A Study of the Efficacy and Safety of Pirfenidone vs. Nintedanib in the Treatment of Fibrotic Lung Disease After Coronavirus Disease-19 Pneumonia

Since the early part of 2020, the entire world has been affected by a pandemic of the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease has a short incubation period (median, 3 days) and is highly transmissible. This disease may manifest as an asymptomatic infection and through an entire range of symptoms of varying severity to severe, life-threatening disease. Although diverse systemic features might be present, the usual presentation is with lower respiratory tract involvement in the form of pneumonia often resulting in the development of the acute respiratory distress syndrome (ARDS). In some patients, multi-organ failure sets in, possibly as a result of a cytokine storm interplaying with a thrombotic microangiopathy.

Early lung disease is characterized pathologically by neutrophilic and exudative capillaritis in the lungs with some evidence of microthrombosis.2 This may be followed by a picture of diffuse alveolar damage along with ongoing intravascular thrombosis in the pulmonary vessels. In late stages, an organizing pneumonia (OP) develops with extensive proliferation of fibroblasts within the airspaces. Clinically, most patients make a complete recovery after COVID pneumonia. Other patients may demonstrate some signs of recovery from the acute illness with resolution of fever and recovery of organ functions, however they continue to have some degree of breathlessness, persistent infiltrates on radiologic studies, and/or hypoxemia. The CT abnormalities in these patients are commonly characterized by patchy, multifocal consolidation and ground-glass opacities suggestive of the OP pattern. Coarse reticulation and parenchymal bands may also be present.

Patients with such diffuse lung disease after COVID-19, herein referred to as post-COVID diffuse lung disease (PC-DLD) are often treated with glucocorticoids. Although most patients with a predominant OP pattern of injury would have a resolution of lung parenchymal abnormalities either spontaneously or with glucocorticoids, some of them might develop signs of lung fibrosis, in the form of traction bronchiectasis and/or honeycombing. Some subjects have ongoing respiratory symptoms despite treatment with steroids, and they may be found to have persistent reticulation or non-resolving consolidation on chest imaging that may represent early fibrosis.

The antifibrotic agents, namely pirfenidone and nintedanib have been found to be effective in the treatment of idiopathic pulmonary fibrosis (IPF). Nintedanib has also been found to be effective in treating systemic sclerosis-related interstitial lung disease (ILD) and non-IPF progressive fibrosing ILDs. Pirfenidone has also been found beneficial unclassifiable ILDs. Whether these drugs would be effective in treating post-COVID lung fibrosis also is unknown. As the final pathway of lung fibrosis appears to be common among different diffuse parenchymal lung diseases (DPLDs), it is hoped that these antifibrotic agents might be helpful in post-COVID fibrosis. There are no randomized studies that have assessed the role of pirfenidone or nintedanib in post COVID fibrosis. In the current study, we aim to assess the efficacy and safety of pirfenidone and compare it with nintedanib in the treatment of post-COVID lung fibrosis.