The FLARE Four
- Up to 25% of acute respiratory distress syndrome (ARDS) survivors develop physiologic evidence of restrictive lung disease within six months of ARDS diagnosis
- More severe, prolonged illness and pulmonary causes of ARDS are thought to be risk factors for progression to fibrosis
- Pre–COVID-19 research suggests post-ARDS fibrosis does not progress
- Proposals are emerging to study antifibrotics in COVID-19 ARDS
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Fibrotic lung disease can be a complication of prolonged respiratory failure from acute respiratory distress syndrome (ARDS). In a fast literature update posted on June 2, 2020, Rachel Knipe, MD, clinician in the Division of Pulmonary and Critical Care Medicine, and Lida Hariri, MD, PhD, pathologist in the Department of Pathology, both at Massachusetts General Hospital, explain why they expect the COVID-19 pandemic to lead to increased numbers of patients with pulmonary fibrosis.
Abnormalities on pulmonary function testing in ARDS survivors usually resolve with time. However, up to 25% of patients have persistent restrictive abnormalities six months after ARDS diagnosis, and many also have residual imaging abnormalities. These findings can be consistent with fibrosis.
More severe, prolonged illness and pulmonary causes of ARDS are thought to be risk factors for progression to fibrosis. Patients with post-ARDS fibrosis demonstrate stable impairment in pulmonary function, not the progression seen in interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF). Similarly, no study of post-ARDS fibrosis has reported acute exacerbations like those seen in IPF.
COVID-19 ARDS and Fibrosis
Past epidemics are instructive in that 30% of SARS and MERS survivors had persistent radiographic abnormalities and 15% had persistent physiologic restriction. Risk factors for fibrosis were older age and ICU admission. Studies from China have reported persistent radiographic findings and abnormal lung function in COVID-19 survivors at discharge.
A Role for Antifibrotics?
A recent opinion piece in the Lancet Respiratory Medicine considers a role for antifibrotic therapy in COVID-19 ARDS. This may be especially important considering the potentially poor outcomes for patients who had pre-existing fibrosis.
The two approved antifibrotic medications, pirfenidone and nintedanib, have been studied for one to five years in the setting of progressive pulmonary fibrosis, and the benefit of nintedanib was evident within four to six weeks. Moreover, both drugs have been tested in fibrotic lung diseases other than IPF, however, neither has been studied in the setting of acute exacerbations or in ARDS.
Nintedanib may reduce rates of acute exacerbations of interstitial lung disease, which might be caused by respiratory viruses. The mechanism of antifibrotic drugs preventing exacerbations might be able to mitigate the effect of COVID-19 on pulmonary fibrosis.
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