Approach to prevention and management of chronic lung allograft dysfunction in North American lung transplant centers

Abstract

Chronic lung allograft dysfunction (CLAD) is the major barrier to long-term survival after lung transplantation, but literature documenting contemporary practice patterns and best practices for management are lacking. We sought to characterize monitoring and lung function–dependent management strategies across adult North American lung transplant centers.

A RedCap survey was distributed to 21 centers accounting for nearly half of North American lung transplants. Routine immunosuppression and post-transplant graft monitoring protocols were similar among centers. Prophylactic azithromycin was routinely used by seven (33.3%) centers and respondents had substantial uncertainty regarding its effectiveness. A persistent ≥10% FEV₁ decline was considered clinically meaningful by most centers and triggered similar evaluations, including bronchoscopy, donor-specific antibody testing, and chest CT. However, both the lung function thresholds prompting intervention and specific therapeutic strategies varied substantially. These findings highlight significant heterogeneity in CLAD management and support the need for prospective studies to inform evidence-based approaches.

There has been substantial progress in standardizing the diagnosis and classification of chronic lung allograft dysfunction (CLAD) after lung transplantation (LTx),^1,2 but robust data to guide optimal monitoring and management strategies are lacking. Consequently, clinical practice related to CLAD seems to vary widely, and published data describing contemporary practice patterns are sparse. One study demonstrated significant variability even with azithromycin use among international providers.³ Two recent studies further documented heterogeneity in CLAD management among European centers and pediatric programs,^4,5 but did not examine thresholds that trigger interventions. Our aim was to, for the first time, characterize detailed CLAD monitoring and management strategies among adult North American LTx programs.

The study was conducted by the Cystic Fibrosis-Lung Transplant Consortium (CFLTC), a North American network that maintains a comprehensive registry and biorepository and conducts multicenter research to improve LTx outcomes. To inform the design of a future interventional clinical trial to prevent CLAD, a panel of investigators created a 35-question Redcap survey to summarize current clinical protocols pertaining to CLAD prevention and management among all 15 centers in the CFLTC, and six additional U.S. sites. The survey was piloted among four LTx pulmonologists to ensure clarity and comprehensiveness while maintaining a reasonable completion time (average of seven minutes in the pilot; see Supplement for additional information). The survey was distributed to designated transplant center physicians between Oct-Dec, 2025 and addressed immunosuppression regimens, monitoring/testing for graft function and CLAD risk factors, and centers’ approach to lung function decline that persisted after management of acute clinical entities [e.g., acute rejection, infection (Supplement)]. If more than one response was obtained from a given center, the medical director’s response was used for the study.

Center response rate was 100%. The 21 included centers performed a total of 1,772 lung transplants between July 2024–June 2025, accounting for approximately 46% of U.S. and Canadian lung transplants over this period (Supplemental Table 1).^6,7 Nineteen of 21 centers (90.5%) reported routine use of induction immunosuppression including basiliximab universally in 13/19 (68.4%), basiliximab or thymoglobulin in three (15.8%), and basiliximab or alemtuzumab in three (15.8%). Two centers reported not using induction therapy. All centers utilized tacrolimus, mycophenolate mofetil, and prednisone for routine immunosuppression. Seven (33.3%) reported routinely initiating azithromycin after transplant in all recipients, and two (9.5%) in some recipients, for prophylaxis against CLAD. There was equipoise regarding the utility of prophylactic azithromycin, with representatives from 8 (38.1%) centers reporting a belief that azithromycin prevents lung function loss, and 12 (57.1%) being unsure of its effectiveness.

Following transplant, routine clinic visits were conducted an average of 8.1 times (range 6–14) in the first three months, and 6.8 times (range 3–9) between months 3–12. After 12 months, 14/21 (66.7%) centers reported continuing quarterly visits indefinitely, while five (23.8%) and two (10.5%) centers reported less and more frequent visits, respectively. Many centers also reported monitoring graft function outside of the transplant center, with 18 (85.7%) routinely arranging spirometry at sites closer to recipients’ homes for surveillance, evaluation of symptoms, and/or in conjunction with telemedicine visits, and 12 (57.1%) routinely providing hand-held devices for at-home spirometry. Nineteen (90.5%) centers reported routinely testing for donor specific antibodies (DSAs) as surveillance (in the absence of graft dysfunction), most often coordinated with surveillance bronchoscopies.

As a major CLAD risk factor, centers were surveyed on approach to gastroesophageal reflux (GER) both pre- and post-transplant. GER testing protocols varied significantly, with seven (33.3%) centers reporting evaluating all patients both before and after LTx, and six (28.6%) reporting testing only in selected patients (depending on clinical history). Two centers (9.5%) reported evaluating all patients before, but only selected patients after LTx, while five (23.8%) reported evaluating only selected patients before, but all patients after. The most common tests were ambulatory reflux/pH testing (including catheter-based, wireless/BRAVO, impedance), barium swallow/esophagram, gastric emptying study, esophageal manometry, and endoluminal functional lumen imaging probe (”EndoFLIP”), used either pre- or post-transplant by 20 (95.2%), 18 (85.7%), 15 (71.4%), 14 (66.7%), and three (14.3%) centers, respectively. Post-transplant GER management also varied widely. Of 19 centers who responded to questions regarding proton pump inhibitor (PPI) practices, 12 (63.2%) reported routinely prescribing PPIs to all recipients, four (21.0%) reported prescribing only in those with symptoms, abnormal pre-transplant testing, and/or in recipients who had not previously undergone fundoplication, and three (15.8%) reported other approaches to GER management (Supplemental Table 2). Regarding duration of therapy, nine centers reported prescribing PPIs indefinitely, two reported not routinely prescribing PPIs, and eight reported individualized strategies to PPI discontinuation based on time since transplant, ongoing indication for acid reduction, and/or fundoplication status (Supplemental Table 3).

Centers were asked about approach to graft dysfunction that persisted after management of acute etiologies. Fifteen of 21 (71.4%) reported that a persistent decline in FEV₁ ≥10% was moderately/very clinically meaningful, and all 21 reported that a persistent decline in FEV₁ ≥20% was moderately/very clinically meaningful. The most commonly reported tests that were performed for a persistent decline in FEV₁ were bronchoscopy, DSAs, and CT, reported by 21(100%), 20 (95.2%), and 19 (90.5%) centers, respectively (Figure 1, Supplemental Table 4).

Figure 1:

Heat map showing the distribution of testing routinely considered for a recipient who experiences a persistent FEV₁ decline, with each site represented by a row and each test shown in a column. Blue squares indicate that the test is considered by that center, and grey squares indicate that the test is not routinely considered.

Bronch: bronchoscopy; cfDNA: donor-derived cell-free DNA; CXR: chest radiograph; DLCO: diffusion capacity of carbon monoxide; DSA: donor specific antibodies; Echo: echocardiogram; FEV₁: Forced expiratory volume in one second; Resp virus: respiratory viral testing; Sinus eval: sinus evaluation.

Of 12 centers that did not use azithromycin prophylactically, one (8.3%) reported that the threshold for initiating it was a persistent FEV₁ decline of ≥5–10%, 10 (83.3%) for a threshold decline ≥10%, and one (8.3%) for a threshold decline ≥20%. Interventions that centers reported considering for a persistent decline in FEV₁ despite azithromycin varied significantly (Figure 2, Supplemental Table 5). For an FEV₁ decline of 10–20% the most common therapies considered were intravenous corticosteroids and addition of a new immunosuppression agent, reported by 14 (66.7%) and 13 (61.9%) centers, respectively. Two (9.5%) centers reported that they would not consider additional treatments at this threshold. For a FEV₁ decline >20% the most common therapies considered were extracorporeal photopheresis and addition of a new immunosuppression agent, reported by 17 (81.0%) and 14 (66.7%) centers, respectively.

Figure 2:

Heat map showing the distribution of treatment options considered for a recipient who experiences a persistent 10–20% FEV₁ decline despite azithromycin, with each site represented by a row and each treatment shown in a column. Blue squares indicate that the treatment is considered, and grey squares indicate that the test is not routinely considered. “Other” included: alemtuzumab (one site), evaluate for clinical trial eligibility (one site), and other treatment based on presumptive etiology of lung function decline (one site).

Additional IS: additional immunosuppression (e.g., mTOR inhibitor); ATG: antithymocyte globulin; Change IS: change immunosuppression; FEV₁: Forced expiratory volume in one second; IV steroids: pulse-does intravenous steroids.

Our study does have limitations. We captured responses from centers performing a large percentage of North American lung transplants, but practice patterns could differ in smaller centers, or even between providers within centers. Additionally, to limit respondent burden, we opted to focus the survey on many important aspects of CLAD but were unable to capture all strategies or approaches to causes of acute graft dysfunction. Additionally, although the survey underwent iterative development using input from multiple stakeholders and pilot testing, certain questions may have been subject to variable interpretation among respondents.

Nevertheless, to our knowledge this is the first study to document detailed CLAD practice patterns across North American adult LTx centers and demonstrates both areas of consistency and variability. Centers generally align on baseline immunosuppression, graft monitoring practices, and use of bronchoscopy, CT, and DSAs to evaluate FEV₁ decline, with most centers considering a persistent FEV₁ decline of ≥10% as clinically meaningful. In contrast, significant heterogeneity was observed in azithromycin practices, GER testing and management, along with the FEV₁ threshold prompting intervention and specific therapies employed. Importantly, these findings allow centers to compare local practices against broader North American patterns and highlight key areas of variability that represent important knowledge gaps in CLAD prevention and management, where prospective studies are needed to define evidence-based, optimal practices.

Abbreviations:

CLAD

Chronic lung allograft dysfunction

LTx

Lung transplantation

DSAs

Donor specific antibodies

GER

Gastroesophageal reflux

EndoFLIP

Endoluminal functional lumen imaging probe

CT

Computed tomography

DLCO

Diffusion capacity for carbon monoxide