Key words : Acute cellular rejection, Chronic lung allograft dysfunction, Graft dysfunction phenotypes, Postoperative recovery, Pulmonary function testing

Introduction

Lung transplant has transformed the treatment of end-stage lung diseases, substantially improving quality of life for such patients and extending survival for those with otherwise terminal conditions. Despite progress in surgical techniques, immunosuppression therapies, and donor selection, lung transplant still has the lowest survival rates among solid-organ transplants, with a median survival of 6.5 years.¹

The primary goal of lung transplant is to restore normal lung function to improve quality of life and survival. However, some lung transplant recipients fail to reach expected pulmonary function levels. This condition is known as baseline lung allograft dysfunction (BLAD)2-5 and is associated with poorer long-term outcomes, including reduced survival and a higher risk of complications such as chronic lung allograft dysfunction (CLAD) and premature death. Despite its clinical importance, published data on BLAD remain limited, particularly with regard to its incidence and associated risk factors, and the exact pathophysiology remains poorly understood. Another challenging aspect is determination of the appropriate timing for BLAD diagnosis following lung transplant. Although many patients achieve good lung function (forced expiratory volume in 1 second [FEV1] ≥80%; forced vital capacity [FVC] ≥80%) immediately after surgery, other patients take longer to reach peak FEV1 levels. Because the present definition of BLAD lacks a specific time frame, this retrospective cohort study assessed the overall incidence of BLAD in double-lung transplant recipients but also analyzed the presence of BLAD at 3 months, 6 months, 9 months, and 12 months after transplant by serial pulmonary function testing (PFT), thus potentially allowing to define when BLAD trajectories are detectable at an early stage. Furthermore, this study aimed to identify risk factors associated with the development of BLAD.

Materials and Methods

This retrospective cohort study was conducted at the University Hospital Zurich, Switzerland, and included all adult double-lung transplant recipients from January 1, 2021, through December 31, 2023. These patients had been treated according to our published protocols and data concerning immunosup-pression and bronchoscope evaluations.6-8 Patients were eligible if they had undergone at least 2 PFTs at least 3 months apart during the first postoperative year. Patients with single-lung transplant, retransp-lant, incomplete follow-up, or insufficient PFT data were excluded. We defined BLAD to be the failure to achieve a peak FEV1 and/or FVC ≥80% of predicted on at least 2 separate PFTs, spaced by at least 90 days, within the first postoperative year. This definition aligns with published criteria from Liu and colleague,⁴ Li and colleagues,³ and Keller and colleagues.²

Pretransplant variables studied included age, sex, underlying primary lung disease, and body mass index (BMI). Posttransplant variables evaluated included duration of surgery, intensive care unit (ICU) stay, standard ward stay, rehabilitation duration. Acute cellular rejection episodes were defined according to the Revised Working Formulation of the International Society for Heart and Lung Transplantation9 (ISHLT) at 3 months, 6 months, 9 months, and 12 months, based on available transbronchial lung forceps biopsies and cryobiopsies performed. The presence of rejection was defined as an ISHLT A-score ≥1.

Routine surveillance bronchoscopies were not always feasible because of clinical circumstances, including the COVID-19 pandemic, concurrent infections, severe lung function deterioration after a previous bronchoscopy with transbronchial forceps biopsies or cryobiopsies, other complications, or patient adherence issues. Therefore, not all patients had biopsy data available at each timepoint. The PFT, including FEV1 and FVC, were performed according to the guidelines of the American Thoracic Society and the European Respiratory Society.¹⁰

Posttransplant donor-specific antibodies (DSAs) were assessed using a Luminex-based single-antigen bead assay (LABScreen, One Lambda). Antibodies were defined as positive if the mean fluorescence intensity exceeded 500 U. The DSA screening for most patients was routinely performed at 3 months, 6 months, 9 months, and 12 months after transplant or when clinically indicated.

Continuous variables were compared using independent-sample t tests or the Mann-Whitney U test when appropriate. Categorical variables were compared using the chi-square test or the Fisher exact test. To compare acute cellular rejection, the Fisher exact test was used instead of the chi-square test to determine statistical significance, due to limited group sizes at specific intervals. P < .05 was considered statistically significant. Two-sided tests were used. We used SPSS software (version 29) for statistical analyses. The local Ethics Committee of the Canton of Zurich, Switzerland, approved this study (BASEC-Nr. 2024-02487).

All patients included in the study provided written informed consent. All data were anonymized prior to analyses, and the study was conducted in accordance with the ethical guidelines of the 1975 Helsinki Declaration.

Results

Of the 80 patients included, 47 (58.8%) met the present criteria for BLAD diagnosis, and 33 (41.2%) had normal lung function development within the first postoperative year. Baseline characteristics are presented in Table 1. Patients with BLAD were significantly younger than those without BLAD. Sex distribution and underlying diagnoses (chronic obstructive pulmonary disease, interstitial lung disease, pulmonary hypertension, and cystic fibrosis) did not differ significantly between groups. The BMI values were comparable.

Table 2 shows the postoperative course. Patients with BLAD experienced significantly longer ICU and overall hospitalization durations. There were no significant differences in hospital ward stay duration, rehabilitation time, or frequency of repeat thoraco-tomy. Rates of acute rejection (at 3, 6, 9, and 12 months) and the incidence of DSA were similar between groups. Presence of new-onset DSA was detected in 13 of 33 patients with normal lung function (39.4%) and in 19 of 46 patients with BLAD (40.4%) during the first year after lung transplant (P = 1.000). Although DSA screening was routinely scheduled every 3 months in the first posttransplant year, measure-ments were inconsistently obtained in all patients because testing was typically performed during outpatient visits and was often deferred during inpatient stays due to logistical considerations. Therefore, the denominators in Table 2 reflect the number of patients with available DSA measurements, which may differ slightly from the total cohort sizes.

Lung function (FEV1 and FVC) measurements, by definition, were significantly lower in the BLAD group (Table 3). The differences in pulmonary function of patients with BLAD versus patients without BLAD (visualized in Figure 1 and Figure 2) demonstrated evolution of FEV1 and FVC (as % of predicted value) over time (3-12 months after transplant). Patients with BLAD consistently exhibited lower lung function across all timepoints, with minimal catch-up beyond 6 months.

Discussion

In this retrospective cohort study, we found that 59% of double-lung transplant recipients developed BLAD within the first postoperative year according to the present definition. Patients with BLAD had, by definition, significantly lower pulmonary function at 3 months, 6 months, 9 months, and 12 months, including both FEV1 and FVC values. Patients with BLAD also had significantly longer ICU stays (mean 21.2 vs 9.2 days) and total hospital stays, suggesting increased perioperative complications or delayed allograft recovery. Interestingly, we also observed that BLAD occurred more frequently in younger patients. Although the exact mechanism is unclear, this greater frequency in younger patients may reflect differences in immune system activity, response to early injury, or possible selection bias in transplant allocation. Further prospective studies are needed to understand this age-related trend. This finding highlights BLAD as a clinically burdensome phenotype, not merely a spirometric observation.

Interestingly, no significant differences were found in sex distribution, BMI, or underlying pul-monary diagnosis. This lack of association between pretransplant diagnosis and BLAD development is noteworthy. Although previous assumptions have suggested that fibrotic or suppurative lung diseases could influence graft recovery, our findings support the notion that early graft dysfunction may be influenced more by perioperative, donor, or nonimmunological factors rather than by recipient diagnosis. The frequency of acute cellular rejection and development of DSA was similar between the 2 groups, implying that BLAD may be influenced more by early allograft injury and healing than by classic immunological rejection mechanisms.

In our study we defined BLAD as failure to achieve a peak FEV1 and/or FVC ≥80% of predicted within the first year following double-lung transplant, which reflects the present definition and understanding of BLAD. This definition aligns with previously published criteria,2,4 for which a patient’s best lung function during the first year serves as the reference point to establish early BLAD. Additionally, for increased diagnostic robustness, cases should have persistently reduced FEV1 and/or FVC for at least 2 measurements ≥90 days apart, as described by Li and colleagues in 2021.³ Table 4 provides a side-by-side comparison of BLAD definitions used in prior studies and highlights how our study definition incorporates both peak and persistent dysfunction criteria.

Our findings are consistent with recent multi-center studies that have identified BLAD as a distinct and clinically relevant phenotype following lung transplant. Liu and colleagues4 and Keller and colleagues2 both reported that BLAD was associated with impaired survival after bilateral lung transplant, with hazard ratios of 2.23 and 1.97, respectively. This association appears to be independent of CLAD, as demonstrated in another study3 in which severe primary graft dysfunction (PGD3) increased the risk of BLAD but not CLAD. Our results seem to support these observations by showing significantly worse functional recovery and prolonged hospitalization in patients with BLAD, in the absence of an increased incidence of acute rejection or DSA development. We might conclude that BLAD is a unique clinical phenotype with early lung allograft dysfunction, and not simply an early manifestation of CLAD.

Moreover, although BLAD is associated with worse early outcomes, its direct progression to CLAD remains controversial. Several studies have shown no significant increase in CLAD incidence in patients with BLAD after adjustment for covariates.^2,3 This aligns with our findings, for which the incidence of CLAD did not differ significantly between groups.

The lack of a strong molecular correlate, such as elevated donor-derived cell-free DNA levels in patients with BLAD, as has been reported in a previously published study, further suggests that BLAD may reflect a failure in physiological recovery rather than ongoing immune injury.² Thus, BLAD may represent a distinct and potentially modifiable risk phenotype.

Our study supports the inclusion of BLAD in early posttransplant risk stratification. Identification of patients who fail to achieve normalized pulmo-nary function may allow earlier interventions such as intensified rehabilitation, tailored immunosup-pression, or closer surveillance.

Limitations of our study include its retrospective design and single-center setting, which may limit generalizability. In addition, although we reported differences in functional and clinical outcomes, the sample size limited the multivariable modeling for survival or progression to CLAD. Prospective studies with longitudinal molecular and physiological phenotyping are needed to further explore the mechanisms and clinical implications of BLAD. A clear definition of BLAD is also needed, which remains a matter of scientific debate. Presently, the Advanced Lung Failure and Transplantation network, an expert panel within the ISHLT, is working toward a consensus definition of BLAD, emphasizing its emerging importance as a clinically distinct posttransplant phenotype.

Conclusions

Baseline lung allograft dysfunction is common after lung transplant and is associated with impaired functional recovery and prolonged hospitalization. Although not clearly linked to CLAD, BLAD independently reflects suboptimal graft performance and may hold prognostic value. Future work should focus on identification of mechanisms and modi-fiable risk factors to optimize recovery in this vulnerable subgroup. Given the high incidence of BLAD in our cohort and the lack of immunological correlates, our findings support the inclusion of non-immunological recovery markers in early post-transplant risk stratification. As BLAD gains recognition as an independent phenotype, early identification and supportive strategies may be key for improvement of patient outcomes. Future studies should examine whether early intervention in patients with BLAD can alter the trajectory toward CLAD and improve long-term survival. The association of BLAD withprolonged ICU stays underscores its clinical relevance and the need for targeted early management strategies.

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