Imperial College London

Professor Thomas N Williams

Faculty of MedicineDepartment of Surgery & Cancer

Chair in Haemoglobinopathy Research
 
 
 
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Contact

 

tom.williams Website

 
 
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Location

 

Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
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353 results found

Power-Hays A, Tomlinson GA, Tshilolo L, Santos B, Williams TN, Olupot-Olupot P, Smart LR, Aygun B, Lane A, Stuber SE, Latham T, Ware REet al., 2024, Reducing transfusion utilization for children with sickle cell anemia in sub-Saharan Africa with hydroxyurea: Analysis from the phase I/II REACH trial, American Journal of Hematology, ISSN: 0361-8609

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.

Journal article

Carlier M, Nyamu W, Makale J, Williams T, Rowe A, Kariuki Set al., 2024, Dantu blood group erythrocytes less commonly form large Plasmodium falciparum rosettes, American Journal of Tropical Medicine and Hygiene, ISSN: 0002-9637

Dantu erythrocytes, which express a hybrid glycophorin B/A protein, are protective against severe malaria. Recent studies have shown that Dantu impairs Plasmodium falciparum invasion by increasing erythrocyte membrane tension, but its effects on pathological host-parasite adhesion interactions such as rosetting, the binding of uninfected erythrocytes to P. falciparum-infected erythrocytes, have not been previously investigated. The expression of several putative rosetting receptors, including glycophorin A (GYPA), glycophorin C (GYPC), complement receptor 1 (CR1) and band 3, which complexes with GYPA to form the Wrightb blood group antigen, are altered on Dantu erythrocytes. Here, we compare receptorexpression, and rosetting at both 1 hour (h) and 48h after mixing with mature trophozoite stage Kenyan laboratory-adapted P. falciparum strain 11019 parasites, in Dantu and non-Dantu erythrocytes. Dantu erythrocytes showed lower staining for GYPA and CR1 and higher staining for band 3, as observed previously, while Wrightb and GYPC staining did not vary significantly. No significant between-genotype differences in rosetting were seen after 1h, but the percentage of large rosettes was significantly lower in both Dantu heterozygous (mean 16.4%, SEM 3.2) and homozygous donors (mean 15.4%, standard error of the mean (SEM) 1.4) compared to non-Dantu erythrocytes (mean 32.9%, SEM 7.1, one way ANOVA p=0.025) after 48h. We also found positive correlations between erythrocyte meancorpuscular volume (MCV), the percentage of large rosettes (rs=0.5970, p=0.0043) and mean rosette size (rs=0.5206, p=0.0155). Impaired rosetting, due to altered membrane receptor expression and reduced MCV, might add to the protective effect of Dantu against severe malaria.

Journal article

Otiende M, Williams T, Scott JAG, 2023, Impact of COVID-19 on mortality in coastal Kenya: a longitudinal open cohort study, Nature Communications, Vol: 14, ISSN: 2041-1723

The mortality impact of COVID-19 in Africa remains controversial because most countries lack vital registration. We analysed excess mortality in Kilifi Health and Demographic Surveillance System, Kenya, using 9 years of baseline data. SARS-CoV-2 seroprevalence studies suggest most adults here were infected before May 2022. During 5 waves of COVID-19 (April 2020-May 2022) an overall excess mortality of 4.8% (95% PI 1.2%, 9.4%) concealed a significant excess (11.6%, 95% PI 5.9%, 18.9%) among older adults ( ≥ 65 years) and a deficit among children aged 1–14 years (−7.7%, 95% PI −20.9%, 6.9%). The excess mortality rate for January 2020-December 2021, age-standardised to the Kenyan population, was 27.4/100,000 person-years (95% CI 23.2-31.6). In Coastal Kenya, excess mortality during the pandemic was substantially lower than in most high-income countries but the significant excess mortality in older adults emphasizes the value of achieving high vaccine coverage in this risk group.

Journal article

Oymaboko MA, Olupot-Olupot P, Were W, Namayanja C, Onyas P, Titin H, Baseke J, Muhindo R, Kayembe D, Ndjowo P, Basara B, Okalebo C, Williams T, Uyoga S, Taya C, Bamisaiye A, Fanello C, Maitland K, Day N, Taylor W, Mukaka Met al., 2023, Factors affecting haemoglobin dynamics in African children with acute uncomplicated Plasmodium falciparum malaria treated with single low dose primaquine or placebo, BMC Medicine, Vol: 21, ISSN: 1741-7015

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 li

Journal article

Maitland K, Hamaluba M, Obonyo N, Oguda E, Mogoka C, Williams T, Chaponda M, Miti S, Kamavu LK, Connon R, Gibb D, Dondorp A, Day N, White N, Walker S, George E, Severe Malaria in African Children A Research and Trials SMAART consortiumet al., 2023, SEVUparin as a potential Adjunctive Treatment in children with severe malaria: a phase I trial safety and dose finding trial (SEVUSMAART), Wellcome Open Research, Vol: 8, ISSN: 2398-502X

BackgroundEven on the best antimalarial treatments (injectable artesunate) African children with severe malaria have poor outcomes with most deaths occurring early in the course of hospital admission (<24hours). Lactic acidosis, largely due to impairment of the microcirculatory flow due to parasite sequestration, is a main risk factor for poor outcome. There are no adjuvant treatments for severe malaria that target this complication. Sevuparin, a heparin-like drug, binds to Plasmodium falciparum erythrocyte membrane protein blocking merozoite invasion, preventing cytoadherence and transiently de-sequestering infected erythrocytes. Leading to improved microcirculatory flow by reversing/preventing parasite sequestration. If given early during admission this could result in improvements in outcomes . Sevuparin has been shown to be safe and well tolerated in adults with only some mild transient effects on activated partial thromboplastin time (APTT) were reported, without clinical consequences.MethodsA Phase I trial designed to provide data on safety, dosing, feasibility of sevuparin as an adjuvant therapy in Kenya and Zambian children with severe malaria complicated by lactic acidosis (> 2mmol/l). Three intravenous doses will be given at admission (0 hours), 8 and 16 hours. APPT will be measured 1 hour after each dose (to assess maximum toxicity). Studying 20 children will allow sufficient data on safety to be generated across a range of doses to identify the maximum tolerated dose (MTD) using the Continual Reassessment Method, which adapts or informs subsequent doses for each child based on the data from previously enrolled children. The MTD will be identified based on the dose-toxicity model updated by each previous patient’s APTT results using standard methods.ConclusionsThe results of the Phase I trial will identify the final dose to be tested in a Phase II trial in terms of both efficacy and safety outcomes.RegistrationPACTR number: 202007890194806 (da

Journal article

Mukaka M, Onyamboko MA, Olupot-Olupot P, Peerawaranun P, Suwannasin K, Pagornrat W, Kouhathong J, Madmanee W, Were W, Namayanja C, Onyas P, Titin H, Baseke J, Muhindo R, Kayembe DK, Ndjowo PO, Basara BB, Bongo GS, Okalebo CB, Abongo G, Uyoga S, Williams TN, Taya C, Dhorda M, Dondorp AM, Waithira N, Imwong M, Maitland K, Fanello C, Day NPJ, Tarning J, White NJ, Taylor WRJet al., 2023, Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria, EBioMedicine, Vol: 96, ISSN: 2352-3964

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.Int

Journal article

Opi DH, Ndila CM, Uyoga S, Macharia AW, Fennell C, Ochola LB, Nyutu G, Siddondo BR, Ojal J, Shebe M, Awuondo KO, Mturi N, Peshu N, Tsofa B, Band G, Maitland K, Kwiatkowski DP, Rockett KA, Williams TN, Rowe JAet al., 2023, Non-O ABO blood group genotypes differ in their associations with Plasmodium falciparum rosetting and severe malaria, PLoS Genetics, Vol: 19, Pages: 1-23, ISSN: 1553-7390

Blood group O is associated with protection against severe malaria and reduced size and stability of P. falciparum-host red blood cell (RBC) rosettes compared to non-O blood groups. Whether the non-O blood groups encoded by the specific ABO genotypes AO, BO, AA, BB and AB differ in their associations with severe malaria and rosetting is unknown. The A and B antigens are host RBC receptors for rosetting, hence we hypothesized that the higher levels of A and/or B antigen on RBCs from AA, BB and AB genotypes compared to AO/BO genotypes could lead to larger rosettes, increased microvascular obstruction and higher risk of malaria pathology. We used a case-control study of Kenyan children and in vitro adhesion assays to test the hypothesis that “double dose” non-O genotypes (AA, BB, AB) are associated with increased risk of severe malaria and larger rosettes than “single dose” heterozygotes (AO, BO). In the case-control study, compared to OO, the double dose genotypes consistently had higher odds ratios (OR) for severe malaria than single dose genotypes, with AB (OR 1.93) and AO (OR 1.27) showing most marked difference (p = 0.02, Wald test). In vitro experiments with blood group A-preferring P. falciparum parasites showed that significantly larger rosettes were formed with AA and AB host RBCs compared to OO, whereas AO and BO genotypes rosettes were indistinguishable from OO. Overall, the data show that ABO genotype influences P. falciparum rosetting and support the hypothesis that double dose non-O genotypes confer a greater risk of severe malaria than AO/BO heterozygosity.

Journal article

Kariuki S, Macharia A, Makale J, Williams Tet al., 2023, The Dantu blood group prevents parasite growth in vivo: Evidence from a controlled human malaria infection study, eLife, Vol: 12, Pages: 1-17, ISSN: 2050-084X

Background: The long co-evolution of Homo sapiens and Plasmodium falciparum has resulted in theselection of numerous human genetic variants that confer an advantage against severe malaria anddeath. One such variant is the Dantu blood group antigen, which is associated with 74% protectionagainst severe and complicated P. falciparum malaria infections in homozygous individuals, similarto that provided by the sickle haemoglobin allele (HbS). Recent in vitro studies suggest that Dantuexerts this protection by increasing the surface tension of red blood cells, thereby impeding theability of P. falciparum merozoites to invade them and reducing parasite multiplication. However, nostudies have yet explored this hypothesis in vivo.Methods: We investigated the effect of Dantu on early phase P. falciparum (Pf) infections in acontrolled human malaria infection (CHMI) study. 141 sickle-negative Kenyan adults were inoculatedwith 3.2 × 103 aseptic, purified, cryopreserved Pf sporozoites (PfSPZ Challenge) then monitoredfor blood-stage parasitaemia for 21 days by quantitative polymerase chain reaction (qPCR)analysisof the 18S ribosomal RNA P. falciparum gene. The primary endpoint was blood-stage P. falciparumparasitaemia of ≥500/μl while the secondary endpoint was the receipt of antimalarial treatment inthe presence of parasitaemia of any density. On study completion, all participants were genotypedboth for Dantu and for four other polymorphisms that are associated with protection against severefalciparum malaria: α+-thalassaemia, blood group O, G6PD deficiency, and the rs4951074 allele inthe red cell calcium transporter ATP2B4.Results: The primary endpoint was reached in 25/111 (22.5%) non-Dantu subjects in comparisonto 0/27 (0%) Dantu heterozygotes and 0/3 (0.0%) Dantu homozygotes (p=0.01). Similarly, 49/111(44.1%) non-Dantu subjects reached the secondary endpoint in comparison to only 7/27 (25.9%) and0/3 (0.0%) Dantu heterozygotes and homozygotes, respectively (

Journal article

Taylor WR, Olupot-Olupot P, Onyamboko MA, Peerawaranun P, Weere W, Namayanja C, Onyas P, Titin H, Baseke J, Muhindo R, Kayembe DK, Ndjowo PO, Basara BB, Bongo GS, Okalebo CB, Abongo G, Uyoga S, Williams TN, Taya C, Dhorda M, Tarning J, Dondorp AM, Waithira N, Fanello C, Maitland K, Mukaka M, Day NJPet al., 2023, 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, The Lancet Infectious Diseases, Vol: 23, Pages: 471-483, ISSN: 1473-3099

BackgroundWHO 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.MethodsWe 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.FindingsParticipants 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

Journal article

Otiende M, Bauni E, Nyaguara A, Amadi D, Nyundo C, Tsory E, Walumbe D, Kinuthia M, Kihuha N, Kahindi M, Nyutu G, Moisi J, Deribew A, Agweyu A, Marsh K, Tsofa B, Bejon P, Bottomley C, Williams TN, Scott JAGet al., 2023, Mortality in rural coastal Kenya measured using the Kilifi Health and Demographic Surveillance System: a 16-year descriptive analysis., Wellcome Open Research, Vol: 6, Pages: 1-28, ISSN: 2398-502X

Background: The Kilifi Health and Demographic Surveillance System (KHDSS) was established in 2000 to define the incidence and prevalence of local diseases and evaluate the impact of community-based interventions. KHDSS morbidity data have been reported comprehensively but mortality has not been described. This analysis describes mortality in the KHDSS over 16 years. Methods: We calculated mortality rates from 2003-2018 in four intervals of equal duration and assessed differences in mortality across these intervals by age and sex. We calculated the period survival function and median survival using the Kaplan-Meier method and mean life expectancies using abridged life tables. We estimated trend and seasonality by decomposing a time series of monthly mortality rates. We used choropleth maps and random-effects Poisson regression to investigate geographical heterogeneity. Results: Mortality declined by 36% overall between 2003-2018 and by 59% in children aged <5 years. Most of the decline occurred between 2003 and 2006. Among adults, the greatest decline (49%) was observed in those aged 15-54 years. Life expectancy at birth increased by 12 years. Females outlived males by 6 years. Seasonality was only evident in the 1-4 year age group in the first four years. Geographical variation in mortality was ±10% of the median value and did not change over time. Conclusions: Between 2003 and 2018, mortality among children and young adults has improved substantially. The steep decline in 2003-2006 followed by a much slower reduction thereafter suggests improvements in health and wellbeing have plateaued in the last 12 years. However, there is substantial inequality in mortality experience by geographical location.

Journal article

Olupot-Olupot P, Okiror W, Mnjalla H, Muhindo R, Uyoga S, Mpoya A, Williams T, terHeine R, Burger D, Urban B, Connon R, George E, Gibb D, Walker S, Maitland Ket al., 2023, Pharmacokinetics and pharmacodynamics of azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a protocol for a Phase II randomised controlled trial [version 2; peer review: 1 approved], Wellcome Open Research, Vol: 6, Pages: 1-23, ISSN: 2398-502X

Background: African children with severe malaria are susceptible to Gram-negative bacterial co-infection, largely non-typhoidal Salmonellae, leading to a substantially higher rates of in-hospital and post-discharge mortality than those without bacteraemia. Current evidence for treating co-infection is lacking, and there is no consensus on the dosage or length of treatment required. We therefore aimed to establish the appropriate dose of oral dispersible azithromycin as an antimicrobial treatment for children with severe malaria and to investigate whether antibiotics can be targeted to those at greatest risk of bacterial co-infection using clinical criteria alone or in combination with rapid diagnostic biomarker tests.Methods: A Phase I/II open-label trial comparing three doses of azithromycin: 10, 15 and 20 mg/kg spanning the lowest to highest mg/kg doses previously demonstrated to be equally effective as parenteral treatment for other salmonellae infection. Children with the highest risk of bacterial infection will receive five days of azithromycin and followed for 90 days. We will generate relevant pharmacokinetic data by sparse sampling during dosing intervals. We will use population pharmacokinetic modelling to determine the optimal azithromycin dose in severe malaria and investigate azithromycin exposure to change in C-reactive protein, a putative marker of sepsis at 72 hours, and microbiological cure (seven-day), alone and as a composite with seven-day survival. We will also evaluate whether a combination of clinical, point-of-care diagnostic tests, and/or biomarkers can accurately identify the sub-group of severe malaria with culture-proven bacteraemia by comparison with a control cohort of children hospitalized with severe malaria at low risk of bacterial co-infection.Discussion: We plan to study azithromycin because of its favourable microbiological spectrum, its inherent antimalarial and immunomodulatory properties and dosing and safety profile. This study

Journal article

Nardo-Marino A, Glenthoj A, Brewin JN, Petersen J, Braunstein TH, Kurtzhals JAL, Williams TN, Rees DCet al., 2022, Decreased Red Blood Cell Deformability Contributes to Loss of Splenic Filtration Function and Variations in Spleen Size in Children with Sickle Cell Anaemia, 64th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, Pages: 1639-1640, ISSN: 0006-4971

Conference paper

Olupot-Olupot P, Tomlinson G, Williams T, Tshilolo L, Santos B, Smart L, McElhinney K, Howard T, Aygun B, Stuber S, Lane A, Latham T, Ware Ret al., 2022, Hydroxyurea treatment is associated with lower malaria incidence in children with sickle cell anemia in sub-Saharan Africa: the REACH trial, Blood, Vol: 141, Pages: 1402-1410, ISSN: 0006-4971

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 sickle-related clinical events, documented treatment benefits include ~50% 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 (CI) for baseline demographic, and time-varying laboratory and clinical parameters were estimated in a modified Cox gap-time model for repeated events. A total of 717 clinical malaria episodes occurred in 336 of 606 study participants over 3,387 patient-years of hydroxyurea treatment; 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, a-thalassemia, and G6PD deficiency had no effect. In multivariable regression of confirmed infections, ANC was significant (HR=1.37 per doubled value, CI=1.10-1.70, p=0.0052) and ANC values <3.0 x 109/L were associated with lower malaria incidence. Compared to non-palpable, 1-4cm splenomegaly also was associated with higher malaria risk (HR=2.01, CI=1.41-2.85, p=0.0001). Hydroxyurea at MTD is associated with lower malaria incidence in SCA through incompletely defined mechanisms, but treatment-associated mild myelosuppression with ANC <3.0 x 109/L is salutary. Splenomegaly represents an unexplained risk factor for malaria infections among children with SCA in Africa.

Journal article

Njunge JM, Tickell K, Diallo AH, Sayeem Bin Shahid ASM, Gazi MA, Saleem A, Kazi Z, Ali S, Tigoi C, Mupere E, Lancioni CL, Yoshioka E, Chisti MJ, Mburu M, Ngari M, Ngao N, Gichuki B, Omer E, Gumbi W, Singa B, Bandsma R, Ahmed T, Voskuijl W, Williams TN, Macharia A, Makale J, Mitchel A, Williams J, Gogain J, Janjic N, Mandal R, Wishart DS, Wu H, Xia L, Routledge M, Gong YY, Espinosa C, Aghaeepour N, Liu J, Houpt E, Lawley TD, Browne H, Shao Y, Rwigi D, Kariuki K, Kaburu T, Uhlig HH, Gartner L, Jones K, Koulman A, Walson J, Berkley Jet al., 2022, The Childhood Acute Illness and Nutrition (CHAIN) network nested case-cohort study protocol: a multi-omics approach to understanding mortality among children in sub-Saharan Africa and South Asia, Gates Open Research, Vol: 6, ISSN: 2572-4754

Introduction: Many acutely ill children in low- and middle-income settings have a high risk of mortality both during and after hospitalisation despite guideline-based care. Understanding the biological mechanisms underpinning mortality may suggest optimal pathways to target for interventions to further reduce mortality. The Childhood Acute Illness and Nutrition (CHAIN) Network ( www.chainnnetwork.org) Nested Case-Cohort Study (CNCC) aims to investigate biological mechanisms leading to inpatient and post-discharge mortality through an integrated multi-omic approach. Methods and analysis; The CNCC comprises a subset of participants from the CHAIN cohort (1278/3101 hospitalised participants, including 350 children who died and 658 survivors, and 270/1140 well community children of similar age and household location) from nine sites in six countries across sub-Saharan Africa and South Asia. Systemic proteome, metabolome, lipidome, lipopolysaccharides, haemoglobin variants, toxins, pathogens, intestinal microbiome and biomarkers of enteropathy will be determined. Computational systems biology analysis will include machine learning and multivariate predictive modelling with stacked generalization approaches accounting for the different characteristics of each biological modality. This systems approach is anticipated to yield mechanistic insights, show interactions and behaviours of the components of biological entities, and help develop interventions to reduce mortality among acutely ill children. Ethics and dissemination. The CHAIN Network cohort and CNCC was approved by institutional review boards of all partner sites. Results will be published in open access, peer reviewed scientific journals and presented to academic and policy stakeholders. Data will be made publicly available, including uploading to recognised omics databases. Trial registration NCT03208725.

Journal article

Nardo-Marino A, Glenthoj A, Brewin JN, Petersen J, Braunstein TH, Kurtzhals JAL, Williams TN, Rees DCet al., 2022, The significance of spleen size in children with sickle cell anemia, American Journal of Hematology, Vol: 97, Pages: 1520-1528, ISSN: 0361-8609

It is well established that splenic dysfunction occurs in early childhood in sickle cell anemia (SCA), although the determinants and consequences of splenic injury are not fully understood. In this study, we examined spleen size and splenic function in 100 children with SCA aged 0–16 years at King's College Hospital in London. Spleen size was assessed by abdominal ultrasound (US) and splenic function by pitted red blood cells (PIT counts). In our cohort, 5.6% of children aged 6–10 years and 19.4% of children aged 11–16 years had no visible spleen on US (autosplenectomy). Splenomegaly was common in all age groups, with 28% of children overall having larger spleens than the average for their age. Only one child had a PIT count suggesting preserved splenic function. We found no correlation between hemoglobin F levels and spleen size, nor was there any difference in spleen size between children treated with or without hydroxyurea. Although there was a trend toward increased spleen length in children with co-inherited α-thalassemia, this did not reach statistical significance. Finally, we found a strong association between erythrocyte deformability measured with oxygen gradient ektacytometry, spleen size, and PIT counts. In conclusion, our results do not agree with the general perception that most children with SCA undergo autosplenectomy within the first decade of life and indicate that loss of erythrocyte deformability contributes to loss of splenic filtration capacity in SCA, as well as phenotypical variations in spleen size.

Journal article

White NJ, Watson JA, Uyoga S, Williams TN, Maitland KMet al., 2022, Substantial misdiagnosis of severe malaria in African children, The Lancet, Vol: 400, Pages: 807-807, ISSN: 0140-6736

Journal article

Uyoga S, Olupot-Olupot P, Connon R, Kiguli S, Opoka R, Alaroker F, Muhindo R, Macharia AW, Dondorp A, Gibb D, Walker AS, George E, Maitland K, Williams Tet al., 2022, Sickle cell anaemia and severe P. falciparum malaria: a secondary analysis of the Transfusion and Treatment of African Children (TRACT) trial, The Lancet Child & Adolescent Health, Vol: 6, Pages: 606-613, ISSN: 2352-4642

BackgroundSickle cell anaemia (SCA; HbSS) has historically been associated with high levels of childhood mortality in Africa. While malaria plays a major contribution to this mortality to date, the clinical pathology of malaria among children with SCA has been poorly described. Methods We investigated the burden and severity of malaria infections among children recruited with severe anaemia to the TRACT trial of blood transfusion in Africa. This secondary analysis, conducted after trial completion, is restricted to Uganda, where the birth prevalence of SCA is approximately 1% and malaria transmission is high. Children were classified as normal (HbAA), heterozygous (HbAS) or homozygous (HbSS; SCA) for the rs334 A>T sickle mutation in HBB following batch-genotyping by PCR at the end of trial. To avoid confounding from SCA-specific medical interventions, we considered children with an existing diagnosis of SCA (known-SCA) separately from those diagnosed at the end of the trial (unknown-SCA). Findings Overall, 1,038 of 3,483 (30%) of the Ugandan children recruited to TRACT had SCA. While 1,815/2,321 (78%) of the non-SCA (HbAA) children tested positive for P. falciparum malaria, the prevalence was significantly lower in children with SCA (347/1,038; 33%; p<0.001). Concentrations of plasma P. falciparum Histidine Rich Protein 2 (PfHRP2), a marker of the total burden of malaria parasites within an individual, were significantly lower in children with either known-SCA (median 8 ng/mL; IQR 0-57) or unknown-SCA (7 ng/mL (0-50 ng/mL) than in HbAA children (346 ng/mL; 21-2,121; p<0.001). By contrast to HbAA children, few HbSS children presented with classic features of severe and complicated malaria, but both the frequency and severity of anaemia were higher in HbSS children.Interpretation The current study suggests that children with SCA are innately protected against classic severe malaria. However, it also shows that even low-level infections can precipitate severe

Journal article

Gilchrist JJ, Kariuki S, Watson JA, Band G, Uyoga S, Ndila CM, Mturi N, Mwarumba S, Mohammed S, Mosobo M, Alasoo K, Rockett KA, Mentzer A, Kwiatkowski DP, Hill AVS, Maitland K, Scott JAG, Williams Tet al., 2022, BIRC6 modifies risk of invasive bacterial infection in Kenyan children, eLife, Vol: 11, Pages: 1-23, ISSN: 2050-084X

Invasive bacterial disease is a major cause of morbidity and mortality in African children. Despite being caused by diverse pathogens, children with sepsis are clinically indistinguishable from one another. In spite of this, most genetic susceptibility loci for invasive infection that have been discovered to date are pathogen specific and are not therefore suggestive of a shared genetic architecture of bacterial sepsis. Here we utilise probabilistic diagnostic models to identify children with a high probability of invasive bacterial disease among critically unwell Kenyan children with P. falciparum parasitaemia. We construct a joint dataset including 1,445 bacteraemia cases and 1,143 severe malaria cases, and population controls, among critically unwell Kenyan children that have previously been genotyped for human genetic variation. Using these data we perform a cross-trait genome-wide association study of invasive bacterial infection, weighting cases according to their probability of bacterial disease. In doing so we identify and validate a novel risk locus for invasive infection secondary to multiple bacterial pathogens, that has no apparent effect on malaria risk. The locus identified modifies splicing of BIRC6 in stimulated monocytes, implicating regulation of apoptosis and autophagy in the pathogenesis of sepsis in Kenyan children.

Journal article

Watson J, Uyoga S, Wanjiku P, Makale J, Nyutu G, Mturi N, George E, Woodrow C, Day N, Bejon P, Opoka R, Dondorp A, John C, Maitland K, Williams T, White Net al., 2022, Improving the diagnosis of severe malaria in African children using platelet counts and plasma Pf HRP2 concentrations, Science Translational Medicine, Vol: 14, Pages: 1-10, ISSN: 1946-6234

Severe falciparum malaria is difficult to diagnose accurately in children inhigh transmission settings. Using data from 2,649 patients enrolled in fourstudies of severe illness in three countries (Bangladesh, Kenya, and Uganda),we fitted Bayesian latent class models using two diagnostic biomarkers: theplatelet count and the plasma PfHRP2 concentration. In severely ill patientswith clinical features consistent with severe malaria, a combined platelet count≤ 150,000 per µL and a plasma PfHRP2 concentration ≥ 1,000 ng/mL had anestimated sensitivity of 74% and specificity of 93% in identifying ‘true’ severefalciparum malaria. Compared to misdiagnosed children, patients with truesevere malaria had higher parasite densities, lower hematocrits, lower ratesof invasive bacterial disease, and a lower prevalence of both HbAS and HbSS.We estimate one third of African children enrolled in clinical studies of severemalaria in high transmission settings had another cause of severe illness.

Journal article

Musasia FK, Nkumama IN, Frank R, Kipkemboi V, Schneider M, Mwai K, Odera DO, Rosenkranz M, Fürle K, Kimani D, Tuju J, Njuguna P, Hamaluba M, Kapulu MC, Wardemann H, CHMI-SIKA Study Team, Osier FHAet al., 2022, Phagocytosis of Plasmodium falciparum ring-stage parasites predicts protection against malaria., Nature Communications, Vol: 13, Pages: 1-12, ISSN: 2041-1723

Ring-infected erythrocytes are the predominant asexual stage in the peripheral circulation but are rarely investigated in the context of acquired immunity against Plasmodium falciparum malaria. Here we compare antibody-dependent phagocytosis of ring-infected parasite cultures in samples from a controlled human malaria infection (CHMI) study (NCT02739763). Protected volunteers did not develop clinical symptoms, maintained parasitaemia below a predefined threshold of 500 parasites/μl and were not treated until the end of the study. Antibody-dependent phagocytosis of both ring-infected and uninfected erythrocytes from parasite cultures was strongly correlated with protection. A surface proteomic analysis revealed the presence of merozoite proteins including erythrocyte binding antigen-175 and -140 on ring-infected and uninfected erythrocytes, providing an additional antibody-mediated protective mechanism for their activity beyond invasion-inhibition. Competition phagocytosis assays support the hypothesis that merozoite antigens are the key mediators of this functional activity. Targeting ring-stage parasites may contribute to the control of parasitaemia and prevention of clinical malaria.

Journal article

Macharia AW, Mochamah G, Makale J, Howard T, Mturi N, Olupot-Olupot P, Färnert A, Ware RE, Williams TNet al., 2022, Case report: β-thalassemia major on the East African coast, Wellcome Open Research, Vol: 7, ISSN: 2398-502X

Background: β-thalassemia is rare in sub-Saharan Africa and to our knowledge there has been no case of homozygous β-thalassemia major reported from this region. In a recent cohort study, we identified four β-thalassemia mutations among 83 heterozygous carriers in Kilifi, Kenya. One of the mutations identified was a rare β-globin gene initiation codon mutation (ATG➝ACG) (rs33941849). Here we present a patient with β-thalassemia major resulting from this mutation, only the second homozygous patient to have been reported. Methods: The female patient presented to Kilifi County Hospital aged two years with a one week left sided abdominal swelling. Clinical, hematological and genetic information were collected at admission and follow-up. Results: Admission bloods revealed marked anemia, with a hemoglobin (Hb) value of 6.6 g/dL and a low mean corpuscular volume of 64 fL. High performance liquid chromatography (HPLC) revealed the absence of HbA0 and elevated levels of HbF, suggesting a diagnosis of β-thalassemia major. Sequencing revealed that the child was homozygous for the rs33941849 initiation codon mutation. Conclusions: We hope that this study will create awareness regarding the presence of β-thalassemia as a potential public health problem in the East Africa region and will prompt the development of local guidelines regarding the diagnosis and management of this condition.

Journal article

Abuga K, Muriuki J, Uyoga S, Mwai K, Makale J, Mogire R, Macharia A, Mohammed S, Muthumbi E, Mwarumba S, Mturi N, Bejon P, Scott A, Nairz M, Williams T, Atkinson Set al., 2022, Hepcidin regulation in Kenyan children with severe malaria and non-typhoidal Salmonella bacteremia, Haematologica: the hematology journal, Vol: 107, Pages: 1589-1598, ISSN: 0390-6078

Malaria and invasive non-typhoidal Salmonella (NTS) are life-threatening infections that often co-exist in African children. The iron-regulatory hormone hepcidin is highly upregulated during malaria and controls the availability of iron, a critical nutrient for bacterial growth. We investigated the relationship between Plasmodium falciparum malaria and NTS bacteremia in all pediatric admissions aged ≤5 years between August 1998 and October 2019 (n=75,034). We then assayed hepcidin and measures of iron status in five groups: (1) children with concomitant severe malarial anemia (SMA) and NTS (SMA+NTS, n=16); and in matched children with (2) SMA (n=33); (3) NTS (n=33); (4) cerebral malaria (CM, n=34); and (5) community-based children. SMA and severe anemia without malaria were associated with a two-fold or more increased risk of NTS bacteremia, while other malaria phenotypes were not associated with increased NTS risk. Children with SMA had lower hepcidin/ferritin ratios (0.10 [IQR 0.03, 0.19]) than those with CM (0.24 [0.14, 0.69]; P=0.006) or asymptomatic malaria (0.19 [0.09, 0.46]; P=0.01) indicating suppressed hepcidin levels. Children with SMA+NTS had lower hepcidin levels (9.3 ng/mL [4.7, 49.8]) and hepcidin/ferritin ratios (0.03 [0.01, 0.22]) than those with NTS alone (105.8 ng/mL [17.3, 233.3]; P=0.02 and 0.31 [0.06, 0.66]; P=0.007, respectively). Since hepcidin degrades ferroportin on the Salmonella-containing vacuole (SCV), we hypothesize that reduced hepcidin in children with SMA might contribute to NTS growth by modulating iron availability for bacterial growth. Further studies are needed to understand how the hepcidin-ferroportin axis might mediate susceptibility to NTS in severely anemic children.

Journal article

Uyoga S, Watson J, Wanjiku P, Rop J, Makale J, Macharia A, Kariuki S, Nyutu G, Shebe M, Mosobo M, Mturi N, Rockett K, Woodrow C, Dondorp A, Maitland K, White N, Williams Tet al., 2022, The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria, Nature Communications, Vol: 13, Pages: 1-7, ISSN: 2041-1723

Severe falciparum malaria is a major cause of preventable child mortality in sub-Saharan Africa. Plasma concentrations of P. falciparum Histidine-Rich Protein 2 (PfHRP2) have diagnostic and prognostic value in severe malaria. We investigate the potential use of plasma PfHRP2 and the sequestration index (the ratio of PfHRP2 to parasite density) as quantitative traits for case-only genetic association studies of severe malaria. Data from 2198 Kenyan children diagnosed with severe malaria, genotyped for 14 major candidate genes, show that polymorphisms in four major red cell genes that lead to hemoglobin S, O blood group, α-thalassemia, and the Dantu blood group, are associated with substantially lower admission plasma PfHRP2 concentrations, consistent with protective effects against extensive parasitized erythrocyte sequestration. In contrast the known protective ATP2B4 polymorphism is associated with higher plasma PfHRP2 concentrations, lower parasite densities and a higher sequestration index. We provide testable hypotheses for the mechanism of protection of ATP2B4.

Journal article

Nardo-Marino A, Petersen J, Brewin J, Birgens H, Williams T, Kurtzhals J, Rees D, Glenthøj Aet al., 2022, Oxygen gradient ektacytometry does not predict pain in children with sickle cell anaemia, British Journal of Haematology, Vol: 197, Pages: 609-617, ISSN: 0007-1048

The loss of red blood cell (RBC) deformability in sickle cell anaemia (SCA) is considered the primary factor responsible for episodes of acute pain and downstream progressive organ dysfunction. Oxygen gradient ektacytometry (Oxygenscan) is a recently commercialised functional assay that aims to describe the deformability of RBCs in SCA at differing oxygen tensions. So far, the Oxygenscan has been evaluated only by a small number of research groups and the validity and clinical value of Oxygenscan-derived biomarkers have not yet been fully established. In this study we examined RBC deformability measured with the Oxygenscan in 91 children with SCA at King’s College Hospital in London. We found a significant correlation between Oxygenscan-derived biomarkers and well-recognised modifiers of disease severity in SCA: haemoglobin F and co-inherited α-thalassaemia. We failed, however, to find any independent predictive value of the Oxygenscan in the clinical outcome measure of pain, as well as other important parameters such as hydroxycarbamide treatment. Although the Oxygenscan remains an intriguing tool for basic research, our results question whether it provides any additional information in predicting the clinical course in children with SCA, beyond measuring known markers of disease severity.

Journal article

Olupot-Olupot P, Connon R, Kiguli S, Opoka RO, Alaroker F, Uyoga S, Nakuya M, Okiror W, Nteziyaremye J, Ssenyondo T, Nabawanuka E, Kayaga J, Williams Mukisa C, Amorut D, Muhindo R, Frost G, Walsh K, Macharia AW, Gibb DM, Walker AS, George EC, Maitland K, Williams TN, Williams Tet al., 2022, A predictive algorithm for identifying children with sickle cell anemia among children admitted to hospital with severe anemia in Africa, American Journal of Hematology, Vol: 97, Pages: 527-536, ISSN: 0361-8609

Sickle cell anemia (SCA) is common in sub-Saharan Africa where approximately 1% of births are affected. Severe anemia is a common cause for hospital admission within the region yet few studies have investigated the contribution made by SCA. The Transfusion and Treatment of severe anemia in African Children Trial (ISRCTN84086586) investigated various treatment strategies in 3983 children admitted with severe anemia (hemoglobin < 6.0 g/dl) based on two severity strata to four hospitals in Africa (three Uganda and one Malawi). Children with known-SCA were excluded from the uncomplicated stratum and capped at 25% in the complicated stratum. All participants were genotyped for SCA at trial completion. SCA was rare in Malawi (six patients overall), so here we focus on the participants recruited in Uganda. We present baseline characteristics by SCA status and propose an algorithm for identifying children with unknown-SCA. Overall, 430 (12%) and 608 (17%) of the 3483 Ugandan participants had known- or unknown-SCA, respectively. Children with SCA were less likely to be malaria-positive and more likely to have an affected sibling, have gross splenomegaly, or to have received a previous blood transfusion. Most outcomes, including mortality and readmission, were better in children with either known or unknown-SCA than non-SCA children. A simple algorithm based on seven admission criteria detected 73% of all children with unknown-SCA with a number needed to test to identify one new SCA case of only two. Our proposed algorithm offers an efficient and cost-effective approach to identifying children with unknown-SCA among all children admitted with severe anemia to African hospitals where screening is not widely available.

Journal article

Nardo-Marino A, Braunstein TH, Petersen J, Brewin JN, Mottelson MN, Williams TN, Kurtzhals JAL, Rees DC, Glenthøj Aet al., 2022, Automating pitted red blood cell counts using deep neural network analysis: a new method for measuring splenic function in sickle cell anaemia, Frontiers in Physiology, Vol: 13, ISSN: 1664-042X

The spleen plays an important role in the body's defence against bacterial infections. Measuring splenic function is of interest in multiple conditions, including sickle cell anaemia (SCA), where spleen injury occurs early in life. Unfortunately, there is no direct and simple way of measuring splenic function, and it is rarely assessed in clinical or research settings. Manual counts of pitted red blood cells (RBCs) observed with differential interference contrast (DIC) microscopy is a well-validated surrogate biomarker of splenic function. The method, however, is both user-dependent and laborious. In this study, we propose a new automated workflow for counting pitted RBCs using deep neural network analysis. Secondly, we assess the durability of fixed RBCs for pitted RBC counts over time. We included samples from 48 children with SCA and 10 healthy controls. Cells were fixed in paraformaldehyde and examined using an oil-immersion objective, and microscopy images were recorded with a DIC setup. Manual pitted RBC counts were performed by examining a minimum of 500 RBCs for pits, expressing the proportion of pitted RBCs as a percentage (%PIT). Automated pitted RBC counts were generated by first segmenting DIC images using a Zeiss Intellesis deep learning model, recognising and segmenting cells and pits from background. Subsequently, segmented images were analysed using a small ImageJ macro language script. Selected samples were stored for 24 months, and manual pitted RBC counts performed at various time points. When comparing manual and automated pitted RBC counts, we found the two methods to yield comparable results. Although variability between the measurements increased with higher %PIT, this did not change the diagnosis of asplenia. Furthermore, we found no significant changes in %PIT after storing samples for up to 24 months and under varying temperatures and light exposures. We have shown that automated pitted RBC counts, produced using deep neural

Journal article

Mogire RM, Muriuki JM, Morovat A, Mentzer AJ, Webb EL, Kimita W, Ndungu FM, Macharia AW, Cutland CL, Sirima SB, Diarra A, Tiono AB, Lule SA, Madhi SA, Prentice AM, Bejon P, Pettifor JM, Elliott AM, Adeyemo A, Williams T, Atkinson SHet al., 2022, Vitamin D deficiency and its association with iron deficiency in African children, Nutrients, Vol: 14, ISSN: 2072-6643

Vitamin D regulates the master iron hormone hepcidin, and iron in turn alters vitamin D me-tabolism. Although vitamin D and iron deficiency are highly prevalent globally little is known about their interactions in Africa. To evaluate associations between vitamin D and iron status we measured markers of iron status, inflammation, malaria parasitemia and 25-hydroxyvitamin D (25(OH)D) concentrations in 4509 children aged 0.3 months to 8 years living in Kenya, Uganda, Burkina Faso, The Gambia and South Africa. Prevalence of iron deficiency was 35.1%, and preva-lence of vitamin D deficiency was 0.6% and 7.8% as defined by 25(OH)D concentrations of <30 nmol/L and <50 nmol/L respectively. Children with 25(OH)D concentrations of <50 nmol/L had a 98% increased risk of iron deficiency (OR 1.98 [95% CI 1.52, 2.58]) compared to those with 25(OH)D concentrations >75 nmol/L. 25(OH)D concentrations variably influenced individual markers of iron status. Inflammation interacted with 25(OH)D concentrations to predict ferritin levels. The link between vitamin D and iron status should be considered in strategies to manage these nutrient deficiencies in African children.

Journal article

Williams TN, 2022, Filling the data gaps on sickle cell anaemia in sub-Saharan Africa, The Lancet Haematology, Vol: 9, Pages: e172-e173, ISSN: 2352-3026

Journal article

George EC, Uyoga S, M'baya B, Byabazair DK, Kiguli S, Olupot-Olupot P, Opoka RO, Chagaluka G, Alaroker F, Williams TN, Bates I, Mbanya D, Gibb DM, Walker AS, Maitland K, TRACT trail study groupet al., 2022, Whole blood versus red cell concentrates for children with severe anaemia: a secondary analysis of the Transfusion and Treatment of African Children (TRACT) trial, The Lancet Global Health, Vol: 10, Pages: e360-e368, ISSN: 2214-109X

Background:The multicentre Transfusion and Treatment of African Children (TRACT) trial established best evidence on the timing of transfusion in children with uncomplicated anaemia (haemoglobin 4-6g/dl) and optimal volume (20 versus 30ml/kg whole blood (or 10 vs 15ml/kg red cell concentrates) for transfusion in children hospitalised with severe anaemia (Hb <6g/dl) on Day 28 mortality (primary endpoint) and secondary endpoints including safety. As evidence on the safety of blood components is limited we undertook a secondary analysis comparing children receiving whole blood versus red cell concentrates as their initial transfusion on clinical outcomes. Methods :This analysis includes 3188 children with severe anaemia (Hb <6g/dl) who received either whole blood or red cell concentrates. Whole blood or cell concentrates were issued routinely by the blood transfusion services, but not prespecified on the request form. The impact of blood pack type on haematological correction, re-transfusion, and other clinical endpoints was explored using multivariate regression models. Findings:1632/3992 (41%) transfusions in 3188 children were whole blood. Compared with whole blood, children receiving cell concentrates in their first transfusion had less haemoglobin recovery at 8 hours (packed cells mean(95%CI): -1.3(-1.5,-1.0) 20ml/kg arm,-1.4(-1.6,-1.1) 30ml/kg; settled cells mean(95%CI) -1.1g/dl(-1.2,-0.9) 20ml/kg arm, -1.5g/dl(-1.7,-1.3) 30ml/kg arm; p<0.001 for pack type comparisons, p=0.003 heterogeneity by arm), higher odds of receiving a second transfusion [ORs 2.32 (95%CI 1.30,4.12) and 2.97 (2.18,4.05) respectively; p<0.001], and had a longer time to discharge [sub-Hazard Ratios 0.94 (95%CI 0.81,1.10) and 0.86 (95% CI 0.79,0.94) respectively; p=0.002]. No child developed features of cardio-pulmonary overload. Interpretation: Whole blood is safe to use in children, resulting in superior aematologic

Journal article

Kapulu MC, Kimani D, Njuguna P, Hamaluba M, Otieno E, Kimathi R, Tuju J, Sim BKL, CHMI-SIKA Study Teamet al., 2022, Controlled human malaria infection (CHMI) outcomes in Kenyan adults is associated with prior history of malaria exposure and anti-schizont antibody response, BMC Infect Dis, Vol: 22

BACKGROUND: Individuals living in endemic areas acquire immunity to malaria following repeated parasite exposure. We sought to assess the controlled human malaria infection (CHMI) model as a means of studying naturally acquired immunity in Kenyan adults with varying malaria exposure. METHODS: We analysed data from 142 Kenyan adults from three locations representing distinct areas of malaria endemicity (Ahero, Kilifi North and Kilifi South) enrolled in a CHMI study with Plasmodium falciparum sporozoites NF54 strain (Sanaria® PfSPZ Challenge). To identify the in vivo outcomes that most closely reflected naturally acquired immunity, parameters based on qPCR measurements were compared with anti-schizont antibody levels and residence as proxy markers of naturally acquired immunity. RESULTS: Time to endpoint correlated more closely with anti-schizont antibodies and location of residence than other parasite parameters such as growth rate or mean parasite density. Compared to observational field-based studies in children where 0.8% of the variability in malaria outcome was observed to be explained by anti-schizont antibodies, in the CHMI model the dichotomized anti-schizont antibodies explained 17% of the variability. CONCLUSIONS: The CHMI model is highly effective in studying markers of naturally acquired immunity to malaria. Trial registration Clinicaltrials.gov number NCT02739763. Registered 15 April 2016.

Journal article

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