Last data update: Jun 24, 2024. (Total: 47078 publications since 2009)
Records 1-23 (of 23 Records) |
Query Trace: Houpt ER [original query] |
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Etiology of diarrheal hospitalizations following rotavirus vaccine implementation and association of enteric pathogens with malnutrition among under-five children in India
Varghese T , Mills JAP , Revathi R , Antoni S , Soeters HM , Emmanuel Njambe TO , Houpt ER , Tate JE , Parashar UD , Kang G . Gut Pathog 2024 16 (1) 22 Malnourished children are at higher risk of mortality and morbidity following diarrheal illness and certain enteropathogens have been associated with malnutrition in children. Very few studies have comprehensively looked at the etiology of diarrhea in malnourished children and most have used conventional diagnostic methods with suboptimal sensitivity. We used a highly sensitive molecular approach against a broad range of pathogens causing diarrhea and examined their association with malnutrition. In addition, we looked at the pathogen diversity of pediatric diarrhea, three years after the nationwide rotavirus vaccine introduction to understand the evolving landscape of pathogens, which is crucial for planning strategies to further reduce the diarrhea burden. Clinical details and diarrheal stool samples were collected from hospitalized children aged < 5 years from three sentinel sites in India for a period of one year. The samples were tested by qPCR for 16 established causes of diarrhea using TaqMan Array Cards. A total of 772 children were enrolled, from whom 482 (62.4%) stool specimens were tested. No specific pathogen was associated with diarrhea among children with acute or chronic malnutrition compared to those with better nutritional status. Overall, adenovirus was the leading pathogen (attributable fraction (AF) 16.9%; 95% CI 14.1 to 19.2) followed by rotavirus (AF 12.6%; 95% CI 11.8 to 13.1) and Shigella (AF 10.9%; 95% CI 8.4 to 16.4). The majority of diarrhea requiring hospitalization in children aged < 2 years could be attributed to viruses, while Shigella was the most common pathogen among children aged > 2 years. These data on the prevalence and epidemiology of enteropathogens identified potential pathogens for public health interventions. |
Etiology of acute febrile illness in the peruvian amazon as determined by modular formatted quantitative PCR: a protocol for RIVERA, a health facility-based case-control study.
Peñataro Yori P , Paredes Olórtegui M , Schiaffino F , Colston JM , Pinedo Vasquez T , Garcia Bardales PF , Shapiama Lopez V , Zegarra Paredes LF , Perez K , Curico G , Flynn T , Zhang J , Ramal Asayag C , Meza Sanchez G , Silva Delgado H , Casapia Morales M , Casanova W , Jiu B , Oberhelman R , Munayco Escate C , Silver R , Henao O , Cooper KK , Liu J , Houpt ER , Kosek MN . BMC Public Health 2023 23 (1) 674 ![]() ![]() BACKGROUND: The study of the etiology of acute febrile illness (AFI) has historically been designed as a prevalence of pathogens detected from a case series. This strategy has an inherent unrealistic assumption that all pathogen detection allows for causal attribution, despite known asymptomatic carriage of the principal causes of acute febrile illness in most low- and middle-income countries (LMICs). We designed a semi-quantitative PCR in a modular format to detect bloodborne agents of acute febrile illness that encompassed common etiologies of AFI in the region, etiologies of recent epidemics, etiologies that require an immediate public health response and additional pathogens of unknown endemicity. We then designed a study that would delineate background levels of transmission in the community in the absence of symptoms to provide corrected estimates of attribution for the principal determinants of AFI. METHODS: A case-control study of acute febrile illness in patients ten years or older seeking health care in Iquitos, Loreto, Peru, was planned. Upon enrollment, we will obtain blood, saliva, and mid-turbinate nasal swabs at enrollment with a follow-up visit on day 21-28 following enrollment to attain vital status and convalescent saliva and blood samples, as well as a questionnaire including clinical, socio-demographic, occupational, travel, and animal contact information for each participant. Whole blood samples are to be simultaneously tested for 32 pathogens using TaqMan array cards. Mid-turbinate samples will be tested for SARS-CoV-2, Influenza A and Influenza B. Conditional logistic regression models will be fitted treating case/control status as the outcome and with pathogen-specific sample positivity as predictors to attain estimates of attributable pathogen fractions for AFI. DISCUSSION: The modular PCR platforms will allow for reporting of all primary results of respiratory samples within 72 h and blood samples within one week, allowing for results to influence local medical practice and enable timely public health responses. The inclusion of controls will allow for a more accurate estimate of the importance of specific prevalent pathogens as a cause of acute illness. STUDY REGISTRATION: Project 1791, Registro de Proyectos de Investigación en Salud Pública (PRISA), Instituto Nacional de Salud, Perú. |
Antibiotic-prescribing practices for management of childhood diarrhea in 3 Sub-Saharan African countries: Findings from the vaccine impact on diarrhea in Africa (vida) study, 2015-2018
Awuor AO , Ogwel B , Powell H , Verani JR , Sow SO , Hossain MJ , Ochieng JB , Juma J , Jamka LP , Roose A , Doh S , Deichsel EL , Onwuchekwa U , Keita AM , Antonio M , Jones JCM , Zaman SMA , Badji H , Kasumba IN , Nasrin D , Platts-Mills JA , Houpt ER , Berendes DM , Sugerman CE , Widdowson MA , Tennant SM , Mintz ED , Omore R , Kotloff KL . Clin Infect Dis 2023 76 S32-s40 BACKGROUND: Despite antibiotic prescription being recommended for dysentery and suspected cholera only, diarrhea still triggers unwarranted antibiotic prescription. We evaluated antibiotic-prescribing practices and their predictors among children aged 2-59 months in the Vaccine Impact on Diarrhea in Africa (VIDA) Study performed in The Gambia, Mali, and Kenya. METHODS: VIDA was a prospective case-control study (May 2015-July 2018) among children presenting for care with moderate-to-severe diarrhea (MSD). We defined inappropriate antibiotic use as prescription or use of antibiotics when not indicated by World Health Organization (WHO) guidelines. We used logistic regression to assess factors associated with antibiotic prescription for MSD cases who had no indication for an antibiotic, at each site. RESULTS: VIDA enrolled 4840 cases. Among 1757 (36.3%) who had no apparent indication for antibiotic treatment, 1358 (77.3%) were prescribed antibiotics. In The Gambia, children who presented with a cough (adjusted odds ratio [aOR]: 2.05; 95% confidence interval [95% CI]: 1.21-3.48) were more likely to be prescribed an antibiotic. In Mali, those who presented with dry mouth (aOR: 3.16; 95% CI: 1.02-9.73) were more likely to be prescribed antibiotics. In Kenya, those who presented with a cough (aOR: 2.18; 95% CI: 1.01-4.70), decreased skin turgor (aOR: 2.06; 95% CI: 1.02-4.16), and were very thirsty (aOR: 4.15; 95% CI: 1.78-9.68) were more likely to be prescribed antibiotics. CONCLUSIONS: Antibiotic prescription was associated with signs and symptoms inconsistent with WHO guidelines, suggesting the need for antibiotic stewardship and clinician awareness of diarrhea case-management recommendations in these settings. |
Exploring survey-based water, sanitation, and animal associations with enteric pathogen carriage: Comparing results in a cohort of cases with moderate-to-severe diarrhea to those in controls in the Vaccine Impact on Diarrhea in Africa (VIDA) Study, 2015-2018
Berendes DM , Omore R , Prentice-Mott G , Fagerli K , Kim S , Nasrin D , Powell H , Jahangir Hossain M , Sow SO , Doh S , Jones JCM , Ochieng JB , Juma J , Awuor AO , Ogwel B , Verani JR , Widdowson MA , Kasumba IN , Tennant SM , Roose A , Zaman SMA , Liu J , Sugerman CE , Platts-Mills JA , Houpt ER , Kotloff KL , Mintz ED . Clin Infect Dis 2023 76 S140-s152 BACKGROUND: The magnitude of pediatric enteric pathogen exposures in low-income settings necessitates substantive water and sanitation interventions, including animal feces management. We assessed associations between pediatric enteric pathogen detection and survey-based water, sanitation, and animal characteristics within the Vaccine Impact on Diarrhea in Africa case-control study. METHODS: In The Gambia, Kenya, and Mali, we assessed enteric pathogens in stool of children aged <5 years with moderate-to-severe diarrhea and their matched controls (diarrhea-free in prior 7 days) via the TaqMan Array Card and surveyed caregivers about household drinking water and sanitation conditions and animals living in the compound. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using modified Poisson regression models, stratified for cases and controls and adjusted for age, sex, site, and demographics. RESULTS: Bacterial (cases, 93%; controls, 72%), viral (63%, 56%), and protozoal (50%, 38%) pathogens were commonly detected (cycle threshold <35) in the 4840 cases and 6213 controls. In cases, unimproved sanitation (RR, 1.56; 95% CI, 1.12-2.17), as well as cows (RR, 1.61; 95% CI, 1.16-2.24) and sheep (RR, 1.48; 95% CI, 1.11-1.96) living in the compound, were associated with Shiga toxin-producing Escherichia coli. In controls, fowl (RR, 1.30; 95% CI, 1.15-1.47) were associated with Campylobacter spp. In controls, surface water sources were associated with Cryptosporidium spp., Shigella spp., heat-stable toxin-producing enterotoxigenic E. coli, and Giardia spp. CONCLUSIONS: Findings underscore the importance of enteric pathogen exposure risks from animals alongside more broadly recognized water and sanitation risk factors in children. |
Clinical and epidemiologic features of cryptosporidium-associated diarrheal disease among young children living in Sub-Saharan Africa: The Vaccine Impact on Diarrhea in Africa (VIDA) Study
Hossain MJ , Powell H , Sow SO , Omore R , Roose A , Jones JCM , Zaman SMA , Badji H , Sarwar G , Kasumba IN , Onwuchekwa U , Doh S , Awuor AO , Ochieng JB , Verani JR , Liu J , Tennant SM , Nasrin D , Jamka LP , Liang Y , Howie SRC , Antonio M , Houpt ER , Kotloff KL . Clin Infect Dis 2023 76 S97-s105 ![]() BACKGROUND: As part of the Vaccine Impact on Diarrhea in Africa (VIDA) Study, we examined the prevalence, clinical presentation, and seasonality of Cryptosporidium in children to understand its relative burden after the introduction of rotavirus vaccine. METHODS: VIDA was a 3-year, age-stratified, matched case-control study of medically attended acute moderate-to-severe diarrhea (MSD) in children aged 0-59 months residing in censused populations at sites in Kenya, Mali, and The Gambia. Clinical and epidemiologic data were collected at enrollment, and a stool sample was tested for enteropathogens by quantitative PCR. An algorithm was created based on the organism's cycle threshold (Ct) and association with MSD to identify the subset of Cryptosporidium PCR-positive (Ct <35) cases most likely to be attributed to MSD. Clinical outcomes were assessed at 2-3 months after enrollment. RESULTS: One thousand one hundred six (22.9%) cases of MSD and 873 controls (18.1%) were PCR positive for Cryptosporidium; 465 cases (42.0%) were considered attributable to Cryptosporidium, mostly among children 6-23 months. Cryptosporidium infections peaked in The Gambia and Mali during the rainy season, while in Kenya they did not have clear seasonality. Compared with cases with watery MSD who had a negative PCR for Cryptosporidium, cases with watery MSD attributed to Cryptosporidium were less frequently dehydrated but appeared more severely ill using a modified Vesikari scale (38.1% vs 27.0%; P < 0.001), likely due to higher rates of hospitalization and intravenous fluid administration, higher prevalence of being wasted or very thin very thin (23.4% vs 14.7%; P < 0.001), and having severe acute malnutrition (midupper arm circumference <115 mm, 7.7% vs 2.5%; P < 0.001). On follow-up, Cryptosporidium-attributed cases had more prolonged and persistent episodes (43.2% vs 32.7%; P <0 .001) and linear growth faltering (change in height-for-age z score between enrollment and follow-up: -0.29 vs -0.17; P < 0.001). CONCLUSIONS: The burden of Cryptosporidium remains high among young children in sub-Saharan Africa. Its propensity to cause illness and further impact children longer term by compromising nutritional status early in life calls for special attention to enable appropriate management of clinical and nutritional consequences. |
Prevalence, clinical severity, and seasonality of adenovirus 40/41, astrovirus, sapovirus, and rotavirus among young children with moderate-to-severe diarrhea: Results from the Vaccine Impact on Diarrhea in Africa (VIDA) Study
Keita AM , Doh S , Sow SO , Powell H , Omore R , Jahangir Hossain M , Ogwel B , Ochieng JB , Jones JCM , Zaman SMA , Awuor AO , Juma J , Nasrin D , Liu J , Traoré A , Onwuchekwa U , Badji H , Sarwar G , Antonio M , Houpt ER , Tennant SM , Kasumba IN , Jamka LP , Roose A , Platts-Mills JA , Verani JR , Tate JE , Parashar UD , Neuzil KM , Kotloff KL . Clin Infect Dis 2023 76 S123-s131 ![]() BACKGROUND: While rotavirus causes severe diarrheal disease in children aged <5 years, data on other viral causes in sub-Saharan Africa are limited. METHODS: In the Vaccine Impact on Diarrhea in Africa study (2015-2018), we analyzed stool from children aged 0-59 months with moderate-to-severe diarrhea (MSD) and without diarrhea (controls) in Kenya, Mali, and The Gambia using quantitative polymerase chain reaction. We derived the attributable fraction (AFe) based on the association between MSD and the pathogen, accounting for other pathogens, site, and age. A pathogen was attributable if the AFe was ≥0.5.The severity of attributable MSD was defined by a modified Vesikari score (mVS). Monthly cases were plotted against temperature and rainfall to assess seasonality. RESULTS: Among 4840 MSD cases, proportions attributed to rotavirus, adenovirus 40/41, astrovirus, and sapovirus were 12.6%, 2.7%, 2.9%, and 1.9%, respectively. Attributable rotavirus, adenovirus 40/41, and astrovirus MSD cases occurred at all sites, with mVS of 11, 10, and 7, respectively. MSD cases attributable to sapovirus occurred in Kenya, with mVS of 9. Astrovirus and adenovirus 40/41 peaked during the rainy season in The Gambia, while rotavirus peaked during the dry season in Mali and The Gambia. CONCLUSIONS: In sub-Saharan Africa, rotavirus was the most common cause of MSD; adenovirus 40/41, astrovirus, and sapovirus contributed to a lesser extent among children aged <5 years. Rotavirus- and adenovirus 40/41-attributable MSD were most severe. Seasonality varied by pathogen and location. Efforts to increase the coverage of rotavirus vaccines and to improve prevention and treatment for childhood diarrhea should continue. |
Giardia detection and codetection with other enteric pathogens in young children in the Vaccine Impact on Diarrhea in Africa (VIDA) Case-Control Study: 2015-2018
Marcenac P , Traoré A , Kim S , Prentice-Mott G , Berendes DM , Powell H , Kasumba IN , Nasrin D , Jones JCM , Zaman SMA , Ochieng JB , Juma J , Sanogo D , Widdowson MA , Verani JR , Liu J , Houpt ER , Jahangir Hossain M , Sow SO , Omore R , Tennant SM , Mintz ED , Kotloff KL . Clin Infect Dis 2023 76 S106-s113 BACKGROUND: Giardia has been associated with reduced risk of diarrhea in children in low-resource settings, but the mechanism underlying this association is unknown. To assess whether Giardia may shape colonization or infection with other enteric pathogens and impact associations with diarrhea, we examined Giardia and enteric pathogen codetection among children <5 years old in Kenya, The Gambia, and Mali as part of the Vaccine Impact on Diarrhea in Africa study. METHODS: We tested for Giardia and other enteric pathogens using enzyme-linked immunosorbent assays and real-time polymerase chain reaction (PCR) on stool, respectively. We evaluated associations between Giardia and enteric pathogen detection using multivariable logistic regression models separately for children with moderate-to-severe diarrhea (MSD, cases) and free of diarrhea (controls). RESULTS: Among 11 039 enrolled children, Giardia detection was more common among controls (35%) than cases (28%, P < .001). Campylobacter coli/jejuni detection was associated with Giardia in controls in The Gambia (adjusted odds ratio [aOR] [95% confidence interval {CI}]: 1.51 [1.22‒1.86]) and cases across all sites (1.16 [1.00‒1.33]). Among controls, the odds of astrovirus (1.43 [1.05‒1.93]) and Cryptosporidium spp. (1.24 [1.06‒1.46]) detection were higher among children with Giardia. Among cases, the odds of rotavirus detection were lower in children with Giardia in Mali (.45 [.30‒.66]) and Kenya (.31 [.17‒.56]). CONCLUSIONS: Giardia was prevalent in children <5 years old and was associated with detection of other enteric pathogens, with differing associations in cases versus controls and by site. Giardia may affect colonization or infection by certain enteric pathogens associated with MSD, suggesting an indirect mechanism of clinical impact. |
Epidemiology of enteroaggregative, enteropathogenic, and shiga toxin-producing escherichia coli among children aged <5 years in 3 countries in Africa, 2015-2018: Vaccine Impact on Diarrhea in Africa (VIDA) Study
Ochieng JB , Powell H , Sugerman CE , Omore R , Ogwel B , Juma J , Awuor AO , Sow SO , Sanogo D , Onwuchekwa U , Keita AM , Traoré A , Badji H , Hossain MJ , Jones JCM , Kasumba IN , Nasrin D , Roose A , Liang Y , Jamka LP , Antonio M , Platts-Mills JA , Liu J , Houpt ER , Mintz ED , Hunsperger E , Onyango CO , Strockbine N , Widdowson MA , Verani JR , Tennant SM , Kotloff KL . Clin Infect Dis 2023 76 S77-s86 ![]() BACKGROUND: To address knowledge gaps regarding diarrheagenic Escherichia coli (DEC) in Africa, we assessed the clinical and epidemiological features of enteroaggregative E. coli (EAEC), enteropathogenic E. coli (EPEC), and Shiga toxin-producing E. coli (STEC) positive children with moderate-to-severe diarrhea (MSD) in Mali, The Gambia, and Kenya. METHODS: Between May 2015 and July 2018, children aged 0-59 months with medically attended MSD and matched controls without diarrhea were enrolled. Stools were tested conventionally using culture and multiplex polymerase chain reaction (PCR), and by quantitative PCR (qPCR). We assessed DEC detection by site, age, clinical characteristics, and enteric coinfection. RESULTS: Among 4840 children with MSD and 6213 matched controls enrolled, 4836 cases and 1 control per case were tested using qPCR. Of the DEC detected with TAC, 61.1% were EAEC, 25.3% atypical EPEC (aEPEC), 22.4% typical EPEC (tEPEC), and 7.2% STEC. Detection was higher in controls than in MSD cases for EAEC (63.9% vs 58.3%, P < .01), aEPEC (27.3% vs 23.3%, P < .01), and STEC (9.3% vs 5.1%, P < .01). EAEC and tEPEC were more frequent in children aged <23 months, aEPEC was similar across age strata, and STEC increased with age. No association between nutritional status at follow-up and DEC pathotypes was found. DEC coinfection with Shigella/enteroinvasive E. coli was more common among cases (P < .01). CONCLUSIONS: No significant association was detected between EAEC, tEPEC, aEPEC, or STEC and MSD using either conventional assay or TAC. Genomic analysis may provide a better definition of the virulence factors associated with diarrheal disease. |
Norovirus disease among children <5 years in 3 Sub-Saharan African countries: Findings from the Vaccine Impact on Diarrhea in Africa (VIDA) Study, 2015-2018
Omore R , Powell H , Sow SO , Jahangir Hossain M , Ogwel B , Doh S , Ochieng JB , Jones JCM , Zaman SMA , Awuor AO , Juma J , Kasumba IN , Roose A , Jamka LP , Nasrin D , Liu J , Keita AM , Traoré A , Onwuchekwa U , Badji H , Sarwar G , Antonio M , Sugerman CE , Mintz ED , Houpt ER , Verani JR , Widdowson MA , Tennant SM , Platts-Mills JA , Tate JE , Parashar UD , Kotloff KL . Clin Infect Dis 2023 76 S114-s122 ![]() BACKGROUND: To address a paucity of data from sub-Saharan Africa, we examined the prevalence, severity, and seasonality of norovirus genogroup II (NVII) among children <5 years old in The Gambia, Kenya, and Mali following rotavirus vaccine introduction. METHODS: Population-based surveillance was conducted to capture medically-attended moderate-to-severe diarrhea (MSD) cases, defined as a child 0-59 months old passing ≥3 loose stools in a 24-hour period with ≥1 of the following: sunken eyes, poor skin turgor, dysentery, intravenous rehydration, or hospitalization within 7 days of diarrhea onset. Diarrhea-free matched controls randomly selected from a censused population were enrolled at home. Stools from cases and controls were tested for enteropathogens, including norovirus and rotavirus, by TaqMan quantitative polymerase chain reaction (PCR) and conventional reverse transcription PCR. We used multiple logistic regression to derive adjusted attributable fractions (AFe) for each pathogen causing MSD, which takes into consideration the prevalence in both cases and controls, for each site and age. A pathogen was considered etiologic if AFe was ≥0.5. In further analyses focusing on the predominant NVII strains, we compared rotavirus and NVII severity using a 20-point modified Vesikari score and examined seasonal fluctuations. RESULTS: From May 2015 to July 2018, we enrolled 4840 MSD cases and 6213 controls. NVI was attributed to only 1 MSD episode. NVII was attributed to 185 (3.8%) of all MSD episodes and was the sole attributable pathogen in 139 (2.9%); peaking (36.0%) at age 6-8 months with majority (61.2%) aged 6-11 months. MSD cases whose episodes were attributed to NVII alone compared with rotavirus alone were younger (median age, 8 vs 12 months, P < .0001) and had less severe illness (median Vesikari severity score, 9 vs 11, P = .0003) but equally likely to be dehydrated. NVII occurred year-round at all study sites. CONCLUSIONS: Infants aged 6-11 months bear the greatest burden of norovirus disease, with NVII predominating. An early infant vaccine schedule and rigorous adherence to guidelines recommended for management of dehydrating diarrhea may offer substantial benefit in these African settings. |
Aetiology and incidence of diarrhoea requiring hospitalisation in children under 5 years of age in 28 low-income and middle-income countries: findings from the Global Pediatric Diarrhea Surveillance network
Cohen AL , Platts-Mills JA , Nakamura T , Operario DJ , Antoni S , Mwenda JM , Weldegebriel G , Rey-Benito G , deOliveira LH , Ortiz C , Daniels DS , Videbaek D , Singh S , Njambe E , Sharifuzzaman M , Grabovac V , Nyambat B , Logronio J , Armah G , Dennis FE , Seheri ML , Magagula N , Mphahlele J , Fumian TM , Maciel ITA , GagliardiLeite JP , Esona MD , Bowen MD , Samoilovich E , Semeiko G , Abraham D , Giri S , Praharaj I , Kang G , Thomas S , Bines J , Liu N , Kyu HH , Doxey M , RogawskiMcQuade ET , McMurry TL , Liu J , Houpt ER , Tate JE , Parashar UD , Serhan F . BMJ Glob Health 2022 7 (9) INTRODUCTION: Diarrhoea remains a leading cause of child morbidity and mortality. Systematically collected and analysed data on the aetiology of hospitalised diarrhoea in low-income and middle-income countries are needed to prioritise interventions. METHODS: We established the Global Pediatric Diarrhea Surveillance network, in which children under 5 years hospitalised with diarrhoea were enrolled at 33 sentinel surveillance hospitals in 28 low-income and middle-income countries. Randomly selected stool specimens were tested by quantitative PCR for 16 causes of diarrhoea. We estimated pathogen-specific attributable burdens of diarrhoeal hospitalisations and deaths. We incorporated country-level incidence to estimate the number of pathogen-specific deaths on a global scale. RESULTS: During 2017-2018, 29 502 diarrhoea hospitalisations were enrolled, of which 5465 were randomly selected and tested. Rotavirus was the leading cause of diarrhoea requiring hospitalisation (attributable fraction (AF) 33.3%; 95% CI 27.7 to 40.3), followed by Shigella (9.7%; 95% CI 7.7 to 11.6), norovirus (6.5%; 95% CI 5.4 to 7.6) and adenovirus 40/41 (5.5%; 95% CI 4.4 to 6.7). Rotavirus was the leading cause of hospitalised diarrhoea in all regions except the Americas, where the leading aetiologies were Shigella (19.2%; 95% CI 11.4 to 28.1) and norovirus (22.2%; 95% CI 17.5 to 27.9) in Central and South America, respectively. The proportion of hospitalisations attributable to rotavirus was approximately 50% lower in sites that had introduced rotavirus vaccine (AF 20.8%; 95% CI 18.0 to 24.1) compared with sites that had not (42.1%; 95% CI 33.2 to 53.4). Globally, we estimated 208 009 annual rotavirus-attributable deaths (95% CI 169 561 to 259 216), 62 853 Shigella-attributable deaths (95% CI 48 656 to 78 805), 36 922 adenovirus 40/41-attributable deaths (95% CI 28 469 to 46 672) and 35 914 norovirus-attributable deaths (95% CI 27 258 to 46 516). CONCLUSIONS: Despite the substantial impact of rotavirus vaccine introduction, rotavirus remained the leading cause of paediatric diarrhoea hospitalisations. Improving the efficacy and coverage of rotavirus vaccination and prioritising interventions against Shigella, norovirus and adenovirus could further reduce diarrhoea morbidity and mortality. |
The Clinical Presentation of Culture-positive and Culture-negative, Quantitative Polymerase Chain Reaction (qPCR)-Attributable Shigellosis in the Global Enteric Multicenter Study and Derivation of a Shigella Severity Score: Implications for Pediatric Shigella Vaccine Trials.
Pavlinac PB , Platts-Mills JA , Tickell KD , Liu J , Juma J , Kabir F , Nkeze J , Okoi C , Operario DJ , Uddin MJ , Ahmed S , Alonso PL , Antonio M , Becker SM , Breiman RF , Faruque ASG , Fields B , Gratz J , Haque R , Hossain A , Hossain MJ , Jarju S , Qamar F , Iqbal NT , Kwambana B , Mandomando I , McMurry TL , Ochieng C , Ochieng JB , Ochieng M , Onyango C , Panchalingam S , Kalam A , Aziz F , Qureshi S , Ramamurthy T , Roberts JH , Saha D , Sow SO , Stroup SE , Sur D , Tamboura B , Taniuchi M , Tennant SM , Roose A , Toema D , Wu Y , Zaidi A , Nataro JP , Levine MM , Houpt ER , Kotloff KL . Clin Infect Dis 2020 73 (3) e569-e579 ![]() BACKGROUND: Shigella is a leading cause of childhood diarrhea and target for vaccine development. Microbiologic and clinical case definitions are needed for pediatric field vaccine efficacy trials. METHODS: We compared characteristics of moderate to severe diarrhea (MSD) cases in the Global Enteric Multicenter Study (GEMS) between children with culture positive Shigella to those with culture-negative, qPCR-attributable Shigella (defined by an ipaH gene cycle threshold <27.9). Among Shigella MSD cases, we determined risk factors for death and derived a clinical severity score. RESULTS: Compared to culture-positive Shigella MSD cases (n=745), culture-negative/qPCR-attributable Shigella cases (n=852) were more likely to be under 12 months, stunted, have a longer duration of diarrhea, and less likely to have high stool frequency or a fever. There was no difference in dehydration, hospitalization, or severe classification from a modified Vesikari score. Twenty-two (1.8%) Shigella MSD cases died within the 14-days after presentation to health facilities, and 59.1% of these deaths were in culture-negative cases. Age < 12 months, diarrhea duration prior to presentation, vomiting, stunting, wasting, and hospitalization were associated with mortality. A model-derived score assigned points for dehydration, hospital admission, and longer diarrhea duration but was not significantly better at predicting 14-day mortality than a modified Vesikari score. CONCLUSIONS: A composite severity score consistent with severe disease or dysentery may be a pragmatic clinical endpoint for severe shigellosis in vaccine trials. Reliance on culture for microbiologic confirmation may miss a substantial number of Shigella cases but is currently required to measure serotype specific immunity. |
Diarrhoeal disease and subsequent risk of death in infants and children residing in low-income and middle-income countries: analysis of the GEMS case-control study and 12-month GEMS-1A follow-on study
Levine MM , Nasrin D , Acacio S , Bassat Q , Powell H , Tennant SM , Sow SO , Sur D , Zaidi AKM , Faruque ASG , Hossain MJ , Alonso PL , Breiman RF , O'Reilly CE , Mintz ED , Omore R , Ochieng JB , Oundo JO , Tamboura B , Sanogo D , Onwuchekwa U , Manna B , Ramamurthy T , Kanungo S , Ahmed S , Qureshi S , Quadri F , Hossain A , Das SK , Antonio M , Saha D , Mandomando I , Blackwelder WC , Farag T , Wu Y , Houpt ER , Verweiij JJ , Sommerfelt H , Nataro JP , Robins-Browne RM , Kotloff KL . Lancet Glob Health 2019 8 (2) e204-e214 BACKGROUND: The Global Enteric Multicenter Study (GEMS) was a 3-year case-control study that measured the burden, aetiology, and consequences of moderate-to-severe diarrhoea (MSD) in children aged 0-59 months. GEMS-1A, a 12-month follow-on study, comprised two parallel case-control studies, one assessing MSD and the other less-severe diarrhoea (LSD). In this report, we analyse the risk of death with each diarrhoea type and the specific pathogens associated with fatal outcomes. METHODS: GEMS was a prospective, age-stratified, matched case-control study done at seven sites in Africa and Asia. Children aged 0-59 months with MSD seeking care at sentinel health centres were recruited along with one to three randomly selected matched community control children without diarrhoea. In the 12-month GEMS-1A follow-on study, children with LSD and matched controls, in addition to children with MSD and matched controls, were recruited at six of the seven sites; only cases of MSD and controls were enrolled at the seventh site. We compared risk of death during the period between enrolment and one follow-up household visit done about 60 days later (range 50-90 days) in children with MSD and LSD and in their respective controls. Approximately 50 pathogens were detected using, as appropriate, classic bacteriology, immunoassays, gel-based PCR and reverse transcriptase PCR, and quantitative real-time PCR (qPCR). Specimens from a subset of GEMS cases and controls were also tested by a TaqMan Array Card that compartmentalised probe-based qPCR for 32 enteropathogens. FINDINGS: 223 (2.0%) of 11 108 children with MSD and 43 (0.3%) of 16 369 matched controls died between study enrolment and the follow-up visit at about 60 days (hazard ratio [HR] 8.16, 95% CI 5.69-11.68, p<0.0001). 12 (0.4%) of 2962 children with LSD and seven (0.2%) of 4074 matched controls died during the follow-up period (HR 2.78, 95% CI 0.95-8.11, p=0.061). Risk of death was lower in children with dysenteric MSD than in children with non-dysenteric MSD (HR 0.20, 95% CI 0.05-0.87, p=0.032), and lower in children with LSD than in those with non-dysenteric MSD (HR 0.29, 0.14-0.59, p=0.0006). In children younger than 24 months with MSD, infection with typical enteropathogenic Escherichia coli, enterotoxigenic E coli encoding heat-stable toxin, enteroaggregative E coli, Shigella spp (non-dysentery cases), Aeromonas spp, Cryptosporidium spp, and Entamoeba histolytica increased risk of death. Of 61 deaths in children aged 12-59 months with non-dysenteric MSD, 31 occurred among 942 children qPCR-positive for Shigella spp and 30 deaths occurred in 1384 qPCR-negative children (HR 2.2, 95% CI 1.2-3.9, p=0.0090), showing that Shigella was strongly associated with increased risk of death. INTERPRETATION: Risk of death is increased following MSD and, to a lesser extent, LSD. Considering there are approximately three times more cases of LSD than MSD in the population, more deaths are expected among children with LSD than in those with MSD. Because the major attributable LSD-associated and MSD-associated pathogens are the same, implementing vaccines and rapid diagnosis and treatment interventions against these major pathogens are rational investments. FUNDING: Bill & Melinda Gates Foundation. |
Potential of minimally invasive tissue sampling for attributing specific causes of childhood deaths in South Africa: A pilot, epidemiological study
Chawana R , Baillie V , Izu A , Solomon F , Bassat Q , Blau DM , Breiman RF , Hale M , Houpt ER , Lala SG , Martines RB , Mathunjwa A , Nzenze S , Pathirana J , Petersen KL , Raghunathan PL , Ritter JM , Wadula J , Zaki SR , Madhi SA . Clin Infect Dis 2019 69 S361-s373 BACKGROUND: Current estimates for causes of childhood deaths are mainly premised on modeling of vital registration and limited verbal autopsy data and generally only characterize the underlying cause of death (CoD). We investigated the potential of minimally invasive tissue sampling (MITS) for ascertaining the underlying and immediate CoD in children 1 month to 14 years of age. METHODS: MITS included postmortem tissue biopsies of brain, liver, and lung for histopathology examination; microbial culture of blood, cerebrospinal fluid (CSF), liver, and lung samples; and molecular microbial testing on blood, CSF, lung, and rectal swabs. Each case was individually adjudicated for underlying, antecedent, and immediate CoD by an international multidisciplinary team of medical experts and coded using the International Classification of Diseases, Tenth Revision (ICD-10). RESULTS: An underlying CoD was determined for 99% of 127 cases, leading causes being congenital malformations (18.9%), complications of prematurity (14.2%), human immunodeficiency virus/AIDS (12.6%), diarrheal disease (8.7%), acute respiratory infections (7.9%), injuries (7.9%), and malignancies (7.1%). The main immediate CoD was pneumonia, sepsis, and diarrhea in 33.9%, 19.7%, and 10.2% of cases, respectively. Infection-related deaths were either an underlying or immediate CoD in 78.0% of cases. Community-acquired pneumonia deaths (n = 32) were attributed to respiratory syncytial virus (21.9%), Pneumocystis jirovecii (18.8%), cytomegalovirus (15.6%), Klebsiella pneumoniae (15.6%), and Streptococcus pneumoniae (12.5%). Seventy-one percent of 24 sepsis deaths were hospital-acquired, mainly due to Acinetobacter baumannii (47.1%) and K. pneumoniae (35.3%). Sixty-two percent of cases were malnourished. CONCLUSIONS: MITS, coupled with antemortem clinical information, provides detailed insight into causes of childhood deaths that could be informative for prioritization of strategies aimed at reducing under-5 mortality. |
Detection of dengue virus among children with suspected malaria, Accra, Ghana
Amoako N , Duodu S , Dennis FE , Bonney JHK , Asante KP , Ameh J , Mosi L , Hayashi T , Agbosu EE , Pratt D , Operario DJ , Fields B , Liu J , Houpt ER , Armah GE , Stoler J , Awandare GA . Emerg Infect Dis 2018 24 (8) 1544-1547 We report new molecular evidence of locally acquired dengue virus infections in Ghana. We detected dengue viral RNA among children with suspected malaria by using a multipathogen real-time PCR. Subsequent sequence analysis revealed a close relationship with dengue virus serotype 2, which was implicated in a 2016 outbreak in Burkina Faso. |
Use of TaqMan Array Cards to Screen Outbreak Specimens for Causes of Febrile Illness in Tanzania.
Abade A , Eidex RB , Maro A , Gratz J , Liu J , Kiwelu I , Mujaga B , Kelly ME , Mmbaga BT , Gibson JJ , Mosha F , Houpt ER . Am J Trop Med Hyg 2018 98 (6) 1640-1642 ![]() We describe the deployment of a custom-designed molecular diagnostic TaqMan Array Card (TAC) to screen for 31 bacterial, protozoal, and viral etiologies in blood from outbreaks of acute febrile illness in Tanzania during 2015-2017. On outbreaks notified to the Tanzanian Ministry of Health, epidemiologists were dispatched and specimens were collected, transported to a central national laboratory, and tested by TAC within 2 days. This algorithm streamlined investigation, diagnosed a typhoid outbreak, and excluded dozens of other etiologies. This method is usable in-country and may be incorporated into algorithms for diagnosing outbreaks. |
Etiology of severe acute watery diarrhea in children in the Global Rotavirus Surveillance Network using quantitative polymerase chain reaction
Operario DJ , Platts-Mills JA , Nadan S , Page N , Seheri M , Mphahlele J , Praharaj I , Kang G , Araujo IT , Leite JPG , Cowley D , Thomas S , Kirkwood CD , Dennis F , Armah G , Mwenda JM , Wijesinghe PR , Rey G , Grabovac V , Berejena C , Simwaka CJ , Uwimana J , Sherchand JB , Thu HM , Galagoda G , Bonkoungou IJO , Jagne S , Tsolenyanu E , Diop A , Enweronu-Laryea C , Borbor SA , Liu J , McMurry T , Lopman B , Parashar U , Gentsch J , Steele AD , Cohen A , Serhan F , Houpt ER . J Infect Dis 2017 216 (2) 220-227 Background: The etiology of acute watery diarrhea remains poorly characterized, particularly after rotavirus vaccine introduction. Methods: We performed quantitative polymerase chain reaction for multiple enteropathogens on 878 acute watery diarrheal stools sampled from 14643 episodes captured by surveillance of children <5 years of age during 2013-2014 from 16 countries. We used previously developed models of the association between pathogen quantity and diarrhea to calculate pathogen-specific weighted attributable fractions (AFs). Results: Rotavirus remained the leading etiology (overall weighted AF, 40.3% [95% confidence interval {CI}, 37.6%-44.3%]), though the AF was substantially lower in the Americas (AF, 12.2 [95% CI, 8.9-15.6]), based on samples from a country with universal rotavirus vaccination. Norovirus GII (AF, 6.2 [95% CI, 2.8-9.2]), Cryptosporidium (AF, 5.8 [95% CI, 4.0-7.6]), Shigella (AF, 4.7 [95% CI, 2.8-6.9]), heat-stable enterotoxin-producing Escherichia coli (ST-ETEC) (AF, 4.2 [95% CI, 2.0-6.1]), and adenovirus 40/41 (AF, 4.2 [95% CI, 2.9-5.5]) were also important. In the Africa Region, the rotavirus AF declined from 54.8% (95% CI, 48.3%-61.5%) in rotavirus vaccine age-ineligible children to 20.0% (95% CI, 12.4%-30.4%) in age-eligible children. Conclusions: Rotavirus remained the leading etiology of acute watery diarrhea despite a clear impact of rotavirus vaccine introduction. Norovirus GII, Cryptosporidium, Shigella, ST-ETEC, and adenovirus 40/41 were also important. Prospective surveillance can help identify priorities for further reducing the burden of diarrhea. |
Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study.
Liu J , Platts-Mills JA , Juma J , Kabir F , Nkeze J , Okoi C , Operario DJ , Uddin J , Ahmed S , Alonso PL , Antonio M , Becker SM , Blackwelder WC , Breiman RF , Faruque AS , Fields B , Gratz J , Haque R , Hossain A , Hossain MJ , Jarju S , Qamar F , Iqbal NT , Kwambana B , Mandomando I , McMurry TL , Ochieng C , Ochieng JB , Ochieng M , Onyango C , Panchalingam S , Kalam A , Aziz F , Qureshi S , Ramamurthy T , Roberts JH , Saha D , Sow SO , Stroup SE , Sur D , Tamboura B , Taniuchi M , Tennant SM , Toema D , Wu Y , Zaidi A , Nataro JP , Kotloff KL , Levine MM , Houpt ER . Lancet 2016 388 (10051) 1291-301 ![]() BACKGROUND: 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). METHODS: 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. FINDINGS: 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 1.5 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 89.3% (95% CI 83.2-96.0) at the population level, compared with 51.5% (48.0-55.0) in the original GEMS analysis. The top six pathogens accounted for 77.8% (74.6-80.9) of all attributable diarrhoea. With use of model-derived quantitative cutoffs to assess individual diarrhoeal cases, 2254 (42.5%) of 5304 cases had one diarrhoea-associated pathogen detected and 2063 (38.9%) had two or more, with Shigella spp and rotavirus being the pathogens most strongly associated with diarrhoea in children with mixed infections. INTERPRETATION: 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. FUNDING: Bill & Melinda Gates Foundation. |
The burden of cryptosporidium diarrheal disease among children < 24 months of age in moderate/high mortality regions of Sub-Saharan Africa and South Asia, utilizing data from the Global Enteric Multicenter Study (GEMS)
Sow SO , Muhsen K , Nasrin D , Blackwelder WC , Wu Y , Farag TH , Panchalingam S , Sur D , Zaidi AK , Faruque AS , Saha D , Adegbola R , Alonso PL , Breiman RF , Bassat Q , Tamboura B , Sanogo D , Onwuchekwa U , Manna B , Ramamurthy T , Kanungo S , Ahmed S , Qureshi S , Quadri F , Hossain A , Das SK , Antonio M , Hossain MJ , Mandomando I , Nhampossa T , Acacio S , Omore R , Oundo JO , Ochieng JB , Mintz ED , O'Reilly CE , Berkeley LY , Livio S , Tennant SM , Sommerfelt H , Nataro JP , Ziv-Baran T , Robins-Browne RM , Mishcherkin V , Zhang J , Liu J , Houpt ER , Kotloff KL , Levine MM . PLoS Negl Trop Dis 2016 10 (5) e0004729 BACKGROUND: The importance of Cryptosporidium as a pediatric enteropathogen in developing countries is recognized. METHODS: Data from the Global Enteric Multicenter Study (GEMS), a 3-year, 7-site, case-control study of moderate-to-severe diarrhea (MSD) and GEMS-1A (1-year study of MSD and less-severe diarrhea [LSD]) were analyzed. Stools from 12,110 MSD and 3,174 LSD cases among children aged <60 months and from 21,527 randomly-selected controls matched by age, sex and community were immunoassay-tested for Cryptosporidium. Species of a subset of Cryptosporidium-positive specimens were identified by PCR; GP60 sequencing identified anthroponotic C. parvum. Combined annual Cryptosporidium-attributable diarrhea incidences among children aged <24 months for African and Asian GEMS sites were extrapolated to sub-Saharan Africa and South Asian regions to estimate region-wide MSD and LSD burdens. Attributable and excess mortality due to Cryptosporidium diarrhea were estimated. FINDINGS: Cryptosporidium was significantly associated with MSD and LSD below age 24 months. Among Cryptosporidium-positive MSD cases, C. hominis was detected in 77.8% (95% CI, 73.0%-81.9%) and C. parvum in 9.9% (95% CI, 7.1%-13.6%); 92% of C. parvum tested were anthroponotic genotypes. Annual Cryptosporidium-attributable MSD incidence was 3.48 (95% CI, 2.27-4.67) and 3.18 (95% CI, 1.85-4.52) per 100 child-years in African and Asian infants, respectively, and 1.41 (95% CI, 0.73-2.08) and 1.36 (95% CI, 0.66-2.05) per 100 child-years in toddlers. Corresponding Cryptosporidium-attributable LSD incidences per 100 child-years were 2.52 (95% CI, 0.33-5.01) and 4.88 (95% CI, 0.82-8.92) in infants and 4.04 (95% CI, 0.56-7.51) and 4.71 (95% CI, 0.24-9.18) in toddlers. We estimate 2.9 and 4.7 million Cryptosporidium-attributable cases annually in children aged <24 months in the sub-Saharan Africa and India/Pakistan/Bangladesh/Nepal/Afghanistan regions, respectively, and ~202,000 Cryptosporidium-attributable deaths (regions combined). ~59,000 excess deaths occurred among Cryptosporidium-attributable diarrhea cases over expected if cases had been Cryptosporidium-negative. CONCLUSIONS: The enormous African/Asian Cryptosporidium disease burden warrants investments to develop vaccines, diagnostics and therapies. |
Effect of substituting IPV for tOPV on immunity to poliovirus in Bangladeshi infants: An open-label randomized controlled trial
Mychaleckyj JC , Haque R , Carmolli M , Zhang D , Colgate ER , Nayak U , Taniuchi M , Dickson D , Weldon WC , Oberste MS , Zaman K , Houpt ER , Alam M , Kirkpatrick BD , Petri WA Jr . Vaccine 2015 34 (3) 358-66 BACKGROUND: The Polio Endgame strategy includes phased withdrawal of oral poliovirus vaccines (OPV) coordinated with introduction of inactivated poliovirus vaccine (IPV) to ensure population immunity. The impact of IPV introduction into a primary OPV series of immunizations in a developing country is uncertain. METHODS: Between May 2011 and November 2012, we enrolled 700 Bangladeshi infant-mother dyads from Dhaka slums into an open-label randomized controlled trial to test whether substituting an injected IPV dose for the standard Expanded Program on Immunization (EPI) fourth tOPV dose at infant age 39 weeks would reduce fecal shedding and enhance systemic immunity. The primary endpoint was mucosal immunity to poliovirus at age one year, measured by fecal excretion of any Sabin virus at five time points up to 25 days post-52 week tOPV challenge, analyzed by the intention to treat principle. FINDINGS: We randomized 350 families to the tOPV and IPV vaccination arms. Neither study arm resulted in superior intestinal protection at 52 weeks measured by the prevalence of infants shedding any of three poliovirus serotypes, but the IPV dose induced significantly higher seroprevalence and seroconversion rates. This result was identical for poliovirus detection by cell culture or RT-qPCR. The non-significant estimated culture-based shedding risk difference was -3% favoring IPV, and the two vaccination schedules were inferred to be equivalent within a 95% confidence margin of -10% to +4%. Results for shedding analyses stratified by poliovirus type were similar. CONCLUSIONS: Neither of the vaccination regimens is superior to the other in enhancing intestinal immunity as measured by poliovirus shedding at 52 weeks of age and the IPV regimen provides similar intestinal immunity to the four tOPV series, although the IPV regimen strongly enhances humoral immunity. The IPV-modified regimen may be considered for vaccination programs without loss of intestinal protection. |
Molecular genotyping and quantitation assay for rotavirus surveillance.
Liu J , Lurain K , Sobuz SU , Begum S , Kumburu H , Gratz J , Kibiki G , Toney D , Gautam R , Bowen MD , Petri WA Jr , Haque R , Houpt ER . J Virol Methods 2014 213 157-63 ![]() Rotavirus genotyping is useful for surveillance purposes especially in areas where rotavirus vaccination has been or will be implemented. RT-PCR based molecular methods have been applied widely, but quantitative assays targeting a broad spectrum of genotypes have not been developed. Three real time RT-PCR panels were designed to identify G1, G2, G9, G12 (panel GI), G3, G4, G8, G10 (panel GII), and P[4], P[6], P[8], P[10], P[11] (panel P), respectively. An assay targeting NSP3 was included in both G panels as an internal control. The cognate assays were also formulated as one RT-PCR-Luminex panel for simultaneous detection of all the genotypes listed above plus P[9]. The assays were evaluated with various rotavirus isolates and 89 clinical samples from Virginia, Bangladesh and Tanzania, and exhibited 95% (81/85) sensitivity compared with the conventional RT-PCR-Gel-electrophoresis method, and 100% concordance with sequencing. Real time assays identified a significantly higher rate of mixed genotypes in Bangladeshi samples than the conventional gel-electrophoresis-based RT-PCR assay (32.5% versus 12.5%, P<0.05). In these mixed infections, the relative abundance of the rotavirus types could be estimated by Cq values. These typing assays detect and discriminate a broad range of G/P types circulating in different geographic regions with high sensitivity and specificity and can be used for rotavirus surveillance. |
A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for cryptosporidium
Checkley W , White AC Jr , Jaganath D , Arrowood MJ , Chalmers RM , Chen XM , Fayer R , Griffiths JK , Guerrant RL , Hedstrom L , Huston CD , Kotloff KL , Kang G , Mead JR , Miller M , Petri WA Jr , Priest JW , Roos DS , Striepen B , Thompson RC , Ward HD , Van Voorhis WA , Xiao L , Zhu G , Houpt ER . Lancet Infect Dis 2014 15 (1) 85-94 Cryptosporidium spp are well recognised as causes of diarrhoeal disease during waterborne epidemics and in immunocompromised hosts. Studies have also drawn attention to an underestimated global burden and suggest major gaps in optimum diagnosis, treatment, and immunisation. Cryptosporidiosis is increasingly identified as an important cause of morbidity and mortality worldwide. Studies in low-resource settings and high-income countries have confirmed the importance of cryptosporidium as a cause of diarrhoea and childhood malnutrition. Diagnostic tests for cryptosporidium infection are suboptimum, necessitating specialised tests that are often insensitive. Antigen-detection and PCR improve sensitivity, and multiplexed antigen detection and molecular assays are underused. Therapy has some effect in healthy hosts and no proven efficacy in patients with AIDS. Use of cryptosporidium genomes has helped to identify promising therapeutic targets, and drugs are in development, but methods to assess the efficacy in vitro and in animals are not well standardised. Partial immunity after exposure suggests the potential for successful vaccines, and several are in development; however, surrogates of protection are not well defined. Improved methods for propagation and genetic manipulation of the organism would be significant advances. |
Febrile illness and pro-inflammatory cytokines are associated with lower neurodevelopmental scores in Bangladeshi infants living in poverty
Jiang NM , Tofail F , Moonah SN , Scharf RJ , Taniuchi M , Ma JZ , Hamadani JD , Gurley ES , Houpt ER , Azziz-Baumgartner E , Haque R , Petri WA Jr . BMC Pediatr 2014 14 (1) 50 BACKGROUND: An estimated one-third of children younger than 5 years in low- and middle-income countries fail to meet their full developmental potential. The first year of life is a period of critical brain development and is also when most of the morbidity from infection is suffered. We aimed to determine if clinical and biological markers of inflammation in the first year of life predict cognitive, language, and motor outcomes in children living in an urban slum in Bangladesh. METHODS: Children living in Dhaka, Bangladesh were observed from birth until 24 months of age. Febrile illness was used as a clinical marker of inflammation and elevated concentrations of inflammation-related cytokines (IL-1beta, IL-6, TNF-alpha, IL-4, IL-10) in sera collected from a subset of the cohort (N = 127) at 6 months of age were used as biomarkers of inflammation. Psychologists assessed cognitive, language, and motor development using a culturally adapted version of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 12 (N = 398) and 24 months of age (N = 210). We tested for the ability of febrile illness and elevated cytokine levels to predict developmental outcomes, independent of known predictors of stunting, family income, and maternal education. RESULTS: Every additional 10 days of fever was associated with a 1.9 decrease in language composite score and a 2.1 decrease in motor composite score (p = 0.005 and 0.0002, respectively). Elevated levels of the pro-inflammatory cytokines IL-1beta (> 7.06 pg/mL) and IL-6 (> 10.52 pg/mL) were significantly associated with a 4.9 and 4.3 decrease in motor score, respectively. Conversely, an elevated level of the Th-2 cytokine IL-4 (> 0.70 pg/mL) was associated with a 3.6 increase in cognitive score (all p < 0.05). CONCLUSIONS: Clinical and biological markers of inflammation in the first year of life were significantly associated with poor neurodevelopmental outcomes. Conversely, a Th2-like response was associated with a better outcome. These findings suggest that markers of inflammation could serve as prognostic indicators and potentially lead to immune-based therapies to prevent developmental delays in at-risk children. |
Quantitative PCR for detection of Shigella improves ascertainment of Shigella burden in children with moderate-to-severe diarrhea in low-income countries
Lindsay B , Ochieng JB , Ikumapayi UN , Toure A , Ahmed D , Li S , Panchalingam S , Levine MM , Kotloff K , Rasko DA , Morris CR , Juma J , Fields BS , Dione M , Malle D , Becker SM , Houpt ER , Nataro JP , Sommerfelt H , Pop M , Oundo J , Antonio M , Hossain A , Tamboura B , Stine OC . J Clin Microbiol 2013 51 (6) 1740-6 ![]() Estimates of the prevalence of Shigella spp. are limited by the suboptimal sensitivity of current diagnostic and surveillance methods. We used a quantitative PCR (qPCR) assay to detect Shigella in the stool samples of 3,533 children aged <59 months from the Gambia, Mali, Kenya, and Bangladesh, with or without moderate-to-severe diarrhea (MSD). We compared the results from conventional culture to those from qPCR for the Shigella ipaH gene. Using MSD as the reference standard, we determined the optimal cutpoint to be 2.9 x 10(4) ipaH copies per 100 ng of stool DNA for set 1 (n = 877). One hundred fifty-eight (18%) specimens yielded >2.9 x 10(4) ipaH copies. Ninety (10%) specimens were positive by traditional culture for Shigella. Individuals with ≥ 2.9 x 10(4) ipaH copies have 5.6-times-higher odds of having diarrhea than those with <2.9 x 10(4) ipaH copies (95% confidence interval, 3.7 to 8.5; P < 0.0001). Nearly identical results were found using an independent set of samples. qPCR detected 155 additional MSD cases with high copy numbers of ipaH, a 90% increase from the 172 cases detected by culture in both samples. Among a subset (n = 2,874) comprising MSD cases and their age-, gender-, and location-matched controls, the fraction of MSD cases that were attributable to Shigella infection increased from 9.6% (n = 129) for culture to 17.6% (n = 262) for qPCR when employing our cutpoint. We suggest that qPCR with a cutpoint of approximately 1.4 x 10(4) ipaH copies be the new reference standard for the detection and diagnosis of shigellosis in children in low-income countries. The acceptance of this new standard would substantially increase the fraction of MSD cases that are attributable to Shigella. |
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