Uncomplicated Vivax Malaria Research Articles

A randomised controlled trial to compare the efficacy, safety, and tolerability of low dose, short course primaquine in adults with uncomplicated P. vivax malaria in two hospitals in India

BackgroundPlasmodium vivax remains a major challenge for malaria control and elimination due to its ability to cause relapsing illness. To prevent relapses the Indian National Center for Vector Borne Diseases Control (NCVBDC) recommends treatment with primaquine at a dose of 0.25 mg/kg/day provided over 14 days. Shorter treatment courses may improve adherence and treatment effectiveness.MethodsThis is a hospital-based, randomised, controlled, open-label trial in two centres in India. Patients above the age of 16 years, with uncomplicated vivax malaria, G6PD activity of ≥ 30% of the adjusted male median (AMM) and haemoglobin levels ≥ 8 g/dL will be recruited into the study and randomised in a 1:1 ratio to receive standard schizonticidal treatment plus 7-day primaquine at 0.50 mg/kg/day or standard care with schizonticidal treatment plus 14-day primaquine at 0.25 mg/kg/day. Patients will be followed up for 6 months. The primary endpoint is the incidence risk of any P. vivax parasitaemia at 6 months. Safety outcomes include the incidence risk of severe anaemia (haemoglobin < 8 g/dL), the risk of blood transfusion, a > 25% fall in haemoglobin and an acute drop in haemoglobin of > 5 g/dL during primaquine treatment.DiscussionThis study will evaluate the efficacy and safety of a 7-day primaquine regimen compared to the standard 14-day regimen in India. Results from this trial are likely to directly inform national treatment guidelines.Trial registrationTrial is registered on CTRI portal, Registration No: CTRI/2022/12/048283.

Therapeutic efficacy of dihydroartemisinin–piperaquine for the treatment of uncomplicated Plasmodium vivax malaria in Seacha area, Arbaminch Zuria District, South West Ethiopia

BackgroundDeclining efficacy of chloroquine against Plasmodium vivax malaria has been documented in Ethiopia. Thus, there is a need to assess the efficacy of alternative schizontocidal anti-malarials such as dihydroartemisinin–piperaquine (DHA–PPQ) in P. vivax malaria-infected patients. This study was conducted to evaluate the therapeutic efficacy of DHA–PPQ drug in South West Ethiopia.MethodsThis is a single-arm, prospective therapeutic efficacy study in patients with uncomplicated P. vivax malaria. The study was conducted from May 2021 to August 2021, based on the standard World Health Organization study protocol for surveillance of anti-malarial therapeutic efficacy. The study endpoint was adequate clinical and parasitological response on day 42.ResultsA total of 86 patients with uncomplicated vivax malaria were enrolled. Of these, 79 patients completed the scheduled follow up; all showing adequate clinical and parasitological responses to day 42, with a successful cure rate of 100% (95% CI 96–100). Parasitaemias were cleared rapidly (86% by day 1 and 100% by day 3), as were clinical symptoms (100% by day 1). Gametocyte carriage decreased from 44% on Day 0 to 1% on day 1 and 0% on Day 2. Mean haemoglobin concentrations increased between day 0 (mean 12.2 g/dL) and day 42 (mean 13.3 g/dL). Treatment was well tolerated and no severe adverse events were observed.ConclusionIn summary, treatment with DHA–PPQ demonstrated excellent efficacy for uncomplicated P. vivax, with no recurrences to day 42, and no safety concerns. This treatment, which is also effective against P. falciparum, appears to be an ideal alternative for P. vivax as part of the malaria elimination programme.

Increased circulating myeloid-derived suppressor cells in vivax malaria and severe falciparum malaria

BackgroundCirculating myeloid-derived-suppressor-cells (MDSC) with immunosuppressive function are increased in human experimental Plasmodium falciparum infection, but have not been studied in clinical malaria.MethodsUsing flow-cytometry, circulating polymorphonuclear-MDSC were evaluated in cryopreserved samples from patients with uncomplicated Plasmodium vivax (n = 8) and uncomplicated (n = 4) and severe (n = 16) falciparum malaria from Papua, Indonesia.ResultsThe absolute number of circulating polymorphonuclear-MDSC were significantly elevated in severe falciparum malaria patients compared to controls (n = 10). Polymorphonuclear-MDSC levels in uncomplicated vivax malaria were also elevated to levels comparable to that seen in severe falciparum malaria.ConclusionControl of expansion of immunosuppressive MDSC may be important for development of effective immune responses in falciparum and vivax malaria.

A study of clinical profile and outcome of malaria in adults at government general hospital, Nizamabad

What has to be stressed is the need to be cautious with such individuals and to broaden our differentials to include P. vivax as a possible cause of severe malaria. Patients who are aggressively handled and treated can have a better outcome.To study the clinical profile and outcome of malaria in adults at Government General Hospital in our local area. A Cross-sectional, observational study done in Department of general medicine in Fifty smear positive malaria patients admitted to the medical wards and intensive care units are included in the study. Study done for a period of 1 Year . Patients of either gender, above 18 years of age and below 60 years of age, diagnosed with malaria on peripheral smear were included in study.: A total number of 50 smear positive malaria patients were included in the study. Majority of the patients belongs to the age group of 18-30 years [36%] CNS findings: Altered Sensorium was seen in 20% patients and convulsions were seen in 20% patients. Complicated malaria was present in 76% patients and uncomplicated malaria was present in 24% patients. Complicated falciparum malaria was present in 30% patients and Complicated Vivax malaria was present in 46% patients. Uncomplicated falciparum malaria was present in 4% patients and Uncomplicated Vivax malaria was present in 20% patients. Mortality was seen in 6% patients. Mortality was seen in the age group of 41- 50 years [66.7%] and 31-40 years [33.3%]. : Malaria complications can be reduced by studying the clinical profile of the disease and using proper antimalarial medication treatment. This aids in the reduction of malaria morbidity and death, as well as the country's long-term economic prosperity.

Duffy blood system and G6PD genetic variants in vivax malaria patients from Manaus, Amazonas, Brazil

BackgroundOver a third of the world’s population is at risk of Plasmodium vivax-induced malaria. The unique aspect of the parasite’s biology and interactions with the human host make it harder to control and eliminate the disease. Glucose-6-phosphate dehydrogenase (G6PD) deficiency and Duffy-negative blood groups are two red blood cell (RBC) variations that can confer protection against malaria.MethodsMolecular genotyping of G6PD and Duffy variants was performed in 225 unrelated patients (97 with uncomplicated and 128 with severe vivax malaria) recruited at a Reference Centre for Infectious Diseases in Manaus. G6PD and Duffy variants characterizations were performed using Real Time PCR (qPCR) and PCR–RFLP, respectively.ResultsThe Duffy blood group system showed a phenotypic distribution Fy(a + b−) of 70 (31.1%), Fy(a + b +) 96 (42.7%), Fy(a−b +) 56 (24.9%) and Fy(a−b−) 1 (0.44%.) The genotype FY*A/FY*B was predominant in both uncomplicated (45.3%) and severe malaria (39.2%). Only one Duffy phenotype Fy(a-b) was found and this involved uncomplicated vivax malaria. The G6PD c.202G > A variant was found in 11 (4.88%) females and 18 (8.0%) males, while c.376A > G was found in 20 females (8.88%) and 23 (10.22%) male patients. When combined GATA mutated and c.202G > A and c.376A > G mutated, was observed at a lower frequency in uncomplicated (3.7%) in comparison to severe malaria (37.9%). The phenotype Fy(a−b +) (p = 0.022) with FY*B/FY*B (p = 0.015) genotype correlated with higher parasitaemia.ConclusionsA high prevalence of G6PD c202G > A and c.376A > G and Duffy variants is observed in Manaus, an endemic area for vivax malaria. In addition, this study reports for the first time the Duffy null phenotype Fy(a-b-) in the population of the Amazonas state. Moreover, it is understood that the relationship between G6PD and Duffy variants can modify clinical symptoms in malaria caused by P. vivax and this deserves to be further investigated and explored among this population.

Total parasite biomass but not peripheral parasitaemia is associated with endothelial and haematological perturbations in Plasmodium vivax patients.

Plasmodium vivax is the major cause of human malaria in the Americas. How P. vivax infection can lead to poor clinical outcomes, despite low peripheral parasitaemia, remains a matter of intense debate. Estimation of total P. vivax biomass based on circulating markers indicates existence of a predominant parasite population outside of circulation. In this study, we investigate associations between both peripheral and total parasite biomass and host response in vivax malaria. We analysed parasite and host signatures in a cohort of uncomplicated vivax malaria patients from Manaus, Brazil, combining clinical and parasite parameters, multiplexed analysis of host responses, and ex vivo assays. Patterns of clinical features, parasite burden, and host signatures measured in plasma across the patient cohort were highly heterogenous. Further data deconvolution revealed two patient clusters, here termed Vivaxlow and Vivaxhigh. These patient subgroups were defined based on differences in total parasite biomass but not peripheral parasitaemia. Overall Vivaxlow patients clustered with healthy donors and Vivaxhigh patients showed more profound alterations in haematological parameters, endothelial cell (EC) activation, and glycocalyx breakdown and levels of cytokines regulating different haematopoiesis pathways compared to Vivaxlow. Vivaxhigh patients presented more severe thrombocytopenia and lymphopenia, along with enrichment of neutrophils in the peripheral blood and increased neutrophil-to-lymphocyte ratio (NLCR). When patients' signatures were combined, high association of total parasite biomass with a subset of markers of EC activation, thrombocytopenia, and lymphopenia severity was observed. Finally, machine learning models defined a combination of host parameters measured in the circulation that could predict the extent of parasite infection outside of circulation. Altogether, our data show that total parasite biomass is a better predictor of perturbations in host homeostasis in P. vivax patients than peripheral parasitaemia. This supports the emerging paradigm of a P. vivax tissue reservoir, particularly in the haematopoietic niche of bone marrow and spleen.

Platelet disturbances correlate with endothelial cell activation in uncomplicated Plasmodium vivax malaria

Platelets drive endothelial cell activation in many diseases. However, if this occurs in Plasmodium vivax malaria is unclear. As platelets have been reported to be activated and to play a role in inflammatory response during malaria, we hypothesized that this would correlate with endothelial alterations during acute illness. We performed platelet flow cytometry of PAC-1 and P-selectin. We measured platelet markers (CXCL4, CD40L, P-selectin, Thrombopoietin, IL-11) and endothelial activation markers (ICAM-1, von Willebrand Factor and E-selectin) in plasma with a multiplex-based assay. The values of each mediator were used to generate heatmaps, K-means clustering and Principal Component analysis. In addition, we determined pair-wise Pearson’s correlation coefficients to generate correlation networks. Platelet counts were reduced, and mean platelet volume increased in malaria patients. The activation of circulating platelets in flow cytometry did not differ between patients and controls. CD40L levels (Median [IQ]: 517 [406–651] vs. 1029 [732–1267] pg/mL, P = 0.0001) were significantly higher in patients, while P-selectin and CXCL4 showed a nonsignificant trend towards higher levels in patients. The network correlation approach demonstrated the correlation between markers of platelet and endothelial activation, and the heatmaps revealed a distinct pattern of activation in two subsets of P. vivax patients when compared to controls. Although absolute platelet activation was not strong in uncomplicated vivax malaria, markers of platelet activity and production were correlated with higher endothelial cell activation, especially in a specific subset of patients.

New laboratory perspectives for evaluation of vivax malaria infected patients: a useful tool for infection monitoring

In recent years, the number of cases with severe Plasmodium vivax malaria has shown an increasing trend. It is, therefore, important to identify routine laboratory markers that best characterize the acute disease phase and can serve as a tool for clinical follow-up of patients. In a cohort study, we followed 87 patients with acute P. vivax monoinfection acquired in an endemic region of the Brazilian Amazon. Forty-two different biochemical and hematological parameters frequently tested in clinical routine were evaluated at the acute phase and the convalescent phase. A total of 42 laboratory tests were performed: biochemical parameters measured were serum lipids levels, aminotransferases, bilirubin, amylase, glucose, urea, creatinine, albumin, globulin, uric acid, C-reactive protein, and alpha-1-acid glycoprotein. Hematological parameters included total and differential white blood cell and platelet counts, hemoglobin concentration, mean platelet volume, platelet width distribution, and plateletcrit. Our results show that several biochemical and hematological parameters were associated with acute phase P. vivax malaria and these parameters reverted to normal values in the convalescent phase. The use of these parameters during diagnosis and follow-up of the infection is a useful clinical tool to evaluate the clinical course and therapeutic response of patients with uncomplicated vivax malaria.

Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate in comparison with chloroquine phosphate in children with acute uncomplicated Plasmodium vivax malaria: A phase III, randomised, multicentric study

In India, the burden of Plasmodium vivax malaria has been projected to be highest in some areas. This study investigated the efficacy and safety of fixed dose combination (FDC) of arterolane maleate (AM) 37.5 mg and piperaquine phosphate 187.5 mg (PQP) dispersible tablets and (not with) chloroquine in the treatment of uncomplicated vivax malaria in pediatric patients. This multicentric, open-label trial was carried out at 12 sites in India. A total of 164 patients aged 6 months to 12 years with P. vivax malaria were randomized in a ratio of 2:1 to AM-PQP (111 patients) or chloroquine (53 patients) arms. The duration of follow up was 42 days. At 72 hours, the proportion of a parasitaemic and afebrile patients was 100% in both treatment arms in per protocol (PP) population, and 98.2% and 100% [95% CI: -1.8 (-6.33 to 5.08)] in AM-PQP and chloroquine arms, respectively, in intent to treat (ITT) population. The efficacy and safety of AM-PQP was found to be comparable to chloroquine in the treatment of uncomplicated P. vivax malaria in pediatric patients. Overall, the cure rate at Day 28 and 42 was >95% for both AM-PQP or CQ. The commonly reported clinical adverse event was vomiting. No patient was discontinued for any QTc abnormality. The efficacy and safety of FDC of arterolane maleate and piperaquine phosphate was found to be comparable to chloroquine for treatment of uncomplicated P. vivax malaria in pediatric patients.

Apical membrane protein 1‐specific antibody profile and temporal changes in peripheral blood B‐cell populations in Plasmodium vivax malaria

Plasmodium falciparum-specific antibodies tend to be short-lived, but their cognate memory B cells (MBCs) circulate in the peripheral blood of exposed subjects for several months or years after the last infection. However, the time course of antigen-specific antibodies and B-cell responses to the relatively neglected parasite Plasmodium vivax remains largely unexplored. Here, we showed that uncomplicated vivax malaria elicits short-lived antibodies but long-lived MBC responses to a major blood-stage P vivax antigen, apical membrane protein 1 (PvAMA-1), in subjects exposed to declining malaria transmission in the Amazon Basin of Brazil. We found that atypical (CD19+ CD10- CD21- CD27- ) MBCs, which appear to share a common precursor with classical MBCs but are unable to differentiate into antibody-secreting cells, significantly outnumbered classical MBCs by 5:1 in the peripheral blood of adult subjects currently or recently infected with P vivax and by 3:1 in healthy residents in the same endemic communities. We concluded that malaria can drive classical MBCs to differentiate into functionally impaired MBCs not only in subjects repeatedly exposed to P falciparum, but also in subjects living in areas with low levels of P vivax transmission in the Amazon, leading to an impaired B-cell memory that may affect both naturally acquired and vaccine-induced immunity.

Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial

SummaryBackgroundPrimaquine is the only widely used drug that prevents Plasmodium vivax malaria relapses, but adherence to the standard 14-day regimen is poor. We aimed to assess the efficacy of a shorter course (7 days) of primaquine for radical cure of vivax malaria.MethodsWe did a randomised, double-blind, placebo-controlled, non-inferiority trial in eight health-care clinics (two each in Afghanistan, Ethiopia, Indonesia, and Vietnam). Patients (aged ≥6 months) with normal glucose-6-phosphate dehydrogenase (G6PD) and presenting with uncomplicated vivax malaria were enrolled. Patients were given standard blood schizontocidal treatment and randomly assigned (2:2:1) to receive 7 days of supervised primaquine (1·0 mg/kg per day), 14 days of supervised primaquine (0·5 mg/kg per day), or placebo. The primary endpoint was the incidence rate of symptomatic P vivax parasitaemia during the 12-month follow-up period, assessed in the intention-to-treat population. A margin of 0·07 recurrences per person-year was used to establish non-inferiority of the 7-day regimen compared with the 14-day regimen. This trial is registered at ClinicalTrials.gov (NCT01814683).FindingsBetween July 20, 2014, and Nov 25, 2017, 2336 patients were enrolled. The incidence rate of symptomatic recurrent P vivax malaria was 0·18 (95% CI 0·15 to 0·21) recurrences per person-year for 935 patients in the 7-day primaquine group and 0·16 (0·13 to 0·18) for 937 patients in the 14-day primaquine group, a difference of 0·02 (−0·02 to 0·05, p=0·3405). The incidence rate for 464 patients in the placebo group was 0·96 (95% CI 0·83 to 1·08) recurrences per person-year. Potentially drug-related serious adverse events within 42 days of starting treatment were reported in nine (1·0%) of 935 patients in the 7-day group, one (0·1%) of 937 in the 14-day group and none of 464 in the control arm. Four of the serious adverse events were significant haemolysis (three in the 7-day group and one in the 14-day group).InterpretationIn patients with normal G6PD, 7-day primaquine was well tolerated and non-inferior to 14-day primaquine. The short-course regimen might improve adherence and therefore the effectiveness of primaquine for radical cure of P vivax malaria.FundingUK Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust through the Joint Global Health Trials Scheme (MR/K007424/1) and the Bill & Melinda Gates Foundation (OPP1054404).

Monitoring the Efficacy of Chloroquine-Primaquine Therapy for Uncomplicated Plasmodium vivax Malaria in the Main Transmission Hot Spot of Brazil.

Emerging Plasmodium vivax resistance to chloroquine (CQ) may undermine malaria elimination efforts in South America. CQ-resistant P. vivax has been found in the major port city of Manaus but not in the main malaria hot spots across the Amazon Basin of Brazil, where CQ is routinely coadministered with primaquine (PQ) for radical cure of vivax malaria. Here we randomly assigned 204 uncomplicated vivax malaria patients from Juruá Valley, northwestern Brazil, to receive either sequential (arm 1) or concomitant (arm 2) CQ-PQ treatment. Because PQ may synergize the blood schizontocidal effect of CQ and mask low-level CQ resistance, we monitored CQ-only efficacy in arm 1 subjects, who had PQ administered only at the end of the 28-day follow-up. We found adequate clinical and parasitological responses in all subjects assigned to arm 2. However, 2.2% of arm 1 patients had microscopy-detected parasite recrudescences at day 28. When PCR-detected parasitemias at day 28 were considered, response rates decreased to 92.1% and 98.8% in arms 1 and 2, respectively. Therapeutic CQ levels were documented in 6 of 8 recurrences, consistent with true CQ resistance in vivo In contrast, ex vivo assays provided no evidence of CQ resistance in 49 local P. vivax isolates analyzed. CQ-PQ coadministration was not found to potentiate the antirelapse efficacy of PQ over 180 days of surveillance; however, we suggest that larger studies are needed to examine whether and how CQ-PQ interactions, e.g., CQ-mediated inhibition of PQ metabolism, modulate radical cure efficacy in different P. vivax-infected populations. (This study has been registered at ClinicalTrials.gov under identifier NCT02691910.).

Malaria: An Update

India is endemic for malaria with unstable transmission inhibiting the development of immunity and predisposing all age groups to the disease. Children under five are the greatest sufferers with maximum mortality. P. falciparum and P. vivax cause majority of cases. Fever is the cardinal symptom, though no set of signs and symptoms reliably distinguishes malaria from other causes of fever. In all suspected cases parasitological diagnosis should be confirmed before starting the treatment. Microscopy of blood smears is the gold standard for diagnosis. Rapid diagnostic tests are to be used where microscopy results are not available within 24h. In complicated malaria and high risk patients like HIV, treatment can be commenced before confirmation, though all efforts to establish the diagnosis should be made. Chloroquine is used for uncomplicated vivax malaria while artemisinin based combination therapy (ACTs) is used for uncomplicated falciparum malaria. For complicated malaria, IV artesunate is the drug of choice irrespective of the Plasmodium species. It is important to follow recommendations diligently to decrease morbidity and mortality due to malaria and to avoid the problem of drug resistance. The gains of the past decade should be scaled up to make malaria elimination and eradication a reality.

Efficacy of Artesunate-mefloquine for Chloroquine-resistant Plasmodium vivax Malaria in Malaysia: An Open-label, Randomized, Controlled Trial.

Chloroquine (CQ)-resistant Plasmodium vivax is increasingly reported throughout southeast Asia. The efficacy of CQ and alternative artemisinin combination therapies (ACTs) for vivax malaria in Malaysia is unknown. A randomized, controlled trial of CQ vs artesunate-mefloquine (AS-MQ) for uncomplicated vivax malaria was conducted in 3 district hospitals in Sabah, Malaysia. Primaquine was administered on day 28. The primary outcome was the cumulative risk of treatment failure by day 28 by Kaplan-Meier analysis. From 2012 to 2014, 103 adults and children were enrolled. Treatment failure by day 28 was 61.1% (95% confidence interval [CI], 46.8-75.6) after CQ and 0% (95% CI, 0-.08) following AS-MQ (P < .001), of which 8.2% (95% CI, 2.5-9.6) were early treatment failures. All patients with treatment failure had therapeutic plasma CQ concentrations at day 7. Compared with CQ, AS-MQ was associated with faster parasite clearance (normalized clearance slope, 0.311 vs 0.127; P < .001) and fever clearance (mean, 19.0 vs 37.7 hours; P =001) and with lower risk of anemia at day 28 (odds ratio = 3.7; 95% CI, 1.5-9.3; P =005). Gametocytes were present at day 28 in 23.8% (10/42) of patients following CQ vs none with AS-MQ (P < .001). AS-MQ resulted in lower bed occupancy: 4037 vs 6510 days/1000 patients (incidence rate ratio 0.62; 95% CI, .60-.65; P < .001). One patient developed severe anemia not regarded as related to their AS-MQ treatment. High-grade CQ-resistant P. vivax is prevalent in eastern Malaysia. AS-MQ is an efficacious ACT for all malaria species. Wider CQ-efficacy surveillance is needed in vivax-endemic regions with earlier replacement with ACT when treatment failure is detected.Clinical Trials Registration NCT01708876.

Per protocol analysis of therapeutic efficacy of chloroquine for the treatment of Plasmodium vivax malaria in children

Background: High incidence of chloroquine-resistant vivax malaria has led to increasing case fatality and incidence of complicated malaria with Plasmodium vivax contributing to morbidity and mortality. Current guidelines recommend the use of chloroquine along with tissue schizontcides like primaquine for the treatment of Plasmodium vivax malaria. There were reports of increasing resistance to chloroquine in Plasmodium vivax species especially from Asia during the period when this study was taken up. Methods: Present study is a one arm, 28 day follow up, hospital based prospective observational study including 150 children aged 1 to 12 years with smear positive isolated Plasmodium vivax infections. Chloroquine was administered at the standard dose of 25 mg base/kg body weight over three days. Recurrence of parasitaemia and clinical conditions of patients were assessed on days 1, 2, 3, 7, 14, and 28 during the 28-day follow-up period. Results: All 150 children included in the study, completed their 28 day follow up. Mean age for enrolment was 5.96±2.38 years. The mean parasite index (%) on enrolment was 1.22±0.46. Based on the per protocol analysis, chloroquine efficacy (adequate clinical and parasitological response) was 92.7%. Treatment was well tolerated. Early treatment failure was seen in 2.7% of study population, late clinical failure in 2% and late parasitological failure in 2.7% of study population, suggesting that response to chloroquine was good in the study population. Conclusions: In the present study the chloroquine therapy showed high therapeutic efficacy (92.7%) in the treatment of uncomplicated vivax malaria. It was also well tolerated and equally safe when used in therapeutic doses. Regular monitoring of the pattern of resistance to chloroquine is needed in vivax malaria endemic areas of the country and measures are taken rapidly and effectively to control spread of resistance.

Ultrasound findings in pregnant women with uncomplicated vivax malaria in the Brazilian Amazon: a cohort study.

BackgroundDuring pregnancy, Plasmodium falciparum-induced malaria can cause placental lesions and intrauterine growth restriction (IUGR). There are few published studies on Plasmodium vivax-induced malaria in pregnancy. Ultrasound is an efficient method for evaluating foetal biometry and placenta. The present study aimed to investigate the occurrence of increased placental thickness, foetal biometry and the amniotic fluid via ultrasound in a cohort of pregnant women with vivax malaria in Manaus, Amazonas, Brazil.MethodsA cohort study was conducted among 118 pregnant women with vivax malaria and 191 pregnant women without malaria. Foetal biometry, placental thicknesses and the amniotic fluid were evaluated via ultrasound. Biometric data were distributed by the trimester in which the infection occurred and converted to Z scores. The results were compared between the groups.ResultsAmong pregnant women from the cohort, increased placental thickness was observed in ten women with malaria (8.5 vs 0%; p <0.001). The Z scores of biometric parameters were not statistically significant when comparing the groups or according to the time of infection. In ultrasound results of the 118 pregnant women with malaria, seven (6%) showed low foetal weight, two (1.7%) showed oligohydramnios and one (0.85%) showed foetal malformation. There was no significant difference when these variables were compared to those of the control group.ConclusionsThe placental thickness changes were significant but caused no foetal repercussions at birth. The ultrasound findings except placental thickness were similar in both groups, possibly because this is a low-endemic area and the pregnant women in the study were followed up in an active detection system that allowed early diagnosis and treatment of new malaria episodes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0627-1) contains supplementary material, which is available to authorized users.

Diagnosis and management of malaria in children: Recommendations and IAP plan of action

The problem of malaria is further exacerbated by development of resistance to first line antimalarial chloroquine (CQ). This is mainly due to presumptive use of CQ with increase drug pressure. Hence every case of suspected malaria needs a parasitological diagnosis. Rapid diagnostic test (RDT) are ready to use test available even in remote parts which does not need any expertise. For management of uncomplicated vivax malaria CQ is still the drug of choice. Whereas, falciparum malaria should be treated with artemisinin based combination therapy (ACT). The choice of ACT will depend upon the geographical locality of the patient. For severe and complicated malaria irrespective of species parenteral artemisinin or quinine is the drug of choice with former being more effective.

Efficacy and safety of dihydroartemisinin-piperaquine in Indonesian children infected with uncomplicated Plasmodium falciparum and Plasmodium vivax

Background Dihydroartemisinin-piperaquine (DPQ) has been used since 2006 in Papua, Indonesia and is planned as an alternative artemisinin-based combination therapy for wider use in Indonesia. Confirmation of the drug’s efficacy and safety in children outside Papua is needed.Objective To measure the day-42 clinical and parasitological efficacy of DPQ in children with uncomplicated falciparum and vivax malaria.Methods This cross-sectional and observational study was held in Kalimantan and Sulawesi in 2010. Seventy and sixty children under 15 years of age with uncomplicated falciparum and vivax malaria were selected according to the 2003 WHO protocol for monitoring therapeutic efficacy of antimalarial treatments and was confirmed by microscopy and PCR. All subjects were treated with DPQ based on a dosage regimen of dihydroartemisinin 2-4 mg/kg BW/dose and piperaquine 16-32 mg/kg BW/dose, in single daily doses for 3 days and closely observed for 42 days. Data was analyzed using intention-to-treat (ITT) and per protocol (PP) populations.Results The mean fever and asexual parasite clearance times were 1.0 day and 1.6 days, respectively, in children with uncomplicated falciparum malaria, and 1.1 days and 1.2 days, respectively, in children with uncomplicatedvivax malaria. Clinical symptoms reduced over 50% by day 7. Hemoglobin recoveries showed improvement on days 14, 28 and 42, at 70.6%, 83.8%and 89.1%, respectively, in the falciparum malaria group, and 60.3%, 65,5% and 83.6%, respectively, in thevivax malaria group. Adequate clinical and parasitological response to DPQ on day 42 in the ITT and PP populations were reported as 98.6% (95% CI 92.3 to 99.7%) and 100% (95% CI 94.7 to 100%), respectively, in the falciparum group, and 91.7% (95% CI 81.9 to 96.4%) and 96.5% (95% CI 88.1 to 99.0%), respectively, the vivax group. Mild adverse events commonly noted were cough, abdominal pain, diarrhea, anorexia, and vomiting.Conclusion DPQ was effective against falciparum and vivax malaria with adequate clinical and parasitological response of ≥ 95%, rapid fever and asexual parasite clearance, good hematological recovery and mild adverse events.

Failure of artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria in southern Cambodia

BackgroundResistance to anti-malarial drugs hampers control efforts and increases the risk of morbidity and mortality from malaria. The efficacy of standard therapies for uncomplicated Plasmodium falciparum and Plasmodium vivax malaria was assessed in Chumkiri, Kampot Province, Cambodia.MethodsOne hundred fifty-one subjects with uncomplicated falciparum malaria received directly observed therapy with 12 mg/kg artesunate (over three days) and 25 mg/kg mefloquine, up to a maximum dose of 600 mg artesunate/1,000 mg mefloquine. One hundred nine subjects with uncomplicated vivax malaria received a total of 25 mg/kg chloroquine, up to a maximum dose of 1,500 mg, over three days. Subjects were followed for 42 days or until recurrent parasitaemia was observed. For P. falciparum infected subjects, PCR genotyping of msp1, msp2, and glurp was used to distinguish treatment failures from new infections. Treatment failure rates at days 28 and 42 were analyzed using both per protocol and Kaplan-Meier survival analysis. Real Time PCR was used to measure the copy number of the pfmdr1 gene and standard 48-hour isotopic hypoxanthine incorporation assays were used to measure IC50 for anti-malarial drugs.ResultsAmong P. falciparum infected subjects, 47.0% were still parasitemic on day 2 and 11.3% on day 3. The PCR corrected treatment failure rates determined by survival analysis at 28 and 42 days were 13.1% and 18.8%, respectively. Treatment failure was associated with increased pfmdr1 copy number, higher initial parasitaemia, higher mefloquine IC50, and longer time to parasite clearance. One P. falciparum isolate, from a treatment failure, had markedly elevated IC50 for both mefloquine (130 nM) and artesunate (6.7 nM). Among P. vivax infected subjects, 42.1% suffered recurrent P. vivax parasitaemia. None acquired new P. falciparum infection.ConclusionThe results suggest that artesunate-mefloquine combination therapy is beginning to fail in southern Cambodia and that resistance is not confined to the provinces at the Thai-Cambodian border. It is unclear whether the treatment failures are due solely to mefloquine resistance or to artesunate resistance as well. The findings of delayed clearance times and elevated artesunate IC50 suggest that artesunate resistance may be emerging on a background of mefloquine resistance.

Chloroquine-ResistantPlasmodiumvivax, Brazilian Amazon

To the Editor: Plasmodium vivax is the protozoan that causes the second most common form of malaria. Some resistant strains to chloroquine (CQ) occur in a few places in Asia and the Indo-Pacific Region (1–4). Although resistance of P. vivax to CQ has already been described in South America (5–7), there are limited data regarding this issue. CQ plus primaquine is the standard treatment for vivax malaria worldwide. Presently, this drug regimen exhibits satisfactory efficacy in the Brazilian Amazon. However, in recent years several treatment failures presumably related to CQ resistance, have been reported in the city of Manaus (Amazonas) where vivax malaria predominates (7). This observation warrants local attention despite these cases having no confirmation of CQ blood levels on the basis of the appearance of asexual parasites against CQ plus desethylchloroquine levels exceeding the minimally effective plasma concentration proposed for sensitive parasite strains (>10 ng/mL) (8), according to Pan American Health Organization recommendations (9). From September 2004 to February 2005, a 28-day in vivo test was conducted at the Foundation for Tropical Medicine of Amazonas (FMTAM) in Manaus, Brazil, to assess the efficacy of standard supervised CQ therapy. The test involved 166 volunteers with uncomplicated vivax malaria. Each volunteer was administered uncoated, scored, 150-mg CQ tablets (10 + 7.5 + 7.5 mg/kg at 24-hour intervals) (9). Primaquine was withheld until day 28 (dose regimen of 30 mg/day for 7 days). Among the 109 volunteers who completed the in vivo test, 19 had positive blood smears within the 28-day follow-up (1 on day 14, 3 on day 21, and 15 on day 28). All were required to undergo alternative therapy (mefloquine). Adequate CQ absorption was confirmed in these cases on day 2 with a mean ± SD CQ plasma concentration of 785.4 ± 800.1 ng/mL) (10) Suspected therapeutic failure (P. vivax CQ resistance) was confirmed in 11 (10.1%) of 109 persons with a mean isolated choloroquine plasma concentration >10 ng/mL (356.6 ± 296.1 ng/mL) (9). Desethylchloroquine levels in plasma were not measured. Previously, a CQ efficacy study demonstrated that 4.4% of those tested had CQ-resistant P. vivax (7). In comparison, the proportion of failures (10.1%) in the current study seems to be relevant; even though most of the P. vivax infections (98, 89.9%) were successfully evaluated and adequate clinical and parasitologic responses were obtained. Currently, the FMTAM Manaus Outpatient Clinic is detecting patients from different areas of the city who show parasitologic recurrences after correct treatment within 28 days of the routine clinical follow-up. This observation is an indirect indicator of the possible regional spread of P. vivax CQ-resistant strains (unpub. data). We believe our findings are important and merit the attention of local public health authorities. Considering the possibility of emerging underestimated P. vivax CQ resistance in Manaus, we feel it is essential to quickly clarify whether such documented resistance can copromote vivax malaria outbreaks in malaria-endemic areas within the Amazon.