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Individuals who continue to experience shortness of breath post-acute COVID-19 despite normal chest imaging and pulmonary function tests appear to have respiratory and circulatory abnormalities that are detectable with cardiopulmonary exercise testing (CPET), new research suggests.
Circulatory impairment and abnormal ventilatory patterns were identified with CPET in a majority of 41 patients with post-acute sequelae of SARS-CoV-2 infection (PASC) who had normal chest x-rays, chest computed tomography (CT), and pulmonary function tests (PFTs).
Moreover, nearly half also met criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a population in whom similar abnormalities have also been detected prior to the COVID-19 pandemic using CPET.
The new data were published online November 29 in the Journal of the American College of Cardiology: Heart Failure by Donna M. Mancini, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, and director of the heart failure and transplant programs at the Mount Sinai Health System, New York City.
“Their chest x-rays are now normal, their chest CT scans are now normal, their PFTs are now normal, but yet they’re short of breath,” Mancini told theheart.org | Medscape Cardiology. “Clinicians don’t know how to explain the symptom. Possible explanations are anxiety, and in addition other potential causes that need further workup.”
But, she said, current guidelines for evaluating patients with long COVID only advise short, rather than maximal, exercise testing out of concern for making patients worse. In addition, CPET isn’t available everywhere and it generates a large amount of data that may be difficult to interpret. Still, she said, such testing is especially warranted in this group of previously-healthy, relatively younger people who continue to experience symptoms following what are often less-severe cases of COVID-19 that may not have necessitated hospitalization.
“When we see patients with unexplained shortness of breath, one of the tests we do is CPET. It gives us a lot of additional information compared to standard exercise testing,” Mancini said.
However, she cautioned that even with CPET, the signs of dysfunctional breathing can be very subtle and laboratory reports might not tell the whole story. It’s important to look specifically at breathing frequency and tidal volume and to request those data if the report doesn’t include it, she advised. “It’s not an easy diagnosis to make, and unless you really look at what the patients are doing you don’t see it.”
New Findings Align With Previous Data
These data align completely with prior work in patients with both PASC and ME/CFS by David M. Systrom, MD, director of the Advanced CPET program and Dyspnea Clinic at Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, and colleagues.
“There are many arrows that lead to the sensation of shortness of breath, and they come from virtually every body part. One can be short of breath from parenchymal lung disease and heart disease and that’s what most people think about initially. Those things are obviously worth ruling out in this setting. But, more often it’s something entirely different,” Systrom told theheart.org | Medscape Cardiology.
He said that while some patients who have symptoms following acute COVID-19 illness have some parenchymal lung disease, pulmonary hypertension, or residual cardiomyopathy, “the majority of the patients we’ve seen at the Brigham with PASC don’t have any of those things. They’re more typically patients who are younger and who have milder disease acutely, who were perfectly fine predating the acute COVID infection. Then they end up having what we’ve been studying for nearly 10 years now in people with a diagnosis of ME/CFS: evidence of dysautonomia and neurovascular dysfunction.”
Systrom’s lab actually uses invasive CPET (iCPET), in which patients exercise upright with catheters placed into their pulmonary and radial arteries to allow continuous pulmonary and systemic hemodynamic and gas exchange monitoring.
Using that method in 10 patients with PASC who did not have cardiopulmonary disease, Systrom and colleagues found reductions in peak VO2 from a peripheral, rather than a central limit in exercise capacity, along with an exaggerated hyperventilatory response during exercise just as Mancini’s group had found. Those data were published in August 2021 in Chest.
In another iCPET study conducted pre-COVID-19 in 160 patients with ME/CFS, Systrom’s team identified two types of peripheral neurovascular dysregulation that could contribute to exercise intolerance: depressed cardiac output from impaired venous return and impaired peripheral oxygen extraction.
In skin biopsies, nearly a third were found to have evidence of small-fiber neuropathy. In those patients, neuropathic dysregulation causing vascular dilation may limit exertion by shunting oxygenated blood away from exercising muscle and reducing venous return to the right heart, the authors suggested.
Those findings were also published in August 2021 in Chest. Systrom presented the data in part in 2019 at a National Institutes of Health meeting devoted to ME/CFS.
Systrom and colleagues are now collaborating with the National Institutes of Health to develop plasma biomarkers that could be used in combination with CPET to either avoid or minimize the invasiveness, yet still allow for obtaining gas exchange and VO2 peak estimates for use in both ME/CFS and PASC patients. “We have some emerging evidence that there are distinct metabolomic, proteomic, and cytokine profiles or signatures in plasma, elicited by a brief bout of exercise in the blood that are very different from normal,” he said, noting that it’s possible these markers can be obtained via a small catheter in an antecubital vein rather than directly into the radial and pulmonary arteries.
For now, he said noninvasive CPET is certainly useful in patients with PASC or ME/CFS, as is autonomic nervous system evaluation with available methods including tilt-table testing, quantitative sudomotor axon reflex test (QSART), sudomotor scans, and skin biopsy. In addition, he said, “I would also expand an autoimmune workup because many of these patients post-COVID have inflammatory biomarkers, both traditional and nontraditional. The Mayo Clinic paraneoplastic autoantibody panel will have positive results in a significant proportion of these patients.”
Such evaluations may lead to treatments to tamp down the inflammatory processes. Systrom’s team has recently completed a prospective randomized trial using the acetylcholinesterase inhibitor pyridostigmine (Mestinon) or placebo in 50 patients with ME/CFS. The aim was to improve hemodynamic, ventilatory and oxygen exchange variables such as biventricular filling pressures and systemic oxygen extraction, evaluated using a replicate iCPET.
Those data will soon be submitted for publication and might be presented at an upcoming conference sooner.
“The Start of a Line of Research”
In Mancini’s study, the 41 patients performed CPET and underwent symptom assessment for ME/CFS using the 1994 “Fukuda” criteria an average of 8.9 months after acute COVID-19. Average left ventricular ejection fraction was 59%. Peak VO2 averaged 20.3 mL/kg/min (77% of predicted VO2). The slope of minute ventilation to CO2 production (VE/VCO2 slope) was 30. End tidal pressure of CO2 at rest was 33.5 mmHg.
Over half (58.5%) of the patients had peak VO2 of less than 80% predicted, and all of those individuals had a circulatory exercise limitation. Among the 17 with normal peak VO2, ventilatory abnormalities were identified, including three with peak respiratory rate greater than 55 and 26 with dysfunctional (rapid and erratic) breathing. Overall, 88% (36) had ventilatory abnormalities with dysfunctional breathing, increased VE/VCO2, and/or hypocapnia PetCO2 < 35.
Finally, 19 patients (46%) met the 1994 “chronic fatigue syndrome” criteria. Mancini said that she didn’t think the results would differ significantly had they used the more recent Institute (now Academy) of Medicine criteria published in 2015.
“I think that this is the start of a line of research. I think there need to be future studies of breathing retraining to see if we can help them feel better by addressing the hyperventilation,” Mancini added. “That hasn’t been done yet. I think this is all hypothesis-generating.”
On the bright side, she noted that this dysfunctional breathing isn’t associated with a high mortality. For now, she advises patients to consider yoga and, to the best of their ability, “breath slow and deep.”
Mancini has no disclosures. Systrom has received consulting fees and research support from Astellas Pharma.
JACC Heart Fail. 2021;9(12):927-937. Abstract
Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on Twitter @MiriamETucker.
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