Understanding Exertional Dyspnea and Exercise Intolerance in COVID-19

Study Overview
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Brief Summary
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A novel corona virus emerged in 2019 causing Corona Virus Disease 2019 (covid-19). In one year more than 80 000 000 cases worldwide were documented. Some patients experience symptoms, specifically shortness of breath, long after the viral infection has passed. These patients are colloquially known as Covid-19 Long-Haulers and it is currently unknown why symptoms remain after infection. Shortness of breath and exercise intolerance may be caused by corona virus infection, covid-19 therapy, and reduced physical activity. Exercise intolerance may be due to lung, heart, blood vessel and muscle changes. During infection, the corona virus appears to cause lung blood vessel and gas exchange surface damage. Early reports show heart dysfunction, secondary to pulmonary blood vessel dysfunction or damage. Critically, no data is available on lung blood vessel function or cardiac function during exercise. Moreover, no data are available to link persistent symptoms to physiology parameters. To better understand symptom persistence in Covid-19, the investigators aim to measure exercise tolerance and heart and lung function in covid-19 survivors and compare them to covid-19 free controls.

Detailed Description
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Purpose and Justification: In less than one year, the novel coronavirus has infected more than 80 000 000 people worldwide. Infection causes Corona Virus Disease 2019 (covid-19) and in some cases severe acute respiratory syndrome. Overall risk of mortality from covid-19 is low, however, risk radically increases with age and cardiovascular comorbidity. The long-term consequences of covid-19 are not known. Already a phenotype of survivors with prolonged symptom burden has presented; this phenotype is characterized by persistent respiratory (cough, sputum, dyspnea, wheeze) and musculoskeletal (pain, fatigue) symptoms. Preliminary data from clinical exercise testing conducted at the UofA pulmonary function laboratory suggests covid-19 survivors with prolonged symptoms have significantly reduced exercise tolerance and increased exertional dyspnea. Impaired exercise tolerance measured as peak oxygen uptake (VO2peak) is the strongest independent predictor of cardiovascular and all-cause mortality. The investigators preliminary data in seven persistently symptomatic covid-19 survivors (PS-CoV) 3-months post molecular confirmation of infection shows a mean 30% impairment in VO2peak relative to age-, sex- and body mass index matched controls. Several facets of covid-19, including treatment and recovery, may contribute to the range and severity of debilitation and impairment in VO2peak in PS-CoV. The purpose of this study is to investigate impairments in VO2peak, and pulmonary, cardiac and peripheral factors contributing to impaired VO2peak, exercise intolerance, and persistent dyspnea in PS-CoV. Coronavirus gains cellular entry through binding angiotensin converting enzyme in the lungs, making the lungs and pulmonary vasculature a logical starting point for investigation of persistent symptomology. During active infection, pulmonary vascular dysfunction, microthromboemboli, micro-angiopathy and pulmonary inflammation and/or fibrosis are reported. Accompanying this is a reduction in diffusion capacity at rest, increased tortuosity of pulmonary vasculature, and elevated pulmonary vascular resistance. One mechanistic explanation is that regions downstream of micro-thromboemboli become fibrotic secondary to reduced blood flow resulting in reduced diffusion capacity. Physiological adaptation through intussusceptive angiogenesis results in increased tortuosity of pulmonary vasculature, with a secondary consequence of increased pulmonary vascular resistance. However, evidence of isolated decreases in diffusion capacity in the absence of pulmonary fibrosis are at odds with this theory. An alternative explanation is that pulmonary vascular dysfunction precedes lesions viewed by computed tomography (CT) and changes in lung volumes. Regardless of incipient damage, for  1/3 of hospitalized covid-19 patients, the end result is pulmonary fibrosis, impaired diffusion capacity (measured as the diffusion limitation of carbon monoxide, DLCO), reduced forced vital capacity (FVC) and proportionately reduced forced expiratory volume in one second (FEV1). In PS-CoV, lung impairment at 3-month follow-up is characterized by reduced resting DLCO, FVC and FEV1, and incomplete normalization of pulmonary CT consolidation and opacities.13 The investigators preliminary data in PS-CoV show increased respiratory rate and VE/VCO2 (indicative of increased deadspace or excessive ventilatory drive) at peak exercise- characteristic of parenchymal or restrictive lung disease and consistent with pathology of covid-19 including parenchymal cell death and pulmonary fibrosis. Despite these findings, initial data suggest that PS-CoV patients' operating lung volumes during exercise and peak breathing reserve are relatively preserved. Previous work in COPD has shown that an elevated VE/VCO2 during exercise is explained by higher deadspace, and this increased VE/VCO2 contributes to increased dyspnea secondary to increased drive to breathe. The investigators work in COPD has shown that the increase VE/VCO2 is due to hypoperfusion of the pulmonary capillaries as demonstrated by a reduced DLCO and reduced pulmonary capillary blood volume during exercise, and that when pulmonary perfusion is improved by using inspired NO, VE/VCO2 and dyspnea are decreased resulting in an increase in VO2peak. No data are currently available examining symptoms of dyspnea, pulmonary mechanics, VE/VCO2, and impaired VO2peak in PS-CoV. Moreover, no data are available examining diffusion capacity or pulmonary capillary blood volume responses during exercise, which may contribute to increased VE/VCO2, pulmonary inefficiency, perceived dyspnea, and secondary cardiac consequences. Cardiac complications of covid-19 have been demonstrated and may contribute to impaired VO2peak through a reduction in peak cardiac output (Qpeak). Limited data are available, but, cardiac effects appear to be (mal)adaptation secondary to pulmonary vascular dysfunction, angiopathy and increased pulmonary vascular resistance. Importantly, pulmonary vascular dysfunction may impose a cardiac limitation to exercise in the absence of or preceding structural cardiac changes as in early pulmonary hypertension (exercise induced pulmonary hypertension). Complications mimic those observed in pulmonary hypertension whereby the thin walled right ventricle insidiously adapts to and eventually fails against chronically increased pulmonary artery pressure. This includes right ventricular hypertrophy, dilation and hypokinesis, and in failure, uncoupling of tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP). In a study of 100 consecutive covid-19 patients at rest, 39% of patients had right ventricular dilation and dysfunction and 16% of patients had left ventricular diastolic dysfunction. No reports of cardiac function during exercise or cardiac mechanics in response to stress are available following covid-19, and it is unknown whether cardiac consequences of covid-19 limit VO2peak or contribute to symptom persistence in PS-CoV. Detrimental changes in body composition occur in hospitalized covid-19 patients. During active infection, frailty (in part characterized by muscle loss) is associated with increased covid-19 severity and mortality. Reduced lean tissue mass and increased adiposity, particularly in the thigh, are reported following bedrest and are known to impair VO2peak. Reductions in VO2peak are twofold: absolute VO2peak is reduced due to loss of muscle mass, and relative VO2peak (ml/kg/min) is reduced due to a combination of reduced absolute VO2peak and a decrease in the ratio of muscle mass to total body mass. Moreover, bedrest is associated with reduced mitochondrial density and oxidative enzymatic activity. No data are available linking increased adiposity, reduced thigh muscle, or impaired muscle quality to VO2peak or symptom persistence in PS-CoV. The investigators preliminary data indicate VO2peak is impaired in PS-CoV survivors. The magnitude of VO2peak, pulmonary, cardiac and peripheral impairment is not known in PS-CoV or symptom free covid-19 survivors. Through this proposed study, the investigators aim to comprehensively test VO2peak impairment in PS-CoV survivors and link physiology to symptom persistence in covid-19. Objectives: There are 3 objectives of this study: 1) to evaluate VO2peak in PS-CoV and recovered covid-19 survivors (no longer symptomatic) compared to covid-19 naïve controls matched for age, sex and body mass index; 2) to evaluate DLCO and pulmonary capillary blood volume at rest and during exercise in these three groups; and 3) evaluate cardiac structure and function at rest and during exercise in the three groups. Hypotheses: The investigators hypothesize that: VO2peak will be impaired in PS-CoV relative to recovered (symptom free) covid-19 survivors and covid naïve controls, and that recovered covid-19 survivors will have impaired VO2peak relative to covid naïve controls; Relative to covid-19 naïve controls, PS-CoV will have reduced rest and exercise pulmonary capillary blood volume and diffusion capacity, which will be correlated with exercise VE/VCO2. PS-CoV will have reduced peak cardiac output, increased PASP, and uncoupling of PASP:TAPSE.

Official Title
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Understanding Exertional Dyspnea and Exercise Intolerance in COVID-19

Conditions
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Covid19, Dyspnea

Intervention / Treatment
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* Other: No Intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Covid-19/Symptom status as defined under each group. Exclusion Criteria: Previous diagnosis of pulmonary hypertension Obesity (body mass index >30 kg/m2) Absolute contraindication to exercise testing or an orthopedic limitation that may interfere with cardiopulmonary exercise testing

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Persistently Symptomatic Covid-19 (PS-CoV)<br>PS-CoV will be defined as individuals with a history of molecular testing confirmed COVID-19 infection, recovered from acute infection but with ongoing symptoms (self-reported, pulmonary, cardiac, musculoskeletal or other symptoms) of at least 4 weeks' duration. Recovery from acute infection will be defined according to provincial health guidelines: at least 10 days' (14 in those hospitalized; 21 in those with immunocompromise) from onset of symptoms with at least 24 hours without a fever, without taking anti-pyretic medications and improvement of other symptoms. | Other: No Intervention<br>* Cross-sectional study, no intervention.<br>|
| Recovered Covid-19<br>Recovered Covid-19 Survivors will be defined as individuals without complaint of a persisting covid-19 symptom. Recovered Covid-19 survivors will be matched to PS-CoV for age, sex, body mass index and time post corona virus infection. | Other: No Intervention<br>* Cross-sectional study, no intervention.<br>|
| Control<br>Covid Naïve Controls will be defined as individuals who have no known history of covid-19. Control participants will be matched to PS-CoV for age, sex and body mass index. | Other: No Intervention<br>* Cross-sectional study, no intervention.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Oxygen Uptake (VO2peak) | Staged cardiopulmonary exercise test | Within 20-30 seconds of completion of trial | 
| Peak Cardiac Output (Qpeak) | Impedance cardiography derived Qpeak from staged CPET | Within 20-30 seconds of completion of trial | 
| Pulmonary Capillary Blood Volume (Vc) | Multiple fraction of inspired oxygen DLCO derived pulmonary capillary blood volume at rest and during exercise. | Averaged across trials | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilatory Efficiency (VE/VCO2) | Measured from expired gas analysis during cardiopulmonary exercise testing. | Averaged across trial | 
| Dyspnea | Measured using the modified Borg scale (1-10, 10=maximal dyspnea), perceived dyspnea during cardiopulmonary exercise testing. Scale = 1-10 | Assessed every 2-minutes until completion of the exercise trial; anticipating  10-14 minute tests | 
| Membrane Diffusion Capacity (Dm) | Measured at rest and during exercise using the multiple fraction of inspired oxygen DLCO technique. | Averaged across trials | 
| Pulmonary Artery Systolic Pressure (PASP) | Echocardiography estimated pulmonary artery systolic pressure. | Assessed for five consecutive cardiac cycles and are measured in triplicate during the cardiac ultrasound trial | 
| Right Ventricular Function | Reported as PASP:TAPSE (tricuspid annular plane systolic excursion) measured using echocardiography. | Assessed for five consecutive cardiac cycles and are measured in triplicate during the cardiac ultrasound trial | 
| Left Ventricular Stiffness | Estimated from E/e' using echocardiography. | Assessed for five consecutive cardiac cycles and are measured in triplicate during the cardiac ultrasound trial | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DLCO, Pulmonary Capillary Blood Volume, VO2peak, Exercise Capacity, Cardiac Function, Impedance Cardiography, Echocardiography, Shortness of Breath, Ventilatory Efficiency, Lung Restriction