
==== Front
Transplant Direct
Transplant Direct
TXD
Transplantation Direct
2373-8731
Lippincott Williams & Wilkins Hagerstown, MD

39220217
TXD-2024-0082
00013
10.1097/TXD.0000000000001676
3
Lung Transplantation
A Single-center Experience With >200 Lung Transplant Recipients With COVID-19 Infection
https://orcid.org/0000-0003-1411-1062
Kehara Hiromu MD, PhD hiromu.kehara@tuhs.temple.edu
1
Johnson-Whiting Ashley NP-C Ashley.JohnsonWhiting@tuhs.temple.edu
1
Yanagida Roh MD, PhD Roh.Yanagida@tuhs.temple.edu
1
Krishan Kewal MD Kewal.Krishan@tuhs.temple.edu
1
Zhao Huaqing PhD zhao@temple.edu
2
Mishkin Aaron MD Aaron.Mishkin@tuhs.temple.edu
3
Cordova Francis MD Francis.Cordova@tuhs.temple.edu
4
Criner Gerard J. MD Gerard.Criner@tuhs.temple.edu
4
Toyoda Yoshiya MD, PhD Yoshiya.Toyoda@tuhs.temple.edu
1
https://orcid.org/0000-0003-3747-5088
Shigemura Norihisa MD, PhD 14
1 Division of Cardiovascular Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA.
2 Department of Biomedical Education and Data Science, Center for Biostatistics and Epidemiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA.
3 Section of Infectious Diseases, Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA.
4 Department of Thoracic Medicine and Surgery, Temple University Hospital, Philadelphia, PA.
Correspondence: Norihisa Shigemura, MD, PhD, Division of Cardiovascular Surgery, Lewis Katz School of Medicine at Temple University, 3401 N Broad St, Zone C, 3rd Floor, Suite 301, Philadelphia, PA 19140; Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, 200 Lothrop St, C-920, Pittsburgh, PA 15213. (shigemuran3@upmc.edu).
29 8 2024
9 2024
10 9 e167619 3 2024
22 4 2024
15 5 2024
Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Background.

Although COVID-19 is no longer a declared global health emergency, data remain limited on the impact of COVID-19 in lung transplant recipients.

Methods.

We identified lung transplant recipients who were diagnosed with COVID-19 from March 2020 through August 2022 in our institutional database and investigated clinical outcomes. We then analyzed outcomes based on date of COVID-19 diagnosis (first wave March 2020–October 2020; second wave November 2020–2021; third wave December 2021–September 2022) and compared these results.

Results.

Of the 210 lung transplant recipients (median age 67; 67% men) enrolled, 140 (67%) required hospital admission. Among admitted recipients, 35 (25%) were intubated and 7 (5%) were placed on extracorporeal membrane oxygenation. Overall survival was 67.1% at 1 y and 59.0% at 2 y post-COVID-19 diagnosis. COVID-19 led to mortality in all 5 patients diagnosed during their index admission for lung transplantation. Although overall survival was significantly better in recipients with COVID-19 during the third wave, in-hospital mortality remained high (first wave 28%, second wave 38%, and 28% third wave). Vaccination (partially vaccinated versus none and fully vaccinated versus none) was the only significant protective factor for hospital admission, and age 70 y and older and partially vaccinated (versus none or fully vaccinated) were independent risk factors for in-hospital mortality.

Conclusions.

Overall survival after COVID-19 infection in lung transplant recipients continues to improve; however, in-hospital mortality remains remarkably high. Vaccination appears to have been impactful in preventing hospital admission, but its impact on in-hospital mortality is still unclear. Further research is needed to better identify lung transplant recipients at high risk for mortality from COVID-19.

OPEN-ACCESSTRUE
SDCT
==== Body
pmcAlthough case numbers and death rates associated with the SARS-CoV-2/COVID-19 pandemic are declining and the end of COVID-19 as a global health emergency has been declared, the assessment of its impact in many fields of medicine remains to be completed. Analysis is particularly important in the field of lung transplantation because a new COVID-19 variant or another virus affecting the respiratory system could precipitate another pandemic.

COVID-19 had a huge impact on the organ transplant community. The number of organ transplants performed has significantly decreased all over the world since early 2020.1 Moreover, COVID-19 can be life-threatening to organ transplant recipients because of their coexisting medical comorbidities and need for immunosuppression. Although treatment options, including vaccines and antiviral therapeutics, continue to evolve, the virus itself has also been changing (eg, the emergence of the Delta and Omicron variants), resulting in a waning effect from vaccines.2 Outcomes after COVID-19 infection in organ transplant recipients have been increasingly reported (Table S1, SDC, http://links.lww.com/TXD/A676),3-10 but data specific to lung transplant recipients remain sparse.11,12

Our high-volume lung transplant center is located in a geographical area with a persistently high COVID-19 infection rate. We have been trying to continue lung transplantation with extremely cautious steps, including dual COVID-19 screening through reverse transcription polymerase chain reaction testing and high-resolution CT chest imaging because lung transplantation is a life-saving procedure.13 We also have cared for many patients infected with COVID-19 after lung transplantation as well as patients who developed acute respiratory distress syndrome and progressive post-COVID-19 pulmonary fibrosis as a result of COVID-19, some of whom then required a lung transplant. Our multidisciplinary team approach to COVID-19 has included screening, diagnosis, and management of patients and has been consistently used during the course of the pandemic.13-17 In this study, we analyzed outcomes after COVID-19 infection in lung transplant recipients using our large institutional data set and compared the outcomes during 3 time periods characterized by different circulating virus variants to evaluate our institutional approach to these enduring challenges.

MATERIALS AND METHODS

Study Design

Of the 1040 patients who received a lung transplant at Temple University Hospital (TUH) from 2012 through September 2022, lung transplant recipients who were diagnosed with COVID-19 between March 26, 2020, and September 6, 2022, were identified for inclusion in this study. Additionally, 342 patients who received a lung transplant at TUH from January 1, 2020, to September 6, 2022, were identified to compare the survival of lung transplant recipients diagnosed with COVID-19 with recipients without a COVID-19 diagnosis.

We reviewed medical charts to identify patient characteristics, treatments for COVID-19, and early outcomes. Survival after COVID-19 infection was determined from clinical records. The last follow-up date was September 14, 2022. We investigated the prevalence and clinical outcomes of the entire cohort and then divided the cohort into 3 groups depending on the date of COVID-19 diagnosis based on well-characterized waves of the COVID-19 pandemic (first wave: March 26, 2020, to October 31, 2020, second wave: November 1, 2020, to November 30, 2021, and third wave: December 1, 2021, to September 6, 2022). Patients were considered COVID-19-positive based on polymerase chain reaction testing or on the consensus opinion of the multidisciplinary team that included surgeons, pulmonologists, and infectious disease specialists after considering chest computed tomography (CT) findings and clinical presentation. The CT findings were also compared between single lung transplant (SLT) and double lung transplant (DLT) recipients.

This study was approved by the Temple University Institutional Review Board (protocol No. 30385). The requirement for the patient’s informed consent was waived because of the minimal risk posed by the study.

Vaccination

Patients were classified as “partially vaccinated” after the second dose of the BNT162b2 (Pfizer) or mRNA-1273 (Moderna) vaccines or after 1 dose of the JNJ-78436735 (Johnson & Johnson) vaccine. They were classified as “fully vaccinated” if they received any subsequent doses of any COVID-19 vaccine.

Vaccination was strongly advised to lung transplant recipients after it became available. Vaccination also became mandatory for the patients to be listed as lung transplant candidates in April 2021.

COVID-19 Treatment

The criteria for hospital admission have been described in detail elsewhere.5 The patients requiring hospital admission received COVID-19 treatment at an outside institution or TUH. Regarding immunosuppressive medications during treatment for COVID-19, calcineurin inhibitors were continued, mycophenolate was held, and steroids were augmented on the basis of the patient’s clinical status. When possible, efforts were made to enroll patients in clinical trials for COVID-19 treatments, including remdesivir and convalescent plasma. Each patient’s treatment was determined by the multidisciplinary team. Tixagevimab and cilgavimab were used routinely beginning in late 2021.

Statistical Analysis

Continuous variables are shown as median with interquartile range. Categorical variables are shown as absolute numbers with percentages. The Mann-Whitney U test was used for comparison of continuous variables, and Pearson’s χ2 test or Fisher exact test was used for comparison of categorical variables between the 3 groups. Overall survival and conditional survival were estimated using the Kaplan-Meier method and compared using the log-rank test. Survival probability with 95% confidence intervals is shown. Risk factors for hospital admission and hospital mortality were assessed using univariate and multivariable logistic regression models. Variables with a P value of <0.10 in univariate analysis were incorporated into the multivariable logistic regression models. A P value of <0.05 was considered significant. All statistical analyses were conducted with JMP Pro 15 software (SAS Institute, Cary, NC).

RESULTS

Study Population

In total, 210 lung transplant recipients with a COVID-19 diagnosis were assessed in this study. Patient demographics are shown in Table 1. Their median age was 67 y, and 79 (38%) were older than 70 y (Table 1). SLT was performed in 147 of the patients (70%), and DLT was performed in 63 (30%). The median time from lung transplant to COVID-19 diagnosis was 2.1 y. Five patients were diagnosed with COVID-19 during their index admission for lung transplantation.

TABLE 1. Patient demographics

Variable	Total (N = 210)	First (N = 35)	Second (N = 69)	Third (N = 106)	P	
Age, y	67 (61–73)	65 (59–72)	67 (63–73)	67 (61–73)	0.293	
 ≥70	79 (38%)	12 (34%)	26 (38%)	41 (39%)	0.897	
Male	141 (67%)	27 (77%)	44 (64%)	70 (66%)	0.368	
Race					0.312	
 White	153 (73%)	27 (77%)	50 (72%)	76 (72%)		
 Black	34 (16%)	5 (14%)	14 (20%)	15 (14%)		
 Asian	10 (5%)	3 (9%)	1 (1%)	6 (6%)		
 Other	13 (6%)	0 (0%)	4 (6%)	9 (8%)		
Transplant indication					0.120	
 Pulmonary fibrosis	122 (58%)	15 (43%)	45 (65%)	62 (58%)		
 Chronic obstructive pulmonary disease	66 (31%)	17 (49%)	19 (28%)	30 (28%)		
 Chronic lung allograft dysfunction	7 (3%)	1 (3%)	0 (0%)	6 (6%)		
 Other	15 (7%)	2 (6%)	5 (7%)	8 (8%)		
Transplant type					0.053	
 Single lung transplantation	147 (70.0%)	20 (57%)	54 (78%)	73 (69%)		
 Double lung transplantation	63 (30.0%)	15 (43%)	15 (22%)	33 (31%)		
Body mass index,a kg/m2	28.0 (24.0–31.0)	23.5 (20.8–28.5)	29.0 (25.5–32.0)	28.0 (24.8–32.3)	0.005	
Coronary artery disease	23 (11%)	3 (9%)	10 (14%)	10 (9%)	0.512	
Baseline creatinine,a mg/dL	1.62 (1.36–2.19)	1.43 (0.86–2.00)	1.74 (1.49–2.36)	1.60 (1.35–2.27)	0.022	
Hemoglobin A1c,a %	6.0 (5.6–6.8)	5.9 (5.3–6.2)	6.2 (5.6–6.8)	6.0 (5.7–6.8)	0.185	
Baseline O2 requirementa	9 (6%)	3 (9%)	2 (4%)	4 (8%)	0.507	
Baseline forced expiratory volume in 1 s,a L	1.79 (1.24–2.35)	1.88 (1.24–2.68)	1.89 (1.33–2.32)	1.56 (1.08–2.34)	0.284	
Years since transplant	2.1 (0.9–3.6)	0.5 (0.1–1.9)	2.2 (1.0–3.6)	2.4 (1.0–4.0)	<0.001	
 Index admission	5 (2%)	4 (11%)	0 (0%)	1 (1%)	<0.001	
 Within 1 y	54 (26%)	18 (51%)	13 (19%)	23 (22%)	<0.001	
Vaccination status					<0.001	
 None	89 (42%)	35 (100%)	41 (59%)	9 (8%)		
 Partially vaccinated	58 (28%)	0 (0%)	20 (29%)	40 (38%)		
 Fully vaccinated	63 (30%)	0 (0%)	8 (12%)	57 (54%)		
Recurrent COVID infection	24 (11%)	5 (14%)	7 (10%)	12 (11%)	0.821	
Readmission prior 1–3 moa	24 (17%)	6 (19%)	9 (16%)	9 (17%)	0.949	
6-mo survival	71.2%	68.5%	62.3%	78.9%		
Continuous variables are shown as median (interquartile range). Categorical variables are shown as absolute numbers (percentages).

aOnly admission patients (n = 140).

When the lung transplant recipients were divided into 3 groups based on the date of COVID diagnosis: 35 contracted COVID during the first wave of the pandemic (16.7%), 69 had COVID illness during the second wave (32.9%), and half (n = 106; 50.5%) had COVID during the third wave of the pandemic (Figure 1). The patients in the first wave were diagnosed with COVID-19 significantly sooner after lung transplant than patients diagnosed with COVID-19 during the second and third waves (0.5 versus 2.2 versus 2.4 y, P < 0.001), including 18 patients (51%) who were diagnosed with COVID-19 within 1 y after lung transplant.

FIGURE 1. Number of monthly COVID-19 infections in LTRs divided into 3 waves. LT, lung transplantation; LTR, lung transplant recipient.

At the time of their COVID-19 diagnosis, 89 patients (42%) were unvaccinated and 121 patients (58%) were vaccinated, including 63 patients (30%) fully vaccinated (Table 1). More patients were vaccinated over time; nonetheless, there were still 9 patients (8%) diagnosed with during the third wave who were not vaccinated at the time of their COVID-19 diagnosis.

Hospital Treatment and Early Outcomes

Two-thirds of the lung transplant recipients with COVID-19 illness (n = 140; 67%) required hospital admission, including 46 (33%) who required an intensive care unit (ICU) stay. Among patients admitted to the ICU, 35 (25%) were intubated, 7 (5%) required hemodialysis, and 7 (5%) were placed on venovenous extracorporeal membrane oxygenation. Characteristics of hospitalized patients are summarized in Table 2. Of the 140 lung transplant recipients admitted for COVID-19 infection, 44 died while hospitalized (mortality rate of 31%). The cause of death was attributed to COVID-19 in 35 patients and manifested as acute respiratory failure (n = 8), multiorgan failure (n = 10), or a superimposed infection (n = 17; Table S2, SDC, http://links.lww.com/TXD/A676). All 5 patients diagnosed with COVID-19 during their index admission for lung transplant died during this admission.

TABLE 2. Characteristics of hospitalized patients

Variable	Total (N = 140)	First (N = 32)	Second (N = 56)	Third (N = 52)	Recent (N = 24)a	P	
Baseline characteristics							
 Race						0.332	
  White	96 (68%)	24 (75%)	40 (72%)	32 (61%)			
  Black	28 (20%)	5 (16%)	12 (21%)	11 (21%)			
  Asian	8 (6%)	3 (9%)	1 (2%)	4 (8%)			
  Other	8 (6%)	0 (0%)	3 (5%)	5 (10%)			
Clinical presentation							
 Duration of symptoms before admission, d	2 (1–5)	2 (1–3)	2 (0.5–5)	2.5 (0–5.3)		0.771	
 4C score at the time of admission	11 (9–14)	11 (8–13)	12 (10–14)	13 (9–15)		0.077	
 SOFA score at the time of  admission	3 (2–4)	3 (2–4)	3 (2–4)	4 (2–5)		0.211	
 C-reactive protein, peak, mg/dL	10.2 (4.9–16.2)	11.4 (8.7–15.6)	10.4 (3.2–18.8)	8.7 (3.3–14.1)		0.258	
 Ferritin, peak, ng/mL	494 (230–1274)	696 (206–3812)	563 (286–1162)	403 (211–826)		0.501	
 D-dimer, peak, g/mL	1994 (978–6406)	4421 (1043–6431)	3120 (1125–7410)	1260 (903–4896)		0.163	
Treatment							
 Medication							
  Steroid	84 (60%)	17 (53%)	38 (68%)	29 (56%)		0.293	
   Pulse dose	16 (11%)	13 (41%)	3 (5%)	0 (0%)		<0.001	
  Remdesivir	87 (62%)	10 (31%)	42 (75%)	35 (67%)		<0.001	
  Anakinra	16 (11%)	3 (9%)	5 (9%)	8 (15%)		0.527	
  Baricitinib	17 (12%)	0 (0%)	12 (21%)	5 (10%)		0.010	
  Tocilizumab	36 (26%)	5 (16%)	16 (29%)	15 (29%)		0.331	
  Intravenous immunoglobulin	25 (18%)	9 (28%)	8 (14%)	8 (15%)		0.223	
  Convalescent plasma	9 (6%)	3 (9%)	6 (11%)	0 (0%)		0.057	
 Intensive care unit treatment	46 (33%)	11 (34%)	24 (43%)	11 (21%)		0.052	
 Highest oxygen requirement						0.093	
  Mechanical ventilation	35 (25%)	9 (28%)	17 (30%)	9 (17%)			
  High flow nasal cannula	11 (8%)	6 (19%)	1 (2%)	4 (8%)			
  Noninvasive ventilation	4 (3%)	0 (0%)	3 (5%)	1 (2%)			
  Non-rebreather	1 (0.7%)	0 (0%)	1 (2%)	0 (0%)			
  Nasal cannula	40 (29%)	10 (31%)	15 (27%)	15 (29%)			
  Room air	47 (34%)	7 (22%)	19 (34%)	21 (40%)			
  Unknown	2 (1%)	0 (0%)	0 (0%)	2 (4%)			
 Hemodialysis	7 (5%)	3 (9%)	1 (2%)	3 (6%)		0.276	
 Extracorporeal membrane oxygenation	7 (5%)	4 (13%)	2 (4%)	1 (2%)		0.079	
Outcomes							
 Hospital mortality	44 (31%)	9 (28%)	21 (38%)	14 (28%)	0 (0%)	0.461	
 Length of hospital stay, d	7 (5–14)	12 (6–23)	8 (4–13)	7 (5–9)	4 (3–16)	0.022	
 O2 requirement on discharge	25 (18%)	11 (34%)	5 (9%)	9 (17%)		0.011	
Continuous variables are shown as median (interquartile range). Categorical variables are shown as absolute numbers (percentages).

aBetween September 7, 2022, and September 1, 2023, at least 24 patients were confirmed as COVID-19 positive. These data are not included in statistical analysis.

4C score, coronavirus clinical characterization consortium score; SOFA, sequential organ failure assessment.

The need for hospitalization among lung transplant recipients with COVID-19 decreased as the pandemic progressed; 32 (91%) required hospitalization during the first wave, 56 (81%) during the second wave, and 52 (49%) during the third wave (P < 0.001). Whereas pulse-dose steroids were used more frequently for treatment during the first wave, remdesivir and baricitinib were used more frequently during the second and third waves (Table 2). The number of lung transplant recipients who required ICU admission and mechanical ventilation decreased during the third wave, but this difference was not significant. Although the length of hospital stay was significantly shorter for lung transplant recipients who contracted COVID-19 during the second or third wave, in-hospital mortality did not change over time (first wave: 28%, second wave: 38%, and third wave: 28%).

Factors Associated With Hospital Admission and In-hospital Mortality

Vaccination was the only significant protective factor for hospital admission (partially vaccinated versus none: odds ratio [OR] 0.24; fully vaccinated versus none: OR 0.30; Table 3). Age 70 y and older (OR 2.96) and partially vaccinated (versus none: OR 2.60; versus fully vaccinated: OR 3.41) were independent risk factors for in-hospital mortality (Table 4).

TABLE 3. Factors associated with hospital admission

	Single variable analysis	
OR (95% CI)	P	
Age ≥70 y	1.50 (0.82-2.75)	0.192	
Male	1.00 (0.54-1.84)	1.000	
SLT (vs DLT)	1.25 (0.67-2.33)	0.474	
Years since transplant	0.91 (0.81-1.03)	0.140	
 Within 1 y	1.60 (0.80-3.19)	0.183	
Vaccination status			
 Partially vaccinated vs none	0.24 (0.12-0.52)	<0.001	
 Fully vaccinated vs none	0.30 (0.14-0.63)	0.002	
 Partially vaccinated vs fully vaccinated	0.81 (0.40-1.65)	0.564	
Recurrent COVID-19 infection	2.04 (0.73-5.72)	0.175	
Coronary artery disease	1.47 (0.55-3.92)	0.437	
CI, confidence interval; DLT, double lung transplantation; OR, odds ratio; SLT, single lung transplantation.

TABLE 4. Factors associated with in-hospital mortality

	Single variable analysis	Multivariable analysis	
OR (95% CI)	P	OR (95% CI)	P	
Age ≥70 y	2.76 (1.32-5.78)	0.007	2.96 (1.29-6.77)	0.010	
Male	1.65 (0.74-3.69)	0.222			
SLT (vs DLT)	2.70 (1.08-6.74)	0.034	1.79 (0.66-4.81)	0.250	
Years since transplant	1.05 (0.88-1.25)	0.589			
 Within 1 y	0.65 (0.28-1.49)	0.308			
Vaccination status					
 Partially vaccinated vs none	2.47 (1.02-5.95)	0.044	2.60 (1.02-6.61)	0.044	
 Fully vaccinated vs none	0.97 (0.40-2.39)	0.955	0.76 (0.29-2.00)	0.581	
 Partially vaccinated vs fully vaccinated	2.53 (0.92-6.96)	0.072	3.41 (1.14-10.20)	0.028	
Recurrent COVID-19 infection	0.52 (0.16-1.67)	0.272			
Readmission prior 1–3 mo	1.66 (0.67-4.11)	0.273			
Baseline O2 requirement	1.06 (0.25-4.45)	0.936			
Baseline FEV1, per L	1.13 (0.61-2.08)	0.698			
Body mass index, per kg/m2	1.01 (0.94-1.08)	0.872			
Coronary artery disease	0.49 (0.13-1.85)	0.295			
Baseline creatinine, per mg/dL	1.20 (0.94-1.53)	0.151			
Hemoglobin A1c, per %	1.20 (0.80-1.81)	0.379			
Steroid	1.34 (0.63-2.82)	0.448			
Remdesivir	1.22 (0.58-2.58)	0.602			
CI, confidence interval; DLT, double lung transplantation; FEV1, forced expiratory volume in 1 s; OR, odds ratio; SLT, single lung transplantation.

Overall Survival

During a median follow-up of 245 d (range, 0–892), overall survival for all lung transplant recipients in our cohort was 67.1% ± 3.5% at 1 y and 59.0% ± 4.4% at 2 y post-COVID-19 infection (Figure 2A). Survival conditional on hospital discharge after COVID-19 infection was 86.1% ± 3.3% at 1 y and 75.7% ± 4.9% at 2 y (Figure S1, SDC, http://links.lww.com/TXD/A676). Survival was significantly better in lung transplant recipients who contracted COVID-19 during the third wave (P = 0.017; Figure 2B) compared with those with COVID-19 during the first or second wave.

FIGURE 2. Survival after COVID-19 infection in lung transplant recipients. A, Overall survival in all patients. Overall survival was 67.1% ± 3.5% at 1 y and 59.0% ± 4.4% at 2 y post-COVID-19 infection. B, Overall survival stratified by the 3 temporal waves of the COVID-19 global pandemic. Survival was significantly better during the third wave (P = 0.017). Shading indicates 95% confidence intervals.

To better understand the impact of COVID-19 on lung transplant surgery during the pandemic, we performed subgroup analysis. Between January 1, 2020, and September 6, 2022, 342 lung transplants were performed at TUH, and 71 of these recipients (21%) subsequently became infected with COVID-19. In recipients who contracted COVID-19, overall survival was 87.0% ± 4.0% at 1 y and 76.6% ± 5.4% at 2 y after lung transplant in patients with COVID-19. In the 271 transplant recipients who did not develop COVID-19, overall survival was 91.3% ± 1.9% at 1 y and 80.3 ± 3.6% at 2 y. There was no significant difference between these 2 groups (P = 0.425; Figure S2, SDC, http://links.lww.com/TXD/A676). Pulmonary function test was obtained for hospitalized patients who survived COVID-19 (n = 71). Pre-COVID-19 and post-COVID-19 forced expiratory volume in 1 s were 1.83 and 1.56 L, respectively (median interval was 18 mo, P = 0.002). One patient (0.5%) required a redo lung transplant after COVID-19 infection.17

CT Findings

Chest CT was obtained in 101 patients (48%), including 30 DLT recipients and 71 SLT recipients (Table 5). Most of DLT recipients (n = 22; 73%) had ground glass opacity (GGO) findings bilaterally. In SLT patients, GGO was observed bilaterally in 16 patients (23%), unilaterally in the allograft in 40 patients (56%), and unilaterally in the native lung in 5 patients (7%). Thus, in SLT recipients, GGO was found on CT in 79% of allografts (n = 56) and 30% of the native lungs (n = 21; Figure S3, SDC, http://links.lww.com/TXD/A676).

TABLE 5. CT findings with ground glass opacity

CT findings	N = 101	
Double lung transplant recipients, N = 30		
 Bilateral	22 (73%)	
 Unilateral	4 (13%)	
 None	4 (13%)	
Single lung transplant recipients, N = 71		
 Bilateral (allograft and native lung)	16 (23%)	
 Unilateral (allograft)	40 (56%)	
 Unilateral (native lung)	5 (7%)	
 None	10 (14%)	
Trinary read for suspected airborne infectiona		
 Category 1	66 (65%)	
 Category 2	19 (19%)	
 Category 3	16 (16%)	
aCategory 1: consistent with multifocal pneumonia including viral/atypical pneumonia. Category 2: indeterminate. Category 3: consistent with other diagnosis.

CT, computed tomography.

Chest CT was also classified into 3 categories: category 1 (consistent with multifocal pneumonia including viral/atypical pneumonia, n = 66), category 2 (indeterminate, n = 19), and category 3 (consistent with other diagnoses, n = 16; Table 5).18

DISCUSSION

This study of 210 lung transplant recipients who were diagnosed with COVID-19 revealed that, although the overall survival of these patients improved significantly as the pandemic progressed and treatments evolved, in-hospital mortality did not change. Although vaccination appears to have been impactful in preventing hospital admission, vaccination demonstrated inconsistent results in reducing mortality in lung transplant recipients who required hospital admission because of COVID-19 infection. To our knowledge, this is the largest single-center experience reported to date.

Persistently High In-hospital Mortality in Lung Transplant Recipients

Treatment options for COVID-19 continue to evolve, and recent studies have demonstrated significantly decreased mortality of patients with COVID-19.19 Similar to our findings, other centers have also reported improved survival rates during the course of the pandemic in lung transplant recipients, who are thought to be particularly vulnerable to COVID-19 infection because of intense immunosuppression and the fact that the virus directly infects the transplanted organ and affects its function.11 The group at Columbia University Medical Center reported their outcomes with a 2-y follow-up recently and observed decreased mortality, hospitalizations, and severity of COVID illness in the third wave of the pandemic compared with the first and second waves, which they attributed to less virulence of the Omicron variant and improved treatment options including vaccines and remdesivir.11,20,21 Our current study agrees with the findings of the Columbia group, and overall mortality as a result of COVID-19 in lung transplant recipients decreased. However, when a lung transplant recipient was sick enough to be admitted as a result of COVID-19 illness, in-hospital mortality was still as high at ~30%. Notably, at our center, all lung transplant recipients with COVID-19 during their index hospital admission for lung transplant died, despite the most recent patient being infected in 2022. Our study suggests that even if patients are vaccinated, mortality from COVID-19 remains extremely high in lung transplant recipients if the patient requires hospitalization. Encouragingly, however, preliminary data from our most recently treated lung transplant recipients alluded to improved clinical outcomes (Table S3, SDC, http://links.lww.com/TXD/A676).

Vaccinations in Lung Transplant Recipients

Conflicting results have been reported regarding serologic response and clinical effectiveness of vaccines in solid organ transplant recipients.12,22-24 In our study, vaccination appeared to have been impactful in preventing hospital admission but demonstrated inconsistent results for reducing in-hospital mortality. Although this finding requires additional and further follow-up, we interpret that during the pandemic, vaccination was helpful but not sufficiently robust to prevent the infected patients from progressing to death unless they were fully immunized. Research has been ongoing to understand the effects of vaccinations on organ transplant recipients taking immunosuppressants. Because immunosuppression, especially with antiproliferative drugs, has been associated with poor antibody response after vaccination, recent studies have demonstrated the efficacy of a temporary reduction of immunosuppression in the weeks before and after vaccination.25,26 However, data regarding the development of antibody-mediated rejection or chronic lung allograft dysfunction (CLAD) using this strategy are lacking. Despite negative seroconversion, a positive cellular (T cell) response has been reported.27 Further information regarding not only humoral but also cellular responses to vaccines, along with the clinical significance of this divergence, is needed in lung transplant recipients to develop an optimal vaccine strategy.

COVID-19 in SLT Recipients

DLT is currently the preferred approach for lung transplantation nationwide, but because we have approximately 3 times more patients older than 70 y on our transplant waitlist proportional to our yearly lung transplant volume than on all other center waitlists in the United States,28 approximately half of our patients undergo SLT to minimize their surgical burden. This is unique to our center. Infectious complications in SLT recipients have been described, and it has been reported that allografts tend to be infected more frequently than native lungs because of disrupted lymphatic and neural connections.29 Our results support this with 79% of SLT recipients exhibiting GGO CT findings in their allograft compared with 30% in the native lung. Because a significant loss of lung function and new onset of CLAD were observed in lung transplant recipients who survived COVID-19,30 further studies are warranted regarding the development of CLAD after COVID-19 infection specifically in SLT recipients compared with DLT recipients. Although our univariate analysis identified SLT as a risk factor for in-hospital mortality from COVID-19, after matching other factors, such as age, SLT was not an independent risk factor for in-hospital mortality, which is concordant with another report.31

The Pandemic Crisis and Its Enduring Impacts on Lung Transplantation, in Light of Pandemic History

Although overall mortality from COVID-19 in lung transplant recipients has been improving during the last 2 y, we wonder what lies ahead for the survivors. Within 2 decades, there have been 4 pandemics caused by respiratory viruses—SARS-CoV, influenza H1N1, Middle East respiratory syndrome-CoV, and SARS-CoV2 (COVID-19; Table 6). SARS-CoV and Middle East respiratory syndrome-CoV belong to the same coronavirus family as SARS-CoV2 and have high mortality rates of 9.1% and 36%, respectively;32,33 however, likely because of the fact the outbreaks did not spread worldwide, there are few data on the effects of these viruses specifically in organ transplant recipients. In contrast, influenza H1N1 caused 151 700–575 400 deaths worldwide,34 and there have been several reports on outcomes after influenza H1N1 in lung transplant recipients.35-37 An Australian group reported mortality of 21% and worsening bronchiolitis obliterans syndrome grade among lung transplant recipients infected with influenza H1N1.37 One might predict a subsequent demand for redo lung transplantation as a result; however, no cases were reported in the decade that followed. Carefully planned prospective studies should be conducted to assess the impact of COVID-19 on redo lung transplantation. One lung transplant recipient in our patient cohort underwent retransplantation, and we do not know whether more redo transplants will become necessary. Lessons and experiences from the COVID-19 pandemic are invaluable to the lung transplant community, and this experience must be carried forward to provide the best care during this enduring pandemic and during possible future pandemics.

TABLE 6. Summary of respiratory virus pandemics

	SARS-CoV	Influenza H1N1	MERS-CoV	SARS-CoV-2 (COVID-19)	
Year of the first reported case	2003	2009	2012	2019	
Country of the first case	China	Mexico	Saudi Arabia	China	
Deaths/total number of cases (fatality rate)	774/~8000
(9.1%)	151 700–575 400 deaths (0.02%)	935/2600
(36%)	6.64M/644Ma
(1%)	
Deaths/total number of cases in the United States	0/8	12 469/60.8M	0/2	1M/98Ma	
The availability of vaccine	No	Yes	No	Currently, yes	
Early outcomes in LTR	NA	Mortality 0%–21%	NA	Mortality 20%–40%	
Mid- and long-term outcomes in LTR	NA	NA	NA	?	
aAs of December 1, 2022.

LTR, lung transplant recipient; M, million; MERS, Middle East respiratory syndrome; NA, not applicable.

Limitations

The present study has several limitations. First, this was a single-center, retrospective observational study, which confers an inherent selection bias. The duration of follow-up in the patients infected with COVID-19 during the third wave was short. Second, although our multidisciplinary team approach to treating COVID-19 and its sequelae has been consistent during the course of the pandemic, treatment options, including vaccines and antiviral treatments, have evolved during the last 2 y. Third, while this study was the largest single-center study to date, our cohort included patients treated both at home and in the hospital, which may make the interpretation of data somewhat demanding.

CONCLUSIONS

Overall survival post-COVID-19 infection in lung transplant recipients continues to improve; however, in-hospital mortality remains remarkably high in these patients. Whereas vaccination appeared to have been impactful in preventing hospital admission, the relationship between vaccination and in-hospital mortality was complex in our cohort. Further research focused on how to identify, monitor, and care for lung transplant recipients at high risk for mortality after COVID-19 infection is warranted and is being continued by our group.

ACKNOWLEDGMENTS

The authors thank Shannon Wyszomierski for editing a draft of the article.

Supplementary Material

The authors declare no funding or conflicts of interest.

H.K. participated in study design, data collection and analysis, and writing the article. A.J.-W. participated in data collection. R.Y., K.K., A.M., F.C., G.J.C., and Y.T. participated in critical revision. H.Z. participated in data analysis. N.S. participated in study design, writing the article, and critical revision.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantationdirect.com).

This article was presented at the oral session of the 43rd annual meeting and scientific session of The International Society for Heart and Lung Transplantation, Denver, CO, April 19 to 22, 2023.
==== Refs
REFERENCES

1. Aubert O Yoo D Zielinski D . COVID-19 pandemic and worldwide organ transplantation: a population-based study. Lancet Public Health. 2021;6 :e709–e719.34474014
2. McLean G Kamil J Lee B . The impact of evolving SARS-CoV-2 mutations and variants on COVID-19 vaccines. MBio. 2022;13 :e0297921.35352979
3. Messika J Eloy P Roux A ; French Group of Lung Transplantation. COVID-19 in lung transplant recipients. Transplantation. 2021;105 :177–186.33141808
4. Gottlieb J Kolditz M Gade N . Benefit of monoclonal antibodies in early treatment of COVID-19 after lung transplantation: a retrospective analysis in two centres. Eur Respir J. 2022;60 :2200124.35618274
5. Hazan F Verdonk C Coutance G . Severity of SARS-CoV-2 Omicron variant infection in heart transplant recipients. J Heart Lung Transplant. 2023;42 :558–561.36822931
6. Cherrett C Cao J Adams C . Coronavirus disease 2019 outcomes in heart transplant recipients: a large Australian cohort. J Heart Lung Transplant. 2024;43 :346–349.37716497
7. Belli LS Fondevila C Cortesi PA ; ELITA-ELTR COVID-19 Registry. Protective role of tacrolimus, deleterious role of age and comorbidities in liver transplant recipients with COVID-19: results from the ELITA/ELTR multi-center European study. Gastroenterology. 2021;160 :1151–1163.e3.33307029
8. Webb GJ Marjot T Cook JA . Outcomes following SARS-CoV-2 infection in liver transplant recipients: an International Registry Study. Lancet Gastroenterol Hepatol. 2020;5 :1008–1016.32866433
9. Cravedi P Mothi SS Azzi Y . COVID-19 and kidney transplantation: results from the TANGO International Transplant Consortium. Am J Transplant. 2020;20 :3140–3148.32649791
10. Zimmerman A Rogers R Tan CS . Expecting the unexpected: COVID-19 in kidney transplant recipients within United Network for organ sharing region 1. Transpl Int. 2020;33 :1843–1844.33000866
11. Hum J Laothamatas K Scheffert J . Impact of omicron on lung transplant recipients: a third COVID-19 surge with different outcomes. Ann Am Thorac Soc. 2022;20 :148–151.
12. Trindade AJ Chapin KC Gannon WD . Clinical course of SARS-CoV-2 infection and recovery in lung transplant recipients. Transpl Infect Dis. 2022;24 :e13967.36271645
13. Shigemura N Cordova F Hayanga AJ . Lung transplantation and coronavirus disease 2019 (COVID-19): a roadmap for the enduring pandemic. J Thorac Dis. 2021;13 :6755–6759.35070359
14. Chowdhury JM Patel M Zheng M . Mobilization and preparation of a large urban academic center during the COVID-19 pandemic. Ann Am Thorac Soc. 2020;17 :922–925.32315201
15. Myers CN Scott JH Criner GJ ; Temple University COVID-19 Research Group. COVID-19 in lung transplant recipients. Transpl Infect Dis. 2020;22 :1–5.
16. Pandya A Kaur NA Sacher D ; COVID-19 Research Group. Ventilatory mechanics in early vs late intubation in a cohort of coronavirus disease 2019 patients with ARDS: a single center’s experience. Chest. 2021;159 :653–656.32882246
17. Kehara H Mangukia C Sunagawa G . Lung transplantation for COVID-19 pulmonary sequelae. Transplantation. 2023;107 :449–456.36525557
18. Simpson S Kay FU Abbara S . Radiological Society of North America Expert Consensus Statement on reporting chest CT findings related to COVID-19. Endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA—secondary publication. J Thorac Imaging. 2020;35 :219–227.32324653
19. Yeates EO Nahmias J Chinn J . Improved outcomes over time for adult COVID-19 patients with acute respiratory distress syndrome or acute respiratory failure. PLoS One. 2021;16 :e0253767–e0253768.34170950
20. Aversa M Benvenuto L Anderson M ; From the Columbia University Lung Transplant Program. COVID-19 in lung transplant recipients: a single center case series from New York City. Am J Transplant. 2020;20 :3072–3080.32881315
21. Laothamatas K Hum J Benvenuto L . One Year into the pandemic: evolving COVID-19 outcomes in lung transplant recipients, a single-center experience. Transplant Direct. 2022;8 :e1296.35368985
22. Demir E Dheir H Safak S . Differences in clinical outcomes of COVID-19 among vaccinated and unvaccinated kidney transplant recipients. Vaccine. 2022;40 :3313–3319.35504784
23. Lerner AH Arvanitis P Vieira K . mRNA vaccination decreases COVID-19-associated morbidity and mortality among organ transplant recipients: a contemporary cohort study. Open Forum Infect Dis. 2022;9 :1–7.
24. Dauriat G Beaumont L Luong Nguyen LB . Efficacy of 3 COVID-19 vaccine doses in lung transplant recipients: a multicentre cohort study. Eur Respir J. 2023;61 :2200502.36265877
25. Schrezenmeier E Rincon-Arevalo H Jens A . Temporary antimetabolite treatment hold boosts SARS-CoV-2 vaccination-specific humoral and cellular immunity in kidney transplant recipients. JCI Insight. 2022;7 :e157836.35349490
26. Frey S Ruck JM Alejo JL . Perivaccination antimetabolite hold and third dose of SARS-CoV-2 vaccine in lung transplant recipients: preliminary report. Transplantation. 2022;106 :e426–e428.35698264
27. Hall VG Ferreira VH Ierullo M . Humoral and cellular immune response and safety of two-dose SARS-CoV-2 mRNA-1273 vaccine in solid organ transplant recipients. Am J Transplant. 2021;21 :3980–3989.34347934
28. Scientific Registry of Transplant Recipients, Temple University Hospital. Scientific Registry of Transplant Recipients, Program-Specific Report. 2021. Available at https://www.srtr.org/reports/program-specific-reports/. Accessed August 17, 2024.
29. Horvath J Dummer S Loyd J . Infection in the transplanted and native lung after single lung transplantation. Chest. 1993;104 :681–685.8365275
30. Mahan LD Lill I Halverson Q . Post-infection pulmonary sequelae after COVID-19 among patients with lung transplantation. Transpl Infect Dis. 2021;23 :1–9.
31. Heldman MR Kates OS Safa K ; UW COVID-19 SOT Study Team. COVID-19 in hospitalized lung and non-lung solid organ transplant recipients: a comparative analysis from a multicenter study. Am J Transplant. 2021;21 :2774–2784.34008917
32. Peiris JSM Yuen KY Osterhaus ADME . The severe acute respiratory syndrome. N Engl J Med. 2003;349 :2431–2441.14681510
33. Memish ZA Perlman S Van Kerkhove MD . Middle East respiratory syndrome. Lancet. 2020;395 :1063–1077.32145185
34. Rockman S Laurie K Barr I . Pandemic influenza vaccines: what did we learn from the 2009 pandemic and are we better prepared now? Vaccines (Basel) 2020;8 :211.32392812
35. Kumar D Michaels MG Morris MI ; American Society of Transplantation H1N1 Collaborative Study Group. Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study. Lancet Infect Dis. 2010;10 :521–526.20620116
36. Fox BD Raviv Y Rozengarten D . Pandemic influenza (H1N1): impact on lung transplant recipients and candidates. J Heart Lung Transplant. 2010;29 :1034–1038.20558087
37. Ng BJH Glanville AR Snell G . The impact of pandemic influenza A H1N1 2009 on Australian lung transplant recipients. Am J Transplant. 2011;11 :568–574.21299829
