Thomas Neil Williams

Quantitative measurement of fetal hemoglobin (HbF) using high-performance liquid chromatography (HPLC) is standard but expensive and widely unavailable in low-income settings. The newer Gazelle™ method, which employs single-use alkaline electrophoresis cartridges, provides a portable and relatively inexpensive potential alternative. In the current study, we tested 3055 venous blood samples collected from 1780 children with sickle cell anemia who were enrolled into the H-PRIME trial by both Gazelle and the Bio-Rad D-10 HPLC instrument, before and during hydroxyurea treatment. Data reinterpretation was required to quantify accurately high HbF values derived using the D-10. Mean (standard deviation) baseline HbF values by HPLC and Gazelle (N=2042) were 11.4% (SD 5.9%) versus 16.3% (SD 7.5%), respectively, while mean on-treatment HbF values (N=1013) were 18.9% (SD 9.0%) versus 25.4% (SD 11.5%), respectively. While overall agreement was good (Lin’s concordance 0.76, 95% CI 0.75-0.78), HbF values derived using Gazelle were modestly higher than HPLC values (Bland-Altman agreement mean +5.4%, 95%CI −2.4% to +13.2%), with the difference between measures increasing at higher HbF percentages. With strong concordance and more easily interpretable HbF values, Gazelle represents an attractive and inexpensive alternative to HPLC for HbF quantification in the low-income settings where most patients with sickle cell anemia live. Key Points: Point-of-care Gazelle electrophoresis compares favorably to standard HPLC hemoglobin separation to quantify fetal hemoglobin. Gazelle HbF quantitation is accurate, inexpensive, and suitable for use in low-income settings including sub-Saharan Africa.

Rotavirus (RV) is a major cause of diarrhoeal disease and mortality in African children. The impact of RV vaccination on child health has been limited by low vaccine effectiveness in resource-constrained settings. We urgently need better vaccines to control RV disease, delivery of which will require an improved understanding of RV biology. We hypothesised that the genetics of RV disease and immunity are likely to be mutually informative of RV biology. We performed genome-wide association studies of infection-induced and vaccine-derived RV immunity, hospitalised RV gastroenteritis (RVGE) risk and all-cause diarrhoeal disease risk in > 3,000 Ugandan, Kenyan and Zambian children. In doing so, we expand on the role of human blood group antigen secretion in RV infection and immunity, resolving complex interactions between secretor status, ABO blood group, Lewis antigen and viral genotype. We further identify a separate, novel locus at chromosome 2q12, rs59241810:T, associated with increased anti-RV IgA responses and lower risk of RVGE and all-cause diarrhoea with dehydration. Variation at rs59241810 regulates monocyte LIMS1 expression, thereby impacting IFNγ-induced hepatocyte growth factor (HGF) secretion, suggesting a role for monocyte-derived HGF in the generation of anti-RV IgA responses. Our data reveal the complex interplay between immunity, disease, pathogen variation and host genetics in RV infections, and identify LIMS1/HGF signalling as a target to design more effective anti-RV vaccines.

Background Sickle cell disease is the most common and severe genetic disease in humans worldwide. The majority of those affected are born in sub-Saharan Africa, where resources to diagnose and manage them are often limited. Fresh approaches to the pragmatic management of children with sickle cell disease in Africa that improve both morbidity and mortality are urgently needed. Methods Hydroxyurea - Pragmatic Reduction In Mortality and Economic burden (H-PRIME) is a 2 × 2 × 2 factorial randomized open-label trial that is investigating three separate interventions. Eighteen hundred children aged 1–10 years attending sickle cell clinics at one of four sites in Eastern Uganda are being randomized to: (1) hydroxyurea administered at a low dose (10 mg/kg/day) versus high dose (25 mg/kg/day), prescribed pragmatically through a weight-band-based approach and with clinically, rather than laboratory-guided monitoring; (2) enhanced malaria prophylaxis with weekly doses of dihydroartemisinin-piperaquine versus monthly doses of sulfadoxine-pyrimethamine (standard of care); and (3) enhanced antibacterial prophylaxis with daily cotrimoxazole throughout life versus twice daily penicillin until the age of 5 years (standard of care). All children will be followed up for 48 months after the date on which the first child was randomized. The primary endpoint for the hydroxyurea randomization will be mortality, for the antimalarial randomization will be malaria-associated hospital admission, and for the antimicrobial randomization will be all-cause hospital admission. Secondary outcomes will include the incidence of sickle-specific complications, receipt of blood transfusions, hemoglobin and fetal hemoglobin concentrations, and economic costs and benefits of the three interventions. Conclusions The first participant was recruited for the trial on January 16, 2024. In total, 1487 of the 1800 target children were recruited by February 17, 2025. H-PRIME will efficiently answer three important pragmatic questions regarding the management of children with sickle cell disease in Africa. Registration PACTR number 202401802272880 (09/01/2024). ISRCTN15724013 (25/02/2020).

Children with sickle cell anemia (SCA) have poor growth and pubertal development. REACH (Realizing Effectiveness Across Continents with Hydroxyurea) is a prospective trial evaluating the feasibility, safety, and benefits of hydroxyurea at maximum tolerated dose (MTD) for children with SCA in sub-Saharan Africa. Children aged 1 to 10 years received open-label hydroxyurea with longitudinal follow-up. Height, weight, and pubertal staging were collected over 7 years of treatment. Biomarkers included insulin-like growth factor I (IGF-I), IGF-binding protein 3, luteinizing hormone, follicle-stimulating hormone, and anti-Mullerian hormone (AMH). Hydroxyurea commenced at an average (mean ± 1 standard deviation [SD]) age of 5.9 ± 2.4 years (range, 1.6-10.2) for girls (n = 296) and 5.4 ± 2.4 years (range, 1.3-10.1) for boys (n = 310). Using natural history SCA-specific reference curves, the mean weight-for-age z score improved from 0.47 ± 0.90 at enrollment to 0.69 ± 1.00 on hydroxyurea treatment. Height increased from 0.26 ± 0.90 to 0.42 ± 1.00 on treatment, and body mass index from 0.46 ± 1.00 to 0.85 ± 1.20. IGF-I remained low in many participants. Puberty was delayed in 25% to 30% of children, with gradual progress on treatment. AMH was low (<2.5th percentile) in 4% of girls, whereas 52% of boys had low AMH at baseline and 28% at follow-up. Long-term hydroxyurea treatment at MTD is associated with beneficial effects on growth with improved weight and height, and does not negatively affect pubertal developmenty in children with SCA in sub-Saharan Africa. This study was registered at www.clinicaltrials.gov initially as NCT01966731 and is now registered as NCT06171217 for long-term follow-up.

In much of sub-Saharan Africa (SSA), malaria remains a key cause of paediatric hospital admission, and makes a substantial contribution to under 5-year mortality, estimated at 600,000 deaths annually. Despite implementing currently effective, fast-acting artemisinin-based combination therapies inpatient mortality for paediatric severe malaria remains unacceptably high at ~8%. The Severe malaria in Africa Research and Trials consortium-Master Adaptive Platform Trial (SMAART-MAP trial (ISRCTN79071535)) is a multi-country trial enrolling children aged >3 months and < 12 years who are admitted to hospital with evidence of Plasmodium falciparum malaria (slide or rapid diagnostic test (RDT) positive and one of the following complications: cerebral malaria (One or more reported seizures with altered consciousness (Blantyre Coma Score, BCS ≤ 4) or presence of coma (BCS ≤2); severe anaemia (haemoglobin 1.5 upper limited of normal). The platform trial is simultaneously evaluating three adjunctive therapies in Phase II trials across SSA, addressing interventions against specific severe malaria complications, specifically, 1) Seizure prophylaxis with levetiracetam for children presenting with cerebral malaria; 2) Whole blood or red cell concentrates transfusion for children presenting with severe anaemia and 3) renal protection with paracetamol (15 mg/kg every 6 hours) in children with renal impairment. The trial is being run in eight hospitals across six African countries (Ghana, Democratic Republic of Congo, Uganda, Kenya, Zambia and Mozambique). Each trial has an early (~72 h) biomarker or clinical therapeutic efficacy endpoint based on putative mechanisms of action. The overarching goal is to identify the most promising interventions to take forward into a large Phase III/IV mortality endpoint trial.

Introduction Heterozygous β-thalassaemia occurs at low frequency in coastal Kenya, but its clinical significance is poorly understood. While some evidence suggests protection against malaria, its influence on childhood health and survival in African children remains unknown. Methods We conducted the prospective analysis of a cohort of 15,077 children recruited at age 3–12 months of age (72 β-thalassaemia heterozygotes and 15,005 controls) and followed passively for disease-specific hospital admission and survival until their fifth birthday. Results β-thalassaemia heterozygotes were more frequently admitted than controls with severe (Hb <5 g/dl) [adjusted Incidence Rate Ratio 5.1 (95% CI 1.3–20.0; P = 0.02)] and moderate (Hb <10 g/dl) anaemia [aIRR 2.3 (95% CI 1.3–3.9; P = 0.004)]. No other significant differences were found. Conclusion Heterozygous β-thalassaemia increased the risk of anaemia-related hospital admissions within this cohort, highlighting the need to investigate the underlying triggers of anaemia in such children.

Sickle Cell Disease (SCD) is highly prevalent in sub‐Saharan Africa. Epidemiological data remain sparse, but regional screening and research initiatives are expanding. Due to genetic, environmental, and socioeconomic factors, the disease course differs markedly from that in high‐income countries. Although mortality is improving and can be further lowered with simple interventions, it remains high, especially among undiagnosed children. Genetic factors, poor healthcare infrastructure, and poverty contribute to disease severity. While recent collaborative programs like SickleInAfrica offer hope, national policies that foster the training of healthcare workers, newborn screening, and access to treatment are crucial to reducing the burden of SCD across the region.

Introduction Heterozygous β-thalassaemia occurs at low frequency in coastal Kenya, but its clinical significance is poorly understood. While some evidence suggests protection against malaria, its influence on childhood health and survival in African children remains unknown. Methods We conducted the prospective analysis of a cohort of 15,077 children recruited at age 3–12 months of age (72 β-thalassaemia heterozygotes and 15,005 controls) and followed passively for disease-specific hospital admission and survival until their fifth birthday. Results β-thalassaemia heterozygotes were more frequently admitted than controls with severe (Hb <5g/dl) [adjusted Incidence Rate Ratio 5.1 (95% CI 1.3-20.0; P=0.02)] and moderate (Hb <10g/dl) anaemia [aIRR 2.3 (95% CI 1.3-3.9; P=0.004)]. No other significant differences were found. Conclusion Heterozygous β-thalassaemia increased the risk of anaemia-related hospital admissions within this cohort, highlighting the need to investigate the underlying triggers of anaemia in such children.

Hydroxyurea provides effective disease-modifying treatment for people with sickle cell anemia (SCA), especially when escalated to maximum tolerated dose (MTD), which has wide interpatient dosing variability due to pharmacokinetic (PK) differences. Whether hydroxyurea PK parameters differ among children with SCA in different global regions is unknown. We compared hydroxyurea PK parameters among children with SCA from 5 clinical trials: HUSTLE (United States), TREAT (United States), NOHARM (Uganda), REACH (Uganda and Kenya), and EXTEND (Jamaica). Key hydroxyurea PK parameters were determined using HdxSim, a validated hydroxyurea PK software program. The results were compared across regions by analysis of variance. PK profiles from 451 children with SCA (146 from the United States, 265 from Africa, and 40 from the Caribbean) were included. Children from Africa had slightly lower volumes of distribution, but absorption rate and clearance were similar across regions. The PK-recommended doses to achieve MTD were statistically different but clinically similar across the United States (26.6 ± 5.9 mg/kg per day), Africa (27.6 ± 6.5 mg/kg per day), and the Caribbean (25.2 ± 4.7 mg/kg per day) (P = .04). In multivariable regression, younger age and increased reticulocyte counts were associated with higher PK-recommended doses. Hydroxyurea PK parameters in children with SCA differ minimally across global populations, predicting clinically similar doses to achieve MTD. Individualized hydroxyurea dosing based on a PK-population model derived from US children with SCA can be used broadly to maximize the benefits of this critical medication in other global populations. These trials were registered at www.ClinicalTrials.gov as #NCT00305175 (HUSTLE), #NCT02286154 (TREAT), #NCT01976416 (NOHARM), #NCT01966731 (REACH), and #NCT02556099 (EXTEND).