Etiology of diarrheal disease in India - The INCLEN Trust

Etiology of Diarrheal Disease inIndiaAnuradha BoseChristian Medical College,Vellore

Objectives1. Why is etiology of diarrhea important?2. Describe the challenges in determining diarrheaetiology3. Characterize the etiology of diarrhea in South Asia4. Describe key findings from locally relevant andpivotal international sources of data5. Describe the epidemiology of rotavirus2

Why is etiology important?• For linking clinical presentations to organismscausing them• To facilitate evidence based treatmentprotocols• To provide estimates of burden of disease,particularly in diseases for which vaccines areavailable.3

Clinical management of diarrhoea• Syndromic approach as in IMNCI• ORS• Zinc• Promotion of (continued) breast feeding• Water, Sanitation and Hygiene interventions.• Protocols vary where there is blood in stools.4

Methods for determining etiology of diarrheaEtiology generally determined by examination of astood sample from a child with diarrhea:Culture: bacteriaImmunoassay: viruses and parasitesAntigen detection: virusesNucleic acid detection: viruses5

Leading Pathogens Causing Diarrhea in ChildrenBacterial pathogensEscherichia coliShigella sp.Salmonella speciesCampylobacter jejuniVibrio choleraeParasitic PathogensGiardia lambliaCryptosporidium speciesViral PathogensRotavirusMeasles virusNorwalk virusAdenovirusesAstrovirusEffective vaccinesavailable6

Challenges in determining the etiology of diarrhea• Diagnosis based on caregiver’s report• Availability of a well equipped clinical microbiologylaboratory is a prerequisite• Conventional assays, immunological and moleculardetection methods• Enteric pathogens isolation in asymptomatic controls• Colonization with potential pathogenic bacteria• Isolation of multiple pathogens in same case• Prior antibiotic exposure7

Global data of relevance:• Global Enteric Multicentric study; GEMS• Malnutrition and Enteral Diseases:Mal-ED8

Etiology of diarrhea: GEMS studyObjective: Estimate the population-based burden, microbiologicetiology, and adverse clinical consequences of moderate to severediarrhea among children 0 to 59 months of age living in sub-Saharan Africa and S. AsiaSites: Countries with moderate/high under 5 mortalityAfrica: The Gambia, Mali, Mozambique, KenyaAsia: India, Bangladesh, PakistanMethods:Eligible cases enrolled throughout the year within age strataAge, gender, village-matched controls enrolledAll children provided a stool sample or rectal swab prior toantibiotic use9

Frequency Distribution of Putative Pathogens in Casesand Controls, Africa (0-11 mos.) excluding Giardia0% 5% 10% 15% 20% 25% 30%RotavirusCryptosporidiumEAEC (aata only)GiardiaEAEC (aaic only)ETEC (LT/ST or ST)EPEC (eae+bfpA+)Norovirus GIIETEC (LT only)C. jejuniEPEC (eae- bfpA+)Adenovirus (non-40/41)EPEC (eae+ bfpA-)SapovirusShigella (any)EAEC (aata/aaic)E. histolyticaAstrovirusNon-typhoidal SalmonellaNorovirus GICampylobacter coliAdenovirus 40/41AeromonasV. cholerae O1V. cholerae O139S. typhiCases (n=1578)Controls (n=1787)1

GEMS study India; results 588 casesRotavirus 151 Astrovirus 19Giardia 138 tEPEC 18Cryptosporidium 98 ETEC - LT only 17Campylobacter jejuni 83 E. histolytica 14EAEC 72 Adenovirus non-40-41 11Norovirus GII 51 Campylobacter coli 5Shigella 40 Norovirus GI 4Adenovirus 40/41 29 Aeromonas 2ST-onlyETEC 26 EHEC 2Sapovirus 24 Non-typhoidal Salm 1V. cholerae O1 21 ETEC - LT/S 2111

Most Common Etiologic Agents by Age0-11 12-23 24-59Rotavirus X X XShigella X X XCryptosporidium X X XETEC (ST or LT/ST) X X XV. cholerae O1 X XC. jejuni (Asia only) X XAeromonas (mainly Asia) X X XNTS (Africa) X XtEPEC X XaEPECXEAggECAdenoviruses 40/41XNorovirus GII X XSapovirusXE. histolytica X X12

Risk factors for death in GEMSIn a multivariate model, risk of death wasincreased in• Younger age• Low weight for age• Offering less fluids during illness• Isolation of tEPEC and Cryptosporidium13

Nationally available data:14

Comparison of infection status by different enteric pathogens in < 5 and ≥5age groups. GB Nair et al; Gut Pathol 2010; Vol2 :415

Emerging trends observed in diarrhoeal disease surveillance inKolkata: GB Nair: Gut path 2010 : 2 ;4Increase in V. cholerae O1 infection among

Etiology of Diarrhea: IndiaCases with Specific Pathogen Isolated, %Etiology of diarrhea in hospitalized children

Global and national estimatesof rotavirus disease18

Estimated rotavirus deaths for children under 5, 2008Global estimate: 435,00020

Estimated rotavirus deaths for children under 5, 2008Global estimate: 435,000India (21.8%)Nigeria (9.1%)Pakistan (8.6%)DR Congo (7.2%)Ethiopia (6.2%)Afghanistan (5.6%)Uganda (2.3%)Indonesia (2.2%)Bangladesh (2.2%)Angola (1.9%)10,6379,9709,8578,78832,65328,21825,42341,05739,14498,621% is percent of total globalrotavirus deaths67% of all rotavirus deathsoccur in these 10 countriesSource: http://www.who.int/immunization_monitoring/burden/rotavirus_estimates/en/index.html21

Estimated rotavirus morbidity in India for children under 5EventsRisk122,000-153,000 deaths 1 in every 177-196 children457,000-884,000 hospitalizations 1 in every 31-59 children2 million outpatient visits1 in every 13 childrenTate et al. Vaccine 2009: F18-F24 22

Epidemiology of Rotavirus23

RotavirusRNA virus in the family ReoviridaeFive types: A, B, C, D, ERotavirus A causes >90% of infections in humansWithin rotavirus A there are differentstrainsSerotypes classified based on two surfaceproteins (G and P)Charles D. Humphrey, CDC24

Common strains worldwide4-5 rotavirus strains are common worldwideP[8]G47.5%P[4]G211.5%P[8]G32.8%P[8]G152.2%other18.2%P[6]; G1 toG4, G85%P[6]G9P[8]G92.3%Gentsch JID 200525

Common strains in IndiaRotavirus G serotype diversity in Northern and Southern India*Northern India9%Southern India5%G110%38%18%35%G2G411%8%4%21%5%7%8%21%G9GMGNTOther* Southern India was defined as Andhra Pradesh, Maharashtra, and states south of theseKahn et al. 201226

Common strains in IndiaRotavirus P serotype diversity in Northern and Southern India*Northern IndiaSouthern India13%12%1%37%26%0%36%P[8]P[4]P[6]6%P[M]14%4%P[NT]22%27%Other* Southern India was defined as Andhra Pradesh, Maharashtra, and states south of theseKahn et al. 201227

Age of infectionPrimarily affects childrenBy five years of age nearly all children will have been infected withrotavirus at least onceImmunity develops with each infectionSubsequent infections are less severeAdults rarely develop clinical disease28

PercentageAge Distribution of Rotavirus Infections Identified through theIndian Rotavirus Surveillance Network, 2007-200950454035302520151050Kolkata Pune Vellore & Trichy Delhi Mumbai0 - 2 3 - 5 6 - 11 12 - 23 24 - 35 36 - 47 48 - 59Age (Months)Kang et al, JID, 2009 29

Distribution of community and hospital rotavirusinfections by age : Banerjee et al: Jl Clin Micro 2006 JulAgeNo. ofdiarrhealepisodes incommunityNo. (%) of RVpositive casesin communityNo. of diarrhealepisodes inhospitalNo. (%) of RVpositive casesin hospital0-5 522 25 (4.8) 85 11 (12.9)6-11 431 39 (9.0) 123 52 (42.3)12-17 157 18 (11.5) 71 19 (26.7)18 and 42 0 (0.0) 57 12 (21.1)aboveUnknown 0 0 7 0Total 1152 82 (7.1) 343 94 (27.4)

AgeRelationship of age with severity of rotavirusdiarrhea in the community and the hospitalBanerjee et al: Jl Clin Micro 2006 JulNo. ofchildren withrotavirusdiarrhea incommunityNo. (%) ofsevere cases incommunityNo. ofchildren withrotavirusdiarrhea inhospitalNo. of severecases / totalno.of cases inhospital (%)0-5 25 6 (24) 11 5/10 (50.0)6-11 39 6 (15.4) 52 31/50 (62.0)12-17 18 6 (33.3) 19 11/19 (57.9)18 and 0 0 12 4/11 (36.4)aboveTotal 82 18 (22.0) 94 51/90 (56.7)

What does this disease mean in terms ofhow much it costs society?32

Economic Burden of Rotavirus in IndiaTotal direct medical cost burden of rotavirus diarrheain children

Economic evaluation of vaccines:• Cost-saving: averted costs are greater thanintervention.• Cost-effectiveness: compare net costs withhealth gains• Decisions for vaccine intro depend, amongother factors, on: Health burdenVaccine effectivenessCost effectiveness of the programRheingans et al: JID 2009; 20034

• Vaccination would be cost saving in Lower andupper middle income countries with a vaccineprice of < $0.53 -$2.00 per dose• The cost effectiveness is reduced if vaccinecoverage is lowered or with delays invaccination35

Recommendations based on preliminaryGEMS results:Introduce licensed Rotavirus vaccines into the EPI ofhigh burden countries.Consider cholera vaccines in high risk pre-schoolchildrenGiven the burden of Cryptosporidium, invest indevelopment of diagnostics, therapy and vaccinesImplement WASH interventions36

Summary• Rotavirus disease is present in India• It largely affects the vulnerable young• Mortality with diarrhoea is increased withassociated malnutrition• (India has a lot of malnutrition)• Death due to diarrhoea in children occursoften in cases which have not accessed healthcare for the diarrhoeal episode• Vaccines might help avert these deaths.37

Thank youwww.indvac.org38