Dear Editors,
During the COVID-19 pandemic, lung transplant eligibility criteria were expanded to include patients with COVID-associated acute respiratory distress syndrome (CARDS) and post-COVID pulmonary fibrosis (PCPF). CARDS carries high mortality and often requires prolonged extracorporeal membrane oxygenation (ECMO) support and extended intensive care [1]. We previously reported the feasibility of lung transplantation in CARDS recipients, showing early survival comparable to non-CARDS recipients despite higher primary graft dysfunction (PGD) rates [2–6].
Long-term graft assessment in CARDS is essential to guide treatment and optimize resource use. Chronic lung allograft dysfunction (CLAD)—encompassing bronchiolitis obliterans syndrome (BOS), restrictive allograft syndrome (RAS), mixed, and undefined phenotypes—is the leading cause of late mortality [7]. Defined as sustained spirometric decline, CLAD affects approximately 30% of recipients within 3 years [8]. The incidence following CARDS remains unknown. This study evaluates long-term outcomes and the association between PGD and CLAD in CARDS recipients.
We conducted a single-center retrospective study of adult lung transplant recipients from January 2018 to December 2022. Patients were excluded if they died within 1Â year, underwent multiorgan or repeat transplantation, or lacked sufficient spirometry (Supplementary Figure 1). Twenty-nine recipients which died within the first year (CARDS: 6; non-CARDS: 23) were excluded.
The primary outcome was CLAD incidence. Secondary outcomes included perioperative outcomes and multivariable CLAD predictors. PGD and CLAD were assessed by a multidisciplinary transplant team according to standard definitions [8]. CARDS transplant referrals followed our prior criteria (Supplemental Methods) [2–4].
A total of 252 patients were analyzed: 36 (14%) CARDS and 216 (86%) non-CARDS. Non-CARDS indications comprised interstitial lung disease (43%), chronic obstructive pulmonary disease (21%), pulmonary Artery Hypertension (8%), and others (28%). Compared with non-CARDS, CARDS recipients were younger (52.4 vs. 59.3 years; p = 0.002), less often smokers (19% vs. 53%; p < 0.001), more frequently bridged with venovenous (VV) ECMO use (50% vs. 4%; p < 0.001), had lower hemoglobin (9.1 vs. 12.0 g/dL; p < 0.001), and more often underwent bilateral lung transplantation (94% vs. 58%; p < 0.001). Median time from disease onset to listing was 104 days [IQR: 85–170]. Three-year survival was 79.8% overall and did not differ significantly between CARDS and non-CARDS (87.0% vs. 78.6%; HR 0.65, 95% CI 0.22–1.91; p = 0.17; Supplementary Figure 2) after adjustment for bilateral versus unilateral transplantation. Donor characteristics, including age, gender, and cause of death were comparable between groups and not associated with CLAD (Table 1).
TABLE 1
| Variable | No CARDS (n = 216) | CARDS (n = 36) | P Value |
|---|---|---|---|
| Recipient factors | |||
|  Age, years | 59.3 ± 12.4 | 52.4 ± 10.8 | 0.002 |
|  Female | 88 (40.7%) | 16 (44.4%) | 0.72 |
| Body Mass Index, kg/m2 | 25.8 ± 4.5 | 26.2 ± 4.6 | 0.56 |
|  Smoking history | 116 (53.7%) | 7 (19.4%) | <0.001 |
|  Hypertension | 112 (51.9%) | 16 (44.4%) | 0.47 |
|  Diabetes | 64 (29.6%) | 12 (33.3%) | 0.70 |
|  Chronic Kidney Disease | 12 (5.6%) | 0 (0%) | 0.23 |
|  Pre-operative ECMO use | 9 (4.2%) | 18 (50.0%) | <0.001 |
|  Bilateral Transplantation | 126 (58.3%) | 34 (94.4%) | <0.001 |
|  Lung Allocation Score | 50.3 ± 15.8 | 77.9 ± 16.4 | <0.001 |
|  Follow-Up Days | 808 [538–1,327] | 1,079 [935–1,208] | 0.02 |
| Laboratory Values | |||
|  Hemoglobin, g/dL | 12.0 ± 2.4 | 9.1 ± 1.9 | <0.001 |
|  BUN, mg/dL | 16.0 ± 6.0 | 20.3 ± 12.8 | 0.001 |
|  Creatinine, mg/dL | 0.80 ± 0.22 | 0.60 ± 0.21 | <0.001 |
|  PRA | 85 (39.4%) | 18 (50.0%) | 0.27 |
|  Donor-specific antibodies | 20 (9.3%) | 9 (25.0%) | 0.007 |
| Donor | |||
|  Age, years | 32.6 ± 11.8 | 30.8 ± 12.5 | 0.41 |
|  Female | 65 (30.1%) | 14 (38.9%) | 0.33 |
| Donor cause of death | |||
| Head trauma | 84 (38.9%) | 17 (47.2%) | 0.36 |
|  Anoxia | 81 (37.5%) | 16 (44.5%) | 0.46 |
|  Other | 51 (23.6%) | 3 (8.3%) | 0.05 |
| Intra-operative outcomes | |||
|  Operative time (hours) | 5.8 (4.8–7.5) | 8.2 (7.4–9.5) | <0.001 |
|  Intra-op blood transfusion; pRBC | 0 (0–2) | 6 (2–11) | <0.001 |
|  Ischemic time (hours) | 4.9 (4.1–5.8) | 5.6 (5.1–6.0) | 0.001 |
|  VA ECMO use | 123 (56.9%) | 34 (94.4%) | <0.001 |
|  VA ECMO time (hours) | 1.7 (0–3.0) | 3.1 (2.6–3.6) | <0.001 |
| Postoperative outcomes – Univariate Analysis | |||
|  PGD | 82 (38.0%) | 21 (58.3%) | 0.03 |
|  PGD Grade 3 | 14 (6.5%) | 7 (19.4%) | 0.02 |
|  Acute rejection | 58 (38.9%) | 2 (6.1%) | <0.001 |
|  post ECMO use | 8 (3.7%) | 13 (36.1%) | <0.001 |
|  Acute Kidney Injury | 79 (36.6%) | 18 (50.0%) | 0.14 |
| PE | 7 (3.2%) | 0 (0%) | 0.60 |
|  Dialysis | 17 (7.9%) | 8 (22.2%) | 0.01 |
|  CMV infection | 15 (10.1%) | 6 (18.2%) | 0.23 |
|  ICU stay (days) | 7 (5–11) | 16 (10–22) | <0.001 |
|  Post-transplant ventilator (days) | 2 (1–3) | 4 (2–17) | <0.001 |
| Hospital stay (days) | 15 (11–27) | 23 (17–37) | <0.001 |
| Chronic Lung Allograft Dysfunction | 46 (21.3%) | 8 (22.2%) | 1.00 |
|  BOS | 36 (78.3%) | 4 (50.0%) | 0.18 |
|  RAS | 6 (13.0%) | 1 (12.5%) | 1.00 |
|  Mixed | 3 (6.5%) | 3 (37.5%) | 0.04 |
|  Undefined | 1 (2.2%) | 0 (0%) | 1.00 |
| Multivariable Analysis* | HR | P value | 95% CI |
| Recipient Factors | |||
|  Body Mass Index, kg/m2 | 1.07 | 0.03 | 1.01–1.14 |
|  Lung Allocation Score | 0.99 | 0.18 | 0.97–1.01 |
|  Hemoglobin, g/dL | 1.06 | 0.41 | 0.93–1.20 |
Characteristics and outcomes of patients and multivariate cox proportional hazards regression analysis to predict CLAD.
Continuous data are shown as means ± standard deviation (SD) for age and laboratory data, and as medians and interquartile ranges [Q1-Q3] for days. *Variables with biological plausibility and a p-value <0.10 on univariate analysis were included in multivariable analysis.
CARDS recipients had longer operative (8.2 vs. 5.8 h; p < 0.001) and ischemic times (5.6 vs. 4.9 h; p < 0.001), more intraoperative VA-ECMO (94% vs. 56%; p < 0.001), greater blood transfusion (p < 0.001), higher PGD Grade 3 (19% vs. 7%; p = 0.02), and more dialysis (22% vs. 8%; p = 0.01). They also required longer ventilation (median 4 vs. 2 days; p < 0.001), ICU stays (16 vs. 7 days; p < 0.001), and hospitalization (23 vs. 15 days; p < 0.001) (Table 1). CLAD incidence was similar: 22% in CARDS (8/36) and 21% in non-CARDS (46/216; p = 1.00). The mixed phenotype was more common in CARDS with CLAD (38% vs. 7%; p = 0.04, possibly reflecting distinct immune activation or airway injury patterns after severe viral ARDS. In multivariable models, only BMI predicted CLAD (HR 1.07, CI 1.01–1.14; p = 0.03). Donor-specific antibodies, CMV infection, acute rejection, and transplant type were not significant predictors (Supplementary Table 1).
Although the coronavirus pandemic has subsided, lung transplantation remains a salvage option for patients with COVID–related respiratory failure and is currently being studied as a treatment for ARDS [9]. In this single-center case series, we report a 22% incidence of CLAD in CARDS patients undergoing lung transplantation, with an average follow-up of 1,079 days. This rate is not significantly different from the incidence in patients transplanted for other indications within our cohort (21%, p = 1.00) or from the 30% incidence reported at 1,095 days in international data [8]. These findings highlight the potential for long-term graft sustainability in this population and provide valuable single-center evidence on the feasibility of lung transplantation for ARDS in the post-COVID era.
CARDS recipients demonstrated significantly higher rates of PGD grade 3 compared to non-CARDS recipients (58.3% vs. 38.0%, p = 0.02), a key risk factor for CLAD [10]. Interpretation of this finding is complex, as the acute manifestations of CARDS—including inflammation, endothelial dysfunction, and pulmonary edema—can require prolonged ECMO support and impact PGD diagnostic criteria. Elevated PGD rates in CARDS patients may reflect acute disease severity rather than the traditional PGD pathophysiology described in lung transplant recipients with more chronic disease. Notably, only BMI was a significant predictor of CLAD in our 252-patient cohort (HR 1.07, CI 1.01–1.14, p = 0.03). Known risk factors such as PGD grade 3 was not significant [7–10]. This may reflect the limited sample size and the time-dependent nature of CLAD.
This study has several limitations, including modest sample size and mid-term follow-up, as well as a higher incidence of bilateral lung transplants in CARDS patients, which is associated with a longer time to CLAD diagnosis by a median of 150 days. In addition, 29 patients which died within the first year were excluded from the CLAD analysis. While this approach was necessary to meet the diagnostic definition of CLAD, it introduces the possibility of selection bias. We also acknowledge that death represents a competing risk when evaluating CLAD incidence, which was not formally modeled in this study. CARDS recipients in our cohort were younger and overall healthier compared with typical lung transplant candidates, which could partly explain the comparable CLAD rates observed. Although our study focused on CARDS, these findings may have implications for other acute respiratory failure syndromes, such as influenza-related ARDS; however, further research is needed before generalizing these results to other indications. In summary, our findings suggest CARDS is not associated with increased CLAD risk, and long-term outcomes remain favorable. Multi-center studies with extended follow-up are warranted.
Statements
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.
Ethics statement
The studies involving humans were approved by Northwestern University, IRB Approval (STU00207250 and STU00213616) has been obtained for this publication. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin because Patient consent was not required.
Author contributions
Participated in research design: BT, TK, AB, CK. Participated in the writing of the paper: BT and CK. Participated in the performance of the research: BT, TK, AC, YM, TT, AA, AB, GB, CK. Participated in data analysis: TK and TT. All authors contributed to the article and approved the submitted version.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by the National Institutes of Health (NIH) grant HL176632 to CK.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontierspartnerships.org/articles/10.3389/ti.2025.14848/full#supplementary-material
References
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Summary
Keywords
lung transplant, chronic lung allograft dysfunction (CLAD), COVID-19, acute respiratory distress syndrome, primary graft dysfunction
Citation
Thomae B, Kaiho T, Chang A, Miyashita Y, Toyoda T, Arunachalam A, Bharat A, Budinger G.R.S and Kurihara C (2025) Chronic Lung Allograft Dysfunction in Patients Receiving Lung Transplantation for COVID-19 ARDS. Transpl. Int. 38:14848. doi: 10.3389/ti.2025.14848
Received
01 May 2025
Accepted
20 October 2025
Published
04 November 2025
Volume
38 - 2025
Updates
Copyright
© 2025 Thomae, Kaiho, Chang, Miyashita, Toyoda, Arunachalam, Bharat, Budinger and Kurihara.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Chitaru Kurihara, chitaru.kurihara@northwestern.edu
†These authors have contributed equally to this work and share first authorship
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