Background In Sub-Saharan Africa, infectious diarrhea is a major cause of morbidity and mortality. A case-control study was conducted to identify the etiology of diarrhea and to describe its main epidemiologic risk factors among hospitalized children under five years old in Bangui, Central African Republic. Methods All consecutive children under five years old hospitalized for diarrhea in the Pediatric Complex of Bangui for whom a parent’s written consent was provided were included. Controls matched by age, sex and neighborhood of residence of each case were included. For both cases and controls, demographic, socio-economic and anthropometric data were recorded. Stool samples were collected to identify enteropathogens at enrollment. Clinical examination data and blood samples were collected only for cases. Results A total of 333 cases and 333 controls was recruited between December 2011 and November 2013. The mean age of cases was 12.9 months, and 56% were male. The mean delay between the onset of first symptoms and hospital admission was 3.7 days. Blood was detected in 5% of stool samples from cases. Cases were significantly more severely or moderately malnourished than controls. One of the sought-for pathogens was identified in 78% and 40% of cases and controls, respectively. Most attributable cases of hospitalized diarrhea were due to rotavirus, with an attributable fraction of 39%. Four other pathogens were associated with hospitalized diarrhea: Shigella/EIEC, Cryptosporidium parvum/hominis, astrovirus and norovirus with attributable fraction of 9%, 10%, 7% and 7% respectively. Giardia intestinalis was found in more controls than cases, with a protective fraction of 6%. Conclusions Rotavirus, norovirus, astrovirus, Shigella/EIEC, Cryptosporidium parvum/hominis were found to be positively associated with severe diarrhea: while Giardia intestinalis was found negatively associated. Most attributable episodes of severe diarrhea were associated with rotavirus, highlighting the urgent need to introduce the rotavirus vaccine within the CAR’s Expanded Program on Immunization. The development of new medicines, vaccines and rapid diagnostic tests that can be conducted at the bedside should be high priority for low-resource countries.
References
[1]
Liu L, Oza S, Hogan D, Perin J, Rudan I, Lawn JE, et al. Global, regional, and national causes of child mortality in 2000–13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet. 2015; 385:430–40. doi: 10.1016/S0140-6736(14)61698-6. pmid:25280870
[2]
UN. We Can End Poverty: Millennium Development Goals and Beyond. Goal 4: reduce child mortality. 2015. Available from: . Accessed 27th October 2015.
[3]
USAID, UNICEF, WHO. Diarrhoea treatment guidelines including new recommendations for the use of ORS and zinc supplementation for clinic-based healthcare workers. 2005. Available from: . Accessed 27th October 2015.
[4]
UNICEF, WHO. Diarrhoea: why children are still dying and what can be done. 2009. Available from: . Accessed 27th October 2015.
[5]
UNICEF. Multiple Indicator Cluster Survey Round 4 (MICS4). 2010. Available from: . Accessed 27th October 2015.
[6]
Giles-Vernick T, Bainilago L, Fofana M, Bata P, Vray M. Home Care of Children With Diarrhea in Bangui's Therapeutic Landscape (Central African Republic). Qual Health Res. 2015. doi: 10.1177/1049732315570117.
[7]
Sire JM, Garin B, Chartier L, Fall NK, Tall A, Seck A, et al. Community-acquired infectious diarrhoea in children under 5 years of age in Dakar, Senegal. Paediatr Int Child Health. 2013;33: 139–44. doi: 10.1179/2046905512Y.0000000046. pmid:23930725
[8]
Müller D, Greune L, Heusipp G, Karch H, Fruth A, Tsch？pe H, et al. Identification of unconventional intestinal pathogenic Escherichia coli isolates expressing intermediate virulence factor profiles by using a novel single-step multiplex PCR. Appl Environ Microbiol. 2007;73: 3380–90. doi: 10.1128/AEM.02855-06. pmid:17400780
[9]
Sethabutr O, Venkatesan M, Murphy GS, Eampokalap B, Hoge CW, Echeverria P. Detection of Shigellae and enteroinvasive Escherichia coli by amplification of the invasion plasmid antigen H DNA sequence in patients with dysentery. J Infect Dis. 1993;167: 458–61. pmid:8421181 doi: 10.1093/infdis/167.2.458
[10]
Platts-Mills JA, Gratz J, Mduma E, Svensen E, Amour C, Liu J, et al. Association between stool enteropathogen quantity and disease in Tanzanian children using TaqMan array cards: a nested case-control study. Am J Trop Med Hyg. 2014;90: 133–8. doi: 10.4269/ajtmh.13-0439. pmid:24189366
[11]
Kotloff KL, Nataro JP, Blackwelder WC, Nasrin D, Farag TH, Panchalingam S, et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study. Lancet. 2013;382: 209–22. doi: 10.1016/S0140-6736(13)60844-2. pmid:23680352
[12]
WHO. Diarrhoeal disease, Fact sheet N°330 2013. Available from: . Accessed 27th October 2015.
[13]
Moyo SJ, Gro N, Matee MI, Kitundu J, Myrmel H, Mylvaganam H, et al. Age specific aetiological agents of diarrhoea in hospitalized children aged less than five years in Dar es Salaam, Tanzania. BMC Pediatr. 2011; 11:19. doi: 10.1186/1471-2431-11-19. pmid:21345186
[14]
Bonkoungou IJ, Haukka K, ？sterblad M, Hakanen AJ, Traoré AS, Barro N, et al. Bacterial and viral etiology of childhood diarrhea in Ouagadougou, Burkina Faso. BMC Pediatr. 2013;13: 36. doi: 10.1186/1471-2431-13-36. pmid:23506294
[15]
Mwenda JM, Ntoto KM, Abebe A, Enweronu-Laryea C, Amina I, McHomvu J, et al. Burden and epidemiology of rotavirus diarrhea in selected African countries: preliminary results from the African Rotavirus Surveillance Network. J Infect Dis. 2010;202 Suppl:S5–S11. doi: 10.1086/653557. pmid:20684718
[16]
Ahmed SM, Lopman BA, Levy K. A systematic review and meta-analysis of the global seasonality of norovirus. PLoS One. 2013;8: e75922. doi: 10.1371/journal.pone.0075922. pmid:24098406
[17]
Payne DC, Vinje J, Szilagyi PG, Edwards KM, Staat MA, Weinberg GA, et al. Norovirus and medically attended gastroenteritis in U.S. children. N Engl J Med. 2013;368: 1121–30. doi: 10.1056/NEJMsa1206589. pmid:23514289
[18]
Veenemans J, Mank T, Ottenhof M, Baidjoe A, Mbugi EV, Demir AY, et al. Protection against diarrhea associated with Giardia intestinalis Is lost with multi-nutrient supplementation: a study in Tanzanian children. PLoS Negl Trop Dis. 2011;5: e1158. doi: 10.1371/journal.pntd.0001158. pmid:21666789
[19]
Krumkamp R, Sarpong N, Schwarz NG, Adelkofer J, Loag W, Eibach D, et al. Gastrointestinal infections and diarrheal disease in Ghanaian infants and children: an outpatient case-control study. PLoS Negl Trop Dis. 2015;9: e0003568. doi: 10.1371/journal.pntd.0003568. pmid:25738935
[20]
Gouandijka-Vasilache I, Manirakiza A, Gody JC, Banga-Mingo V, Kongombe OO, Esona MD, et al. Rotavirus epidemiology in Bangui, Central African Republic, 2008. Emerg Infect Dis. 2014;20: 1254–5. doi: 10.3201/eid2007.131839. pmid:24959927
[21]
Banga-Mingo V, Waku-Kouomou D, Gody JC, Esona MD, Yetimbi JF, Mbary-Daba R, et al. Molecular surveillance of rotavirus infection in Bangui, Central African Republic, October 2011-September 2013. Infect Genet Evol. 2014;28: 476–9. doi: 10.1016/j.meegid.2014.08.023. pmid:25193563
[22]
Velázquez FR, Matson DO, Calva JJ, Guerrero L, Morrow AL, Carter-Campbell S, et al. Rotavirus infections in infants as protection against subsequent infections. N Engl J Med. 1996;335: 1022–8. doi: 10.1056/NEJM199610033351404. pmid:8793926
[23]
Jiang V, Jiang B, Tate J, Parashar UD, Patel MM. Performance of rotavirus vaccines in developed and developing countries. Hum Vaccin. 2010;6: 532–42. pmid:20622508 doi: 10.4161/hv.6.7.11278
[24]
SAGE. Meeting of the immunization Strategic Advisory Group of Experts (SAGE), April 2009—conclusions and recommendations. Wkly Epidemiol Rec. 2009;84: 220–36. pmid:19499606
[25]
Checkley W, White AC, Jaganath D, Arrowood MJ, Chalmers RM, Chen XM, et al. A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for Cryptosporidium. Lancet Infect Dis. 2015;15: 85–94. doi: 10.1016/S1473-3099(14)70772-8. pmid:25278220
[26]
Meng CY, Smith BL, Bodhidatta L, Richard SA, Vansith K, Thy B, et al. Etiology of diarrhea in young children and patterns of antibiotic resistance in Cambodia. Pediatr Infect Dis J. 2011;30: 331–5. pmid:21412204 doi: 10.1097/inf.0b013e3181fb6f82
[27]
Swierczewski BE, Odundo EA, Koech MC, Ndonye JN, Kirera RK, Odhiambo CP, et al. Surveillance for enteric pathogens in a case-control study of acute diarrhea in Western Kenya. Trans R Soc Trop Med Hyg. 2013;107: 83–90. doi: 10.1093/trstmh/trs022. pmid:23222955
[28]
Kotloff KL, Nataro JP, Losonsky GA, Wasserman SS, Hale TL, Taylor DN, et al. A modified Shigella volunteer challenge model in which the inoculum is administered with bicarbonate buffer: clinical experience and implications for Shigella infectivity. Vaccine. 1995;13: 1488–94. pmid:8578831. doi: 10.1016/0264-410x(95)00102-7
[29]
Tacket CO, Kotloff KL, Losonsky G, Nataro JP, Michalski J, Kaper JB, et al. Volunteer studies investigating the safety and efficacy of live oral El Tor Vibrio cholerae O1 vaccine strain CVD 111. Am J Trop Med Hyg. 1997;56: 533–7. pmid:9180604.
[30]
Taylor DN, Tacket CO, Losonsky G, Castro O, Gutierrez J, Meza R, et al. Evaluation of a bivalent (CVD 103-HgR/CVD 111) live oral cholera vaccine in adult volunteers from the United States and Peru. Infect Immun. 1997;65: 3852–6. pmid:9284163.
[31]
Lindsay B, Ochieng JB, Ikumapayi UN, Toure A, Ahmed D, Li S, et al. Quantitative PCR for detection of Shigella improves ascertainment of Shigella burden in children with moderate-to-severe diarrhea in low-income countries. J Clin Microbiol. 2013;51: 1740–6. doi: 10.1128/JCM.02713-12. pmid:23536399
[32]
Lopman B, Simmons K, Gambhir M, Vinje J, Parashar U. Epidemiologic implications of asymptomatic reinfection: a mathematical modeling study of norovirus. Am J Epidemiol. 2014;179: 507–12. doi: 10.1093/aje/kwt287. pmid:24305574
[33]
Swart AN, Tomasi M, Kretzschmar M, Havelaar AH, Diekmann O. The protective effects of temporary immunity under imposed infection pressure. Epidemics. 2012;4: 43–7. doi: 10.1016/j.epidem.2011.12.002. pmid:22325013
[34]
Schlaudecker EP, Steinhoff MC, Moore SR. Interactions of diarrhea, pneumonia, and malnutrition in childhood: recent evidence from developing countries. Curr Opin Infect Dis. 2011;24: 496–502. pmid:21734569 doi: 10.1097/qco.0b013e328349287d
[35]
Opintan JA, Newman MJ, Ayeh-Kumi PF, Affrim R, Gepi-Attee R, Sevilleja JE, et al. Pediatric diarrhea in southern Ghana: etiology and association with intestinal inflammation and malnutrition. Am J Trop Med Hyg. 2010;83: 936–43. doi: 10.4269/ajtmh.2010.09-0792. pmid:20889896
[36]
ACF. Accès à l’eau et sécurité alimentaire en République Centrafricaine by Action contre la Faim International. Available from: . Accessed 27th October 2015.
[37]
Woerther PL, Angebault C, Jacquier H, Hugede HC, Janssens AC, Sayadi S, et al. Massive increase, spread, and exchange of extended spectrum β-lactamase-encoding genes among intestinal Enterobacteriaceae in hospitalized children with severe acute malnutrition in Niger. Clin Infect Dis. 2011;53: 677–85. doi: 10.1093/cid/cir522. pmid:21890771
[38]
Woerther PL, Burdet C, Chachaty E, Andremont A. Trends in human fecal carriage of extended-spectrum β-lactamases in the community: toward the globalization of CTX-M. Clin Microbiol Rev. 2013;26: 744–58. doi: 10.1128/CMR.00023-13. pmid:24092853
[39]
Rafai C, Frank T, Manirakiza A, Gaudeuille A, Mbecko JR, Nghario L, et al. Dissemination of IncF-type plasmids in multiresistant CTX-M-15-producing Enterobacteriaceae isolates from surgical-site infections in Bangui, Central African Republic. BMC Microbiol. 2015;15: 15. doi: 10.1186/s12866-015-0348-1. pmid:25648151
[40]
Panchalingam S, Antonio M, Hossain A, Mandomando I, Ochieng B, Oundo J, et al. Diagnostic microbiologic methods in the GEMS-1 case/control study. Clin Infect Dis. 2012;55 Suppl 4:S294–302. doi: 10.1093/cid/cis754. pmid:23169941
[41]
Elfving K, Andersson M, Msellem MI, Welinder-Olsson C, Petzold M, Bjorkman A, et al. Real-time PCR threshold cycle cutoffs help to identify agents causing acute childhood diarrhea in Zanzibar. J Clin Microbiol. 2014;52: 916–23. doi: 10.1128/JCM.02697-13. pmid:24403298
[42]
Bucardo F, Nordgren J, Carlsson B, Paniagua M, Lindgren PE, Espinoza F, et al. Pediatric norovirus diarrhea in Nicaragua. J Clin Microbiol. 2008;46: 2573–80. doi: 10.1128/JCM.00505-08. pmid:18562593
