IMPORTANCEThere is no specific antiviral therapy recommended for coronavirus disease 2019 . In vitro studies indicate that the antiviral effect of chloroquine diphosphate (CQ) requires a high concentration of the drug. OBJECTIVE To evaluate the safety and efficacy of 2 CQ dosages in patients with severe COVID-19. DESIGN, SETTING, AND PARTICIPANTSThis parallel, double-masked, randomized, phase IIb clinical trial with 81 adult patients who were hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was conducted from March 23 to April 5, 2020, at a tertiary care facility in Manaus, Brazilian Amazon. INTERVENTIONS Patients were allocated to receive high-dosage CQ (ie, 600 mg CQ twice daily for 10 days) or low-dosage CQ (ie, 450 mg twice daily on day 1 and once daily for 4 days). MAIN OUTCOMES AND MEASURES Primary outcome was reduction in lethality by at least 50% in the high-dosage group compared with the low-dosage group. Data presented here refer primarily to safety and lethality outcomes during treatment on day 13. Secondary end points included participant clinical status, laboratory examinations, and electrocardiogram results. Outcomes will be presented to day 28. Viral respiratory secretion RNA detection was performed on days 0 and 4. RESULTS Out of a predefined sample size of 440 patients, 81 were enrolled (41 [50.6%] to highdosage group and 40 [49.4%] to low-dosage group). Enrolled patients had a mean (SD) age of 51.1 (13.9) years, and most (60 [75.3%]) were men. Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and more heart disease (5 of 28 [17.9%] vs 0) were seen in the high-dose group. Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and highdosage groups, respectively. Lethality until day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40). The high-dosage group presented more instance of QTc interval greater than 500 milliseconds (7 of 37 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%). CONCLUSIONS AND RELEVANCEThe preliminary findings of this study suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 because of its potential (continued) Key Points Question How safe and effective are 2 different regimens of chloroquine diphosphate in the treatment of severe coronavirus disease 2019 (COVID-19)? Findings In this phase IIb randomized clinical trial of 81 patients with COVID-19, an unplanned interim analysis recommended by an independent data safety and monitoring board found that a higher dosage of chloroquine diphosphate for 10 days was associated with more toxic effects and lethality, particularly affecting QTc interval prolongation. The limited sample size did not allow the study to show any benefit overall regarding treatment efficacy. Meaning The preliminary findings from the CloroCovid-19 trial suggest that higher dosage of chloro...
robust clinical studies on the safety and/or efficacy of chloroquine (CQ) and/or hydroxychloroquine (HCQ) for the treatment of COVID-19 during the recent 2020 pandemic.We searched PubMed and also MedRxiv.org (pre-print server for health sciences, without peer review), without any language restrictions and including Chinese publications, for studies published between Dec 2019 and April 5, 2020, using the search terms 'COVID-19, coronavirus, SARS-Cov-2'. We found three non-randomized studies with limited sample sizes in which (1) HCQ use led to a decrease in SARS-Cov-2 detected in respiratory secretions five days after treatment, together with azithromycin (France, 36 patients); (2) HCQ use shortened time to clinical recovery (China, 62 patients); and (3) CQ was superior to control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, and promoting virus-negative conversion and shortening the disease course (China, 100 patients). We found no published studies comparing different dosages of CQ/HCQ and their thorough safety assessment. Added value of this studyIn a larger patient population, we found that a higher dosage of CQ for 10 days presented toxicity red flags, particularly affecting QTc prolongation. The limited sample size recruited so far does not allow to show any benefit regarding treatment efficacy, however the higher fatality associated with the higher dosage by day 13 of follow-up resulted in a premature halting of this arm. This is the first double-blinded, randomized clinical trial addressing different dosages of CQ for the treatment of severe patients with COVID-19 in the absence of a control group using placebo. Due to the impossibility of not using the drug recommended at the national level, we used historical data from the literature to infer comparisons for lethality endpoints. Follow-up until day 28 is ongoing with a larger sample size, in which long-term lethality will be better estimated.
Dengue is a major public health problem in tropical and subtropical areas worldwide. There is a lack of information on the risk factors for death due to severe dengue fever in developing countries, including Brazil where the state of Amazonas is located. This knowledge is important for decision making and the implementation of effective measures for patient care. This study aimed to identify factors associated with death among patients with severe dengue, in Amazonas from 2001 to 2013. We conducted a retrospective cohort study based on secondary data from the epidemiological surveillance of dengue provided by the Fundação de Vigilância em Saúde do Amazonas, FVS (Health Surveillance Foundation) of the Secretaria de Saúde do Amazonas, SUSAM (Health Secretariat of the State of Amazonas). Data on dengue cases were obtained from the SINAN (Notifiable Diseases Information System) and SIM (Mortality Information System) databases. We selected cases of severe dengue with laboratory confirmation, including dengue-related deaths of residents in the state of Amazonas from January 1, 2001, to December 31, 2013. The explanatory variables analyzed were sex, age, level of education, spontaneous hemorrhagic manifestations, plasma extravasation and platelet count. Patients who died due to severe dengue had more hematuria, gastrointestinal bleeding, and thrombocytopenia than the survivors. Considering the simultaneous effects of demographic and clinical characteristics with a multiple logistic regression model, it was observed that the factors associated with death were age >55 years (odds ratio [OR] 4.98), gastrointestinal bleeding (OR 10.26), hematuria (OR 5.07), and thrombocytopenia (OR 2.55). Gastrointestinal bleeding was the clinical sign most strongly associated with death, followed by hematuria and age >55 years. The study results showed that the best predictor of death from severe dengue is based on the characteristic of age >55 years, together with the clinical signs of gastrointestinal bleeding, hematuria, and low platelet count.
BackgroundMalaria is a major public health problem worldwide. In Brazil, an average of 420,000 cases of malaria have been reported annually in the last 12 years, of which 99.7 % occurred in the Amazon region. This study aimed to analyse the distribution of malaria in the State of Amazonas and the influence of indigenous malaria in this scenario, to evaluate the correlation between incidence rates and socio-economic and environmental factors, and to evaluate the performance of health surveillance services.MethodsThis ecological study used secondary data obtained from the SIVEP-MALARIA malaria surveillance programme. The relationship between demographic, socio-economic and environmental factors, the performance of health surveillance services and the incidence of malaria in Amazonas, a multiple linear regression model was used.ResultsThe crude rate of malaria in Amazonas was 4142.72 cases per 100,000 inhabitants between 2003 and 2012. The incidence rates for the indigenous and non-indigenous populations were 12,976.02 and 3749.82, respectively, with an indigenous population attributable fraction of only 8 %. The results of the linear regression analysis indicated a negative correlation between the two socio-economic indicators (municipal human development index (MHDI) and poverty rate) and the incidence of malaria in the period. With regard to the environmental indicators (average annual deforestation rate and percentage of areas under the influence of watercourses), the correlation with the incidence rate was positive.ConclusionsThe findings underscore the importance of implementing economic and social development policies articulated with strategic actions of environmental protection and health care for the population.
BackgroundBrazil is among the 30 countries with high-burden of tuberculosis worldwide, and Manaus is the capital with the highest tuberculosis incidence. The accelerated economic and population growth in Manaus in the last 30 years has strengthened the process of social stratification that may result in population groups that are less favored in terms of healthcare and are vulnerable to infection and illness due to tuberculosis. This study aimed to characterize inequalities associated with tuberculosis incidence in relation to the socioeconomic and demographic characteristics of the resident population of Manaus and to identify their determinants from 2007 to 2016.MethodsAn ecological study was conducted using the data from the Diseases Notification Information System. Tuberculosis incidence rates by population characteristics (gender, ethnicity, and socioeconomic level) were calculated for each year, studied, and represented in equiplot charts. To measure the disparity of tuberculosis incidence in the resident population in Manaus, the Gini index of tuberculosis in each neighborhood was calculated based on the incidence rates of the census sectors. A thematic map was constructed to represent the spatial distribution of tuberculosis incidence inequality. Linear regression models were used to identify the relationship between the tuberculosis incidence inequality and its social determinants.ResultsFrom 2007 to 2016, there was an increase in the tuberculosis incidence in Manaus, together with an increase in incident inequality among genders, ethnic groups, and socioeconomic level. The incidence of tuberculosis inequality was associated with the inequalities of its possible determinants (Gini of the proportion of male population, Gini of the proportion of indigenous population, Gini of the proportion of illiteracy, Gini of income, Gini of the proportion of households connected to the water network, and Gini of the mean number of bathrooms per inhabitant), the per capita income, and the proportion of cases with laboratory confirmation.ConclusionsDisparities in tuberculosis incidence in the resident population in neighborhoods can be explained by the sociodemographic and economic heterogeneity. Our findings recommend that public policies and tuberculosis control strategies consider differences in the determinants of tuberculosis inequality for the development of specific actions for each population group.
BackgroundDengue is the most prevalent arboviral disease affecting humans. The frequency and magnitude of dengue epidemic have significantly increased over recent decades. This study aimed to identify dengue epidemic types and risk factors for the extensive epidemics that occurred in 2010–2011, across the municipalities of Amazonas state, Brazil.MethodsUsing an ecological approach, secondary data were obtained from the dengue fever surveillance system. Epidemic waves were classified according to three indices: duration, intensity, and coverage. A hierarchical model of multiple logistic regression was used for the identification of risk factors, with the occurrence of extensive dengue epidemic.ResultsDuring the study period, dengue virus affected 49 of the 62 Amazonas municipalities. In 22 of these, the epidemics were of high intensity, wide range, and long time span, and therefore categorized as “extensive epidemics”. The final multivariable model revealed a significant association between extensive dengue epidemics occurrence and the average number of days with precipitation (adjusted OR = 1.40, 95% CI: 1.01–1.94) and the number of years with infestation (adjusted OR = 1.53, 95% CI: 1.18–1.98).ConclusionsOur results indicate that it is crucial to integrate vector control, case management, epidemiological investigation, and health education, in order to respond to the growing threat of multiple mosquito-borne diseases, such as dengue, Zika and chikungunya, which are highly prevalent in the South America region.Electronic supplementary materialThe online version of this article (10.1186/s12889-018-5251-x) contains supplementary material, which is available to authorized users.
We report an ongoing measles outbreak in Manaus, Amazonas state, Brazil. As at 3 November 2018, 1,631 cases were confirmed corresponding to an incidence of 75.3 per 100,000 inhabitants; all five sanitary districts presented confirmed cases. Reintroduction of measles virus in Manaus is likely related to the current outbreak in Venezuela and due to recent decline in measles vaccine coverage. Given the current scenario, prevention and control measures should target individuals aged 15–29 years.
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