Association of Inhibitory Killer Cell Immunoglobulin-like Receptor Ligands With Higher Plasmodium falciparum Parasite Prevalence.

Killer cell immunoglobulin-like receptors (KIRs) and their HLA ligands influence the outcome of many infectious diseases. We analyzed the relationship of compound KIR-HLA genotypes with risk of Plasmodium falciparum infection in a longitudinal cohort of 890 Ugandan individuals. We found that presence of HLA-C2 and HLA-Bw4, ligands for inhibitory KIR2DL1 and KIR3DL1, respectively, increased the likelihood of P. falciparum parasitemia in an additive manner. Individuals homozygous for HLA-C2, which mediates strong inhibition via KIR2DL1, had the highest odds of parasitemia, HLA-C1/C2 heterozygotes had intermediate odds, and individuals homozygous for HLA-C1, which mediates weaker inhibition through KIR2DL2/3, had the lowest odds of parasitemia. In addition, higher surface expression of HLA-C, the ligand for inhibitory KIR2DL1/2/3, was associated with a higher likelihood of parasitemia. Together these data indicate that stronger KIR-mediated inhibition confers a higher risk of P. falciparum parasitemia and suggest that KIR-expressing effector cells play a role in mediating antiparasite immunity.

Iron Status of Burkinabé Adolescent Girls Predicts Malaria Risk in the Following Rainy Season.

High levels of storage iron may increase malaria susceptibility. This risk has not been investigated in semi-immune adolescents. We investigated whether baseline iron status of non-pregnant adolescent girls living in a high malaria transmission area in Burkina Faso affected malaria risk during the following rainy season. For this prospective study, we analysed data from an interim safety survey, conducted six months into a randomised iron supplementation trial. We used logistic regression to model the risk of P. falciparum infection prevalence by microscopy, the pre-specified interim safety outcome, in relation to iron status, nutritional indicators and menarche assessed at recruitment. The interim survey was attended by 1223 (82%) of 1486 eligible participants, 1084 (89%) of whom were <20 years at baseline and 242 (22%) were pre-menarcheal. At baseline, prevalence of low body iron stores was 10%. At follow-up, 38% of adolescents had predominantly asymptomatic malaria parasitaemias, with no difference by menarcheal status. Higher body iron stores at baseline predicted an increased malaria risk in the following rainy season (OR 1.18 (95% CI 1.05, 1.34, p = 0.007) after adjusting for bed net use, age, menarche, and body mass index. We conclude that routine iron supplementation should not be recommended without prior effective malaria control.

Reactivation of Plasmodium infection during a treatment with infliximab: A case report.

We describe a symptomatic Plasmodium falciparum infection in a 29-year-old Guinean man receiving Infliximab for one year and without recent travel. The reactivation of submicroscopic malaria following the inhibition of TNF-alpha by infliximab is suspected.

New Insights into Malaria Pathogenesis.

Malaria remains a major public health threat in tropical and subtropical regions across the world. Even though less than 1% of malaria infections are fatal, this leads to about 430,000 deaths per year, predominantly in young children in sub-Saharan Africa. Therefore, it is imperative to understand why a subset of infected individuals develop severe syndromes and some of them die and what differentiates these cases from the majority that recovers. Here, we discuss progress made during the past decade in our understanding of malaria pathogenesis, focusing on the major human parasite Plasmodium falciparum.

Hypertension is associated with an increased risk for severe imported falciparum malaria: a tertiary care hospital based observational study from Berlin, Germany.

BACKGROUND: Increasing numbers of aging individuals with chronic co-morbidities travel to regions where falciparum malaria is endemic. Non-communicable diseases are now leading risk factors for death in such countries. Thus, the influence of chronic diseases on the outcome of falciparum malaria is an issue of major importance. Aim of the present study was to assess whether non-communicable diseases increase the risk for severe imported falciparum malaria. METHODS: A retrospective observational study of all adult cases with imported falciparum malaria hospitalized between 2001 and 2015 in the tertiary care Charité University Hospital, Berlin, was performed. RESULTS: A total of 536 adult patients (median age 37 years; 31.3% female) were enrolled. Of these, 329 (61.4%) originated from endemic countries, 207 patients (38.6%) from non-endemic regions. Criteria for severe malaria were fulfilled in 68 (12.7%) cases. With older age, lack of previous malaria episodes, being a tourist, and delayed presentation, well-characterized risk factors were associated with severe malaria in univariate analysis. After adjustment for these potential confounders hypertension (adjusted odds ratio aOR, 3.06 95% confidence interval, CI 1.34-7.02), cardiovascular diseases (aOR, 8.20 95% CI 2.30-29.22), and dyslipidaemia (aOR, 6.08 95% CI 1.13-32.88) were individual diseases associated with severe disease in multivariable logistic regression. Hypertension proved an independent risk factor among individuals of endemic (aOR, 4.83, 95% CI 1.44-16.22) as well as of non-endemic origin (aOR, 3.60 95% CI 1.05-12.35). CONCLUSIONS: In imported falciparum malaria hypertension and its related diseases are risk factors for severe disease.

Post transfusion malaria: current state in Tunisia (new case reported in 2016).

Since the elimination of indigenous transmission of malaria in Tunisia in 1979, almost all the cases observed are imported cases related to travel. We report a recent case of highly probable post-transfusion malaria (PTM) in a 27-year-old Tunisian who has never left Tunisia. He has been allografted and has received of the globular pellets and the platelet units along with his hospitalization. The evolution was marked by the appearance of a fever resistant to antibiotics 15 days later. On day 11 of fever, a thick drop (TD) and a blood smear (BS) showed trophozoites of Plasmodium falciparum with 20% parasitaemia. The evolution was favorable under quinine. The epidemiological survey concluded that among blood donors an African donor from Ivory Coast, in Tunisia for 2 months, had a TD, a BS, a rapid test and a nested PCR for P. falciparum species were negative, only the serology was positive by indirect immunofluorescence (1/20). Real-time PCR was positive for P. falciparum, and the diagnosis of highly probable PTM was retained. Blood transfusion is a transmission pathway for Plasmodium and contamination can occur with a very few parasites. As a result, the PTM must be considered for any unexplained fever arising in the aftermath of a blood transfusion that and establish strict prevention recommendations for PTM in our country.

Investigating causal pathways in severe falciparum malaria: A pooled retrospective analysis of clinical studies.

BACKGROUND: Severe falciparum malaria is a medical emergency characterised by potentially lethal vital organ dysfunction. Patient fatality rates even with parenteral artesunate treatment remain high. Despite considerable research into adjuvant therapies targeting organ and tissue dysfunction, none have shown efficacy apart from renal replacement therapy. Understanding the causal contributions of clinical and laboratory abnormalities to mortality is essential for the design and evaluation of novel therapeutic interventions. METHODS AND FINDINGS: We used a structural model causal inference approach to investigate causal relationships between epidemiological, laboratory, and clinical variables in patients with severe falciparum malaria enrolled in clinical trials and their in-hospital mortality. Under this causal model, we analysed records from 9,040 hospitalised children (0-12 years, n = 5,635) and adults (n = 3,405, 12-87 years) with severe falciparum malaria from 15 countries in Africa and Asia who were studied prospectively over the past 35 years. On admission, patient covariates associated with increased in-hospital mortality were severity of acidosis (odds ratio [OR] 2.10 for a 7-mEq/L increase in base deficit [95% CI 1.93-2.28]), renal impairment (OR 1.71 for a 2-fold increase in blood urea nitrogen [95% CI 1.58, 1.86]), coma (OR 3.59 [95% CI 3.07-4.21]), seizures (OR 1.40 [95% CI 1.16-1.68]), shock (OR 1.51 [95% CI 1.14-1.99]), and presumed pulmonary oedema (OR 1.58 [95% CI 1.04-2.39]). Lower in-hospital mortality was associated with moderate anaemia (OR 0.87 for a decrease of 10 percentage points in haematocrit [95% CI 0.80-0.95]). Circulating parasite density was not associated with mortality (OR 1.02 for a 6-fold increase [95% CI 0.94-1.11]), so the pathological effects of parasitaemia appear to be mediated entirely by the downstream effects of sequestration. Treatment with an artemisinin derivative decreased mortality compared with quinine (OR 0.64 [95% CI 0.56-0.74]). These estimates were consistent across children and adults (mainly representing African and Asian patients, respectively). Using inverse probability weighting, transfusion was not estimated to be beneficial in children with admission haematocrit values between 15% and 25% (OR 0.99 [95% CI 0.97-1.02]). Except for the effects of artemisinin treatment and transfusion, causal interpretations of these estimates could be biased by unmeasured confounding from severe bacterial sepsis, immunity, and duration of illness. CONCLUSION: These data suggest that moderate anaemia is associated with a reduced risk of death in severe falciparum malaria. This is possibly a direct causal association. The severe anaemia threshold criteria for a definition of severe falciparum malaria should be reconsidered.

Dengue, chikungunya, and scrub typhus are important etiologies of non-malarial febrile illness in Rourkela, Odisha, India.

BACKGROUND: We conducted a diagnostic surveillance study to identify Plasmodium, dengue virus, chikungunya virus, and Orientia tsutsugamushi infections among febrile patients who underwent triage for malaria in the outpatient department at Ispat General Hospital, Rourkela, Odisha, India. METHODS: Febrile patients were enrolled from January 2016-January 2017. Blood smears and small volumes or vacutainers of blood were collected from study participants to carry out diagnostic assays. Malaria was diagnosed using rapid diagnostic tests (RDT), microscopy, and PCR. Dengue, chikungunya, and scrub typhus infections were identified using rapid diagnostic test kits and ELISA. RESULTS: Nine hundred and fifty-four patients were prospectively enrolled in our study. The majority of patients were male (58.4%) and more than 15 years of age (66.4%). All 954 enrollees underwent additional testing for malaria; a subset of enrollees (293/954) that had larger volumes of plasma available was also tested for dengue, chikungunya and scrub typhus by either RDT or ELISA or both tests. Fifty-four of 954 patients (5.7%) were positive for malaria by RDT, or microscopy, or PCR. Seventy-four of 293 patients (25.3%) tested positive for dengue by either RDT or ELISA, and 17 of 293 patients (5.8%) tested positive for chikungunya-specific IgM by either ELISA or RDT. Ten of 287 patients tested (3.5%) were positive for scrub typhus by ELISA specific for scrub typhus IgM. Seventeen patients among 290 (5.9%) with results for ≥3 infections tested positive for more than one infection. Patients with scrub typhus and chikungunya had high rates of co-infection: of the 10 patients positive for scrub typhus, six were positive for dengue (p = 0.009), and five of 17 patients positive for chikungunya (by RDT or ELISA) were also diagnosed with malaria (p < 0.001). CONCLUSIONS: Dengue, chikungunya and scrub typhus are important etiologies of non-malarial febrile illness in Rourkela, Odisha, and comorbidity should be considered. Routine febrile illness surveillance is required to accurately establish the prevalence of these infections in this region, to offer timely treatment, and to implement appropriate methods of control.

A population-based study of the prevalence and risk factors of low-grade Plasmodium falciparum malaria infection in children aged 0-15 years old in northern Tanzania.

OBJECTIVES: Northern Tanzania experiences significant malaria-related morbidity and mortality, but accurate data are scarce. We update the data on patterns of low-grade Plasmodium falciparum malaria infection among children in northern Tanzania. METHODS: Plasmodium falciparum malaria prevalence (pfPR) was assessed in a representative sample of 819 children enrolled in 94 villages in northern Tanzania between October 2015 and August 2016, using a complex survey design. Individual- and household-level risk factors for pfPR were elicited using structured questionnaires. pfPR was assessed using rapid diagnostic tests (RDTs) and thick film microscopy (TFM). Associations with pfPR, based on RDT, were assessed using adjusted odds ratios (aOR) and confidence intervals (CI) from weighted survey logistic regression models. RESULTS: Plasmodium falciparum malaria prevalence (pfPR) was 39.5% (95% CI: 31.5, 47.5) by RDT and 33.4% (26.0, 40.6) by TFM. pfPR by RDT was inversely associated with higher-education parents, especially mothers (5-7 years of education: aOR 0.55; 95% CI: 0.31, 0.96, senior secondary education: aOR 0.10; 95% CI: 0.02, 0.55), living in a house near the main road (aOR 0.34; 95% CI: 0.15, 0.76), in a larger household (two rooms: aOR 0.40; 95% CI: 0.21, 0.79, more than two rooms OR 0.35; 95% CI: 0.20, 0.62). Keeping a dog near or inside the house was positively associated with pfPR (aOR 2.01; 95% CI: 1.26, 3.21). pfPR was not associated with bed-net use or indoor residual spraying. CONCLUSIONS: Nearly 40% of children in northern Tanzania had low-grade malaria antigenaemia. Higher parental education and household metrics but not mosquito bed-net use were inversely associated with pfPR.

OBJECTIFS: La Tanzanie connaît une morbidité et une mortalité importantes liées au paludisme, mais les données précises sont rares. Nous mettons à jour les données sur les profils en matière d'infection par le paludisme à Plasmodium falciparum de faible grade chez les enfants dans le nord de la Tanzanie. MÉTHODES: La prévalence du paludisme à P. falciparum (pfPR) a été évaluée sur un échantillon représentatif de 819 enfants inscrits dans 94 villages dans le nord de la Tanzanie entre octobre 2015 et août 2016, à l'aide d'un plan d'enquête complexe. Des facteurs de risque de pfPR au niveau individuel et au niveau du ménage ont été déterminés à l'aide de questionnaires structurés. La pfPR a été évaluée à l'aide de tests de diagnostic rapides (TDR) et de microscopie à film épais (TFM). Les associations avec la pfPR, sur la base des TDR, ont été évaluées à l'aide des rapports de cotes ajustés (aOR) et des intervalles de confiance (IC) de modèles de régression logistique de surveillances pondérées. RÉSULTATS: La pfPR était de 39,5% (IC95%: 31,5-47,5) avec les TDR et de 33,4% (26,0-40,6) avec la TFM. La pfPR par les TDR était inversement associée aux parents avec un niveau d'éducation plus élevé, en particulier les mères (5-7 ans d'études: aOR: 0,55; IC95%: 0,31-0,96, enseignement secondaire supérieur: aOR: 0,10; IC95%: 0,02-0,55), vivre dans une maison proche de la route principale (aOR: 0,34; IC95%: 0,15-0,76), dans un ménage plus grand (2 chambres: aOR: 0,40; IC95%: 0,21-0,79, plus de 2 pièces aOR: 0,35; IC95%: 0,20-0,62). Garder un chien près ou à l'intérieur de la maison était positivement associé à la pfPR (aOR: 2,01; IC95%: 1,26-3,21). La pfPR n'était pas associée à l'utilisation de moustiquaire ou à la pulvérisation de résidus à l'intérieur. CONCLUSIONS: Près de 40% des enfants dans nord de la Tanzanie présentaient une antigénémie paludéenne de faible grade. Un niveau d'éducation parentale plus élevé et les indicateurs du ménage, mais pas l'utilisation de moustiquaires, étaient inversement associés à la pfPR.

Risk factors of severe imported malaria in Anhui province, China.

We aimed to determine risk factors for developing severe illness in patients infected with imported Plasmodium falciparum, and identify factors that can be implemented in preventive public health actions. Data of patients in Anhui province were collected from the China Information System for Disease Control and Prevention and Information System for Parasitic Disease Control and Prevention from 2012 to 2018. Epidemiological characteristics, clinical severity, and preventive measures were analyzed using descriptive statistics. Risk factors for severe malaria were identified by logistic regression. During the study period, 8.01% (53/662) of patients infected with P. falciparum developed severe malaria; the annual severe incidence rate varied from 5.93% to 10.77% and the fatality rate was 0.6%. Two models were built to analyze the delay from symptom onset to treatment; one analyzed data by stage, whereas the other analyzed data combined from all stages. In model 1, multivariate analysis identified misdiagnosis at first medical visit and patient delay as risk factors for severe malaria (odds ratio: 3.108 and 3.385, respectively, all p < 0.01). In model 2, overall delay was a significant factor of severe malaria onset (odds ratio: 4.719, p = 0.000). In both models, patients with a history of previous infection had a significantly reduced risk of developing severe malaria; high parasitemia (≥2.5%) was associated with an increased risk of severe infection. Delay between symptom onset and treatment was an important cause for development of severe disease in Anhui province. Measures to reduce delays should be used and implemented in preventive public health actions.

Risk factors for Plasmodium falciparum infection in the Kenyan Highlands: a cohort study.

BACKGROUND: Malaria transmission in African highland areas can be prone to epidemics, with minor fluctuations in temperature or altitude resulting in highly heterogeneous transmission. In the Kenyan Highlands, where malaria prevalence has been increasing, characterising malaria incidence and identifying risk factors for infection is complicated by asymptomatic infection. METHODS: This all-age cohort study, one element of the Malaria Transmission Consortium, involved monthly follow-up of 3155 residents of the Kisii and Rachuonyo South districts during June 2009-June 2010. Participants were tested for malaria using rapid diagnostic testing at every visit, regardless of symptoms. RESULTS: The incidence of Plasmodium falciparum infection was 0.2 cases per person, although infections were clustered within individuals and over time, with the majority of infections detected in the last month of the cohort study. Overall, incidence was higher in the Rachuonyo district and infections were detected most frequently in 5-10-year-olds. The majority of infections were asymptomatic (58%). Travel away from the study area was a notable risk factor for infection. CONCLUSIONS: Identifying risk factors for malaria infection can help to guide targeting of interventions to populations most likely to be exposed to malaria.

Case Report: Delayed or Recurrent Plasmodium falciparum Malaria in Migrants: A Report of Three Cases with a Literature Review.

Emerging evidence indicates that migrants from Plasmodium falciparum endemic regions are at risk of delayed presentation of P. falciparum malaria. We report three cases of P. falciparum malaria occurring years after arrival in Europe. All patients were originally from Sub-Saharan Africa. Two subjects had controlled human immunodeficiency virus infection and one was a pregnant woman. We performed a literature review of all published cases of delayed presentation of P. falciparum in migrants and identified 32 additional cases. All cases but one originate from sub-Saharan Africa. There was a median time of 36 months between the last visit to a malaria-endemic country and clinical malaria (range: 3 months to 10 years). Pregnancy was the most frequently reported risk factor (11/35 or 31.4%). Parasitemia was ≤ 0.1% in 38% of cases (11/29 reported), and no death was reported. The underlying possible mechanisms for this delayed presentation in migrants from an endemic area probably include the persistence of submicroscopic parasitemia combined with decaying P. falciparum-specific immunity. Suspicion of P. falciparum delayed malaria should remain high in migrants, mainly from sub-Saharan Africa, even without a recent travel history, especially in those presenting risk factors for impaired parasite clearance or distinct immune responses such as pregnancy and HIV infection. In these patients, new prevention and screening strategies should be studied and blood safety policies adapted.

A randomized, control and comparative study of polyherbal formulation use for Malaria (Plasmodium falciparum).

Plasmodium falciparum is the most well-known reason for extreme and life-debilitating malaria. Falciparum malaria causes more than 1 million deaths annually. Malaria remains a noteworthy reason for major morbidity and mortality in the tropics, with Plasmodium falciparum accountable for the mainstream of the disease weight and Plasmodium vivax being the geologically greatest broadly dispersed cause of malaria. The controlling of severe malaria comprises quick direction of suitable parenteral anti-malarial agents and initial acknowledgement and treatment of the complications. This clinical trial was piloted in 100 patients, in which 50 received the test drug (Malarina) and 50 received the control drug (Quinine Bisulphate). The age range of patients was 12 years to above 50 years. The sample paired t-test was applied to evaluate the significant level. Malarina was very effective in treating malaria sign and symptoms. The new treatment Malarina was safe and well tolerated in all patients.

[Plasmodium falciparum infection by blood transfusion：a case report].

This paper reported one acute lymphoblastic leukemia patient who infected with Plasmodium falciparum after blood transfusion. Through the epidemiological investigation on this patient and the related blood donors as well as laboratory detections, the source of infection was ascertained. This blood donor was an overseas student from Africa, whose blood sample was positive in the rapid diagnostic test, and the results of microscopic examination of peripheral blood smear and PCR both suggested P. falciparum positive.

The role of the red blood cell in host defence against falciparum malaria: an expanding repertoire of evolutionary alterations.

The malaria parasite has co-evolved with its human host as each organism struggles for resources and survival. The scars of this war are carried in the human genome in the form of polymorphisms that confer innate resistance to malaria. Clinical, epidemiological and genome-wide association studies have identified multiple polymorphisms in red blood cell (RBC) proteins that attenuate malaria pathogenesis. These include well-known polymorphisms in haemoglobin, intracellular enzymes, RBC channels, RBC surface markers, and proteins impacting the RBC cytoskeleton and RBC morphology. A better understanding of how changes in RBC physiology impact malaria pathogenesis may uncover new strategies to combat the disease.

A Case Series of Imported Malaria Caused by Plasmodium falciparum in Kayseri and Review of Literature.

Malaria is a major worldwide public health problem. In the last years, no domestic cases of malaria have been detected and cases of imported malaria exist only in Turkey. In this study, clinical and laboratory findings of five Plasmodium falciparum (P. falciparum) malaria patients who were admitted to the emergency department between January 2013 and December 2015 were retrospectively presented. One of the patients was an African student, and the other patients had a history of travelling to Africa. Ring formation was observed when Giemsa staining was performed on the blood smears of all patients, and in three patients, P. falciparum was also detected using multiplex polymerase chain reaction (PCR) (Bio-Rad, United States of America). P. falciparum was not detected by PCR in the other two patients. Malaria should be primarily considered in febrile patients who have a history of travelling to endemic regions, and peripheral blood smears should definitely be examined.

High Iron Levels Are Associated with Increased Malaria Risk in Infants during the First Year of Life in Benin.

The World Health Organization (WHO) estimates that 40% of children in low-income countries are anemic. Therefore, iron supplements are recommended by WHO in areas with high anemia rates. However, some studies have set into question the benefits of iron supplementation in malaria-endemic regions. In Benin, a west African country with high prevalence of anemia and malaria, no iron supplements are given systematically to infants so far despite the WHO recommendations. In this context, we wanted to investigate the effect of iron levels during the first year of life on malarial risk in Benin considering complementary risk factors. We followed 400 women and their offspring between January 2010 and June 2012 in Allada (Benin). Environmental, obstetric, and numerous clinical, maternal, and infant risk factors were considered. In multilevel models, high iron levels were significantly associated with the risk of a positive blood smear (adjusted odds ratio = 2.90, P < 0.001) and Plasmodium falciparum parasitemia (beta estimate = 0.38, P < 0.001). Infants with iron levels in the lowest quartile were less likely to have a positive blood smear (P < 0.001), and the risk increased with higher iron levels. Our results appeal for additional evaluation of the effect of different doses of iron supplements on the infant health status, including malaria incidence. Thus, the health status of infants should be compared between cohorts where iron is given either for prevention or anemia treatment, to better understand the effect of iron supplements on infant health.

Prevalence and associated risk factors of malaria among adults in East Shewa Zone of Oromia Regional State, Ethiopia: a cross-sectional study.

BACKGROUND: Malaria is one of the most important causes of morbidity and mortality in sub-Saharan Africa. The disease is prevalent in over 75% of the country's area making it the leading public health problems in the country. Information on the prevalence of malaria and its associated factors is vital to focus and improve malaria interventions. METHODS: A cross-sectional study was carried out from October to November 2012 in East Shewa zone of Oromia Regional State, Ethiopia. Adults aged 16 or more years with suspected malaria attending five health centers were eligible for the study. Logistic regression models were used to examine the effect of each independent variable on risk of subsequent diagnosis of malaria. RESULTS: Of 810 suspected adult malaria patients who participated in the study, 204 (25%) had microscopically confirmed malaria parasites. The dominant Plasmodium species were P. vivax (54%) and P. falciparum (45%), with mixed infection of both species in one patient. A positive microscopic result was significantly associated with being in the age group of 16 to 24 years [Adjusted Odds Ratio aOR 6.7; 95% CI: 2.3 to 19.5], 25 to 34 years [aOR 4.2; 95% CI: 1.4 to 12.4], and 35 to 44 years [aOR 3.7; 95% CI: 1.2-11.4] compared to 45 years or older; being treated at Meki health center [aOR 4.1; 95% CI: 2.4 to 7.1], being in Shashemene health center [aOR = 2.3; 95% CI: 1.5 to 4.5], and living in a rural area compared to an urban area [aOR 1.7; 95% CI: 1.1 to 2.6)]. CONCLUSION: Malaria is an important public health problem among adults in the study area with a predominance of P. vivax and P. falciparum infection. Thus, appropriate health interventions should be implemented to prevent and control the disease.

Anemia Offers Stronger Protection Than Sickle Cell Trait Against the Erythrocytic Stage of Falciparum Malaria and This Protection Is Reversed by Iron Supplementation.

BACKGROUND: Iron deficiency causes long-term adverse consequences for children and is the most common nutritional deficiency worldwide. Observational studies suggest that iron deficiency anemia protects against Plasmodium falciparum malaria and several intervention trials have indicated that iron supplementation increases malaria risk through unknown mechanism(s). This poses a major challenge for health policy. We investigated how anemia inhibits blood stage malaria infection and how iron supplementation abrogates this protection. METHODS: This observational cohort study occurred in a malaria-endemic region where sickle-cell trait is also common. We studied fresh RBCs from anemic children (135 children; age 6-24months; hemoglobin <11g/dl) participating in an iron supplementation trial (ISRCTN registry, number ISRCTN07210906) in which they received iron (12mg/day) as part of a micronutrient powder for 84days. Children donated RBCs at baseline, Day 49, and Day 84 for use in flow cytometry-based in vitro growth and invasion assays with P. falciparum laboratory and field strains. In vitro parasite growth in subject RBCs was the primary endpoint. FINDINGS: Anemia substantially reduced the invasion and growth of both laboratory and field strains of P. falciparum in vitro (~10% growth reduction per standard deviation shift in hemoglobin). The population level impact against erythrocytic stage malaria was 15.9% from anemia compared to 3.5% for sickle-cell trait. Parasite growth was 2.4 fold higher after 49days of iron supplementation relative to baseline (p<0.001), paralleling increases in erythropoiesis. INTERPRETATION: These results confirm and quantify a plausible mechanism by which anemia protects African children against falciparum malaria, an effect that is substantially greater than the protection offered by sickle-cell trait. Iron supplementation completely reversed the observed protection and hence should be accompanied by malaria prophylaxis. Lower hemoglobin levels typically seen in populations of African descent may reflect past genetic selection by malaria. FUNDING: National Institute of Child Health and Development, Bill and Melinda Gates Foundation, UK Medical Research Council (MRC) and Department for International Development (DFID) under the MRC/DFID Concordat.