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Background: Adults with diabetes mellitus (DM) in malaria-endemic areas might be more susceptible to Plasmodium infection than healthy individuals. Herein, the study was aimed at verifying the hypothesis that increased fasting blood glucose (FBG) promotes parasite growth as reflected by increased parasite density., Methods: Seven adults without DM were recruited in rural Ghana to determine the relationships between FBG and malaria parasite load. Socio-economic data were recorded in questionnaire-based interviews. Over a period of 6 weeks, FBG and Plasmodium sp. Infection were measured in peripheral blood samples photometrically and by polymerase chain reaction (PCR)-assays, respectively. Daily physical activity and weather data were documented via smartphone recording. For the complex natural systems of homeostatic glucose control and Plasmodium sp. life cycle, empirical dynamic modelling was applied., Results: At baseline, four men and three women (median age, 33 years; interquartile range, 30-48) showed a median FBG of 5.5 (5.1-6.0 mmol/L); one participant had an asymptomatic Plasmodium sp. infection (parasite density: 240/µL). In this participant, convergent cross mapping (CCM) for 34 consecutive days, showed that FBG was causally affected by parasite density (p < 0.02), while the reciprocal relationship was not discernible (p > 0.05). Additionally, daily ambient temperature affected parasite density (p < 0.01)., Conclusion: In this study population living in a malaria-endemic area, time series analyses were successfully piloted for the relationships between FBG and Plasmodium sp. density. Longer observation periods and larger samples are required to confirm these findings and determine the direction of causality., (© 2022. The Author(s).)

Background: Duffy blood group antigens serve as receptors for Plasmodium vivax invasion into erythrocytes, and they are determined by polymorphisms of the Duffy antigen receptor for chemokines (DARC), also known as Fy glycoprotein (FY). Duffy negativity, i.e., absence of the antigens, protects against P. vivax infection and is rare among non-African populations. However, data on DARC polymorphisms and their impact on Plasmodium infection in India are scarce., Methods: In a case-control study among 909 malaria patients and 909 healthy community controls in Mangaluru, southwestern India, DARC polymorphisms T-33C (rs2814778), G125A (rs12075), C265T (rs34599082), and G298A (rs13962) were genotyped. Associations of the polymorphisms with the odds of malaria, parasite species and manifestation were assessed., Results: Among patients, vivax malaria (70%) predominated over falciparum malaria (9%) and mixed species infections (21%). DARC T-33C was absent and C265T was rare (1%). FYB carriage (deduced from DARC G125A) was not associated with the risk of malaria per se but it protected against severe falciparum malaria (P = 0.03), and hospitalization (P = 0.006) due to falciparum malaria. Vice versa, carriage of DARC 298A was associated with increased odds of malaria (aOR, 1.46 (1.07-1.99), P = 0.015) and vivax malaria (aOR, 1.60 (1.14-2.22), P = 0.006) and with several reported symptoms and findings of the patients., Conclusion: This report from southern India is the first to show an independent effect of the DARC 298A polymorphism on the risk of malaria. Functional studies are required to understand the underlying mechanism. Moreover, FYB carriage appears to protect against severe falciparum malaria in southern India.

Background: Plasmodium falciparum infection during pregnancy is a major cause of poor maternal health, adverse foetal outcome and infant mortality in sub-Saharan Africa. Genetic disposition is involved in susceptibility to malaria in pregnancy and its manifestation. MicroRNAs (miRNAs) influence gene regulation including that of innate immune responses. A miRNA-146a rs2910164 G > C single nucleotide polymorphism (SNP) has been associated with increased risks of several diseases, but no data as to malaria are available., Methods: The association between miRNA-146a rs2910164 and P. falciparum infection among 509 Ghanaian women attending antenatal care (ANC) and 296 delivering Ghanaian primiparae was investigated. Malaria parasites were diagnosed by microscopy and PCR. Leukocyte-associated hemozoin in placental samples was recorded as well. Proportions were compared between groups by Fisher's exact test, and logistic regression models were used to adjust for possible confounders., Results: By PCR, P. falciparum infection was detected in 63% and 67% of ANC attendees and delivering primiparae, respectively. In both groups, two in three women were either heterozygous or homozygous for miRNA-146a rs2910164. Among ANC attendees, homozygosity conferred increased odds of infection (adjusted odds ratio (aOR), 2.3; 95% CI, 1.3-4.0), which was pronounced among primigravidae (aOR, 5.8; 95% CI, 1.6-26) but only marginal in multigravidae. Likewise, homozygosity for miRNA-146a rs2910164 in primiparae increased the odds of past or present placental P. falciparum infection almost six-fold (aOR, 5.9; 95% CI, 2.1-18)., Conclusions: These results indicate that SNP rs2910164 G > C is associated with increased odds for P. falciparum infection in first-time pregnant women who are considered to lack sufficient acquired immune responses against pregnancy-specific strains of P. falciparum. These findings suggest that miRNA-146a is involved in protective malarial immunity, and specifically in the innate component.

Background: Severe and fatal vivax malaria is increasingly reported from India. In Mangaluru, southern India, malaria is focused in urban areas and associated with importation by migrant workers. In Wenlock Hospital, the largest governmental hospital, the clinical, parasitological and biochemical characteristics of malaria patients were assessed., Methods: During the peak malaria season in 2015 (June to December), outpatients were interviewed and clinically assessed. Malaria was ascertained by microscopy and PCR assays, concentrations of haemoglobin, creatinine and bilirubin, as well as thrombocyte count, were determined, and severe malaria was defined according to WHO criteria., Results: Among 909 malaria patients, the vast majority was male (93%), adult (median, 26 years) and of low socio-economic status. Roughly half of them were migrants from beyond the local Karnataka state, mostly from northern and northeastern states. Vivax malaria (69.6%) predominated over mixed Plasmodium vivax-Plasmodium falciparum infection (21.3%) and falciparum malaria (9.0%). The geometric mean parasite density was 3412/µL. As compared to vivax malaria, patients with falciparum malaria had higher parasite density and more frequently showed impaired general condition, affected consciousness and splenomegaly. Also, they tended to more commonly have anaemia and increased creatinine levels, and to be hospitalized (7.3%). Mixed-species infections largely assumed an interim position. Severe malaria (3.5%) was not associated with parasite species. No fatality occurred., Conclusion: In this study, uncomplicated cases of malaria predominated, with P. falciparum causing slightly more intense manifestation. Severe malaria was infrequent and fatalities absent. This contrasts with the reported pattern of manifestation in other parts of India, which requires the analysis of underlying causes.

Background: Plasmodium infection and malaria in school children are increasingly recognized as a relevant public health problem, but data on actual prevalence and health consequences are insufficient. The present study from highland southern Rwanda aimed at estimating infection prevalence among children attending school, at identifying associated factors and at assessing the clinical consequences of these infections., Methods: In a survey including 12 schools in the Huye district of Rwanda, 1089 children aged 6-10 years were clinically and anthropometrically examined, malaria parasites were diagnosed by microscopy and PCR, haemoglobin concentrations were measured, and socio-economic and behavioural parameters as well as medical histories were obtained., Results: Upon examination, the vast majority of children was asymptomatic (fever 2.7%). Plasmodium infection was detected in 22.4% (Plasmodium falciparum, 18.8%); 41% of these were submicroscopic. Independent predictors of infection included low altitude, higher age, preceding antimalarial treatment, and absence of electricity or a bicycle in the household. Plasmodium infection was associated with anaemia (mean haemoglobin difference of -1.2 g/dL; 95% CI, -0.8 to -1.5 g/dL), fever, underweight, clinically assessed malnutrition and histories of fever, tiredness, weakness, poor appetite, abdominal pain, and vomiting. With the exception of underweight, these conditions were also increased at submicroscopic infection., Conclusion: Malaria infection is frequent among children attending school in southern highland Rwanda. Although seemingly asymptomatic in the vast majority of cases, infection is associated with a number of non-specific symptoms in the children´s histories, in addition to the impact on anaemia. This argues for improved malaria surveillance and control activities among school children.

Background: Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is widely implemented in sub-Saharan Africa for the prevention of malaria in pregnancy and adverse birth outcomes. However, in areas of intense SP resistance, the efficacy of IPTp may be compromised., Methods: A cross-sectional study among 915 delivering women (728 analysable live singleton deliveries) was conducted in Fort Portal, western Uganda, to assess associations of reported IPTp use, Plasmodium falciparum infection, maternal anaemia, low birth weight, and preterm delivery, and to estimate the degree of SP resistance as reflected by pfdhfr/pfdhps mutations., Results: Plasmodium falciparum infection was detected by PCR in 8.9 % and by microscopy of placental blood samples in 4.0 %. Infection was significantly associated with stillbirth, early neonatal death, anaemia, low birth weight, and pre-term delivery. Eighty percent of the women had taken at least one dose of IPTp, and more than half had taken two doses. As compared to women without chemoprophylaxis against malaria, IPTp had no significant influence on the presence of P. falciparum infection (13.8 vs. 9.6 %, P = 0.31). Nor was it associated with reductions in anaemia, low birth weight or preterm delivery. P. falciparum with intense SP resistance (pfdhfr/pfdhps quintuple or sextuple mutations) were observed in 93 % (pfdhps 581G, 36 %), and the additional high resistance allele pfhdr 164L in 36 %., Conclusions: In Fort Portal, Uganda, reported use of IPTp with SP does not provide an observable benefit. The molecular markers of P. falciparum indicate high grade SP resistance reaching the threshold set by WHO for the discontinuation of IPTp with SP. Alternative approaches for the prevention of malaria in pregnancy are urgently needed.

Background: Blood group O protects African children against severe malaria and has reached high prevalence in malarious regions. However, its role in malaria in pregnancy is ambiguous. In 839 delivering Ghanaian women, associations of ABO blood groups with Plasmodium falciparum infection were examined., Methods: Plasmodium falciparum infection was diagnosed in placental blood samples by microscopy and PCR assays. Present or past infection was defined as the detection of parasitaemia or haemozoin by microscopy, or a positive PCR result. Blood groups were inferred from genotyping rs8176719 (indicating the O allele) and rs8176746/rs8176747 (distinguishing the B allele from the A allele)., Results: The majority of women had blood group O (55.4%); present or past P. falciparum infection was seen in 62.3% of all women. Among multiparae, the blood groups had no influence on P. falciparum infection. In contrast, primiparae with blood group O had significantly less present or past infection than women with non-O blood groups (61.5 vs 76.2%, P = 0.007). In multivariate analysis, the odds of present or past placental P. falciparum infection were reduced by 45% in blood group O primiparae (aOR, 0.55 [95% CI, 0.33-0.94])., Conclusions: The present study shows a clear protective effect of blood group O against malaria in primiparae. This accords with findings in severe malaria and in vitro results. The data underline the relevance of host genetic protection among primiparae, i.e. the high-risk group for malaria in pregnancy, and contribute to the understanding of high O allele frequencies in Africa.

Background: Innate immunity plays a crucial role in the host defense against malaria including Plasmodium falciparum malaria in pregnancy, but the roles of the various underlying genes and mechanisms predisposing to the disease are poorly understood., Methods: 98 single-nucletoide polymorphisms were genotyped in a set of 17 functionally related genes of the complement system in 145 primiparous Ghanaian women with placental malaria, defined by placental parasitaemia or malaria pigment, and as a control, in 124 non-affected primiparae., Results: Placental malaria was significantly associated with SNPs in the lectin pathway genes MBL2, MASP2, FCN2 and in properdin. In particular, the main African mannose-binding lectin deficiency variant (MBL2*G57E, rs1800451) increased the odds of placental malaria (OR 1.6; permuted p-value 0.014). In contrast, a common MASP2 mutation (R439H, rs12085877), which reduces the activity of MBL-MASP2 complexes occurred in 33% of non-affected women and in 22% primiparae with placental malaria (OR 0.55, permuted p-value 0.020)., Conclusions: Excessive complement activation is of importance in the pathogenesis of placental malaria by mediating inflammation, coagulation, and endothelial dysfunction. Mutated MBL and MASP2 proteins could have direct intrinsic effects on the susceptibility to placental malaria, in addition to their roles in regulation of downstream complement activation.

Background: Increased control has produced remarkable reductions of malaria in some parts of sub-Saharan Africa, including Rwanda. In the southern highlands, near the district capital of Butare (altitude, 1,768 m), a combined community-and facility-based survey on Plasmodium infection was conducted early in 2010., Methods: A total of 749 children below five years of age were examined including 545 randomly selected from 24 villages, 103 attending the health centre in charge, and 101 at the referral district hospital. Clinical, parasitological, haematological, and socio-economic data were collected., Results: Plasmodium falciparum infection (mean multiplicity, 2.08) was identified by microscopy and PCR in 11.7% and 16.7%, respectively; 5.5% of the children had malaria. PCR-based P. falciparum prevalence ranged between 0 and 38.5% in the villages, and was 21.4% in the health centre, and 14.9% in the hospital. Independent predictors of infection included increasing age, low mid-upper arm circumference, absence of several household assets, reported recent intake of artemether-lumefantrine, and chloroquine in plasma, measured by ELISA. Self-reported bed net use (58%) reduced infection only in univariate analysis. In the communities, most infections were seemingly asymptomatic but anaemia was observed in 82% and 28% of children with and without parasitaemia, respectively, the effect increasing with parasite density, and significant also for submicroscopic infections., Conclusions: Plasmodium falciparum infection in the highlands surrounding Butare, Rwanda, is seen in one out of six children under five years of age. The abundance of seemingly asymptomatic infections in the community forms a reservoir for transmission in this epidemic-prone area. Risk factors suggestive of low socio-economic status and insufficient effectiveness of self-reported bed net use refer to areas of improvable intervention.

Background: Intermittent preventive treatment in infants with sulphadoxine-pyrimethamine (IPTi-SP) reduces malaria morbidity by 20% to 33%. Potentially, however, this intervention may compromise the acquisition of immunity, including the tolerance towards multiple infections with Plasmodium falciparum., Methods: Plasmodium falciparum isolates were obtained from children participating in two Ghanaian IPTi-SP trials (Tamale, Afigya Sekyere) at 15 months of age, i.e., six months after they had received the second dose of IPTi-SP or placebo. By typing the polymorphic merozoite surface protein 1 (msp1) and msp2 genes, multiplicity of infection (MOI) was assessed in 389 isolates. A total of additional 133 samples were collected in Tamale at 3, 6, 9, and 12 months of age. Comparisons of MOI between groups were done by non-parametric statistical tests., Results: The number of distinguishable P. falciparum clones (MOI) ranged between one and six. Mean MOI in Tamale was stable at 2.13 - 2.17 during the first year of life, and increased to 2.57 at age 15 months (P = 0.01). At no age did MOI differ between the IPTi-SP and placebo groups (each, P ≥ 0.5). At 15 months of age, i.e., six months after the second dose, MOI was very similar for children who had received IPTi or placebo (means, 2.25 vs. 2.33; P = 0.55) as was the proportion of polyclonal infections (69.6% vs. 69.7%; P = 0.99). Adjusting for study site, current and prior malaria, parasite density, and season did not change this finding., Conclusions: IPTi-SP appears to have no impact on the multiplicity of infection during infancy and thereafter. This suggests that tolerance of multiple infections, a component of protective immunity in highly endemic areas, is not affected by this intervention.

In non-endemic areas, malaria is rare and locally acquired infections, particularly with Plasmodium falciparum, are exceptional events. The diagnosis is, therefore, likely to be delayed or missed in patients without a relevant travel history. This report describes a case of falciparum malaria in Berlin, Germany, in a patient who had not been to an endemic area for more than a decade. Potential routes of vector-related and direct transmission were evaluated, particularly with regard to a possible danger to the public. A review of the literature was conducted regarding possible routes of transmission and their probability assessed. Genotyping of parasite isolates of this and another patient with malaria admitted 16 days before revealed homology between the two strains. In a local entomological survey, anopheline vectors on the hospital grounds as well as in the residential area of both patients were found. Despite intensive investigations, the mode of transmission remained obscure. In this context, possible routes of vector-borne and direct occupational/accidental transmission in a major European city are reviewed and discussed, providing information and guidance in case other similar events occur elsewhere. Examples for investigations and measures to be taken in such a situation are provided. When local malaria transmission within a large non-immune population cannot be ruled out, genotyping of parasite isolates, local entomological surveys, preparedness for secondary cases, expert consultations in a multidisciplinary team and careful information management are essential. Malaria acquired in non-endemic areas remains an unlikely, but possible event for which awareness needs to be maintained.

Background: Combination therapy has become a new paradigm in malaria treatment. Amodiaquine is a common partner drug in different malaria combination therapies used or investigated in sub-Saharan Africa, but data on its efficacy as a single drug are scarce., Methods: The objective of the study was to determine the efficacy of amodiaquine against falciparum malaria in neighbouring rural and urban areas of north-western Burkina Faso. The study was designed as an uncontrolled trial in children aged 6-59 months with uncomplicated falciparum malaria in the Nouna Health District., Results: During the rainy season 2005, 117 children were enrolled, 62 from the rural and 55 from the urban study area. The crude adequate clinical and parasitological response (ACPR) rate was 103/117 (88%) by day 14 but decreased to 28/117 (24%) by day 28. After PCR correction for reinfections, ACPR rates were 108/117 (92%) and 71/117 (61%) by day 14 and day 28, respectively. There were no significant differences in efficacy between urban and rural areas. The Plasmodium falciparum crt K76T mutation not predict AQ failure, but was selected in parasites re-appearing following treatment. No serious adverse events occurred and only 16 other adverse events were recorded., Conclusion: Compared to chloroquine, amodiaquine is more effective against uncomplicated falciparum malaria in Burkina Faso. However, a considerable degree of amodiaquine resistance already exists and it is currently unclear how this resistance will develop when amodiaquine in combination with other drugs is used on a large scale., Trial Registration: Current Controlled Trials ISRCTN73824458.

Background: Intermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) has been adopted as policy by many countries in sub-Saharan Africa. However, data on the post-implementation effectiveness of this measure are scarce., Methods: Clinical and parasitological parameters were assessed among women delivering at a district hospital in rural southern Ghana in the year 2000 when pyrimethamine chemoprophylaxis was recommended (n = 839) and in 2006 (n = 226), approximately one year after the implementation of IPTp-SP. Examinations were performed in an identical manner in 2000 and 2006 including the detection of placental Plasmodium falciparum infection by microscopy, histidine-rich protein 2, and PCR., Results: In 2006, 77% of the women reported to have taken IPTp-SP at least once (26%, twice; 24%, thrice). In 2006 as compared to 2000, placental P. falciparum infection was reduced by 43-57% (P < 0.0001) and maternal anaemia by 33% (P = 0.0009), and median birth weight was 130 g higher (P = 0.02). In 2006, likewise, women who had taken > or = 1 dose of IPTp-SP revealed less infection and anaemia and their children tended to have higher birth weights as compared to women who had not used IPTp-SP. However, placental P. falciparum infection was still observed in 11% (microscopy) to 26% (PCR) of those women who had taken three doses of IPTp-SP., Conclusion: In southern Ghana, placental malaria and maternal anaemia have declined substantially and birth weight has increased after the implementation of IPTp-SP. Likely, these effects can further be increased by improving IPTp-SP coverage and adherence. However, the remnant prevalence of infection in women having taken three doses of IPTp-SP suggests that additional antimalarial measures are needed to prevent malaria in pregnancy in this region.

Background: Plasmodium falciparum can be detected by microscopy, histidine-rich-protein-2 (HRP2) capture test or PCR but the respective clinical relevance of the thereby diagnosed infections in pregnant women is not well established., Methods: In a cross-sectional, year-round study among 839 delivering women in Agogo, Ghana, P. falciparum was screened for in both, peripheral and placental blood samples, and associations with maternal anaemia, low birth weight (LBW) and preterm delivery (PD) were analysed., Results: In peripheral blood, P. falciparum was observed in 19%, 34%, and 53% by microscopy, HRP2 test, and PCR, respectively. For placental samples, these figures were 35%, 41%, and 59%. Irrespective of diagnostic tool, P. falciparum infection increased the risk of anaemia. Positive peripheral blood results of microscopy and PCR were not associated with LBW or PD. In contrast, the HRP2 test performed well in identifying women at increased risk of poor pregnancy outcome, particularly in case of a negative peripheral blood film. Adjusting for age, parity, and antenatal visits, placental HRP2 was the only marker of infection associated with LBW (adjusted odds ratio (aOR), 1.5 (95%CI, 1.0-2.2)) and, at borderline statistical significance, PD (aOR, 1.4 (1.0-2.1)) in addition to anaemia (aOR, 2.3 (1.7-3.2)). Likewise, HRP2 in peripheral blood of seemingly aparasitaemic women was associated with PD (aOR, 1.7 (1.0-2.7)) and anaemia (aOR, 2.1 (1.4-3.2))., Conclusion: Peripheral blood film microscopy not only underestimates placental malaria. In this highly endemic setting, it also fails to identify malaria as a cause of foetal impairment. Sub-microscopic infections detected by a HRP2 test in seemingly aparasitaemic women increase the risks of anaemia and PD. These findings indicate that the burden of malaria in pregnancy may be even larger than thought and accentuate the need for effective anti-malarial interventions in pregnancy.

Background: In Ethiopia, malaria is caused by both Plasmodium falciparum and Plasmodium vivax. Drug resistance of P. falciparum to sulfadoxine-pyrimethamine (SP) and chloroquine (CQ) is frequent and intense in some areas., Methods: In 100 patients with uncomplicated malaria from Dilla, southern Ethiopia, P. falciparum dhfr and dhps mutations as well as P. vivax dhfr polymorphisms associated with resistance to SP and P. falciparum pfcrt and pfmdr1 mutations conferring CQ resistance were assessed., Results: P. falciparum and P. vivax were observed in 69% and 31% of the patients, respectively. Pfdhfr triple mutations and pfdhfr/pfdhps quintuple mutations occurred in 87% and 86% of P. falciparum isolates, respectively. Pfcrt T76 was seen in all and pfmdr1 Y86 in 81% of P. falciparum. The P. vivax dhfr core mutations N117 and R58 were present in 94% and 74%, respectively., Conclusion: These data point to an extraordinarily high frequency of drug-resistance mutations in both P. falciparum and P. vivax in southern Ethiopia, and strongly support that both SP and CQ are inadequate drugs for this region.

Background: Both chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) are failing drugs in much of sub-Saharan Africa. Previous findings suggest an association between resistance to CQ and to SP in vivo, in vitro, and on the molecular level., Methods: In 126 Ghanaian children with uncomplicated malaria, associations between mutations conferring resistance in the Plasmodium falciparum dihydrofolate reductase (dhfr; SP) and chloroquine resistance transporter (crt; CQ) genes, concentrations of residual antimalarial drugs, and gametocyte carriage were examined., Results: Mutant dhfr alleles and the CQ-resistance allele crt T76 were strongly associated with each other. Isolates exhibiting the dhfr triple mutation seven times more likely also contained crt T76 parasites as compared to isolates without the dhfr triple variant (P = 0.0001). Moreover, both, isolates with the dhfr triple mutation (adjusted OR, 3.2 (95%CI, 1.0-10.4)) and with crt T76 (adjusted OR, 14.5 (1.4-150.8)) were associated with an increased likelihood of pre-treatment gametocytaemia. However, crt T76 did not correlate with gametocytaemia following SP treatment and no selection of crt T76 in SP treatment failure isolates was observed., Conclusion: These results confirm an association between CQ and SP resistance markers in isolates from northern Ghana. This could indicate accelerated development of resistance to SP if CQ resistance is already present, or vice versa. Considering the enhanced transmission potential as reflected by the increased proportion of isolates containing gametocytes when resistant parasites are present, co-resistance can be expected to spread in this area. However, the underlying mechanism leading to this constellation remains obscure.

Malarone (atovaquone-proguanil) is an effective drug for the treatment and prophylaxis of multidrug-resistant falciparum malaria. However, first cases of resistance have been reported, which are associated with mutations at codon 268 of the parasite's cytochrome b gene. We report the first case of Malarone treatment failure from Central Africa.Drug concentration was well within curative range. Pre- and post-treatment Plasmodium falciparum isolates revealed codon 268 wild-type alleles, and no other mutations of the putative atovaquone-binding domain.These findings illustrate the spread of atovaquone-proguanil-resistance in Africa and question the usefulness of codon 268 as the only target for the surveillance of its emergence.

Background: The erythrocyte binding antigen-175 (EBA-175) on Plasmodium falciparum merozoites mediates sialic acid dependent binding to glycophorin A on host erythrocytes and, therefore, plays a crucial role in cell invasion. Dimorphic allele segments have been found in its encoding gene with a 342 bp segment present in FCR-3 strains (F-segment) and a 423 bp segment in CAMP strains (C-segment). Possible associations of the dimorphism with severe malaria have been analysed in a case-control study in northern Ghana., Methods: Blood samples of 289 children with severe malaria and 289 matched parasitaemic but asymptomatic controls were screened for eba-175 F- and C-segments by nested polymerase chain reaction., Results: In children with severe malaria, prevalences of F-, C- and mixed F-/C-segments were 70%, 19%, and 11%, respectively. The C-segment was found more frequently in severe malaria cases whereas mixed infections were more common in controls. Infection with strains harbouring the C-segment significantly increased the risk of fatal outcome., Conclusion: The results show that the C-segment is associated with fatal outcome in children with severe malaria in northern Ghana, suggesting that it may contribute to the virulence of the parasite.