Children with severe malnutrition: can those at highest risk of death be identified with the WHO protocol?

Background With strict adherence to international recommended treatment guidelines, the case fatality for severe malnutrition ought to be less than 5%. In African hospitals, fatality rates of 20% are common and are often attributed to poor training and faulty case management. Improving outcome will depend upon the identification of those at greatest risk and targeting limited health resources. We retrospectively examined the major risk factors associated with early (<48 h) and late in-hospital death in children with severe malnutrition with the aim of identifying admission features that could distinguish a high-risk group in relation to the World Health Organization (WHO) guidelines. Methods and Findings Of 920 children in the study, 176 (19%) died, with 59 (33%) deaths occurring within 48 h of admission. Bacteraemia complicated 27% of all deaths: 52% died before 48 h despite 85% in vitro antibiotic susceptibility of cultured organisms. The sensitivity, specificity, and likelihood ratio of the WHO-recommended “danger signs” (lethargy, hypothermia, or hypoglycaemia) to predict early mortality was 52%, 84%, and 3.4% (95% confidence interval [CI] = 2.2 to 5.1), respectively. In addition, four bedside features were associated with early case fatality: bradycardia, capillary refill time greater than 2 s, weak pulse volume, and impaired consciousness level; the presence of two or more features was associated with an odds ratio of 9.6 (95% CI = 4.8 to 19) for early fatality (p < 0.0001). Conversely, the group of children without any of these seven features, or signs of dehydration, severe acidosis, or electrolyte derangements, had a low fatality (7%). Conclusions Formal assessment of these features as emergency signs to improve triage and to rationalize manpower resources toward the high-risk groups is required. In addition, basic clinical research is necessary to identify and test appropriate supportive treatments

Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia

Malaria has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor One (CR1) gene, named Sl2 and McCb, occur at high frequencies, suggesting selection by malaria. Previous studies have been inconclusive. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, we demonstrate that Sl2 and McCb have opposing malaria associations. The Sl2 polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the McCb polymorphism is associated with increased odds of cerebral malaria. We also identified an unexpected interaction between Sl2 and α+thalassaemia, revealing that the protective association of Sl2 was greatest in children with normal α-globin. The complex relationship between these three mutations may explain previous conflicting findings, and the data highlight the importance of considering genetic interactions in disease-association studies

Children with severe malnutrition: can those at highest risk of death be identified with the WHO protocol?

BACKGROUND: With strict adherence to international recommended treatment guidelines, the case fatality for severe malnutrition ought to be less than 5%. In African hospitals, fatality rates of 20% are common and are often attributed to poor training and faulty case management. Improving outcome will depend upon the identification of those at greatest risk and targeting limited health resources. We retrospectively examined the major risk factors associated with early (&lt;48 h) and late in-hospital death in children with severe malnutrition with the aim of identifying admission features that could distinguish a high-risk group in relation to the World Health Organization (WHO) guidelines. METHODS AND FINDINGS: Of 920 children in the study, 176 (19%) died, with 59 (33%) deaths occurring within 48 h of admission. Bacteraemia complicated 27% of all deaths: 52% died before 48 h despite 85% in vitro antibiotic susceptibility of cultured organisms. The sensitivity, specificity, and likelihood ratio of the WHO-recommended "danger signs" (lethargy, hypothermia, or hypoglycaemia) to predict early mortality was 52%, 84%, and 3.4% (95% confidence interval [CI] = 2.2 to 5.1), respectively. In addition, four bedside features were associated with early case fatality: bradycardia, capillary refill time greater than 2 s, weak pulse volume, and impaired consciousness level; the presence of two or more features was associated with an odds ratio of 9.6 (95% CI = 4.8 to 19) for early fatality (p &lt; 0.0001). Conversely, the group of children without any of these seven features, or signs of dehydration, severe acidosis, or electrolyte derangements, had a low fatality (7%). CONCLUSIONS: Formal assessment of these features as emergency signs to improve triage and to rationalize manpower resources toward the high-risk groups is required. In addition, basic clinical research is necessary to identify and test appropriate supportive treatments

Assessment of myocardial function in Kenyan children with severe, acute malnutrition

Importance Mortality among African children hospitalized with severe malnutrition remains high, with sudden, unexpected deaths leading to speculation about potential cardiac causes. Malnutrition is considered high risk for cardiac failure, but evidence is limited. Objective To investigate the role of cardiovascular dysfunction in African children with severe, acute malnutrition (SAM). Design, Setting, and Participants A prospective, matched case-control study, the Cardiac Physiology in Malnutrition (CAPMAL) study, of 88 children with SAM (exposed) vs 22 severity-matched patients without SAM (unexposed) was conducted between March 7, 2011, and February 20, 2012; data analysis was performed from October 1, 2012, to March 1, 2016. Exposures Echocardiographic and electrocardiographic (ECG) recordings (including 7-day Holter monitoring) at admission, day 7, and day 28. Main Outcomes and Measures Findings in children with (cases) and without (controls) SAM and in marasmus and kwashiorkor phenotypes were compared. Results Eighty-eight children (52 with marasmus and 36 with kwashiorkor) of the 418 admitted with SAM and 22 severity-matched controls were studied. A total of 63 children (57%) were boys; median age at admission was 19 months (range, 12-39 months). On admission, abnormalities more common in cases vs controls included severe hypokalemia (potassium 4.2 mU/L) (18 of 74 [24%] vs 1 of 21 [5%]) and were associated with typical electrocardiographic changes (T-wave inversion: odds ratio, 7.3; 95% CI, 1.9-28.0; P = .001), which corrected as potassium levels improved. Fourteen children with SAM (16%) but no controls died. Myocardial mass was lower in cases on admission but not by day 7. Results of the Tei Index, a measure of global cardiac function, were within the reference range and similar in cases (median, 0.37; interquartile range [IQR], 0.26-0.45) and controls (median, 0.36; IQR, 0.28-0.42). Echocardiography detected no evidence of cardiac failure among children with SAM, including those receiving intravenous fluids to correct hypovolemia. Cardiac dysfunction was generally associated with comorbidity and typical of hypovolemia, with low cardiac index (median, 4.9 L/min/m2; IQR, 3.9-6.1 L/min/m2), high systemic vascular resistance index (median, 1333 dyne seconds/cm5/m2; IQR, 1133-1752 dyne seconds/cm5/m2), and with few differences between the marasmus and kwashiorkor manifestations of malnutrition. Seven-day continuous ECG Holter monitoring during the high-risk initial refeeding period demonstrated self-limiting significant ventricular arrhythmias in 33 of 55 cases (60%) and 6 of 18 controls (33%) (P = .049); none were temporally related to adverse events, including fatalities. Conclusions and Relevance There is little evidence that African children with SAM are at greater risk of cardiac dysfunction or clinically significant arrhythmias than those without SAM or that marasmus and kwashiorkor differed in cardiovascular profile. These findings should prompt a review of current guidelines

Prognostic indicators of early and late death in children admitted to district hospital in Kenya: cohort study

OBJECTIVES: To identify clinical indicators of immediate, early, and late mortality in children at admission to a sub-Saharan district hospital and to develop prognostic scores. DESIGN: Prospective cohort study. SETTING: One district hospital in Kenya. PARTICIPANTS: Children aged over 90 days admitted to hospital from 1 July 1998 to 30 June 2001. MAIN OUTCOME MEASURES: Prognostic indicators of mortality. RESULTS: Of 8091 children admitted up to 1 June 2000, 436 (5%) died. Sixty (14%) died within four hours after admission (immediate), 193 (44%) after 4-48 hours (early), and 183 (42%) after 48 hours (late). There were marked differences in the clinical features associated with immediate, early, and late death. Seven indicators (neurological status, respiratory distress (subcostal indrawing or deep breathing), nutritional status (wasting or kwashiorkor), severe anaemia, jaundice, axillary temperature, and length of history) were included in simplified prognostic scores. Data from 4802 children admitted from 1 July 2000 to 30 June 2001 were used to validate the scores. For simplified prognostic scores the areas under the receiver operating characteristic curves were 0.93 (95% confidence interval 0.92 to 0.94), 0.82 (0.80 to 0.83), and 0.82 (0.81 to 0.84) for immediate, early, and late death, respectively. CONCLUSION: In children admitted to a sub-Saharan hospital, the prognostic indicators of early and late deaths differ but a small number of simple clinical signs predict outcome well

Plasma Plasmodium falciparum Histidine-Rich Protein-2 concentrations in children with malaria infections of differing severity in Kilifi, Kenya

Background Most previous studies support a direct link between total parasite load and the clinical severity of Plasmodium falciparum malaria infections. Methods We estimated P. falciparum parasite loads in three groups of children with malaria infections of differing severity: (1) children with WHO-defined severe malaria (n=1,544); (2) children admitted with malaria but without features of severity (n=200) and; (3) children in the community with asymptomatic parasitemia (n=33). Results Peripheral parasitemias were highest in those with uncomplicated malaria (geometric mean 111,064; 95%CI 86,798-141,819 parasites/μl), being almost three times higher than those with severe malaria (39,588; 34,990-44,791 parasites/μl) and >100 times higher than in those with asymptomatic malaria (1,092; 523-2,280 parasites/μl). However, geometric mean PfHRP2 values (95% CI) increased with severity, being 7 (4-12) ng/ml in asymptomatic malaria, 843 (655-1,084) ng/ml in uncomplicated malaria and 1,369 (1,244-1,506) ng/ml in severe malaria. PfHRP2 concentrations were markedly lower in the sub-group of severe malaria patients with concomitant invasive bacterial infections (IBIs) of blood or CSF (GM 312 ng/ml; 95%CI 175-557; p<0.0001) than in those without IBIs (GM 1,439 ng/ml; 1,307-1,584; P<0.001). Conclusions The clinical severity of malaria infections related strongly to the total burden of P. falciparum parasites. A quantitative test for plasma concentrations of PfHRP2 could be useful in identifying children at the greatest clinical risk and to identify critically ill children in whom malaria is not the primary cause