Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis.

OBJECTIVES: This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis. METHODS: Pharmacokinetic data were collected in 59 neonates receiving ampicillin and gentamicin for suspected or proven sepsis in the NeoFosfo trial (NCT03453177). A panel of 23 clinical Escherichia coli isolates from neonates with sepsis, resistant to either ampicillin, gentamicin or both, were tested for susceptibility using chequerboards. Pharmacokinetic/pharmacodynamic (PKPD) modelling and simulations were used to compare single-agent (EUCAST MIC) and combination (chequerboard MIC) target attainment with standard dosing regimens. RESULTS: A model was established that simultaneously estimated parameters of a one-compartment ampicillin model and a two-compartment gentamicin model. A common clearance for both drugs was used (6.89 L/h/70 kg) relating to glomerular filtration (CLGFR), with an additional clearance term added for ampicillin (5.3 L/h/70 kg). Covariate modelling included a priori allometric weight and post-menstrual age scaling of clearance. Further covariate relationships on renal clearance were postnatal age and serum creatinine.Simulation-based PKPD assessments suggest good Gram-positive (MIC ≤ 0.25 mg/L) cover. However, less than one-quarter of neonates were predicted to receive efficacious coverage against Enterobacterales (MIC ≤ 2 mg/L). The benefit of the ampicillin/gentamicin combination was limited, with only 2/23 E. coli clinical strains showing FIC index < 0.5 (synergy) and most in the range 0.5-1 (suggesting additivity). Simulations showed that feasible dosing strategies would be insufficient to cover resistant strains. CONCLUSIONS: PKPD simulations showed ampicillin and gentamicin combination therapy was insufficient to cover Enterobacterales, suggesting the need for alternative empirical treatment options for neonatal sepsis.

Predicting the risk of mortality during hospitalization in sick severely malnourished children using daily evaluation of key clinical warning signs.

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.

IV and oral fosfomycin pharmacokinetics in neonates with suspected clinical sepsis.

BACKGROUND: Fosfomycin has the potential to be re-purposed as part of a combination therapy to treat neonatal sepsis where resistance to current standard of care (SOC) is common. Limited data exist on neonatal fosfomycin pharmacokinetics and estimates of bioavailability and CSF/plasma ratio in this vulnerable population are lacking. OBJECTIVES: To generate data informing the appropriate dosing of IV and oral fosfomycin in neonates using a population pharmacokinetic analysis of plasma and CSF data. METHODS: The NeoFosfo study (NCT03453177) was a randomized trial that examined the safety and pharmacokinetics of fosfomycin comparing SOC versus SOC plus fosfomycin. Sixty-one neonates received fosfomycin (100 mg/kg IV q12h for 48 h) and then they converted to oral therapy at the same dose. Two plasma pharmacokinetic samples were taken following the first IV and oral doses, sample times were randomized to cover the whole pharmacokinetic profile and opportunistic CSF pharmacokinetic samples were collected. A population pharmacokinetic model was developed in NONMEM and simulations were performed. RESULTS: In total, 238 plasma and 15 CSF concentrations were collected. A two-compartment disposition model, with an additional CSF compartment and first-order absorption, best described the data. Bioavailability was estimated as 0.48 (95% CI = 0.347-0.775) and the CSF/plasma ratio as 0.32 (95% CI = 0.272-0.409). Allometric weight and postmenstrual age (PMA) scaling was applied; additional covariates included postnatal age (PNA) on clearance and CSF protein on CSF/plasma ratio. CONCLUSIONS: Through this analysis a population pharmacokinetic model has been developed that can be used alongside currently available pharmacodynamic targets to select a neonatal fosfomycin dose based on an infant's PMA, PNA and weight.

Phenotype is sustained during hospital readmissions following treatment for complicated severe malnutrition among Kenyan children: A retrospective cohort study.

Hospital readmission is common among children with complicated severe acute malnutrition (cSAM) but not well-characterised. Two distinct cSAM phenotypes, marasmus and kwashiorkor, exist, but their pathophysiology and whether the same phenotype persists at relapse are unclear. We aimed to test the association between cSAM phenotype at index admission and readmission following recovery. We performed secondary data analysis from a multicentre randomised trial in Kenya with 1-year active follow-up. The main outcome was cSAM phenotype upon hospital readmission. Among 1,704 HIV-negative children with cSAM discharged in the trial, 177 children contributed a total of 246 readmissions with cSAM. cSAM readmission was associated with age<12 months (p = .005), but not site, sex, season, nor cSAM phenotype. Of these, 42 children contributed 44 readmissions with cSAM that occurred after a monthly visit when SAM was confirmed absent (cSAM relapse). cSAM phenotype was sustained during cSAM relapse. The adjusted odds ratio for presenting with kwashiorkor during readmission after kwashiorkor at index admission was 39.3 [95% confidence interval (95% CI) [2.69, 1,326]; p = .01); and for presenting with marasmus during readmission after kwashiorkor at index admission was 0.02 (95% CI [0.001, 0.037]; p = .01). To validate this finding, we examined readmissions to Kilifi County Hospital, Kenya occurring at least 2 months after an admission with cSAM. Among 2,412 children with cSAM discharged alive, there were 206 readmissions with cSAM. Their phenotype at readmission was significantly influenced by their phenotype at index admission (p < .001). This is the first report describing the phenotype and rate of cSAM recurrence.

A reduced-carbohydrate and lactose-free formulation for stabilization among hospitalized children with severe acute malnutrition: A double-blind, randomized controlled trial.

BACKGROUND: Children with medically complicated severe acute malnutrition (SAM) have high risk of inpatient mortality. Diarrhea, carbohydrate malabsorption, and refeeding syndrome may contribute to early mortality and delayed recovery. We tested the hypothesis that a lactose-free, low-carbohydrate F75 milk would serve to limit these risks, thereby reducing the number of days in the stabilization phase. METHODS AND FINDINGS: In a multicenter double-blind trial, hospitalized severely malnourished children were randomized to receive standard formula (F75) or isocaloric modified F75 (mF75) without lactose and with reduced carbohydrate. The primary endpoint was time to stabilization, as defined by the World Health Organization (WHO), with intention-to-treat analysis. Secondary outcomes included in-hospital mortality, diarrhea, and biochemical features of malabsorption and refeeding syndrome. The trial was registered at clinicaltrials.gov (NCT02246296). Four hundred eighteen and 425 severely malnourished children were randomized to F75 and mF75, respectively, with 516 (61%) enrolled in Kenya and 327 (39%) in Malawi. Children with a median age of 16 months were enrolled between 4 December 2014 and 24 December 2015. One hundred ninety-four (46%) children assigned to F75 and 188 (44%) to mF75 had diarrhea at admission. Median time to stabilization was 3 days (IQR 2-5 days), which was similar between randomized groups (0.23 [95% CI -0.13 to 0.60], P = 0.59). There was no evidence of effect modification by diarrhea at admission, age, edema, or HIV status. Thirty-six and 39 children died before stabilization in the F75 and in mF75 arm, respectively (P = 0.84). Cumulative days with diarrhea (P = 0.27), enteral (P = 0.42) or intravenous fluids (P = 0.19), other serious adverse events before stabilization, and serum and stool biochemistry at day 3 did not differ between groups. The main limitation was that the primary outcome of clinical stabilization was based on WHO guidelines, comprising clinical evidence of recovery from acute illness as well as metabolic stabilization evidenced by recovery of appetite. CONCLUSIONS: Empirically treating hospitalized severely malnourished children during the stabilization phase with lactose-free, reduced-carbohydrate milk formula did not improve clinical outcomes. The biochemical analyses suggest that the lactose-free formulae may still exceed a carbohydrate load threshold for intestinal absorption, which may limit their usefulness in the context of complicated SAM. TRIAL REGISTRATION: ClinicalTrials.gov NCT02246296.

The impact of rickets on growth and morbidity during recovery among children with complicated severe acute malnutrition in Kenya: A cohort study.

The effects of rickets on children recovery from severe acute malnutrition (SAM) are unknown. Rickets may affect both growth and susceptibility to infectious diseases. We investigated the associations of clinically diagnosed rickets with life-threatening events and anthropometric recovery during 1 year following inpatient treatment for complicated SAM. This was a secondary analysis of clinical trial data among non-human immunodeficiency virus-infected Kenyan children with complicated SAM (2-59 months) followed for 1 year posthospital discharge (ClinicalTrials.gov ID NCT00934492). The outcomes were mortality, hospital readmissions, and growth during 12 months. The main exposure was clinically diagnosed rickets at baseline. Of 1,778 children recruited, 230 (12.9%, 95% CI [11.4, 14 .6]) had clinical signs of rickets at baseline. Enrolment at an urban site, height-for-age and head circumference-for-age z scores were associated with rickets. Rickets at study enrolment was associated with increased mortality (adjusted Hazard Ratio [aHR] 1.61, 95% CI [1.14, 2.27]), any readmission (aHR 1.37, 95% CI [1.09, 1.72]), readmission for severe pneumonia (aHR 1.37, 95% CI [1.05, 1.79]), but not readmission with diarrhoea (aHR 1.05, 95% CI [0.73, 1.51]). Rickets was associated with increased height gain (centimetres), adjusted regression coefficient 0.19 (95% CI [0.10, 0.28]), but not changes in head circumference, mid-upper arm circumference, or weight. Rickets was common among children with SAM at urban sites and associated with increased risks of severe pneumonia and death. Increased height gain may have resulted from vitamin D and calcium treatment. Future work should explore possibility of other concurrent micronutrient deficiencies and optimal treatment of rickets in this high-risk population.

Ready-to-use therapeutic food with elevated n-3 polyunsaturated fatty acid content, with or without fish oil, to treat severe acute malnutrition: a randomized controlled trial.

BACKGROUND: Ready-to-use therapeutic foods (RUTF) are lipid-based pastes widely used in the treatment of acute malnutrition. Current specifications for RUTF permit a high n-6 polyunsaturated fatty acid (PUFA) content and low n-3 PUFA, with no stipulated requirements for preformed long-chain n-3 PUFA. The objective of this study was to develop an RUTF with elevated short-chain n-3 PUFA and measure its impact, with and without fish oil supplementation, on children's PUFA status during treatment of severe acute malnutrition. METHODS: This randomized controlled trial in children with severe acute malnutrition in rural Kenya included 60 children aged 6 to 50 months who were randomized to receive i) RUTF with standard composition; ii) RUTF with elevated short chain n-3 PUFA; or iii) RUTF with elevated short chain n-3 PUFA plus fish oil capsules. Participants were followed-up for 3 months. The primary outcome was erythrocyte PUFA composition. RESULTS: Erythrocyte docosahexaenoic acid (DHA) content declined from baseline in the two arms not receiving fish oil. Erythrocyte long-chain n-3 PUFA content following treatment was significantly higher for participants in the arm receiving fish oil than for those in the arms receiving RUTF with elevated short chain n-3 PUFA or standard RUTF alone: 3 months after enrollment, DHA content was 6.3% (interquartile range 6.0-7.3), 4.5% (3.9-4.9), and 3.9% (2.4-5.7) of total erythrocyte fatty acids (P <0.001), respectively, while eicosapentaenoic acid (EPA) content was 2.0% (1.5-2.6), 0.7% (0.6-0.8), and 0.4% (0.3-0.5) (P <0.001). RUTF with elevated short chain n-3 PUFA and fish oil capsules were acceptable to participants and carers, and there were no significant differences in safety outcomes. CONCLUSIONS: PUFA requirements of children with SAM are not met by current formulations of RUTF, or by an RUTF with elevated short-chain n-3 PUFA without additional preformed long-chain n-3 PUFA. Clinical and growth implications of revised formulations need to be addressed in large clinical trials. TRIAL REGISTRATION: Clinicaltrials.gov NCT01593969. Registered 4 May 2012.

Childhood malnutrition: toward an understanding of infections, inflammation, and antimicrobials.

BACKGROUND: Undernutrition in childhood is estimated to cause 3.1 million child deaths annually through a potentiating effect on common infectious diseases, such as pneumonia and diarrhea. In turn, overt and subclinical infections, and inflammation, especially in the gut, alter nutrient intake, absorption, secretion, diversion, catabolism, and expenditure. OBJECTIVE: A narrative overview of the current understanding of infections, inflammation, and antimicrobials in relation to childhood malnutrition. METHODS: Searches for pivotal papers were conducted using PUBMED 1966-January 2013; hand searches of the references of retrieved literature; discussions with experts; and personal experience from the field. RESULTS: Although the epidemiological evidence for increased susceptibility to life-threatening infections associated with malnutrition is strong, we are only just beginning to understand some of the mechanisms involved. Nutritional status and growth are strongly influenced by environmental enteric dysfunction (EED), which is common among children in developing countries, and by alterations in the gut microbiome. As yet, there are no proven interventions against EED. Antibiotics have long been used as growth promoters in animals. Trials of antibiotics have shown striking efficacy on mortality and on growth in children with uncomplicated severe acute malnutrition (SAM) or HIV infection. Antibiotics act directly by preventing infections and may act indirectly by reducing subclinical infections and inflammation. We describe an ongoing multicenter, randomized, placebo-controlled trial of daily cotrimoxazole prophylaxis to prevent death in children recovering from complicated SAM. Secondary outcomes include growth, frequency and etiology of infections, immune activation and function, the gut microbiome, and antimicrobial resistance. The trial is expected to be reported in mid-2014. CONCLUSIONS: As well as improving nutritional intake, new case management strategies need to address infection, inflammation, and microbiota and assess health outcomes rather than only anthropometry.

Childhood growth during recovery from acute illness in Africa and South Asia: a secondary analysis of the childhood acute illness and nutrition (CHAIN) prospective cohort.

Background: Growth faltering is well-recognized during acute childhood illness and growth acceleration during convalescence, with or without nutritional therapy, may occur. However, there are limited recent data on growth after hospitalization in low- and middle-income countries. Methods: We evaluated growth following hospitalization among children aged 2-23 months in sub-Saharan Africa and South Asia. Between November 2016 and January 2019, children were recruited at hospital admission and classified as: not-wasted (NW), moderately-wasted (MW), severely-wasted (SW), or having nutritional oedema (NO). We describe earlier (discharge to 45-days) and later (45- to 180-days) changes in length-for-age [LAZ], weight-for-age [WAZ], mid-upper arm circumference [MUACZ], weight-for-length [WLZ] z-scores, and clinical, nutritional, and socioeconomic correlates. Findings: We included 2472 children who survived to 180-days post-discharge: NW, 960 (39%); MW, 572 (23%); SW, 682 (28%); and NO, 258 (10%). During 180-days, LAZ decreased in NW (-0.27 [-0.36, -0.19]) and MW (-0.23 [-0.34, -0.11]). However, all groups increased WAZ (NW, 0.21 [95% CI: 0.11, 0.32]; MW, 0.57 [0.44, 0.71]; SW, 1.0 [0.88, 1.1] and NO, 1.3 [1.1, 1.5]) with greatest gains in the first 45-days. Of children underweight (<-2 WAZ) at discharge, 66% remained underweight at 180-days. Lower WAZ post-discharge was associated with age-inappropriate nutrition, adverse caregiver characteristics, small size at birth, severe or moderate anaemia, and chronic conditions, while lower LAZ was additionally associated with household-level exposures but not with chronic medical conditions. Interpretation: Underweight and poor linear growth mostly persisted after an acute illness. Beyond short-term nutritional supplementation, improving linear growth post-discharge may require broader individual and family support. Funding: Bill & Melinda Gates FoundationOPP1131320; National Institute for Health ResearchNIHR201813.

Intestinal disturbances associated with mortality of children with complicated severe malnutrition.

BACKGROUND: Children admitted to hospital with complicated severe malnutrition (CSM) have high mortality despite compliance with standard WHO management guidelines. Limited data suggests a relationship between intestinal dysfunction and poor prognosis in CSM, but this has not been explicitly studied. This study aimed to evaluate the role of intestinal disturbances in CSM mortality. METHODS: A case-control study nested within a randomized control trial was conducted among children hospitalized with CSM in Kenya and Malawi. Children who died (cases, n = 68) were compared with those who were discharged, propensity matched to the cases on age, HIV and nutritional status (controls, n = 68) on fecal metabolomics that targeted about 70 commonly measured metabolites, and enteropathy markers: fecal myeloperoxidase (MPO), fecal calprotectin, and circulating intestinal fatty acid binding protein (I-FABP). RESULTS: The fecal metabolomes of cases show specific reductions in amino acids, monosaccharides, and microbial fermentation products, when compared to controls. SCFA levels did not differ between groups. The overall fecal metabolomics signature moderately differentiates cases from controls (AUC = 0.72). Enteropathy markers do not differ between groups overall, although serum I-FABP is elevated in cases in a sensitivity analysis among non-edematous children. Integrative analysis with systemic data suggests an indirect role of intestinal inflammation in the causal path of mortality. CONCLUSIONS: Intestinal disturbances appear to have an indirect association with acute mortality. Findings of the study improve our understanding of pathophysiological pathways underlying mortality of children with CSM.

Malnourished children are at a high risk of dying when exposed to an acute illness. They often have symptoms like diarrhea that indicate their gut is not working properly. It is unclear whether these gut problems contribute to their deaths. Feces contain numerous small molecules processed by the gut that reflect gut health. We compare these fecal molecules between malnourished children who died during hospitalization to those who survived, and relate them to signs of inflammation in the body. We show that the fecal molecules are different between children who died and those who survived. These differences reveal that poor gut health could increase risk of death, potentially by perturbing the body's defensive response to an acute illness. These findings underscore that treatment for ill severely malnourished children should focus on improving gut health.

The microbiologic safety of umbilical cord blood transfusion for children with severe anemia in Mombasa, Kenya.

BACKGROUND: Severe anemia requiring blood transfusion is common in hospitalized young children in sub-Saharan Africa but blood is often in short supply. Umbilical cord blood may be a useful source of blood if microbiologic safety concerns can be addressed. STUDY DESIGN AND METHODS: Cord blood, donated on the labor ward at the provincial hospital in Mombasa, was cultured soon after collection (screening culture) and after a period of storage (poststorage culture). Conventional blood transfused to children at the hospital was cultured only at the time of issue (poststorage culture). Maternal sera (cord blood) and conventional blood donations were also screened for transfusion-transmitted infection. RESULTS: At poststorage culture, the overall contamination rate of cord blood was one-third that of conventional blood (13/449 vs. 38/434; odds ratio [OR], 0.31; 95% confidence interval [CI], 0.15-0.61) and for bacteria of high pathogenic potential it was half that of conventional blood (4/449 vs. 7/434; OR, 0.55; 95% CI, 0.12-2.18). Screening cultures were positive in 50% (2/4) of cord blood packs where an organism of high pathogenic potential was isolated at poststorage culture. Cord blood donors had a lower seroreactivity than conventional donors for human immunodeficiency virus (OR, 0.63; 95% CI, 0.29-1.18), hepatitis B virus (OR, 0.32; 95% CI, 0.16-0.59), and hepatitis C virus (OR, 0.20; 95% CI, 0.24-0.76). For syphilis, initial seroreactivity in cord blood donors was 3.8% compared to 1.8% in conventional blood donors (OR, 2.10; 95% CI, 1.15-3.60) but was 0.5% after retesting. CONCLUSION: With respect to bacterial contamination and seroreactivity for transfusion-transmitted infection, the safety of cord blood in Mombasa compares favorably with conventional blood. Clinical trials of cord blood transfusion are justified.

Randomised controlled trial of fosfomycin in neonatal sepsis: pharmacokinetics and safety in relation to sodium overload.

OBJECTIVE: To assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis. DESIGN: A single-centre open-label randomised controlled trial. SETTING: Kilifi County Hospital, Kenya. PATIENTS: 120 neonates aged ≤28 days admitted being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and gentamicin between March 2018 and February 2019. INTERVENTION: We 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 OUTCOMES AND MEASURES: Serum sodium, AEs and fosfomycin pharmacokinetics. RESULTS: 61 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 RELEVANCE: Fosfomycin 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.

The role of albumin and the extracellular matrix on the pathophysiology of oedema formation in severe malnutrition.

BACKGROUND: While fluid flows in a steady state from plasma, through interstitium, and into the lymph compartment, altered fluid distribution and oedema can result from abnormal Starling's forces, increased endothelial permeability or impaired lymphatic drainage. The mechanism of oedema formation, especially the primary role of hypoalbuminaemia, remains controversial. Here, we explored the roles of albumin and albumin-independent mechanisms in oedema formation among children with severe malnutrition (SM). METHODS: We performed secondary analysis of data obtained from two independent clinical trials in Malawi and Kenya (NCT02246296 and NCT00934492). We then used an unconventional strategy of comparing children with kwashiorkor and marasmus by matching (discovery cohort, n = 144) and normalising (validation cohort, n = 98, 2 time points) for serum albumin. Untargeted proteomics was used in the discovery cohort to determine plausible albumin-independent mechanisms associated with oedema, which was validated using enzyme-linked immunosorbent assay and multiplex assays in the validation cohort. FINDINGS: We demonstrated that low serum albumin is necessary but not sufficient to develop oedema in SM. We further found that markers of extracellular matrix (ECM) degradation rather than markers of EG degradation distinguished oedematous and non-oedematous children with SM. INTERPRETATION: Our results show that oedema formation has both albumin-dependent and independent mechanisms. ECM integrity appears to have a greater role in oedema formation than EG shedding in SM. FUNDING: Research Foundation Flanders (FWO), Thrasher Foundation (15122 and 9403), VLIR-UOS-Ghent University Global Minds Fund, Bill & Melinda Gates Foundation (OPP1131320), MRC/DfID/Wellcome Trust Global Health Trials Scheme (MR/M007367/1), Canadian Institutes of Health Research (156307), Wellcome Trust (WT083579MA).

Systemic inflammation and metabolic disturbances underlie inpatient mortality among ill children with severe malnutrition.

Children admitted to hospital with an acute illness and concurrent severe malnutrition [complicated severe malnutrition (CSM)] have a high risk of dying. The biological processes underlying their mortality are poorly understood. In this case-control study nested within a multicenter randomized controlled trial among children with CSM in Kenya and Malawi, we found that blood metabolomic and proteomic profiles robustly differentiated children who died (n = 92) from those who survived (n = 92). Fatalities were characterized by increased energetic substrates (tricarboxylic acid cycle metabolites), microbial metabolites (e.g., propionate and isobutyrate), acute phase proteins (e.g., calprotectin and C-reactive protein), and inflammatory markers (e.g., interleukin-8 and tumor necrosis factor-α). These perturbations indicated disruptions in mitochondria-related bioenergetic pathways and sepsis-like responses. This study identified specific biomolecular disturbances associated with CSM mortality, revealing that systemic inflammation and bioenergetic deficits are targetable pathophysiological processes for improving survival of this vulnerable population.

Diagnostic performance of visible severe wasting for identifying severe acute malnutrition in children admitted to hospital in Kenya.

OBJECTIVE: To determine the diagnostic value of visible severe wasting in identifying severe acute malnutrition at two public hospitals in Kenya. METHODS: This was a cross-sectional study of children aged 6 to 59.9 months admitted to one rural and one urban hospital. On admission, mid-upper arm circumference (MUAC), weight and height were measured and the presence of visible severe wasting was assessed. The diagnostic performance of visible severe wasting was evaluated against anthropometric criteria. FINDINGS: Of 11,166 children admitted, 563 (5%) had kwashiorkor and 1406 (12.5%) were severely wasted (MUAC < 11.5 cm). The combined sensitivity and specificity of visible severe wasting at the two hospitals, as assessed against a MUAC < 11.5 cm, were 54% (95% confidence interval, CI: 51-56) and 96% (95% CI: 96-97), respectively; at one hospital, its sensitivity and specificity against a weight-for-height z-score below -3 were 44.7% (95% CI: 42-48) and 96.5% (95% CI: 96-97), respectively. Severely wasted children who were correctly identified by visible severe wasting were consistently older, more severely wasted, more often having kwashiorkor, more often positive to the human immunodeficiency virus, ill for a longer period and at greater risk of death. Visible severe wasting had lower sensitivity for determining the risk of death than the anthropometric measures. There was no evidence to support measuring both MUAC and weight-for-height z-score. CONCLUSION: Visible severe wasting failed to detect approximately half of the children admitted to hospital with severe acute malnutrition diagnosed anthropometrically. Routine screening by MUAC is quick, simple and inexpensive and should be part of the standard assessment of all paediatric hospital admissions in the study setting.

Model for developing context-sensitive responses to vulnerability in research: managing ethical dilemmas faced by frontline research staff in Kenya.

Health research in low-resource settings often involves individuals and populations defined as 'vulnerable'. There is growing attention in the literature to the ethical dilemmas that frontline research staff face while conducting such research. However, there is little documented as to how research staff might support one another in identifying and handling these dilemmas in different contexts. Over the course of conducting empirical ethics research embedded in the Childhood Acute Illness & Nutrition Network, we developed an approach to examine and respond to the ethical issues and dilemmas faced by the study teams, particularly frontline staff. In this paper we describe the specific tools and approach we developed, which centred on regular cross-team ethics reflection sessions, and share lessons learnt. We suggest that all studies involving potentially vulnerable participants should incorporate activities and processes to support frontline staff in identifying, reflecting on and responding to ethical dilemmas, throughout studies. We outline the resources needed to do this and share piloted tools for further adaptation and evaluation. Such initiatives should complement and feed into-and certainly not in any way replace or substitute for-strong institutional ethics review, safeguarding and health and safety policies and processes, as well broader staff training and career support initiatives.

The quality of stored umbilical cord and adult-donated whole blood in Mombasa, Kenya.

BACKGROUND: In sub-Saharan Africa umbilical cord blood may be a useful source of blood for transfusion. Before clinical trials, evidence is needed that cord blood donations, which vary greatly in volume, can be collected and stored into a fixed volume of anticoagulant-preservative solution obviating the need for prestorage processing. STUDY DESIGN AND METHODS: Twenty-four umbilical cord whole blood (UC-WB) donations were collected into 21 mL of CPDA-1 and refrigerated for 35 days. The Kenya Blood Transfusion Service provided 12 adult-donated whole blood (AD-WB) controls. Supernatant hemoglobin (Hb) and potassium were assayed at 7-day intervals. RESULTS: UC-WB red blood cell hemolysis and potassium loss increased throughout storage but did not differ significantly with cord blood volume. Hemolysis rates did not differ significantly between UC-WB and AD-WB but UC-WB potassium loss was slightly but significantly greater than AD-WB on Days 2, 7, and 14 (p < 0.05). In the AD-WB controls, eight were low volume (<405 mL), two had total Hb of less than 45 g, and two showed hemolysis greater than 0.8% by Day 28. CONCLUSION: Variable volumes of UC-WB can be stored for 35 days without prestorage processing and further work into its suitability for transfusion to children is justified. The quality of conventional AD-WB is a concern and needs further evaluation.

Systemic inflammation is negatively associated with early post discharge growth following acute illness among severely malnourished children - a pilot study.

Background: Rapid growth should occur among children with severe malnutrition (SM) with medical and nutritional management. Systemic inflammation (SI) is associated with death among children with SM and is negatively associated with linear growth. However, the relationship between SI and weight gain during therapeutic feeding following acute illness is unknown. We hypothesised that growth post-hospital discharge is associated with SI among children with SM. Methods: We conducted secondary analysis of data from HIV-uninfected children with SM (n=98) who survived and were not readmitted to hospital during one year of follow-up. We examined the relationship between changes in absolute deficits in weight and mid-upper-arm circumference (MUAC) from enrolment at stabilisation to 60 days and one year later, and untargeted plasma proteome, targeted cytokines/chemokines, leptin, and soluble CD14 using multivariate regularized linear regression. Results: The mean change in absolute deficit in weight and MUAC was -0.50kg (standard deviation; SD±0.69) and -1.20cm (SD±0.89), respectively, from enrolment to 60 days later. During the same period, mean weight and MUAC gain was 3.3g/kg/day (SD±2.4) and 0.22mm/day (SD±0.2), respectively. Enrolment interleukins; IL17-alpha and IL-2, and serum amyloid P were negatively associated with weight and MUAC gain during 60 days. Lipopolysaccharide binding protein and complement component 2 were negatively associated with weight gain only. Leptin was positively associated with weight gain. Soluble CD14, beta-2 microglobulin, and macrophage inflammatory protein 1 beta were negatively associated with MUAC gain only. Glutathione peroxidase 3 was positively associated with weight and MUAC gain during one year. Conclusions: Early post-hospital discharge weight and MUAC gain were rapid and comparable to children with uncomplicated SM treated in the community. Higher concentrations of SI markers were associated with less weight and MUAC gain, suggesting inflammation negatively impacts recovery from wasting. This finding warrants further research on reducing inflammation on growth among children with SM.

Prediction of mortality in severe acute malnutrition in hospitalized children by faecal volatile organic compound analysis: proof of concept.

Children with severe acute malnutrition (SAM) display immature, altered gut microbiota and have a high mortality risk. Faecal volatile organic compounds (VOCs) reflect the microbiota composition and may provide insight into metabolic dysfunction that occurs in SAM. Here we determine whether analysis of faecal VOCs could identify children with SAM with increased risk of mortality. VOC profiles from children who died within six days following admission were compared to those who were discharged alive using machine learning algorithms. VOC profiles of children who died could be separated from those who were discharged with fair accuracy (AUC) = 0.71; 95% CI 0.59-0.87; P = 0.004). We present the first study showing differences in faecal VOC profiles between children with SAM who survived and those who died. VOC analysis holds potential to help discover metabolic pathways within the intestinal microbiome with causal association with mortality and target treatments in children with SAM.Trial Registration: The F75 study is registered at clinicaltrials.gov/ct2/show/NCT02246296.

Linear growth following complicated severe malnutrition: 1-year follow-up cohort of Kenyan children.

BACKGROUND: Stunting 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. METHODS: We 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. RESULTS: Among 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. CONCLUSIONS: Interventions to improve dietary quality and prevent illness over a longer period may provide opportunities to improve linear growth.