Malaria.

Malaria is resurging in many African and South American countries, exacerbated by COVID-19-related health service disruption. In 2021, there were an estimated 247 million malaria cases and 619 000 deaths in 84 endemic countries. Plasmodium falciparum strains partly resistant to artemisinins are entrenched in the Greater Mekong region and have emerged in Africa, while Anopheles mosquito vectors continue to evolve physiological and behavioural resistance to insecticides. Elimination of Plasmodium vivax malaria is hindered by impractical and potentially toxic antirelapse regimens. Parasitological diagnosis and treatment with oral or parenteral artemisinin-based therapy is the mainstay of patient management. Timely blood transfusion, renal replacement therapy, and restrictive fluid therapy can improve survival in severe malaria. Rigorous use of intermittent preventive treatment in pregnancy and infancy and seasonal chemoprevention, potentially combined with pre-erythrocytic vaccines endorsed by WHO in 2021 and 2023, can substantially reduce malaria morbidity. Improved surveillance, better access to effective treatment, more labour-efficient vector control, continued drug development, targeted mass drug administration, and sustained political commitment are required to achieve targets for malaria reduction by the end of this decade.

Impact of Chemoprophylaxis on Plasmodium vivax and Plasmodium ovale Infection Among Civilian Travelers: A Nested Case-Control Study With a Counterfactual Approach on 862 Patients.

BACKGROUND: The impact of chemoprophylaxis targeting Plasmodium falciparum on Plasmodium vivax and Plasmodium ovale, which may remain quiescent as hypnozoites in the liver, is debated. METHODS: We conducted a nested case-control analysis of the outcomes of P. vivax and P. ovale infections in imported malaria cases in France among civilian travelers from 1 January 2006, to 31 December 2017. Using adjusted logistic regression, we assessed the effect of chemoprophylaxis on the incubation period, time from symptoms to diagnosis, management, blood results, symptoms, and hospitalization duration. We analyzed the effect of blood-stage drugs (doxycycline, mefloquine, chloroquine, chloroquine-proguanil) or atovaquone-proguanil on the incubation period. We used a counterfactual approach to ascertain the causal effect of chemoprophylaxis on postinfection characteristics. RESULTS: Among 247 P. vivax- and 615 P. ovale-infected travelers, 30% and 47%, respectively, used chemoprophylaxis, and 7 (3%) and 8 (1%) were severe cases. Chemoprophylaxis users had a greater risk of presenting symptoms >2 months after returning for both species (P. vivax odds ratio [OR], 2.91 [95% confidence interval {CI}, 1.22-6.95], P = .02; P. ovale OR, 2.28 [95% CI, 1.47-3.53], P < .001). Using drugs only acting on the blood stage was associated with delayed symptom onset after 60 days, while using atovaquone-proguanil was not. CONCLUSIONS: Civilian travelers infected with P. vivax or P. ovale reporting chemoprophylaxis use, especially of blood-stage agents, had a greater risk of delayed onset of illness. The impact of chemoprophylaxis on the outcomes of infection with relapse-causing species calls for new chemoprophylaxis acting against erythrocytic and liver stages.

What make malarial adenosine deaminase from PLASMODIUM VIVAX recognise adenosine and 5'-methylthioadenosine: simulation studies.

Malaria is a life-threatening disease in humans caused by Plasmodium parasites. Plasmodium vivax (P. vivax) is one of the prevalent species found worldwide. An increase in an anti-malarial drug resistance suggests the urgent need for new drugs. Zn2+-containing adenosine deaminase (ADA) is a promising drug target because the ADA inhibition is fatal to the parasite. Malarial ADA accepts both adenosine (ADN) and 5'-methylthioadenosine (MTA) as substrates. The understanding of the substrate binding becomes crucial for an anti-malarial drug development. In this work, ADA from P. vivax (pvADA) is of interest due to its prevalence worldwide. The binding of ADN and MTA are studied here using Molecular Dynamics (MD) simulations. Upon binding, the open and closed states of pvADA are captured. The displacement of α7, linking loops of ß3/α12, ß4/α13, ß5/α15, and α10/α11 is involved in the cavity closure and opening. Also, the inappropriate substrate orientation induces a failure in a complete cavity closure. Interactions with D46, D172, S280, D310, and D311 are important for ADN binding, whereas only hydrogen bonds with D172 and D311 are sufficient to anchor MTA inside the pocket. No Zn2+-coordinated histidine residues is acquired for substrate binding. D172 is found to play a role in ribose moiety recognition, while D311 is crucial for trapping the amine group of an adenine ring towards the Zn2+ site. Comparing between ADN and MTA, the additional interaction between D310 and an amine nitrogen on ADN supports a tighter fit that may facilitate the deamination.Communicated by Ramaswamy H. Sarma.

[A Case of Plasmodium vivax Complicated with Reactive Hemophagocytic Syndrome]. / Reaktif Hemofagositik Sendrom ile Komplike Olan Plasmodium vivax Olgusu.

Plasmodium vivax is the most common malaria agent in the world, transmitted by vectoring of anopheles mosquitoes. In the clinical course of the disease, non-specific signs of infection (fever, myalgia, joint pain, nausea, vomiting, etc.) can be seen. Hemophagocytic lymphohistiocytosis; also known as hemophagocytic syndrome, is a rapid-onset and life-threatening clinical condition that develops as a result of uncontrolled immune activation and hypercytokinemia. In this case report, a case who developed hemophagocytic syndrome while under treatment for P.vivax infection was presented. A 37-year-old male patient applied to us with the complaints of high fever, chills-shivering and weakness, started on his return from Sudan. Upon admission, the fever was 40°C, the pulse was rhythmic and 115/minute, the respiratory rate was 24/minute, and the blood pressure was 80/49 mmHg, and he was followed up in the intensive care unit due to the signs of systemic inflammatory response syndrome. During the investigation of the etiology of fever, it was learned that he did not receive prophylaxis for malaria during his stay in Sudan. Thin and thick blood smears were examined. P.vivax infection was detected in the patient and the treatment was initiated, a bone marrow aspiration biopsy was performed with the prediagnosis of hemophagocytic syndrome with persistent fever, deepening of thrombocytopenia, findings of hyperferritinemia, hypertriglyceridemia, hepatosplenomegaly, and myeloid serial hemophagocytosis in the 48th hour of the treatment. In addition to antimalarial therapy, clinical and laboratory response was obtained with polyclonal intravenous immunoglobulin (IVIG) therapy.

G6PD testing and radical cure for Plasmodium vivax in Cambodia: A mixed methods implementation study.

INTRODUCTION: Cambodia aims to eliminate malaria by 2025, however tackling Plasmodium vivax (P.v) presents multiple challenges. The prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency has prevented the deployment of 8-aminoquinolones for "radical cure", due to the risk of severe haemolysis. Patients with P. vivax have therefore continued to experience recurrent relapses leading to cumulative health and socioeconomic burden. The recent advent of point of care testing for G6PD deficiency has made radical cure a possibility, however at the time of the study lack of operational experience and guidance meant that they had not been introduced. This study therefore aimed to design, implement and evaluate a new care pathway for the radical cure of P.vivax. METHODS: This implementation study took place in Pursat province, Western Cambodia. The interventions were co-developed with key stakeholders at the national, district, and local level, through a continuous process of consultations as well as formal meetings. Mixed methods were used to evaluate the feasibility of the intervention including its uptake (G6PD testing rate and the initiation of primaquine treatment according to G6PD status); adherence (self-reported); and acceptability, using quantitative analysis of primary and secondary data as well as focus group discussions and key informant interviews. RESULTS: The co-development process resulted in the design of a new care pathway with supporting interventions, and a phased approach to their implementation. Patients diagnosed with P.v infection by Village Malaria Workers (VMWs) were referred to local health centres for point-of-care G6PD testing and initiation of radical cure treatment with 14-day or 8-week primaquine regimens depending on G6PD status. VMWs carried out follow-up in the community on days 3, 7 and 14. Supporting interventions included training, community sensitisation, and the development of a smartphone and tablet application to aid referral, follow-up and surveillance. The testing rate was low initially but increased rapidly over time, reflecting the deliberately cautious phased approach to implementation. In total 626 adults received G6PD testing, for a total of 675 episodes. Of these 555 occurred in patients with normal G6PD activity and nearly all (549/555, 98.8%) were initiated on PQ14. Of the 120 with deficient/intermediate G6PD activity 61 (50.8%) were initiated on PQ8W. Self-reported adherence was high (100% and 95.1% respectively). No severe adverse events were reported. The pathway was found to be highly acceptable by both staff and patients. The supporting interventions and gradual introduction were critical to success. Challenges included travel to remote areas and mobility of P.v patients. CONCLUSION: The new care pathway with supporting interventions was highly feasible with high levels of uptake, adherence and acceptability in this setting where high prevalence of G6PD deficiency is high and there is a well-established network of VMWs. Scaling up of the P.v radical cure programme is currently underway in Cambodia and a decline in reduction in the burden of malaria is being seen, bringing Cambodia a step closer to elimination.

Rhino-orbital mucormycosis in a patient with no susceptibility following P.vivax malaria infection-a case report.

BACKGROUND: Mucormycosis is a potentially lethal, angioinvasive fungal infection caused by the Mucoracea family comprising Mucor, Rhizopus, and Absidia species. It is commonly associated with uncontrolled diabetes mellitus, the use of corticosteroids, immunosuppressive drugs, and Covid-19 infection. The occurrence of mucormycosis in an immunocompetent patient is rare. Also, only a few case reports have been published where patients developed mucormycosis with associated malarial infection. CASE PRESENTATION: A young female presented with a 3-weeks history of painful swelling and outward protrusion of the right eye with complete loss of vision. She had a history of P.vivax malaria two weeks before her ocular symptoms. On ocular examination, there was proptosis and total ophthalmoplegia with loss of corneal sensations in the right eye. Hematological examination revealed normocytic normochromic anemia and thrombocytopenia. MRI was suggestive of right-sided pansinusitis and orbital cellulitis with right superior ophthalmic vein thrombosis and bulky cavernous sinus. Nasal biopsy was negative for fungal culture. An emergency surgical debridement of all the sinuses was done with right orbital exenteration. Histopathology confirmed the diagnosis of mucormycosis and the patient improved post-operatively on systemic antifungals. CONCLUSION: Such an association of mucormycosis with malaria infection is rarely reported in the literature and is hypothesized to be a result of immunosuppression caused by malaria. Also, emphasis is laid upon having a high index of suspicion for fungal infection in the setting of pansinusitis even if the risk factors are absent. We hereby report a case of rhino-orbital mucormycosis following P.vivax malaria in a 20-year-old female with anemia and thrombocytopenia.

The assessment of antimalarial drug efficacy in vivo.

Currently recommended methods of assessing the efficacy of uncomplicated falciparum malaria treatment work less well in high-transmission than in low-transmission settings. There is also uncertainty how to assess intermittent preventive therapies and seasonal malaria chemoprevention (SMC), and Plasmodium vivax radical cure. A pharmacometric antimalarial resistance monitoring (PARM) approach is proposed specifically for evaluating slowly eliminated antimalarial drugs in areas of high transmission. In PARM antimalarial drug concentrations at recurrent parasitaemia are measured to identify outliers (i.e., recurrent parasitaemias in the presence of normally suppressive drug concentrations) and to evaluate changes over time. PARM requires characterization of pharmacometric profiles but should be simpler and more sensitive than current molecular genotyping-based methodologies. PARM does not require parasite genotyping and can be applied to the assessment of both prevention and treatment.

Recurrent Plasmodium vivax Cases of Both Short and Long Latency Increased with Transmission Intensity and Were Distributed Year-Round in the Most Affected Municipalities of the RACCN, Nicaragua, 2013-2018.

The characteristics of P. vivax recurrent episodes were examined using a centralized secondary source of malaria records in Nicaragua and in the two most affected municipalities in the RACCN. The study of 36,787 malaria cases due to P. vivax or P. falciparum revealed that, nationwide, 3624 patients had at least one recurrent infection. This was achieved by matching names, gender, age, community/municipality, ethnicity, etc. P. vivax was responsible for 88% of recurrent infections of 25-450 days of latency (51.9% were women and 48.1% were men), and these were assumed to be relapse episodes. Of them, 88.2% and 4.4% occurred in the municipalities of Puerto Cabezas and Rosita, respectively. The proportion of P. vivax patients having presumed relapse episodes rose with elevated transmission rates in both municipalities, reaching 7% in Rosita (2017) and 14.5% in Puerto Cabezas (2018). In both areas, relapse episodes were evident over time and were characterized by the production of a continuous stippling pattern with a slope evolving from one transmission peak to the next. During the dry season, short-latency relapse episodes were more robust, while long-latency ones increased just before the P. vivax transmission season began, with a high proportion of long-latency relapses during this period. The abundance of recurrent P. vivax infections, the wide range of relapse latency lengths, and temporal distribution tended to favor year-round transmission. It is necessary to evaluate compliance with and the effectiveness of primaquine treatment and contemplate the use of an alternative drug, among other actions.

Paludismo importado no falciparum: aspectos de interés para el tratamiento de los pacientes / Imported non-falciparum malaria: aspects of interest for patient therapeutic management

Introducción: El paludismo es una enfermedad febril aguda potencialmente mortal causada por parásitos transmitidos por el mosquito Anopheles. El paludismo no falciparum (PNF), producido por otras especies de Plasmodium, está menos documentado en la literatura internacional, a pesar de su prevalencia. Objetivos: Describir aspectos clínicos y epidemiológicos de interés para el tratamiento en pacientes ingresados con diagnóstico de PNF importado, y determinar la relación existente entre la respuesta al tratamiento y otras variables. Métodos: Se realizó un estudio transversal analítico de 89 pacientes adultos con PNF importado, ingresados en el Departamento de Medicina del Instituto de Medicina Tropical Pedro Kourí, entre enero de 1997 a diciembre de 2017. Se determinó la pauta de profilaxis y tratamiento según los criterios de las guías publicadas y los fármacos disponibles en Cuba, y la definición de paludismo complicado según la OMS en 2003. Hubo respuesta demorada al tratamiento, cuando el paciente demoraba más de 7 días en negativizar la gota gruesa. Resultados: Predominaron los pacientes del sexo masculino, y una media de edad de 37,2 años. El 55,1 por ciento de los pacientes provenía de la región de las Américas y en el 85,4 por ciento se aisló Plasmodium vivax. La respuesta al tratamiento fue excelente con los esquemas combinados utilizados a base de cloroquina. Fue significativa la relación existente entre la demorada respuesta al tratamiento con la gravedad del cuadro clínico y el estado no inmune de los pacientes. Conclusiones: El PNF es una importante causa de paludismo importado en pacientes provenientes de áreas endémicas, fundamentalmente de América. Se distingue por parasitemias bajas, un cuadro clínico caracterizado por fiebre, escalofríos, cefaleas y evolución hacia cuadros no complicados. La cloroquina fue el medicamento de elección, aunque la repuesta demorada al tratamiento no justifica su suspensión o variación(AU)

Introduction: Malaria is a potentially fatal acute febrile illness caused by parasites transmitted by the Anopheles mosquito. Non-falciparum malaria (NFM), caused by other Plasmodium species, is less documented in the international literature, despite its prevalence. Objectives: To describe clinical and epidemiological aspects of interest for the treatment of patients hospitalized with a diagnosis of imported NFM, and to determine the relationship between response to treatment and other variables. Methods: It was conducted an analytical cross-sectional study of 89 adult patients with imported NFM, admitted to the Department of Medicine of the Institute of Tropical Medicine Pedro Kourí, between January 1997 to December 2017. The prophylaxis and treatment guideline was determined according to the published guidelines and drugs available in Cuba, and the definition of severe malaria by WHO in 2003. There was delayed response to treatment when the patient took more than 7 days to become negative for thick blood smear. Results: Patients were predominantly male, with a mean age of 37.2 years. Plasmodium vivax was isolated in 85.4 percent of the patients and 55.1 percent were from the Americas region. The response to treatment was excellent with the chloroquine-based combination regimens used. The relationship between the delayed response to treatment and the severity of the clinical picture and the non-immune status of the patients was significant. Conclusions: NFM is an important cause of imported malaria in patients from endemic areas, mainly from the Americas. It is characterized by low parasitemia, clinical manifestations of fever, chills, headache and evolution towards uncomplicated symptoms. Chloroquine was the drug of choice, although the delayed response to treatment does not justify its suspension or variation(AU)

Four Times of Relapse of Plasmodium vivax Malaria Despite Primaquine Treatment in a Patient with Impaired Cytochrome P450 2D6 Function.

Plasmodium vivax exhibits dormant liver-stage parasites, called hypnozoites, which can cause relapse of malaria. The only drug currently used for eliminating hypnozoites is primaquine. The antimalarial properties of primaquine are dependent on the production of oxidized metabolites by the cytochrome P450 isoenzyme 2D6 (CYP2D6). Reduced primaquine metabolism may be related to P. vivax relapses. We describe a case of 4 episodes of recurrence of vivax malaria in a patient with decreased CYP2D6 function. The patient was 52-year-old male with body weight of 52 kg. He received total gastrectomy and splenectomy 7 months before the first episode and was under chemotherapy for the gastric cancer. The first episode occurred in March 2019 and each episode had intervals of 34, 41, and 97 days, respectively. At the first and second episodes, primaquine was administered as 15 mg for 14 days. The primaquine dose was increased with 30 mg for 14 days at the third and fourth episodes. Seven gene sequences of P. vivax were analyzed and revealed totally identical for all the 4 samples. The CYP2D6 genotype was analyzed and intermediate metabolizer phenotype with decreased function was identified.

Cryptic erythrocytic infections in Plasmodium vivax, another challenge to its elimination.

Human malaria caused by Plasmodium vivax infection (vivax malaria) is a major global health issue. It is the most geographically widespread form of the disease, accounting for 7 million annual clinical cases, the majority of cases in America and Asia and an estimation of over 2.5 billion people living under risk of infection. The general perception towards vivax malaria has shifted recently, following a series of reports, from being viewed as a benign infection to the recognition of its potential for more severe manifestations including fatal cases. However, the underlying pathogenic mechanisms of vivax malaria remain largely unresolved. Asymptomatic carriers of malaria parasites are a major challenge for malaria elimination. In the case of P. vivax, it has been widely accepted that the only source of cryptic parasites is hypnozoite dormant stages. Here, we will review new evidence indicating that cryptic erythrocytic niches outside the liver, in particular in the spleen and bone marrow, can represent a major source of asymptomatic infections. The origin of such parasites is being controversial and many key gaps in the knowledge of such infections remain unanswered. Yet, as parasites in these niches seem to be sheltered from immune response and antimalarial drugs, research on this area should be reinforced if elimination of malaria is to be achieved. Last, we will glimpse into the role of reticulocyte-derived exosomes, extracellular vesicles of endocytic origin, as intercellular communicators likely involved in the formation of such cryptic erythrocytic infections.

Basic Research of Plasmodium vivax Biology Enabling Its Management as a Clinical and Public Health Problem.

The emerging understanding of Plasmodium vivax as an infection seated in extravascular spaces of its human host carries fundamentally important implications for its management as a complex clinical and public health problem. This progress begins to reverse decades of neglected research borne of the false dogma of P. vivax as an intrinsically benign and inconsequential parasite. This Review provides real world context for the on-going laboratory explorations of the molecular and cellular events in the life of this parasite. Chemotherapies against the latent reservoir impose extraordinarily complex and difficult problems of science and medicine, but great strides in studies of the biology of hepatic P. vivax promise solutions. Fundamental assumptions regarding the interpretation of parasitaemia in epidemiology, clinical medicine, and public health are being revisited and reassessed in light of new studies of P. vivax cellular/molecular biology and pathogenesis. By examining these long overlooked complexities of P. vivax malaria, we open multiple new avenues to vaccination, chemoprevention, countermeasures against transmission, epidemiology, diagnosis, chemotherapy, and clinical management. This Review expresses how clarity of vision of biology and pathogenesis may rationally and radically transform the multiple means by which we may combat this insidiously harmful infection.

Transmission-blocking compound candidates against Plasmodium vivax using P. berghei as an initial screening

BACKGROUND Different strategies for improvement of malaria control and elimination are based on the blockage of malaria parasite transmission to the mosquito vector. These strategies include the drugs that target the plasmodial sexual stages in humans and the early developmental stages inside mosquitoes. OBJECTIVES Here we tested Malaria Box compounds in order to evaluate their activity against male and female gametocytes in Plasmodium berghei, mosquito infection in P. vivax and ookinete formation in both species. METHODS/FINDINGS The membrane feeding assay and the development of ookinetes by a 24 h ex vivo culture and the ookinete yield per 1000 erythrocytes were used to test transmission-blocking potential of the Malaria Box compounds in P. vivax. For P. berghei we used flow cytometry to evaluate male and female gametocyte time course and fluorescence microscopy to check the ookinete development. The two species used in this study showed similar results concerning the compounds' activity against gametocytes and ookinetes, which were different from those in P. falciparum. In addition, from the eight Malaria Box compounds tested in both species, compounds MMV665830, MMV665878 and MMV665941 were selected as a hit compounds due the high inhibition observed. CONCLUSION Our results showed that P. berghei is suitable as an initial screening system to test compounds against P. vivax.

Plasmodium Vivax Malaria: Usual Illness with Dysregulated Immune Profile.

Afebrile Plasmodium vivax disease is believed to be extremely rare; and so is the association of a secondary immune thrombocytopenia due to Plasmodiun vivax malaria. This is a case of malaria presenting in an atypical manner. A middle aged male (31 years) came with occasional bleeding around gums, small petechial haemorrhages over chest and abdomen, and blood in stools for a few months, but no fever. In addition, the cervical lymph nodes were slightly enlarged. Spleen was 3 cm below costal margin. Platelets were found to have markedly decreased with clusters of megakaryocytes in the bone marrow. A possibility of Immune thrombocytopenic purpura was considered and immunoglobulin started intravenously, however platelet counts remained low. Later, in a follow up smear, trophozoites of P. vivax were discovered. Antimalarial drugs (Artesunate) were administrated for the patient along with IV immunoglobulins, to which he responded. It was revealed by flow cytometry that the ratio of helper to cytotoxic cells was reversed (0.9). This highlighted a rare case of afebrile malaria in association with immune dysregulation. Accordingly, malaria, though uncommon, could trigger immune thrombocytopenia.

Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax.

Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select Plasmodium falciparum and Plasmodium vivax proteins as potential drug targets and analyzed them using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among the seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation. Epirubicin was shown to be potent in vitro against sensitive and multidrug-resistant P. falciparum strains and P. vivax field isolates in the nanomolar range, as well as being effective against an in vivo murine model of Plasmodium yoelii Transmission-blocking activity was observed for epirubicin in vitro and in vivo Finally, using yeast-based haploinsufficiency chemical genomic profiling, we aimed to get insights into the mechanism of action of epirubicin. Beyond the target predicted in silico (a DNA gyrase in the apicoplast), functional assays suggested a GlcNac-1-P-transferase (GPT) enzyme as a potential target. Docking calculations predicted the binding mode of epirubicin with DNA gyrase and GPT proteins. Epirubicin is originally an antitumoral agent and presents associated toxicity. However, its antiplasmodial activity against not only P. falciparum but also P. vivax in different stages of the parasite life cycle supports the use of this drug as a scaffold for hit-to-lead optimization in malaria drug discovery.

Cost-Effectiveness Analysis of Sex-Stratified Plasmodium vivax Treatment Strategies Using Available G6PD Diagnostics to Accelerate Access to Radical Cure.

Tafenoquine has been licensed for the single-dose radical cure of Plasmodium vivax in adults; however, it is only recommended in patients with > 70% of normal glucose-6-phosphate dehydrogenase (G6PD) activity. Because this may hinder widespread use, we investigated sex-based treatment strategies in which all adult patients are tested with a qualitative G6PD rapid diagnostic test (RDT). Glucose-6-phosphate dehydrogenase normal males are prescribed tafenoquine in all three strategies, whereas G6PD normal females are prescribed either a low-dose 14-day primaquine regimen (PQ14, total dose 3.5 mg/kg) or a high-dose 7-day primaquine regimen (PQ7, total dose 7 mg/kg), or referred to a healthcare facility for quantitative G6PD testing before prescribing tafenoquine. Patients testing G6PD deficient are prescribed a weekly course of primaquine for 8 weeks. We compared the cost-effectiveness of these three strategies to usual care in four countries using a decision tree model. Usual care in Ethiopia does not include radical cure, whereas Afghanistan, Indonesia, and Vietnam prescribe PQ14 without G6PD screening. The cost per disability-adjusted life-year (DALY) averted was expressed through incremental cost-effectiveness ratios (ICERs). Compared with usual care, the ICERs for a sex-based treatment strategy with PQ7 for females from a healthcare provider perspective were $127 per DALY averted in Vietnam, $466 in Ethiopia, $1,089 in Afghanistan, and $4,443 in Indonesia. The PQ14 and referral options cost more while averting fewer DALYs than PQ7. This study provides an alternative cost-effective mode of rolling out tafenoquine in areas where initial testing with only a G6PD RDT is feasible.

Case Report: Primaquine Failure for Radical Cure of Plasmodium vivax Malaria in Gambella, Ethiopia.

Failures of primaquine for the treatment of relapsed Plasmodium vivax malaria is a serious challenge to malaria elimination in Ethiopia, where P. vivax accounts for up to 40% of malaria infections. We report here occurrence of a total of 15 episodes of primaquine treatment failure for radical cure in three historical P. vivax malaria patients from Gambella, Ethiopia, during 8-16 months of follow-up in 1985-1987. The total primaquine doses received were 17.5 mg/kg, 25.8 mg/kg, and 35.8 mg/kg, respectively. These total doses are much higher than in previous reports of patients with treatment failure in Ethiopia and East Africa. The possibility of new infection was excluded for these cases as the treatment and follow-up were carried out in Addis Ababa, a malaria-free city. Recrudescences were unlikely, considering the short duration pattern of the recurrences. The cytochrome P450 2D6 (CYP2D6) status for these patients is unknown, but polymorphisms have been described in Ethiopia and may have contributed to primaquine treatment failures. It is suggested that further studies be carried out in Ethiopia to determine the prevalence and distribution of primaquine treatment failures in different ethnic groups, considering the impact of CYP2D6 polymorphisms and the potential value of increasing the primaquine dose to avoid relapse.

Malaria epidemiology in Kobeni department, southeastern Mauritania from 2015 to 2017.

BACKGROUND: Plasmodium falciparum malaria is endemic in the southern sahelian zone of Mauritania where intense internal and trans-border human and livestock movement occurs. The risk of importation and spread of drug-resistant parasites need to be regularly assessed in this region. The objective of the study was to assess the recent malaria situation near the Mauritania-Mali border. METHODS: Between February 2015 and December 2017, patients with fever or history of fever during the previous 48 h, presenting at the health centre of Kobeni city, were screened for malaria using a rapid diagnostic test (RDT) and microscopic examination of blood smears. The diagnosis was later confirmed by PCR. Cohen's kappa statistics was used to estimate the degree of agreement between diagnostic methods. Fisher's exact test was used to compare proportions. The odds ratio was calculated to measure the association between the use of bed nets and malaria infection. RESULTS: A total of 2326 febrile patients (mean age, 20.2 years) were screened for malaria. The presence of malaria parasites was detected by RDT and microscopy in 53.0% and 49.3% of febrile patients, respectively, and was confirmed by PCR in 59.7% (45 missing data). Of 1361 PCR-positive samples, 1205 (88.5%) were P. falciparum, 47 (3.5%) P. vivax, and 99 (7.3%) P. falciparum-P. vivax mixed infection. Malaria transmission occurred mostly during and shortly after the rainy season. The annual rainfall was relatively low in 2016 (267 mm) and 2017 (274 mm), compared to 2015 (448 mm), and coincided with a decline in malaria prevalence in 2016-2017. Although 71.8% of febrile patients reported to possess at least one bed net in the household in our questionnaire, its reported use was not protective against malaria infection (odds ratio: 1.1, 95% CI: 0.91-1.32). CONCLUSIONS: Our study confirmed that P. falciparum is the dominant species in the sahelian zone and that malaria transmission is seasonal and associated with rainfall in this zone. The application of the current national policy based on rapid and reliable malaria diagnosis, case management with artemisinin-based combination therapy, intermittent preventive treatment for pregnant women, distribution and use of long-lasting insecticide impregnated bed nets, and the planned introduction of seasonal malaria chemoprevention for all children under 6 years old is expected to sustainably reduce malaria transmission in this zone.

Hemolytic Dynamics of Weekly Primaquine Antirelapse Therapy Among Cambodians With Acute Plasmodium vivax Malaria With or Without Glucose-6-Phosphate Dehydrogenase Deficiency.

BACKGROUND: Hemoglobin (Hb) data are limited in Southeast Asian glucose-6-phosphate dehydrogenase (G6PD) deficient (G6PD-) patients treated weekly with the World Health Organization-recommended primaquine regimen (ie, 0.75 mg/kg/week for 8 weeks [PQ 0.75]). METHODS: We treated Cambodians who had acute Plasmodium vivax infection with PQ0.75 and a 3-day course of dihydroartemisinin/piperaquine and determined the Hb level, reticulocyte count, G6PD genotype, and Hb type. RESULTS: Seventy-five patients (male sex, 63) aged 5-63 years (median, 24 years) were enrolled. Eighteen were G6PD deficient (including 17 with G6PD Viangchan) and 57 were not G6PD deficient; 26 had HbE (of whom 25 were heterozygous), and 6 had α-/ß-thalassemia. Mean Hb concentrations at baseline (ie, day 0) were similar between G6PD deficient and G6PD normal patients (12.9 g/dL [range, 9‒16.3 g/dL] and 13.26 g/dL [range, 9.6‒16 g/dL], respectively; P = .46). G6PD deficiency (P = <.001), higher Hb concentration at baseline (P = <.001), higher parasitemia level at baseline (P = .02), and thalassemia (P = .027) influenced the initial decrease in Hb level, calculated as the nadir level minus the baseline level (range, -5.8-0 g/dL; mean, -1.88 g/dL). By day 14, the mean difference from the day 7 level (calculated as the day 14 level minus the day 7 level) was 0.03 g/dL (range, -0.25‒0.32 g/dL). Reticulocyte counts decreased from days 1 to 3, peaking on day 7 (in the G6PD normal group) and day 14 (in the G6PD deficient group); reticulocytemia at baseline (P = .001), G6PD deficiency (P = <.001), and female sex (P = .034) correlated with higher counts. One symptomatic, G6PD-deficient, anemic male patient was transfused on day 4. CONCLUSIONS: The first PQ0.75 exposure was associated with the greatest decrease in Hb level and 1 blood transfusion, followed by clinically insignificant decreases in Hb levels. PQ0.75 requires monitoring during the week after treatment. Safer antirelapse regimens are needed in Southeast Asia. CLINICAL TRIALS REGISTRATION: ACTRN12613000003774.

Acute kidney injury due to acute cortical necrosis following vivax malaria.

Malaria is a parasitic infection of global importance but has a high prevalence in the developing countries. Renal failure is a common complication of severe Plasmodium falciparum malaria and has been reported in up to 40% of all cases. Acute kidney injury (AKI), however, is not commonly associated with Plasmodium vivax infection. In those patients who develop AKI following P. vivax infection, the cause is commonly attributed to mixed undiagnosed falciparum infection or coexistent sepsis, dehydration, or hypotension. Infrequently, an association of P. vivax infection with thrombotic microangiopathy (TMA) has been reported. The purpose of this report is to describe renal failure due to TMA following malaria caused by P. vivax. A 24-year-old female presented with a history of fever and jaundice of two weeks duration followed by progressive oliguria and swelling of the face and feet five days after the onset of fever. The evaluation revealed normal blood pressure, anemia, thrombocytopenia, azotemia, unconjugated hyperbilirubinemia with mildly elevated transaminases, and elevated lactate dehydrogenase. Peripheral smear was positive for P. vivax, and schistocytes were seen. She was given intravenous artesunate followed by oral primaquine for 14 days. Urine examination showed proteinuria and microscopic hematuria. She remained oliguric and dialysis dependent, and her kidney biopsy revealed patchy cortical necrosis involving 40% of sampled cortex with widespread fibrinoid necrosis of the vessel wall, red blood cell fragmentation, and luminal thrombotic occlusion. Hemodialysis was discontinued after three weeks when there was the improvement of renal function over time, and her serum creatinine decreased to 2.2 mg/dL by six weeks. Patients with P. vivax malaria developing renal failure may have TMA. Renal biopsy, if performed early in the course of the disease, may identify TMA and institution of plasma exchange in such patients could help in early recovery.