Understanding Exertional Dyspnea and Exercise Intolerance in COVID-19

Purpose and Justification:

In less than one year, the novel coronavirus has infected more than 80 000 000 people worldwide. Infection causes Corona Virus Disease 2019 (covid-19) and in some cases severe acute respiratory syndrome. Overall risk of mortality from covid-19 is low, however, risk radically increases with age and cardiovascular comorbidity. The long-term consequences of covid-19 are not known. Already a phenotype of survivors with prolonged symptom burden has presented; this phenotype is characterized by persistent respiratory (cough, sputum, dyspnea, wheeze) and musculoskeletal (pain, fatigue) symptoms. Preliminary data from clinical exercise testing conducted at the UofA pulmonary function laboratory suggests covid-19 survivors with prolonged symptoms have significantly reduced exercise tolerance and increased exertional dyspnea.

Impaired exercise tolerance measured as peak oxygen uptake (VO2peak) is the strongest independent predictor of cardiovascular and all-cause mortality. The investigators preliminary data in seven persistently symptomatic covid-19 survivors (PS-CoV) 3-months post molecular confirmation of infection shows a mean 30% impairment in VO2peak relative to age-, sex- and body mass index matched controls. Several facets of covid-19, including treatment and recovery, may contribute to the range and severity of debilitation and impairment in VO2peak in PS-CoV. The purpose of this study is to investigate impairments in VO2peak, and pulmonary, cardiac and peripheral factors contributing to impaired VO2peak, exercise intolerance, and persistent dyspnea in PS-CoV.

Coronavirus gains cellular entry through binding angiotensin converting enzyme in the lungs, making the lungs and pulmonary vasculature a logical starting point for investigation of persistent symptomology. During active infection, pulmonary vascular dysfunction, microthromboemboli, micro-angiopathy and pulmonary inflammation and/or fibrosis are reported. Accompanying this is a reduction in diffusion capacity at rest, increased tortuosity of pulmonary vasculature, and elevated pulmonary vascular resistance. One mechanistic explanation is that regions downstream of micro-thromboemboli become fibrotic secondary to reduced blood flow resulting in reduced diffusion capacity. Physiological adaptation through intussusceptive angiogenesis results in increased tortuosity of pulmonary vasculature, with a secondary consequence of increased pulmonary vascular resistance. However, evidence of isolated decreases in diffusion capacity in the absence of pulmonary fibrosis are at odds with this theory. An alternative explanation is that pulmonary vascular dysfunction precedes lesions viewed by computed tomography (CT) and changes in lung volumes. Regardless of incipient damage, for ~1/3 of hospitalized covid-19 patients, the end result is pulmonary fibrosis, impaired diffusion capacity (measured as the diffusion limitation of carbon monoxide, DLCO), reduced forced vital capacity (FVC) and proportionately reduced forced expiratory volume in one second (FEV1).

In PS-CoV, lung impairment at 3-month follow-up is characterized by reduced resting DLCO, FVC and FEV1, and incomplete normalization of pulmonary CT consolidation and opacities.13 The investigators preliminary data in PS-CoV show increased respiratory rate and VE/VCO2 (indicative of increased deadspace or excessive ventilatory drive) at peak exercise- characteristic of parenchymal or restrictive lung disease and consistent with pathology of covid-19 including parenchymal cell death and pulmonary fibrosis. Despite these findings, initial data suggest that PS-CoV patients' operating lung volumes during exercise and peak breathing reserve are relatively preserved. Previous work in COPD has shown that an elevated VE/VCO2 during exercise is explained by higher deadspace, and this increased VE/VCO2 contributes to increased dyspnea secondary to increased drive to breathe. The investigators work in COPD has shown that the increase VE/VCO2 is due to hypoperfusion of the pulmonary capillaries as demonstrated by a reduced DLCO and reduced pulmonary capillary blood volume during exercise, and that when pulmonary perfusion is improved by using inspired NO, VE/VCO2 and dyspnea are decreased resulting in an increase in VO2peak.