Frequency of Electrocardiographic Alterations and Pericardial Effusion in Patients With Uncomplicated Malaria.

Studies have proposed that malaria may lead to electrocardiographic (ECG) changes and pericardial inflammation. We aimed to investigate the frequency of ECG alterations, determined by ECG and Holter monitoring, and pericardial effusion in patients with malaria infection. We performed a prospective observational study of adult patients with uncomplicated malaria in Amazonas, Brazil. Peripheral blood smears, ECG, and bedside echocardiography were conducted before antimalarial treatment and repeated at follow-up after completed treatment. We evaluated the diagnostic value of PR-segment depression, PR-segment elevation, and Spodick's sign for detecting pericardial effusion. A subset of patients underwent Holter monitoring at baseline. Among 98 cases of uncomplicated malaria (55% men; mean age 40 years; median parasite density 1,774/µl), 75 had Plasmodium vivax, 22 Plasmodium falciparum, and 1 had mixed infection. At baseline, 17% (n = 17) had PR-segment depression, 12% (n = 12) PR-segment elevation, 3% (n = 2) Spodick's sign, and the prevalence of pericardial effusion was 9% (n = 9). ECG alterations had sensitivities of 22% to 89% and specificities of 88% to 100% for detecting pericardial effusion at baseline. PR-segment depression had the best accuracy (sensitivity 89%, specificity 90%). Of the 25 patients, 4 patients who did not have pericardial effusion, displayed nonsustained ventricular tachycardia, determined by Holter monitoring (median duration 43 hours). Follow-up examination data were obtained for 71 patients (median 31 days), for whom PR-segment depression, elevation, and pericardial effusion had reduced significantly (p <0.05). In conclusion, our findings suggest that ECG alterations may be useful to detect pericardial effusion in malaria and that these findings decrease after completed antimalarial treatment.

Cardiopulmonary alterations by ultrasound in a patient with uncomplicated mixed malaria infection: a case report from the Amazon Basin.

BACKGROUND: Information on cardiopulmonary complications in clinical malaria is sparse and diagnosis may be difficult in resource-limited areas due to lack of proper diagnostic tools and access to medical care. A case of pericardial effusion and pulmonary alterations assessed by ultrasound in a patient with uncomplicated mixed malaria infection is described. CASE PRESENTATION: A previously healthy 23-year-old male from the Amazon Basin was diagnosed with mixed infection of Plasmodium vivax and Plasmodium falciparum by peripheral blood smear. The patient presented with mild malaria symptoms without signs of severe malaria, but reported moderate chest pain and shortness of breath. Laboratory analyses revealed thrombocytopenia and anemia. The electrocardiogram had PR depressions and bedside ultrasound of the cardiopulmonary system showed pericardial effusion (18 mm) accompanied by multiple B-lines in the lungs, identified as vertical artifacts extending from the pleural line. Cardiac biomarkers were normal. The patient was treated according to national guidelines for malaria and suspected pericarditis, respectively. At follow-up on day 5, the pericardial effusion (9mm) and B-lines had markedly decreased. By day 21 the patient was asymptomatic, had completed the treatment, and the electrocardiogram and ultrasound findings had normalized. CONCLUSIONS: This case report highlight the usefulness of bedside ultrasound to identify cardiopulmonary involvement in patients with uncomplicated malaria and relevant symptoms.

Association of Malaria Infection During Pregnancy With Head Circumference of Newborns in the Brazilian Amazon.

Importance: Malaria during pregnancy is associated with adverse events for the fetus and newborn, but the association of malaria during pregnancy with the head circumference of the newborn is unclear. Objective: To investigate the association of malaria during pregnancy with fetal head growth. Design, Setting, and Participants: Two cohort studies were conducted at the general maternity hospital of Cruzeiro do Sul (Acre, Brazil) in the Amazonian region. One cohort study prospectively enrolled noninfected and malaria-infected pregnant women who were followed up until delivery, between January 2013 and April 2015. The other cohort study was assembled retrospectively using clinical and malaria data from all deliveries that occurred between January 2012 and December 2013. Data analyses were conducted from January to August 2017 and revised in November 2018. Clinical data from pregnant women and anthropometric measures of their newborns were evaluated. A total of 600 pregnant women were enrolled through volunteer sampling (prospective cohort study), and 4697 pregnant women were selected by population-based sampling (retrospective cohort study). After application of exclusion criteria, data from 251 (prospective cohort study) and 232 (retrospective cohort study) malaria-infected and 158 (prospective cohort study) and 3650 (retrospective cohort study) noninfected women were evaluated. Exposure: Malaria during pregnancy. Main Outcomes and Measures: The primary end point was the incidence of altered head circumference in newborns delivered from malaria-infected mothers compared with that from noninfected mothers. Secondary end points included measures of placental pathology relative to newborn head circumference. Results: In total, 4291 maternal-child pairs were analyzed. Among 409 newborns in the prospective cohort study, the mothers of 251 newborns had malaria during pregnancy, infected with Plasmodium vivax, Plasmodium falciparum, or both. Among 3882 newborns in the retrospective cohort study, 232 were born from mothers that had malaria during pregnancy. The prevalence of newborns with a small head (19 [30.7%] in the prospective cohort study and 30 [36.6%] in the retrospective cohort study) and the prevalence of microcephaly among newborns (5 [8.1%] in the prospective cohort study and 6 [7.3%] in the retrospective cohort study) were higher among newborns from women infected with P falciparum during pregnancy. Multivariate logistic regression analyses revealed that P falciparum infection during pregnancy represented a significant risk factor for the occurrence of small head circumference in newborns (prospective cohort study: odds ratio, 3.15; 95% CI, 1.52-6.53; P = .002; retrospective cohort study: odds ratio, 1.91; 95% CI, 1.21-3.04; P = .006). Placental pathologic findings corroborated this association, with more syncytial nuclear aggregates and inflammatory infiltrates occurring in placentas of newborns born with decreased head circumference. Conclusions and Relevance: This study indicates that falciparum malaria during pregnancy is associated with decreased head circumference in newborns, which is in turn associated with evidence of placental malaria.

Association between anthropometry-based nutritional status and malaria: a systematic review of observational studies.

BACKGROUND: Multiple studies in various parts of the world have analysed the association of nutritional status on malaria using anthropometric measures, but results differ due to the heterogeneity of the study population, species of the parasite, and other factors involved in the host and parasite relationship. The aim of this study was to perform a systematic review on the inter-relationship of nutritional status based on anthropometry and malarial infection. METHODS: Two independent reviewers accessed the MEDLINE and LILACS databases using the same search terms related to malaria and anthropometry. Prospective studies associating anthropometry and malaria (incidence or severity) were selected. References from the included studies and reviews were used to increase the review sensitivity. Data were extracted using a standardized form and the quality of the prospective studies was assessed. Selected articles were grouped based on exposures and outcomes. RESULTS: The search identified a total of 1688 studies: 1629 from MEDLINE and 59 from LILACS. A total of 23 met the inclusion criteria. Five additional studies were detected by reading the references of the 23 included studies and reviews, totaling 28 studies included. The mean sample size was 662.1 people, ranging from 57 to 5620. The mean follow-up was 365.8 days, ranging from 14 days to 1 year and 9 months, and nine studies did not report the follow-up period. Prospective studies assessing the relationship between malaria and malnutrition were mostly carried out in Africa. Of the 20 studies with malarial outcomes, fifteen had high and five had average quality, with an average score of 80.5 %. Most anthropometric parameters had no association with malaria incidence (47/52; 90.4 %) or parasite density (20/25; 80 %). However, the impact of malnutrition was noted in malaria mortality and severity (7/17; 41.2 %). Regarding the effects of malaria on malnutrition, malaria was associated with very few anthropometric parameters (8/39; 20.6 %). CONCLUSIONS: This systematic review found that most of the evidence associating malaria and malnutrition comes from P. falciparum endemic areas, with a significant heterogeneity in studies' design. Apparently malnutrition has not a great impact on malaria morbidity, but could have a negative impact on malaria mortality and severity. Most studies show no association between malaria and subsequent malnutrition in P. falciparum areas. In Plasmodium vivax endemic areas, malaria was associated with malnutrition in children. A discussion among experts in the field is needed to standardize future studies to increase external validity and accuracy.

New Concepts in Malaria Pathogenesis: The Role of the Renin-Angiotensin System.

Malaria is a worldwide health problem leading the death of millions of people. The disease is induced by different species of protozoa parasites from the genus Plasmodium. In humans, Plasmodium falciparum is the most dangerous species responsible for severe disease. Despite all efforts to establish the pathogenesis of malaria, it is far from being fully understood. In addition, resistance to existing drugs has developed in several strains and the development of new effective compounds to fight these parasites is a major issue. Recent discoveries indicate the potential role of the renin-angiotensin system (RAS) in malaria infection. Angiotensin receptors have not been described in the parasite genome, however several reports in the literature suggest a direct effect of angiotensin-derived peptides on different aspects of the host-parasite interaction. The aim of this review is to highlight new findings on the involvement of the RAS in parasite development and in the regulation of the host immune response in an attempt to expand our knowledge of the pathogenesis of this disease.

Submicroscopic infection of placenta by Plasmodium produces Th1/Th2 cytokine imbalance, inflammation and hypoxia in women from north-west Colombia.

BACKGROUND: A large-scale study was set up in order to study the epidemiology, clinical aspects, and immunopathology of gestational and placental malaria in north-west Colombia. In this region, recent reports using a qPCR technique, confirmed frequencies of infection, by Plasmodium falciparum or Plasmodium vivax, up to 45%. Given the high rates of infection observed both in mother and placenta, a first exploratory study was proposed in order to characterize the effect on the inflammation status, tissue damage and hypoxia in Plasmodium spp. infected placentas. METHODS: A descriptive, prospective, cross-sectional design was applied to pregnant women with (PM+) and without (PM-) placental malaria. Messenger RNA expression of Fas, FasL; COX-1, COX-2, HIF, VEGF, and the cytokines IL-2, IL-4, IL-10, IFN-γ and TNF, were measured in peripheral and placental blood using a quantitative PCR. The percentage of apoptotic cells was determined with a TUNEL assay. RESULTS: In total 50 placentas were studied: 25 were positive for submicroscopic infection and 25 were negative for Plasmodium infection. Expression of IL-4 and IL-10 was observed high in placental tissue of PM+, while IL-2 was high in peripheral blood of the same group. Expression of TNF and IFNγ in peripheral blood of the PM + group was high. Similarly, the apoptotic index and Fas expression were significantly high in PM+. However, FasL expression was observed low in PM + compared to PM-. Inflammation markers (HIF, VEGF) and hypoxia markers (COX-1, COX-2) were high in the PM + group. CONCLUSION: During placental malaria expression of some pro-inflammatory cytokines is up-regulated and markers of hypoxia and tissue damage are increased in cases of submicroscopic infection.

Specificity of vascular reactivity and altered response in experimental malaria.

OBJECTIVE: Adherence of erythrocytes infected with Plasmodium falciparum (P falciparum) to microvascular endothelial cells (sequestration) is considered to play an important role in parasite virulence and pathogenesis. In this study, we have examined the possibility that there is altered vascular reactivity due to the direct interaction between the parasitized erythrocytes and vascular endothelial cells and that it could be tissue specific. METHOD: Ring preparations of blood vessels from the rabbit carotid and rat aorta were studied using standard organ bath techniques. Dose response curves for phenylephrine (PE) and acetylcholine (Ach)-induced relaxation were constructed in rings pre-contracted with PE. RESULTS: Incubation of rat aortic rings with parasitized blood resulted in a significant (p < 0.05) increase in maximum contractile response to phenylephrine in the rat aortic rings but there was no effect on the rabbit carotid artery. The dose-response curve showed a significant (p < 0.05) left-ward shift following the addition of parasitized blood. Parasitised blood had no effect on baseline in both tissues. Following exposure to parasitized blood, the magnitude of Ach-induced relaxation responses reduced significantly (p < 0.05) in rat aortic rings and (p < 0.05) in rabbit carotid rings; relaxations to acetylcholine was more pronounced in the aortic compared to the carotid rings. CONCLUSIONS: Malaria altered vascular reactivity through an endothelium-dependent mechanism. The regulation of vascular tone by various vasoactive agents following exposure to malaria parasites might be altered in a vessel-specific manner. This may contribute to or exacerbate the abnormal haemodynamics observed in the microcirculation of numerous vascular beds in malaria.

Pattern of humoral immune response to Plasmodium falciparum blood stages in individuals presenting different clinical expressions of malaria.

BACKGROUND: The development of protective immunity against malaria is slow and to be maintained, it requires exposure to multiple antigenic variants of malaria parasites and age-associated maturation of the immune system. Evidence that the protective immunity is associated with different classes and subclasses of antibodies reveals the importance of considering the quality of the response. In this study, we have evaluated the humoral immune response against Plasmodium falciparum blood stages of individuals naturally exposed to malaria who live in endemic areas of Brazil in order to assess the prevalence of different specific isotypes and their association with different malaria clinical expressions. METHODS: Different isotypes against P. falciparum blood stages, IgG, IgG1, IgG2, IgG3, IgG4, IgM, IgE and IgA, were determined by ELISA. The results were based on the analysis of different clinical expressions of malaria (complicated, uncomplicated and asymptomatic) and factors related to prior malaria exposure such as age and the number of previous clinical malaria attacks. The occurrence of the H131 polymorphism of the FcgammaIIA receptor was also investigated in part of the studied population. RESULTS: The highest levels of IgG, IgG1, IgG2 and IgG3 antibodies were observed in individuals with asymptomatic and uncomplicated malaria, while highest levels of IgG4, IgE and IgM antibodies were predominant among individuals with complicated malaria. Individuals reporting more than five previous clinical malaria attacks presented a predominance of IgG1, IgG2 and IgG3 antibodies, while IgM, IgA and IgE antibodies predominated among individuals reporting five or less previous clinical malaria attacks. Among individuals with uncomplicated and asymptomatic malaria, there was a predominance of high-avidity IgG, IgG1, IgG2 antibodies and low-avidity IgG3 antibodies. The H131 polymorphism was found in 44.4% of the individuals, and the highest IgG2 levels were observed among asymptomatic individuals with this allele, suggesting the protective role of IgG2 in this population. CONCLUSION: Together, the results suggest a differential regulation in the anti-P. falciparum antibody pattern in different clinical expressions of malaria and showed that even in unstable transmission areas, protective immunity against malaria can be observed, when the appropriated antibodies are produced.

Endemias e epidemias na Amazônia: malária e doenças emergentes em áreas ribeirinhas do Rio Madeira: um caso de escola / Endemics and epidemics in the Amazon

Após fazer uma análise da evolução da malária na Amazônia brasileira, detalhando em particular a situação em Rondônia e no município de Porto Velho, onde ocorreram episódios dramáticos de epidemias de malária no passado, os autores apresentam o quadro atual da prevalência de malária nas áreas do Vale do Rio Madeira, que sofrerão impactos com a construção das hidrelétricas de Santo Antônio e Jirau, e alertam sobre a situação particular da malária em áreas ribeirinhas. Nessas áreas, observam-se alta incidência de malária vivax e falciparum, a presença de grande número de portadores assintomáticos de parasitas e altas densidades do vetor Anopheles darlingi o ano todo. Esses elementos, associados à provável chegada de migrantes oriundos de áreas não-endêmicas de Rondônia e de outros Estados do país, atraídos pela possibilidade de trabalho nessas hidrelétricas e oportunidades de comércio, lazer, educação e atividades domésticas, criam condições favoráveis à ocorrência de epidemias de malária e de outras doenças tropicais se não forem realizadas intervenções adequadas de controle, em particular no domínio do saneamento.

Immunomodulatory therapy associated to anti-parasite drugs as a way to prevent severe forms of malaria.

Malaria is an important problem of public health. It is estimated that 350 to 500 million clinical cases occur annually, which cause 1.1 and 1.3 million deaths every year. The excessive activation of the immune system plays an important role in the pathogenesis of the disease. The cells of the immune system of Plasmodium-infected individuals not only produce large amounts of cytokines, which have anti-parasite effects, but also participate in the pathogenesis of the severe complications of malaria. A central feature of P. falciparum infection is the sequestration of parasitized erythrocytes within the small vessels of major organs. This involves molecular interactions between antigens of parasitized erythrocytes and host receptors, expressed on the surface of endothelial cells. The increased production of pro-inflammatory cytokines and nitric oxide, followed by the up regulation of endothelial cell adhesion molecules, influences the progression of cerebral lesions. The association of drugs capable of modulating the immune response to anti plasmodial drugs has been evaluated. Antibodies to tumor necrosis factor, pentoxifylline, and thalidomide have been tried for this purpose with variable success. This review submitted this subject to a critical assessment and suggests ways to take advantage of immunomodulatory drugs, associated to anti parasite therapy, to reduce the morbimortality of malaria.

[Clinical profiles of patients with uncomplicated Plasmodum falciparum malaria in northwestern Colombia]. / Perfiles clínicos del paludismo no complicado por Plasmodium falciparum en Córdoba, Colombia.

INTRODUCTION: Few studies describe the clinical presentations of uncomplicated Plasmodium falciparum malaria in the province of Córdoba in an endemic area of northwestern Colombia. OBJECTIVE: Profiles of patients with uncomplicated Plasmodium falciparum malaria were described from two twons of Córdoba, Tierrata and Puerto Libertador, based on clinical, epidemiological and laboratory variables. MATERIALS AND METHODS: Patients were examined according to standard WHO/PAHO protocols for assessment of antimalarial drug efficacy. Clinical data and parasitological information was collected as well. A multiple correspondence multivariate analysis was used to compare the profiles of 127 patients with uncomplicated Plasmodium falciparum malaria. RESULTS: Of the 127 patients,105 completed the 14-day follow-up and 7 had adequate clinical response. Between 80% and 98% of patients exhibited at least one of the most frequent symptoms of uncomplicated malaria, and 80.3% had asthenia as the most frequent symptom. The multivariate analysis grouped the variables into five distinguishable clusters of clinical profiles. These groups showed similarities with the classical clinical descriptions of uncomplicated malaria encountered in the literature. The low frequency of patients with adequate clinical response hampered the association analysis. CONCLUSIONS: In Córdoba, therapeutic failure to chloroquine treatment is high in treating uncomplicated Plasmodium falciparum malaria. Multivariate analysis summarized variables related to epidemiological and clinical aspects and permitted a more objective approach to the interpretation of the findings.

Some aspects of the behavior of the hypothalamus-pituitary-adrenal axis in patients with uncomplicated Plasmodium falciparum malaria: Cortisol and dehydroepiandrosterone levels.

We studied the behavior of cortisol and dehydroepiandrosterone (DHEA) in 24 patients with uncomplicated Plasmodium falciparum malaria of the Evandro Chagas Institute, Belém, Pará, Brazil. The patients were evaluated before treatment (Day 0), 24h after the beginning of medication (Day 1) and on Day 8 of follow-up (Day 7). Steroid levels were correlated with parasitemia, temperature and time of the disease. The levels of these hormones were found to be significantly higher on Day 0 than on Day 7, showing no correlation with parasitemia or temperature, but temperature had a positive effect on the correlation between cortisol and dehydroepiandrosterone. Cortisol was not correlated with the time of disease, but a significant negative correlation was observed between DHEA and time of disease on Day 7, suggesting a decline in the adrenal reserve of this steroid. In conclusion, an increase in cortisol and dehydroepiandrosterone is observed in patients with falciparum malaria, with these levels declining with decreasing parasitemia. The finding that temperature interfered with the correlation between cortisol and dehydroepiandrosterone suggests a common mechanism for the activation of these hormones in malaria.

Hemoglobin levels related to days of illness, race, and Plasmodium species in Colombian patients with uncomplicated malaria.

Prevalence of malaria-related anemia in disease-endemic regions of the American continents has been poorly studied. We describe the relationships between hemoglobin level and race, Plasmodium species, and days of illness in 150 Colombian patients with uncomplicated malaria diagnosed by thick blood smear. Hemoglobin was measured at admission and a standardized questionnaire was used to determine days of illness and other variables. Associations between hemoglobin and the variables were estimated and adjusted according to the other covariates using regression analysis. Plasmodium falciparum and P. vivax were found in similar proportions and mild anemia was present in 50% of the patients. Volunteers were classified as Afro-Colombians (61%) and non-Afro-Colombians (39%). An inverse relationship between hemoglobin and days of illness was identified, and a statistical interaction was found between race and P. falciparum infection in determining the hemoglobin concentration. These observations could guide the design of research to better understand malarial anemia.

Calcium homeostasis and signaling in the blood-stage malaria parasite.

The nature of the mechanisms underlying Ca2+ homeostasis in malaria parasites has puzzled investigators for almost two decades. This review summarizes the current knowledge about Ca2+ homeostasis in Plasmodium spp and highlights some key aspects of this process that are specific to this parasite. Plasmodium spp are exposed, during their intracellular stage, not to the usual millimolar concentrations of Ca2+ found in body fluids, but rather to the very low Ca2+ environment of the host cell cytoplasm. Two crucial questions then arise: (1) how is Ca2+ homeostasis achieved by these protozoa; and (2) do they use Ca2+-based signaling pathways? By critically reviewing the recent literature in the field, Célia Garcia here provides at least some partial answers to these questions.

Severe falciparum malaria with hyperparasitaemia: management without exchange blood transfusion.

The risk of complication in falciparum malaria is associated with parasite load. Drug therapy alone may be insufficient, and blood exchange transfusion is indicated when more than 10% of erythrocytes are parasitized with concurrent pulmonary, renal, cerebral or haemostatic complications; without complications, when the parasitized erythrocytes exceed 30%. The successful use of conventional malaria therapy without exchange transfusion in a young woman with severe falciparum malaria is reported.

[Changes in gastric mucosa in acute malaria]. / Alteraciones de la mucosa gástrica en malaria aguda.

A high incidence rate of Malaria is observed at Bolívar state (Venezuela) and, beside classic acute symptomatology, we have observed gastric symptoms like epigastralgia, anorexia, nausea and vomits. The scope of this study is to establish changes of gastric mucosa related to Plasmodium infection, using macro and microscopic technics. One hundred both sex patients with Malaria diagnosis done with thick drop technic and gastric symptomatology were studied in our department from March 1990 to February 1991. The esophagus, stomach and duodenum of all patients were evaluated with upper digestive tract endoscopy and still photographs, and biopsies of fundus, body and antrum were taken, fixed in 10% formaldehyde and stained with hematoxylin-eosine method. P. falciparum was found in 52 cases, P. vivax in 39 and 9 infected with both, most of patients complained of shivering fever, epigastralgia (76%), nausea and vomits (72%), tartness (25%) and burning pain (21%). Mucosal edema and congestion (gastritis) were the endoscopic findings in 88% of cases, usually located at antrum (67%) and fundus (33%). The microscopic findings were: mucosal edema (90%), superficial bleeding (87%), microthrombosis (60%), gastric atrophy (40%) and intestinal metaplasia (8%). Acute gastric symptomatology we have observed in patients with acute malaria my be due to microthrombosis and arteriolar occlusion, leading to ischemic changes and mucosal edema. These pathophysiological changes explain most of upper digestive tract symptoms in acute malaria, particularly when agent is P. falciparum. We have not found related papers in bibliography.

[Pulmonary involvement in malaria (review)]. / Comprometimento pulmonar na malária (revisão).

Pulmonary involvement occurs in 3 to 10% of the cases of Plasmodium falciparum malaria and represents the most serious complication of this infection, with a lethality of about 70%. The understanding of its pathogenesis is still very fragmentary, however it is recognized that activation of the immune system by antigens released by the parasite plays an important role in the induction and worsening of lung damage. Capillary endothelial cells, which control the flux of fluids to the interstitial space, appear to be the most involved structure. These cells are activated by cytokines, produced by lymphocytes and macrophages during the immune response, and express receptors and molecules of adhesion, allowing for sequestration of parasitized erythrocytes and adherence of cells, which will produce locally inflammatory mediators. The inflammatory reaction and lesion of endothelial cells that ensue, together with the hemodynamic alterations induced by the capillary blockade due to the sequestration of parasitized erythrocytes and leukocytes, cause alterations of the vascular permeability and transfer of liquid to intertitial space and alveoles. Severe cases are clinically expressed by a picture of Adult Respiratory Distress Syndrome. The clinical manifestations of pulmonary involvement may start suddenly at any time during the course of malaria, even after disappearance of circulating parasites. The inducing factors are unknown. Hyperparasitemia, renal failure and pregnancy are predisposing factors. The prognosis will depend on how fast the diagnosis is established and convenient treatment initiated. If parasites are present they shall be treated with schizonticidal drugs, hemodynamic parameters continuously evaluated, preferably through a Swam-Ganz catheter. Appropriate oxygen supply and fluid balance have to be warranted. Other complications of malaria, frequently associated to the pulmonary involvement, need special attention and proper treatment. A better understanding of the pathogenesis of lung damage associated to malaria will certainly help to improve treatment and reduce morbidity and mortality.