Nutritional supplementation in children with severe pneumonia in Uganda and Kenya (COAST-Nutrition): a phase 2 randomised controlled trial.

Background: Severe pneumonia in African children results in poor long-term outcomes (deaths/readmissions) with undernutrition as a key risk factor. We hypothesised additional energy/protein-rich Ready-to-Use Therapeutic Foods (RUTF) would meet additional nutritional requirements and improve outcomes. Methods: COAST-Nutrition was an open-label Phase 2 randomised controlled trial in children (aged 6 months-12 years) hospitalised with severe pneumonia (and hypoxaemia, SpO2 <92%) in Mbale, Soroti, Jinja, Masaka Regional Referral Hospitals, Uganda and Kilifi County Hospital, Kenya (ISRCTN10829073 (registered 6th June 2018) PACTR202106635355751 (registered 2nd June 2021)). Children were randomised (ratio 1:1) to enhanced nutritional supplementation with RUTF (plus usual diet) for 56 days vs usual diet (control). The primary outcome was change in mid-upper arm circumference (MUAC) at 90 days as a composite with mortality. Secondary outcomes include anthropometric status, mortality, and readmissions at Days 28, 90 and 180. Findings: Between 12 August 2018 and 22 April 2022, 846 eligible children were randomised, 424 to RUTF and 422 to usual diet, and followed for 180-days [12 (1%) lost-to-follow-up]. RUTF supplement was initiated in 417/419 (>99%). By Day 90, there was no significant difference in the composite endpoint (probabilistic index 0.49, 95% CI 0.45-0.53, p = 0.74). Respective 90-day mortality (13/420 3.1% vs 14/421 3.3%) and MUAC increment (0.54 (SD 0.85) vs 0.55 (SD 0.81)) were similar between arms. There was no difference in any anthropometric secondary endpoints to Day 28, 90 or 180 except skinfold thickness at Day 28 and Day 90 was greater in the RUTF arm. Serious adverse events were higher in the RUTF arm (n = 164 vs 108), mainly due to hospital readmission for acute illness (54/387 (14%) vs 37/375 (10%). Interpretation: Our study suggested that nutritional supplementation with RUTF did not improve outcomes to 180 days in children with severe pneumonia. Funding: This trial is part of the EDCTP2 programme (grant number RIA-2016S-1636-COAST-Nutrition) supported by the European Union, and UK Joint Global Health Trials scheme: Medical Research Council, Department for International Development, Wellcome Trust (grant number MR/L004364/1, UK).

Hydroxyurea dose optimisation for children with sickle cell anaemia in sub-Saharan Africa (REACH): extended follow-up of a multicentre, open-label, phase 1/2 trial.

BACKGROUND: Realizing Effectiveness Across Continents with Hydroxyurea (REACH) is an open-label non-randomised trial of hydroxyurea (hydroxycarbamide) in children with sickle cell anaemia in sub-Saharan Africa. The short-term results of REACH on safety, feasibility, and effectiveness of hydroxyurea were published previously. In this paper we report results from extended hydroxyurea treatment in the REACH cohort up to 8 years. METHODS: In this open-label, non-randomised, phase 1/2 trial, participants were recruited from four clinical sites in Kilifi, Kenya; Mbale, Uganda; Luanda, Angola; and Kinshasa, Democratic Republic of Congo. Eligible children were 1-10 years old with documented haemoglobin SS or haemoglobin Sß zero thalassaemia, weighing at least 10 kg. Participants received fixed-dose hydroxyurea of 17.5 (±2.5) mg/kg per day for 6 months (fixed-dose phase), followed by 6 months of dose escalation (2·5-5·0 mg/kg increments every 8 weeks) as tolerated, up to 20-35 mg/kg per day (maximum tolerated dose; MTD), defined as mild myelosuppression. After the MTD was reached, hydroxyurea dosing was optimised for each participant on the basis of changes in bodyweight and laboratory values over time (MTD with optimisation phase). After completion of the first 12 months, children with an acceptable toxicity profile and favourable responses were given the opportunity to continue hydroxyurea until the age of 18 years. The safety and feasibility results after 3 years has been reported previously. Here, haematological responses, clinical events, and toxicity rates were compared across the dosing phases (fixed-dose hydroxyurea vs MTD with optimisation phase) as protocol-specified outcomes. REACH is registered on ClinicalTrials.gov (NCT01966731) and is ongoing. FINDINGS: We enrolled 635 children between July 4, 2014, and Nov 11, 2016. 606 children were given hydroxyurea and 522 (86%; 266 [51%] boys and 256 [49%] girls) received treatment for a median of 93 months (IQR 84-97) with 4340 patient-years of treatment. The current (Oct 5, 2023) mean dose is 28·2 (SD 5·2) mg/kg per day with an increased mean haemoglobin concentration (7·3 [SD 1·1] g/dL at baseline to 8·5 [1·5] g/dL) and mean fetal haemoglobin level (10·9% [SD 6·8] to 23·3% [9·5]) and decreased absolute neutrophil count (6·8 [3·0] × 109 cells per L to 3·6 [2·2] × 109 cells per L). Incidence rate ratios (IRR) comparing MTD with fixed-dose hydroxyurea indicate decreased vaso-occlusive episodes (0·60; 95% CI 0·52-0·70; p<0·0001), acute chest syndrome events (0·21; 0·13-0·33; p<0·0001), recurrent stroke events (0·27; 0·07-1·06; p=0·061), malaria infections (0·58; 0·46-0·72; p<0·0001), non-malarial infections (0·52; 0·46-0·58; p<0·0001), serious adverse events (0·42; 0·27-0·67; p<0·0001), and death (0·70; 0·25-1·97; p=0·50). Dose-limiting toxicity rates were similar between the fixed-dose (24·1 per 100 patient-years) and MTD phases (23·2 per 100 patient-years; 0·97; 0·70-1·35; p=0·86). Grade 3 and 4 adverse events were infrequent (18·5 per 100 patient-years) and included malaria infection, non-malarial infections, vaso-occlusive pain, and acute chest syndrome. Serious adverse events were uncommon (3·6 per 100 patient-years) and included malaria infections, parvovirus-associated anaemia, sepsis, and stroke, with no treatment-related deaths. INTERPRETATION: Hydroxyurea dose escalation to MTD with dose optimisation significantly improved clinical responses and treatment outcomes, without increasing toxicities in children with sickle cell anaemia in sub-Saharan Africa. FUNDING: US National Heart, Lung, and Blood Institute and Cincinnati Children's Research Foundation.

Reducing transfusion utilization for children with sickle cell anemia in sub-Saharan Africa with hydroxyurea: Analysis from the phase I/II REACH trial.

Children with sickle cell anemia (SCA) in Africa frequently require transfusions for SCA complications. Despite limited blood supplies, strategies to reduce their transfusion needs have not been widely evaluated or implemented. We analyzed transfusion utilization in children with SCA before and during hydroxyurea treatment. REACH (Realizing Effectiveness Across Continents with Hydroxyurea, NCT01966731) is a longitudinal Phase I/II trial of hydroxyurea in children with SCA from Angola, Democratic Republic of Congo, Kenya, and Uganda. After enrollment, children had a two-month pre-treatment screening period followed by 6 months of fixed-dose hydroxyurea (15-20 mg/kg/day), 18 months of dose escalation, and then stable dosing at maximum tolerated dose (MTD). Characteristics associated with transfusions were analyzed with univariate and multivariable models. Transfusion incidence rate ratios (IRR) across treatment periods were calculated. Among 635 enrolled children with 4124 person-years of observation, 258 participants (40.4%) received 545 transfusions. The transfusion rate per 100 person-years was 43.2 before hydroxyurea, 21.7 on fixed-dose, 14.5 during dose escalation, and 10.8 on MTD. During MTD, transfusion incidence was reduced by 75% compared to pre-treatment (IRR 0.25, 95% confidence interval [CI] 0.18-0.35, p < .0001), and by 50% compared to fixed dose (IRR 0.50, 95% CI 0.39-0.63, p < .0001). Hydroxyurea at MTD decreases transfusion utilization in African children with SCA. If widely implemented, universal testing and hydroxyurea treatment at MTD could potentially prevent 21% of all pediatric transfusions administered in sub-Saharan Africa. Increasing hydroxyurea access for SCA should decrease the transfusion burden and increase the overall blood supply.

High burden of wasting among children under-five with hydrocephalus receiving care at CURE children's hospital in Uganda: a cross-sectional study.

BACKGROUND: Hydrocephalus is one of the most common neurological disabilities presenting in children. Although there are limited studies on its association with wasting, neurological comorbidities such as dysphagia have been associated with an increased risk of wasting in children. In this study, we aimed to determine the prevalence and factors associated with wasting in children less than five years with hydrocephalus. METHODS: We conducted a cross-sectional study at various satellite clinics of CURE Children's Hospital in Uganda between September and November 2021. Children with hydrocephalus were identified at the outpatient departments of the satellite clinics of the Cure Children's Hospital and these include Mbale, Gulu, Lira, Jinja and Katalemwa. A structured questionnaire was used to collect information on several variables including (1) for the mother: socio-demographic characteristics, partner support, and wealth index (2) for the child: socio-demographic characteristics, clinical symptoms, feeding difficulties and neural comorbidity. Anthropometric measurements were also taken and these included the mid-upper arm circumference. Data were analysed using Stata version 14. We estimated adjusted odds ratios and their corresponding 95% confidence intervals while relying on multivariable logistic regression models. RESULTS: The prevalence of wasting among children with hydrocephalus was 23.2% (n = 89/384) (95%CI: 19 - 27.7%). Their mean age was 19.5 months (SD 16.8). Most of the children were below 12 months (47.9%) and were male (57.5%). The factors associated with wasting among children with hydrocephalus included: having; difficulty in chewing and swallowing (AOR = 2.6, (95%CI:1.05-3.94), a poor appetite (AOR = 1.74, (95%CI: 1.31-2.32), difficulty in breathing (AOR = 1.9, (95%CI: 1.18-3.16), chocking on food (AOR = 1.42, (95%CI:1.1-1.9) and attending the Mbale satellite clinic (AOR = 2.1 (95% CI 1.19-3.7). Children under 5 years of age with hydrocephalus that were born to women whose highest level of education was 7 to 10 years of formal schooling (AOR = 0.32, 95%CI: (0.12-0.87) were less likely to be wasted. CONCLUSIONS AND RECOMMENDATIONS: The prevalence of wasting among children with hydrocephalus was high. The factors associated with wasting were mainly feeding challenges. We recommend that children with hydrocephalus should be given greater attention regarding their nutrition especially those with various forms of feeding difficulties. The caregivers of children with hydrocephalus should receive counseling on nutrition and on the best modalities to rely on while feeding their children.

Effect of COVID-19 lock down on teenage pregnancies in Northern Uganda: an interrupted time series analysis.

BACKGROUND: Pregnancy and childbirth complications are the leading cause of death among girls aged 15-19 years globally, with low- and middle-income countries (LMICs) accounting for 99% of global maternal deaths of women aged 15-49 years. Despite teenage pregnancies declining in many developing countries in recent years, the COVID-19 period intensified the problem and altered the trend for most countries. We determined the effect of the COVID-19 lockdown on the teenage pregnancy trend in Pakwach district, Uganda, to understand its magnitude in our study population. METHODS: Using interrupted time series analysis (ITS), sometimes known as quasi-experimental time series analysis. We constructed a time series of the first ANC service utilization records for girls aged 10-19 years in Pakwach district, Uganda, and conducted an interrupted series analysis. We compared the two periods of March 2019 to March 2020 and March 2020 to March 2021. We used Stata 15 to conduct our analysis, performed OLS, and plotted the results. RESULTS: The teenage pregnancy trend before the lockdown was decreasing by - 0.203 pregnancies per month, but in the first month after the institution of the lockdown (March 20, 2020), there was an increase in the teenage pregnancy rate of 13.9 pregnancies [95% CI: - 33.6 to 61.5], which corresponds to an increase in the monthly trend in teenage pregnancies (relative to the period before the COVID-19 lockdown trend) of 1.53 girls per month. CONCLUSION: Teenage pregnancies increased during the lockdown. This slight increase depicted the impact of the pandemic on the teenage pregnancy trend associated with the COVID-19 outbreak. The government needs to focus on intervention to reduce this trend and avoid any further increases.

Health workers' adherence to the malaria test, treat and track strategy during the COVID-19 pandemic in malaria high transmission area in Eastern Uganda.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic affected malaria control activities in sub-Saharan Africa (SSA) resulting in 690,000 excess deaths in the year 2021. The authors hypothesized that COVID-19 affected the World Health Organization (WHO) Test, Treat and Track (T3) strategy that has been implemented in Uganda since 2010. In this study, health worker's adherence to the T3 strategy during COVID-19 pandemic in Eastern Uganda was studied by assessing their knowledge, skills and practices. METHODS: A cross-sectional study utilizing mixed quantitative and qualitative data collections methods was conducted at Mbale Regional Referral Hospital in Eastern Uganda between November and December in 2020. Data were captured on demographics, knowledge, skills and practices for both health workers (HWs) and patients. Quantitative data were analysed using STATA 15.0 and reported as descriptive statistics, proportions and statistical associations. Moreover, qualitative data were collected via key informant interviews (KII) among purposively sampled study participants and analysed thematically using NVIVO software. Ethical approval was obtained prior to the study. RESULTS: A total of 436 study participants, of whom 103/436 (24%) and 333/436 (76%) were HWs and patients, respectively were studied. Among the HWs with mean age of 34 years (SD = 8.8 years), 81/103 (79%) had good practices, most 63/103 (61%) had good knowledge, and only 11/103 (10.7%) had good skills. Specifically, on the cadres, the laboratory personnel 19/103 (18%) had good knowledge 14/19 (74%) OR: 2.0 (95% CI 0.7-6) and were highly skilled OR: 4.6 (95% CI 1.2-18.1; P < 0.0150) compared to other cadres, respectively. Among the patients whose age ranged 3 months to 80 years (mean 17.8 years) and females 177/333 (53%); a majority 257/333 (77%) were tested, of whom 139/333 (42%) tested positive. Out of the positive cases, 115/333 (35%) were treated and tracked. About 75/333 (23%) were not tested but treated for malaria. Of the 168/239 (70.3%) patients tested, 115/168 (68.5%) were positive and treated, P = 0.0001. The KII revealed low level of In-service training, overwhelming number of patients and stock-out of supplies as a key factor for poor HW adherence to T3 strategy. CONCLUSIONS: During COVID-19 pandemic period HWs adherence to T3 initiative was low as 27% malaria patients did not receive treatment.

Severe malaria burden, clinical spectrum and outcomes at Apac district hospital, Uganda: a retrospective study of routine health facility-based data.

BACKGROUND: Most data describing severe malaria (SM) in sub-Saharan Africa (SSA) are from research settings outside disease endemic areas. Using routinely collected data from Apac District Hospital, this study aimed at determining the burden and clinical spectrum of severe malaria. METHODS: This was a retrospective study that reviewed all paediatric admission records for malaria in the 24 months period from Jan 2019 to Dec 2020 at Apac District Hospital. Data on children aged 60 days to 12 years who at admission tested positive for malaria and fulfilled the World Health Organization clinical criteria for surveillance of severe malaria were abstracted using a customized proforma designed to capture variables on social demographic, clinical presentation, treatment, and outcomes. In addition, the tool included laboratory variables for complete blood counts, haemoglobin, and glucose levels. Data were analysed using STATA V15.0. The study had ethical approval from Mbale Regional Referral Hospital REC, Approval No. MRRH-REC 053/2019. RESULTS: A total of 5631 admission records were retrieved for this study period. Of these, 3649 (64.8%) were malaria admissions and 3422/3649 were children below 12years, with only 1864 (54.5%) of children having complete data. Of the 1864 children, 745 (40.0%) fulfilled the severe malaria inclusion criteria. Of the 745 children, 51.4% (n = 381) were males. The median age at admission was 31 months (IQR = 17-60). The most common clinical presentations among children with severe malaria were fever 722 (97.3%), cough 478 (64.2%), and difficulty in breathing 122 (17.9%). The median length of hospital stay was 2 (IQR; 2-4) days and 133 (17.9%) had prolonged hospital stay (> 4 days). Factors independently associated with prolonged hospital stay were, presenting with difficulty in breathing, aOR 1.83 (95% CI 1.02-3.27, P = 0.042) and prostration aOR 8.47 (95% CI 1.94-36.99, P = 0.004). A majority of admitted children, 735 (98.7%) survived, while 10 (1.3%) died of SM. CONCLUSION: A high proportion (40.0%) of malaria admissions were due to SM. Prolonged Hospital stay was associated with prostration and difficulty in breathing. Overall mortality was low, 1.3% compared to mortality in the previously reported series. This study was able to use routinely collected data to describe the burden and clinical spectrum of SM. Improvement in the quality of data from such settings would improve disease descriptions for policy, monitoring of epidemics, response to interventions and to inform research.

Factors affecting haemoglobin dynamics in African children with acute uncomplicated Plasmodium falciparum malaria treated with single low-dose primaquine or placebo.

BACKGROUND: Single low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in patients with glucose-6-phopshate dehydrogenase (G6PD) deficiency. We, therefore, examined the independent effects of several factors on haemoglobin (Hb) dynamics in falciparum-infected children with a particular interest in SLDPQ and G6PD status. METHODS: This randomised, double-blind, placebo-controlled, safety trial was conducted in Congolese and Ugandan children aged 6 months-11 years with acute uncomplicated P. falciparum and day (D) 0 Hbs ≥ 6 g/dL who were treated with age-dosed SLDPQ/placebo and weight-dosed artemether lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPP). Genotyping defined G6PD (G6PD c.202T allele), haemoglobin S (HbS), and α-thalassaemia status. Multivariable linear and logistic regression assessed factor independence for continuous Hb parameters and Hb recovery (D42 Hb > D0 Hb), respectively. RESULTS: One thousand one hundred thirty-seven children, whose median age was 5 years, were randomised to receive: AL + SLDPQ (n = 286), AL + placebo (286), DHAPP + SLDPQ (283), and DHAPP + placebo (282). By G6PD status, 284 were G6PD deficient (239 hemizygous males, 45 homozygous females), 119 were heterozygous females, 418 and 299 were normal males and females, respectively, and 17 were of unknown status. The mean D0 Hb was 10.6 (SD 1.6) g/dL and was lower in younger children with longer illnesses, lower mid-upper arm circumferences, splenomegaly, and α-thalassaemia trait, who were either G6PDd or heterozygous females. The initial fractional fall in Hb was greater in younger children with higher D0 Hbs and D0 parasitaemias and longer illnesses but less in sickle cell trait. Older G6PDd children with lower starting Hbs and greater factional falls were more likely to achieve Hb recovery, whilst lower D42 Hb concentrations were associated with younger G6PD normal children with lower fractional falls, sickle cell disease, α-thalassaemia silent carrier and trait, and late treatment failures. Ten blood transfusions were given in the first week (5 SLDPQ, 5 placebo). CONCLUSIONS: In these falciparum-infected African children, posttreatment Hb changes were unaffected by SLDPQ, and G6PDd patients had favourable posttreatment Hb changes and a higher probability of Hb recovery. These reassuring findings support SLDPQ deployment without G6PD screening in Africa. TRIAL REGISTRATION: The trial is registered at ISRCTN 11594437.

Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria.

BACKGROUND: There are no pharmacokinetic data of single low dose primaquine (SLDPQ) as transmission blocking in African children with acute Plasmodium falciparum and glucose-6-phosphate dehydrogenase deficiency (G6PDd). METHODS: Primaquine pharmacokinetics of age-dosed SLDPQ (shown previously to be gametocytocidal with similar tolerability as placebo) were characterised in falciparum-infected Ugandan and Congolese children aged 6 months to 11 years, treated on admission with standard 3-day dihydroartemisinin-piperaquine or artemether-lumefantrine plus SLDPQ: 6 m-<1 y: 1.25 mg, 1-5 y: 2.5 mg, 6-9 y: 5 mg, 10-11 y: 7.5 mg. LC-MS/MS-measured plasma primaquine and carboxyprimaquine (baseline, 1, 1.5, 2, 4, 8, 12, 24 h) were analysed by noncompartmental analysis. Multivariable linear regression modelled associations between covariates, including cytochrome-P450 2D6 metaboliser status, and outcomes. FINDINGS: 258 children (median age 5 [interquartile range (IQR) 3-7]) were sampled; 8 (3.1%) with early vomiting were excluded. Primaquine doses of 0.10-0.40 (median 0.21, IQR 0.16-0.25) mg base/kg resulted in primaquine maximum plasma concentrations (Cmax) of 2.3-447 (median 103.0, IQR 72.1-140.0) ng/mL between 1.0 and 8.0 (median 2) hours (Tmax) and median areas under the drug concentration curves (AUC0-last) 730.2 (6 m-<1 y, n = 12), 582.8 (1-5 y, n = 126), 871.1 (6-9 y, n = 80), and 931.0 (10-11 y, n = 32) ng∗h/mL. Median elimination half-live (T½) was 4.7 (IQR 3.8-5.6) hours. Primaquine clearance/kg peaked at 18 months, plateauing at 4 y. Increasing CYP2D6 metaboliser activity score [poor (3/250), intermediate (52/250), normal (150/250), ultrarapid (5/250), indeterminate (40/250)] and baseline haemoglobin were significantly associated with a lower primaquine AUC0-last,which increased with increasing mg/kg dose and age but was independent of the artemisinin treatment used. INTERPRETATION: Age-dosed SLDPQ resulted in variable primaquine exposure that depended on bodyweight-adjusted dose, age, baseline haemoglobin and CYP2D6 metaboliser status, but not on dihydroartemisinin-piperaquine or artemether-lumefantrine. These data support age-dosed SLDPQ for transmission blocking in sub-Saharan Africa. FUNDING: This work was cofunded by the UK Medical Research Council, Wellcome Trust, and UK Aid through the Global Health Trials (grant reference MR/P006973/1). The funders had no role in the study design, execution, and analysis and decisions regarding publication.

Caregivers' use of herbal and conventional medicine to treat children with sickle cell disease at Jinja Regional Referral Hospital, Eastern Uganda: A cross-sectional study.

BACKGROUND: Evidence suggests use of herbal and conventional medicines in the treatment of Sickle Cell Disease (SCD). We examined factors associated with caregivers' use of combined herbal and conventional medicine to treat children with SCD. METHODS: A cross-sectional study was conducted at Jinja Regional Referral Hospital between January and March 2022. Caregivers of children with SCD aged 1 to 18 years attending the Sickle Cell Clinic were interviewed using structured questionnaires. We collected data on caregivers' socio-demographic characteristics, perceptions of and intentions to use either or both therapies, self-reported use of either or both therapies and community and health-related factors. A multivariable logistic regression model was computed to assess the factors independently associated with caregivers' use of combined therapy, using Stata version 15.0. RESULTS: 372 caregivers were interviewed. On average, respondents were aged 34.3 years (Standard Deviation [SD]: ±9.8 years). 37% (n = 138) of the caregivers reported the use of both herbal and conventional medicine, 58.3% (n = 217) reported use of only conventional medicine, while 4.6% (n = 17) reported use of herbal medicine only. Higher odds of using combination therapy were found in caregivers aged 60+ years (adjusted odds ratio [AOR] = 11.8; 95% CI: 1.2, 115.2), those with lower secondary education (AOR = 6.2; 95% CI: 1.5, 26.0), those who believed in the safety of herbal medicine (AOR = 3.3; 95% CI: 1.5, 7.6) and those who thought that use of both therapies were safe (AOR = 7.7; 95% CI: 3.5, 17.0). CONCLUSION: More than one-third of the caregivers reported use of combined herbal and conventional medicine, most of whom were older (>60%) and had lower secondary education. There is need for targeted health promotion to educate caregivers about the dangers of using both herbal and conventional medicines in treating children with SCD.

Prevalence and Factors Associated With Cryptoccocal Antigenemia Among Patients With Advanced Human Immunodeficiency Virus in Eastern Uganda: A Facility-Based Cross-sectional Study.

Background: Cryptoccocal infection remains an important cause of morbidity and mortality among people with advanced human immunodeficiency virus disease (AHD). In resource-limited settings, there is a paucity of data on cryptoccocal infections. We described the prevalence and factors associated with cryptoccocal antigenemia among people with AHD in Mbale Regional Referral Hospital in Eastern Uganda. Methods: In this cross-sectional study, data on sociodemographic, clinical, and laboratory characteristics of adults with AHD were collected, and factors associated with cryptoccocal antigenemia were determined using multivariate logistic regression models. Results: We enrolled 228 participants with a median CD4 cell count of 194/µL (interquartile range, 129-370/µL). The prevalence of cryptoccocal antigen was 10 in 228 (4.4% [95% confidence interval, 2.4%-80%]). CD4 cell counts <100/µL (adjusted odds ratio, 3.70) and poultry keeping were risk factors. The main predictors were headaches (adjusted odds ratio, 1), neck pains (8.817), confusion (6.323), and neck stiffness (676.217). No notable significant associations were found in the multivariate analysis. Conclusions: The prevalence of cryptoccocal antigen was 4.4%, and antiretroviral therapy was protective.

PARIST study protocol: a phase I/II randomised, controlled clinical trial to assess the feasibility, safety and effectiveness of paracetamol in resolving acute kidney injury in children with severe malaria.

BACKGROUND: Acute kidney injury (AKI) has in the past been considered a rare complication of malaria in children living in high-transmission settings. More recently, however, a growing number of paediatric case series of AKI in severe malaria studies in African children have been published (Artesunate vs Quinine in the Treatment of Severe P. falciparum Malaria in African children and Fluids Expansion as Supportive Therapy trials). The Paracetamol for Acute Renal Injury in Severe Malaria Trial (PARIST) therefore, aims to assess feasibility, safety and determine the effective dose of paracetamol, which attenuates nephrotoxicity of haemoproteins, red-cell free haemoglobin and myoglobin in children with haemoglobinuric severe malaria. METHODS: PARIST is a phase I/II unblinded randomised controlled trial of 40 children aged >6 months and <12 years admitted with confirmed haemoglobinuric severe malaria (blackwater fever), a positive blood smear for P. falciparum malaria and either serum creatinine (Cr) increase by ≥0.3 mg/dL within 48 hours or to ≥1.5 times baseline and elevated blood urea nitrogen (BUN) >20 mg/dL. Children will be randomly allocated on a 1:1 basis to paracetamol intervention dose arm (20 mg/kg orally 6-hourly for 48 hours) or to a control arm to receive standard of care for temperature control (ie, tepid sponging for 30 min if fever persists give rescue treatment). Primary outcome is renal recovery at 48 hours as indicated by stoppage of progression and decrease of Cr level below baseline, BUN (<20 mg/dL). Data analysis will be on the intention-to-treat principle and a per-protocol basis.Results from this phase I/II clinical trial will provide preliminary effectiveness data of this highly potential treatment for AKI in paediatric malaria (in particular for haemoglobinuric severe malaria) for a larger phase III trial. ETHICS AND DISSEMINATION: Ethical and regulatory approvals have been granted by the Mbale Hospital Institutional Ethics Review Committee (MRRH-REC OUT 002/2019), Uganda National Council of Science and Technology (UNCST-HS965ES) and the National drug Authority (NDA-CTC 0166/2021). We will be disseminating results through journals, conferences and policy briefs to policy makers and primary care providers. TRIAL REGISTRATION NUMBER: ISRCTN84974248.

Neonatal Paenibacilliosis: Paenibacillus Infection as a Novel Cause of Sepsis in Term Neonates With High Risk of Sequelae in Uganda.

BACKGROUND: Paenibacillus thiaminolyticus may be an underdiagnosed cause of neonatal sepsis. METHODS: We prospectively enrolled a cohort of 800 full-term neonates presenting with a clinical diagnosis of sepsis at 2 Ugandan hospitals. Quantitative polymerase chain reaction specific to P. thiaminolyticus and to the Paenibacillus genus were performed on the blood and cerebrospinal fluid (CSF) of 631 neonates who had both specimen types available. Neonates with Paenibacillus genus or species detected in either specimen type were considered to potentially have paenibacilliosis, (37/631, 6%). We described antenatal, perinatal, and neonatal characteristics, presenting signs, and 12-month developmental outcomes for neonates with paenibacilliosis versus clinical sepsis due to other causes. RESULTS: Median age at presentation was 3 days (interquartile range 1, 7). Fever (92%), irritability (84%), and clinical signs of seizures (51%) were common. Eleven (30%) had an adverse outcome: 5 (14%) neonates died during the first year of life; 5 of 32 (16%) survivors developed postinfectious hydrocephalus (PIH) and 1 (3%) additional survivor had neurodevelopmental impairment without hydrocephalus. CONCLUSIONS: Paenibacillus species was identified in 6% of neonates with signs of sepsis who presented to 2 Ugandan referral hospitals; 70% were P. thiaminolyticus. Improved diagnostics for neonatal sepsis are urgently needed. Optimal antibiotic treatment for this infection is unknown but ampicillin and vancomycin will be ineffective in many cases. These results highlight the need to consider local pathogen prevalence and the possibility of unusual pathogens when determining antibiotic choice for neonatal sepsis.

Paenibacillus spp infection among infants with postinfectious hydrocephalus in Uganda: an observational case-control study.

BACKGROUND: Paenibacillus thiaminolyticus is a cause of postinfectious hydrocephalus among Ugandan infants. To determine whether Paenibacillus spp is a pathogen in neonatal sepsis, meningitis, and postinfectious hydrocephalus, we aimed to complete three separate studies of Ugandan infants. The first study was on peripartum prevalence of Paenibacillus in mother-newborn pairs. The second study assessed Paenibacillus in blood and cerebrospinal fluid (CSF) from neonates with sepsis. The third study assessed Paenibacillus in CSF from infants with hydrocephalus. METHODS: In this observational study, we recruited mother-newborn pairs with and without maternal fever (mother-newborn cohort), neonates (aged ≤28 days) with sepsis (sepsis cohort), and infants (aged ≤90 days) with hydrocephalus with and without a history of neonatal sepsis and meningitis (hydrocephalus cohort) from three hospitals in Uganda between Jan 13, 2016 and Oct 2, 2019. We collected maternal blood, vaginal swabs, and placental samples and the cord from the mother-newborn pairs, and blood and CSF from neonates and infants. Bacterial content of infant CSF was characterised by 16S rDNA sequencing. We analysed all samples using quantitative PCR (qPCR) targeting either the Paenibacillus genus or Paenibacillus thiaminolyticus spp. We collected cranial ultrasound and computed tomography images in the subset of participants represented in more than one cohort. FINDINGS: No Paenibacillus spp were detected in vaginal, maternal blood, placental, or cord blood specimens from the mother-newborn cohort by qPCR. Paenibacillus spp was detected in 6% (37 of 631 neonates) in the sepsis cohort and, of these, 14% (5 of 37 neonates) developed postinfectious hydrocephalus. Paenibacillus was the most enriched bacterial genera in postinfectious hydrocephalus CSF (91 [44%] of 209 patients) from the hydrocephalus cohort, with 16S showing 94% accuracy when validated by qPCR. Imaging showed progression from Paenibacillus spp-related meningitis to postinfectious hydrocephalus over 1-3 months. Patients with postinfectious hydrocephalus with Paenibacillus spp infections were geographically clustered. INTERPRETATION: Paenibacillus spp causes neonatal sepsis and meningitis in Uganda and is the dominant cause of subsequent postinfectious hydrocephalus. There was no evidence of transplacental transmission, and geographical evidence was consistent with an environmental source of neonatal infection. Further work is needed to identify routes of infection and optimise treatment of neonatal Paenibacillus spp infection to lessen the burden of morbidity and mortality. FUNDING: National Institutes of Health and Boston Children's Hospital Office of Faculty Development.

Unusual clinical spectra of childhood severe malaria during malaria epidemic in eastern Uganda: a prospective study.

BACKGROUND: In sub-Saharan Africa (SSA), malaria remains a public health problem despite recent reports of declining incidence. Severe malaria is a multiorgan disease with wide-ranging clinical spectra and outcomes that have been reported to vary by age, geographical location, transmission intensity over time. There are reports of recent malaria epidemics or resurgences, but few data, if any, focus on the clinical spectrum of severe malaria during epidemics. This describes the clinical spectrum and outcomes of childhood severe malaria during the disease epidemic in Eastern Uganda. METHODS: This prospective cohort study from October 1, 2021, to September 7, 2022, was nested within the 'Malaria Epidemiological, Pathophysiological and Intervention studies in Highly Endemic Eastern Uganda' (TMA2016SF-1514-MEPIE Study) at Mbale Regional Referral Hospital, Uganda. Children aged 60 days to 12 years who at admission tested positive for malaria and fulfilled the clinical WHO criteria for surveillance of severe malaria were enrolled on the study. Follow-up was performed until day 28. Data were collected using a customized proforma on social demographic characteristics, clinical presentation, treatment, and outcomes. Laboratory analyses included complete blood counts, malaria RDT (SD BIOLINE Malaria Ag P.f/Pan, Ref. 05FK60-40-1) and blood slide, lactate, glucose, blood gases and electrolytes. In addition, urinalysis using dipsticks (Multistix® 10 SG, SIEMENS, Ref.2300) at the bedside was done. Data were analysed using STATA V15.0. The study had prior ethical approval. RESULTS: A total of 300 participants were recruited. The median age was 4.6 years, mean of 57.2 months and IQR of 44.5 months. Many children, 164/300 (54.7%) were under 5 years, and 171/300 (57.0%) were males. The common clinical features were prostration 236/300 (78.7%), jaundice in 205/300 (68.3%), severe malarial anaemia in 158/300 (52.7%), black water fever 158/300 (52.7%) and multiple convulsions 51/300 (17.0%), impaired consciousness 50/300(16.0%), acidosis 41/300(13.7%), respiratory distress 26/300(6.7%) and coma in 18/300(6.0%). Prolonged hospitalization was found in 56/251 (22.3%) and was associated with acidosis, P = 0.041. The overall mortality was 19/300 (6.3%). Day 28 follow-up was achieved in 247/300 (82.3%). CONCLUSION: During the malaria epidemic in Eastern Uganda, severe malaria affected much older children and the spectrum had more of prostration, jaundice severe malarial anaemia, black water fever and multiple convulsions with less of earlier reported respiratory distress and cerebral malaria.

A cluster randomised trial to evaluate the effectiveness of household alcohol-based hand rub for the prevention of sepsis, diarrhoea, and pneumonia in Ugandan infants (the BabyGel trial): a study protocol.

BACKGROUND: Infections are one of the leading causes of death in the neonatal period. This trial aims to evaluate if the provision of alcohol-based hand rub (ABHR) to pregnant women for postnatal household use prevents severe infections (including sepsis, diarrhoea, pneumonia, or death) among infants during the first three postnatal months. METHODS: Through a cluster-randomised trial in eastern Uganda, 72 clusters are randomised in a 2-arm design with rural villages as units of randomisation. We estimate to include a total of 5932 pregnant women at 34 weeks of gestation. All women and infants in the study are receiving standard antenatal and postnatal care. Women in the intervention group additionally receive six litres of ABHR and training on its use. Research midwives conduct follow-up visits at participants' homes on days 1, 7, 28, 42, and 90 after birth and telephone calls on days 14, 48, and 60 to assess the mother and infant for study outcomes. Primary analyses will be by intention to treat. DISCUSSION: This study will provide evidence on the effectiveness of a locally available and low-cost intervention in preventing neonatal sepsis and early infant infections. If ABHR is found effective, it could be implemented by adding it to birthing kits. TRIAL REGISTRATION: Pan African Clinical Trial Registry, PACTR202004705649428. Registered 1 April 2020, https://pactr.samrc.ac.za/ .

Adherence to severe malaria treatment guidelines in children at a Ugandan regional hospital: a baseline assessment for a malaria treatment quality improvement project.

BACKGROUND: Malaria is one of the most common causes of hospital admission and death in children under the age of five. The World Health Organization (WHO) has issued guidelines for the identification and treatment of severe malaria. Evidence has shown that adherence to standardized malaria treatment protocols improves outcomes. As a baseline assessment in preparation for a malaria treatment quality improvement project, this study aimed to determine adherence to the WHO severe malaria treatment guidelines in children at a Ugandan Regional Referral Hospital. METHODS: A retrospective review was performed on a convenience sample of children discharged between June 2021 and March 2022 from the Mbale Regional Referral Hospital Paediatrics Ward with a diagnosis of severe malaria. Data were collected using a standardized case report form. Demographics, presenting symptoms, laboratory results, treatments, length of stay, and mortality were extracted. Comparison of treatments received to items recommended in the WHO guidelines was undertaken to determine adherence. RESULTS: 147 patients were included. The median age was 5 years (IQR 2-7 years), and 55% were male. The most common features of severe malaria were haemoglobinuria (49%), haemoglobin < 5 mg/dL (34%), and altered mentation (24%). Median hospital length of stay was 3 days (IQR 2-4 days), and the mortality rate was 27% (n = 40). Overall adherence to all aspects of the WHO severe malaria guidelines was achieved in 3% (n = 4) of patients. The most common areas of deficiency were not testing to confirm malaria diagnosis (34%) and inadequate administration of artesunate (82%). Fewer than the three recommended doses of artesunate occurred in 22% of patients. Additionally, a delay in the administration of the second dose occurred in 67% (n = 78) and in the third dose in 77% (n = 71) of patients. While the recommended time between doses is 12 h, the median interval between dose one and dose two was 15 h (12-20) and the median interval from dose two to dose three was 17 h (14-25). CONCLUSIONS: Current adherence to severe malaria treatment guidelines in children at this Ugandan regional referral hospital is poor, but this study has identified target areas for improvement.

Safety of age-dosed, single low-dose primaquine in children with glucose-6-phosphate dehydrogenase deficiency who are infected with Plasmodium falciparum in Uganda and the Democratic Republic of the Congo: a randomised, double-blind, placebo-controlled, non-inferiority trial.

BACKGROUND: WHO recommends gametocytocidal, single low-dose primaquine for blocking the transmission of Plasmodium falciparum; however, safety concerns have hampered the implementation of this strategy in sub-Saharan Africa. We aimed to investigate the safety of age-dosed, single low-dose primaquine in children from Uganda and the Democratic Republic of the Congo. METHODS: We conducted this randomised, double-blind, placebo-controlled, non-inferiority trial at the Mbale Regional Referral Hospital, Mbale, Uganda, and the Kinshasa Mahidol Oxford Research Unit, Kinshasa, Democratic Republic of the Congo. Children aged between 6 months and 11 years with acute uncomplicated P falciparum infection and haemoglobin concentrations of at least 6 g/dL were enrolled. Patients were excluded if they had a comorbid illness requiring inpatient treatment, were taking haemolysing drugs for glucose-6-phosphate dehydrogenase (G6PD) deficiency, were allergic to the study drugs, or were enrolled in another clinical trial. G6PD status was defined by genotyping for the G6PD c.202T allele, the cause of the G6PD-deficient A- variant. Participants were randomly assigned (1:1) to receive single low-dose primaquine combined with either artemether-lumefantrine or dihydroartemisinin-piperaquine, dosed by bodyweight. Randomisation was stratified by age and G6PD status. The primary endpoint was the development of profound (haemoglobin <4 g/dL) or severe (haemoglobin <5 g/dL) anaemia with severity features, within 21 days of treatment. Analysis was by intention to treat. The sample size assumed an incidence of 1·5% in the placebo group and a 3% non-inferiority margin. The trial is registered at ISRCTN, 11594437, and is closed to new participants. FINDINGS: Participants were recruited at the Mbale Regional Referral Hospital between Dec 18, 2017, and Oct 7, 2019, and at the Kinshasa Mahidol Oxford Research Unit between July 17, 2017, and Oct 5, 2019. 4620 patients were assessed for eligibility. 3483 participants were excluded, most owing to negative rapid diagnostic test or negative malaria slide (n=2982). 1137 children with a median age of 5 years were enrolled and randomly assigned (286 to the artemether-lumefantrine plus single low-dose primaquine group, 286 to the artemether-lumefantrine plus placebo group, 283 to the dihydroartemisinin-piperaquine plus single low-dose primaquine group, and 282 to the dihydroartemisinin-piperaquine plus placebo group). Genotyping of G6PD identified 239 G6PD-c.202T hemizygous males and 45 G6PD-c.202T homozygous females (defining the G6PD-deficient group), 119 heterozygous females, 418 G6PD-c.202C normal males and 299 G6PD-c.202C normal females (defining the non-G6PD-deficient group), and 17 children of unknown status. 67 patients were lost to follow-up and four patients withdrew during the study-these numbers were similar between groups. No participants developed profound anaemia and three developed severe anaemia: from the G6PD-deficient group, none (0%) of 133 patients who received placebo and one (0·66%) of 151 patients who received primaquine (difference -0·66%, 95% CI -1·96 to 0·63; p=0·35); and from the non-G6PD-deficient group, one (0·23%) of 430 patients who received placebo and one (0·25%) of 407 patients who received primaquine (-0·014%, -0·68 to 0·65; p=0·97). INTERPRETATION: Gametocytocidal, age-dosed, single low-dose primaquine was well tolerated in children from Uganda and the Democratic Republic of the Congo who were infected with P falciparum, and the safety profile of this treatment was similar to that of the placebo. These data support the wider implementation of single low-dose primaquine in Africa. FUNDING: UK Government Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust Joint Global Health Trials Scheme.

Hydroxyurea treatment is associated with lower malaria incidence in children with sickle cell anemia in sub-Saharan Africa.

Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) provides hydroxyurea at maximum tolerated dose (MTD) for children with sickle cell anemia (SCA) in sub-Saharan Africa. Beyond reducing SCA-related clinical events, documented treatment benefits include ∼50% reduction in malaria incidence. To identify associations and propose mechanisms by which hydroxyurea could be associated with lower malaria rates, infections were recorded across all clinical sites (Angola, Democratic Republic of Congo, Kenya, and Uganda). Hazard ratios (HR) with 95% confidence intervals (CIs) for baseline demographics, and time-varying laboratory and clinical parameters were estimated in a modified Cox gap-time model for repeated events. Over 3387 patient-years of hydroxyurea treatment, 717 clinical malaria episodes occurred in 336 of 606 study participants; over half were confirmed by blood smear and/or rapid diagnostic testing with 97.8% Plasmodium falciparum. In univariate analysis limited to 4 confirmed infections per child, malaria risk was significantly associated with absolute neutrophil count (ANC), splenomegaly, hemoglobin, and achieving MTD; age, malaria season, MTD dose, fetal hemoglobin, α-thalassemia, and glucose-6-phosphate dehydrogenase deficiency had no effect. In multivariable regression of confirmed infections, ANC was significant (HR, 1.37 per doubled value; 95% CI, 1.10-1.70; P = .0052), and ANC values <3.0 × 109/L were associated with lower malaria incidence. Compared with nonpalpable spleen, 1- to 4-cm splenomegaly also was associated with higher malaria risk (HR, 2.01; 95% CI, 1.41-2.85; P = .0001). Hydroxyurea at MTD is associated with lower malaria incidence in SCA through incompletely defined mechanisms, but treatment-associated mild myelosuppression with ANC <3.0 × 109/L is salutary. Splenomegaly is an unexplained risk factor for malaria infections among children with SCA in Africa.

Characteristics, treatment outcomes and experiences of COVID-19 patients under home-based care in Kapelebyong district in Uganda: a mixed-methods study.

BACKGROUND: A rapid increase in community transmission of COVID-19 across the country overwhelmed Uganda's health care system. In response, the Ministry of Health adopted the home-based care strategy for COVID-19 patients with mild-to-moderate disease. We determined the characteristics, treatment outcomes and experiences of COVID-19 patients under home-based care during the second wave in Kapelebyong district, in eastern Uganda. METHODS: We conducted a sequential explanatory mixed-methods study. We first collected quantitative data using an interviewer-administered questionnaire to determine characteristics and treatment outcomes of COVID-19 patients under home-based care. Cured at home was coded as 1 (considered a good outcome) while being admitted to a health facility and/or dying were coded as 0 (considered poor outcomes). Thereafter, we conducted 11 in-depth interviews to explore the experiences of COVID-19 patients under home-based care. Multivariable logistic regression was used to assess factors associated with poor treatment outcomes using Stata v.15.0. Thematic content analysis was used to explore lived experiences of COVID-19 patients under home-based care using NVivo 12.0.0 RESULTS: A total of 303 study participants were included. The mean age ± standard deviation of participants was 32.2 years ± 19.9. Majority of the participants [96.0% (289/303)] cured at home, 3.3% (10/303) were admitted to a health facility and 0.7% (2/303) died. Patients above 60 years of age had 17.4 times the odds of having poor treatment outcomes compared to those below 60 years of age (adjusted odds ratio (AOR): 17.4; 95% CI: 2.2-137.6). Patients who spent more than one month under home-based care had 15.3 times the odds of having poor treatment outcomes compared to those that spent less than one month (AOR: 15.3; 95% CI: 1.6-145.7). From the qualitative interviews, participants identified stigma, fear, anxiety, rejection, not being followed up by health workers and economic loss as negative experiences encountered during home-based care. Positive lived experiences included closeness to friends and family, more freedom, and easy access to food. CONCLUSION: Home-based care of COVID-19 was operational in eastern Uganda. Older age (> 60 years) and prolonged illness (> 1 months) were associated with poor treatment outcomes. Social support was an impetus for home-based care.