*5.2. Risk Factors*

In a prospective study of 173 patients with COVID-19, evidence of pulmonary fibrosis was observed in 90 patients (52%) at 3-month CT follow-ups [26]. Risk factors were pulmonary consolidation (odds ratio [OR] = 2.84), severe disease (OR 2.40), and a higher CT severity score (OR 1.10) at admission [26]. Of 62 patients who underwent chest CT scans again at 6 months of follow-up, in 41 patients (66.1%) the fibrosis remained unchanged, whereas in 21 patients (33.9%) a radiological improvement was documented [26]. In addition, older age, cigarette smoking, high-dose systemic corticosteroid use, and longterm mechanical ventilation were risk factors in another study [27]. The study of Han et al. showed that in older patients, high-dose systemic corticosteroid use and mechanical ventilation are risk factors as well [28]. Aging may cause a shift to a more profibrotic and irreversible senescent phenotype of fibroblasts [29].

Other risk factors were higher C-reactive protein (CRP) and lower lymphocyte counts [30–32].

### *5.3. Radiology*

The fibrotic changes include traction bronchiectasis, honeycombing, parenchymal bands, and interlobar septal thickening (IST) [26]. Nabahati et al. did not see any patients with progressive pulmonary fibrosis at the 6-month chest CT follow-up [26]. For this study cohort, a longer follow-up has not yet been published.

Two other studies demonstrated fibrotic abnormalities in the 6-month chest CT followup of 35% and 32% of patients, respectively [27,28]. Importantly, studies are difficult to compare because of different patient characteristics at diagnosis. It has been suggested that PCPF's course could be similar to other well-documented forms of postviral pulmonary fibrosis, such as those occurring after SARS, MERS, or influenza H1N1 infections [33]. Although in SARS patients, fibrosis could be demonstrated in more than 50% of patients after an average of 37 days, only 5% of patients continued to show fibrotic changes after a 15-year follow-up [33].

### *5.4. Pathophysiology*

The key site of SARS-CoV-2 infection is the angiotensin converting enzyme 2 (ACE2). To enter the human host cell, the virus uses the spike "S" protein, which results in binding to ACE2. In human cells, the ACE2 gene expression is the highest in nasal epithelial cells and decreases throughout the lower respiratory tract, including epithelial cells of the trachea, bronchi, and alveolar cells. In normal human cells, the function of ACE2 is converting angiotensin II (Ang II) into angiotensin 1–7 (Ang 1–7), in order to regulate the cardiovascular system and blood pressure. Ang II has a fibrotic effect by upregulating the level of a pro-fibrotic cytokine named transforming growth factor-1β (TGF-β), which transforms fibroblasts into myofibroblasts and promotes extensive collagen deposition [24,34]. On the contrary, Ang 1–7 has an anti-fibrotic effect. When the spike "S" protein of the SARS-CoV-2 down-regulates the level of ACE2, it increases the level of Ang II and decreases the level of Ang 1–7, resulting in promoting inflammation and pulmonary fibrosis [24].

#### **6. How Should We Treat COVID-19-Related End Stage Lung Disease?**

The cause of COVID-related end stage lung disease still remains unclear, and more studies are needed to build our understanding of why some patients develop lung fibrosis, and other patients do not. This question is important, as these patients will require longterm medical care and the number of patients is considerable. Moreover, the long-term behavior of fibrotic changes is still unknown, as most studies have a relatively short follow-up period, which is an inherent problem when dealing with a relatively new virus. Although the long-term pulmonary consequences of COVID-19-related pulmonary fibrosis remain speculative, the large number of individuals affected by COVID-19-related fibrosis could lead to a worldwide healthcare challenge of unprecedented magnitude [35]. Another unanswered question is whether other variants of SARS-CoV-2 will influence disease severity. The omicron variant of SARS-CoV-2 (PANGO lineage B.1.1.529) was reported on

24 November 2021 and has been associated with a more proximal adherence in the airways, in contrast to the delta variant, which has a more distal distribution in the airways. The omicron variant replicates significantly less efficiently than other SARS-CoV-2 variants in both nasal turbinates and lungs and induces substantially attenuated lung pathology [36].

Currently, there is no consensus on the use of antifibrotics in patients with COVID-19-related end stage lung disease. Only two drugs (pirfenidone and nintedanib) are used to treat idiopathic pulmonary fibrosis (IPF). Both drugs have been approved by both the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) and can decrease the rate of pulmonary fibrosis progression. Pamrevlumab (FG-3019), a new antifibrotic drug for intravenous use, is currently being investigated in phase 2 trials and has shown promising results in patients with IPF in the phase 2 PRAISE trial [37]. It is a monoclonal antibody against connective tissue growth factor (CTGF) in IPF. However, in COVID-19-associated pulmonary fibrosis, there are no published studies on pamrevlumab yet.

Pirfenidone is an orally administered pyridine with combined anti-inflammatory, antioxidant, and antifibrotic properties. The mechanism of action includes the inhibition of fibroblast proliferation, but details have not yet been fully determined. Nintedanib is an inhibitor of multiple receptor tyrosine kinases and was initially developed as an antiproliferative and anti-angiogenic drug for cancer treatment.

IPF is defined as a spontaneously occurring (idiopathic) specific form of chronic fibrosing interstitial pneumonia associated with a pattern of Usual Interstitial Pneumonia (UIP) on imaging or histology [38]. It has been shown that both pirfenidone and nintedanib also show efficacy in non-IPF patients with progressive fibrosis [39]. This was shown both for nintedanib (INBUILD) and for pirfenidone [40,41]. The INBUILD study showed a reduction in FVC decline of about 60% compared to placebo. For both antifibrotic drugs, pirfenidone and nintedanib, a meta-analysis showed a reduced decline in the forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis (IPF) and also non-IPF patients [39]. As suggested by Wells et al., there may be a common pathway in non-IPF disease with IPF-like disease progression [42]. Based on this hypothesis, antifibrotics might be effective in COVID-19-associated lung fibrosis in an early stage. The similar cytokine profile in both IPF and COVID-19 also suggests a common pathway [43]. Although it is currently uncertain to which extent COVID-19-associated lung fibrosis will be progressive, the early treatment seems prudent considering the autopsy study in ARDS patients, showing that a longer disease duration led to a higher risk of lung fibrosis [44]. Using a score to assess the risk of progression to severe disease may help in the timing of treatment escalation [45]. Another argument for antifibrotic treatment early in the disease course is that previous coronavirus outbreaks have been associated with substantial postviral lung fibrosis and physical impairment [46]. In one interventional study of 30 patients with COVID-19 requiring mechanical ventilation, the patients were treated with nintedanib, showing no significant differences in 28-day mortality compared to the control group without nintedanib, but it showed significantly shorter lengths of mechanical ventilation and lower percentages of high-attenuation in computed tomography volumetry [47].

The results of four ongoing trials investigating antifibrotic drugs in COVID-19-associated lung fibrosis probably will shed some light on this important and urgent question [48–51]. Interestingly, the mTOR inhibitor rapamycin, a well-known drug in transplant medicine, has been suggested to have both antiviral action and antifibrotic properties. The latter is also known for the treatment of lymphangioleiomyomatosis [46].

In severe lung fibrosis, only lung transplantation as the ultimate therapy could be an option for selected patients. The number of COVID-19-related lung transplantations is relatively small but increasing. In the United States, a query of the United Network for Organ Sharing showed that as of 30 April 2021, only 78 lung transplantations had been performed (50 for CARDS and 28 for PCPF) [14], increasing to 299 (183 for CARDS and 107 for PCPF) as of 31 January 2022 [52]. In Europe, the Eurotransplant consortium reported only 21 patients undergoing lung transplantation for COVID-19-related end stage lung disease [14]. In the scientific literature, only a limited number of case reports and case series have been published so far with limited follow-up data. The difficult question is whether patients benefit from lung transplantation in COVID-19-related end stage lung disease and how their perioperative and long-term disease course differs in comparison to lung transplant experiences with other fibrotic lung diseases. Since COVID-19 frequently affects multiple organ systems the short-term and long-term outcomes may differ. ECMO is being used increasingly for COVID-19 patients with improved outcomes [53–55]. In the case reports and case series, early outcomes have been acceptable for these marginal lung transplant recipient candidates, although Cypel et al. warned about publication bias in the context of a new disease [56]. The ideal "transplant window" is transplantation that is not too early (e.g., in patients that may recover spontaneously or due to medical therapy) and not too late (e.g., in extremely debilitated patients with muscle wasting, critical illness polyneuropathy, and myopathy, lacking good potential for recovery and rehabilitation, relevant pulmonary hypertension with right-sided heart failure, or even with multi-organ failure). Some potential for recovery has been described in patients with severe COVID-19-related ARDS [55]. Unfortunately, regarding the risk factors for COVID-19-associated fibrosis, many patients will be excluded from being transplant candidates due to comorbidities, and/or secondary complications such as renal dysfunction, muscle wasting, or multiple organ failure while in the intensive care unit (ICU) [56]. Importantly, the patients should be completely free of the coronavirus infection to prevent harboring the virus and developing a relapse of the infection later, especially during chronic triple immunosuppressive therapy after lung transplantation. Another important issue is that there is a general consensus described in the latest consensus document of the International Society of Heart and Lung Transplantation (ISHLT), that patients should be awake and able to discuss the lung transplantation and provide consent for the procedure [57,58]. The enormous impact of lung transplantation on quality of life should be fully understood. Waking up after intubation for an acute viral illness and being informed that lung transplantation has been performed, implicating a life with chronic triple immunosuppression and potential complications ahead, can lead to a severe psychotrauma, that can be too difficult to deal with [56]. The ten considerations that should be carefully evaluated when assessing a patient with COVID-19-associated lung transplantation have been published in 2020. In very experienced high-volume centers some criteria may be disregarded on a case-by-case basis. As mentioned by Lepper et al., the case series of lung transplantation for COVID-19 described by Bharat et al. showed that many patients had a complicated intraoperative and postoperative course, including mass transfusions, continued extracorporeal support, re-thoracotomy, primary graft dysfunction, and prolonged postoperative stay in the ICU [54,59]. However, in this case series, patients did not necessarily fulfill all requirements as mentioned by some other authors [54,56]. Defining the ideal recipient in this situation remains difficult, in which increased in-hospital SARS-CoV-2 transmission, and depleting healthcare resourses should also be taken into account. Those patients who have a risk of imminent death and those who are on mechanical ventilation or ECMO should have priority if there are no absolute or important relative contraindications or major risk factors.

An unanswered question is whether patients with pre-existing lung fibrosis should be vaccinated with the SARS-CoV-2 vaccination. Prevention of COVID-19 seems to be the best strategy. However, acute exacerbations of idiopathic pulmonary fibrosis after the SARS-CoV-2 vaccination have been described, and this could be underreported as many cases will not necessarily be published in the medical literature [60]. Another study described the development of pulmonary fibrosis in a previously healthy patient after the SARS-CoV-2 vaccination [61]. VigiAccess, the global pharmacovigilance database of the World Health Organization (WHO), reports 679 patients with ARDS, 346 patients with lung consolidation, 159 patients with organizing pneumonia, and 280 patients with pulmonary fibrosis, related to Comirnaty (Pfizer) COVID-19 vaccination. In relation to the Spikevax (Moderna) vaccination, ARDS was reported in 679 patients, interstitial lung disease in 678 patients, idiopathic pulmonary fibrosis in 56 patients, acute lung injury in 12 patients, and idiopathic interstitial pneumonia in 3 patients [62].
