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High mortality after discharge from hospital following acute illness has been observed among children with Severe Acute Malnutrition (SAM). However, mechanisms that may be amenable to intervention to reduce risk are unknown. We performed a nested case-control study among HIV-uninfected children aged 2–59 months treated for complicated SAM according to WHO recommendations at four Kenyan hospitals. Blood was drawn from 1778 children when clinically judged stable before discharge from hospital. Cases were children who died within 60 days. Controls were randomly selected children who survived for one year without readmission to hospital. Untargeted proteomics, total protein, cytokines and chemokines, and leptin were assayed in plasma and corresponding biological processes determined. Among 121 cases and 120 controls, increased levels of calprotectin, von Willebrand factor, angiotensinogen, IL8, IL15, IP10, TNFα, and decreased levels of leptin, heparin cofactor 2, and serum paraoxonase were associated with mortality after adjusting for possible confounders. Acute phase responses, cellular responses to lipopolysaccharide, neutrophil responses to bacteria, and endothelial responses were enriched among cases. Among apparently clinically stable children with SAM, a sepsis-like profile is associated with subsequent death. This may be due to ongoing bacterial infection, translocated bacterial products or deranged immune response during nutritional recovery.

ObjectiveTo assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis.DesignA single-centre open-label randomised controlled trial.SettingKilifi County Hospital, Kenya.Patients120 neonates aged ≤28 days admitted being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and gentamicin between March 2018 and February 2019.InterventionWe randomly assigned half the participants to receive additional intravenous then oral fosfomycin at 100 mg/kg two times per day for up to 7 days (SOC-F) and followed up for 28 days.Main outcome(s) and measure(s)Serum sodium, AEs and fosfomycin pharmacokinetics.Results61 and 59 infants aged 0–23 days were assigned to SOC-F and SOC, respectively. There was no evidence of impact of fosfomycin on serum sodium or gastrointestinal side effects. We observed 35 AEs among 25 SOC-F participants and 50 AEs among 34 SOC participants during 1560 and 1565 infant-days observation, respectively (2.2 vs 3.2 events/100 infant-days; incidence rate difference −0.95 events/100 infant-days (95% CI −2.1 to 0.20)). Four SOC-F and 3 SOC participants died. From 238 pharmacokinetic samples, modelling suggests an intravenous dose of 150 mg/kg two times per day is required for pharmacodynamic target attainment in most children, reduced to 100 mg/kg two times per day in neonates aged <7 days or weighing <1500 g.Conclusion and relevanceFosfomycin offers potential as an affordable regimen with a simple dosing schedule for neonatal sepsis. Further research on its safety is needed in larger cohorts of hospitalised neonates, including very preterm neonates or those critically ill. Resistance suppression would only be achieved for the most sensitive of organisms so fosfomycin is recommended to be used in combination with another antimicrobial.Trial registration number NCT03453177.

BackgroundStunting is the most common manifestation of childhood undernutrition worldwide. Children presenting with severe acute malnutrition (SAM) are often also severely stunted. We evaluated linear growth and its determinants after medically complicated SAM.MethodsWe performed secondary analysis of clinical trial data (NCT00934492) from HIV-uninfected Kenyan children aged 2–59 months hospitalised with SAM. Outcome was change in height/length-for-age z-score (HAZ) between enrolment and 12 months later. Exposures were demographic, clinical, anthropometric characteristics and illness episodes during follow-up.ResultsAmong 1169 children with HAZ values at month 12 (66% of those in original trial), median (IQR) age 11 (7–17) months and mean (SD) HAZ −2.87 (1.6) at enrolment, there was no change in mean HAZ between enrolment and month 12: −0.006Z (95% CI −0.07 to 0.05Z). While 262 (23%) children experienced minimal HAZ change (within ±0.25 HAZ), 472 (40%) lost >0.25 and 435 (37%) gained >0.25 HAZ. After adjusting for regression to the mean, inpatient or outpatient episodes of diarrhoea and inpatient severe pneumonia during follow-up were associated with HAZ loss. Premature birth and not being cared by the biological parent were associated with HAZ gain. Increases in mid-upper arm circumference and weight-for-age were associated with HAZ gain and protected against HAZ loss. Increase in weight-for-height was not associated with HAZ gain but protected against HAZ loss. No threshold of weight gain preceding linear catch-up growth was observed.ConclusionsInterventions to improve dietary quality and prevent illness over a longer period may provide opportunities to improve linear growth.

Background Children with complicated severe malnutrition (CSM) face high mortality after hospital discharge, yet the underlying mechanisms remain poorly understood. While early post-discharge mortality (< 2 months) has been linked to a sepsis-like inflammatory profile measured at discharge, it is unclear whether this relationship persists (later mortality; 2–6 months post-discharge). This study investigated whether immune, inflammatory, and endothelial dysfunction at 2 months post-discharge are associated with later mortality in children recovering from CSM. Methods We conducted a case–control study nested within a randomised placebo-controlled trial of daily co-trimoxazole in HIV-negative children aged 2–59 months with CSM in four Kenyan hospitals. Cases were children who died between 2 and 6 months post-discharge; controls were survivors frequency-matched by sex, site, and trial arm. Plasma cytokines, chemokines, endothelial markers, and untargeted proteomics were measured at discharge and 2 months post-discharge. Conditional Cox regression, adjusted for age, sex, site, mid-upper arm circumference (MUAC), and randomisation arm, was used to identify biomarkers associated with later mortality. Results Cases were younger (had a median of 7 vs. 11 months), had longer hospital stays (14 vs. 10 days), and showed lower anthropometry (MUAC = 10.7 vs. 12.0 cm) and lower haemoglobin (9.7 vs. 10.6 g/dL) at 2 months post-discharge (all p  < 0.05). Mortality 2–6 months post-discharge was associated with elevated inflammatory mediators (e.g. IL-10 [hazard ratio, HR: 1.47, 95% confidence interval, CI: 1.00–2.14], IL-15 [1.65, 95% CI: 1.08–2.51], IFN-α2 [1.51, 95% CI: 1.02–2.23]), acute phase proteins, apolipoproteins and coagulation markers, including fibrinogen, histidine-rich glycoprotein (1.40, 95% CI: 1.01–1.94), protein C inhibitor (SERPINA5, 1.50, 95% CI: 1.07–2.08), SERPINA10 (1.42, 95% CI: 1.02–1.99), and ADAMTS13 (0.41, 95% CI: 0.24–0.70). Additionally, cardiovascular and muscle-related proteins such as angiotensinogen (1.46, 95% CI: 1.03–2.08), α- and β-tropomyosin (0.68, 95% CI: 0.48–0.98), PI16 (0.72, 95% CI:0.54–0.97), and zyxin (0.61, 95% CI: 0.40–0.92) were elevated in cases. Conclusions Later mortality in children recovering from CSM is associated with persistent immune activation, a sepsis-like phenotype involving multiple systems. These findings suggest that children at risk of later mortality may benefit from biomarker-guided interventions initiated at discharge.

Background Despite adherence to WHO guidelines, inpatient mortality among sick children admitted to hospital with complicated severe acute malnutrition (SAM) remains unacceptably high. Several studies have examined risk factors present at admission for mortality. However, risks may evolve during admission with medical and nutritional treatment or deterioration. Currently, no specific guidance exists for assessing daily treatment response. This study aimed to determine the prognostic value of monitoring clinical signs on a daily basis for assessing mortality risk during hospitalization in children with SAM. Methods This is a secondary analysis of data from a randomized trial (NCT02246296) among 843 hospitalized children with SAM. Daily clinical signs were prospectively collected during ward rounds. Multivariable extended Cox regression using backward feature selection was performed to identify daily clinical warning signs (CWS) associated with time to death within the first 21 days of hospitalization. Predictive models were subsequently developed, and their prognostic performance evaluated using Harrell’s concordance index (C-index) and time-dependent area under the curve (tAUC). Results Inpatient case fatality ratio was 16.3% ( n =127). The presence of the following CWS during daily assessment were found to be independent predictors of inpatient mortality: symptomatic hypoglycemia, reduced consciousness, chest indrawing, not able to complete feeds, nutritional edema, diarrhea, and fever. Daily risk scores computed using these 7 CWS together with MUAC<10.5cm at admission as additional CWS predict survival outcome of children with SAM with a C-index of 0.81 (95% CI 0.77–0.86). Moreover, counting signs among the top 5 CWS (reduced consciousness, symptomatic hypoglycemia, chest indrawing, not able to complete foods, and MUAC<10.5cm) provided a simpler tool with similar prognostic performance (C-index of 0.79; 95% CI 0.74–0.84). Having 1 or 2 of these CWS on any day during hospitalization was associated with a 3 or 11-fold increased mortality risk compared with no signs, respectively. Conclusions This study provides evidence for structured monitoring of daily CWS as recommended clinical practice as it improves prediction of inpatient mortality among sick children with complicated SAM. We propose a simple counting-tool to guide healthcare workers to assess treatment response for these children. Trial registration NCT02246296

In resource-limited settings, children often experience poor growth following illness, but the mechanisms are poorly understood. This cohort study in six countries in sub-Saharan Africa and south Asia investigates pathways linking inflammation and post-discharge weight gain among children hospitalised with acute illness. We determine associations between inflammation, enteropathy, growth mediators and other exposures at hospital discharge and weight gain during 90 days and explain how these exposures influence growth. Here, we show that systemic inflammation impacts mediators of linear growth including the Growth hormone/Insulin-like growth factor 1 axis and bone metabolism to a larger extent and weight gain via enteroendocrine peptide YY and glucagon pathways to a lesser extent. Systemic inflammation negatively affects weight gain directly. Enteropathy impacts growth through systemic inflammation. Adverse household and chronic medical conditions predominantly influence weight gain through inflammation. It is critical to address inflammation, the intestinal mucosal barrier and other exposures driving inflammation to optimise recovery. It is not well understood why in resource-poor settings some children fail to gain weight and stunting increases following hospital discharge. Here, the authors show inflammation driven by illness, enteropathy and social factors redirects recovery away from linear growth and limits weight gain.

In sub-Saharan Africa, children with severe malnutrition (SM) and HIV have substantially worse outcomes than children with SM alone, facing higher mortality risk and impaired nutritional recovery post-hospitalisation. Biological mechanisms underpinning this risk remain incompletely understood. This case-control study nested within the CHAIN cohort in Kenya, Uganda, Malawi, and Burkina Faso examined effect of HIV on six months post-discharge growth among children with SM and those at risk of malnutrition, assessed proteomic signatures associated with HIV in these children, and investigated how these systemic processes impact post-discharge growth in children with SM. Using SomaScan TM assay, 7335 human plasma proteins were quantified. Linear mixed models identified HIV-associated biological processes and their associations with post-discharge growth. Using structural equation modelling, we examined directed paths explaining how HIV influences post-discharge growth. Here, we show that at baseline, HIV is associated with lower anthropometry. Additionally, HIV is associated with protein profiles indicating increased complement activation and decreased insulin-like growth factor signalling and bone mineralisation. HIV indirectly affects post-discharge growth by influencing baseline anthropometry and modulating proteins involved in bone mineralisation and humoral immune responses. These findings suggest specific biological pathways linking HIV to poor growth, offering insights for targeted interventions in this vulnerable population. Here the authors show in a case-control study with more than 800 children that HIV indirectly affects early post-discharge growth in children recovering from severe malnutrition by impacting baseline anthropometry and altering proteins key to bone mineralisation, growth signalling, and humoral immune response.

Accelerating progress in reducing child deaths is needed in order to achieve the Sustainable Development Goal child mortality target. This will require a focus on vulnerable children-including young children, those who are undernourished or with acute illnesses requiring hospitalization. Improving adherence to inpatient guidelines may be an important strategy to reduce child mortality, including among the most vulnerable. The aim of our assessment of nine sub-Saharan African and South Asian hospitals was to determine adherence to pediatric inpatient care recommendations, in addition to capacity for and barriers to implementation of guideline-adherent care prior to commencing the Childhood Acute Illness and Nutrition (CHAIN) Cohort study. The CHAIN Cohort study aims to identify modifiable risk factors for poor inpatient and post discharge outcomes above and beyond implementation of guidelines. Hospital infrastructure, staffing, durable equipment, and consumable supplies such as medicines and laboratory reagents, were evaluated through observation and key informant interviews. Inpatient medical records of 2-23 month old children were assessed for adherence to national and international guidelines. The records of children with severe acute malnutrition (SAM) were oversampled to reflect the CHAIN study population. Seven core adherence indicators were examined: oximetry and oxygen therapy, fluids, anemia diagnosis and transfusion, antibiotics, malaria testing and antimalarials, nutritional assessment and management, and HIV testing. All sites had facilities and equipment necessary to implement care consistent with World Health Organization and national guidelines. However, stockouts of essential medicines and laboratory reagents were reported to be common at some sites, even though they were mostly present during the assessment visits. Doctor and nurse to patient ratios varied widely. We reviewed the notes of 261 children with admission diagnoses of sepsis (17), malaria (47), pneumonia (70), diarrhea (106), and SAM (119); 115 had multiple diagnoses. Adherence to oxygen therapy, antimalarial, and malnutrition refeeding guidelines was >75%. Appropriate antimicrobials were prescribed for 75% of antibiotic-indicative conditions. However, 20/23 (87%) diarrhea and 20/27 (74%) malaria cases without a documented indication were prescribed antibiotics. Only 23/122 (19%) with hemoglobin levels meeting anemia criteria had recorded anemia diagnoses. HIV test results were infrequently documented even at hospitals with universal screening policies (66/173, 38%). Informants at all sites attributed inconsistent guideline implementation to inadequate staffing. Assessed hospitals had the infrastructure and equipment to implement guideline-consistent care. While fluids, appropriate antimalarials and antibiotics, and malnutrition refeeding adherence was comparable to published estimates from low- and high-resource settings, there were inconsistencies in implementation of some other recommendations. Stockouts of essential therapeutics and laboratory reagents were a noted barrier, but facility staff perceived inadequate human resources as the primary constraint to consistent guideline implementation.

IntroductionMedicine quality can be influenced by environmental factors. In low- and middle-income countries (LMICs) with tropical climates, storage facilities of medicines in healthcare settings and homes may be suboptimal. However, knowledge of the effects of temperature and other climatic and environmental factors on the quality of medicines is limited. A better understanding of the effects of climates may assist in the development of control strategies to help reduce factors contributing to poor-quality medicines. Therefore, this systematic review aims to synthesise data from published studies describing the effects of storage conditions on the quality of antibiotic medicines commonly used in LMICs.Methods and analysisWe will search literature from databases, including the PubMed, Web of Science, Scopus and Google Scholar, and grey literature between 1987 and 2022. Experimental studies that evaluate the influence of temperature, humidity and sunlight on the quality of antibiotics applicable to Africa and South Asia will be included. Experimental studies that assess naturally occurring and simulated storage conditions and medicines prepared from powder with water and stored in hospitals or at home to be used across several doses will be also included. The key search terms related to the tropical climate, quality and commonly used antibiotics, such as temperature, storage condition, humidity, sunlight and moisture; quality, assay, purity, dissolution, disintegration, hardness, friability, weight variation, weight uniformity, degradation, impurities and stability; and amoxicillin, ceftriaxone, azithromycin, ciprofloxacin, doxycycline, metronidazole, trimethoprim-sulfamethoxazole, erythromycin, ampicillin and gentamicin, respectively, will be connected using the appropriate Boolean operators (OR, AND). The search terms will be used in correspondence with Medical Subject Heading terms by keyword arrangement. The available evidence for the poor quality of commonly used antibiotics is summarised by the type of diagnosis, type of drug and region. Meta-analysis using random effects will be performed using RevMan software to determine the pooled effects of environmental exposures. The degree of heterogeneity will be evaluated by the inverse of variance (I2). Forest plots will be used to present the meta-analysis data.Ethics and disseminationEthical approval is not required as the study is a systematic review. This review will be disseminated through open-access peer-reviewed publication.PROSPERO registration numberCRD42023432848.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.