hib disease burden – review of literature

1

Hib Disease Burden – Review of literature

Dr Raju Shah

Causes of under-five deaths India: WHO 2008

Pneumonia 20.3% (0.371 million)

Diarrhea 12.9% (0.237 million)

Others 12.8% (0.218 million)

Neonatal 54% (1.003 million)

1.829 million under-five deaths (20.8% of world)

Black RE et al, Lancet 2010;375:1969-87 2

Pneumonia deaths: Top 10 countries

Black RE et al, Lancet 2010;375:1969-87

Number Country Pneumonia deaths (N) (2008)

% of world

01 India 371,605 23.5%

02 Nigeria 177,212 11.2%

03 DR Congo 112,655 7.1%

04 Pakistan 084,210 5.3%

05 Afghanistan 080,694 5.1%

726,376 52.3%

06 China 062,229 3.9%

07 Ethiopia 048,892 3.1%

08 Angola 033,078 2.1%

09 Kenya 030,406 1.9%

10 Indonesia 038,331 2.4%

Total 1,031,392 65.8%

World 1,575,257 100%

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Clinical Pneumonia burden – Top 15 countriesCountry Predicted no. of

new cases (millions)Estimated incidence(epi/child yr)

India 43.0 0.37

China 21.1 0.22

Pakistan 09.8 0.41

Bangladesh 06.4 0.41

Nigeria 06.1 0.34

Indonesia 06.0 0.28

Ethiopia 03.9 0.35

Democratic Republic of the Congo 03.9 0.39

Viet Nam 02.9 0.35

Philippines 02.7 0.27

Sudan 02.0 0.48

Afghanistan 02.0 0.45

United Republic of Tanzania 01.9 0.33

Myanmar 01.8 0.43

Brazil 01.8 0.11

World 155.84 0.26Rudan I Bull WHO 2008;86:408-16 4

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• 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

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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

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There is marked variability in reported burden of Hib disease in India

• A study by Panjarathinam R, Shah RK. (Pyogenic meningitis 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

Trop Paediatr 1985; 5:33–6) have shown Hib to be a common cause of meningitis in infants and young children

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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

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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

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Good published studiesAuthor/year Syndrome Age range Study Site Study Size % Hib

positive

Deivanayagam, et al. 1993

suspected meningitis

2 mo - 11 y

Chennai 114 25

Singhi, et al. 2002

suspected meningitis

1 mo - 12 y

Chandigarh 107 35

Suvarna Devi, et al. 1982

acute meningitis

<15 y Behrampur 70 19

Mani, et al. 2007

bacterial meningitis

<5 y Bangalore 51 14

Chinchankar, et al. 2002

bacterial meningitis

1 mo - 5 y Pune 54 26

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S.N. Study ID State Year Age group No. of cases HaemophilusInfluenza (%)

1 Achar and Rao (1953)

Tamil Nadu

1950–1951 Paeds 98 45 (45.9)

2 Taneja and Ghai (1955)

Delhi 1953–1955 <12 years 33 0 (0.0)

3 Ahmed et al. (1964)

Tamil Nadu

1953–1960 < 12 years 87 33 (37.9)

4 Paul (1963)

Delhi 1956–1959 <12 years 48 10 (20.8)

5 Srivastava et al. (1968)

Uttar Pradesh

1964 <12 years 33 0 (0.0)

6 Gandhi (1969)

Gujarat 1966–1967 <12 years 60 4(6.7)

7 Reddi et al. (1973)

Andrha Pradesh

1970–1971 Paeds 85 5(5.9)

8 Tamaskar andBhandari (1976)

Madhya Pradesh

1971–1972 <12 years 21 3(14.3)

The proportion of Haemophilus influenzae Type B isolates in case series of endemic bacterial meningitis

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S.N.

Study ID State Year Age group No. of cases HaemophilusInfluenza (%)

9 Kalra and Dayal (1977)

Uttar Pradesh

1966–1969 1 month–12 years

196 0(0.0)

10 Ayyagari et al. (1980)

Chandigarh 1976–1978 Paeds 176 11(6.3)

11 Kumar et al. (1980)

Chandigarh 1977–1979 1 month–12 years

66 17(25.8)

12 Suvarna Devi et al.(1982)

Orissa 1978–1981 <15 years 70 13(18.6)

13 Pal and Sant (1982)

Maharashtra

- - 64 0(0.0)

14 Venkatesh et al.(1985)–

Tamil Nadu 1982 9 day–12 years

44 8(18.2)

15 Bhat (1991)

Pondicherry 1972–1980 Paeds 256 6(2.3)

16 Vincent et al. (1987)

Kerala 1983–1984 1 month–12 years

51 0(0.0)

The proportion of Haemophilus influenzae Type B isolates in case series of endemic bacterial meningitis (cont)

S.N. Study ID State Year Age group No. of cases HaemophilusInfluenza (%)

17 Kabra et al. (1991)

Various 1989 <12 years 852 8(0.9)

18 Deivanayagam (1993)

Tamil Nadu 1989–1990 2 months–11 years

114 28(24.6)

19 Panjarathinam andShah (1993)

Gujarat 1990 <10 years 135 0(0.0)

20 Javadekar et al. (1997)

Gujarat - Paeds 50 1(2.0)

21 Bhaumik (1998)

Delhi - 12–75 years 30 -

22 Jain et al. (2000)

Delhi - 3 months–12 years

32 7(21.9)

23 Sahai et al. (2001)

Pondicherry 1994–1996 1 month–12 years

100 17(17.0)

24 John et al. (2001)

Tamil Nadu 1997–1998 0–60 years 61 1(1.6)

25 Singhi et al. (2002a)

Chandigarh – 1 month–12 years

107 23(21.5)

26 Singhi et al. (2002b)

Chandigarh 1998–1999 3 months–12 years

69 6(8.7)


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S.N Study ID State Year Age group No. of cases HaemophilusInfluenza (%)

26 Singhi et al. (2002b)

Chandigarh 1998–1999 3 months–12 years

69 6(8.7)

27 Chinchankar et al.(2002)

Maharashtra

1997–1999 1 month–5 years

54 14(25.9)

28 Hemalatha et al.(2002)

Andrha Pradesh

1998–2000 1–5 years 120 6(5.0)

29 Shivaprakash et al.(2004)

Karnataka – Paeds 204 3(1.5)

30 Singhi et al. (2004)

Chandigarh 1993–1996 1–12 years 88 9(10.2)

31 Mani et al. (2007)

Karnataka 1996–2005 All ages 385 7(1.8)

32 Shameem et al. (2008)

Karnataka 2003–2007 Paeds 236 61(25.8)

33 Minz et al. (2008)

Tamil Nadu 1997–1999 0–4 years 97 6(6.2)


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Case Fatality RatesAuthor/Year Syndrome Site CFR (%)

Kabra 1991 Hib meningitis Jaipur,Jodhpur, Delhi , Kolkata

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Steinhoff 1998 Hib meningitis Vellore 29

Thomas 2002 Hib meningitis IBIS 20

Chinchankar 2002 Hib meningitis Pune 21

Thomas 2002 Any invasive Hib disease

IBIS/1994-1997 16

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

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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 empyema thoracis 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

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Hib Pneumonia in India Author/Year Syndrome Location Age Study Size % disease

due to Hib %

isolation rate of any organism

Bahl 1995 Pneumonia Delhi 0-5 years 110* 19 55

Kumar 1984 Pneumonia Chandigarh

< 11 years 64* 13 42

Patwari 1996

Pneumonia Delhi < 12 years 132* 15 88

13% to 19% of pneumonia and LRTI due to Hib

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Multi-center surveillance for pneumonia & meningitis among children (<2 yr) for Hib vaccine probe trial preparation in India Indian 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

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• 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

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Drug Resistant Hib

• 1st cases of Drug 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. Hib disease in children in India.Pediatric Infec Dis J. 1998;17(9):5169-71 3. Agarwal v et al. Characterisation of invasive hemophilus Influenza isolated in Nagpur,

Central India. Indian J Med Res. 1996;103:296-98 4. Invasive Hemophillus Influenza disease in India: a preliminary report of prospective

multihospital surveillance IBIS. Pediatr Infect Dis J. 1998; 17:3172-75

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HIB-Multicentric Study (IBIS)Antimicrobial % of Isolates agents Resistant Intermediate Total Ampicillin 33 7 40 Cefotaxime 0 0 0 Chloramphenicol 43 10 53 Trimetho.-sulfamethox 38 3 41 Erythromycin 5 33 38

Antibiotic Resistance of 57 Haemophilus influenzae isolates from 6 IBIS centres, 1993 to 1995

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Nasopharyngeal Carriage• Hib nasopharyngeal 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%*

* Sekhar S, Chakraborti A, Kumar R. Haemophilus influenzae colonization and its risk factors in children aged <2 years in northern India. Epidemiol Infect. 2009; 137:156-60

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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

1. John TJ, Cherian T, Raghupathy P. Haemophilus influenzae disease in children in India: a hospital perspective. Pediatr Infect Dis J 1998; 9: S169–712. 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.

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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

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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

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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

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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%

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The Gambia Hib vaccine program resulted in virtual disease elimination

Adapted from Adegbola R et al. Lancet, 2005

Incidence of Hib Meningitis/ 100,000 (children <5 years) in the Western Region of the Gambia

Despite supply interruptions, disease

has been virtually eliminated

Hib trial National Immunization with Hib

0

20

40

60

80

100

120

140

160

180

1996 1997 1998 1999 2000

CA

SE

S

0

2

4

6

8

10

12

INC

IDE

NC

E

Cases Incidence/100,000

Hib Cases and IncidenceCHILE, 1996-2000

Children <5 years of age

Source: Notificación Obligatoria, MINSAL. 29

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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

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THANKS

hib disease burden – review of literature

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