Johnstone Thitiri

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.

Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trial

Summary 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

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.

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.

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.

Safety and efficacy of allogeneic umbilical cord red blood cell transfusion for children with severe anaemia in a Kenyan hospital: an open-label single-arm trial

Summary Background In sub-Saharan Africa, children are frequently admitted with severe anaemia needing an urgent blood transfusion, but blood is often unavailable. When conventional blood supplies are inadequate, allogeneic umbilical cord blood could be a feasible alternative. The aim of this study was to assess the safety and efficacy of cord blood transfusion in children with severe anaemia. Methods Between June 26, 2007, and May 20, 2008, 413 children needing an urgent blood transfusion were admitted to Kilifi District Hospital in Kenya. Of these, 87 children were eligible for our study—ie, younger than 12 years, no signs of critical illness, and haemoglobin 100 g/L or lower (if aged 3 months or younger) or 40 g/L or lower (if older than 3 months). Cord blood was donated at Coast Provincial General Hospital, Mombasa, and screened for transfusion-transmitted infections and bacterial contamination. Red blood cells were stored vertically at 2–6°C to enable sedimentation. After transfusion, children were monitored closely for adverse events and followed up for 28 days. The primary outcome measure was the frequency and nature of adverse reactions associated with the transfusion. Secondary outcomes were the changes in haemoglobin concentrations 24 h and 28 days after transfusion, compared with pretransfusion levels. This trial is registered on ISRCTN.com, number ISRCTN66687527. Findings Of the 87 children eligible for the study, cord blood was unavailable for 24, six caregivers declined consent, and two children were withdrawn before transfusion. Therefore, 55 children received umbilical cord red blood cells from 74 donations. Ten (18%) children had ten serious adverse events and 43 (78%) had 94 adverse events; the most frequent adverse events were anaemia (n=14), weight loss (n=12), and vomiting (n=10). An independent expert panel judged none of these adverse events to be probably or certainly caused by the cord blood transfusion (one-sided 97·5% CI 0–6·5). Haemoglobin increased by a median of 26 g/L (IQR 21–31) 24 h after transfusion and by 50 g/L (10–68) a median of 29 days (28–35) after transfusion. Interpretation These preliminary data suggest that cord blood could be an important supplementary source of blood for transfusion in children in sub-Saharan Africa. Further studies are needed to compare the safety and efficacy of cord blood with conventional adult-donated blood for transfusions. Challenges associated with cost, infrastructure, and scale up also need investigating. Funding Wellcome Trust.

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

Abstract 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.

Should First-line Empiric Treatment Strategies For Neonates Cover Coagulase-negative Staphylococcal Infections In Kenya?

Background: Neonatal mortality remains high in sub-Saharan Africa, and a third of deaths are estimated to result from infection. While coagulase-negative staphylococci (CoNS) are leading neonatal pathogens in resource-rich settings, their role, and the need for early anti-Staphylococcal treatment in empiric antibiotic guidelines, is unknown in sub-Saharan Africa. Methods: We examined systematic clinical and microbiologic surveillance data from all neonatal admissions to Kilifi County Hospital (1998–2013) to determine associated case fatality and/or prolonged duration of admission associated with CoNS in neonates treated according to standard World Health Organization guidelines. Results: CoNS was isolated from blood culture in 995 of 9552 (10%) neonates. Case fatality among neonates with CoNS isolated from blood did not differ from other neonatal admissions (P = 0.2), and duration of admission was not prolonged [odds ratio (OR) = 0.9 (0.7–1.0), P = 0.040]. Neonates with CoNS were more likely to have convulsions [OR = 1.4 (1.0–1.8), P = 0.031] but less likely to have impaired consciousness or severe indrawing [OR = 0.8 (0.7–0.9), P = 0.025; OR = 0.9 (0.7–1.0), P = 0.065]. Conclusions: CoNS isolation in blood cultures at admission was not associated with adverse clinical outcomes in neonates treated according to standard World Health Organization guidelines for hospital care in this setting. There is no evidence that first-line antimicrobial treatment guidelines should be altered to increase cover for CoNS infections in neonates in this setting.

CAN HIV TREATMENTS INFORM OTHER CONTEXTS? A TRIAL OF AN ADDITIONAL INDICATION FOR CO-TRIMOXAZOLE PROPHYLAXIS

Background Co-trimoxazole prophylaxis is part of HIV management of opportunistic infections. However, it is not known if co-trimoxazole prophylaxis can prevent opportunistic infections among other vulnerable population such as people with complicated severe acute malnutrition (SAM). It is unclear if and how nutritional recovery may reduce susceptibility to infectious diseases like pneumonia with co-trimoxazole prophylaxis. We share secondary analysis results of multicentre, double-blinded, randomised clinical trial (ClinicalTrials. gov, number NCT00934492) of daily co-trimoxazole prophylaxis among HIV non-infected children with SAM in Kenya. Methods We recruited 1781 hospitalised SAM children and randomised to either daily co-trimoxazole prophylaxis or matching placebo for six months and followed up for 12 months. Our outcome of interest was risk of subsequent pneumonia after index admission discharge, defined using the WHO guidelines. To determine changing susceptibility after discharge, cox regression model with monthly weight-for-height and height-for-age z-scores as time-varying covariates were used to identify risk factors of developing pneumonia. Results Overall, 257 children died, 122 (14%) among the co-trimoxazole group and 135 (15%) of placebo group; Hazard ratio (HR) 0.90 (95% CI: 0.71−1.16, p=0.43). There were 1257 episodes of pneumonia, 603 (21%) among co-trimoxazole group and 654 (22%) among placebo; HR 0.93 (95% CI:0.79−1.08, p=0.34) during 1556.6 child-years of observation (cyo). The monthly incidence rate for pneumonia and severe pneumonia declined over time (p=0.002 & p=0.001). Young age, urban residence, index admission with clinical signs of rickets and severe pneumonia, were associated with subsequent pneumonia. Index admission with diarrhoea and monthly weight-for-length z-score had protective effect. Protective effect of improving monthly anthropometric measures were evident from month two onwards. Proportion of pneumonia progressing to severe form declined with time (p=0.01) but there was no evidence case fatality ratios changed over time (p=0.41). Conclusions Improving nutritional status during recovery correlates directly with reduced susceptibility, but not with case fatality of pneumonia.

BLOOD COMPONENTS: 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.