Lung Function, Exercise Capacity and Health-Related Quality of Life After Severe COVID-19

Study Overview
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Brief Summary
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Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a newly emergent coronavirus (SARS-CoV-2) that can progress to severe disease requiring hospitalization and oxygen support in around14% of the cases and 5% require admission in intensive care unit. The medium and long-term impact in survivors of severe COVID-19 on lung function, exercise capacity and health-related quality of life remains to be determined.

Detailed Description
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Background: Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a newly emergent coronavirus (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) that was first recognized in Wuhan, China, in December 2019. Currently, this infection reached pandemic levels causing serious diseases in 14% of cases and the potential to progress to acute respiratory distress syndrome (ARDS) with the need for invasive ventilatory support and prolonged hospitalization in intensive care units (ICU). The overall lethality is 2% and the lethality of cases admitted to the ICU varies from 26 to 50%. The medium and long-term impact in survivors of severe COVID-19 on lung function, exercise capacity and health related quality of life (HRQoL) remains to be determined. Aims: To evaluate the early (Visit1: 2-6 months after acute disease) and late (Visit 2: 9-15 months and Visit 3: 18-24 months) effects of severe acute respiratory syndrome on lung function, exercise capacity, respiratory symptoms and HRQoL in patients with confirmed diagnosis of SARS-CoV-2 infection. Material and methods: Prospective cohort of subjects with laboratory confirmed severe COVID-19 (respiratory rate> 30 breaths/ min; severe respiratory distress; oxyhemoglobin saturation in room air ≤93% or pulmonary involvement> 50% in chest images). Participants will perform spirometry before and after bronchodilator, lung volumes by body plethysmography, lung diffusion capacity of carbon monoxide, respiratory system resistance by impulse oscillometry and 6-minute walk test (6MWT) after 2-6 months (Visit 1) , 9-15 months (Visit 2), and 18-24 months (Visit 3) of severe COVID-19. When abnormalities in these pulmonary function tests and/or 6MWT were detected, a cardiopulmonary exercise test will be performed. Clinical, laboratory and chest image data during the severe COVID-19 hospitalization will be obtained from medical records. The minimum sample size was estimated as 134 participants to assess at least 5 independent factors to predict lung function, HRQoL and exercise capacity at the early assessment. Notwithstanding, the investigators plan to invite to participate all survivors of severe COVID-19 admitted in hospitals of the state of Rio Grande do Sul (Brazil).

Official Title
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Short and Long Term Assessment of Lung Function, Exercise Capacity and Health-Related Quality of Life in Survivors of Severe COVID-19

Conditions
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COVID-19, SARS-CoV-2 Infection

Intervention / Treatment
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* Diagnostic Test: Lung Function tests
* Diagnostic Test: Exercise capacity
* Diagnostic Test: Exercise physiology
* Diagnostic Test: Health-related quality of life
* Diagnostic Test: Respiratory symptoms, symptoms of anxiety and depression, and post-traumatic stress screening


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previous laboratory confirmation of SARS-Cov-2 infection defined as a positive result of reverse polymerase-transcriptase chain reaction test in real-time of a sample taken by nasal and/or pharyngeal swab; and Severe pneumonia defined by the presence of fever or suspected lower respiratory infection, plus one of the following criteria: respiratory rate> 30 movements/min; severe respiratory distress; SpO2≤93% in room air; or pulmonary infiltrates>50% on chest imaging within 24-48hrs of acute symptoms onset; and/or Acute respiratory distress syndrome (ARDS) defined according to COVID-19 operational management guide of World Health Organization and classified as mild (200 mmHg <PaO2 / FiO2 ≤ 300 mmHg), moderate (100 mmHg <PaO2 / FiO2 ≤ 200 mmHg) or severe (PaO2 / FiO2 ≤ 100 mmHg). When the PaO2 is not available, SpO2 / FiO2 ≤ 315 suggests ARDS. Exclusion Criteria: Lack of clinical stability for 2 months before inclusion (including those who remain hospitalized); Active respiratory tract infection (of any cause); or Any clinical condition that prevents the performance of the study procedures.
Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Severe Pneumonia<br>Presence of fever or suspected lower respiratory infection, plus one of the following criteria: 1) respiratory rate> 30 movements / min; 2) severe respiratory distress 3) Pulse oximetry (SpO2) ≤93% in room air; and/or 3) Pulmonary infiltrates> 50% on chest imaging within 24-48hrs of symptom onset. | Diagnostic Test: Lung Function tests<br>* Spirometry before and after bronchodilator, lung volumes by body plethysmography, lung diffusion capacity of carbon monoxide (DLCO), respiratory system resistance by impulse oscillometry (IOS)<br>Diagnostic Test: Exercise capacity<br>* 6-minute walk test (6MWT distance)<br>Diagnostic Test: Exercise physiology<br>* Cardiopulmonary exercise test (CPET)<br>Diagnostic Test: Health-related quality of life<br>* Short-Form Health Survey Questionnaire (SF-36)<br>Diagnostic Test: Respiratory symptoms, symptoms of anxiety and depression, and post-traumatic stress screening<br>* Adapted translation American Thoracic Society respiratory symptoms questionnaire; Beck Anxiety Inventory (BAI) and Beck's depression Inventory (BDI); Questionnaire for screening for post-traumatic stress symptoms (PTSD).<br>|
| Acute respiratory distress syndrome (ARDS)<br>Onset: acute, i.e. within 1 week of known clinical insult or new or worsening respiratory symptoms; and Chest imaging (e.g. X-ray or CT scan): bilateral opacities, not fully explained by effusions, lobar/lung collapse or nodules; and Origin of pulmonary edema: respiratory failure not fully explained by cardiac failure or fluid overload; and Degree of hypoxemia: arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) ≤ 300 mm Hg with positive end-expiratory pressure ≥ 5 cm H2O. | Diagnostic Test: Lung Function tests<br>* Spirometry before and after bronchodilator, lung volumes by body plethysmography, lung diffusion capacity of carbon monoxide (DLCO), respiratory system resistance by impulse oscillometry (IOS)<br>Diagnostic Test: Exercise capacity<br>* 6-minute walk test (6MWT distance)<br>Diagnostic Test: Exercise physiology<br>* Cardiopulmonary exercise test (CPET)<br>Diagnostic Test: Health-related quality of life<br>* Short-Form Health Survey Questionnaire (SF-36)<br>Diagnostic Test: Respiratory symptoms, symptoms of anxiety and depression, and post-traumatic stress screening<br>* Adapted translation American Thoracic Society respiratory symptoms questionnaire; Beck Anxiety Inventory (BAI) and Beck's depression Inventory (BDI); Questionnaire for screening for post-traumatic stress symptoms (PTSD).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced expiratory volume in the first second/forced vital capacity | ratio obtained from measured values during spirometry | 6 months | 
| Total lung capacity | obtained from plethysmography (% of predicted) | 6 months | 
| Lung diffusion capacity for carbon monoxide | obtained from single-breathe maneuver (% of predicted) | 6 months | 
| 6-minute walk test distance | distance walked during the test (m) | 6 months | 
| Short-form 36 questionnaire (SF-36) | scores range between 0 and 100 with higher scores indicating a better HRQoL | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced expiratory volume in the first second/forced vital capacity | ratio obtained from measured values during spirometry | 12 and 24 months | 
| Forced vital capacity | % of predicted | 6, 12 and 24 months | 
| Residual volume/total lung capacity | ratio obtained from measured values during plethysmography | 6, 12 and 24 months | 
| Inspiratory capacity/total lung capacity | ratio obtained from measured values during plethysmography | 6, 12 and 24 months | 
| Airway resistance (Raw) | obtained from body plethysmography | 6, 12 and 24 months | 
| Lung diffusion capacity for carbon monoxide | obtained from single-breathe maneuver (% of predicted) | 12 and 24 months | 
| Resistance at 20Hz and 5Hz (R5-R20) | obtained from Impulse oscillometry | 6, 12 and 24 months | 
| Reactance at 5Hz (X5) | obtained from Impulse oscillometry | 6, 12 and 24 months | 
| Resonant frequency (Fres) | obtained from Impulse oscillometry | 6, 12 and 24 months | 
| Reactance area (AХ) | obtained from Impulse oscillometry | 6, 12 and 24 months | 
| 6-minute walk test distance | distance walked during the test (m) | 12 and 24 months | 
| Pulse oximetry (SpO2) at rest | before 6-minute walk test | 6, 12 and 24 months | 
| Pulse oximetry (SpO2) during exercise | at the end of 6-minute walk test | 6, 12 and 24 months | 
| Respiratory symptoms adapted from American Thoracic Society Questionnaire | descriptive/qualitative questionnaire | 6, 12 and 24 months | 
| Short-form 36 questionnaire (SF-36) | scores range between 0 and 100 with higher scores indicating a better HRQoL | 12 and 24 months | 
| Oxygen uptake at peak exercise | from incremental Cardiopulmonary exercise test (% of predicted) | 6, 12 and 24 months | 
| Minute-ventilation/carbon dioxide output during exercise | from incremental Cardiopulmonary exercise test (L/L) | 6, 12 and 24 months | 
| Dyspnea during exercise | from incremental Cardiopulmonary exercise test (measured with 10-point categorical Borg scale) | 6, 12 and 24 months | 
| Inspiratory capacity during exercise | from incremental Cardiopulmonary exercise test (L and % of predicted) | 6, 12 and 24 months | 
| Beck Anxiety Inventory (BAI) | total score ranges from 0 to 63; higher score indicating higher anxiety | 6, 12 and 24 months | 
| Beck Depression Inventory (BDI) | total scores ranges from 0 to 63; higher score is worse | 6, 12 and 24 months | 
| Post-traumatic stress symptoms questionnaire | 17-item, 5 likert-scale each item; higher score indicating more symptoms | 6, 12 and 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Severe Acute Respiratory Syndrome Coronavirus 2, Pneumonia, Respiratory Distress Syndrome, Adult, Respiratory Function Tests, Exercise, Quality of Life