**1. Introduction**

Community-acquired respiratory virus (CARV) infections pose a significant challenge among lung transplant recipients (LTRs). The rate of infection among LTRs is much higher than in other solid organ recipients due to the direct exposure of the lung to the potentially hostile external environment. Other risk factors contributing to the infection risk are severe immunosuppression, the blunted cough reflex due to lung denervation, poor lymphatic drainage, and impaired mucociliary clearance as a result of ischemic injury to the bronchial mucosa and narrowing of the bronchial anastomosis [1]. Compared to bacterial respiratory infections, viral infections initially lead to less severe symptoms, but then lead to a greater worsening of the lung function [2]. In LTRs, CARV can lead to both acute and chronic allograft dysfunction [3–8].

The mechanisms behind allograft dysfunction are only partly understood, hampering the establishment of adequate treatment. It has been suggested that symptomatic respiratory viral infections after lung transplantation elicit immune responses to lung self-antigens by inducing circulating exosomes that contain lung-associated self-antigens [9]. CARV infections may activate alloimmune responses, leading to post-CARV chronic lung allograft dysfunction (CLAD) [7].

**Citation:** Hage, R.; Schuurmans, M.M. COVID-Related Chronic Allograft Dysfunction in Lung Transplant Recipients: Long-Term Follow-up Results from Infections Occurring in the Pre-vaccination Era. *Transplantology* **2022**, *3*, 275–282. https://doi.org/10.3390/ transplantology3040028

Academic Editors: Norihisa Shigemura and Maurizio Salvadori

Received: 2 June 2022 Accepted: 19 September 2022 Published: 23 September 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Since the first successful human lung transplantation in 1983 [10], the overall 5-year survival rates in lung transplantation are still only approximately 50–70%, which is considerably worse compared to other solid organ transplantations, even after significant improvements in donor selection, organ preservation, perioperative management, and better treatment of post-operative complications [11].

CLAD is the leading cause of death beyond the first year after lung transplantation. Currently, there is no medical treatment that can cure CLAD. Several treatments have been introduced in an attempt to slow the progression of CLAD such as azithromycin, pravastatin, montelukast, extracorporeal photopheresis, and total lymphoid irradiation [12–16].

Symptomatic respiratory viral infections were shown to be independently associated with CLAD [7]. In LTRs, CLAD is a progressive and in most patients irreversible process, and a major cause of long-term allograft failure and death. CLAD has two different main phenotypes called bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). About 70% of LTRs with CLAD have the BOS phenotype.

In CLAD-BOS, there is a persistent decline in the forced expiratory volume in 1 s (FEV1) associated with an obstructive ventilatory defect; whereas in CLAD-RAS, there is a restrictive defect with an increased FEV1/forced vital capacity (FVC) ratio or a decrease in FVC or total lung capacity (TLC). It was observed in a prior study that CLAD-RAS could develop after COVID-19 [17]. Mahan et al. showed a significant loss of lung function in 18 LTRs (40.9%), of which 3 patients (5.6%) developed CLAD-RAS. Prior studies have shown a strong association between respiratory viral infections and the development of CLAD in which symptomatic viral infections demonstrated a stronger relationship with CLAD [17–20].

Data on long-term effects of CARV due to infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in LTRs are scarce. Infection by SARS-CoV-2 can be highly variable in disease severity, ranging from mild upper respiratory distress to fulminant viral pneumonitis with multi-organ failure and death. In this study, we evaluated the impact of SARS-CoV-2 infection in LTRs during the first year after the infection.

#### **2. Methods**

This was a single-center, retrospective-chart-review study. The study population consisted of consecutive adult LTRs ≥ 18 years of age with COVID-19 at the University Hospital Zurich, Switzerland, in which formal informed consent was given. The infection with SARS-CoV-2 was demonstrated using real-time reverse transcriptase polymerase chain reaction (RT-PCR).

Patients with COVID-19 were classified as "mild" when clinical symptoms consisted of mild constitutional symptoms, fever, or a dry cough. Patients were classified as "moderate" COVID-19 when the clinical symptoms including dyspnea with or without hypoxia and where chest imaging was abnormal (infiltrates and/or ground-glass opacities). The baseline characteristics of these patients were published previously [21]. Full recovery was defined as two negative SARS-CoV-2 RT-PCR tests at least 24 h apart along with the resolution of symptoms. Patients with acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), or cardiac failure were classified as "severe" COVID-19.

All spirometric testing was conducted in the lung transplant clinic using a Geratherm respiratory spirometer (Geratherm Medical AG). The spirometry analysis was performed according to the Standardization of Spirometry by the American Thoracic Society (ATS) and the European Respiratory Society (ERS) [22]. CLAD-BOS and CLAD-RAS were defined according to the classification by Verleden [12]. CLAD-BOS stage 0 was defined as FEV1 > 90% of baseline, BOS stage 1 as FEV1 decline of 66–80% of baseline, BOS stage 2 as FEV1 decline of 51–65%, and BOS stage 3 as an FEV1 decline ≤ 50% of baseline. CLAD-RAS was defined as a total lung capacity (TLC) decline > 10% or an FEV1/FVC > 0.70.

Using the pre-infection baseline FEV1 (FEV1pre) and post-infection FEV1 (FEV1post), we calculated the change in lung function as follows: (FEV1pre − FEV1post)/FEV1pre.

#### **3. Statistical Analysis**

Descriptive statistics were performed; the main data are summarized in Tables 1–4. The results are reported as the mean with the range and categorical variables were calculated as counts (*n*) and percentages (%).


**Table 1.** Non-vaccinated lung transplant recipients with mild and moderate COVID.

Abbreviations: m = male; f = female; FEV1 pre = forced expiratory volume in 1 s pre-COVID; FEV1 1m, 3m, 6m, 12m = forced expiratory volume in 1 s after 1, 3, 6, and 12 months, respectively; %FEV1 Δ 1m, 12m = (FEV1pre − FEV1post)/FEV1pre 1 month or 12 months after recovery from COVID, respectively; FVC = forced vital capacity; %FVC1 Δ 12m = (FVCpre − FVCpost)/FVCpre 12 months after recovery from COVID; NA = not applicable.


Abbreviations: Pat = patient number; m = male; f = female; FEV1 pre = forced expiratory volume in 1 s pre-COVID; FEV1 1m, 3m, 6m, 12m = forced expiratory volume in 1 s after 1, 3, 6, and 12 months, respectively; %FEV1 Δ 1m, 12m = (FEV1pre − FEV1post)/FEV1pre 1 month or 12 months after recovery from COVID, respectively; FVC = forced vital capacity; %FVC1 Δ 12m = (FVCpre − FVCpost)/FVCpre 12 months after recovery from COVID; NA = not applicable.


**Table 3.** Pre-COVID chronic lung allograft dysfunction (CLAD) and donor-specific antibody (DSA) monitoring (mild COVID).

**Table 4.** Pre-COVID chronic lung allograft dysfunction (CLAD) and donor-specific antibody (DSA) monitoring (moderate COVID).

