Bacterial Infection in the Sickle Cell Population: Development and Enabling Factors.

The high frequency of bacterial infections represents a major threat to public health. In developing countries, they are still responsible for significant morbidity and mortality in pediatric populations with sickle cell disease, particularly in children under 5 years of age. Indeed, they have an increased susceptibility to bacterial infections due to their immune deficiency. This susceptibility is even greater for pneumococcal and salmonella infections. In addition, the underdevelopment of some countries and socio-economic factors increases this condition. This review examines the common and specific factors leading to infections in people with sickle cell disease in different types of developed and undeveloped countries. The threat of bacterial infections, particularly those caused by S. pneumoniae and Salmonella, is of increasing concern due to the rise in bacterial resistance to antibiotics. In light of this disturbing data, new strategies to control and prevent these infections are needed. Solutions could be systematic penicillin therapy, vaccinations, and probabilistic antibiotic therapy protocols.

Cell-derived microparticles and sickle cell disease chronic vasculopathy in sub-Saharan Africa: A multinational study.

Although most individuals with sickle cell disease (SCD) live in sub-Saharan Africa, the natural history of the disease on this continent remains largely unknown. Intravascular haemolysis results in activation of circulating blood cells and release of microparticles (MPs) that exert pro-inflammatory effects and contribute to vascular damage. We designed a case-control study nested in the CADRE cohort (Coeur-Artère-DRÉpanocytose, clinical trials.gov identifier NCTO3114137) and based on extreme phenotypes, to analyse blood cell-derived MPs in 232 adult SS patients at steady state in Bamako and Dakar. Thirty-six healthy adult controls matched by age and sex were recruited in Bamako. The MPs concentrations were higher in SS patients compared to AA controls with a predominance of erythrocyte- and reticulocyte-derived MPs. These erythroid-derived MPs were significantly lower in patients with retinopathy (P = 0·022). Reticulocyte-derived MPs were significantly negatively and positively associated with a history of priapism (P = 0·020) and leg ulcers (P = 0·041) respectively. We describe for the first time the comparative patterns of plasma MPs in healthy subjects and patients with SCD living in sub-Saharan Africa and exhibiting various complications. Because our present results show no clear pattern of correlation between erythroid MPs and the classical hyper-haemolytic complications, we hypothesise a weak relevance of the hyper-haemolysis versus hyper-viscous paradigm in Africa.

[Gastrointestinal symptoms revealing COVID-19 in Malian breast cancer patient undergoing chemotherapy]. / Troubles digestifs révélateurs de la COVID-19 chez une patiente sous chimiothérapie pour cancer du sein au Mali.

In this review, we report a case of a bone's metastatic breast cancer in Malian patient treated by chemotherapy in whom SRAS-COV-2's diagnosis was made 9days after the onset gastrointestinal symptoms. Patient quickly died before any COVID-19's treatment. According to the poor outcomes of cancer patients with COVID-19, authors emphasize to an intensive attention to such patients in order to find the best therapeutic balance between the two pathologies during this pandemic.

Epitope-based sieve analysis of Plasmodium falciparum sequences from a FMP2.1/AS02A vaccine trial is consistent with differential vaccine efficacy against immunologically relevant AMA1 variants.

To prevent premature dismissal of promising vaccine programs, it is critical to determine if lack of efficacy in the field is due to allele specific-efficacy, rather than to the lack of immunogenicity of the candidate antigen. Here we use samples collected during a field trial of the AMA1-based FMP2.1/AS02A malaria vaccine, which incorporates the AMA1 variant encoded by the reference Plasmodium falciparum 3D7 strain, to assess the usefulness of epitope-based sieve analysis for the detection of vaccine-induced allele-specific immune responses. The samples used are from volunteers who received the malaria vaccine FMP2.1/AS02A or a control (rabies vaccine), during a vaccine efficacy field trial, and who later developed malaria. In a previous study, P. falciparum DNA was extracted from all samples, and the ama1 locus amplified and sequenced. Here, a sieve analysis was used to measure T and B-cell escape, and difference in 3D7-like epitopes in the two treatment arms. Overall, no difference was observed in mean amino acid distance to the 3D7 AMA1 variant between sequences from vaccinees and controls in B-cell epitopes. However, we found a significantly greater proportion of 3D7-like T-cell epitopes that map to the AMA1 cluster one loop (c1L) region in the control vs. the vaccinee group (p = 0.02), consistent with allele-specific vaccine efficacy. Interestingly, AMA1 epitopes in infections from vaccinees had higher mean IC50, and consequently lower binding affinity, than epitopes generated from the control group (p = 0.01), suggesting that vaccine-induced selection impacted the immunological profile of the strains that pass through the sieve imposed by the vaccine-induced protection. These findings are consistent with a vaccine-derived sieve effect on the c1L region of AMA1 and suggest that sieve analyses of malaria vaccine trial samples targeted to epitopes identified in silico can help identify protective malaria antigens that may be efficacious if combined in a multivalent vaccine.

Identifying Clinical and Research Priorities in Sickle Cell Lung Disease. An Official American Thoracic Society Workshop Report.

Background: Pulmonary complications of sickle cell disease (SCD) are diverse and encompass acute and chronic disease. The understanding of the natural history of pulmonary complications of SCD is limited, no specific therapies exist, and these complications are a primary cause of morbidity and mortality.Methods: We gathered a multidisciplinary group of pediatric and adult hematologists, pulmonologists, and emergency medicine physicians with expertise in SCD-related lung disease along with an SCD patient advocate for an American Thoracic Society-sponsored workshop to review the literature and identify key unanswered clinical and research questions. Participants were divided into four subcommittees on the basis of expertise: 1) acute chest syndrome, 2) lower airways disease and pulmonary function, 3) sleep-disordered breathing and hypoxia, and 4) pulmonary vascular complications of SCD. Before the workshop, a comprehensive literature review of each subtopic was conducted. Clinically important questions were developed after literature review and were finalized by group discussion and consensus.Results: Current knowledge is based on small, predominantly observational studies, few multicenter longitudinal studies, and even fewer high-quality interventional trials specifically targeting the pulmonary complications of SCD. Each subcommittee identified the three or four most important unanswered questions in their topic area for researchers to direct the next steps of clinical investigation.Conclusions: Important and clinically relevant questions regarding sickle cell lung disease remain unanswered. High-quality, multicenter, longitudinal studies and randomized clinical trials designed and implemented by teams of multidisciplinary clinician-investigators are needed to improve the care of individuals with SCD.

Prevalence and correlates of growth failure in young African patients with sickle cell disease.

Growth failure (GF) in children with sickle cell disease (SCD) tends to decline in high-income countries, but data are lacking in sub-Saharan Africa. We performed a cross-sectional study nested in the CADRE (Cœur, Artères et DREpanocytose) cohort in Mali, Senegal, Cameroon, Gabon and the Ivory Coast. SCD patients and healthy controls aged 5-21 years old were recruited (n = 2583). Frequency of GF, defined as a height, weight or body mass index below the 5th percentile on World health Organization growth charts, was calculated. We assessed associations between GF and SCD phenotypic group, clinical and biological characteristics and history of SCD-related complications. GF was diagnosed in 51% of HbSS, 58% of HbSß0 , 44% of HbSC, 38% of HbSß+ patients and 32% of controls. GF in patients was positively associated with parents' lower education level, male sex, age 12-14 years, lower blood pressure, HbSS or HbSß0 phenotypes, icterus, lower haemoglobin level, higher leucocyte count and microalbuminuria. No association was found between GF and clinical SCD-related complications. In sub-Saharan Africa, GF is still frequent in children with SCD, especially in males and during adolescence. GF is associated with haemolysis and microalbuminuria, but not with the history of SCD-related clinical complications.

Diagnostic accuracy in field conditions of the sickle SCAN® rapid test for sickle cell disease among children and adults in two West African settings: the DREPATEST study.

BACKGROUND: Sickle cell disease (SCD) accounts for 5% of mortality in African children aged < 5 years. Improving the care management and quality of life of patients with SCD requires a reliable diagnosis in resource-limited settings. We assessed the diagnostic accuracy of the rapid Sickle SCAN® point-of-care (POC) test for SCD used in field conditions in two West-African countries. METHODS: We conducted a case-control study in Bamako (Mali) and Lomé (Togo). Known cases of sickle cell disease (HbSS, HbSC), trait (HbAS), HbC heterozygotes (HbAC) and homozygous (HbCC), aged ≥6 months were compared to Controls (HbAA), recruited by convenience. All subjects received both an index rapid POC test and a gold standard (high-performance liquid chromatography in Bamako; capillary electrophoresis in Lomé). Personnel conducting tests were blinded from subjects' SCD status. Sensitivity and specificity were calculated for each phenotype. Practicality was assessed by local healthcare professionals familiar with national diagnostic methods and their associated constraints. RESULTS: In Togo, 209 Cases (45 HbAS, 39 HbAC, 41 HbSS, 44 HbSC and 40 HbCC phenotypes) were compared to 86 Controls (HbAA). 100% sensitivity and specificity were observed for AA Controls and HbCC cases. Estimated sensitivity was 97.7% [95% confidence interval: 88.0-99.9], 97.6% [87.1-99.9%], 95.6% [84.8-99.5%], and 94.9% [82.7-99.4], for HbSC, HbSS, HbAS, and HbAC, respectively. Specificity exceeded 99.2% for all phenotypes. Among 160 cases and 80 controls in Mali, rapid testing was 100% sensitive and specific. Rapid testing was well accepted by local healthcare professionals. CONCLUSION: Rapid POC testing is 100% accurate for homozygote healthy people and excellent (Togo) or perfect (Mali) for sickle cell trait and disease patients. In addition to its comparable diagnostic performance, this test is cheaper, easier to implement, and logistically more convenient than the current standard diagnostic methods in use. Its predictive value indicators and diagnostic accuracy in newborns should be further evaluated prior to implementation in large-scale screening programs in resource-limited settings where SCD is prevalent.

Children with cerebral malaria or severe malarial anaemia lack immunity to distinct variant surface antigen subsets.

Variant surface antigens (VSAs) play a critical role in severe malaria pathogenesis. Defining gaps, or "lacunae", in immunity to these Plasmodium falciparum antigens in children with severe malaria would improve our understanding of vulnerability to severe malaria and how protective immunity develops. Using a protein microarray with 179 antigen variants from three VSA families as well as more than 300 variants of three other blood stage P. falciparum antigens, reactivity was measured in sera from Malian children with cerebral malaria or severe malarial anaemia and age-matched controls. Sera from children with severe malaria recognized fewer extracellular PfEMP1 fragments and were less reactive to specific fragments compared to controls. Following recovery from severe malaria, convalescent sera had increased reactivity to certain non-CD36 binding PfEMP1s, but not other malaria antigens. Sera from children with severe malarial anaemia reacted to fewer VSAs than did sera from children with cerebral malaria, and both of these groups had lacunae in their seroreactivity profiles in common with children who had both cerebral malaria and severe malarial anaemia. This microarray-based approach may identify a subset of VSAs that could inform the development of a vaccine to prevent severe disease or a diagnostic test to predict at-risk children.

Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia.

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.

Phase 1 randomized controlled trial to evaluate the safety and immunogenicity of recombinant Pichia pastoris-expressed Plasmodium falciparum apical membrane antigen 1 (PfAMA1-FVO [25-545]) in healthy Malian adults in Bandiagara.

BACKGROUND: The safety and immunogenicity of PfAMA1, adjuvanted with Alhydrogel(®) was assessed in malaria-experienced Malian adults. The malaria vaccine, PfAMA1-FVO [25-545] is a recombinant protein Pichia pastoris-expressed AMA-1 from Plasmodium falciparum FVO clone adsorbed to Alhydrogel(®), the control vaccine was tetanus toxoid produced from formaldehyde detoxified and purified tetanus toxin. METHODS: A double blind randomized controlled phase 1 study enrolled and followed 40 healthy adults aged 18-55 years in Bandiagara, Mali, West Africa, a rural setting with intense seasonal transmission of P. falciparum malaria. Volunteers were randomized to receive either 50 µg of malaria vaccine or the control vaccine. Three doses of vaccine were given on Days 0, 28 and 56, and participants were followed for 1 year. Solicited symptoms were assessed for seven days and unsolicited symptoms for 28 days after each vaccination. Serious adverse events were assessed throughout the study. The titres of anti-AMA-1 antibodies were measured by ELISA and P. falciparum growth inhibition assays were performed. RESULTS: Commonest local solicited adverse events were the injection site pain and swelling more frequent in the PfAMA1 group. No vaccine related serious adverse events were reported. A significant 3.5-fold increase of anti-AMA-1 IgG antibodies was observed in malaria vaccine recipients four weeks after the third immunization compared to the control group. CONCLUSION: The PfAMA1 showed a good safety profile. Most adverse events reported were of mild to moderate intensity. In addition, the vaccine induced a significant though short-lived increase in the anti-AMA1 IgG titres. Registered on www.clinicaltrials.gov with the number NCT00431808.

Hemoglobin C Trait Provides Protection From Clinical Falciparum Malaria in Malian Children.

BACKGROUND: Hemoglobin C trait, like hemoglobin S trait, protects against severe malaria in children, but it is unclear whether hemoglobin C trait also protects against uncomplicated malaria. We hypothesized that Malian children with hemoglobin C trait would have a lower risk of clinical malaria than children with hemoglobin AA. METHODS: Three hundred children aged 0-6 years were enrolled in a cohort study of malaria incidence in Bandiagara, Mali, with continuous passive and monthly active follow-up from June 2009 to June 2010. RESULTS: Compared to hemoglobin AA children (n = 242), hemoglobin AC children (n = 39) had a longer time to first clinical malaria episode (hazard ratio [HR], 0.19; P = .001; 364 median malaria-free days vs 181 days), fewer episodes of clinical malaria, and a lower cumulative parasite burden. Similarly, hemoglobin AS children (n = 14) had a longer time to first clinical malaria episode than hemoglobin AA children (HR, 0.15; P = .015; 364 median malaria-free days vs 181 days), but experienced the most asymptomatic malaria infections of any group. CONCLUSIONS: Both hemoglobin C and S traits exerted a protective effect against clinical malaria episodes, but appeared to do so by mechanisms that differentially affect the response to infecting malaria parasites.

Interethnic diversity of the CD209 (rs4804803) gene promoter polymorphism in African but not American sickle cell disease.

Elucidating the genomic diversity of CD209 gene promoter polymorphism could assist in clarifying disease pathophysiology as well as contribution to co-morbidities. CD209 gene promoter polymorphism has been shown to be associated with susceptibility to infection. We hypothesize that CD209 mutant variants occur at a higher frequency among Africans and in sickle cell disease. We analyzed the frequency of the CD209 gene (rs4804803) in healthy control and sickle cell disease (SCD) populations and determined association with disease. Genomic DNA was extracted from blood samples collected from 145 SCD and 231 control Africans (from Mali), 331 SCD and 379 control African Americans and 159 Caucasians. Comparative analysis among and between groups was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Per ethnic diversification, we found significant disparity in genotypic (23.4% versus 16.9% versus 3.2%) and allelic frequencies (48.7% versus 42.1% versus 19.8%) of the homozygote mutant variant of the CD209 (snp 309A/G) gene promoter between Africans, African Americans and Caucasians respectively. Comparative evaluation between disease and control groups reveal a significant difference in genotypic (10.4% versus 23.4%; p = 0.002) and allelic frequencies (39.7% versus 48.7%; p = 0.02) of the homozygote mutant variant in African SCD and healthy controls respectively, an observation that is completely absent among Americans. Comparing disease groups, we found no difference in the genotypic (p = 0.19) or allelic (p = 0.72) frequencies of CD209 homozygote mutant variant between Africans and Americans with sickle cell disease. The higher frequency of CD209 homozygote mutant variants in the African control group reveals a potential impairment of the capacity to mount an immune response to infectious diseases, and possibly delineate susceptibility to or severity of infectious co-morbidities within and between groups.

Extensive genomic variability of knops blood group polymorphisms is associated with sickle cell disease in Africa.

Sickle cell disease (SCD) is a multisystem disorder characterized by chronic hemolytic anemia, vaso-occlusive crises, and marked variability in disease severity. Patients require transfusions to manage disease complications, with complements, directed by complement regulatory genes (CR1) and its polymorphisms, implicated in the development of alloantibodies. We hypothesize that CR1 polymorphisms affect complement regulation and function, leading to adverse outcome in SCD. To this end, we determined the genomic diversity of complement regulatory genes by examining single nucleotide polymorphisms associated with Knops blood group antigens. Genomic DNA samples from 130 SCD cases and 356 control Africans, 331 SCD cases and 497 control African Americans, and 254 Caucasians were obtained and analyzed, utilizing a PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) assay. Analyzing for ethnic diversity, we found significant differences in the genotypic and allelic frequencies of Sl1/Sl2 (rs17047661) and McCa/b (rs17047660) polymorphisms between Africans, African Americans, and Caucasians (P < 0.05). The homozygote mutant variants had significantly higher frequencies in Africans and African Americans but were insignificant in Caucasians (80.2% and 59.6% vs 5.9% for Sl1/2; and 36% and 24% vs 1.8% for McCa/b). With SCD, we did not detect any difference among cases and controls either in Africa or in the United States. However, we found significant difference in genotypic (P < 0.0001) and allelic frequencies (P < 0.0001) of Sl1/Sl2 (rs17047661) and McCa/b (rs17047660) polymorphisms between SCD groups from Africa and the United States. There was no difference in haplotype frequencies of these polymorphisms among or between groups. The higher frequency of CR1 homozygote mutant variants in Africa but not United States indicates a potential pathogenic role, possibly associated with complicated disease pathophysiology in the former and potentially protective in the latter. The difference between sickle cell groups suggests potential genetic drift or founder effect imposed on the disease in the United States, but not in Africa, and a possible confirmation of the ancestral susceptibility hypothesis. The lower haplotype frequencies among sickle cell and control populations in the United States may be due to the admixture and the dilution of African genetic ancestry in the African American population.

Endothelin-1 but not Endothelial Nitric Oxide Synthase Gene Polymorphism is Associated with Sickle Cell Disease in Africa.

Sickle cell disease shows marked variability in severity and pathophysiology among individuals, probably linked to differential expression of various adhesion molecules. In this study, we investigated the differential distribution, genomic diversity and haplotype frequency of endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) polymorphisms, recently implicated as important in modification of disease severity. One hundred and forty five sickle cell disease patients (HbSS) and 244 adult and pediatric controls, without sickle cell disease (HbAA), were recruited from Mali. Genotypic analysis of the functionally significant eNOS variants (T786C, G894T and intron 4) and endothelin-1 (G5665T) was carried out with a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Our results show that the wild type alleles are the most frequent for all eNOS variants between cases and controls. Allelic and genotypic frequencies of eNOS polymorphic groups are not significantly different between cases and controls (P > 0.05). In addition, there is no association between eNOS variants and sickle cell disease, contrary to published reports. On the other hand, we report that endothelin-1 (G5665T) mutant variant had the lowest allelic frequency, and is significantly associated with sickle cell disease in Africa (P < 0.05). Similarly, haplotype frequencies were the same between cases and controls, except for the haplotype combining all mutant variants (T, C, 4a; P = 0.01). eNOS polymorphic variants are less frequent, with no significance with sickle cell disease in Africa. On the other hand, endothelin-1 is associated with sickle cell disease, and has the capacity to redefine pathophysiology and possibly serve as modulator of disease phenotype.

Sickle cell disease in sub-Saharan Africa: stakes and strategies for control of the disease.

PURPOSE OF REVIEW: In the late 1990s publications on cohorts of sickle cell disease (SCD) patients, followed since birth, showed that the life expectancy of SCD patients in developed countries could approach that of those without SCD, when managed appropriately. Between 2005 and 2008, SCD was declared as a public health priority issue worldwide. In 2006, the WHO recommended that African states should include the fight against SCD in their health policies. Nevertheless, there are, as of yet, no data on effective strategies to implement SCD control in these countries. This review discusses the stakes and proposes strategies for SCD management and research in sub-Saharan Africa. RECENT FINDINGS: This work is a review of the recent literature on the burden of SCD in sub-Saharan Africa; on approaches that resulted in improved survival and comfort for SCD patients in developed countries; and, in contrast, on the inadequacies of most issues relating to the fight against SCD in Africa. SUMMARY: Multiple constraints require an organization based on a network of health professionals working in sickle cell referral centers with specific missions of research, communication, teaching, establishment of guidelines for diagnosis, treatment, and prevention, and the centers of competence that will focus primarily on the screening, diagnosis, and management of SCD patients favoring equity in access to care.

Extended safety, immunogenicity and efficacy of a blood-stage malaria vaccine in malian children: 24-month follow-up of a randomized, double-blinded phase 2 trial.

BACKGROUND: The FMP2.1/AS02A candidate malaria vaccine was tested in a Phase 2 study in Mali. Based on results from the first eight months of follow-up, the vaccine appeared well-tolerated and immunogenic. It had no significant efficacy based on the primary endpoint, clinical malaria, but marginal efficacy against clinical malaria in secondary analyses, and high allele-specific efficacy. Extended follow-up was conducted to evaluate extended safety, immunogenicity and efficacy. METHODS: A randomized, double-blinded trial of safety, immunogenicity and efficacy of the candidate Plasmodium falciparum apical membrane antigen 1 (AMA1) vaccine FMP2.1/AS02A was conducted in Bandiagara, Mali. Children aged 1-6 years were randomized in a 1∶1 ratio to receive FMP2.1/AS02A or control rabies vaccine on days 0, 30 and 60. Using active and passive surveillance, clinical malaria and adverse events as well as antibodies against P. falciparum AMA1 were monitored for 24 months after the first vaccination, spanning two malaria seasons. FINDINGS: 400 children were enrolled. Serious adverse events occurred in nine participants in the FMP2.1/AS02A group and three in the control group; none was considered related to study vaccination. After two years, anti-AMA1 immune responses remained significantly higher in the FMP2.1/AS02A group than in the control group. For the entire 24-month follow-up period, vaccine efficacy was 7.6% (p = 0.51) against first clinical malaria episodes and 9.9% (p = 0.19) against all malaria episodes. For the final 16-month follow-up period, vaccine efficacy was 0.9% (p = 0.98) against all malaria episodes. Allele-specific efficacy seen in the first malaria season did not extend into the second season of follow-up. INTERPRETATION: Allele-specific vaccine efficacy was not sustained in the second malaria season, despite continued high levels of anti-AMA1 antibodies. This study presents an opportunity to evaluate correlates of partial protection against clinical malaria that waned during the second malaria season. TRIAL REGISTRATION: Clinicaltrials.gov NCT00460525 NCT00460525.

Extensive ethnogenomic diversity of endothelial nitric oxide synthase (eNOS) polymorphisms.

Nitric oxide (NO) is highly reactive, produced in endothelial cells by endothelial NO synthase (eNOS) and has been implicated in sickle cell pathophysiology. We evaluated the distribution of functionally significant eNOS variants (the T786C variant in the promoter region, the Glu298Asp variant in exon 7, and the variable number of tandem repeats (VNTR) in intron 4) in Africans, African Americans and Caucasians. The C-786 variant was more common in Caucasians than in Africans and African Americans. Consistent with other findings, the Asp-298 variant had the highest frequency in Caucasians followed by African Americans, but was completely absent in Africans. The very rare intron 4 allele, eNOS 4c, was found in some Africans and African Americans, but not in Caucasians. eNOS 4d allele was present in 2 Africans. These findings suggest a consistent and widespread genomic diversity in the distribution of eNOS variants in Africans, comparative to African Americans and Caucasians.

Circulating Immune Complex Levels are Associated with Disease Severity and Seasonality in Children with Malaria from Mali.

Complement receptor one (CR1) is essential for removing circulating immune complexes (CIC), with malaria infection contributing to the formation of large amounts of CIC. We investigated CIC levels in children with malaria, of varying severity and seasonality. Two hundred age and sex-matched severe and mild malaria cases were studied during and after active disease. Pediatric controls had increased CIC levels (mean = 32 µg mEq/mL) compared to adult controls (mean = 26.9 µg mEq/mL). The highest levels of CIC were reported in severe malaria (mean = 39 µg mEq/mL). Higher levels of CIC were recorded in younger children and those with low E-CR1 copy numbers. Our data suggest that low levels of E-CR1 copy numbers, found in children with severe malaria, may adversely affect the ability to remove IC. Furthermore, the high background for circulating immune complex imply that Malian children are under constant assault by other pathogens that evoke a strong immune response.