Introduction The underlying causes of exertional dyspnoea and exercise limitation in post-COVID syndrome remain uncertain. We performed deep-phenotyping of post-COVID patients to evaluate limitations of ventilation, gas exchange and cardiopulmonary circulation in a multicentre, cross-sectional study.

Methods The dyspnoea index and aerobic exercise performance (peakVO2) were determined by questionnaires and cardiopulmonary exercise testing, respectively, in a cohort of 86 post-COVID patients and 12 controls. Lung function, gas exchange and ventilation-perfusion mismatch were evaluated. Cardiac parameters were measured by echocardiography and, in a subgroup, systemic vascular characteristics by pulse wave analysis.

Results Post-COVID patients showed low ventilation at peak exercise [VE(peak)], ventilatory inefficiency, low right heart dimensions and low basal oxygen uptake. In a multivariate regression analysis, ventilatory parameters – high breathing frequency at peak exercise (β=0.15, p=0.004) and low forced expiratory volume in 1 s (β=–0.33, p=0.007) – and right atrial end-systolic area index (RA ESAi; β=–0.34, p<0.001) were independent predictors of dyspnoea, while low VE(peak) (β=0.46, p<0.001) and low aerobic capacity (β=0.51, p<0.001) independently predicted low peakVO2. Low RA ESAi was associated with a low diffusion coefficient (r=0.36), low end-tidal pCO2 (r=0.39) and high heart rate (r=–0.31). Subgroup analysis of patients showed specific associations between dyspnoea and diastolic and bronchial function, low blood pressure, hyperventilation or oxygen uptake.

Conclusion Preload insufficiency associated with gas exchange disturbances contributes to the sensation of dyspnoea in post-COVID patients, as well as ventilatory limitations, while peakVO2 was predominantly associated with aerobic capacity. Three phenotypes were defined, indicating the need for tailored interventions.

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; K. Lo has received research grants from DFG and was supported under JLU-CAREER- program; K. Krueger has received payment honorariums from Amgen; Amicus Therapeutics; AstraZeneca; Bayer; Novartis; Takeda; Boehringer Ingelheim; Bristol Myers-Squibb; Pfizer; Amgen; Daichii-Sankyo; DGK and for leadership/fiduciary role in the working group Sports Cardiology of the german cardiac society (DGK); K. Milger has received a grant from Bundesministerium fuer Bildung und Forschung BMBF. C. Tabeling has received honorariums from AstraZeneca, Berlin-Chemie, he was was supported for attedning meetings at AstraZeneca, GlaxoSmithKline and participated on data safety monitoring board at AstraZeneca, GlaxoSmithKline; I. Pink has received grant from DZL (Deutsches Zentrum fuer Lungenforschung), COFONI (COVID-19-Research Network of the State of Lower Saxony) and honorariums from GAIA GmbH, AstraZeneca, and Streamedup. I. Pink also participated on Advisory Board at BioNTech. N. Kremer has received consulting fees from MSD and OrphanCare and got payment from MSD. N.Kremer was also supported for attending meetings at AOP. M- Hecker has received grants from Bundesministerium fuer Bildung und Forschung BMBF and consulting fees from Olympus; S. Kuhnert has received consulting fees from AstraZeneca, GSK and Sanofi and gpt honorariums from AstraZeneca, GSK, Sanofi and BerlinChemie. S. Kuhnert also received payment for expert testimony at Sanofi; S. Herold has received research grants from German Research Foundation: KFO309, Hessen State Ministry of Higher Education, Research and the Arts (HMWK): Pandemic Network Hessen, Landes-Offensive zur Entwicklung Wissenschaftlich-oekonomischer Exzellenz, LOEWE, German Center for Lung Research (DZL), German Center for Infection Research (DZIF) Excellence Cluster Cardio-Pulmonary System/Cardio- Pulmonary Institute (CPI), The Network of University Medicine (NUM, Collaborative Immunity Platform of the NUM (COVIM), NUM Study Network Infections German National Pandemic Cohort Network (NAPKON) and VolkswagenStiftung; J. Wilhelm has received payment for leadership and participation on data safety monitoring at PRVi GoDeep; M. Witzenrath has received research grants from Bundesministerium fuer Bildung und Forschung (BMBF; Federal Ministry of Education and Research), Deutsche Forschungsgemeinschaft (DFG; German Research Foundation), Gemeinsamer Bundesausschuss (G-BA; The Federal Joint Committee), Bundesministerium fuer Gesundheit (BMG; Federal Ministry of Health) Grant Biotest, Pantherna, Aptarion and consulting fees at Biotest, Pantherna, Aptarion and got honorariums from Astra Zeneca, Chiesi, Insmed, Gilead, Pfizer and Boehringer; N. Weissmann has received received research grants from German Research Foundation, Excellence Cluster Cardiopulmonary Institute (CPI); H.-A. Ghofrani has received support, consulting fees, honoararium, payment for expert testimony, participation on data safety monitoring and leadership at Gosasamer Bio, Inc., Aerovate, Altavant, Attgeno, Bayer AG (ended 16 Nov 2023), CSL Behring, Janssen/Actelion, Insmed, MSD/Acceleron, Pfizer, Keros, Morphic Therapeutics, Pulmovant; W. Seeger has received consulting fees from United Therapeutics, Tiakis Biotech AG, Lung Biotechnology, Pfizer and Resyca BV. K. Tello has received research grants from Gossamer, Msd, Aop, OMT, Orphanet, Boehringer nad consulting fees from Gossamer. K. Tello got honorariums from MSD, Boehringer, AOP, OMT and was supported for attending meetings at AOP; N. Sommer has received research grants from German Research Foundation and Network of University Medicine (NUM, Collaborative Immunity Platform of the NUM, COVIM) and consulting fees from Janssen, Deloitte and got honorarium from Charite Berlin for lecture.

The study was funded by the Federal Ministry of Education and Research (BMBF) (AZ: 01EP2102A). K. Lo was funded by the Justus Liebig University (JLU) CAREER Programm, number GU 405/14-1. C. Tabeling received honoraria for lectures and advisory from AstraZeneca, Berlin-Chemie, GlaxoSmithKline, and for non-financial support from AstraZeneca and GlaxoSmithKline. S. Herold was supported by the German Research Foundation grant KFO309 (reference number 284237345, projects P2, P8); Hessen State Ministry of Higher Education, Research and the Arts (HMWK, Pandemic Network Hessen and Landes-Offensive zur Entwicklung Wissenschaftlich-oekonomischer Exzellenz, LOEWE, Foerderlinie 4a project ID III L7-519/05.00.002 and CoroPan P2); the German Center for Lung Research (DZL, reference number 82DZL005B1 and 82DZLT85C1), the German Center for Infection Research (DZIF); the Excellence Cluster Cardio-Pulmonary System/Cardio- Pulmonary Institute (EXC 2026, reference number 390649896); and the Network of University Medicine (NUM, Collaborative Immunity Platform of the NUM (COVIM), NUM Study Network Infections, German National Pandemic Cohort Network (NAPKON), reference number 01KX2121); VolkswagenStiftung (project Swarm Learning). N. Sommer was supported by the German Research Foundation grant KFO309 (reference number 284237345, project P10), the Excellence Cluster Cardio-Pulmonary System/Cardio- Pulmonary Institute (EXC 2026, reference number 390649896) and the Network of University Medicine (NUM, Collaborative Immunity Platform of the NUM, COVIM).

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