Articles Mortality after hospital discharge among children younger than 5 years admitted with suspected sepsis in Uganda: a prospective, multisite, observational cohort study Matthew O Wiens, Jeffrey N Bone, Elias Kumbakumba, Stephen Businge, Abner Tagoola, Sheila Oyella Sherine, Emmanuel Byaruhanga, Edward Ssemwanga, Celestine Barigye, Jesca Nsungwa, Charles Olaro, J Mark Ansermino, Niranjan Kissoon, Joel Singer, Charles P Larson, Pascal M Lavoie, Dustin Dunsmuir, Peter P Moschovis, Stefanie Novakowski, Clare Komugisha, Mellon Tayebwa, Douglas Mwesigwa, Cherri Zhang, Martina Knappett, Nicholas West, Vuong Nguyen, Nathan Kenya Mugisha, Jerome Kabakyenga Summary Background Substantial mortality occurs after hospital discharge in children younger than 5 years with suspected Lancet Child Adolesc Health 2023 sepsis, especially in low-income countries. A better understanding of its epidemiology is needed for effective Published Online interventions to reduce child mortality in these countries. We evaluated risk factors for death after discharge in May 11, 2023 children admitted to hospital for suspected sepsis in Uganda, and assessed how these differed by age, time of https://doi.org/10.1016/ S2352-4642(23)00052-4 death, and location of death. Centre for International Child Health (M O Wiens PhD, Methods In this prospective, multisite, observational cohort study, we recruited and consecutively enrolled children J N Bone MSc, aged 0–60 months admitted with suspected sepsis from the community to the paediatric wards of six Ugandan hospitals. Prof J M Ansermino MBBCh, Suspected sepsis was defined as the need for admission due to a suspected or proven infectious illness. At admission, D Dunsmuir MSc, S Novakowski PhD, trained study nurses systematically collected data on clinical variables, sociodemographic variables, and baseline C Zhang MHSc, M Knappett BSc, characteristics with encrypted study tablets. Participants were followed up for 6 months after discharge by field V Nguyen PhD), BC Children’s officers who contacted caregivers at 2 months and 4 months after discharge by telephone and at 6 months after Hospital Research Institute discharge in person to measure vital status, health-care seeking after discharge, and readmission details. We assessed (M O Wiens, J N Bone, Prof J M Ansermino, 6-month mortality after hospital discharge among those discharged alive, with verbal autopsies conducted for children Prof N Kissoon MD, who had died after hospital discharge. P M Lavoie MDCM, D Dunsmuir, N West MSc), BC Children’s Findings Between July 13, 2017, and March 30, 2020, 16 991 children were screened for eligibility. 6545 children Hospital, Vancouver, BC, Canada; Department of (2927 [44·72%] female children and 3618 [55·28%] male children) were enrolled and 6191 were discharged from Anesthesiology, Pharmacology, hospital alive. 6073 children (2687 [44·2%] female children and 3386 [55·8%] male children) completed follow-up. and Therapeutics (M O Wiens, 366 children died in the 6-month period after discharge (weighted mortality rate 5·5%). Median time from Prof J M Ansermino, discharge to death was 28 days (IQR 9–74). For the 360 children for whom location of death was documented, S Novakowski), Department of Paediatrics (Prof N Kissoon, deaths occurred at home (162 [45·0%]), in transit to care (66 [18·3%]), or in hospital (132 [36·7%]) during a P M Lavoie), School of subsequent readmission. Death after hospital discharge was strongly associated with weight-for-age Z scores less Population and Public Health 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 (Prof J Singer PhD), University 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) of British Columbia, Vancouver, BC, Canada; Department of 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 Paediatrics and Child Health (3·1–8·5) in the third time tertile. HRs for some discharge vulnerabilities decreased significantly with increasing (E Kumbakumba MMed), 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 Maternal Newborn and Child 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, Health Institute (Prof J Kabakyenga PhD), including reduced weight-for-age Z score, severe anaemia, and reduced admission temperature. Department of Community Health, Faculty of Medicine Interpretation Paediatric mortality following hospital discharge after suspected sepsis is common, with diminishing, (Prof J Kabakyenga), Mbarara although persistent, risk during the first 6 months after discharge. Efforts to improve outcomes after hospital University of Science and Technology, Mbarara, Uganda; discharge are crucial to achieving Sustainable Development Goal 3.2 (ending preventable childhood deaths under Holy Innocents Children’s age 5 years). Hospital, Mbarara, Uganda (S Businge MMed); Department Funding of Paediatrics, Jinja Regional Grand Challenges Canada, Thrasher Research Fund, BC Children’s Hospital Foundation, and Mining4Life. Referral Hospital, Jinja City, Uganda (A Tagoola MMed); Copyright © 2023 Elsevier Ltd. All rights reserved. Department of Paediatrics, Masaka Regional Referral Introduction Hospital, Masaka, Uganda low-income countries. Successful transition between (S O Sherine MMed); Kawempe Although substantial improvements in child mortality facility and community care is a crucial component of National Referral Hospital, have been achieved during the past three decades,1 comprehensive care for acute illness and should not be Kampala, Uganda mortality after hospital discharge has emerged as a key decoupled from hospital care, as is often the case.2 A (E Byaruhanga MMed); Villa Maria Hospital, Masaka, priority to further improve child survival, especially in more granular understanding of events occurring Uganda (E Ssemwanga MBChB); www.thelancet.com/child-adolescent Published online May 11, 2023 https://doi.org/10.1016/S2352-4642(23)00052-4 1 Articles Mbarara Regional Referral Hospital, Mbarara, Uganda Research in context (C Barigye MBChB); Ministry of Health for the Republic of Evidence before this study populations of risk, important risk factors for mortality after Uganda, Kampala, Uganda We conducted a systematic literature search of MEDLINE, hospital discharge, and the approximate proportion of overall (J Nsungwa PhD, C Olaro MMed); Embase, and CINAHL, from database inception to May 27, 2022, deaths that occur after hospital discharge. The large number of School of Population and Global Health, McGill for studies conducted in low-income or low-middle-income outcomes in this study facilitated novel analyses that have not University, Montreal, QC, countries that enrolled more than 100 children who had been been possible previously, including an assessment of how age Canada (Prof C P Larson MDCM); admitted to hospital, had at least 8 days of follow-up after and the timing of mortality after discharge act as effect Division of Global Health, discharge, and that obtained vital status at the end of follow-up modifiers for various risk factors. We found that age interacts Massachusetts General Hospital, Boston, MA, USA (appendix pp 17–21). 46 eligible studies were identified and used with many risk factors, but particularly with nutritional status (P P Moschovis MD); Walimu, to calculate pooled mortality 6 months after hospital discharge. (with the association with risk of mortality decreasing with Kampala, Uganda (M O Wiens, Children enrolled in studies of malnutrition had the highest increasing age) and anaemia (with the association with risk of C Komugisha BSc, pooled rates of mortality 6 months after hospital discharge mortality increasing with increasing age). We also reported the M Tayebwa MA, D Mwesigwa BA, N K Mugisha MMed) (pooled mortality 10·3%, 95% CI 6·0–15·5), followed by studies varying associations between risk factors and risk of mortality Correspondence to: of anaemia (6·3%, 3·4–9·9), studies of diarrhoeal illness (4·2%, during the first 14 days, days 15–58, and days 59–183 following Dr Matthew O Wiens, Centre for 2·7–6·1), studies enrolling all hospital admissions (4·2%, 3·1–5·3), discharge. HRs for mortality increased up to four times between International Child Health, studies of pneumonia (3·5%, 0·9–7·6), and studies of malaria the first and last of these observation periods after discharge for BC Children’s Hospital, (3·2%, 1·9–4·7; appendix pp 22–24). Of the studies that provided those with sociodemographic vulnerabilities or severe anaemia. Vancouver, BC V5Z 2X8, Canada matthew.wiens@bcchr.ca proportions of deaths after discharge versus deaths in hospital, Discharge vulnerabilities, such as unplanned discharges or poor studies of children with anaemia had the highest proportion of feeding, showed diminishing HRs over time, decreasing as much deaths after discharge (71%), whereas studies of children with as six times between the first and last observation periods. pneumonia (28%) and malaria (42%) had the lowest Implications of all the available evidence proportions. Among risk factors that were measured and eligible To date, care after hospital discharge has not received sufficient for pooling, unplanned discharges (hazard ratio [HR] 4·60, attention in policy or clinical practice. The results of this study, 95% CI 2·41–8·79), severe malnutrition (3·61, 2·66–4·91), being along with previous findings, help to establish a robust HIV positive (3·56, 3·01–4·20), and previous admissions to evidence base that can be used to inform the development of hospital (2·75, 1·43–5·29) were associated with the highest programmes that facilitate an evidence-based, child-centred overall pooled HRs for mortality after hospital discharge. approach to ensuring safe transitions between hospital-based Added value of this study and community-based care. Combined with risk-stratification To our knowledge, this multisite observational cohort study is criteria, which are currently under development, interventions the largest prospective study to date to evaluate mortality after can be developed that ensure that optimal follow-up continues hospital discharge in a low-income country. Our findings are during key periods of increased risk of mortality after discharge largely in line with previous work, substantiating key on the basis of individual characteristics of the child. during the period after hospital discharge is urgently discharge include malnutrition, illness severity (at required to guide interventions and policy decisions admission and discharge), and socioeconomic factors See Online for appendix regarding resource allocation.3 (eg, poverty or maternal education; appendix pp 17–24).2,8 Robust epidemiological data for paediatric mortality However, substantial epidemiological gaps remain, after hospital discharge in low-income countries are including how age interacts with known risk factors. scarce, although several studies have been published in Furthermore, although several studies have reported the past 5 years.2,4–7 Mortality after discharge results high levels of at-home deaths,2 risk factors for these from the complex convergence of a series of causal deaths are poorly understood. Moreover, although many factors, outlined in the 2022 Childhood Acute Illness deaths occur early during the period after hospital and Nutrition (CHAIN) Network study.5 This discharge, how factors at admission affect the timing of prospective cohort study of 3101 children aged deaths after discharge is unclear. These data are 2–23 months with acute illness admitted to hospital in imperative in establishing prediction models and diverse sites across sub-Saharan Africa and south Asia interventional programmes that address the complexities established that almost half of mortality occurs of paediatric mortality after hospital discharge. following hospital discharge. These findings suggest The Global Burden of Diseases reported that in 2017, that mortality after discharge involves a heterogeneous an estimated 2·9 million deaths of children under 5 years set of circumstances and that efforts to improve survival of age were due to sepsis, the majority of which occurred after discharge should entail interventions across in low-income and-middle income countries.9 In the several domains. same year, the World Health Assembly and WHO Our systematic review found that consistently reported unanimously adopted a resolution to improve, prevent, features of children at increased risk of mortality after diagnose, and manage sepsis.10 Although most studies 2 www.thelancet.com/child-adolescent Published online May 11, 2023 https://doi.org/10.1016/S2352-4642(23)00052-4 Articles that have examined mortality after hospital admission syndrome combined with a confirmed or suspected have included high proportions of children admitted infection.16 Children who resided outside the hospital because of infectious diseases, sepsis has not previously catchment area or who were admitted for a short-term been the focus of these studies.2 observation period (<24 h), trauma, or immediately after This study aimed to improve understanding of the birth (ie, without first being discharged home) were heterogeneous nature of mortality after hospital excluded. Written informed consent was obtained from discharge by examining risk factors by age, location of the parent or legal guardian of all study participants. death, and time of death among children younger than 5 years admitted to hospital with suspected sepsis in Procedures Uganda. This is necessary if the Sustainable Development All data collection tools are available through the Smart Goal 3.2 of ending preventable deaths of newborns and Discharges study dataverse.17 All data were collected at children under 5 years of age is to be met.11,12 the point of care with encrypted study tablets and these data were then uploaded to a Research Electronic Data Methods Capture18,19 database hosted at the BC Children’s Hospital Study design Research Institute (Vancouver, BC, Canada). Studies of This prospective, multisite, observational cohort study both cohorts were conducted by the same investigative analysed outcomes after discharge of a combined dataset team who used the same research staff to enrol and comprising two prospective observational cohorts of follow up all participants. Enrolment of each cohort was children with suspected sepsis aged 0 months to less independently funded, but the protocols were the same than 6 months and aged 6 months to 60 months at the for both cohorts, including the frequency and duration of time of admission to hospitals in Uganda. The study follow-up. enrolled participants aged 0 months to less than 6 months At admission, trained study nurses systematically and 6 months to 60 months from four hospitals in collected data on clinical variables, sociodemographic Uganda: Mbarara Regional Referral Hospital (Mbarara, variables, and baseline characteristics. Clinical data southwest Uganda), Holy Innocents Children’s Hospital included anthropometry (to establish malnutrition status), (Mbarara, southwest Uganda), Masaka Regional Referral vital signs, simple laboratory variables (eg, glucose, malaria Hospital (Masaka, central Uganda), and Jinja Regional rapid diagnostic test [RDT], HIV RDT, haematocrit, and Referral Hospital (Jinja City, east Uganda). Children aged lactate), clinical signs and symptoms, comorbidities, and 0 months to less than 6 months were also enrolled from health-care history, including previous hospital Villa Maria Hospital (Masaka, central Uganda) and admissions. Sociodemographic variables and baseline Uganda Martyrs Hospital (Ibanda, southwest Uganda). characteristics included maternal and household details In total, these public and faith-based facilities have a such as maternal age, education, and HIV status; distance catchment area that includes 30 districts with a total of home from facility; household size; use of bed-nets; and population of approximately 8·2 million individuals, the availability of clean drinking water. Information on sex including approximately 1·4 million children younger was extracted from medical records. At discharge, study than 5 years during the study period.13 Participants were nurses also obtained discharge status (ie, routine followed up until 6 months after discharge. discharge, referral to higher level of care, or unplanned This study was approved by the Mbarara University of discharge) and feeding status (subjectively defined as Science and Technology Research Ethics Committee feeding well or feeding poorly). The discharge diagnosis (15/10–16), the Uganda National Institute of Science and was abstracted from the medical record. Field officers Technology (HS 2207), and the University of British contacted caregivers at 2 months and 4 months after Columbia–Children and Women’s Health Centre of discharge by telephone and at 6 months after discharge in British Columbia Research Ethics Board (H16–02679). person to measure vital status, any occurrence of health- This Article adheres to the guidelines for Strengthening care seeking after discharge, and readmission details. the Reporting of Observational Studies in Epidemiology Verbal autopsies were conducted for children who had (STROBE).14 The study protocol is available online. died after hospital discharge (appendix p 9). For the study protocol, see https://doi.org/10.5683/SP3/ Participants Statistical analysis QRUMNQ In both cohorts, we consecutively enrolled children who The primary goal of the cohort study was to develop required admission to hospital and had a confirmed or separate post-discharge mortality prediction models for suspected infection (both of which were measured by the both age cohorts. For the cohort aged 0 months to less treating medical team). We have previously shown that than 6 months, we established that a target sample size approximately 90% of children admitted to hospital with of 2700 children would be sufficient, assuming an a proven or suspected infection in Uganda meet the expected outcome rate of 7·5%; for the 6 month to International Pediatric Sepsis Consensus Conference 60 month cohort, we calculated a sample size of 3500 (IPSCC) definition for sepsis,15 which defines sepsis as assuming an outcome rate of 5·0%. These models will the presence of systemic inflammatory response be reported in a subsequent publication. Furthermore, www.thelancet.com/child-adolescent Published online May 11, 2023 https://doi.org/10.1016/S2352-4642(23)00052-4 3 Articles on the basis of these sample sizes and assumed outcome last follow-up date (censored), date of death, or 6 months rates, we are able to estimate the mortality rates to within after hospital discharge. 1·0% in the cohort aged 0 months to less than 6 months To assess clinical and sociodemographic factors and to within 0·7% in the cohort aged 6–60 months. associated with mortality 6 months after hospital discharge, Data from both cohorts were combined and analysed we used Poisson models with robust standard errors to as a single dataset. We used periods of overlapping estimate risk ratios (RRs) adjusted for age, sex, and site of enrolment (72% of total enrolment months) between the enrolment.20 We opted to treat the mortality outcome as two cohorts to establish site-specific proportions of binary as a low proportion (2%) of children did not children aged 0 to <6 months and 6 to 60 months complete 6-month follow-up. Site of enrolment was (appendix p 10). These proportions were used to weight included as a fixed effect (as opposed to a random effect) the cohorts to estimate overall mortality. We assessed because of the low number of sites included.21 For all 6-month mortality after hospital discharge among those continuous predictors, we analysed the relationship in discharged alive. two ways, with a linear term and using regression splines Descriptive data were used to describe the population, to allow for possible non-linearity (specifically, with including medians with IQRs for continuous variables regression cubic polynomial splines, via B-spline bases, and counts with percentages for categorical variables. with knots at the boundaries, 25th, 50th, and Age-stratified Kaplan-Meier survival curves were used to 75th percentiles). Furthermore, when different thresholds estimate the cumulative hazard for overall mortality and are used clinically for a continuous variable (eg, mid- mortality after discharge according to four predefined upper-arm circumference [MUAC]), we also categorised age strata (ie, 0 to <2 months, 2 to 6 months, the variable and analysed these thresholds. >6 to 24 months, and >24 to 60 months). For Kaplan- Based on findings from our analyses, we further Meier curves, follow-up began at discharge and ended at described the participants who died by assessing possible interactions with age and potential time- dependency in the association between risk factors and 16 991 participants screened for eligibility mortality after discharge. Because of the number of factors, we opted to restrict these analyses to those with p<0·01 for the estimated RR, recognising that this 10 446 excluded 3522 no suspected infection approach might exclude other factors that could interact 1997 observation <24 h with age or vary over time. Possible multiplicative 1818 direct from maternity ward 1036 did not provide consent interactions were assessed with logistic regression 924 outside catchment area models, including an interaction between a regression 694 previously enrolled 11 scheduled appointment spline for age and the other factor of interest. Results 76 language barrier have been displayed graphically as marginal effects 139 died before consent could be provided plots with corresponding 95% CIs.22 To assess the 225 too long since admission 4 withdrew consent possible time-dependency of risk factors, we divided the 6-month period after hospital discharge into tertiles, dividing deaths after discharge evenly between these 6545 enrolled tertiles and fitting Cox models to each. For each of these models, participants were followed up to the earliest of three dates (ie, death, loss to follow-up, or end of the 2707 aged 0–6 months 3838 aged 6–60 months tertile). A heatmap was produced to visualise the magnitude of change in hazard ratios (HRs) across the three periods with the HR from the first period as the 190 died in hospital 164 died in hospital reference. To assess the possible association of predictors on 2517 survived to discharge 3674 survived to discharge location of death, a multinomial logistic regression was fitted with location of death as the categorical outcome variable. The categories were: dying in hospital at 50 lost to follow-up 68 lost to follow-up readmission (the reference category), dying at home, or dying in transit to seeking care. Results were summarised as odds ratios, with corresponding 95% CIs and p values. 2467 had complete data at 6 months 3606 had complete data at 6 months Statistical significance was defined as p<0·05. These models were restricted only to those who died after discharge. We compared our results to the existing 2273 survived 194 died 3434 survived 172 died literature by conducting a random effects meta-analysis to pool proportions of those who died by available risk Figure 1: Study profile factors using generalised linear mixed effect models. 4 www.thelancet.com/child-adolescent Published online May 11, 2023 https://doi.org/10.1016/S2352-4642(23)00052-4 Articles Missing values were low and imputed with k-nearest n (%) or median aRR (95% CI) neighbours in all analyses. The primary aim of all analyses (IQR) was to describe characteristics of participants who died, and not to assess causal effects or possible interventions Baseline characteristics to reduce mortality after hospital discharge. We did not Sex adjust for multiple comparisons. Analyses were conducted Male 3386 (55·8%) 1·0 (0·8 to 1·2) in Stata/MP version 15.0, R version 4.1.3, and Female 2687 (44·2%) 1·03 (0·84 to 1·26) RStudio version 2022.2.3 (RStudio, Boston, MA, USA). Age, years 0·8 (0·2 to 1·6) 0·9 (0·8 to 1·0) Hospital of admission Role of the funding source Mbarara Regional Referral 1034 (17·0%) ·· Hospital The funders had no role in study design, data collection, Holy Innocents Children’s 1259 (20·7%) ·· data analysis, data interpretation, or writing of the report, Hospital or in the decision to submit for publication. Masaka Regional Referral 1327 (21·9%) ·· Hospital Results Jinja Regional Referral 2018 (33·2%) ·· Participants were recruited to the cohort of children aged Hospital 6–60 months between July 13, 2017, and July 2, 2019, and Villa Maria Hospital 121 (2·0%) ·· to the cohort aged 0 months to less than 6 months between Uganda Martyrs Hospital 314 (5·2%) ·· Jan 11, 2018, and March 30, 2020. Enrolment in these Admission anthropometry cohorts ended when the desired sample size was reached. MUAC, mm* 130 (115 to 144) 1·0 (1·0 to 1·0) 16 991 consecutively admitted children aged 0–60 months <110 or <115 1195 (19·7%) 5·2 (3·9 to 7·0) were screened. After exclusion of 10 446 children who did 110–120 or 115–125 1110 (18·3%) 2·3 (1·6 to 3·1) not meet study inclusion criteria, 6545 were enrolled; >120 or >125 3768 (62·1%) 0 (ref) 2707 were enrolled into the 0–6-month cohort and Weight-for-age Z score –1·0 (–2·1 to –0·0) 0·7 (0·7 to 0·8) 3838 were enrolled into the 6–60-month cohort (figure 1). <–3 818 (13·5%) 4·7 (3·7 to 5·8) 603 (9·9%) of 6073 participants had missing haemoglobin –3 to –2 836 (13·8%) 2·3 (1·7 to 3·0) data and 200 (3·3%) of 6073 participants had missing >–2 4419 (72·8%) 0 (ref) feeding-at-discharge data; all other variables had minimal Length-for-age Z score –0·7 (–2·0 to 0·4) 0·8 (0·7 to 0·8) or no missing data (appendix p 26). Baseline characteristics <–3 729 (12·0%) 3·6 (2·9 to 4·5) are provided in the table. –3 to –2 784 (12·9%) 2·0 (1·5 to 2·7) Overall, the weighted 6-month mortality rate (in >–2 4560 (75·1%) 0 (ref) hospital and after discharge) was 10·9%. The overall BMI Z score –0·9 (–2·2 to 0·3) 0·8 (0·8 to 0·9) median duration between hospital admission and death <–3 933 (15·4%) 3·0 (2·4 to 3·8) was 9 days (IQR 2–45). The mean follow-up time was –3 to –2 790 (13·01%) 2·02 (1·53 to 2·67) 175 days, and the maximum was 183 days. >–2 4350 (71·6%) 0 (ref) 6191 children were discharged from hospital alive, of Weight-for-length Z score –0·9 (–2·3 to 0·3) 0·9 (0·8 to 0·9) whom 118 (1·9%) were lost to follow-up at 6 months. <–3 949 (15·6%) 2·2 (1·8 to 2·8) Of the 6073 children for whom we have data, –3 to –2 771 (12·7%) 1·6 (1·2 to 2·1) 194 (7·9%) of 2467 died after hospital discharge in the >–2 4353 (71·7%) 0 (ref) cohort aged 0–6 months and 172 (4·8%) of 3606 died Admission clinical assessment variables after hospital discharge in the cohort aged 6–60 months, Time since last admission corresponding to a weighted 6-month mortality after None 4078 (67·2%) 0 (ref) discharge of 5·5%. Of 720 deaths, 366 occurred after hospital discharge, constituting 50·8% of total mortality. <1 month 679 (11·2%) 2·0 (1·5 to 2·6) Of 361 verbal autopsies completed for deaths after 1 month to 1 year 1042 (17·2%) 1·3 (1·0 to 1·7) discharge, the most common specific diagnoses assigned >1 year 274 (4·5%) 0·4 (0·2 to 1·0) were pneumonia (96 [26·6%]), malaria (31 [8·6%]), Care sought for current 4025 (66·3%) 1·8 (1·4 to 2·2)illness before admission diarrhoea (29 [8·0%]), and meningitis (27 [7·5%]; Parent-reported previous poor health appendix p 9). Suspected sepsis deaths were also Good health before this 5266 (86·7%) 0 (ref) common (81 [22·4%]) and represented cases in which a illness generalised infection was suspected. <1 week before this illness 164 (2·7%) 1·6 (0·9 to 2·6) Malnutrition was commonly identified at admission 1 week to 1 month before 349 (5·8%) 2·4 (1·8 to 3·3) and was associated with increased risk of mortality after this illness hospital discharge (table). All anthropometric measures 1 month to 1 year before 294 (4·8%) 3·8 (2·9 to 5·1) were also associated with increased risk of mortality after this illness hospital discharge; for example, a weight-for-age Z score (Table continues in next column) less than –3 had an adjusted RR (aRR) of 4·7 (95% CI www.thelancet.com/child-adolescent Published online May 11, 2023 https://doi.org/10.1016/S2352-4642(23)00052-4 5 Articles n (%) or median aRR (95% CI) n (%) or median aRR (95% CI) (IQR) (IQR) (Continued from previous column) (Continued from previous column) Referral 1852 (30·5%) 2·0 (1·7 to 2·5) Maternal and sociodemographic characteristics Previous antibiotic use 2673 (44·0%) 1·3 (1·1 to 1·6) Travel time to hospital Previous antimalarial use 1402 (23·1%) 1·2 (1·0 to 1·6) <30 min 1299 (21·4%) 0 (ref) SpO2 97 (93 to 99) 1·0 (1·0 to 1·0) 30 min to <1 h 2138 (35·2%) 1·6 (1·1 to 2·3) <90% 929 (15·3%) 1·7 (1·4 to 2·2) 1 h to <2 h 1580 (26·0%) 2·8 (2·0 to 4·0) 90–95% 1423 (23·4%) 1·0 (0·8 to 1·3) 2 h to < 3 h 720 (11·9%) 2·7 (1·8 to 4·1) >95% 3721 (61·3%) 0 (ref) ≥3 h 336 (5·5%) 3·7 (2·3 to 5·8) Heart rate 146 (132 to 161) 1·0 (1·0 to 1·0) Distance to facility, km 15·0 (4·6 to 32·1) 1·0 (1·0 to 1·0) Respiratory rate 49 (38 to 61) 1·0 (1·0 to 1·0) per km Systolic blood pressure 93 (83 to 102) 1·0 (1·0 to 1·0) Maternal age, years 26 (23 to 30) 1·0 (1·0 to 1·0) per year Diastolic blood pressure 51 (43 to 60) 1·0 (1·0 to 1·0) Household size 5 (3 to 6) 1·0 (1·0 to 1·1) Axillary temperature, °C per additional <36·5 734 (12·1%) 1·0 (0·7 to 1·4) household member 36·5–37·5 2906 (47·9%) 0 (ref) Maternal education 2 (2 to 3) 0·7 (0·6 to 0·8) 37·6–39 1931 (31·8%) 0·9 (0·7 to 1·1) No school or ≤P3 615 (10·1%) 0 (ref) >39 502 (8·3%) 0·4 (0·2 to 0·7) P4 to P7 2524 (41·6%) 0·7 (0·6 to 1·0) Respiratory distress 1079 (17·8%) 1·4 (1·1 to 1·8) S1 to S6 2088 (34·4%) 0·6 (0·4 to 0·8) Capillary refill ≥3 s 732 (12·1%) 1·4 (1·1 to 1·9) >S6 788 (13·0%) 0·3 (0·2 to 0·5) Atypical BCS score 505 (8·3%) 2·0 (1·5 to 2·7) Maternal HIV status Symptoms during the illness Negative 5280 (86·9%) 0 (ref) None 0 0 (ref) Positive 476 (7·8%) 1·5 (1·1 to 2·0) Rash 634 (10·4%) 0·7 (0·5 to 1·0) Unknown 317 (5·2%) 1·6 (1·0 to 2·3) Cough <14 days 3615 (59·5%) 1·0 (0·8 to 1·2) Bed-net use Cough ≥14 days 452 (7·4%) 1·3 (0·9 to 1·8) Never 579 (9·5%) 1·2 (0·9 to 1·7) Diarrhoea <14 days 1835 (30·2%) 0·9 (0·7 to 1·1) Sometimes 466 (7·7%) 1·1 (0·8 to 1·6) Diarrhoea ≥14 days 150 (2·5%) 1·7 (1·0 to 2·9) Always 5028 (82·8%) 0 (ref) Fever <7 days 4968 (81·8%) 0·8 (0·6 to 1·0) Boil, disinfect, or filter water 4409 (72·6%) 0·7 (0·6 to 0·9) Fever ≥7 days 371 (6·1%) 1·2 (0·8 to 1·8) Discharge characteristics Vomiting everything 1029 (16·9%) 1·1 (0·9 to 1·5) Length of stay, days 4 (3 to 6) 1·0 (1·0 to 1·0) Atypically tired 1215 (20·0%) 1·1 (0·9 to 1·5) per day Swelling of both feet 298 (4·9%) 2·0 (1·4 to 2·9) Discharge status Changes in urine colour 696 (11·5%) 1·6 (1·2 to 2·1) Routine discharge 5122 (84·3%) 0 (ref) Producing less urine than 379 (6·2%) 1·6 (1·2 to 2·2) Referred to higher level of 189 (3·1%) 7·3 (5·6 to 9·5) usual care Blood in faeces 107 (1·8%) 2·1 (1·3 to 3·5) Unplanned discharge 762 (12·6%) 3·2 (2·5 to 4·0) Seizure 854 (14·1%) 1·1 (0·8 to 1·4) Feeding at discharge† Coma 41 (0·7%) 2·1 (0·9 to 4·8) Feeding well 5607 (92·3%) 0 (ref) Positive malaria test 1303 (21·5%) 0·7 (0·6 to 1·0) Feeding poorly 466 (7·7%) 4·0 (3·2 to 5·0) RDT positive for HIV 173 (2·9%) 1·9 (1·3 to 3·0) Discharge diagnosis Haemoglobin status 12 (10 to 13) 0·9 (0·9 to 1·0) Malaria 1297 (21·4%) 0·7 (0·5 to 0·9) Not anaemic: ≥11 g/dL 3961 (65·2%) 0 (ref) Pneumonia 1893 (31·2%) 1·3 (1·1 to 1·6) Mild anaemia: 7–10 g/dL 1606 (26·4%) 1·3 (1·0 to 1·7) Bronchiolitis 306 (5·0%) 0·7 (0·4 to 1·2) Severe anaemia: <7 g/dL 506 (8·3%) 2·7 (2·1 to 3·6) Upper respiratory tract 499 (8·2%) 0·5 (0·3 to 0·8) infection Lactate, mmol/L 2·1 (1·4 to 3·1) 1·1 (1·0 to 1·1) per mmol/L Reactive airway disease or 35 (0·6%) 0·6 (0·1 to 4·0) asthma Glucose, mmol/L Gastroenteritis or 940 (15·5%) 0·7 (0·5 to 0·9) <2·5 150 (2·5%) 1·8 (1·1–2·9) diarrhoea 2·5–8·3 5235 (86·2%) 0 (ref) HIV-related or AIDS-related 53 (0·9%) 3·0 (1·7 to 5·3) >8·3 688 (11·3%) 1·1 (0·8–1·5) disease (Table continues in next column) Meningitis or encephalitis 210 (3·5%) 2·1 (1·5 to 3·1) (Table continues in next column) 6 www.thelancet.com/child-adolescent Published online May 11, 2023 https://doi.org/10.1016/S2352-4642(23)00052-4 Articles n (%) or median aRR (95% CI) 0·100 Age (months) (IQR) <2 2 to 6 (Continued from previous column) >6 to 24 >24 Malnutrition 410 (6·8%) 3·0 (2·3 to 3·8) 0·075 Tuberculosis 81 (1·3%) 3·9 (2·5 to 6·0) Skin or soft-tissue 187 (3·1%) 0·8 (0·5 to 1·6) infection Measles 413 (6·8%) 0·4 (0·2 to 0·7) 0·050 Sepsis 1733 (28·5%) 0·9 (0·7 to 1·2) Genetic or congenital 114 (1·9%) 4·9 (3·5 to 6·7) disease 0·025 Sickle cell anaemia 61 (1·0%) 0·9 (0·3 to 2·8) Febrile seizure 24 (0·4%) ·· Other infection 131 (2·2%) 1·6 (0·9 to 2·8) Other non-infection 234 (3·9%) 3·9 (2·9 to 5·1) 0 0 30 60 90 120 150 180 Data are n (%), median (IQR), or aRR (95% CI). All aRRs were adjusted for age, sex, and site of enrolment. aRR=adjusted risk ratio. BCS=Blantyre Coma Scale. Number at risk Time since discharge (days) HR (95%CI) MUAC=middle-upper-arm circumference. P=primary school, where the following Age <2 months 1382 1329 1305 1297 1294 1289 1246 1·34 (0·98–1·85) number represents school years. RDT=rapid diagnostic test. S=secondary school, Age 2 to 6 months 1097 1045 1028 1018 1011 1005 980 1 ·70 (1·24 – 2·34) where the following number represents school years. SpO =oxygen saturation. Age >6 to 24 months 2426 2372 2352 2341 2329 2322 2224 0 ·85 (0·63–1·17)2 *MUAC thresholds are given in mm for the 0 month to <6 month cohort and for Age >24 months 1168 1140 1132 1127 1121 1114 1046 (ref) the 6–60-month cohort. †Subjectively defined by study nurse. Figure 2: Hazard curves for mortality after hospital discharge by age Table: Clinical risk factors for mortality 6 months after hospital p value estimated from log-rank test. discharge (n=6073) Among variables collected only in the cohort aged 3·7–5·8), with 818 (13·5%) of 6073 participants in this 0–6-months, all measured indicators of acuity were stratum. Most clinical signs and symptoms indicating associated with an increased risk of mortality after more severe illness at admission conferred increased hospital discharge, including atypical tone, pallor, and risk of mortality after discharge, although increased poor sucking when breastfeeding (appendix p 11). All axillary temperatures at admission were associated with measures of anthropometry (ie, MUAC, weight-for-age a reduced risk (table). Children with an RDT positive for Z score, length-for-age Z score, BMI Z score, and weight- HIV were also at increased risk of mortality after for-length Z score), oxygen saturation, and haemoglobin discharge (1·9, 1·3–3·0), whereas children with an RDT status showed non-linearity in their relationship with positive for malaria had a reduced risk (0·7, 0·6–1·0). mortality (appendix p 25). Other factors associated with increased risk of mortality Among the four pre-defined age strata, younger age after discharge included severe anaemia (2·7, 2·1–3·6), generally conferred a higher risk of mortality after elevated lactate (1·1 per 1 mmol/L increase, 1·0–1·1), and discharge, although participants aged 2–6 months had hypoglycaemia (1·8, 1·1–2·9). Several factors reflecting the highest overall rate of mortality after discharge maternal and sociodemographic vulnerabilities were also (figure 2). Several clinical variables showed differing associated with increased risk of mortality after discharge, associations with mortality depending on age (figure 3; including lower levels of maternal education, increased appendix pp 2–7). Children presenting with axillary distance from hospital (both travel time and actual temperatures less than 36·5°C had an increasing distance), maternal HIV, and not using boiled, probability of mortality after discharge with increasing disinfected, or filtered water (table). age. However, other vital signs showed no interactive Regarding factors related to hospital discharge, effect with age, including heart rate, respiratory rate, participants with an increased risk of mortality after oxygen saturation, and systolic and diastolic blood discharge included those discharged with referral to pressure. Children with severe anaemia appeared to have another hospital for a higher level of care (7·3, 5·6–9·5), a consistent risk of mortality across all age strata, whereas those with an unplanned discharge (3·2, 2·5–4·0), and probability of death declined with increasing age among those with poor feeding at discharge (4·0, 3·2–5·0). those with moderate or no anaemia. The effect of severely Discharge diagnoses associated with increased risk of reduced weight-for-age and BMI-for-age Z scores mortality after discharge included pneumonia, HIV- appeared to diminish with increasing age (appendix p 2), related illnesses, tuberculosis, malnutrition, CNS although other anthropometric measures did not show infections, and genetic or congenital diseases. Diagnoses clear interactions with age. Poor feeding at discharge and associated with a reduced risk of mortality after discharge unplanned discharge also were associated with a greater included upper respiratory tract infections, malaria, risk of mortality in younger children than in older acute gastroenteritis, and measles (table). children (appendix p 7). www.thelancet.com/child-adolescent Published online May 11, 2023 https://doi.org/10.1016/S2352-4642(23)00052-4 7 Cumulative hazard Articles of care, the HR reduced from HR 17·7 (11·4–27·4) in the A first tertile to 3·1 (1·3–7·1) in the third tertile (p<0·0001; 100 Temperature (ºC) <36·5 appendix p 12). Social vulnerability, defined by little 30 36·5 to 37·5 maternal education and further distance between home 37·6 to 39·0 and admitting facility (both in terms of travel time and >39·0 20 actual distance), showed increasing HRs with time after p=0·0022 discharge. Mortality after hospital discharge most often 10 occurred at home (n=162 [45·0%] of 360 children for whom data were available) or in hospital during a 0 readmission (n=132 [36·7%] of 360), although nearly B a fifth occurred in transit while seeking care (n=66 [18·3%] of 360. Neither travel time nor distance 100 Haemoglobin status No anaemia from home to the admitting hospital were associated 30 Mild or moderate anaemia with at-home or in-transit deaths. A discharge diagnosis Severe anaemia p=0·018 of malnutrition was associated with at-home deaths, with 20 an odds ratio of 1·9 (95% CI 1·0–3·6) compared with in- hospital deaths during a readmission (appendix p 13). 10 Degree of malnutrition was only moderately associated with location of death, with lower age-adjusted MUAC, 0 weight-for-length, and BMI-for-age Z scores associated C with at-home (but not in-transit) deaths compared with in-hospital deaths during a readmission. 100 Weight-for-age Z score <–3 30 p=0·0094 –3 to –2 Discussion >–2 In this prospective, multisite, observational cohort study 20 of children younger than 5 years admitted to hospital in Uganda with suspected sepsis, we found that mortality 10 after discharge was frequent, generally occurred in the first several weeks after discharge, was more common 0 0 20 40 60 among younger children, and more often occurred in the Age (months) community than during a readmission to hospital. Risk factors for mortality after discharge, including mal- Figure 3: Interactions between age and risk factors at hospital admission and nutrition, were largely in line with those reported in their associations with risk of mortality after discharge previous studies.4,5,23 As such, strategies to improve care (A) Interaction between age and temperature at hospital admission. (B) Interaction between age and haemoglobin status at hospital admission. during the hospital-to-home transition should become (C) Interaction between age and weight-for-age Z score at hospital admission. urgent priorities in research, health policy, and practice. Indicated p values are for the test of multiplicative interaction between age and In these two cohorts, more than half of all deaths after the corresponding risk factor and are estimated by the likelihood ratio test hospital discharge occurred during the first month after comparing models with and without the interaction term. Shaded areas represent 95% CIs. discharge. The associations between specific risk factors and the timing of mortality was notable, especially the Median time from hospital discharge to death was increasing risk over time among children with severe 28 days (IQR 9–74). When time since discharge was anaemia and the decreasing risk over time among children separated into tertiles by deaths after discharge, we with poor feeding at discharge and with unplanned observed significant variation among several risk factors discharges. A child-centred and resource-efficient approach (figure 4; appendix p 12). Anthrop ometric measures to care should therefore ensure that interventions, and showed persistent risk during the entire period, with peak their timing, are linked to periods with the greatest risk of HRs for several measures during the middle tertile. For mortality. Early mortality could be partly addressed with a severe anaemia, risk of mortality increased with time discharge readiness checklist, which has been effective in from discharge, with HRs increasing from 1·7 (95% CI other settings.24 A 2022 meta-analysis of mortality after 0·9–3·0) to 5·2 (3·1–8·5) between the first and discharge in malaria-endemic areas found that malarial third tertiles (p=0·00077). HRs for some discharge anaemia conferred a lower risk of mortality after discharge vulnerabilities decreased significantly with increasing risk than non-malarial anaemia,6 which was also time since discharge, including unplanned discharge reflected in our study. A randomised controlled trial (from 4·5 [95% CI 2·9–6·9] in the first tertile to 2·0 published in 2020 found that management of malarial [1·3–3·2] in the third tertile [p<0·0001]) and poor feeding anaemia after hospital discharge with malaria chemo- status (from 7·7 [5·4–11·0] to 1·84 [1·0–3·3; p<0·0001]). prophylaxis reduced readmission and mortality after Similarly, for children who were referred to a higher level discharge25 and WHO have included recomme ndations for 8 www.thelancet.com/child-adolescent Published online May 11, 2023 https://doi.org/10.1016/S2352-4642(23)00052-4 Predicted probability (%) Predicted probability (%) Predicted probability (%) Articles Variable Overall aHR (95% CI) Admission anthropometry MUAC <110 or <115 mm 5·56 (4·16–7·43) Magnitude Length-for-age Z score ≤–3 3·85 (3·03–4·89) aHR change from period 1 Weight-for-age Z score ≤–3 5 ·04 (3·97–6·37) BMI-for-age Z score ≤–3 2·97 (2·35–3·76) 2 Weight-for-length Z score ≤–3 2·32 (1·82–2·95) 0 Admission laboratory –2 RDT positive for HIV 1 ·97 (1·25–3·11) –4 Severe anaemia 2 ·81 (2·08–3·81) Lactate >5 mmol/L 1·68 (1·23–2·30) Admission factors Temperature >39ºC 0·40 (0·23–0·70) Capillary refill ≥3 s 1 ·44 (1·07–1·95) Poor health >1 month 4·14 (3·07–5·59) Swelling of both feet 2·09 (1·44–3·02) SpO₂ <90% 1 ·79 (1·39–2·30) Previous antibiotic use 1·33 (1·08–1·65) Changes in urine colour 1 ·63 (1·20–2·22) Referral 2 ·08 (1·68–2·56) Previous admission <1 month before current admission 2·03 (1·55–2·66) Respiratory distress 1 ·44 (1·13–1·83) Making less urine than usual 1 ·64 (1·17–2·30) Atypical BCS score 2·04 (1·53–2·71) Previous care seeking 1·79 (1·39–2·30) Blood in faeces 2·24 (1·31–3·84) Social characteristics Maternal education ≤P3 3·09 (1·91–5·01) Distance to facility >32 km 3·25 (2·34–4·53) Travel time to hospital >3 h 3 ·81 (2·38–6·10) Discharge characteristics Length of hospital stay >5 days 1 ·89 (1·39–2·58) Unplanned discharge 3 ·36 (2·64–4·28) Poor feeding 4 ·53 (3·57–5·73) Referred to higher level of care 9·08 (6·68–12·34) Period 1 Period 2 Period 3 Day 0–14 Day 15–58 Day 59–183 Figure 4: Change in aHR over time The 6-month period after hospital discharge was divided into tertiles according to when deaths occurred and tertile-specific aHRs were calculated. The colours of the second and third periods show the magnitude change from the first period. Boxes containing diagonal lines represent aHRs that are not statistically significant, meaning that no significant association is observed between that particular risk factor and post-discharge mortality in that time period. For MUAC, the threshold of <110 mm applies to the cohort aged 0–6 months and <115 mm applies to the cohort aged 6–60 months. Feeding status was prospectively assessed at discharge by the study nurse and subjectively defined as either feeding well or feeding poorly. Actual aHR estimates are reported in the appendix (p 12). aHR=adjusted hazard ratio. BCS=Blantyre Coma Scale. MUAC=middle-upper-arm circumference. P=primary school. RDT=rapid diagnostic test. SpO2=oxygen saturation. malaria chemoprevention in children in their guidelines.26,27 Immune dysfunction among people who have recovered However, antibacterial chemop rophylaxis (co-trimoxazole), from sepsis, risks related to persistent vulnerability in iron, or folate supplem entation do not appear to improve the home and social environments, and new or existing outcomes after hospital discharge among children comorbidities are all thought to be related to vulnerability admitted with severe anaemia.28 to recurrent illness and death after discharge.5,29,30 A better Nearly half of the deaths that we observed occurred understanding of these and other potentially causal after the first month after discharge. Persistent factors could help to accelerate the development of vulnerability during the period after hospital admission strategies to improve outcomes after hospital discharge.12 is well described and is the subject of substantial and Although younger children had higher rates of increasing interest. Although late deaths are not likely to mortality after discharge than older children, the group be related to exacerbations of the index infection, several at highest risk were those aged 2–6 months. This could factors have been posited to be related to such deaths. be because neonates admitted to hospital directly after www.thelancet.com/child-adolescent Published online May 11, 2023 https://doi.org/10.1016/S2352-4642(23)00052-4 9 Articles birth were excluded. The differences in clinical risk at home, 90% considered seeking care but could not do factors by age was notable, especially for anaemia, axillary so. This was due to various constraints, including temperature, and anthropometry. We found that the financial limitations, lack of transportation, and sudden association between anaemia and risk of mortality after illness onset.35 Although disentangling the causal discharge was greatest in older children. The contribution complexity of deaths after discharge is difficult, reducing of anaemia to mortality after discharge in older children barriers to accessing existing care in a timely way is has been described in a prospective cohort study in clearly important. Improving communication and Tanzania,31 although the study did not include young transportation linkages between facilities and providing children and was not large enough to examine age as an scheduled follow-up within communities, especially interactive factor. The reasons for the interaction we among children vulnerable to recurrent illness and found are unclear, although the protective features of death, are important strategies that could improve fetal haemoglobin or fewer comorbid causes of anaemia outcomes after hospital discharge.36 (eg, chronic malnutrition or HIV) among younger Facilities across a range of locations in Uganda were children could be important.6 involved in enrolment during this study, including both Almost half of the children enrolled in this study had rural and urban populations, providing a reasonable axillary temperatures between 36·5°C and 37·5°C. representation of the national Ugandan paediatric Higher temperature was associated with reduced population outside the capital city of Kampala. However, mortality after discharge; those with temperatures higher this study has some important limitations. First, the than 39°C had an aRR of 0·4 (95% CI 0·2–0·7). study was largely exploratory and included a substantial Furthermore, as children grew up, those who died tended number of analytical comparisons. Many variables to have lower temperatures (<36·5°C) at hospital measured overlapping associations, especially variables admission than those who did not die. These observations related to sociodemographic determinants of health. are based on predictive axillary surface temperatures, Additional studies are required to substantiate many of and whether true core temperatures would differ in their these results, and, if relevant, should include adjustments association with mortality after discharge and interaction for possible confounding variables. In particular, our with age is unclear. Together, these findings indicate the inclusion criteria, which were chosen to be generalisable, need for a more granular understanding of how required only that children had a suspected infection temperature relates to suspected sepsis. according to the admitting medical team and were Although the associations of axillary temperature and admitted to hospital. These two criteria alone suggest haemoglobin concentration with risk of mortality that approximately 90% of the children included in this increased with age, the associations of weight-for-age and study had sepsis according to the IPSCC definition.15 BMI-for-age Z scores with risk of mortality decreased Second, the study was conducted at sites that were largely with age. Those who were severely underweight were at rural or semirural. Large urban settings are likely to have increased risk of death after hospital discharge across all unique contextual issues compared with rural areas, age strata, but the association between moderately especially availability of care. However, this could also be reduced weight-for-age Z scores (–2 to –3) and risk of a strength, as much of the previous literature has focused mortality largely disappeared at older ages. A similar on urban settings. Third, the study was conducted in a observation was noted in an analysis after discharge from single country. Although the results largely reflect studies a surveillance programme in Kenya examining risk conducted in other countries, its geographical limitation factors for children aged 5–12 years; only severely could affect its external validity. Finally, as this was an underweight children had an increased risk of death.32 observational study, we cannot exclude the possibility Of concern are the high proportion of deaths after that unmeasured variables could influence mortality hospital discharge (>60%) that occurred in the after hospital discharge. Our analyses here were meant to community. Similar proportions of community deaths describe the population who died, but subsequent casual have also been observed in community-based death analyses with these data might be subject to unmeasured audits, although most caregivers reported having confounding. consulted a health-care provider at some point during the Paediatric mortality in the context of suspected sepsis fatal illness.33 These observations suggest that health- is a common occurrence during the first 6 months after seeking fatigue over time might be a key factor in hospital discharge, necessitating a robust response community deaths. A nested Kenyan sub-study within among clinicians, researchers, and health policy the CHAIN Network highlighted the often long and leaders. In this study, we found that more than half of complex treatment pathways that acutely ill children these deaths occurred during the first month after navigate; intersecting vulnerabilities at individual, discharge; half occurred at home and a fifth occurred household, and facility levels frequently delay and in-transit to care. Mortality after discharge was prevent timely and quality care, often resulting in poor associated with several risk factors including outcomes.34 A previous analysis of deaths after hospital anthropometric indices, sociod emographic charac- discharge in Uganda found that, among those who died teristics obtained at admission, and discharge 10 www.thelancet.com/child-adolescent Published online May 11, 2023 https://doi.org/10.1016/S2352-4642(23)00052-4 Articles circumstances. These findings might help to guide the 6 Kwambai TK, Mori AT, Nevitt S, et al. Post-discharge morbidity and allocation of additional resources to improve the mortality in children admitted with severe anaemia and other health conditions in malaria-endemic settings in Africa: a hospital-to-home transition. systematic review and meta-analysis. Lancet Child Adolesc Health Contributors 2022; 6: 474–83. MOW, JNB, EK, AT, CB, CO, JMA, NK, JS, CPL, PML, PPM, SN, NKM, 7 Mukasa O, Masanja H, DeSavigny D, Schellenberg J. A cohort study JN, and JK contributed to funding applications. MOW, EK, AT, CB, CO, of survival following discharge from hospital in rural Tanzanian JMA, NK, JS, CPL, PML, PPM, NKM, JK, and DD designed the study. children using linked data of admissions with community-based demographic surveillance. Emerg Themes Epidemiol 2021; 18: 4. MOW, EK, CK, MT, DM, and JK coordinated study implementation. SB, AT, SOS, EB, ES, CB, DD, CK, MT, and DM supervised data 8 Wiens MO, Pawluk S, Kissoon N, et al. Pediatric post-discharge mortality in resource poor countries: a systematic review. PLoS One collection. MOW, DD, CK, MT, DM, CZ, and MK managed the data. 2013; 8: e66698. MOW, JNB, CZ, MK, CK, and VN analysed the data. MOW, JNB, EK, AT, 9 Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and JMA, NK, JS, CPL, PML, PPM, SN, NKM, NW, VN, JN, and JK national sepsis incidence and mortality, 1990–2017: analysis for the interpreted the data. MOW, JNB, and NW drafted the manuscript. All Global Burden of Disease Study. Lancet 2020; 395: 200–11. authors reviewed the manuscript and had full access to all data in the 10 Zick M. WHA adopts resolution on sepsis. Global Sepsis Alliance. study, which was verified by MOW, JNB, CK, JK, DD, CZ, and VN. All May 26, 2017. https://www.global-sepsis-alliance.org/ authors have approved the final manuscript and accept responsibility for news/2017/5/26/wha-adopts-resolution-on-sepsis (accessed the decision to submit for publication. April 17, 2023). Declaration of interests 11 UNICEF. Levels and trends in child mortality.United Nations Inter- We declare no competing interests. Agency Group for Child Mortality Estimation, Report 2022. January, 2023. https://data.unicef.org/resources/levels-and-trends- Data sharing in-child-mortality/ (accessed April 16, 2023). Study materials including the study protocol, consent form, data 12 Akech S, Kwambai T, Wiens MO, Chandna A, Berkley JA, collection tools, de-identified participant data, data dictionary, and the Snow RW. Tackling post-discharge mortality in children living in analysis code will be available with publication on request to the LMICs to reduce child deaths. Lancet Child Adolesc Health 2023; corresponding author or through the published protocol and dataset. 7: 149–51. For the dataset, see https://doi. Owing to the sensitive nature of clinical data, access to the de-identified 13 Uganda Bureau of Statistics. Population and censuses. 2022. org/10.5683/SP3/REPMSY data is granted on a case-by-case basis and will require the signing of a https://www.ubos.org/explore-statistics/20/ (accessed data sharing agreement. Sept 5, 2022). 14 von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Acknowledgments Vandenbroucke JP. The Strengthening the Reporting of This study was funded by Grand Challenges Canada (TTS-1809-1939), the Observational Studies in Epidemiology (STROBE) statement: Thrasher Research Fund (13878), the BC Children’s Hospital Foundation, guidelines for reporting observational studies. J Clin Epidemiol and Mining4Life. We would like to thank individuals from the Smart 2008; 61: 344–49. Discharges Research programme (at the Mbarara University of Science 15 Wiens MO, Larson CP, Kumbakumba E, et al. Application of sepsis and Technology, Mbarara, Uganda; Walimu, Kampala, Uganda; and the definitions to pediatric patients admitted with suspected infections Centre for International Child Health, Vancouver, BC, Canada) for their in Uganda. Pediatr Crit Care Med 2016; 17: 400–05. efforts in data collection, administration, logistics support, and all study 16 Goldstein B, Giroir B, Randolph A. International pediatric sepsis activities, including but not limited to: Tumwebaze Godfrey, Agaba consensus conference: definitions for sepsis and organ dysfunction Collins, Tumukunde Goreth, Naturinda Mackline, Assimwe Abibu, in pediatrics. Pediatr Crit Care Med 2005; 6: 2–8. Nakafero Joan, Kiiza Israel, Kitenda Julius, Kamba Ayub, Kuguminkiriza 17 Wiens MO, Bone JN, Kumbakumba E, et al. Post-discharge Brenda, Kabajasi Olive, Kembabazi Brenda, Happy Annet, Tusingwire mortality among children under 5 years admitted with suspected Fredson, Nuwasasira Agaston, Ankatse Christine, Naturinda Rabecca, sepsis in Uganda: a prospective multi-site study ~ Smart Nabawanuka Abbey Onyachi, Kamazima Justine, Kairangwa Racheal, Discharges. 2022. https://doi.org/10.5683/SP3/REPMSY (accessed Dec 19, 2022). Ounyesiga Thomas, Mwoya Yuma, Twebaze Florence, Bulage Mary, Tugumenawe Darius, Tuhame Dyonisius, Twesigye Leonidas, 18 Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven Kamusiime Olivia, Ainembabazi Harriet, Abaho Samuel, methodology and workflow process for providing translational Nakabiri Zaituni, Naigaga Shaminah, Kisame Zorah, Babirye Clare, research informatics support. J Biomed Inform 2009; 42: 377–81. Kayegi Maliza, Opuko Wilson, Mwaka Savio, Baryahirwa Hassan, 19 Harris PA, Taylor R, Minor BL, et al. The REDCap consortium: Mutungi Alexander, Charlene Kanyali, Catherine Kiggundu, building an international community of software platform partners. Alexia Krepiakevich, Brooklyn Derksen, Jessica Trawin, J Biomed Inform 2019; 95: 103208. Maryum Chaudhry, Peter Lewis, Rishika Bose, Sahar Zandi Nia, and 20 Zou G. A modified poisson regression approach to prospective Tamara Dudley. Without their effort and support, this study would not studies with binary data. Am J Epidemiol 2004; 159: 702–06. have been possible. 21 McNeish D, Stapleton LM. Modeling clustered data with very few References clusters. Multivariate Behav Res 2016; 51: 495–518. 1 Sharrow D, Hug L, You D, et al. Global, regional, and national 22 Fox J. Effect displays in R for generalised linear models. J Stat Softw trends in under-5 mortality between 1990 and 2019 with scenario- 2003; 8: 1–27. based projections until 2030: a systematic analysis by the UN Inter- 23 Hau DK, Chami N, Duncan A, et al. Post-hospital mortality in agency Group for Child Mortality Estimation. Lancet Glob Health children aged 2–12 years in Tanzania: a prospective cohort study. 2022; 10: e195–206. PLoS One 2018; 13: e0202334. 2 Nemetchek B, English L, Kissoon N, et al. Paediatric postdischarge 24 Weiss ME, Yakusheva O, Bobay KL, et al. Effect of implementing mortality in developing countries: a systematic review. BMJ Open discharge readiness assessment in adult medical-surgical units on 2018; 8: e023445. 30-day return to hospital: the READI randomized clinical trial. 3 Wiens MO, Kissoon N, Holsti L. Challenges in pediatric post-sepsis JAMA Netw Open 2019; 2: e187387. care in resource limited settings: a narrative review. Transl Pediatr 25 Kwambai TK, Dhabangi A, Idro R, et al. Malaria chemoprevention 2021; 10: 2666–77. in the postdischarge management of severe anemia. N Engl J Med 4 Madrid L, Casellas A, Sacoor C, et al. Postdischarge mortality 2020; 383: 2242–54. prediction in sub-Saharan Africa. Pediatrics 2019; 143: e20180606. 26 WHO. Updated WHO recommendations for malaria 5 Childhood Acute Illness and Nutrition (CHAIN) Network. chemoprevention among children and pregnant women. 2022. Childhood mortality during and after acute illness in Africa and https://www.who.int/news/item/03-06-2022-Updated-WHO- south Asia: a prospective cohort study. Lancet Glob Health 2022; recommendations-for-malaria-chemoprevention-among-children- 10: e673–84. and-pregnant-women (accessed Feb 12, 2023). www.thelancet.com/child-adolescent Published online May 11, 2023 https://doi.org/10.1016/S2352-4642(23)00052-4 11 Articles 27 WHO. WHO Guidelines for malaria. 2023. https://www.who.int/ 33 Willcox ML, Kumbakumba E, Diallo D, et al. Circumstances of child publications/i/item/guidelines-for-malaria (accessed Feb 12, 2023). deaths in Mali and Uganda: a community-based confidential 28 Maitland K, Olupot-Olupot P, Kiguli S, et al. Co-trimoxazole or enquiry. Lancet Glob Health 2018; 6: e691–702. multivitamin multimineral supplement for post-discharge 34 Zakayo SM, Njeru RW, Sanga G, et al. Vulnerability and agency outcomes after severe anaemia in African children: a randomised across treatment-seeking journeys for acutely ill children: how controlled trial. Lancet Glob Health 2019; 7: e1435–47. family members navigate complex healthcare before, during and 29 van der Slikke EC, An AY, Hancock REW, Bouma HR. Exploring the after hospitalisation in a rural Kenyan setting. Int J Equity Health pathophysiology of post-sepsis syndrome to identify therapeutic 2020; 19: 136. opportunities. EBioMedicine 2020; 61: 103044. 35 English L, Kumbakumba E, Larson CP, et al. Pediatric out-of- 30 Delano MJ, Ward PA. The immune system’s role in sepsis hospital deaths following hospital discharge: a mixed-methods progression, resolution, and long-term outcome. Immunol Rev 2016; study. Afr Health Sci 2016; 16: 883–91. 274: 330–53. 36 Wiens MO, Kissoon N, Kabakyenga J. Smart hospital discharges to 31 Chami N, Hau DK, Masoza TS, et al. Very severe anemia and address a neglected epidemic in sepsis in low- and middle-income one year mortality outcome after hospitalization in Tanzanian countries. JAMA Pediatr 2018; 172: 213–14. children: a prospective cohort study. PLoS One 2019; 14: e0214563. 32 Ngari MM, Obiero C, Mwangome MK, et al. Mortality during and following hospital admission among school-aged children: a cohort study. Wellcome Open Res 2021; 5: 234. 12 www.thelancet.com/child-adolescent Published online May 11, 2023 https://doi.org/10.1016/S2352-4642(23)00052-4