Mecanismos da dispneia, fadiga e redução da aptidão cardiorrespiratória no pós Covid-19: contribuição integrada da DLCO, da função endotelial e do TECP com análise longitudinal

Abstract

Study I. Introduction: Although they did not present signs and symptoms of severe disease during the acute infection, adult COVID-19 survivors may exhibit impairments in pulmonary function and cardiorespiratory capacity after recovery. Objective: To compare performance on pulmonary function tests and cardiopulmonary exercise testing (CPET) between COVID-19 survivors and a control group (CG). Methods: This was a cross-sectional study. Volunteers diagnosed with COVID-19 who had not experienced severe signs and symptoms were evaluated one month after infection. Healthy volunteers matched for sex and age comprised the CG. All volunteers underwent the following assessments: I) clinical evaluation; II) complete pulmonary function testing; and III) cycle ergometer CPET. Metabolic variables were measured using the CareFusion Oxycon Mobile system. In addition, heart rate responses, peak systolic and diastolic blood pressure, and perceived exertion were recorded. Results: Twenty-nine COVID-19 survivors and 18 healthy control volunteers were evaluated. COVID-19 survivors had a mean age of 40 years, a higher body mass index, and persistent symptoms compared with the CG (p<0.05). In addition, they exhibited a greater number of comorbidities, a higher number of medications in use, and greater impairment in pulmonary function (p<0.05). During CPET, COVID-19 survivors showed lower peak work rate, oxygen uptake (V̇O₂), carbon dioxide output (V̇CO₂), circulatory power (CP), and end-tidal carbon dioxide pressure (PETCO₂) (p<0.05). Moreover, survivors exhibited blunted chronotropic and ventilatory responses, lower peak peripheral oxygen saturation, and greater muscle fatigue (p<0.05) compared with the CG. Conclusion: Despite not having experienced signs and symptoms of severe disease during the acute infection, adult survivors exhibited reduced pulmonary function and cardiorespiratory capacity one month after recovery from COVID-19. Furthermore, cardiovascular and ventilatory responses and lower-limb fatigue were the main exercise-limiting factors. Study II. Introduction: COVID-19 negatively affects cardiorespiratory fitness (CRF), increasing the likelihood of exertional symptoms, such as fatigue and dyspnea, and adversely affecting vascular function, thereby impairing cardiovascular health. Objective: To investigate endothelial function and its relationship with CRF in individuals who had recovered from COVID-19. Methods: Volunteers were evaluated one month after infection and underwent clinical assessment, pulmonary function testing, endothelial function assessment, measured by flow-mediated dilation, and cardiopulmonary exercise testing. Results: COVID-19 survivors exhibited reduced exercise capacity, with lower peak V̇O₂ and FMD (%) values according to disease severity. However, endothelial function was worse in volunteers with previous COVID-19, regardless of disease severity, compared with the control group. Significant associations were observed between lower FMD (%) and lower peak V̇O₂, work rate, circulatory power, and peak V̇O₂/work rate values. Conclusion: Endothelial function was significantly associated with CRF in COVID-19 survivors according to disease severity. Strategies aimed at improving CRF and mitigating the negative effects resulting from endothelial dysfunction should be investigated in future studies. Study III. Introduction: Reduced diffusing capacity of the lungs for carbon monoxide (DLCO) is a common abnormality after COVID-19. However, its recovery trajectory over one year according to the severity of the acute disease and its relationship with persistent symptoms remain incompletely understood. Objective: To evaluate the recovery trajectory of DLCO over one year according to the severity of acute COVID-19 and its relationship with persistent dyspnea and fatigue. Methods: In this longitudinal observational study, 60 volunteers who had recovered from COVID-19, including 20 with mild, 20 with moderate, and 20 with severe disease, and 20 control participants underwent pulmonary function testing, including DLCO, carbon monoxide transfer coefficient (KCO), and alveolar volume (VA), expressed as absolute values and percentages of predicted values. Survivors were evaluated at baseline, after the acute phase of infection, one month after infection, and at the one-year follow-up. Two-way analysis of variance (ANOVA) was used to assess between-group and within-group differences over time. Receiver operating characteristic curve analysis identified the optimal DLCO% cutoff for dyspnea and fatigue, and symptom persistence at 12 months was assessed using Kaplan–Meier curves. Results: At baseline, DLCO% and VA% were significantly reduced in the moderate and severe groups compared with the mild and control groups. Over one year, DLCO% showed a significant interaction between time and disease severity, with minimal variation in mild cases (approximately +1%) and modest improvement in moderate cases (approximately +3%), but a marked increase among volunteers who had experienced severe COVID-19, from 66% to 83% of predicted values (approximately +26%). VA% improved predominantly in the moderate and severe groups (approximately +7% and +6%, respectively), whereas KCO% remained largely stable, with a small increase only in the severe group. A DLCO% cutoff of ≤80% of predicted values at one year identified individuals with dyspnea and/or fatigue with high diagnostic accuracy, with a sensitivity of 85.7%, specificity of 81.8%, and an area under the curve of 0.82. Conclusion: One year after COVID-19, pulmonary gas-exchange abnormalities persisted in a substantial proportion of volunteers but showed significant recovery among those who initially had severe forms of the disease, primarily driven by improvements in DLCO% and VA%. A DLCO% <80% of predicted values identifies individuals at greater risk of persistent dyspnea and fatigue and should be incorporated into long-term follow-up strategies for COVID-19 survivors. Study IV. Introduction: Post-COVID-19 condition may be accompanied by exercise intolerance and possible persistent vascular abnormalities. Endothelial dysfunction, estimated by flow-mediated dilation (FMD), and the hemodynamic stimulus represented by shear stress may act as mechanistic links between cardiorespiratory fitness and functional recovery. Objective: To compare cardiopulmonary exercise testing (CPET), FMD, and shear stress outcomes between an initial assessment and long-term follow-up in COVID-19 survivors stratified by disease severity, and to investigate associations between fitness markers and vascular variables. Methods: This was a longitudinal study with groups matched for disease severity, sex, and age. CPET parameters and vascular measurements, including FMD and shear stress, were analyzed at the initial assessment and follow-up. Group-by-time comparisons were performed using a general linear model for repeated measures, adjusted for age, sex, and body mass index. Associations were tested using correlation analyses and simple linear regression, considering r, R², and p values. Results: Longitudinal improvements in cardiorespiratory fitness and vascular markers were observed. However, recovery remained incomplete in the severe group, which maintained a poorer functional profile and greater ventilatory cost at follow-up. FMD increased over time but remained reduced in survivors of severe COVID-19. Shear stress differed among groups and increased at follow-up, although lower values persisted in the severe group. Correlation and regression analyses demonstrated positive associations between FMD and V̇O₂ and between FMD and circulatory power. Stronger associations were observed between shear stress and CPET variables, indicating physiological coupling among exercise performance, hemodynamic stimulus, and endothelial function. Conclusion: After COVID-19, cardiorespiratory fitness and endothelial function show partial recovery that is strongly modulated by disease severity, and shear stress emerges as a relevant integrative marker of the relationship between CPET and FMD.