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Persistent Dyspnea After COVID-19 May Have Another Cause

Key findings

  • The aim of this study was to characterize dyspnea and exercise limitation in 18 patients with pulmonary post-acute sequelae of SARS-CoV-2 infection (PASC) and 18 age- and sex-matched controls who presented in the pre–COVID-19 era
  • Cardiopulmonary exercise testing (CPET) results were normal in 67% of patients in both groups
  • The two groups were similar with respect to resting heart rate, peak workload, peak oxygen consumption, ventilatory anerobic threshold, oxygen pulse and ventilatory efficiency
  • Pulmonary vascular disease and hyperventilatory response to exercise, hypothesized to be part of the pathology of PASC, did not seem to be features of PASC in this cohort. Physiologic abnormalities on CPET were mild across a range of initial COVID-19 severity
  • These results suggest persistent dyspnea/exercise intolerance after COVID-19 is due to heterogeneous pathophysiology. The similarity of the COVID-19 patients compared to pre-COVID patients with unexplained dyspnea suggests that in many patients, dyspnea after mild COVID-19 may be caused by disorders not directly related to COVID-19

About 10% of people who recover from COVID-19 experience symptoms lasting at least one month, and about 2.5% have symptoms for more than three months. Among the most common symptoms of long COVID, more formally termed post-acute sequelae of SARS-CoV-2 infection (PASC), are dyspnea and exercise intolerance.

The physiologic abnormalities that cause these two symptoms are unknown. Prior studies that made use of cardiopulmonary exercise testing (CPET) have detected ventilatory inefficiency, impaired heart rate recovery, and skeletal muscle deconditioning after acute COVID-19, but this research was conducted close to the time of hospital discharge.

Now, Corey Hardin, MD, PhD, and George A. Alba, MD, both physicians in the Division of Pulmonary and Critical Care Medicine at Massachusetts General Hospital, and colleagues have conducted CPET in COVID-19 patients with long-term symptoms. In EClinicalMedicine, they describe the remarkable similarities between those patients and matched controls who presented with unexplained dyspnea in the pre–COVID-19 era.

Study Methods

The researchers compared two groups of adult outpatients who underwent CPET at Mass General:

  • PASC group—The first 18 patients referred by the Coronavirus Recovery Pulmonary Clinic for CPET because of persistent dyspnea and/or exercise intolerance; they were evaluated between August 1, 2020, and March 1, 2021, at a median of 258 days since infection
  • Comparator group—18 patients age- and sex-matched to the PASC group who underwent CPET between January 1, 2019, and January 1, 2020, for unexplained dyspnea and/or exercise intolerance

CPET Results

PASC group

  • Normal—12 patients (67%)
  • Abnormal cardiovascular response with impaired cardiac output during ventriculography—2 patients
  • Early ventilatory anaerobic threshold (VAT)—2 patients
  • Decreased oxygen pulse—4 patients, of whom three had normal cardiac function; in the other patient, invasive CPET showed impaired peripheral oxygen extraction was the chief exercise limitation

Comparator group

  • Normal—12 patients (67%)
  • Abnormal cardiovascular response due to chronotropic incompetence—2 patients
  • Doubling in VO2 at the onset of unloaded exercise suggesting a high internal cost of work observed in obesity—1 patient
  • Decreased oxygen pulse—3 patients; in one of them invasive CPET confirmed impaired peripheral oxygen extraction

Comparison of Physiologic Variables

The PASC and comparator groups were similar with respect to resting heart rate, peak workload, peak oxygen consumption, VAT, oxygen pulse and ventilatory efficiency. Neither pulmonary vascular disease nor hyperventilatory response to exercise seemed to be a feature of PASC in this sample.

Physiologic abnormalities on CPET were generally mild regardless of initial COVID-19 severity. The exceptions were observed in the two survivors of acute respiratory distress syndrome: one had impaired cardiac output due to chronotropic incompetence and the other had residual cardiomyopathy.

Applying the Findings to Practice

These results suggest persistent dyspnea/exercise intolerance after COVID-19 is due to heterogeneous pathophysiology. It is important to investigate the cause, especially as other conditions may develop concurrently with SARS-CoV-2 infection. This study further highlights the importance of non-COVID-19 controls in studies of PASC.

In this study, most patients in both groups had normal findings on routine diagnostics, such as pulmonary function testing and high-resolution computed tomography. CPET may be needed to guide diagnosis and treatment.

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