**1. Introduction**

Pulmonary transplant physicians are confronted with a new type of lung transplant referral, linked to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in which the clinical condition is named Coronavirus Disease 2019 (COVID-19), and the respiratory tract is the primary site of infection and of subsequent complications.

A small number of COVID-19 survivors suffer from COVID-19-related pulmonary fibrosis as a long-term consequence. Although COVID-19-related pulmonary fibrosis is a relatively rare disease, even a small percentage of the COVID-19 survivors affected by this condition can pose a significant healthcare problem due to the very large number of COVID-19 patients worldwide. Patients with COVID-19-related pulmonary fibrosis typically suffer from significant physical impairments and are at higher risk of death after COVID-19 when compared to patients without interstitial lung disease [1]. The burden of disease of COVID-19-related end stage lung disease, therefore, may be larger than previously assumed.

It is difficult to predict which patients will develop COVID-19-related pulmonary fibrosis, but known risk factors include male sex, a lung function with a forced vital capacity (FVC) of <80% predicted, and obesity [1]. So far two different phenotypes of COVID-19-related pulmonary fibrosis have emerged, both showing different clinical behaviors, risk factors, radiologic characteristics, and prognoses [2]. The COVID-19-related acute respiratory distress syndrome (CARDS) is a well-known condition leading to end stage lung disease. The other condition has been termed post-COVID-19 pulmonary fibrosis (PCPF). Both conditions appear to have different pathophysiological pathways, which could potentially be influenced by new treatments.

**Citation:** Hage, R.; Schuurmans, M.M. COVID-19-Associated Lung Fibrosis: Two Pathways and Two Phenotypes, Lung Transplantation, and Antifibrotics. *Transplantology* **2022**, *3*, 230–240. https://doi.org/ 10.3390/transplantology3030024

Academic Editor: Norihisa Shigemura

Received: 19 May 2022 Accepted: 1 July 2022 Published: 6 July 2022

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In this article, we summarize the features of the two different phenotypes of COVID-19-related pulmonary fibrosis based on the relatively few number of studies available in the medical literature. A narrative literature search was performed from 26 September 2021 to 19 May 2022, using the following databases: MEDLINE, EMBASE, Cochrane Library, and Google Scholar. Keywords included "fibrosis", "post-COVID", "ARDS", and "lung transplantation". The search was filtered for adults older than 18 years. The reference list of identified articles was searched for additional relevant studies. Possible treatment options, including lung transplantation, are discussed as well.

## **2. What Is the Risk of Pulmonary Fibrosis in COVID-19?**

Many patients who have survived COVID-19 report dyspnea as a persistent symptom after recovery. Dyspnea has been reported in over 40% of patients after recovery from COVID-19 [3]. In many of these patients, dyspnea can be attributed to extrapulmonary effects, including cardiovascular, neurological, and muscular dysfunction. Dyspnea can also be related to persistent pulmonary lesions after COVID-19 and can lead to substantial disability, even after initial recovery from COVID-19. Sometimes dyspnea and pulmonary alterations after COVID-19-related lung disease are associated with a dependency on supplemental oxygen. Persistent pulmonary lesions, including ground-glass opacities, consolidations, and reticulations, have been described in twenty percent of patients at 6 months after hospitalization for COVID-19 pneumonia [4]. One study showed that risk factors in patients who had not recovered after COVID-19 pneumonia, were older age, male sex, a longer in-hospital stay, and a lower PaO2/FiO2 ratio at admission [4]. These patients also showed more severe chest computed tomography (CT) scan abnormalities at hospital admission [4]. In the other two highly pathogenic coronaviral diseases, severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS), persistent pulmonary lesions have been reported as well. In SARS, one study completed a 15-year follow-up, showing pulmonary lesions on chest CT scans initially in 9.4% of patients, which diminished to 3.2% after one year and remained stable thereafter [5]. Studies in MERS patients showed comparable data [6].
