An important chapter in the infection–malnutrition story
Authors: Indi Trehan, Mark J Manary
Journal: The Lancet Global Health (2016)

In this issue of The Lancet Global Health, Jay Berkley and colleagues in Kenya present the results of their outstanding clinical trial of antibiotic prophylaxis for children who recovered from complicated severe acute malnutrition (SAM).1Berkley JA Ngari M Thitiri J et al.Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trial.Lancet Glob Health. 2016; (published online June 2.)http://dx.doi.org/10.1016/S2214-109X(16)30096-1Google Scholar The high rates of mortality and nutritional relapse observed among children who recover from SAM2Bahwere P Mtimuni A Sadler K Banda T Collins S Long term mortality after community and facility based treatment of severe acute malnutrition: analysis of data from Bangladesh, Kenya, Malawi and Niger.J Public Health Epidemiol. 2012; 4: 215-225Crossref Google Scholar, 3Kerac M Bunn J Chagaluka G et al.Follow-up of post-discharge growth and mortality after treatment for severe acute malnutrition (FuSAM study): a prospective cohort study.PLoS One. 2014; 9: e96030Crossref PubMed Scopus (109) Google Scholar have also been seen in children recovering from moderate acute malnutrition.4Chang CY Trehan I Wang RJ et al.Children successfully treated for moderate acute malnutrition remain at risk for malnutrition and death in the subsequent year after recovery.J Nutr. 2013; 143: 215-220Crossref PubMed Scopus (58) Google Scholar These children may require a higher anthropometric threshold for recovery,5Trehan I Banerjee S Murray E et al.Extending supplementary feeding for children younger than 5 years with moderate acute malnutrition leads to lower relapse rates.J Pediatr Gastroenterol Nutr. 2015; 60: 544-549Crossref PubMed Scopus (22) Google Scholar which may serve as a marker of improved immune status and decreased susceptibility to infection.6Rytter MJ Kolte L Briend A Friis H Christensen VB The immune system in children with malnutrition—a systematic review.PLoS One. 2014; 9: e105017Crossref PubMed Scopus (305) Google Scholar The option tested by Berkley and colleagues is the use of prolonged antimicrobial prophylaxis after clinical nutritional recovery. The concept of empirical broad-spectrum antimicrobial therapy in high-risk immunocompromised populations is not novel, as there have been decades now of demonstrated benefit of co-trimoxazole prophylaxis among HIV-infected patients, with decreased rates of infection across a range of bacterial, fungal, and protozoal pathogens.7Church JA Fitzgerald F Walker AS Gibb DM Prendergast AJ The expanding role of co-trimoxazole in developing countries.Lancet Infect Dis. 2015; 15: 327-339Summary Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 8Bwakura-Dangarembizi M Kendall L Bakeera-Kitaka S et al.A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa.N Engl J Med. 2014; 370: 41-53Crossref PubMed Scopus (91) Google Scholar More recently, two large clinical trials in sub-Saharan Africa have demonstrated improvements in rates of nutritional recovery9Trehan I Goldbach HS LaGrone LN et al.Antibiotics as part of the management of severe acute malnutrition.N Engl J Med. 2013; 368: 425-435Crossref PubMed Scopus (223) Google Scholar, 10Isanaka S Langendorf C Berthe F et al.Routine amoxicillin for uncomplicated severe acute malnutrition in children.N Engl J Med. 2016; 374: 444-453Crossref PubMed Scopus (73) Google Scholar and mortality9Trehan I Goldbach HS LaGrone LN et al.Antibiotics as part of the management of severe acute malnutrition.N Engl J Med. 2013; 368: 425-435Crossref PubMed Scopus (223) Google Scholar when antibiotics were routinely added to nutritional therapy in the acute phase of treatment for uncomplicated SAM. Even more broadly, antibiotic therapy has been shown in a number of randomised trials conducted in low-income and middle-income settings to improve height and weight gain in young children.10Isanaka S Langendorf C Berthe F et al.Routine amoxicillin for uncomplicated severe acute malnutrition in children.N Engl J Med. 2016; 374: 444-453Crossref PubMed Scopus (73) Google Scholar Thus Berkley and colleagues' results, whether positive or negative, add another important chapter to the global health community's collective knowledge about the infection–malnutrition link. Berkley and colleagues enrolled nearly 1800 HIV-negative children with complicated SAM and randomised them to 6 months of daily co-trimoxazole or placebo therapy once they achieved initial inpatient stabilisation. Children were followed closely throughout this 6-month period and for another 6 months after the intervention ended. Follow-up was not only scheduled on a periodic basis at the health centres, but also to collect important microbiological data. Caretakers were also encouraged to bring enrolled children back any time there was an acute illness. To improve the completeness of the data collected, caretakers were provided with a telephone hotline they could contact at any time, as well as financial reimbursement for their clinic visits and transportation costs. With regards to the primary outcome of decreasing mortality after 12 months, daily co-trimoxazole showed no benefit compared to placebo, with a hazard ratio of 0·90 (95% CI 0·71–1·16, p=0·429). Among those who survived their initial hospitalisation, a staggering 8·7% died in the first 6 months of follow-up while on co-trimoxazole. Of those who survived those first 6 months, another 3% perished during the 6 months of observation after the study interventions were complete. There was a strong trend towards decreased mortality in the intervention group during this second 6-month timespan even though co-trimoxazole had been discontinued by that time (hazard ratio 0·56; 95% CI 0·31–1·02). The total combined rate of rehospitalisation or death was 57 per 100 years of observation, demonstrating again very clearly how vulnerable these children are to continued illness despite having achieved nutritional “recovery”. Only 68% of the subjects were alive and had a mid-upper arm circumference above 12·5 cm at the end of the year-long observation period. Mortality was highest among younger children. The investigators are to be commended for their rigorous trial design and thorough implementation. When considering the methodological aspects of how to conduct an exceptional clinical trial in a resource-limited setting, future researchers and students should look to this study. Among the many strengths of the study are its low drop-out rate, a feat likely only achieved thanks to the investigators' heavy investment in the human and technological resources to ensure close participant tracking. Another powerful feature of the trial design was the adaptive sample size based on interim blinded independent statistical reviews, allowing the investigators to maximise the likelihood that the trial would be neither underpowered nor overpowered. Berkley and colleagues also did not hesitate to “keep up with the times” by updating enrolment criteria for SAM in children older than 6 months as the standards of care evolved during the course of the study. They also took the insightful step of enrolling children as young as 2 months, recognising that SAM is a significant problem among children younger than 6 months, that these children have extremely high mortality, and that the knowledge base on how best to care for these children remains limited.11Angood C McGrath M Mehta S et al.Research priorities to improve the management of acute malnutrition in infants aged less than six months (MAMI).PLoS Med. 2015; 12: e1001812Crossref PubMed Scopus (23) Google Scholar The trial provides a goldmine of information on the natural history of post-discharge growth and survival for children who recover from SAM—more data than has ever previously been collected. Despite observing a decrease in a number of specific infections, including skin and soft tissue infections, urinary tract infections, and episodes of malaria, there was no overall decrease in the frequency of outpatient health centre visits or hospital admissions. No significant difference was observed in the rates of bacteraemia between the two groups, and both groups demonstrated similarly high rates of co-trimoxazole-resistant pathogens isolated from blood and urine cultures. Despite prior evidence that ponderal growth is improved with antibiotics during the initial management of uncomplicated SAM,9Trehan I Goldbach HS LaGrone LN et al.Antibiotics as part of the management of severe acute malnutrition.N Engl J Med. 2013; 368: 425-435Crossref PubMed Scopus (223) Google Scholar, 10Isanaka S Langendorf C Berthe F et al.Routine amoxicillin for uncomplicated severe acute malnutrition in children.N Engl J Med. 2016; 374: 444-453Crossref PubMed Scopus (73) Google Scholar this was not observed during the extended follow-up period of this study. The rates of pneumonia were similar between the two groups and the co-trimoxazole group had significantly more diarrhoea overall and a trend towards more severe diarrhoea—findings that may explain why no survival or growth benefit from co-trimoxazole was identified. In addition to the higher rate of diarrhoea, the co-trimoxazole group did have lower neutrophil counts. Since this study did not demonstrate any survival or hospitalisation benefit from co-trimoxazole for children who have recovered from SAM, such empirical antibiotic therapy cannot be recommended. In fact, it should be explicitly rejected, especially considering the potential collateral damage to the individual (potential myelosuppression and increased diarrhoea) and to the community (increased antimicrobial resistance) from such widespread usage. Co-trimoxazole remains under investigation as part of a bundle of interventions for children discharged from hospital with severe malaria in Uganda and Malawi12Mpoya A Kiguli S Olupot-Olupot P et al.Transfusion and treatment of severe anaemia in African children (TRACT): a study protocol for a randomised controlled trial.Trials. 2015; 16: 593Crossref PubMed Scopus (32) Google Scholar and thus there remains the possibility that this recommendation might need refinement when those results become available. We declare no competing interests. Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trialDaily 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. Full-Text PDF Open Access