The role of cardiopulmonary exercise test in post-acute sequelae of SARS-CoV-2 infection: back to the future

The study of the mechanisms underlying "long-COVID" or post-acute sequalae of SARS-CoV-2 infection (PASC) has rapidly emerged in literature as a priority, since the early follow-up of COVID-19 survivors. Cardiopulmonary exercise test (CPET), which is the gold standard for exercise capacity evaluation and is considered a valuable tool to assess cardiopulmonary reserve, has been employed since the first follow-up phase to assess the meaning and magnitude of functional and radiological impairments seen at rest in early recovery and to explore mechanisms behind exercise limitation in these patients. Although the initial fear, in the light of the intensity of the multiorgan involvement in the acute phase, substantial cardio-pulmonary sequelae were identified only in a limited share of patients. Nevertheless, CPET revealed mostly diagnoses such as deconditioning, dysfunctional breathing and chronotropic incompetence at the base of post-COVID impairment in exercise response. This prompted a reappraisal in literature of the pathophysiology of these conditions, traditionally considered as diagnoses of exclusion, after overt cardio-respiratory and metabolic causes were ruled out. In addition, advanced techniques such as combined invasive hemodynamic-CPET (iCPET) and combined exercise stress echocardiography-CPET (ESE-CPET) were employed to overcome the intrinsic limitations of non-invasive CPET and examine in depth the multiple components of these phenomena. The aim of this review was to summarize the evidence on the most commonly identified causes of PASC during exercise, providing an overview of how COVID-19 has had an impact on exercise capacity evaluation.