Short-Course of Methylprednisolone Improves Respiratory Functional Parameters After 120 Days in Hospitalized COVID-19 Patients (Metcovid Trial): A Randomized Clinical Trial.

Background: The use of corticosteroids may help control the cytokine storm occurring in acute respiratory failure due to the severe form of COVID-19. We evaluated the postacute effect of corticosteroids used during the acute phase, such as impairment in pulmonary function parameters, on day 120 (D120)-follow-up, in participants who survived over 28 days. Methods: This is a parallel, double-blind, randomized, placebo-controlled phase IIb clinical trial carried out between April 18 and October 9, 2020, conducted in hospitalized patients with clinical-radiological suspicion of COVID-19, aged 18 years or older, with SpO2 ≤ 94% on room air or requiring supplementary oxygen, or under invasive mechanical ventilation (IMV) in a referral center in Manaus, Western Brazilian Amazon. Intravenous methylprednisolone (MP) (0.5 mg/kg) was given two times daily for 5 days to these patients. The primary outcome used for this study was pulmonary function testing at day 120 follow-up visit. Results: Out of the total of surviving patients at day 28 (n = 246) from the Metcovid study, a total of 118 underwent satisfactory pulmonary function testing (62 in the placebo arm and 56 in the MP arm). The supportive treatment was similar between the placebo and MP groups (seven [11%] vs. four [7%]; P = 0.45). At hospital admission, IL-6 levels were higher in the MP group (P < 0.01). Also, the need for ICU (P = 0.06), need for IMV (P = 0.07), and creatine kinase (P = 0.05) on admission also tended to be higher in this group. In the univariate analysis, forced expiratory volume on 1st second of exhalation (FEV1) and forced vital capacity (FVC) at D120 follow-up were significantly higher in patients in the MP arm, being this last parameter also significantly higher in the multivariate analysis independently of IMV and IL-6 levels on admission. Conclusion: The use of steroids for at least 5 days in severe COVID-19 was associated with a higher FVC, which suggests that hospitalized COVID-19 patients might benefit from the use of MP in its use in the long-term, with less pulmonary restrictive functions, attributed to fibrosis. Trial Registration: ClinicalTrials.gov, Identifier: NCT04343729.

Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With Coronavirus Disease 2019 (COVID-19; Metcovid): A Randomized, Double-blind, Phase IIb, Placebo-controlled Trial.

BACKGROUND: Steroid use for coronavirus disease 2019 (COVID-19) is based on the possible role of these drugs in mitigating the inflammatory response, mainly in the lungs, triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aimed to evaluate the efficacy of methylprednisolone (MP) among hospitalized patients with suspected COVID-19. METHODS: A parallel, double-blind, placebo-controlled, randomized, Phase IIb clinical trial was performed with hospitalized patients aged ≥18 years with clinical, epidemiological, and/or radiological suspected COVID-19 at a tertiary care facility in Manaus, Brazil. Patients were randomly allocated (1:1 ratio) to receive either intravenous MP (0.5 mg/kg) or placebo (saline solution) twice daily for 5 days. A modified intention-to-treat (mITT) analysis was conducted. The primary outcome was 28-day mortality. RESULTS: From 18 April to 16 June 2020, 647 patients were screened, 416 were randomized, and 393 were analyzed as mITT, with 194 individuals assigned to MP and 199 to placebo. SARS-CoV-2 infection was confirmed by reverse transcriptase polymerase chain reaction in 81.3%. The mortality rates at Day 28 were not different between groups. A subgroup analysis showed that patients over 60 years old in the MP group had a lower mortality rate at Day 28. Patients in the MP arm tended to need more insulin therapy, and no difference was seen in virus clearance in respiratory secretion until Day 7. CONCLUSIONS: The findings of this study suggest that a short course of MP in hospitalized patients with COVID-19 did not reduce mortality in the overall population. CLINICAL TRIALS REGISTRATION: NCT04343729.

Case Report: Adrenal Pathology Findings in Severe COVID-19: An Autopsy Study.

Although high mortality has been reported in many COVID-19 studies, very limited postmortem information from complete autopsies is available. We report the findings in the adrenal glands in 28 autopsies with confirmed SARS-CoV-2 infection. Microscopic lesions were identified in the adrenal glands in 12/28 patients (46%). Seven cases showed necrosis, generally ischemic; four showed cortical lipid degeneration; two showed hemorrhage; and one unspecific focal adrenalitis. Vascular thrombosis in one patient and focal inflammation in association with other findings in three patients were observed. No case presented adrenal insufficiency. In conclusion, adrenal lesions are frequent in patients with severe COVID-19. The lesions are mild but could contribute to the lethal outcome.

Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial.

Importance: There is no specific antiviral therapy recommended for coronavirus disease 2019 (COVID-19). 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 Participants: This 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 high-dosage 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 high-dosage 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 Relevance: The 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 safety hazards, especially when taken concurrently with azithromycin and oseltamivir. These findings cannot be extrapolated to patients with nonsevere COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04323527.

Micronutrient Deficiencies and Plasmodium vivax Malaria among Children in the Brazilian Amazon.

BACKGROUND: There is a growing body of evidence linking micronutrient deficiencies and malaria incidence arising mostly from P. falciparum endemic areas. We assessed the impact of micronutrient deficiencies on malaria incidence and vice versa in the Brazilian state of Amazonas. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated children <10 years old living in rural communities in the state of Amazonas, Brazil, from May 2010 to May 2011. All children were assessed for sociodemographic, anthropometric and laboratory parameters, including vitamin A, beta-carotene, zinc and iron serum levels at the beginning of the study (May 2010) and one year later (May 2011). Children were followed in between using passive surveillance for detection of symptomatic malaria. Those living in the study area at the completion of the observation period were reassessed for micronutrient levels. Univariate Cox-proportional Hazards models were used to assess whether micronutrient deficiencies had an impact on time to first P. vivax malaria episode. We included 95 children median age 4.8 years (interquartile range [IQR]: 2.3-6.6), mostly males (60.0%) and with high maternal illiteracy (72.6%). Vitamin A deficiencies were found in 36% of children, beta-carotene deficiency in 63%, zinc deficiency in 61% and iron deficiency in 51%. Most children (80%) had at least one intestinal parasite. During follow-up, 16 cases of vivax malaria were diagnosed amongst 13 individuals. Micronutrient deficiencies were not associated with increased malaria incidence: vitamin A deficiency [Hazard ratio (HR): 1.51; P-value: 0.45]; beta-carotene [HR: 0.47; P-value: 0.19]; zinc [HR: 1.41; P-value: 0.57] and iron [HR: 2.31; P-value: 0.16]). Upon reevaluation, children with al least one episode of malaria did not present significant changes in micronutrient levels. CONCLUSION: Micronutrient serum levels were not associated with a higher malaria incidence nor the malaria episode influenced micronutrient levels. Future studies targeting larger populations to assess micronutrients levels in P. vivax endemic areas are warranted in order to validate these results.

The association between nutritional status and malaria in children from a rural community in the Amazonian region: a longitudinal study.

BACKGROUND: The relationship between malaria and undernutrition is controversial and complex. Synergistic associations between malnutrition and malaria morbidity and mortality have been suggested, as well as undernutrition being protective against infection, while other studies found no association. We sought to evaluate the relationship between the number of malaria episodes and nutritional statuses in a cohort of children below 15 years of age living in a rural community in the Brazilian Amazon. METHODOLOGY/PRINCIPAL FINDINGS: Following a baseline survey of clinical, malaria and nutritional assessment including anthropometry measurements and hemoglobin concentration, 202 children ranging from 1 month to 14 years of age were followed for one year through passive case detection for malaria episodes. After follow-up, all children were assessed again in order to detect changes in nutritional indicators associated with malaria infection. We also examined the risk of presenting malaria episodes during follow-up according to presence of stunting at baseline. Children who suffered malaria episodes during follow-up presented worse anthropometric parameters values during this period. The main change was a reduction of the linear growth velocity, associated with both the number of episodes and how close the last or only malaria episode and the second anthropometric assessment were. Changes were also observed for indices associated with chronic changes, such as weight-for-age and BMI-for-age, which conversely, were more frequently observed in children with the last or only episode occurring between 6 and 12 months preceding the second nutritional assessment survey. Children with inadequate height-for-age at baseline (Z-score < -2) presented lower risk of suffering malaria episodes during follow-up as assessed by both the log-rank test (p =0.057) and the multivariable Cox-proportional hazards regression (Hazard Ratio = 0.31, 95%CI [0.10; 0.99] p=0.049). CONCLUSIONS: Malaria was associated with impaired nutritional status amongst children in an endemic area of the Western Brazilian Amazon where P. vivax predominates. Our data all supports that the association presents differential effects for each age group, suggesting distinct pathophysiology pathways. We were also able to demonstrate that undernourishment at baseline was protective to malaria during follow-up. These findings support an intriguing interaction between these conditions in the rural Amazon and the need for a more integrative approach by health systems in endemic areas.

Transfusion-transmitted malaria in endemic zone: epidemiological profile of blood donors at the Fundação HEMOAM and use of rapid diagnostic tests for malaria screening in Manaus.

OBJECTIVE: With 99% of the cases in Brazil, malaria is endemic in the Amazon region. Transfusion-transmitted malaria, an important risk in endemic areas, has been reported. The aim of this study was to describe the epidemiological profile of blood donor candidates at the Fundação de Hematologia e Hemoterapia do Amazonas and evaluate the efficacy of rapid diagnostic tests used for malaria screening of blood donors within endemic regions. METHODS: Between May 2008 and May 2009, 407 blood donor candidates were selected and grouped based on the Malaria Annual Parasite Index of the geographic area in which they originated: Group 1 (eligible donors - n=265) originated from areas of low to medium risk of exposure to malaria and Group 2 (ineligible donors - n=142) originated from high-risk areas. All samples were concurrently screened using two immunochromatic antigen-based rapid tests and by the thick smear test. RESULTS: All samples were negative by all three methods. The demographic profile indicated that the majority of participants were male, ages ranged from 18 to 39 years and less than half the candidates had only elementary schooling. Two issues need to be addressed: one is the ineligibility of donors and its impact on blood donor centers as, in this study, 22.7% of the donors were considered ineligible. The other is the limited sensitivity of the parasitological tests used, allowing a risk of false-negative results. CONCLUSION: New methods are needed to ensure transfusion safety without rejecting potential donors, which would ensure safe transfusion without harming the blood supply.

Transfusion-transmitted malaria in endemic zone: epidemiological profile of blood donors at the Fundação HEMOAM and use of rapid diagnostic tests for malaria screening in Manaus

OBJECTIVE: With 99% of the cases in Brazil, malaria is endemic in the Amazon region. Transfusion-transmitted malaria, an important risk in endemic areas, has been reported. The aim of this study was to describe the epidemiological profile of blood donor candidates at the Fundação de Hematologia e Hemoterapia do Amazonas and evaluate the efficacy of rapid diagnostic tests used for malaria screening of blood donors within endemic regions. METHODS: Between May 2008 and May 2009, 407 blood donor candidates were selected and grouped based on the Malaria Annual Parasite Index of the geographic area in which they originated: Group 1 (eligible donors - n = 265) originated from areas of low to medium risk of exposure to malaria and Group 2 (ineligible donors - n = 142) originated from high-risk areas. All samples were concurrently screened using two immunochromatic antigen-based rapid tests and by the thick smear test. RESULTS: All samples were negative by all three methods. The demographic profile indicated that the majority of participants were male, ages ranged from 18 to 39 years and less than half the candidates had only elementary schooling. Two issues need to be addressed: one is the ineligibility of donors and its impact on blood donor centers as, in this study, 22.7% of the donors were considered ineligible. The other is the limited sensitivity of the parasitological tests used, allowing a risk of false-negative results. CONCLUSION: New methods are needed to ensure transfusion safety without rejecting potential donors, which would ensure safe transfusion without harming the blood supply...

Risk factors and characterization of Plasmodium vivax-associated admissions to pediatric intensive care units in the Brazilian Amazon.

BACKGROUND: Plasmodium vivax is responsible for a significant proportion of malaria cases worldwide and is increasingly reported as a cause of severe disease. The objective of this study was to characterize severe vivax disease among children hospitalized in intensive care units (ICUs) in the Western Brazilian Amazon, and to identify risk factors associated with disease severity. METHODS AND FINDINGS: In this retrospective study, clinical records of 34 children, 0-14 years of age hospitalized in the 11 public pediatric and neonatal ICUs of the Manaus area, were reviewed. P. falciparum monoinfection or P. falciparum/P. vivax mixed infection was diagnosed by microscopy in 10 cases, while P. vivax monoinfection was confirmed in the remaining 24 cases. Two of the 24 patients with P. vivax monoinfection died. Respiratory distress, shock and severe anemia were the most frequent complications associated with P. vivax infection. Ninety-one children hospitalized with P. vivax monoinfections but not requiring ICU were consecutively recruited in a tertiary care hospital for infectious diseases to serve as a reference population (comparators). Male sex (p = 0.039), age less than five years (p = 0.028), parasitemia greater than 500/mm(3) (p = 0.018), and the presence of any acute (p = 0.023) or chronic (p = 0.017) co-morbidity were independently associated with ICU admission. At least one of the WHO severity criteria for malaria (formerly validated for P. falciparum) was present in 23/24 (95.8%) of the patients admitted to the ICU and in 17/91 (18.7%) of controls, making these criteria a good predictor of ICU admission (p = 0.001). The only investigated criterion not associated with ICU admission was hyperbilirubinemia (p = 0.513)]. CONCLUSIONS: Our study points to the importance of P. vivax-associated severe disease in children, causing 72.5% of the malaria admissions to pediatric ICUs. WHO severity criteria demonstrated good sensitivity in predicting severe P. vivax infection in this small case series.

[HIV-1 infection after occupational accidents in the State of Amazonas: first reported case]. / Infecção pelo HIV-1 após acidente ocupacional, no Estado do Amazonas: primeiro caso documentado.

The medical care of occupational accidents in Tropical Medicine Foundation Dr. Heitor Dourado (FMT-HVD), involving blood and body fluids, started routinely in 1999. The objective of this report is to emphasize the importance of the measures used for the control of accidents with biological material. This study is carried out after a detailed epidemiological investigation confirmed one case of human immunodeficiency virus (HIV) seroconversion after an occupational accident involving bodily fluids and sharp instruments.

Infecção pelo HIV-1 após acidente ocupacional, no Estado do Amazonas: primeiro caso documentado / HIV-1 infection after occupational accidents in the State of Amazonas: first reported case

O atendimento de acidentes ocupacionais na Fundação de Medicina Tropical Dr. Heitor Dourado (FMT- HVD), envolvendo sangue e fluídos corpóreos, iniciou-se de forma rotineira em 1999. O objetivo deste relato é enfatizar a importância da utilização de medidas para o controle dos acidentes com material biológico. Após investigação epidemiológica detalhada, confirmamos um caso de soroconversão ao vírus da imunodeficiência humana (HIV) após acidente ocupacional, envolvendo fluído corpóreo e perfurocortante.

The medical care of occupational accidents in Tropical Medicine Foundation Dr. Heitor Dourado (FMT-HVD), involving blood and body fluids, started routinely in 1999. The objective of this report is to emphasize the importance of the measures used for the control of accidents with biological material. This study is carried out after a detailed epidemiological investigation confirmed one case of human immunodeficiency virus (HIV) seroconversion after an occupational accident involving bodily fluids and sharp instruments.