Severe Malaria Patients Research Articles

NCR3 polymorphism, haematological parameters, and severe malaria in Senegalese patients.

BackgroundHost factors, including host genetic variation, have been shown to influence the outcome of Plasmodium falciparum infection. Genome-wide linkage studies have mapped mild malaria resistance genes on chromosome 6p21, whereas NCR3-412 polymorphism (rs2736191) lying within this region was found to be associated with mild malaria.MethodsBlood samples were taken from 188 Plasmodium falciparum malaria patients (76 mild malaria patients, 85 cerebral malaria patients, and 27 severe non-cerebral malaria patients). NCR3-412 (rs2736191) was analysed by sequencing, and haematological parameters were measured. Finally, their association with clinical phenotypes was assessed.ResultsWe evidenced an association of thrombocytopenia with both cerebral malaria and severe non-cerebral malaria, and of an association of high leukocyte count with cerebral malaria. Additionally, we found no association of NCR3-412 with either cerebral malaria, severe non-cerebral malaria, or severe malaria after grouping cerebral malaria and severe non-cerebral malaria patients.ConclusionsOur results suggest that NCR3 genetic variation has no effect, or only a small effect on the occurrence of severe malaria, although it has been strongly associated with mild malaria. We discuss the biological meaning of these results. Besides, we confirmed the association of thrombocytopenia and high leukocyte count with severe malaria phenotypes.

Diversity analysis of MSP1 identifies conserved epitope organization in block 2 amidst high sequence variability in Indian Plasmodium falciparum isolates

BackgroundDespite its immunogenicity, the polymorphic nature of merozoite surface protein 1, an important vaccine candidate for Plasmodium falciparum malaria, remains a concern. This study analyses the impact of genetic variability and parasite population structure on epitope organization of different MSP1 segments.MethodsAltogether 98 blood samples collected from P. falciparum infected mild and severe malaria patients of Chhattisgarh and West Bengal were used to sequence regions encoding block 2 and MSP1-19 of msp1. Sequences were analysed using MEGA7, DnaSPv5, Arlequin3.5 and BepiPred.ResultsAll three major MSP1 block 2 allele families namely K1, MAD20 and RO33 were detected in the samples and they together resulted in 41 indel variants. Chhattisgarh samples displayed an average MOI of 2.07 ± 1.59 which was higher in mild malaria and in age group < 18 years. Ultra-structure of block 2 alleles revealed that mutation and repeat expansion were two major mechanisms responsible for allelic variability of K1 and MAD20. Regions flanking block 2 were highly variable in Chhattisgarh with average mismatch differences (k) ranging from 1.198 to 5.156 for three families. In contrast, region encompassing MSP1-19 exhibited limited heterogeneity (kChhattisgarh = 1.45, kWest Bengal = 1.363). Of the 50 possible B cell linear epitopes predicted from block 2 variants, 94.9% (131 of 138) of the parasites could be represented by three conserved antigens.ConclusionsPresent data indicates that natural selection and transmission intensity jointly play a role in controlling allelic diversity of MSP1 in Indian parasite isolates. Despite remarkable genetic variability, a limited number of predominant and conserved epitopes are present in Indian parasite isolates reinstating the importance of MSP1 as a promising malaria vaccine candidate.

Diabetes and Severe Malaria—Clinical Profile and Outcome

Introduction: Diabetes mellitus is a global burden and India having second largest diabetics in the world. Malaria is a common vector borne disease in developing countries and so also in India. Diabetes mellitus may aggravate malaria infection like other infections. Aim: To study the clinical profile and outcome of severe malaria in diabetes mellitus. Methods: This was a descriptive analytical study where 200 adult patients of severe malaria according to WHO criteria admitted to our hospital (SCB Medical College and Hospital, Odisha, India) were studied for clinical profiles, associated comorbid conditions and outcome for a period of two years. We analysed patients with comorbid conditions like diabetes mellitus, hypertension and hypothyroid vs. no comorbid conditions. Only smear positive severe malaria patients were included and detailed clinical examination and laboratory investigations were done in all patients. Patients with other associated conditions like pregnancy, chronic kidney disease and immunocompromised states were excluded. The observed data was statistically analyzed. Result: Out of 200 severe malaria patients 99 were males and 101 were females with mean age of 46.51± SD 3.67 years. Patients with established diabetes mellitus were 54 (male-27, female-27), hypertension were 36 (male-21, female-15), hypothyroid state were 36 (male-10, female-26) and no comorbidities were 74 (male-41, female-33). The mixed malarial infection of both Plasmodium falciparum and Plasmodium vivax was found more in diabetics vs. nondiabetics i.e., 22 (40.74%) vs. 23 (15.75%). There was more multi-organ involvement, shorter coma onset time and longer duration of coma observed on diabetics than nondiabetics. Nineteen (35.18%) patients died amongst 54 diabetics than 20 (13.69%) patients died amongst 146 nondiabetics. Conclusion: There was more death and severity of malaria observed in diabetics than nondiabetics and then other comorbid conditions. Disclosure P.K. Thatoi: None.

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.

Monitoring health systems readiness and inpatient malaria case-management at Kenyan county hospitals

BackgroundChange of severe malaria treatment policy from quinine to artesunate, a major malaria control advance in Africa, is compromised by scarce data to monitor policy translation into practice. In Kenya, hospital surveys were implemented to monitor health systems readiness and inpatient malaria case-management.MethodsAll 47 county referral hospitals were surveyed in February and October 2016. Data collection included hospital assessments, interviews with inpatient health workers and retrospective review of patients’ admission files. Analysis included 185 and 182 health workers, and 1162 and 1224 patients admitted with suspected malaria, respectively, in all 47 hospitals. Cluster-adjusted comparisons of the performance indicators with exploratory stratifications were performed.ResultsMalaria microscopy was universal during both surveys. Artesunate availability increased (63.8–85.1%), while retrospective stock-outs declined (46.8–19.2%). No significant changes were observed in the coverage of artesunate trained (42.2% vs 40.7%) and supervised health workers (8.7% vs 12.8%). The knowledge about treatment policy improved (73.5–85.7%; p = 0.002) while correct artesunate dosing knowledge increased for patients < 20 kg (42.7–64.6%; p < 0.001) and > 20 kg (70.3–80.8%; p = 0.052). Most patients were tested on admission (88.6% vs 92.1%; p = 0.080) while repeated malaria testing was low (5.2% vs 8.1%; p = 0.034). Artesunate treatment for confirmed severe malaria patients significantly increased (69.9–78.7%; p = 0.030). No changes were observed in artemether–lumefantrine treatment for non-severe test positive patients (8.0% vs 8.8%; p = 0.796). Among test negative patients, increased adherence to test results was observed for non-severe (68.6–78.0%; p = 0.063) but not for severe patients (59.1–62.1%; p = 0.673). Overall quality of malaria case-management improved (48.6–56.3%; p = 0.004), both for children (54.1–61.5%; p = 0.019) and adults (43.0–51.0%; p = 0.041), and in both high (51.1–58.1%; p = 0.024) and low malaria risk areas (47.5–56.0%; p = 0.029).ConclusionMost health systems and malaria case-management indicators improved during 2016. Gaps, often specific to different inpatient populations and risk areas, however remain and further programmatic interventions including close monitoring is needed to optimize policy translation.

Study clinical response and parasite clearance response to Artemisinins in severe malaria in children

Background: The research was conducted to study the clinical response and parasite clearance response to Artesunate therapy, in children admitted with severe malaria at a tertiary care centre in Central India.Methods: It is a prospective analytical study. 18 microscopy positive children diagnosed with severe malaria were included. Baseline blood samples collected for microscopy and biochemical tests. All patients were administered standard intravenous Artesunate therapy and were watched every 12 hourly for: 1. Resolution of clinical signs and symptoms. Clinical parameters included level of consciousness in form of GCS, vital signs like pulse rate, respiration, signs of bleeding, development of icterus, pallor, urine output and laboratory parameters included blood sugar levels, renal and liver function tests. 2. Time taken for conversion of microscopic Smear positive to Smear negative.Results: The mean age was 8.34±4.35 years. Males and females were equally affected. 61% of severe malaria patients were infected by P. falciparum and remaining were infected by P. vivax. The most common clinical features were Pallor: 100%, Respiratory distress: 66.7%, Cerebral malaria: 55.6%. After giving Artesunate therapy, Mean GCS in Cerebral malaria patients showed improvement (on admission: 9±1.15, at 72 hours: 12.5±3.7). Effect was marginally better in P. vivax cases. Respiratory distress and tachycardia improved in majority of patients (75% and 80% respectively). The number of patients with icterus progressively increased. Improvement in liver function and renal function was minimal. 100% parasite clearance was achieved. The mean parasite clearance time is 46±9.43 hours. 72.2% were successfully discharged, 22.2% took Leave Against Medical Advice (LAMA) and 5.6% certified dead.Conclusions: Artesunate is an effective drug in severe malaria patients in terms of rapid improvement of cerebral function, improvement and stabilization of vitals, parasite clearance with favorable long-term outcome. There is no evidence of plasmodium resistance to Artesunate currently as per the present study.

Acidosis and acute kidney injury in severe malaria

BackgroundIn severe falciparum malaria metabolic acidosis and acute kidney injury (AKI) are independent predictors of a fatal outcome in all age groups. The relationship between plasma acids, urine acids and renal function was investigated in adult patients with acute falciparum malaria.MethodsPlasma and urinary acids which previously showed increased concentrations in proportion to disease severity in patients with severe falciparum malaria were quantified. Patients with uncomplicated malaria, sepsis and healthy volunteers served as comparator groups. Multiple regression and multivariate analysis were used to assess the relationship between organic acid concentrations and clinical syndromes, in particular AKI.ResultsPatients with severe malaria (n = 90), uncomplicated malaria (n = 94), non-malaria sepsis (n = 19), and healthy volunteers (n = 61) were included. Univariate analysis showed that both plasma and creatinine-adjusted urine concentrations of p-hydroxyphenyllactic acid (pHPLA) were higher in severe malaria patients with AKI (p < 0.001). Multiple regression analysis, including plasma or creatinine-adjusted urinary acids, and PfHRP2 as parasite biomass marker as independent variables, showed that pHPLA was independently associated with plasma creatinine (β = 0.827) and urine creatinine (β = 0.226). Principal component analysis, including four plasma acids and seven urinary acids separated a group of patients with AKI, which was mainly driven by pHPLA concentrations.ConclusionsBoth plasma and urine concentrations of pHPLA closely correlate with AKI in patients with severe falciparum malaria. Further studies will need to assess the potential nephrotoxic properties of pHPLA.

A Competing-Risk Approach for Modeling Length of Stay in Severe Malaria Patients in South-East Asia and the Implications for Planning of Hospital Services.

Management of severe malaria with limited resources requires comprehensive planning. Expected length of stay (LOS) and the factors influencing it are useful in the planning and optimisation of service delivery. A secondary, competing-risk approach to survival analysis was performed for 1217 adult severe malaria patients from the South-East Asia Quinine Artesunate Malaria Trial. Twenty percent of patients died; 95.4% within 7 days compared to 70.3% of those who were discharged. Median time to discharge was 6 days. Compared to quinine, artesunate increased discharge incidence (subdistribution-Hazard ratio, 1.24; [95% confidence interval 1.09-1.40]; P = .001) and decreased incidence of death (0.60; [0.46-0.80]; P < .001). Low Glasgow coma scale (discharge, 1.08 [1.06-1.11], P < .001; death, 0.85 [0.82-0.89], P < .001), high blood urea-nitrogen (discharge, 0.99 [0.99-0.995], P < .001; death, 1.00 [1.00-1.01], P = .012), acidotic base-excess (discharge, 1.05 [1.03-1.06], P < .001; death, 0.90 [0.88-0.93], P < .001), and development of shock (discharge, 0.25 [0.13-0.47], P < .001; death, 2.14 [1.46-3.12], P < .001), or coma (discharge, 0.46 [0.32-0.65], P < .001; death, 2.30 [1.58-3.36], P < .001) decreased cumulative incidence of discharge and increased incidence of death. Conventional Kaplan-Meier survival analysis overestimated cumulative incidence compared to competing-risk model. Clinical factors on admission and during hospitalisation influence LOS in severe malaria, presenting targets to improve health and service efficiency. Artesunate has the potential to increase LOS, which should be accounted for when planning services. In-hospital death is a competing risk for discharge; an important consideration in LOS models to reduce overestimation of risk and misrepresentation of associations.

Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial.

Acute kidney injury independently predicts mortality in falciparum malaria. It is unknown whether acetaminophen's capacity to inhibit plasma hemoglobin-mediated oxidation is renoprotective in severe malaria. This phase 2, open-label, randomized controlled trial conducted at two hospitals in Bangladesh assessed effects on renal function, safety, pharmacokinetic (PK) properties and pharmacodynamic (PD) effects of acetaminophen. Febrile patients (>12 years) with severe falciparum malaria were randomly assigned to receive acetaminophen (1 g 6-hourly for 72 hours) or no acetaminophen, in addition to intravenous artesunate. Primary outcome was the proportional change in creatinine after 72 hours stratified by median plasma hemoglobin. Between 2012 and 2014, 62 patients were randomly assigned to receive acetaminophen (n = 31) or no acetaminophen (n = 31). Median (interquartile range) reduction in creatinine after 72 hours was 23% (37% to 18%) in patients assigned to acetaminophen, versus 14% (29% to 0%) in patients assigned to no acetaminophen (P = .043). This difference in reduction was 37% (48% to 22%) versus 14% (30% to -71%) in patients with hemoglobin ≥45000 ng/mL (P = .010). The proportion with progressing kidney injury was higher among controls (subdistribution hazard ratio, 3.0; 95% confidence interval, 1.1 to 8.5; P = .034). PK-PD analyses showed that higher exposure to acetaminophen increased the probability of creatinine improvement. No patient fulfilled Hy's law for hepatotoxicity. In this proof-of-principle study, acetaminophen showed renoprotection without evidence of safety concerns in patients with severe falciparum malaria, particularly in those with prominent intravascular hemolysis. NCT01641289.

Sequence analysis of DBL2β domain of vargene of Indonesian Plasmodium falciparum

Malaria is a major health problem in tropical countries including Indonesia. The most deadly agent is Plasmodium falciparum. In P. falciparum infection, PfEMP1 is supposed to play an important role in the pathogenesis of malaria. PfEMP1 is encoded by var gene family, it is a polymorphic protein where the extra-cellular portion contains of three distinct binding domains: Duffy binding-like (DBL), Cysteine-rich interdomain regions (CIDR) and C2. PfEMP1 varies in domain composition and binding specificity. The study explored the characteristic of Indonesian DBL2β-var genes and investigated its role to the malaria outcome. Twenty blood samples from clinically mild to severe malaria patients in Jember, East Java were collected for DNA extraction. Diagnosis was confirmed by Giemsa-stained thick blood smear. PCR was conducted using specific primer targeting on the full-length of DBL2ß and resulted approximately single band of 1,7 kb in a sample. This band was observed only from severe malaria sample. Sequence analysis directly from PCR product showed 74-99% similarities with previous sequences in Gene Bank. In conclusion, the DBL2β domain of vargene of Indonesian isolates was 1603 nucleotides in length and there was a possible association of the existence of DBL2β domain with the severity of malaria outcome.

Malaria severity: Possible influence of the E670G PCSK9 polymorphism: A preliminary case-control study in Malian children.

AimProprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a hepatic secretory protein which promotes the degradation of low-density lipoprotein receptors leading to reduced hepatic uptake of plasma cholesterol. Non-synonymous single-nucleotide polymorphisms in its gene have been linked to hypo- or hyper- cholesterolemia, depending on whether they decrease or increase PCSK9 activity, respectively. Since the proliferation and the infectivity of Plasmodium spp. partially depend on cholesterol from the host, we hypothesize that these PCSK9 genetic polymorphisms could influence the course of malaria infection in individuals who carry them. Here we examined the frequency distribution of one dominant (C679X) and two recessive (A443T, I474V) hypocholesterolemic polymorphisms as well as that of one recessive hypercholesterolemic polymorphism (E670G) among healthy and malaria-infected Malian children.MethodsDried blood spots were collected in Bandiagara, Mali, from 752 age, residence and ethnicity-matched children: 253 healthy controls, 246 uncomplicated malaria patients and 253 severe malaria patients. Their genomic DNA was extracted and genotyped for the above PCSK9 polymorphisms using Taqman assays. Associations of genotype distributions and allele frequencies with malaria were evaluated.ResultsThe minor allele frequency of the A443T, I474V, E670G, and C679X polymorphisms in the study population sample was 0.12, 0.20, 0.26, and 0.02, respectively. For each polymorphism, the genotype distribution among the three health conditions was statistically insignificant, but for the hypercholesterolemic E670G polymorphism, a trend towards association of the minor allele with malaria severity was observed (P = 0.035). The association proved to be stronger when allele frequencies between healthy controls and severe malaria cases were compared (Odd Ratio: 1.34; 95% Confidence Intervals: 1.04–1.83); P = 0.031).ConclusionsCarriers of the minor allele of the E670G PCSK9 polymorphism might be more susceptible to severe malaria. Further investigation of the cholesterol regulating function of PCSK9 in the pathophysiology of malaria is needed.

-308G&gt;A (rs1800629)and -244G&gt;A(rs673) polymorphisms at the promoter region of the TNF-α gene in severe malaria patients in north-central Nigeria

Tumour Necrosis Factor (TNF-α) is a multifunctional pro-inflammatory cytokine that has been shown to play an important role in the pathogenesis of malaria. The level of expression of this cytokine is however suggested to be under genetic control. This study evaluated the frequency of two single nucleotide polymorphisms (SNPs) at the promoter region of the TNF-α gene and their association with susceptibility to severe malaria in north-central Nigeria. A total of 201children (86 severe malaria cases and 115 asymptomatic controls) were recruited into the study. Blood sample was collected from each participant and DNA was isolated using the QIAamp® DNA Mini Kit. Genotyping for SNPs was carried out using the ABI PRISM® 3100 Genetic Analyzer. The distributions of the observed genotypes for the -308G>A (rs1800629) and -244G>A(rs673) polymorphismswere in conformity with the expected distribution when tested for Hardy-Weinberg equilibrium in the two groups. No significant difference (p>0.05) was found in the allelic distributions of the -308G>A and-244G>A between the severe malaria cases and the asymptomatic controls. The most common genotype in the study-population for the TNF-α (-308G>A and-244G>A) loci was homozygote GG. The AA homozygote genotype was not found in any of the study groups. However, a higher frequency of the -308GA and -244GA genotypes were found among individuals with severe malaria compared with the asymptomatic subjects although, this did not reach a statistically significant level (p=0.174; p=0.126 respectively).This study found no association of the TNF-α (-308G>A and -244G>A) polymorphisms with susceptibility to severe malaria. Further studies with larger population sizes are however needed to confirm this result.Keywords: Malaria; cytokines; Plasmodium species; TNF-α; polymorphisms; PCR; north-central Nigeria

Illness experiences of diabetes in the context of malaria in settings experiencing double burden of disease in southeastern Tanzania.

BackgroundTanzania is doubly burdened with both non-communicable and infectious diseases, but information on how Tanzanians experience the co-existence of these conditions is limited. Using Kleinman’s eight prompting questions the study synthesizes explanatory models from patients to describe common illness experiences of diabetes in a rural setting where malaria is the predominant health threat.MethodsWe conducted 17 focus group discussions with adult members of the general community, diabetes patients, neighbours and relatives of diabetes patients to gain insight into shared experiences. To gain in-depth understanding of the individual illness experiences, we conducted 41 in-depth interviews with malaria or diabetes patients and family members of diabetes patients. The analysis followed grounded theory principles and the illness experiences were derived from the emerging themes.ResultsThe illness experiences showed that malaria and diabetes are both perceived to be severe and fatal conditions, but over the years people have learned to live with malaria and the condition is relatively manageable compared with diabetes. In contrast, diabetes was perceived as a relatively new disease, with serious life-long consequences. Uncertainty, fear of those consequences, and the increased risk for severe malaria and other illnesses impacted diabetes patients and their families’ illness experiences. Unpredictable ailments and loss of consciousness, memory, libido, and functional incapability were common problems reported by diabetes patients. These problems had an effect on their psychological and emotional health and limited their social life. Direct and indirect costs of illness pushed individuals and their families further into poverty and were more pronounced for diabetes patients.ConclusionThe illness experiences revealed both malaria and diabetes as distressing conditions, however, diabetes showed a higher level of stress because of its chronicity. Strategies for supporting social, emotional, and psychological well-being that build on the patient accounts are likely to improve illness experiences and quality of life for the chronically ill patient.

Health worker adherence to malaria treatment guidelines at outpatient health facilities in southern Malawi following implementation of universal access to diagnostic testing

BackgroundAppropriate diagnosis and treatment are essential for reducing malaria mortality. A cross-sectional outpatient health facility (HF) survey was conducted in southern Malawi from January to March 2015 to determine appropriate malaria testing and treatment practices four years after implementation of a policy requiring diagnostic confirmation before treatment.MethodsEnrolled patients were interviewed, examined and had their health booklet reviewed. Health workers (HWs) were asked about training, supervision and access to the 2013 national malaria treatment guidelines. HFs were assessed for malaria diagnostic and treatment capacity. Weighted descriptive analyses and logistic regression of patient, HW and HF characteristics related to testing and treatment were performed.ResultsAn evaluation of 105 HFs, and interviews of 150 HWs and 2342 patients was completed. Of 1427 suspect uncomplicated malaria patients seen at HFs with testing available, 1072 (75.7%) were tested, and 547 (53.2%) tested positive. Testing was more likely if patients spontaneously reported fever (odds ratio (OR) 2.6; 95% confidence interval (CI) 1.7–4.0), headache (OR 1.5; 95% CI 1.1–2.1) or vomiting (OR 2.0; 95% CI 1.0–4.0) to HWs and less likely if they reported skin problems (OR 0.4; 95% CI 0.2–0.6). Altogether, 511 (92.7%) confirmed cases and 98 (60.3%) of 178 presumed uncomplicated malaria patients (at HFs without testing) were appropriately treated, while 500 (96.6%) of 525 patients with negative tests did not receive anti-malarials. Only eight (5.7%) suspect severe malaria patients received appropriate pre-referral treatment. Appropriate treatment was more likely for presumed uncomplicated malaria patients (at HFs without testing) with elevated temperature (OR 1.5/1 °C increase; 95% CI 1.1–1.9), who reported fever to HWs (OR 5.7; 95% CI 1.9–17.6), were seen by HWs with additional supervision visits in the previous 6 months (OR 1.2/additional visit; 95% CI 1.0–1.4), or were seen by older HWs (OR 1.1/year of age; 95% CI 1.0–1.1).ConclusionsCorrect testing and treatment practices were reasonably good for uncomplicated malaria when testing was available. Pre-referral treatment for suspect severe malaria was unacceptably rare. Encouraging HWs to elicit and appropriately respond to patient symptoms may improve practices.

Clinical features of severe malaria: Protective effect of mixed plasmodial malaria

ObjectiveTo investigate clinically severe malaria patients with Plasmodium falciparum (P. falciparum), Plasmodium vivax (P. vivax) and mixed species infections. MethodsThis study was conducted at Dr. Saiful Anwar General Hospital, Malang, Indonesia, from December 2011 to May 2013. Twenty nine patients (mean age of 41 years, 22% female), who suffered from severe malaria according to World Health Organization criteria (major and minor) and other criteria based on previous studies, were selected by consecutive sampling. Blood samples were obtained at admission from peripheral blood for microscopic diagnostic, nested PCR and laboratory examination of blood chemistry. Laboratory results were compared between the groups and correlated to each other. ResultsFrom 29 samples, eight (28%) were diagnosed as P. falciparum mono-infection, 12 (41%) as P. vivax mono-infection and nine (31%) as mixed infections, confirmed by PCR. Cerebral malaria occurred in P. falciparum or mixed species infection only. Parasitaemia was highest in P. falciparum mono-infection. Mean haemoglobin was significantly lower in P. falciparum than P. vivax infection (P = 0.01). Mean thrombocyte count (77138/μL) was low in all groups. Mean urea, creatinine, total and direct bilirubin were significantly higher in P. falciparum mono-infection compared to other groups, whereas aspartate aminotransferase and alanine aminotransferase showed no significant differences. Parasitaemia was positively correlated with an increase in urea, creatinine, bilirubin and leucocytosis in all species. ConclusionsBoth Plasmodium species can solely or in combination cause severe malaria. Mixed infection was generally more benign than P. falciparum mono-infection and seemed to have some protective effects.

Factors associated with the severity and complication of patients with malaria hospitalized between 2009 and 2013 in three municipalities of Colombia, case control study.

BackgroundMalaria worldwide annual reported cases range between 250 and 500 million and nearly half a million deaths are reported every year. Colombia has a vast expanse of territory with environmental and social conditions conducive to malaria transmission, which is the reason why it has second place in Latin America for the number of cases of malaria.MethodsThis is a retrospective, paired, case–control study that compares patients with severe malaria and malaria patients without mention of complication. Medical records of patients with confirmed malaria diagnosis were reviewed. The objective of this study was to identify factors associated with complicated malaria in three municipalities of Colombia during the period 2009–2013.ResultsA total sample of 180 medical records was collected, 60 corresponding to cases and 120 to controls following a 1:2 ratio. From the total sample, 88.33 % (159) of subjects were originally from Tumaco, 7.78 %, most of the patients of the study (104) were diagnosed and treated in 2013. Among the laboratory findings, the platelet count was found to have statistically significant differences between cases and controls; this was also true for total bilirubin value and transaminases. The most prevalent severity finding was clinical jaundice, followed by elevated bilirubin (25 %) and elevated transaminases (44.4 %). Thrombocytopenia was found in 11/44 cases (20 %) and only five of 60 patients (8.3 %) presented severe anaemia. The multivariate analysis showed that a platelet count <100,000 and clinical jaundice not associated with organ failure, were the two variables associated with severe malaria in the patients described.ConclusionsMost of the cases studied, despite meeting criteria of severity, were shown not to be as morbid or severe as in other countries. Clinical jaundice and thrombocytopaenia are associated with severe malaria, and they can be used by general practitioners or primary care physicians to promptly identify patients who may have severe malaria.

Adherence to national guidelines for the diagnosis and management of severe malaria: a nationwide, cross-sectional survey in Malawi, 2012.

BackgroundSevere malaria has a case fatality rate of 10-20 %; however, few studies have addressed the quality of severe malaria case management. This study evaluated the diagnostic and treatment practices of malaria patients admitted to inpatient health facilities (HF) in Malawi.MethodsIn July–August 2012, a nationwide, cross-sectional survey of severe malaria management was conducted in 36 HFs selected with equal probability from all eligible public sector HFs in Malawi. Patient records from all admissions during October 2011 and April 2012 (low and high season, respectively) were screened for an admission diagnosis of malaria or prescription of any anti-malarial. Eligible records were stratified by age (< 5 or ≥ 5 years). A maximum of eight records was randomly selected within each age and month stratum. Severe malaria was defined by admission diagnosis or documentation of at least one sign or symptom of severe malaria. Treatment with intravenous (IV) quinine or artesunate was considered correct. Patients without documentation of severe malaria were analysed as uncomplicated malaria patients; treatment with an artemisinin-based combination therapy (ACT) or oral quinine based on malaria test results was considered correct. All analyses accounted for HF level clustering and sampling weights.ResultsThe analysis included 906 records from 35 HFs. Among these, 42 % (95 % confidence interval [CI] 35–49) had a severe malaria admission diagnosis and 50 % (95 % CI 44–57) had at least one severe malaria sign or symptom documented. Severe malaria patients defined by admission diagnosis (93, 95 % CI 86–99) were more likely to be treated correctly compared to patients defined by a severe sign (82, 95 % CI 75–89) (p < 0.0001). Among uncomplicated malaria patients, 26 % (95 % CI 18–35) were correctly treated and 53 % (95 % CI 42–64) were adequately treated with IV quinine alone or in combination with an ACT or oral quinine.ConclusionsA majority of patients diagnosed with severe malaria received the recommended IV therapy in accordance with national treatment guidelines. However, the inconsistencies between diagnosis of severe malaria and documentation of severe signs and symptoms highlight the need to improve healthcare worker recognition and documentation of severe signs and symptoms.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1423-2) contains supplementary material, which is available to authorized users.

Multiplicity of infection and genetic diversity of Plasmodium falciparum isolates from patients with uncomplicated and severe malaria in Gezira State, Sudan.

BackgroundMultiplicity and genetic diversity of Plasmodium falciparum infection might play a role in determining the clinical outcome of malaria infection and could be a fair reflection of the disease transmission rate. This study investigated the genetic diversity of P. falciparum and multiplicity of infection in relation to the severity of malaria and age of patients in Gezira State, Sudan.MethodsA cross-sectional health facilities-based survey was conducted in Gezira State, Sudan in January 2012. A total of 140 P. falciparum malaria patients diagnosed with microscopy and confirmed using nested PCR were recruited and classified into uncomplicated malaria and severe malaria states according to the standard WHO criteria. DNA was extracted and MSP1 and MSP2 allelic families were determined using nested PCR.ResultsThe overall multiplicity of infection (MOI) was 2.25 and 2.30 and 2.15 for uncomplicated and severe malaria respectively. There were no statistically significant differences between uncomplicated and severe malaria (SM) patient groups in MOI with regard to MSP1, MSP2 and overall MOI (Mann-Whitney U-test; all P < 0.05). The predominant MSP1 allelic families were MAD20 for uncomplicated malaria and RO33 for severe malaria. The distribution of both FC27 and IC1/3D7 MSP2 allelic families were approximately the same across disease severity. One hundred and eleven P. falciparum isolates (81 %) consisted of multiple genotypes; 71/90 (78.9 %) in uncomplicated malaria and 40/50 (85.1 %) in severe malaria patient groups. Neither MSP1 nor MSP2 allelic families showed association with malaria severity. No statistically significant differences in multiplicity of infection were observed between different age groups.ConclusionIn this study the majority of P. falciparum isolates from uncomplicated and severe malaria patients consisted of multiple genotypes. Further molecular epidemiological studies delineate the link between P. falciparum genotype with the malaria phenotype in different regions are encouraged.

Plasmodium falciparum var genes expressed in children with severe malaria encode CIDRα1 domains.

Most severe Plasmodium falciparum infections are experienced by young children. Severe symptoms are precipitated by vascular sequestration of parasites expressing a particular subset of the polymorphic P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion molecules. Parasites binding human endothelial protein C receptor (EPCR) through the CIDRα1 domain of certain PfEMP1 were recently associated with severe malaria in children. However, it has remained unclear to which extend the EPCR‐binding CIDRα1 domains epitomize PfEMP1 expressed in severe malaria. Here, we characterized the near full‐length transcripts dominating the var transcriptome in children with severe malaria and found that the only common feature of the encoded PfEMP1 was CIDRα1 domains. Such genes were highly and dominantly expressed in both children with severe malarial anaemia and cerebral malaria. These observations support the hypothesis that the CIDRα1‐EPCR interaction is key to the pathogenesis of severe malaria and strengthen the rationale for pursuing a vaccine or adjunctive treatment aiming at inhibiting or reducing the damaging effects of this interaction.

Evidence of IL-17, IP-10, and IL-10 involvement in multiple-organ dysfunction and IL-17 pathway in acute renal failure associated to Plasmodium falciparum malaria.

BackgroundPlasmodium falciparum malaria in India is characterized by high rates of severe disease, with multiple organ dysfunction (MOD)—mainly associated with acute renal failure (ARF)—and increased mortality. The objective of this study is to identify cytokine signatures differentiating severe malaria patients with MOD, cerebral malaria (CM), and cerebral malaria with MOD (CM-MOD) in India. We have previously shown that two cytokines clusters differentiated CM from mild malaria in Maharashtra. Hence, we also aimed to determine if these cytokines could discriminate malaria subphenotypes in Odisha.MethodsP. falciparum malaria patients from the SCB Medical College Cuttack in the Odisha state in India were enrolled along with three sets of controls: healthy individuals, patients with sepsis and encephalitis (n = 222). We determined plasma concentrations of pro- and anti-inflammatory cytokines and chemokines for all individuals using a multiplex assay. We then used an ensemble of statistical analytical methods to ascertain whether particular sets of cytokines/chemokines were predictors of severity or signatures of a disease category.ResultsOf the 26 cytokines/chemokines tested, 19 increased significantly during malaria and clearly distinguished malaria patients from controls, as well as sepsis and encephalitis patients. High amounts of IL-17, IP-10, and IL-10 predicted MOD, decreased IL-17 and MIP-1α segregated CM-MOD from MOD, and increased IL-12p40 differentiated CM from CM-MOD. Most severe malaria patients with ARF exhibited high levels of IL-17.ConclusionWe report distinct differences in cytokine production correlating with malarial disease severity in Odisha and Maharashtra populations in India. We show that CM, CM-MOD and MOD are clearly distinct malaria-associated pathologies. High amounts of IL-17, IP-10, and IL-10 were predictors of MOD; decreased IL-17 and MIP-1α separated CM-MOD from MOD; and increased IL-12p40 differentiated CM from CM-MOD. Data also suggest that the IL-17 pathway may contribute to malaria pathogenesis via different regulatory mechanisms and may represent an interesting target to mitigate the pathological processes in malaria-associated ARF.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0731-6) contains supplementary material, which is available to authorized users.