In Long COVID, CPET finds anomalies other tests don’t

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People who continue to experience shortness of breath after acute COVID-19 despite chest imaging and normal lung function tests appear to have respiratory and circulatory abnormalities detectable with cardiopulmonary stress tests (CPET), according to a new study.

Circulatory disorders 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 chest x-rays, computed tomography (CT) ) normal pulmonary and pulmonary function tests (PFT).

In addition, almost half also met the criteria for myalgic encephalomyelitis/ chronic fatigue syndrome (ME / CFS), a population in which similar abnormalities were also detected before the COVID-19 pandemic using the CPET.

The new data were published online November 29 to the Journal of the American College of Cardiology: Heart failure by Donna M. Mancini, MD, Professor of Medicine at Icahn School of Medicine at Mount Sinai and Director of Heart Failure and Transplant Programs at Mount Sinai Health System, New York.

“Their chest x-rays are now normal, their chest CT scans are now normal, their PFTs are now normal, yet they are short of breath,” Mancini said. theheart.org | Cardiology Medscape. “Clinicians don’t know how to explain the symptom. Possible explanations are anxiety and, in addition, other potential causes that require further investigation.”

But, she said, current guidelines To assess patients with long COVID, advise only short stress tests, rather than maximum, for the sake of making patients worse. In addition, CPET is not available everywhere and it generates a large amount of data which can be difficult to interpret. Yet, she said, such testing is particularly warranted in this group of previously healthy and relatively younger people who continue to show symptoms as a result of often milder cases of COVID-19 that have not. may not have required 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 stress tests,” Mancini said.

However, she warned that even with CPET, signs of respiratory dysfunction can be very subtle and lab reports might not tell it all. It’s important to look specifically at respiratory rate and tidal volume and ask for that data if the report doesn’t include it, she advised. “It’s not an easy diagnosis to make, and if you don’t really look at what patients are doing, you don’t see it.”

New results align with previous data

These data align completely with previous work on patients with both PASC and ME / CFS by David M. Systrom, MD, director of the Advanced CPET program and the Dyspnea Clinic at Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, and colleagues.

“There are many arrows that lead to the feeling of shortness of breath, and they come from almost every part of the body. You can be short of breath from parenchymal lung disease and heart disease and that’s what it is. what most people initially think. It’s worth dismissing in this context. But, more often than not, it’s something completely different, “Systrom said. theheart.org | Medscape Cardiology.

He said that while some patients who show symptoms as a result of acute COVID-19 illness have parenchymal lung disease, pulmonary hypertension, or residual cardiomyopathy, “the majority of the patients we’ve seen at Brigham with PASC don’t have any of these things. They’re more typically patients who are younger and have acutely milder disease, who were perfectly fine. long before the acute COVID infection. Then they end up having what we’ve been studying for almost 10 years now in people diagnosed with ME / CFS: evidence of autonomic dysfunction and neurovascular dysfunction. “

Systrom’s lab actually uses an invasive CPET (iCPET), in which patients exercise standing with catheters placed in their pulmonary and radial arteries to allow continuous monitoring of pulmonary and system hemodynamics and gas exchange.

Using this method in 10 PASC patients who did not have cardiopulmonary disease, Systrom and his colleagues found reductions in peak VO2 a peripheral rather than a central limit in exercise capacity, as well as an exaggerated hyperventilatory response during exercise, just as Mancini’s group had discovered. Those data have been published in August 2021 at Chest.

In another iCPET study conducted before COVID-19 in 160 ME / CFS patients, the Systrom team identified two types of peripheral neurovascular dysregulation that could contribute to exercise intolerance: decreased cardiac output due to impaired venous return and impaired peripheral oxygen extraction.

In skin biopsies, almost a third showed evidence of small-fiber neuropathy. In these patients, neuropathic deregulation causing vascular dilation may limit effort by diverting oxygenated blood from the exercising muscle and reducing venous return to the right heart, the authors suggested.

These findings were also published in August 2021 at 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 avoid or minimize invasiveness, while still providing gas exchange and VO.2 maximum estimates for use in both ME / CFS and PASC patients. “We have emerging evidence that there are distinct metabolomic, proteomic and cytokine profiles or signatures in plasma caused by a brief period of exercise in the blood that are very different from normal,” he said. stated, noting that it is possible that these markers could be obtained via a small catheter into an antecubital vein rather than directly into the radial and pulmonary arteries.

So far, he has stated that non-invasive CPET is certainly helpful in patients with PASC or ME / CFS, as is assessing the autonomic nervous system with available methods including tilt table test, quantitative sudomotor axonal reflex test (QSART), sudomotor scans and skin biopsy. Further, he said, “I would also develop an autoimmune workup because many of these post-COVID patients have inflammatory biomarkers, both traditional and non-traditional. The paraneoplastic autoantibody panel of the Mayo Clinic will have positive results in a significant proportion of these patients. “

Such evaluations can lead to treatments to slow down inflammatory processes. The Systrom team recently completed a prospective randomized trial using the acetylcholinesterase inhibitor pyridostigmine (Mestinon) or placebo in 50 ME / CFS patients. The objective was to improve hemodynamic, ventilatory and oxygen exchange variables such as biventricular filling pressures and systemic oxygen extraction, assessed using a replicated iCPET.

These data will soon be submitted for publication and could be presented earlier at a future conference.

“The beginning of a research axis”

In Mancini’s study, all 41 patients underwent a CPET and underwent symptom assessment for ME / CFS using the 1994 “Fukuda” criteria an average of 8.9 months after acute COVID-19. The mean left ventricular ejection fraction was 59%. Peak VO2 on average 20.3 ml / kg / min (77% of the predicted VO2). The slope of the CO minute ventilation2 production (VE / VCO2 slope) was 30. End tidal pressure of CO2 at rest was 33.5 mmHg.

Over half (58.5%) of patients had peak VO2 less than 80% predicted, and all of these individuals had circulatory exercise limitation. Among the 17 with a normal peak VO2, ventilatory abnormalities were identified, including three with a maximum respiratory rate greater than 55 and 26 with dysfunctional breathing (rapid and erratic). Overall, 88% (36) had ventilatory abnormalities with dysfunctional breathing, increased EV / OCV2, and / or PetCO hypocapnia2

Finally, 19 patients (46%) met the criteria for “chronic fatigue syndrome” from 1994. Mancini said she did not think the results would differ significantly if they had used the more recent criteria of the. Institute (now Academy) of Medicine published in 2015.

“I think this is the start of a line of research. I think there needs to be future studies on respiratory rehabilitation to see if we can help them feel better by addressing hyperventilation,” said added Mancini. “It hasn’t been done yet. I think all of this is speculating.”

On the positive side, she noted that this dysfunctional breathing is not associated with high mortality. For now, she advises patients to consider yoga and, to the best of their ability, to “breathe slowly and deeply”.

Mancini has no disclosure. Systrom received consulting fees and research support from Astellas Pharma.

JACC heart failure. 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 published in The Washington Post, NPR Shots Blog, and Diabetes Forecast Magazine. She’s on Twitter @MiriamETucker.

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