Invasive Cardiopulmonary Exercise Testing Identifies Distinct Physiologic Endotypes in Postacute Sequelae of SARS-CoV-2 Infection

Background

Exercise intolerance and dyspnea on exertion are prominent symptoms in postacute sequelae of COVID-19 (PASC) that significantly impact quality of life, but underlying physiologic contributors are not well understood. Invasive cardiopulmonary exercise testing (iCPET) uses right heart catheterization, arterial access, and standard cardiopulmonary exercise testing to identify pathophysiology in undifferentiated exercise intolerance.

Research Question

What are the distinguishing clinical and physiologic features of exercise intolerant PASC and associated physiologic endotypes?

Study Design and Methods

We performed a cross-sectional observational study with prospective enrollment of consecutive patients with dyspnea and/or exercise-intolerant PASC who were referred for iCPET > 3 months after SARS-CoV-2 infection. All patients underwent history, physical examination, pulmonary function testing, echocardiogram, laboratory work, and chest imaging. We completed a detailed cardiopulmonary and hemodynamic analysis of 37 patients with iCPET to categorize PASC endotypes.

Results

We evaluated 37 patients with PASC and dyspnea on exertion and/or exercise intolerance for a median of 323 days after COVID-19 diagnosis. We compared 12 patients (32.4%) who demonstrated a normal exercise capacity (normal oxygen consumption [$\dot{\text{V}}$o₂]) with 25 patients (67.6%) that had a reduced peak $\dot{\text{V}}$o₂. We then identified distinct PASC endotypes with iCPET including preload insufficiency, decreased oxygen extraction, mixed preload insufficiency with decreased oxygen extraction, exercise pulmonary hypertension, chronic pulmonary embolism, deconditioning, and ventilatory limitation, which included physiologic abnormalities in patients with PASC with normal exercise capacity. Nine of the 12 patients with normal $\dot{\text{V}}$o₂ had normal exercise physiology (one had evidence of exercise pulmonary hypertension and two had decreased oxygen extraction) yet still presented with symptoms of exercise intolerance.

Interpretation

iCPET identified heterogeneous physiologic endotypes in patients with PASC presenting with similar symptoms of exercise intolerance or dyspnea on exertion. Future studies are needed to define associated pathogenesis and target effective therapies based on these physiologic endotypes.