Evaluating post-acute sequelae of COVID-19 using cardiopulmonary exercise testing

In a recent study posted to the medRxiv* pre-print server, researchers demonstrated reduced exercise capacity due to persistent cardiopulmonary symptoms among coronavirus disease 2019 (COVID-19) survivors hospitalized for acute infection and those with long COVID (LC).

Background

LC, a type of post-acute sequelae of COVID-19 (PASC), is quite common after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Studies have shown that 3-30% of individuals, including non-hospitalized and COVID-19-vaccinated individuals, suffer from LC that may persist for a minimum of 12 months.

Cardiopulmonary exercise testing (CPET) aids in the differential diagnosis of a patient's exercise limitations. It measures resting cardiopulmonary parameters and monitors cardiopulmonary symptoms while exercising on the treadmill. The oxygen consumption measurements allow the determination of the exercise capacity, and peak oxygen consumption or VO₂ (in ml/kg/min).

This data is clinically significant and routinely used to diagnose dyspnea and prognostically in heart failure, lung diseases, and pre-operative evaluations. More importantly, CPET data helps evaluate reduced exercise capacity among adults with and without LC. However, the association between exercise intolerance and LC and the underlying pathophysiology is uncertain.

About the study

In the present study, researchers extensively searched research studies that used CPET to evaluate exercise capacity in adults who contracted SARS-CoV-2 infection at least three months previous. The search covered Publisher MEDLINE (PubMed), Excerpta Medica (EMBASE), and Web of Science databases; the team used keywords such as SARS-CoV-2 with cardiopulmonary exercise test, CPET, CPX, CPEX, exercise capacity, VO₂, anaerobic threshold, customized to the database.

The researchers collected cohort studies, case series, and baseline data from interventional studies. They first ran this search on December 20, 2021, then again on May 24, 2022; however, they searched pre-prints through June 9, 2022. The team used REDCap for independent data extraction in duplicates. Likewise, they used the Cochrane’s Quality in Prognostic Studies tool to assess study populations, the quality of CPET exercise protocols, peak VO₂ and sub-maximal test assessments, confounding, reporting, and statistical analysis.

Further, they performed a random-effects meta-analysis to estimate the mean difference in peak VO₂ between those with and without LC and SARS-CoV-2 infection. The patient and control selection introduced a high degree of heterogeneity in the studies screened for this work. The researchers used forest plots, funnel plots, and I2 to assess this heterogeneity. The estimated standard deviation was interquartile range (IQR)/1.35 for studies that reported median and IQR, while they combined those reporting subgroups as per the Cochrane Handbook.

Study findings

The authors identified 39 observational studies, including 33 published manuscripts, three conference abstracts, and three pre-prints. All the studies performed CPET on over 2000 individuals, with nearly 1000 suffering from LC. While most of these studies performed CPET evaluations between three to six months following SARS-CoV-2 infection, one study investigated CPET after one year of infection. Notably, there was one cardiac rehabilitation study reporting baseline CPETs.

The remaining 85% of studies were single-center case series of patients attending LC clinics, and three studies included longitudinal CPET. Around 41% of included studies only evaluated hospitalized individuals, and an average of 89% of studies examined symptomatic cases. Since the number of included studies was small, the researchers did not perform tests for publication bias.

Meta-analysis results confirmed that compared to uninfected controls, SARS-CoV-2 infected individuals had significantly lower peak VO₂ and high heterogeneity. Similarly, between LC vs. COVID-19 recovered individuals, the meta-analysis showed a reduced exercise capacity among those with LC. Since no study evaluated pre-COVID-19 CPETs, the authors could not compare within-individual changes. Few studies addressed confounding factors, such as age, gender, body mass index, pre-infection fitness, and comorbid cardiac and pulmonary conditions. Only two studies, including the current study, demonstrated an adjusted difference in peak VO₂ between those with and without LC.

Concerning mechanisms of reduced exercise capacity in LC, the authors most commonly identified deconditioning, although identifying direct effects was challenging. Other reported patterns included dysfunctional breathing, changes in peripheral oxygen use, chronotropic incompetence, and lower stroke volume augmentation. The findings clarified that direct heart or lung damage was not the primary driver of exercise limitations.

Conclusions

To conclude, the study demonstrated that individuals hospitalized for severe COVID-19 and those with LC had reduced exercise capacity. However, due to heterogeneity in inclusion criteria, diverse interpretations, and multiple underlying mechanisms rather than one; thus, the study could not establish mechanisms of LC or etiology of reduced exercise capacity.

Therefore, the authors emphasized performing longitudinal studies to investigate the trajectory of exercise capacity. They also recommended using CPET in interventional trials for potential LC therapeutics.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.