Prediction models for post-discharge mortality among under-five children with suspected sepsis in Uganda: A multicohort analysis.

In many low-income countries, over five percent of hospitalized children die following hospital discharge. The lack of available tools to identify those at risk of post-discharge mortality has limited the ability to make progress towards improving outcomes. We aimed to develop algorithms designed to predict post-discharge mortality among children admitted with suspected sepsis. Four prospective cohort studies of children in two age groups (0-6 and 6-60 months) were conducted between 2012-2021 in six Ugandan hospitals. Prediction models were derived for six-months post-discharge mortality, based on candidate predictors collected at admission, each with a maximum of eight variables, and internally validated using 10-fold cross-validation. 8,810 children were enrolled: 470 (5.3%) died in hospital; 257 (7.7%) and 233 (4.8%) post-discharge deaths occurred in the 0-6-month and 6-60-month age groups, respectively. The primary models had an area under the receiver operating characteristic curve (AUROC) of 0.77 (95%CI 0.74-0.80) for 0-6-month-olds and 0.75 (95%CI 0.72-0.79) for 6-60-month-olds; mean AUROCs among the 10 cross-validation folds were 0.75 and 0.73, respectively. Calibration across risk strata was good: Brier scores were 0.07 and 0.04, respectively. The most important variables included anthropometry and oxygen saturation. Additional variables included: illness duration, jaundice-age interaction, and a bulging fontanelle among 0-6-month-olds; and prior admissions, coma score, temperature, age-respiratory rate interaction, and HIV status among 6-60-month-olds. Simple prediction models at admission with suspected sepsis can identify children at risk of post-discharge mortality. Further external validation is recommended for different contexts. Models can be digitally integrated into existing processes to improve peri-discharge care as children transition from the hospital to the community.

Pediatric post-discharge mortality in resource-poor countries: a systematic review and meta-analysis.

Background: Under-five mortality remains concentrated in resource-poor countries. Post-discharge mortality is becoming increasingly recognized as a significant contributor to overall child mortality. With a substantial recent expansion of research and novel data synthesis methods, this study aims to update the current evidence base by providing a more nuanced understanding of the burden and associated risk factors of pediatric post-discharge mortality after acute illness. Methods: Eligible studies published between January 1, 2017 and January 31, 2023, were retrieved using MEDLINE, Embase, and CINAHL databases. Studies published before 2017 were identified in a previous review and added to the total pool of studies. Only studies from countries with low or low-middle Socio-Demographic Index with a post-discharge observation period greater than seven days were included. Risk of bias was assessed using a modified version of the Joanna Briggs Institute critical appraisal tool for prevalence studies. Studies were grouped by patient population, and 6-month post-discharge mortality rates were quantified by random-effects meta-analysis. Secondary outcomes included post-discharge mortality relative to in-hospital mortality, pooled risk factor estimates, and pooled post-discharge Kaplan-Meier survival curves. PROSPERO study registration: #CRD42022350975. Findings: Of 1963 articles screened, 42 eligible articles were identified and combined with 22 articles identified in the previous review, resulting in 64 total articles. These articles represented 46 unique patient cohorts and included a total of 105,560 children. For children admitted with a general acute illness, the pooled risk of mortality six months post-discharge was 4.4% (95% CI: 3.5%-5.4%, I2 = 94.2%, n = 11 studies, 34,457 children), and the pooled in-hospital mortality rate was 5.9% (95% CI: 4.2%-7.7%, I2 = 98.7%, n = 12 studies, 63,307 children). Among disease subgroups, severe malnutrition (12.2%, 95% CI: 6.2%-19.7%, I2 = 98.2%, n = 10 studies, 7760 children) and severe anemia (6.4%, 95% CI: 4.2%-9.1%, I2 = 93.3%, n = 9 studies, 7806 children) demonstrated the highest 6-month post-discharge mortality estimates. Diarrhea demonstrated the shortest median time to death (3.3 weeks) and anemia the longest (8.9 weeks). Most significant risk factors for post-discharge mortality included unplanned discharges, severe malnutrition, and HIV seropositivity. Interpretation: Pediatric post-discharge mortality rates remain high in resource-poor settings, especially among children admitted with malnutrition or anemia. Global health strategies must prioritize this health issue by dedicating resources to research and policy innovation. Funding: No specific funding was received.

Verbal Autopsy to Assess Postdischarge Mortality in Children With Suspected Sepsis in Uganda.

BACKGROUND: Reducing child mortality in low-income countries is constrained by a lack of vital statistics. In the absence of such data, verbal autopsies provide an acceptable method to determining attributable causes of death. The objective was to assess potential causes of pediatric postdischarge mortality in children younger than age 5 years (under-5) originally admitted for suspected sepsis using verbal autopsies. METHODS: Secondary analysis of verbal autopsy data from children admitted to 6 hospitals across Uganda from July 2017 to March 2020. Structured verbal autopsy interviews were conducted for all deaths within 6 months after discharge. Two physicians independently classified a primary cause of death, up to 4 alternative causes, and up to 5 contributing conditions using the Start-Up Mortality List, with discordance resolved by consensus. RESULTS: Verbal autopsies were completed for 361 (98.6%) of the 366 (5.9%) children who died among 6191 discharges (median admission age: 5.4 months [interquartile range, 1.8-16.7]; median time to mortality: 28 days [interquartile range, 9-74]). Most deaths (62.3%) occurred in the community. Leading primary causes of death, assigned in 356 (98.6%) of cases, were pneumonia (26.2%), sepsis (22.1%), malaria (8.5%), and diarrhea (7.9%). Common contributors to death were malnutrition (50.5%) and anemia (25.7%). Reviewers were less confident in their causes of death for neonates than older children (P < .05). CONCLUSIONS: Postdischarge mortality frequently occurred in the community in children admitted for suspected sepsis in Uganda. Analyses of the probable causes for these deaths using verbal autopsies suggest potential areas for interventions, focused on early detection of infections, as well as prevention and treatment of underlying contributors such as malnutrition and anemia.

Mortality after hospital discharge among children younger than 5 years admitted with suspected sepsis in Uganda: a prospective, multisite, observational cohort study.

BACKGROUND: Substantial mortality occurs after hospital discharge in children younger than 5 years with suspected sepsis, especially in low-income countries. A better understanding of its epidemiology is needed for effective interventions to reduce child mortality in these countries. We evaluated risk factors for death after discharge in children admitted to hospital for suspected sepsis in Uganda, and assessed how these differed by age, time of death, and location of death. METHODS: In this prospective, multisite, observational cohort study, we recruited and consecutively enrolled children aged 0-60 months admitted with suspected sepsis from the community to the paediatric wards of six Ugandan hospitals. Suspected sepsis was defined as the need for admission due to a suspected or proven infectious illness. At admission, trained study nurses systematically collected data on clinical variables, sociodemographic variables, and baseline characteristics with encrypted study tablets. Participants were followed up for 6 months after discharge by field officers who contacted caregivers at 2 months and 4 months after discharge by telephone and at 6 months after discharge in person to measure vital status, health-care seeking after discharge, and readmission details. We assessed 6-month mortality after hospital discharge among those discharged alive, with verbal autopsies conducted for children who had died after hospital discharge. FINDINGS: Between July 13, 2017, and March 30, 2020, 16 991 children were screened for eligibility. 6545 children (2927 [44·72%] female children and 3618 [55·28%] male children) were enrolled and 6191 were discharged from hospital alive. 6073 children (2687 [44·2%] female children and 3386 [55·8%] male children) completed follow-up. 366 children died in the 6-month period after discharge (weighted mortality rate 5·5%). Median time from discharge to death was 28 days (IQR 9-74). For the 360 children for whom location of death was documented, deaths occurred at home (162 [45·0%]), in transit to care (66 [18·3%]), or in hospital (132 [36·7%]) during a subsequent readmission. Death after hospital discharge was strongly associated with weight-for-age Z scores less than -3 (adjusted risk ratio [aRR] 4·7, 95% CI 3·7-5·8 vs a Z score of >-2), discharge or referral to a higher level of care (7·3, 5·6-9·5), and unplanned discharge (3·2, 2·5-4·0). Hazard ratios (HRs) for severe anaemia (<7g/dL) increased with time since discharge, from 1·7 (95% CI 0·9-3·0) for death occurring in the first time tertile to 5·2 (3·1-8·5) in the third time tertile. HRs for some discharge vulnerabilities decreased significantly with increasing time since discharge, including unplanned discharge (from 4.5 [2·9-6·9] in the first tertile to 2·0 [1·3-3·2] in the third tertile) and poor feeding status (from 7·7 [5·4-11·0] to 1·84 [1·0-3·3]). Age interacted with several variables, including reduced weight-for-age Z score, severe anaemia, and reduced admission temperature. INTERPRETATION: Paediatric mortality following hospital discharge after suspected sepsis is common, with diminishing, although persistent, risk during the first 6 months after discharge. Efforts to improve outcomes after hospital discharge are crucial to achieving Sustainable Development Goal 3.2 (ending preventable childhood deaths under age 5 years). FUNDING: Grand Challenges Canada, Thrasher Research Fund, BC Children's Hospital Foundation, and Mining4Life.

Pediatric post-discharge mortality in resource-poor countries: A protocol for an updated systematic review and meta-analysis.

BACKGROUND: More than 50 countries, mainly in Sub-Saharan Africa and South Asia, are not on course to meet the neonatal and under-five mortality target set by the Sustainable Development Goals (SDGs) for the year 2030. One important, yet neglected, aspect of child mortality rates is deaths occurring during the post-discharge period. For children living in resource-poor countries, the rate of post-discharge mortality within the first several months after discharge is often as high as the rates observed during the initial admission period. This has generally been observed within the context of acute illness and has been closely linked to underlying conditions such as malnutrition, HIV, and anemia. These post-discharge mortality rates tend to be underreported and present a major oversight in the efforts to reduce overall child mortality. This review will explore recurrent illness following discharge through determination of rates of, and risk factors for, pediatric post-discharge mortality in resource-poor settings. METHODS: Eligible studies will be retrieved using MEDLINE, EMBASE, and CINAHL databases. Only studies with a post-discharge observation period of more than 7 days following discharge will be eligible for inclusion. Secondary outcomes will include post-discharge mortality relative to in-hospital mortality, overall readmission rates, pooled estimates of risk factors (e.g. admission details vs discharge factors, clinical vs social factors), pooled post-discharge mortality Kaplan-Meier survival curves, and outcomes by disease subgroups (e.g. malnutrition, anemia, general admissions). A narrative description of the included studies will be synthesized to categorize commonly affected patient population categories and a random-effects meta-analysis will be conducted to quantify overall post-discharge mortality rates at the 6-month time point. DISCUSSION: Post-discharge mortality contributes to global child mortality rates with a greater burden of deaths occurring in resource-poor settings. Literature concentrated on child mortality published over the last decade has expanded to focus on the fatal outcomes of children post-discharge and associated risk factors. The results from this systematic review will inform current policy and interventions on the epidemiological burden of post-discharge mortality and morbidity following acute illness among children living in resource-poor settings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO Registration ID: CRD42022350975.

Primary prophylaxis of cryptococcal disease with fluconazole in HIV-positive Ugandan adults: a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Cryptococcal disease remains an important cause of morbidity and mortality in HIV-infected individuals in sub-Saharan Africa, despite the introduction of antiretroviral therapy. We studied fluconazole as primary prophylaxis against cryptococcal disease in patients awaiting or starting antiretroviral therapy in Uganda. METHODS: In this prospective, double-blind randomised controlled trial, we enrolled HIV-positive adults with CD4 counts less than 200 cells per µL, cryptococcal antigen (CrAg)-negative, naive for antiretroviral therapy, and coming from five local AIDS organisations in Masaka district, Uganda. Enrolment took place between Sept 14, 2004, and Feb 1, 2008. Participants were randomly allocated to placebo or 200 mg fluconazole three times per week (1:1) in blocks of 40. Randomisation was done with ralloc procedure in Stata. Participants were reviewed after 4 weeks and referred for antiretroviral therapy, then seen every 8 weeks. Participants discontinued trial treatment when CD4 counts reached 200 cells per µL (median 197 days). Primary endpoints were invasive cryptococcal disease and all-cause mortality. Secondary endpoints were time to first episode and incidence of oesophageal candidosis, time to first episode and incidence of oropharyngeal or vaginal candidosis, and time to first hospital admission or death. The primary safety endpoint was cessation of trial drug because of transaminase concentrations higher than five times the upper limit of normal (ULN), or other major adverse events. Analyses were done by intention to treat and included all participants enrolled in the trial. Participants and researchers were masked to group assignment. This trial is registered with controlled-trials.com, number ISRCTN 76481529. RESULTS: Of 1519 individuals enrolled, 760 participants received fluconazole and 759 received placebo. 19 developed cryptococcal disease, one in the fluconazole group and 18 in the placebo group (p=0·0001); adjusted HR (aHR) 18·7 (95% CI 2·5-140·7). One case of cryptococcal disease could be prevented by treating 44·6 patients with baseline CD4 counts lower than 200 cells per µL. Fluconazole was effective against cryptococcal disease both before (aHR=11·0 [1·4-85·3]) and after start of antiretroviral therapy (no cases in fluconazole vs seven cases on placebo). Seven participants died from cryptococcal disease, none in the fluconazole group. All-cause mortality (n=189) did not differ between the two groups (p=0·46). Fluconazole reduced the time to first episode of oesophageal, and oropharyngeal and vaginal candidosis, as well as the incidence of all candidosis (p<0·0001), but had no effect on hospital admission or death. The frequency of elevated transaminases (>5×ULN) was similar between groups (aHR=0·94 [0·65-1·35]). CONCLUSIONS: Fluconazole was safe and effective as primary prophylaxis against cryptococcal disease, both before and during early antiretroviral treatment. Cryptococcal infection was less common than anticipated because of the rapid commencement of antiretroviral therapy and exclusion of those with positive CrAg. In patients with negative CrAg on screening, fluconazole prophylaxis can prevent cryptococcal disease while waiting for and in the early weeks of antiretroviral therapy, particularly in those with CD4 counts of less than 100 cells per µL. FUNDING: Medical Research Council, UK, and Rockefeller Foundation.