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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., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use., Methods and Findings: Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507., Interpretation: In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs., Trial Registration: ClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947., Competing Interests: NJW and LvS are members of the PLOS Medicine Editorial Board. The rest of the authors have declared that no competing interests exist., (Copyright: © 2024 Schilling et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., Competing Interests: Members of the writing group declare having received support from the Bill and Melinda Gates Foundation (BMGF) for staff and research activities directly linked to this project which was paid to their universities or institutions (JAB, JLW, RHJB). Reimbursement for travel directly related to this project was also provided by BMGF and paid through the universities (JLW, JAB). JAB participated in a leadership role for the Commonwealth Association for Paediatic Gastroenterology & Nutrition (CAPGAN) and on a Data Safety Monitoring Board (DSMB) for a study regarding vitamin D., (© 2024 The Authors.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Infants and young children with severe acute malnutrition (SAM) are treated with empiric broad-spectrum antimicrobials. Parenteral ceftriaxone is currently a second-line agent for invasive infection. Oral metronidazole principally targets small intestinal bacterial overgrowth. Children with SAM may have altered drug absorption, distribution, metabolism, and elimination. Population pharmacokinetics of ceftriaxone and metronidazole were studied, with the aim of recommending optimal dosing. Eighty-one patients with SAM (aged 2-45 months) provided 234 postdose pharmacokinetic samples for total ceftriaxone, metronidazole, and hydroxymetronidazole. Ceftriaxone protein binding was also measured in 190 of these samples. A three-compartment model adequately described free ceftriaxone, with a Michaelis-Menten model for concentration and albumin-dependent protein binding. A one-compartment model was used for both metronidazole and hydroxymetronidazole, with only 1% of hydroxymetronidazole predicted to be formed during first-pass. Simulations showed 80 mg/kg once daily of ceftriaxone and 12.5 mg/kg twice daily of metronidazole were sufficient to reach therapeutic targets., (© 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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., (© 2017 The Authors. Maternal and Child Nutrition Published by John Wiley & Sons, Ltd.)

Background: Goals of treating childhood severe acute malnutrition (SAM), in addition to anthropometric recovery and preventing short-term mortality, include reducing the risks of subsequent serious infections. How quickly and how much the risk of serious illness changes during rehabilitation are unknown but could inform improving the design and scope of interventions., Objective: The aim of this study was to investigate changes in the risk of life-threatening events (LTEs) in relation to anthropometric recovery from SAM., Design: This was a secondary analysis of a clinical trial including 1778 HIV-uninfected Kenyan children aged 2-59 mo with complicated SAM, enrolled after the inpatient stabilization phase of treatment, and followed for 12 mo. The main outcome was LTEs, defined as infections requiring rehospitalization or causing death. We examined anthropometric variables measured at months 1, 3, and 6 after enrollment in relation to LTEs occurring during the 6 mo after each of these time points., Results: Over 12 mo, there were 823 LTEs (257 fatal), predominantly severe pneumonia and diarrhea. At months 1, 3, and 6, 557 (34%), 764 (49%), and 842 (56%) children had a weight-for-height or -length z score (WHZ) ≥-2, respectively, which, compared with a WHZ <-3, was associated with lower risks of subsequent LTEs [adjusted HRs (95% CIs): 0.50 (0.40, 0.64), 0.30 (0.23, 0.39), and 0.23 (0.16, 0.32), respectively]. However, children with a WHZ ≥-2 at 1, 3, and 6 mo still had 39 (95% CI: 32, 47), 26 (95% CI: 22, 32), and 15 (95% CI: 12, 20) LTEs/100 child-years of observation during the following 6 mo. WHZ at study enrollment predicted subsequent WHZ but not the risk of LTEs. Changes in height-for-age z score did not predict LTEs., Conclusions: Anthropometric response was associated with a rapid and substantial reduction in risk of LTEs. However, reduction in susceptibility lagged behind anthropometric improvement. Disease events, together with anthropometric assessment, may provide a clearer picture of the effectiveness of interventions. Robust protocols for detecting and treating poor anthropometric recovery and addressing broader vulnerabilities that complicated SAM indicates may save lives. This trial was registered at www.clinicaltrials.gov as NCT00934492.

Background: Children with complicated severe acute malnutrition (SAM) have a greatly increased risk of mortality from infections while in hospital and after discharge. In HIV-infected children, mortality and admission to hospital are prevented by daily co-trimoxazole prophylaxis, despite locally reported bacterial resistance to co-trimoxazole. We aimed to assess the efficacy of daily co-trimoxazole prophylaxis on survival in children without HIV being treated for complicated SAM., Methods: We did a multicentre, double-blind, randomised, placebo-controlled study in four hospitals in Kenya (two rural hospitals in Kilifi and Malindi, and two urban hospitals in Mombasa and Nairobi) with children aged 60 days to 59 months without HIV admitted to hospital and diagnosed with SAM. We randomly assigned eligible participants (1:1) to 6 months of either daily oral co-trimoxazole prophylaxis (given as water-dispersible tablets; 120 mg per day for age <6 months, 240 mg per day for age 6 months to 5 years) or matching placebo. Assignment was done with computer-generated randomisation in permuted blocks of 20, stratified by centre and age younger or older than 6 months. Treatment allocation was concealed in opaque, sealed envelopes and patients, their families, and all trial staff were masked to treatment assignment. Children were given recommended medical care and feeding, and followed up for 12 months. The primary endpoint was mortality, assessed each month for the first 6 months, then every 2 months for the second 6 months. Secondary endpoints were nutritional recovery, readmission to hospital, and illness episodes treated as an outpatient. Analysis was by intention to treat. This trial was registered at ClinicalTrials.gov, number NCT00934492., Findings: Between Nov 20, 2009, and March 14, 2013, we recruited and assigned 1778 eligible children to treatment (887 to co-trimoxazole prophylaxis and 891 to placebo). Median age was 11 months (IQR 7-16 months), 306 (17%) were younger than 6 months, 300 (17%) had oedematous malnutrition (kwashiorkor), and 1221 (69%) were stunted (length-for-age Z score <-2). During 1527 child-years of observation, 122 (14%) of 887 children in the co-trimoxazole group died, compared with 135 (15%) of 891 in the placebo group (unadjusted hazard ratio [HR] 0·90, 95% CI 0·71-1·16, p=0·429; 16·0 vs 17·7 events per 100 child-years observed (CYO); difference -1·7 events per 100 CYO, 95% CI -5·8 to 2·4]). In the first 6 months of the study (while participants received study medication), 63 suspected grade 3 or 4 associated adverse events were recorded among 57 (3%) children; 31 (2%) in the co-trimoxazole group and 32 (2%) in the placebo group (incidence rate ratio 0·98, 95% CI 0·58-1·65). The most common adverse events of these grades were urticarial rash (grade 3, equally common in both groups), neutropenia (grade 4, more common in the co-trimoxazole group), and anaemia (both grades equally common in both groups). One child in the placebo group had fatal toxic epidermal necrolysis with concurrent Pseudomonas aeruginosa bacteraemia., Interpretation: Daily co-trimoxazole prophylaxis did not reduce mortality in children with complicated SAM without HIV. Other strategies need to be tested in clinical trials to reduce deaths in this population., Funding: Wellcome Trust, UK., (Copyright © 2016 Berkley et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Background: Environmental enteric dysfunction (EED) is an acquired syndrome of impaired gastrointestinal mucosal barrier function that is thought to play a key role in the pathogenesis of stunting in early life. It has been conceptualized as an adaptive response to excess environmental pathogen exposure. However, it is clinically similar to other inflammatory enteropathies, which result from both host and environmental triggers, and for which immunomodulation is a cornerstone of therapy., Methods: In this pilot double-blind randomized placebo-controlled trial, 44 children with severe acute malnutrition and evidence of EED were assigned to treatment with mesalazine or placebo for 28 days during nutritional rehabilitation. Primary outcomes were safety and acceptability of the intervention., Results: Treatment with mesalazine was safe: there was no excess of adverse events, evidence of deterioration in intestinal barrier integrity or impact on nutritional recovery. There were modest reductions in several inflammatory markers with mesalazine compared to placebo. Depression of the growth hormone--insulin-like growth factor-1 axis was evident at enrollment and associated with inflammatory activation. Increases in the former and decreases in the latter correlated with linear growth., Conclusions: Intestinal inflammation in EED is non-essential for mucosal homeostasis and is at least partly maladaptive. Further trials of gut-specific immunomodulatory therapies targeting host inflammatory activation in order to optimize the growth benefits of nutritional rehabilitation and to address stunting are warranted. Funded by The Wellcome Trust., Trial Registration: Registered at Clinicaltrials.gov NCT01841099.

Background: Early rapid fluid resuscitation (boluses) in African children with severe febrile illnesses increases the 48-hour mortality by 3.3% compared with controls (no bolus). We explored the effect of boluses on 48-hour all-cause mortality by clinical presentation at enrolment, hemodynamic changes over the first hour, and on different modes of death, according to terminal clinical events. We hypothesize that boluses may cause excess deaths from neurological or respiratory events relating to fluid overload., Methods: Pre-defined presentation syndromes (PS; severe acidosis or severe shock, respiratory, neurological) and predominant terminal clinical events (cardiovascular collapse, respiratory, neurological) were described by randomized arm (bolus versus control) in 3,141 severely ill febrile children with shock enrolled in the Fluid Expansion as Supportive Therapy (FEAST) trial. Landmark analyses were used to compare early mortality in treatment groups, conditional on changes in shock and hypoxia parameters. Competing risks methods were used to estimate cumulative incidence curves and sub-hazard ratios to compare treatment groups in terms of terminal clinical events., Results: Of 2,396 out of 3,141 (76%) classifiable participants, 1,647 (69%) had a severe metabolic acidosis or severe shock PS, 625 (26%) had a respiratory PS and 976 (41%) had a neurological PS, either alone or in combination. Mortality was greatest among children fulfilling criteria for all three PS (28% bolus, 21% control) and lowest for lone respiratory (2% bolus, 5% control) or neurological (3% bolus, 0% control) presentations. Excess mortality in bolus arms versus control was apparent for all three PS, including all their component features. By one hour, shock had resolved (responders) more frequently in bolus versus control groups (43% versus 32%, P <0.001), but excess mortality with boluses was evident in responders (relative risk 1.98, 95% confidence interval 0.94 to 4.17, P = 0.06) and 'non-responders' (relative risk 1.67, 95% confidence interval 1.23 to 2.28, P = 0.001), with no evidence of heterogeneity (P = 0.68). The major difference between bolus and control arms was the higher proportion of cardiogenic or shock terminal clinical events in bolus arms (n = 123; 4.6% versus 2.6%, P = 0.008) rather than respiratory (n = 61; 2.2% versus 1.3%, P = 0.09) or neurological (n = 63, 2.1% versus 1.8%, P = 0.6) terminal clinical events., Conclusions: Excess mortality from boluses occurred in all subgroups of children. Contrary to expectation, cardiovascular collapse rather than fluid overload appeared to contribute most to excess deaths with rapid fluid resuscitation. These results should prompt a re-evaluation of evidence on fluid resuscitation for shock and a re-appraisal of the rate, composition and volume of resuscitation fluids., Trial Registration: ISRCTN69856593.

Objectives: A previous meta-analysis has shown a consistent survival benefit in children with severe malaria receiving human albumin solution compared to other resuscitation fluids. Human albumin solution is expensive and not readily available in Africa. We examined the safety and efficacy of the fluid resuscitation with two synthetic colloids, Dextran 70 and hydroxyethyl starch, to inform future trial design., Design: An open-label randomized, controlled, phase II safety and efficacy trial., Setting: High-dependency unit, Kilifi District Hospital, Kenya., Patients: Children aged >6 months with severe falciparum malaria and acidosis (base deficit >8 mmol)., Interventions: Boluses (20-40 mL/kg) of 6% Dextran 70 and 6% hydroxyethyl starch (130/0.4)., Measurements and Main Results: Primary end point: resolution of shock over 8 hrs. Secondary end points include resolution of acidosis, in-hospital mortality, and adverse events (allergic reactions, pulmonary edema, and neurologic sequelae). A total of 79 children were enrolled: 39 received Dextran 70 and 40 received hydroxyethyl starch. No significant difference was observed in Dextran 70 and hydroxyethyl starch groups for shock resolution at 8 hrs: 23/37 (62%) and 25/39 (64%), respectively (p = .99). Acidosis resolution and respiratory distress were marginally superior in the hydroxyethyl starch group: 3/39 (8%) remained acidotic at 8 hrs versus 10/37 (27%) in the Dextran 70 arm (p = .05). There were four deaths (5%): two per arm, including three deaths in the coma subgroup (3/39, 8%). No other new adverse event was reported., Conclusions: Correction of shock by volume expansion with either Dextran 70 or hydroxyethyl starch in children with severe malaria acidosis is safe with low mortality, including the highest risk cases admitted in coma. Both solutions present an attractive and practical option for consideration in future volume resuscitation trials in severe malaria.

Objectives: Mortality from severe malaria remains unacceptably high in sub-Saharan Africa. Several markers of cardiovascular compromise and metabolic acidosis correlate with mortality. The role of cardiac dysfunction in the pathogenesis of severe childhood malaria remains unknown., Design: We examined 30 children admitted with severe malaria by using portable echocardiography to assess their cardiac function and hemodynamic status on admission (day 0), day 1, and discharge. We compared hemodynamic parameters in two study groups: children presenting with metabolic acidosis (base deficit >8) and children without acidosis., Setting: High-dependency unit, Kilifi District Hospital, Kenya., Interventions: Acidotic patients received fluid resuscitation with either dextran 70 or starch at admission., Measurements and Main Results: Several markers of hemodynamic compromise were noted on admission, including severe tachycardia, low stroke volume index, and high inferior vena cava collapsibility index, which improved with subsequent readings. Overall, cardiac function assessed by ejection fraction (63.1% +/- 5.2% vs. 71.9% +/- 2.8%; p < .001) and left myocardial performance index (0.32 +/- 0.16 vs. 0.25 +/- 0.08; p = .03) was mildly abnormal on admission compared with discharge. Acidotic patients had worse hemodynamic indicators, with a significantly higher inferior vena cava collapsibility index on day 0 than nonacidotic patients (52.1 +/- 21 .9 vs. 37.7 +/- 15.4; p = .03), plus lower stroke volume index and worse cardiac function with higher left myocardial performance index (0.38 +/- 0.18 vs. 0.26 +/- 0.11; p = .05). Stroke volume index increased after first fluid bolus in 80% of children., Conclusions: Children with severe malaria and metabolic acidosis have evidence of hypovolemia and evidence of cardiac dysfunction.