Clinical Trial Finder

Patients will be eligible for inclusion if they fulfil all the following criteria:

• - Patients aged ≥ 18 years.

• - Confirmed diagnosis of SARS-Cov-2 infection by nasal swab, other viral sample (i.e. sputum, bronchoalveolar lavage) or Chest imaging suggestive of SARS-CoV-2 pneumonia (Chest X-ray or CT-scan).

• - Requirement for oxygen supplementation.

• - Persistent respiratory symptoms (i.e. dyspnoea, cough) or asthenia.

• - Abnormal 6MWT at 3 months (distance < 90% predicted or desaturation ≥ 3% or Borg >5) and/or abnormal lung function as described by the international recommendations.

Patients will be excluded if they:

• - Already had existing severe and symptomatic pulmonary condition before COVID-19 pneumonia.

• - Are unable to execute the different tests and surveys because of cognitive or physical limitations.

• - Are already included in a structured rehabilitation program.

• - Have comorbidities with a life expectancy of less than 12 months.

• - Any relevant acute medical disorder/acute disease state judged by the investigators as likely to represent a risk for the patient to fulfil a rehabilitation program or requiring urgent investigations.

COVID-19 is an emerging pandemic disease caused by a novel coronavirus (SARS-CoV-2) since December 2019. This condition may be associated with a severe pneumonia and an acute respiratory distress syndrome (ARDS) resulting in a high mortality and morbidity.A standardized follow up of COVID-19 patients after discharge from Geneva University Hospitals (Covicare) was implemented since March 29th 2020 by the divisions of infectious disease and respiratory medicine, in association with the primary care medicine department. A follow-up is ensured until one month after discharge. All patients are registered in a database (REDCapTM,Tennessee, USA). The pathophysiological mechanisms of ARDS in COVID-19 and its long-term consequences on respiratory and cardiovascular systems remain unclear. Several histopathological studies have demonstrated occurrence of interstitial lung disease. Furthermore, there are some reports of associated endothelitis, thrombosis in the microcirculation5 and a high prevalence of venous thrombo-embolic events in ICU admitted patients, with pulmonary embolism accounting for 85% of those events.Both these changes contribute to increase heterogeneity of ventilation

• - perfusion ratio (VA/Q), thereby widening the alveolar - arterial oxygen gradient, and thus causing serious hypoxaemia, with remarkable fall of arterial oxygen saturation (SaO2).

Finally, the interstitial pneumopathy may cause a persisting reduction of lung diffusing capacity for carbon monoxide (DLCO), further decreasing SaO2 even after recovery from COVID-19 pneumonia. Chest Dual-Energy Computed Tomography (DECT) enables a combined functional and morphological analysis of the lung in a single and simple acquisition. Because of the attenuation properties of iodine at two different photon energies (80 and 140kV), DECT is able to reveal pulmonary blood volume distribution and generate color-coded pulmonary iodine volume maps, corresponding to the pulmonary perfusion. These pulmonary perfusion maps allow a qualitative analysis of the perfusion.Furthermore, the iodine concentration of the lung confers an objective and quantitative regional analysis of the perfusion. In comparison with a conventional CT, no additional intravenous iodine contrast medium injection or radiation doses are needed; a functional image processing is simply added. We recently demonstrated how DECT may help to define lung perfusion changes after therapeutic measures in patients with chronic obstructive pulmonary disease. Moreover, DECT offers an excellent correlation with perfusion scintigraphy (V/Q scan). DECT also offers a superior anatomic and functional comprehension by simultaneously recording the vascular anatomy, parenchymal morphology, and functional perfusion. Consequently, DECT may provide important information both on persisting parenchymal and perfusion alteration after COVID-19. In addition to the pulmonary component, the systemic inflammation state due to the concurring "cytokine storm syndrome" may have an important role in the development of neuromuscular alterations, independently of direct consequences of hospitalization in intensive care unit. Neuromuscular alterations concur with lung function impairment in compromising the functional state of the patient. As a consequence, we ought to expect a reduction of physical exercise capacity, which is normally determined by a VO2max measurement during cardiopulmonary exercise test (CPET) and by means of the six-minute walk test (6MWT). Moreover, it is well described that ARDS is associated with a significant long-term morbidity. At one year, 80% of ARDS survivors have a reduced diffusing capacity and 20% suffer from an airflow obstruction. 35% of patients have an exercise limitation based on the 6MWT at two years. Moreover, impairment in lung function, musculoskeletal dysfunction and functional limitation are linked to health-related quality of life (HRQL) decrement. Studies from a cohort of patients who suffered from ARDS due to SARS-CoV-1 in 2002 showed a positive correlation between lung function and the HRQL physical functioning domain. Distance performed during 6MWT correlated also with almost all Short Form Health Survey-36 (SF-36) domains. Furthermore, mood disorders are commonly described in ARDS survivors, with studies reporting up to 50% of depression at one year in this population. Depression and anxiety are themselves associated with lower HRQL scores. Pulmonary rehabilitation has been shown to improve HRQL, maximal exercise capacity and 6MWD in chronic pulmonary disease. It was also shown that 2 months of ambulatory pulmonary rehabilitation improved pulmonary function and the St. George's Respiratory Questionnaire (SGRQ) at 3 and 6 months post-discharge following recovery from ARDS due to severe influenza A (H1N1 in 2009) pneumonitis. The purpose of this study is 1/ to explore the long-term impact of COVID-19 on physiological respiratory parameters, functional capacity, HRQL and mood disturbances ; 2/ to assess the benefit of a pulmonary rehabilitation program on these outcomes through a randomized-control study, and 3/ to determine the contribution of DECT to the understanding of the pathophysiological alterations in patients with functional sequelae of COVID-19 infection.

Arms

No Intervention: Control

Patients in this arm will receive standard of care

Experimental: Pulmonary Rehabilitation

Patients will undergo a 12-weeks Pulmonary rehabilitation program. It will include 3 sessions of supervised exercise per week, as initially proposed on COPD patients. Patients will exercise on electromagnetically braked cycle ergometers for 45 min by alternating 30-s exercise intervals at 100% of peak-work rate estimated during the initial incremental test, with 30-s rest periods. Total workload will be increased (by 5%) on a weekly basis. Strength training of lower and upper limbs, will also be included.

Interventions

Other: - Pulmonary rehabilitation

pulmonary rehabilitation for 12 weeks, 3 times a week. control will take place at 3, 6 and 12 months