ORCID Profile
0000-0003-3374-9985
Current Organisations
University of Texas Medical Branch
,
Ministério da Saúde
,
Fundação de Medicina Tropical Dr Heitor Vieira Dourado
,
Instituto Leônidas e Maria Deane - ILMD/Fiocruz Amaônia
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Related Links
Publications
Accelerating towards P. vivax elimination with a novel serological test-and-treat strategy: a modelling case study in Brazil
Publisher: Elsevier BV
Date: 06-2023
Severe haemolysis during primaquine radical cure ofPlasmodium vivaxmalaria: two systematic reviews and individual patient data descriptive analyses
Publisher: Cold Spring Harbor Laboratory
Date: 05-03-2023
DOI: 10.1101/2023.03.02.23286587
Abstract: Primaquine (PQ) kills Plasmodium vivax hypnozoites but can cause haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We did two systematic reviews: the first used data from clinical trials to determine the spectrum of definitions and frequency of haematological serious adverse events (SAE) related to PQ treatment of vivax malaria. The second used data from prospective studies and case reports to describe the clinical presentation, management and outcome of ‘severe’ PQ-associated haemolysis necessitating hospitalisation. In the first review, SAEs were reported in 70 of 249 clinical trials. There were 34 haematological SAEs amongst 9,824 patients with vivax malaria treated with PQ, 9 of which necessitated hospitalisation or blood transfusion. Criteria used to define SAEs were erse. In the second review, 21 of 8,487 articles screened reported 163 patients hospitalised following PQ radical cure 79.9% (123/154) of whom were prescribed PQ at ≥0.5mg/kg/day. Overall, 101 patients were categorised as having probable or possible ‘severe’ PQ-associated haemolysis, 96.8% of whom were G6PD deficient ( % activity). The first symptoms of haemolysis were mostly reported on day 2 or 3 (45.5%) and all patients were hospitalised within 7 days of PQ commencement. 57.9% (77/133) of patients had blood transfusion. Seven (6.9%) patients with probable or possible haemolysis died. Even when G6PD testing is available, enhanced monitoring for haemolysis is warranted following PQ treatment. Clinical review within the first 5 days of treatment may facilitate early detection and management of haemolysis. More robust definitions of severe PQ-associated haemolysis are required. WHO-TDR, Australian National Health and Medical Research (NHMRC), The Bill & Melinda Gates Foundation.
Heterogeneity in response to serological exposure markers of recent Plasmodium vivax infections in contrasting epidemiological contexts
Publisher: Public Library of Science (PLoS)
Date: 16-02-2021
DOI: 10.1371/JOURNAL.PNTD.0009165
Abstract: Antibody responses as serological markers of Plasmodium vivax infection have been shown to correlate with exposure, but little is known about the other factors that affect antibody responses in naturally infected people from endemic settings. To address this question, we studied IgG responses to novel serological exposure markers (SEMs) of P . vivax in three settings with different transmission intensity. We validated a panel of 34 SEMs in a Peruvian cohort with up to three years’ longitudinal follow-up using a multiplex platform and compared results to data from cohorts in Thailand and Brazil. Linear regression models were used to characterize the association between antibody responses and age, the number of detected blood-stage infections during follow-up, and time since previous infection. Receiver Operating Characteristic (ROC) analysis was used to test the performance of SEMs to identify P . vivax infections in the previous 9 months. Antibody titers were associated with age, the number of blood-stage infections, and time since previous P . vivax infection in all three study sites. The association between antibody titers and time since previous P . vivax infection was stronger in the low transmission settings of Thailand and Brazil compared to the higher transmission setting in Peru. Of the SEMs tested, antibody responses to RBP2b had the highest performance for classifying recent exposure in all sites, with area under the ROC curve (AUC) = 0.83 in Thailand, AUC = 0.79 in Brazil, and AUC = 0.68 in Peru. In low transmission settings, P . vivax SEMs can accurately identify in iduals with recent blood-stage infections. In higher transmission settings, the accuracy of this approach diminishes substantially. We recommend using P . vivax SEMs in low transmission settings pursuing malaria elimination, but they are likely to be less effective in high transmission settings focused on malaria control.
Genetic Variants of Glucose-6-Phosphate Dehydrogenase and Their Associated Enzyme Activity: A Systematic Review and Meta-Analysis
Publisher: MDPI AG
Date: 14-09-2022
DOI: 10.3390/PATHOGENS11091045
Abstract: Low glucose-6-phosphate dehydrogenase enzyme (G6PD) activity is a key determinant of drug-induced haemolysis. More than 230 clinically relevant genetic variants have been described. We investigated the variation in G6PD activity within and between different genetic variants. In this systematic review, in idual patient data from studies reporting G6PD activity measured by spectrophotometry and corresponding the G6PD genotype were pooled (PROSPERO: CRD42020207448). G6PD activity was converted into percent normal activity applying study-specific definitions of 100%. In total, 4320 in iduals from 17 studies across 10 countries were included, where 1738 (40.2%) had one of the 24 confirmed G6PD mutations, and 61 observations (3.5%) were identified as outliers. The median activity of the hemi-/homozygotes with A-(c.202G A/c.376A G) was 29.0% (range: 1.7% to 76.6%), 10.2% (range: 0.0% to 32.5%) for Mahidol, 16.9% (range 3.3% to 21.3%) for Mediterranean, 9.0% (range: 2.9% to 23.2%) for Vanua Lava, and 7.5% (range: 0.0% to 18.3%) for Viangchan. The median activity in heterozygotes was 72.1% (range: 16.4% to 127.1%) for A-(c.202G A/c.376A G), 54.5% (range: 0.0% to 112.8%) for Mahidol, 37.9% (range: 20.7% to 80.5%) for Mediterranean, 53.8% (range: 10.9% to 82.5%) for Vanua Lava, and 52.3% (range: 4.8% to 78.6%) for Viangchan. A total of 99.5% of hemi/homozygotes with the Mahidol mutation and 100% of those with the Mediterranean, Vanua Lava, and Viangchan mutations had % activity. For A-(c.202G A/c.376A G), 55% of hemi/homozygotes had % activity. The G6PD activity for each variant spanned the current classification thresholds used to define clinically relevant categories of enzymatic deficiency.
A multinational Delphi consensus to end the COVID-19 public health threat
Publisher: Springer Science and Business Media LLC
Date: 03-11-2022
DOI: 10.1038/S41586-022-05398-2
Abstract: Despite notable scientific and medical advances, broader political, socioeconomic and behavioural factors continue to undercut the response to the COVID-19 pandemic 1,2 . Here we convened, as part of this Delphi study, a erse, multidisciplinary panel of 386 academic, health, non-governmental organization, government and other experts in COVID-19 response from 112 countries and territories to recommend specific actions to end this persistent global threat to public health. The panel developed a set of 41 consensus statements and 57 recommendations to governments, health systems, industry and other key stakeholders across six domains: communication health systems vaccination prevention treatment and care and inequities. In the wake of nearly three years of fragmented global and national responses, it is instructive to note that three of the highest-ranked recommendations call for the adoption of whole-of-society and whole-of-government approaches 1 , while maintaining proven prevention measures using a vaccines-plus approach 2 that employs a range of public health and financial support measures to complement vaccination. Other recommendations with at least 99% combined agreement advise governments and other stakeholders to improve communication, rebuild public trust and engage communities 3 in the management of pandemic responses. The findings of the study, which have been further endorsed by 184 organizations globally, include points of unanimous agreement, as well as six recommendations with % disagreement, that provide health and social policy actions to address inadequacies in the pandemic response and help to bring this public health threat to an end.
Naturally acquired antibody responses to more than 300 Plasmodium vivax proteins in three geographic regions
Publisher: Public Library of Science (PLoS)
Date: 11-09-2017
IgG antibody responses are preferential compared to IgM for use as serological markers for detecting recent exposure to Plasmodium vivax infection
Publisher: Cold Spring Harbor Laboratory
Date: 07-08-2020
DOI: 10.1101/2020.08.07.20169862
Abstract: To achieve malaria elimination, new tools are required to explicitly target Plasmodium vivax . Recently, a novel panel of P. vivax proteins were identified and validated as serological markers for detecting recent exposure to P. vivax within the last 9 months. In order to improve the sensitivity and specificity of these markers, IgM in addition to IgG antibody responses were assessed to a down-selected panel of 20 P. vivax proteins. IgM was tested using archival plasma s les from observational cohort studies conducted in malaria-endemic regions of Thailand and Brazil. IgM responses to these proteins generally had poorer classification performance than IgG.
The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis
Publisher: eLife Sciences Publications, Ltd
Date: 06-12-2022
DOI: 10.7554/ELIFE.83433
Abstract: Tafenoquine is a newly licensed antimalarial drug for the radical cure of Plasmodium vivax malaria. The mechanism of action and optimal dosing are uncertain. We pooled in idual data from 1102 patients and 72 healthy volunteers studied in the pre-registration trials. We show that tafenoquine dose is the primary determinant of efficacy. Under an Emax model, we estimate the currently recommended 300 mg dose in a 60 kg adult (5 mg/kg) results in 70% of the maximal obtainable hypnozoiticidal effect. Increasing the dose to 7.5 mg/kg (i.e. 450 mg) would result in 90% reduction in the risk of P. vivax recurrence. After adjustment for dose, the tafenoquine terminal elimination half-life, and day 7 methaemoglobin concentration, but not the parent compound exposure, were also associated with recurrence. These results suggest that the production of oxidative metabolites is central to tafenoquine’s hypnozoiticidal efficacy. Clinical trials of higher tafenoquine doses are needed to characterise their efficacy, safety and tolerability.
Quantifying primaquine effectiveness and improving adherence: a round table discussion of the APMEN Vivax Working Group
Publisher: Springer Science and Business Media LLC
Date: 20-06-2018
Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials
Publisher: Springer Science and Business Media LLC
Date: 15-04-2021
DOI: 10.1038/S41467-021-22446-Z
Abstract: Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications reprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications reprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total s le size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20 I² = 0% 26 trials 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0% 4 trials 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.
BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial)
Publisher: BMJ
Date: 10-2021
DOI: 10.1136/BMJOPEN-2021-052101
Abstract: BCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19. This international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood s les. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections. Ethical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system. ClinicalTrials.gov NCT04327206
A molecular barcode and web-based data analysis tool to identify imported Plasmodium vivax malaria
Publisher: Springer Science and Business Media LLC
Date: 23-12-2022
DOI: 10.1038/S42003-022-04352-2
Abstract: Traditionally, patient travel history has been used to distinguish imported from autochthonous malaria cases, but the dormant liver stages of Plasmodium vivax confound this approach. Molecular tools offer an alternative method to identify, and map imported cases. Using machine learning approaches incorporating hierarchical fixation index and decision tree analyses applied to 799 P. vivax genomes from 21 countries, we identified 33-SNP, 50-SNP and 55-SNP barcodes (GEO33, GEO50 and GEO55), with high capacity to predict the infection’s country of origin. The Matthews correlation coefficient (MCC) for an existing, commonly applied 38-SNP barcode (BR38) exceeded 0.80 in 62% countries. The GEO panels outperformed BR38, with median MCCs 0.80 in 90% countries at GEO33, and 95% at GEO50 and GEO55. An online, open-access, likelihood-based classifier framework was established to support data analysis (vivaxGEN-geo). The SNP selection and classifier methods can be readily amended for other use cases to support malaria control programs.
Heterogeneity in response to serological exposure markers of recentPlasmodium vivaxinfections in contrasting epidemiological contexts
Publisher: Cold Spring Harbor Laboratory
Date: 02-07-2020
DOI: 10.1101/2020.07.01.20143503
Abstract: Antibody responses as serological markers of Plasmodium vivax infection have been shown to correlate with exposure, but little is known about the other factors that affect antibody responses in naturally infected people from endemic settings. To address this question, we studied IgG responses to novel serological exposure markers (SEMs) of P. vivax in three settings with different transmission intensity. We validated a panel of 34 SEMs in a Peruvian cohort with up to three years’ longitudinal follow-up using a multiplex platform and compared results to data from cohorts in Thailand and Brazil. Linear regression models were used to characterize the association between antibody responses and age, the number of detected blood-stage infections during follow-up, and time since previous infection. Receiver Operating Characteristic (ROC) analysis was used to test the performance of SEMs to identify P. vivax infections in the previous 9 months. Antibody titers were associated with age, the number of blood-stage infections, and time since previous P. vivax infection in all three study sites. The association between antibody titers and time since previous P. vivax infection was stronger in the low transmission settings of Thailand and Brazil compared to the higher transmission setting in Peru. Of the SEMs tested, antibody responses to RBP2b had the highest performance for classifying recent exposure in all sites, with area under the ROC curve (AUC) = 0.83 in Thailand, AUC = 0.79 in Brazil, and AUC = 0.68 in Peru. In low transmission settings, P. vivax SEMs can accurately identify in iduals with recent blood-stage infections. In higher transmission settings, the accuracy of this approach diminishes substantially. We recommend using P. vivax SEMs in low transmission settings pursuing malaria elimination, but they are likely to be less effective in high transmission settings focused on malaria control. Plasmodium vivax still poses a threat in many countries due to its ability to cause recurrent infections. Key to achieving the goal of malaria elimination is the ability to quickly detect and treat carriers of relapsing parasites. Failing to identify this transmission reservoir will hinder progress towards malaria elimination. Recently, novel serological markers of recent exposure to P. vivax (SEM) have been developed and validated in low transmission settings. It is still poorly understood what factors affect the antibody response to these markers when evaluated in contrasting endemic contexts. To determine the factors that influence the antibody response to SEM, we compared the antibody levels in three sites with different transmission intensity: Thailand (low), Brazil (moderate) and Peru (high). In this study, we found that transmission intensity plays a key role in the acquisition of the antibody repertoire to P . vivax . In highly endemic sites, it is likely that immunological memory resulting from a constant and sustained exposure will impact the performance of SEMs to detect in iduals with recent exposure to P . vivax . In summary, SEMs that perform well in low transmission sites do not perform as well in high transmission regions.
Correction: Quantification of glucose-6-phosphate dehydrogenase activity by spectrophotometry: A systematic review and meta-analysis
Publisher: Public Library of Science (PLoS)
Date: 24-07-2020
Association between the proportion of Plasmodium falciparum and Plasmodium vivax infections detected by passive surveillance and the magnitude of the asymptomatic reservoir in the community: a pooled
Publisher: Elsevier BV
Date: 08-2020
Development and validation of serological markers for detecting recent exposure toPlasmodium vivaxinfection
Publisher: Cold Spring Harbor Laboratory
Date: 30-11-2018
DOI: 10.1101/481168
Abstract: In order to accelerate towards malaria elimination, improved targeting of limited resources is essential. A major gap in our elimination toolkit for Plasmodium vivax malaria is the identification of in iduals carrying arrested liver stages, called hypnozoites. These clinically silent but frequently relapsing hypnozoites are key to P. vivax persistence. Whilst hypnozoites cannot be directly detected, in iduals who have had recent exposure to P. vivax and have not been treated are likely to harbor these parasites. By measuring IgG antibody responses to over 300 P. vivax proteins, a panel of serological markers capable of detecting exposure to P. vivax infections in the prior 9-month period was identified and validated. Using antibody responses to 8 P. vivax proteins, 80% sensitivity and specificity for detecting recent infections were achieved in three independent studies conducted in Thailand, Brazil and the Solomon Islands. As these in iduals have a high likelihood of harboring hypnozoites, the suite of these 8 antibody responses can serve as biomarkers for the identification of in iduals who should be targeted for treatment with liver-stage drugs such as primaquine and tafenoquine in mass drug administration programs aimed at controlling and eliminating P. vivax malaria. The manuscript describes identification and validation of a novel panel of P. vivax proteins that can be used to detect recent exposure to P. vivax infections within the prior 9 months.
Rosettes integrity protects Plasmodium vivax of being phagocytized
Publisher: Springer Science and Business Media LLC
Date: 07-10-2020
DOI: 10.1038/S41598-020-73713-W
Abstract: Plasmodium vivax is the most prevalent cause of malaria outside of Africa. P. vivax biology and pathogenesis are still poorly understood. The role of one highly occurring phenotype in particular where infected reticulocytes cytoadhere to noninfected normocytes, forming rosettes, remains unknown. Here, using a range of ex vivo approaches, we showed that P. vivax rosetting rates were enhanced by plasma of infected patients and that total immunoglobulin M levels correlated with rosetting frequency. Moreover, rosetting rates were also correlated with parasitemia, IL-6 and IL-10 levels in infected patients. Transcriptomic analysis of peripheral leukocytes from P. vivax -infected patients with low or moderated rosetting rates identified differentially expressed genes related to human host phagocytosis pathway. In addition, phagocytosis assay showed that rosetting parasites were less phagocyted. Collectively, these results showed that rosette formation plays a role in host immune response by h ering leukocyte phagocytosis. Thus, these findings suggest that rosetting could be an effective P. vivax immune evasion strategy.
Identification of the asymptomatic Plasmodium falciparum and Plasmodium vivax gametocyte reservoir under different transmission intensities
Publisher: Public Library of Science (PLoS)
Date: 27-08-2021
DOI: 10.1371/JOURNAL.PNTD.0009672
Abstract: Understanding epidemiological variables affecting gametocyte carriage and density is essential to design interventions that most effectively reduce malaria human-to-mosquito transmission. Plasmodium falciparum and P . vivax parasites and gametocytes were quantified by qPCR and RT-qPCR assays using the same methodologies in 5 cross-sectional surveys involving 16,493 in iduals in Brazil, Thailand, Papua New Guinea, and Solomon Islands. The proportion of infections with detectable gametocytes per survey ranged from 44–94% for P . falciparum and from 23–72% for P . vivax . Blood-stage parasite density was the most important predictor of the probability to detect gametocytes. In moderate transmission settings (prevalence by qPCR %), parasite density decreased with age and the majority of gametocyte carriers were children. In low transmission settings (prevalence %), % of gametocyte carriers were adults. Per survey, 37–100% of all in iduals positive for gametocytes by RT-qPCR were positive by light microscopy for asexual stages or gametocytes (overall: P . falciparum 178/348, P . vivax 235/398). Interventions to reduce human-to-mosquito malaria transmission in moderate-high endemicity settings will have the greatest impact when children are targeted. In contrast, all age groups need to be included in control activities in low endemicity settings to achieve elimination. Detection of infections by light microscopy is a valuable tool to identify asymptomatic blood stage infections that likely contribute most to ongoing transmission at the time of s ling.
Plasmodium vivax molecular diagnostics in community surveys: pitfalls and solutions
Publisher: Springer Science and Business Media LLC
Date: 30-01-2018
Variability in white blood cell count during uncomplicated malaria and implications for parasite density estimation: a WorldWide Antimalarial Resistance Network individual patient data meta-analysis
Publisher: Springer Science and Business Media LLC
Date: 06-06-2023
DOI: 10.1186/S12936-023-04583-6
Abstract: The World Health Organization (WHO) recommends that when peripheral malarial parasitaemia is quantified by thick film microscopy, an actual white blood cell (WBC) count from a concurrently collected blood s le is used in calculations. However, in resource-limited settings an assumed WBC count is often used instead. The aim of this study was to describe the variability in WBC count during acute uncomplicated malaria, and estimate the impact of using an assumed value of WBC on estimates of parasite density and clearance. Uncomplicated malaria drug efficacy studies that measured WBC count were selected from the WorldWide Antimalarial Resistance Network data repository for an in idual patient data meta-analysis of WBC counts. Regression models with random intercepts for study-site were used to assess WBC count variability at presentation and during follow-up. Inflation factors for parasitaemia density, and clearance estimates were calculated for methods using assumed WBC counts (8000 cells/µL and age-stratified values) using estimates derived from the measured WBC value as reference. Eighty-four studies enrolling 27,656 patients with clinically uncomplicated malaria were included. Geometric mean WBC counts (× 1000 cells/µL) in age groups 1, 1–4, 5–14 and ≥ 15 years were 10.5, 8.3, 7.1, 5.7 and 7.5, 7.0, 6.5, 6.0 for in iduals with falciparum (n = 24,978) and vivax (n = 2678) malaria, respectively. At presentation, higher WBC counts were seen among patients with higher parasitaemia, severe anaemia and, for in iduals with vivax malaria, in regions with shorter regional relapse periodicity. Among falciparum malaria patients, using an assumed WBC count of 8000 cells/µL resulted in parasite density underestimation by a median (IQR) of 26% (4–41%) in infants 1 year old but an overestimation by 50% (16–91%) in adults aged ≥ 15 years. Use of age-stratified assumed WBC values removed systematic bias but did not improve precision of parasitaemia estimation. Imprecision of parasite clearance estimates was only affected by the within-patient WBC variability over time, and remained 10% for 79% of patients. Using an assumed WBC value for parasite density estimation from a thick smear may lead to underdiagnosis of hyperparasitaemia and could adversely affect clinical management but does not result in clinically consequential inaccuracies in the estimation of the prevalence of prolonged parasite clearance and artemisinin resistance.
Effect of primaquine dose on the risk of recurrence in patients with uncomplicated Plasmodium vivax: a systematic review and individual patient data meta-analysis
Publisher: Elsevier BV
Date: 09-2023
IgG Antibody Responses Are Preferential Compared With IgM for Use as Serological Markers for Detecting Recent Exposure to Plasmodium vivax Infection.
Publisher: Oxford University Press (OUP)
Date: 22-05-2021
DOI: 10.1093/OFID/OFAB228
Abstract: To achieve malaria elimination, new tools are required to explicitly target Plasmodium vivax. Recently, a novel panel of P. vivax proteins were identified and validated as serological markers for detecting recent exposure to P. vivax within the last 9 months. In order to improve the sensitivity and specificity of these markers, immunoglobulin M (IgM) in addition to immunoglobulin G (IgG) antibody responses were compared with a down-selected panel of 20 P. vivax proteins. IgM was tested using archival plasma s les from observational cohort studies conducted in malaria-endemic regions of Thailand and Brazil. IgM responses to these proteins generally had poorer classification performance than IgG.
Study on the persistence of Zika virus (ZIKV) in body fluids of patients with ZIKV infection in Brazil
Publisher: Springer Science and Business Media LLC
Date: 22-01-2018
On the pathogenesis of Plasmodium vivax malaria: Perspectives from the Brazilian field
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.IJPARA.2012.08.007
Abstract: Life-threatening Plasmodium vivax malaria cases, while uncommon, have been reported since the early 20th century. Unfortunately, the pathogenesis of these severe vivax malaria cases is still poorly understood. In Brazil, the proportion of vivax malaria cases has been steadily increasing, as have the number of cases presenting serious clinical complications. The most frequent syndromes associated with severe vivax malaria in Brazil are severe anaemia and acute respiratory distress. Additionally, P. vivax infection may also result in complications associated with pregnancy. Here, we review the latest findings on severe vivax malaria in Brazil. We also discuss how the development of targeted field research infrastructure in Brazil is providing clinical and ex vivo experimental data that benefits local and international efforts to understand the pathogenesis of P. vivax.
Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers
Publisher: Massachusetts Medical Society
Date: 27-04-2023
Global genetic diversity of the Plasmodium vivax transmission-blocking vaccine candidate Pvs48/45
Publisher: Springer Science and Business Media LLC
Date: 12-04-2016
Yellow Fever Reemergence Risk in the Guiana Shield: a Comprehensive Review of Cases Between 1990 and 2022
Publisher: Springer Science and Business Media LLC
Date: 18-07-2023
Tafenoquine following G6PD screening versus primaquine for the treatment of vivax malaria in Brazil: a cost-effectiveness analysis using a transmission model
Publisher: Cold Spring Harbor Laboratory
Date: 05-06-2023
DOI: 10.1101/2023.06.02.23290864
Abstract: Malaria transmission modelling has demonstrated the potential impact of semi-quantitative glucose-6-phosphate dehydrogenase (G6PD) testing and treatment with single-dose tafenoquine for Plasmodium vivax radical cure. This modelling has focused on predicting the number of vivax cases averted, rather than its cost-effectiveness. We explored the cost-effectiveness of using tafenoquine after G6PD screening as compared to usual practice (7-day low-dose primaquine (0.5 mg/kg/day) without G6PD screening) in Brazil using a 10-year time horizon with 5% discounting considering four scenarios: 1) tafenoquine for adults only assuming 66.7% primaquine treatment adherence, 2) tafenoquine for adults and children aged years assuming 66.7% primaquine adherence, 3) tafenoquine for adults only assuming 90% primaquine adherence, 4) tafenoquine for adults only assuming 30% primaquine adherence. The incremental cost-effectiveness ratios (ICERs) were estimated by iding the incremental costs by the disability-adjusted life-years (DALYs) averted. These were compared to a willingness to pay threshold of US$7,800 for Brazil, and one-way and probabilistic sensitivity analyses were performed. All four scenarios were cost-effective using this willingness to pay threshold with ICERs ranging from US$154–1836. One-way sensitivity analyses showed that the results were most sensitive to severity and mortality due to vivax malaria, the lifetime and number of semi-quantitative G6PD analysers needed, cost per malaria episode and per G6PD test strips, and life expectancy. All scenarios had a 100% likelihood of being cost-effective at the willingness to pay threshold. Tafenoquine prescribed after a semi-quantitative G6PD testing is highly likely to be cost-effective in Brazil.
The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis
Publisher: Public Library of Science (PLoS)
Date: 07-09-2021
DOI: 10.1371/JOURNAL.PMED.1003766
Abstract: Amodiaquine is a 4-aminoquinoline antimalarial similar to chloroquine that is used extensively for the treatment and prevention of malaria. Data on the cardiovascular effects of amodiaquine are scarce, although transient effects on cardiac electrophysiology (electrocardiographic QT interval prolongation and sinus bradycardia) have been observed. We conducted an in idual patient data meta-analysis to characterise the cardiovascular effects of amodiaquine and thereby support development of risk minimisation measures to improve the safety of this important antimalarial. Studies of amodiaquine for the treatment or prevention of malaria were identified from a systematic review. Heart rates and QT intervals with study-specific heart rate correction (QTcS) were compared within studies and in idual patient data pooled for multivariable linear mixed effects regression. The meta-analysis included 2,681 patients from 4 randomised controlled trials evaluating artemisinin-based combination therapies (ACTs) containing amodiaquine ( n = 725), lumefantrine ( n = 499), piperaquine ( n = 716), and pyronaridine ( n = 566), as well as monotherapy with chloroquine ( n = 175) for uncomplicated malaria. Amodiaquine prolonged QTcS (mean = 16.9 ms, 95% CI: 15.0 to 18.8) less than chloroquine (21.9 ms, 18.3 to 25.6, p = 0.0069) and piperaquine (19.2 ms, 15.8 to 20.5, p = 0.0495), but more than lumefantrine (5.6 ms, 2.9 to 8.2, p 0.001) and pyronaridine (−1.2 ms, −3.6 to +1.3, p 0.001). In in iduals aged ≥12 years, amodiaquine reduced heart rate (mean reduction = 15.2 beats per minute [bpm], 95% CI: 13.4 to 17.0) more than piperaquine (10.5 bpm, 7.7 to 13.3, p = 0.0013), lumefantrine (9.3 bpm, 6.4 to 12.2, p 0.001), pyronaridine (6.6 bpm, 4.0 to 9.3, p 0.001), and chloroquine (5.9 bpm, 3.2 to 8.5, p 0.001) and was associated with a higher risk of potentially symptomatic sinus bradycardia (≤50 bpm) than lumefantrine (risk difference: 14.8%, 95% CI: 5.4 to 24.3, p = 0.0021) and chloroquine (risk difference: 8.0%, 95% CI: 4.0 to 12.0, p 0.001). The effect of amodiaquine on the heart rate of children aged years compared with other antimalarials was not clinically significant. Study limitations include the unavailability of in idual patient-level adverse event data for most included participants, but no serious complications were documented. While caution is advised in the use of amodiaquine in patients aged ≥12 years with concomitant use of heart rate–reducing medications, serious cardiac conduction disorders, or risk factors for torsade de pointes, there have been no serious cardiovascular events reported after amodiaquine in widespread use over 7 decades. Amodiaquine and structurally related antimalarials in the World Health Organization (WHO)-recommended dose regimens alone or in ACTs are safe for the treatment and prevention of malaria.
Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data
Publisher: Public Library of Science (PLoS)
Date: 05-03-2020
Quantification of glucose-6-phosphate dehydrogenase activity by spectrophotometry: A systematic review and meta-analysis
Publisher: Public Library of Science (PLoS)
Date: 14-05-2020
Paucity of Plasmodium vivax Mature Schizonts in Peripheral Blood Is Associated With Their Increased Cytoadhesive Potential
Publisher: Oxford University Press (OUP)
Date: 09-01-2014
Abstract: There is now a growing body of evidence that challenges the current view that Plasmodium vivax-infected erythrocyte (Pv-iE) are unable to sequester. Here we used ex vivo adhesion assays with Pv-iE before and after maturation to demonstrate a higher binding potential of schizonts compared to other asexual stages. These experimental results are correlated with our observations in a panel of 50 vivax malaria patients where schizonts were completely absent in 27 isolates, and few schizonts were observed in the remaining patients. These observations prompt a paradigm shift in P. vivax biology and open avenues to investigate the role of Pv-iE sequestration.
G6PD testing in support of treatment and elimination of malaria: recommendations for evaluation of G6PD tests
Publisher: Springer Science and Business Media LLC
Date: 04-11-2013
Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.
Publisher: Springer Science and Business Media LLC
Date: 10-10-2023
Clinical performance validation of the STANDARD G6PD Test: A multi-country pooled analysis
Publisher: Cold Spring Harbor Laboratory
Date: 13-12-2022
DOI: 10.1101/2022.12.11.22282391
Abstract: Screening for G6PD deficiency can inform disease management including malaria. Treatment with the antimalarial drugs primaquine and tafenoquine can be guided by point-of-care testing for G6PD deficiency. Data from similar clinical studies evaluating the performance of the STANDARD ™ G6PD Test (SD Biosensor, South Korea) conducted in Bangladesh, Brazil, Ethiopia, India, Thailand, the United Kingdom, and the United States were pooled. Test performance was assessed in a retrospective analysis on capillary and venous specimens. All study sites used spectrophotometry for reference G6PD testing, and either the HemoCue or complete blood count for reference hemoglobin measurement. The sensitivity of the STANDARD ™ G6PD Test using the manufacturer thresholds for G6PD deficient and intermediate cases in capillary specimens from 4212 study participants was 100% (95% Confidence Interval (CI): 97.5%–100%) for G6PD deficient cases with % activity and 77% (95% CI 66.8%– 85.4%) for females with intermediate activity between 30%–70%. Specificity was 98.1% (95% CI 97.6%–98.5%) and 92.8% (95% CI 91.6%–93.9%) for G6PD deficient in iduals and intermediate females, respectively. The majority (12/20) of G6PD intermediate females with false normal results had activity levels % on the reference assay. Negative predictive values for females with G6PD activity % was 99.6% (95% CI 99.1%–99.8%) on capillary specimens. Test sensitivity among 396 P. vivax malaria cases was 100% (69.2%–100.0%) for both deficient and intermediate cases. In the study population, a high proportion of those classified as G6PD deficient or intermediate resulted from true normal cases. Despite this, the majority cases would receive the correct medication and no true G6PD deficient cases would be treated inappropriately. The STANDARD G6PD Test enables safe access to drugs which are contraindicated for in iduals with G6PD deficiency. Operational considerations will inform test uptake in specific settings.
Antibodies to Plasmodium vivax reticulocyte binding protein 2b are associated with protection against P. vivax malaria in populations living in low malaria transmission regions of Brazil and Thailand
Publisher: Public Library of Science (PLoS)
Date: 19-08-2019
Estimated impact of tafenoquine for Plasmodium vivax control and elimination in Brazil: A modelling study
Publisher: Public Library of Science (PLoS)
Date: 23-04-2021
DOI: 10.1371/JOURNAL.PMED.1003535
Abstract: Despite recent intensification of control measures, Plasmodium vivax poses a major challenge for malaria elimination efforts. Liver-stage hypnozoite parasites that cause relapsing infections can be cleared with primaquine however, poor treatment adherence undermines drug effectiveness. Tafenoquine, a new single-dose treatment, offers an alternative option for preventing relapses and reducing transmission. In 2018, over 237,000 cases of malaria were reported to the Brazilian health system, of which 91.5% were due to P . vivax . We evaluated the impact of introducing tafenoquine into case management practices on population-level transmission dynamics using a mathematical model of P . vivax transmission. The model was calibrated to reflect the transmission dynamics of P . vivax endemic settings in Brazil in 2018, informed by nationwide malaria case reporting data. Parameters for treatment pathways with chloroquine, primaquine, and tafenoquine with glucose-6-phosphate dehydrogenase deficiency (G6PDd) testing were informed by clinical trial data and the literature. We assumed 71.3% efficacy for primaquine and tafenoquine, a 66.7% adherence rate to the 7-day primaquine regimen, a mean 5.5% G6PDd prevalence, and 8.1% low metaboliser prevalence. The introduction of tafenoquine is predicted to improve effective hypnozoite clearance among P . vivax cases and reduce population-level transmission over time, with heterogeneous levels of impact across different transmission settings. According to the model, while achieving elimination in only few settings in Brazil, tafenoquine rollout in 2021 is estimated to improve the mean effective radical cure rate from 42% (95% uncertainty interval [UI] 41%–44%) to 62% (95% UI 54%–68%) among clinical cases, leading to a predicted 38% (95% UI 7%–99%) reduction in transmission and over 214,000 cumulative averted cases between 2021 and 2025. Higher impact is predicted in settings with low transmission, low pre-existing primaquine adherence, and a high proportion of cases in working-aged males. High-transmission settings with a high proportion of cases in children would benefit from a safe high-efficacy tafenoquine dose for children. Our methodological limitations include not accounting for the role of imported cases from outside the transmission setting, relying on reported clinical cases as a measurement of community-level transmission, and implementing treatment efficacy as a binary condition. In our modelling study, we predicted that, provided there is concurrent rollout of G6PDd diagnostics, tafenoquine has the potential to reduce P . vivax transmission by improving effective radical cure through increased adherence and increased protection from new infections. While tafenoquine alone may not be sufficient for P . vivax elimination, its introduction will improve case management, prevent a substantial number of cases, and bring countries closer to achieving malaria elimination goals.
An open dataset of Plasmodium vivax genome variation in 1,895 worldwide samples
Publisher: F1000 Research Ltd
Date: 14-04-2022
DOI: 10.12688/WELLCOMEOPENRES.17795.1
Abstract: This report describes the MalariaGEN Pv4 dataset, a new release of curated genome variation data on 1,895 s les of Plasmodium vivax collected at 88 worldwide locations between 2001 and 2017. It includes 1,370 new s les contributed by MalariaGEN and VivaxGEN partner studies in addition to previously published s les from these and other sources. We provide genotype calls at over 4.5 million variable positions including over 3 million single nucleotide polymorphisms (SNPs), as well as short indels and tandem duplications. This enlarged dataset highlights major compartments of parasite population structure, with clear differentiation between Africa, Latin America, Oceania, Western Asia and different parts of Southeast Asia. Each s le has been classified for drug resistance to sulfadoxine, pyrimethamine and mefloquine based on known markers at the dhfr , dhps and mdr1 loci. The prevalence of all of these resistance markers was much higher in Southeast Asia and Oceania than elsewhere. This open resource of analysis-ready genome variation data from the MalariaGEN and VivaxGEN networks is driven by our collective goal to advance research into the complex biology of P. vivax and to accelerate genomic surveillance for malaria control and elimination.
Difference in clinical features of SARS-CoV-2 in pediatric patients before and after emergence of P.1
Publisher: Springer Science and Business Media LLC
Date: 13-04-2022
DOI: 10.1038/S41390-022-02046-3
Abstract: The P.1 variant is a Variant of Concern announced by the WHO. The present work aimed to characterize the clinical features of pediatric patients with SARS-CoV-2 before and after the emergence of P.1. This is a cohort study. Data of symptomatic patients younger than 18 years diagnosed with COVID-19 by PCR tests registered in Painel COVID-19 Amazonas were analyzed. A total of 4080 symptomatic pediatric patients were identified in the database between March 2020 and July 2021, of which 1654 were categorized as pre-P.1 and 978 as P.1-dominant cases, based on the prevalence of P.1 of % in the North Region, Brazil. Lower case-fatality rate was observed in non-infants infected during the P.1-dominant period (0.9% vs. 2.2%). In general, patients infected during the P.1-dominant period had less fever (70.8% vs. 74.2%) and less lower respiratory tract symptoms (respiratory distress: 11.8% vs. 18.9%, dyspnea: 27.9% vs. 34.5%) yet higher prevalence of neurological symptoms, headache for ex le (42.8% vs. 5.9%). The prevalence of symptoms of COVID-19 can differ across different periods of variant dominance. Lower prevalence of fever during the P.1-dominant period may reduce the effectiveness of symptom-based screening in public premises where laboratory diagnostic tests are not available. The prevalence rate of symptoms of SARS-CoV-2 infection can differ among different variants. The present work documents the difference in the clinical features of SARS-CoV-2 in patients aged below 18 years before and after the emergence of P.1, the first study of its kind. Unlike previous studies that focus solely on hospitalized cases, the present work considers both mild and severe cases. While non-infants had a lower fatality rate, lower prevalence of fever associated with the emergence of P.1 may reduce the effectiveness of symptom-based screening in public premises where laboratory diagnostic tests are not available.
On the Cytoadhesion ofPlasmodium vivax–Infected Erythrocytes
Publisher: Oxford University Press (OUP)
Date: 15-08-2010
DOI: 10.1086/654815
Abstract: Plasmodium falciparum and Plasmodium vivax are responsible for most of the global burden of malaria. Although the accentuated pathogenicity of P. falciparum occurs because of sequestration of the mature erythrocytic forms in the microvasculature, this phenomenon has not yet been noted in P. vivax. The increasing number of severe manifestations of P. vivax infections, similar to those observed for severe falciparum malaria, suggests that key pathogenic mechanisms (eg, cytoadherence) might be shared by the 2 parasites. Mature P. vivax-infected erythrocytes (Pv-iEs) were isolated from blood s les collected from 34 infected patients. Pv-iEs enriched on Percoll gradients were used in cytoadhesion assays with human lung endothelial cells, Saimiri brain endothelial cells, and placental cryosections. Pv-iEs were able to cytoadhere under static and flow conditions to cells expressing endothelial receptors known to mediate the cytoadhesion of P. falciparum. Although Pv-iE cytoadhesion levels were 10-fold lower than those observed for P. falciparum-infected erythrocytes, the strength of the interaction was similar. Cytoadhesion of Pv-iEs was in part mediated by VIR proteins, encoded by P. vivax variant genes (vir), given that specific antisera inhibited the Pv-iE-endothelial cell interaction. These observations prompt a modification of the current paradigms of the pathogenesis of malaria and clear the way to investigate the pathophysiology of P. vivax infections.
In silico epitope mapping and experimental evaluation of the Merozoite Adhesive Erythrocytic Binding Protein (MAEBL) as a malaria vaccine candidate
Publisher: Springer Science and Business Media LLC
Date: 10-01-2018
A Worldwide Map ofPlasmodium falciparumK13-Propeller Polymorphisms
Publisher: Massachusetts Medical Society
Date: 23-06-2016
The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine: a WorldWide Antimalarial Resistance Network systematic review and individual patien
Publisher: Springer Science and Business Media LLC
Date: 08-2019
Development and validation of serological markers for detecting recent Plasmodium vivax infection
Publisher: Springer Science and Business Media LLC
Date: 05-2020
Challenges for Diagnosis of Malaria and Neglected Tropical Diseases in Elimination Settings
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/270756
Severe Hemolysis during Primaquine Radical Cure of Plasmodium vivax Malaria: Two Systematic Reviews and Individual Patient Data Descriptive Analyses
Publisher: American Society of Tropical Medicine and Hygiene
Date: 21-08-2023
Abstract: Primaquine (PQ) kills Plasmodium vivax hypnozoites but can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We conducted two systematic reviews. The first used data from clinical trials to determine the variety of definitions and frequency of hematological serious adverse events (SAEs) related to PQ treatment of vivax malaria. The second used data from prospective studies and case reports to describe the clinical presentation, management, and outcome of severe PQ-associated hemolysis necessitating hospitalization. In the first review, SAEs were reported in 70 of 249 clinical trials. There were 34 hematological SAEs among 9,824 patients with P. vivax malaria treated with PQ, nine of which necessitated hospitalization or blood transfusion. Criteria used to define SAEs were erse. In the second review, 21 of 8,487 articles screened reported 163 patients hospitalized after PQ radical cure 79.9% of whom (123 of 154) were prescribed PQ at ≥ 0.5 mg/kg/day. Overall, 101 patients were categorized as having probable or possible severe PQ-associated hemolysis, 96.8% of whom were G6PD deficient ( 30% activity). The first symptoms of hemolysis were reported primarily on day 2 or 3 (45.5%), and all patients were hospitalized within 7 days of PQ commencement. A total of 57.9% of patients (77 of 133) had blood transfusion. Seven patients (6.9%) with probable or possible hemolysis died. Even when G6PD testing is available, enhanced monitoring for hemolysis is warranted after PQ treatment. Clinical review within the first 5 days of treatment may facilitate early detection and management of hemolysis. More robust definitions of severe PQ-associated hemolysis are required.
Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials
Publisher: Springer Science and Business Media LLC
Date: 14-05-2021
Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis
Publisher: Elsevier BV
Date: 10-2023
Primaquine dose and the risk of haemolysis in patients with uncomplicated Plasmodium vivax malaria: a systematic review and individual patient data meta-analysis
Publisher: Elsevier BV
Date: 09-2023
Clinical performance validation of the STANDARD G6PD test: A multi-country pooled analysis.
Publisher: Public Library of Science (PLoS)
Date: 12-10-2023
The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis
Publisher: Elsevier BV
Date: 09-2018
Off-target effects of bacillus Calmette–Guérin vaccination on immune responses to SARS-CoV-2: implications for protection against severe COVID-19
Publisher: Wiley
Date: 2022
DOI: 10.1002/CTI2.1387
Abstract: Because of its beneficial off‐target effects against non‐mycobacterial infectious diseases, bacillus Calmette–Guérin (BCG) vaccination might be an accessible early intervention to boost protection against novel pathogens. Multiple epidemiological studies and randomised controlled trials (RCTs) are investigating the protective effect of BCG against coronavirus disease 2019 (COVID‐19). Using s les from participants in a placebo‐controlled RCT aiming to determine whether BCG vaccination reduces the incidence and severity of COVID‐19, we investigated the immunomodulatory effects of BCG on in vitro immune responses to SARS‐CoV‐2. This study used peripheral blood taken from participants in the multicentre RCT and BCG vaccination to reduce the impact of COVID‐19 on healthcare workers (BRACE trial). The whole blood taken from BRACE trial participants was stimulated with γ‐irradiated SARS‐CoV‐2‐infected or mock‐infected Vero cell supernatant. Cytokine responses were measured by multiplex cytokine analysis, and single‐cell immunophenotyping was made by flow cytometry. BCG vaccination, but not placebo vaccination, reduced SARS‐CoV‐2‐induced secretion of cytokines known to be associated with severe COVID‐19, including IL‐6, TNF‐α and IL‐10. In addition, BCG vaccination promoted an effector memory phenotype in both CD4 + and CD8 + T cells, and an activation of eosinophils in response to SARS‐CoV‐2. The immunomodulatory signature of BCG’s off‐target effects on SARS‐CoV‐2 is consistent with a protective immune response against severe COVID‐19.
Related Organisations
University Of Texas Medical Branch
Location: United States of America
Fundação De Medicina Tropical Dr Heitor Vieira Dourado
Location: Brazil
Instituto Leônidas E Maria Deane - ILMD/Fiocruz Amaônia
Location: Brazil
Fundação De Medicina Tropical Doutor Heitor Vieira Dourado
Location: Brazil
Related Funding Activities
No related grants have been discovered for Marcus Vinicius Guimarães de Lacerda.