Professor
Professor Peter Olupot-Olupot
Project Title
Strengthening Malaria Epidemiological, Pathophysiological and Intervention Studies in Highly Endemic Eastern Uganda
EDCTP Project
TMA2016SF1514
EDCTP Program
EDCTP2
EDCTP Project Call
Senior Fellowship (SF)
Project Objectives
1. To conduct epidemiological studies on acute kidney injury in childhood severe malaria at Mbale Regional Referral Hospital to characterise the disease over a period of 48months. 2. To describe the pathophysiology of haemoglobinuric malaria at Mbale Regional Referral Hospital to understanding the disease process. a. To explore the dose and effect of paracetamol in treatment of renal impairment in children with haemoglobinuric malaria. b. To train two junior researchers in malaria research including clinical trials. 3. To study safety and early efficacy of paracetamol in ameliorating acute kidney injury in children with severe malaria.
Study Design
Prospective cross sectional studies are being conducted for malaria epidemiological and pathophysiological studies. Phase I/II randomised clinical trial will be conducted for evaluation of feasibility, safety and early effectiveness of paracetamol for treatment of AKI
Project Summary
Severe malaria remains a public health problem despite intense implementation of multipronged preventative methods and effective antimalarial drugs in the past decade. In the sub Saharan Africa, the disease killed an estimated 475,000 children in 2013, especially in the under 5year olds. Malaria research is priority in the draft Uganda National Research Agenda (2015). However, capacity to initiate and conduct high quality clinical research on malaria in Uganda still lags behind that in other areas such as HIV. There is a paucity of data especially from applied malaria research. These trends suggest limited capacity to conduct comprehensive high quality malaria research. Evidently, trials in general constitute only 16% of all clinical research conducted in Uganda, and about 5% of all research registered by the Uganda National Council for Science and Technology (UNCST). Trials on malaria remain among the least in number. Of these malaria trials, research questions are often formulated with little involvement of the local Uganda collaborators, or consultation of the country’s research. The methods in this Senior Fellowship include a number of approaches. Firstly, to systematically deliver on the research aims and objectives of this project. Secondly, in a “Target-Indicator-Activity” framework, I will work with my mentors to strengthen my research capacity on malaria through achievement of clear milestones on specifically needed skills and competences on epidemiology, pathophysiology and conduct of Phase I/II clinical trials. And lastly, to build research capacity through hands-on mentorship training of 2 masters’ students selected to tackle complementary fields in malaria research with the aim of contributing to the building of a vibrant research team in Eastern Uganda (www.mcru.ac.ug). Using this framework we will conduct studies on: (i). Malaria epidemiology. (ii). Epidemiology and Pathophysiology of Acute Kidney Injury (AKI) in childhood severe malaria, and (iii) A nested clinical trial on feasibility of use of paracetamol in ameliorating AKI in children with haemoglobinuric severe malaria. We will use each of the above (i) – (iii) study areas as practicum training areas for hands-on mentorship of two masters students on malaria and clinical trials. We target 5 key publications from our work including a publication on malaria epidemiology, pathophysiology, acute kidney injury in severe malaria, outcomes of phase I/II study on paracetamol in acute kidney injury in severe malaria and methods of capacity building through hands-on training in resources limited setting. These publications will inform academia, practice and design of future clinical trials on malaria. The Senior Fellow will in addition acquire skills in advanced research methods and applied epidemiology.
Host Organisation
| Department | Institution | Country |
|---|---|---|
| Clinical | Mbale Regional Referral Hospital | Uganda |
Sites
Current Organisation
Busitema University/Mbale Clinical Research Institute
Current Job Title
Professor/Clinical Scientist
Biography
Publications
Neonatal tetanus remains a significant, yet avoidable, cause of neonatal death. Despite the 34,000 deaths that occur globally from neonatal tetanus every year, there has been little research into the management of neonatal tetanus. Until worldwide elimination of neonatal tetanus is achieved, the case management of this devastating illness needs to be improved. We describe an improved outcome of neonatal tetanus following the introduction of a neonatal tetanus protocol including diazepam, magnesium sulphate, bubble continuous positive airway pressure and broad-spectrum antibiotics in a low-resource setting in eastern Uganda.
Background: Severe anemia (hemoglobin level, <6 g per deciliter) is a leading cause of hospital admission and death in children in sub-Saharan Africa. The World Health Organization recommends transfusion of 20 ml of whole-blood equivalent per kilogram of body weight for anemia, regardless of hemoglobin level.
Methods: In this factorial, open-label trial, we randomly assigned Ugandan and Malawian children 2 months to 12 years of age with a hemoglobin level of less than 6 g per deciliter and severity features (e.g., respiratory distress or reduced consciousness) to receive immediate blood transfusion with 20 ml per kilogram or 30 ml per kilogram. Three other randomized analyses investigated immediate as compared with no immediate transfusion, the administration of postdischarge micronutrients, and postdischarge prophylaxis with trimethoprim-sulfamethoxazole. The primary outcome was 28-day mortality.
Results: A total of 3196 eligible children (median age, 37 months; 2050 [64.1%] with malaria) were assigned to receive a transfusion of 30 ml per kilogram (1598 children) or 20 ml per kilogram (1598 children) and were followed for 180 days. A total of 1592 children (99.6%) in the higher-volume group and 1596 (99.9%) in the lower-volume group started transfusion (median, 1.2 hours after randomization). The mean (±SD) volume of total blood transfused per child was 475±385 ml and 353±348 ml, respectively; 197 children (12.3%) and 300 children (18.8%) in the respective groups received additional transfusions. Overall, 55 children (3.4%) in the higher-volume group and 72 (4.5%) in the lower-volume group died before 28 days (hazard ratio, 0.76; 95% confidence interval [CI], 0.54 to 1.08; P = 0.12 by log-rank test). This finding masked significant heterogeneity in 28-day mortality according to the presence or absence of fever (>37.5°C) at screening (P=0.001 after Sidak correction). Among the 1943 children (60.8%) without fever, mortality was lower with a transfusion volume of 30 ml per kilogram than with a volume of 20 ml per kilogram (hazard ratio, 0.43; 95% CI, 0.27 to 0.69). Among the 1253 children (39.2%) with fever, mortality was higher with 30 ml per kilogram than with 20 ml per kilogram (hazard ratio, 1.91; 95% CI, 1.04 to 3.49). There was no evidence of differences between the randomized groups in readmissions, serious adverse events, or hemoglobin recovery at 180 days.
Conclusions: Overall mortality did not differ between the two transfusion strategies. (Funded by the Medical Research Council and Department for International Development, United Kingdom; TRACT Current Controlled Trials number, ISRCTN84086586.).
Malnutrition is a major concern in low- and middle-income countries (LMIC), but the full extent of nutritional deficiencies remains unknown largely due to lack of accurate assessment methods. This study seeks to develop and validate an objective, passive method of estimating food and nutrient intake in households in Ghana and Uganda. Household members (including under-5s and adolescents) are assigned a wearable camera device to capture images of their food intake during waking hours. Using custom software, images captured are then used to estimate an individual's food and nutrient (i.e., protein, fat, carbohydrate, energy, and micronutrients) intake. Passive food image capture and assessment provides an objective measure of food and nutrient intake in real time, minimizing some of the limitations associated with self-reported dietary intake methods. Its use in LMIC could potentially increase the understanding of a population's nutritional status, and the contribution of household food intake to the malnutrition burden. This project is registered at clinicaltrials.gov (NCT03723460).
The authors reply: At screening, all the children in the TRACT trial were tested for malaria by means of rapid diagnostic tests and were then treated if the results were positive. In the two trials, we found no evidence that Plasmodium falciparum malaria affected the relative difference in 28-day mortality (the primary end point in both trials) between immediate transfusion and no immediate transfusion (P=0.18 for heterogeneity) or between transfusion with 30 ml per kilogram or 20 ml per kilogram (P=0.13 for heterogeneity). (Details are provided in Fig. S7 and Fig. S4 of the Supplementary Appendixes accompanying the respective articles.)
Furthermore, malaria positivity did not explain the strong interaction between fever at screening and the effect of the transfusion volume of 30 ml per kilogram on 28-day mortality. Among the children without fever, estimates of benefits regarding mortality at 28 days for the volume of 30 ml per kilogram, as compared with the volume of 20 ml per kilogram, were similar in those with malaria (hazard ratio, 0.66; 95% confidence interval [CI], 0.36 to 1.21) and in those without malaria (hazard ratio, 0.24; 95% CI, 0.10 to 0.53). Among the children with fever, estimates of harms regarding mortality at 28 days were also similar in those with malaria (hazard ratio, 1.99; 95% CI, 0.85 to 4.66) and in those without malaria (hazard ratio, 1.77; 95% CI, 0.75 to 4.18). Finally, in malaria-endemic regions, blood donors (predominantly adults and older children) are largely immune to malaria, so the prevalence of malaria among donors is low (<1.5%).1 Consequently, the use of costly pathogen-inactivation techniques and high-sensitivity malaria screening is unlikely to add benefit.
Kathryn Maitland, M.D., Ph.D.
Imperial College London, London, United Kingdom
k.maitland@imperial.ac.uk
Peter Olupot-Olupot, M.B., Ch.B., Ph.D.
Mbale Regional Referral Hospital, Mbale, Uganda
A. Sarah Walker, Ph.D.
Medical Research Council Clinical Trials Unit at University College London, London, United Kingdom
Since publication of their articles, the authors report no further potential conflict of interest.
Background: In Uganda to date, there are neither established registries nor descriptions of facility-based sickle cell disease (SCD) patient characteristics beyond the central region. Here, we summarize data on the baseline clinical characteristics and routine care available to patients at four clinics in Eastern Uganda as a prelude to a clinical trial. Methods: Between February and August 2018, we conducted a cross-sectional survey of patients attending four SCD clinics in Mbale, Soroti, Atutur and Ngora, all in Eastern Uganda, the planned sites for an upcoming clinical trial (H-PRIME: ISRCTN15724013). Data on socio-demographic characteristics, diagnostic methods, clinic schedules, the use of prophylactic and therapeutic drugs, clinical complications and patient understanding of SCD were collected using a structured questionnaire. Results: Data were collected on 1829 patients. Their ages ranged from 0 to 64 years with a median (IQR) of 6 (3-11) years. 49.1% of participants were male. The majority (1151; 62.9%) reported a positive family history for SCD. Approximately half knew that SCD is inherited from both parents but a substantial proportion did not know how SCD is transmitted and small numbers believed that it is acquired by either transfusion or from other people. Only 118/1819 (6.5%) participants had heard about or were using hydroxyurea while 356/1794 (19.8%) reported stigmatization. Participants reported a median of three (IQR 1-4) hospital admissions during the preceding 12 months; 80.8% had been admitted at least once, while 14.2% had been admitted more than five times. Pain was the most common symptom, while 83.9% of those admitted had received at least one blood transfusion. Conclusion:The majority of patients attending SCD clinics in Eastern Uganda are children and few are currently being treated with hydroxyurea. The data collected through this facility-based survey will provide background data that will be useful in planning for the H-PRIME trial.
Postinfectious hydrocephalus (PIH), which often follows neonatal sepsis, is the most common cause of pediatric hydrocephalus worldwide, yet the microbial pathogens underlying this disease remain to be elucidated. Characterization of the microbial agents causing PIH would enable a shift from surgical palliation of cerebrospinal fluid (CSF) accumulation to prevention of the disease. Here, we examined blood and CSF samples collected from 100 consecutive infant cases of PIH and control cases comprising infants with non-postinfectious hydrocephalus in Uganda. Genomic sequencing of samples was undertaken to test for bacterial, fungal, and parasitic DNA; DNA and RNA sequencing was used to identify viruses; and bacterial culture recovery was used to identify potential causative organisms. We found that infection with the bacterium Paenibacillus, together with frequent cytomegalovirus (CMV) coinfection, was associated with PIH in our infant cohort. Assembly of the genome of a facultative anaerobic bacterial isolate recovered from cultures of CSF samples from PIH cases identified a strain of Paenibacillus thiaminolyticus This strain, designated Mbale, was lethal when injected into mice in contrast to the benign reference Paenibacillus strain. These findings show that an unbiased pan-microbial approach enabled characterization of Paenibacillus in CSF samples from PIH cases, and point toward a pathway of more optimal treatment and prevention for PIH and other proximate neonatal infections.
Background: The World Health Organization recommends not performing transfusions in African children hospitalized for uncomplicated severe anemia (hemoglobin level of 4 to 6 g per deciliter and no signs of clinical severity). However, high mortality and readmission rates suggest that less restrictive transfusion strategies might improve outcomes.
Methods: In this factorial, open-label, randomized, controlled trial, we assigned Ugandan and Malawian children 2 months to 12 years of age with uncomplicated severe anemia to immediate transfusion with 20 ml or 30 ml of whole-blood equivalent per kilogram of body weight, as determined in a second simultaneous randomization, or no immediate transfusion (control group), in which transfusion with 20 ml of whole-blood equivalent per kilogram was triggered by new signs of clinical severity or a drop in hemoglobin to below 4 g per deciliter. The primary outcome was 28-day mortality. Three other randomizations investigated transfusion volume, postdischarge supplementation with micronutrients, and postdischarge prophylaxis with trimethoprim-sulfamethoxazole.
Results: A total of 1565 children (median age, 26 months) underwent randomization, with 778 assigned to the immediate-transfusion group and 787 to the control group; 984 children (62.9%) had malaria. The children were followed for 180 days, and 71 (4.5%) were lost to follow-up. During the primary hospitalization, transfusion was performed in all the children in the immediate-transfusion group and in 386 (49.0%) in the control group (median time to transfusion, 1.3 hours vs. 24.9 hours after randomization). The mean (±SD) total blood volume transfused per child was 314±228 ml in the immediate-transfusion group and 142±224 ml in the control group. Death had occurred by 28 days in 7 children (0.9%) in the immediate-transfusion group and in 13 (1.7%) in the control group (hazard ratio, 0.54; 95% confidence interval [CI], 0.22 to 1.36; P = 0.19) and by 180 days in 35 (4.5%) and 47 (6.0%), respectively (hazard ratio, 0.75; 95% CI, 0.48 to 1.15), without evidence of interaction with other randomizations (P>0.20) or evidence of between-group differences in readmissions, serious adverse events, or hemoglobin recovery at 180 days. The mean length of hospital stay was 0.9 days longer in the control group.
Conclusions: There was no evidence of differences in clinical outcomes over 6 months between the children who received immediate transfusion and those who did not. The triggered-transfusion strategy in the control group resulted in lower blood use; however, the length of hospital stay was longer, and this strategy required clinical and hemoglobin monitoring. (Funded by the Medical Research Council and Department for International Development; TRACT Current Controlled Trials number, ISRCTN84086586.).
Background: Adolescent medicine (AM) has been increasingly recognized as critically important to the health of individuals during their transition to adulthood. On a global scale, AM is often underprioritized and underfunded. In low- and middle-income countries (LMICs), education and AM training is developing, and AM physicians often are from general medicine backgrounds.
Objective: The objective of our scoping review was to identify existing training curricula and educational tools designed to teach AM skills to health care workers in LMICs.
Methods: We followed PRISMA guidelines for scoping reviews for article identification and inclusion. Online databases, including MEDLINE, Embase, CINAHL, and Scopus, were used to identify papers. We included studies that took place in a LMIC, were available in English, and described any of the following: published educational curricula in AM, education-based intervention for HCWs that focused on AM, or a training opportunity in AM located in a LMIC.
Results: Our review includes 14 publications: 5 published curricula and 9 articles describing educational interventions or training opportunities in AM in LMICs. Curricula were relatively consistent in the topics included, although they varied in implementation and teaching strategies. The scholarly articles described educational materials and identified a number of innovative strategies for training programs.
Conclusions: Our review found existing high-quality AM curricula designed for LMICs. However, there is limited published data on their implementation and utilization. There is a continued need for funding and implementation of education in AM in resource-constrained settings.
Background: Few recent descriptions of severe childhood malaria have been published from high-transmission regions. In the current study, the clinical epidemiology of severe malaria in Mbale, Eastern Uganda, is described, where the entomological inoculation rate exceeds 100 infective bites per year.
Methods: A prospective descriptive study was conducted to determine the prevalence, clinical spectrum and outcome of severe Plasmodium falciparum malaria at Mbale Regional Referral Hospital in Eastern Uganda. All children aged 2 months-12 years who presented on Mondays to Fridays between 8.00 am and 5.00 pm from 5th May 2011 until 30th April 2012 were screened for parasitaemia. Clinical and laboratory data were then collected from all P. falciparum positive children with features of WHO-defined severe malaria by use of a standardized proforma.
Results: A total of 10 208 children were screened of which 6582 (64%) had a positive blood film. Of these children, 662 (10%) had clinical features of severe malaria and were consented for the current study. Respiratory distress was the most common severity feature (554; 83.7%), while 365/585 (62.4%) had hyperparasitaemia, 177/662 (26.7%) had clinical jaundice, 169 (25.5%) had severe anaemia, 134/660 (20.2%) had hyperlactataemia (lactate ≥ 5 mmol/L), 93 (14.0%) had passed dark red or black urine, 52 (7.9%) had impaired consciousness and 49/662 (7.4%) had hypoxaemia (oxygen saturations < 90%). In-hospital mortality was 63/662 (9.5%) overall but was higher in children with either cerebral malaria (33.3%) or severe anaemia (19.5%). Factors that were independently associated with mortality on multivariate analysis included severe anaemia [odds ratio (OR) 5.36; 2.16-1.32; P = 0.0002], hyperlactataemia (OR 3.66; 1.72-7.80; P = 0.001), hypoxaemia (OR) 3.64 (95% CI 1.39-9.52; P = 0.008), and hepatomegaly (OR 2.29; 1.29-4.06; P = 0.004). No independent association was found between mortality and either coma or hyperparasitaemia.
Conclusions: Severe childhood malaria remains common in Eastern Uganda where it continues to be associated with high mortality. An unusually high proportion of children with severe malaria had jaundice or gave a history of having recently passed dark red or black urine, an issue worthy of further investigation.
Background: Complications of prematurity are the leading cause of deaths in children under the age of five. The predominant reason for these preterm deaths is respiratory distress syndrome (RDS). In low-income countries (LICs) there are limited treatment options for RDS. Due to their simplicity and affordability, low-cost bubble continuous positive airway pressure (bCPAP) devices have been introduced in neonatal units in LICs to treat RDS. This study is the first observational study from a LIC to compare outcomes of very-low-birth-weight (VLBW) neonates in pre- and post-CPAP periods.
Methods: This was a retrospective study of VLBW neonates (weight < 1500 g) in Mbale Regional Referral Hospital Neonatal Unit (MRRH-NNU), a government hospital in eastern Uganda. It aimed to measure the outcome of VLBW neonates in two distinct study periods: A 14-month period beginning at the opening of MRRH-NNU and covering the period until bCPAP was introduced (pre-bCPAP) and an 18-month period following the introduction of bCPAP (post-bCPAP). After the introduction of bCPAP, it was applied to preterm neonates with RDS when clinically indicated and if a device was available. Clinical features and outcomes of all neonates < 1500 g were compared before and after the introduction of bCPAP.
Results: The admission records of 377 VLBW neonates < 1500 g were obtained. One hundred fifty-eight were admitted in the pre-bCPAP period and 219 in the post-bCPAP period. The mortality rate in the pre- bCPAP period was 39.2% (62/158) compared with 26.5% (58/219, P = 0.012) in the post-bCPAP period. Overall, there was a 44% reduction in mortality (OR 0.56, 95%CI 0.36-0.86, P = 0.01). There were no differences in birthweight, sex, presence of signs of respiratory distress or apnoea between the two groups.
Conclusion: Specialized and resource-appropriate neonatal care, that appropriately addresses the challenges of healthcare provision in LICs, has the potential to reduce neonatal deaths. The use of a low-cost bCPAP to treat RDS in VLBW neonates resulted in a significant improvement in their survival in a neonatal unit in eastern Uganda. Since RDS is one of the leading causes of neonatal mortality, it is possible that this relatively simple and affordable intervention could have a huge impact on global neonatal mortality.
Background: Severe anaemia is a leading cause of paediatric admission to hospital in Africa; post-discharge outcomes remain poor, with high 6-month mortality (8%) and re-admission (17%). We aimed to investigate post-discharge interventions that might improve outcomes.
Methods: Within the two-stratum, open-label, multicentre, factorial randomised TRACT trial, children aged 2 months to 12 years with severe anaemia, defined as haemoglobin of less than 6 g/dL, at admission to hospital (three in Uganda, one in Malawi) were randomly assigned, using sequentially numbered envelopes linked to a second non-sequentially numbered set of allocations stratified by centre and severity, to enhanced nutritional supplementation with iron and folate-containing multivitamin multimineral supplements versus iron and folate alone at treatment doses (usual care), and to co-trimoxazole versus no co-trimoxazole. All interventions were administered orally and were given for 3 months after discharge from hospital. Separately reported randomisations investigated transfusion management. The primary outcome was 180-day mortality. All analyses were done in the intention-to-treat population; follow-up was 180 days. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN84086586, and follow-up is complete.
Findings: From Sept 17, 2014, to May 15, 2017, 3983 eligible children were randomly assigned to treatment, and followed up for 180 days. 164 (4%) were lost to follow-up. 1901 (95%) of 1997 assigned multivitamin multimineral supplement, 1911 (96%) of 1986 assigned iron and folate, and 1922 (96%) of 1994 assigned co-trimoxazole started treatment. By day 180, 166 (8%) children in the multivitamin multimineral supplement group versus 169 (9%) children in the iron and folate group had died (hazard ratio [HR] 0·97, 95% CI 0·79-1·21; p=0·81) and 172 (9%) who received co-trimoxazole versus 163 (8%) who did not receive co-trimoxazole had died (HR 1·07, 95% CI 0·86-1·32; p=0·56). We found no evidence of interactions between these randomisations or with transfusion randomisations (p>0·2). By day 180, 489 (24%) children in the multivitamin multimineral supplement group versus 509 (26%) children in the iron and folate group (HR 0·95, 95% CI 0·84-1·07; p=0·40), and 500 (25%) children in the co-trimoxazole group versus 498 (25%) children in the no co-trimoxazole group (1·01, 0·89-1·15; p=0·85) had had one or more serious adverse events. Most serious adverse events were re-admissions, occurring in 692 (17%) children (175 [4%] with at least two re-admissions).
Interpretation: Neither enhanced supplementation with multivitamin multimineral supplement versus iron and folate treatment or co-trimoxazole prophylaxis improved 6-month survival. High rates of hospital re-admission suggest that novel interventions are urgently required for severe anaemia, given the burden it places on overstretched health services in Africa.