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INTRODUCTION: Children with moderate or severe wasting are at particularly high risk of recurrent or persistent diarrhoea, nutritional deterioration and death following a diarrhoeal episode. Lactoferrin and lysozyme are nutritional supplements that may reduce the risk of recurrent diarrhoeal episodes and accelerate nutritional recovery by treating or preventing underlying enteric infections and/or improving enteric function. METHODS AND ANALYSIS: In this factorial, blinded, placebo-controlled randomised trial, we aim to determine the efficacy of lactoferrin and lysozyme supplementation in decreasing diarrhoea incidence and improving nutritional recovery in Kenyan children convalescing from comorbid diarrhoea and wasting. Six hundred children aged 6-24 months with mid-upper arm circumference <12.5 cm who are returning home after an outpatient visit or inpatient hospital stay for diarrhoea will be enrolled. Children will be randomised to 16 weeks of lactoferrin, lysozyme, a combination of the two, or placebo and followed for 24 weeks, with biweekly home visits by community health workers and clinic visits at 4, 10, 16 and 24 weeks. The primary analysis will compare the incidence of moderate-to-severe diarrhoea and time to nutritional recovery between each intervention arm and placebo. The trial will also test whether these interventions reduce enteric pathogen carriage, decrease enteric permeability and/or increase haemoglobin concentration in enrolled children. Finally, we will evaluate the acceptability, adherence and cost-effectiveness of lactoferrin and/or lysozyme. ETHICS AND DISSEMINATION: The trial has been approved by the institutional review boards of the Kenya Medical Research Institute, the University of Washington, the Kenyan Pharmacy and Poisons Board, and the Kenyan National Commission on Science, Technology and Innovation. The results of this trial will be shared with local and international stakeholders and published in peer-reviewed journals, and the key findings will be presented at relevant conferences. TRIAL REGISTRATION NUMBER: NCT05519254, PACTR202108480098476.
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Diarrea , Suplementos Dietéticos , Lactoferrina , Muramidasa , Humanos , Lactoferrina/uso terapéutico , Lactante , Muramidasa/uso terapéutico , Kenia/epidemiología , Preescolar , Ensayos Clínicos Controlados Aleatorios como Asunto , Femenino , MasculinoRESUMEN
BACKGROUND: Clinical trial scenarios can be modeled using data from observational studies, providing critical information for design of real-world trials. The Huntington's Disease Integrated Staging System (HD-ISS) characterizes disease progression over an individual's lifespan and allows for flexibility in the design of trials with the goal of delaying progression. Enrichment methods can be applied to the HD-ISS to identify subgroups requiring smaller estimated sample sizes. OBJECTIVE: Investigate time to the event of functional decline (HD-ISS Stage 3) as an endpoint for trials in HD and present sample size estimates after enrichment. METHODS: We classified individuals from observational studies according to the HD-ISS. We assessed the ability of the prognostic index normed (PIN) and its components to predict time to HD-ISS Stage 3. For enrichment, we formed groups from deciles of the baseline PIN distribution for HD-ISS Stage 2 participants. We selected enrichment subgroups closer to Stage 3 transition and estimated sample sizes, using delay in the transition time as the effect size. RESULTS: In predicting time to HD-ISS Stage 3, PIN outperforms its components. Survival curves for each PIN decile show that groups with PIN from 1.48 to 2.74 have median time to Stage 3 of approximately 2 years and these are combined to create enrichment subgroups. Sample size estimates are presented by enrichment subgroup. CONCLUSIONS: PIN is predictive of functional decline. A delay of 9 months or more in the transition to Stage 3 for an enriched sample yields feasible sample size estimates, demonstrating that this approach can aid in planning future trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Attributing infectious causes of diarrhea is critical to inform treatment and burden estimates. The attributable fraction (AF) approach based on the association between pathogen quantity and diarrhea has been frequently used but may underestimate incidence. We leveraged data from the multisite birth-cohort Malnutrition and Enteric Disease (MAL-ED) Study, where diarrheal and non-diarrheal stools were collected from 1,715 children from 0-2 years. We compared attribution using a longitudinal AF (LAF) method that considers the temporal association between pathogen quantity and diarrhea symptoms to previously-published AF estimates. For rotavirus and Shigella, attribution did not meaningfully change. For others like adenovirus 40 & 41, astrovirus, norovirus GII, sapovirus, Campylobacter jejuni or C coli, ST ETEC, typical EPEC, and Cryptosporidium, attribution increased, demonstrating longitudinal data may be informative for pathogens with weak associations between quantity and diarrhea. We further derived accuracy-based, pathogen-specific quantity cut-offs that may improve attribution in the absence of longitudinal data.
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OBJECTIVE: To evaluate in a rural Tanzanian birth cohort the association between birth timing in relation to the preharvest lean season and early-life growth and cognitive development. STUDY DESIGN: Children were enrolled within 14 days of birth and followed up for 18 months. Child anthropometry was measured every 3 months. The Malawi Developmental Assessment Test was administered at the end of follow-up. We estimated the association between timing of birth in the context of other early childhood risk factors and both growth and Malawi Developmental Assessment Test scores. RESULTS: Children born in the preharvest months September and October had the lowest cognitive scores at 18 months, compared with birth in July and August (-1.05 change in overall Malawi Developmental Assessment Test development-for-age Z score, 95% CI: -1.23, -0.86). This association was observed for the language (-1.67 change in development-for-age Z score; 95% CI: -1.93, -1.40) and fine motor subcomponent scores (-1.67; 95% CI: -1.96, -1.38) but not for gross motor (-0.07; 95% CI: -0.23, 0.10) or social subcomponents (-0.07; 95% CI: -0.23, 0.10). Children born in September and October were the longest at birth but had the largest declines in growth Z scores during the first 6 months. CONCLUSIONS: There was a strong association between birth at the beginning of the preharvest season and poor growth and cognitive development. If these associations were mediated by the preharvest postnatal environment, targeted maternal and child interventions for children born during high-risk periods may improve these outcomes. TRIAL REGISTRATION: NCT03268902 (https://clinicaltrials.gov/study/NCT03268902).
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To evaluate how breakthrough rotavirus disease contributes to transmission, we examined the impact of rotavirus vaccination on fecal shedding and duration of illness. We used multivariable linear regression to analyze rotavirus quantity by RT-qPCR and duration among 184 episodes of rotavirus diarrhea positive by ELISA in the PROVIDE study. Vaccinated children had less fecal viral shedding compared to unvaccinated children (mean difference = -0.59 log copies per gram of stool; 95% confidence interval [CI], -.99 to -.19). Duration of illness was on average 0.47 days (95% CI, -.23 to 1.17 days) shorter among vaccinated children. Rotarix vaccination reduces shedding burden among breakthrough cases of rotavirus gastroenteritis. Clinical Trials Registration . NCT01375647.
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Heces , Infecciones por Rotavirus , Vacunas contra Rotavirus , Rotavirus , Vacunas Atenuadas , Esparcimiento de Virus , Humanos , Vacunas contra Rotavirus/administración & dosificación , Vacunas contra Rotavirus/inmunología , Infecciones por Rotavirus/prevención & control , Infecciones por Rotavirus/epidemiología , Infecciones por Rotavirus/virología , Lactante , Bangladesh/epidemiología , Rotavirus/inmunología , Heces/virología , Femenino , Masculino , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología , Gastroenteritis/virología , Gastroenteritis/prevención & control , Gastroenteritis/epidemiología , Vacunación , Diarrea/virología , Diarrea/prevención & control , Diarrea/epidemiología , Administración OralRESUMEN
Purpose: Monotherapy with vancomycin or daptomycin remains guideline-based care for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) despite concerns regarding efficacy. Limited data support potential benefit of combination therapy with ceftaroline as initial therapy. We present an assessment of outcomes of patients initiated on early combination therapy for MRSA-B. Methods: This was a single-center, retrospective study of adult patients admitted with MRSA-B between July 1, 2017 and April 31, 2023. During this period, there was a change in institutional practice from routine administration of monotherapy to initial combination therapy for most patients with MRSA-B. Combination therapy included vancomycin or daptomycin plus ceftaroline within 72 hours of index blood culture and monotherapy was vancomycin or daptomycin alone. The primary outcome was a composite of persistent bacteremia, 30-day all-cause mortality, and 30-day bacteremia recurrence. Time to microbiological cure and safety outcomes were assessed. All outcomes were assessed using propensity score-weighted logistic regression. Results: Of 213 patients included, 118 received monotherapy (115 vancomycin, 3 daptomycin) and 95 received combination therapy with ceftaroline (76 vancomycin, 19 daptomycin). The mean time from MRSA-positive molecular diagnostic blood culture result to combination therapy was 12.1 hours. There was no difference between groups for the primary composite outcome (OR 1.58, 95% CI 0.60, 4.18). Time to microbiological cure was longer with combination therapy (mean difference 1.50 days, 95% CI 0.60, 2.41). Adverse event rates were similar in both groups. Conclusions: Early initiation of ceftaroline-based combination therapy did not improve outcomes for patients with MRSA-B in comparison to monotherapy therapy.
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Background: Water, sanitation, hygiene (WSH), nutrition (N), and combined (N+WSH) interventions are often implemented by global health organizations, but WSH interventions may insufficiently reduce pathogen exposure, and nutrition interventions may be modified by environmental enteric dysfunction (EED), a condition of increased intestinal permeability and inflammation. This study investigated the heterogeneity of these treatments' effects based on individual pathogen and EED biomarker status with respect to child linear growth. Methods: We applied cross-validated targeted maximum likelihood estimation and super learner ensemble machine learning to assess the conditional treatment effects in subgroups defined by biomarker and pathogen status. We analyzed treatment (N+WSH, WSH, N, or control) randomly assigned in-utero, child pathogen and EED data at 14 months of age, and child LAZ at 28 months of age. We estimated the difference in mean child length for age Z-score (LAZ) under the treatment rule and the difference in stratified treatment effect (treatment effect difference) comparing children with high versus low pathogen/biomarker status while controlling for baseline covariates. Results: We analyzed data from 1,522 children, who had median LAZ of -1.56. We found that myeloperoxidase (N+WSH treatment effect difference 0.0007 LAZ, WSH treatment effect difference 0.1032 LAZ, N treatment effect difference 0.0037 LAZ) and Campylobacter infection (N+WSH treatment effect difference 0.0011 LAZ, WSH difference 0.0119 LAZ, N difference 0.0255 LAZ) were associated with greater effect of all interventions on growth. In other words, children with high myeloperoxidase or Campylobacter infection experienced a greater impact of the interventions on growth. We found that a treatment rule that assigned the N+WSH (LAZ difference 0.23, 95% CI (0.05, 0.41)) and WSH (LAZ difference 0.17, 95% CI (0.04, 0.30)) interventions based on EED biomarkers and pathogens increased predicted child growth compared to the randomly allocated intervention. Conclusions: These findings indicate that EED biomarker and pathogen status, particularly Campylobacter and myeloperoxidase (a measure of gut inflammation), may be related to impact of N+WSH, WSH, and N interventions on child linear growth.
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This study examined the relative proportion of enteric pathogens associated with severe gastroenteritis (GE) among children younger than 2 years in a phase III efficacy trial of the ROTASIIL® vaccine in India, evaluated the impact of co-infections on vaccine efficacy (VE), and characterized the association between specific pathogens and the clinical profile of severe GE. Stored stool samples collected from cases of severe GE in the phase III trial were tested by quantitative polymerase chain reaction using TaqMan™ Array Cards. Etiology was attributed by calculating the adjusted attributable fraction (AF) for each pathogen. A test-negative design was used to estimate VE. The pathogens with the highest AFs for severe diarrhea were rotavirus (23.5%), adenovirus 40/41 (17.0%), Shigella spp./enteroinvasive Escherichia coli, norovirus GII, enterotoxigenic E. coli, and Cryptosporidium spp. A considerable proportion of the disease in these children could not be explained by the pathogens tested. Severe GE cases associated with rotavirus and Shigella spp. were more likely to have a longer duration of vomiting and diarrhea, respectively. Cases attributed to Cryptosporidium spp. were more severe and required hospitalization. In the intention-to-treat population, VE was estimated to be 43.9% before and 46.5% after adjustment for co-infections; in the per-protocol population, VE was 46.7% before and 49.1% after adjustments. Rotavirus continued to be the leading cause of severe GE in this age group. The adjusted VE estimates obtained did not support co-infections as a major cause of lower vaccine performance in low- and middle-income countries.
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Coinfección , Diarrea , Gastroenteritis , Infecciones por Rotavirus , Vacunas contra Rotavirus , Rotavirus , Humanos , Vacunas contra Rotavirus/uso terapéutico , Vacunas contra Rotavirus/inmunología , Vacunas contra Rotavirus/administración & dosificación , Lactante , Gastroenteritis/virología , Gastroenteritis/microbiología , Gastroenteritis/prevención & control , Infecciones por Rotavirus/prevención & control , Infecciones por Rotavirus/epidemiología , Diarrea/virología , Diarrea/microbiología , Diarrea/prevención & control , Diarrea/epidemiología , Coinfección/microbiología , Coinfección/virología , Rotavirus/inmunología , Femenino , Eficacia de las Vacunas , Shigella/inmunología , Masculino , India/epidemiología , Heces/virología , Heces/microbiología , Vacunas Atenuadas , Norovirus/inmunología , Escherichia coli Enterotoxigénica/inmunologíaRESUMEN
BACKGROUND: Information on the causes of deaths from diarrhoea in children younger than 5 years is needed to design improved preventive and therapeutic approaches. We aimed to conduct a systematic analysis of studies to report estimates of the causes of deaths from diarrhoea in children younger than 5 years at global and regional levels during 2000-21. METHODS: For this systematic review and Bayesian multinomial analysis, we included 12 pathogens with the highest attributable incidence in the Global Enteric Multicenter Study. We searched PubMed, Scopus, Embase, Web of Science, Global Health Index Medicus, Global Health OVID, IndMed, Health Information Platform for the Americas (PLISA), Africa-Wide Information, and Cochrane Collaboration for articles published between Jan 1, 2000, and Dec 31, 2020, using the search terms "child", "hospital", "diarrhea", "diarrhoea", "dysentery", "rotavirus", "Escherichia coli", "salmonella", "shigella", "campylobacter", "Vibrio cholerae", "cryptosporidium", "norovirus", "astrovirus", "sapovirus", and "adenovirus". To be included, studies had to have a patient population of children younger than 5 years who were hospitalised for diarrhoea (at least 90% of study participants), at least a 12-month duration, reported prevalence in diarrhoeal stools of at least two of the 12 pathogens, all patients with diarrhoea being included at the study site or a systematic sample, at least 100 patients with diarrhoea, laboratory tests done on rectal swabs or stool samples, and standard laboratory methods (ie, quantitative PCR [qPCR] or non-qPCR). Studies published in any language were included. Studies were excluded if they were limited to nosocomial, chronic, antibiotic-associated, or outbreak diarrhoea or to a specific population (eg, only children with HIV or AIDS). Each article was independently reviewed by two researchers; a third arbitrated in case of disagreement. If both reviewers identified an exclusion criterion, the study was excluded. Data sought were summary estimates. Data on causes from published studies were adjusted when necessary to account for the poor sensitivity of non-qPCR methods and for attributable fraction based on quantification of pathogens in children who are ill or non-ill. The causes of deaths from diarrhoea were modelled on the causes of hospitalisations for diarrhoea. We separately modelled studies reporting causes of diarrhoea in children who were hospitalised in low-income and middle-income countries (LMICs) and in high-income countries (HICs). FINDINGS: Of 74â282 papers identified in the initial database search, we included 138 studies (91 included data from LMICs and 47 included data from HICs) from 73 countries. We modelled estimates for 194 WHO member states (hereafter referred to as countries), including 42 HICs and 152 LMICs. We could attribute a cause to 1â003â448 (83·8%) of the estimated 1â197â044 global deaths from diarrhoea in children younger than 5 years in 2000 and 360â730 (81·3%) of the estimated 443â833 global deaths from diarrhoea in children younger than 5 years in 2021. The cause with the largest estimated global attribution was rotavirus; in LMICs, the proportion of deaths from diarrhoea due to rotavirus in children younger than 5 years appeared lower in 2021 (108â322 [24·4%] of 443â342, 95% uncertainty interval 21·6-29·5) than in 2000 (316â382 [26·5%] of 1â196â134, 25·7-28·5), but the 95% CIs overlapped. In 2000, the second largest estimated attribution was norovirus GII (95â817 [8·0%] of 1â196â134 in LMICs and 225 [24·7%] of 910 in HICs); in 2021, Shigella sp had the second largest estimated attribution in LMICs (36â082 [8·1%] of 443â342), but norovirus remained with the second largest estimated attribution in HICs (84 [17·1%] of 490). INTERPRETATION: Our results indicate progress in the reduction of deaths from diarrhoea caused by 12 pathogens in children younger than 5 years in the past two decades. There is a need to increase efforts for prevention, including with rotavirus vaccine, and treatment to eliminate further deaths. FUNDING: Bill & Melinda Gates Foundation via Johns Hopkins University and the University of Virginia.
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Teorema de Bayes , Causas de Muerte , Diarrea , Salud Global , Humanos , Diarrea/epidemiología , Diarrea/mortalidad , Diarrea/virología , Lactante , Preescolar , Salud Global/estadística & datos numéricos , Recién NacidoRESUMEN
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.
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Background: Shigella is a leading cause of acute watery diarrhea, dysentery, and diarrhea-attributed linear growth faltering, a precursor to stunting and lifelong morbidity. Several promising Shigella vaccines are in development and field efficacy trials will require a consortium of potential vaccine trial sites with up-to-date Shigella diarrhea incidence data. Methods: The Enterics for Global Health (EFGH) Shigella surveillance study will employ facility-based enrollment of diarrhea cases aged 6-35 months with 3 months of follow-up to establish incidence rates and document clinical, anthropometric, and financial consequences of Shigella diarrhea at 7 country sites (Mali, Kenya, The Gambia, Malawi, Bangladesh, Pakistan, and Peru). Over a 24-month period between 2022 and 2024, the EFGH study aims to enroll 9800 children (1400 per country site) between 6 and 35 months of age who present to local health facilities with diarrhea. Shigella species (spp.) will be identified and serotyped from rectal swabs by conventional microbiologic methods and quantitative polymerase chain reaction. Shigella spp. isolates will undergo serotyping and antimicrobial susceptibility testing. Incorporating population and healthcare utilization estimates from contemporaneous household sampling in the catchment areas of enrollment facilities, we will estimate Shigella diarrhea incidence rates. Conclusions: This multicountry surveillance network will provide key incidence data needed to design Shigella vaccine trials and strengthen readiness for potential trial implementation. Data collected in EFGH will inform policy makers about the relative importance of this vaccine-preventable disease, accelerating the time to vaccine availability and uptake among children in high-burden settings.
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Background: Molecular diagnostics on human fecal samples have identified a larger burden of shigellosis than previously appreciated by culture. Evidence of fold changes in immunoglobulin G (IgG) to conserved and type-specific Shigella antigens could be used to validate the molecular assignment of type-specific Shigella as the etiology of acute diarrhea and support polymerase chain reaction (PCR)-based microbiologic end points for vaccine trials. Methods: We will test dried blood spots collected at enrollment and 4 weeks later using bead-based immunoassays for IgG to invasion plasmid antigen B and type-specific lipopolysaccharide O-antigen for Shigella flexneri 1b, 2a, 3a, and 6 and Shigella sonnei in Shigella-positive cases and age-, site-, and season-matched test-negative controls from all sites in the Enterics for Global Health (EFGH) Shigella surveillance study. Fold antibody responses will be compared between culture-positive, culture-negative but PCR-attributable, and PCR-positive but not attributable cases and test-negative controls. Age- and site-specific seroprevalence distributions will be identified, and the association between baseline antibodies and Shigella attribution will be estimated. Conclusions: The integration of these assays into the EFGH study will help support PCR-based attribution of acute diarrhea to type-specific Shigella, describe the baseline seroprevalence of conserved and type-specific Shigella antibodies, and support correlates of protection for immunity to Shigella diarrhea. These insights can help support the development and evaluation of Shigella vaccine candidates.
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Background: Quantitative polymerase chain reaction (qPCR) targeting ipaH has been proven to be highly efficient in detecting Shigella in clinical samples compared to culture-based methods, which underestimate Shigella burden by 2- to 3-fold. qPCR assays have also been developed for Shigella speciation and serotyping, which is critical for both vaccine development and evaluation. Methods: The Enterics for Global Health (EFGH) Shigella surveillance study will utilize a customized real-time PCR-based TaqMan Array Card (TAC) interrogating 82 targets, for the detection and differentiation of Shigella spp, Shigella sonnei, Shigella flexneri serotypes, other diarrhea-associated enteropathogens, and antimicrobial resistance (AMR) genes. Total nucleic acid will be extracted from rectal swabs or stool samples, and assayed on TAC. Quantitative analysis will be performed to determine the likely attribution of Shigella and other particular etiologies of diarrhea using the quantification cycle cutoffs derived from previous studies. The qPCR results will be compared to conventional culture, serotyping, and phenotypic susceptibility approaches in EFGH. Conclusions: TAC enables simultaneous detection of diarrheal etiologies, the principal pathogen subtypes, and AMR genes. The high sensitivity of the assay enables more accurate estimation of Shigella-attributed disease burden, which is critical to informing policy and in the design of future clinical trials.
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Background: The measurement of fecal inflammatory biomarkers among individuals presenting to care with diarrhea could improve the identification of bacterial diarrheal episodes that would benefit from antibiotic therapy. We reviewed prior literature in this area and describe our proposed methods to evaluate 4 biomarkers in the Enterics for Global Health (EFGH) Shigella surveillance study. Methods: We systematically reviewed studies since 1970 from PubMed and Embase that assessed the diagnostic characteristics of inflammatory biomarkers to identify bacterial diarrhea episodes. We extracted sensitivity and specificity and summarized the evidence by biomarker and diarrhea etiology. In EFGH, we propose using commercial enzyme-linked immunosorbent assays to test for myeloperoxidase, calprotectin, lipocalin-2, and hemoglobin in stored whole stool samples collected within 24 hours of enrollment from participants in the Bangladesh, Kenya, Malawi, Pakistan, Peru, and The Gambia sites. We will develop clinical prediction scores that incorporate the inflammatory biomarkers and evaluate their ability to identify Shigella and other bacterial etiologies of diarrhea as determined by quantitative polymerase chain reaction (qPCR). Results: Forty-nine studies that assessed fecal leukocytes (n = 39), red blood cells (n = 26), lactoferrin (n = 13), calprotectin (n = 8), and myeloperoxidase (n = 1) were included in the systematic review. Sensitivities were high for identifying Shigella, moderate for identifying any bacteria, and comparable across biomarkers. Specificities varied depending on the outcomes assessed. Prior studies were generally small, identified red and white blood cells by microscopy, and used insensitive gold standard diagnostics, such as conventional bacteriological culture for pathogen detection. Conclusions: Our evaluation of inflammatory biomarkers to distinguish diarrhea etiologies as determined by qPCR will provide an important addition to the prior literature, which was likely biased by the limited sensitivity of the gold standard diagnostics used. We will determine whether point-of-care biomarker tests could be a viable strategy to inform treatment decision making and increase appropriate targeting of antibiotic treatment to bacterial diarrhea episodes.
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Background: Accurate estimation of diarrhea incidence from facility-based surveillance requires estimating the population at risk and accounting for case patients who do not seek care. The Enterics for Global Health (EFGH) Shigella surveillance study will characterize population denominators and healthcare-seeking behavior proportions to calculate incidence rates of Shigella diarrhea in children aged 6-35 months across 7 sites in Africa, Asia, and Latin America. Methods: The Enterics for Global Health (EFGH) Shigella surveillance study will use a hybrid surveillance design, supplementing facility-based surveillance with population-based surveys to estimate population size and the proportion of children with diarrhea brought for care at EFGH health facilities. Continuous data collection over a 24 month period captures seasonality and ensures representative sampling of the population at risk during the period of facility-based enrollments. Study catchment areas are broken into randomized clusters, each sized to be feasibly enumerated by individual field teams. Conclusions: The methods presented herein aim to minimize the challenges associated with hybrid surveillance, such as poor parity between survey area coverage and facility coverage, population fluctuations, seasonal variability, and adjustments to care-seeking behavior.
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The prevalence of Campylobacter infection is generally high among children in low- and middle-income countries (LMIC), but the dynamics of its acquisition and clearance are understudied. We aim to quantify this process among children under two years old in eight LMIC using a statistical modeling approach, leveraging enzyme-immunoassay-based Campylobacter genus data and quantitative-PCR-based Campylobacter jejuni/coli data from the MAL-ED study. We developed a Markov model to compare the dynamics of acquisition and clearance of Campylobacter across countries and to explore the effect of antibiotic usage on Campylobacter clearance. Clearance rates were generally higher than acquisition rates, but their magnitude and temporal pattern varied across countries. For C. jejuni/coli, clearance was faster than acquisition throughout the two years at all sites. For Campylobacter spp., the acquisition rate either exceeded or stayed very close to the clearance rate after the first half year in Bangladesh, Pakistan and Tanzania, leading to high prevalence. Bangladesh had the shortest (28 and 57 days) while Brazil had the longest (328 and 306 days) mean times from last clearance to acquisition for Campylobacter spp. and C. jejuni/coli, respectively. South Africa had the shortest (10 and 8 days) while Tanzania had the longest (53 and 41 days) mean times to clearance for Campylobacter spp. and C. jejuni/col, respectively. The use of Macrolide accelerated clearance of C. jejuni/coli in Bangladesh and Peru and of Campylobacter spp. in Bangladesh and Pakistan. Fluoroquinolone showed statistically meaningful effects only in Bangladesh but for both Campylobacter groups. Higher prevalence of Campylobacter infection was mainly driven by a high acquisition rate that was close to or surpassing the clearance rate. Acquisition rate usually peaked in 11-17 months of age, indicating the importance of targeting the first year of life for effective interventions to reduce exposures.
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Infecciones por Campylobacter , Campylobacter jejuni , Campylobacter , Niño , Humanos , Lactante , Infecciones por Campylobacter/tratamiento farmacológico , Infecciones por Campylobacter/epidemiología , Países en Desarrollo , Antibacterianos/uso terapéutico , Antibacterianos/farmacologíaRESUMEN
BACKGROUND: An incomplete understanding of preterm birth is especially concerning for low-middle income countries, where preterm birth has poorer prognoses. While systemic proinflammatory processes are a reportedly normal component of gestation, excessive inflammation has been demonstrated as a risk factor for preterm birth. There is minimal research on the impact of excessive maternal inflammation in the first trimester on the risk of preterm birth in low-middle income countries specifically. METHODS: Pregnant women were enrolled at the rural Bangladesh site of the National Institute of Child Health Global Network Maternal Newborn Health Registry. Serum samples were collected to measure concentrations of the inflammatory markers C-reactive protein (CRP) and Alpha-1-acid glycoprotein (AGP), and stool samples were collected and analyzed for enteropathogens. We examined associations of maternal markers in the first-trimester with preterm birth using logistic regression models. CRP and AGP were primarily modeled with a composite inflammation predictor. RESULTS: Out of 376 singleton births analyzed, 12.5% were preterm. First trimester inflammation was observed in 58.8% of all births, and was significantly associated with increased odds of preterm birth (adjusted odds ratio [aOR] = 2.23; 95% confidence interval [CI]: 1.03, 5.16), independent of anemia. Maternal vitamin B12 insufficiency (aOR = 3.33; 95% CI: 1.29, 8.21) and maternal anemia (aOR = 2.56; 95% CI: 1.26, 5.17) were also associated with higher odds of preterm birth. Atypical enteropathogenic E. coli detection showed a significant association with elevated AGP levels and was significantly associated with preterm birth (odds ratio [OR] = 2.36; 95% CI: 1.21, 4.57), but not associated with CRP. CONCLUSIONS: Inflammation, anemia, and vitamin B12 insufficiency in the first trimester were significantly associated with preterm birth in our cohort from rural Bangladesh. Inflammation and anemia were independent predictors of premature birth in this low-middle income setting where inflammation during gestation was widespread. Further research is needed to identify if infections such as enteropathogenic E. coli are a cause of inflammation in the first trimester, and if intervention for infection would decrease preterm birth.
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Anemia , Escherichia coli Enteropatógena , Nacimiento Prematuro , Oligoelementos , Recién Nacido , Embarazo , Niño , Femenino , Humanos , Micronutrientes , Estudios Prospectivos , Primer Trimestre del Embarazo , Nacimiento Prematuro/epidemiología , Bangladesh/epidemiología , Inflamación , Proteína C-Reactiva , Vitamina B 12RESUMEN
The global nonprofit organization PATH hosted the third Vaccines Against Shigella and Enterotoxigenic Escherichia coli (VASE) Conference in Washington, DC, on November 29 to December 1, 2022. With a combination of plenary sessions and posters, keynote presentations, and breakout workshops, the 2022 VASE Conference featured key updates on research related to the development of vaccines against neglected diarrheal pathogens including Shigella, enterotoxigenic Escherichia coli (ETEC), Campylobacter, and Salmonella. The presentations and discussions highlighted the significant impact of these diarrheal pathogens, particularly on the health of infants and young children in low- and middle-income countries, reflecting the urgent need for the development and licensure of new enteric vaccines. Oral and poster presentations at the VASE Conference explored a range of topics, including: the global burden and clinical presentation of disease, epidemiology, and the impact of interventions; the assessment of the value of vaccines against enteric pathogens; preclinical evaluations of vaccine candidates and models of enteric diseases; vaccine candidates in clinical trials and human challenge models; host parameters and genomics that predict responses to infection and disease; the application of new omics technologies for characterization of emerging pathogens and host responses; novel adjuvants, vaccine delivery platforms, and immunization strategies; and strategies for combination/co-administered vaccines. The conference agenda also featured ten breakout workshop sessions on topics of importance to the enteric vaccine field, which are summarized separately. This article reviews key points and highlighted research presented in each of the plenary conference sessions and poster presentations at the 2022 VASE Conference.
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Disentería Bacilar , Escherichia coli Enterotoxigénica , Infecciones por Escherichia coli , Vacunas contra Escherichia coli , Oligopéptidos , Vacunas contra la Shigella , Shigella , Humanos , Diarrea/epidemiologíaRESUMEN
BACKGROUND: Bacterial pathogens cause substantial diarrhea morbidity and mortality among children living in endemic settings, yet antimicrobial treatment is only recommended for dysentery or suspected cholera. METHODS: AntiBiotics for Children with severe Diarrhea was a 7-country, placebo-controlled, double-blind efficacy trial of azithromycin in children 2-23 months of age with watery diarrhea accompanied by dehydration or malnutrition. We tested fecal samples for enteric pathogens utilizing quantitative polymerase chain reaction to identify likely and possible bacterial etiologies and employed pathogen-specific cutoffs based on genomic target quantity in previous case-control diarrhea etiology studies to identify likely and possible bacterial etiologies. RESULTS: Among 6692 children, the leading likely etiologies were rotavirus (21.1%), enterotoxigenic Escherichia coli encoding heat-stable toxin (13.3%), Shigella (12.6%), and Cryptosporidium (9.6%). More than one-quarter (1894 [28.3%]) had a likely and 1153 (17.3%) a possible bacterial etiology. Day 3 diarrhea was less common in those randomized to azithromycin versus placebo among children with a likely bacterial etiology (risk difference [RD]likely, -11.6 [95% confidence interval {CI}, -15.6 to -7.6]) and possible bacterial etiology (RDpossible, -8.7 [95% CI, -13.0 to -4.4]) but not in other children (RDunlikely, -0.3% [95% CI, -2.9% to 2.3%]). A similar association was observed for 90-day hospitalization or death (RDlikely, -3.1 [95% CI, -5.3 to -1.0]; RDpossible, -2.3 [95% CI, -4.5 to -.01]; RDunlikely, -0.6 [95% CI, -1.9 to .6]). The magnitude of risk differences was similar among specific likely bacterial etiologies, including Shigella. CONCLUSIONS: Acute watery diarrhea confirmed or presumed to be of bacterial etiology may benefit from azithromycin treatment. CLINICAL TRIALS REGISTRATION: NCT03130114.
Asunto(s)
Infecciones Bacterianas , Criptosporidiosis , Cryptosporidium , Disentería , Shigella , Niño , Humanos , Lactante , Antibacterianos/uso terapéutico , Azitromicina/uso terapéutico , Criptosporidiosis/tratamiento farmacológico , Patología Molecular , Diarrea/epidemiología , Infecciones Bacterianas/tratamiento farmacológico , Bacterias , Disentería/complicaciones , Disentería/tratamiento farmacológicoRESUMEN
BACKGROUND: Shigella is a leading cause of diarrhea and dysentery in children in low-resource settings, which is frequently treated with antibiotics. The primary goal of a Shigella vaccine would be to reduce mortality and morbidity associated with Shigella diarrhea. However, ancillary benefits could include reducing antibiotic use and antibiotic exposures for bystander pathogens carried at the time of treatment, specifically for fluoroquinolones and macrolides (F/M), which are the recommended drug classes to treat dysentery. The aim of the study was to quantify the reduction in Shigella attributable diarrhea, all diarrhea, and antibiotic use in the first 2 years of life that could be prevented by a Shigella vaccine. METHODS AND FINDINGS: We used data from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study, a birth cohort study that followed 1,715 children with twice weekly surveillance for enteric infections, illnesses, and antibiotic use for the first 2 years of life from November 2009 to February 2014 at 8 sites. We estimated the impact of 2 one-dose (6 or 9 months) and 3 two-dose (6 and 9 months, 9 and 12 months, and 12 and 15 months) Shigella vaccines on diarrheal episodes, overall antibiotic use, and F/M use. Further, we considered additional protection through indirect and boosting effects. We used Monte Carlo simulations to estimate the absolute and relative reductions in the incidence of diarrhea and antibiotic use comparing each vaccination scenario to no vaccination. We analyzed 9,392 diarrhea episodes and 15,697 antibiotic courses among 1,715 children in the MAL-ED birth cohort study. There were 273.8 diarrhea episodes, 30.6 shigellosis episodes, and 457.6 antibiotic courses per 100 child-years. A Shigella vaccine with a mean vaccine efficacy of 60% against severe disease given at 9 and 12 months prevented 10.6 (95% CI [9.5, 11.5]) Shigella diarrhea episodes of any severity per 100 child-years (relative 34.5% reduction), 3.0 (95% CI [2.5, 3.5]) F/M courses for Shigella treatment per 100 child-years (relative 35.8% reduction), and 5.6 (95% CI [5.0, 6.3]) antibiotic courses of any drug class for Shigella treatment per 100 child-years (relative 34.5% reduction). This translated to a relative 3.8% reduction in all diarrhea, a relative 2.8% reduction in all F/M courses, a relative 3.1% reduction in F/M exposures to bystander pathogens, and a relative 0.9% reduction in all antibiotic courses. These results reflect Shigella incidence and antibiotic use patterns at the 8 MAL-ED sites and may not be generalizable to all low-resource settings. CONCLUSIONS: Our simulation results suggest that a Shigella vaccine meeting WHO targets for efficacy could prevent about a third of Shigella diarrhea episodes, antibiotic use to treat shigellosis, and bystander exposures due to shigellosis treatment. However, the reductions in overall diarrhea episodes and antibiotic use are expected to be modest (<5%).