Hib Disease Burden – Review of literature

1. Hib Disease Burden – Review of literature Dr Raju Shah

2. Causes of under-five deaths India: WHO 2008 Neonatal 54% (1.003 million) Diarrhea 12.9% (0.237 million) Pneumonia 20.3% (0.371 million) Others 12.8% (0.218 million) 1.829 million under-five deaths (20.8% of world) Black RE et al, Lancet 2010;375:1969-87

3. Pneumoniadeaths: Top 10 countries Black RE et al, Lancet 2010;375:1969-87

4. Clinical Pneumonia burden – Top 15 countries Rudan I Bull WHO 2008;86:408-16

5. In India, data on Hib particularly on population-based incidence is sparse • There is marked variability in reported burden of Hib disease in India • However, a number of hospital-based studies have shown that, as in other parts of the world, Hib is the most common endemic cause of bacterial meningitis in children

6. Challenges in establishing Hib disease burden • Fastidious organism, difficult to grow • High threshold for cultures • Lack of good microbiology services • Antibiotic treatment before culture • Only severe cases reach the hospitals

7. There is marked variability in reported burden of Hib disease in India • A study by Panjarathinam R, Shah RK. (Pyogenicmeningitis in Ahmedabad Indian J Pediatr 1993; 60:669–73) - of 135 CSF samples obtained from children with meningitis - cultures yielded no Hib organisms at all • Study by Venkatesh VC, Steinhoff MC, Moses P, Jadhav M, Pereira SM. (Latex agglutination: an appropriate technology for the diagnosis of bacterial meningitis in developing countries. Ann TropPaediatr 1985; 5:33–6) have shown Hib to be a common cause of meningitis in infants and young children

8. Incidence of Hib meningitis in IndiaS. Minz, V. Balraj, M. K. Lalitha*, N. Murali**, T. Cherian**, G. Manoharan†, S. Kadirvan†, A. Joseph & M.C. Steinhoff††Indian J Med Res 128, July 2008, pp 57-64 • Prospective study • 1997 to 99 – for 24 months • Vellore district with 56,153 U5 children • 97 possible meningitis • Annual incidence Rate per 100,000 (AIR) • (86 for 0-4y while 357 for 0 to 11 m) • 18 ABM (AIR 15.9 for 0-59 months) • 8 Hib (AIR 7.1 for 0-59m - 32 for 0-11m, - 19 for 0-23m ) • Vellore study site is well-served and not typical of all of India – Vellore data would be underestimating for most other regions* *Indian J Med Res 132, October 2010, pp 450-455

9. Hib Meningitis in India • 0.5 to 2.6% of all hospital admissions (Kabra SK, et al. Bacterial meningitis in India: an IJP survey. Indian J Pediatr 1991; 58: 505-511) • 25% (range: 14-35%) of bacterial meningitis attributable to Hib in India

10. Good published studies

11. The proportion of Haemophilusinfluenzae Type B isolates in case series of endemic bacterial meningitis

12. The proportion of Haemophilusinfluenzae Type B isolates in case series of endemic bacterial meningitis (cont)

13. The proportion of Haemophilusinfluenzae Type B isolates in case series of endemic bacterial meningitis (cont)

14. The proportion of Haemophilusinfluenzae Type B isolates in case series of endemic bacterial meningitis (cont)

15. Case Fatality Rates CFR in Hib Meningitis – 20-29% Hib invasive disease CFR – 16% • In ICMR study even the 0.03 per cent death rate in spite of hospital treatment amounts to • 1 per cent case fatality; 50 times higher would be 50 per cent case fatality (~15 deaths/1000) • – very likely if untreated * • UNICEF projection of 14 deaths due to pneumonia per 1000 under-five children is not at all • inconsistent with the ICMR study data – even though they derive through • different routes and from different denominators* *Indian J Med Res 132, October 2010, pp 450-455

16. Bacterial Pneumonia • A similar pattern is observed in Indian studies of pneumonia also • A study by Kumar L, Ayyagari A. (The etiology of lobar pneumonia and empyemathoracis in children. Indian Pediatr 1984; 21:133–137) found no blood or pus cultures positive for Hib for 64 children with acute pneumonia or empyema, - but 2 (8%) of 26 blood and 6 (16%) of 38 pleural fluid specimens were positive for Hib by use of antigen detection methods

17. Hib Pneumonia in India 13% to 19% of pneumonia and LRTI due to Hib

18. Multi-center surveillance for pneumonia & meningitis among children (<2 yr) for Hib vaccine probe trial preparation in IndiaIndian J Med Res 131, May 2010, pp 649-658 • Chandigarh, Vellore, Kolkata • 18 m to 24 m – N 17951 • Enrollment from July 05 to Dec 06 • Parents explained about s/s of pneuonia and meningitis • Pneumonia and meningitis admitted to hospitals also enrolled • CSF culture, PCR, LAT, Bl culture, CXR

19. Severe clinical pneumonia • 2717 to 7890 per 100,000 child-years • Suspected meningitis • 1971 to 2433 per 100,000 child-years • NP carriage • 6 to 7.6 % • Incidence of clinical pneumonia comparable with other studies from India and a higher incidence of suspected meningitis

20. Drug Resistant Hib • 1st cases ofDrug resistant Hib from Chandigarh (1990)1 • Vellore study (1992) reported – 42.5% of Hib isolate MDR strains2 • Nagpur study (1996) reported – 80% MDR srains3 • IBIS (1999) reported – 56% resistance to Chloramphenicol - 40% resistance to Ampicillin4 1. Singh N et al. Multiple resistant Hib meningitis. Indian Pediatrics 1990;27:502-04. 2. John TJ et al. Hibdisease in children in India.PediatricInfec Dis J. 1998;17(9):5169-71 3. Agarwal v et al. Characterisation of invasive hemophilus Influenza isolated in Nagpur, Central India. IndianJ Med Res. 1996;103:296-98 4. Invasive Hemophillus Influenza disease in India: a preliminary report of prospective multihospital surveillance IBIS. PediatrInfect Dis J. 1998; 17:3172-75

21. HIB-Multicentric Study (IBIS)Antimicrobial% of Isolates agents Resistant Intermediate Total Ampicillin 33 7 40 Cefotaxime 0 0 0 Chloramphenicol 43 10 53 Trimetho.-sulfamethox38 3 41 Erythromycin 5 33 38 Antibiotic Resistance of 57 Haemophilusinfluenzae isolates from 6 IBIS centres, 1993 to 1995

22. Nasopharyngeal Carriage • Hibnasopharyngeal carriage among infants was found to be common in India • Study from Chandigarh, researchers found 11.2% of 1000 children below 2 years were carriers of H. influenza - 69% belonged to type b and the rest were non-typable* • Hib carriage rates increases throughout infancy and into the second year of life, peaking at age 18-21 months at a prevalence of 20.3%* * SekharS, Chakraborti A, Kumar R. Haemophilusinfluenzae colonization and its risk factors in children aged <2 years in northern India. Epidemiol Infect. 2009; 137:156-60

23. Estimates • From available studies reviewers estimated that there may be as many as 75 to 100 cases of meningitis caused by this organism per year per 100,000 children <5 years of age1 • Hib vaccine probe - total pneumonia cases caused by Hib would be 2,083,333 or 2 million cases per year. These are crude extrapolations from the multi-centre study2 John TJ, Cherian T, Raghupathy P. Haemophilusinfluenzae disease in children in India: a hospital perspective. Pediatr Infect Dis J 1998; 9: S169–71 2. Gupta M, Kumar R, Deb AK, Bhattacharya SK, Bose A, John J et al. A multi-centre surveillance for pneumonia and meningitis among children (<2 yr) for Hib vaccine probe trial preparation in India. Indian J Med Res 2010; 131; 649-658.

24. Prospective culture based studies for pneumonia in world • Pneumococcus: 30-50% • Hib: 10-30% • Others: • NTHi: • New Papua Guinea (Lung culture) • Pakistan (Blood isolates) • S. Aureus: • Chile (Lung aspirate) • WHO 42% (Blood aspirate) • Non-typhoid salmonella: • Africa, Malawi (severe pneumonia) • Viruses: 30-50% • RSV: 15-40% • Others: Rudan I Bull WHO 2008;86:408-16

25. Vaccine probe studies • Pneumococcus and Hib are two important vaccine preventable causes of pneumonia • Vaccine effectiveness against radiological proven pneumonia studies in developing countries • Hib: 15-30% (Hib conjugate vaccine) Rudan I Bull WHO 2008;86:408-16

26. 3 Hib probe studies • Pilot or Probe introduction of specific vaccine, with measurement of syndromes pre-and post-vaccination, necessary to quantify the pre-vaccination prevalence/incidence • Gambia , Chile, Indonesia • 21- 23% of hospitalized pneumonia cases with radiographic infiltrates were prevented

27. Hib impact studies • >95% efficacy- Europe, US and Gambia • Also in Chile, Brazil, Columbia, Kenya, Malawi • Lombok • Measurable impact on clinical pneumonia but no impact on radiological pneumonia • Bangladesh (SEA) • Meningitis reduced by 90% • Radiological pneumonia reduced by 16-32%

28. The Gambia Hib vaccine program resulted in virtual disease elimination Incidence of Hib Meningitis/ 100,000 (children <5 years) in the Western Region of the Gambia Hib trial National Immunization with Hib Despite supply interruptions, disease has been virtually eliminated Adapted from Adegbola R et al. Lancet, 2005

29. Hib Cases and IncidenceCHILE, 1996-2000Children <5 years of age Source: Notificación Obligatoria, MINSAL.

30. WHO statement The lack of local surveillance data should not delay the introduction of the vaccine especially in countries where regional evidence indicates a high burden of disease

31. Thanks