The coronavirus disease-19 (COVID-19), an infection caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), continues to affect the health system globally. It not only causes health effects in the acute phase, but it also has long-term manifestations.^[1] Although most of the people infected by SARS-CoV-2 have common cold-like symptoms and usually recover well, significant clinical involvement of other organ systems also occurs in a few. Severe COVID-19 infection usually affects the lungs and can progress to develop full-fledged acute respiratory distress syndrome (ARDS). Such individuals require hospitalization or intensive care unit (ICU) admission with or without mechanical ventilation and even mortality. If postacute symptoms persist in such individuals for more than 12 weeks, it is defined as post-COVID-19 syndrome.^[2] Respiratory manifestations top the list among COVID patients that need attention during follow-up predominantly in patients who had pulmonary involvement in the acute phase of the disease.^[3]

Various mechanisms have been described for the cause of lung injury in COVID-19. It includes both viral and immune-mediated mechanisms.^[4] The pathogenesis of pulmonary fibrosis can be attributed to either chronic ongoing inflammation or an idiopathic, genetically influenced by the age-related fibroproliferative process. Pulmonary fibrosis is the sequel of ARDS which happened during the acute phase of COVID-19 infection. However, the exact definition, prevalence pathophysiology, and treatment of pulmonary fibrosis secondary to COVID-19 are new entities and not fully understood.^[5]

In a systematic review of five studies on the incidence of pulmonary fibrosis after COVID-19, it was found to be 7%.^[2] There are multiple published case reports, case series, and studies that describe pulmonary fibrosis after COVID-19 and its potential treatment. Predominant patterns of pulmonary abnormalities, such as ground-glass opacities and consolidations, may improve approximately 6 months after the acute phase.^[4,6,7] Incidence of pulmonary fibrosis was found to be 35% and 32% in previous studies conducted by Han et al.,^[8] and Ali and Ghonimy,^[9] respectively. Furthermore, the study by Ali and Ghonimy^[9] also showed that patients with consolidation and higher computed tomography severity score had a high risk of post-COVID-19 pulmonary fibrosis compared with those without. The other risks for increased risk of lung fibrosis were related to the patient, such as older age, obesity, diabetes, cigarette smoking, the severity of infection, high levels of C-reactive protein, D-dimer and interleukin-6, and long-term mechanical ventilation.^[10–12]

In addition, the hyperstimulation of the immune system associated with systemic inflammation secondary to COVID-19 can trigger autoimmune responses, with the production of cytokines and autoantibodies, which may contribute to the development and progression of pulmonary parenchymal lesions.^[13,14] Genetic predisposition, such as the identification of shortening of leukocyte telomeres, is also speculated as a potential risk factor for the occurrence of definitive pulmonary fibrosis after COVID-19.^[13,14] Patients with chronic interstitial lung diseases are at increased risk of progression of lung parenchymal lesions after the acute phase of COVID-19.^[12] Out of all cases of COVID-19, 40% develop ARDS, and 20% of those are severe ARDS.^[14] More than one-third of such cases after hospital discharge develop fibrotic abnormality. It was highlighted in previous studies that the duration of the disease is an important determinant for lung fibrosis post-ARDS. This study showed that, 4% of patients with a disease duration of <1 week, 24% of patients with a disease duration of between weeks 1 and 3, and 61% of patients with a disease duration of >3 weeks, developed fibrosis.^[14]

The presence of diffuse alveolar damage in different stages, microthrombosis, organizing pneumonia, and pulmonary fibrosis were the main findings in autopsies and explanted lungs from patients with COVID-19.^[10] Bronchiolocentric interstitial pneumonia, with architectural distortion and extracellular matrix deposition, was the main finding in a series of patients that underwent transbronchial biopsy 4–15 months after the acute phase in a study by Baldi and Tanni.^[12] Three different histopathological clusters comprising chronic fibrosing pneumonia, the usual interstitial pneumonia, smoking-related fibrosis, an acute/subacute injury, with organizing pneumonia, nonspecific interstitial pneumonia, and diffuse alveolar damage, and a pattern with vascular modifications pattern were found in 10 patients who underwent transbronchial lung cryo biopsy on average 3.5 months after recovery from COVID-19.^[15] Further studies with a greater number of patients are necessary to determine the most common histopathological patterns in post-COVID-19 pulmonary fibrosis.

As per many studies, the most common lung function abnormality seen in survivors with COVID-19 is impairment of diffusion capacity, followed by restrictive ventilatory defects, both associated with the severity of the disease.^[16,17] Impaired diffusion capacity is caused by both: reduction in alveolar volume and carbon monoxide transfer coefficient (KCO).^[18] Residual pulmonary function abnormalities were observed in 25% of patients at 3 months after discharge, which was lower than the abnormal pulmonary function in COVID-19 patients when discharged.^[10] In one study, it was found that 14 out of 55 patients had lung function abnormalities and the measurement of D-dimer levels at admission may help in the prediction of impaired diffusion defect.^[19]

At present, there are no proven options available for the treatment of post-COVID-19 pulmonary fibrosis. Various treatment strategies are under evaluation. Prolonged use of anti-viral, anti-inflammatory, and anti-fibrotic drugs has been proposed to diminish the probability of the development of lung fibrosis. However, the role of early and prolonged anti-viral agents in preventing the remodeling of the lung is yet to be ascertained. Prolonged use of low-dose corticosteroids may be tried to prevent the remodeling of the lung in survivors after considering the risk–benefit ratio.^[20] Pirfenidone and nintedanib are anti-fibrotic drugs with anti-inflammatory effects as well and may be used even in the acute phase of COVID-19 pneumonia.^[21] Pirfenidone exerts anti-fibrotic, antioxidative, and anti-inflammatory effects. Hepatotoxicity is a known side effect of both antifibrotics (pirfenidone and nintedanib), and hepatic dysfunction in the form of raised transaminases is also common in many COVID-19 patients.^[22] Hence, the use of ant fibrotic in the early phase of COVID-19 is a matter of concern. In addition, most of the COVID-19 patients are on anticoagulants and nintedanib is associated with increased risk of bleeding risk too.^[23] Considering all these factors, there is a need for biomarkers that can identify patients who are likely to progress to pulmonary fibrosis in the early phase itself. In the era of precision medicine, the use of antifibrotic therapy should be rationalized on a case-to-case basis as per patient characteristics. Pulmonary rehabilitation is very beneficial not only in the acute phase of the disease but also for early recovery. It helps in improving respiratory function and exercise endurance, which helps patients in daily living activities.^[24] For patients with irreversible disease and those who are undergoing extracorporeal membrane oxygenation for longer periods, lung transplantation may be a valid alternative. However, the main indications and contraindications for lung transplants remain a matter of discussion.^[25]

The COVID-19 pandemic has affected huge numbers of individuals worldwide, so even rare complications such as post-COVID pulmonary fibrosis will have major health effects at the population level. Patients with comorbidities and elderly patients who require ICU care and mechanical ventilation are at the highest risk of developing lung fibrosis. No fully proven options are available for the treatment of postinflammatory COVID-19 pulmonary fibrosis at present. A multidisciplinary approach in the form of regular clinical, functional, and radiological follow-up and organizing support health services will be the best practice for such cases.

We, pulmonologists, see patients who attribute their respiratory and nonrespiratory complaints to past COVID-19 infection daily. The worst affected are those who have developed post-COVID pulmonary fibrosis. In this issue of “Pulmon” we have an article addressing the same problem. The article is the need of the hour so that we pay adequate attention to this rare even when COVID-19 has been declared as “no more a health threat” by the WHO.^[26]