SummaryBackgroundMany investigators have suggested that malaria infection predisposes individuals to bacteraemia. We tested this hypothesis with mendelian randomisation studies of children with the malaria-protective phenotype of sickle-cell trait (HbAS).MethodsThis study was done in a defined area around Kilifi District Hospital, Kilifi, Kenya. We did a matched case-control study to identify risk factors for invasive bacterial disease, in which cases were children aged 3 months to 13 years who were admitted to hospital with bacteraemia between Sept 16, 1999, and July 31, 2002. We aimed to match two controls, by age, sex, location, and time of recruitment, for every case. We then did a longitudinal case-control study to assess the relation between HbAS and invasive bacterial disease as malaria incidence decreased. Cases were children aged 0–13 years who were admitted to hospital with bacteraemia between Jan 1, 1999, and Dec 31, 2007. Controls were born in the study area between Jan 1, 2006, and June 23, 2009. Finally, we modelled the annual incidence of bacteraemia against the community prevalence of malaria during 9 years with Poisson regression.ResultsIn the matched case-control study, we recruited 292 cases—we recruited two controls for 236, and one for the remaining 56. Sickle-cell disease, HIV, leucocyte haemozoin pigment, and undernutrition were positively associated with bacteraemia and HbAS was strongly negatively associated with bacteraemia (odds ratio 0·36; 95% CI 0·20–0·65). In the longitudinal case-control study, we assessed data from 1454 cases and 10 749 controls. During the study period, the incidence of admission to hospital with malaria per 1000 child-years decreased from 28·5 to 3·45, with a reduction in protection afforded by HbAS against bacteraemia occurring in parallel (p=0·0008). The incidence of hospital admissions for bacteraemia per 1000 child-years also decreased from 2·59 to 1·45. The bacteraemia incidence rate ratio associated with malaria parasitaemia was 6·69 (95% CI 1·31–34·3) and, at a community parasite prevalence of 29% in 1999, 62% (8·2–91) of bacteraemia cases were attributable to malaria.InterpretationMalaria infection strongly predisposes individuals to bacteraemia and can account for more than half of all cases of bacteraemia in malaria-endemic areas. Interventions to control malaria will have a major additional benefit by reducing the burden of invasive bacterial disease.FundingWellcome Trust.

The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria 1 . In sub-Saharan Africa, two such conditions occur at particularly high frequencies: presence of the structural variant hemoglobin S and α + -thalassemia, a condition characterized by reduced production of the normal α-globin component of hemoglobin. Individually, each is protective against severe Plasmodium falciparum malaria 2-4 , but little is known about their malaria-protective effects when inherited in combination. We investigated this question by studying a population on the coast of Kenya and found that the protection afforded by each condition inherited alone was lost when the two conditions were inherited together, to such a degree that the incidence of both uncomplicated and severe P. falciparum malaria was close to baseline in children heterozygous with respect to the mutation underlying the hemoglobin S variant and homozygous with respect to the mutation underlying α + -thalassemia. Negative epistasis could explain the failure of α + -thalassemia to reach fixation in any population in subSaharan Africa.The mutation underlying the hemoglobin S variant (HbS) is a prototypical example of a balanced polymorphism: its frequency in populations is determined both by positive selection for heterozygosity (HbAS) 5 and negative selection for homozygosity (HbSS), which causes sickle cell disease, a debilitating condition associated with chronic anemia and premature death. Negative selection has not been shown to affect the frequency of α + -thalassemias. Perhaps as a consequence, these conditions approach fixation in a number of populations; for unknown reasons, however, frequencies remain relatively low in much of sub-Saharan Africa 1 .Despite conclusive evidence that both HbAS and α + -thalassemia protect against severe and fatal P. falciparum malaria 2-4 , the mechanisms underlying this protection are poorly 6,7 , and parasite-infected HbAS erythrocytes also seem to be targeted for premature destruction by the spleen 6,8,9 . These hypothetical mechanisms are supported by both the reduced incidence of clinical malaria and the lower parasite densities observed in children with HbAS erythrocytes when they suffer from clinical attacks 3,10 . Much less is known about α + -thalassemia. Although both heterozygosity (-α/αα) and homozygosity (-α/-α) with respect to the underlying mutation protect against severe and fatal malaria 2,4 , neither protects against uncomplicated malaria 11 or affects parasite densities during incident episodes 2,12 . We believe that a better understanding of how these conditions protect against malaria might provide insights into both the pathophysiology of severe malaria and the hostparasite relationship more generally 10 . Accordingly, we studied the effects of both HbAS and α + -thalassemia on the epidemiology of malaria in children living on the coast of Kenya.We measured the incidence of P. falciparum malaria in two cohorts of children from Kilifi District, where al...

The spread of SARS-CoV-2 in Africa is poorly described. The first case of SARS-CoV-2 in Kenya was reported on March 12, 2020 and an overwhelming number of cases and deaths were expected but by July 31, 2020 there were only 20,636 cases and 341 deaths. However, the extent of SARS-CoV-2 exposure in the community remains unknown. We determined the prevalence of anti–SARS-CoV-2 IgG among blood donors in Kenya in April-June 2020. Crude seroprevalence was 5.6% (174/3098). Population-weighted, test-performance-adjusted national seroprevalence was 4.3% (95% CI 2.9–5.8%) and was highest in urban counties, Mombasa (8.0%), Nairobi (7.3%) and Kisumu (5.5%). SARS-CoV-2 exposure is more extensive than indicated by case-based surveillance and these results will help guide the pandemic response in Kenya, and across Africa.

SummaryBackgroundIn sub-Saharan Africa, more than 90% of children with sickle-cell anaemia die before the diagnosis can be made. The causes of death are poorly documented, but bacterial sepsis is probably important. We examined the risk of invasive bacterial diseases in children with sickle-cell anaemia.MethodsThis study was undertaken in a rural area on the coast of Kenya, with a case–control approach. We undertook blood cultures on all children younger than 14 years who were admitted from within a defined study area to Kilifi District Hospital between Aug 1, 1998, and March 31, 2008; those with bacteraemia were defined as cases. We used two sets of controls: children recruited by random sampling in the same area into several studies undertaken between Sept 1, 1998, and Nov 30, 2005; and those born consecutively within the area between May 1, 2006, and April 30, 2008. Cases and controls were tested for sickle-cell anaemia retrospectively.FindingsWe detected 2157 episodes of bacteraemia in 38 441 admissions (6%). 1749 of these children with bacteraemia (81%) were typed for sickle-cell anaemia, of whom 108 (6%) were positive as were 89 of 13 492 controls (1%). The organisms most commonly isolated from children with sickle-cell anaemia were Streptococcus pneumoniae (44/108 isolates; 41%), non-typhi Salmonella species (19/108; 18%), Haemophilus influenzae type b (13/108; 12%), Acinetobacter species (seven of 108; 7%), and Escherichia coli (seven of 108; 7%). The age-adjusted odds ratio for bacteraemia in children with sickle-cell anaemia was 26·3 (95% CI 14·5–47·6), with the strongest associations for S pneumoniae (33·0, 17·4–62·8), non-typhi Salmonella species (35·5, 16·4–76·8), and H influenzae type b (28·1, 12·0–65·9).InterpretationThe organisms causing bacteraemia in African children with sickle-cell anaemia are the same as those in developed countries. Introduction of conjugate vaccines against S pneumoniae and H influenzae into the childhood immunisation schedules of African countries could substantially affect survival of children with sickle-cell anaemia.FundingWellcome Trust, UK.

Background There are no data on SARS-CoV-2 seroprevalence in Africa though the COVID-19 epidemic curve and reported mortality differ from patterns seen elsewhere. We estimated the anti-SARS-CoV-2 antibody prevalence among blood donors in Kenya. Methods We measured anti-SARS-CoV-2 spike IgG prevalence by ELISA on residual blood donor samples obtained between April 30 and June 16, 2020. Assay sensitivity and specificity were 83% (95% CI 59, 96%) and 99.0% (95% CI 98.1, 99.5%), respectively. National seroprevalence was estimated using Bayesian multilevel regression and post-stratification to account for non-random sampling with respect to age, sex and region, adjusted for assay performance. Results Complete data were available for 3098 of 3174 donors, aged 15-64 years. By comparison with the Kenyan population, the sample over-represented males (82% versus 49%), adults aged 25-34 years (40% versus 27%) and residents of coastal Counties (49% versus 9%). Crude overall seroprevalence was 5.6% (174/3098). Population-weighted, test-adjusted national seroprevalence was 5.2% (95% CI 3.7, 7.1%). Seroprevalence was highest in the 3 largest urban Counties; Mombasa (9.3% [95% CI 6.4, 13.2%)], Nairobi (8.5% [95% CI 4.9, 13.5%]) and Kisumu (6.5% [95% CI 3.3, 11.2%]). Conclusions We estimate that 1 in 20 adults in Kenya had SARS-CoV-2 antibodies during the study period. By the median date of our survey, only 2093 COVID-19 cases and 71 deaths had been reported through the national screening system. This contrasts, by several orders of magnitude, with the numbers of cases and deaths reported in parts of Europe and America when seroprevalence was similar.

Many human genetic associations with resistance to malaria have been reported but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. There was strong evidence of association with the HBB, ABO, ATP2B4, G6PD and CD40LG loci but previously reported associations at 22 other loci did not replicate in the multi-centre analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anaemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.

Although the ␣ ؉ thalassemias almost certainly confer protection against death from malaria, this has not been formally documented. We have conducted a study involving 655 case patients with rigorously defined severe malaria and 648 controls, frequency matched on area of residence and ethnic group. The prevalence of both heterozygous and homozygous ␣ ؉ thalassemia was reduced in both case patients with severe malaria (ad-

BackgroundThe α-thalassaemias are the commonest genetic disorders of humans. It is generally believed that this high frequency reflects selection through a survival advantage against death from malaria; nevertheless, the epidemiological description of the relationships between α-thalassaemia, malaria, and other common causes of child mortality remains incomplete.Methods and FindingsWe studied the α +-thalassaemia-specific incidence of malaria and other common childhood diseases in two cohorts of children living on the coast of Kenya. We found no associations between α +-thalassaemia and the prevalence of symptomless Plasmodium falciparum parasitaemia, the incidence of uncomplicated P. falciparum disease, or parasite densities during mild or severe malaria episodes. However, we found significant negative associations between α +-thalassaemia and the incidence rates of severe malaria and severe anaemia (haemoglobin concentration < 50 g/l). The strongest associations were for severe malaria anaemia (> 10,000 P. falciparum parasites/μl) and severe nonmalaria anaemia; the incidence rate ratios and 95% confidence intervals (CIs) for α +-thalassaemia heterozygotes and homozygotes combined compared to normal children were, for severe malaria anaemia, 0.33 (95% CI, 0.15,0.73; p = 0.006), and for severe nonmalaria anaemia, 0.26 (95% CI, 0.09,0.77; p = 0.015). ConclusionsOur observations suggest, first that selection for α +-thalassaemia might be mediated by a specific effect against severe anaemia, an observation that may lead to fresh insights into the aetiology of this important condition. Second, although α +-thalassaemia is strongly protective against severe and fatal malaria, its effects are not detectable at the level of any other malaria outcome; this result provides a cautionary example for studies aimed at testing malaria interventions or identifying new malaria-protective genes.