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.