Chronic lung allograft dysfunction: a narrative review of evolving concepts in diagnosis and management

Introduction

Chronic lung allograft dysfunction (CLAD) describes a sustained loss of graft function, defined by a persistent decline of at least 20% in forced expiratory volume in one second (FEV₁) from a patient’s post-operative baseline. That baseline is typically calculated as the average of the two highest FEV1 measurements obtained after transplant, separated by at least three weeks (1). CLAD remains one of the most significant long-term complications after lung transplantation, affecting nearly one-third of recipients by three years and roughly half by five years (2). The two major phenotypes include: bronchiolitis obliterans syndrome (BOS), which reflects airway-predominant injury and accounts for about 70% of cases, and restrictive allograft syndrome (RAS), a parenchymal-predominant process that makes up the remainder. Together, these syndromes are responsible for more than 40% of deaths occurring beyond the first post-transplant year (1,3). Additionally, CLAD has major implications on functional status, worsening lung transplant recipient distress, and introduces complex management decisions for patients and clinicians (4).

Despite advances in lung transplantation, the diagnosis and management of CLAD remain limited by several important challenges. Current diagnostic frameworks rely heavily on spirometric decline, which often reflects established and potentially irreversible injury rather than early disease. In addition, heterogeneity in CLAD phenotypes complicates prognostication and treatment selection, while available therapies are largely focused on slowing disease progression rather than reversing allograft dysfunction. The absence of validated early biomarkers and limited prospective data further constrain efforts toward timely intervention and individualized care.

Several prior reviews have examined individual aspects of CLAD, including immunopathogenesis, diagnostic approaches, imaging findings, or therapeutic strategies. However, many of these reviews focused on isolated domains of disease or preceded more recent advances in quantitative imaging, oscillometry, molecular biomarkers, and phenotype-specific management strategies (5-13). In addition, the rapidly evolving understanding of CLAD phenotypes and multimodal diagnostic integration has created a need for updated synthesis across classification, pathophysiology, diagnosis, and treatment. This review aims to provide a contemporary and clinically focused overview of CLAD while highlighting current limitations, emerging diagnostic modalities, and future directions in personalized management.

The objective of this narrative review is to provide a contemporary synthesis of CLAD classification, pathophysiology, diagnosis, and management. We present this article in accordance with the Narrative Review reporting checklist (available at https://ccts.amegroups.com/article/view/10.21037/ccts-2026-1-0004/rc).

Methods

This narrative review was conducted through a structured literature search to identify relevant studies on CLAD. The search was performed using PubMed and Google Scholar, with the final search conducted on January 10, 2026. Studies published between January 2000 and January 2026 were considered. A summary of the search strategy and study selection process is provided in Table 1.

Search terms included combinations of “chronic lung allograft dysfunction”, “bronchiolitis obliterans syndrome”, “restrictive allograft syndrome”, “lung transplantation”, “biomarkers”, “imaging”, and “immunomodulation.” The search strategy was adapted for each database and supplemented by manual review of references from selected articles.

Articles were included based on relevance to the pathophysiology, diagnosis, and management of CLAD, with priority given to randomized controlled trials, large observational studies, and high-impact reviews. Only English-language publications were included.

Classification

CLAD is currently divided into BOS, RAS, a mixed phenotype with features of both, and an undefined form that meets spirometric criteria for CLAD but does not fulfill physiologic or radiographic criteria for BOS or RAS (1). This framework has helped clarify the diverse pathways of chronic rejection, allows for a more tailored approach to diagnosis and management as well as prognostication. Phenotyping relies primarily on the pattern of physiologic impairment and the presence or absence of radiographic abnormalities.

BOS is characterized by an obstructive pattern on pulmonary function testing, typically reflected by an FEV₁/forced vital capacity (FVC) ratio below 70%, preserved lung volumes (total lung capacity greater than 90% of baseline and FVC above 80%), and evidence of air trapping on CT imaging. The severity of the disease will be based on the FEV₁ decline. When histopathology is available, obliterative bronchiolitis supports the diagnosis. RAS, in contrast, combines a persistent decline in FEV₁ of at least 20% from baseline with reduced lung volumes, defined by a total lung capacity drop of 10% or more or, when TLC is not available, an FVC decline of at least 20%. Imaging shows persistent pleuroparenchymal opacities, and biopsy specimens may reveal pleuroparenchymal fibroelastosis (1,12,14).

Mixed CLAD describes patients who display both obstructive and restrictive physiology with radiographic opacities, suggesting combined airway and parenchymal involvement. Undefined CLAD includes patients who meet criteria for obstruction and have CT infiltrates but do not demonstrate the restrictive thresholds required for RAS. These patients may represent early or evolving disease that does not yet fit a definitive phenotype (11).

Accurate classification carries important prognostic weight. Median survival after RAS diagnosis is markedly shorter—often 6 to 18 months—compared with the 3 to 5 years commonly observed in BOS. This gap remains evident even after re-transplantation, underscoring the aggressive nature of restrictive CLAD and the importance of early and precise phenotyping (11,13,15).

Pathophysiology

CLAD develops from a sustained interaction between innate and adaptive immune pathways that begin with epithelial injury and progress toward chronic inflammation, dysregulated repair, and fibrosis within the airway or parenchyma of the transplanted lung (5). Because the lung is continuously exposed to the external environment, innate immune pathways are activated readily in response to microbial products and endogenous danger signals (16). Pattern recognition receptors, including toll-like receptors, sense pathogen-associated molecular patterns as well as damage-associated molecular patterns released during epithelial stress and cell death (17). These signals initiate downstream inflammatory cascades and recruit innate effector cells, creating a microenvironment that can prime subsequent alloimmune responses. Experimental work has shown that inflammatory cell death programs, such as necroptosis, amplify these early pathways by promoting rapid neutrophil activation and cytokine release (18).

Innate immune cells contribute in multiple ways to the development of chronic lung allograft injury. Neutrophils can intensify inflammation through proteolytic enzymes, extracellular traps, reactive oxygen species, and enhancement of costimulatory signaling (19). Eosinophils may support profibrotic remodeling through transforming growth factor beta signaling, eosinophil cationic protein–mediated fibroblast activation, and direct epithelial injury, and their presence in transbronchial biopsies has been independently associated with substantially increased risks of CLAD and death after lung transplantation (20). Monocytes and macrophages respond to early epithelial signals, shape antigen presentation, and participate in long-term remodeling; high-resolution profiling demonstrates substantial macrophage heterogeneity in CLAD, with subpopulations that can either propagate inflammation or engage in regulatory programs (9). Natural killer cells demonstrate heightened cytotoxic activity and Th1-type cytokine production in the CLAD allograft, reflecting another layer of innate immune activation (21). Together, these innate pathways create a persistent inflammatory milieu that supports the transition from acute injury to chronic structural remodeling.

Adaptive immunity reinforces and sustains these early signals. Alloantibody formation represents a major humoral pathway, arising when injury-driven antigen presentation and germinal center activation promote the development of donor-specific antibodies (19). These antibodies can injure the allograft through complement activation, endothelial stimulation, and cytokine signaling. Autoantibodies to lung-restricted antigens, including collagen V and K-alpha-1 tubulin, may emerge when repeated epithelial disruption exposes previously sequestered antigens, linking tissue injury to loss of self-tolerance (22,23). Cell-mediated mechanisms operate in parallel. Allorecognition through direct, semidirect, and indirect pathways activates multiple T-cell subsets. Th1 and Th17 cells participate in macrophage activation, neutrophil recruitment, epithelial activation, and autoimmune responses (24). Follicular helper T cells promote B-cell maturation and alloantibody production, bridging cellular and humoral immunity (25). Regulatory T cells counterbalance these pathways, and reduced regulatory activity has been associated with greater susceptibility to chronic alloimmune injury. Expansion of regulatory programs may also contribute to the immunomodulatory effects seen with therapies such as extracorporeal photopheresis (ECP) (26).

These processes unfold within a distinctive immunologic landscape in the transplanted lung. Tertiary lymphoid structures, including bronchus-associated lymphoid tissue (BALT), frequently develop within the allograft and serve as sites where local antigen presentation, T-cell differentiation, and B-cell activation can occur (27). Depending on context, these structures may support either tolerance or chronic immune activation. Experimental models demonstrate that BALT enriched with Foxp3⁺ regulatory T cells promote stable graft acceptance, with local accumulation and lymphatic egress of these cells enabling suppression of alloimmune responses both within the lung allograft and at peripheral donor-matched sites. Disruption of these regulatory networks permits unchecked local immune activation and propagation of alloimmune and humoral responses (28). This dynamic interplay between innate signaling, adaptive immunity, and local lymphoid architecture creates a self-reinforcing injury-repair loop that drives the airway-predominant or parenchymal fibrosis characteristic of CLAD.

Histopathologic studies have shown that CLAD represents a continuum of airway, parenchymal, and pleural fibrosis rather than discrete, isolated processes. Explant analyses from patients undergoing re-transplantation demonstrate higher semi-quantitative scores for airway fibrosis, parenchymal remodeling, pleural thickening, and epithelial and vascular abnormalities compared with control lungs (29). Although BOS and RAS share many of these structural changes, the distribution and severity differ. BOS is dominated by small airway fibrosis and obliteration, whereas RAS shows a broader pattern of injury that includes marked subpleural and interstitial fibrosis, elastin deposition, and more pronounced vascular remodeling (30). These distinctions mirror the physiologic divergence between the phenotypes: airway-predominant narrowing and air trapping in BOS, and pleuroparenchymal fibroelastosis with restrictive physiology in RAS. Together, these findings highlight that CLAD encompasses overlapping but regionally distinct patterns of chronic injury and repair, shaped by the underlying immune and epithelial responses described above.

Diagnosis

Although CLAD is formally defined by a sustained decline in FEV₁ of at least 20% from post-transplant baseline, most transplant centers initiate a comprehensive evaluation much earlier, typically when a decline of 10% or more is detected (6,12). This early investigation reflects the understanding that spirometric decline often precedes established CLAD and may represent reversible injury. Additionally, earlier modification to the immunosuppression therapy can stabilize the lung function and progression of CLAD. Evaluation should focus on identifying pulmonary and extrapulmonary contributors to reduced lung function and addressing them promptly. Key pulmonary processes to assess include acute infection, acute cellular rejection, antibody-mediated rejection, and aspiration, all of which are not only common causes of spirometric decline but also important contributors to the development of CLAD. Mechanical and systemic factors must also be considered, including weight gain, persistent pleural effusions, pulmonary edema related to cardiac, hepatic, or renal dysfunction, airway stenosis, recurrence of underlying lung disease, findings of progressive rheumatological diseases, and neuromuscular conditions such as myopathy or neuropathy (1,6,12,14).

When lung function declines by at least 20% from baseline and remains reduced for three weeks after the initial drop despite evaluation and treatment of alternative causes, the condition is classified as possible CLAD. If this decline persists beyond three weeks but less than three months, it is termed probable CLAD. Definite CLAD is diagnosed when lung function remains reduced by at least 20% for more than three months despite appropriate investigation and management of potentially reversible contributors (1). Importantly, clinical intervention should not be delayed until the diagnosis of definite CLAD is established, as earlier recognition and treatment may influence disease trajectory. Once CLAD is diagnosed, disease severity can be staged according to the degree of FEV₁ decline from baseline: stage 0 is defined by an FEV₁ greater than 80% of baseline, stage 1 by an FEV₁ greater than 65% but less than or equal to 80%, stage 2 by an FEV₁ greater than 50% but less than or equal to 65%, stage 3 by an FEV₁ greater than 35% but less than or equal to 50%, and stage 4 by an FEV₁ less than or equal to 35% of baseline (1). Advanced stages of CLAD are associated with substantial morbidity and mortality. In one study, the one-year survival following progression to CLAD stage 3 or 4 was approximately 25%, with nearly half of affected patients dying during follow-up, including those with long-standing advanced disease (31).

The diagnosis of CLAD relies primarily on spirometric assessment, with imaging and transbronchial biopsy used to support phenotyping, yet this approach has important limitations. Spirometry lacks sensitivity for detecting early allograft injury and often reflects structural damage only after substantial pathologic change has occurred. Recent data suggest that while FEV₁-based criteria are effective for defining established CLAD, they are less reliable for early detection. In one study, a single decline in FEV₁ of at least 10% had a positive predictive value of only 35% and a negative predictive value of 63% for subsequent CLAD or death, while a repeated decline of at least 10% persisting for three weeks modestly improved predictive performance, with a positive predictive value of 44% and a negative predictive value of 65% (32). These findings underscore the limited ability of spirometry alone to distinguish transient or reversible injury from evolving chronic allograft dysfunction. Importantly, a decline in FEV₁ of 10% or greater should be interpreted as a trigger for clinical evaluation rather than a diagnostic threshold for CLAD. While early investigation may allow identification of reversible causes and timely modification of therapy, a single decline should be interpreted with caution.

Spirometric measures may also fail to capture early small airway disease, which has prompted interest in alternative parameters such as forced expiratory flow between 25% and 75% of vital capacity (FEF_25–75). Although earlier studies suggested that declines in FEF_25–75 preceded the development of BOS, this metric was removed from the CLAD diagnostic framework in 2019 because of poor reproducibility, dependence on effort and lung volumes, and reliance on relatively small and heterogeneous cohorts (1,33,34). Single lung transplantation presents a unique challenge for CLAD diagnosis when relying on physiologic criteria, as spirometric measurements can be influenced by the native lung, particularly for those with chronic obstructive pulmonary disease and lymphangioleiomyomatosis. In a retrospective study, only 73% of single lung transplant recipients who met spirometric criteria for CLAD based on the 2019 ISHLT consensus guidelines were ultimately adjudicated to have CLAD by two independent observers, highlighting the limited specificity of physiology-based thresholds in this population (29).

These limitations have driven growing interest in adjunctive diagnostic strategies aimed at earlier detection, improved phenotyping, and mechanistic risk stratification of CLAD. Computed tomography (CT) is emerging as an important adjunct to spirometry for the evaluation of CLAD, providing regional and structural information that precedes global physiologic decline. In a study using automated quantitative analysis of paired inspiratory and expiratory CT scans, CT-derived markers of air trapping and small airway disease demonstrated strong diagnostic performance for BOS. Expiratory mean lung density achieved an area under the curve (AUC) of approximately 0.91, while measures of severe air trapping demonstrated sensitivities approaching 100% with specificities around 70%. Parametric response mapping-derived functional small airway disease showed high specificity (approximately 95%) and correlated closely with FEV₁ decline. Importantly, quantitative CT abnormalities were detectable up to one to two years before spirometric criteria for CLAD were met, with negative predictive values ranging from 95% to 100% for near-term disease progression (35). Complementary findings were observed in a separate cohort evaluating quantitative CT lung density at the time of an early 10–19% decline in FEV₁, where density metrics predicted subsequent CLAD development within three years. Predictive performance was particularly strong in single lung transplant recipients, with an AUC of 0.89, underscoring the added value of CT in settings where spirometry is confounded by native lung contribution. In bilateral transplant recipients, CT density alone showed more modest discrimination (AUC 0.63), but performance improved when combined with physiologic and radiographic features, highlighting the role of CT as part of a multimodal approach to earlier CLAD detection and phenotyping (36). Magnetic resonance imaging (MRI) is also emerging as a potential imaging modality for CLAD assessment, offering radiation-free evaluation of regional lung function and ventilation. Several MRI-based techniques, including phase-resolved functional lung MRI (37), Fourier decomposition MRI (38), oxygen-enhanced T1 mapping (39), and hyperpolarized gas imaging (40), have demonstrated the ability to detect functional abnormalities and predict adverse outcomes before overt spirometric decline in research settings. However, the use of MRI remains largely investigational (41). Limited availability, lack of standardized protocols, need for specialized expertise, and logistical constraints currently restrict its routine clinical use.

Impulse oscillometry (IOS) is a noninvasive physiologic modality based on the forced oscillation technique, in which pressure waves at multiple frequencies, typically 5–35 Hz, are applied to the respiratory system during tidal breathing. The resulting pressure and flow signals are used to calculate respiratory impedance, composed of resistance, reflecting opposition to airflow, and reactance, reflecting the elastic and inertial properties of the respiratory system. Given its sensitivity to small airway dysfunction, IOS has been proposed as a tool for earlier detection of CLAD (10). However, in the largest prospective longitudinal study to date involving bilateral lung transplant recipients, IOS parameters, while correlated with spirometric measures of airflow obstruction and reflective of established BOS, did not reliably predict future BOS or precede spirometric decline. Baseline IOS abnormalities were not independently associated with BOS progression after adjustment for FEV₁, suggesting that IOS, like spirometry, primarily reflects established disease rather than enabling early detection (42). More recent data suggest that oscillometry may aid in CLAD phenotyping at disease onset, distinguishing BOS from CLAD-free states and from RAS, but its utility appears greatest for characterizing established disease rather than enabling early diagnosis (43).

Beyond physiologic and imaging-based approaches, growing interest has focused on molecular biomarkers derived from blood, bronchoalveolar lavage, and airway tissue to enable earlier detection and improved risk stratification of CLAD. Circulating inflammatory proteins, chemokines, microRNAs, and cell-free nucleic acids have been associated with CLAD development, phenotype, and outcomes, while BAL-based markers of epithelial injury, inflammation, and cell-free DNA correlate with disease severity and survival (44-49). Among emerging biomarkers, donor-derived cell-free DNA (50,51) and chemokines such as CXCL9 and CXCL10 (45) have demonstrated the most consistent performance across multicenter and prospective studies, with potential utility in detecting subclinical injury and predicting CLAD risk. In contrast, other biomarkers, including circulating inflammatory proteins (52,53) and microRNAs (46), are supported by smaller and more heterogeneous studies, with variability in study design, patient populations, and endpoints limiting their reproducibility and clinical generalizability. Notably, while several markers show promise for phenotype differentiation or early detection, their performance has not been consistently validated across cohorts. As a result, no single biomarker has demonstrated sufficient robustness to support routine clinical implementation, highlighting the need for standardized prospective studies.

Transcriptomic profiling of blood, airway brushings, and transbronchial biopsies has further identified immune activation and wound-response gene signatures that may precede clinical CLAD by several months and predict graft failure (54,55). More recently, integrative multi-omic approaches combining clinical, immunologic, proteomic, and transcriptomic data have generated predictive signatures associated with CLAD onset and progression (56).

Management

Management of CLAD is fundamentally limited by the largely irreversible nature of established allograft injury. Once CLAD develops, therapeutic strategies are primarily aimed at slowing further functional decline, mitigating ongoing immune-mediated damage, and optimizing quality of life rather than restoring lost lung function. Current approaches focus on supportive care focused on symptom control and preservation of functional status, and interventions directed at suppressing or modulating ongoing alloimmune and inflammatory injury. These include targeted pharmacologic therapies affecting immune effector pathways, as well as more global immunomodulatory strategies such as ECP and total lymphoid irradiation (Table 2). The strength of evidence supporting current CLAD therapies varies considerably. While some interventions are supported by randomized controlled trials, many are based on observational studies or small cohorts, which should be considered when interpreting their clinical utility.

Azithromycin

Azithromycin is one of the most well-established pharmacologic therapies in CLAD management, with evidence supporting its use in both prophylaxis and treatment. Its beneficial effects appear to be mediated primarily through anti-inflammatory and immunomodulatory mechanisms rather than antimicrobial activity. Azithromycin reduces airway neutrophilia, decreases bronchoalveolar lavage levels of IL-8, IL-1β, and other proinflammatory mediators, lowers systemic C-reactive protein, and has demonstrated efficacy in treating lymphocytic airway inflammation (57,58). The standard dosing regimen is 250 mg three times weekly, used consistently across both prophylactic and therapeutic settings.

Multiple studies support the use of prophylactic azithromycin to reduce CLAD incidence and improve CLAD-free survival. In a randomized controlled trial, prophylactic azithromycin reduced the development of BOS from 44.2% to 12.5% at two years post-transplant and significantly improved BOS-free survival [hazard ratio 0.27, 95% confidence interval (CI): 0.092–0.816] (59). Long-term follow-up of this cohort demonstrated sustained benefit at seven years, with CLAD occurring in 28% of azithromycin-treated patients compared with 51% of placebo-treated patients (60). Observational data suggest that earlier initiation may confer greater protection, with initiation as early as three weeks post-transplant associated with lower CLAD incidence and severity at one, three, and five years, although protective effects are observed when azithromycin is started at any time while lung function remains preserved (61). A recent meta-analysis confirmed these findings, demonstrating a reduced risk of CLAD onset (relative risk 0.64, 95% CI: 0.51–0.81) and improved three- and five-year CLAD-free survival (62). Prophylactic azithromycin has also been associated with improved overall survival, with one large cohort study reporting a 41% reduction in mortality (hazard ratio 0.59, 95% CI: 0.42–0.82), potentially mediated through mitigation of early allograft dysfunction (63). Despite this, there is a wide practice variability (64), with Kapnadak et al. noted that only 29% of lung transplant programs prescribe azithromycin prophylactically.

In the treatment of established BOS, azithromycin produces a clinically meaningful response in approximately half of patients, particularly among those with elevated BAL neutrophilia, typically defined as ≥15–20% and previously known and neutrophil reactive allograft dysfunction. Responders most often demonstrate stabilization or improvement in lung function, with FEV₁ increases of at least 10% (57). In one open-label study, 52.2% of patients with established BOS experienced FEV₁ improvement following azithromycin initiation, supporting its role as a first-line therapy in neutrophilic and inflammation-predominant CLAD phenotypes (59). Notably, the evidence supporting azithromycin includes randomized controlled trial data as well as observational studies, although variability in study design and patient selection remains a limitation.

Leukotriene receptor antagonist

Leukotriene receptor antagonism represents another anti-inflammatory strategy for the management of established CLAD. Montelukast has been shown to attenuate the rate of FEV₁ decline in patients with progressive disease, particularly after failure of azithromycin therapy. In the largest study to date, which included 153 lung transplant recipients with CLAD (predominantly BOS but also including restrictive phenotypes) who had failed at least three months of azithromycin, montelukast significantly slowed FEV₁ decline at both three and six months (P<0.001). Approximately 81% of patients demonstrated stabilization or improvement in lung function after three months of therapy, and this response was associated with significantly improved progression-free survival and overall survival. Patients with continued FEV₁ decline had a markedly higher risk of mortality, with a risk-adjusted hazard ratio for death of 2.8 (65). The therapeutic effect of montelukast is thought to relate to inhibition of leukotriene-mediated airway inflammation and fibrotic remodeling, pathways implicated in CLAD pathogenesis (66). Although the supporting evidence is largely derived from retrospective and uncontrolled studies, montelukast is generally well tolerated and is often used as a second-line agent following azithromycin failure, either alone or as part of combination regimens such as the fluticasone-azithromycin-montelukast (FAM) protocol (6). Although generally well tolerated, montelukast has been associated with neuropsychiatric adverse effects, including mood and behavioral changes, prompting an FDA boxed warning; clinicians should counsel patients regarding these risks and monitor for new or worsening symptoms during therapy (67). However, the supporting evidence is derived primarily from retrospective and uncontrolled studies, which limits the strength of conclusions regarding efficacy.

Inhaled cyclosporine

Inhaled cyclosporine has been explored as a rescue therapy for established CLAD, with several single-center and case-control studies suggesting stabilization of lung function and improved survival when added to conventional immunosuppression. Across these studies, aerosolized cyclosporine was associated with attenuation of FEV₁ decline and, in some cohorts, a survival advantage compared with historical or contemporaneous controls, with particularly favorable signals observed in single-lung transplant recipients (68-70). The proposed benefit relates to high local allograft drug delivery with minimal systemic absorption, resulting in limited nephrotoxicity and acceptable tolerability. However, the evidence base consists largely of small, nonrandomized studies, and a phase 3 trial of liposomal inhaled cyclosporine was terminated early before meeting enrollment targets (71). Taken together, inhaled cyclosporine remains infrequently used in contemporary practice and is generally reserved for highly selected, refractory cases rather than routine CLAD management.

Lymphocyte depleting therapy

Lymphocyte-depleting therapies have been used as salvage strategies in patients with rapidly progressive CLAD refractory to conventional immunomodulation, with the primary goal of slowing disease progression rather than reversing established injury (7). Anti-thymocyte globulin (ATG) has demonstrated partial physiologic response in a majority of treated patients, with approximately 70–80% showing attenuation in the rate of FEV₁ decline, although absolute improvement in lung function is uncommon (72). Benefit appears greatest in patients with more rapid pre-treatment decline and earlier-stage disease, with better stabilization and longer survival observed when ATG is initiated in CLAD stages 1–2 compared with more advanced stages. Across studies, patients achieving stabilization after ATG have significantly longer survival than non-responders, highlighting the importance of patient selection and timing (73).

Alemtuzumab, a monoclonal anti-CD52 antibody that induces profound lymphocyte depletion, has also been evaluated in both refractory acute rejection and established CLAD. In BOS cohorts, alemtuzumab has been associated with stabilization or improvement in disease severity in approximately two-thirds of patients, with sustained freedom from progression in a substantial subset at two years (74). Comparative data suggest similar effects on lung function stabilization when compared with ECP, though alemtuzumab carries a higher risk of cytopenias and infectious complications, which often limits its use (6,75).

Total lymphoid irradiation represents another lymphocyte-depleting approach that has shown the ability to stabilize lung function in both BOS and restrictive CLAD phenotypes. Small studies demonstrate marked attenuation of FEV₁ decline following treatment, particularly among patients with preserved functional status at baseline, while radiation-related toxicity has generally been manageable (76). However, the evidence base consists largely of small, nonrandomized studies, limiting generalizability and routine clinical application.

ECP

ECP is a second-line immunomodulatory therapy for CLAD that exerts its effects by inducing apoptosis of circulating leukocytes, leading to downstream immune tolerance through reduced proinflammatory cytokine signaling and expansion of regulatory T cells. Through these mechanisms, ECP dampens alloimmune injury without causing broad lymphocyte depletion (8). Across studies, ECP stabilizes or improves lung function in approximately 50–70% of treated patients, and responders demonstrate significantly better long-term survival compared with non-responders (7,77,78). ECP’s role in lung transplant may be evolving.

In addition to its therapeutic role, ECP has been evaluated as a prophylactic strategy. A landmark randomized controlled trial demonstrated that the addition of prophylactic ECP to standard triple immunosuppression significantly reduced the incidence of high-grade acute cellular rejection, cytomegalovirus infection, and CLAD. In this study, only 19.4% of patients receiving ECP met the composite endpoint within 24 months compared with 61.3% in the control group, with significantly greater freedom from CLAD at three years and lower cumulative acute rejection scores (79).

For established CLAD, the largest multicenter European cohort to date, including 631 patients, showed that 42% achieved long-term stabilization and 9% experienced improvement following ECP. Survival differed markedly by response, with five-year survival of 70% among responders, 56% among those with stabilized disease, and 35% among non-responders. Both stabilization and improvement were independently associated with reduced mortality (78). ECP also significantly attenuates the rate of FEV₁ decline in responders, with multiple studies demonstrating a marked reduction in post-treatment decline compared with pre-treatment trajectories or placebo (8,80).

Response to ECP is strongly influenced by disease phenotype and timing. Patients with BOS derive greater benefit than those with RAS, which has consistently been associated with poorer outcomes and higher mortality after ECP (77,78). Higher baseline FEV₁ at the time of ECP initiation predicts improved survival, underscoring the importance of early referral before advanced functional decline (77,78). Additional factors associated with reduced response include rapid pre-treatment FEV₁ decline, absence of bronchoalveolar lavage neutrophilia, female sex, neutropenia, and prior exposure to lymphocyte-depleting therapies (81).

Overall, ECP is well tolerated, with a favorable safety profile and lower infectious risk compared with lymphocyte-depleting agents. Although the absence of large contemporary randomized trials remains a limitation, the consistency of observational data and balance of efficacy and safety position ECP as one of the most effective disease-modifying therapies currently available for progressive CLAD.

Re-transplantation

Lung re-transplantation remains the only definitive therapy for end-stage CLAD and can achieve survival outcomes comparable to primary lung transplantation when patients are carefully selected. Contemporary single-center and multicenter studies demonstrate similar one- and five-year survival between re-transplantation for CLAD and primary transplantation, particularly in patients with BOS and preserved functional status (82,83). Outcomes are consistently worse in patients with RAS, early re-transplantation within two years post-transplant, or those requiring intensive care unit support, mechanical ventilation and/or extracorporeal support at the time of listing (84). Although re-transplantation is associated with greater perioperative complexity, functional improvement and quality-of-life gains are meaningful, supporting its role in select patients with advanced CLAD (85).

Supportive care

Supportive care is a central component of CLAD management and focuses on symptom control, preservation of functional capacity, and quality-of-life optimization as allograft dysfunction progresses (14). Because current therapies can at best slow or stabilize lung function decline, supportive interventions are essential throughout the disease course and include close physiologic surveillance, pulmonary rehabilitation, supplemental oxygen, optimization of bronchodilator therapy, management of comorbidities such as infection and gastroesophageal reflux, and adjustment of maintenance immunosuppression (12,14). Early integration of palliative care is particularly important in advanced CLAD to address symptom burden, guide advance care planning, and provide support and resources to patients and their caregivers who are not candidates for re-transplantation (14,86).

Conclusions

CLAD remains the principal barrier to durable long-term survival after lung transplantation, reflecting the cumulative consequences of immune-mediated injury, dysregulated repair, and progressive fibrosis. Although current diagnostic criteria rely on spirometric decline, emerging imaging, physiologic, and molecular tools highlight important opportunities for earlier detection, improved phenotyping, and more precise risk stratification. Management strategies remain largely focused on slowing disease progression rather than reversing established injury, with therapies such as azithromycin, leukotriene receptor antagonists, ECP, and selective immunomodulation offering benefit in carefully selected patients. Retransplantation provides meaningful survival and quality-of-life gains for a subset of patients with advanced disease, while supportive and palliative care remain essential across all stages of CLAD. Taken together, these advances support a shift toward a multimodal framework that integrates physiologic, imaging, and molecular data for earlier detection, improved phenotyping, and more precise risk stratification in CLAD. In addition, studies evaluating phenotype-specific therapeutic approaches are needed to better define which patients are most likely to benefit from targeted immunomodulation. Finally, multicenter efforts will be critical to validate emerging biomarkers and establish clinically actionable thresholds for intervention.

This review has several strengths, including a comprehensive synthesis of evolving concepts in CLAD and integration of emerging diagnostic and therapeutic approaches across multiple domains. However, it is limited by its narrative design, potential selection bias, and reliance on heterogeneous studies with varying levels of evidence. These limitations reflect broader challenges within the CLAD literature and underscore the need for more standardized and prospective studies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://ccts.amegroups.com/article/view/10.21037/ccts-2026-1-0004/rc

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-2026-1-0004/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-2026-1-0004/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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