Cardiopulmonary Exercise Testing for Prognostic Assessment of Clinical Outcomes in COPD: A Systematic Review and Meta-Analysis

Michaël Staes,1,2,* Jonas Dong,3,* Iwein Gyselinck,1,2 Stephanie Everaerts,1,2 Wim Janssens1,2 1Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium; 2Clinical Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium; 3Faculty of Medicine, KU Leuven, Leuven, Belgium*These authors contributed equally to this workCorrespondence: Wim Janssens, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Herestraat 49, Box 706, Leuven, 3000, Belgium, Email [email protected]: Chronic obstructive pulmonary disease (COPD) is a heterogeneous, progressive lung disorder. Despite its high prevalence, predicting clinical outcomes remains challenging. Various cardiopulmonary exercise testing (CPET) variables have been suggested as prognostic markers in COPD, but their role in clinical practice remains unclear. After registration in PROSPERO (ID CRD42024569879), a literature search of the Pubmed, Embase, Web of Science, Cochrane library and Scopus databases was carried out in August 2024. Study selection followed the PRISMA guidelines. Prospective and retrospective cohort studies evaluating associations between CPET variables and clinical outcomes in patients with COPD were included. Risk of bias was evaluated using the QUIPS tool. Data were extracted and synthesized narratively. A random-effects meta-analysis was planned if multiple studies reported comparable CPET variables, outcomes, and effect measures. Sixteen articles were included, three of which had an overall high risk of bias. Peak oxygen uptake (VO2peak) was consistently associated with mortality in univariate analyses, but its independent prognostic value in multivariable models was inconsistent. A random-effects meta-analysis of three studies evaluating VO2peak expressed as mL/kg/min did not demonstrate a statistically significant independent association with mortality (pooled HR 0.94, 95% CI 0.87– 1.00; I2 = 63%). Ventilatory efficiency (VE/VCO2) was identified as a significant prognostic marker in multiple studies. Other CPET-derived variables failed to show an independent association with mortality, although heterogeneity in metrics and adjustment strategies limited comparability. Evidence for other CPET-derived variables and for predicting severe acute exacerbations of COPD (AECOPD) or hospitalization was limited and inconsistent. CPET-derived variables, particularly VO2peak and VE/VCO2, are associated with mortality in COPD, but evidence for their independent prognostic value and incremental benefit over established composite indices remains limited. Current data do not support routine use of CPET variables for prognostic stratification in COPD, apart from VO2peak as a marker of exercise capacity within the modified BODE index.Keywords: pulmonary disease, chronic obstructive, cardiopulmonary exercise testing, prognosis, risk stratification