modern fad of producing CATs (Clinically appraised Topics) is axiomatic of this. (Jacob M. Puliyel, Noopur Baijal, Dherain Narula Evidence-Based Investigation into The Relation Between Sexual Intercourse And Pregnancy Electronic Letters Archives of Disease in Childhood 15 March 2004;742 ) The true measure of the impact of academic medicine is not how many people in the community utilize the research results, but the effect research has on the researcher and how it modifies his or her understanding and responses in medical practice. Academic medicine is far deeper and more involved than doing a CAT � it in fact provides the grist for the mills that churn out CATs To my mind all science is scholarly and the concept of non-academic medicine is a contradiction in terms and akin to quackery. It is a sad commentary on our times that the term �academic� has now acquired the connotation; �not being of practical relevance�. The effort to revitalize academic medicine is to revitalize medicine itself. I hope you succeed in your effort to raise the profile of academic medicine and thereby that of the science as a whole. I will willingly volunteer time and energy to this noble effort
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  Play in orphanages.

  Indian J Pediatr. 2004 Apr;71(4):297-9.
  Taneja V, Beri RS, Puliyel JM.
  OBJECTIVES: This paper attempts to validate the programme of structured play lasting 90 minutes a day, for use in orphanages, to check if it can be replicated in other orphanages, with similar results. METHODS: A 2-week workshop on the structured play scheme was conducted at the Missionaries of Charity Orphanage in Delhi, the venue of the original project. 15 MOC sisters from 6 centers attended the workshop. The authors selected the MOC orphanage at Chandigarh to track the benefits of the progra Show More...OBJECTIVES: This paper attempts to validate the programme of structured play lasting 90 minutes a day, for use in orphanages, to check if it can be replicated in other orphanages, with similar results. METHODS: A 2-week workshop on the structured play scheme was conducted at the Missionaries of Charity Orphanage in Delhi, the venue of the original project. 15 MOC sisters from 6 centers attended the workshop. The authors selected the MOC orphanage at Chandigarh to track the benefits of the programme. The development quotient of all the residents between the ages of 6 months - 3 years was assessed by a pediatric-clinical-psychologist using the Development Assessment Scale for Indian Infants (DAS II) scale. A reassessment of all these children was done again 3 months after initiating the programme of structured play here. RESULTS: The mean motor and mental scores at the orphanage in Chandigarh before the start of the intervention were 57.9 and 58.2 respectively. Post intervention assessments showed a rise of 23 points in both the scores. CONCLUSION: The development of children in orphanages rises dramatically after initiating a programme of play. The pre-intervention development scores is similar to that in a pilot study and the benefits after play was also similar. The play programme can be easily replicated in other orphanages with similar results.
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  Citing the evidence for IAP vaccine recommendations

  Pediascene Mar-June 2004
  Puliyel JM.
  ‘IAP Policies, Guidelines and Recommendations on Immunization 2003’ Citing the Evidence
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  IAP policies,guidelines and recommendations on immunization 2003: Citing the evidence

  Pediascene March - June 2004 Pg 16 www.pediascene.com
  Baijal N, Puliyel JM.
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  Plea to restore public funding for vaccine development.

  Lancet. 2004 Feb 21;363(9409):659.
  Puliyel JM.
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  Screening for auditory impairment in resource-poor countries

  J Postgrad Med 2004;50:178-179
  Rai S, Puliyel JM
  Loss of hearing, very early in life, can affect the development of speech and language, social and emotional development, and influence behaviour and academic achievement.[1] The critical or sensitive period for the acquisition of language extends from 1 to 5 years of age. However, impairment of hearing commencing after 5 years of age can also have serious consequences. Ninety-five per cent of school children suffer from middle-ear disease, sometime in the first 10 years of their life.[2] Otorrh Show More...Loss of hearing, very early in life, can affect the development of speech and language, social and emotional development, and influence behaviour and academic achievement.[1] The critical or sensitive period for the acquisition of language extends from 1 to 5 years of age. However, impairment of hearing commencing after 5 years of age can also have serious consequences. Ninety-five per cent of school children suffer from middle-ear disease, sometime in the first 10 years of their life.[2] Otorrhoea and multiple ear infections are the risk factors associated with loss of hearing in this age group.[3]
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  Determining the point of indifference - where costs of selective and universal immunization against hepatitis B are identical, in a cost-minimization exercise

  Indian Journal of Gastroenterology , Year 2004, Volume 23, Issue 4 154-156
  Varghese R Mathew, Abraham Jacob, James Jyotsna, Puliyel Jacob M
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  Evidence-Based Investigation into the Relation Between Sexual Intercourse and Pregnancy

  Rapid response in ebmj to BMJ 2004; 329: 1051
  Jacob M. Puliyel, Noopur Baijal, Dherain Narula.
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  Hepatitis B immunization: cost calculation in a community-based study in India.

  Indian J Gastroenterol. 2004 Jan-Feb;23(1):16-8
  Sahni M, Jindal K, Abraham N, Aruldas K, Puliyel J.M
  Hepatitis B immunization: cost calculation in a community-based study in India. (REPLY)Keyords: BACKGROUND AND AIM: In India, approximately 65% of mothers deliver at home, and a community-based study evaluating the cost of vaccinating newborns with the first dose of hepatitis B vaccine within 48 hours has not been undertaken previously. This policy planning study was done to evaluate the costs of such immunization in India. METHODS: All mothers delivering in the study area (population 65,000) o Show More...Hepatitis B immunization: cost calculation in a community-based study in India. (REPLY)Keyords: BACKGROUND AND AIM: In India, approximately 65% of mothers deliver at home, and a community-based study evaluating the cost of vaccinating newborns with the first dose of hepatitis B vaccine within 48 hours has not been undertaken previously. This policy planning study was done to evaluate the costs of such immunization in India. METHODS: All mothers delivering in the study area (population 65,000) over a 1-year period were tested for hepatitis B surface antigen (HBsAg; ELISA), and babies of positive mothers were vaccinated starting at birth. The cost of such selective vaccination was calculated. The cost of nursing time required for universal immunization was calculated from the data on nursing time required for vaccination in the selective vaccination program. The national cost of universal immunization without testing was calculated as well as cost-benefit and cost-utility in terms of cost per quality-adjusted life-year (QALY) saved. Sensitivity testing considering economies of scale was also factored in. RESULTS: 1100 mothers delivered during the study period. 252 were primiparous. Nationwide universal vaccination would cost Rs 48,000 per QALY saved, which was double the per capita GNP of the country; discounted at 3% the cost was Rs 260,000. CONCLUSIONS: Universal immunization vaccination with hepatitis B vaccine is not cost-beneficial in India, since cost of every life-year gained with it will exceed India's per capita GNP Sahni M, Jindal K, Abraham N, Aruldas K, Puliyel J.M Indian J Gastroenterol. 2004 Jan-Feb;23(1):16-8
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  Selective decontamination of digestive tract in intensive care.

  Lancet. 2003 Dec 20;362(9401):2119; author reply 2119-20.
  Sahni M, Varghese RM, Puliyel JM.
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  A primer on health economics for Pediatricians

  Recent Advances in Pediatrics 13. Editor Suraj Gupte. Publisher Jaypee Brothers New Delhi Page 261-6
  Puliyel JM, Anish James Thomas, Kapil Jindal.
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  Computerised-hepatitis B-model is subject to processing axiom: garbage in, garbage out.

  J Hepatol. 2003 Jul;39(1):133; author reply 134-5.
  Tiwari L, Varghese RM, Puliyel JM.
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  Community based retrospective study of sex in infant mortality in India.

  BMJ. 2003 Jul 19;327(7407):126
  Khanna R, Kumar A, Vaghela JF, Sreenivas V, Puliyel JM.
  OBJECTIVE: To determine whether the imbalance in the sex ratio in India can be explained by less favourable treatment of girls in infancy. DESIGN: Analysis of results of verbal autopsy reports over a five year period. SETTING: Community health project in urban India. MAIN OUTCOME MEASURES: Deaths from all causes in infants aged less than 1 year. RESULTS: The sex ratio at birth was 869 females per 1000 males. The mean infant mortality was 1.3 times higher in females than in males (72 v 55 per 100 Show More...OBJECTIVE: To determine whether the imbalance in the sex ratio in India can be explained by less favourable treatment of girls in infancy. DESIGN: Analysis of results of verbal autopsy reports over a five year period. SETTING: Community health project in urban India. MAIN OUTCOME MEASURES: Deaths from all causes in infants aged less than 1 year. RESULTS: The sex ratio at birth was 869 females per 1000 males. The mean infant mortality was 1.3 times higher in females than in males (72 v 55 per 1000). Diarrhoea was responsible for 22% of deaths overall, though twice as many girls died from diarrhoea. There were no significant differences in the numbers of deaths from causes such as birth asphyxia, septicaemia, prematurity, and congenital anomalies. In 10% of deaths there was no preceding illness and no satisfactory cause was found. Three out of every four such deaths were in girls. CONCLUSIONS: The excess number of unexplained deaths and deaths due to treatable conditions such as diarrhoeal disease in girls may be because girls are regarded and treated less favourably in India.
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  Not By Bread Alone : Proposal for funding from BBC Blue Peter

  Jacob Puliyel
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  Ketoacid levels may alter osmotonicity in diabetic ketoacidosis and precipitate cerebral edema.

  Arch Dis Child. 2003 Apr;88(4):366.
  Puliyel JM, Bhambhani V.
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  Osmotonicity of acetoacetate: possible implications for cerebral edema in diabetic ketoacidosis.

  Med Sci Monit. 2003 Apr;9(4):BR130-3.
  Puliyel JM.
  BACKGROUND: Rapid drops in blood glucose and sodium levels during treatment of diabetic ketoacidosis (DKA) can cause a drop in the osmotonicity of plasma, resulting in cerebral edema. Ketone bodies are assumed to move freely in and out of cells, so it is assumed that they do not contribute to the tonicity of plasma or influence fluid shifts. The assumption that ketone bodies do not contribute to osmotonicity has not been tested previously. The experiment described here was done to check if aceto Show More...BACKGROUND: Rapid drops in blood glucose and sodium levels during treatment of diabetic ketoacidosis (DKA) can cause a drop in the osmotonicity of plasma, resulting in cerebral edema. Ketone bodies are assumed to move freely in and out of cells, so it is assumed that they do not contribute to the tonicity of plasma or influence fluid shifts. The assumption that ketone bodies do not contribute to osmotonicity has not been tested previously. The experiment described here was done to check if acetoacetate has osmotonicity. MATERIAL/METHODS: A modified erythrocyte fragility test was used to check the osmotonic and osmoprotective effects of the ketone body. Red blood cells were suspended in different test tubes containing distilled water, normal saline, glucose, urea and acetoacetic acid (lithium salt C4H5O3Li). All solutions (except the tube with distilled water) were made to match the osmolality of plasma. We hypothesized that solutions in which red cell hemolysis does not take place have greater tonicity than the tonicity of 0.45% saline. RESULTS: Spectrophotometry showed that there was no hemolysis in the solutions of normal saline or solutions containing glucose or acetoacetate. Complete hemolysis was demonstrated in the tube with plain distilled water and also in the solutions containing urea. CONCLUSIONS: This study shows that acetoacetate is functionally similar to glucose in that it contributes to increased osmotonicity. The drop in ketone body levels can produce a drop in the osmolar tonicity of plasma and precipitate cerebral edema.
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  Triage score for severity of illness.

  Indian Pediatr. 2003 Mar;40(3):204-10
  Kumar N, Thomas N, Singhal D, Puliyel JM, Sreenivas V.
  Sick score, sick calculator. OBJECTIVE: To evolve a triage scoring system for severity of illness based on clinical variables related to systemic inflammatory response syndrome (SIRS). DESIGN: Prospective study in a tertiary-care hospital. METHODS: Consecutive pediatric patients admitted to the ward or pediatric intensive care unit (PICU) were studied. The respiratory rate, heart rate, capillary refill time, oxygen saturation (SpO2), systolic blood pressure and temperature were noted, Sensorium Show More...Sick score, sick calculator. OBJECTIVE: To evolve a triage scoring system for severity of illness based on clinical variables related to systemic inflammatory response syndrome (SIRS). DESIGN: Prospective study in a tertiary-care hospital. METHODS: Consecutive pediatric patients admitted to the ward or pediatric intensive care unit (PICU) were studied. The respiratory rate, heart rate, capillary refill time, oxygen saturation (SpO2), systolic blood pressure and temperature were noted, Sensorium level was assessed on AVPU score. Variables were based on SIRS criteria and criteria mentioned in Advanced Pediatric Life Support (APLS). Each study variable was scored as 0 or 1 (normal or abnormal) and total score for each child obtained. The survival at discharge was correlated with the study variables and the total score. Another score based on the magnitudes of the coefficients in multiple logistic regression analysis was computed and the correlation between this score and mortality was also studied. ROC curve analysis was performed to see the overall predictive ability of the score as well as a cut off at which maximum discrimination occurred. RESULTS: Of 1099 children studied, 44 died. Of the seven variables, only five variables were abnormal in the study subjects. Except heart rate and respiratory rate, all other variables and age showed significant association with survival status (P < 0.01). The mortality increased with increase in the number of abnormal variables: 0.4% 2.2% 6.1% 15.3% 19.4% and 29.4%for scores of 0,1,2,3,4 and 5 respectively and the linear trend was significant (P < 0.01). Mortality also increased with a decrease in age (P < 0.01). Children with a score of 2 or more (2 or more abnormal clinical variables) had significantly higher mortality as compared to those with no abnormal clinical variables (score = 0). Based on the regression coefficients, the maximum possible score was 9.8. Regression based score was found to predict survival status well. The area under the ROC curve was 0.887, indicating that overall 88.7% of the subjects could be predicted correctly. Maximum discrimination was observed at a score of 2.5 (sensitivity 84.1% specificity 82.2%). CONCLUSION: For triage scoring, any child with 2 or more abnormal clinical variables should be taken as serious that might lead to death. With a more detailed scoring, score of 2.5 can be taken as cut-off to select children who possibly need admission and closer observation.
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  Routine hepatitis B immunization in India: cost effectiveness needs reassessment.

  Indian J Pediatr. 2003 Feb;70(2):188.
  Puliyel JM, Mittal R, Tyagi V, Gupta S.
  Kane M, Miller MA.
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  Long QT syndrome manifesting as pulseless epilepsy.

  Indian J Pediatr. 2003 Jan;70(1):97-100.
  Abass FA, Shahi M, Kumar N, Bhargava M, Gupta S, Puliyel JM.
  A-10-year-old child admitted with repeated seizures due to the long QT syndrome is described. The cardiac origin of the epilepsy was suggested by the fact that during the episode of convulsions his peripheral pulses were not palpable.
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  Using gross national product to calculate acceptable immunisation costs: deploying cost-effectiveness calculations in reverse.

  Pharmacoeconomics. 2003;21(7):497-9.
  Tyagi V, Singh SK, Sawhney A, Taneja V, Puliyel JM.
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  Building for the future: influence of housing on intelligence quotients of children in an urban slum.

  Health Policy Plan. 2002 Dec;17(4):420-4.
  Choudhary R, Sharma A, Agarwal KS, Kumar A, Sreenivas V, Puliyel JM.
  NTRODUCTION: Interventions on behalf of the marginalized in society can assume many formats. In an urban slum the Government of Delhi built one-room houses for some of the residents in what is termed a 'plot area'. Not all residents could be accommodated in the project and the remainder continued to live next door in shanty houses of the slum. Nineteen years later, young children who had migrated with their parents, have grown up and have children of their own. We looked at the development of th Show More...NTRODUCTION: Interventions on behalf of the marginalized in society can assume many formats. In an urban slum the Government of Delhi built one-room houses for some of the residents in what is termed a 'plot area'. Not all residents could be accommodated in the project and the remainder continued to live next door in shanty houses of the slum. Nineteen years later, young children who had migrated with their parents, have grown up and have children of their own. We looked at the development of the children living in the two types of accommodation. METHODS: A total of 373 children were studied. All children (n = 200) between the ages of 3.5 and 5.5 years in a cluster of five residential blocks in the plot area were studied. As a control, children in two large clusters of shanty houses (n = 173) were also studied. For development assessment the Central Institute of Education (CIE) Test was performed. This is an Indian adaptation of the Standford-Binet Test. Multiple regression analysis was utilized to determine the factors that influenced IQ most. RESULTS: The mean IQ of the children in the plot area was 92.5 (s.d. 13.38) and in the shanty houses 89.5 (s.d. 12.9) (p = 0.05). Analysis showed that the most significant factors affecting IQ were malnutrition in the first 6 months of life and attendance of the child at pre-school. For nutrition in the first 6 months, there was no difference between the groups. For attendance at pre-school, 110 of 200 in the plot area and 47 of 173 in the shanty houses were attending pre-school (p < 0.01). CONCLUSION: We find that children living in the permanent houses had a significantly better IQ than those in shanty houses. A review of the literature did not reveal a comparable study.
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  The clinical risk index of babies (CRIB) score in India.

  Indian J Pediatr. 2002 Nov;69(11):957-60.
  Khanna R, Taneja V, Singh SK, Kumar N, Sreenivas V, Puliyel JM.
  OBJECTIVE: To assess the usefulness of clinical risk index of babies (CRIB score) in predicting neonatal mortality in extremely preterm neonates, compared to birth weight and gestation. METHODS: 97 preterm neonates with gestational age less than 31 weeks or birth weight less than or equal to 1500 g were enrolled for the prospective longitudinal study. Relevant neonatal data was recorded. Blood gas analysis results and the maximum and the minimum FiO2 required by babies in first 12 hours of life  Show More...OBJECTIVE: To assess the usefulness of clinical risk index of babies (CRIB score) in predicting neonatal mortality in extremely preterm neonates, compared to birth weight and gestation. METHODS: 97 preterm neonates with gestational age less than 31 weeks or birth weight less than or equal to 1500 g were enrolled for the prospective longitudinal study. Relevant neonatal data was recorded. Blood gas analysis results and the maximum and the minimum FiO2 required by babies in first 12 hours of life were noted. Mortality was taken as death while the baby was in nursery. The prediction of mortality by birth weight, gestational age and CRIB score was done using the Logistic model, and expressed as area under the ROC curve. RESULTS: The area under the ROC curve for birth weight, gestational age and CRIB score was almost the same, the areas being 0.829, 0.819 and 0.823 respectively. Hence CRIB score did not fare better than birth weight and gestational age in predicting neonatal mortality. CONCLUSION: The CRIB score did not improve on the ability of birth weight and gestational age to predict neonatal mortality in the study.
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  The impact of atmospheric pollution on vitamin D status of infants and toddlers in Delhi, India.

  Arch Dis Child. 2002 Aug;87(2):111-3.
  Agarwal KS, Mughal MZ, Upadhyay P, Berry JL, Mawer EB, Puliyel JM.
  AIMS: To compare the vitamin D status of 34 children, 9-24 months old, living in an area of Delhi renowned for high levels of atmospheric pollution (Mori Gate), with a comparable age matched group of children from a less polluted (Gurgaon) area of the city. METHODS: Serum concentrations of calcium, alkaline phosphatase (ALP), parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D), and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured. Haze scores, regarded as a surrogate marker of solar UVB r Show More...AIMS: To compare the vitamin D status of 34 children, 9-24 months old, living in an area of Delhi renowned for high levels of atmospheric pollution (Mori Gate), with a comparable age matched group of children from a less polluted (Gurgaon) area of the city. METHODS: Serum concentrations of calcium, alkaline phosphatase (ALP), parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D), and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured. Haze scores, regarded as a surrogate marker of solar UVB radiation reaching ground level, were measured in both areas. RESULTS: Mean 25(OH)D of children in the Mori Gate area was 12.4 (7) ng/ml, compared with 27.1 (7) ng/ml in children living in the Gurgaon area (p < 0.001). The median ALP (p < 0.05) and mean PTH (p < 0.001) concentrations were higher in children living in the Mori Gate area than in the Gurgaon area. The mean haze score in the Mori Gate area (2.1 (0.5)) was significantly lower (p < 0.05) than in the Gurgaon area (2.7 (0.4)), indicating less solar UVB reaching the ground in Mori Gate. CONCLUSION: We suggest that children living in areas of high atmospheric pollution are at risk of developing vitamin D deficiency rickets and should be offered vitamin D supplements.
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  The dummies' guide to risk-benefit analysis of vaccines.

  Pediatrics. 2002 Jul;110(1 Pt 1):193.
  Puliyel J
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  Vaccine promotion is circumventing market forces.

  BMJ. 2002 Apr 20;324(7343):975.
  Ojha RK, Abraham J, Khosla M, Puliyel JM.
  No abstract Global alliance on vaccines and immunizations.
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  Plasma exchange in a child with systemic lupus erythematosus antiphospholipid antibodies and profound deafness.

  Ann Trop Paediatr. 2002 Mar;22(1):109-10.
  Agarwal K, Thomas N, Taneja V, Beri RS, Khanduri U, Puliyel JM.
•   Download (PDF) 387.4 kB

  Not by bread alone: Impact of a structured 90-minute play session on the development of children in an orphanage

  Child: Care Health & Development 2002; 28:95-100
  Taneja V, Sriram S, Beri RS, Sreenivas V, Aggarwal R, Kaur S, Puliyel JM.
•   Download (PDF) 329.5 kB

  Screening for Down's syndrome. Ratio of femoral length to tibial length needs to be evaluated extensively.

  BMJ. 2002 Jan 12;324(7329):112.
  Sachdev P, Bahl S, Puliyel JM.
•   Download (html) 74.7 kB

  An indigenous leucocyte esterase test along with Pandy's test for the diagnosis of bacterial meningitis.

  Indian Pediatr. 2001 Nov;38(11):1281-6.
  Srivastava RK, Gupta S, Bhargava M, Kumar N, Upadhyay P, Puliyel JM.
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  Magnitude of the problem of retinopathy of prematurity. experience in a large maternity unit with a medium size level-3 nursery.

  Indian J Ophthalmol. 2001 Sep;49(3):187-8.
  Varughese S, Jain S, Gupta N, Singh S, Tyagi V, Puliyel JM.
  Neonates Delhi St Stephens Hospital. This report describes the extent and severity of retinopathy of prematurity (ROP) in a large maternity unit. The screening of 79 preterm babies showed that ophthalmic examinations should become an important part of neonatal care.
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  Natural immunity to Haemophilus influenza in Indian children.

  Vaccine. 2001 Sep 14;19(32):4592-4.
  Puliyel JM, Agarwal KS, Abed Abass F.
  Puliyel JM, Agarwal KS, Abed Abass F.
•   Download (Word) 332.8 kB

  Full correspondence with Health Economics calling for retraction of Millers Paper on estimate of Deaths of Hepatitis B in India

  Puliyel JM, Miller M, Alan Maynard
  Mark Miller, CDC Atlanta, WHO
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  Prediction of mortality by application of PRISM score in intensive care unit.

  Indian Pediatr. 2001 Jul;38(7):714-9.
  Singhal D, Kumar N, Puliyel JM, Singh SK, Sreenivas V.
  OBJECTIVE: Prediction of mortality by application of Pediatric Risk of Mortality (PRISM) score in Pediatric Intensive Care Unit (PICU) patients under Indian circumstances. DESIGN: Prospective study. SETTING: PICU of a tertiary care multi-specialty hospital. METHODS: 100 sick pediatric patients admitted consecutively in PICU were taken for this study. PRISM score was calculated. Hospital outcome was recorded as (died/survived). The predicted death was calculated by the formula: RESULTS: Of 100 pa Show More...OBJECTIVE: Prediction of mortality by application of Pediatric Risk of Mortality (PRISM) score in Pediatric Intensive Care Unit (PICU) patients under Indian circumstances. DESIGN: Prospective study. SETTING: PICU of a tertiary care multi-specialty hospital. METHODS: 100 sick pediatric patients admitted consecutively in PICU were taken for this study. PRISM score was calculated. Hospital outcome was recorded as (died/survived). The predicted death was calculated by the formula: RESULTS: Of 100 patients, 18 died and 82 survived. By PRISM score 49 children had the score of 1-9. The expected death in this group was 10.3% (n = 5.03) and the observed death was 8.2% (n = 4). Among 45 children with the score of 10-19, the expected mortality was 21.2% (n = 9.6) and observed was 24.4% (n = 11). There were 3 patients with the score of 20-29, the expected mortality in this group was 39.3% (n = 1.18) and observed mortality 33.3% (n = 1). There were 3 patients with score > or = 30, observed death 66.3% (n = 2) and expected mortality was 74.7% (n = 2.24). There was no significant difference between expected and observed mortality in any group. (p > 0.5). ROC analysis showed area under the curve of 72%. CONCLUSION: PRISM score has good predictive value in assessing the probability of mortality in relation to children admitted to a PICU under Indian circumstances.
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  Ultrasonographic femur-tibial length ratio: a marker of Down syndrome from the late second trimester.

  Am J Perinatol. 2001 Jun;18(4):217-24.
  Gupta R, Thomas RD, Sreenivas V, Walter S, Puliyel JM.
  An observational prospective study reported that newborn babies with Down syndrome (DS) had short upper limbs that reach up to their pelvis. The shortening was most marked in the forearm (the middle segment of the upper limb) and this relative shortening resulted in an alteration of the proximal to middle segment length ratio. This study assumes that there is a similar alteration in the ratio of the lower limb. We propose to study the proximal to middle segment ratio in the lower limb in normal  Show More...An observational prospective study reported that newborn babies with Down syndrome (DS) had short upper limbs that reach up to their pelvis. The shortening was most marked in the forearm (the middle segment of the upper limb) and this relative shortening resulted in an alteration of the proximal to middle segment length ratio. This study assumes that there is a similar alteration in the ratio of the lower limb. We propose to study the proximal to middle segment ratio in the lower limb in normal fetuses at different gestational ages. Against these norms we propose to study the ratio in fetuses with DS to see at what stage in intrauterine life the altered ratio becomes evident. We also propose to take postnatal measurements of upper and middle segments of both upper and lower limbs of babies born with DS and compare them with normal babies. Fetal femoral and tibial lengths were measured by routine antenatal ultrasound scans at a General hospital with 6000 deliveries a year. All babies delivered were examined for phenotypical evidence of DS. The in utero measurements recorded of babies born with DS were compared with the measurements in normal babies. Postnatal measurements of the arm and forearm, and the thigh and leg of babies with DS were taken soon after birth. These were compared with a control group of 20 consecutive normal babies born over 2 days. There were 3690 readings of 3075 normal fetuses and 8 measurements of 7 Down fetuses. The leg, the upper arm, and arm of newborns with DS were significantly shorter than controls (p<0.01). The upper limb reached up to the pelvis in infants with DS and not up to mid thigh as in normal babies. The forearm was shorter than the arm in infants with DS. This is a reversal of the ratio seen in controls. The ratio of femoral to tibial length remains near constant at 1.1 after 13 weeks' gestation in normal fetuses. It rises from 1.2 to 1.4 from 22 weeks' to 38 weeks' gestation in fetuses with DS. The mean standard deviation score of fetuses with DS was 4.53 compared with norms (SD 1.7, p<0.01). Conclusions of this study are: (1) short upper limbs (reaching only up to the pelvis) is a clinical feature of DS at birth; and (2) after 20 weeks' gestation, the ratio of femoral-tibial length can be a marker of DS in utero.
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  Controlling perinatally acquired Hepatitis B

  Ind J of Pediatrics 2001;68:365
  Abass F, Thomas RT, A Rajkumar, N Gupta, Puliyel J
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  The impact of admospheric pollution related haze on vitamin D status of two year olds in Delhi India

  Archives of disease in childhood 2001;84:(Suppl 1) A43
  Mughal Z, Agarwal K, Puliyel J, Upadhyaya P, Berry J, Mawer EB.
•   Download (html) 20.0 kB

  Sudden onset profound deafness in association with antiphospholipid antibodies in a child with SLE.

  Indian Pediatr. 2000 Nov;37(11):1274-6.
  Agarwal KS, Puliyel JM, Khanduri U.
•   Download (html) 13.8 kB

  Evaluation of Leukocyte Esterase Reagent Strips for Rapid Diagnosis of Pyogenic Meningitis

  Indian Pediatrics 1999;36: 955-956
  Angom Bisharda, Ruchie Chowdhury, Jacob M. Puliyel.
  The detection of polymorphonuclear leukocytes in the CSF is a fairly reliable indicator of pyogenic meningitis but facilities required for its detection are not always available in rural hospitals in developing countries. To circumvent this problem Moosa et al.(1) tested the ability of urine dipsticks on CSF to help in the early diagnosis of pyogenic meningitis. The urine dipstick leukocyte esterase test uses the ability of esterase enzyme present in the polymorphonuclear leucocytes to conv Show More... The detection of polymorphonuclear leukocytes in the CSF is a fairly reliable indicator of pyogenic meningitis but facilities required for its detection are not always available in rural hospitals in developing countries. To circumvent this problem Moosa et al.(1) tested the ability of urine dipsticks on CSF to help in the early diagnosis of pyogenic meningitis. The urine dipstick leukocyte esterase test uses the ability of esterase enzyme present in the polymorphonuclear leucocytes to convert a cetates to phenols. The resultant alcohol is detected by a color change in an indicator. The urine dipstics that detects leukocyte esterase are not available at present at India. However, the chemistry involved in the test is quite simple. We conducted this study using imported urine dipsticks to see if the test could be used reliably to detect CSF polymorphonuclear leukocytes in India, as a prelude to developing an indigenous leukocyte esterase test. Thirty six patients with clinical suspicion of pyogenic meninigitis had lumbar puncture performed on them. The CSF was cultured and tested for cells, protein and glucose by standard laboratory techniques. The CSF was also tested by the Bayer Multistix (Bayer Diagnostics, Bayer plc, Evans House, Hamilton Close, Basingstoke Hampshire RG21 2YE UK). Laboratory values of CSF glucose, protein and leukocytes and cultures were used to arrive at the diagnosis of meningitis using the criteria utilized by Moosa et al.(1). The dispstick leukocyte was tested against microscopic evidence of leukocytes and also against the diagnosis of meningitis reached using the above criteria. Fourteen of the 36 cases were confirmed to have meningitis by laboratory criteria. All 14 of them had microscopic evidence of CSF polymorphonuclear leukocytosis. Of these, 12 were picked up by dipstick. Five samples tested positive by dipstick although their microscopic results were negative. Thus dipstick had a sensitivity of 85.26% and specificity of 77.27% in detecting pyogenic meningitis. Protein was raised above 45 mg/dl in 20 of the 36 patients. All but one of those with menin-gitis had a rise in protein. The one patient with meningitis but low protein had CSF pleocytosis detected by dipstick. Our results are comparable to that of Molyneux and Walsh(2) who also used the Bayers urine dipstick to detect CSF polymorphonuclear leukocytes. They found a sensiti-vity of 66% for diagnosis of pyogenic meningitis. The sensitivity was 100% for cloudy CSF and 33% for clear CSF. Two cases of meningitis in our sample would have been missed if the leukocyte esterase test was used alone to make the diagnosis. This is an unacceptably high number. In their original study, Moosa et al.(1) found that using the additional dipstick tests for protein (>50 mg/dl) and sugar (<2.8 mmol/1) alongside the leukocyte esterase test, as available in the Combur reagent strip, the pickup rate was 100%. The addition of a test for protein like the Pandy test(3) which is a saturated solution of phenol and which becomes turbid on addition of CSF with protein >40 mg/dl may improve the pick up rate of meningitis. In our study, one patient with pyogenic meningitis had protein less than 40 mg/dl, but had CSF polymorphonuclear leukocytosis which was picked up by leukocyte esterase test. In conclusion, our study shows that results comparable to western literature can be achieved in India by using the leukocyte esterase test to detect CSF pleocytosis. An indigenously developed leukocyte esterase test, especially if used along with the Pandy test, may have a role in the diagnosis of meningitis. Angom Bisharda, Ruchie Chowdhury, Jacob M. Puliyel, Department of Pediatrics, St. Stephens Hospital, Tis Hazari, Delhi 110 054, India. E-mail: puliyel@vsnl.com References 1. Moosa AA. Quotum HA, Ibrahim MD, Rapid diagnosis of bacterial meningitis with reagent strips. Lancet 1995; 345: 1290-1291. 2. Molyneux E. Walsh A. Caution in the use of reagent strips to diagnose acute bacterial meningitis. Lancet 1996; 348: 1170-1171. 3. Kjeldsberg (R) Krieg AF. Pandy test: Cerebrospinal fluid and other body fluids. In: Clinical Diagnosis and Management by Laboratory Methods, 17th edn. Henry JB. Delhi. W.B. Saunders, 1st Indian Edition, All India Travellers Book Seller. 1989; pp 459-492.
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  A simple strategy to improve first breath oxygen delivery by self inflating bag.

  Resuscitation. 2000 Aug 1;45(3):221-4.
  Agarwal KS, Puliyel JM.
  The text book of Pediatric Advanced Life Support of the American Heart Association recommends that a reservoir is used with a self inflating bag valve device. The figure in the book suggests that if such a device is connected to an oxygen supply, the oxygen will fill the bag first and then go on to fill the reservoir. However the valve structure of the self-inflating device does not permit active entry of oxygen into the bag, unless the bag is deflated and allowed to reinflate, drawing oxygen fr Show More...The text book of Pediatric Advanced Life Support of the American Heart Association recommends that a reservoir is used with a self inflating bag valve device. The figure in the book suggests that if such a device is connected to an oxygen supply, the oxygen will fill the bag first and then go on to fill the reservoir. However the valve structure of the self-inflating device does not permit active entry of oxygen into the bag, unless the bag is deflated and allowed to reinflate, drawing oxygen from the reservoir. We did this study to test the concentration of oxygen delivered in the first few breaths with the help of a Miniox-III oxygen monitor probe (MSA Medical Products, Pittsburgh, PA 15230) inserted into a self inflating bag (AMBU). Twenty-one percent oxygen is delivered with first breath and it rose to 42 and 58% with the second and third inflations, respectively. Eighty percent oxygen was achieved after eight reinflation cycles. We developed a formula to calculate the concentration of oxygen in the bag after each inflation effort, assuming that there was no passive diffusion of oxygen. We suggest that compressing the bag 8-12 times prior to putting the mask to the face of the patient will allow 80% oxygen to be delivered with first breath.
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  Gall bladder wall edema in serology proven pediatric dengue hemorrhagic fever: a useful diagnostic finding which may help in prognostication.

  J Trop Pediatr. 2000 Jun;46(3):179-81.
  Gupta S, Singh SK, Taneja V, Goulatia RK, Bhagat A, Puliyel JM.
•   Download (html) 15.2 kB

  Repeated unifocal seizure in post neonatal infants with hypocalcemia.

  Indian Pediatr. 2000 Feb;37(2):203-5.
  Agarwal KS, Beri RS, Puliyel JM.
•   Download (html) 21.9 kB

  Universal immunization with hepatitis B vaccine- what it will cost.

  Indian Pediatr. 2000 Jan;37(1):107-10.
  Puliyel J
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  Acute pancreatitis with cholestatic hepatitis: an unusual manifestation of hepatitis A.

  Ann Trop Paediatr. 1999 Dec;19(4):391-4.
  Agarwal KS, Puliyel JM, Mathew A, Lahoti D, Gupta R.
  Acute hepatitis A infection is an uncommon cause of pancreatitis in children. To date, only four cases have been reported in the paediatric literature. We report a 7-year-old girl with acute pancreatitis associated with hepatitis A infection who made a satisfactory recovery. The report highlights the CT findings including focal necrosis not previously reported. Because of the extreme rarity of the complication, the four previous reports have also been single case reports. This paper reviews all these cases with a view to elucidating the aetiopathogenesis of the pancreatitis.
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  Melas syndrome.

  Indian J Pediatr. 1999 Jul-Aug;66(4):621-5.
  Singh SK, Sarin D, Puliyel JM, Srivastav R, Gupta R, Kumar N, Mathews A.
  An 11 year old male presented with headache, vomiting and weakness of right side of body. One day after admission he developed right focal seizures. He had 5 previous episodes of stroke, the first at 11 months age. His milestones were normal upto the first episode but subsequent mile stones were delayed. His serum and CSF lactic acids were raised. Muscle biopsy showed ragged red fibres on modified Gomori-trichrome staining. His EEG, CT scan and MRI were normal this time. The child improved spont Show More...An 11 year old male presented with headache, vomiting and weakness of right side of body. One day after admission he developed right focal seizures. He had 5 previous episodes of stroke, the first at 11 months age. His milestones were normal upto the first episode but subsequent mile stones were delayed. His serum and CSF lactic acids were raised. Muscle biopsy showed ragged red fibres on modified Gomori-trichrome staining. His EEG, CT scan and MRI were normal this time. The child improved spontaneously after 7 days. His recovery time progressively became shorter with each episode of stroke. Maximum time for recovery was noted during first episode and least in current episode. This is the first report of Melas syndrome in Indian literature.
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  Should immunisation against hepatitis B take priority over provision of clean drinking water?

  BMJ 1999;319:188
  Puliyel J
•   Download (PDF) 1.1 MB

  Newer vaccines: like Marie Antoinette said, "let the poor eat cake".

  Indian Pediatr. 1998 Dec;35(12):1245-9.
  Puliyel JM.
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  Newer vaccines--to vaccinate or not to vaccinate is the question: ethical and medicolegal issues.

  Indian Pediatr. 1998 Aug;35(8):791-5.
  Puliyel JM.
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  Hypertonicity in diabetic ketoacidosis: unexpected biochemical correlates and clinical implications.

  Presented at the Joint Meeting of the International Symposium on Diabetes and Endocrine Disorders of the Young and the 4th Asian Symposium of Childhood and Juvenile Diabetes, Chaing Mai, Thailand, January 6-9, 1997.
  Puliyel J, Puliyel M, Hincliff R.
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  Hypertonicity in diabetic ketoacidosis: Unexpected biochemical correlates and clinical implications

  Conference: Joint Meeting of International Symposium on Diabetes and Endocrine disorders of the young and 4th Asian Symposium of Childhood and Juvenile Diabetes: Chaing Mai Thailand Jan 26-9 1997
  Puliyel J, Puliyel M, Hincliff R.
•   Download (html) 42.5 kB

  Adverse local reactions from accidental BCG overdose in infants.

  BMJ. 1996 Aug 31;313(7056):528-9.
  Puliyel JM, Hughes A, Chiswick ML, Mughal MZ.
•   Download (Other) 5.6 MB

  Hypertonicity may contribute to overestimation of dehydration in diabetic ketoacidosis

  Conference: Second European Pediatric Congress24-7 April 1996. Berlin Germany
  Puliyel J, Puliyel M, Hincliff R.
•   Download (html) 73.7 kB

  Overseas Doctor Training Scheme. More visiting registrar posts are needed.

  BMJ. 1994 Jul 30;309(6950):338-9.
  Puliyel J
•   Download (PDF) 5.2 MB

  Determination of bone width in malnourished children under 5, and its inter relationship with mid arm muscle thickness, subcutaneous fat thickness and the mid upper arm girth.

  Indian J Pediatr. 1992 Mar-Apr;59(2):197-202.
  Khare M, Shrivastava DK, Puliyel JM.
  The mid upper arm of 516 malnourished children (one to five years) were studied radiographically for changes in bone width, muscle mass and subcutaneous fat, of malnutrition at different ages. The data was studied by statistical analysis, determining the correlation coefficients of each of the factors. The findings indicate that previous assumptions about the components and the changes of the mid upper arm girth (MUG) in chronic severe malnutrition, were perhaps too simplistic.
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  Trichorhinophalangeal syndrome with repeated dislocation of the patella

  Clin Genet. 1992 Mar;41(3):139-42.
  Puliyel JM, Puliyel MM, Varughese S.
  The trichorhinophalangeal syndrome associated with laxity of the skin and joints has been mistaken for Ehlers-Danlos syndrome (Jones 1988). We report a case of the trichorhinophalangeal syndrome which we mistook for the Larsen syndrome. Literature and published photographs of the Larsen syndrome are reviewed to highlight the similarities between these two entities. These observations may be of value in the genetic mapping of the Larsen syndrome, which perhaps is a contiguous gene syndrome.
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  Prenatal diagnosis of Down's Syndrome: Use of the Circus Dwarf Sign.

  Ind Pediatr 1991;28:1083
  Puliyel J
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  Ocular atropine induced psychosis--is there a direct access route to the brain?

  J Assoc Physicians India. 1990 Jun;38(6):444-5.
  Varghese S, Vettath N, Iyer K, Puliyel JM, Puliyel MM.
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  The circus dwarf--a new sign for early diagnosis of Down's syndrome.

  Indian Pediatr. 1989 Oct;26(10):1062-3.
  Puliyel J, Nair LT.
•   Download (PDF) 2.9 MB

  Type II Waardenburg syndrome.

  Indian Pediatr. 1988 Apr;25(4):384-6.
  Varughese S, Kumar A, Rao S, Puliyel JM.
•   Download (Other) 2.7 MB

  The components of the Mid-Upper-Arm Girth

  J of Tropical Pediatrics 1988;34:201
  Khare M, Shivastava DK, Puliyel J.
•   Download (Other) 1.5 MB

  Ellis-van Creveld syndrome in Kerala.

  Trop Geogr Med. 1987 Oct;39(4):385-7
  Puliyel JM, Daniel A, Mathew CH.
  A case of the Ellis-van Creveld syndrome is described. Emphasis is laid on the probable relation to the frequency of consanguineous marriages among the Hindu community in Kerala.
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  Salk vs Sabin controversy

  Indian Pediatr. 1987 Aug;24(8):690.
  Puliyel JM
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  A syndrome of keratosis palmo-plantaris congenita, pes planus, onychogryphosis, periodontosis, arachnodactyly and a peculiar acro-osteolysis.

  Br J Dermatol. 1986 Aug;115(2):243-8.
  Puliyel JM, Sridharan Iyer KS.
  A family with a symptom complex of pes planus, onychogryphosis, palmoplantar hyperkeratosis and periodontosis is reported. A detailed pedigree is given and the mode of inheritance is suggested
•   Download (PDF) 4.4 MB

  Cushingoid adrenal hyperplasia in infancy.

  Aust Paediatr J. 1986 May;22(2):139-41.
  Puliyel JM, Komaranchath A, Kumar KR.
  Cushing's syndrome, a characteristic pattern of obesity with hypertension due to the hyperfunction of the adrenal cortex, is relatively rare in infancy. Thirty-six infants have been reported in world literature, most of whom have had adrenal tumours. There are only eight reported cases of infants under the age of 1 year with adrenal hyperplasia responsible for Cushing's syndrome. This is a report of an 8 month old child with bilateral nodular adrenal hyperplasia.
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  Detection of PEM

  Indian Pediatrics 1985;22:249
  Puliyel JM
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  Childhood immunization in developing countries

  Indian Pediatrics1984;21:258
  Varughese S, Puliyel M, Puliyel J
•   Download (PDF) 1.9 MB

  Lesch Nyhan syndrome.

  Indian Pediatr. 1984 Mar;21(3):251-2.
  Puliyel JM, Kumar M.
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  BCG vaccination

  Indian Pediatr. 1984 Mar;21(3):258.
  Puliyel J
•   Download (PDF) 3.1 MB

  Hypothyroidism with multiple congenital anomalies.

  Indian Pediatr. 1983 Nov;20(11):865-7.
  Puliyel JM, Thomas PG.
•   Download (Other) 5.4 MB

  Comparative study of the personality correlates and nature of drug abuse in schools and colleges.

  Indian J Pediatr. 1982 Sep-Oct;49(400):671-9.
  Agrawal RK, Puliyel JM, Chansoria M, Mukerjee B, Kaul KK.
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  The incidence and nature of drug abuse in adolescence personality correlates and predictive models.

  Indian Pediatr. 1981 Jul;18(7):443-8.
  : Puliyel JM, Agrawal RK, Chansoria M.
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