Falciparum Malaria In Adults Research Articles

Pharmacokinetics of Ganaplacide and Lumefantrine in Adults, Adolescents, and Children with Plasmodium falciparum Malaria Treated with Ganaplacide Plus Lumefantrine Solid Dispersion Formulation: Analysis of Data from a Multinational Phase 2 Study.

The novel antimalarial ganaplacide combined with lumefantrine solid dispersion formulation (LUM-SDF) was effective and well tolerated in the treatment of uncomplicated falciparum malaria in adults, adolescents, and children in a multinational, prospective, randomized, active-controlled Phase II study conducted between August 2017 and June 2021 (EudraCT 2020-003284-25, Clinicaltrials.gov NCT03167242). Pharmacokinetic data from that study are reported here. The trial comprised three parts: a run-in part in 12 adult/adolescent patients treated with a single dose of ganaplacide 200 mg plus LUM-SDF 960 mg assessed potential pharmacokinetic (PK) interactions between ganaplacide and lumefantrine; in Part A, adult/adolescent patients received one of the six ganaplacide-LUM-SDF regimens or artemether-lumefantrine; and in Part B, three dose regimens identified in Part A, and artemether-lumefantrine, were assessed in children aged 2 to <12 years, with body weight ≥10 kg. A rich blood sampling schedule was used for all 12 patients in the PK run-in part and a subset of patients (N = 32) in Part A, with sparse sampling for remaining patients in Parts A (N = 275) and B (N = 159). Drug concentrations were determined by a validated protein precipitation and reverse phase liquid chromatography with tandem mass spectrometry detection method. Parameters including AUCinf, AUClast, AUC0-t, Cmax, and tmax were reported where possible, using non-compartmental analysis. In the PK run-in part, there was no notable increase in ganaplacide or lumefantrine exposure when co-administered. In Parts A and B, ganaplacide exposures increased with dose, but lumefantrine exposure was numerically under dose-proportional. Lumefantrine exposure was higher with ganaplacide-LUM-SDF than with artemether-lumefantrine, although high variability was observed. Ganaplacide and lumefantrine exposures (Cmax and AUC0-24 h) were comparable across age and body weight groups. Drug exposures needed for efficacy were achieved using the dose regimen 400 mg ganaplacide plus lumefantrine 960 mg once daily for 3 days under fasted conditions.

Safety and efficacy of photodynamic therapy for the treatment of malaria in adults in Nigeria: Phase 2 trial

Background: This is the first randomized controlled trial assessing the efficacy and safety of photodynamic therapy in the treatment of uncomplicated falciparum Malaria in adults. The aim of the current study is to evaluate the use of photodynamic therapy as a possible novel treatment option.

Effect of α+ Thalassemia on the Severity of Plasmodium falciparum Malaria in Different Sickle Cell Genotypes in Indian Adults: A Hospital-Based Study

There is a paucity of literature on the association of α+-thalassemia, sickle-cell hemoglobin disorders, and malaria in India. This study aimed to understand the effect of α+-thalassemia on the severity of Plasmodium falciparum malaria in adults with respect to sickle-cell genotypes. The study subjects were categorized into ‘severe-malaria’ and ‘uncomplicated-malaria’ and age-gender matched ‘control’ groups. Sickle-cell and α+-thalassemia were investigated in all the recruited subjects. The effect of α+-thalassemia on the severity of malaria was analyzed in HbAA and sickle-cell genotypes (HbAS and HbSS) separately. The prevalence of α+-thalassemia in various groups ranged from 41.5% to 81.8%. The prevalence of α+-thalassemia was lower (OR = 1.64; p = 0.0013) in severe malaria (41.5%) as compared to healthy controls (53.8%) with HbAA genotype. In contrast, in HbAS genotype, the prevalence of α+-thalassemia was higher (OR = 4.11; p = 0.0002) in severe malaria (81.8%) compared to controls (52.2%). In severe malaria with HbAA genotype, there was a significantly higher hemoglobin level and low MCV and MCH level in patients with α+-thalassemia compared to the normal α-globin genotype. Further, the incidence of cerebral malaria, hepatopathy, and mortality was lower in patients (HbAA) with α+-thalassemia as compared to normal α-globin genotype (HbAA). In severe malaria with either HbAS or HbSS genotype, only a few parameters showed statistical differences with respect to α+-thalassemia. Low prevalence of α+-thalassemia in severe malaria with HbAA genotype compared to healthy controls with HbAA genotype indicates the protective effect of α+-thalassemia against severe malaria. However, the high prevalence of α+-thalassemia in patients with HbAS genotype depicts its interference in the protective effect of sickle-cell against severe malaria.

Endothelial glycocalyx degradation and disease severity in Plasmodium vivax and Plasmodium knowlesi malaria

Degradation of the endothelial glycocalyx is associated with mortality in adult falciparum malaria. However, its role in the pathogenesis of non-falciparum malaria is unknown. In Malaysian patients with knowlesi (n = 200) and vivax (n = 61) malaria, and in healthy controls (n = 50), we measured glycocalyx breakdown products plasma syndecan-1 and urinary glycosaminoglycans, and evaluated correlations with biomarkers of disease severity. Urinary glycosaminoglycans were increased in patients with knowlesi and vivax malaria compared to healthy controls, and in knowlesi malaria were highest in those with severe disease. In knowlesi malaria, plasma syndecan-1 was also highest in those with severe disease, and correlated with markers of endothelial activation (angiopoietin-2, osteoprotegerin, ICAM-1), asymmetric dimethylarginine (ADMA) and impaired microvascular reactivity. Syndecan-1 also correlated with endothelial activation (ICAM-1, angiopoietin-2) and ADMA in vivax malaria. In knowlesi malaria increased syndecan-1 was associated with acute kidney injury, after controlling for age and parasitemia. In knowlesi malaria, the difference in median syndecan-1 between severe and non-severe disease was more marked in females than males. Endothelial glycocalyx degradation is increased in knowlesi and vivax malaria, and associated with disease severity and acute kidney injury in knowlesi malaria. Agents that inhibit glycocalyx breakdown may represent adjunctive therapeutics for severe non-falciparum malaria.

Atovaquone-proguanil for treating uncomplicated Plasmodium falciparum malaria.

BackgroundThe World Health Organization (WHO) in 2015 stated atovaquone‐proguanil can be used in travellers, and is an option in malaria‐endemic areas in combination with artesunate, as an alternative treatment where first‐line artemisinin‐based combination therapy (ACT) is not available or effective. This review is an update of a Cochrane Review undertaken in 2005.ObjectivesTo assess the efficacy and safety of atovaquone‐proguanil (alone and in combination with artemisinin drugs) versus other antimalarial drugs for treating uncomplicated Plasmodium falciparum malaria in adults and children.Search methodsThe date of the last trial search was 30 January 2020. Search locations for published trials included the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, and LILACS. To include recently published and unpublished trials, we also searched ClinicalTrials.gov, the metaRegister of Controlled Trials and the WHO International Clinical Trials Registry Platform Search Portal.Selection criteriaRandomized controlled trials (RCTs) reporting efficacy and safety data for atovaquone‐proguanil or atovaquone‐proguanil with a partner drug compared with at least one other antimalarial drug for treating uncomplicated Plasmodium falciparum infection.Data collection and analysisFor this update, two review authors re‐extracted data and assessed certainty of evidence. We meta‐analyzed data to calculate risk ratios (RRs) with 95% confidence intervals (CI) for treatment failures between comparisons, and for safety outcomes between and across comparisons. Outcome measures include unadjusted treatment failures and polymerase chain reaction (PCR)‐adjusted treatment failures. PCR adjustment differentiates new infection from recrudescent infection.Main resultsSeventeen RCTs met our inclusion criteria providing 4763 adults and children from Africa, South‐America, and South‐East Asia. Eight trials reported PCR‐adjusted data to distinguish between new and recrudescent infection during the follow‐up period. In this abstract, we report only the comparisons against the three WHO‐recommended antimalarials which were included within these trials.There were two comparisons with artemether‐lumefantrine, one trial from 2008 in Ethiopia with 60 participants had two failures with atovaquone‐proguanil compared to none with artemether‐lumefantrine (PCR‐adjusted treatment failures at day 28). A second trial from 2012 in Colombia with 208 participants had one failure in each arm (PCR‐adjusted treatment failures at day 42).There was only one comparison with artesunate‐amodiaquine from a 2014 trial conducted in Cameroon. There were six failures with atovaquone‐proguanil at day 28 and two with artesunate‐amodiaquine (PCR‐adjusted treatment failures at day 28: 9.4% with atovaquone‐proguanil compared to 2.9% with artesunate‐amodiaquine; RR 3.19, 95% CI 0.67 to 15.22; 1 RCT, 132 participants; low‐certainty evidence), although there was a similar number of PCR‐unadjusted treatment failures (9 (14.1%) with atovaquone‐proguanil and 8 (11.8%) with artesunate‐amodiaquine; RR 1.20, 95% CI 0.49 to 2.91; 1 RCT, 132 participants; low‐certainty evidence).There were two comparisons with artesunate‐mefloquine from a 2012 trial in Colombia and a 2002 trial in Thailand where there are high levels of multi‐resistant malaria. There were similar numbers of PCR‐adjusted treatment failures between groups at day 42 (2.7% with atovaquone‐proguanil compared to 2.4% with artesunate‐mefloquine; RR 1.15, 95% CI 0.57 to 2.34; 2 RCTs, 1168 participants; high‐certainty evidence). There were also similar PCR‐unadjusted treatment failures between groups (5.3% with atovaquone‐proguanil compared to 6.6% with artesunate‐mefloquine; RR 0.8, 95% CI 0.5 to 1.3; 1 RCT, 1063 participants; low‐certainty evidence).When atovaquone‐proguanil was combined with artesunate, there were fewer treatment failures with and without PCR‐adjustment at day 28 (PCR‐adjusted treatment failures at day 28: 2.16% with atovaquone‐proguanil compared to no failures with artesunate‐atovaquone‐proguanil; RR 5.14, 95% CI 0.61 to 43.52; 2 RCTs, 375 participants, low‐certainty evidence) and day 42 (PCR‐adjusted treatment failures at day 42: 3.82% with atovaquone‐proguanil compared to 2.05% with artesunate‐atovaquone‐proguanil (RR 1.84, 95% CI 0.95 to 3.56; 2 RCTs, 1258 participants, moderate‐certainty evidence). In the 2002 trial in Thailand, there were fewer treatment failures in the artesunate‐atovaquone‐proguanil group compared to the atovaquone‐proguanil group at day 42 with PCR‐adjustment.Whilst there were some small differences in which adverse events were more frequent in the atovaquone‐proguanil groups compared to comparator drugs, there were no recurrent associations to suggest that atovaquone‐proguanil is strongly associated with any specific adverse event.Authors' conclusionsAtovaquone‐proguanil was effective against uncomplicated P falciparum malaria, although in some instances treatment failure rates were between 5% and 10%. The addition of artesunate to atovaquone‐proguanil may reduce treatment failure rates. Artesunate‐atovaquone‐proguanil and the development of parasite resistance may represent an area for further research.

Time for pragmatic, prospective clinical trials to determine the role of empirical antibacterial therapy in critically ill adults hospitalized with malaria

BackgroundChildren with severe falciparum malaria in malaria-endemic regions are predisposed to developing life-threatening bacterial co-infection. International guidelines therefore recommend empirical broad-spectrum antibacterial therapy in these children. Few studies have examined co-infection in adults, although it has been believed to be relatively rare; antibacterial therapy is therefore not routinely recommended in adults with falciparum malaria. DiscussionHowever, the fundamental pathophysiology of falciparum malaria in adults and children is the same; it is therefore unclear why adults would not also be predisposed to bacterial infection. Indeed, recent studies have identified bacteraemia in >10% of adults hospitalized with malaria. Some have suggested that these adults probably had bacterial sepsis, with the parasitaemia an incidental finding. However, it is usually impossible in resource-limited settings to determine–at presentation–whether critically ill, parasitaemic adults have severe malaria, bacterial sepsis, or both. Given the significant case-fatality rates of severe malaria and bacterial sepsis, the pragmatic initial approach would be to cover both possibilities. ConclusionsLife-threatening bacterial co-infection may be more common in critically ill adults with malaria than previously believed. While further prospective data are awaited to confirm these findings, it might be more appropriate to provide empirical aantibacterial cover in these patients than current guidelines suggest.

Correction to: Imported falciparum malaria in adults: host- and parasite-related factors associated with severity. The French prospective multicenter PALUREA cohort study

The members of the Palurea Study Group were provided in such a way that they could not be indexed as collaborators on PubMed. The publisher apologizes for this error and is pleased to list the members of the group here.

High Rate of Treatment Failures in Nonimmune Travelers Treated With Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria in Sweden: Retrospective Comparative Analysis of Effectiveness and Case Series.

Artemisinin-based combination therapy (ACT) is the first-line treatment of Plasmodium falciparum malaria. Since the introduction of artemether-lumefantrine (AL) for treatment of uncomplicated malaria in Sweden, treatment failures have been reported in adults. A retrospective comparative analysis of treatment regimen for P. falciparum malaria in adults in Stockholm during 2000-2015 was performed to evaluate the effectiveness of AL. Parasite genotyping and drug concentrations were investigated in the AL treatment failures. Among the total 397 P. falciparum episodes, 310 were treated with oral regimen only (95 AL, 162 mefloquine, 36 atovaquone-proguanil [AP], and 17 others), and 87 were administered initial intravenous therapy (38 artesunate and 49 quinine) followed by oral treatments. Five late treatment failures were detected after AL and one slow response to AP. The effectiveness of AL alone was 94.7% (95% confidence interval [CI], 88.1%-98.3%), compared with 99.5% for other oral regimens (P = .003). All AL failures occurred in European men and the effectiveness in this group was only 73.7% (95% CI, 48.8%-90.0%). Genotyping confirmed recrudescence of the initial parasite populations and drug resistance markers revealed no clinically significant resistance patterns. Lumefantrine concentrations suggested subtherapeutic concentrations in at least 2 cases. Our findings indicate a high rate of symptomatic late treatment failures after 6-dose AL regime in nonimmune adults, especially in men. Our report warrants the need to establish optimal dosing of AL in adults and to alert clinicians about the importance of informing patients regarding the risk of parasites reappearing weeks after AL treatment.

Imported falciparum malaria in adults: host- and parasite-related factors associated with severity. The French prospective multicenter PALUREA cohort study.

Prospective data on potential factors associated with severity of imported Plasmodium falciparum malaria are lacking. We evaluated whether several host- and parasite-related biomarkers may improve early severity evaluation. Prospective multicenter observational study comparing uncomplicated and severe imported falciparum malaria in adults conducted in France in 52 units, from 2007 to 2010. Association of several host- and parasite-related biomarkers with severity of malaria was tested using univariate and multivariate analyses. Of 295 patients, 140 had uncomplicated malaria and 155 severe malaria (including very severe and less severe cases according to predefined criteria). Curative intravenous quinine treatment was used in 154/155 patients with severe malaria and atovaquone/proguanil in 74% of patients with uncomplicated malaria. Hospital mortality was 5.2% (8 patients), all in the severe malaria group. Among host-related biomarkers, CRP, procalcitonin, and sTREM-1 were significantly higher and albumin was significantly lower in severe versus uncomplicated malaria; only the last three biomarkers also differed significantly between the very and less severe malaria groups. Among parasite-related biomarkers, only plasma PfHRP2 was significantly higher in severe versus uncomplicated malaria and in very severe versus less severe malaria; parasitemia did not differ between very and less severe malaria. By multivariate analysis, only lower plasma albumin and higher sTREM-1 were associated with greater severity, with intermediate accuracies. During imported malaria, the most useful biomarkers associated with severity seem to be plasma albumin and sTREM-1; and among parasite-related parameters, PfHRP2 was more strongly associated with severity than parasitemia was.

Asymmetric Dimethylarginine in Adult Falciparum Malaria: Relationships With Disease Severity, Antimalarial Treatment, Hemolysis, and Inflammation.

Background. Endothelial nitric oxide (NO) bioavailability is impaired in severe falciparum malaria (SM). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase (NOS), contributes to endothelial dysfunction and is associated with mortality in adults with falciparum malaria. However, factors associated with ADMA in malaria, including the NOS-substrate l-arginine, hemolysis, and antimalarial treatment, are not well understood. Methods. In a prospective observational study of Malaysian adults with SM (N = 22) and non-SM (NSM; N = 124) and healthy controls (HCs), we investigated factors associated with plasma ADMA including the effects of antimalarial treatment. Results. Compared with HCs, ADMA levels were lower in NSM (0.488 µM vs 0.540 µM, P = .001) and in the subset of SM patients enrolled before commencing treatment (0.453 µM [N = 5], P = .068), but levels were higher in SM patients enrolled after commencing antimalarial treatment (0.610 µM [N = 17], P = .026). In SM and NSM, ADMA levels increased significantly to above-baseline levels by day 3. Baseline ADMA was correlated with arginine and cell-free hemoglobin in SM and NSM and inversely correlated with interleukin-10 in NSM. Arginine and the arginine/ADMA ratio (reflective of arginine bioavailability) were lower in SM and NSM compared with HCs, and the arginine/ADMA ratio was lower in SM compared with NSM. Conclusions. Pretreatment ADMA concentrations and l-arginine bioavailability are reduced in SM and NSM. Asymmetric dimethylarginine increases to above-baseline levels after commencement of antimalarial treatment. Arginine, hemolysis, and posttreatment inflammation all likely contribute to ADMA regulation, with ADMA likely contributing to the reduced NO bioavailability in SM.

Retinal Changes in Uncomplicated and Severe Plasmodium knowlesi Malaria.

Plasmodium knowlesi causes severe malaria, but its pathogenesis is poorly understood. Retinal changes provide insights into falciparum malaria pathogenesis but have not been studied in knowlesi malaria. An observational study was conducted in Malaysian adults hospitalized with severe (n = 20) and nonsevere (n = 24) knowlesi malaria using indirect ophthalmoscopy (n = 44) and fundus photography (n = 29). The patients' median age was 44 years (range, 18-74 years). No coma or deaths occurred. Photography detected retinal changes in 11 of 12 patients (92%) with severe and 14 of 17 (82%) with nonsevere knowlesi malaria. Nonspecific retinal whitening occurred in 3 (35%) and 5 (29%) patients with severe and nonsevere disease, respectively; hemorrhages in 2 (17%) and 3 (18%); loss of retinal pigment epithelium in 1 (8%) and 4 (24%); and drusen in 9 (71%) and 12 (75%). All changes were mild, with no significant differences between severe and nonsevere disease. Patients with retinal hemorrhages had lower platelet counts than those without (median, 22 vs 43 × 10(9)/L; P= .04). The paucity of specific retinal findings associated with disease severity in knowlesi malaria contrasts with the retinopathy of severe adult falciparum malaria with and without coma, suggesting that falciparum-like microvascular sequestration in the brain is not a major component in severe knowlesi malaria pathogenesis.

Microvascular obstruction and endothelial activation are independently associated with the clinical manifestations of severe falciparum malaria in adults: an observational study.

BackgroundMicrovascular obstruction and endothelial dysfunction have both been linked to tissue hypoperfusion in falciparum malaria, but their relative contributions to the disease’s pathogenesis and outcome are unknown.MethodsMicrovascular blood flow was quantified in adults with severe falciparum malaria on their admission to hospital; plasma biomarkers of endothelial function were measured simultaneously. The relationship between these indices and the patients’ clinical findings and in-hospital course was examined.ResultsMicrovascular obstruction was observed in 119/142 (84 %) patients; a median (interquartile range (IQR)) of 14.9 % (6.6–34.9 %) of capillaries were obstructed in patients that died versus 8.3 % (1.7–26.6 %) in survivors (P = 0.039). The proportion of obstructed capillaries correlated with the estimated parasite biomass (rs = 0.25, P = 0.004) and with plasma lactate (rs = 0.38, P <0.0001), the strongest predictor of death in the series. Plasma angiopoietin-2 (Ang-2) concentrations were markedly elevated suggesting widespread endothelial activation; the median (IQR) Ang-2 concentration was 21.9 ng/mL (13.4–29.4 ng/mL) in patients that died versus 14.9 ng/mL (9.8–29.3 ng/mL) in survivors (P = 0.035). Ang-2 concentrations correlated with estimated parasite biomass (rs = 0.35, P <0.001) and plasma lactate (rs = 0.37, P <0.0001). Microvascular obstruction and Ang-2 concentrations were not significantly correlated with each other (rs = 0.17, P = 0.06), but were independently associated with plasma lactate (P <0.001 and P = 0.002, respectively).ConclusionsMicrovascular obstruction and systemic endothelial activation are independently associated with plasma lactate, the strongest predictor of death in adults with falciparum malaria. This supports the hypothesis that the two processes make an independent contribution to the pathogenesis and clinical manifestations of the disease.

Treatment of imported Plasmodium falciparum malaria: role of the combination of dihydroartemisinin and piperaquine

The dihydroartemisinin-piperaquine combination is an antimalarial agent newly available in Europe. It is an artemisinin-combined therapy (ACT) that has been used for more than 10 years in malaria-endemic areas and is recommended since 2010 by the WHO as a first-line treatment of uncomplicated Plasmodium falciparum malaria. In Europe, it has recently been authorized for the treatment of uncomplicated P. falciparum malaria in adults, children, and infants aged 6 months or older and weighing at least 5 kg. Its efficacy is similar to the combination of artemether and lumefantrine, and the regimen is easier. The tolerability profile is nearly the same as the other ACTs. Prolongation of the QT interval appears to be greater than with the artemether-lumefantrine combination in the first 48 hours of treatment, although no clinical consequences have been described. This side effect requires the use of electrocardiographic monitoring in some patients. A risk management plan has been set up by the manufacturer.

Rapid Clinical Assessment to Facilitate the Triage of Adults with Falciparum Malaria, a Retrospective Analysis

BackgroundMost adults dying from falciparum malaria will die within 48 hours of their hospitalisation. An essential component of early supportive care is the rapid identification of patients at greatest risk. In resource-poor settings, where most patients with falciparum malaria are managed, decisions regarding patient care must frequently be made using clinical evaluation alone.MethodsWe retrospectively analysed 4 studies of 1801 adults with severe falciparum malaria to determine whether the presence of simple clinical findings might assist patient triage.ResultsIf present on admission, shock, oligo-anuria, hypo- or hyperglycaemia, an increased respiratory rate, a decreased Glasgow Coma Score and an absence of fever were independently predictive of death. The variables were used to construct a simple clinical algorithm. When applied to the 1801 patients, this algorithm’s positive predictive value for survival to 48 hours was 99.4 (95% confidence interval (CI) 97.8–99.9) and for survival to discharge 96.9% (95% CI 94.3–98.5). In the 712 patients receiving artesunate, the algorithm’s positive predictive value for survival to 48 hours was 100% (95% CI 97.3–100) and to discharge was 98.5% (95% CI 94.8–99.8).ConclusionsSimple clinical findings are closely linked to the pathophysiology of severe falciparum malaria in adults. A basic algorithm employing these indices can facilitate the triage of patients in settings where intensive care services are limited. Patients classified as low-risk by this algorithm can be safely managed initially on a general ward whilst awaiting senior clinical review and laboratory data.

Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria.

BackgroundThe World Health Organization (WHO) recommends Artemisinin‐based Combination Therapy (ACT) for treating uncomplicated Plasmodium falciparum malaria. This review aims to assist the decision‐making of malaria control programmes by providing an overview of the relative effects of dihydroartemisinin‐piperaquine (DHA‐P) versus other recommended ACTs.ObjectivesTo evaluate the effectiveness and safety of DHA‐P compared to other ACTs for treating uncomplicated P. falciparum malaria in adults and children.Search methodsWe searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library; MEDLINE; EMBASE; LILACS, and the metaRegister of Controlled Trials (mRCT) up to July 2013.Selection criteriaRandomized controlled trials comparing a three‐day course of DHA‐P to a three‐day course of an alternative WHO recommended ACT in uncomplicated P. falciparum malaria.Data collection and analysisTwo authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy’ and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on gametocytes, haemoglobin, and adverse events. We assessed the quality of evidence using the GRADE approach.Main resultsWe included 27 trials, enrolling 16,382 adults and children, and conducted between 2002 and 2010. Most trials excluded infants aged less than six months and pregnant women.DHA‐P versus artemether‐lumefantrineIn Africa, over 28 days follow‐up, DHA‐P is superior to artemether‐lumefantrine at preventing further parasitaemia (PCR‐unadjusted treatment failure: RR 0.34, 95% CI 0.30 to 0.39, nine trials, 6200 participants, high quality evidence), and although PCR‐adjusted treatment failure was below 5% for both ACTs, it was consistently lower with DHA‐P (PCR‐adjusted treatment failure: RR 0.42, 95% CI 0.29 to 0.62, nine trials, 5417 participants, high quality evidence). DHA‐P has a longer prophylactic effect on new infections which may last for up to 63 days (PCR‐unadjusted treatment failure: RR 0.71, 95% CI 0.65 to 0.78, two trials, 3200 participants, high quality evidence).In Asia and Oceania, no differences have been shown at day 28 (four trials, 1143 participants, moderate quality evidence), or day 63 (one trial, 323 participants, low quality evidence).Compared to artemether‐lumefantrine, no difference was seen in prolonged QTc (low quality evidence), and no cardiac arrhythmias were reported. The frequency of other adverse events is probably similar with both combinations (moderate quality evidence).DHA‐P versus artesunate plus mefloquineIn Asia, over 28 days follow‐up, DHA‐P is as effective as artesunate plus mefloquine at preventing further parasitaemia (PCR‐unadjusted treatment failure: eight trials, 3487 participants, high quality evidence). Once adjusted by PCR to exclude new infections, treatment failure at day 28 was below 5% for both ACTs in all eight trials, but lower with DHA‐P in two trials (PCR‐adjusted treatment failure: RR 0.41 95% CI 0.21 to 0.80, eight trials, 3482 participants, high quality evidence). Both combinations contain partner drugs with very long half‐lives and no consistent benefit in preventing new infections has been seen over 63 days follow‐up (PCR‐unadjusted treatment failure: five trials, 2715 participants, moderate quality evidence).In the only trial from South America, there were fewer recurrent parastaemias over 63 days with artesunate plus mefloquine (PCR‐unadjusted treatment failure: RR 6.19, 95% CI 1.40 to 27.35, one trial, 445 participants, low quality evidence), but no differences were seen once adjusted for new infections (PCR‐adjusted treatment failure: one trial, 435 participants, low quality evidence).DHA‐P is associated with less nausea, vomiting, dizziness, sleeplessness, and palpitations compared to artesunate plus mefloquine (moderate quality evidence). DHA‐P was associated with more frequent prolongation of the QTc interval (low quality evidence), but no cardiac arrhythmias were reported.Authors' conclusionsIn Africa, dihydroartemisinin‐piperaquine reduces overall treatment failure compared to artemether‐lumefantrine, although both drugs have PCR‐adjusted failure rates of less than 5%. In Asia, dihydroartemisinin‐piperaquine is as effective as artesunate plus mefloquine, and is better tolerated.

Clinical relevance of different biomarkers in imported plasmodium falciparum malaria in adults: a case control study

BackgroundFor rapid initiation of anti-malarial treatment and prevention of complications, early diagnosis and risk stratification is important in patients with Plasmodium falciparum malaria. Routine laboratory values do not correlate well with disease severity. The aim of this study was to determine the diagnostic and prognostic value of several biomarkers related to inflammation; endothelial and cardiac dysfunction; coagulation, and haemolysis in imported P. falciparum malaria.MethodsIn a prospective case-control study, 79 adult travellers with both uncomplicated and complicated P. falciparum malaria were included between 2007 and 2011. Forty-one healthy subjects were included as controls. Blood samples were obtained within 24 hours after first consultation to assess routine laboratory values as well as markers related to inflammation (PAPP-A, copeptin, CRP), endothelial activation (MPO, elastase-2, endothelin-1, sICAM-1, sVCAM-1), cardiac function (NT-proBNP, MR-proANP), coagulation (fibrinogen, D-dimers, platelet count), and haemolysis (LDH). Prognostic performance was assessed using the receiver operating characteristic curve (area under the curve = AUROC).ResultsTwelve (15.2%) patients had severe P. falciparum malaria. In the patient group, significant thrombocytopaenia was found, all other markers but PAPP-A were significantly elevated. Diagnostic performance was best for CRP with an AUROC of 1.00, followed by MPO (0.99), D-dimers (0.98), elastase-2 (0.98), and sICAM-1 (0.98). Biomarker levels did not correlate well with disease severity.ConclusionThe combination of travel history, fever prior to blood sampling, and CRP serum levels above or below 10.8 mg/l upon hospital admission, best discriminated between malaria patients and control persons. None of the biomarkers studied predicted the presence or the development of malaria complications, neither at the time of admission, nor during hospitalization.

Increased Carboxyhemoglobin in Adult Falciparum Malaria is Associated With Disease Severity and Mortality

Heme oxygenase 1 expression is increased in pediatric patients with malaria. The carboxyhemoglobin level (a measure of heme oxygenase 1 activity) has not been assessed in adult patients with malaria. Results of pulse co-oximetry revealed that the mean carboxyhemoglobin level was elevated in 29 Indonesian adults with severe falciparum malaria (10%; 95% confidence interval [CI], 8%-13%) and in 20 with severe sepsis (8%; 95% CI, 5%-12%), compared with the mean levels in 32 patients with moderately severe malaria (7%; 95% CI, 5%-8%) and 36 controls (3.6%; 95% CI, 3%-5%; P < .001). An increased carboxyhemoglobin level was associated with an increased odds of death among patients with severe malaria (odds ratio, 1.2 per percentage point increase; 95% CI, 1.02-1.5). While also associated with severity and fatality, methemoglobin was only modestly increased in patients with severe malaria. Increased carboxyhemoglobin levels during severe malaria and sepsis may exacerbate organ dysfunction by reducing oxygen carriage and cautions against the use of adjunctive CO therapy, which was proposed on the basis of mouse models.

Efficacy and tolerability of a new formulation of artesunate-mefloquine for the treatment of uncomplicated malaria in adult in Senegal: open randomized trial

BackgroundPrompt treatment of malaria attacks with arteminisin-based combination therapy (ACT) is an essential tool for malaria control. A new co-blister tablet of artesunate-mefloquine (AM) with 25 mg/kg mefloquine has been developed for the management of uncomplicated malaria attacks. This non-inferiority randomized trial, was conducted to evaluate the efficacy and safety of the new formulation of AM in comparison to artemether-lumefantrine (AL) for the treatment of acute uncomplicated Plasmodium falciparum malaria in adults in Senegal.MethodsThe study was carried out from September to December 2010 in two health centres in Senegal. The study end points included (i) PCR corrected adequate clinical and parasitological response (ACPR) at day 28, (ii) ACPR at days 42 and 63, (iii) parasites and fever clearance time, (iv) incidence of adverse events and patients biological profile at day 7 using the WHO 2003 protocol for anti-malarial drug evaluation.ResultsOverall, 310 patients were randomized to receive either AM (n = 157) or AL (n = 153). PCR corrected ACPR at day 28 was at 95.5% in the AM arm while that in the AL arm was at 96.7% (p = 0.83). Therapeutic efficacy was at 98.5% in the AM arm versus 98.2% in the AL group at day 42 (p = 1). At day 63, ACPR in the AM and AL arms was at 98.2% and 97.7%, respectively (p = 0.32). The two treatments were well tolerated with similar biological profile at day 7. However, dizziness was more frequent in the AM arm.ConclusionArtesunate-mefloquine (25 mg/Kg mefloquine) is efficacious and well-tolerated for the treatment of uncomplicated P. falciparum malaria in adult patients.

Association of ABO blood group with severe falciparum malaria in adults: case control study and meta-analysis

Association of ABO blood group with severe falciparum malaria in adults: case control study and meta-analysis

Therapy of uncomplicated falciparum malaria in Europe: MALTHER - a prospective observational multicentre study.

BackgroundMalaria continues to be amongst the most frequent infectious diseases imported to Europe. Whilst European treatment guidelines are based on data from studies carried out in endemic areas, there is a paucity of original prospective treatment data. The objective was to summarize data on treatments to harmonize and optimize treatment for uncomplicated malaria in Europe.MethodsA prospective observational multicentre study was conducted, assessing tolerance and efficacy of treatment regimens for imported uncomplicated falciparum malaria in adults amongst European centres of tropical and travel medicine.ResultsBetween December 2003 and 2009, 504 patients were included in 16 centres from five European countries. Eighteen treatment regimens were reported, the top three being atovaquone-proguanil, mefloquine, and artemether-lumefantrine. Treatments significantly differed with respect to the occurrence of treatment changes (p = 0.005) and adverse events (p = 0.001), parasite and fever clearance times (p < 0.001), and hospitalization rates (p = 0.0066) and durations (p = 0.001). Four recrudescences and two progressions to severe disease were observed. Compared to other regimens, quinine alone was associated with more frequent switches to second line treatment, more adverse events and longer inpatient stays. Parasite and fever clearance times were shortest with artemether-mefloquine combination treatment. Vomiting was the most frequent cause of treatment change, occurring in 5.5% of all patients but 9% of the atovaquone-proguanil group.ConclusionsThis study highlights the heterogeneity of standards of care within Europe. A consensus discussion at European level is desirable to foster a standardized management of imported falciparum malaria.