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

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: COVID-19
• Intervention / Treatment: Other: pulmonary vascular dysfunction; Other: pulmonary vascular function

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.

• Study Type: Observational
• Enrollment (Actual): 200

Contacts and Locations

Study Locations

• Germany
  • Giessen, Germany
    • Natascha Sommer

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with a post-COVID-19 syndrome or a long-COVID-19 syndrome at least 3 months after SARS-CoV-2 infection (symptomatic or asymptomatic); Patients at least 3 months after a SARS-CoV-2 infection (symptomatic or asymptomatic) without post/long-COVID-19.

Description

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).

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with a suspected diagnosis of post/long-COVID-19; 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; 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)
Patients without post/long-COVID-19 Syndrome; Patients at least 3 months after a SARS-CoV-2 infection (symptomatic or asymptomatic) without post/long-COVID-19.	Other: pulmonary vascular function; 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.

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)

Collaborators and Investigators

• Sponsor: University of Giessen
• Investigators: Principal Investigator: Natascha Sommer, PD, Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC)

Publications and helpful links

General Publications

• Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, Cook JR, Nordvig AS, Shalev D, Sehrawat TS, Ahluwalia N, Bikdeli B, Dietz D, Der-Nigoghossian C, Liyanage-Don N, Rosner GF, Bernstein EJ, Mohan S, Beckley AA, Seres DS, Choueiri TK, Uriel N, Ausiello JC, Accili D, Freedberg DE, Baldwin M, Schwartz A, Brodie D, Garcia CK, Elkind MSV, Connors JM, Bilezikian JP, Landry DW, Wan EY. Post-acute COVID-19 syndrome. Nat Med. 2021 Apr;27(4):601-615. doi: 10.1038/s41591-021-01283-z. Epub 2021 Mar 22.
• Gierhardt M, Pak O, Walmrath D, Seeger W, Grimminger F, Ghofrani HA, Weissmann N, Hecker M, Sommer N. Impairment of hypoxic pulmonary vasoconstriction in acute respiratory distress syndrome. Eur Respir Rev. 2021 Sep 15;30(161):210059. doi: 10.1183/16000617.0059-2021. Print 2021 Sep 30.
• Nuzzi V, Castrichini M, Collini V, Roman-Pognuz E, Di Bella S, Luzzati R, Berlot G, Confalonieri M, Merlo M, Stolfo D, Sinagra G. Impaired Right Ventricular Longitudinal Strain Without Pulmonary Hypertension in Patients Who Have Recovered From COVID-19. Circ Cardiovasc Imaging. 2021 Apr;14(4):e012166. doi: 10.1161/CIRCIMAGING.120.012166. Epub 2021 Apr 8. No abstract available.
• Rossi R, Coppi F, Monopoli DE, Sgura FA, Arrotti S, Boriani G. Pulmonary arterial hypertension and right ventricular systolic dysfunction in COVID-19 survivors. Cardiol J. 2022;29(1):163-165. doi: 10.5603/CJ.a2021.0159. Epub 2021 Dec 13. No abstract available.
• Reichenberger F, Voswinckel R, Schulz R, Mensch O, Ghofrani HA, Olschewski H, Seeger W. Noninvasive detection of early pulmonary vascular dysfunction in scleroderma. Respir Med. 2009 Nov;103(11):1713-8. doi: 10.1016/j.rmed.2009.05.004. Epub 2009 Jun 3.
• Kjaergaard S, Rees S, Malczynski J, Nielsen JA, Thorgaard P, Toft E, Andreassen S. Non-invasive estimation of shunt and ventilation-perfusion mismatch. Intensive Care Med. 2003 May;29(5):727-34. doi: 10.1007/s00134-003-1708-0. Epub 2003 Apr 16.
• Thomsen LP, Karbing DS, Smith BW, Murley D, Weinreich UM, Kjaergaard S, Toft E, Thorgaard P, Andreassen S, Rees SE. Clinical refinement of the automatic lung parameter estimator (ALPE). J Clin Monit Comput. 2013 Jun;27(3):341-50. doi: 10.1007/s10877-013-9442-9. Epub 2013 Feb 21.
• Trinkmann F, Benck U, Halder J, Semmelweis A, Saur J, Borggrefe M, Akin I, Kaden JJ. Automated Noninvasive Central Blood Pressure Measurements by Oscillometric Radial Pulse Wave Analysis: Results of the MEASURE-cBP Validation Studies. Am J Hypertens. 2021 Apr 20;34(4):383-393. doi: 10.1093/ajh/hpaa174.
• Winkler J, Hagert-Winkler A, Wirtz H, Hoheisel G. [Modern impulse oscillometry in the spectrum of pulmonary function testing methods]. Pneumologie. 2009 Aug;63(8):461-9. doi: 10.1055/s-0029-1214938. Epub 2009 Aug 7. German.
• Wagner PD. The multiple inert gas elimination technique (MIGET). Intensive Care Med. 2008 Jun;34(6):994-1001. doi: 10.1007/s00134-008-1108-6. Epub 2008 Apr 18.
• Sonnweber T, Sahanic S, Pizzini A, Luger A, Schwabl C, Sonnweber B, Kurz K, Koppelstatter S, Haschka D, Petzer V, Boehm A, Aichner M, Tymoszuk P, Lener D, Theurl M, Lorsbach-Kohler A, Tancevski A, Schapfl A, Schaber M, Hilbe R, Nairz M, Puchner B, Huttenberger D, Tschurtschenthaler C, Asshoff M, Peer A, Hartig F, Bellmann R, Joannidis M, Gollmann-Tepekoylu C, Holfeld J, Feuchtner G, Egger A, Hoermann G, Schroll A, Fritsche G, Wildner S, Bellmann-Weiler R, Kirchmair R, Helbok R, Prosch H, Rieder D, Trajanoski Z, Kronenberg F, Woll E, Weiss G, Widmann G, Loffler-Ragg J, Tancevski I. Cardiopulmonary recovery after COVID-19: an observational prospective multicentre trial. Eur Respir J. 2021 Apr 29;57(4):2003481. doi: 10.1183/13993003.03481-2020. Print 2021 Apr.
• Augustin M, Schommers P, Stecher M, Dewald F, Gieselmann L, Gruell H, Horn C, Vanshylla K, Cristanziano VD, Osebold L, Roventa M, Riaz T, Tschernoster N, Altmueller J, Rose L, Salomon S, Priesner V, Luers JC, Albus C, Rosenkranz S, Gathof B, Fatkenheuer G, Hallek M, Klein F, Suarez I, Lehmann C. Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study. Lancet Reg Health Eur. 2021 Jul;6:100122. doi: 10.1016/j.lanepe.2021.100122. Epub 2021 May 18.
• Shah W, Hillman T, Playford ED, Hishmeh L. Managing the long term effects of covid-19: summary of NICE, SIGN, and RCGP rapid guideline. BMJ. 2021 Jan 22;372:n136. doi: 10.1136/bmj.n136. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2022
• Primary Completion (Actual): March 31, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: April 29, 2022
• First Submitted That Met QC Criteria: May 13, 2022
• First Posted (Actual): May 16, 2022

Study Record Updates

• Last Update Posted (Estimated): September 4, 2025
• Last Update Submitted That Met QC Criteria: September 3, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; COVID-19
• Other Study ID Numbers: KKS-300

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No