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Distinct inflammatory profile underlies pathological increases in creatinine levels associated with Plasmodium vivax malaria clinical severity.

ABSTRACT: Although Plasmodium vivax infection is a frequent cause of malaria worldwide, severe presentations have been more regularly described only in recent years. In this setting, despite clinical descriptions of multi-organ involvement, data associating it with kidney dysfunction are relatively scarce. Here, renal dysfunction is retrospectively analyzed in a large cohort of vivax malaria patients with an attempt to dissect its association with disease severity and mortality, and to determine the role of inflammation in its progression.A retrospective analysis of a databank containing 572 individuals from the Brazilian Amazon, including 179 patients with P. vivax monoinfection (161 symptomatic malaria, 12 severe non-lethal malaria, and 6 severe lethal disease) and 165 healthy controls, was performed. Data on levels of cytokines, chemokines, C-reactive protein (CRP), fibrinogen, creatinine, hepatic enzymes, bilirubin levels, free heme, and haptoglobin were analyzed to depict and compare profiles from patients per creatinine levels.Elevated creatinine levels were found predominantly in women. Vivax malaria severity was highly associated with abnormal creatinine increases, and nonsurvivors presented the highest values of serum creatinine. Indication of kidney dysfunction was not associated with parasitemia levels. IFN-?/IL-10 ratio and CRP values marked the immune biosignature of vivax malaria patients, and could distinguish subjects with elevated creatinine levels who did not survive from those who did. Patients with elevated serum creatinine or severe vivax malaria displayed indication of cholestasis. Biomarkers of hemolysis did not follow increases in serum creatinine.These findings reinforce the hypothesis that renal dysfunction is a key component in P. vivax malaria associated with clinical severity and mortality, possibly through intense inflammation and immune imbalance. Our study argues for systematic evaluation of kidney function as part of the clinical assessment in vivax malaria patients, and warrants additional studies in experimental models for further mechanism investigations.

SUBMITTER: Cruz LAB

PROVIDER: S-EPMC5875744 | biostudies-other | 2018 Mar

REPOSITORIES: biostudies-other

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Distinct inflammatory profile underlies pathological increases in creatinine levels associated with Plasmodium vivax malaria clinical severity.

Cruz Luís A B LAB Barral-Netto Manoel M Andrade Bruno B BB

PLoS neglected tropical diseases 20180329 3

<h4>Background</h4>Although Plasmodium vivax infection is a frequent cause of malaria worldwide, severe presentations have been more regularly described only in recent years. In this setting, despite clinical descriptions of multi-organ involvement, data associating it with kidney dysfunction are relatively scarce. Here, renal dysfunction is retrospectively analyzed in a large cohort of vivax malaria patients with an attempt to dissect its association with disease severity and mortality, and to ...[more]

PMID: 29596409

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Project description:Malaria transmission in Latin America is generally hypoendemic and unstable, with Plasmodium vivax as the most prevalent species. However, only a few studies have been carried out in areas with low and unstable transmission, whereas the clinical profile of malaria has been broadly described in hyperendemic areas. The pattern of clinical manifestations and laboratory findings in low to moderate endemic areas of Colombia is reported here.A passive surveillance study was conducted between 2011 and 2013 involving 1,328 patients with Plasmodium falciparum, P. vivax or mixed malaria infections attending malaria points-of-care of four malaria endemic-areas with distinct transmission intensities and parasite distribution. Trained physicians recorded clinical symptoms and signs as well as socio-demographic characteristics of study participants. Haematological, biochemical and urine tests were performed at the time of diagnosis.Out of 1,328 cases, 673 (50.7%) were caused by P. vivax; 650 (48.9%) were due to P. falciparum; and five (0.4%) patients had mixed infections (P. falciparum/P. vivax). Most patients (92.5%) presented with uncomplicated malaria characterized by fever, chills, headache, sweating, myalgia/arthralgia and parasitaemia ≤ 20,000 parasites/μL. Fever, tachycardia, pallor and abdominal pain on palpation were more frequent in P. falciparum patients, whereas mild hepatomegaly and splenomegaly were mostly observed with P. vivax. Non-severe anaemia (Hb 7.0-10.9 g/dL) was observed in 20% of the subjects, whereas severe anaemia (Hb < 7.0 g/dL) was present in four patients. Half of the patients presented thrombocytopaenia regardless of parasite species. Leukopaenia, neutrophilia and monocytosis were frequently observed in patients infected with P. falciparum. Mild-to-moderate biochemical alterations were present in ~25% of the patients, particularly abnormal bilirubin in those with P. falciparum and abnormal transaminases in P. vivax malaria patients. Proteinuria was present in ~50% of the patients regardless of parasite species, whereas haemoglobinuria was more common in P. vivax infections. Only 7.5% of the cases were classified as clinically severe malaria, caused by both P. vivax and P. falciparum.The high prevalence of uncomplicated malaria associated with moderate parasitaemia suggests the importance of timely diagnosis and effective treatment and encourages new activities to further decrease complicated malaria cases and mortality.

Project description:Globally, malaria and human immunodeficiency virus (HIV) are both independently associated with a massive burden of disease and death. While their co-infection has been well studied for Plasmodium falciparum, scarce data exist regarding the association of P. vivax and HIV. In this cohort study, we assessed the effect of HIV on the risk of vivax malaria infection and recurrence during a 4-year follow-up period in an endemic area of the Brazilian Amazon. For the purpose of this study, we obtained clinical information from January 2012 to December 2016 from two databases. HIV screening data were acquired from the clinical information system at the tropical hospital Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD). The National Malaria Surveillance database (SIVEP malaria) was utilized to identify malaria infections during a 4-year follow-up period after diagnosis of HIV. Both datasets were combined via data linkage. Between 2012 and 2016, a total of 42,121 people were screened for HIV, with 1569 testing positive (3.7%). Out of all the patients diagnosed with HIV, 198 had at least one episode of P. vivax malaria in the follow-up. In the HIV-negative group, 711 participants had at least one P. vivax malaria episode. When comparing both groups, HIV patients had a 6.48 [(5.37-7.83); P < 0.0001] (adjusted relative risk) greater chance of acquiring P. vivax malaria. Moreover, being of the male gender [ARR = 1.41 (1.17-1.71); P < 0.0001], Amerindian ethnicity [ARR = 2.77 (1.46-5.28); P < 0.0001], and a resident in a municipality of the Metropolitan region of Manaus [ARR = 1.48 (1.02-2.15); P = 0.038] were independent risk factors associated with an increased risk of clinical malaria. Education ≥ 8 years [ARR = 0.41 (0.26-0.64); P < 0.0001] and living in the urban area [ARR = 0.44 (0.24-0.80); P = 0.007] were associated to a lower risk of P. vivax malaria. A total of 28 (14.1%) and 180 (25.3%) recurrences (at least a second clinical malaria episode) were reported in the HIV-positive and HIV-negative groups, respectively. After adjusting for sex and education, HIV-positive status was associated with a tendency towards protection from P. vivax malaria recurrences [ARR = 0.55 (0.27-1.10); P = 0.090]. HIV status was not associated with hospitalizations due to P. vivax malaria. CD4 + counts and viral load were not associated with recurrences of P. vivax malaria. No significant differences were found in the distribution of parasitemia between HIV-negative and HIV-positive P. vivax malaria patients. Our results suggest that HIV-positive status is a risk factor for vivax malaria infection, which represents an additional challenge that should be addressed during elimination efforts.

Project description:BackgroundMounting reports on severe Plasmodium vivax malaria from across the globe have raised concerns among the scientific community. However, the risk of P. vivax resulting in complicated malaria and mortality is not as firmly established as it is with Plasmodium falciparum. This study was conducted to determine the severity proportion and factors associated with severity in cases of vivax and falciparum malaria.MethodsAdult patients microscopically diagnosed to have P. vivax/P. falciparum infections from the year 2007-2011 were evaluated based on their hospital records. Severe malaria was defined as per the World Health Organization's guidelines. Comparison was made across species and binary logistic regression was used to determine risk factors of severity.ResultsOf 922 malaria cases included in the study, P. vivax was the largest (63.4%, 95% confidence interval (CI) 60.3-66.5%) infecting species, followed by P. falciparum (34.4%, 95% CI 31.3-37.5%) and their mixed infection (2.2%, 95% CI 1.3-3.2%). Severity in P. vivax and P. falciparum was noted to be 16.9% (95% CI 13.9-19.9%) and 36.3% (95% CI 31.0-41.6%) respectively. Plasmodium falciparum had significantly higher odds [adjusted odds ratio (95% CI), 2.80 (2.04-3.83)] of severe malaria than P. vivax. Rising respiratory rate [1.29 (1.15-1.46)], falling systolic blood pressure [0.96 (0.93-0.99)], leucocytosis [12.87 (1.43-115.93)] and haematuria [59.36 (13.51-260.81)] were the independent predictors of severity in P. vivax. Increasing parasite index [2.97 (1.11-7.98)] alone was the independent predictor of severity in P. falciparum. Mortality in vivax and falciparum malaria was 0.34% (95% CI -0.13-0.81%) and 2.21% (95% CI 0.59-3.83%), respectively. Except hyperparasitaemia and shock, other complications were associated (P < 0.05) with mortality in falciparum malaria. Pulmonary oedema/acute respiratory distress syndrome was associated (P = 0.003) with mortality in vivax malaria. Retrospective design of this study possesses inherent limitations.ConclusionsPlasmodium vivax does cause severe malaria and mortality in substantial proportion but results in much lesser amalgamations of multi-organ involvements than P. falciparum. Pulmonary oedema/acute respiratory distress syndrome in P. vivax infection could lead to mortality and therefore should be diagnosed and treated promptly. Mounting complications and its broadening spectrum in 'not so benign' P. vivax warrants global vigilance for any probable impositions.

Project description:BACKGROUND:Plasmodium vivax imposes substantial morbidity and mortality burdens in endemic zones. Detailed understanding of the contemporary spatial distribution of this parasite is needed to combat it. We used model based geostatistics (MBG) techniques to generate a contemporary map of risk of Plasmodium vivax malaria in Indonesia in 2010. METHODS:Plasmodium vivax Annual Parasite Incidence data (2006-2008) and temperature masks were used to map P. vivax transmission limits. A total of 4,658 community surveys of P. vivax parasite rate (PvPR) were identified (1985-2010) for mapping quantitative estimates of contemporary endemicity within those limits. After error-checking a total of 4,457 points were included into a national database of age-standardized 1-99 year old PvPR data. A Bayesian MBG procedure created a predicted PvPR(1-99) endemicity surface with uncertainty estimates. Population at risk estimates were derived with reference to a 2010 human population surface. RESULTS:We estimated 129.6 million people in Indonesia lived at risk of P. vivax transmission in 2010. Among these, 79.3% inhabited unstable transmission areas and 20.7% resided in stable transmission areas. In western Indonesia, the predicted P. vivax prevalence was uniformly low. Over 70% of the population at risk in this region lived on Java and Bali islands, where little malaria transmission occurs. High predicted prevalence areas were observed in the Lesser Sundas, Maluku and Papua. In general, prediction uncertainty was relatively low in the west and high in the east. CONCLUSION:Most Indonesians living with endemic P. vivax experience relatively low risk of infection. However, blood surveys for this parasite are likely relatively insensitive and certainly do not detect the dormant liver stage reservoir of infection. The prospects for P. vivax elimination would be improved with deeper understanding of glucose-6-phosphate dehydrogenase deficiency (G6PDd) distribution, anti-relapse therapy practices and manageability of P. vivax importation risk, especially in Java and Bali.

Project description:BackgroundControl of vivax malaria in endemic areas requires management of recurrence. The Brazilian National Malaria Surveillance System (SIVEP-Malária) records every case of malaria in Brazil, but is not designed to differentiate between primary and recurrent infections. The aim of this study was to explore whether the information provided by SIVEP-Malária could be used to identify Plasmodium vivax recurrences, its risk factors and evaluate the effectiveness of short course primaquine (7-9 days: total dose 3-4.2 mg/kg) in preventing relapses.MethodsIn this observational retrospective cohort study, data matching of SIVEP-Malária records was undertaken using bloom filters to identify potential recurrences defined as microscopically-confirmed P. vivax episodes from the same individual occurring within a year. Generalized Estimation Equation (GEE) models were used to determine predictors of recurrence. Extended Cox-based conditional Prentice-Williams-Peterson models (PWP) models were used to evaluate time to recurrence.ResultsBetween June 1, 2014 and May 31, 2015, 26,295 episodes fulfilled the criteria of potential recurrence among 154,970 reported malaria episodes. Age ≤ 3 years, being male, literate, not-indigenous and having domestic working activities were identified as risk factors for recurrence. There was no difference in time to recurrence or recurrence frequency between patients treated with 14-day or 7-9 day primaquine regimens (HR = 1.02, 0.96-1.09) and RR = 0.97 (0.90-1.04), respectively. The use of chloroquine alone was associated with a 1.43 (1.29-1.58, p < 0.0001) increased risk of P. vivax recurrence compared to patients who used chloroquine combined with short-course primaquine, the Brazilian standard of care. This was RR = 2.06 (1.48-2.86, p < 0.0001), RR = 1.90 (1.60-2.25, p = 0.0001) and RR = 1.14 (1.00-1.29, p = 0.05) for recurrences occurring between 3-28, 29-60 and > 60 days, respectively. PWP models showed that the time to recurrence was longer in recipients of both primaquine and artemisinin-based combination therapy (ACT) compared to patients treated with chloroquine alone or with concomitant primaquine, HR = 2.2 (1.62-2.99, p < 0.0001), HR = 1.27 (0.97-1.66, p = 0.08), respectively.ConclusionShort course primaquine was as effective as 14-day regimens and associated with a halving of the risk and delay in time to recurrence of P. vivax infections in comparison to chloroquine alone. The study demonstrates the feasibility of using record linkage on routine surveillance data to identify potential P. vivax recurrences, associated risk factors and impact of treatment.

Project description:BackgroundMalaria-associated anaemia, arising from symptomatic, asymptomatic and submicroscopic infections, is a significant cause of morbidity worldwide. Induced blood stage malaria volunteer infection studies (IBSM-VIS) provide a unique opportunity to evaluate the haematological response to early Plasmodium falciparum and Plasmodium vivax infection.MethodsThis study was an analysis of the haemoglobin, red cell counts, and parasitaemia data from 315 participants enrolled in IBSM-VIS between 2012 and 2019, including 269 participants inoculated with the 3D7 strain of P. falciparum (Pf3D7), 15 with an artemisinin-resistant P. falciparum strain (PfK13) and 46 with P. vivax. Factors associated with the fractional fall in haemoglobin (Hb-FF) were evaluated, and the malaria-attributable erythrocyte loss after accounting for phlebotomy-related losses was estimated. The relative contribution of parasitized erythrocytes to the malaria-attributable erythrocyte loss was also estimated.ResultsThe median peak parasitaemia prior to treatment was 10,277 parasites/ml (IQR 3566-27,815), 71,427 parasites/ml [IQR 33,236-180,213], and 34,840 parasites/ml (IQR 13,302-77,064) in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively. The median Hb-FF was 10.3% (IQR 7.8-13.3), 14.8% (IQR 11.8-15.9) and 11.7% (IQR 8.9-14.5) in those inoculated with Pf3D7, PfK13 and P. vivax, respectively, with the haemoglobin nadir occurring a median 12 (IQR 5-21), 15 (IQR 7-22), and 8 (IQR 7-15) days following inoculation. In participants inoculated with P. falciparum, recrudescence was associated with a greater Hb-FF, while in those with P. vivax, the Hb-FF was associated with a higher pre-treatment parasitaemia and later day of anti-malarial treatment. After accounting for phlebotomy-related blood losses, the estimated Hb-FF was 4.1% (IQR 3.1-5.3), 7.2% (IQR 5.8-7.8), and 4.9% (IQR 3.7-6.1) in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively. Parasitized erythrocytes were estimated to account for 0.015% (IQR 0.006-0.06), 0.128% (IQR 0.068-0.616) and 0.022% (IQR 0.008-0.082) of the malaria-attributable erythrocyte loss in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively.ConclusionEarly experimental P. falciparum and P. vivax infection resulted in a small but significant fall in haemoglobin despite parasitaemia only just at the level of microscopic detection. Loss of parasitized erythrocytes accounted for < 0.2% of the total malaria-attributable haemoglobin loss.

Dataset Information

Distinct inflammatory profile underlies pathological increases in creatinine levels associated with Plasmodium vivax malaria clinical severity.

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Distinct inflammatory profile underlies pathological increases in creatinine levels associated with Plasmodium vivax malaria clinical severity.

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