Findings suggest chronic pulmonary abnormalities may underlie long Covid symptoms

A substantial number of patients with post-acute sequelae of Covid-19 (PASC)—a.k.a. Covid long-haulers—have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and other circulatory and pulmonary issues after initial infection, researchers found.

Many patients with previous SARS-CoV-2 infection have reported long-haul Covid symptoms—such as atypical chest pain, fatigue, palpitations, or dyspnea—months after their initial infection, regardless of whether or not they ever required hospitalization. The major symptoms of PASC include severe fatigue, cognitive difficulty, unrefreshing sleep, and myalgias, all of which are also symptoms of ME/CFS, Donna M. Mancini, MD, of Icahn School of Medicine at Mount Sinai, New York, and colleagues explained in JACC: Heart Failure, a journal of the American College of Cardiology (ACC).

To better understand the underlying mechanisms behind long-haul Covid, Mancini and colleagues performed cardiopulmonary exercise testing (CPET) and targeted histories for ME/CFS in a cohort of 41 patients with PASC.

“In this observational report of CPET in patients with PASC, there are several notable findings,” Mancini and colleagues reported. “First, almost all patients (88%) exhibited variability in ventilation consistent with [dysfunctional breathing], resting hypocapnia, and/or an excessive ventilatory response to exercise (elevated VE/VCO2 slope). Second, the majority of the patients (58%) had evidence of circulatory impairment to peak exercise performance. Finally, a large percentage (46%) met criteria for ME/CFS.”

“These findings suggest that in a subgroup of long-haulers, hyperventilation and/or dysfunctional breathing may underlie their symptoms. This is important as these abnormalities may be addressed with breathing exercises or ’retraining,’” Mancini said in an ACC press release.

The study authors noted that, to their knowledge, this is the first report to suggest a high rate of PASC patients meeting the criteria for ME/CFS, which is “consistent with what was found after the SARS Covid-1 outbreak.” However, one important difference between PASC patients and those with ME/CFS independent of Covid is the frequent report of chest pain, cough, and palpitations in the former group, they noted. “Further research comparing the two cohorts will be needed to determine if they are the same or different,” they wrote.

For their prospective study, Mancini and colleagues used data from a cohort of patients with PCR-confirmed SARS-CoV-2 infection who developed new and persistent shortness of breath for more than three months after initial recovery; patients were referred by pulmonologists or cardiologists and had normal pulmonary function tests, chest x rays, chest CT scans, and echocardiograms.

Prior to exercise, patients underwent a targeted interview for elements of ME/CFS.

“The patients were asked to estimate how much during the prior six months: 1) had their fatigue reduced their activity at work, in their personal life, and/or in school (Life Spheres criteria); and 2) to quantify symptom burden of sore throat, tender nodes, headache, myalgia, arthralgia, unrefreshing sleep, difficulty concentrating, or worsening of symptoms after mild exertion (Symptom criteria),” they explained. “ME/CFS was considered present if at least one life sphere criteria was impacted substantially and at least four symptoms were rated moderate or greater.”

Patients were hooked up to an electrocardiogram, a pulse oximeter, and a blood pressure cuff and seated on a stationary exercise bicycle. A disposable mouthpiece was used to measure peak oxygen consumption (VO22), and forced expiratory volume in one second (FEV1). Resting data was collected for three minutes, then patients initiated incremental bicycle exercise at 0 W, which was increased by 25 W every three minutes until exhaustion.

The final cohort consisted of 41 patients, of whom 23 were women; average age was 45.2±12.5 years, and average body mass index was 28.3±6.4. Nine of 42 patients had been hospitalized—eight with acute Covid infection, and one with Covid with atypical chest pain. None were intubated.

“Peak VO2 averaged 20.3±7 mL/kg/min (77%±21% predicted VO2). VE/VCO2 slope was 30±7. [Resting end tidal CO2] PetCO2 at rest was 33.5±4.5 mm Hg. Twenty-four patients (58.5%) had a peak VO2 <80% predicted. All patients with peak VO2 <80% had a circulatory limitation to exercise. Fifteen of 17 patients with normal peak VO2 had ventilatory abnormalities including peak respiratory rate >55 (n=3) or dysfunctional breathing (n=12). For the whole cohort, 88% of patients (n=36) had ventilatory abnormalities with dysfunctional breathing (n=26), increased VE/VCO2 (n=17), and/or hypocapnia PetCO2 <35 (n=25). Nineteen patients (46%) met criteria for ME/CFS.”

Mancini and colleagues pointed out that circulatory impairment, such as that seen among patients in their study, includes both intrinsic cardiac disease and abnormalities in pulmonary or peripheral perfusion. As for ventilatory abnormalities, dysfunctional breathing and persistent hypocapnia, or low resting CO2 (PetCO2 <35 mm Hg) consistent with chronic hyperventilation, “can be associated with many of the symptoms experienced by patients with PASC, such as dyspnea, fatigue, chest pain, and palpitations,” they wrote. “The identification of DB and resting hypocapnia in this cohort is an important observation because it may represent a target for treatment.”

Study limitations included its small, single-center design; consecutive patients presenting to the hospital for post-Covid care were not referred; they did not measure arterial blood gases during exercise; and with non-invasive CPET, “the classification into pulmonary, cardiac, or muscle function as the primary limitation to exercise can be problematic,” they noted.

“Further study is needed with patients undergoing CPETs with hemodynamic and arterial gas measurements,” they added. “Correlation of CPET findings to lung and cardiac imaging should also be performed.”

  1. A substantial number of patients with post-acute sequelae of Covid-19 (PASC), or long-haul Covid, met the criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and had circulatory and ventilatory abnormalities.

  2. These findings suggest that chronic hyperventilation and dysfunctional breathing may underlie the symptoms of PASC and may represent a target for treatment.

John McKenna, Associate Editor, BreakingMED™

The study authors had no relevant relationships to disclose.

Cat ID: 190

Topic ID: 79,190,730,933,914,190,926,192,927,151,928,195,929,925,934