This study investigated mortality and associated factors among 270 children under five years of age admitted to Mulago Hospital for care of severe acute malnutrition (SAM). The main findings were an overall mortality of 25% which is higher among children with HIV infection, positive blood cultures and low estimated GFR. Age, diarrhoea, hypoglycaemia, hypothermia, electrolyte imbalance, pneumonia and oral thrush were not associated with mortality in this cohort of children with SAM.
This mortality is similar to the 24% recorded by Bachou et al. over ten years earlier among patients receiving the standard of care at Mulago hospital . However, the mortality recorded in this study is much higher than that reported by more recent studies conducted in elected populations: 14% in 2017 and 9.8% in 2018 by Rytter et al. and Nabukeera et al. respectively [6, 7]. Our observational study included all severely malnourished children receiving routine care. Nabukeera et al.’s study was a nested randomised control study (RCT) including a selected population with frequent patient monitoring and access to more resources. Rytter et al.’s study was an observational study but excluded critically ill children.
The mortality in our study is higher than that recorded in retrospective studies from South Sudan (9.3%) and the Democratic Republic of Congo (DRC)(7.5%) [16, 17]. A prospective study in Malawi reported a comparable mortality of 18% . The higher mortality in our population could be explained by the fact that our study was done in a tertiary referral hospital. In addition, we followed up patients discharged against medical advice. The higher HIV prevalence in Uganda compared to South Sudan and DRC could also explain the difference. Patients in tertiary hospitals are often the most severely ill patients following referral from smaller centres. Eleven of the study participants died at home following discharge against medical advice; which likely contributed to the high mortality. This finding is not surprising considering that a number of children in Uganda and Malawi are documented to die at home following official medical discharge [10, 19].
Mortality among children with SAM in Mulago is still significantly higher than the set targets of 5% and 10% by the WHO and Sphere standards, respectively, yet the findings in RCTs suggest the mortality can significantly be improved. Most of the deaths, 42 (67%) in this study occurred in the first week of admission, which is consistent with other observational studies in the same population and sub-Saharan Africa [5, 6, 20, 21]. Closer patient monitoring in the first week of admission could bring us closer to these targets.
HIV-positive children had a significantly shorter survival time than HIV-negative children. These findings are similar to the systematic review done by Fergusson et al., and observational studies in Uganda and Malawi [6, 9, 10, 22-24]. A significant number of HIV-positive children in this study were diagnosed prior to admission. However, our findings are different from those of Nabukeera et al. where the mortality was lower among HIV-positive children on ART .
Children in the ART group in this study tended to have a higher mortality when compared to the ART naïve group. This finding could be attributed to the Immune Reconstitution Inflammatory syndrome (IRIS) which occurs in the early days of ART initiation since the mean duration on ART in this group was 8 (SD 9.7) days. Alternatively, these children may have been more severely ill prior to admission, resulting in investigation for HIV and initiation of ART, compared to the ART naïve children who had not yet been identified. In this study, there was no difference in mortality among the HIV exposed infected (HEI) and HIV exposed uninfected (HEU) infants, possibly due to the small numbers. Similarly there was no difference between the HIV unexposed uninfected (HUU) and the HEU. On the other hand, a study in Uganda comparing morbidity between HEU and HUU children showed a higher risk of SAM among the HEU group, partially attributed to early breastfeeding cessation .Despite the reduction in prevalence of HIV among children with SAM from 40 – 50% in 2006-2009[5, 11], to less than 15% in 2016-2018 [6, 7] and 12.2% in this study, mortality from SAM has remains high and HIV has remained an important contributor to these deaths. Prevention of HIV, early initiation of ART, nutritional support for HIV-positive children, and close monitoring of HIV-positive children on ART to prevent malnutrition and its complications could help reduce severe malnutrition, which is associated with poor outcomes.
A positive blood culture was associated with a significantly reduced survival time among these children. Children with SAM are expected to have severe infections due to the immune suppression caused by malnutrition . Although the prevalence of bacteraemia in this study was lower than that reported in other studies [11, 27-29], it still significantly influenced mortality among children with SAM. Only 15% of the participants in this study reported receiving treatment prior to admission. Only those with written evidence of previous treatment were included in this category. We, however, suspect that more children received antibiotics prior to admission as Mulago hospital is a tertiary centre where difficult cases from other centres are referred after failing to respond to treatment. Such treatment regularly includes antibiotics, but this is often not documented. Furthermore, use of non-prescription antibiotics is a common practice in low-income countries like Uganda and contributes to antibiotic resistance . This might explain the low prevalence of bacteraemia and might also suggest that the patients who had bacteraemia most likely had overwhelming sepsis or were colonised by bacteria strains that were resistant to the antibiotics they had received. Such children are therefore more likely to die compared to those who might have been infected with susceptible bacteria. Contrary to other studies in which the most frequently isolated organism was Staphylococcus aureus, the isolated organisms in this study were, Escherichia coli , Streptococcus pneumoniae, Candida species, Salmonella species, Citrobacter freundii, and Rhodococcus species [27, 29]. Resistance to WHO-recommended ampicillin was very high (71.4%), a finding that is consistent with other studies of SAM children in Africa [11, 27, 29, 31, 32]. Resistance to ceftriaxone was also high (57.1%). This calls for further evaluation of the optimal antibiotics for use among children with SAM.
The survival time of children with a low eGFR below 60 mL/min/1.73m2 was 3.2 times less than that of those with eGFR more than 60 mL/min/1.73m2. There is a paucity of data on the relationship between poor kidney function and survival among children with malnutrition. However, studies have demonstrated that kidney injury is a risk factor for mortality in children who are critically ill and those with malaria [33, 34]. In our study, even after controlling for factors that indicate compromised perfusion (dehydration, shock, diarrhoea), reduced eGFR remained an independent predictor of reduced survival time. A study of 32 malnourished Jamaican children reported reduced eGFR, which normalised as they recovered from malnutrition. Only a single serum creatinine test at admission was done in our e study , therefore we cannot ascertain whether children developed acute kidney injury or had pre-existing chronic kidney disease. However, acute kidney injury in these children may result from hypovolemia following diarrhoea and vomiting, sepsis, renal toxic medications such as gentamicin, or non-steroidal anti-inflammatory agents.. The relationship between malnutrition and reduced eGFR and its impact on mortality among children with SAM needs to be explored further as it may have significant implications on the management of these children.
Other factors associated with mortality in previous studies including diarrhoea, hypoglycaemia, hypothermia, electrolyte derangements, pneumonia and oral thrush among others were not significant in this study. This may be attributed to the difference in severity of these factors among the participants in this study compared to other studies. Some factors including hypothermia and hypoglycaemia occurred infrequently in this study, (9/263, 3.4%) and (10/269, 3.7%) respectively and may not have reached significance as a result. The correlation between HIV and diarrhoea resulting in interaction may explain why diarrhoea was not significant in this study.
The strengths of the study include: the prospective cohort study design, which is ideal for establishing temporal relationship between mortality and associated factors. The study investigated factors associated with time to mortality which not only guides clinicians on which patients need close follow-up but also helps identify those whose interventions are time-sensitive. The sample size was sufficient to answer the study questions, and participants who left the hospital against medical advice were followed up, thus significantly reducing the rate of loss-to-follow-up. The main limitations include: the results cannot be generalized to all centres in Uganda since the study participants were recruited from a tertiary referral site that may include more severely ill children than those from other facilities. On the other hand, they provide insights into management of children with SAM in hospitals with a similar set-up in other countries within sub-Saharan Africa. All laboratory tests were done once on admission and chest x-rays were not done for a number of the participants due to lack of consent, and frequent dysfunction of the x-ray machine. The study assessed the association between admission characteristics and survival time, however these could have changed during follow-up. We cannot comment on the causes of death for these children as autopsies were not done.