Relapsing Plasmodium vivax malaria in a 12-year-old Brazilian girl: A case report.

Plasmodium vivax causes the vast majority of malaria cases in Brazil. The lifecycle of this parasite includes a latent stage in the liver, the hypnozoite. Reactivation of hypnozoites induces repeated relapses. We report a case of two relapses of vivax malaria in a teenage girl after conventional treatment with chloroquine and primaquine. Chloroquine prophylactic treatment for three months was prescribed with a favourable outcome of the case.

Is Brazil reaching malaria elimination? A time series analysis of malaria cases from 2011 to 2023.

In Brazil, 99% of malaria cases occur in the Amazon region, mainly caused by Plasmodium vivax (~83%) and Plasmodium falciparum (Pf) species. Aligned with the Sustainable Development Goals, Brazil aims to eliminate autochthonous malaria by 2035. This study aims to analyse epidemiological patterns of malaria in Brazil to discuss if Brazil is on track to meet malaria control targets. A time-series study was conducted analysing autochthonous malaria new infections notifications in the Brazilian Amazon region from 2011 until June 2023. Descriptive analyses were conducted, along with joinpoint regression and forecast models to verify trend and future behaviour. A total of 2,067,030 malaria cases were reported in the period. Trend analysis indicated a decreasing trend in all malaria infections since late 2017 (monthly reduction = 0.81%, p-value <0.05), while Pf infections have increased progressively since 2015 (monthly increase = 0.46%, p-value <0.05). Forecast models predict over 124,000 malaria cases in 2023 and over 96,000 cases in 2024. Predictions for Pf infections are around 23,900 cases in 2023 and 22,300 in 2024. Cases in indigenous population villages are predicted to reach 48,000 cases in 2023 and over 51,000 in 2024. In gold mining areas it is expected over 21,000 cases in 2023 and over 20.000 in 2024. Malaria elimination in Brazil has advanced over the last decade, but its speed has slowed. The country exhibits noteworthy advancements in the reduction of overall malaria cases. It is imperative, however, to proactively target specific issues such as the incidence raise among indigenous populations and in gold mining areas. Pf infections remain a persistent challenge to control in the country and may require novel measures for containment. Current government supporting actions towards combating illegal goldmining activities and protecting indigenous populations may help malaria control indicators for the following years.

Live, Attenuated, Tetravalent Butantan-Dengue Vaccine in Children and Adults.

BACKGROUND: Butantan-Dengue Vaccine (Butantan-DV) is an investigational, single-dose, live, attenuated, tetravalent vaccine against dengue disease, but data on its overall efficacy are needed. METHODS: In an ongoing phase 3, double-blind trial in Brazil, we randomly assigned participants to receive Butantan-DV or placebo, with stratification according to age (2 to 6 years, 7 to 17 years, and 18 to 59 years); 5 years of follow-up is planned. The objectives of the trial were to evaluate overall vaccine efficacy against symptomatic, virologically confirmed dengue of any serotype occurring more than 28 days after vaccination (the primary efficacy end point), regardless of serostatus at baseline, and to describe safety up to day 21 (the primary safety end point). Here, vaccine efficacy was assessed on the basis of 2 years of follow-up for each participant, and safety as solicited vaccine-related adverse events reported up to day 21 after injection. Key secondary objectives were to assess vaccine efficacy among participants according to dengue serostatus at baseline and according to the dengue viral serotype; efficacy according to age was also assessed. RESULTS: Over a 3-year enrollment period, 16,235 participants received either Butantan-DV (10,259 participants) or placebo (5976 participants). The overall 2-year vaccine efficacy was 79.6% (95% confidence interval [CI], 70.0 to 86.3) - 73.6% (95% CI, 57.6 to 83.7) among participants with no evidence of previous dengue exposure and 89.2% (95% CI, 77.6 to 95.6) among those with a history of exposure. Vaccine efficacy was 80.1% (95% CI, 66.0 to 88.4) among participants 2 to 6 years of age, 77.8% (95% CI, 55.6 to 89.6) among those 7 to 17 years of age, and 90.0% (95% CI, 68.2 to 97.5) among those 18 to 59 years of age. Efficacy against DENV-1 was 89.5% (95% CI, 78.7 to 95.0) and against DENV-2 was 69.6% (95% CI, 50.8 to 81.5). DENV-3 and DENV-4 were not detected during the follow-up period. Solicited systemic vaccine- or placebo-related adverse events within 21 days after injection were more common with Butantan-DV than with placebo (58.3% of participants, vs. 45.6%). CONCLUSIONS: A single dose of Butantan-DV prevented symptomatic DENV-1 and DENV-2, regardless of dengue serostatus at baseline, through 2 years of follow-up. (Funded by Instituto Butantan and others; DEN-03-IB ClinicalTrials.gov number, NCT02406729, and WHO ICTRP number, U1111-1168-8679.).

Record Linkage for Malaria Deaths Data Recovery and Surveillance in Brazil.

OBJECTIVE: The objective is to describe the results and the methodological processes of record linkage for matching deaths and malaria cases. METHODS: A descriptive cross-sectional study was conducted with probabilistic record linkage of death and malaria cases data in Brazil from 2011 to 2020 using death records from the Mortality Information System (SIM) and epidemiological data from the Notifiable Diseases Information System (Sinan) and Epidemiological Surveillance Information Systems for malaria (Sivep-Malaria). Three matching keys were used: patient's name, date of birth, and mother's name, with an analysis of cosine and Levenshtein dissimilarity measures. RESULTS: A total of 490 malaria deaths were recorded in Brazil between 2011 and 2020. The record linkage resulted in the pairing of 216 deaths (44.0%). Pairings where all three matching keys were identical accounted for 30.1% of the total matched deaths, 39.4% of the matched deaths had two identical variables, and 30.5% had only one of the three key variables identical. The distribution of the variables of the matched deaths (216) was similar to the distribution of all recorded deaths (490). Out of the 216 matched deaths, 80 (37.0%) had poorly specified causes of death in the SIM. CONCLUSIONS: The record linkage allowed for the detailing of the data with additional information from other epidemiological systems. Record linkage enables data linkage between information systems that lack interoperability and is an extremely useful tool for refining health situation analyses and improving malaria death surveillance in Brazil.

Assessing the impact of the "malaria supporters project" intervention to malaria control in the Brazilian Amazon: an interrupted time-series analysis.

BACKGROUND: In 2021, Brazil was responsible for more than 25% of malaria cases in the Americas. Although the country has shown a reduction of cases in the last decades, in 2021 it reported over 139,000 malaria cases. One major malaria control strategy implemented in Brazil is the "Malaria Supporters Project", which has been active since 2012 and is directed to municipalities responsible for most Brazil's cases. The objective of this study is to analyse the intervention effect on the selected municipalities. METHODS: An ecological time-series analysis was conducted to assess the "Malaria Supporters Project" effect. The study used data on Annual Parasitic Incidence (API) spanning the period from 2003 to 2020 across 48 intervention municipalities and 88 control municipalities. To evaluate the intervention effect a Prais-Winsten segmented regression model was fitted to the difference in malaria Annual Parasitic Incidence (API) between control and intervention areas. RESULTS: The intervention group registered 1,104,430 cases between 2012 and 2020, a 50.6% reduction compared to total cases between 2003 and 2011. In 2020 there were 95,621 cases, 50.4% fewer than in 2011. The number of high-risk municipalities (API > 50 cases/1000) reduced from 31 to 2011 to 17 in 2020. The segmented regression showed a significant 42.0 cases/1000 residents annual decrease in API compared to control group. CONCLUSIONS: The intervention is not a silver bullet to control malaria, but it has reduced API in locations with high malaria endemicity. Furthermore, the model has the potential to be replicated in other countries with similar epidemiological scenarios.

Multicenter study of the natural history and therapeutic responses of patients with chikungunya, focusing on acute and chronic musculoskeletal manifestations - a study protocol from the clinical and applied research in Chikungunya (REPLICK network).

BACKGROUND: Chikungunya is associated with high morbidity and the natural history of symptomatic infection has been divided into three phases (acute, post-acute, and chronic) according to the duration of musculoskeletal symptoms. Although this classification has been designed to help guide therapeutic decisions, it does not encompass the complexity of the clinical expression of the disease and does not assist in the evaluation of the prognosis of severity nor chronic disease. Thus, the current challenge is to identify and diagnose musculoskeletal disorders and to provide the optimal treatment in order to prevent perpetuation or progression to a potentially destructive disease course. METHODS: The study is the first product of the Clinical and Applied Research Network in Chikungunya (REPLICK). This is a prospective, outpatient department-based, multicenter cohort study in Brazil. Four work packages were defined: i. Clinical research; ii) Translational Science - comprising immunology and virology streams; iii) Epidemiology and Economics; iv) Therapeutic Response and clinical trials design. Scheduled appointments on days 21 (D21) ± 7 after enrollment, D90 ± 15, D120 ± 30, D180 ± 30; D360 ± 30; D720 ± 60, and D1080 ± 60 days. On these visits a panel of blood tests are collected in addition to the clinical report forms to obtain data on socio-demographic, medical history, physical examination and questionnaires devoted to the evaluation of musculoskeletal manifestations and overall health are performed. Participants are asked to consent for their specimens to be maintained in a biobank. Aliquots of blood, serum, saliva, PAXgene, and when clinically indicated to be examined, synovial fluid, are stored at -80° C. The study protocol was submitted and approved to the National IRB and local IRB at each study site. DISCUSSION: Standardized and harmonized patient cohorts are needed to provide better estimates of chronic arthralgia development, the clinical spectra of acute and chronic disease and investigation of associated risk factors. This study is the largest evaluation of the long-term sequelae of individuals infected with CHIKV in the Brazilian population focusing on musculoskeletal manifestations, mental health, quality of life, and chronic pain. This information will both define disease burden and costs associated with CHIKV infection, and better inform therapeutic guidelines.

Lessons Learned from a Global Perspective of Coronavirus Disease-2019.

Coronavirus disease-2019 has impacted the world globally. Countries and health care organizations across the globe responded to this unprecedented public health crisis in a varied manner in terms of public health and social measures, vaccination development and rollout, the conduct of research, developments of therapeutics, sharing of information, and in how they continue to deal with the widespread aftermath. This article reviews the various elements of the global response to the pandemic, focusing on the lessons learned and strategies to consider during future pandemics.

Brain damage serum biomarkers induced by COVID-19 in patients from northeast Brazil.

Neurological symptoms have been often reported in COVID-19 disease. In the present study, we evaluated brain damage associated with the increase of serum levels of neurological biomarkers S100B and neuron-specific enolase (NSE) induced by SARS-CoV-2 infection, in a population from Northeastern Brazil. Thirty-six healthy control (G1) individuals and 141 patients with confirmed COVID-19 were enrolled in this study. Positive-COVID-19 patients were divided into two groups according to the severity of illness by the National Institute of Health (NIH) criteria, 76 patients with mild symptoms for COVID-19 and (G2) and 65 with acute respiratory conditions requiring supplemental oxygenation via intensive care unit (ICU) admission (G3). A follow-up study was conducted with 23 patients from G2 14 (D14) and 21 (D21) days after the onset of symptoms. Serum levels of NSE and S100B were measured using the enzyme-linked immunoassay method (ELISA). Results revealed a significant positive association between G3 patients and S100B serum expression (p = 0.0403). The serum levels of NSE were also significantly enhanced in the G3 group compared to the control (p < 0.0001) and G2 group (p < 0.0001). In addition, clinical features such as symptoms and oxygenation status were not correlated with NSE or S100B serum expression. The follow-up study demonstrated a decrease over time (21 days) in NSE serum expression (p < 0.0001). These results suggest that brain damage is followed by acute virus exposure, with no long-term effects. Future work examining COVID-19 recovery will shed light on chronic neurological damage of SARS-CoV-2 infection.

Post-Mortem Diagnosis of Pediatric Dengue Using Minimally Invasive Autopsy during the COVID-19 Pandemic in Brazil.

We report the first pediatric disease in which the use of minimally invasive autopsy (MIA) confirmed severe dengue as the cause of death. During the COVID-19 pandemic, a previously healthy 10-year-old girl living in north-eastern Brazil presented fever, headache, diffuse abdominal pain, diarrhoea, and vomiting. On the fourth day, the clinical symptoms worsened and the patient died. An MIA was performed, and cores of brain, lungs, heart, liver, kidneys, and spleen were collected with 14G biopsy needles. Microscopic examination showed diffuse oedema and congestion, pulmonary intra-alveolar haemorrhage, small foci of midzonal necrosis in the liver, and tubular cell necrosis in the kidneys. Dengue virus RNA and NS1 antigen were detected in blood and cerebrospinal fluid samples. Clinical, pathological, and laboratory findings, in combination with the absence of other lesions and microorganisms, allowed concluding that the patient had died from complications of severe dengue.

Mapping the global landscape of chikungunya rapid diagnostic tests: A scoping review.

BACKGROUND: Chikungunya (CHIKV) is a reemerging arboviral disease and represents a global health threat because of the unprecedented magnitude of its spread. Diagnostics strategies rely heavily on reverse transcriptase-polymerase chain reaction (RT-PCR) and antibody detection by enzyme-linked Immunosorbent assay (ELISA). Rapid diagnostic tests (RDTs) are available and promise to decentralize testing and increase availability at lower healthcare system levels. OBJECTIVES: We aim to identify the extent of research on CHIKV RDTs, map the global availability of CHIKV RDTs, and evaluate the accuracy of CHIKV RDTs for the diagnosis of CHIKV. ELIGIBILITY CRITERIA: We included studies reporting symptomatic individuals suspected of CHIKV, tested with CHIKV RDTs, against the comparator being a validated laboratory-based RT-PCR or ELISA assay. The primary outcome was the accuracy of the CHIKV RDT when compared with reference assays. SOURCES OF EVIDENCE: Medline, EMBASE, and Scopus were searched from inception to 13 October 2021. National regulatory agencies (European Medicines Agency, US Food and Drug Administration, and the Brazilian National Health Surveillance Agency) were also searched for registered CHIKV RDTs. RESULTS: Seventeen studies were included and corresponded to 3,222 samples tested with RDTs between 2005 and 2018. The most development stage of CHIKV RDTs studies was Phase I (7/17 studies) and II (7/17 studies). No studies were in Phase IV. The countries that manufacturer the most CHIKV RDTs were Brazil (n = 17), followed by the United States of America (n = 7), and India (n = 6). Neither at EMA nor FDA-registered products were found. Conversely, the ANVISA has approved 23 CHIKV RDTs. Antibody RDTs (n = 43) predominated and demonstrated sensitivity between 20% and 100%. The sensitivity of the antigen RDTs ranged from 33.3% to 100%. CONCLUSIONS: The landscape of CHIKV RDTs is fragmented and needs coordinated efforts to ensure that patients in CHIKV-endemic areas have access to appropriate RDTs. Further research is crucial to determine the impact of such tests on integrated fever case management and prescription practices for acute febrile patients.

Household clustering supports a novel chemoprophylaxis trial design for a mosquito-borne viral disease.

Infections because of chikungunya and other mosquito-borne viruses, such as dengue and Zika, represent an area of significant unmet medical need. There are currently no approved medicines for prophylaxis or treatment of these diseases, and the development and implementation of vaccines against these viruses have proved problematic. Although antiviral molecules with treatment and prophylactic potential against the chikungunya virus have been identified, no successful field trials have been reported. Chemoprophylaxis may be attractive for unvaccinated at-risk populations; however, performing a successful chemoprophylaxis trial during a chikungunya outbreak will require a clearly identifiable at-risk population. We propose the application of a household transmission model as used in testing drugs against respiratory viruses. Current evidence on household clustering of chikungunya and other Aedes mosquito-borne viral infections is supportive. We suggest that this model may improve prophylaxis trial feasibility and focus research and future treatment on a population likely to benefit.

The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis.

BACKGROUND: 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 individual 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. METHODS AND FINDINGS: 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 individual 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 individuals 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 <12 years compared with other antimalarials was not clinically significant. Study limitations include the unavailability of individual patient-level adverse event data for most included participants, but no serious complications were documented. CONCLUSIONS: 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.

The emergence of novel SARS-CoV-2 variant P.1 in Amazonas (Brazil) was temporally associated with a change in the age and sex profile of COVID-19 mortality: A population based ecological study.

BACKGROUND: Since the end of 2020, there has been a great deal of international concern about the variants of SARS-COV-2 B.1.1.7, identified in the United Kingdom; B.1.351 discovered in South Africa and P.1, originating from the Brazilian state of Amazonas. The three variants were associated with an increase in transmissibility and worsening of the epidemiological situation in the places where they expanded. The lineage B.1.1.7 was associated with the increase in case fatality rate in the United Kingdom. There are still no studies on the case fatality rate of the other two variants. The aim of this study was to analyze the mortality profile before and after the emergence of the P.1 strain in the Amazonas state. METHODS: We analyzed data from the Influenza Epidemiological Surveillance Information System, SIVEP-Gripe (Sistema de Informação de Vigilância Epidemiológica da Gripe), comparing two distinct epidemiological periods: during the peak of the first wave, between April and May 2020, and in January 2021 (the second wave), the month in which the new variant came to predominate. We calculated mortality rates, overall case fatality rate and case fatality rate among hospitalized patients; all rates were calculated by age and gender and 95% confidence intervals (95% CI) were determined. FINDINGS: We observed that in the second wave there were a higher incidence and an increase in the proportion of cases of COVID-19 in the younger age groups. There was also an increase in the proportion of women among Severe Acute Respiratory Infection (SARI) cases from 40% (2,709) in the first wave to 47% (2,898) in the second wave and in the proportion of deaths due to COVID-19 between the two periods varying from 34% (1,051) to 47% (1,724), respectively. In addition, the proportion of deaths among people between 20 and 59 years old has increased in both sexes. The case fatality rate among those hospitalized in the population between 20 and 39 years old during the second wave was 2.7 times the rate observed in the first wave (female rate ratio = 2.71; 95% CI: 1.9-3.9], p <0.0001; male rate ratio = 2.70, 95%CI:2.0-3.7), and in the general population the rate ratios were 1.15 (95% CI: 1.1-1.2) in females and 0.78 (95% CI: 0.7-0.8) in males]. INTERPRETATION: Based on this prompt analysis of the epidemiological scenario in the Amazonas state, the observed changes in the pattern of mortality due to COVID-19 between age groups and gender simultaneously with the emergence of the P.1 strain suggest changes in the pathogenicity and virulence profile of this new variant. Further studies are needed to better understanding of SARS-CoV-2 variants profile and their impact for the health population. FUNDING: There was no funding for this study.

Effectiveness of CoronaVac among healthcare workers in the setting of high SARS-CoV-2 Gamma variant transmission in Manaus, Brazil: A test-negative case-control study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, Gamma, emerged in the city of Manaus in late 2020 during a large resurgence of coronavirus disease (COVID-19), and has spread throughout Brazil. The effectiveness of vaccines in settings with widespread Gamma variant transmission has not been reported. METHODS: We performed a matched test-negative case-control study to estimate the effectiveness of an inactivated vaccine, CoronaVac, in healthcare workers (HCWs) in Manaus, where the Gamma variant accounted for 86% of genotyped SARS-CoV-2 samples at the peak of its epidemic. We performed an early analysis of effectiveness following administration of at least one vaccine dose and an analysis of effectiveness of the two-dose schedule. The primary outcome was symptomatic SARS-CoV-2 infection. FINDINGS: For the early at-least-one-dose and two-dose analyses the study population was, respectively, 53,176 and 53,153 HCWs residing in Manaus and aged 18 years or older, with complete information on age, residence, and vaccination status. Among 53,153 HCWs eligible for the two-dose analysis, 47,170 (89%) received at least one dose of CoronaVac and 2,656 individuals (5%) underwent RT-PCR testing from 19 January, 2021 to 13 April, 2021. Of 3,195 RT-PCR tests, 885 (28%) were positive. 393 and 418 case-control pairs were selected for the early and two-dose analyses, respectively, matched on calendar time, age, and neighbourhood. Among those who had received both vaccine doses before the RT-PCR sample collection date, the average time from second dose to sample collection date was 14 days (IQR 7-24). In the early analysis, vaccination with at least one dose was associated with a 0.50-fold reduction (adjusted vaccine effectiveness (VE), 49.6%, 95% CI 11.3 to 71.4) in the odds of symptomatic SARS-CoV-2 infection during the period 14 days or more after receiving the first dose. However, we estimated low effectiveness (adjusted VE 36.8%, 95% CI -54.9 to 74.2) of the two-dose schedule against symptomatic SARS-CoV-2 infection during the period 14 days or more after receiving the second dose. A finding that vaccinated individuals were much more likely to be infected than unvaccinated individuals in the period 0-13 days after first dose (aOR 2.11, 95% CI 1.36-3.27) suggests that unmeasured confounding led to downward bias in the vaccine effectiveness estimate. INTERPRETATION: Evidence from this test-negative study of the effectiveness of CoronaVac was mixed, and likely affected by bias in this setting. Administration of at least one vaccine dose showed effectiveness against symptomatic SARS-CoV-2 infection in the setting of epidemic Gamma variant transmission. However, the low estimated effectiveness of the two-dose schedule underscores the need to maintain non-pharmaceutical interventions while vaccination campaigns with CoronaVac are being implemented. FUNDING: Fundação Oswaldo Cruz (Fiocruz); Municipal Health Secretary of Manaus; Fundação de Vigilância em Saúde do Amazonas.

Increased primaquine total dose prevents Plasmodium vivax relapses in patients with impaired CYP2D6 activity: report of three cases.

BACKGROUND: The relapsing nature of Plasmodium vivax infection is a major barrier to its control and elimination. Factors such as adequate dosing, adherence, drug quality, and pharmacogenetics can impact the effectiveness of radical cure of P. vivax and need to be adequately evaluated. CYP2D6 pathway mediates the activation of primaquine (primaquine) into an active metabolite(s) in hepatocytes, and impaired activity has been linked to a higher risk of relapse. CASES PRESENTATION: Three patients diagnosed with P. vivax malaria presented repeated relapses after being initially treated with chloroquine (25 mg/kg) and primaquine (3.5 mg/kg in 14 days) at a non-endemic travel clinic. Recurring episodes were subsequently treated with a higher dose of primaquine (7 mg/kg in 14 days), which prevented further relapses in two patients. However, one patient still presented two episodes after a higher primaquine dose and was prescribed 300 mg of chloroquine weekly to prevent further episodes. Impaired CYP2D6 function was observed in all of them. CONCLUSION: Lack of response to primaquine was associated with impaired CYP2D6 activity in three patients presenting multiple relapses followed in a non-endemic setting. Higher primaquine dosage was safe and effectively prevented relapses in two patients and should be further investigated as an option in Latin America. It is crucial to investigate the factors associated with unsuccessful radical cures and alternative therapeutic options.

Short-Time Recurrences of Plasmodium vivax Malaria as a Public Health Proxy for Chloroquine-Resistance Surveillance: A Spatio-Temporal Study in the Brazilian Amazon.

In Brazil, malaria caused by Plasmodium vivax presents control challenges due to several reasons, among them the increasing possibility of failure of P. vivax treatment due to chloroquine-resistance (CQR). Despite limited reports of CQR, more extensive studies on the actual magnitude of resistance are still needed. Short-time recurrences of malaria cases were analyzed in different transmission scenarios over three years (2005, 2010, and 2015), selected according to malaria incidence. Multilevel models (binomial) were used to evaluate association of short-time recurrences with variables such as age. The zero-inflated Poisson scan model (scanZIP) was used to detect spatial clusters of recurrences up to 28 days. Recurrences compose less than 5% of overall infection, being more frequent in the age group under four years. Recurrences slightly increased incidence. No fixed clusters were detected throughout the period, although there are clustering sites, spatially varying over the years. This is the most extensive analysis of short-time recurrences worldwide which addresses the occurrence of P. vivax CQR. As an important step forward in malaria elimination, policymakers should focus their efforts on young children, with an eventual shift in the first line of malaria treatment to P. vivax.

Real-life implementation of a G6PD deficiency screening qualitative test into routine vivax malaria diagnostic units in the Brazilian Amazon (SAFEPRIM study).

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency greatly hinders Plasmodium vivax malaria radical cure and further elimination due to 8-aminoquinolines-associated hemolysis. Although the deleterious health effects of primaquine in G6PD deficient individuals have been known for over 50 years, G6PD testing is not routinely performed before primaquine treatment in most P. vivax endemic areas. METHOD/PRINCIPAL FINDINGS: The qualitative CareStart G6PD screening test was implemented in 12 malaria treatment units (MTUs) in the municipality of Rio Preto da Eva, Western Brazilian Amazon, a malaria endemic area, between February 2019 and early January 2020. Training materials were developed and validated; evaluations were conducted on the effectiveness of training health care professionals (HCPs) to perform the test, the interpretation and reliability of routine testing performed by HCPs, and perceptions of HCPs and patients. Most HCPs were unaware of G6PD deficiency and primaquine-related adverse effects. Most of 110 HCPs trained (86/110, 78%) were able to correctly perform the G6PD test after a single 4-hour training session. The test performed by HCPs during implementation showed 100.0% (4/4) sensitivity and 68.1% (62/91) specificity in identifying G6PD deficient patients as compared to a point-of-care quantitative test (Standard G6PD). CONCLUSIONS/SIGNIFICANCE: G6PD screening using the qualitative CareStart G6PD test performed by HCPs in MTUs of an endemic area showed high sensitivity and concerning low specificity. The amount of false G6PD deficiency detected led to substantial loss of opportunities for radical cure.

Risk of chronic arthralgia and impact of pain on daily activities in a cohort of patients with chikungunya virus infection from Brazil.

OBJECTIVES: To investigate risk factors for persistent arthralgia in patients with chikungunya, and describe its impact on daily activities. METHODS: From September 2014 to July 2016, a surveillance study enrolled patients with acute febrile illness in Salvador, Brazil, and detected those with chikungunya virus infection using IgM enzyme-linked immunosorbent assay or reverse transcriptase polymerase chain reaction. Telephone follow-ups were performed to ascertain the progression of disease. RESULTS: Of 153 followed cases, 65 (42.5%) reported chronic arthralgia that lasted >3 months, and 47 (30.7%) were still symptomatic at the time of the interview (approximately 1.5 years after symptom onset). Limitations in daily activities and mental distress were reported by 93.8% and 61.5% of those with chronic arthralgia, respectively. Female sex [risk ratio (RR) 1.79, 95% confidence interval (CI) 1.95-2.69] and age (RR 1.02 for each 1-year increase, 95% CI 1.01-1.03) were independent risk factors for chronic arthralgia. Chronic arthralgia was not associated with co-infection with dengue virus (RR 0.97, 95% CI 0.48-1.94) or chikungunya viral load at diagnosis (median chikungunya virus RNA of 5.60 and 5.52 log10 copies/µL for those with and without chronic arthralgia, respectively; P = 0.75). CONCLUSIONS: These findings reinforce the high frequency of chronic chikungunya arthralgia, and highlight the substantial disability associated with the persistence of pain. Development of novel strategies to mitigate the transmission of chikungunya virus and to provide long-term medical assistance for patients with chikungunya are needed urgently.

The top 1%: quantifying the unequal distribution of malaria in Brazil.

BACKGROUND: As malaria endemic countries strive towards elimination, intensified spatial heterogeneities of local transmission could undermine the effectiveness of traditional intervention policy. METHODS: The dynamic nature of large-scale and long-term malaria heterogeneity across Brazilian Amazon basin were explored by (1) exploratory analysis of Brazil's rich clinical malaria reporting database from 2004 to 2018, and (2) adapting Gini coefficient to study the distribution of malaria cases in the region. RESULTS: As transmission declined, heterogeneity increased with cases clustering into smaller subpopulations across the territory. In 2004, the 1% of health units with the greatest number of cases accounted for 46% of all reported Plasmodium vivax cases, whereas in 2018 52% of P. vivax cases occurred in the top 1% of health units. Plasmodium falciparum had lower levels of transmission than P. vivax, and also had greater levels of heterogeneity with 75% of cases occurring in the top 1% of health units. Age and gender stratification of cases revealed peri-domestic and occupational exposure settings that remained relatively stable. CONCLUSION: The pathway to decreasing incidence is characterized by higher proportions of cases in males, in adults, due to importation, and caused by P. vivax. Characterization of spatio-temporal heterogeneity and risk groups can aid stratification for improved malaria control towards elimination with increased heterogeneity potentially allowing for more efficient and cost-effective targeting. Although distinct epidemiological phenomena were clearly observed as malaria transmission declines, the authors argue that there is no canonical path to malaria elimination and a more targeted and dynamic surveillance will be needed if Brazil decides to adopt the elimination target.

The emergence of novel SARS-CoV-2 variant P.1 in Amazonas (Brazil) was temporally associated with a change in the age and sex profile of COVID-19 mortality: a population based ecological study

Background Since the end of 2020, there has been a great deal of international concern about the variants of SARS-COV-2 B.1.1.7, identified in the United Kingdom; B.1.351 discovered in South Africa and P.1, originating from the Brazilian state of Amazonas. The three variants were associated with an increase in transmissibility and worsening of the epidemiological situation in the places where they expanded. The lineage B.1.1.7 was associated with the increase in case fatality rate in the United Kingdom. There are still no studies on the case fatality rate of the other two variants. The aim of this study was to analyze the mortality profile before and after the emergence of the P.1 strain in the Amazonas state. Methods We analyzed data from the Influenza Epidemiological Surveillance Information System, SIVEP-Gripe (Sistema de Informação de Vigilância Epidemiológica da Gripe), comparing two distinct epidemiological periods: during the peak of the first wave, between April and May 2020, and in January 2021 (the second wave), the month in which the new variant came to predominate. We calculated mortality rates, overall case fatality rate and case fatality rate among hospitalized patients; all rates were calculated by age and gender and 95% confidence intervals (95% CI) were determined. Findings We observed that in the second wave there were a higher incidence and an increase in the proportion of cases of COVID-19 in the younger age groups. There was also an increase in the proportion of women among Severe Acute Respiratory Infection (SARI) cases from 40% (2,709) in the first wave to 47% (2,898) in the second wave and in the proportion of deaths due to COVID-19 between the two periods varying from 34% (1,051) to 47% (1,724), respectively. In addition, the proportion of deaths among people between 20 and 59 years old has increased in both sexes. The case fatality rate among those hospitalized in the population between 20 and 39 years old during the second wave was 2.7 times the rate observed in the first wave (female rate ratio = 2.71; 95% CI: 1.9-3.9], p <0.0001; male rate ratio = 2.70, 95%CI:2.0-3.7), and in the general population the rate ratios were 1.15 (95% CI: 1.1-1.2) in females and 0.78 (95% CI: 0.7-0.8) in males]. Interpretation Based on this prompt analysis of the epidemiological scenario in the Amazonas state, the observed changes in the pattern of mortality due to COVID-19 between age groups and gender simultaneously with the emergence of the P.1 strain suggest changes in the pathogenicity and virulence profile of this new variant. Further studies are needed to better understanding of SARS-CoV-2 variants profile and their impact for the health population.