Severe Plasmodium vivax Malaria, Brazilian Amazon

We describe a case series of 17 patients hospitalized in Manaus (western Brazilian Amazon) with PCR-confirmed Plasmodium vivax infection who were treated with chloroquine and primaquine. The major complications were jaundice and severe anemia. No in vivo chloroquine resistance was detected. These data help characterize the clinical profile of severe P. vivax malaria in Latin America

Unravelling the patterns of host immune responses in Plasmodium vivax malaria and dengue co‑infection

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2016-04-26T17:20:49Z No. of bitstreams: 1 Mendonça VRR Unravelling the....pdf: 1769522 bytes, checksum: 9e588aa167adfadd6783622be1f69634 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2016-04-26T17:32:23Z (GMT) No. of bitstreams: 1 Mendonça VRR Unravelling the....pdf: 1769522 bytes, checksum: 9e588aa167adfadd6783622be1f69634 (MD5)Made available in DSpace on 2016-04-26T17:32:23Z (GMT). No. of bitstreams: 1 Mendonça VRR Unravelling the....pdf: 1769522 bytes, checksum: 9e588aa167adfadd6783622be1f69634 (MD5) Previous issue date: 2015Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório Integrado de Microbiogia e Imunoregulação. LIMI. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório Integrado de Microbiogia e Imunoregulação. LIMI. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório Integrado de Microbiogia e Imunoregulação. LIMI. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, BrasilFundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Universidade do Estado do Amazonas. Manaus, AM, BrasilFundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Universidade do Estado do Amazonas. Manaus, AM, BrasilFundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Universidade do Estado do Amazonas. Manaus, AM, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório Integrado de Microbiogia e Imunoregulação. LIMI. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil / Instituto Nacional de Ciência e Tecnologia. Instituto de Investigação em Imunologia. São Paulo, SP, BrasilBackground: Concurrent malaria and dengue infection is frequently diagnosed in endemic countries, but its immunopathology remains largely unknown. In the present study, a large panel of cytokines/chemokines and clinical laboratory markers were measured in patients with Plasmodium vivax and dengue co-infection as well as in individuals with malaria or dengue mono-infections in order to identify biosignatures of each clinical condition. Methods: Individuals from the Brazilian Amazon were recruited between 2009 and 2013 and classified in three groups: vivax malaria (n = 52), dengue (n = 30) and vivax malaria and dengue co-infection (n = 30). P. vivax malaria was diagnosed by thick blood smear and confirmed by PCR; dengue cases were detected by IgM ELISA or NS1 protein. The plasma levels of cytokines and chemokines were determined by multiplex assay. Results: Individuals with malaria and dengue co-infection displayed lower levels of platelets and haemoglobin than those with malaria or dengue mono-infections (p = 0.0047 and p = 0.0001, respectively). The group of individuals coinfected exhibited the highest median concentrations of IFN-γ, IL-6, CCL4 than the mono-infected groups. Network analyses of plasma cytokines/chemokines revealed that malaria and dengue co-infection exhibits a distinct immune profile with critical roles for TNF, IL-6 and IFN-γ. Further, parasitaemia levels displayed positive significant interactions with IL-6, CCL4 and IL-10 in the group of patients co-infected with malaria and dengue. No differences were observed in distribution of dengue virus serotypes and Plasmodium parasitaemia levels between the groups. Conclusions: The findings described here identify unique patterns of circulating immunological markers in cases of malaria and dengue co-infection and provide insights on the immunopathology of this co-morbid condition

DDX39B (BAT1), TNF and IL6 gene polymorphisms and association with clinical outcomes of patients with Plasmodium vivax malaria.

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2014-08-08T18:48:38Z No. of bitstreams: 1 Mendonça VRR DDX39B Bat1....pdf: 1174442 bytes, checksum: 1c795f10853ff55ec140429586c673db (MD5)Made available in DSpace on 2014-08-08T18:48:38Z (GMT). No. of bitstreams: 1 Mendonça VRR DDX39B Bat1....pdf: 1174442 bytes, checksum: 1c795f10853ff55ec140429586c673db (MD5) Previous issue date: 2014Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, BrasilFndação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilFundação de Medicina Tropical Dr Heitor Vieira Dourado. Manaus, BrasilFundação de Medicina Tropical Dr Heitor Vieira Dourado. Manaus, BrasilNational Institutes of Health. Immunobiology Section, Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases. Bethesda, MD, USAFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, Brasil / Instituto Nacional de Ciência e Tecnologia. Instituto de Investigação em Imunologia. São Paulo, SP, BrasilBACKGROUND: DDX39B (BAT1) encodes an RNA helicase known to regulate expression of TNF and IL-6. Elevated levels of these two cytokines are associated with increased severity of clinical malaria. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in the DDX39B, TNF and IL6 genes and the clinical outcomes of patients with Plasmodium vivax malaria. METHODS: Cross-sectional investigations were carried out in two regions of the Brazilian Amazon where several studies on the pathogenesis of vivax malaria had been performed. Individuals were categorized according to infection status as well as clinical presentation into the following groups: uninfected, asymptomatic infection, mild infection, or complicated infection. Polymorphisms were identified using PCR restriction fragment-length polymorphism analysis and the restriction enzymes NlaIII or NcoI. The plasma levels of cytokines were determined using ELISA. RESULTS: The G allele of DDX39B-22C > G was associated with absent or decreased manifestations of malaria and the C allele was a risk factor for disease complications. Study participants heterozygous for TNF-308 (GA) and DDX39B-348 (CT) had higher TNF levels than wild-type participants. Haplotypes that included DDX39B (-22C > G and -348C > T) and TNF polymorphisms were not directly associated with mild or complicated malaria infections; however, haplotypes AGC, ACC, GGT, AGT and ACT were associated with increased TNF levels. Participants with genotype combinations GC/CC/GG/GG and GG/CT/GG/GG (DDX39B-22/DDX39B-348/TNF-308/IL6-176) had decreased and increased risk of mild malaria, respectively, compared with asymptomatic and uninfected participants. GC/CC/GG/GG was linked to decreased TNF and IL-6 levels. CONCLUSIONS: This is the first study to describe patients with DDX39B and IL6 SNPs who had vivax malaria. These findings support the postulation that a set of mutations in immune-related genes is associated with inflammatory mediators and the clinical outcomes of patients with malaria

Characterization of Plasmodium vivax-associated admissions to reference hospitals in Brazil and India

BACKGROUND: The benign character formerly attributed to Plasmodium vivax infection has been dismantled by the increasing number of reports of severe disease associated with infection with this parasite, prompting the need for more thorough and comprehensive characterization of the spectrum of resulting clinical complications. Endemic areas exhibit wide variations regarding severe disease frequency. This study, conducted simultaneously in Brazil and India, constitutes, to our knowledge, the first multisite study focused on clinical characterization of P. vivax severe disease. METHODS: Patients admitted with P. vivax mono-infection at reference centers in Manaus (Amazon - Brazil) and Bikaner (Rajasthan - India), where P. vivax predominates, were submitted to standard thorough clinical and laboratory evaluations in order to characterize clinical manifestations and identify concurrent co-morbidities. RESULTS: In total, 778 patients (88.0% above 12 years old) were hospitalized at clinical discretion with PCR-confirmed P. vivax mono-infection (316 in Manaus and 462 in Bikaner), of which 197 (25.3%) presented at least one severity criterion as defined by the World Health Organization (2010). Hyperlactatemia, respiratory distress, hypoglycemia, and disseminated intravascular coagulation were more frequent in Manaus. Noteworthy, pregnancy status was associated as a risk factor for severe disease (OR = 2.03; 95% CI = 1.2-3.4; P = 0.007). The overall case fatality rate was 0.3/1,000 cases in Manaus and 6.1/1,000 cases in Bikaner, with all deaths occurring among patients fulfilling at least one severity criterion. Within this subgroup, case fatality rates increased respectively to 7.5% in Manaus and 4.4% in Bikaner. CONCLUSION: P. vivax-associated severity is not negligible, and although lethality observed for complicated cases was similar, the overall fatality rate was about 20-fold higher in India compared to Brazil, highlighting the variability observed in different settings. Our observations highlight that pregnant women and patients with co-morbidities need special attention when infected by this parasite due to higher risk of complications

Expression gene levels of <i>pvcrt-o</i> and <i>pvmdr-1</i> in all the groups.

<p>Relative quantification of <i>pvcrt-o</i> (A) and <i>pvmdr1</i> (B) transcript levels in total RNA obtained from parasites from severe patients with chloroquine-resistant <i>P. vivax</i>, patients susceptible to CQ, severe patients and patients without severity symptoms. Chloroquine-resistant <i>P. vivax</i> parasites (R). Chloroquine-susceptible <i>P. vivax</i> parasites at D0 (S). Severe cases (Sev). Non-severe cases (NS). *p<0.05.</p

Expression Levels of <i>pvcrt-o</i> and <i>pvmdr-1</i> Are Associated with Chloroquine Resistance and Severe <i>Plasmodium vivax</i> Malaria in Patients of the Brazilian Amazon

<div><p>Molecular markers associated with the increase of chloroquine resistance and disease severity in <i>Plasmodium vivax</i> are needed. The objective of this study was to evaluate the expression levels of <i>pvcrt-o</i> and <i>pvmdr-1</i> genes in a group of patients presenting CQRPv and patients who developed severe complications triggered exclusively by <i>P. vivax</i> infection. Two different sets of patients were included to this comprehensive study performed in the Brazilian Amazon: 1) patients with clinically characterized chloroquine-resistant <i>P. vivax</i> compared with patients with susceptible parasites from <i>in</i><i>vivo</i> studies and 2) patients with severe vivax malaria compared with patients without severity. Quantitative real-time PCR was performed to compare the transcript levels of two main transporters genes, <i>P. vivax</i> chloroquine resistance transporter (<i>pvcrt-o</i>) and the <i>P. vivax</i> multidrug resistance transporter (<i>pvmdr-1</i>). Twelve chloroquine resistant cases and other 15 isolates from susceptible cases were included in the first set of patients. For the second set, seven patients with <i>P. vivax</i>-attributed severe and 10 mild manifestations were included. Parasites from patients with chloroquine resistance presented up to 6.1 (95% CI: 3.8–14.3) and 2.4 (95% CI: 0.53–9.1) fold increase in <i>pvcrt-o</i> and <i>pvmdr-1</i> expression levels, respectively, compared to the susceptible group. Parasites from the severe vivax group had a 2.9 (95% CI: 1.1–8.3) and 4.9 (95% CI: 2.3–18.8) fold increase in <i>pvcrt-o</i> and <i>pvmdr-1</i> expression levels as compared to the control group with mild disease. These findings suggest that chloroquine resistance and clinical severity in <i>P. vivax</i> infections are strongly associated with increased expression levels of the <i>pvcrt-o</i> and <i>pvmdr-1</i> genes likely involved in chloroquine resistance.</p></div

Expression level of chloroquine resistance genes in severe patients.

<p>Relative quantification of <i>pvcrt-o</i> (A) and <i>pvmdr1</i> (B) transcript levels in total RNA obtained from parasites from severe patients vs a pool of total RNA obtained from parasites susceptible to CQ. Severe cases (S). Non-severe cases (NS). The error bars in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0105922#pone-0105922-g001" target="_blank">Figures 1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0105922#pone-0105922-g003" target="_blank">3</a> reflect the average standard error of the Ct.</p

Frequency of polymorphisms in the <i>pvmdr1 and pvcrt-o</i> genes for the different set of patients.

<p>Not significant (NS).</p><p>Frequency of polymorphisms in the <i>pvmdr1 and pvcrt-o</i> genes for the different set of patients.</p

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