The clinical significance of baseline lung allograft dysfunction in single and bilateral lung transplant recipients

Abstract

Purpose

Baseline lung allograft dysfunction (BLAD), defined as failure to achieve normal peak lung function after transplant, is associated with decreased survival in bilateral orthotopic lung transplant recipients. Limited data exist regarding the BLAD outcome in single orthotopic lung transplant (SOLT). We hypothesized that post-transplant survival in SOLT recipients with BLAD would differ according to native lung disease physiology.

Methods

In our single-center retrospective cohort study, we reviewed the pulmonary function test data of 1,086 first lung transplant recipients between January 2000 and January 2020. We performed a landmark analysis examining survival landmarked at 1-year post-transplant. We used Cox proportional hazards regression to assess the baseline forced expiratory volume in one second (FEV1) percent predicted in the first year post-transplant with survival after 1 year. In SOLT patients, analysis was stratified by interstitial lung disease (ILD) and obstructive lung disease (OLD).

Results

Our final cohort included 797 patients, 446 BOLT and 351 SOLT. Among SOLT patients, 263 had native ILD and 88 had native OLD. We confirmed that BLAD is associated with decreased survival in BOLT driven by BLAD grades 3 & 4. In recipients of SOLT, we found similar decreased survival with BLAD among those with native ILD, driven by grades 2, 3, & 4. However, BLAD was not associated with decreased survival in SOLT patients with native OLD, except at grade 4 (FEV1<35%).

Conclusion

In SOLT recipients with native ILD, BLAD was associated with worse post-transplant survival, particularly at higher BLAD grades, similar to patterns observed in BOLT recipients. In contrast, among SOLT recipients with native OLD, variable native lung hyperinflation and mechanical effects will affect post-transplant baseline lung function with less clear implications for graft function and survival.

Background

Lung transplant is a therapeutic option for a wide variety of advanced lung diseases. Improving quality of life and extending survival are the primary goals of lung transplant.1, 2 Despite advances in surgical techniques, immunosuppression regimens, and management of allograft injuries, survival after lung transplant remains inferior to other solid organ transplants, with a median survival of 6.7 years.3, 4

Although many lung transplant recipients achieve normal pulmonary function within 6 to 12 months after transplant, a subset of patients fail to gain normal lung function.5, 6 Baseline lung allograft dysfunction (BLAD)⁴ is defined as the failure to achieve normal peak function after transplant.1, 7 The mechanisms associated with the development of BLAD are not fully understood.⁸ Reported mechanisms include disproportionate pulmonary mechanics (e.g., donor/recipient size mismatch or a restrictive chest wall cavity in the recipient), severe primary graft dysfunction (PGD), or identifiable biological contributors.1, 7, 8, 9

BLAD is associated with worse post-transplant survival, reduced quality of life, and impaired exercise capacity compared to patients who achieve normal lung function.⁹ Previous BLAD studies have predominantly focused on bilateral orthotopic lung transplant (BOLT) recipients. Less is known about the clinical significance of BLAD in single orthotopic lung transplant (SOLT). In SOLT recipients, the native restrictive or obstructive lung ventilatory mechanics may affect lung allograft function after transplant.

In this study, we characterized BLAD in a relatively large single-center cohort of SOLT recipients and compared associated clinical outcomes with those in the BOLT cohort. We included BOLT as a reference group because most of the previous studies on BLAD have been conducted in BOLTs, and confirmation of expected findings in BOLT would lend confidence to any novel finding in SOLT. Furthermore, we evaluated whether native lung ventilatory mechanics modified the relationship between BLAD and post-transplant outcomes in SOLT recipients.

Materials and methods

Study design and patient population

We retrospectively collected data from the electronic medical record of first lung transplant recipients at the University of California Los Angeles (UCLA) between 1/1/2000 and 1/1/2020. We excluded patients with bronchial stenosis, malignancy, or less than 1-year post-transplant available follow-up. The study was approved by the UCLA institutional review board (IRB #11–3042). The IRB waived the need for informed consent.

All participants received induction immunesuppression after lung transplant. For the majority of the era, patients over the age of 60 received basiliximab 20 mg IV on post-operative days 0 and 4. Patients under the age of 60 without contraindications (cystic fibrosis and chronic infections) received 3 doses of rabbit Anti-Thymocyte Globulin (ATG) 1.5 mg/kg IV on postoperative days 0, 1, and 2. Beginning in 2017, our threshold for finding contraindications to ATG was lowered (increased risk of infection or malignancy as perceived by the treating pulmonologist), resulting in greater use of basiliximab. There were no changes in maintenance immunosuppression protocols over the course of the study.

All patients received intra-operative methylprednisolone 7 mg/kg IV, followed by methylprednisolone 125 mg IV every 12 hours for 3 doses. Patients were then started on prednisone 0.5 mg/kg daily for the first week and subsequently tapered by 5 mg per week down to a maintenance dose of 5 to 10 mg daily. Additional maintenance immune suppression included tacrolimus dosed for a 12-hour trough level of 8 to 12 ng/mL and mycophenolate mofetil 1,000 mg orally BID.

PGD was determined according to ISHLT guidelines based on radiographic findings and oxygenation levels.¹⁰ Severity was graded on a scale from 0 to 3. Patients with PaO₂/FiO₂ (P/F) < 200 and radiographic findings of pulmonary edema were considered as grade 3.

Donor-recipient size mismatch was defined based on the ratio of predicted total lung capacity (pTLC), calculated as donor pTLC divided by recipient pTLC. The predicted TLC values for donors and recipients were derived from GLI reference equations.¹¹ According to the 2026 American Association for Thoracic Surgery Expert Consensus on donor/recipient size-matching,¹² a donor to recipient pTLC ratio of 0.8 to 1.2 was considered as size-matched. If the ratio was below 0.8, the donor lung was considered undersized, and if the ratio was above 1.2, the donor lung was considered oversized.

BLAD definition

Based on our lung transplant protocol, pulmonary function was evaluated at each clinic visit, typically starting within the first post-transplant month and at least once per month for the first 6 months, every 2 months for months 7 to 12, and every 3 months thereafter. We determined BLAD at 1-year post-transplant, as most lung transplant recipients achieve their post-transplant baseline pulmonary function by this timepoint.¹³ Global Lung Function Initiative (GLI) reference equations using recipient characteristics determined the predicted values.¹¹ Participants who achieved ≥80% predicted forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) simultaneously on 2 consecutive measurements at least 3 weeks apart were considered to have normal lung function.

BOLT and SOLT recipients who failed to attain a normal baseline FEV1 and FVC percent of reference within the first year post-transplant were considered to have BLAD. Furthermore, we categorized patients’ BLAD grade as follows: a baseline FEV1 ≥65% and less than 80% predicted was grade 1 BLAD, a baseline FEV1 ≥50% and <65% predicted was grade 2 BLAD, a baseline FEV1 ≥35% and <50% predicted was grade 3 BLAD, and a baseline FEV1 <35% predicted was grade 4 BLAD. Patients who achieved a normal FEV1 but the baseline FVC was <80% predicted were considered as grade 1.¹⁴

Outcome

The primary outcome of interest was time to death from 1-year post-transplant. The secondary outcome of interest was freedom from chronic lung allograft dysfunction (CLAD). CLAD was defined as a 20% or greater decline in FEV1 as compared to the average of the 2 best post-transplant FEV1s, sustained for at least 3 weeks in the absence of confounders, consistent with the 2019 ISHLT consensus statement definition of probable CLAD.¹⁵ Since the outcome analysis was landmarked at 1-year post-transplant, patients who developed CLAD before 1 year were excluded from the CLAD outcome analysis.

Statistical analysis

Continuous variables were presented as median and interquartile range, while categorical variables were reported as counts and percentages. We used the Kruskal-Wallis test for comparing continuous variables and the Chi-square or Fisher’s exact tests for categorical variables. We performed univariable logistic regression analyses to evaluate the association between donor and recipient characteristics and development of BLAD grade ≥ 2. Variables with a p value <0.10 were included in the multivariable logistic regression model. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were reported.

Survival analyses were landmarked at 1-year post-transplant. Kaplan-Meier survival curves were generated to estimate survival and CLAD probabilities, with group comparisons performed using the log-rank test. We ran a multivariable Cox proportional hazards analysis to evaluate the association between BLAD grade and post-BLAD survival, adjusting for transplant type, age, and sex. Hazard ratios (HRs) with 95% CIs were reported. All statistical analyses were conducted using JMP and Prism GraphPad software. Statistical significance was defined as p < 0.05.

Results

Study population and baseline characteristics

In our center, a total of 1,086 patients were transplanted between 1/1/2000 and 1/1/2020. We excluded 289 patients due to the presence of alternative causes of pulmonary function test (PFT) decline (n = 154) (e.g., bronchial stenosis or malignancy) or insufficient 1-year follow-up after transplant (n = 135). The final cohort included 797 patients, including 446 BOLT and 351 SOLT (263 patients with native ILD and 88 with native obstructive lung disease), as shown in Figure 1. The patient demographic and clinical data for each group is presented in Table 1.

Figure 1.

Description of the study cohort.

Table 1.

The Main Demographic and Clinical Characteristic of the BOLT and SOLT Cohorts

Variable	BOLT (n = 446)	SOLT-ILD (n = 263)	SOLT-OLD (n = 88)
Age, year (median, IQR)	55 (45-60)	67 (63-69)	65 (62-68)
Male sex (n, %)	263 (58)	179 (68)	45 (51)
Race (n, %)
White	294 (65)	191 (72)	82 (93)
Hispanic	95 (21)	47 (18)	1 (1)
Black	31 (7)	10 (3)	3 (4)
Asian	23 (6)	15 (7)	2 (2)
Hawaiian/Pacific Islander	3 (1)	0 (0)	0 (0)
UNOS group diagnosis (n, %)
Obstructive lung disease	80 (18)	0 (0)	88 (100)
Pulmonary vascular disease	39 (8)	0 (0)	0 (0)
Cystic fibrosis	47 (11)	0 (0)	0 (0)
Restrictive lung disease	280 (63)	263 (100)	0 (0)
BMI at transplant (median, IQR)	24 (21-28)	27 (24-29)	24 (21-27)
Donor/Recipient size mismatch (n, %)
Undersized	17 (4)	8 (3)	3 (3)
Size- matched	392 (87)	237 (90)	72 (82)
Oversized	37 (9)	18 (7)	13 (15)
LAS (median, IQR)	46.86 (38-64)	43.42 (37-53)	32.57 (30-35)
Induction
ATG (n, %)	220 (49)	27 (10)	26 (29)
Basiliximab (n, %)	226 (51)	236 (90)	62 (71)
PGD Grade 3 at 72 hours (n, %)	38 (8)	16 (6)	5 (5)
Days to peak lung function (median,IQR)	107 (46-280)	87 (38-197)	62 (51-145)
BLAD grade (n, %)
0 (FEV1 ≥80%)	189 (42)	71 (27)	5 (6)
1 (FEV1 65%-79%)	154 (34)	105 (40)	23 (26)
2 (FEV1 50%-64%)	61 (14)	63 (24)	32 (36)
3 (FEV1 35%-49%)	30 (7)	15 (6)	23 (26)
4 (<35%)	12 (3)	9 (3)	5 (6)

ATG, Anti-Thymocyte Globulin; BOLT, Bilateral Orthotopic Lung Transplant; BLAD, Baseline Lung Allograft Dysfunction; BMI, Body Mass Index; ILD, Interstitial Lung disease; LAS, Lung Allocation Score; OLD, Obstructive Lung Disease; PGD, Primary Graft Dysfunction; SOLT, Single Orthotopic Lung Transplant.

In the BOLT cohort, 189 (42%) recipients achieved a normal baseline FEV1 and FVC percent predicted by 1-year post-transplant. The median time to peak lung function among all BOLT recipients was 107 days (IQR: 46-280). Among SOLT recipients, only 71(27%) of SOLT-ILD and 5 (6%) of SOLT-OLD achieved normal lung function 1 year post-transplant. The median time to peak lung function among SOLT-ILD patients was 87 days (IQR: 38-197), and in SOLT-OLD was 62 days (IQR: 51-145). The distribution of FEV1 percent predicted at 1-year post-transplant in the BOLT, SOLT-ILD, and SOLT-OLD cohorts is shown in Figure 2.

Figure 2.

Distribution of FEV1 percent predicted at 1-year post-transplant in bilateral orthotopic lung transplant (BOLT), single orthotopic lung transplant with native ILD (SOLT-ILD), and single orthotopic lung transplant with native OLD (SOLT-OLD).

Donor and recipient characteristics associated with BLAD

The use of ATG induction declined over time and especially after 2017, as shown in Supplemental Table 1. Despite this change in induction choice, the prevalence of BLAD did not differ significantly between the pre- and post-2017 periods in any cohort (BOLT: 59% vs. 50%, p = 0.10; SOLT-ILD: 74% vs. 66%, p = 0.41; SOLT-OLD: 94% vs 100%, p = 0.98).

The main demographic and clinical characteristics of BLAD vs non-BLAD groups in each cohort are presented in Supplemental Table 2. In both BOLT and SOLT cohorts, no differences were observed in donor age between recipients with BLAD and those with normal lung function. The incidence of severe PGD at 72 hours post-transplant was higher in BOLT recipients with BLAD compared to patients with normal lung function (9% vs 2%, respectively, p=0.005). There was no statistically significant difference in incidence of severe PGD at 72 hours in SOLT cohorts with or without BLAD. The proportion of undersized donors was not higher in patients with BLAD compared to those with normal lung function in the BOLT and SOLT cohorts. Moreover, there was no statistically significant difference in the frequency of recipient obesity (BMI>30) in patients with BLAD and normal lung function in all cohorts. In the BOLT cohort, BLAD incidence was higher in recipients with native ILD compared to other UNOS group diagnoses (62% vs 51%, p = 0.03).

Predictors of moderate to severe BLAD (BLAD grade ≥ 2)

Given the existing literature suggesting that mild BLAD is not a risk factor for mortality,1, 14 we decided to explore risk factors of moderate to severe BLAD in our full cohort. We performed univariable regression analyses, including clinical characteristics of donor (age and sex) and recipient (age, sex, transplant type, BMI>30, and PGD grade 3 at 72 hours), to assess their associations with BLAD grade ≥ 2. Compared with BOLT, SOLT-ILD recipients had higher odds of BLAD ≥ 2 (OR 1.65, 95% CI 1.17-2.31, p = 0.004), while SOLT-OLD recipients had substantially higher odds (OR 7.14, 95% CI 4.33-11.76, p < 0.001). PGD grade 3 at 72 hours was also associated with an increased risk of BLAD grade ≥2 (OR 1.74, 95% CI 1.02-2.98, p = 0.04), and older donor age was similarly associated with BLAD grade ≥ 2 (OR 1.01 per year of life, 95% CI 1.00-1.02, p = 0.01).

In the multivariable model, transplant type (BOLT vs SOLT), PGD grade 3 at 72 hours, and donor age were included (Table 2). SOLT-ILD (adjusted OR¹² 1.67, 95%CI 1.18-2.36, p < 0.001) and SOLT-OLD (aOR 7.23, 95% CI 4.40-12.13, p < 0.001) remained independently associated with BLAD grade ≥ 2 compared to BOLT. PGD grade 3 at 72 hours was associated with nearly 2fold higher odds of BLAD grade ≥ 2 (aOR 1.95, 95% CI 1.10-3.42, p = 0.02). Increasing donor age remained independently associated with BLAD grade ≥ 2 (aOR 1.02 per year, 95% CI 1.01-1.03, p = 0.01).

Table 2.

Univariable and Multivariable Logistic Regression Analyses of Factors Associated With Moderate-to-Severe BLAD (Grade >2)^†

Variable	Univariable OR (95% CI)	p-value	Adjusted OR (95% CI)	p value
Recipient age (per year)	1.01 (1.00-1.02)	0.124	____	_____
Recipient sex (male vs female)	1.09 (0.80-1.49)	0.566	____	_____
Donor age (per year)	1.01 (1.00-1.03)	0.011*	1.01 (1.00-1.02)	0.031*
Donor sex (male vs female)	1.01 (0.74-1.39)	0.927	____	_____
Recipient BMI>30	1.03 (0.68-1.56)	0.877	____	____
Transplant Type
SOLT-ILD vs BOLT	1.65 (1.17-2.31)	0.004*	1.67 (1.18-2.36)	0.003*
SOLT-OLD vs BOLT	7.14 (4.33-11.76)	<0.001*	7.23 (4.40-12.13)	<0.001*
PGD grade 3 at 72 hours	1.74 (1.02-2.98)	0.041*	1.95 (1.10-3.42)	0.021*

BOLT, Bilateral Orthotopic Lung Transplant; BLAD, Baseline Lung Allograft Dysfunction; BMI, Body Mass Index; ILD, Interstitial Lung disease; OLD, Obstructive Lung Disease; PGD, Primary Graft Dysfunction; SOLT, Single Orthotopic Lung Transplant.

^†Variables with p < 0.10 in univariable analysis were entered into the multivariable logistic regression model.

^*p < 0.05 was considered as significant.

Association of BLAD with survival in BOLT and SOLT cohorts

Post-BLAD survival over a 5-year follow-up period is shown in Figure 3. In the BOLT cohort, lung transplant recipients with BLAD demonstrated significantly worse survival compared with patients who achieved normal lung function (Figure 3A). SOLT-ILD cohort showed similar results (Figure 3B). However, in the SOLT-OLD cohort, survival was not different between patients with BLAD and normal lung function (Figure 3C).

Figure 3.

The post-transplant survival with Kaplan-Meier (KM) plots over 5-year follow-up in Bilateral Orthotopic Lung Transplant (A), Single Orthotopic Lung Transplant with native ILD (B) and Single Orthotopic Lung Transplant with native OLD (C) recipients with BLAD versus normal lung function.

Association of BLAD severity with survival

In BOLT recipients, higher BLAD severity grades (3 and 4) were associated with worse survival, as shown in Figure 4A. Similarly, in the SOLT-ILD recipients, higher BLAD grades were associated with worse survival (Figure 4B). However, in the SOLT-OLD cohort, only patients with BLAD grade 4 had significantly worse survival compared with recipients with normal lung function (Figure 4C). We also examined BLAD severity in an adjusted Cox model for mortality. After adjustment for transplant type, recipient age, and sex, BLAD grade was independently associated with increased risk of mortality (Table 3).

Figure 4.

Forest plots showing the hazard ratio for death and 95% confidence intervals associated with different BLAD grades in Bilateral Orthotopic Lung Transplant (A), Single Orthotopic Lung Transplant with native ILD (B), and Single Orthotopic Lung Transplant with native OLD (C).

Table 3.

Multivariable Cox Proportional Hazards Regression for Mortality After BLAD Adjusted for Transplant Type, Age, and Sex

Variable	Hazard Ratio (HR), 95% CI	p-value
BLAD Grades
Grade 1 vs 0	1.31 (1.03-1.68)	0.029*
Grade 2 vs 0	1.68 (1.27-2.21)	0.003*
Grade 3 vs 0	1.71 (1.18-2.47)	0.004*
Grade 4 vs 0	6.46 (4.05-10.31)	<0.001*

BLAD, Baseline lung allograft dysfunction.

^*p < 0.05 was considered as significant.

Association of BLAD severity with subsequent CLAD

For the CLAD analysis, 31 patients from the BOLT, 18 patients from the SOLT-ILD, and 5 patients from the SOLT OLD cohorts who developed CLAD before the 1-year post-transplant landmark were excluded. Across the BOLT, SOLT-ILD, and SOLT-OLD cohorts, BLAD severity was not associated with subsequent CLAD risk (Figure 5).

Figure 5.

Forest plots showing the hazard ratio for chronic lung allograft dysfunction (CLAD) and 95% confidence intervals associated with different BLAD grades in Bilateral Orthotopic Lung Transplant (A), Single Orthotopic Lung Transplant with native ILD (B) and Single Orthotopic Lung Transplant with native OLD (C).

Discussion

In our relatively large single-center study, we confirmed that BLAD is associated with worse post-transplant survival in BOLT recipients. We found that the prognostic significance of BLAD in SOLT recipients varies according to native lung disease. Among SOLT recipients with native ILD, BLAD was associated with worse survival as compared to patients with normal lung function, similar to the pattern observed in BOLT recipients. In contrast, among SOLT recipients with native OLD, BLAD was not associated with worse survival except in those with the most severe impairment, defined as grade 4 of BLAD with FEV1< 35% predicted.

A substantial number of lung transplant recipients achieve peak FEV1 at around 9 months post-transplant and peak FVC around 12 months after transplant.13, 16 The optimal timing for defining BLAD has not been well established. Prior studies have adopted BLAD definitions and timing from previous CLAD guidelines.¹³ In this study, we defined BLAD at the 1-year post-transplant landmark, a timepoint by which most lung transplant recipients are expected to have achieved their peak post-transplant lung function.13, 16

Our findings in BOLT recipients are consistent with prior reports. Graham and colleagues showed that 53% of their BOLT cohort had abnormal FEV1 and FVC at 1-year post-transplant.¹³ Moreover, Paraskeva et al had 49% of BOLT recipients with abnormal lung function at 1-year post-transplant.¹⁷ In our BOLT cohort, 58% of recipients failed to achieve normal lung function by 1-year post-transplant.

The application of standard BLAD criteria to SOLT recipients is more complex. Because SOLT recipients retain a native lung that can influence measured spirometry, thresholds developed in BOLT populations may not directly translate to SOLT populations. Gerckens et al used FEV1% and FVC% predicted < 60% as a cutoff for the definition of BLAD in SOLTs based on their observation that baseline lung function is typically 10% to 20% lower after SOLT compared to BOLT.¹⁸ This cutoff was considered a practical threshold that was consistent with the baseline lung function distribution of SOLT recipients compared with BOLTs. Using this lower cutoff, 43% of SOLT recipients in their cohort met BLAD criteria. Using this 60% cutoff to define BLAD in our SOLT cohorts, we found that BLAD developed in 33% of patients with SOLT-ILD and in 56% of patients with SOLT-OLD. Of note, the 60% cutoff was associated with worse survival only in SOLT-ILD (Supplemental Figure 1). The difference in BLAD prevalence between our SOLT-ILD and SOLT-OLD cohort likely reflects differences in the influence of the retained native lung on airflow mechanics. We suspect that the gas transfer efficiency component of graft function would be less affected by native lung disease in SOLT, but diffusion capacity is not routinely performed posttransplant in our center. Regardless, it seems that the BLAD definition in SOLT recipients needs further study and refinement.

There are potential underlying donor and recipient factors that can be related to the development of BLAD. In our BOLT cohort, pre-transplant diagnosis of ILD was associated with BLAD. This finding was in agreement with the previous studies that the risk of BLAD is greater in bilateral lung transplant recipients with ILD due to the restricted chest wall cavity.14, 18, 19 The reduced chest cavity may limit graft expansion, which could adversely affect early allograft function and achievement of peak lung function. However, in our SOLT cohort, native obstructive lung disease was more associated with BLAD. Gerckens et al found similar results in their single lung transplant recipients and concluded that the mechanisms or contributors of BLAD are different in SOLTs compared to BOLTs.¹⁸ Native lung hyperinflation with compressive effect can limit allograft flows and volumes through the mechanical effect on it. We observed an association between PGD and BLAD in BOLT recipients. Specifically, PGD grade 3 at 72 hours was higher in BOLT recipients with BLAD compared to normal lung function. Few studies showed that PGD grade 3 is highly associated with the development of BLAD, and some studies did not.5, 17 As mentioned earlier, there has been some evolution of practice with induction immune suppression over time in this cohort; however, we did not find any difference in prevalence of BLAD.

Extracorporeal life support (ECLS) has an important role during the perioperative course of lung transplant, as emphasized in the recent ISHLT consensus statement.²⁰ Since ECLS is frequently required in lung transplant recipients with severe cardiopulmonary dysfunction or PGD, its use may reflect early allograft injury that contributes to a failure to achieve peak lung function after transplant. However, the direct relationship between ECLS and BLAD remains uncertain and probably related to PGD. Further studies are needed to better define this relationship.

Perioperative ventilation could have a role in causing or perpetuating early allograft injury and potentially lead to BLAD. Fessler and colleagues recently highlighted the importance of disease-specific mechanical ventilation in end-stage lung disease due to different lung mechanics and susceptibility to ventilator-induced injury across these groups.²¹ Given the retrospective nature of our study, we do not have detailed perioperative ventilation data in order to explore the potential association. Prospective studies are needed to better understand the potential relationship with BLAD.

SOLT recipients had significantly higher risk of moderate to severe BLAD compared to BOLT recipients, with the greatest risk observed in SOLT-OLD. Severe PGD at 72 hours was also independently associated with BLAD grade ≥ 2, supporting previous studies that severe ischemia-reperfusion injury impairs the functional potential of lung allograft.⁷ Donor age was associated with an increased risk of BLAD grade ≥ 2. Prior studies have shown that higher donor age independently increases BLAD risk in BOLT and was linked to more severe PGD and poorer survival in some cohorts.1, 22

BLAD is presumed to be associated with worse post-transplant survival because patients have limited reserve to tolerate different allograft injuries.²³ Consistent with this concept, we found that BLAD was associated with worse survival in the BOLT cohort. Furthermore, increasing BLAD severity was associated with progressively higher mortality risk, with significantly worse outcomes observed among recipients with grade 3 and 4 BLAD, corresponding to FEV1<50% predicted.

As we noted earlier, there are few studies that address BLAD outcomes in single lung transplant recipients. In our study, SOLT-ILD recipients with BLAD had similar worse post-transplant survival as seen with BOLT recipients. Increasing BLAD grade in SOLT-ILD recipients was also associated with a stepwise effect on survival. However, in SOLT-OLD, only BLAD grade 4 was associated with worse post-transplant survival. It must be noted that the number of SOLT-OLD recipients in this study is relatively small, especially the number of those who achieve normal lung function. Therefore, the survival curves should be interpreted with caution, and these findings should be validated with a larger cohort. A minority of patients achieved normal lung function in our center, although a majority of BOLT and SOLT-ILD patients achieved at least mild (grade 1) BLAD or better. BLAD grade 1 was not associated with increased mortality in any cohort. Therefore, a reasonable interpretation of our data is to set a posttransplant lung function goal at BLAD grade 1 or better for BOLT and SOLT-ILD. Among SOLT-OLD, the bar may be even lower. It will be important to validate our findings and incorporate gas transfer efficiency measurement, as well as quality of life measures, in future studies.

Some studies have suggested an increased risk of future CLAD in patients with BLAD.⁸ Other studies argue that BLAD and CLAD are 2 different entities that can lead to mortality, and BLAD is not associated with increased risk of CLAD.1, 14 In our BOLT and SOLT cohorts, we confirm that there was no increased risk of CLAD in BLAD patients versus normal lung function.

Our study has several limitations. The single-center design may limit the generalizability. However, our center includes a relatively diverse population, and our findings are in line with other single-center studies. The small number of SOLT recipients with native obstructive lung disease constrained our ability to investigate BLAD outcomes in more depth. Finally, given the retrospective nature of this study, detailed perioperative data were not consistently available. Therefore, we could not fully assess the impact of the complicated perioperative course on the development of BLAD.

Conclusions

Our findings suggest that post-lung transplant survival in single lung transplant is strongly influenced by native lung disease. Among SOLT recipients with native ILD, BLAD was associated with worse survival, with progressively higher mortality across increasing BLAD grades. In contrast, among SOLT patients with native OLD, BLAD was not associated with worse survival except in recipients with very severe lung function impairment, defined as FEV1<35%. These findings highlight the important contribution of native lung mechanics to post-transplant spirometry and suggest that the prognostic significance of BLAD differs in SOLT recipients with restrictive and obstructive native lung disease.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary material

Supplementary material

Supplementary material

Supplementary material