Prophylactic azithromycin for chronic lung allograft dysfunction following lung transplantation: a systematic review and meta-analysis

Introduction

Lung transplantation (LTx) has evolved into an established life-extending option for selected patients with end-stage lung disease (1,2). Chronic lung allograft dysfunction (CLAD) has been the leading obstacle responsible for the long-term survival of LTx recipients being apparently lagged behind that of other solid organ transplant recipients (3-6). CLAD threatens approximately 50% of LTx recipients in the first 5 years and is marked by the progressive and substantial decline in pulmonary function (5-7). In addition to alloimmune-dependent pathways, concurrent alloimmune-independent factors (e.g., inflammatory conditions) are also widely recognized as contributor to the onset of CLAD (8-10). Due to mixed disease mechanisms, the available medical treatments, after the failure of augmented or switching immunosuppression, have been rarely successful in reversing CLAD deterioration (3,9,11,12).

Azithromycin (AZI), a macrolide antibiotic known to inhibit bacterial protein synthesis and reduce the formation of biofilm, has been the most extensively investigated drug option for alleviating CLAD, as the adjunct to conventional immunosuppressive therapy (3,11,13). Many transplant series have revealed that AZI could halt or even reverse partial pulmonary function decline in one-third of patients with CLAD, due to its antibiotic, immunomodulatory, and anti-inflammatory properties (14-19). To some extent, the therapeutic effects of AZI on CLAD have been corroborated in clinical practice, particularly for bronchiolitis obliterans syndrome (BOS) phenotype associated with bronchoalveolar lavage (BAL) neutrophilia (14,15,19-21).

However, “prophylaxis” is frequently the most effective “treatment” for patients with irreversible clinical progression. The Leuven Lung Transplant Group conducted an unprecedented randomized controlled trial (RCT) in 2011 and eventually confirmed that the recipients in the prophylactic azithromycin (pAZI) group possessed lower BOS incidence and better BOS-free survival at 2 years postoperatively compared to the placebo group (22). These promising prophylactic effects of AZI were sustained up to the post hoc analysis after 7 years (23). However, some subsequent studies, including another RCT from the same center, did not demonstrate consistent superiority of pAZI in CLAD onset or CLAD-free survival, indicating that the prophylactic effects of AZI on CLAD remain equivocal (24-26). pAZI has indeed been applied increasingly in the international LTx community despite not being considered a standard intervention for preventing CLAD (13).

Herein, we conducted a systematic review and meta-analysis to elucidate the effects of pAZI on the risk of CLAD onset and relevant survival outcomes following LTx, aiming to reconcile the existing controversy and provide a reference for clinical decision-making. We present this article in accordance with the PRISMA reporting checklist (27) (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-365/rc).

Methods

Literature search strategy

We conducted a comprehensive systematic literature search across three major databases (PubMed, Embase, and Cochrane Library) from their inception through August 2024. The search strategy incorporated the following key terms: “azithromycin”, “prophylactic”, “chronic lung allograft dysfunction”, “bronchiolitis obliterans syndromes” and “lung transplantation”. More details of the search strategy were displayed in Table S1. This meta-analysis was registered with the International Prospective Register of Systematic Reviews (PROSPERO; Registration No. CRD42024579327).

Selection criteria

RCTs and observational studies on pAZI for CLAD following LTx were considered for inclusion. Titles and abstracts were reviewed for relevance to the research purposes, and the full texts were subsequently assessed for eligibility. Articles would be confirmed as eligible if they met the following inclusion criteria: (I) studies that included LTx recipients with pAZI intervention and a corresponding control group with placebo or no intervention; (II) studies that reported the CLAD incidence, CLAD-free survival or overall survival (OS); (III) studies that included sufficient data to estimate relative risk (RR) or hazard ratio (HR) with 95% confidence intervals (CIs). Moreover, reviews, conference abstracts, case reports, comments and basic research were not under consideration. Since the concept of CLAD (or BOS) has evolved over the past two decades, the CLAD (or BOS) definition in each included study should align with the criteria of the corresponding era (3,11,28). In most circumstances, CLAD (or BOS) was described as a substantial and persistent decline (≥20%) in measured forced expiratory volume in 1 second (FEV₁) from the reference value, in the absence of other known pulmonary and extra-pulmonary causes (3). Furthermore, pAZI was defined as initiating AZI before CLAD onset.

Data extraction and quality assessment

Two authors independently executed the selection, evaluation and extraction of data. If necessary, a third author was involved to resolve any disagreement. Extracted data included first author, publication year, study period, location, study design, sample size, dosage regimen and others. The primary outcomes were the risk of CLAD onset and 3- and 5-year CLAD-free survival, while the secondary outcomes were 3- and 5-year OS. The GetData Graph Digitizer 2.26 software was employed to extract data points continuously and generate new survival curves to calculate HR with 95% CI when CLAD-free survival or OS data were unavailable in the original manuscripts (29). In addition, the Jadad scale and Newcastle-Ottawa Scale (NOS) were applied to assess the methodological quality of the included RCTs and cohort studies, respectively (30,31). Studies with Jadad scores ≥3 or NOS scores ≥6 were identified as adequate quality for inclusion.

Statistical analysis

The pooled RR of baseline characteristics was calculated using the Mantel-Haenszel method for dichotomous data, while for continuous data, the mean difference (MD) was calculated and pooled by the inverse-variance weighting method. Moreover, all pooled estimates of outcomes were calculated through the random-effect or fixed-effect model: fixed-effect model for I²<50% and random-effect model for I²≥50%. Heterogeneity among studies was assessed using Cochran’s Q-test and I² statistics, with significant heterogeneity defined as I²>50% and P value <0.1 in the Q-test. Sensitivity analysis was employed to evaluate the robustness of the pooled results, while a funnel plot was utilized to assess the publication bias. All statistical analyses were performed using Review Manager (Version 5.3, Cochrane Collaboration) and STATA (Version 15.0, Stata Corporation) software.

Results

Study selection

We retrieved 475 articles from online databases. After removing 51 duplicates, 304 publications were further excluded due to being non-original articles. Subsequently, 120 publications were reviewed by titles and abstracts, leading to the exclusion of 105 publications that did not meet the inclusion criteria. Of the remaining 15 full-text articles assessed, nine publications without pAZI intervention or target outcomes data were excluded. Ultimately, six studies met the criteria and were included in the current meta-analysis (22-26,32) (Figure 1).

Figure 1 Flow chart of the study inclusion and exclusion for this systematic review and meta-analysis. CLAD, chronic lung allograft dysfunction; LTx, lung transplantation.

Study characteristics and quality assessment

A total of 1,251 LTx recipients were enrolled from two RCTs (22,24), one post-hoc analysis (23) and three retrospective cohort studies (25,26,32). The post-hoc analysis and original RCT will not appear in the same pooled analysis (23). There was no significant difference between the pAZI and control groups regarding donor/recipient age and gender, underlying disease, surgical approach, ischemia time, hospital stay and CMV mismatch (P>0.05), except follow-up periods (P=0.002). More baseline characteristics are displayed in Tables 1,2. Additionally, quality assessment scores are displayed in Table 1 and Table S2. Jadad scores >3 and all NOS scores >6 indicated the high quality of the included studies.

Risk of CLAD onset

Four studies involving 920 patients reported the overall incidence of CLAD (22,24,26,32). Pooled analysis revealed that the risk of CLAD onset was significantly lower in the pAZI group compared to the control group without substantial heterogeneity (RR 0.64, 95% CI: 0.51–0.81, P<0.001; heterogeneity: I²=39%, P=0.18) (Figure 2A). In addition, the pooled incidences of CLAD were 21% (95% CI: 0.15–0.27; heterogeneity: I²=57.78%, P=0.07) and 32% in the pAZI and control groups (95% CI: 0.21–0.43; heterogeneity: I²=75.19%, P=0.01), respectively.

Figure 2 Forest plots of the prophylactic effects of azithromycin on the risk of CLAD onset. (A) The overall risk of CLAD onset, (B) the medium- to long-term risk of CLAD onset. The colored squares and corresponding horizontal lines are the estimates and 95% CI. Significant heterogeneity was defined as I²>50% and P value <0.1 in the Q-test. In this figure, “Azithromycin group” included recipients who received prophylactic AZI before CLAD onset, whereas “Control group” included recipients who received placebo or no intervention. AZI, azithromycin; CLAD, chronic lung allograft dysfunction; CI, confidence interval; df, degrees of freedom; M-H, Mantel-Haenszel method.

Regarding the mid- to long-term risk of CLAD onset, we determined three additional studies with follow-up periods of >3 years (23,26,32). Pooled analysis revealed that the pAZI group maintained a superiority over the control group in reducing the risk of CLAD onset (RR 0.66, 95% CI: 0.53–0.82, P<0.001; heterogeneity I²=0%, P=0.72) (Figure 2B), with the pooled incidences of CLAD of 24% (95% CI: 0.21–0.28; heterogeneity: I²=6.23%, P=0.34) and 39% (95% CI: 0.30–0.48; heterogeneity: I²=50.38%, P=0.13), respectively.

Three- and 5-year CLAD-free survival

Five studies involving 1,251 patients reported the 3-year CLAD-free survival data (23-26,32). Pooled analysis revealed that the 3-year CLAD-free survival was more favorable in the pAZI group compared to the control group (HR 0.57, 95% CI: 0.39–0.83, P=0.003; heterogeneity: I²=20%, P=0.29) (Figure 3A). Comparably, the 5-year CLAD-free survival also indicated superiority in the pAZI group, based on the data from three additional studies (HR 0.61, 95% CI: 0.43–0.86, P=0.005; heterogeneity: I²=0%, P=0.40) (23,25,26) (Figure 3B).

Figure 3 Forest plots of the prophylactic effects of azithromycin on the CLAD-free survival. (A) 3-year CLAD-free survival, (B) 5-year CLAD-free survival. The colored squares and corresponding horizontal lines are the estimates and 95% CI. Significant heterogeneity was defined as I²>50% and P value <0.1 in the Q-test. In this figure, “Azithromycin group” included recipients who received prophylactic AZI before CLAD onset, whereas “Control group” included recipients who received placebo or no intervention. AZI, azithromycin; CLAD, chronic lung allograft dysfunction; CI, confidence interval; df, degrees of freedom; IV, inverse-variance weighting method; SE, standard error.

Three- and 5-year OS

The 3-year OS data were available in three studies (23,24,26), which demonstrated no significant difference between the pAZI and control groups after pooling (HR 0.69, 95% CI: 0.31–1.54, P=0.36; heterogeneity: I²=0%, P=0.94) (Figure 4A). Similarly, pooled analysis of two additional studies (23,26) on 5-year OS also revealed a comparable trend, without significant difference between the pAZI and control groups (HR 0.59, 95% CI: 0.30–1.14, P=0.12; heterogeneity: I²=0%, P=0.90) (Figure 4B).

Figure 4 Forest plots of the prophylactic effects of azithromycin on the overall survival. (A) 3-year overall survival, (B) 5-year overall survival. The colored squares and corresponding horizontal lines are the estimates and 95% CI. Significant heterogeneity was defined as I²>50% and P value <0.1 in the Q-test. In this figure, “Azithromycin group” included recipients who received prophylactic AZI before CLAD onset, whereas “Control group” included recipients who received placebo or no intervention. AZI, azithromycin; CLAD, chronic lung allograft dysfunction; CI, confidence interval; df, degrees of freedom; IV, inverse-variance weighting method; SE, standard error.

Subgroup analysis based on the latest definition

The subgroup consisting of two studies published after the latest definition of CLAD [2019] was separately analyzed (3,26,32). The risk of CLAD onset in the pAZI group was also lower than that in the control group (RR 0.68, 95% CI: 0.54–0.87, P=0.002; heterogeneity: I²=0%, P=0.76) (Figure 5A). Moreover, three studies (25,26,32) and two studies (25,26) were selected to pool the 3- and 5-year CLAD-free survival data, respectively, which displayed that both the 3-year (HR 0.53, 95% CI: 0.30–0.96, P=0.04; heterogeneity: I²=52%, P=0.12) and 5-year (HR 0.62, 95% CI: 0.43–0.90, P=0.01; heterogeneity: I²=32%, P=0.22) CLAD-free survival in the pAZI group were more favorable compared to the control group (Figure 5B,5C).

Figure 5 Forest plots of the prophylactic effects of azithromycin on CLAD based on the latest definition. (A) The risk of CLAD onset, (B) 3-year CLAD-free survival, and (C) 5-year CLAD-free survival. The colored squares and corresponding horizontal lines are the estimates and 95% CI. Significant heterogeneity was defined as I²>50% and P value <0.1 in the Q-test. In this figure, “Azithromycin group” included recipients who received prophylactic AZI before CLAD onset, whereas “Control group” included recipients who received placebo or no intervention. AZI, azithromycin; CLAD, chronic lung allograft dysfunction; CI, confidence interval; df, degrees of freedom; IV, inverse-variance weighting method; M-H, Mantel-Haenszel method; SE, standard error.

Subgroup analysis based on the relatively long-term pAZI

Moreover, we excluded one study with a short-term pAZI duration (every other day from post-transplant day 1 to day 31) to assess the effect of relatively long-term pAZI (24). The results in the subgroup analyses were similar to that in the whole cohort, with lower risk of CLAD onset (RR 0.62, 95% CI: 0.49–0.78, P<0.001; heterogeneity: I²=46%, P=0.16), better 3-year CLAD-free survival (HR 0.39, 95% CI: 0.23–0.66, P<0.001; heterogeneity: I²=0%, P=0.65), and comparable 3-year OS (HR 0.66, 95% CI: 0.28–1.29, P=0.36; heterogeneity: I²=0%, P=0.77) (Figure 6A-6C).

Figure 6 Forest plots of the prophylactic effects of azithromycin on CLAD and overall survival based on the relatively long-term AZI duration. (A) The risk of CLAD onset, (B) 3-year CLAD-free survival, and (C) 3-year overall survival. The colored squares and corresponding horizontal lines are the estimates and 95% CI. Significant heterogeneity was defined as I²>50% and P value <0.1 in the Q-test. In this figure, “Azithromycin group” included recipients who received prophylactic AZI before CLAD onset, whereas “Control group” included recipients who received placebo or no intervention. AZI, azithromycin; CLAD, chronic lung allograft dysfunction; CI, confidence interval; df, degrees of freedom; IV, inverse-variance weighting method; M-H, Mantel-Haenszel method; SE, standard error.

Subgroup analysis based on the study types

We further conducted subgroup analysis based on study types to avoid potential bias. Notably, the retrospective cohort study subgroup yielded findings entirely consistent with those derived from the latest definition subgroup (refer above Figure 5A-5C) (25,26,32). However, the results from two RCTs demonstrated high heterogeneity and low significance, including the pooled risk of CLAD onset (RR 0.48, 95% CI: 0.25–0.92, P=0.03; heterogeneity: I²=76%, P=0.04), 3-year CLAD-free survival (HR 0.41, 95% CI: 0.10–1.72, P=0.22; heterogeneity: I²=0%, P=0.45) and 3-year OS (HR 0.65, 95% CI: 0.16–2.57, P=0.54; heterogeneity: I²=0%, P=0.73) (22,24) (Figure 7A-7C).

Figure 7 Forest plots of the prophylactic effects of azithromycin on CLAD and overall survival based on RCT studies. (A) The risk of CLAD onset, (B) 3-year CLAD-free survival, and (C) 3-year overall survival. The colored squares and corresponding horizontal lines are the estimates and 95% CI. Significant heterogeneity was defined as I²>50% and P value <0.1 in the Q-test. In this figure, “Azithromycin group” included recipients who received prophylactic AZI before CLAD onset, whereas “Control group” included recipients who received placebo or no intervention. AZI, azithromycin; CLAD, chronic lung allograft dysfunction; RCT, randomized controlled trial; CI, confidence interval; df, degrees of freedom; IV, inverse-variance weighting method; M-H, Mantel-Haenszel method; SE, standard error.

Adverse events

Adverse events were mentioned in four studies. Vos et al. (22) documented mild cardiac arrhythmias (9.3% vs. 2.5%) and gastrointestinal events (2.3% vs. 7.5%) in the placebo and pAZI groups. The gastrointestinal events included nausea, diarrhea, and pseudomembranous colitis. The post hoc analysis by Ruttens et al. (23) did not detect any death associated with arrhythmias. In addition, Li et al. (26) reported comparable cardiovascular deaths in the placebo and pAZI groups (9% vs. 10%). In the study by Van Heck et al. (24), none of the previously reported adverse events were observed.

Assessment of publication bias and sensitivity

Based on the relative symmetry of the funnel plots, no significant publication bias was detected for primary and secondary outcomes. Additionally, sensitivity analyses indicated that our results were generally robust. Noteworthily, the publication bias and sensitivity assessment may be limited by the number of included studies. Further details and visualizations are presented in Figures S1-S4.

Discussion

This systematic review and meta-analysis comprehensively assessed the prophylactic effects of AZI in LTx recipients and demonstrated that pAZI may reduce the risk of CLAD onset and improved 3- and 5-year CLAD-free survival, although it exhibited no noticeable effects on 3- and 5-year OS. To our knowledge, this study represents the first meta-analysis specifically focused on pAZI in LTx. At least, these findings provide reference that AZI may be utilized as a prophylactic intervention prior to CLAD onset in LTx recipients.

On account of the satisfactory efficacy of therapeutic AZI in the last two decades, a prolonged course of AZI initiation (at least 8 weeks) has been highly recommended in multiple consensuses and guidelines when recipients exhibited persistent pulmonary function decline, aiming to eliminate any reversible clinical short-term injuries before “definite CLAD” (3,11). Despite that, a non-negligible proportion of patients with possible or probable CLAD only experienced temporary alleviation or stabilization. The concept of “prophylactic azithromycin” was first introduced in 2011 and preliminarily revealed favorable outcomes on CLAD onset and CLAD-free survival (22). It has often been speculated that the mechanism involved alleviation of the local airway and systemic inflammatory injuries caused by alloimmune-independent events, such as microbial colonization (e.g., Pseudomonas) and gastroesophageal reflux, or other alloimmune-dependent events, which will significantly reduce the risk of CLAD onset (16,22,24). Discussion also increased about the superiority of AZI for prevention over cure, or its potential as a lifelong regimen (22,33,34). However, the pAZI concept has not yet been widely translated into clinical practice. A survey of AZI practice patterns among lung transplant physicians internationally has revealed that most respondents would initiate AZI only after a CLAD-associated clinical risk event, whereas only 29% of respondents would prescribe it during initial transplant hospitalization (13).

The current meta-analysis revealed a decreased overall risk of CLAD onset in the pAZI group than that in the control group without substantial heterogeneity, indicating the prophylactic effect of pAZI on CLAD (22,23,26,32). Noteworthily, two RCTs conducted at the same transplant center reported conflicting 2-year incidence of BOS in the pAZI group (22,24). The primary speculation for this observation related to the evolving concepts of CLAD phenotypes. In earlier studies, the term CLAD was predominantly used to refer to BOS, for which the therapeutic effects of AZI were well-established—particularly in neutrophilic reversible allograft dysfunction (NRAD). The study by Vos et al. (22) demonstrated significantly lower BAL neutrophilia in patients receiving pAZI versus placebo within the first two years post-transplant, indicating that pAZI could mitigate CLAD/BOS onset through reducing inflammatory injuries. However, subsequent work by Van Heck et al. (24) regarded CLAD as an umbrella term encompassing more phenotypes, wherein the pAZI effects on CLAD might become less apparent and early postoperative BAL neutrophilia differences might be not consistently significant. Similarly, in the study by Santos et al. (25), pAZI demonstrated no significant association with CLAD development, including BOS and restrictive allograft syndrome (RAS) phenotypes; however, whether pAZI exerts preventive effects against the NRAD remains undetermined. These findings underscored the necessity to investigate both therapeutic and prophylactic effects of AZI across distinct CLAD phenotypes to identify specific patient population most likely to benefit. In addition, with a CLAD incidence of roughly 10% per year, a 2-year follow-up was seemingly insufficient for assessing long-term CLAD onset (35). More importantly, it would be ideal to yield sustained effects of pAZI to decrease the burden of CLAD in LTx (33). Therefore, selecting three studies with follow-up periods of >3 years (23,26,32), the pooled results demonstrated a concordant superiority in the pAZI group, further supporting AZI’s prophylaxis for CLAD.

Similarly, CLAD-free survival is crucial for evaluating recipients’ pulmonary function and quality of life. The pooled results demonstrated more favorable 3- and 5-year CLAD-free survival in the pAZI group compared to the control group, suggesting pAZI’s potential to delay or even prevent the onset of CLAD. Moreover, recipients in the pAZI group demonstrated superior postoperative pulmonary function, as evidenced by consistently higher FEV₁% predicted values during scheduled routine follow-up assessments (22,26). Despite that, it remains uncertain why many recipients encounter CLAD despite pAZI; for instance, a recent study indicated that approximately 69% of recipients developed CLAD despite relatively long-term pAZI, which may also be associated with the institutional experience and different phenotypes of CLAD (36). Therefore, the international LTx community is supposed to continuously promote high-quality studies, to establish evidence-based reference for pAZI and further identify specific phenotypes that respond more favorably to this intervention.

Previous studies have documented improved OS in CLAD patients after therapeutic AZI, but pAZI exhibited limited benefits on OS (21,26,37). Likewise, the pooled analyses in our study revealed no significant difference in either 3- or 5-year OS between the pAZI and control groups. For those who developed CLAD despite pAZI, continuing further AZI administration would aim to decelerate further decline in pulmonary function in clinical practice, which may make the effects of AZI (prophylactic or therapeutic) on OS indistinguishable (22,37). Therefore, well-designed prospective studies, and ideally RCTs, are warranted to determine the efficacy of prophylactic and therapeutic AZI on improving long-term outcomes such as CLAD-free and OS.

The latest consensus on CLAD from the International Society for Heart and Lung Transplantation (ISHLT) was published in 2019, providing a comprehensive description of CLAD’s updated definition and management (3). However, the shortage of studies focusing on AZI for either CLAD onset or definite CLAD since the latest definition has been notable (3,25,26,32). We conducted the subgroup analysis based on the publications using the latest CLAD definition, and confirmed the similar prophylactic superiority of pAZI to be extended into the current new CLAD era. More high-quality studies based on the updated definition are needed to shed further light on the effects of AZI or pAZI in the field, rather than relying on outdated definitions to guide new strategies.

The initiating regimen of pAZI to achieve the optimal prophylactic effect on CLAD remains not sufficiently investigated. Initiating time, dose and duration varied markedly across different transplant centers (22,24-26,32). The majority of included studies have adopted a dosing regimen of 250 mg AZI, typically initiated within the first month post-transplant and administered three times weekly or every other day, with a (5-day) loading period variably reported (13,22,24-26,32). The study by Cristeto Porras et al. (32) displayed that either AZI initiation, early or at any time, could reduce the incidence and severity of CLAD, as long as the recipients’ FEV₁ was preserved. Van Herck et al. (24) attempted to initiate pAZI of 1,000 mg once immediately before LTx, which may help alleviate the inflammatory injuries in the short term postoperatively. However, the duration of pAZI ranged from as brief as one month to several years of continuous administration. Ideally, continued administration could result in more sustained immunomodulatory effects on CLAD onset. After excluding the short-term duration of pAZI, the subgroup meta-analysis revealed a satisfactory trend in the risk of CLAD onset and 3-year CLAD-free survival with acceptable heterogeneity.

However, there have also been concerns regarding the long-term adverse events with AZI therapy, such as previously reported hearing loss, antibiotic resistance, gastrointestinal disorders, cardiac arrhythmias, and even cardiovascular deaths (22,38). Interestingly, almost none of the included studies reporting adverse events demonstrated frequent or severe complications associated with pAZI (22,23,26). Infection management remains a critical challenge in post-transplant care. Notably, Mollicutes infections caused by Mycoplasma and Ureaplasma species represent particularly severe complications following LTx (39,40). Current antimicrobial options with demonstrated activity against these pathogens include tetracyclines (e.g., doxycycline), fluoroquinolones (levofloxacin, moxifloxacin, ciprofloxacin), and also macrolides (AZI) (39). However, the long-term duration of pAZI in LTx recipients may raise significant concerns regarding the potential selection of antimicrobial resistance, not only in Mycoplasma pneumoniae but across multiple opportunistic pathogens. This threat highlights the clinical dilemma of maintaining delicate balance between adequate immunosuppression and infection prevention in organ transplantation (39). Further dedicated studies are required to evaluate the medical risk in prophylactic and therapeutic regimens. In addition, consensuses on initiating time, dose, and duration of pAZI in the international LTx community and even within the transplant centers are also warranted, which may promote the consistency of pAZI initiating patterns and a better understanding of CLAD mechanisms.

Our meta-analysis should be viewed with caution due to the inevitable limitations. First, the limited sample sizes and retrospective design of the included studies should be mentioned, which may affect the robustness and extensibility to some extent. Second, the studies published before 2019 and after 2019 utilized different CLAD definitions in the persistent time of FEV₁ decline and the date of CLAD onset, which may have caused bias in the disease incidence reported by earlier studies. Third, initiation time and duration of AZI varied, but this may not significantly affect the pooled results because whether pAZI was administered or not was the key point. Fourthly, we did not pool the pulmonary function and adverse events due to the unavailable data. Finally, some survival data were estimated through survival curve simulation derived from the original studies, perhaps causing bias, which was necessary because original data were unavailable in some cases.

Conclusions

This meta-analysis provided supporting evidence that pAZI may somewhat reduce the risk of CLAD onset and improve the 3- and 5-year CLAD-free survival following LTx. However, pAZI application and promotion have a long way to go in this new era of CLAD, with more high-quality and well-designed studies urgently required to investigate optimal dosage regimens, more clinical outcomes and adverse events as well as mechanisms of action.

Acknowledgments

We would like to appreciate Enago Company (www.enago.jp) for the English language review.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-365/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-365/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-365/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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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