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We conducted a genome-wide association study of host resistance to severePlasmodium falciparummalaria in over 17,000 individuals from 11 malaria-endemic countries, undertaking a wide ranging analysis which identifies five replicable associations with genome-wide levels of evidence. Our findings include a newly implicated variant on chromosome 6 associated with risk of cerebral malaria, and the discovery of an erythroid-specific transcription start site underlying the association inATP2B4. Previously reported HLA associations cannot be replicated in this dataset. We estimate substantial heritability of severe malaria (h2~ 23%), of which around 10% is explained by the currently identified associations. Our dataset will provide a major building block for future research on the genetic determinants of disease in these diverse human populations.

Many human genetic associations with resistance to malaria have been reported, but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. We tested 55 SNPs in 27 loci previously reported to associate with severe malaria. There was evidence of association at P < 1 × 10(-4) with the HBB, ABO, ATP2B4, G6PD and CD40LG loci, but previously reported associations at 22 other loci did not replicate in the multicenter analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, with a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.

The genetic basis for susceptibility to malaria has been studied widely in African populations but less is known of the contribution of specific genetic variants in Asian populations. We genotyped 67 single-nucleotide polymorphisms (SNPs) in 1030 severe malaria cases and 2840 controls from Vietnam. After data quality control, genotyping data of 956 cases and 2350 controls were analysed for 65 SNPs (3 gender confirmation, 62 positioned in/near 42 malarial candidate genes). A total of 14 SNPs were monomorphic and 2 (rs8078340 and rs33950507) were not in Hardy-Weinberg equilibrium in controls (P

Background By 2009, there were worrying signs from western Cambodia that parasitological responses to artesunate-containing treatment regimens for uncomplicated Plasmodium falciparum malaria were slower than elsewhere which suggested the emergence of artemisinin resistance. Vietnam shares a long land border with Cambodia with a large number of migrants crossing it on a daily basis. Therefore, there is an urgent need to investigate whether there is any evidence of a change in the parasitological response to the artemisinin derivatives in Vietnam. Methods From August 2010 to May 2011, a randomized controlled clinical trial in uncomplicated falciparum malaria was conducted to compare two doses of artesunate (AS) (2mg/kg/day versus 4 mg/kg/day for three days) followed by dihydroartemisinin-piperaquine (DHA-PPQ) and a control arm of DHA-PPQ. The goal was characterization of the current efficacy of artesunate in southern Vietnam. The primary endpoint of this study was the parasite clearance half-life; secondary endpoints included the parasite reduction ratios at 24 and 48 hours and the parasite clearance time. Results 166 patients were recruited into the study. The median parasite clearance half-lives were 3.54 (AS 2mg/kg), 2.72 (AS 4mg/kg), and 2.98 hours (DHA-PPQ) (p=0.19). The median parasite-reduction ratio at 24 hours was 48 in the AS 2mg/kg group compared with 212 and 113 in the other two groups, respectively (p=0.02). The proportions of patients with a parasite clearance time of >72 hours for AS 2mg/kg, AS 4mg/kg and DHA-PPQ were 27%, 27%, and 22%, respectively. Early treatment failure occurred in two (4%) and late clinical failure occurred in one (2%) of the 55 patients in the AS 2mg/kg group, as compared with none in the other two study arms. The PCR-corrected adequate clinical and parasitological response (APCR) rates in the three groups were 94%, 100%, and 100% (p=0.04). Conclusions This study demonstrated faster P. falciparum parasite clearance in southern Vietnam than in western Cambodia but slower clearance in comparison with historical data from Vietnam. Further studies to determine whether this represents the emergence of artemisinin resistance in this area are needed. Currently, the therapeutic response to DHA-PPQ remains satisfactory in southern Vietnam. Trial registration NTC01165372

A total of 128 Vietnamese patients with symptomatic Plasmodium vivax mono-infections were enrolled in a prospective, open-label, randomized trial to receive either chloroquine or dihydroartemisinin–piperaquine (DHA-PPQ). The proportions of patients with adequate clinical and parasitological responses were 47% in the chloroquine arm (31 of 65 patients) and 66% in the DHA-PPQ arm (42 of 63 patients) in the Kaplan–Meier intention-to-treat analysis (absolute difference 19%, 95% confidence interval = 0–37%), thus establishing non-inferiority of DHA-PPQ. Fever clearance time (median 24 versus 12 hours, P = 0.02), parasite clearance time (median 36 versus 18 hours, P < 0.001), and parasite clearance half-life (mean 3.98 versus 1.80 hours, P < 0.001) were all significantly shorter in the DHA-PPQ arm. All cases of recurrent parasitemia in the chloroquine arm occurred from day 33 onward, with corresponding whole blood chloroquine concentration lower than 100 ng/mL in all patients. Chloroquine thus remains efficacious for the treatment of P. vivax malaria in southern Vietnam, but DHA-PPQ provides more rapid symptomatic and parasitological recovery.

We describe an analysis of genome variation in 825 Plasmodium falciparum samples from Asia and Africa that reveals an unusual pattern of parasite population structure at the epicentre of artemisinin resistance in western Cambodia. Within this relatively small geographical area we have discovered several distinct but apparently sympatric parasite subpopulations with extremely high levels of genetic differentiation. Of particular interest are three subpopulations, all associated with clinical resistance to artemisinin, which have skewed allele frequency spectra and remarkably high levels of haplotype homozygosity, indicative of founder effects and recent population expansion. We provide a catalogue of SNPs that show high levels of differentiation in the artemisinin-resistant subpopulations, including codon variants in various transporter proteins and DNA mismatch repair proteins. These data provide a population genetic framework for investigating the biological origins of artemisinin resistance and for defining molecular markers to assist its elimination.

In July, 2012, a 25-year-old man was admitted to our hospital with headache, fever, and reduced consciousness. He had an unremarkable medical history and took no regular medications. He worked as a peanut vendor and before becoming unwell had visited relatives in the countryside. During this time he had attended a wedding and dived for pearls in a freshwater lake. 1 week after returning to the city he developed headache and fever, for which he took paracetamol. The next day his headache worsened in severity and he presented to his local hospital, where staff noted that he was confused. He was given a dose of ceftriaxone to cover bacterial meningitis and was transferred to our hospital. On initial assessment, he had a temperature of 39°C. His Glasgow coma scale score was 10 (M=5, V=2, E=3). His neck was stiff . He had no rash and was haemodynamically stable. Initial blood tests showed raised white cell count of 13·34×109 per L with 89% neutrophils. Lumbar puncture was done, which showed an opening pressure of 38 cm H2O. Cerebrospinal fl uid (CSF) contained 3260 × 103 per mL white cells with 88% neutrophils. CSF protein was 7·9 g/L, and glucose was 0·15 mmol/L. Plasma glucose was 8·62 mmol/L. Gram and Zeil-Neilsen stains were negative. However, on wet mount microscopy numerous amoebae were seen (see fi gure and webvideo). He had already started ceftriaxone and dexamethasone for presumed bacterial meningitis. In view of the CSF fi ndings and history of exposure to freshwater a diagnosis of primary amoebic meningoencephalitis was considered. Amphotericin B and rifampicin were started. Later on the day of admission his condition deteriorated and he required intubation and ventilation. He subsequently went into cardiac arrest and could not be resuscitated. Polymerase chain reaction Lancet 2013; 381: 176

In order to obtain an approximate assessment of the public health burden that will be posed by the inherited disorders of haemoglobin in southern Vietnam, several thousand individuals were screened for these conditions. A smaller sample was screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency. The important haemoglobin disorders identified were beta thalassaemia, haemoglobin E and a variety of different forms of alpha thalassaemia. There were sufficient G6PD-deficient individuals to materially affect malaria control programme design. The most remarkable finding was wide variation in the gene frequencies of these conditions among the ethnic groups sampled. The approximate number of babies expected to be born with clinically significant haemoglobin disorders in Vietnam was estimated from the gene-frequency data. This study emphasizes the importance of wide-scale population screening, including ethnic subgroups, to establish the requirements for inherited haemoglobin disorder programmes in resource-limited settings.