Clinical trial NCT04987528: Pulmonary Fibrosis During Severe COVID-19 Pneumonia
Official title: Incidence, Risk Factors and Prognosis of Pulmonary Fibrosis During Severe COVID-19 Pneumonia
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Severe Acute Respiratory Syndrome Coronavirus 2
Acute Respiratory Distress Syndrome
Pulmonary Fibrosis
Keywords: Mechanical Ventilation
Lead sponsor: Hôpital Européen Marseille
Sponsor class: OTHER
First posted: 2021-08-03
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The population will focused on patients with severe SARS Cov-2 pneumonia requiring ICU admission.

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Ventilator-free days
timeFrame: Day 90
Secondary outcomes:
measure: Day 90 mortality
timeFrame: Day 90
measure: Day 28 mortality
timeFrame: Day 28
measure: ICU Mortality
timeFrame: From date of ICU admission until the date of ICU liberation, assessed up to 6 months
measure: In-hospital Mortality
timeFrame: From date of hospital admission until the date of hospital liberation, assessed up to 12 months
measure: Length of MV
timeFrame: From date of ICU admission until the date of ICU liberation, assessed up to 6 months
measure: Length of ICU stay
timeFrame: From date of ICU admission until the date of ICU liberation, assessed up to 6 months
measure: Length of hospital stay
timeFrame: From date of hospital admission until the date of hospital liberation, assessed up to 12 months
measure: Time to viral clearance
timeFrame: From date of first symptom until the date of ICU liberation, assessed up to 6 months
measure: Corticosteroid dose
timeFrame: From date of ICU admission until the date of ICU liberation, assessed up to 6 months
measure: Lung herpesviridae reactivation
timeFrame: From date of ICU admission until the date of ICU liberation, assessed up to 6 months
measure: Blood herpesviridae reactivation
timeFrame: From date of ICU admission until the date of ICU liberation, assessed up to 6 months
Other outcomes:
Locations:
city: Marseille
country: France
facility: Hopital Europeen Marseille
Study officials:
References:
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citation: Grasselli G, Tonetti T, Protti A, Langer T, Girardis M, Bellani G, Laffey J, Carrafiello G, Carsana L, Rizzuto C, Zanella A, Scaravilli V, Pizzilli G, Grieco DL, Di Meglio L, de Pascale G, Lanza E, Monteduro F, Zompatori M, Filippini C, Locatelli F, Cecconi M, Fumagalli R, Nava S, Vincent JL, Antonelli M, Slutsky AS, Pesenti A, Ranieri VM; collaborators. Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study. Lancet Respir Med. 2020 Dec;8(12):1201-1208. doi: 10.1016/S2213-2600(20)30370-2. Epub 2020 Aug 27.
citation: Forel JM, Guervilly C, Hraiech S, Voillet F, Thomas G, Somma C, Secq V, Farnarier C, Payan MJ, Donati SY, Perrin G, Trousse D, Dizier S, Chiche L, Baumstarck K, Roch A, Papazian L. Type III procollagen is a reliable marker of ARDS-associated lung fibroproliferation. Intensive Care Med. 2015 Jan;41(1):1-11. doi: 10.1007/s00134-014-3524-0. Epub 2014 Oct 30.
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