COVID-19 Pneumonia: Pulmonary Physiology, Health-related Quality of Life and Benefit of a Rehabilitation Program

The pathophysiological processes involved in COVID-19 pneumonia are not fully understood. Specific alterations of the airways, lung parenchyma and pulmonary vascular tree could explain a severe ventilation/perfusion heterogeneity resulting in severe hypoxemia during the active phase of the disease. Additional skeletal muscle impairment related to systemic inflammation may also explain persisting symptoms in the follow-up phase. The first aim of the present project is to explore these different processes by evaluating the impact of the COVID-19 pneumonia on exercise capacity, pulmonary function and perfusion by a physiological and radiologic study. An ambulatory pulmonary rehabilitation will also be studied to assess its impact on the physiological parameter mentioned and the health-related quality of life questionnaire as a potential long-term treatment. The investigators propose a single center randomized controlled study at the University Hospitals of Geneva. 60 adult patients having suffered a hypoxemic COVID-19 pneumonia with persistent symptoms at 3-months after hospital discharge will be included. A functional and physiological study will be performed, including a six-minute walk test, pulmonary function testing, diffusing capacity for carbon monoxide, maximal inspiratory pressure and sniff nasal inspiratory pressure. Those with at least one abnormal value will be invited to fill the Saint Georges Respiratory Questionnaire, the Short Form 36 and the Hospital Anxiety and Depression Scale and will undergo a chest dual energy computed tomography (DECT), a cardiopulmonary exercise testing with non-invasive cardiac output and stroke volume evaluation and an evaluation of the pulmonary shunt by hyperoxia (100% oxygen breathing) at rest and during light effort. Then patients will be randomized on a 1:1 basis for pulmonary rehabilitation program or usual care. All work-up except DECT will be repeated at 6 and 12 months after hospital discharge. The investigators hypothesize that our study will allow a better understanding of pathophysiological mechanisms involved in COVID-19. This will potentially determine therapeutic target for patients with persisting symptoms and functional decay after COVID-19. The investigators also expect to see an improvement of exercise capacity and physiological parameters in the pulmonary rehabilitation group, as compared to the control group, suggesting pulmonary rehabilitation as a possible long-term treatment of this condition.

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.

Eligibility Criteria:
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.