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      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

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          Abstract

          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.

          Abstract

          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 necessitates appropriate management of clinical and nutritional consequences.

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          Most cited references43

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          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.

          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. 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. We enrolled 9439 children with moderate-to-severe diarrhoea and 13,129 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. 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. The Bill & Melinda Gates Foundation. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Estimates of the global, regional, and national morbidity, mortality, and aetiologies of diarrhoea in 195 countries: a systematic analysis for the Global Burden of Disease Study 2016

            Summary Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 provides an up-to-date analysis of the burden of diarrhoea in 195 countries. This study assesses cases, deaths, and aetiologies in 1990–2016 and assesses how the burden of diarrhoea has changed in people of all ages. Methods We modelled diarrhoea mortality with a Bayesian hierarchical modelling platform that evaluates a wide range of covariates and model types on the basis of vital registration and verbal autopsy data. We modelled diarrhoea incidence with a compartmental meta-regression tool that enforces an association between incidence and prevalence, and relies on scientific literature, population representative surveys, and health-care data. Diarrhoea deaths and episodes were attributed to 13 pathogens by use of a counterfactual population attributable fraction approach. Diarrhoea risk factors are also based on counterfactual estimates of risk exposure and the association between the risk and diarrhoea. Each modelled estimate accounted for uncertainty. Findings In 2016, diarrhoea was the eighth leading cause of death among all ages (1 655 944 deaths, 95% uncertainty interval [UI] 1 244 073–2 366 552) and the fifth leading cause of death among children younger than 5 years (446 000 deaths, 390 894–504 613). Rotavirus was the leading aetiology for diarrhoea mortality among children younger than 5 years (128 515 deaths, 105 138–155 133) and among all ages (228 047 deaths, 183 526–292 737). Childhood wasting (low weight-for-height score), unsafe water, and unsafe sanitation were the leading risk factors for diarrhoea, responsible for 80·4% (95% UI 68·2–85·0), 72·1% (34·0–91·4), and 56·4% (49·3–62·7) of diarrhoea deaths in children younger than 5 years, respectively. Prevention of wasting in 1762 children (95% UI 1521–2170) could avert one death from diarrhoea. Interpretation Substantial progress has been made globally in reducing the burden of diarrhoeal diseases, driven by decreases in several primary risk factors. However, this reduction has not been equal across locations, and burden among adults older than 70 years requires attention. Funding Bill & Melinda Gates Foundation.
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              A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for cryptosporidium.

              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. Copyright © 2015 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Clin Infect Dis
                Clin Infect Dis
                cid
                Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
                Oxford University Press (US )
                1058-4838
                1537-6591
                01 April 2023
                19 April 2023
                19 April 2023
                : 76
                : Suppl 1 , Rotavirus Vaccine Impact on Diarrhea in Africa: The VIDA Study
                : S97-S105
                Affiliations
                Medical Research Council Unit, The Gambia at the London School of Hygiene & Tropical Medicine , Banjul, The Gambia
                Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Center for Vaccine Development and Global Health, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Centre pour le Développement des Vaccins du Mali (CVD-Mali) , Bamako, Mali
                Center for Global Health Research, Kenya Medical Research Institute , Kisumu, Kenya
                Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Center for Vaccine Development and Global Health, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Medical Research Council Unit, The Gambia at the London School of Hygiene & Tropical Medicine , Banjul, The Gambia
                Medical Research Council Unit, The Gambia at the London School of Hygiene & Tropical Medicine , Banjul, The Gambia
                Medical Research Council Unit, The Gambia at the London School of Hygiene & Tropical Medicine , Banjul, The Gambia
                Medical Research Council Unit, The Gambia at the London School of Hygiene & Tropical Medicine , Banjul, The Gambia
                Center for Vaccine Development and Global Health, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Department of Medicine, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Centre pour le Développement des Vaccins du Mali (CVD-Mali) , Bamako, Mali
                Centre pour le Développement des Vaccins du Mali (CVD-Mali) , Bamako, Mali
                Center for Global Health Research, Kenya Medical Research Institute , Kisumu, Kenya
                Center for Global Health Research, Kenya Medical Research Institute , Kisumu, Kenya
                Division of Global Health Protection, US Centers for Disease Control and Prevention , Nairobi, Kenya
                Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia , Charlottesville, Virginia, USA
                School of Public Health, Qingdao University , Qingdao, China
                Center for Vaccine Development and Global Health, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Department of Medicine, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Center for Vaccine Development and Global Health, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Department of Medicine, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Center for Vaccine Development and Global Health, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Department of Medicine, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Center for Vaccine Development and Global Health, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Department of Epidemiology and Public Health, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Medical Research Council Unit, The Gambia at the London School of Hygiene & Tropical Medicine , Banjul, The Gambia
                Medical Research Council Unit, The Gambia at the London School of Hygiene & Tropical Medicine , Banjul, The Gambia
                Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia , Charlottesville, Virginia, USA
                Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Center for Vaccine Development and Global Health, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Department of Medicine, University of Maryland School of Medicine , Baltimore, Maryland, USA
                Author notes

                Present affiliation: Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA.

                Correspondence: M. J. Hossain, Medical Research Council Unit, The Gambia at the London School of Hygiene & Tropical Medicine, Atlantic Road, Fajara, PO Box-273, Banjul, The Gambia ( Jahangir.Hossain@ 123456lshtm.ac.uk ).

                Potential conflicts of interest . E. R. H. reports financial support from the Bill and Melinda Gates Foundation (OPP1129479). K. L. K. reports consultation fees and travel support from PATH and the University of Washington related to diarrheal diseases and grant support to her institution from the National Institutes of Health, Institut Pasteur, and the Bill & Melinda Gates Foundation. S. M. T. reports multiple grants paid to her institution from the National Institutes of Health (NIH), Bill & Melinda Gates Foundation (BMGF), Wellcome Trust, Affinivax, Lumen Biosciences, PATH, and Medical Research Council. She also reports payments as royalties related to intellectual property for Salmonella vaccines and Klebsiella/ Pseudomonas vaccines and consulting fees and travel support from the University of Washington for a grant proposal. She also reports holding multiple planned, issued, and pending patents on Salmonella, Klebsiella, and Pseudomonas vaccines and hold multiple unpaid committee roles with the American Society of Tropical Medicine and Hygiene. S. R. C. H. reports salary funding from the UK Medical Research Council and the University of Auckland. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

                Article
                ciad044
                10.1093/cid/ciad044
                10116562
                37074443
                df302424-db52-4513-8202-d5f05b3ac842
                © The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Page count
                Pages: 9
                Funding
                Funded by: Bill & Melinda Gates Foundation, doi 10.13039/100000865;
                Categories
                VIDA Supplement
                AcademicSubjects/MED00290

                Infectious disease & Microbiology
                diarrhea,cryptosporidium,prevalence,severity,children
                Infectious disease & Microbiology
                diarrhea, cryptosporidium, prevalence, severity, children

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