Pulmonary Vascular Dysfunction as a Cause of Persistent Exertional Dyspnea After Coronavirus Disease (COVID-19)

Study Overview
=================
Brief Summary
-----------------
To identify pulmonary vascular disease in post/long-COVID-19 patients as a cause of dyspnea/exercise limitation and to differentiate it from other causes of dyspnea

Detailed Description
-----------------
The aim is to identify pulmonary vascular disease in post/long-COVID-19 patients as a cause of dyspnea/exercise limitation and to differentiate it from other causes of dyspnea (muscular, left cardiac, psychological, deconditioning-related causes) by investigating ventilation-perfusion (V/Q) mismatch and (exercise-induced) pulmonary hypertension (PH) or right heart dysfunction.

Official Title
-----------------
Pulmonary Vascular Dysfunction as a Cause of Persistent Exertional Dyspnea After COVID-19 (PulmVasC)- A Multicenter, Prospective Cohort/Observational Study

Conditions
-----------------
COVID-19

Intervention / Treatment
-----------------
* Other: pulmonary vascular dysfunction
* Other: pulmonary vascular function


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years, patients with a suspected diagnosis of post/long-COVID-19 syndrome who present to our pneumology or infectious disease outpatient clinic or corresponding ward from the start of the study and whose SARS-CoV-2 infection was diagnosed at least 3 and not longer than 18 months prior to presentation Patients at least 3 and not longer than 18 months after a SARS-CoV-2 infection without post/long-COVID-19 syndrome who present to our post-infection outpatient clinic for follow-up Exclusion Criteria: Patients who refuse to participate in the study Severe underlying chronic pulmonary, cardiac, or systemic disease (e.g., Chronic obstructive pulmonary disease (COPD), severe heart failure, neuromuscular disease) that was diagnosed prior to acute COVID-19 disease and whose progression appears likely as the cause of dyspnea Other non pneumologic causes of dyspnea (e.g., hemoglobin < 100 g/L) Unstable or acute disease (e.g., acute infection, acute renal failure, acute coronary syndrome) Inability to perform spiroergometry, including transient orthopedic problems, contraindications to central venous and arterial catheter placement (e.g., severe bleeding tendency).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with a suspected diagnosis of post/long-COVID-19<br>Patients with a suspected post-COVID-19 syndrome or a long-COVID-19 syndrome at least 3 months after severe acute respiratory syndrome coronavirus(CoV) type 2 (SARS-CoV-2) infection (symptomatic or asymptomatic) | Other: pulmonary vascular dysfunction<br>* Right ventricular function determined by echocardiography at rest and during exercise (non-invasive estimation of ventilation-perfusion mismatch), systemic endothelial function, left heart function, and plasma levels of vasoactive biomarkers compared with clinical parameters of dyspnea and exercise capacity. Further examinations will be performed in patients with still unclear cause of persistent shortness of breath after 3 months of follow-up (subgroup RHC)<br>|
| Patients without post/long-COVID-19 Syndrome<br>Patients at least 3 months after a SARS-CoV-2 infection (symptomatic or asymptomatic) without post/long-COVID-19. | Other: pulmonary vascular function<br>* Right ventricular function determined by echocardiography at rest and during exercise (non-invasive estimation of ventilation-perfusion mismatch), systemic endothelial function, and plasma levels of vasoactive biomarkers compared with clinical parameters of dyspnea and exercise capacity.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of gas exchange under different inhaled oxygen concentrations | Non-invasive estimation of ventilation/perfusion (V/Q) mismatch | At the time of presentation (on day 1) | 
| Spiroergometric capacity- maximal oxygen uptake (VO2max; ml/min/kg) | Determination of exercise capacity by cardiopulmonary exercise testing (CPET) | At the time of presentation (on day 1) | 
| Echocardiographic right heart parameters - pulmonary arterial systolic pressure (PASP; mmHg) | Echocardiographic determination of right heart parameters under rest and during exercise | At the time of presentation (on day 1) | 
| Echocardiographic right heart parameters - Tricuspid annular plane systolic excursion (TAPSE; mm) | Echocardiographic determination of right heart parameters under rest and during exercise | At the time of presentation (on day 1) | 
| Echocardiographic right heart parameters - right ventricular (RV) end-ventricular volume (EDV; ml) | Echocardiographic determination of right heart parameters under rest and during exercise | At the time of presentation (on day 1) | 
| Echocardiographic right heart - right volume (RV) end-systolic volume (ESV; ml) | Echocardiographic determination of right heart parameters under rest and during exercise | At the time of presentation (on day 1) | 
| Echocardiographic right heart - right ventricular longitudinal global strain (%) | Echocardiographic determination of right heart parameters under rest and during exercise | At the time of presentation (on day 1) | 
| Dyspnoea Index | Determination of dyspnea and functional capacity a questionaire measure of shortness of breath for determining exertion levels | At the time of presentation (on day 1) | 
| Invasive hemodynamics - pulmonary vascular resistance (PVR; WU) | Invasive measurement of pulmonary hemodynamics by right heart catheterization (RHC subgroup) | At the time of presentation (on day 1) | 
| Invasive hemodynamics - cardiac Index (CI; l/min/m2) | Invasive measurement of pulmonary hemodynamics by right heart catheterization (RHC subgroup) | At the time of presentation (on day 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left heart parameters - (E/e' ratio) | Determination of left heart parameters during rest and exercise | At the time of presentation (on day 1) | 
| Left heart parameters - left ventricular ejection fraction (%) | Determination of left heart parameters during rest and exercise | At the time of presentation (on day 1) | 
| Pulmonary vascular function | Increase of echocardiographically estimated systolic pulmonary arterial pressure during inhalation of hypoxic gas | At the time of presentation (on day 1) | 
| Airway Impedance | Determination of airway impedance by oscillometry | At the time of presentation (on day 1) | 
| Peripheral blood mononuclear cells | Determination of characteristics of peripheral immune cells by fluorescence activated cell sorter (FACS) and functional assays | At the time of presentation (on day 1) | 
| Shunt measurement | Shunt measurement by contrast-enhanced echocardiography (optional) | At the time of presentation (on day 1) | 
| Ventilation/Perfusion mismatch | Determination of V/Q mismatch using the gold standard multiple inert gas elimination technique (MIGET) (only in RHC subgroup) | At the time of presentation (on day 1) | 
| Static and dynamic lung function parameters - vital capacity (VC; L) | Determination of lung function by body plethysmography at rest | At the time of presentation (on day 1) | 
| Static and dynamic lung function parameters - forced expiratory volume in 1 s (FEV1; L) | Determination of lung function by body plethysmography at rest | At the time of presentation (on day 1) | 
| Static and dynamic lung function parameters - diffusion capacity (DLCO; %) | Determination of lung function by body plethysmography at rest | At the time of presentation (on day 1) | 
| Static and dynamic lung function parameters - diffusion coefficient (DLCO/VA; %) | Determination of lung function by body plethysmography at rest | At the time of presentation (on day 1) |