High levels of pro-inflammatory SARS-CoV-2-specific biomarkers revealed by in vitro whole blood cytokine release assay (CRA) in recovered and long-COVID-19 patients.

BACKGROUND: Cytokines induced by SARS-CoV-2 infection play a crucial role in the pathophysiology of COVID-19 and hyperinflammatory responses have been associated with poor clinical outcomes, with progression to severe conditions or long-term subacute complications named as long-COVID-19. METHODS: In this cross-sectional study, we aimed to evaluate a set of antigen-specific inflammatory cytokines in blood from recovered COVID-19 individuals or who suffered a post-acute phase of SARS-CoV-2 infection compared to healthy individuals with no history of COVID-19 exposition or infection. Interferon-gamma (IFN-γ), IFN-γ-induced protein 10 (IP-10), tumor necrosis factor (TNF), IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, and IL-17A were quantified by multiplex cytometric bead assay and enzyme-linked immunosorbent assay after stimulation of whole blood with recombinant Spike protein from SARS-CoV-2. Additionally, all participants have evaluated for anti-(S) protein-specific IgG antibodies. Clinical specimens were collected within two months of COVID-19 diagnosis. RESULTS: A total of 47 individuals were enrolled in the study, a median age of 43 years (IQR = 14.5), grouped into healthy individuals with no history of infection or exposure to SARS-CoV-2 (unexposed group; N = 21); and patients from the Health Complex of the Rio de Janeiro State University (UERJ), Brazil, who were SARS-CoV-2 positive by RT-PCR (COVID-19 group)-categorized as recovered COVID-19 (N = 11) or long-COVID-19 (N = 15). All COVID-19 patients presented at least one signal or symptom during the first two weeks of infection. Six patients were hospitalized and required invasive mechanical ventilation. Our results showed that COVID-19 patients had significantly higher levels of IFN-γ, TNF, IL-1ß, IL-2, IL-6, IL-8, and IP-10 than the unexposed group. The long-COVID-19 group has presented significantly high levels of IL-1ß and IL-6 compared to unexposed individuals, but not from recovered COVID-19. A principal-component analysis demonstrated 84.3% of the total variance of inflammatory-SARS-CoV-2 response in the first two components, and it was possible to stratify IL-6, TNF, IL-1ß, IL-10, and IL-2 as the top-five cytokines which are candidates to discriminate COVID-19 group (including long-COVID-19 subgroup) and healthy unexposed individuals. CONCLUSION: We revealed important S protein-specific differential biomarkers in individuals affected by COVID-19, bringing new insights into the inflammatory status or SARS-CoV-2 exposition determination.

Inflammasome genes polymorphisms are associated with progression to mechanical ventilation and death in a cohort of hospitalized COVID-19 patients in a reference hospital in Rio de Janeiro, Brazil.

COVID-19 has a broad spectrum of clinical manifestations. We assessed the impact of single nucleotide polymorphisms (SNPs) of inflammasome genesas risk factors for progression toCOVID-19 critical outcomes, such as mechanical ventilation support (MVS) or death.The study included 451 hospitalized individuals followed up at the INI/FIOCRUZ, Rio de Janeiro, Brazil, from 06/2020 to 03/2021. SNPs genotyping was determined by Real-Time PCR. We analyzed risk factors for progression to MVS (n = 174[38.6 %]) or death (n = 175[38.8 %])as a result of COVID-19 by Cox proportional hazardmodels.Slower progression toMVSwas associated with allele G (aHR = 0.66;P = 0.005) or the genotype G/G (aHR = 0.391;P = 0.006) in the NLRP3 rs10754558 or the allele G (aHR = 0.309;P = 0.004) in the IL1ßrs1143634, while C allele in the NLRP3 rs4612666 (aHR = 2.342;P = 0.006) or in the rs10754558 (aHR = 2.957;P = 0.005) were associated with faster progression to death. Slower progression to death was associated to allele G (aHR = 0.563;P = 0.006) or the genotype A/G (aHR = 0.537;P = 0.005) in the CARD8 rs6509365; the genotype A/C in the IFI16 rs1101996 (aHR = 0.569;P = 0.011); the genotype T/T (aHR = 0.394;P = 0.004) or allele T (aHR = 0.68;P = 0.006) in the NLRP3 rs4612666, and the genotype G/G (aHR = 0.326;P = 0.005) or allele G (aHR = 0,68;P = 0.014) in the NLRP3 rs10754558. Our results suggest that inflammasome genetic variations might influence the critical clinical course of COVID-19.

Inflammasome Genetic Variants Are Associated with Protection to Clinical Severity of COVID-19 among Patients from Rio de Janeiro, Brazil.

COVID-19 has a broad spectrum of clinical manifestations, from asymptomatic or mild/moderate symptoms to severe symptoms and death. The mechanisms underlying its clinical evolution are still unclear. Upon SARS-CoV-2 infection, host factors, such as the inflammasome system, are activated by the presence of the virus inside host cells. The search for COVID-19 risk factors is of relevance for clinical management. In this study, we investigated the impact of inflammasome single-nucleotide polymorphisms (SNPs) in SARS-CoV-2-infected individuals with distinct severity profiles at clinical presentation. Patients were divided into two groups according to disease severity at clinical presentation based on the WHO Clinical Progression Scale. Group 1 included patients with mild/moderate disease (WHO < 6; n = 76), and group 2 included patients with severe/critical COVID-19 (WHO ≥ 6; n = 357). Inpatients with moderate to severe/critical profiles were recruited and followed-up at Hospital Center for COVID-19 Pandemic - National Institute of Infectology (INI)/FIOCRUZ, RJ, Brazil, from June 2020 to March 2021. Patients with mild disease were recruited at Oswaldo Cruz Institute (IOC)/FIOCRUZ, RJ, Brazil, in August 2020. Genotyping of 11 inflammasome SNPs was determined by real-time PCR. Protection and risk estimation were performed using unconditional logistic regression models. Significant differences in NLRP3 rs1539019 and CARD8 rs2043211 were observed between the two groups. Protection against disease severity was associated with the A/A genotype (ORadj = 0.36; P = 0.032), allele A (ORadj = 0.93; P = 0.010), or carrier-A (ORadj = 0.45; P = 0.027) in the NLRP3 rs1539019 polymorphism; A/T genotype (ORadj = 0.5; P = 0.045), allele T (ORadj = 0.93; P = 0.018), or carrier-T (ORadj = 0.48; P = 0.029) in the CARD8 rs2043211 polymorphism; and the A-C-G-C-C (ORadj = 0.11; P = 0.018), A-C-G-C-G (ORadj = 0.23; P = 0.003), C-C-G-C-C (ORadj = 0.37; P = 0.021), and C-T-G-A-C (ORadj = 0.04; P = 0.0473) in NLRP3 genetic haplotype variants. No significant associations were observed for the other polymorphisms. To the best of our knowledge, this is the first study demonstrating an association between CARD8 and NLRP3 inflammasome genetic variants and protection against COVID-19 severity, contributing to the discussion of the impact of inflammasomes on COVID-19 outcomes.

Were the socio-economic determinants of municipalities relevant to the increment of COVID-19 related deaths in Brazil in 2020?

BACKGROUND: The COVID-19 pandemic in Brazil has been showing a pattern of distribution of related deaths associated with individual socioeconomic status (SES). However, little is known about the role of SES in the distribution of the mortality rate in different population, from an ecological perspective. OBJECTIVE: The objective of this study was to evaluate the role of socioeconomic factors in the distribution of the COVID-19-related mortality rate among Brazilian municipalities in 2020. METHODS: We conducted a retrospective, cross-sectional, observational, population-wide, and ecological study, using data of COVID-19-related deaths from the Influenza Epidemiological Surveillance Information System database (SIVEP-Gripe) and SES from the Social Vulnerability Index (SVI), the Human Development Index (HDI), the Geographic Index of the Socioeconomic Context and Social Studies (GeoSES), and 2010 Demographic Census (IBGE/Brazil). We computed crude, age- and sex-standardized, and the latter offset by the time of exposure to the epidemic mortality rates. To determine socioeconomic factors associated with mortality rates we used log-linear models with state codes as a random effect and Haversine variance-covariance matrix. RESULTS: 191,528 deaths were related to COVID-19 and distributed in 4,928 (88.55%) Brazilian municipalities. Whatever the socioeconomic indexes used, the R2 were very small to explain SMRT. Consistent across all socioeconomic indexes used, high-income, more educated, and well infrastructure municipalities generally had higher mortality rates. CONCLUSION: Excluding the effect of demographic structure and pandemic timing from mortality rates, the contribution of SES to explain differences in COVID-19-related mortality rates among municipalities in Brazil became very low. The impact of SES on COVID-19-related mortality may vary across levels of aggregation. Urban infrastructure, which includes mobility structures, more complex economic activities and connections, may have influenced the average municipal death rate.

What Are We Measuring When We Evaluate Digital Interventions for Improving Lifestyle? A Scoping Meta-Review.

Background: Lifestyle Medicine (LM) aims to address six main behavioral domains: diet/nutrition, substance use (SU), physical activity (PA), social relationships, stress management, and sleep. Digital Health Interventions (DHIs) have been used to improve these domains. However, there is no consensus on how to measure lifestyle and its intermediate outcomes aside from measuring each behavior separately. We aimed to describe (1) the most frequent lifestyle domains addressed by DHIs, (2) the most frequent outcomes used to measure lifestyle changes, and (3) the most frequent DHI delivery methods. Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-ScR) Extension for Scoping Reviews. A literature search was conducted using MEDLINE, Cochrane Library, EMBASE, and Web of Science for publications since 2010. We included systematic reviews and meta-analyses of clinical trials using DHI to promote health, behavioral, or lifestyle change. Results: Overall, 954 records were identified, and 72 systematic reviews were included. Of those, 35 conducted meta-analyses, 58 addressed diet/nutrition, and 60 focused on PA. Only one systematic review evaluated all six lifestyle domains simultaneously; 1 systematic review evaluated five lifestyle domains; 5 systematic reviews evaluated 4 lifestyle domains; 14 systematic reviews evaluated 3 lifestyle domains; and the remaining 52 systematic reviews evaluated only one or two domains. The most frequently evaluated domains were diet/nutrition and PA. The most frequent DHI delivery methods were smartphone apps and websites. Discussion: The concept of lifestyle is still unclear and fragmented, making it hard to evaluate the complex interconnections of unhealthy behaviors, and their impact on health. Clarifying this concept, refining its operationalization, and defining the reporting guidelines should be considered as the current research priorities. DHIs have the potential to improve lifestyle at primary, secondary, and tertiary levels of prevention-but most of them are targeting clinical populations. Although important advances have been made to evaluate DHIs, some of their characteristics, such as the rate at which they become obsolete, will require innovative research designs to evaluate long-term outcomes in health.

The impact of healthcare-associated infections on COVID-19 mortality: a cohort study from a Brazilian public hospital.

OBJECTIVE: This study aims to analyze the risk factors for in-hospital mortality in a cohort of patients admitted to a newly adapted intensive care unit in a public hospital in Rio de Janeiro. METHODS: This was an observational, retrospective, and descriptive study. Data were obtained from electronic medical records. Coronavirus disease 2019 (COVID-19) was diagnosed by detecting viral ribonucleic acid using reverse transcription polymerase chain reaction. Factors associated with the risk/protection from death were determined using the odds ratio and adjusted odds ratio. RESULTS: Fifty-one patients were admitted to the hospital. The median age of the patients was 63 years, 60% were male patients, and 54% were white patients. Sixty-seven percent of the patients were diagnosed with COVID-19. Sepsis at admission increased the chance of in-hospital death by 21 times (adjusted odds ratio=21.06 [0.79-555.2]; p=0.06). The strongest risk factor for death was the development of septic shock during hospitalization (adjusted odds ratio=98.56 [2.75-352.5]; p=0.01), and one in four patients had multidrug-resistant bacteria. Mechanical ventilation, vasopressors, neuromuscular blockers, and sedatives were also the risk factors for in-hospital mortality. The in-hospital mortality rate was 41%, and the mortality rate of patients on mechanical ventilation was 60%. The diagnosis of COVID-19 was not statistically related to the adverse outcomes. CONCLUSIONS: In this cohort, the strongest risk factor for in-hospital death was the development of nosocomial septic shock. Healthcare-associated infections have a significant impact on mortality rates. Therefore, to have a better outcome, it is important to consider not only the availability of beds but also the way healthcare is delivered.

The cumulative effect of multiple dimensions of lifestyle on risky drinking during the Covid-19 pandemic.

Lifestyle impacts morbidity and mortality worldwide. Herein, we evaluated the association of a multidimensional lifestyle measure and its domains (diet/nutrition, substance use, physical activity, social, stress management, sleep, environmental exposure) with risky drinking. Also, we analyzed the cumulative effect of unhealthy domains in the likelihood of presenting risky drinking. To reach these objectives, data from a web survey conducted in Brazil and Spain was analyzed. The main outcome was risky drinking assessed by the AUDIT-C. Lifestyle was measured using the Short Multidimensional Inventory Lifestyle Evaluation (SMILE). Fixed logistic models were used to evaluate associations between lifestyle and risky drinking. Between April and May 2020, 22,785 individuals answered the survey. The prevalence of risky drinking was 45.6% in Brazil and 30.8% in Spain. The SMILE score was lower (unhealthier lifestyle) among at-risk drinkers. Worse scores on Diet, Substance use, Stress management and Environment were associated with an increased likelihood of risky drinking. The higher the number of unhealthy domains, the higher the likelihood of presenting risky drinking: adjusted odds ratio (aOR) for risky drinking was 1.15 (IC95% 0.98-1.35) and 23.42 (IC95% 3.08-178.02) for those presenting worse lifestyle in 1 and 5 domains, respectively. Finally, interactions suggest that improvement in lifestyle domains would have a larger effect in Spain than in Brazil. Our results suggest that future interventions aiming at reducing Risky drinking may benefit from strategies targeting multiple domains of lifestyle.

Association between ACE2 and TMPRSS2 nasopharyngeal expression and COVID-19 respiratory distress.

ACE2 and TMPRSS2 are key players on SARS-CoV-2 entry into host cells. However, it is still unclear whether expression levels of these factors could reflect disease severity. Here, a case-control study was conducted with 213 SARS-CoV-2 positive individuals where cases were defined as COVID-19 patients with respiratory distress requiring oxygen support (N = 38) and controls were those with mild to moderate symptoms of the disease who did not need oxygen therapy along the entire clinical course (N = 175). ACE2 and TMPRSS2 mRNA levels were evaluated in nasopharyngeal swab samples by RT-qPCR and logistic regression analyzes were applied to estimate associations with respiratory outcomes. ACE2 and TMPRSS2 levels positively correlated with age, which was also strongly associated with respiratory distress. Increased nasopharyngeal ACE2 levels showed a protective effect against this outcome (adjOR = 0.30; 95% CI 0.09-0.91), while TMPRSS2/ACE2 ratio was associated with risk (adjOR = 4.28; 95% CI 1.36-13.48). On stepwise regression, TMPRSS2/ACE2 ratio outperformed ACE2 to model COVID-19 severity. When nasopharyngeal swabs were compared to bronchoalveolar lavages in an independent cohort of COVID-19 patients under mechanical ventilation, similar expression levels of these genes were observed. These data suggest nasopharyngeal TMPRSS2/ACE2 as a promising candidate for further prediction models on COVID-19.

Social inequalities and the pandemic of COVID-19: the case of Rio de Janeiro.

BACKGROUND: The novel coronavirus (SARS-CoV-2) is a global pandemic. The lack of protective vaccine or treatment led most of the countries to follow the flattening of the infection curve with social isolation measures. There is evidence that socioeconomic inequalities have been shaping the COVID-19 burden among low and middle-income countries. This study described what sociodemographic and socioeconomic factors were associated with the greatest risk of COVID-19 infection and mortality and how did the importance of key neighbourhood-level socioeconomic factors change over time during the early stages of the pandemic in the Rio de Janeiro municipality, Brazil. METHODS: We linked socioeconomic attributes to confirmed cases and deaths from COVID-19 and computed age-standardised incidence and mortality rates by domains such as age, gender, crowding, education, income and race/ethnicity. RESULTS: The evidence suggests that although age-standardised incidence rates were higher in wealthy neighbourhoods, age-standardised mortality rates were higher in deprived areas during the first 2 months of the pandemic. The age-standardised mortality rates were also higher in males, and in areas with a predominance of people of colour, which are disproportionately represented in more vulnerable groups. The population also presented COVID-19 'rejuvenation', that is, people became risk group younger than in developed countries. CONCLUSION: We conclude that there is a strong health gradient for COVID-19 death risk during the early stages of the pandemic. COVID-19 cases continued to move towards the urban periphery and to more vulnerable communities, threatening the health system functioning and increasing the health gradient.

Avaliação de tecnologias em saúde: tensões metodológicas durante a pandemia de Covid-19

ABSTRACT Covid-19 is a global threat that attracts researchers from all areas to understand the natural history of the disease and its epidemiological parameters. The technological development of vaccines, diagnostic tests, and therapeutic targets has mobilized many resources in a short time. Health technology assessment (HTA), based on a systematic analysis of the properties, effects and/or impacts of health technologies through internationally-validated methods and instruments to assess the quality and methodological rigor of studies that demonstrate effectiveness, efficacy, and safety, is under unprecedented pressure due to the pandemic. This article also reflects on the emergency authorization of the use of treatments and diagnostic tests that conflict with HTA precepts. We will also evaluate non-pharmacological technologies of containment of the disease and their impacts on the domestic and international economy, as well as the judicial interventions that impact the decisions of managers in the exceptional context of the covid-19 pandemic.