key: cord-0701848-ldcim3cw
authors: Singh, Inderjit; Joseph, Phillip; Heerdt, Paul M.; Cullinan, Marjorie; Lutchmansingh, Denyse D.; Gulati, Mridu; Possick, Jennifer D.; Systrom, David M.; Waxman, Aaron B.
title: Persistent Exertional Intolerance after COVID-19: Insights from Invasive Cardiopulmonary Exercise Testing.
date: 2021-08-11
journal: Chest
DOI: 10.1016/j.chest.2021.08.010
sha: 4a7d8e196d8c3305aa402ef4ba7954bce81a3cad
doc_id: 701848
cord_uid: ldcim3cw

Background Some Coronavirus disease 2019 (COVID-19) patients who have recovered from their acute infection after experiencing only mild symptoms continue to exhibit persistent exertional limitation that is often unexplained by conventional investigative studies. Research question What is the patho-physiological mechanism of exercise intolerance that underlies the post-COVID-19 long haul syndrome following COVID-19 in patients without cardio-pulmonary disease? Study Design and Methods This study examined the systemic and pulmonary hemodynamics, ventilation, and gas exchange in 10 post-COVID-19 patients without cardio-pulmonary disease during invasive cardiopulmonary exercise testing (iCPET) and compared the results to 10 age- and sex matched controls. These data were then used to define potential reasons for exertional limitation in the post-COVID-19 cohort. Results Post-COVID-19 patients exhibited markedly reduced peak exercise aerobic capacity (VO2) compared to controls (70±11%predicted vs. 131±45%predicted; p<0.0001). This reduction in peak VO2 was associated with impaired systemic oxygen extraction (i.e., narrow CaVO2/CaO2) compared to controls (0.49±0.1 vs. 0.78±0.1, p<0.0001) despite a preserved peak cardiac index (7.8±3.1 vs. 8.4±2.3 L/min, p>0.05). Additionally, post-COVID-19 patients demonstrated greater ventilatory inefficiency (i.e., abnormal VE/VCO2 slope: 35±5 vs. 27±5, p=0.01) compared to controls without an increase in dead space ventilation. Interpretation Post-COVID-19 patients without cardiopulmonary disease demonstrate a marked reduction in peak VO2 from a peripheral rather than a central cardiac limit along with an exaggerated hyper-ventilatory response during exercise.

Globally, over 100 million confirmed cases of coronavirus disease 2019 caused by severe acute respiratory syndrome cornovirus-2 (SARS-CoV-2) infection have been reported. The acute manifestations of SARS-CoV-2 can involve the pulmonary, cardiovascular, neurological, hematological, and gastrointestinal systems 1 . Persistent physical symptoms following acute COVID-19 are common and includes fatigue, dyspnea, chest pain, cough, and neuro-cognitive complaints [2] [3] [4] [5] [6] . In one retrospective study of approximately 1300 hospitalized COVID-19 patients discharged to home, only 40 percent of patients were independent in all activities of daily living at 30 days 6 and almost 40 percent of patients were unable to return to normal activities at 60 days following hospital discharge 7 . Several recent studies have reported persistent symptoms amongst patients who acquired mild COVID-19 months following recovery from their acute illness [8] [9] [10] . Persistent cardiorespiratory symptoms in COVID-19 survivors can be categorized into two clinical entities: a) those directly related to organ injury or iatrogenic consequences during the acute phase; and b). those with persistent symptomatology including a decrease in exercise capacity objectively determined by cardio-pulmonary exercise testing (CPET) with normal pulmonary function testing, resting echocardiogram, and computed tomography (CT) scan of the chest months following the onset of acute symptoms 11, 12 , the so called "post-COVID-19 long haul syndrome".

In a recent study, Baratto and colleagues showed that during CPET performed at time of hospital discharge, post-COVID-19 patients exhibited a hyper-ventilatory response and reduced exercise capacity. The latter was primarily attributed to underlying anemia resulting in both reduced systemic O2 (oxygen) delivery and extraction 13 . However, the patho-physiological basis for the persistent exertional and functional limitation amongst post-COVID-19 patients who have long since recovered from mild acute illness remains unknown. Accordingly, in the current study, we aim to help further characterize persistent exercise intolerance amongst post-COVID-19 patients without evidence of cardio-pulmonary disease or anemia using invasive CPET (iCPET).

J o u r n a l P r e -p r o o f

We consecutively enrolled all post-COVID- 19 All patients underwent conventional investigative testing, during their out-patient clinic evaluation, including CT scan of chest, pulmonary function test, and resting echocardiogram. In none of the patients were test results deemed contributory to their persistent exertional limitation prior to iCPET referral. Specifically, there was no evidence of parenchymal lung disease on CT chest, and all patients had left ventricle ejection fraction>50% with no evidence of moderate or severe valvular heart disease, no evidence of right to left intra-cardiac shunt defect on resting right heart catheterization (RHC) and echocardiography, and no evidence of acute coronary syndrome defined by ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, and/or unstable angina during exercise testing.

Our method for invasive CPET has been previously described [14] [15] [16] [17] [18] . RHC was performed in the supine position with a 5-port pacing pulmonary artery catheter (Edwards LifeSciences, Irvine, CA, USA) inserted percutaneously under fluoroscopic and ultrasound guidance into the internal jugular vein and a radial artery catheter concurrently placed in the radial artery. Patients underwent a symptom-limited incremental CPET using an upright cycle ergometer with a breath-J o u r n a l P r e -p r o o f by-breath assessment of gas exchange (ULTIMA CPX; Medical Graphics Corporation, St Paul, MN, USA) along with continuous 12 lead electrocardiogram monitoring. Patients underwent two minutes of rest followed by two minutes of unloaded cycling at 40-60 RPM. Work rate was then continuously increased using a ramp protocol at 5, 10, 15 or 20 W/min depending on the patient's functional status until peak exercise was achieved as evident either by peak respiratory exchange ratio (RER) >1.10 or peak heart rate >85% predicted. Pulmonary and systemic hemodynamics were continuously and simultaneously monitored during exercise (Xper Cardio Physiomonitoring System; Phillips, Melborne, FL, USA). Pulmonary pressures were recorded at the end of passive exhalation. When respirophasic changes persisted, an electronic average over three respiratory cycles was used 19 . Arterial and mixed venous blood gases and pH were collected during each minute of exercise, and the arterial-mixed venous oxygen content difference (CavO2) was calculated. Systemic oxygen extraction (EO2) was calculated as CaO2 minus CvO2 divided by CaO2. Fick cardiac output and stroke volume were determined every minute. Oxygen delivery (DO2) was calculated by multiplying cardiac output by the arterial oxygen content (CaO2).

Physiologic dead space was calculated as dead space volume (VD) divided by tidal volume (VT), VD/VT = (PaCO2 -PETCO2) / PaCO2, where PaCO2 is the partial pressure of carbon dioxide in arterial blood and PETCO2 is the mixed expired partial pressure of carbon dioxide.

Pulmonary vascular resistance (PVR) was calculated as [mean pulmonary artery pressure (mPAP)pulmonary artery wedge pressure (PAWP) / cardiac output] and expressed in Woods Unit (WU). Stroke volume (SV) was calculated as cardiac output (CO) divided by the heart rate. CO and SV were indexed to body surface area to obtain both cardiac index and SV index. Pulmonary artery (PA) compliance was calculated as the ratio of SV to PA pulse pressure and expressed as mL/mmHg. Total pulmonary resistance (TPR) was calculated as mPAP divided by CO as expressed in WU.

To further investigative the determinants of exercise limitation in post-COVID-19 patients, we identified 10 age-and sex matched controls from our iCPET database. This cohort J o u r n a l P r e -p r o o f consisted of symptomatic subjects who previously underwent iCPET for clinical investigation of exertional intolerance but who exhibited a normal physiological limit to exercise defined by a peak oxygen uptake (peak VO2) and peak cardiac output (CO) of 80% predicted.

Unless otherwise stated, values are presented as mean and standard deviation.

Comparison of baseline characteristics, resting hemodynamics, and CPET parameters between post-COVID-19 patients and controls were performed using independent t-test for normally distributed data and Wilcoxon rank sum test for data not normally distributed. Chi-square test were used to analyze dichotomous variables. A p value of <0.05 was considered significant.

Statistical analyses were performed using GraphPad Prism 9 (GraphPad Software) and SAS 9.4 (SAS Institute Inc., Cary, NC, USA).

We included 10 post-COVID-19 patients who at the time of iCPET were PCR-negative.

Nine patients had previously experienced mild acute SARS-CoV-2 infection that did not require hospitalization 20 while one patient had brief two-day in-patient stay during which Remdesivir and corticosteroids were administered. Two patients were excluded during the enrollment period.

One patient with long-standing history of fibrotic interstitial lung disease and the other who exhibited iatrogenic chronotropic incompetence from B-adrenergic blocker therapy. The latter patient did not attain maximum exercise effort by either by peak RER >1.10 or peak heart rate >85% predicted. There were no differences in age, hemoglobin concentration, body mass index (BMI), medication use, and co-morbidities between post-COVID-19 patients and controls. Importantly, the average interval time between onset of acute COVID-19 illness (i.e., from time of SARS-J o u r n a l P r e -p r o o f CoV-2 PCR positivity) to iCPET was 11 months (table 1) . Post-COVID-19 patients demonstrated normal resting right heart hemodynamic values. The baseline characteristics, comorbidities, resting right heart hemodynamics and pulmonary function test are summarized in table 1.

The maximum invasive CPET and cardio-pulmonary hemodynamic data are summarized in table 2. At peak exercise, post-COVID-19 patients exhibited markedly reduced aerobic capacity (i.e., peak VO2 <80% predicted) with a normal peak DO2 and reduced EO2 patients, only one patient had a VE/VCO2 slope <30 at 28 21 . In the post-COVID-19 patients, there was a trend towards lower peak right atrial pressure (3±4 mmHg vs. 6±3 mmHg; p=0.08) along with a significantly reduced left sided filling pressure (PAWP: 8±4 vs. 13±3 mmHg; p=0.01). There was appropriate decrease in dead space ventilation in post-COVID patients from rest to peak exercise (0.39±0.1 vs. 0.22±0.1, p=0.001) (figure 3). The total pulmonary resistance (TPR) at peak exercise was normal in both groups (i.e., peak TPR <3 WU).

In the current study, we demonstrate that nearly 1 year after recovery from mild disease, post-COVID-19 patients with decreased exercise tolerance but no long term cardio-pulmonary J o u r n a l P r e -p r o o f disease sequalae exhibited a peripheral rather than a central cardiac limit to aerobic exercise characterized by impaired systemic EO2 with resulting increased peak exercise MvO2 and pVO2 content. Additionally, they also demonstrate a hyper-ventilatory response during exercise from enhanced chemoreflex sensitivity.

According to the Fick principle, in the absence of a pulmonary mechanical limitation, reduced peak VO2 is the result of a blunted CO/CI response and/or impaired systemic EO2 (i.e., CavO2 difference). In the current study, the depressed peak VO2 in post-COVID-19 patients was driven primarily by reduced systemic EO2 (figure 1) . In fact, their peak CO response was robust representing on average 115% of the predicted value and the DO2 was preserved. We also demonstrated that in both controls and post-COVID-19 patients, throughout incremental exercise testing, increases in VO2 were driven by increments in both EO2 and CI (figure 1).

However, unlike controls, at 75% of peak VO2 and at peak VO2, further increases in VO2 in post-COVID-19 patients were attenuated by limitations imposed by EO2 rather than CI. J o u r n a l P r e -p r o o f patients did not have associated anemia or parenchymal lung disease. Importantly, we found that convective O2 transport in the post-COVID-19 patients was preserved (i.e., normal DO2). Therefore, the impaired EO2 observed in the current study is primarily attributed to reduced O2 diffusion in the peripheral micro-circulation resulting in increased peak exercise MvO2 and pVO2 content (table 2) .

More recently, two non-invasive CPET studies in post-COVID-19 patients have been reported 22,23 . The first study by Rinaldo et al evaluated 75 patients 3-months following hospital discharge. 52% and 24% of the post-COVID-19 patients were categorized as having critical and severe disease, respectively while 63% of patients demonstrated residual parenchymal lung disease on CT chest 22 . The authors found that patients with reduced peak exercise capacity (defined by peak VO2 <85% predicted) attained anerobic threshold early but exhibited no pulmonary mechanical limit to exercise (i.e., preserved breathing reserve index) with preserved ventilatory efficiency (i.e., VE/VCO2 slope of 28±3). There was also no correlation between reduction in peak exercise capacity with reduced diffusing capacity on lung function test or parenchymal lung disease on CT chest. Based on these findings, the authors concluded that the reduced peak exercise capacity seen in their post-COVID-19 cohort is because of deconditioning.

The second study by Skjorten et al examined 189 patients also 3-months following hospital discharge of which 20% required intensive care unit (ICU) management 23 . The peak VO2 (% predicted) was lower amongst post-COVID-19 patients who required ICU management but there was no difference in the breathing reserve and VE/VCO2 slope between ICU and non-ICU patients 23 . Across the entire cohort, reduced peak VO2 (<80% predicted) was observed in 31% of participants. When compared to a reference population, post-COVID-19 patients exhibited preserved ventilatory efficiency (i.e., VE/VCO2 slope was 28±5) and breathing reserve (30±17%) along with preserved O2 pulse (15±4 mL.stroke -1 ). Accordingly, the authors concluded that deconditioning was the major cause of exercise limitation in their post-COVID-19 cohort. In our study of patient approximately 11 months after recovery from mild disease, deconditioning is an J o u r n a l P r e -p r o o f unlikely explanation for the impaired systemic EO2. In fact, the findings of our study argue against muscle deconditioning as the cause of impaired EO2. This is because the hallmark of deconditioning is reduced peak CO 24 . In the current study, amongst the post-COVID-19 patients, the peak CO (% predicted) was normal at 115±44% predicted. Additionally, deconditioning causes little or no change in peak exercise EO2 24,25 . Furthermore, our post-COVID-19 patients demonstrated lower low bi-ventricular filling pressures rather than the higher pressures encountered in detrained individuals which is attributable to cardiac atrophy and reduced ventricular compliance 26, 27 .

During exercise, the greater need for local tissue metabolism coupled with reduced availability of tissue O2 results in greater production of local vasodilatory substances in the skeletal muscles. This mechanism along with sympathetic nervous system mediated vasoconstriction to non-exercising areas allows for increased tissue oxygen delivery during exercise 28 . We recently demonstrated in a cohort of patients with chronic fatigue syndrome that systemic micro-circulatory dysfunction with micro-vascular shunting (impaired systemic O2 extraction) was prevalent particularly among patients that also exhibited small fiber neuropathy on skin biopsy 29 . Immunohistochemical studies have shown that these small fibers regulate microvascular tone through sympathetic and parasympathetic cholinergic synapses of perivascular myocytes 30 (figures 2 and 3) . The abnormal ventilatory efficiency in our post-COVID-19 cohort can thus be attributed to enhanced peripheral mechano-and metabo-ergoreflex sensitivity rather than a primary cardio-pulmonary or central mediated hyperventilation process 33 . In patients with heart failure, for example, skeletal muscle group III / IV afferents play an important role the exaggerated hyper-ventilatory response seen during exercise. These mechano-and metabo-receptors detect changes in muscle length, volume (i.e., muscle loss or wasting), and by-products of muscle metabolism and stimulate group III / IV afferents of the spinal cord to the medullary respiratory centers to stimulate ventilation 34, 35 . Muscle weakness and fatigue are a common manifestation of the post-COVID-19 syndrome 36 , even amongst those who acquired mild COVID-19 infection 37 . It is possible that, in the post-COVID-19 patients, similar to heart failure patients, a skeletal muscle myopathic process characterized by a shift in fiber type 38 and/or reduced muscle aerobic enzyme activity with early dependance on anerobic metabolism 39 culminates in over-activation of group III / IV skeletal muscle afferent activity with resulting exaggerated hyper-ventilation.

Results from the current study need to be interpreted in the context of limitations. Data for this study consisted of small number of post-COVID-19 patients. However, the peripheral limitation to exercise intolerance exhibited by the post-COVID-19 patients were striking compared to controls and the finding of ventilatory inefficiency (i.e., abnormal VE/VCO2 slope) is in keeping with a recent report 13 . Additionally, by utilizing iCPET, we provided a comprehensive and unparalleled insight into the long term sequalae of SARS-CoV-2 infection that is otherwise not apparent on conventional investigative testing.

Our normal controls were derived from iCPET evaluation for unexplained exertional dyspnea and therefore the controls may not be representative of a completely healthy population. However, the controls were selected based on a preserved peak exercise capacity defined by a normal cardiac limit to exercise (peak VO2 and peak CO ≥ 80% predicted).

J o u r n a l P r e -p r o o f Therefore, they represent a studied population with a normal physiologic response to exercise and reflect "symptomatic normal" individuals.

Exercise limitation is common manifestation of the post-COVID-19 syndrome months following resolution of mild acute COVID-19 illness. A peripheral rather than a central cardiac of pVO2, 50% of pVO2, 75% of pVO2, and at pVO2. Data presented as mean ± standard deviation. VO2oxygen consumption and pVO2peak oxygen consumption representing data at rest and red dots representing data at peak exercise. PaCO2partial pressure of carbon dioxide in arterial blood; PaO2partial pressure of oxygen in arterial blood; VD/VTratio of dead space to tidal volume. P-value obtained using independent t-test.

J o u r n a l P r e -p r o o f (%) or mean  SD or median (IQR). VO2 -oxygen consumption; ETCO2 -end tidal carbon dioxide; SaO2 -oxygen saturation in arterial blood; MvO2 -mixed venous oxygen saturation; PO2 -partial pressure of oxygen; PaCO2 -partial pressure of carbon dioxide in arterial blood; VE/VCO2ventilatory efficiency; RA -right atrial; mPAP -mean pulmonary artery pressure; PAWP -pulmonary artery wedge pressure; PVR -pulmonary vascular resistance; WU -Woods unit; TPR -total pulmonary resistance; PA -pulmonary artery; SVR -systemic vascular resistance.

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