key: cord-0989888-5c1r2ml2
authors: Mancini, Donna M.; Brunjes, Danielle L.; Lala, Anuradha; Trivieri, Maria Giovanna; Contreras, Johanna P.; Natelson, Benjamin H.
title: Use of Cardiopulmonary Stress Testing for Patients With Unexplained Dyspnea Post–Coronavirus Disease
date: 2021-11-29
journal: JACC Heart Fail
DOI: 10.1016/j.jchf.2021.10.002
sha: 6444abefe01f391f5565a255fae3ca2ef7170c5a
doc_id: 989888
cord_uid: 5c1r2ml2

OBJECTIVES: The authors used cardiopulmonary exercise testing (CPET) to define unexplained dyspnea in patients with post-acute sequelae of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection (PASC). We assessed participants for criteria to diagnose myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). BACKGROUND: Approximately 20% of patients who recover from coronavirus disease (COVID) remain symptomatic. This syndrome is named PASC. Its etiology is unclear. Dyspnea is a frequent symptom. METHODS: The authors performed CPET and symptom assessment for ME/CFS in 41 patients with PASC 8.9 ± 3.3 months after COVID. All patients had normal pulmonary function tests, chest X-ray, and chest computed tomography scans. Peak oxygen consumption (peak VO(2)), slope of minute ventilation to CO(2) production (VE/VCO(2) slope), and end tidal pressure of CO(2) (PetCO(2)) were measured. Ventilatory patterns were reviewed with dysfunctional breathing defined as rapid erratic breathing. RESULTS: Eighteen men and 23 women (average age: 45 ± 13 years) were studied. Left ventricular ejection fraction was 59% ± 9%. Peak VO(2) averaged 20.3 ± 7 mL/kg/min (77% ± 21% predicted VO(2)). VE/VCO(2) slope was 30 ± 7. PetCO(2) at rest was 33.5 ± 4.5 mm Hg. Twenty-four patients (58.5%) had a peak VO(2) <80% predicted. All patients with peak VO(2) <80% had a circulatory limitation to exercise. Fifteen of 17 patients with normal peak VO(2) 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/VCO(2) (n = 17), and/or hypocapnia PetCO(2) <35 (n = 25). Nineteen patients (46%) met criteria for ME/CFS. CONCLUSIONS: Circulatory impairment, abnormal ventilatory pattern, and ME/CFS are common in patients with PASC. The dysfunctional breathing, resting hypocapnia, and ME/CFS may contribute to symptoms. CPET is a valuable tool to assess these patients.

I nfection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can result in a wide range of illnesses from no symptoms to multisystem failure (1, 2) . The acute disease process can lead to residual organ damage with long-term sequelae (3) . Surveys of patients with coronavirus disease (COVID) who recover from COVID have described persistent symptoms, such as atypical chest pain, fatigue, palpitations, or dyspnea, months after the initial infection (4, 5) . In social media these patients are called "long haulers," whereas in the medical published reports they are referred to as patients with postacute sequelae of SARS-CoV-2 infection (PASC). Many of these patients were never hospitalized. Symptoms associated with PASC can be remitting, relapsing, or disabling and can persist without evidence of residual injury on imaging studies leaving the etiology of postrecovery symptoms undefined (4, 5) .

Potential mechanisms for this syndrome include pulmonary and/or cardiac dysfunction. Longitudinal changes on chest computed tomography (CT), such as pulmonary fibrosis and vascular changes after recovery, have been described (4) . Cardiac dysfunction may be detected with cardiac magnetic resonance after acute COVID infection, but this has not been reported specifically in patients with PASC (6) . The major symptoms in PASC 

is frequently used to evaluate unexplained dyspnea and may be valuable in identifying the cause of dyspnea and exercise intolerance in these patients. The addition of hemodynamic monitoring to the respiratory data can identify additional mechanisms, including exercise-induced pulmonary hypertension and preload failure (8, 9) . Only 3 small single-center reports of CPET studies in post-COVID patients have been described (10) (11) (12) , and none exclusively focused on PASC. In this study, we performed CPET and did targeted histories for ME/CFS in 41 patients with PASC. For hemodynamic CPET, exercise-induced pulmonary hypertension was defined by a mean pulmonary artery pressure $30 mm Hg and/or a total pulmonary resistance (ie, mean pulmonary artery pressure/cardiac output) >3 WUs. Preload failure was defined as peak right atrial (RA) pressure #8 mm Hg or change in rest to peak exercise RA pressure <3 mm Hg and a peak mean pulmonary artery <25 mm Hg (8, 9) . Poor systemic oxygen extraction was defined as maximal arteriovenous oxygen difference/hemoglobin of #0.8 (8, 9) . The relationship between the cardiac output and VO 2 was plotted (DQ/DVO 2 ) with normal approximating 5. High values indicate defects in skeletal muscle blood flow and/or extraction. Most patients had an appropriate increase in PetCO 2 at with decrease at peak exercise. However, 3 patients showed continued low PetCO 2 throughout exercise.

Analysis was also performed excluding morbidly obese patients (BMI >35 kg/m 2 ; n ¼ 8). For the patients with BMI <35 kg/m 2 , 64% had peak VO 2 <80% predicted, 52% elevated VE/VCO 2 , 67%, reduced PetCO 2 , and 60% DB. Table 2) . In these individual patient graphs of RR and TV vs ventilation, the reverse of normal exercise ventilatory pattern is observed. In these patients, the RR rapidly increases on exercise rather than the TV. Abbreviations as in Figure 1 . These authors speculated that exercise hyperventilation contributed to the persistent symptoms. We Values are n, %, or mean AE SD.

CO ¼ cardiac output; EX ¼ exercise; ME/CFS ¼ myalgic encephalomyelitis/chronic fatigue syndrome; mPA ¼ mean pulmonary artery pressure; PCW ¼ pulmonary capillary wedge; RA ¼ right atrial; SVI ¼ stroke volume index. Clavario et al (11) reported CPET results in 110 patients with "nonsevere" COVID 3 months after the infection. Approximately 70% of these patients had persistent symptoms. PFTs were normal. Also, 36% had a peak VO 2 <85% predicted. These investigators attributed the reduction in VO 2 to muscle impairment because a weak correlation was observed between lower maximal muscle strength and % predicted VO 2 .

Generally, muscle mass predicts a subject's ability to perform isometric rather than isotonic exercise. Similar to this report, 58% of our patients had reduced peak VO 2 . Autonomic dysfunction has also been postulated as contributing to PASC. Sinus arrhythmia is heart rate variability that is linked to the respiratory cycle. During inspiration, thoracic pressure is decreased, the chest cavity expands, air flows into the lungs, arterial blood pressure is lowered, which activates the arterial baroreceptors, vagal tone is suppressed, and heart rate increases. During expiration the reverse occurs. DB can interrupt this cardiopulmonary interaction and result in increase in dead space ventilation and intrapulmonary blood shunting (19) .

VENTILATORY RESPONSE IN PASC. In our study, a primary ventilatory limitation to exercise was not seen. This is not surprising because we selected patients who had normal PFTs, chest X rays, and CT scans. However, the use of CPET in these patients revealed several resting and peak exercise ventilatory variables that were abnormal. Many patients with PASC had a rapid, irregular breathing pattern consistent with DB. DB is most often reported in asthmatic patients (20) . Prolonged hypoxemia, metabolic abnormalities, and/or anxiety can trigger DB. It is associated with chronic hyperventilation syndromes and is characterized by rapid shallow breaths with or without hypocapnia (20, 21 TRANSLATIONAL OUTLOOK 2: Almost 50% of these patients met criteria for ME/CFS.

Pathophysiology, transmission, diagnosis, and treatment of Coronavirus Disease 2019 (COVID-19): a review

COVID-19 and the cardiovascular system

Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery

Persistent symptoms 3 months after a SARS-CoV-2 infection: the post-COVID-19 syndrome?

Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent symptoms in patients after acute COVID-19

Cardiovascular magnetic resonance findings in competitive athletes recovering from CoVid 19 infection

Chronic widespread musculoskeletal pain, fatigue, depression and sleep disordered breathing in chronic post SARS syndrome

The invasive cardiopulmonary exercise test

Unexplained exertional dyspnea caused by low ventricular filling pressures: results from clinical invasive cardiopulmonary exercise testing

Hyperventilation: a possible explanation for longlasting exercise intolerance in mild COVID-19 survivors

Assessment of functional capacity with cardiopulmonary exercise testing in non-severe COVID-19 patients at three months follow-up. medRxiv

Medium term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge

The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group

Oxygen uptake efficiency slope: a new index of cardiorespiratory functional reserve derived from the relation between oxygen uptake and minute ventilation during incremental exercise

Cardiopulmonary exercise testing in the assessment of dysfunctional breathing

Principles of interpretation: a flowchart approach

despite hemodynamic and pulmonary abnormalities

Respiratory sinus arrhythmia. A phenomenon improving pulmonary gas exchange and circulatory efficiency

Increased ventilatory variability and complexity in patients with hyperventilation disorder

Cardiopulmonary exercise testing for identification of patients with hyperventilation syndrome

Breathing retraining for dysfunctional breathing in asthma: a randomized controlled trial

Respiratory muscles and dyspnea

Does the stressed patient with chronic fatigue syndrome hyperventilate?

The authors have reported that they have no relationships relevant to the contents of this paper to disclose. 

Hodges LD, Nielsen T, Baken D. Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study. Clin Physiol Funct Imaging. 2018;38:639-644.KEY WORDS cardiopulmonary exercise testing, dyspnea, post-acute sequelae of severe acute respiratory syndrome coronavirus 2 infection