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Kotloff K.L.,University of Maryland Baltimore County | Nataro J.P.,University of Maryland Baltimore County | Nataro J.P.,University of Virginia | Blackwelder W.C.,University of Maryland Baltimore County | And 43 more authors.
The Lancet | Year: 2013

Summary Background Diarrhoeal diseases cause illness and death among children younger than 5 years in low-income countries. We designed the Global Enteric Multicenter Study (GEMS) to identify the aetiology and population-based burden of paediatric diarrhoeal disease in sub-Saharan Africa and south Asia. Methods The GEMS is a 3-year, prospective, age-stratified, matched case-control study of moderate-to-severe diarrhoea in children aged 0-59 months residing in censused populations at four sites in Africa and three in Asia. We recruited children with moderate-to-severe diarrhoea seeking care at health centres along with one to three randomly selected matched community control children without diarrhoea. From patients with moderate-to-severe diarrhoea and controls, we obtained clinical and epidemiological data, anthropometric measurements, and a faecal sample to identify enteropathogens at enrolment; one follow-up home visit was made about 60 days later to ascertain vital status, clinical outcome, and interval growth. Findings We enrolled 9439 children with moderate-to-severe diarrhoea and 13â€̂129 control children without diarrhoea. By analysing adjusted population attributable fractions, most attributable cases of moderate-to-severe diarrhoea were due to four pathogens: rotavirus, Cryptosporidium, enterotoxigenic Escherichia coli producing heat-stable toxin (ST-ETEC; with or without co-expression of heat-labile enterotoxin), and Shigella. Other pathogens were important in selected sites (eg, Aeromonas, Vibrio cholerae O1, Campylobacter jejuni). Odds of dying during follow-up were 8·5-fold higher in patients with moderate-to-severe diarrhoea than in controls (odd ratio 8·5, 95% CI 5·8-12·5, p<0·0001); most deaths (167 [87·9%]) occurred during the first 2 years of life. Pathogens associated with increased risk of case death were ST-ETEC (hazard ratio [HR] 1·9; 0·99-3·5) and typical enteropathogenic E coli (HR 2·6; 1·6-4·1) in infants aged 0-11 months, and Cryptosporidium (HR 2·3; 1·3-4·3) in toddlers aged 12-23 months. Interpretation Interventions targeting five pathogens (rotavirus, Shigella, ST-ETEC, Cryptosporidium, typical enteropathogenic E coli) can substantially reduce the burden of moderate-to-severe diarrhoea. New methods and accelerated implementation of existing interventions (rotavirus vaccine and zinc) are needed to prevent disease and improve outcomes. Funding The Bill & Melinda Gates Foundation. © 2013 Elsevier Ltd.

PubMed | Centers for Disease Control and Prevention, Center for Immunization Research, University of Maryland Baltimore County, Boston University and 9 more.
Type: Journal Article | Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | Year: 2016

Few data exist describing pertussis epidemiology among infants and children in low- and middle-income countries to guide preventive strategies.Children 1-59 months of age hospitalized with World Health Organization-defined severe or very severe pneumonia in 7 African and Asian countries and similarly aged community controls were enrolled in the Pneumonia Etiology Research for Child Health study. They underwent a standardized clinical evaluation and provided nasopharyngeal and oropharyngeal swabs and induced sputum (cases only) for Bordetella pertussis polymerase chain reaction. Risk factors and pertussis-associated clinical findings were identified.Bordetella pertussis was detected in 53 of 4200 (1.3%) cases and 11 of 5196 (0.2%) controls. In the age stratum 1-5 months, 40 (2.3% of 1721) cases were positive, all from African sites, as were 8 (0.5% of 1617) controls. Pertussis-positive African cases 1-5 months old, compared to controls, were more often human immunodeficiency virus (HIV) uninfected-exposed (adjusted odds ratio [aOR], 2.2), unvaccinated (aOR, 3.7), underweight (aOR, 6.3), and too young to be immunized (aOR, 16.1) (all P .05). Compared with pertussis-negative African cases in this age group, pertussis-positive cases were younger, more likely to vomit (aOR, 2.6), to cough 14 days (aOR, 6.3), to have leukocyte counts >20 000 cells/L (aOR, 4.6), and to have lymphocyte counts >10 000 cells/L (aOR, 7.2) (all P .05). The case fatality ratio of pertussis-infected pneumonia cases 1-5 months of age was 12.5% (95% confidence interval, 4.2%-26.8%; 5/40); pertussis was identified in 3.7% of 137 in-hospital deaths among African cases in this age group.In the postneonatal period, pertussis causes a small fraction of hospitalized pneumonia cases and deaths; however, case fatality is substantial. The propensity to infect unvaccinated infants and those at risk for insufficient immunity (too young to be vaccinated, premature, HIV-infected/exposed) suggests that the role for maternal vaccination should be considered along with efforts to reduce exposure to risk factors and to optimize childhood pertussis vaccination coverage.

PubMed | Centers for Disease Control and Prevention, University of Barcelona, Indian National Institute of Cholera and Enteric Diseases, University of Maryland Baltimore County and 6 more.
Type: Journal Article | Journal: Lancet (London, England) | Year: 2016

Diarrhoea is the second leading cause of mortality in children worldwide, but establishing the cause can be complicated by diverse diagnostic approaches and varying test characteristics. We used quantitative molecular diagnostic methods to reassess causes of diarrhoea in the Global Enteric Multicenter Study (GEMS).GEMS was a study of moderate to severe diarrhoea in children younger than 5 years in Africa and Asia. We used quantitative real-time PCR (qPCR) to test for 32 enteropathogens in stool samples from cases and matched asymptomatic controls from GEMS, and compared pathogen-specific attributable incidences with those found with the original GEMS microbiological methods, including culture, EIA, and reverse-transcriptase PCR. We calculated revised pathogen-specific burdens of disease and assessed causes in individual children.We analysed 5304 sample pairs. For most pathogens, incidence was greater with qPCR than with the original methods, particularly for adenovirus 40/41 (around five times), Shigella spp or enteroinvasive Escherichia coli (EIEC) and Campylobactor jejuni o C coli (around two times), and heat-stable enterotoxin-producing E coli ([ST-ETEC] around 15 times). The six most attributable pathogens became, in descending order, Shigella spp, rotavirus, adenovirus 40/41, ST-ETEC, Cryptosporidium spp, and Campylobacter spp. Pathogen-attributable diarrhoeal burden was 893% (95% CI 832-960) at the population level, compared with 515% (480-550) in the original GEMS analysis. The top six pathogens accounted for 778% (746-809) of all attributable diarrhoea. With use of model-derived quantitative cutoffs to assess individual diarrhoeal cases, 2254 (425%) of 5304 cases had one diarrhoea-associated pathogen detected and 2063 (389%) had two or more, with Shigella spp and rotavirus being the pathogens most strongly associated with diarrhoea in children with mixed infections.A quantitative molecular diagnostic approach improved population-level and case-level characterisation of the causes of diarrhoea and indicated a high burden of disease associated with six pathogens, for which targeted treatment should be prioritised.Bill & Melinda Gates Foundation.

PubMed | University of the Republic of Uruguay, Public Health England, University of Liverpool, University of Würzburg and 14 more.
Type: Journal Article | Journal: Nature genetics | Year: 2016

An epidemiological paradox surrounds Salmonella enterica serovar Enteritidis. In high-income settings, it has been responsible for an epidemic of poultry-associated, self-limiting enterocolitis, whereas in sub-Saharan Africa it is a major cause of invasive nontyphoidal Salmonella disease, associated with high case fatality. By whole-genome sequence analysis of 675 isolates of S. Enteritidis from 45 countries, we show the existence of a global epidemic clade and two new clades of S. Enteritidis that are geographically restricted to distinct regions of Africa. The African isolates display genomic degradation, a novel prophage repertoire, and an expanded multidrug resistance plasmid. S. Enteritidis is a further example of a Salmonella serotype that displays niche plasticity, with distinct clades that enable it to become a prominent cause of gastroenteritis in association with the industrial production of eggs and of multidrug-resistant, bloodstream-invasive infection in Africa.

Sow S.O.,Center Pour le Developpement des Vaccins | Okoko B.J.,Medical Research Council Laboratories | Diallo A.,Institute Of Recherche Pour Le Developpement | Viviani S.,Voltaire | And 21 more authors.
New England Journal of Medicine | Year: 2011

Background: Group A meningococci are the source of major epidemics of meningitis in Africa. An affordable, highly immunogenic meningococcal A conjugate vaccine is needed. Methods: We conducted two studies in Africa to evaluate a new MenA conjugate vaccine (PsA-TT). In study A, 601 children, 12 to 23 months of age, were randomly assigned to receive PsA-TT, a quadrivalent polysaccharide reference vaccine (PsACWY), or a control vaccine (Haemophilus influenzae type b conjugate vaccine [Hib-TT]). Ten months later, these children underwent another round of randomization within each group to receive a full dose of PsA-TT, a one-fifth dose of PsACWY, or a full dose of Hib-TT, with 589 of the original participants receiving a booster dose. In study B, 900 subjects between 2 and 29 years of age were randomly assigned to receive PsA-TT or PsACWY. Safety and reactogenicity were evaluated, and immunogenicity was assessed by measuring the activity of group A serum bactericidal antibody (SBA) with rabbit complement and performing an IgG group A - specific enzyme-linked immunosorbent assay. Results: In study A, 96.0% of the subjects in the PsA-TT group and 63.7% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline; in study B, 78.2% of the subjects in the PsA-TT group and 46.2% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline. The geometric mean SBA titers in the PsA-TT groups in studies A and B were greater by factors of 16 and 3, respectively, than they were in the PsACWY groups (P<0.001). In study A, the PsA-TT group had higher antibody titers at week 40 than the PsACWY group and had obvious immunologic memory after receiving a polysaccharide booster vaccine. Safety profiles were similar across vaccine groups, although PsA-TT recipients were more likely than PsACWY recipients to have tenderness and induration at the vaccination site. Adverse events were consistent with age-specific morbidity in the study areas; no serious vaccine-related adverse events were reported. Conclusions: The PsA-TT vaccine elicited a stronger response to group A antibody than the PsACWY vaccine. (Funded by the Meningitis Vaccine Project through a grant from the Bill and Melinda Gates Foundation; Controlled-Trials.com numbers, ISRCTN78147026 and ISRCTN87739946.) Copyright © 2011 Massachusetts Medical Society.

Breiman R.F.,Centers for Disease Control and Prevention | Zaman K.,International Center for Diarrheal Disease Research | Armah G.,University of Ghana | Sow S.O.,Center pour le Developpement des Vaccins | And 7 more authors.
Vaccine | Year: 2012

Background: Efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq®, against severe rotavirus gastroenteritis (RVGE) was evaluated in two double-blind, placebo-controlled, multicenter Phase III clinical trials conducted in GAVI-eligible countries in Africa (Ghana, Kenya, and Mali) and in Asia (Bangladesh and Vietnam) from March 2007 through March 2009. The findings from each continent have been analyzed and presented separately, according to a single identical protocol. Ad hoc analyses combining data from the five sites were performed to further assess the impact of PRV. Methods: 6674 infants (4705 infants from Africa and 1969 infants from Asia), randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6-, 10-, and 14-weeks of age according to each country's EPI schedule, were included in the per protocol efficacy analysis. Breastfeeding and concomitant administration of EPI vaccines, including OPV, were allowed. Episodes of gastroenteritis (GE) in infants who presented to study facilities were captured and scored using the 20-point Vesikari scale. Stool samples were analyzed by rotavirus-specific EIA to detect presence of rotavirus antigen and RT-PCR to determine the G/P genotypes. We assessed efficacy to prevent all-cause GE and RVGE at a variety of cut-off points (score ≥ 11, severe; score ≥ 15, very severe). Results: Vaccine efficacy (VE) against RVGE, regardless of serotype, through the entire follow-up period for any severity, severe (score ≥ 11), and very severe (score ≥ 15) was 33.9%, 95% CI (22.7, 43.5), 42.5%, 95% CI (27.4, 54.6), and 51.2%, 95% CI (26.3, 68.2), respectively. Through the first year of life, VE against severe RVGE was 58.9%, 95% CI (40.0, 72.3) and against all-cause severe GE was 23.0%, 95% CI (5.4, 37.3). VE against severe RVGE caused by non-vaccine G serotypes, G8 and G9, through the entire follow-up period was 87.5%, 95% CI (6.8, 99.7) and 48.0%, 95% CI (-5.5, 75.6), respectively. All G8 strains were associated with P2A[6] (a P-type not contained in PRV), while the majority of the G9 strains were associated with P1A[8] (a P-type contained in PRV). Conclusions: Combining data from the 5 sites strengthens the precision of VE estimates and reveals rising VE with increased RVGE severity. Extrapolating data from VE against severe GE and RVGE suggest that 39% of severe GE episodes during the first year of life were due to rotavirus, highlighting substantial, potentially preventable, public health burden of RVGE. PRV provides protection against non-vaccine serotypes (G8P2A[6]). © 2011.

Armah G.E.,University of Ghana | Breiman R.F.,Centers for Disease Control and Prevention | Tapia M.D.,Center pour le Developpement des Vaccins | Tapia M.D.,University of Maryland College Park | And 10 more authors.
Vaccine | Year: 2012

We recently completed a double-blind, placebo-controlled, multicenter Phase III clinical trial of the pentavalent rotavirus vaccine (PRV) in three African countries, Ghana, Kenya, and Mali, from April 2007 to March 2009. The immunogenicity of PRV in African infants is described. In total, 5468 infants were randomized 1:1 to receive 3 doses of PRV or placebo at approximately 6, 10, and 14 weeks of age. Breastfeeding and concomitant administration of EPI vaccines, including OPV, were allowed, and HIV-infected infants were not excluded. Immunogenicity of PRV was assessed by measuring serum anti-rotavirus IgA responses, as well as serum neutralization antibody (SNA) to the human rotavirus serotypes G1, G2, G3, G4 and P1A[8] in approximately 150 infants per country. Sera were collected pre-dose 1 (pD1) and approximately 14 days post-dose 3 (PD3) for immunological analysis. For the sero-response rates (≥3-fold rise from pD1 to PD3), the number of subjects evaluable included those with both pD1 and PD3 data available. PRV was immunogenic in African children and significantly reduced severe RVGE in African children through the first two years of life. The pooled anti-rotavirus IgA sero-response rate was 78.3%, with consistent rates in each of the African sites: 73.8% (Kenya), 78.9% (Ghana), and 82.5% (Mali); but generally lower than that reported in Europe and USA. PD3 GMTs (28.2 dilution-units) were 5-10 times lower than those assessed in subjects in clinical trials in developed countries. SNA responses to human rotavirus serotypes G1-G4 and P1A[8] ranged from 6.3% (G3) to 26.5% (G4). PD3 SNA GMTs to G1 and P1A[8] were 4-fold and 3-fold lower respectively, when compared to the corresponding GMTs in subjects who received PRV in similar studies conducted in developed countries. PRV was immunogenic in African infants, and the anti-rotavirus IgA sero-response rates were similar across all three African sites although lower than those observed in Europe and USA. While immune correlates of protection have not been established for rotavirus, the findings are consistent with lower efficacy rates demonstrated during this trial. Further investigation is needed to understand the reason for the lower immunogenicity observed. © 2012.

PubMed | Centers for Disease Control and Prevention, University of Barcelona, Indian National Institute of Cholera and Enteric Diseases, University of Maryland Baltimore County and 5 more.
Type: Journal Article | Journal: PLoS medicine | Year: 2016

Diarrheal disease is the second leading cause of disease in children less than 5 y of age. Poor water, sanitation, and hygiene conditions are the primary routes of exposure and infection. Sanitation and hygiene interventions are estimated to generate a 36% and 48% reduction in diarrheal risk in young children, respectively. Little is known about whether the number of households sharing a sanitation facility affects a childs risk of diarrhea. The objective of this study was to describe sanitation and hygiene access across the Global Enteric Multicenter Study (GEMS) sites in Africa and South Asia and to assess sanitation and hygiene exposures, including shared sanitation access, as risk factors for moderate-to-severe diarrhea (MSD) in children less than 5 y of age.The GEMS matched case-control study was conducted between December 1, 2007, and March 3, 2011, at seven sites in Basse, The Gambia; Nyanza Province, Kenya; Bamako, Mali; Manhia, Mozambique; Mirzapur, Bangladesh; Kolkata, India; and Karachi, Pakistan. Data was collected for 8,592 case children aged <5 y old experiencing MSD and for 12,390 asymptomatic age, gender, and neighborhood-matched controls. An MSD case was defined as a child with a diarrheal illness <7 d duration comprising 3 loose stools in 24 h and 1 of the following: sunken eyes, skin tenting, dysentery, intravenous (IV) rehydration, or hospitalization. Site-specific conditional logistic regression models were used to explore the association between sanitation and hygiene exposures and MSD. Most households at six sites (>93%) had access to a sanitation facility, while 70% of households in rural Kenya had access to a facility. Practicing open defecation was a risk factor for MSD in children <5 y old in Kenya. Sharing sanitation facilities with 1-2 or 3 other households was a statistically significant risk factor for MSD in Kenya, Mali, Mozambique, and Pakistan. Among those with a designated handwashing area near the home, soap or ash were more frequently observed at control households and were significantly protective against MSD in Mozambique and India.This study suggests that sharing a sanitation facility with just one to two other households can increase the risk of MSD in young children, compared to using a private facility. Interventions aimed at increasing access to private household sanitation facilities may reduce the burden of MSD in children. These findings support the current World Health Organization/ United Nations Childrens Emergency Fund (UNICEF) system that categorizes shared sanitation as unimproved.

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