Recrudescence Of Malaria Research Articles

Artemisinin Partial Resistance in Ugandan Children With Complicated Malaria

This study assesses artemisinin partial resistance, Pfkelch13 variations, and malaria recrudescence in Ugandan children with complicated malaria.

Putative Contribution of 8-Aminoquinolines to Preventing Recrudescence of Malaria.

Enhanced therapeutic efficacy achieved in treating Plasmodium vivax malaria with an 8-aminoquinoline (8-AQ) drug such as primaquine (PQ) together with a partner drug such as chloroquine (CQ) is usually explained as CQ inhibiting asexual parasites in the bloodstream and PQ acting against liver stages. However, PQ's contribution, if any, to inactivating non-circulating, extra-hepatic asexual forms, which make up the bulk of the parasite biomass in chronic P. vivax infections, remains unclear. In this opinion article, I suggest that, considering its newly described mode of action, PQ might be doing something of which we are currently unaware.

Delayed Malaria Recrudescence and Relapse in the Setting of COVID-19

It is unknown whether COVID-19 can trigger malaria recrudescence or relapse. Although Plasmodium falciparum recrudescence occurring years after infection is extremely rare, delayed Plasmodium vivax and Plasmodium ovale relapse from the latent hypnozoite stage is well described. We report a case of acute P falciparum and P ovale co-infection that occurred 2 weeks after COVID-19 in an otherwise immunocompetent patient living in a malaria nonendemic country and without exposure to malaria in the preceding 5 years. This case highlights a potential mechanism by which COVID-19–associated immune depletion and/or dysregulation may trigger a delayed presentation of malaria.

Artemether-lumefantrine, mefloquine and atovaquone-proguanil in the treatment of uncomplicated Plasmodium falciparum malaria in travellers: A retrospective comparative study of efficacy and treatment failures.

The aim of this study was to evaluate the rates of parasitaemia clearance and the prevalence of treatment failure in patients with uncomplicated Plasmodium falciparum malaria treated with artemether-lumefantrine (AL), mefloquine (MQ), and atovaquone-proguanil (AP). The retrospective descriptive study included adult patients with uncomplicated P. falciparum malaria treated at the University Hospital Bulovka in Prague from 2006 to 2019. Parasitaemia clearance was estimated using a linear regression model. The study included 72 patients with a median age of 33 years (IQR 27-45) and a male to female ratio of 3.2:1. Thirty-six patients (50.0%) were treated with AL, 27 (37.5%) with MQ and 9 (12.5%) with AP. The proportion of VFR and migrants was 22.2% with no significant differences among the three groups. The median time to the parasitaemia clearance was two days (IQR 2-3) in patients treated with AL versus four days in the MQ (IQR 3-4) and AP (IQR 3-4) groups, p<0.001. The clearance rate constant was 3.3/hour (IQR 2.5-4.0) for AL, 1.6/hour (IQR 1.3-1.9) for MQ, and 1.9/hour (IQR 1.3-2.4) for AP, p<0.001. Malaria recrudescence occurred in 5/36 (13.9%) patients treated with AL and in no patients treated with MQ or AP. The findings demonstrate the superior efficacy of AL compared to other oral antimalarials in early malaria treatment. However, we observed a higher rate of late treatment failure in patients treated with AL than previously reported. This issue warrants further investigation of possible dose adjustments, extended regimens, or alternative artemisinin-based combinations.

Co-exposure to aflatoxin B1 and therapeutic coartem worsens hepatic and renal function through enhanced oxido-inflammatory responses and apoptosis in rats

Aflatoxin B1 (AFB1) is a mycotoxin synthesised as a secondary metabolite by members of the Aspergillus species contaminating agricultural produce. Aspergillus species thrive in tropical climes, endemic to malaria. Artemisinin-based combination therapies (ACTs) effectively treat and prevent malaria recrudescence; Coartem (COA) is an ACT whose toxicity is evident. Although there are scanty studies on COA toxicity, the scientific literature is replete on AFB1 toxic effects -including carcinogenicity. The current research investigates AFB1 and COA toxicity in experimental Wistar rats' hepatorenal systems. Thirty albino rats were randomly grouped into five cohorts (n = 6) and treated as follows: Group I: Untreated control (2 mL/kg of corn oil); group II: AFB1 alone (70 μg/kg); group III: COA alone (5 mg/kg); group IV: COA and a low dose of AFB11 (5 mg/kg & 35 μg/kg); while Group V: COA and a high dose AFB12 (5 mg/kg & 70 μg/kg) by gavage. Our results show that exposure to AFB1 and COA significantly (p < 0.05) reduced superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase activities, besides reduced glutathione and total sulfhydryl groups level. Reactive oxygen and nitrogen species, lipid peroxidation, 8-hydroxy-2′-deoxyguanosine, nitric oxide, xanthine oxidase, and myeloperoxidase levels were increased (p < 0.05) in rats co-treated with COA and AFB1. Cell death was aggravated in COA and AFB1 groups, exemplified by increased Caspase-3 and 9 activities and alterations in the typical histological features of experimental rats’ livers and kidneys. Finally, rats co-treated with AFB1 and COA experienced increased hepatorenal dysregulation, oxidative and inflammatory tissue damage, and apoptotic cell death. All the observed systemic perturbations occurred dose-dependently. It is crucial, therefore, to prevent AFB1 dietary contaminations during COA therapeutic regimen due to increased pathophysiological damage exerted on experimental rat liver and kidneys, as evidenced in this study.

Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy: an individual participant data meta-analysis

BackgroundThe duration of trial follow-up affects the ability to detect recrudescent infections following anti-malarial treatment. The aim of this study was to explore the proportions of recrudescent parasitaemia as ascribed by genotyping captured at various follow-up time-points in treatment efficacy trials for uncomplicated Plasmodium falciparum malaria.MethodsIndividual patient data from 83 anti-malarial efficacy studies collated in the WorldWide Antimalarial Resistance Network (WWARN) repository with at least 28 days follow-up were available. The temporal and cumulative distributions of recrudescence were characterized using a Cox regression model with shared frailty on study-sites. Fractional polynomials were used to capture non-linear instantaneous hazard. The area under the density curve (AUC) of the constructed distribution was used to estimate the optimal follow-up period for capturing a P. falciparum malaria recrudescence. Simulation studies were conducted based on the constructed distributions to quantify the absolute overestimation in efficacy due to sub-optimal follow-up.ResultsOverall, 3703 recurrent infections were detected in 60 studies conducted in Africa (15,512 children aged < 5 years) and 23 studies conducted in Asia and South America (5272 patients of all ages). Using molecular genotyping, 519 (14.0%) recurrences were ascribed as recrudescent infections. A 28 day artemether-lumefantrine (AL) efficacy trial would not have detected 58% [95% confidence interval (CI) 47–74%] of recrudescences in African children and 32% [95% CI 15–45%] in patients of all ages in Asia/South America. The corresponding estimate following a 42 day dihydroartemisinin-piperaquine (DP) efficacy trial in Africa was 47% [95% CI 19–90%] in children under 5 years old treated with > 48 mg/kg total piperaquine (PIP) dose and 9% [95% CI 0–22%] in those treated with ≤ 48 mg/kg PIP dose. In absolute terms, the simulation study found that trials limited to 28 days follow-up following AL underestimated the risk of recrudescence by a median of 2.8 percentage points compared to day 63 estimates and those limited to 42 days following DP underestimated the risk of recrudescence by a median of 2.0 percentage points compared to day 42 estimates. The analysis was limited by few clinical trials following patients for longer than 42 days (9 out of 83 trials) and the imprecision of PCR genotyping which overcalls recrudescence in areas of higher transmission biasing the later distribution.ConclusionsRestricting follow-up of clinical efficacy trials to day 28 for AL and day 42 for DP will miss a proportion of late recrudescent treatment failures but will have a modest impact in derived efficacy. The results highlight that as genotyping methods improve consideration should be given for trials with longer duration of follow-up to detect early indications of emerging drug resistance.

The Dynamic Change of Immune Responses Between Acute and Recurrence Stages of Rodent Malaria Infection

Malaria infections are persistent as frequent recrudescence of the disease may occur following the acute infection stage, but the different immune responses that control the acute and recrudescence stages are still largely unknown. Using single-cell RNA sequencing (scRNA-seq), we showed that the number of Th1 and plasma cells in the spleen was significantly reduced during the recurrence stage compared to the acute stage of Plasmodium chabaudi chabaudi AS (P. chabaudi) infection. Additionally, the ability of both CD4+ T cell responses and B cells to control P. chabaudi recurrence was significantly reduced compared to their roles in the control of acute infection. In contrast, the number of innate immune cells, including red pulp macrophages (RPMs), gamma delta (γδ) T cells, and Dendritic cells (DCs) were significantly increased during the recurrence stage and showed to be critical for P. chabaudi infection recurrence control. Thus, our data strongly suggest the complementary role of innate immune responses in controlling malaria recrudescence when adaptive immune responses are suppressed. These findings shed new light on the development of immune interventions against malaria.

Population pharmacokinetics and pharmacodynamics of the artesunate\u2013mefloquine fixed dose combination for the treatment of uncomplicated falciparum malaria in African children

BackgroundThe World Health Organization (WHO) recommends combinations of an artemisinin derivative plus an anti-malarial drug of longer half-life as treatment options for uncomplicated Plasmodium falciparum infections. In Africa, artesunate–mefloquine (ASMQ) is an infrequently used artemisinin-based combination therapy (ACT) because of perceived poor tolerance to mefloquine. However, the WHO has recommended reconsideration of the use of ASMQ in Africa. In this large clinical study, the pharmacokinetics (PK) of a fixed dose combination of ASMQ was investigated in an African paediatric population to support dosing recommendations used in Southeast Asia and South America.MethodsAmong the 472 paediatric patients aged 6–59 months from six African centres included in the large clinical trial, a subset of 50 Kenyan children underwent intensive sampling to develop AS, its metabolite dihydroartemisinin (DHA) and MQ PK models. The final MQ PK model was validated using sparse data collected in the remaining participants (NONMEM®). The doses were one or two tablets containing 25/55 mg AS/MQ administered once a day for 3 days according to patients’ age. A sensitive LC–MS/MS method was used to quantify AS, DHA and MQ concentrations in plasma. An attempt was made to investigate the relationship between the absence/presence of malaria recrudescence and MQ area under the curve (AUC) using logistic regression.ResultsAS/DHA concentration–time profiles were best described using a one-compartment model for both compounds with irreversible AS conversion into DHA. AS/DHA PK were characterized by a significant degree of variability. Body weight affected DHA PK parameters. MQ PK was characterized by a two-compartment model and a large degree of variability. Allometric scaling of MQ clearances and volumes of distribution was used to depict the relationship between MQ PK and body weight. No association was found between the model predicted AUC and appearance of recrudescence.ConclusionsThe population pharmacokinetic models developed for both AS/DHA and MQ showed a large variability in drug exposure in the investigated African paediatric population. The largest contributor to this variability was body weight, which is accommodated for by the ASMQ fixed dose combination (FDC) dosing recommendation. Besides body weight considerations, there is no indication that the dosage should be modified in children with malaria compared to adults.Trial registration Pan African Clinical Trials Registry PACTR201202000278282 registration date 2011/02/16

Clinical impact of the two ART resistance markers, K13 gene mutations and DPC3 in Vietnam.

BackgroundIn Vietnam, a rapid decline of P. falciparum malaria cases has been documented in the past years, the number of Plasmodium falciparum malaria cases has rapidly decreased passing from 19.638 in 2012 to 4.073 cases in 2016. Concomitantly, the spread of artemisinin resistance markers is raising concern on the future efficacy of the ACTs. An evaluation of the clinical impact of the artemisinin resistance markers is therefore of interest.MethodsThe clinical effectiveness of dihydroartemisinin-piperaquine therapy (DHA-PPQ) has been evaluated in three districts characterized by different rates of ART resistance markers: K13(C580Y) mutation and delayed parasite clearance on day 3 (DPC3). Patients were stratified in 3 groups a) no markers, b) one marker (suspected resistance), c) co-presence of both markers (confirmed resistance). In the studied areas, the clinical effectiveness of DHA-PPQ has been estimated as malaria recrudescence within 60 days.ResultsThe rate of K13(C580Y) ranged from 75.8% in Krong Pa to 1.2% in Huong Hoa district. DPC3 prevalence was higher in Krong Pa than in Huong Hoa (86.2% vs 39.3%). In the two districts, the prevalence of confirmed resistance was found in 69.0% and 1.2% of patients, respectively. In Thuan Bac district, we found intermediate prevalence of confirmed resistance. Treatment failure was not evidenced in any district. PPQ resistance was not evidenced. Confirmed resistance was associated to the persistence of parasites on day 28 and to 3.4-fold higher parasite density at diagnosis. The effectiveness of malaria control strategies was very high in the studied districts.ConclusionNo treatment failure has been observed in presence of high prevalence of ART resistance and in absence of PPQ resistance. K13(C580Y) was strongly associated to higher parasitemia at admission, on days 3 and 28. Slower parasite clearance was also observed in younger patients.

Plasmodium Peekaboo: PK4 Mediates Parasite Latency

In this issue of Cell Host & Microbe, Zhang etal. (2017) show that translational repression through eIF2α phosphorylation mediated by PK4 kinase activity plays a key role in artemisinin resistance in recrudescent malaria infections. Targeting this druggable process could extend the lifespan of current frontline treatments.

A Case of Blackwater Fever after Treatment for &lt;i&gt;Plasmodium falciparum &lt;/i&gt;Malaria

Blackwater fever (BWF), which causes massive intravascular hemolysis and the passage of black-colored urine, is a poorly understood condition that is rarely seen during the course of malaria. Here, we present a case of BWF that developed after treatment for falciparum malaria complicated by hyperparasitemia in a Japanese traveler. A 29-year-old woman returning from Ghana visited our travel clinic with complaints of sudden fever and headache on the third day of illness. She had taken anti-malarial drugs for intermittent malaria prophylaxis and the treatment of malaria while in Ghana. Falciparum malaria was diagnosed based on the results of a blood smear and was confirmed using PCR. She was successfully treated with a single artesunate suppository and one dose of intravenous quinine followed by artemether-lumefantrin for 3 days. She was discharged without complications on the 11th day of illness. However, she was re-admitted for fever and headache on the 16th day of illness. The recrudescence of malaria was excluded by peripheral blood smear results. BWF was diagnosed based on the presence of fever, black-colored urine, and laboratory findings suggesting intravascular hemolysis. She was treated with supportive care, including the transfusion of 10 packs of red blood cells and the maintenance of fluid and electrolyte balance, and she gradually improved within two weeks. BWF is a rare but severe complication induced by severe falciparum malaria and/or the use of the aryl-amino alcohol group of antimalarial drugs. Thus, consideration of BWF is particularly important for a rapid and accurate diagnosis.

Malaria in cynomolgus monkeys used in toxicity studies in Japan.

Plasmodium spp. protozoa cause malaria and are known to infect humans and a variety of animal species including macaque monkeys. Here we report both our experience with malaria recrudescence in cynomolgus monkeys (Macaca fascicularis) in a toxicity study and the results of a survey on Plasmodium infection in cynomolgus monkeys imported to Japan for laboratory use. A cynomolgus monkey from the toxicity study presented with severe anemia and Plasmodium protozoa in erythrocytes on a thin blood smear and was subsequently diagnosed with symptomatic malaria. In this animal, congestion and accumulation of hemozoin (malaria pigment) in macrophages were noted in the enlarged and darkly discolored spleen. As a follow-up for the experience, spleen sections from 800 cynomolgus monkeys in toxicity studies conducted between 2003 and 2013 were retrospectively examined for hemozoin deposition as a marker of Plasmodium infection. The origin of the animals included Cambodia, China, Indonesia, and Vietnam. Hemozoin deposition was confirmed in 44% of all examined monkeys. Monkeys from Indonesia showed the highest incidence of hemozoin deposition (approx. 80%). A high prevalence of Plasmodium infection in laboratory monkeys was also confirmed with polymerase chain reaction (PCR) by using Plasmodium genus-specific primers. Although Japan is not a country with endemic malaria, it is important to be aware of the prevalence and potential impact of background infection with Plasmodium spp. and recrudescence of symptomatic malaria in imported laboratory monkeys on pharmaceutical toxicity studies.

Geographical origin of post-landmine injury malaria infections.

In Cambodia, a highly landmine-contaminated country with endemic malaria, symptomatic falciparum malaria has been observed in patients presenting with traumatic landmine injuries. Because a link between recrudescence of symptomatic Plasmodium falciparum malaria and severe trauma is well established, we explored whether a link could be demonstrated between the geolocation of landmine amputations and malaria cases. Landmine amputation data in Cambodia (2005-2008) were compared with predicted measures of malaria endemicity. Data of injuries that had resulted in amputation were plotted over a surface of P falciparum parasite rates. No statistically significant correlation was found, possibly because the P falciparum endemicity surface was drawn from a model-based geostatistical prediction of infection prevalence and did not distinguish cases of recrudescence. The implication of this finding is that where symptomatic falciparum malaria has been observed in patients with landmine injuries, the cases were likely to be reactivated falciparum infections and not new cases. Further research is needed to understand the relationship between P falciparum and trauma. To distinguish P falciparum recrudescence from new cases, a prospective registry is needed. Also, practitioners need to be aware of the possibility of post-injury malaria recrudescence in complex emergencies.

Malaria cases treated with artemether/lumefantrine in Japanese travelers

Artemisinin-based combination therapy (ACT) has been the standard treatment for uncomplicated malaria. Although not licensed in Japan, artemether/lumefantrine (AL), one type of ACT, has been administered to patients with malaria since 2002 by the Research Group on Chemotherapy of Tropical Diseases. Herein, we reviewed malaria cases treated with AL in Japanese travelers. A retrospective study was conducted at the National Center for Global Health and Medicine from October 2005 to March 2013. There were 19 malaria patients treated with AL, and 10 falciparum malaria patients treated with AL only. In these 10 patients treated with AL only, the median time of fever clearance was 25.0 hours (range:14-66 hours), and the median time of parasite clearance was 36.0 hours (range:16-62 hours). There was a positive correlation between parasitemia and time from the start of therapy to the disappearance of the parasites. Parasitemia was higher (4.05% vs. 0.24%; p = 0.044) and parasite clearance time was longer (55.5 hours vs. 31.5 hours; p = 0.044) in the cases of recrudescence than non-recrudescence, respectively. Three of the 19 malaria patients showed recrudescence of malaria after treatment with AL. The reason that treatment failure was more frequently observed in this study than in previous reports may be related to poor absorption of lumefantrine owing to gastrointestinal symptoms, insufficiently ingested fatty foods, or high parasitemia on admission. The World Health Organization recommends that intravenous antimalarials should be administered in cases of severe malaria however, this is not applicable in Japan. Further studies are needed to distinguish patients with malaria who are treatable with ACT from those who should be treated initially with other intravenous antimalarials.

Effective treatment with a tetrandrine/chloroquine combination for chloroquine-resistant falciparum malaria in Aotus monkeys

BackgroundIn vitro evidence indicates that tetrandrine (TT) can potentiate the action of chloroquine 40-fold against choloquine-resistant Plasmodium falciparum. The key question emanating from that study is “would tetrandine and chloroquine be highly effective in a live Aotus monkey model with chloroquine-resistant parasites”. This study was designed to closely mimic the pharmacological/anti-malarial activity in man.MethodsThe Vietnam Smith/RE strain of P. falciparum, which is chloroquine-resistant was used in this study. Previous experimental procedures were followed. Panamanian owl monkeys (Aotus) were inoculated with 5×106 erythrocytes parasitized with the CQ-resistant strain of P. falciparum. Oral drug treatment was with CQ (20 mg/kg) and/or tetrandrine at 15 mg/Kg, 30 mg/Kg or 60 mg/Kg or 25 mg/Kg depending on experimental conditions.Results and DiscussionParasitaemia was cleared rapidly with CQ and TT while CQ treatment alone was ineffective. Recrudescence of malaria occurred after seven days post-infection. However, four animals were treated orally with TT and CQ parasites were cleared. It is likely that monkeys were cured via a combination of both drug and host immune responses. A single Aotus monkey infected with P. falciparum and untreated with drugs, died. No side effects were observed with these drug treatments.ConclusionsThis combination of chloroquine and tetrandrine forms the basis of a new attack on chloroquine-resistant malaria - one based upon inhibition of the basis of chloroquine resistance, the multiple drug resistance pump. Previous studies demonstrated that the parasite MDR pump was found on parasite membranes using 3H azidopine photoaffinity labelling.Since MDR-based choloroquine resistance is induced by chloroquine, the basis of the action of tetrandrine is the following: 1) tetrandrine inhibits the MDR pump by stimulating MDR ATPase which limits the energy of the pump by depletion of parasite ATP, 2) tetrandrine blocks the genetic factor which controls the induction of the pump. Therefore, it appears that the parasite cannot outsmart these mechanisms and produce a new mode of resistance. Only time will tell if this is correct.

Clinical manifestations of new versus recrudescent malaria infections following anti-malarial drug treatment

BackgroundDistinguishing new from recrudescent infections in post-treatment episodes of malaria is standard in anti-malarial drug efficacy trials. New infections are not considered malaria treatment failures and as a result, the prevention of subsequent episodes of malaria infection is not reported as a study outcome. However, in moderate and high transmission settings, new infections are common and the ability of a short-acting medication to cure an initial infection may be outweighed by its inability to prevent the next imminent infection. The clinical benefit of preventing new infections has never been compared to that of curing the initial infection.MethodsChildren enrolled in a sulphadoxine-pyrimethamine efficacy study in Blantyre, Malawi from 1998–2004 were prospectively evaluated. Six neutral microsatellites were used to classify new and recrudescent infections in children aged less than 10 years with recurrent malaria infections. Children from the study who did not experience recurrent parasitaemia comprised the baseline group. The odds of fever and anaemia, the rate of haemoglobin recovery and time to recurrence were compared among the groups.ResultsFever and anemia were more common among children with parasitaemia compared to those who remained infection-free throughout the study period. When comparing recrudescent vs. new infections, the incidence of fever was not statistically different. However, children with recrudescent infections had a less robust haematological recovery and also experienced recurrence sooner than those whose infection was classified as new.ConclusionsThe results of this study confirm the paramount importance of providing curative treatment for all malaria infections. Although new and recrudescent infections caused febrile illnesses at a similar rate, recurrence due to recrudescent infection did have a worsened haemological outcome than recurrence due to new infections. Local decision-makers should take into account the results of genotyping to distinguish new from recrudescent infections when determining treatment policy on a population level. It is appropriate to weigh recrudescent malaria more heavily than new infection in assessing treatment efficacy.

Preliminary studies on the antiplasmodial potential of aqueous and methanol extracts of eucalyptus camadulensis leaf

ObjectiveThe rising problem of resistance to the classical drugs like chloroquine and the problem of recrudescence of malaria after treatment with artemisinin suggest the need for new antimalaria agents. This project was designed to explore the antiplasmodial potential of Eucalyptus camaldulensis leaf extracts. MethodsThe antiplasmodial potential of the methanol and aqueous extracts of Eucalyptus camadulensis (leaf) were evaluated in a mouse model of malaria. Swiss albino mice were intraperitoneally infected with plasmodium berghei (NK65), a rodent malaria parasite. The level of parasitemia, life span, variation in weight and percentage packed cell volume (% PCV) of infected and treated mice were used to assess the efficacy of extracts. Treatment with the extracts at dose levels of 100, 200 and 400mg/kg body weight commenced 72 hours post infection for the test groups, while a standard antimalarial drug, Artesunate, at a dose of 50mg/kg body weight was administered on the positive control group. The negative control group was left untreated. ResultsAnimals treated with the methanol extract showed a significant decrease in parasitaemia (p < 0.05), and survived for 29 days compared with those treated with the aqueous extract which survived for 19 days with a higher level of parasitemia. However, the control group treated with Artesunate showed a significantly lower parasitaemia (p < 0.05) and survived for 34 days when compared with the groups treated with methanol and aqueous extracts. The level of parasitemia, decrease in weight and %PCV in all the treated groups was significantly lower (P < 0.05) compared with the infected but untreated group (negative control) which survived for only 7 days. ConclusionsThe methanol extract of the leaves of E. camadulensis has an antimalarial potential that could be exploited for the benefit of mankind.

Synthesis of Artemiside and Its Effects in Combination with Conventional Drugs against Severe Murine Malaria

This research describes the use of novel antimalarial combinations of the new artemisinin derivative artemiside, a 10-alkylamino artemisinin. It is a stable, highly crystalline compound that is economically prepared from dihydroartemisinin in a one-step process. Artemiside activity was more pronounced than that of any antimalarial drug in use, both in Plasmodium falciparum culture and in vivo in a murine malaria model depicting cerebral malaria (CM). In vitro high-throughput testing of artemiside combinations revealed a large number of conventional antimalarial drugs with which it was additive. Following monotherapy in mice, individual drugs reduced parasitemias to nondetectable levels. However, after a period of latency, parasites again were seen and eventually all mice became terminally ill. Treatment with individual drugs did not prevent CM in mice with recrudescent malaria, except for piperaquine at high concentrations. Even when CM was prevented, the mice developed later of severe anemia. In contrast, most of the mice treated with drug combinations survived. A combination of artemiside and mefloquine or piperaquine may confer an optimal result because of the longer half life of both conventional drugs. The use of artemiside combinations revealed a significant safety margin of the effective artemiside doses. Likewise, a combination of 1.3 mg/kg of body weight artemiside and 10 mg/kg piperaquine administered for 3 days from the seventh day postinfection was completely curative. It appears possible to increase drug concentrations in the combination therapy without reaching toxic levels. Using the drug combinations as little as 1 day before the expected death of control animals, we could prevent further parasite development and death due to CM or anemic malaria. Earlier treatment may prevent cognitive dysfunctions which might occur after recovery from CM.

Frequency of glucose-6-phosphate dehydrogenase deficiency in malaria patients from six African countries enrolled in two randomized anti-malarial clinical trials

BackgroundGlucose-6-phosphate dehydrogenase (G6PD) deficiency is common in populations living in malaria endemic areas. G6PD genotype and phenotype were determined for malaria patients enrolled in the chlorproguanil-dapsone-artesunate (CDA) phase III clinical trial programme.MethodsStudy participants, aged > 1 year, with microscopically confirmed uncomplicated Plasmodium falciparum malaria, and haemoglobin ≥ 70 g/L or haematocrit ≥ 25%, were recruited into two clinical trials conducted in six African countries (Burkina Faso, Ghana, Kenya, Nigeria, Tanzania, Mali). G6PD genotype of the three most common African forms, G6PD*B, G6PD*A (A376G), and G6PD*A- (G202A, A542T, G680T and T968C), were determined and used for frequency estimation. G6PD phenotype was assessed qualitatively using the NADPH fluorescence test. Exploratory analyses investigated the effect of G6PD status on baseline haemoglobin concentration, temperature, asexual parasitaemia and anti-malarial efficacy after treatment with CDA 2/2.5/4 mg/kg or chlorproguanil-dapsone 2/2.5 mg/kg (both given once daily for three days) or six-dose artemether-lumefantrine.ResultsOf 2264 malaria patients enrolled, 2045 had G6PD genotype available and comprised the primary analysis population (1018 males, 1027 females). G6PD deficiency prevalence was 9.0% (184/2045; 7.2% [N = 147] male hemizygous plus 1.8% [N = 37] female homozygous), 13.3% (273/2045) of patients were heterozygous females, 77.7% (1588/2045) were G6PD normal. All deficient G6PD*A- genotypes were A376G/G202A. G6PD phenotype was available for 64.5% (1319/2045) of patients: 10.2% (134/1319) were G6PD deficient, 9.6% (127/1319) intermediate, and 80.2% (1058/1319) normal. Phenotype test specificity in detecting hemizygous males was 70.7% (70/99) and 48.0% (12/25) for homozygous females. Logistic regression found no significant effect of G6PD genotype on adjusted mean baseline haemoglobin (p = 0.154), adjusted mean baseline temperature (p = 0.9617), or adjusted log mean baseline parasitaemia (p = 0.365). There was no effect of G6PD genotype (p = 0.490) or phenotype (p = 0.391) on the rate of malaria recrudescence, or reinfection (p = 0.134 and p = 0.354, respectively).ConclusionsG6PD deficiency is common in African patients with malaria and until a reliable and simple G6PD test is available, the use of 8-aminoquinolines will remain problematic. G6PD status did not impact baseline haemoglobin, parasitaemia or temperature or the outcomes of anti-malarial therapy.Trial registrationClinicaltrials.gov: NCT00344006 and NCT00371735.

The Agro Pontino, climate change and malaria

Recently in Italy a case of malaria was reported (November 2009). The patient was an Italian man of 44 years of age who had not travelled out of the country. The man apparently contracted malaria during a 2 weeks stay in August 2009 in a former malaria endemic area, the “Agro Pontino” (60-100 km South of Rome). Although confirmation of the Plasmodium species and the results of the epidemiological investigation undertaken by the Ministry of Health are still not available, the case seems unlikely to be linked with accidental contact of the patient with imported vectors or contaminated blood. This case raised concern over the possible recrudescence of malaria in Italy, especially in light of current and future climate change. Given the importance of the topic, this article will provide a brief review of the history of malaria in the Agro Pontino and the recent discussions that have appeared in scientific journals concerning the link between malaria and climate change.