The US COVID-19 Trends and Impact Survey: Continuous real-time measurement of COVID-19 symptoms, risks, protective behaviors, testing, and vaccination.

The US COVID-19 Trends and Impact Survey (CTIS) is a large, cross-sectional, internet-based survey that has operated continuously since April 6, 2020. By inviting a random sample of Facebook active users each day, CTIS collects information about COVID-19 symptoms, risks, mitigating behaviors, mental health, testing, vaccination, and other key priorities. The large scale of the survey-over 20 million responses in its first year of operation-allows tracking of trends over short timescales and allows comparisons at fine demographic and geographic detail. The survey has been repeatedly revised to respond to emerging public health priorities. In this paper, we describe the survey methods and content and give examples of CTIS results that illuminate key patterns and trends and help answer high-priority policy questions relevant to the COVID-19 epidemic and response. These results demonstrate how large online surveys can provide continuous, real-time indicators of important outcomes that are not subject to public health reporting delays and backlogs. The CTIS offers high value as a supplement to official reporting data by supplying essential information about behaviors, attitudes toward policy and preventive measures, economic impacts, and other topics not reported in public health surveillance systems.

Global monitoring of the impact of the COVID-19 pandemic through online surveys sampled from the Facebook user base.

Simultaneously tracking the global impact of COVID-19 is challenging because of regional variation in resources and reporting. Leveraging self-reported survey outcomes via an existing international social media network has the potential to provide standardized data streams to support monitoring and decision-making worldwide, in real time, and with limited local resources. The University of Maryland Global COVID-19 Trends and Impact Survey (UMD-CTIS), in partnership with Facebook, has invited daily cross-sectional samples from the social media platform's active users to participate in the survey since its launch on April 23, 2020. We analyzed UMD-CTIS survey data through December 20, 2020, from 31,142,582 responses representing 114 countries/territories weighted for nonresponse and adjusted to basic demographics. We show consistent respondent demographics over time for many countries/territories. Machine Learning models trained on national and pooled global data verified known symptom indicators. COVID-like illness (CLI) signals were correlated with government benchmark data. Importantly, the best benchmarked UMD-CTIS signal uses a single survey item whereby respondents report on CLI in their local community. In regions with strained health infrastructure but active social media users, we show it is possible to define COVID-19 impact trajectories using a remote platform independent of local government resources. This syndromic surveillance public health tool is the largest global health survey to date and, with brief participant engagement, can provide meaningful, timely insights into the global COVID-19 pandemic at a local scale.

Pathogens Associated With Linear Growth Faltering in Children With Diarrhea and Impact of Antibiotic Treatment: The Global Enteric Multicenter Study.

BACKGROUND: The association between childhood diarrheal disease and linear growth faltering in developing countries is well described. However, the impact attributed to specific pathogens has not been elucidated, nor has the impact of recommended antibiotic treatment. METHODS: The Global Enteric Multicenter Study enrolled children with moderate to severe diarrhea (MSD) seeking healthcare at 7 sites in sub-Saharan Africa and South Asia. At enrollment, we collected stool samples to identify enteropathogens. Length/height was measured at enrollment and follow-up, approximately 60 days later, to calculate change in height-for-age z scores (ΔHAZ). The association of pathogens with ΔHAZ was tested using linear mixed effects regression models. RESULTS: Among 8077 MSD cases analyzed, the proportion with stunting (HAZ below -1) increased from 59% at enrollment to 65% at follow-up (P < .0001). Pathogens significantly associated with linear growth decline included Cryptosporidium (P < .001), typical enteropathogenic Escherichia coli (P = .01), and untreated Shigella (P = .009) among infants (aged 0-11 months) and enterotoxigenic E. coli encoding heat-stable toxin (P < .001) and Cryptosporidium (P = .03) among toddlers (aged 12-23 months). Shigella-infected toddlers given antibiotics had improved linear growth (P = .02). CONCLUSIONS: Linear growth faltering among children aged 0-23 months with MSD is associated with specific pathogens and can be mitigated with targeted treatment strategies, as demonstrated for Shigella.

Rotavirus disease burden pre-vaccine introduction in young children in Rural Southern Mozambique, an area of high HIV prevalence.

BACKGROUND: Rotavirus vaccines have been adopted in African countries since 2009, including Mozambique (2015). Disease burden data are needed to evaluate the impact of rotavirus vaccine. We report the burden of rotavirus-associated diarrhea in Mozambique from the Global Enteric Multicenter Study (GEMS) before vaccine introduction. METHODS: A case-control study (GEMS), was conducted in Manhiça district, recruiting children aged 0-59 months with moderate-to-severe diarrhea (MSD) and less-severe-diarrhea (LSD) between December 2007 and November 2012; including 1-3 matched (age, sex and neighborhood) healthy community controls. Clinical and epidemiological data and stool samples (for laboratory investigation) were collected. Association of rotavirus with MSD or LSD was determined by conditional logistic regression and adjusted attributable fractions (AF) calculated, and risk factors for rotavirus diarrhea assessed. RESULTS: Overall 915 cases and 1,977 controls for MSD, and 431 cases and 430 controls for LSD were enrolled. Rotavirus positivity was 44% (217/495) for cases and 15% (160/1046) of controls, with AF = 34.9% (95% CI: 32.85-37.06) and adjusted Odds Ratio (aOR) of 6.4 p< 0.0001 in infants with MSD compared to 30% (46/155) in cases and 14% (22/154) in controls yielding AF = 18.7%, (95% CI: 12.02-25.39) and aOR = 2.8, p = 0.0011 in infants with LSD. The proportion of children with rotavirus was 32% (21/66) among HIV-positive children and 23% (128/566) among HIV-negative ones for MSD. Presence of animals in the compound (OR = 1.9; p = 0.0151) and giving stored water to the child (OR = 2.0, p = 0.0483) were risk factors for MSD; while animals in the compound (OR = 2.37, p = 0.007); not having routine access to water on a daily basis (OR = 1.53, p = 0.015) and washing hands before cooking (OR = 1.76, p = 0.0197) were risk factors for LSD. CONCLUSION: The implementation of vaccination against rotavirus may likely result in a significant reduction of rotavirus-associated diarrhea, suggesting the need for monitoring of vaccine impact.

Characteristics of Salmonella Recovered From Stools of Children Enrolled in the Global Enteric Multicenter Study.

BACKGROUND: The Global Enteric Multicenter Study (GEMS) determined the etiologic agents of moderate-to-severe diarrhea (MSD) in children under 5 years old in Africa and Asia. Here, we describe the prevalence and antimicrobial susceptibility of nontyphoidal Salmonella (NTS) serovars in GEMS and examine the phylogenetics of Salmonella Typhimurium ST313 isolates. METHODS: Salmonella isolated from children with MSD or diarrhea-free controls were identified by classical clinical microbiology and serotyped using antisera and/or whole-genome sequence data. We evaluated antimicrobial susceptibility using the Kirby-Bauer disk-diffusion method. Salmonella Typhimurium sequence types were determined using multi-locus sequence typing, and whole-genome sequencing was performed to assess the phylogeny of ST313. RESULTS: Of 370 Salmonella-positive individuals, 190 (51.4%) were MSD cases and 180 (48.6%) were diarrhea-free controls. The most frequent Salmonella serovars identified were Salmonella Typhimurium, serogroup O:8 (C2-C3), serogroup O:6,7 (C1), Salmonella Paratyphi B Java, and serogroup O:4 (B). The prevalence of NTS was low but similar across sites, regardless of age, and was similar among both cases and controls except in Kenya, where Salmonella Typhimurium was more commonly associated with cases than controls. Phylogenetic analysis showed that these Salmonella Typhimurium isolates, all ST313, were highly genetically related to isolates from controls. Generally, Salmonella isolates from Asia were resistant to ciprofloxacin and ceftriaxone, but African isolates were susceptible to these antibiotics. CONCLUSIONS: Our data confirm that NTS is prevalent, albeit at low levels, in Africa and South Asia. Our findings provide further evidence that multidrug-resistant Salmonella Typhimurium ST313 can be carried asymptomatically by humans in sub-Saharan Africa.

Oral rehydration therapies in Senegal, Mali, and Sierra Leone: a spatial analysis of changes over time and implications for policy.

BACKGROUND: Oral rehydration solution (ORS) is a simple intervention that can prevent childhood deaths from severe diarrhea and dehydration. In a previous study, we mapped the use of ORS treatment subnationally and found that ORS coverage increased over time, while the use of home-made alternatives or recommended home fluids (RHF) decreased, in many countries. These patterns were particularly striking within Senegal, Mali, and Sierra Leone. It was unclear, however, whether ORS replaced RHF in these locations or if children were left untreated, and if these patterns were associated with health policy changes. METHODS: We used a Bayesian geostatistical model and data from household surveys to map the percentage of children with diarrhea that received (1) any ORS, (2) only RHF, or (3) no oral rehydration treatment between 2000 and 2018. This approach allowed examination of whether RHF was replaced with ORS before and after interventions, policies, and external events that may have impacted healthcare access. RESULTS: We found that RHF was replaced with ORS in most Sierra Leone districts, except those most impacted by the Ebola outbreak. In addition, RHF was replaced in northern but not in southern Mali, and RHF was not replaced anywhere in Senegal. In Senegal, there was no statistical evidence that a national policy promoting ORS use was associated with increases in coverage. In Sierra Leone, ORS coverage increased following a national policy change that abolished health costs for children. CONCLUSIONS: Children in parts of Mali and Senegal have been left behind during ORS scale-up. Improved messaging on effective diarrhea treatment and/or increased ORS access such as through reducing treatment costs may be needed to prevent child deaths in these areas.

Burden of disease in francophone Africa, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.

BACKGROUND: Peer-reviewed literature on health is almost exclusively published in English, limiting the uptake of research for decision making in francophone African countries. We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to assess the burden of disease in francophone Africa and inform health professionals and their partners in the region. METHODS: We assessed the burden of disease in the 21 francophone African countries and compared the results with those for their non-francophone counterparts in three economic communities: the Economic Community of West African States, the Economic Community of Central African States, and the Southern African Development Community. GBD 2017 employed a variety of statistical models to determine the number of deaths from each cause, through the Cause of Death Ensemble model algorithm, using CoDCorrect to ensure that the number of deaths per cause did not exceed the total number of estimated deaths. After producing estimates for the number of deaths from each of the 282 fatal outcomes included in the GBD 2017 list of causes, the years of life lost (YLLs) due to premature death were calculated. Years lived with disability (YLDs) were estimated as the product of prevalence and a disability weight for all mutually exclusive sequelae. Disability-adjusted life-years (DALYs) were calculated as the sum of YLLs and YLDs. All calculations are presented with 95% uncertainty intervals (UIs). A sample of 1000 draws was taken from the posterior distribution of each estimation step; aggregation of uncertainty across age, sex, and location was done on each draw, assuming independence of uncertainty. The lower and upper UIs represent the ordinal 25th and 975th draws of each quantity and attempt to describe modelling as well as sampling error. FINDINGS: In 2017, 779 deaths (95% UI 750-809) per 100 000 population occurred in francophone Africa, a decrease of 45·3% since 1990. Malaria, lower respiratory infections, neonatal disorders, diarrhoeal diseases, and tuberculosis were the top five Level 3 causes of death. These five causes were found among the six leading causes of death in most francophone countries. In 2017, francophone Africa experienced 53 570 DALYs (50 164-57 361) per 100 000 population, distributed between 43 708 YLLs (41 673-45 742) and 9862 YLDs (7331-12 749) per 100 000 population. In 2017, YLLs constituted the majority of DALYs in the 21 countries of francophone Africa. Age-specific and cause-specific mortality and population ageing were responsible for most of the reductions in disease burden, whereas population growth was responsible for most of the increases. INTERPRETATION: Francophone Africa still carries a high burden of communicable and neonatal diseases, probably due to the weakness of health-care systems and services, as evidenced by the almost complete attribution of DALYs to YLLs. To cope with this burden of disease, francophone Africa should define its priorities and invest more resources in health-system strengthening and in the quality and quantity of health-care services, especially in rural and remote areas. The region could also be prioritised in terms of technical and financial assistance focused on achieving these goals, as much as on demographic investments including education and family planning. FUNDING: Bill & Melinda Gates Foundation.

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.

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.

Identifying residual hotspots and mapping lower respiratory infection morbidity and mortality in African children from 2000 to 2017.

Lower respiratory infections (LRIs) are the leading cause of death in children under the age of 5, despite the existence of vaccines against many of their aetiologies. Furthermore, more than half of these deaths occur in Africa. Geospatial models can provide highly detailed estimates of trends subnationally, at the level where implementation of health policies has the greatest impact. We used Bayesian geostatistical modelling to estimate LRI incidence, prevalence and mortality in children under 5 subnationally in Africa for 2000-2017, using surveys covering 1.46 million children and 9,215,000 cases of LRI. Our model reveals large within-country variation in both health burden and its change over time. While reductions in childhood morbidity and mortality due to LRI were estimated for almost every country, we expose a cluster of residual high risk across seven countries, which averages 5.5 LRI deaths per 1,000 children per year. The preventable nature of the vast majority of LRI deaths mandates focused health system efforts in specific locations with the highest burden.

Mapping HIV prevalence in sub-Saharan Africa between 2000 and 2017.

HIV/AIDS is a leading cause of disease burden in sub-Saharan Africa. Existing evidence has demonstrated that there is substantial local variation in the prevalence of HIV; however, subnational variation has not been investigated at a high spatial resolution across the continent. Here we explore within-country variation at a 5 × 5-km resolution in sub-Saharan Africa by estimating the prevalence of HIV among adults (aged 15-49 years) and the corresponding number of people living with HIV from 2000 to 2017. Our analysis reveals substantial within-country variation in the prevalence of HIV throughout sub-Saharan Africa and local differences in both the direction and rate of change in HIV prevalence between 2000 and 2017, highlighting the degree to which important local differences are masked when examining trends at the country level. These fine-scale estimates of HIV prevalence across space and time provide an important tool for precisely targeting the interventions that are necessary to bringing HIV infections under control in sub-Saharan Africa.

Risk factors for death among children 0-59 months of age with moderate-to-severe diarrhea in Manhiça district, southern Mozambique.

BACKGROUND: Despite major improvements in child survival rates, the number of deaths due to diarrhea remains unacceptably high. We aimed to describe diarrhea-associated mortality and evaluate risk factors for death among Mozambican children with moderate-to-severe diarrhea (MSD). METHODS: Between December 2007 and November 2012, children under-five with MSD were enrolled in Manhiça district, as part of the Global Enteric Multicenter study (GEMS). Clinical, epidemiological, and socio-demographic characteristics were collected. Anthropometric measurements were performed and stool samples collected upon recruitment. A follow-up visit ~ 60 days post-enrolment was conducted and verbal autopsies performed in all death cases. RESULTS: Of the 916 MSD-cases analyzed; 90% (821/916) completed 60 days follow-up and 69 patients died. The case fatality rate at follow-up was 8% (69/821), and the mortality rate 10.2 (95%CI: 7.75-13.59) deaths per 1000 persons-week at risk. Nearly half of the deaths 48% (33/69) among study participants clustered within 2 weeks of the onset of diarrhea. Typical enteropathogenic Escherichia coli (typical EPEC) and Cryptosporidium were the two pathogens associated to an increased risk of death in the univariate analysis with (HR = 4.16, p = 0.0461) and (H = 2.84, p = 0.0001) respectively. Conversely, Rotavirus infection was associated to a decreased risk of death (HR = 0.52, p = 0.0198). According to the multivariate analysis, risk factors for death included co-morbidities such as malnutrition (HR = 4.13, p <  0.0001), pneumonia/lower respiratory infection (HR = 3.51, p <  0.0001) or invasive bacterial disease (IBD) (HR = 6.80, p = 0.0009), presenting on arrival with lethargy or overt unconsciousness (HR = 1.73, p = 0.0302) or wrinkled skin (HR = 1.71, p = 0.0393), and cryptosporidium infection (HR = 2.14, p = 0.0038). When restricting the analysis to those with available HIV results (n = 191, 22% of the total study sample), HIV was shown to be a significant risk factor for death (HR = 5.05, p = 0.0009). Verbal autopsies were conducted in 100% of study deaths, and highlighted diarrhea as the main underlying cause of death 39%, (27/69); followed by HIV/AIDS related deaths 29.0% (20/69) and sepsis 11.6% (8/69). CONCLUSION: Preventive strategies targeting Cryptosporidium, malnutrition and early identification and treatment of associated co-morbidities could contribute to the prevention of the majority of diarrhea associated deaths in Mozambican children.

The incidence, aetiology, and adverse clinical consequences of less severe diarrhoeal episodes among infants and children residing in low-income and middle-income countries: a 12-month case-control study as a follow-on to the Global Enteric Multicenter Study (GEMS).

BACKGROUND: Diarrheal diseases remain a leading cause of illness and death among children younger than 5 years in low-income and middle-income countries. The Global Enteric Multicenter Study (GEMS) has described the incidence, aetiology, and sequelae of medically attended moderate-to-severe diarrhoea (MSD) among children aged 0-59 months residing in censused populations in sub-Saharan Africa and south Asia, where most child deaths occur. To further characterise this disease burden and guide interventions, we extended this study to include children with episodes of less-severe diarrhoea (LSD) seeking care at health centres serving six GEMS sites. METHODS: We report a 1-year, multisite, age-stratified, matched case-control study following on to the GEMS study. Six sites (Bamako, Mali; Manhiça, Mozambique; Basse, The Gambia; Mirzapur, Bangladesh; Kolkata, India; and Bin Qasim Town, Karachi, Pakistan) participated in this study. Children aged 0-59 months at each site who sought care at a sentinel hospital or health centre during a 12-month period were screened for diarrhoea. New (onset after ≥7 diarrhoea-free days) and acute (onset within the previous 7 days) episodes of diarrhoea in children who had sunken eyes, whose skin lost turgor, who received intravenous hydration, who had dysentery, or who were hospitalised were eligible for inclusion as MSD. The remaining new and acute diarrhoea episodes among children who sought care at the same health centres were considered LSD. We aimed to enrol the first eight or nine eligible children with MSD and LSD at each site during each fortnight in three age strata: infants (aged 0-11 months), toddlers (aged 12-23 months), and young children (aged 24-59 months). For each included case of MSD or LSD, we enrolled one to three community control children without diarrhoea during the previous 7 days. From patients and controls we collected clinical and epidemiological data, anthropometric measurements, and faecal samples to identify enteropathogens at enrolment, and we performed a follow-up home visit about 60 days later to ascertain vital status, clinical outcome, and interval growth. Primary outcomes were to characterise, for MSD and LSD, the pathogen-specific attributable risk and population-based incidence values, and to assess the frequency of adverse clinical consequences associated with these two diarrhoeal syndromes. FINDINGS: From Oct 31, 2011, to Nov 14, 2012, we recruited 2368 children with MSD, 3174 with LSD, and one to three randomly selected community control children without diarrhoea matched to cases with MSD (n=3597) or LSD (n=4236). Weighted adjusted population attributable fractions showed that most attributable cases of MSD and LSD were due to rotavirus, Cryptosporidium spp, enterotoxigenic Escherichia coli encoding heat-stable toxin (with or without genes encoding heat-labile enterotoxin), and Shigella spp. The attributable incidence per 100 child-years for LSD versus MSD, by age stratum, for rotavirus was 22·3 versus 5·5 (0-11 months), 9·8 versus 2·9 (12-23 months), and 0·5 versus 0·2 (24-59 months); for Cryptosporidium spp was 3·6 versus 2·3 (0-11 months), 4·3 versus 0·6 (12-23 months), and 0·3 versus 0·1 (24-59 months); for enterotoxigenic E coli encoding heat-stable toxin was 4·2 versus 0·1 (0-11 months), 5·2 versus 0·0 (12-23 months), and 1·1 versus 0·2 (24-59 months); and for Shigella spp was 1·0 versus 1·3 (0-11 months), 3·1 versus 2·4 (12-23 months), and 0·8 versus 0·7 (24-59 months). Participants with both MSD and LSD had significantly more linear growth faltering than controls at follow-up. INTERPRETATION: Inclusion of participants with LSD markedly expands the population of children who experience adverse clinical and nutritional outcomes from acute diarrhoeal diseases. Since MSD and LSD have similar aetiologies, interventions targeting rotavirus, Shigella spp, enterotoxigenic E coli producing heat-stable toxin, and Cryptosporidium spp might substantially reduce the diarrhoeal disease burden and its associated nutritional faltering. FUNDING: Bill & Melinda Gates Foundation.

Colonization factors among enterotoxigenic Escherichia coli isolates from children with moderate-to-severe diarrhea and from matched controls in the Global Enteric Multicenter Study (GEMS).

BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) encoding heat-stable enterotoxin (ST) alone or with heat-labile enterotoxin (LT) cause moderate-to-severe diarrhea (MSD) in developing country children. The Global Enteric Multicenter Study (GEMS) identified ETEC encoding ST among the top four enteropathogens. Since the GEMS objective was to provide evidence to guide development and implementation of enteric vaccines and other interventions to diminish diarrheal disease morbidity and mortality, we examined colonization factor (CF) prevalence among ETEC isolates from children age <5 years with MSD and from matched controls in four African and three Asian sites. We also assessed strength of association of specific CFs with MSD. METHODOLOGY/PRINCIPAL FINDINGS: MSD cases enrolled at healthcare facilities over three years and matched controls were tested in a standardized manner for many enteropathogens. To identify ETEC, three E. coli colonies per child were tested by polymerase chain reaction (PCR) to detect genes encoding LT, ST; confirmed ETEC were examined by PCR for major CFs (Colonization Factor Antigen I [CFA/I] or Coli Surface [CS] antigens CS1-CS6) and minor CFs (CS7, CS12, CS13, CS14, CS17, CS18, CS19, CS20, CS21, CS30). ETEC from 806 cases had a single toxin/CF profile in three tested strains per child. Major CFs, components of multiple ETEC vaccine candidates, were detected in 66.0% of LT/ST and ST-only cases and were associated with MSD versus matched controls by conditional logistic regression (p≤0.006); major CFs detected in only 25.0% of LT-only cases weren't associated with MSD. ETEC encoding exclusively CS14, identified among 19.9% of 291 ST-only and 1.5% of 259 LT/ST strains, were associated with MSD (p = 0.0011). No other minor CF exhibited prevalence ≥5% and significant association with MSD. CONCLUSIONS/SIGNIFICANCE: Major CF-based efficacious ETEC vaccines could potentially prevent up to 66% of pediatric MSD cases due to ST-encoding ETEC in developing countries; adding CS14 extends coverage to ~77%.

Clinical features, risk factors, and impact of antibiotic treatment of diarrhea caused by Shigella in children less than 5 years in Manhiça District, rural Mozambique.

OBJECTIVES: During the period from December 2007 to November 2012, the epidemiology of diarrhea caused by Shigella was studied among children <5 years of age residing in Manhiça District, Southern Mozambique. MATERIALS AND METHODS: Children from 0 to 5 years with moderate-to-severe diarrhea (MSD) and less severe diarrhea (LSD) were enrolled along with matched controls (by age, gender, and neighborhood). Age-stratified logistic regression analyses were conducted to identify clinical features and risk factors associated with Shigella positivity in cases of diarrhea. The impact of antibiotic treatment was assessed for patients with known outcome. RESULTS: A total of 916 cases of MSD and 1979 matched controls, and 431 cases of LSD with equal number of controls were enrolled. Shigella was identified as significant pathogen in both cases of MSD and LSD compared to their respective controls. Shigella was detected in 3.9% (17/431) of LSD compared to 0.5% (2/431) in controls (P=0.001) and in 6.1% (56/916) of MSD cases compared to 0.2% (4/1979) in controls (P<0.0001), with an attributable fraction of 8.55% (95% CI: 7.86-9.24) among children aged 12-23 months. Clinical symptoms associated to Shigella among MSD cases included dysentery, fever, and rectal prolapse. Water availability, giving stored water to child, washing hands before preparing baby's food, and mother as caretaker were the protective factors against acquiring diarrhea caused by Shigella. Antibiotic treatment on admission was associated with a positive children outcome. CONCLUSION: Shigella remains a common pathogen associated with childhood diarrhea in Mozambique, with dysentery being a significant clinical feature of shigellosis. Adherence to the basic hygiene rules and the use of antibiotic treatment could contribute to the prevention of most of diarrhea due to Shigella.

Variation in Childhood Diarrheal Morbidity and Mortality in Africa, 2000-2015.

BACKGROUND: Diarrheal diseases are the third leading cause of disease and death in children younger than 5 years of age in Africa and were responsible for an estimated 30 million cases of severe diarrhea (95% credible interval, 27 million to 33 million) and 330,000 deaths (95% credible interval, 270,000 to 380,000) in 2015. The development of targeted approaches to address this burden has been hampered by a paucity of comprehensive, fine-scale estimates of diarrhea-related disease and death among and within countries. METHODS: We produced annual estimates of the prevalence and incidence of diarrhea and diarrhea-related mortality with high geographic detail (5 km2) across Africa from 2000 through 2015. Estimates were created with the use of Bayesian geostatistical techniques and were calibrated to the results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016. RESULTS: The results revealed geographic inequality with regard to diarrhea risk in Africa. Of the estimated 330,000 childhood deaths that were attributable to diarrhea in 2015, more than 50% occurred in 55 of the 782 first-level administrative subdivisions (e.g., states). In 2015, mortality rates among first-level administrative subdivisions in Nigeria differed by up to a factor of 6. The case fatality rates were highly varied at the national level across Africa, with the highest values observed in Benin, Lesotho, Mali, Nigeria, and Sierra Leone. CONCLUSIONS: Our findings showed concentrated areas of diarrheal disease and diarrhea-related death in countries that had a consistently high burden as well as in countries that had considerable national-level reductions in diarrhea burden. (Funded by the Bill and Melinda Gates Foundation.).

Water, Sanitation, and Hygiene Characteristics among HIV-Positive Households Participating in the Global Enteric Multicenter Study in Rural Western Kenya, 2008-2012.

Diarrheal illness, a common occurrence among people living with human immunodeficiency virus (PLHIV), is largely preventable through access to safe drinking water quality, sanitation, and hygiene (WASH) facilities. We examined WASH characteristics among households with and without HIV-positive residents enrolled in the Global Enteric Multicenter Study (GEMS) in rural Western Kenya. Using univariable logistic regression, we examined differences between HIV-positive and HIV-negative households in regard to WASH practices. Among HIV-positive households, we explored the relationship between the length of time knowing their HIV status and GEMS enrollment. No statistically significant differences were apparent in the WASH characteristics among HIV-positive and HIV-negative households. However, we found differences in the WASH characteristics among HIV-positive households who were aware of their HIV status ≥ 30 days before enrollment compared with HIV-positive households who found out their status < 30 days before enrollment or thereafter. Significantly more households aware of their HIV-positive status before enrollment reported treating their drinking water (odds ratio [OR] confidence interval [CI]: 2.34 [1.12, 4.86]) and using effective water treatment methods (OR [CI]: 9.6 [3.09, 29.86]), and had better drinking water storage practices. This suggests that within this region of Kenya, HIV programs are effective in promoting the importance of practicing positive WASH-related behaviors among PLHIV.

Clinical, environmental, and behavioral characteristics associated with Cryptosporidium infection among children with moderate-to-severe diarrhea in rural western Kenya, 2008-2012: The Global Enteric Multicenter Study (GEMS).

BACKGROUND: Cryptosporidium is a leading cause of moderate-to-severe diarrhea (MSD) in young children in Africa. We examined factors associated with Cryptosporidium infection in MSD cases enrolled at the rural western Kenya Global Enteric Multicenter Study (GEMS) site from 2008-2012. METHODOLOGY/PRINCIPAL FINDINGS: At health facility enrollment, stool samples were tested for enteric pathogens and data on clinical, environmental, and behavioral characteristics collected. Each child's health status was recorded at 60-day follow-up. Data were analyzed using logistic regression. Of the 1,778 children with MSD enrolled as cases in the GEMS-Kenya case-control study, 11% had Cryptosporidium detected in stool by enzyme immunoassay; in a genotyped subset, 81% were C. hominis. Among MSD cases, being an infant, having mucus in stool, and having prolonged/persistent duration diarrhea were associated with being Cryptosporidium-positive. Both boiling drinking water and using rainwater as the main drinking water source were protective factors for being Cryptosporidium-positive. At follow-up, Cryptosporidium-positive cases had increased odds of being stunted (adjusted odds ratio [aOR] = 1.65, 95% CI: 1.06-2.57), underweight (aOR = 2.08, 95% CI: 1.34-3.22), or wasted (aOR = 2.04, 95% CI: 1.21-3.43), and had significantly larger negative changes in height- and weight-for-age z-scores from enrollment. CONCLUSIONS/SIGNIFICANCE: Cryptosporidium contributes significantly to diarrheal illness in young children in western Kenya. Advances in point of care detection, prevention/control approaches, effective water treatment technologies, and clinical management options for children with cryptosporidiosis are needed.

The role of HIV infection in the etiology and epidemiology of diarrheal disease among children aged 0-59 months in Manhiça District, Rural Mozambique.

BACKGROUND: Diarrhea is an important health problem among HIV-infected patients. This study evaluated the role of HIV in the epidemiology, etiology, and severity of diarrheal disease among children. METHODS: The Global Enteric Multicenter Study enrolled children with moderate-to-severe diarrhea (MSD) and less-severe diarrhea (LSD) between December 2007 and November 2012. One to three controls for MSD cases and one per LSD case were enrolled and matched by age, sex, and neighborhood. All children were tested for HIV. Clinical data, anthropometric data, and stool samples were collected. Follow-up was performed at 60 days. RESULTS: Two hundred and fourteen MSD cases and 418 controls, together with 349 LSD cases and 214 controls were tested. HIV prevalence was 25% among MSD cases (4% for matched controls) and 6% among LSD cases (6% among matched controls). HIV-infected children were more likely to have MSD (odds ratio 5.6, p<0.0001). Mortality rates were higher among HIV-infected children than among the uninfected (34 vs. 5 per 1000 child-weeks at risk; p=0.0039). Cryptosporidium, Giardia, and enteroaggregative Escherichia coli (aatA only) were more prevalent among HIV-infected MSD cases than among uninfected ones. CONCLUSION: HIV is an important risk factor for MSD. The high mortality rate implies that children with MSD should be screened for HIV and managed accordingly.

The effect of costs on Kenyan households' demand for medical care: why time and distance matter.

In an environment of constrained resources, policymakers must identify solutions for financing and delivering health services that are efficient and sustainable. However, such solutions require that policymakers understand the complex interaction between household utilization patterns, factors influencing household medical decisions, and provider performance. This study examined whether and under what conditions out-of-pocket, transportation, and time costs influenced Kenyan households' choice of medical provider for childhood diarrhoeal illnesses. It compared these decisions with the actual cost and quality of those providers to assess strategies for increasing the utilization of high quality, low-cost primary care. This study analyzed nationally-representative survey data through several multinomial nested logit models. On average, time costs accounted for the greatest share of total costs. Households spent the most time and transportation costs utilizing public care, yet were more likely to incur catastrophic time and out-of-pocket costs seeking private care for their child's diarrhoeal illness. Out-of-pocket, transportation, and time costs influenced households' choice of provider, though demand was cost inelastic and households were most responsive to transportation costs. Poorer households were the most responsive to changes in all cost types and most likely to self-treat or utilize informal care. Many households utilized informal care that, relative to formal care, cost the same but was of worse quality-suggesting that such households were making poor medical decisions for their children. To achieve public policy objectives, such as financial risk protection for childhood illnesses and equitable access to primary care, policymakers could focus on three areas: (1) refine financing strategies for further reducing household out-of-pocket costs; (2) reduce or subsidize time and transportation costs for households seeking public and private care; and (3) increase transparency of costs and quality to improve household decisions.

Mapping under-5 and neonatal mortality in Africa, 2000-15: a baseline analysis for the Sustainable Development Goals.

BACKGROUND: During the Millennium Development Goal (MDG) era, many countries in Africa achieved marked reductions in under-5 and neonatal mortality. Yet the pace of progress toward these goals substantially varied at the national level, demonstrating an essential need for tracking even more local trends in child mortality. With the adoption of the Sustainable Development Goals (SDGs) in 2015, which established ambitious targets for improving child survival by 2030, optimal intervention planning and targeting will require understanding of trends and rates of progress at a higher spatial resolution. In this study, we aimed to generate high-resolution estimates of under-5 and neonatal all-cause mortality across 46 countries in Africa. METHODS: We assembled 235 geographically resolved household survey and census data sources on child deaths to produce estimates of under-5 and neonatal mortality at a resolution of 5 × 5 km grid cells across 46 African countries for 2000, 2005, 2010, and 2015. We used a Bayesian geostatistical analytical framework to generate these estimates, and implemented predictive validity tests. In addition to reporting 5 × 5 km estimates, we also aggregated results obtained from these estimates into three different levels-national, and subnational administrative levels 1 and 2-to provide the full range of geospatial resolution that local, national, and global decision makers might require. FINDINGS: Amid improving child survival in Africa, there was substantial heterogeneity in absolute levels of under-5 and neonatal mortality in 2015, as well as the annualised rates of decline achieved from 2000 to 2015. Subnational areas in countries such as Botswana, Rwanda, and Ethiopia recorded some of the largest decreases in child mortality rates since 2000, positioning them well to achieve SDG targets by 2030 or earlier. Yet these places were the exception for Africa, since many areas, particularly in central and western Africa, must reduce under-5 mortality rates by at least 8·8% per year, between 2015 and 2030, to achieve the SDG 3.2 target for under-5 mortality by 2030. INTERPRETATION: In the absence of unprecedented political commitment, financial support, and medical advances, the viability of SDG 3.2 achievement in Africa is precarious at best. By producing under-5 and neonatal mortality rates at multiple levels of geospatial resolution over time, this study provides key information for decision makers to target interventions at populations in the greatest need. In an era when precision public health increasingly has the potential to transform the design, implementation, and impact of health programmes, our 5 × 5 km estimates of child mortality in Africa provide a baseline against which local, national, and global stakeholders can map the pathways for ending preventable child deaths by 2030. FUNDING: Bill & Melinda Gates Foundation.