Characterising demographics, knowledge, practices and clinical care among patients attending sickle cell disease clinics in Eastern Uganda [version 1; peer review: 1 approved, 1 approved with reservations]

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. 50.9% 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

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

Incidence and predictors of hospital readmission in children presenting with severe anaemia in Uganda and Malawi: a secondary analysis of TRACT trial data

Background: Severe anaemia (haemoglobin < 6 g/dL) is a leading cause of recurrent hospitalisation in African children. We investigated predictors of readmission in children hospitalised with severe anaemia in the TRACT trial (ISRCTN84086586) in order to identify potential future interventions. Methods: Secondary analyses of the trial examined 3894 children from Uganda and Malawi surviving a hospital episode of severe anaemia. Predictors of all-cause readmission within 180 days of discharge were identified using multivariable regression with death as a competing risk. Groups of children with similar characteristics were identified using hierarchical clustering. Results: Of the 3894 survivors 682 (18%) were readmitted; 403 (10%) had ≥2 re-admissions over 180 days. Three main causes of readmission were identified: severe anaemia (n = 456), malaria (n = 252) and haemoglobinuria/dark urine syndrome (n = 165). Overall, factors increasing risk of readmission included HIV-infection (hazard ratio 2.48 (95% CI 1.63–3.78), p < 0.001); ≥2 hospital admissions in the preceding 12 months (1.44(1.19–1.74), p < 0.001); history of transfusion (1.48(1.13–1.93), p = 0.005); and missing ≥1 trial medication dose (proxy for care quality) (1.43 (1.21–1.69), p < 0.001). Children with uncomplicated severe anaemia (Hb 4-6 g/dL and no severity features), who never received a transfusion (per trial protocol) during the initial admission had a substantially lower risk of readmission (0.67(0.47–0.96), p = 0.04). Malaria (among children with no prior history of transfusion) (0.60(0.47–0.76), p < 0.001); younger-age (1.07 (1.03–1.10) per 1 year younger, p < 0.001) and known sickle cell disease (0.62(0.46–0.82), p = 0.001) also decreased risk of readmission. For anaemia re-admissions, gross splenomegaly and enlarged spleen increased risk by 1.73(1.23–2.44) and 1.46(1.18–1.82) respectively compared to no splenomegaly. Clustering identified four groups of children with readmission rates from 14 to 20%. The cluster with the highest readmission rate was characterised by very low haemoglobin (mean 3.6 g/dL). Sickle Cell Disease (SCD) predominated in two clusters associated with chronic repeated admissions or severe, acute presentations in largely undiagnosed SCD. The final cluster had high rates of malaria (78%), severity signs and very low platelet count, consistent with acute severe malaria. Conclusions: Younger age, HIV infection and history of previous hospital admissions predicted increased risk of readmission. However, no obvious clinical factors for intervention were identified. As missing medication doses was highly predictive, attention to care related factors may be important. Trial registration: ISRCTN ISRCTN84086586. Keywords: Severe anaemia, Readmissio

The efficacy of long-lasting nets with declining physical integrity may be compromised in areas with high levels of pyrethroid resistance

Background: Long-lasting insecticide-treated mosquito nets (LLINs) are a primary malaria prevention strategy in sub-Saharan Africa. However, emergence of insecticide resistance threatens the effectiveness of LLINs. Methods. Cross-sectional surveys of LLINs were conducted in houses of seven and four villages in Gem and Bungoma Districts in western Kenya, respectively. Condition (number and area of holes in the nets), number and species of mosquitoes resting inside them, and insecticidal activity of nets were quantified. Mosquitoes collected inside nets were allowed to lay eggs and progeny tested for susceptibility to deltamethrin and permethrin, pyrethoids commonly deployed in LLINs in western Kenya. Results: In Gem, 83.3% of nets were less than three years old and 32.4% had at least one hole of any size; while in Bungoma, 92% were less than three years old and 48% had at least one hole. No anopheline and five Culex spp. mosquitoes were found resting inside nets in Gem regardless of the number and size of holes, while 552 Anopheles gambiae s.l., five Anopheles funestus s.l. and 137 Culex spp. were in nets in Bungoma. The number of mosquitoes resting inside nets increased with hole areas &gt;50 cm in Bungoma. In WHO resistance assays, f1 offspring of samples collected in nets in Bungoma were 94 and 65% resistant to deltamethrin and permethrin, respectively. Nets from Bungoma retained strong activity against a susceptible laboratory strain, but not against f1 offspring of field-collected An. gambiae s.s. All An. gambiae s.s. samples collected in nets were homozygous for the kdr genotype L1014S. Conclusions: In areas with pyrethroid resistant vectors, LLINs with modest hole areas permit mosquito entry and feeding, providing little protection against the vectors. LLIN formulations develop large holes within three years of use, diminishing their presupposed lifetime effectiveness. © 2013 Ochomo et al.; licensee BioMed Central Ltd

Occurrence, abundance and distribution of benthic macroinvertebrates in the Nyando River catchment, Kenya

A baseline study was conducted of the occurrence of macroinvertebrates at 26 sites in the Nyando River catchment in 2005-2006. A total of 13 orders and 16 families of Arthropoda, Mollusca, Platyhelminthes and Annelida were collected, with the order Ephemeroptera being most abundant in the up- and mid-stream reaches, followed by Hemiptera and Plecoptera respectively. The downstream sections of the river were dominated by Hirudinea and tubificids, as the water quality deteriorated mainly due to local land use, raw sewage effluent discharge and annual floods. Insects and annelids were the main invertebrates found and the extent of pollution increased from mid-section (Site 15) downwards as the river flowed into the Winam Gulf. Stringent management measures are required to safeguard the environment and ecosystems of Lake Victoria.Funding Agencies|International Foundation for Science (IFS) [W3982-1]; Higher Education Loans Board (HELB), Kenya</p

Characterising demographics, knowledge, practices and clinical care among patients attending sickle cell disease clinics in Eastern Uganda

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

Characterising demographics, knowledge, practices and clinical care among patients attending sickle cell disease clinics in Eastern Uganda [version 2; peer review: 2 approved]

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

A randomised, double-blind, placebo-controlled, non-inferiority trial to assess the safety of age-dosed single low dose primaquine in falciparum-infected African children with G6PD deficiency

Background: The WHO recommends gametocytocidal, single low dose primaquine (SLDPQ) for blocking Plasmodium falciparum transmission but safety concerns have hampered implementation in Sub-Saharan Africa. We, therefore, investigated the safety of age-dosed SLDPQ. Methods: We conducted a randomised, double-blind, placebo-controlled, non-inferiority trial of SLDPQ combined with either artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DHAPP) in Ugandan and Congolese children aged 6m−11y with acute uncomplicated P. falciparum and haemoglobin (Hb) concentrations ≥ 6 g/dL. A comorbid illness requiring inpatient treatment, on haemolysing drugs in glucose-6-phosphate dehydrogenase deficiency (G6PDd), allergy to study drugs, and enrolment in another trial excluded participation. G6PD status was defined by genotyping for the c.202T A- G6PDd allele. Randomisation was stratified by age and G6PD status. The development of profound (Hb <4 g/dL) or severe anaemia (Hb <5 g/dL) with severity features, within 21 days of treatment, defined the primary end point. The sample size assumed a 1·5% incidence in the placebo arm and a 3% non-inferiority margin. Analysis was by intention to treat. Findings: 1,137 children, median age 5y, were recruited: 286 AL+SLDPQ, 286 AL+Placebo, 283 DHAPP+SLDPQ and 282 DHAPP+Placebo (266, 272, 264, 264 completed the study, respectively): 239 G6PD-c.202T hemizygous males and 45 G6PD-c.202T homozygous females (G6PDd group), 119 heterozygous females, 418 G6PD-c.202C normal males (n=418) and females (n=299), and unknown status 17. None developed profound anaemia and three severe anaemia: G6PDd group 0/133 (0%, Placebo) vs. 1/151 (0·66%, SLDPQ): ∆= -0·66% (95% CI -1·96%, 0·63%, p=0·35), and nonG6PDd group: 1/430 (0·23%, Placebo) vs. 1/407 (0·25%, SLDPQ): ∆= -0·014% (95% CI -0·68%, 0·65%; p=0·97). Ten [0·88 (0·42, 1·61%)] patients were transfused in the first week; four had G6PDd. Early vomiting rates (p=0·525) were 22/568 [3·9 (2·4, 5·8)%, Placebo] vs. 18/569 [3·2 (1·9, 5·0)%, SLDPQ]. Interpretation: Gametocytocidal, age-dosed SLDPQ was well tolerated in falciparum-infected African children and had a similar safety profile as placebo. These data support the wider implementation of SLDPQ in Africa. Funding: The study was funded by the Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust through the Joint Global Health Trials Scheme (Grant Ref: MR/P006973/1

The efficacy of long-lasting nets with declining physical integrity may be compromised in areas with high levels of pyrethroid resistance

BACKGROUND: Long-lasting insecticide-treated mosquito nets (LLINs) are a primary malaria prevention strategy in sub-Saharan Africa. However, emergence of insecticide resistance threatens the effectiveness of LLINs. METHODS: Cross-sectional surveys of LLINs were conducted in houses of seven and four villages in Gem and Bungoma Districts in western Kenya, respectively. Condition (number and area of holes in the nets), number and species of mosquitoes resting inside them, and insecticidal activity of nets were quantified. Mosquitoes collected inside nets were allowed to lay eggs and progeny tested for susceptibility to deltamethrin and permethrin, pyrethoids commonly deployed in LLINs in western Kenya. RESULTS: In Gem, 83.3% of nets were less than three years old and 32.4% had at least one hole of any size; while in Bungoma, 92% were less than three years old and 48% had at least one hole. No anopheline and five Culex spp. mosquitoes were found resting inside nets in Gem regardless of the number and size of holes, while 552 Anopheles gambiae s.l., five Anopheles funestus s.l. and 137 Culex spp. were in nets in Bungoma. The number of mosquitoes resting inside nets increased with hole areas >50 cm in Bungoma. In WHO resistance assays, f1 offspring of samples collected in nets in Bungoma were 94 and 65% resistant to deltamethrin and permethrin, respectively. Nets from Bungoma retained strong activity against a susceptible laboratory strain, but not against f1 offspring of field-collected An. gambiae s.s. All An. gambiae s.s. samples collected in nets were homozygous for the kdr genotype L1014S. CONCLUSIONS: In areas with pyrethroid resistant vectors, LLINs with modest hole areas permit mosquito entry and feeding, providing little protection against the vectors. LLIN formulations develop large holes within three years of use, diminishing their presupposed lifetime effectiveness