Indian J Med Res 137, April 2013, pp 639-641,
Making a case for universal Hib immunization in India; over interpreting the data
This issue of the IJMR features the results of a prospective sentinel surveillance for Hemophilus influenza B (Hib) meningitis. (1) The National Technical Advisory Group on Immunization (NTAGI) in its meeting of 26 August 2010 recommended that Pentavalent vaccine containing Hib be introduced in the states of Kerala and Tamil Nadu. (2) Since there was concern about its adverse effects (AEFI), this was to be monitored in the two states. Further roll-out to other states was to be based on the impact assessment after 1 year. The NTAGI suggested that the ICMR prepare a protocol for the surveillance of Hib meningitis in selected hospitals to understand the trends over time.(2) The data in the IJMR this month represents the first of these surveillance reports. (1)
4 centers, two in Tamil Nadu (ICH&HC Chennai and CMC Vellore), one from Uttar Pradesh (CSMMU Lucknow) and one in Delhi (KSCH) participated. The 4 centers followed different protocols. The latex agglutination test (LAT) was employed to detect antigens and identify the causative organism. In the surveillance period 2912 children under 2 years of age with suspected meningitis, were enrolled in the 4 centers. 62 were found to have Hib meningitis. The break up of incidence at each center is shown in the Table 1. The data in the table, which is not reported in the paper, was provided by the authors. They do not total up accurately but is useful to get the overall picture.
Breakdown of patients recruited for the study
4 Centers CMC CSMMU ICH&HC KSCH
Clinical suspicion of meningitis 2912 382 445 1624 471
Abnormal CSF (>/=10 WBC per mm3) 708 235 252 126 98
Probable Bacterial meningitis WHO Criteria (100 WBC/ raised protein/ low sugar/ cloudy CSF) 441
109 182 76 75
Confirmed Bacterial Meningitis 89 16 27 29 17
Hib confirmed 62 7 21 19 15
Other Bacteria 27 9 6 10 2
Comparison with IBIS Study
The low incidence of Hib meningitis (62 cases) seen in these 4 centers over the study period, is reminiscent of the results of the IBIS study conducted over 4 years in 6 hospitals between 1993 and 1997 where only 125 cases of Hib were identified. (3) The present study, done two decades later and which employs sensitive tools like LAT for Hib antigen detection, validates the findings of the IBIS study, which depended mostly on culture techniques.
Exaggeration of disease burden
The authors assert wrongly in the abstract that 58% of cases of probable meningitis in Vellore (and 74% at the other centers) was caused by Hib. This is misleading as it exaggerates the problem of Hib meningitis. Using the definitions employed by the authors in the article, there were 441 children with ‘probable bacterial meningitis’. There were 60 cases of Hib meningitis among them. Hib was found in only 13.6% of the cases with probable meningitis (and not 58 to 74% as stated in the paper). 2 additional cases were detected in children with abnormal CSF but not fulfilling the CSF criteria for ‘probable bacterial meningitis’. On the whole, 62 cases of Hib meningitis were detected among 708 patients with abnormal CSF. Hib antigen was detected only in 8.75% of patients with an abnormal CSF cytology. The mortality from Hib meningitis was 11%.
This information is important for estimating the burden of Hib meningitis and the benefits of vaccination. There are at least two previous attempts to estimates of the burden of the disease in the country. The Core Committee on Immunization has estimated that there are 52,000 new cases of Hib meningitis in the country each year. (4) This estimate was made projecting data from a surveillance study done in a district of Kerala between July 1999 and June 2001.(5) The surveillance involved collection of reports of clinical disease from within the district – with or without laboratory confirmation. The authors assumed that about one third of the cases of clinical meningitis were pyogenic meningitis and the Core Committee assumed that one third of the cases of pyogenic meningitis were caused by Hib. In the first year of this surveillance there were 75 cases of suspected meningitis and it was presumed by the authors…. that 27 would be due to pyogenic meningitis and the Core Committee assumed that 9 of them must have been due to Hib. In this way about 12% of clinical meningitis was presumed to be due to Hib by the Core Committee. In the next year of surveillance there were only 23 cases of clinical meningitis and it was presumed there were 9 cases of pyogenic meningitis and 3 cases of Hib meningitis. The Core Committee selected the first year of surveillance (when there were 9 cases of presumed Hib meningitis), to make its nationwide projection of 52,000 cases. No justification was provided as to why the data from the next year (when there were only 3 cases of Hib) was not used. In the present study by Ramachandran et al (1), 62 cases of Hib were found among 2912 children with clinically suspected meningitis and it represents 2.1% of the clinically suspected cases (not 12% as used in the Kerala projection).
Minz et al. performed meticulous surveillance in a population of 6.5 lac persons, over a two year period (1997 to 1999). (6) The study involved house to house visits every 2 weeks. They found the incidence of Hib meningitis was 7 per 100,000 in children under 5. In real terms, if the year’s birth cohort of about 25 million is vaccinated against Hib, nation-wide it will prevent 1750 cases of Hib meningitis and would save less than 200 lives (11% mortality). After the short term subsidies provided by GAVI are withdrawn, vaccinating the birth cohort of 25 million with a Pentavalent vaccine that costs Rs 525/child (3 doses) (7) would entail an expenditure of Rs 1300 crores. This is more than the entire immunization budget for 2011-12 (of Rs 1200 crores). (8) After 5 years of the programme vaccinating each birth cohort (with 125 million children vaccinated), 8750 cases of Hib meningitis and 962 deaths will be prevented yearly. The evidence from the present study and that from the Minz study will enable the Core Committee to revise its projection of Hib meningitis in the country.
Inappropriate use of LAT for detection of other organisms
In the present surveillance, the organism was identified by LAT in 84 of 89 samples. However LAT is not uniformly sensitive in detecting all organisms. It is positive in 93% of Haemophilus influenza type b infections but only in 60% of Streptococcus pneumonia and 39% of Neisseria meningitides. (9) Therefore while LAT can identify most cases of Hib, because of its lower sensitivity for other organisms, it is not very useful to examine the relative incidence of different bacteria.
Over-interpretation of benefits of vaccination
In the study reported here, in Vellore 7 of the 16 cases of bacterial meningitis where a pathogen was identified, were due to Hib (44% Hib) compared to 55 out of 73 in the other centers (75% Hib). (44% vs 75%, Exact p=0.02) The authors utilize these differences in proportions, to build up a hypothesis that the ‘lower proportion’ of Hib in Vellore was due to the herd effect of 41% coverage with Hib vaccine (compared to the other centers where only 1% to 8% had received even 1 dose of Hib). This conclusion is perhaps not entirely justified. The manuscript clearly indicates that the maternal educational levels were higher, proportion of children with severely malnourished were significantly lower and the immunization coverage was higher in Tamilnadu as compared to other sites. These factors themselves could be giving better background immunity to the children there, as compared to other sites and hence the observed lower incidence of Hib could be due to these background differences.
Further, as indicated by the authors, one of the 7 confirmed Hib cases in Vellore was vaccinated. Assuming that 41% of the total number of children with suspected meningitis (382) is vaccinated against Hib, the probable picture in Vellore is shown in Table 2
History of Hib immunization in the group studied at Vellore
Hib+ Hib- Total
Vac+ 1 156 157
Vac- 6 219 225
Total 7 375 382
The odds of Hib disease with vaccination is 23% of those without vaccination - this may be promising. However the Exact probability of this is 0.25 which is statistically insignificant. In view of this, it is too early to conclude that vaccine has prevented a sizable incidence of Hib. At best it can be an early indicator of the effect that needs to be confirmed with larger numbers and with more in-depth analysis.
One major limitation at this stage is that we do not know the background incidence of Hib in Vellore before vaccination. Just comparing present incidence in Vellore with other regions which happened to be without vaccination could be misleading as these areas could have higher incidence of Hib than in Vellore from the beginning it self. The argument that the authors make has an implicit assumption that the background incidences of Hib were similar in Vellore and other regions studied, before the vaccination started. This argument is untenable. A better indicator would be reduction in Hib incidence comparing pre and post vaccination periods in the same region.
Conflicts of Interest
One of the authors of the present surveillance has reported possible conflicts of interest. Als-Nielsen and colleagues have shown that when the authors of an article were associated with for-profit organizations, it had little impact on the results or data reported but it influenced the interpretation of the results and the conclusions drawn.(10) The fact that the data is not impacted by conflicts of interest provides persuasive reason to publish the figures from large trial such as this, regardless of the declared conflicts of interests. Publication allows data to be put out in the public domain. It can be interpreted by the scientific community, separately from the interpretations of the authors and that of this editorialist. Discerning readers and decision makers can use the data provided for health policy, based on sound cost–benefit calculations.
1. Ramachandran P etal. Prospective multicenter sentinel surveillance for Haemoplillus influenza type B and other bacterial meningitis in Indian children. IJMR.
2. Government of India. Minutes of Meeting of National Technical Advisory Group on Immunization 26th August 2010, R. No. 155A, Nirman Bhawan [Internet]. Delhi; 2010 Aug. Available from: http://jacob.puliyel.com/#paper_293 Accessed on 4/4/13
3. 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 Apr 1;34(7):949–57.
4. Government of India. Minutes of the meeting of the Core Committee on Vaccines [Internet]. Available from: http://jacob.puliyel.com/#paper_288 Accessed on 4/4/13
5. John TJ, Rajappan K, Arjunan KK. Communicable diseases monitored by disease surveillance in Kottayam district, Kerala state, India. Indian J. Med. Res. 2004 Aug;120(2):86–93.
6. 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 Jul;128(1):57-64.
7. Panacea to cut pentavalent vaccine price [Internet]. The Hindu Business Line. [cited 2012 Nov 10]. Available from: http://www.thehindubusinessline.com/companies/panacea-to-cut-pentavalent-vaccine-price/article2081435.ece Accessed on 4/4/13
8. Bhadoria V, Gobinath A, Mitra P, Narayan M. Transforming India’s vaccine market; Saving lives, creating value [Internet]. Bombay: McKinsey&Company; 2012. Available from: http://www.mckinsey.com/client_service/pharmaceuticals_and_medical_products/people/%7E/media/mckinsey/dotcom/client_service/pharma%20and%20medical%20products/pmp%20new/pdfs/transforming_indias_vaccines_market.ashx Accessed on 4/4/13
9. Finlay FO, Witherow H, Rudd PT. Latex agglutination testing in bacterial meningitis. Arch. Dis. Child. 1995 Aug;73(2):160–1.
10. Als-Nielsen B, Chen W, Gluud C, Kjaergard LL. Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? JAMA. 2003 Aug 20;290(7):921–8.