Severe Falciparum Malaria Patients Research Articles

High Plasma Levels of Neopterin Are Associated with Increased Mortality among Children with Severe Malaria in Benin.

Among the barriers to accessing adequate treatment and high-level monitoring for malaria febrile patients is the lack of effective prognostic markers. Neopterin, which is a marker of monocyte/macrophage activation, was found have increased during severe malaria. In this study, we used quantitative ELISA in order to assess the levels of plasma soluble neopterin in 151 patients from a cohort of Beninese children with severe malaria. We evaluated the prognostic accuracy of this molecule in order to predict the outcome of the disease. Our results show that neopterin levels were not significantly different between patients with different forms of severe malaria, including severe non-cerebral malaria (SNCM) and cerebral malaria (CM). However, the levels of this molecule were found to be higher in patients with severe malarial anemia (SMA) among both CM and SNCM cases (p-value = 0.02). Additionally, the levels of this molecule were found to be higher in patients who died from these pathologies compared to those who survived among the two clinical groups (p-value < 0.0001) and within the same group (p-value < 0.0001 for the CM group, p-value = 0.0046 for the SNCM group). The AUC-ROC for fatality among all the severe cases was 0.77 with a 95%CI of (0.69-0.85). These results suggest that plasma neopterin levels constitute a potential biomarker for predicting fatality among severe falciparum malaria patients.

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.

Electrocardiographic features in children with severe falciparum malaria at the University College Hospital, Ibadan.

Introduction:The high burden of Malaria morbidity and mortality in children is due to its potential to cause multi-organ dysfunction. There is however limited information on the specific electrocardiographic features in falciparum malaria in paediatric age group.Aim:To investigate the electrocardiographic (ECG) features in children with (complicated) severe falciparum malaria (SM) and acute uncomplicated malaria (AUM) at the University College Hospital, Ibadan.Methods:This was a comparative cross-sectional study conducted among 398 children with symptomatic and confirmed Plasmodium falciparum malaria and apparently healthy controls. The frequencies of ECG features were described and compared among these children.Results:The prevalence of ECG abnormality was 79.7% and 63.2% in Severe Malaria SM and Acute uncomplicated malaria AUM patients, respectively. Sinus tachycardia was significantly more frequent in SM than AUM and control groups (p <0.001). The risk of an ECG abnormality was about three times higher in SM than healthy children (p<0.001; OR=2.89;95%CI[1.68,4.99).Conclusion:Severe malaria patients had significant ECG abnormalities (Sinus Tachycardia).

Development and Validation of an In Silico Decision Tool To Guide Optimization of Intravenous Artesunate Dosing Regimens for Severe Falciparum Malaria Patients.

Most deaths from severe falciparum malaria occur within 24 h of presentation to a hospital. Intravenous (i.v.) artesunate is the first-line treatment for severe falciparum malaria, but its efficacy may be compromised by delayed parasitological responses. In patients with severe malaria, the life-saving benefit of the artemisinin derivatives is their ability to clear circulating parasites rapidly, before they can sequester and obstruct the microcirculation. To evaluate the dosing of i.v. artesunate for the treatment of artemisinin-sensitive and reduced ring stage sensitivity to artemisinin severe falciparum malaria infections, Bayesian pharmacokinetic-pharmacodynamic modeling of data from 94 patients with severe malaria (80 children from Africa and 14 adults from Southeast Asia) was performed. Assuming that delayed parasite clearance reflects a loss of ring stage sensitivity to artemisinin derivatives, the median (95% credible interval) percentage of patients clearing ≥99% of parasites within 24 h (PC24≥99%) for standard (2.4 mg/kg body weight i.v. artesunate at 0 and 12 h) and simplified (4 mg/kg i.v. artesunate at 0 h) regimens was 65% (52.5% to 74.5%) versus 44% (25% to 61.5%) for adults, 62% (51.5% to 74.5%) versus 39% (20.5% to 58.5%) for larger children (≥20 kg), and 60% (48.5% to 70%) versus 36% (20% to 53.5%) for smaller children (<20 kg). The upper limit of the credible intervals for all regimens was below a PC24≥99% of 80%, a threshold achieved on average in clinical studies of severe falciparum malaria infections. In severe falciparum malaria caused by parasites with reduced ring stage susceptibility to artemisinin, parasite clearance is predicted to be slower with both the currently recommended and proposed simplified i.v. artesunate dosing regimens.

Intravascular haemolysis in severe Plasmodium knowlesi malaria: association with endothelial activation, microvascular dysfunction, and acute kidney injury

Plasmodium knowlesi occurs throughout Southeast Asia, and is the most common cause of human malaria in Malaysia. Severe disease in humans is characterised by high parasite biomass, reduced red blood cell deformability, endothelial activation and microvascular dysfunction. However, the roles of intravascular haemolysis and nitric oxide (NO)-dependent endothelial dysfunction, important features of severe falciparum malaria, have not been evaluated, nor their role in acute kidney injury (AKI). In hospitalised Malaysian adults with severe (n = 48) and non-severe (n = 154) knowlesi malaria, and in healthy controls (n = 50), we measured cell-free haemoglobin (CFHb) and assessed associations with the endothelial Weibel–Palade body (WPB) constituents, angiopoietin-2 and osteoprotegerin, endothelial and microvascular function, and other markers of disease severity. CFHb was increased in knowlesi malaria in proportion to disease severity, and to a greater extent than previously reported in severe falciparum malaria patients from the same study cohort. In knowlesi malaria, CFHb was associated with parasitaemia, and independently associated with angiopoietin-2 and osteoprotegerin. As with angiopoietin-2, osteoprotegerin was increased in proportion to disease severity, and independently associated with severity markers including creatinine, lactate, interleukin-6, endothelial cell adhesion molecules ICAM-1 and E-selectin, and impaired microvascular reactivity. Osteoprotegerin was also independently associated with NO-dependent endothelial dysfunction. AKI was found in 88% of those with severe knowlesi malaria. Angiopoietin-2 and osteoprotegerin were both independent risk factors for acute kidney injury. Our findings suggest that haemolysis-mediated endothelial activation and release of WPB constituents is likely a key contributor to end-organ dysfunction, including AKI, in severe knowlesi malaria.

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

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

IgE low affinity receptor (CD23) expression, Plasmodium falciparum specific IgE and tumor necrosis factor-alpha production in Thai uncomplicated and severe falciparum malaria patients

Previous studies have suggested that Plasmodium falciparum (P. falciparum) specific IgE in the form of immune complexes crosslinking the low-affinity receptor (CD23) on monocyte results in tumor necrosis factor (TNF)-α and nitric oxide (NO) production. However, the roles of these parameters in severity and immune protection are still unclear. This study aimed to determine the association between CD23 expression on monocytes, plasma soluble CD23 (sCD23), total IgE, malaria-specific IgE and IgG, and TNF-α levels in P. falciparum infected patients. We evaluated 64 uncomplicated (UC) and 25 severe patients (S), admitted at the Hospital for Tropical Diseases, Mahidol University, and 34 healthy controls (C) enrolled in 2001. Flow cytometry and enzyme linked immunosorbent assays (ELISA) demonstrated that trends of the CD23 expression, levels of sCD23 and specific IgE were higher in the S group as compared to those in the UC and C groups. Plasma levels of P. falciparum specific IgE in the UC (p=0.011) and S groups (p=0.025) were significantly higher than those in C group. In contrast the TNF-α levels tended to be higher in the UC than those in the S (p=0.343) and significantly higher than those in C (p=0.004) groups. The specific IgG levels in UC were significantly higher than those in S and C (p<0.001) groups. At admission, a strong significant negative correlation was found between specific IgG and sCD23 (r=−0.762, p=0.028), and TNF-α and IgE–IgG complexes (r=−0.715, p=0.002). Significant positive correlations between levels of specific IgE and TNF-α (r=0.575, p=0.010); and sCD23 (r=0.597, p=0.000) were also observed. In conclusion, our data suggest that CD23 expression and malaria-specific IgE levels may be involved in the severity of the disease while TNF-α and the malaria-specific IgG may correlate with protection against falciparum malaria.

Risk stratification and mortality prediction in Falciparum Malaria

Falciparum malaria has remained an important public health problem in India over the years. WHO enumerates a list of complications to diagnose severe falciparum malaria which was initially provided in 1990 and then revised in 2000. But the importance and prognosis of each complication has not been assigned. Various strategies have been employed for risk stratification in falciparum malaria by various authors in different parts of world. Here we would like to discuss the available literatures from India and some accomplished western literatures to prognosticate severe falciparum malaria patients.

Severe Falciparum malaria in Samarinda, Indonesia

Background: Severe malaria remains a major health problem in Eastern part of Indonesia, although nationally malaria cases are decreasing. Delay in recognizing severe malaria cases and lack of knowledge and facilities contribute to high mortality rate of severe malaria. The aim of this study was to evaluate the clinical apprearances and laboratory findings of severe falciparum malaria patients in Samarinda. Methods & Materials: This study was performed at Abdul Wahab Sjahranie General Hospital, Samarinda, East Kalimantan, Indonesia from August 2011 to October 2013. Subjects were adult severe falciparum malaria patients. Antimalarial given were quinine infusion 10 mg/kg BW/8 hour for at least 48 hours, continued with oral antimalarial artemether-lumefantrine 4 tablets every 12 hour for 3 days when patients’ conditions improved. Results: There were 21 patients observed during this study, consisting of 17 males (81%) and 4 females (19%). All patients were referred from areas out of Samarinda. Patients’ ages were 13 to 56 years (mean age 34.1 years). The most common complications found were jaundice (57.1%), acute kidney injury (42.9%), cerebral malaria (33.3%). Moderate to severe anemia (Hb < 10 g/dl) was found in 47.6% of patients, only one patient had severe anemia (Hb < 5 g/dL). Mean Hb when admitted to hospital was 10.5 g/dL. Moderate to severe thrombocytopenia (platelet < 100,000/mL) was found in 90% of patients, with lowest platelet count 22,000/mL and mean platelet count when admitted was 79,000/ml. The highest total bilirubin level was 26.2 mg/dL and the highest serum creatinine level was 14 mg/dL. The majority of patients had 1 complication (57.1%), while patients with 2 and 3 or more complications were 33.3% and 9.5% respectively. Mortality was 28.6%, one patient was a first trimester pregnant woman. Conclusion: The most common complications of severe falciparum malaria in Samarinda are jaundice (57.1%), acute kidney injury (42.9%) and cerebral malaria (33.3%). Thrombocytopenia is found in almost all patients (90%) while anemia was found in a half of patients (47.6%). Mortality is 28.6%.

Bilirubin Cut-off Level to Predict Fatal Outcome of Severe Falciparum Malaria with Jaundice

Background: Although jaundice is WHO (2010) criteria for severe malaria. However total bilirubin level in the severe malaria patients with jaundice was not mentioned. The objective of this study was to find the cut-off point of total bilirubin level sensitive to detect fatal outcome in severe malaria patients with jaundice. Methods: 174 severe falciparum malaria patients were included into the study. Clinical and laboratory data of the survived severe malaria patients and fatal severe malaria patients were compared. Receiver Operative Curve (ROC) was constructed to evaluate sensitivity of total bilirubin to detect fatal jaundiced patients. Results: There were 29 fatal patients (17%). Out of 117 jaundiced patients, 27 patients were fatal (23%). ROC showed low bilirubin as 2 mg/dl was early observed in 97% fatal severe malaria patients with jaundice. Conclusion: Cut-off of bilirubin level in jaundiced severe malaria patients should be ≥ 2 mg/dl which could detect fatal outcome with sensitivity of 97%.

Essential Role of γδT Cells In Naturally Acquired Immunity to Falciparum Malaria

AbstractAbstract 4877It is important to understand the mechanisms of naturally acquired immunity to malaria for the development of effective malaria vaccines. We have demonstrated that γδT cells expanded in the peripheral blood of the falciparum malaria patients in Thailand but did not expand in patients living in malaria endemic areas of Laos. However, the percentage of Vγ9-T cells, a γδT cell subset, increased in the Laos patients. The levels of naturally acquired antibodies to crude P. falciparum (Pf) antigens also increased with an age dependent manner in individuals living in endemic areas of Laos. In this study, we further investigated the role of Vγ9-T cells in naturally acquired immunity to the falciparum malaria. The peripheral blood lymphocytes (PBLs) and plasma obtained from hospitalized uncomplicated falciparum malaria patients (UMPs) and severe falciparum malaria patients (SMPs) in Thailand and from non-hospitalized UMPs living in endemic areas of Laos were analyzed. The plasma levels of IL-10, which is anti-inflammatory cytokine and associated with antibody production from B cells, were elevated in both hospitalized and non-hospitalized falciparum malaria patients. There was a correlation between the levels of IL-10 and the percentage of Vγ9-T cells in γδT cells. IL-10 and Pf specific antibodies were detected only in culture supernatant of PBLs from non-hospitalized UMPs in the presence of IL-2 for 2 wks. These results indicate that Vγ9-T cells may contribute to acquiring natural immunity to malaria. Disclosures:No relevant conflicts of interest to declare.

Ursodeoxycholic acid and artesunate in the treatment of severe falciparum malaria patients with jaundice

Plasmodium falciparum (PF) infection can lead to severe complications. Ursodeoxycholic acid (UDCA) is increasingly used for the treatment of cholestatic liver diseases. The present study aims to determine the effects of combined UDCA and artesunate compared to placebo and artesunate on the improvement of liver tests in severe PF jaundiced patients. All severe PF jaundiced patients, aged > or = 15 years and diagnosed as having severe malaria according to WHO 2000 criteria, were enrolled. Patients with evidence of biliary obstruction, other cholestatic liver diseases and those who were pregnant were excluded. Patients were randomized to receive either oral UDCA or placebo for 2 weeks in additional to artesunate. All patients were admitted for at least 14 days to monitor the result of the treatment. Seventy-four severe PF malaria patients with jaundice were enrolled. Both groups had similar demographic and laboratory tests, with the exception being more males in the UDCA group than in the placebo group (P = 0.04). The median of percentage change of total bilirubin and aminotransferase levels at the end of weeks 1, 2, 3 and 4 showed no difference between the two groups. Only the median of percentage change of alkaline phosphatase at the end of week one compared with the baseline values showed less increment in the UDCA group than in the placebo group (P = 0.04). No serious adverse events were seen during the 4 weeks of follow up. In severe PF malaria patients with jaundice, combined therapy with UDCA and artesunate is safe, but does not significantly improve liver tests compared to placebo and artesunate.

Prediction of outcome in adults with severe falciparum malaria: a new scoring system

BackgroundMortality of falciparum malaria is related to the presence of severe complications. However, no scoring system is available to predict outcome of these patients. The aim of this paper was to devise a simple and reliable malaria prognosis score (MPS) to predict the outcome of adults with severe malaria.MethodsAll slide-positive severe falciparum malaria patients admitted to Ispat General Hospital were studied. Eight clinical parameters that may potentially differentiate or influence the outcome were identified to predict recovery or deathResultsOf 248 severe malaria cases, 35 died. There were 212 adults (34 deaths) and 36 children (one death). The malaria score for adults was (MSA) = 1(severe anaemia) + 2 (acute renal failure) + 3(Respiratory distress) +4 (cerebral malaria). The MSA ranges from 0 to 10. The mortality was 2% for MSA 0 – 2; 10% for MSA 3–4, 40% for MSA 5–6 and 90% for MSA 7 or more. The sensitivity is 89.9% and positive predictive value is 94.1% when 5 is taken as the cut off value.ConclusionMSA is a simple and sensitive predictor. It can be administered rapidly and repeatedly to prognosticate the outcome of severe malaria in adults. It can help the treating doctor to assess the patient as well as to communicate to the relatives of the patients about prognosis. The score needs revalidation in other geographical areas.