Publications
353 results found
Olupot-Olupot P, Prevatt N, Engoru C, et al., 2019, Evaluation of the diagnostic accuracy and cost of different methods for the assessment of severe anaemia in hospitalised children in Eastern Uganda [version 2; referees: 3 approved], Wellcome Open Research, Vol: 3, ISSN: 2398-502X
Background: Severe anaemia in children requiring hospital admission is a major public health problem in malaria-endemic Africa. Affordable methods for the assessment of haemoglobin have not been validated against gold standard measures for identifying those with severe anaemia requiring a blood transfusion, despite this resource being in short supply. Methods: We conducted a prospective descriptive study of hospitalized children aged 2 months – 12 years at Mbale and Soroti Regional Referral Hospitals, assessed to have pallor at triage by a nurse and two clinicians. Haemoglobin levels were measured using the HemoCue ® Hb 301 system (gold standard); the Haemoglobin Colour Scale; calorimetric and Sahli’s methods. We report clinical assessments of the degree of pallor, clinicians’ intention to transfuse, inter-observer agreement, limits of agreement using the Bland-Altman method, and the sensitivity and specificity of each method in comparison to HemoCue ® Results: We recruited 322 children assessed by the admitting nurse as having severe (164; 51.0%), moderate (99; 30.7%) or mild (57; 17.7%) pallor. Agreement between the clinicians and the nurse were good: Clinician A Kappa=0.68 (0.60–0.76) and Clinician B Kappa=0.62 (0.53–0.71) respectively ( P <0.0001 for both). The nurse, clinicians A and B indicated that of 94/116 (81.0%), 83/121 (68.6%) and 93/120 (77.5%) respectively required transfusion. HemoCue ® readings indicated anaemia as mild (Hb10.0–11.9g/dl) in 8/292 (2.7%), moderate (Hb5.0–9.9g/dl) in 132/292 (45.2%) and severe (Hb<5.0g/dl) in 152/292 (52.1%). Comparing to HemoCue® the Sahli’s method performed best in estimation of severe anaemia, with sensitivity 84.0% and specificity 87.9% and a Kappa score of 0.70 (0.64–0.80). Conclusions : Clinical assessment of severe pallor results has a low specificity for the diagnosis of severe anaemia. To target blood transfusion Hb measurement by eit
Silaba M, Ooko M, Bottomley C, et al., 2019, Effect of 10-valent pneumococcal conjugate vaccine on the incidence of radiologically-confirmed pneumonia and clinically-defined pneumonia in Kenyan children: an interrupted time-series analysis, The Lancet Global Health, Vol: 7, Pages: e337-e346, ISSN: 2214-109X
BACKGROUND: Pneumococcal conjugate vaccines (PCV) are highly protective against invasive pneumococcal disease caused by vaccine serotypes, but the burden of pneumococcal disease in low-income and middle-income countries is dominated by pneumonia, most of which is non-bacteraemic. We examined the effect of 10-valent PCV on the incidence of pneumonia in Kenya. METHODS: We linked prospective hospital surveillance for clinically-defined WHO severe or very severe pneumonia at Kilifi County Hospital, Kenya, from 2002 to 2015, to population surveillance at Kilifi Health and Demographic Surveillance System, comprising 45 000 children younger than 5 years. Chest radiographs were read according to a WHO standard. A 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PCV10) was introduced in Kenya in January, 2011. In Kilifi, there was a three-dose catch-up campaign for infants (aged <1 year) and a two-dose catch-up campaign for children aged 1-4 years, between January and March, 2011. We estimated the effect of PCV10 on the incidence of clinically-defined and radiologically-confirmed pneumonia through interrupted time-series analysis, accounting for seasonal and temporal trends. FINDINGS: Between May 1, 2002 and March 31, 2015, 44 771 children aged 2-143 months were admitted to Kilifi County Hospital. We excluded 810 admissions between January and March, 2011, and 182 admissions during nurses' strikes. In 2002-03, the incidence of admission with clinically-defined pneumonia was 2170 per 100 000 in children aged 2-59 months. By the end of the catch-up campaign in 2011, 4997 (61·1%) of 8181 children aged 2-11 months had received at least two doses of PCV10 and 23 298 (62·3%) of 37 416 children aged 12-59 months had received at least one dose. Across the 13 years of surveillance, the incidence of clinically-defined pneumonia declined by 0·5% per month, independent of vaccine introduction. There was no secular trend in t
Silaba M, Ooko M, Bottomley C, et al., 2019, The impact of 10-valent Pneumococcal Conjugate Vaccine on theincidence of radiologically-confirmed pneumonia and clinically-definedpneumonia in Kenyan children: an interrupted time series analysis, The Lancet Global Health, Vol: 7, Pages: e337-e346, ISSN: 2214-109X
BackgroundPneumococcal conjugate vaccines (PCV) are highly protective against invasive pneumococcal disease caused by vaccine serotypes but the burden of pneumococcal disease in developing countries is dominated by pneumonia, most of which is non-bacteraemic. We examined the impact of 10-valent PCV on pneumonia incidence.MethodsWe linked prospective hospital surveillance for clinically-defined WHO severe or very-severe pneumonia at Kilifi County Hospital from 2002-2015 to population surveillance at Kilifi Health and Demographic Surveillance System, comprising 45,000 children aged <5 years. Chest radiographs were read according to a WHO standard. A 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PCV10) was introduced in Kenya in January 2011. In Kilifi, there was a 3-dose catch-up campaign for infants and a 2-dose catch-up campaign for children aged 1-4 years between January and March 2011. We estimated the impact of PCV10 on the incidence of clinically-defined and radiologically-confirmed pneumonia through interrupted time series analysis accounting for seasonal and temporal trends.FindingsAt the start of the study, in 2002/3, the incidence of admission with clinically-defined pneumonia was 21·7/1000/year in children aged 2-59 months. By the end of the catch-up campaign, 61·1% of children aged 2-11 months had received ≥2 doses and 62·3% of children aged 12-59 months had received ≥1 dose of PCV10. Across the whole 13-years of surveillance the incidence of clinically-defined pneumonia declined by 0.5% per month, independent of vaccine introduction; in contrast, there was no secular trend in the incidence of radiologically-confirmed pneumonia over 8 years of study.After adjusting for secular trend and season, incidence rate ratios for admission with radiologically-confirmed pneumonia, clinically-defined pneumonia, and diarrhoea (control condition), associated temporally with PCV10 introduction and th
Uyoga S, Macharia A, Ndila C, et al., 2019, The indirect health effects of malaria estimated from health advantages of the sickle cell trait, Nature Communications, Vol: 10, ISSN: 2041-1723
Most estimates of the burden of malaria are based on its direct impacts; however, its true burden is likely to be greater because of its wider effects on overall health. Here we estimate the indirect impact of malaria on children’s health in a case-control study, using the sickle cell trait (HbAS), a condition associated with a high degree of specific malaria resistance, as a proxy indicator for an effective intervention. We estimate the odds ratios for HbAS among cases (all children admitted to Kilifi County Hospital during 2000–2004) versus community controls. As expected, HbAS protects strongly against malaria admissions (aOR 0.26; 95%CI 0.22–0.31), but it also protects against other syndromes, including neonatal conditions (aOR 0.79; 0.67–0.93), bacteraemia (aOR 0.69; 0.54–0.88) and severe malnutrition (aOR 0.67; 0.55–0.83). The wider health impacts of malaria should be considered when estimating the potential added benefits of effective malaria interventions.
Maitland K, Ohuma E, Mpoya A, et al., 2019, Informing thresholds for paediatric transfusion in Africa: the need for a trial [version 1; peer review: 2 approved with reservations], Wellcome Open Research, Vol: 4, Pages: 1-23, ISSN: 2398-502X
Background : Provision of adequate supplies of donor blood for paediatric transfusion remains a challenge. Guidelines recommend restrictive transfusion practices, based on expert opinion. We examined whether survival among children admitted to hospital varied by admission haemoglobin status and whether this was influenced by malaria infection and/or transfusion. Methods : A retrospective analysis in an unselected population of children admitted to a rural district hospital in Kenya over an 8-year period. We describe baseline parameters with respect to categories of anaemia and outcome (in-hospital death) with respect to haemoglobin, malaria and transfusion status. Results : Among 29,226 admitted children, 1,143 (3.9%) had profound anaemia (Hb <4g/dl) and 3,469 (11.9%) had severe anaemia (Hb 4-6g/d). In-hospital mortality was; 97/1,143 (8.5%) in those with Hb<4g/dl and 164/2,326 (7.1%) in those with severe anaemia (Hb ≥4.0-<6g/dl). Admission Hb <3g/dl was associated with higher risk of death versus those with higher Hbs (OR=2.41 (95%CI: 1.8 - 3.24; P<0.001), increasing to OR=6.36, (95%CI: 4.21–9.62; P<0.001) in malaria positive children. Conversely, mortality in non-malaria admissions was unrelated to Hb level. Transfusion was associated with a non-significant improvement in outcome if Hb<3g/dl (malaria-only) OR 0.72 (95%CI 0.29 - 1.78), albeit the number of cases were too few to show a statistical difference. For those with Hb levels above 4g/dl, mortality was significantly higher in those receiving a transfusion compared to the non-transfused group. For non-malarial cases, transfusion did not affect survival-status, irrespective of baseline Hb level compared to children who were not transfused at higher Hb levels. Conclusion : Although severe and complicated anaemia is common among children admitted to hospital in sSA (~16%), our data do not indicate that outcome is improved by transfusion irrespective of malaria status. Given the limi
Tshilolo L, Tomlinson G, Williams TN, et al., 2019, Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa, New England Journal of Medicine, Vol: 380, Pages: 121-131, ISSN: 0028-4793
BackgroundHydroxyurea is an effective treatment for sickle cell anemia, but few studies have been conducted in sub-Saharan Africa, where the burden is greatest. Coexisting conditions such as malnutrition and malaria may affect the feasibility, safety, and benefits of hydroxyurea in low-resource settings.MethodsWe enrolled children 1 to 10 years of age with sickle cell anemia in four sub-Saharan countries. Children received hydroxyurea at a dose of 15 to 20 mg per kilogram of body weight per day for 6 months, followed by dose escalation. The end points assessed feasibility (enrollment, retention, and adherence), safety (dose levels, toxic effects, and malaria), and benefits (laboratory variables, sickle cell–related events, transfusions, and survival).ResultsA total of 635 children were fully enrolled; 606 children completed screening and began receiving hydroxyurea at a mean (±SD) dose of 17.5±1.8 mg per kilogram per day. The retention rate was 94.2% at 3 years of treatment. Hydroxyurea therapy led to significant increases in both the hemoglobin and fetal hemoglobin levels. Dose-limiting toxic events regarding laboratory variables occurred in 5.1% of the participants, which was below the protocol-specified threshold for safety. During the treatment phase, 20.6 dose-limiting toxic effects per 100 patient-years occurred, as compared with 20.7 events per 100 patient-years before treatment. As compared with the pretreatment period, the rates of clinical adverse events decreased with hydroxyurea use, including rates of vaso-occlusive pain (98.3 vs. 44.6 events per 100 patient-years; incidence rate ratio, 0.45; 95% confidence interval [CI], 0.37 to 0.56), nonmalaria infection (142.5 vs. 90.0 events per 100 patient-years; incidence rate ratio, 0.62; 95% CI, 0.53 to 0.72), malaria (46.9 vs. 22.9 events per 100 patient-years; incidence rate ratio, 0.49; 95% CI, 0.37 to 0.66), transfusion (43.3 vs. 14.2 events per 100 patient-years; incidence rate ratio, 0
Muthui M, Mogeni P, Mwai K, et al., 2019, Gametocyte carriage in an era of changing malaria epidemiology: A 19-year analysis of a malaria longitudinal cohort
<h4>Background: </h4> Interventions to block malaria transmission from humans to mosquitoes are currently in development. To be successfully implemented, key populations need to be identified where the use of these transmission-blocking and/or reducing strategies will have greatest impact. <h4>Methods: </h4>: We used data from a longitudinally monitored cohort of children from Kilifi county located along the Kenyan coast collected between 1998-2016 to describe the distribution and prevalence of gametocytaemia in relation to transmission intensity, time and age. Data from 2,223 children accounting for 9,134 person-years of follow-up assessed during cross-sectional surveys for asexual parasites and gametocytes were used in logistic regression models to identify factors predictive of gametocyte carriage in this cohort. <h4>Results: </h4>: Our analysis showed that children 1-5 years of age were more likely to carry microscopically detectable gametocytes than their older counterparts. Carrying asexual parasites and recent episodes of clinical malaria were also strong predictors of gametocyte carriage. The prevalence of asexual parasites and of gametocyte carriage declined over time, and after 2006, when artemisinin combination therapy (ACT) was introduced, recent episodes of clinical malaria ceased to be a predictor of gametocyte carriage. <h4>Conclusions: </h4>: Gametocyte carriage in children in Kilifi has fallen over time. Previous episodes of clinical malaria may contribute to the development of carriage, but this appears to be mitigated by the use of ACTs highlighting the impact that gametocidal antimalarials can have in reducing the overall prevalence of gametocytaemia when targeted on acute febrile illness.
Adetifa IMO, Karia B, Mutuku A, et al., 2018, Coverage and timeliness of vaccination and the validity of routine estimates: Insights from a vaccine registry in Kenya, Vaccine, Vol: 36, Pages: 7965-7974, ISSN: 0264-410X
BackgroundThe benefits of childhood vaccines are critically dependent on vaccination coverage. We used a vaccine registry (as gold standard) in Kenya to quantify errors in routine coverage methods (surveys and administrative reports), to estimate the magnitude of survivor bias, contrast coverage with timeliness and use both measures to estimate population immunity.MethodsVaccination records of children in the Kilifi Health and Demographic Surveillance System (KHDSS), Kenya were combined with births, deaths, migration and residence data from 2010 to 17. Using inverse survival curves, we estimated up-to-date and age-appropriate vaccination coverage, calculated mean vaccination coverage in infancy as the area under the inverse survival curves, and estimated the proportion of fully immunised children (FIC). Results were compared with published coverage estimates. Risk factors for vaccination were assessed using Cox regression models.ResultsWe analysed data for 49,090 infants and 48,025 children aged 12–23 months in 6 birth cohorts and 6 cross-sectional surveys respectively, and found 2nd year of life surveys overestimated coverage by 2% compared to birth cohorts. Compared to mean coverage in infants, static coverage at 12 months was exaggerated by 7–8% for third doses of oral polio, pentavalent (Penta3) and pneumococcal conjugate vaccines, and by 24% for the measles vaccine. Surveys and administrative coverage also underestimated the proportion of the fully immunised child by 10–14%. For BCG, Penta3 and measles, timeliness was 23–44% higher in children born in a health facility but 20–37% lower in those who first attended during vaccine stock outs.ConclusionsStandard coverage surveys in 12–23 month old children overestimate protection by ignoring timeliness, and survivor and recall biases. Where delayed vaccination is common, up-to-date coverage will give biased estimates of population immunity. Surveys and administrative methods also
Byrd KA, Williams TN, Lin A, et al., 2018, Sickle cell and α+-Thalassemia traits influence the association between ferritin and hepcidin in rural Kenyan children aged 14–26 months, The Journal of Nutrition, Vol: 148, Pages: 1903-1910, ISSN: 0022-3166
BackgroundThe relation between subclinical hemoglobinopathies and concentrations of the iron-regulatory hormone hepcidin is not well characterized.ObjectiveWe investigated the relation of hepcidin concentration with hemoglobinopathies among young children in Kenya.MethodsWe quantified serum hepcidin and ferritin in 435 Kenyan children aged 14–20 mo in a subsample of the Water, Sanitation, and Handwashing (WASH) Benefits Trial. Blood samples were genotyped for α+-thalassemia and for sickle cell disorder. Hepcidin was compared across sickle cell and α+-thalassemia genotypes separately by using generalized linear models, and children who were normozygous for both conditions were also compared with those who had either of these conditions. In the association between hepcidin and ferritin, we assessed effect modification by genotype.ResultsIn this population, we found that 16.2% had sickle cell trait and 0.2% had sickle cell disorder, whereas 40.0% were heterozygous for α+-thalassemia and 8.2% were homozygous. Hepcidin concentration did not differ by genotype, but effect modification was found by genotype in the association between hepcidin and ferritin (P < 0.1). Among normozygous sickle cell children (HbAA), there was an association between hepcidin and ferritin (β = 0.92; 95% CI: 0.72, 1.10). However, among those with sickle cell trait (HbAS), the association was no longer significant (β = 0.31; 95% CI: −0.04, 0.66). Similarly, among children who were normozygous (αα/αα) or heterozygous (−α/αα) for α+-thalassemia, hepcidin and ferritin were significantly associated [β = 0.94 (95% CI: 0.68, 1.20) and β = 0.77 (95% CI: 0.51, 1.03), respectively]; however, in children who were homozygous for α+-thalassemia (−α/−α), there was no longer a significant association (β = 0.45; 95% CI: −0.10, 1.00).ConclusionHepcidin was not associa
Tshilolo L, Tomlinson G, Williams TN, et al., 2018, Realizing Effectiveness across Continents with Hydroxyurea (REACH): A Prospective Multi-National Trial of Hydroxyurea for Sickle Cell Anemia in Sub-Saharan Africa, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Macharia AW, Uyoga S, Ndila C, et al., 2018, The population dynamics of haemoglobins A, A2, F and S in the context of the haemoglobinopathies HbS and α+thalassaemia in Kenyan infants, Haematologica, Vol: 104, Pages: e184-e186, ISSN: 0390-6078
Few studies have described the dynamics of haemoglobin production in African populations with a high prevalence of haemoglobinopathies. We have used the BioRad Variant ClassicTM HPLC method to document the production patterns of the common haemoglobin variants HbA, HbA2, HbF and HbS, stratified by a+thalassaemia genotype, among 15,301 infants recruited to a study on the Coast of Kenya. Notably, we confirm that HbA2 measurements determined using this instrument are unreliable in HbAS and HbSS subjects. Further, we showed that HbA2 exceeded 4.0%, a level consistent with the presence of a-thalassaemia, in 0.8% of infants of HbAA phenotype who participated in our study. a-thalassaemia, has not been widely reported in the East Africa region and, as such, this finding merits further study.
Ndila C, Uyoga S, Macharia A, et al., 2018, Human candidate gene polymorphisms and malaria in Kilifi, Kenya: A case-control association study, The Lancet Haematology, Vol: 5, Pages: e333-e345, ISSN: 2352-3026
BackgroundHuman genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress.MethodsWe did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria.FindingsBetween June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell tra
Opi DH, Swann O, Macharia A, et al., 2018, Two complement receptor one alleles have opposing associations with cerebral malaria and interact with ethalassaemia, eLife, Vol: 7, ISSN: 2050-084X
Malaria has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor One (CR1) gene, named Sl2 and McCb, occur at high frequencies, consistent with selection by malaria. Previous studies have been inconclusive. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, we estimate the relationship between Sl2 and McCb and malaria phenotypes, and find they have opposing associations. The Sl2 polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the McCb polymorphism is associated with increased odds of cerebral malaria. We also identify an apparent interaction between Sl2 and α+thalassaemia, with the protective association of Sl2 greatest in children with normal α-globin. The complex relationship between these three mutations may explain previous conflicting findings, highlighting the importance of considering genetic interactions in disease-association studies.
Gilchrist JJ, Mentzer AJ, Rautanen A, et al., 2018, Genetic variation inVAC14is associated with bacteremia secondary to diverse pathogens in African children, Proceedings of the National Academy of Sciences, Vol: 115, Pages: E3601-E3603, ISSN: 0027-8424
Williams TN, Thein SL, 2018, Sickle Cell Anemia and Its Phenotypes., Annu Rev Genomics Hum Genet
In the 100 years since sickle cell anemia (SCA) was first described in the medical literature, studies of its molecular and pathophysiological basis have been at the vanguard of scientific discovery. By contrast, the translation of such knowledge into treatments that improve the lives of those affected has been much too slow. Recent years, however, have seen major advances on several fronts. A more detailed understanding of the switch from fetal to adult hemoglobin and the identification of regulators such as BCL11A provide hope that these findings will be translated into genomic-based approaches to the therapeutic reactivation of hemoglobin F production in patients with SCA. Meanwhile, an unprecedented number of new drugs aimed at both the treatment and prevention of end-organ damage are now in the pipeline, outcomes from potentially curative treatments such as allogeneic hematopoietic stem cell transplantation are improving, and great strides are being made in gene therapy, where methods employing both antisickling β-globin lentiviral vectors and gene editing are now entering clinical trials. Encouragingly, after a century of neglect, the profile of the vast majority of those with SCA in Africa and India is also finally improving. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 19 is August 31, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Lisping M, Skoglund P, Spriggs M, et al., 2018, Population turnover in remote oceania shortly after initial settlement, Current Biology, Vol: 28, Pages: 1157-1165.e7, ISSN: 1879-0445
Ancient DNA from Vanuatu and Tonga dating to about 2,900–2,600 years ago (before present, BP) has revealed that the “First Remote Oceanians” associated with the Lapita archaeological culture were directly descended from the population that, beginning around 5000 BP, spread Austronesian languages from Taiwan to the Philippines, western Melanesia, and eventually Remote Oceania. Thus, ancestors of the First Remote Oceanians must have passed by the Papuan-ancestry populations they encountered in New Guinea, the Bismarck Archipelago, and the Solomon Islands with minimal admixture [1]. However, all present-day populations in Near and Remote Oceania harbor >25% Papuan ancestry, implying that additional eastward migration must have occurred. We generated genome-wide data for 14 ancient individuals from Efate and Epi Islands in Vanuatu from 2900–150 BP, as well as 185 present-day individuals from 18 islands. We find that people of almost entirely Papuan ancestry arrived in Vanuatu by around 2300 BP, most likely reflecting migrations a few hundred years earlier at the end of the Lapita period, when there is also evidence of changes in skeletal morphology and cessation of long-distance trade between Near and Remote Oceania [2, 3]. Papuan ancestry was subsequently diluted through admixture but remains at least 80%–90% in most islands. Through a fine-grained analysis of ancestry profiles, we show that the Papuan ancestry in Vanuatu derives from the Bismarck Archipelago rather than the geographically closer Solomon Islands. However, the Papuan ancestry in Polynesia—the most remote Pacific islands—derives from different sources, documenting a third stream of migration from Near to Remote Oceania.
McGann PT, Williams TN, Olupot-Olupot P, et al., 2018, Realizing effectiveness across continents with hydroxyurea: Enrollment and baseline characteristics of the multicenter REACH study in Sub-Saharan Africa, American Journal of Hematology, Vol: 93, Pages: 537-545, ISSN: 0361-8609
Despite its well-described safety and efficacy in the treatment of sickle cell anemia (SCA) in high-income settings, hydroxyurea remains largely unavailable in sub-Saharan Africa, where more than 75% of annual SCA births occur and many comorbidities exist. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) is a prospective, Phase I/II open-label trial of hydroxyurea designed to evaluate the feasibility, safety, and benefits of hydroxyurea treatment for children with SCA in four sub-Saharan African countries. Following comprehensive training of local research teams, REACH was approved by local Ethics Committees and achieved full enrollment ahead of projections with 635 participants enrolled over a 30-month period, despite half of families living >12 km from their clinical site. At enrollment, study participants (age 5.4 ± 2.4 years) had substantial morbidity, including a history of vaso-occlusive pain (98%), transfusion (68%), malaria (85%), and stroke (6%). Significant differences in laboratory characteristics were noted across sites, with lower hemoglobin concentrations (P < .01) in Angola (7.2 ± 1.0 g/dL) and the DRC (7.0 ± 0.9 g/dL) compared to Kenya (7.4 ± 1.1 g/dL) and Uganda (7.5 ± 1.1 g/dL). Analysis of known genetic modifiers of SCA demonstrated a high frequency of α-thalassemia (58.4% with at least a single α-globin gene deletion) and G6PD deficiency (19.7% of males and 2.4% of females) across sites. The CAR β-globin haplotype was present in 99% of participants. The full enrollment to REACH confirms the feasibility of conducting high-quality SCA research in Africa; this study will provide vital information to guide safe and effective dosing of hydroxyurea for children with SCA living in Africa.
Gilchrist J, Rautanen A, Fairfax B, et al., 2018, Risk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4, Nature Communications, Vol: 9, ISSN: 2041-1723
Nontyphoidal Salmonella (NTS) is a major cause of bacteraemia in Africa. The disease typically affects HIV-infected individuals and young children, causing substantial morbidity and mortality. Here we present a genome-wide association study (180 cases, 2677 controls) and replication analysis of NTS bacteraemia in Kenyan and Malawian children. We identify a locus in STAT4, rs13390936, associated with NTS bacteraemia. rs13390936 is a context-specific expression quantitative trait locus for STAT4 RNA expression, and individuals carrying the NTS-risk genotype demonstrate decreased interferon-γ (IFNγ) production in stimulated natural killer cells, and decreased circulating IFNγ concentrations during acute NTS bacteraemia. The NTS-risk allele at rs13390936 is associated with protection against a range of autoimmune diseases. These data implicate interleukin-12-dependent IFNγ-mediated immunity as a determinant of invasive NTS disease in African children, and highlight the shared genetic architecture of infectious and autoimmune disease.
Brent AJ, Nyundo C, Langat J, et al., 2018, Prospective observational study of incidence and preventable burden of childhood tuberculosis, Kenya, Emerging Infectious Diseases, Vol: 24, Pages: 514-523, ISSN: 1080-6040
Substantial progress has been made in the fight against tuberculosis (TB); however, new approaches are needed to achieve the current target set by the World Health Organization (WHO) to reduce TB incidence to 90% of 2016 levels by 2035 (1). A key element of WHO’s End TB Strategy is the prioritization of preventive treatment (2). However, the preventable burden of childhood TB has not been quantified in prospective epidemiologic studies, and globally, only an estimated 7% of eligible children received isoniazid chemoprophylaxis in 2015 (1).Diagnosis of TB is more challenging in children than in adults (3). In low-resource settings, where TB burden is highest, diagnosis often relies on poorly validated clinical algorithms (4). As a result, adequate surveillance data are lacking, and published estimates of the global childhood TB burden vary widely (1,5–11). High-quality prospective data on the TB burden and case detection rate (CDR) in children are recognized priorities (8,11,12), and population-level data showing the preventable burden of childhood TB might reinforce the public health case for chemoprophylaxis in children. We designed the Kilifi Improving Diagnosis and Surveillance of Childhood TB (KIDS TB) Study to estimate the incidence, CDR, risk factors, and preventable burden of childhood TB in Kenya.
Taylor RW, Naw HK, Maitland K, et al., 2018, Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria – a proposed model-derived age-based regimen for sub-Saharan Africa, BMC Medicine, Vol: 16, ISSN: 1741-7015
Background: In 2012, the World Health Organization recommended blocking the transmission of Plasmodiumfalciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), withouttesting for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicatedfalciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa.Methods: Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia,and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectivelydefined therapeutic-dose ranges of 0.15–0.4 mg PQ base/kg for children aged 1–5 years and 0.15–0.5 mg PQ base/kgfor individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged6–11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. Wemodelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals,28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box–Cox transformation powerexponential and tested PQ doses of 1–15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. Results: From the Box–Cox transformation power exponential model, five age categories were selected: (i) 6–11 months(n = 39,886, 6.03%), (ii) 1–5 years (n = 261,036, 45.46%), (iii) 6–9 years (n = 20,770, 3.14%), (iv) 10–14 years (n = 12,155, 1.84%)and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and99th centiles) mg/kg PQ base of: (i) 0.16 (0.12–0.25), (ii) 0.21 (0.13–0.37), (iii) 0.25 (0.16–0.38), (iv) 0.26 (0.15–0.38) and (v) 0.27(0.17–0.40). The proportions of individuals predicted to re
Maitland K, Kiguli S, Opoka R, et al., 2018, Children’s Oxygen Administration Strategies Trial (COAST): A randomised controlled trial of high flow versus oxygen versus control in African children with severe pneumonia, Wellcome Open Research, Vol: 2, Pages: 1-36, ISSN: 2398-502X
Background: In Africa, the clinical syndrome of pneumonia remains the leading cause of morbidity and mortality in children in the post-neonatal period. This represents a significant burden on in-patient services. The targeted use of oxygen and simple, non-invasive methods of respiratory support may be a highly cost-effective means of improving outcome, but the optimal oxygen saturation threshold that results in benefit and the best strategy for delivery are yet to be tested in adequately powered randomised controlled trials. There is, however, an accumulating literature about the harms of oxygen therapy across a range of acute and emergency situations that have stimulated a number of trials investigating permissive hypoxia.Methods: In 4200 African children, aged 2 months to 12 years, presenting to 5 hospitals in East Africa with respiratory distress and hypoxia (oxygen saturation < 92%), the COAST trial will simultaneously evaluate two related interventions (targeted use of oxygen with respect to the optimal oxygen saturation threshold for treatment and mode of delivery) to reduce shorter-term mortality at 48-hours (primary endpoint), and longer-term morbidity and mortality to 28 days in a fractional factorial design, that compares: Liberal oxygenation (recommended care) compared with a strategy that permits hypoxia to SpO2 > or = 80% (permissive hypoxia); and High flow using AIrVO2TM compared with low flow delivery (routine care).Discussion: The overarching objective is to address the key research gaps in the therapeutic use of oxygen in resource-limited setting in order to provide a better evidence base for future management guidelines. The trial has been designed to address the poor outcomes of children in sub-Saharan Africa, which are associated with high rates of in-hospital mortality, 9-10% (for those with oxygen saturations of 80-92%) and 26-30% case fatality for those with oxygen saturations <80%.Clinical trial registration: ISRCTN15622505
Swann O, Harrison E, Opi DH, et al., 2017, No Evidence that Knops Blood Group Polymorphisms Affect Complement Receptor 1 Clustering on Erythrocytes, Scientific Reports, Vol: 7, ISSN: 2045-2322
Clustering of Complement Receptor 1 (CR1) in the erythrocyte membrane is important for immune-complex transfer and clearance. CR1 contains the Knops blood group antigens, including the antithetical pairs Swain-Langley 1 and 2 (Sl1 and Sl2) and McCoy a and b (McCa and McCb), whose functional effects are unknown. We tested the hypothesis that the Sl and McC polymorphisms might influence CR1 clustering on erythrocyte membranes. Blood samples from 125 healthy Kenyan children were analysed by immunofluorescence and confocal microscopy to determine CR1 cluster number and volume. In agreement with previous reports, CR1 cluster number and volume were positively associated with CR1 copy number (mean number of CR1 molecules per erythrocyte). Individuals with the McCb/McCb genotype had more clusters per cell than McCa/McCa individuals. However, this association was lost when the strong effect of CR1 copy number was included in the model. No association was observed between Sl genotype, sickle cell genotype, α+thalassaemia genotype, gender or age and CR1 cluster number or volume. Therefore, after correction for CR1 copy number, the Sl and McCoy polymorphisms did not influence erythrocyte CR1 clustering, and the effects of the Knops polymorphisms on CR1 function remains unknown.
Mogeni P, Williams TN, Omedo I, et al., 2017, Detecting malaria hotspots: a comparison between RDT, microscopy and polymerase chain reaction, Journal of Infectious Diseases, Vol: 216, Pages: 1091-1098, ISSN: 1537-6613
Background:Malaria control strategies need to respond to geographical hotspots of transmission. Detection of hotspots depends on the sensitivity of the diagnostic tool used.Methods:We conducted cross-sectional surveys in three sites within Kilifi County, Kenya, at variable transmission intensities. RDT, Microscopy and PCR testing were used to detect asymptomatic parasitaemia and hotspots were detected using the spatial scan statistic.Results:8581 study participants were surveyed in three sites. There were statistically significant malaria hotspots by RDT, microscopy and PCR for all sites except by microscopy in one low transmission site. Pooled data analysis of hotspots by PCR overlapped with hotspots by microscopy at a moderate setting but not at two lower transmission settings. However, variations in degree of overlap was noted when data were analysed by year. Hotspots by RDT were predictive of PCR/microscopy at the moderate setting, but not at the two low transmission settings. We observed long-term stability of hotspots by PCR and microscopy except for RDT.Conclusion:Malaria control programmes may consider PCR testing to guide asymptomatic malaria hotspot detection once the prevalence of infection falls.
Williams TN, Maitland K, 2017, The clinical epidemiology of sickle cell anemia in Africa, American Journal of Hematology, Vol: 93, Pages: 363-370, ISSN: 0361-8609
Sickle cell anemia (SCA) is the commonest severe monogenic disorders of humans. The disease has been highly characterized in high-income countries but not in sub-Saharan Africa where SCA is most prevalent. We conducted a retrospective cohort study of all children 0-13 years admitted from within a defined study area to Kilifi County Hospital in Kenya over a five-year period. Children were genotyped for SCA retrospectively and incidence rates calculated with reference to population data. Overall, 576 of 18,873 (3.1%) admissions had SCA of whom the majority (399; 69.3%) were previously undiagnosed. The incidence of all-cause hospital admission was 57.2/100 person years of observation (PYO; 95%CI 52.6-62.1) in children with SCA and 3.7/100 PYO (95%CI 3.7-3.8) in those without SCA (IRR 15.3; 95%CI 14.1-16.6). Rates were higher for the majority of syndromic diagnoses at all ages beyond the neonatal period, being especially high for severe anemia (hemoglobin <50g/L) (IRR 58.8; 95%CI 50.3-68.7), stroke (IRR 486; 95%CI 68.4-3,450), bacteremia (IRR 23.4; 95%CI 17.4-31.4), and for bone (IRR 607; 95%CI 284-1,300) and joint (IRR 80.9; 95%CI 18.1-362) infections. The use of an algorithm based on just five clinical features would have identified approximately half of all SCA cases among hospital-admitted children with a number needed to test to identify each affected patient of fourteen. Our study illustrates the clinical epidemiology of SCA in a malaria-endemic environment without specific interventions. The targeted testing of hospital-admitted children using the Kilifi Algorithm provides a pragmatic approach to early-diagnosis in high-prevalence countries where newborn screening is unavailable.
Piel FBJ, Williams TN, 2017, Subphenotypes of sickle cell disease in Africa, Blood, Vol: 130, Pages: 2157-2158, ISSN: 1528-0020
Maitland K, Kiguli S, Opoka RO, et al., 2017, Children’s Oxygen Administration Strategies Trial (COAST): A randomised controlled trial of high flow versus oxygen versus control in African children with severe pneumonia, Wellcome Open Research, Vol: 2, Pages: 100-100, ISSN: 2398-502X
Background: In Africa, the clinical syndrome of pneumonia remains the leading cause of morbidity and mortality in children in the post-neonatal period. This represents a significant burden on in-patient services. The targeted use of oxygen and simple, non-invasive methods of respiratory support may be a highly cost-effective means of improving outcome, but the optimal oxygen saturation threshold that results in benefit and the best strategy for delivery are yet to be tested in adequately powered randomised controlled trials. There is, however, an accumulating literature about the harms of oxygen therapy across a range of acute and emergency situations that have stimulated a number of trials investigating permissive hypoxia.Methods: In 4200 African children, aged 2 months to 12 years, presenting to 5 hospitals in East Africa with respiratory distress and hypoxia (oxygen saturation < 92%), the COAST trial will simultaneously evaluate two related interventions (targeted use of oxygen with respect to the optimal oxygen saturation threshold for treatment and mode of delivery) to reduce shorter-term mortality at 48-hours (primary endpoint), and longer-term morbidity and mortality to 28 days in a fractional factorial design, that compares:Liberal oxygenation (recommended care) compared with a strategy that permits hypoxia to SpO2 > or = 80% (permissive hypoxia); andHigh flow using AIrVO2TM compared with low flow delivery (routine care).Discussion: The overarching objective is to address the key research gaps in the therapeutic use of oxygen in resource-limited setting in order to provide a better evidence base for future management guidelines. The trial has been designed to address the poor outcomes of children in sub-Saharan Africa, which are associated with high rates of in-hospital mortality, 9-10% (for those with oxygen saturations of 80-92%) and 26-30% case fatality for those with oxygen saturations <80%.
Omedo I, Mogeni P, Bousema T, et al., 2017, Micro-epidemiological structuring of Plasmodium falciparum parasite populations in regions with varying transmission intensities in Africa [version 2; peer review: 4 approved], Wellcome Open Research, Vol: 2, ISSN: 2398-502X
Background: The first models of malaria transmission assumed a completely mixed and homogeneous population of parasites. Recent models include spatial heterogeneity and variably mixed populations. However, there are few empiric estimates of parasite mixing with which to parametize such models. Methods: Here we genotype 276 single nucleotide polymorphisms (SNPs) in 5199 P. falciparum isolates from two Kenyan sites (Kilifi county and Rachuonyo South district) and one Gambian site (Kombo coastal districts) to determine the spatio-temporal extent of parasite mixing, and use Principal Component Analysis (PCA) and linear regression to examine the relationship between genetic relatedness and distance in space and time for parasite pairs. Results: Using 107, 177 and 82 SNPs that were successfully genotyped in 133, 1602, and 1034 parasite isolates from The Gambia, Kilifi and Rachuonyo South district, respectively, we show that there are no discrete geographically restricted parasite sub-populations, but instead we see a diffuse spatio-temporal structure to parasite genotypes. Genetic relatedness of sample pairs is predicted by relatedness in space and time. Conclusions: Our findings suggest that targeted malaria control will benefit the surrounding community, but unfortunately also that emerging drug resistance will spread rapidly through the population.
Nardo-Marino A, Williams TN, 2017, The frequency and severity of epistaxis in children with sickle cell anaemia in Eastern Uganda: a case-control study, BMC Hematology, Vol: 17, ISSN: 2052-1839
Background: There are a paucity of data on epistaxis as it pertains to sickle cell anaemia. Some case studies suggestepistaxis to be a significant complication in patients with sickle cell anaemia in sub-Saharan Africa; however, no robuststudies have sought to establish the epidemiology or pathophysiology of this phenomenon.Methods: We conducted a case-control study with the aim of investigating the importance of epistaxis among childrenpresenting with sickle cell anaemia at the Mbale Regional Referral Hospital in eastern Uganda. Cases were children aged2–15 years with an existing diagnosis of laboratory confirmed sickle cell anaemia, while controls were children withoutsickle cell anaemia who were frequency matched to cases on the basis of age group and gender. The frequency andseverity of epistaxis was assessed using a structured questionnaire developed specifically for this study. Odds ratioscontrolled for age group and gender were calculated using unconditional logistic regression.Results: A total of 150 children were included, 73 children with sickle cell anaemia and 77 children without sickle cellanaemia. The overall prevalence of epistaxis among children with sickle cell anaemia and children without sickle cellanaemia was 32.9 and 23.4% respectively. The case-control odds ratios for epistaxis, recurrent epistaxis and severeepistaxis were, 1.6 (95%CI 0.8–3.4; p = 0.2), 7.4 (1.6–34.5; 0.01), and 8.3 (1.0–69.8; 0.05) respectively.Conclusions: Our results suggest that in eastern Uganda, children with sickle cell anaemia experience epistaxismore frequently and with greater severity than children without sickle cell anaemia. Further studies are indicatedto confirm this conclusion and investigate aetiology.
Mugyenyi CK, Elliott SR, Yap XZ, et al., 2017, Declining malaria transmission differentially impacts on the maintenance of humoral immunity to Plasmodium falciparum in children, Journal of Infectious Diseases, Vol: 216, Pages: 887-898, ISSN: 0022-1899
BACKGROUNDWe investigated the poorly understood impact of declining malaria transmission on maintenance of antibodies to P. falciparum merozoite antigens and infected erythrocytes (IEs), including functional immunity.METHODSIn a 3-year longitudinal cohort of 300 Kenyan children, antibodies to different merozoite AMA1 and MSP2 alleles, IE surface antigens, and antibody functional activities were quantified.RESULTSOver a period in which malaria transmission declined markedly, AMA1 and MSP2 antibodies decreased substantially; estimated half-lives of antibody duration were 0.8 and 1-3 years, respectively. However, 69-74% of children maintained their sero-positivity to AMA1 alleles and 42-52% to MSP2 alleles. Levels and prevalence of anti-merozoite antibodies were consistently associated with increasing age and concurrent parasitaemia. Antibodies promoting opsonic phagocytosis of merozoites declined rapidly (half-life 0.15 years). In contrast, complement-fixing antibodies to merozoites did not decline and antibodies to IE surface antigens expressing virulent phenotypes were much better maintained (half-life 4-10 years).CONCLUSIONSA decline in malaria transmission is associated with reduction in naturally-acquired immunity. However, loss of immunity is not universal; some key functional responses and antibodies to IEs were better maintained and these may continue to provide some protection. Findings have implications for malaria surveillance and control measures and informing vaccine development.
Nyundo C, Doyle A, Walumbe D, et al., 2017, Linking health facility data from young adults aged 18-24 years to longitudinal demographic data: Experience from The Kilifi Health and Demographic Surveillance System, Wellcome Open Research, Vol: 2, ISSN: 2398-502X
Background: In 2014, a pilot study was conducted to test the feasibility of linking clinic attendance data for young adults at two health facilities to the population register of the Kilifi Health and Demographic Surveillance System (KHDSS). This was part of a cross-sectional survey of health problems of young people, and we tested the feasibility of using the KHDSS platform for the monitoring of future interventions. Methods: Two facilities were used for this study. Clinical data from consenting participants aged 18-24 years were matched to KHDSS records. Data matching was achieved using national identity card numbers or otherwise using a matching algorithm based on names, sex, date of birth, location of residence and the names of other homestead members. A study form was administered to all matched patients to capture reasons for their visits and time taken to access the services. Distance to health facility from a participants’ homestead was also computed. Results: 628 participated in the study: 386 (61%) at Matsangoni Health Centre, and 242 (39%) at Pingilikani Dispensary. 610 (97%) records were matched to the KHDSS register. Most records (605; 96%) were matched within these health facilities, while 5 (1%) were matched during homestead follow-up visits. 463 (75.9%) of those matched were women. Antenatal care (25%), family planning (13%), respiratory infections (9%) and malaria (9%) were the main reasons for seeking care. Antenatal clinic visits (n=175) and malaria (n=27) were the commonest reasons among women and men, respectively. Participants took 1-1.5 hours to access the services; 490 (81.0%) participants lived within 5 kilometres of a facility. Conclusions: With a full-time research clerk at each health facility, linking health-facility attendance data to a longitudinal HDSS platform was feasible and could be used to monitor and evaluate the impact of health interventions on health care outcomes among young people.
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