ABSTRACT
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.
Subject(s)
Diarrhea , Dietary Supplements , Lactoferrin , Muramidase , Humans , Lactoferrin/therapeutic use , Infant , Muramidase/therapeutic use , Kenya/epidemiology , Child, Preschool , Randomized Controlled Trials as Topic , Female , MaleABSTRACT
Background: Antimicrobial resistance (AMR) is a global threat to infectious disease control, particularly among recently hospitalized children. We sought to determine the prevalence and mitigating factors of resistance in enteric Escherichia coli among children discharged from health facilities in western Kenya. Methods: Between June 2016 and November 2019, children aged 1 to 59 months were enrolled at the point of discharge from the hospital. E coli was isolated by microbiological culture from rectal swabs at baseline. ß-Lactamases and macrolide resistance-conferring genes were detected by polymerase chain reaction. A modified Poisson regression model was used to assess the predictors mph(A) and CTX-M-type extended-spectrum ß-lactamase (ESBL). Results: Of the 238 children whose E coli isolates were tested, 91 (38.2%) and 109 (45.8%) had detectable CTX-M-type ESBL and mph(A) genes, respectively. Antibiotic treatment during hospitalization (adjusted prevalence ratio [aPR], 2.47; 95% CI, 1.12-5.43; P = .025), length of hospitalization (aPR, 1.42; 95% CI, 1.00-2.01; P = .052), and the practice of open defecation (aPR, 2.47; 95% CI, 1.40-4.36; P = .002) were independent predictors for CTX-M-type ESBL and mph(A) genes. Pneumococcal vaccination was associated with a 43% lower likelihood of CTX-M-type ESBL (aPR, 0.57; 95% CI, .38-.85; P = .005), while measles vaccination was associated with a 32% lower likelihood of mph(A) genes (aPR, 0.68; 95% CI, .49-.93; P = .017) in E coli isolates. Conclusions: Among children discharged from the hospital, history of vaccination, shorter hospital stay, lack of in-hospital antibiotic exposure, and improved sanitation were associated with a lower likelihood of AMR genes. To mitigate the continued spread of AMR, AMR control programs should consider strategies beyond antimicrobial stewardship, including improvements in sanitation, increased vaccine coverage, and the development of novel vaccines.
ABSTRACT
BACKGROUND: The emergence and spread of ß-lactamase-producing Klebsiella spp. has been associated with a substantial healthcare burden resulting in therapeutic failures. We sought to describe the proportion of phenotypic resistance to commonly used antibiotics, characterize ß-lactamase genes among isolates with antimicrobial resistance (AMR), and assess the correlates of phenotypic AMR in Klebsiella spp. isolated from stool or rectal swab samples collected from children being discharged from hospital. METHODS: We conducted a cross-sectional study involving 245 children aged 1-59 months who were being discharged from hospitals in western Kenya between June 2016 and November 2019. Whole stool or rectal swab samples were collected and Klebsiella spp. isolated by standard microbiological culture. ß-lactamase genes were detected by PCR whilst phenotypic antimicrobial susceptibility was determined using the disc diffusion technique following standard microbiology protocols. Descriptive analyses were used to characterize phenotypic AMR and carriage of ß-lactamase-producing genes. The modified Poisson regression models were used to assess correlates of phenotypic beta-lactam resistance. RESULTS: The prevalence of ß-lactamase carriage among Klebsiella spp. isolates at hospital discharge was 62.9% (154/245). Antibiotic use during hospitalization (adjusted prevalence ratio [aPR] = 4.51; 95%CI: 1.79-11.4, p < 0.001), longer duration of hospitalization (aPR = 1.42; 95%CI: 1.14-1.77, p < 0.002), and access to treated water (aPR = 1.38; 95%CI: 1.12-1.71, p < 0.003), were significant predictors of phenotypically determined ß-lactamase. All the 154 ß-lactamase-producing Klebsiella spp. isolates had at least one genetic marker of ß-lactam/third-generation cephalosporin resistance. The most prevalent genes were blaCTX-M 142/154 (92.2%,) and blaSHV 142/154 (92.2%,) followed by blaTEM 88/154 (57.1%,) and blaOXA 48/154 (31.2%,) respectively. CONCLUSION: Carriage of ß-lactamase producing Klebsiella spp. in stool is common among children discharged from hospital in western Kenya and is associated with longer duration of hospitalization, antibiotic use, and access to treated water. The findings emphasize the need for continued monitoring of antimicrobial susceptibility patterns to inform the development and implementation of appropriate treatment guidelines. In addition, we recommend measures beyond antimicrobial stewardship and infection control within hospitals, improved sanitation, and access to safe drinking water to mitigate the spread of ß-lactamase-producing Klebsiella pathogens in these and similar settings.
Subject(s)
Anti-Bacterial Agents , Klebsiella Infections , Klebsiella , Microbial Sensitivity Tests , beta-Lactamases , Humans , Kenya/epidemiology , beta-Lactamases/genetics , Infant , Klebsiella/genetics , Klebsiella/drug effects , Klebsiella/enzymology , Klebsiella/isolation & purification , Child, Preschool , Female , Male , Cross-Sectional Studies , Klebsiella Infections/microbiology , Klebsiella Infections/epidemiology , Klebsiella Infections/drug therapy , Anti-Bacterial Agents/pharmacology , Phenotype , Feces/microbiology , Patient Discharge , PrevalenceABSTRACT
Background: Shigella is a major cause of diarrhea in young children worldwide. Multiple vaccines targeting Shigella are in development, and phase 3 clinical trials are imminent to determine efficacy against shigellosis. Methods: The Enterics for Global Health (EFGH) Shigella surveillance study is designed to determine the incidence of medically attended shigellosis in 6- to 35-month-old children in 7 resource-limited settings. Here, we describe the microbiological methods used to isolate and identify Shigella. We developed a standardized laboratory protocol for isolation and identification of Shigella by culture. This protocol was implemented across all 7 sites, ensuring consistency and comparability of results. Secondary objectives of the study are to determine the antibiotic resistance profiles of Shigella, compare isolation of Shigella from rectal swabs versus whole stool, and compare isolation of Shigella following transport of rectal swabs in Cary-Blair versus a modified buffered glycerol saline transport medium. Conclusions: Data generated from EFGH using culture methods described herein can potentially be used for microbiological endpoints in future phase 3 clinical trials to evaluate vaccines against shigellosis and for other clinical and public health studies focused on these organisms.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
Background: Rigorous data management systems and planning are essential to successful research projects, especially for large, multicountry consortium studies involving partnerships across multiple institutions. Here we describe the development and implementation of data management systems and procedures for the Enterics For Global Health (EFGH) Shigella surveillance study-a 7-country diarrhea surveillance study that will conduct facility-based surveillance concurrent with population-based enumeration and a health care utilization survey to estimate the incidence of Shigella--associated diarrhea in children 6 to 35 months old. Methods: The goals of EFGH data management are to utilize the knowledge and experience of consortium members to collect high-quality data and ensure equity in access and decision-making. During the planning phase before study initiation, a working group of representatives from each EFGH country site, the coordination team, and other partners met regularly to develop the data management systems for the study. Results: This resulted in the Data Management Plan, which included selecting REDCap and SurveyCTO as the primary database systems. Consequently, we laid out procedures for data processing and storage, study monitoring and reporting, data quality control and assurance activities, and data access. The data management system and associated real-time visualizations allow for rapid data cleaning activities and progress monitoring and will enable quicker time to analysis. Conclusions: Experiences from this study will contribute toward enriching the sparse landscape of data management methods publications and serve as a case study for future studies seeking to collect and manage data consistently and rigorously while maintaining equitable access to and control of data.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Bacterial Infections , Cryptosporidiosis , Cryptosporidium , Dysentery , Shigella , Child , Humans , Infant , Anti-Bacterial Agents/therapeutic use , Azithromycin/therapeutic use , Cryptosporidiosis/drug therapy , Pathology, Molecular , Diarrhea/epidemiology , Bacterial Infections/drug therapy , Bacteria , Dysentery/complications , Dysentery/drug therapyABSTRACT
Stunting (length/height-for-age z-score < -2) is associated with significant morbidity and mortality among children under 5 years of age in sub-Saharan Africa. Children who are stunted and recently hospitalized for acute illness may be at particularly elevated risk for post-discharge mortality. In this cross-sectional analysis, we measured the prevalence of stunting at hospital discharge and identified host, caregiver, and environmental correlates of stunting among children aged 1-59 months in Western Kenya enrolled in the Toto Bora Trial. Child age- and site-adjusted prevalence ratios were estimated using Poisson regression. Of the 1,394 children included in this analysis, 23% were stunted at hospital discharge. Older children (12-23 months and 24-59 months versus 0-5 months) had a higher prevalence of stunting (adjusted prevalence ratio [aPR]: 1.58; 95% CI: 1.04-2.36 and aPR: 1.59; 95% CI: 1.08-2.34, respectively). HIV-exposed, uninfected children (aPR: 1.94; 95% CI: 1.39-2.70), children with HIV infection (aPR: 2.73; 95% CI: 1.45-5.15), and those who were never exclusively breastfed in early life (aPR 2.51; 95% CI: 1.35-4.67) were more likely to be stunted. Caregiver education (primary school or less) and unimproved sanitation (pit latrine without slab floor or open defecation) were associated with increased risk of stunting (aPR: 1.94; 95% CI: 1.54-2.44; aPR: 1.99; 95% CI: 1.20-3.31; aPR: 3.57; 95% CI: 1.77-7.21, respectively). Hospital discharge represents an important opportunity for both identifying and delivering targeted interventions for nutrition-associated poor outcomes among a high-risk population of children.
Subject(s)
HIV Infections , Humans , Child , Infant , Child, Preschool , Adolescent , Kenya/epidemiology , Prevalence , Acute Disease , Cross-Sectional Studies , Aftercare , Patient Discharge , Growth Disorders/epidemiology , Growth Disorders/etiologyABSTRACT
Dehydration is a major cause of death among children with wasting and diarrhea. We reviewed the evidence for the identification and management of dehydration among these children. Two systematic reviews were conducted to assess 1) the diagnostic performance of clinical signs or algorithms intended to measure dehydration, and 2) the efficacy and safety of low-osmolarity ORS versus ReSoMal on mortality, treatment failure, time to full rehydration, and electrolyte disturbances (management review). We searched PubMed/Medline, Embase, and Global Index Medicus for studies enrolling children 0-60 months old with wasting and diarrhea. The diagnostic review included four studies. Two studies found the Integrated Management of Childhood Illness (IMCI) and the Dehydration: Assessing Kids Accurately (DHAKA) algorithms had similar diagnostic performance, but both algorithms had high false positive rates for moderate (41% and 35%, respectively) and severe (76% and 82%, respectively) dehydration. One further IMCI algorithm study found a 23% false positive rate for moderate dehydration. The management review included six trials. One trial directly compared low osmolarity ORS to ReSoMal and found no difference in treatment failure rates, although ReSoMal had a shorter duration of treatment (16.1 vs. 19.6 hours, p = 0.036) and a higher incidence of hyponatremia. Both fluids failed to correct a substantial number of hypokalemia cases across studies. In conclusion, the IMCI dehydration assessment has comparable performance to other algorithms among wasted children. Low osmolarity ORS may be an alternative to ReSoMal for children with severe wasting, but might require additional potassium to combat hypokalemia.
ABSTRACT
Shigellosis causes considerable public health burden, leading to excess deaths as well as acute and chronic consequences, particularly among children living in low-income and middle-income countries (LMICs). Several Shigella vaccine candidates are advancing in clinical trials and offer promise. Although multiple target populations might benefit from a Shigella vaccine, the primary strategic goal of WHO is to accelerate the development and accessibility of safe, effective, and affordable Shigella vaccines that reduce mortality and morbidity in children younger than 5 years living in LMICs. WHO consulted with regulators and policy makers at national, regional, and global levels to evaluate pathways that could accelerate regulatory approval in this priority population. Special consideration was given to surrogate efficacy biomarkers, the role of controlled human infection models, and the establishment of correlates of protection. A field efficacy study in children younger than 5 years in LMICs is needed to ensure introduction in this priority population.
Subject(s)
Dysentery, Bacillary , Shigella Vaccines , Child , Humans , Developing Countries , Dysentery, Bacillary/prevention & control , Dysentery, Bacillary/epidemiologyABSTRACT
Diarrhea continues to be a leading cause of death for children under-five. Amongst children treated for acute diarrhea, mortality risk remains elevated during and after acute medical management. Identification of those at highest risk would enable better targeting of interventions, but available prognostic tools lack validation. We used clinical and demographic data from the Global Enteric Multicenter Study (GEMS) to build clinical prognostic models (CPMs) to predict death (in-treatment, after discharge, or either) in children aged ≤59 months presenting with moderate-to-severe diarrhea (MSD), in Africa and Asia. We screened variables using random forests, and assessed predictive performance with random forest regression and logistic regression using repeated cross-validation. We used data from the Kilifi Health and Demographic Surveillance System (KHDSS) and Kilifi County Hospital (KCH) in Kenya to externally validate our GEMS-derived CPM. Of 8060 MSD cases, 43 (0.5%) children died in treatment and 122 (1.5% of remaining) died after discharge. MUAC at presentation, respiratory rate, age, temperature, number of days with diarrhea at presentation, number of people living in household, number of children <60 months old living in household, and how much the child had been offered to drink since diarrhea started were predictive of death both in treatment and after discharge. Using a parsimonious 2-variable prediction model, we achieved an area under the ROC curve (AUC) of 0.84 (95% CI: 0.82, 0.86) in the derivation dataset, and an AUC = 0.74 (95% CI 0.71, 0.77) in the external dataset. Our findings suggest it is possible to identify children most likely to die after presenting to care for acute diarrhea. This could represent a novel and cost-effective way to target resources for the prevention of childhood mortality.
ABSTRACT
BACKGROUND: The increasing spread of fluoroquinolone resistant enteric bacteria is a global public health concern. Children recently discharged from the hospital are at high risk of carriage of antimicrobial resistance (AMR) due to frequent exposure to antimicrobials during inpatient stays. This study aimed to determine the prevalence, correlates of ciprofloxacin (CIP) non-susceptibility, and distribution of plasmid-mediated quinolone resistance (PMQR) genes in Escherichia coli (E. coli) and Klebsiella spp isolated from children under five years being discharged from two Kenyan Hospitals. METHODS: E. coli and Klebsiella spp were isolated from fecal samples from children discharged from hospital and subjected to antimicrobial susceptibility testing (AST) by disc diffusion and E-test. CIP non-susceptible isolates were screened for seven PMQR genes using multiplex polymerase chain reaction (PCR). Poisson regression was used to determine the association between the carriage of CIP non-susceptible isolates and patient characteristics. RESULTS: Of the 280 CIP non-susceptible isolates: 188 E. coli and 92 Klebsiella spp isolates identified among 266 discharged children, 195 (68%) were CIP-non-susceptible with minimum inhibitory concentrations (MICs) of ≥ 1 µg/mL. Among these 195 isolates, 130 (67%) had high-level CIP MIC = ≥ 32 µg/mL). Over 80% of the isolates had at least one PMQR gene identified: aac(6')lb-cr (60%), qnrB (24%), oqxAB (22%), qnrS (16%), and qepA (6%), however, qnrA was not identified in any isolates tested. Co-carriage of qnrB with acc(6')-lb-cr was the most predominant accounting for 20% of all the isolates. Ceftriaxone use during hospital admission and the presence of extended spectrum beta-lactamase (ESBL) production were significantly associated with the carriage of CIP non-susceptible E. coli and Klebsiella spp. CONCLUSION: CIP non-susceptibility is common among E. coli and Klebsiella spp isolated from hospital discharged children in Kenya. Carriage and co-carriage of PMQR, including the newly identified qepA gene, were frequently observed. These findings suggest that children leaving the hospital may serve as an important reservoir for transmission of resistant E. coli and Klebsiella spp to the community. Enhanced surveillance for AMR determinants is critical to inform interventions to control antimicrobial-resistant bacteria.
Subject(s)
Ciprofloxacin , Quinolones , Child , Humans , Child, Preschool , Ciprofloxacin/pharmacology , Quinolones/pharmacology , Escherichia coli , Klebsiella/genetics , Kenya/epidemiology , Patient Discharge , Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial/genetics , Plasmids/genetics , Hospitals , Microbial Sensitivity TestsABSTRACT
Background: Diarrheal diseases are a leading cause of death for children aged <5 years. Identification of etiology helps guide pathogen-specific therapy, but availability of diagnostic testing is often limited in low-resource settings. Our goal is to develop a clinical prediction rule (CPR) to guide clinicians in identifying when to use a point-of-care (POC) diagnostic for Shigella in children presenting with acute diarrhea. Methods: We used clinical and demographic data from the Global Enteric Multicenter Study (GEMS) study to build predictive models for diarrhea of Shigella etiology in children aged ≤59 months presenting with moderate to severe diarrhea in Africa and Asia. We screened variables using random forests, and assessed predictive performance with random forest regression and logistic regression using cross-validation. We used the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study to externally validate our GEMS-derived CPR. Results: Of the 5011 cases analyzed, 1332 (27%) had diarrhea of Shigella etiology. Our CPR had high predictive ability (area under the receiver operating characteristic curve = 0.80 [95% confidence interval, .79-.81]) using the top 2 predictive variables, age and caregiver-reported bloody diarrhea. We show that by using our CPR to triage who receives diagnostic testing, 3 times more Shigella diarrhea cases would have been identified compared to current symptom-based guidelines, with only 27% of cases receiving a POC diagnostic test. Conclusions: We demonstrate how a CPR can be used to guide use of a POC diagnostic test for diarrhea management. Using our CPR, available diagnostic capacity can be optimized to improve appropriate antibiotic use.
ABSTRACT
Diarrhea continues to be a leading cause of death for children under-five. Amongst children treated for acute diarrhea, mortality risk remains elevated during and after acute medical management. Identification of those at highest risk would enable better targeting of interventions, but available prognostic tools lack validation. We used clinical and demographic data from the Global Enteric Multicenter Study (GEMS) to build predictive models for death (in-treatment, after discharge, or either) in children aged â¤59 months presenting with moderate-to-severe diarrhea (MSD), in Africa and Asia. We screened variables using random forests, and assessed predictive performance with random forest regression and logistic regression using repeated cross-validation. We used data from the Kilifi Health and Demographic Surveillance System (KHDSS) and Kilifi County Hospital (KCH) in Kenya to externally validate our GEMS-derived clinical prognostic model (CPM). Of 8060 MSD cases, 43 (0.5%) children died in treatment and 122 (1.5% of remaining) died after discharge. MUAC at presentation, respiratory rate, age, temperature, number of days with diarrhea at presentation, number of people living in household, number of children <60 months old living in household, and how much the child had been offered to drink since diarrhea started were predictive of death both in treatment and after discharge. Using a parsimonious 2-variable prediction model, we achieve an AUC=0.84 (95% CI: 0.82, 0.86) in the derivation dataset, and an AUC=0.74 (95% CI 0.71, 0.77) in the external dataset. Our findings suggest it is possible to identify children most likely to die after presenting to care for acute diarrhea. This could represent a novel and cost-effective way to target resources for the prevention of childhood mortality.
ABSTRACT
OBJECTIVES: We conducted a systematic review of the longitudinal consequences of Shigella infection in children to inform the value proposition for an effective vaccine. METHODS: We searched PubMed and Embase for studies published from January 01, 1980 to December 12, 2022 and conducted in low- and middle-income countries that included longitudinal follow-up after Shigella detection among children aged <5 years, irrespective of language. We collected data on all outcomes subsequent to Shigella detection, except mortality. RESULTS: Of 2627 papers identified, 52 met inclusion criteria. The median sample size of children aged <5 years was 66 (range 5-2172). Data were collected in 20 countries; 56% (n = 29) of the publications included Bangladesh. The most common outcomes related to diarrhea (n = 20), linear growth (n = 14), and the mean total cost of a Shigella episode (n = 4; range: $ 6.22-31.10). Among children with Shigella diarrhea, 2.9-61.1% developed persistent diarrhea (≥14 days); the persistence was significantly more likely among children who were malnourished, had bloody stool, or had multidrug-resistant Shigella. Cumulative Shigella infections over the first 2 years of life contributed to the greatest loss in length-for-age z-score. CONCLUSION: We identified evidence that Shigella is associated with persistent diarrhea, linear growth faltering, and economic impact to the family.
Subject(s)
Dysentery, Bacillary , Malnutrition , Shigella , Humans , Child , Infant , Child, Preschool , Dysentery, Bacillary/epidemiology , Diarrhea/epidemiology , Bangladesh/epidemiologyABSTRACT
Background: Nearly 150 million children under-5 years of age were stunted in 2020. We aimed to develop a clinical prediction rule (CPR) to identify children likely to experience additional stunting following acute diarrhea, to enable targeted approaches to prevent this irreversible outcome. Methods: We used clinical and demographic data from the Global Enteric Multicenter Study (GEMS) to build predictive models of linear growth faltering (decrease of ≥0.5 or ≥1.0 in height-for-age z-score [HAZ] at 60-day follow-up) in children ≤59 months presenting with moderate-to-severe diarrhea, and community controls, in Africa and Asia. We screened variables using random forests, and assessed predictive performance with random forest regression and logistic regression using fivefold cross-validation. We used the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study to (1) re-derive, and (2) externally validate our GEMS-derived CPR. Results: Of 7639 children in GEMS, 1744 (22.8%) experienced severe growth faltering (≥0.5 decrease in HAZ). In MAL-ED, we analyzed 5683 diarrhea episodes from 1322 children, of which 961 (16.9%) episodes experienced severe growth faltering. Top predictors of growth faltering in GEMS were: age, HAZ at enrollment, respiratory rate, temperature, and number of people living in the household. The maximum area under the curve (AUC) was 0.75 (95% confidence interval [CI]: 0.75, 0.75) with 20 predictors, while 2 predictors yielded an AUC of 0.71 (95% CI: 0.71, 0.72). Results were similar in the MAL-ED re-derivation. A 2-variable CPR derived from children 0-23 months in GEMS had an AUC = 0.63 (95% CI: 0.62, 0.65), and AUC = 0.68 (95% CI: 0.63, 0.74) when externally validated in MAL-ED. Conclusions: Our findings indicate that use of prediction rules could help identify children at risk of poor outcomes after an episode of diarrheal illness. They may also be generalizable to all children, regardless of diarrhea status. Funding: This work was supported by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award NIH T32AI055434 and by the National Institute of Allergy and Infectious Diseases (R01AI135114).
Subject(s)
Clinical Decision Rules , Diarrhea , Humans , Child , Infant , Infant, Newborn , Diarrhea/diagnosis , Diarrhea/epidemiology , Growth Disorders/diagnosis , Growth Disorders/epidemiology , Growth Disorders/etiology , Asia , AfricaABSTRACT
BACKGROUND: The World Health Organization (WHO) recommends tuberculosis (TB) diagnostic evaluation for children with HIV (CHIV) who have history of TB contact, poor weight gain, cough, or fever. These screening criteria were developed based on studies of symptomatic CHIV with incomplete microbiologic confirmation. We performed routine TB microbiologic evaluation of hospitalized CHIV with and without symptoms to develop a data-driven TB symptom screen. METHODS: Among hospitalized antiretroviral therapy-naive Kenyan CHIV enrolled in the Pediatric Urgent Start of Highly Active Antiretroviral Therapy (PUSH) trial, we performed Xpert MTB/RIF and mycobacterial culture of respiratory and stool specimens independent of TB symptoms. We evaluated performance of WHO and other published pediatric TB screening criteria and derived optimized criteria using a combination of symptoms. RESULTS: Of 168 CHIV who underwent TB microbiologic evaluation, 13 (8%) had confirmed TB. WHO TB symptom screening had 100% sensitivity and 4% specificity to detect confirmed TB. Published TB screening criteria that relied on prolonged symptoms missed cases of confirmed TB (sensitivity 85%-92%). An optimized symptom screen including weight loss, cough, anorexia, or TB contact had 100% sensitivity and improved specificity (31%) compared with the WHO pediatric TB symptom screen. CONCLUSIONS: The WHO TB symptom screen was highly sensitive but resulted in a high proportion of hospitalized CHIV who would require TB diagnostic evaluation. Other published TB screening criteria missed CHIV with confirmed TB. Our optimized screening tool increased specificity while preserving sensitivity. Future multicenter studies are needed to improve TB screening tools for CHIV in both inpatient and outpatient settings.