Seeking interventions to reduce post-discharge mortality among children in sub-Saharan Africa

Children discharged from hospital in sub-Saharan Africa have a high risk of mortality and re-admission.1Wiens MO Pawluk S Kissoon N et al.Pediatric post-discharge mortality in resource poor countries: a systematic review.PLoS One. 2013; 8e66698Crossref PubMed Scopus (58) Google Scholar In many settings, the risk of mortality in the first few months after discharge equals, or even exceeds, in-hospital mortality.1Wiens MO Pawluk S Kissoon N et al.Pediatric post-discharge mortality in resource poor countries: a systematic review.PLoS One. 2013; 8e66698Crossref PubMed Scopus (58) Google Scholar Children hospitalised with severe anaemia (haemoglobin <6 g/dL) are a particularly vulnerable group with poor long-term outcomes. Current WHO guidelines recommend 3 months of iron and folic acid, together with anthelmintic treatment. The trial by Kathryn Maitland and colleagues,2Maitland K Olupot-Olupot P Kiguli S et al.Co-trimoxazole or multivitamin multimineral supplement for post-discharge outcomes after severe anaemia in African children: a randomised controlled trial.Lancet Glob Health. 2019; 7: e1435-e1447Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar reported in The Lancet Global Health, tested two additional interventions during this high-risk period: provision of multiple micronutrients and broad antimicrobial prophylaxis with cotrimoxazole. Maitland and colleagues hypothesised that correcting nutritional deficiencies and preventing bacterial infections during the first 3 months after discharge would reduce mortality and re-admission. The interventions were evaluated within a large, unblinded, factorial trial enrolling 3983 children with severe anaemia in Uganda and Malawi. The trial design was robust, had high follow-up, and was pragmatic. For example, children with HIV taking cotrimoxazole remained on prophylaxis, and children with severe acute malnutrition received additional ready-to-use therapeutic food, reflecting real-world implementation in sub-Saharan Africa. Disappointingly, neither intervention reduced mortality or hospital re-admission over the first 6 months after discharge. Among children receiving multiple micronutrients, 166 (8%) of 1997 died by day 180, compared with 169 (9%) of 1986 children receiving standard iron and folate treatment. Among children receiving cotrimoxazole compared with no cotrimoxazole, 172 (9%) of 1994 versus 163 (8%) of 1989, respectively, died over the same period. There were no interactions between the randomisations. Why did these interventions not improve clinical outcomes? Although provision of additional micronutrients, including iron and folate, seems a logical approach to tackle anaemia, the trial did not investigate baseline micronutrient status or repletion following supplementation. Additionally, most children enrolled in the trial had underlying infectious and inflammatory conditions. Overall, of 3983 children, 2421 (61%) had signs of severe illness, 3863 (97%) had a history of fever, and 2537 (64%) had malaria. Multiple co-existing and interacting conditions unresponsive to oral iron or folate replacement therefore likely contributed to anaemia in these children.3Calis JC Phiri KS Faragher EB et al.Severe anemia in Malawian children.N Engl J Med. 2008; 358: 888-899Crossref PubMed Scopus (249) Google Scholar In addition, many children in low-resource settings have enteric dysfunction, possibly resulting in impaired micronutrient absorptive capacity. It remains unclear which factors need to be addressed to increase haemoglobin sufficiently to reduce mortality and re-admission. Maitland and colleagues compared standard-of-care treatment doses of iron and folate to lower dose supplementary iron and folate with multiple micronutrients. The finding that rates of serious adverse events were similar between low-dose and high-dose iron groups is reassuring, suggesting no additional harm from high-dose iron in these settings. Use of iron has been contentious in malaria-endemic areas because of concerns that it might increase parasite replication and disease severity.4Sazawal S Black RE Ramsan M et al.Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial.Lancet. 2006; 367: 133-143Summary Full Text Full Text PDF PubMed Scopus (717) Google Scholar The results suggest that iron replacement is safe when services to prevent and manage malaria are available,5Neuberger A Okebe J Yahav D Paul M Oral iron supplements for children in malaria-endemic areas.Cochrane Database Syst Rev. 2016; 2CD006589PubMed Google Scholar in line with current WHO guidelines. However, the absence of observed differences in anaemia or change in haemoglobin between groups raises the question of whether iron treatment is warranted after severe anaemia that is not clearly related to iron deficiency or blood loss. The provision of cotrimoxazole for 3 months also had no effects on mortality or re-admission, although it did reduce malaria and potentially sepsis. Recent trials of cotrimoxazole in HIV-exposed uninfected infants6Lockman S Hughes M Powis K et al.Effect of co-trimoxazole on mortality in HIV-exposed but uninfected children in Botswana (the Mpepu Study): a double-blind, randomised, placebo-controlled trial.Lancet Glob Health. 2017; 5: e491-e500Summary Full Text Full Text PDF PubMed Scopus (26) Google Scholar and children discharged from hospital following severe acute malnutrition7Berkley 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; 4: e464-e473Summary Full Text Full Text PDF PubMed Scopus (71) Google Scholar similarly failed to reduce mortality or hospitalisation. The potential benefits of cotrimoxazole might have been attenuated by antimicrobial resistance.8Church 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 (62) Google Scholar Most children would have been exposed to antibiotics while in hospital, and rates of nosocomial acquisition of antimicrobial resistance among pathogens or commensal organisms in sub-Saharan Africa are high.9Kurz MS Bayingana C Ndoli JM et al.Intense pre-admission carriage and further acquisition of ESBL-producing Enterobacteriaceae among patients and their caregivers in a tertiary hospital in Rwanda.Trop Med Int Health. 2017; 22: 210-220Crossref PubMed Scopus (18) Google Scholar The benefits associated with cotrimoxazole might be restricted to people living with HIV, in whom it continues to reduce morbidity and mortality despite high rates of antimicrobial resistance,8Church 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 (62) Google Scholar perhaps in part because of its anti-inflammatory properties.10Bourke CD Gough EK Pimundu G et al.Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation.Sci Transl Med. 2019; 11eaav0537Crossref PubMed Scopus (32) Google Scholar Whether an alternative antimicrobial would have reduced mortality and re-admission in children with severe anaemia is uncertain, but an ongoing trial in Kenya11Pavlinac PB Singa BO John-Stewart GC et al.Azithromycin to prevent post-discharge morbidity and mortality in Kenyan children: a protocol for a randomised, double-blind, placebo-controlled trial (the Toto Bora trial).BMJ Open. 2017; 7e019170Crossref PubMed Scopus (11) Google Scholar is investigating a 5-day course of azithromycin at discharge among children hospitalised for any cause, because community administration of azithromycin reduces child mortality.12Keenan JD Arzika AM Lietman TM Group MS Azithromycin and childhood mortality in Africa.New Engl J Med. 2018; 379: 1383-1384PubMed Google Scholar There is increasing recognition that children leaving hospital are highly vulnerable, regardless of the reason for admission.1Wiens MO Pawluk S Kissoon N et al.Pediatric post-discharge mortality in resource poor countries: a systematic review.PLoS One. 2013; 8e66698Crossref PubMed Scopus (58) Google Scholar For example, in a study13Kotloff KL Nataro JP Blackwelder WC et al.Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study.Lancet. 2013; 382: 209-222Summary Full Text Full Text PDF PubMed Scopus (2023) Google Scholar of children presenting to health facilities with moderate-to-severe diarrhoea, mortality was 8·5-fold higher (odds ratio 8·5, 95% CI 5·8–12·5) than among matched community controls 60 days later. Despite management of acute conditions, many children have ongoing physiological impairment and nutritional deficits, and might be discharged to a socioeconomically disadvantaged household, which together hinder long-term recovery. Given the understandable focus on child survival in hospital, little attention has been paid to convalescence after discharge, yet this is a clear window of vulnerability, which has been termed a post-hospital syndrome.14Krumholz HM Post-hospital syndrome—an acquired, transient condition of generalized risk.N Engl J Med. 2013; 368: 100-102Crossref PubMed Scopus (711) Google Scholar The findings from this trial should not signify the end of the road for post-discharge interventions; rather, they should strengthen our resolve to identify effective and scalable approaches to reduce risk in this exceptionally vulnerable population. In Maitland and colleagues' trial, 8% of enrolled children died and 17% were re-admitted over the first 6 months after discharge. Severe anaemia is probably both a direct contributor to mortality and a surrogate marker of risk. More holistic packages of care that address the network of biomedical and psychosocial causes underlying post-discharge mortality and hospitalisation are probably required. The challenge now is to identify the components of this bundle of care to promote full convalescence following critical illness, so all children can survive, thrive, and reach their full long-term potential. AJP is funded by the Wellcome Trust ( 108065/Z/15/Z ). JLW received funds from the National Institutes of Health and the Bill & Melinda Gates Foundation. Co-trimoxazole or multivitamin multimineral supplement for post-discharge outcomes after severe anaemia in African children: a randomised controlled trialNeither enhanced supplementation with multivitamin multimineral supplement versus iron and folate treatment or co-trimoxazole prophylaxis improved 6-month survival. High rates of hospital re-admission suggest that novel interventions are urgently required for severe anaemia, given the burden it places on overstretched health services in Africa. Full-Text PDF Open Access