Post-COVID-19 Syndrome: Prospective Evaluation of Clinical and Functional Outcomes and Systematic Review

Introduction: Coronavirus disease 2019 (COVID-19) is a systemic disease characterized by a disproportionate inflammatory response in the acute phase. However, long-term clinical, functional, and metabolic consequences are still unknown. This study sought to identify clinical sequelae and its potential intrinsic mechanism among COVID-19 survivors in the follow-up. Methods: We conducted a prospective single-center study (NCT04689490) of previously hospitalized COVID-19 patients with and without dyspnea during mid-term follow-up, an outpatient asymptomatic control group was also evaluated. They underwent serial testing with cardio-pulmonary exercise test (CPET), transthoracic echocardiogram, pulmonary lung test, six-minute walking test, serum biomarker analysis and quality of life questionaries.Results: Patients with dyspnea (n=41, 58.6%), compared with asymptomatic (n=29, 41.4%), had a higher proportion of females (73.2% vs. 51.7%; p= 0.065), with comparable age and prevalence of cardiovascular risk factors. There were no significant differences in transthoracic echocardiogram and pulmonary function test, in either group. Patients who referred dyspnea had a significant decline in predicted peak O2 consumption (77.8 [64-92.5] vs. 99 [88-105]: p<0.00; p<0.001), total distance in the 6-minute walking test (535 [467-600] vs. 611 [550-650] meters; p= 0.001), and quality of life (KCCQ-23 60.1±18.6 vs. 82.8±11.3; p<0.001). Additionally, abnormalities in CPET were suggestive of a ventilation/perfusion characterized by impaired ventilatory efficiency (VE/VCO2 slope 32 [28.1-37.4] vs. 29.4 [26.9-31.4]; p= 0.022) and low O2 pulse (9.2 [7.3-11.3] vs. 10.6 [8.7-13.2]; p= 0.013). Interpretation: In this study >50% of COVID-19 survivors present a symptomatic functional impairment irrespective of age or prior hospitalization. Our findings suggest potential ventilation/perfusion mismatch.Funding Statement: The present study was partially granted by Gerencia Regional de Salud de Castilla y León under grant number GRS COVID 111/A/20 and Grant from the Spanish Society of Cardiology: SEC/FEC-INVCLI 20/030Declaration of Interests: None.Ethics Approval Statement: The institutional local ethics committees approved the study protocol (CASVE PI-20-1894) and all patients provided written informed consent before inclusion.