Pulmonary Fibrosis During Severe COVID-19 Pneumonia

Study Overview
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Brief Summary
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The COVID-19 pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), an emerging coronavirus, which has already infected 192 million people with a case fatality rate close to 2%. About 5% of patients infected with SARS CoV-2 have a critical form with organ failure. Among critical patients admitted to intensive care, about 70% of them will require ventilatory assistance by invasive mechanical ventilation (MV) with a mortality rate of 35% and a median MV duration of 12 days. The most severe lung damage resulting from SARS CoV-2 infection is the acute respiratory distress syndrome (ARDS). The virus infects alveolar epithelial cells and capillary endothelial cells leading to an activation of endothelium, hypercoagulability and thrombosis of pulmonary capillaries. This results in abnormal ventilation / perfusion ratios and profound hypoxemia. To date, the therapeutic management of severe SARS CoV-2 pneumonia lay on the early use of corticosteroids and Interleukin-6 (IL-6) receptor antagonist, which both reduce the need of MV and mortality. The risk factors of death in Intensive Care Unit (ICU) are: advanced age, severe obesity, coronary heart disease, active cancer, severe hypoxemia, and hepatic and renal failure on admission. Among MV patients, the death rate is doubled in those with both reduced thoracopulmonary compliance and elevated D-dimer levels. Patients with severe alveolar damage are at risk of progressing towards irreversible pulmonary fibrosis, the incidence of which still remain unknown. The diagnosis of pulmonary fibrosis is based on histology but there are some non-invasive alternative methods (serum or bronchoalveolar biomarkers, chest CT scan). We aim to assess the incidence of pulmonary fibrosis in patients with severe SARS CoV-2 related pneumonia. We will investigate the prognostic impact of fibrosis on mortality and the number of days alive free from MV at Day 90. Finally, we aim to identify risk factors of fibrosis.

Detailed Description
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Medical charts of patients admitted at the Intensive Care Unit (ICU) of the European Hospital of Marseille between March 2020 and June 2021 will be collected retrospectively using electronic database. Data collected will focus on demography, clinical variables, biological analyses, lung biopsies, and chest CT scans performed during the hospital stay. Our routine protocol for COVID-19 management follows the Coronavirus Disease 2019 (COVID-19) Treatment Guidelines including the early use of corticosteroids (Dexamethasone) and IL-6 receptor antagonist (Tocilizumab). Additionally, we routinely perform, on a weekly basis, measurements of SARS CoV-2 viral load by PCR, SARS CoV-2 antibodies production, and biomarkers of fibrosis including hyaluronic acid (HA) and amino-terminal type I (PINP) and type III (PIIINP) peptides of procollagen. The present study aim to determine the proportion of patients encountering non-invasive criteria of pulmonary fibrosis as defined by either typical CT scan patterns (reticulation and/or bronchiectasia), or increased serum concentration of PIIINP above 16 µg/L, or increased bronchoalveolar lavage (BAL) concentration of PIIINP above 9 µg/L. A definitive diagnosis of lung fibrosis will be established according to lung pathology findings in patients for whom a lung biopsy have been performed during the hospital stay. Patients with a diagnosis of pulmonary fibrosis will be compared with those without fibrosis, both in the population of mechanically ventilated patients and in those remained spontaneously breathing. The primary end-point will be the number of days alive and free from the ventilator (ventilator-free days) at Day 90. The others outcomes of interest will be the duration of mechanical ventilation, the duration of ICU stay, the ICU mortality, the in-hospital mortality, the Day 28 mortality, and the Day 90 mortality. The present study also aims to determine the risk factors of pulmonary fibrosis occurence, focusing on mechanical ventilatory settings, daily dose of corticosteroids, and the occurence of nosocomial pneumonia with special attention to lung reactivation of herpesviridae. Finally, the relation between antibodies production and viral clearance (defined as the time to the first negative SARS CoV-2 PCR) or ICU survival will be investigated.

Official Title
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Incidence, Risk Factors and Prognosis of Pulmonary Fibrosis During Severe COVID-19 Pneumonia

Conditions
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Severe Acute Respiratory Syndrome Coronavirus 2, Acute Respiratory Distress Syndrome, Pulmonary Fibrosis

Intervention / Treatment
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* Diagnostic Test: Aminoterminal type III peptide of procollagen
* Diagnostic Test: Lung computed tomography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute hypoxemic respiratory failure Positive SARS CoV-2 PCR on nasopharyngeal swab or distal airway sampling ICU admission during the hospital stay Exclusion Criteria: Chronic respiratory failure (Oxygen or NIPPV at home) Patients with Do Not Resuscitate order at ICU admission Admission from an other ICU with a stay > 2 days Transfer to an another ICU during the ICU stay

Ages Eligible for Study
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Minimum Age: 18 Years

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 |
| --- | --- |
| Patients with pulmonary fibrosis<br>All ICU patients for which one of the non-invasive criteria of pulmonary fibrosis is reached : Typical CT scan patterns (reticulation and/or bronchiectasia) Serum PIIINP above 16 µg/L BAL PIIINP above 9 µg/L | Diagnostic Test: Aminoterminal type III peptide of procollagen<br>* Serial Measurement of PIIINP in serum and/or BAL<br>* Other names: PIIINP;Diagnostic Test: Lung computed tomography<br>* Screening for the presence of reticulation or bronchiectasia within lung parenchyma<br>* Other names: Chest CT scan;|
| Patients without pulmonary fibrosis<br>All ICU patients for which none of the non-invasive criteria of pulmonary fibrosis are reached. | Diagnostic Test: Aminoterminal type III peptide of procollagen<br>* Serial Measurement of PIIINP in serum and/or BAL<br>* Other names: PIIINP;Diagnostic Test: Lung computed tomography<br>* Screening for the presence of reticulation or bronchiectasia within lung parenchyma<br>* Other names: Chest CT scan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilator-free days | Number of days alive and free from mechanical ventilation | Day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Day 90 mortality | Mortality at Day 90 | Day 90 | 
| Day 28 mortality | Mortality at Day 28 | Day 28 | 
| ICU Mortality | Death from any cause during the ICU stay | From date of ICU admission until the date of ICU liberation, assessed up to 6 months | 
| In-hospital Mortality | Death from any cause during the Hospital stay | From date of hospital admission until the date of hospital liberation, assessed up to 12 months | 
| Length of MV | Duration of mechanical ventilation during the ICU stay | From date of ICU admission until the date of ICU liberation, assessed up to 6 months | 
| Length of ICU stay | Duration of ICU stay | From date of ICU admission until the date of ICU liberation, assessed up to 6 months | 
| Length of hospital stay | Duration of hospital stay | From date of hospital admission until the date of hospital liberation, assessed up to 12 months | 
| Time to viral clearance | Time from first symptom to the first negative SARS CoV-2 PCR | From date of first symptom until the date of ICU liberation, assessed up to 6 months | 
| Corticosteroid dose | Daily corticosteroid dose (methylprednisolone equivalent) | From date of ICU admission until the date of ICU liberation, assessed up to 6 months | 
| Lung herpesviridae reactivation | Presence on BAL of at least one Herpesviridae (Cytomegalovirus, Epstein-Barr Virus, Herpes simplex virus, Human herpes virus-6) | From date of ICU admission until the date of ICU liberation, assessed up to 6 months | 
| Blood herpesviridae reactivation | Presence on serum of at least one Herpesviridae (Cytomegalovirus, Epstein-Barr Virus, Herpes simplex virus, Human herpes virus-6) | From date of ICU admission until the date of ICU liberation, assessed up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mechanical Ventilation