Objective
To evaluate whether colchicine treatment was associated with the inhibition of NLRP3 inflammasome activation in patients with COVID-19.
Methods
We present a post hoc analysis from a ...double-blinded placebo-controlled randomized clinical trial (RCT) on the effect of colchicine for the treatment of COVID-19. Serum levels of NOD-like receptor protein 3 (NLRP3) inflammasome products—active caspase-1 (Casp1p20), IL-1β, and IL-18—were assessed at enrollment and after 48–72 h of treatment in patients receiving standard-of-care (SOC) plus placebo vs. those receiving SOC plus colchicine. The colchicine regimen was 0.5 mg tid for 5 days, followed by 0.5 mg bid for another 5 days.
Results
Thirty-six patients received SOC plus colchicine, and thirty-six received SOC plus placebo. Colchicine reduced the need for supplemental oxygen and the length of hospitalization. On Days 2–3, colchicine lowered the serum levels of Casp1p20 and IL-18, but not IL-1β.
Conclusion
Treatment with colchicine inhibited the activation of the NLRP3 inflammasome, an event triggering the ‘cytokine storm’ in COVID-19.
Trial registration numbers
RBR-8jyhxh
The goal of the present study was to compare pulmonary function test (PFT) and cardiopulmonary exercise test (CPET) performance in COVID-19 survivors with a control group (CG). This was a cross- ...sectional study. Patients diagnosed with COVID-19, without severe signs and symptoms, were evaluated one month after the infection. Healthy volunteers matched for sex and age constituted the control group. All volunteers underwent the following assessments: i) clinical evaluation, ii) PTF; and iii) CPET on a cycle ergometer. Metabolic variables were measured by the CareFusion Oxycon Mobile device. In addition, heart rate responses, peak systolic and diastolic blood pressure, and perceived exertion were recorded. Twenty-nine patients with COVID-19 and 18 healthy control subjects were evaluated. Surviving patients of COVID-19 had a mean age of 40 years and had higher body mass index and persistent symptoms compared to the CG (P<0.05), but patients with COVID-19 had more comorbidities, number of medications, and greater impairment of lung function (P<0.05). Regarding CPET, patients surviving COVID-19 had reduced peak workload, oxygen uptake (VO2), carbon dioxide output (VCO2), circulatory power (CP), and end-tidal pressure for carbon dioxide (P.sub.ETCO.sub.2) (P<0.05). Additionally, survivors had depressed chronotropic and ventilatory responses, low peak oxygen saturation, and greater muscle fatigue (P<0.05) compared to CG. Despite not showing signs and symptoms of severe disease during infection, adult survivors had losses of lung function and cardiorespiratory capacity one month after recovery from COVID-19. In addition, cardiovascular, ventilatory, and lower limb fatigue responses were the main exercise limitations. Key words: COVID-19; Survivors; Pulmonary function; Cardiorespiratory fitness; Cardiopulmonary testing
ObjectiveTo evaluate whether the addition of colchicine to standard treatment for COVID-19 results in better outcomes.DesignWe present the results of a randomised, double-blinded, placebo-controlled ...clinical trial of colchicine for the treatment of moderate to severe COVID-19, with 75 patients allocated 1:1 from 11 April to 30 August 2020. Colchicine regimen was 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days. The primary endpoints were the need for supplemental oxygen, time of hospitalisation, need for admission and length of stay in intensive care unit and death rate.ResultsSeventy-two patients (36 for placebo and 36 for colchicine) completed the study. Median (and IQR) time of need for supplemental oxygen was 4.0 (2.0–6.0) days for the colchicine group and 6.5 (4.0–9.0) days for the placebo group (p<0.001). Median (IQR) time of hospitalisation was 7.0 (5.0–9.0) days for the colchicine group and 9.0 (7.0–12.0) days for the placebo group (p=0.003). At day 2, 67% versus 86% of patients maintained the need for supplemental oxygen, while at day 7, the values were 9% versus 42%, in the colchicine and the placebo groups, respectively (log rank; p=0.001). Two patients died, both in placebo group. Diarrhoea was more frequent in the colchicine group (p=0.26).ConclusionColchicine reduced the length of both, supplemental oxygen therapy and hospitalisation. The drug was safe and well tolerated. Once death was an uncommon event, it is not possible to ensure that colchicine reduced mortality of COVID-19.Trial registration numberRBR-8jyhxh.
Obesity is a chronic disease with a multifaceted treatment approach that includes nutritional counseling, structured exercise training, and increased daily physical activity. Increased body mass ...elicits higher cardiovascular, ventilatory and metabolic demands to varying degrees during exercise. With functional capacity assessment, this variability can be evaluated so individualized guidance for exercise training and daily physical activity can be provided. The aim of the present study was to compare cardiovascular, ventilatory and metabolic responses obtained during a symptom-limited cardiopulmonary exercise test (CPX) on a treadmill to responses obtained by the incremental shuttle walk test (ISWT) in obese women and to propose a peak oxygen consumption (VO2) prediction equation through variables obtained during the ISWT. Forty obese women (BMI ≥30 kg/m2) performed one treadmill CPX and two ISWTs. Heart rate (HR), arterial blood pressure (ABP) and perceived exertion by the Borg scale were measured at rest, during each stage of the exercise protocol, and throughout the recovery period. The predicted maximal heart rate (HRmax) was calculated (210 - age in years) (16) and compared to the HR response during the CPX. Peak VO2 obtained during CPX correlated significantly (P<0.05) with ISWT peak VO2 (r=0.79) as well as ISWT distance (r=0.65). The predictive model for CPX peak VO2, using age and ISWT distance explained 67% of the variability. The current study indicates the ISWT may be used to predict aerobic capacity in obese women when CPX is not a viable option.
Obesity is often associated with increased risk of cardiometabolic morbidities and mortality. However, evidence shows that some obese individuals are more likely to develop such risk factors early in ...life, including those with Metabolic Syndrome (MetS). Whether the presence of MetS in obese people impairs cardiac autonomic modulation (CAM) remains to be investigated.
Cross-sectional study. Sixty-six subjects were classified as normal-weight (NW, n = 24) or obese (BMI ≥ 30 kg·m−2): metabolically healthy (MHO, n = 19) vs unhealthy (MUHO, n = 23: NCEP/ATPIII-MetS criteria). Body composition (bioimpedance), metabolic (glucose-insulin/lipid) and inflammatory profiles were determined. Linear and nonlinear heart rate variability (HRV) indices were computed at rest and during the submaximal six-minute step test (6MST). Blood pressure (BP) and metabolic and ventilatory variables were assessed (oxygen uptake, VO2; carbon dioxide production, VCO2; minute ventilation, VE) during the 6MST and the maximal cardiopulmonary exercise testing (CPX).
All groups reached the same 6MST intensity (VO2 ~ 80% and HR ~ 87% of CPX peak values). Both obese groups, independently of MetS, presented higher BP and lower maximal VO2 than NW. However, HRV differed between groups according to MetS at rest and during exercise: MUHO had lower meanRRi and SD1 than NW and lower RMSSD and pNN50 than MHO at rest; during exercise, the lowest SDNN, TINN, SD1 and Shannon entropy were observed for MUHO. Significant correlations were found between MetS, insulin resistance and HRV indices; and between insulin resistance and aerobic capacity (VO2peak).
Obesity per se impairs aerobic-hemodynamic responses to exercise. However, MetS in obese young adults negatively impacts overall HRV, parasympathetic activity and HRV complexity.
•Cardiorespiratory responses to exercise are influenced by obesity per se.•Obese people with metabolic syndrome have impaired cardiac autonomic modulation.•The functional six-minute step test is useful to evaluate HRV.
Background: Chronic obstructive pulmonary disease (COPD) manifests itself in complex ways, with local and systemic effects; because of this, a multifactorial approach is needed for disease ...evaluation, in order to understand its severity and impact on each individual. Thus, our objective was to study the correlation between easily accessible variables, usually available in clinical practice, and maximum aerobic capacity, and to determine models for peak oxygen uptake (VO2peak) estimation in COPD patients. Subjects and methods: Individuals with COPD were selected for the study. At the first visit, clinical evaluation was performed. During the second visit, the volunteers were subjected to the cardiopulmonary exercise test. To determine the correlation coefficient of VO2peak with forced expiratory volume in 1 second (FEV1) (% pred.) and the COPD Assessment Test score (CATs), Pearson or Spearman tests were performed. VO2 at the peak of the exercise was estimated from the clinical variables by simple and multiple linear regression analyses. Results: A total of 249 subjects were selected, 27 of whom were included after screening (gender: 21M/5F; age: 65.0±7.3 years; body mass index: 26.6±5.0 kg/m2; FEV1 (% pred.): 56.4±15.7, CAT: 12.4±7.4). Mean VO2peak was 12.8±3.0 mL·kg-1·min-1 and VO2peak (% pred.) was 62.1%±14.9%. VO2peak presented a strong positive correlation with FEV1 (% pred.), r: 0.70, and a moderate negative correlation with the CATs, r: -0.54. In the VO2peak estimation model based on the CAT (estimated VO2peak =15.148- 0.185× CATs), the index explained 20% of the variance, with estimated error of 2.826 mL·kg-1·min-1. In the VO2peak estimation model based on FEV1 (estimated VO2peak =6.490+ 0.113× FEV1), the variable explained 50% of the variance, with an estimated error of 2.231 mL·kg-1·min-1. In the VO2peak estimation model based on CATs and FEV1 (estimated VO2peak =8.441- 0.0999× CAT + 0.1000× FEV1), the variables explained 55% of the variance, with an estimated error of 2.156 mL·kg-1·min-1. Conclusion: COPD patients’ maximum aerobic capacity has a significant correlation with easily accessible and widely used clinical variables, such as the CATs and FEV1, which can be used to estimate peak VO2.
COVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to ...promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of SARS-CoV2-infected apoptotic cells exacerbates inflammatory cytokine production, inhibits the expression of efferocytic receptors, and impairs continual efferocytosis by macrophages. We also provide evidence supporting that lung monocytes and macrophages from severe COVID-19 patients have compromised efferocytic capacity. Our findings reveal that dysfunctional efferocytosis of SARS-CoV-2-infected cell corpses suppress macrophage anti-inflammation and efficient tissue repair programs and provide mechanistic insights for the excessive production of pro-inflammatory cytokines and accumulation of tissue damage associated with COVID-19 immunopathogenesis.
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a hyperinflammatory state and lymphocytopenia, a hallmark that appears as both signature and ...prognosis of disease severity outcome. Although cytokine storm and a sustained inflammatory state are commonly associated with immune cell depletion, it is still unclear whether direct SARS-CoV-2 infection of immune cells could also play a role in this scenario by harboring viral replication. We found that monocytes, as well as both B and T lymphocytes, were susceptible to SARS-CoV-2 infection in vitro, accumulating double-stranded RNA consistent with viral RNA replication and ultimately leading to expressive T cell apoptosis. In addition, flow cytometry and immunofluorescence analysis revealed that SARS-CoV-2 was frequently detected in monocytes and B lymphocytes from coronavirus disease 2019 (COVID-19) patients. The rates of SARS-CoV-2-infected monocytes in peripheral blood mononuclear cells from COVID-19 patients increased over time from symptom onset, with SARS-CoV-2-positive monocytes, B cells, and CD4+ T lymphocytes also detected in postmortem lung tissue. These results indicated that SARS-CoV-2 infection of blood-circulating leukocytes in COVID-19 patients might have important implications for disease pathogenesis and progression, immune dysfunction, and virus spread within the host.
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