Molecular surveillance of Pfcrt and k13 propeller polymorphisms of imported Plasmodium falciparum cases to Zhejiang Province, China between 2016 and 2018.

BACKGROUND: Resistance to anti-malarial drugs hinders malaria elimination. Monitoring the molecular markers of drug resistance helps improve malaria treatment policies. This study aimed to assess the distribution of molecular markers of imported Plasmodium falciparum infections. METHODS: In total, 485 P. falciparum cases imported from Africa, Southeast Asia, and Oceania into Zhejiang province, China, from 2016 to 2018 were investigated. Most were imported from Africa, and only a few cases originated in Asia and Oceania. Blood samples were collected from each patient. Plasmodium falciparum chloroquine resistance transporter (Pfcrt) at residues 72-76 and Kelch13-propeller (k13) were determined by nested PCR and DNA sequence. RESULTS: Wild-type Pfcrt at residues 72-76 was predominant (72.61%), but mutant and mixed alleles were also detected, of which CVIET (22.72%) was the most common. Mutant Pfcrt haplotypes were more frequent in patients from West Africa (26.92%), North Africa (25%), and Central Africa (21.93%). The number of cases of P. falciparum infections was small in Southeast Asia and Oceania, and these cases involved Pfcrt mutant type. For the k13 propeller gene, 26 samples presented 19 different point mutations, including eight nonsynonymous mutations (P441S, D464E, K503E, R561H, A578S, R622I, V650F, N694K). In addition, R561H, one of the validated SNPs in k13, was detected in one patient from Myanmar and one patient from Rwanda. A578S, although common in Africa, was found in only one patient from Cameroon. R622I was detected in one sample from Mozambique and one sample from Somalia. The genetic diversity of k13 was low in most regions of Africa and purifying selection was suggested by Tajima's D test. CONCLUSIONS: The frequency and spatial distributions of Pfcrt and k13 mutations associated with drug resistance were determined. Wild-type Pfcrt was dominant in Africa. Among k13 mutations correlated with delayed parasite clearance, only the R561H mutation was found in one case from Rwanda in Africa. Both Pfcrt and k13 mutations were detected in patients from Southeast Asia and Oceania. These findings provide insights into the molecular epidemiological profile of drug resistance markers in the study region.

Forest Goers and Multidrug-Resistant Malaria in Cambodia: An Ethnographic Study.

Multidrug-resistant Plasmodium falciparum malaria on the Cambodia-Thailand border is associated with working in forested areas. Beyond broad recognition of "forest-going" as a risk factor for malaria, little is known about different forest-going populations in this region. In Oddar Meanchey Province in northwestern Cambodia, qualitative ethnographic research was conducted to gain an in-depth understanding of how different populations, mobility and livelihood patterns, and activities within the forest intersect with potentiate malaria risk and impact on the effectiveness of malaria control and elimination strategies. We found that most forest-going in this area is associated with obtaining precious woods, particularly Siamese rosewood. In the past, at-risk populations included large groups of temporary migrants. As timber supplies have declined, so have these large migrant groups. However, groups of local residents continue to go to the forest and are staying for longer. Most forest-goers had experienced multiple episodes of malaria and were well informed about malaria risk. However, economic realities mean that local residents continue to pursue forest-based livelihoods. Severe constraints of available vector control methods mean that forest-goers have limited capacity to prevent vector exposure. As forest-goers access the forest using many different entry and exit points, border screening and treatment interventions will not be feasible. Once in the forest, groups often converge in the same areas; therefore, interventions targeting the mosquito population may have a potential role. Ultimately, a multisectoral approach as well as innovative and flexible malaria control strategies will be required if malaria elimination efforts are to be successful.

Antibody responses to P. falciparum Apical Membrane Antigen 1(AMA-1) in relation to haemoglobin S (HbS), HbC, G6PD and ABO blood groups among Fulani and Masaleit living in Western Sudan.

Fulani and Masaleit are two sympatric ethnic groups in western Sudan who are characterised by marked differences in susceptibility to Plasmodium falciparum malaria. It has been demonstrated that Glucose-6-phosphate dehydrogenase (G6PD) deficiency and Sickle cell trait HbAS carriers are protected from the most severe forms of malaria. This study aimed to investigate a set of specific IgG subclasses against P. falciparum Apical Membrane Antigen 1 (AMA-1 3D7), haemoglobin variants and (G6PD) in association with malaria susceptibility among Fulani ethnic group compared to sympatric ethnic group living in Western Sudan. A total of 124 children aged 5-9 years from each tribe living in an area of hyper-endemic P. falciparum unstable malaria transmission were recruited and genotyped for the haemoglobin (Hb) genes, (G6PD) and (ABO) blood groups. Furthermore, the level of plasma IgG antibody subclasses against P. falciparum antigen (AMA-1) were measured using enzyme linked immunosorbent assays (ELISA). Higher levels of anti-malarial IgG1, IgG2 and IgG3 but not IgG4 antibody were found in Fulani when compared to Masaleit. Individuals carrying the HbCC phenotype were significantly associated with higher levels of IgG1 and IgG2. Furthermore, individuals having the HbAS phenotype were associated with higher levels of specific IgG2 and IgG4 antibodies. In addition, patients with G6PD A/A genotype were associated with higher levels of specific IgG2 antibody compared with those carrying the A/G and G/G genotypes. The results indicate that the Fulani ethnic group show lower frequency of HbAS, HbSS and HbAC compared to the Masaleit ethnic group. The inter-ethnic analysis shows no statistically significant difference in G6PD genotypes (P value = 0.791). However, the intra-ethnic analysis indicates that both ethnic groups have less A/A genotypes and (A) allele frequency of G6PD compared to G/G genotypes, while the HbSA genotype was associated with higher levels of IgG2 (AMA-1) and IgG4 antibodies. In addition, patients carrying the G6PD A/A genotype were associated with higher levels of specific IgG2 antibody compared with those carrying the A/G and G/G genotypes. The present results revealed that the Fulani ethnic group has statistically significantly lower frequency of abnormal haemoglobin resistant to malaria infection compared to the Masaleit ethnic group.

Treatment for Uncomplicated Plasmodium falciparum Malaria in French Soldiers Deployed in Sub-Saharan Africa: Gaps Between Policy and Field Practice.

BACKGROUND: Malaria prevention and treatment are big challenges for the French forces deployed in sub-Saharan Africa. Since December 2013, 1,800 French soldiers have been deployed at any one time in the Central African Republic in the framework of "Operation Sangaris" and European Union Force (EUFOR). Over the 2014-2015 period, about 500 cases of malaria were notified in these troops during the operation or after their return (annual incidence: 13.4 p.100 person-year). The recommendation to use dihydroartemisinin-piperaquine (DHA-PQ) as the first-line treatment for French soldiers suffering from uncomplicated Plasmodium falciparum malaria in endemic areas is not always followed in practice in the field by French military general practitioners (GPs). METHODS: We conduced a retrospective Knowledge-Attitude-Practice study by self-administered questionnaire, to all military French doctors who were in mission in Central African Republic from January 2014 to July 2015 to try to understand what were the reasons for the GP not to prescribe DHA-PQ on the field. FINDINGS: Thirty-six GPs (53%) answered to the questionnaire. Eighty-three percent of them knew about the recommendation to use DHA-PQ for un uncomplicated Pf malaria. Fifty-eight percent had a favorable attitude toward DHA-PQ. The factors associated with the prescription of another drug (Atovaquone-proguanil) were: the habit (odds ratio [OR] 0.1, confidence interval (CI) 0-0.6], the fact that Atovaquone-proguanil is more practical to use [OR 0.01, CI 0-0.1]. In practice, only 37.5% prescribed DHA-PQ the most of the time during their mission. Factors associated with a non-favorable attitude toward DHA-PQ were: the necessity to calculate a QTc interval during the treatment [OR 0.2, confidence interval 0-0.9], and the fact that DHA-PQ must be taken on an empty stomach [OR 0.3, CI 0.1-0.8]. GP who received a formation before their mission about malaria and treatment had a favorable attitude toward DHA-PQ. DISCUSSION: There is very satisfactory knowledge by the military GPs stationed in the Central African Republic on both the recommendations and prescription of antimalarial drugs. The present study highlights some difficulties in implementing the recommendations in an operational context, notably factors limiting the prescription of DHA-PQ during military deployment (need for ECG monitoring, empty stomach, and lack of habit). Proposals can be made to improve the efficacy, tolerance, and practicability of malaria treatment in the field. The main focus should be a more flexible application of the French DHA-PQ risk management plan in the field, specific training and communication about DHA-PQ use, the generalization of ECG printing equipment in the field, and the switch from DHA-PQ to an alternative artemisinin-based combination therapy during deployments in malaria-endemic areas.

Pharmacokinetic considerations for use of artemisinin-based combination therapies against falciparum malaria in different ethnic populations.

INTRODUCTION: Artemisinin-based combination therapy (ACT) is used extensively as first-line treatment for uncomplicated falciparum malaria. There has been no rigorous assessment of the potential for racial/ethnic differences in the pharmacokinetic properties of ACTs that might influence their efficacy. Areas covered: A comprehensive literature search was performed that identified 72 publications in which the geographical origin of the patients could be ascertained and the key pharmacokinetic parameters maximum drug concentration (Cmax), area under the plasma concentration-time curve (AUC) and elimination half-life (t½ß) were available for one or more of the five WHO-recommended ACTs (artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine and artesunate-sulfadoxine-pyrimethamine). Comparisons of each of the three pharmacokinetic parameters of interest were made by drug (artemisinin derivative and long half-life partner), race/ethnicity (African, Asian, Caucasian, Melanesian, South American) and patient categories based on age and pregnancy status. Expert opinion: The review identified no evidence of a clinically significant influence of race/ethnicity on the pharmacokinetic properties of the nine component drugs in the five ACTs currently recommended by WHO for first-line treatment of uncomplicated falciparum malaria. This provides reassurance for health workers in malaria-endemic regions that ACTs can be given in recommended doses with the expectation of adequate blood concentrations regardless of race/ethnicity.

Obesity and Diabetes as Risk Factors for Severe Plasmodium falciparum Malaria: Results From a Swedish Nationwide Study.

BACKGROUND: Noncommunicable diseases and obesity are increasing in prevalence globally, also in populations at risk of malaria. We sought to investigate if comorbidity, in terms of chronic diseases and obesity, is associated with severe Plasmodium falciparum malaria. METHODS: We performed a retrospective observational study in adults (≥18 years of age) diagnosed with malaria in Sweden between January 1995 and May 2015. We identified cases through the surveillance database at the Public Health Agency of Sweden and reviewed clinical data from 18 hospitals. Multivariable logistic regression was used to assess associations between comorbidities and severe malaria. RESULTS: Among 937 adults (median age, 37 years; 66.5% were male), patients with severe malaria had higher prevalence of chronic diseases (28/92 [30.4%]) compared with nonsevere cases (151/845 [17.9%]) (P = .004). Charlson comorbidity score ≥1 was associated with severe malaria (adjusted odds ratio [aOR], 2.63 [95% confidence interval {CI}, 1.45-4.77), as was diabetes among individual diagnoses (aOR, 2.98 [95% CI, 1.25-7.09]). Median body mass index was higher among severe (29.3 kg/m2) than nonsevere cases (24.7 kg/m2) (P < .001). Obesity was strongly associated with severe malaria, both independently (aOR, 5.58 [95% CI, 2.03-15.36]) and in combination with an additional metabolic risk factor (hypertension, dyslipidemia, or diabetes) (aOR, 6.54 [95% CI, 1.87-22.88]). The associations were observed among nonimmune travelers as well as immigrants from endemic areas. CONCLUSIONS: Comorbidities, specifically obesity and diabetes, are previously unidentified risk factors for severe malaria in adults diagnosed with P. falciparum. Noncommunicable diseases should be considered in the acute management and prevention of malaria.

The High Blood Pressure-Malaria Protection Hypothesis.

RATIONALE: A recently proposed hypothesis states that malaria may contribute to hypertension in endemic areas,1 but the role of angiotensin II (Ang II), a major regulator of blood pressure, was not considered. Elevated levels of Ang II may confer protection against malaria morbidity and mortality, providing an alternative explanation for hypertension in malaria endemic areas. OBJECTIVE: To discuss a possible alternative cause for hypertension in populations who have been under the selective pressure of malaria. METHODS AND RESULTS: We reviewed published scientific literature for studies that could establish a link between Ang II and malaria. Both genetic and functional studies suggested that high levels of Ang II may confer protection against cerebral malaria by strengthening the integrity of the endothelial brain barrier. We also describe strong experimental evidence supporting our hypothesis through genetic, functional, and interventional studies. CONCLUSIONS: A causal association between high levels of Ang II and protection from malaria pathogenesis can provide a likely explanation for the increased prevalence in hypertension observed in populations of African and South Asian origin. Furthermore, this potential causative connection might also direct unique approaches for the effective treatment of cerebral malaria.

Epidemic and Non-Epidemic Hot Spots of Malaria Transmission Occur in Indigenous Comarcas of Panama.

From 2002-2005, Panama experienced a malaria epidemic that has been associated with El Niño Southern Oscillation weather patterns, decreased funding for malaria control, and landscape modification. Case numbers quickly decreased afterward, and Panama is now in the pre-elimination stage of malaria eradication. To achieve this new goal, the characterization of epidemiological risk factors, foci of transmission, and important anopheline vectors is needed. Of the 24,681 reported cases in these analyses (2000-2014), ~62% occurred in epidemic years and ~44% in indigenous comarcas (5.9% of Panama's population). Sub-analyses comparing overall numbers of cases in epidemic and non-epidemic years identified females, comarcas and some 5-year age categories as those disproportionately affected by malaria during epidemic years. Annual parasites indices (APIs; number of cases per 1,000 persons) for Plasmodium vivax were higher in comarcas compared to provinces for all study years, though P. falciparum APIs were only higher in comarcas during epidemic years. Interestingly, two comarcas report increasing numbers of cases annually, despite national annual decreases. Inclusion of these comarcas within identified foci of malaria transmission confirmed their roles in continued transmission. Comparison of species distribution models for two important anophelines with Plasmodium case distribution suggest An. albimanus is the primary malaria vector in Panama, confirmed by identification of nine P. vivax-infected specimen pools. Future malaria eradication strategies in Panama should focus on indigenous comarcas and include both active surveillance for cases and comprehensive anopheline vector surveys.

Hemoglobin E Prevalence among Ethnic Groups Residing in Malaria-Endemic Areas of Northern Thailand and Its Lack of Association with Plasmodium falciparum Invasion In Vitro.

Hemoglobin E (HbE) is one of the most common hemoglobin variants caused by a mutation in the ß-globin gene, and found at high frequencies in various Southeast Asian groups. We surveyed HbE prevalence among 8 ethnic groups residing in 5 villages selected for their high period malaria endemicity, and 5 for low endemicity in northern Thailand, in order to uncover factors which may affect genetic persistence of HbE in these groups. We found the overall HbE prevalence 6.7%, with differing frequencies from 0% in the Pwo Karen, the Lawa, and the Skaw Karen to 24% in the Mon. All HbE genes were heterozygous (AE). Differences in HbE prevalence among the studied ethnic groups indirectly documents that ancestries and evolutionary forces, such as drift and admixture, are the important factors in the persistence of HbE distribution in northern Thailand. Furthermore, the presence of HbE in groups of northern Thailand had no effect on the in vitro infectivity and proliferation of Plasmodium falciparum, nor the production of hemozoin, a heme crystal produced by malaria parasites, when compared to normal red-blood-cell controls. Our data may contribute to a better understanding on the persistence of HbE among ethnic groups and its association with malaria.

The selective outpatient treatment of adults with imported falciparum malaria: a prospective cohort study.

BACKGROUND: Current UK malaria treatment guidelines recommend admission for all patients diagnosed with falciparum malaria. However, evidence suggests that certain patients are at lower risk of severe malaria and death and may be managed as outpatients. AIM: To prospectively assess the risk of post-treatment severe falciparum malaria in selected cases managed as outpatients. The readmission rate and treatment tolerability were assessed as secondary outcomes. DESIGN: Prospective cohort study. METHODS: Adults (>15 years old) diagnosed with falciparum malaria between May 2008 and July 2012 were selected for outpatient treatment using locally defined clinical and laboratory indicators based on known risk factors for severity and death. Treatment outcomes were assessed in clinic or by telephone 4-6 weeks after treatment. RESULTS: 269 adults were diagnosed with falciparum malaria on blood film between May 2008 and July 2012. Of 255 eligible participants, 106 patients were offered ambulatory treatment, of which 95 completed the study. The severe malaria rate was 0% (95% confidence interval (CI) 0-3.8%) and the readmission rate was 5.3% (95% CI 1.7-11.9) in the outpatient group. In addition, 10.6% (95% CI 5.2-18.7%) of outpatients reported drug-related side effects. CONCLUSIONS: The outpatient treatment of selected cases of falciparum malaria is effective in our high volume UK setting. We recommend adopting a similar approach to managing this infection in other non-endemic settings where immediate access to specialist advice is available.

Ethnic differences in susceptibility to malaria: what have we learned from immuno-epidemiological studies in West Africa?

There are many fundamental aspects of the immunobiology of Plasmodium falciparum infections that are not fully understood, therefore limiting our comprehension of how people become immune to malaria and why some ethnic groups living in malaria endemic areas are less susceptible than others. The complexity of parasite-host interactions and the genetic diversity of the parasites as well as the human host complicate our strategy to address this issue. In this mini-review we discuss and summarize what we have learned about African ethnic differences in susceptibility to malaria from immuno-epidemiological studies. Additionally, we suggest research topics that might be of great value for dissecting the mechanisms of protection by providing new insights into molecular interactions between the parasite and the host.

Killer cell immunoglobulin-like receptor (KIR) gene diversity in a population naturally exposed to malaria in Porto Velho, Northern Brazil.

Killer cell immunoglobulin-like receptors (KIR) are expressed mainly in natural killer cells and specifically recognize human leukocyte antigen (HLA) class I molecules. The repertoire of KIR genes and KIR-HLA pairs is known to play a key role in the susceptibilities to and the outcomes of several diseases, including malaria. The aim of this study was to investigate the distribution of KIR genes, KIR genotypes and KIR-HLA pair combinations in a population naturally exposed to malaria from Brazilian Amazon. All 16 KIR genes investigated were present in the studied population. Overall, 46 KIR genotypes were defined. The two most common genotypes in the Porto Velho communities, genotypes 1 and 2, were present at similar frequencies as in the Americas. Principal component analysis based on the frequencies of the KIR genes placed the Porto Velho population closer to the Venezuela Mestizos, USA California hispanic and Brazil Paraná Mixed in terms of KIR gene frequencies. This analysis highlights the multi-ethnic profile of the Porto Velho population. Most of the individuals were found to have at least one inhibitory KIR-HLA pair. Seventy-five KIR-HLA pair combinations were identified. The KIR-2DL2/3_HLA-C1, KIR3DL1_HLA-Bw4 and KIR2DL1_HLA-C2 pairs were the most common. There was no association between KIR genes, KIR genotypes or KIR-HLA pair combinations and malaria susceptibility in the studied population. This is the first report on the distribution of KIR and known HLA ligands in the Porto Velho population. Taken together, these results should provide baseline information that will be relevant to population evolutionary history, malaria and other diseases studies in populations of the Brazilian Amazon.

Geographically weighted regression of land cover determinants of Plasmodium falciparum transmission in the Ashanti Region of Ghana.

BACKGROUND: Malaria is a mosquito-borne parasitic disease that causes severe mortality and morbidity, particularly in Sub-Saharan Africa. As the vectors predominantly bite between dusk and dawn, risk of infection is determined by the abundance of P. falciparum infected mosquitoes in the surroundings of the households. Remote sensing is commonly employed to detect associations between land use/land cover (LULC) and mosquito-borne diseases. Due to challenges in LULC identification and the fact that LULC merely functions as a proxy for mosquito abundance, assuming spatially homogenous relationships may lead to overgeneralized conclusions. METHODS: Data on incidence of P. falciparum parasitaemia were recorded by active and passive follow-up over two years. Nine LULC types were identified through remote sensing and ground-truthing. Spatial associations of LULC and P. falciparum parasitaemia rate were described in a semi-parametric geographically weighted Poisson regression model. RESULTS: Complete data were available for 878 individuals, with an annual P. falciparum rate of 3.2 infections per person-year at risk. The influences of built-up areas (median incidence rate ratio (IRR): 0.94, IQR: 0.46), forest (median IRR: 0.9, IQR: 0.51), swampy areas (median IRR: 1.15, IQR: 0.88), as well as banana (median IRR: 1.02, IQR: 0.25), cacao (median IRR: 1.33, IQR: 0.97) and orange plantations (median IRR: 1.11, IQR: 0.68) on P. falciparum rate show strong spatial variations within the study area. Incorporating spatial variability of LULC variables increased model performance compared to the spatially homogenous model. CONCLUSIONS: The observed spatial variability of LULC influence in parasitaemia would have been masked by traditional Poisson regression analysis assuming a spatially constant influence of all variables. We conclude that the spatially varying effects of LULC on P. falciparum parasitaemia may in fact be associated with co-factors not captured by remote sensing, and suggest that future studies assess small-scale spatial variation of vegetation to circumvent generalised assumptions on ecological associations that may in fact be artificial.

Risk factors for UK Plasmodium falciparum cases.

BACKGROUND: An increasing proportion of malaria cases diagnosed in UK residents with a history of travel to malaria endemic areas are due to Plasmodium falciparum. METHODS: In order to identify travellers at most risk of acquiring malaria a proportional hazards model was used to estimate the risk of acquiring malaria stratified by purpose of travel and age whilst adjusting for entomological inoculation rate (EIR) and duration of stay in endemic countries. RESULTS: Travellers visiting friends and relatives and business travellers were found to have significantly higher hazard of acquiring malaria (adjusted hazard ratio (HR) relative to that of holiday makers 7.4, 95% CI 6.4-8.5, p < 0. 0001 and HR 3.4, 95% CI 2.9-3.8, p < 0. 0001, respectively). All age-groups were at lower risk than children aged 0-15 years. CONCLUSIONS: These estimates of the increased risk for business travellers and those visiting friends and relatives should be used to inform programmes to improve awareness of the risks of malaria when travelling.

Glucose-6-phosphate dehydrogenase polymorphisms and susceptibility to mild malaria in Dogon and Fulani, Mali.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with protection from severe malaria, and potentially uncomplicated malaria phenotypes. It has been documented that G6PD deficiency in sub-Saharan Africa is due to the 202A/376G G6PD A-allele, and association studies have used genotyping as a convenient technique for epidemiological studies. However, recent studies have shown discrepancies in G6PD202/376 associations with severe malaria. There is evidence to suggest that other G6PD deficiency alleles may be common in some regions of West Africa, and that allelic heterogeneity could explain these discrepancies. METHODS: A cross-sectional epidemiological study of malaria susceptibility was conducted during 2006 and 2007 in the Sahel meso-endemic malaria zone of Mali. The study included Dogon (n = 375) and Fulani (n = 337) sympatric ethnic groups, where the latter group is characterized by lower susceptibility to Plasmodium falciparum malaria. Fifty-three G6PD polymorphisms, including 202/376, were genotyped across the 712 samples. Evidence of association of these G6PD polymorphisms and mild malaria was assessed in both ethnic groups using genotypic and haplotypic statistical tests. RESULTS: It was confirmed that the Fulani are less susceptible to malaria, and the 202A mutation is rare in this group (<1% versus Dogon 7.9%). The Betica-Selma 968C/376G (~11% enzymatic activity) was more common in Fulani (6.1% vs Dogon 0.0%). There are differences in haplotype frequencies between Dogon and Fulani, and association analysis did not reveal strong evidence of protective G6PD genetic effects against uncomplicated malaria in both ethnic groups and gender. However, there was some evidence of increased risk of mild malaria in Dogon with the 202A mutation, attaining borderline statistical significance in females. The rs915942 polymorphism was found to be associated with asymptomatic malaria in Dogon females, and the rs61042368 polymorphism was associated with clinical malaria in Fulani males. CONCLUSIONS: The results highlight the need to consider markers in addition to G6PD202 in studies of deficiency. Further, large genetic epidemiological studies of multi-ethnic groups in West Africa across a spectrum of malaria severity phenotypes are required to establish who receives protection from G6PD deficiency.

Preliminary investigation of the contribution of CYP2A6, CYP2B6, and UGT1A9 polymorphisms on artesunate-mefloquine treatment response in Burmese patients with Plasmodium falciparum malaria.

CYP2A6, CYP2B6, and UGT1A9 genetic polymorphisms and treatment response after a three-day course of artesunate-mefloquine was investigated in 71 Burmese patients with uncomplicated Plasmodium falciparum malaria. Results provide evidence for the possible link between CYP2A6 and CYP2B6 polymorphisms and plasma concentrations of artesunate/dihydroartemisinin and treatment response. In one patient who had the CYP2A6*1A/*4C genotype (decreased enzyme activity), plasma concentration of artesunate at one hour appeared to be higher, and the concentration of dihydroartemisinin was lower than for those carrying other genotypes (415 versus 320 ng/mL). The proportion of patients with adequate clinical and parasitologic response who had the CYP2B6*9/*9 genotype (mutant genotype) was significantly lower compared with those with late parasitologic failure (14.0% versus 19.0%). Confirmation through a larger study in various malaria-endemic areas is required before a definite conclusion on the role of genetic polymorphisms of these drug-metabolizing enzymes on treatment response after artesunate-based combination therapy can be made.

Imported malaria is stable from Africa but declining from Asia.

INTRODUCTION: In this study, we describe patients with imported malaria seen at the Department of Infectious Diseases (DID), Hvidovre Hospital, Denmark. Our aim was to address possible risk factors for contracting malaria and risk factors for developing complicated malaria. MATERIAL AND METHODS: We searched patient databases for all cases of malaria seen at the DID from 1994 to 2012. Various parameters were registered. RESULTS: A total of 320 cases were identified. We found a significant 3.39 % decrease in the incidence of cases per year (p = 0.0008). Plasmodium falciparum infection was predominant (n = 217) followed by P. vivax infection (n = 76). 37% of all cases were Africans visiting relatives and friends (VRF). A total of 12 patients had one or more re-lapses of their P. vivax infection. In all, 53 (17%) cases were defined as severe malaria. 36% (n = 112) reported using some type of chemoprophylaxis. 14% (n = 26) of patients traveling to Africa in 1999-2012 reported taking chemoprophylaxis as recommended in the current guidelines. Complicated malaria was significantly associated with failure to take any chemoprophylaxis (p = 0.0317, χ(2)-test). CONCLUSION: Imported malaria is decreasing at the DID. The patients who carry the highest risk of imported malaria are ethnic Africans who travel as VRF without using chemoprophylaxis. Recrudescence from P. vivax malaria is a substantial risk. Complicated malaria is associated with failure to take any chemoprophylaxis. It is important that travelers receive expedient advice on the use of efficient chemoprophylaxis to bring down the number of imported malaria cases. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Relative undernourishment and food insecurity associations with Plasmodium falciparum among Batwa pygmies in Uganda: evidence from a cross-sectional survey.

Although malnutrition and malaria co-occur among individuals and populations globally, effects of nutritional status on risk for parasitemia and clinical illness remain poorly understood. We investigated associations between Plasmodium falciparum infection, nutrition, and food security in a cross-sectional survey of 365 Batwa pygmies in Kanungu District, Uganda in January of 2013. We identified 4.1% parasite prevalence among individuals over 5 years old. Severe food insecurity was associated with increased risk for positive rapid immunochromatographic test outcome (adjusted relative risk [ARR] = 13.09; 95% confidence interval [95% CI] = 2.23-76.79). High age/sex-adjusted mid-upper arm circumference was associated with decreased risk for positive test among individuals who were not severely food-insecure (ARR = 0.37; 95% CI = 0.19-0.69). Within Batwa pygmy communities, where malnutrition and food insecurity are common, individuals who are particularly undernourished or severely food-insecure may have elevated risk for P. falciparum parasitemia. This finding may motivate integrated control of malaria and malnutrition in low-transmission settings.

IgG1 and IgG4 antibody responses to the Anopheles gambiae salivary protein gSG6 in the sympatric ethnic groups Mossi and Fulani in a malaria hyperhendemic area of Burkina Faso.

Human antibody response to the Anopheles gambiae salivary protein gSG6 has recently emerged as a potentially useful tool for malaria epidemiological studies and for the evaluation of vector control interventions. However, the current understanding of the host immune response to mosquito salivary proteins and of the possible crosstalk with early response to Plasmodium parasites is still very limited. We report here the analysis of IgG1 and IgG4 subclasses among anti-gSG6 IgG responders belonging to Mossi and Fulani from Burkina Faso, two ethnic groups which are known for their differential humoral response to parasite antigens and for their different susceptibility to malaria. The IgG1 antibody response against the gSG6 protein was comparable in the two groups. On the contrary, IgG4 titers were significantly higher in the Fulani where, in addition, anti-gSG6 IgG4 antibodies appeared in younger children and the ratio IgG4/IgG1 stayed relatively stable throughout adulthood. Both gSG6-specific IgG1 and IgG4 antibodies showed a tendency to decrease with age whereas, as expected, the IgG response to the Plasmodium circumsporozoite protein (CSP) exhibited an opposite trend in the same individuals. These observations are in line with the idea that the An. gambiae gSG6 salivary protein induces immune tolerance, especially after intense and prolonged exposure as is the case for the area under study, suggesting that gSG6 may trigger in exposed individuals a Th2-oriented immune response.

Fc gamma receptor IIa-H131R polymorphism and malaria susceptibility in sympatric ethnic groups, Fulani and Dogon of Mali.

It has been previously shown that there are some interethnic differences in susceptibility to malaria between two sympatric ethnic groups of Mali, the Fulani and the Dogon. The lower susceptibility to Plasmodium falciparum malaria seen in the Fulani has not been fully explained by genetic polymorphisms previously known to be associated with malaria resistance, including haemoglobin S (HbS), haemoglobin C (HbC), alpha-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Given the observed differences in the distribution of FcγRIIa allotypes among different ethnic groups and with malaria susceptibility that have been reported, we analysed the rs1801274-R131H polymorphism in the FcγRIIa gene in a study of Dogon and Fulani in Mali (n = 939). We confirm that the Fulani have less parasite densities, less parasite prevalence, more spleen enlargement and higher levels of total IgG antibodies (anti-CSP, anti-AMA1, anti-MSP1 and anti-MSP2) and more total IgE (P < 0.05) compared with the Dogon ethnic group. Furthermore, the Fulani exhibit higher frequencies of the blood group O (56.5%) compared with the Dogon (43.5%) (P < 0.001). With regard to the FcγRIIa polymorphism and allele frequency, the Fulani group have a higher frequency of the H allele (Fulani 0.474, Dogon 0.341, P < 0.0001), which was associated with greater total IgE production (P = 0.004). Our findings show that the FcγRIIa polymorphism might have an implication in the relative protection seen in the Fulani tribe, with confirmatory studies required in other malaria endemic settings.