In most clinical scenarios, bronchoscopy procedures such as transbronchial lung biopsy (TBLB) and bronchoalveolar lavage (BAL) are typically sufficient to diagnose acute cellular rejection (ACR) in lung transplant recipients, often making surgical lung biopsy unnecessary for diagnostic confirmation.1–3 Yet, the limited sample size and presence of extrusion artifacts in tissue samples from transbronchial forceps biopsy (TBFB) present significant challenges for pathologists in confidently diagnosing ACR.4 This limitation is evidenced in the literature by the low sensitivity of TBFB for this condition.5 Although BAL is effective in identifying infections, its efficacy in conclusively diagnosing rejection is less clear.6 Conversely, while surgical biopsy yields an ample amount of pathological tissue for detailed analysis, its invasive nature increases the risk of secondary infection, delayed wound healing, and other complications associated with immunosuppression, which in turn limits its clinical utility.

In recent years, transbronchial cryobiopsy (TBCB) has emerged as a viable alternative bronchoscopic procedure for histological sampling in the diagnostic evaluation of lung diseases.7 TBCB has been extensively utilized for the collection of samples from a range of diseases, including lung tumors, interstitial lung diseases, and pulmonary infections,8–10 owing to its capacity to procure larger pathological tissue samples and minimize the occurrence of artifacts. Numerous studies have substantiated the efficacy and safety of this technique, thereby potentially addressing the shortcomings associated with TBFB and surgical lung biopsy.11,12 However, due to the limited data currently available on the safety and efficacy of post-lung transplantation monitoring, the application value of TBCB in ACR after lung transplantation, especially in terms of safety, remains controversial compared to TBFB.13–18 The conclusions regarding the incidence rates of moderate to severe bleeding and pneumothorax for these two techniques vary significantly across different studies.

A prior meta-analysis examined the utility of TBCB in monitoring patients after lung transplantation, indicating that compared to TBFB, this procedure yields more tissue samples and fewer artifacts.19 However, the meta-analysis did not address the diagnostic efficacy and safety of TBCB in detecting acute cellular rejection (ACR) in lung transplant recipients. Additionally, the value of the meta-analysis for guiding clinical practice is limited as it is based solely on a conference abstract that includes four studies. After conducting a review of the literature, it was found that a number of additional original studies have been published subsequent to the aforementioned meta-analysis. Due to the variability in reporting methods among these original studies, the shortcomings of the prior meta-analysis, and the influx of new research in this field, it was deemed necessary to conduct a new meta-analysis. Therefore, the aim of this meta-analysis is to incorporate newly published literature for a comprehensive and thorough review, assessing the effectiveness and safety of TBCB compared to TBFB in diagnosing ACR post-lung transplantation.

This study conducted a meta-analysis of existing data in accordance with the guidelines outlined in the preferred reporting items for systematic reviews and meta-analyses statement (PRISMA-DTA).20 As a result, ethics committee approval was deemed unnecessary. Furthermore, the meta-analysis has been registered in PROSPERO under the registration number CRD42024513485 (https://www.crd.york.ac.uk/p rospero/).

Lung transplantation is a critical therapeutic intervention for patients with end-stage lung diseases, aimed at extending survival and improving quality of life.30 In contemporary medical practice, this procedure is primarily indicated for conditions like interstitial lung disease and chronic obstructive pulmonary disease. A notable hurdle faced by postoperative recipients is ACR, with approximately 27% of recipients experiencing rejection within the initial year following transplantation.31 The association of ACR with chronic rejection and its potential to adversely affect prognosis highlights the importance of its timely and accurate detection, as any delays in diagnosis could compromise graft function.32 Therefore, the implementation of effective detection methods for ACR is essential in refining treatment strategies and enhancing patient outcomes.

The diagnosis of lung transplant rejection is primarily dependent on microbiological and pathological data obtained through bronchoscopy.33 Given the limitations of TBFB and BAL, TBCB is increasingly acknowledged as a valuable alternative for post-lung transplantation monitoring. It is acclaimed for its innovative, safe, and effective approach, enabling the collection of larger tissue samples without compromising morphological integrity, thereby reducing the need for repeated procedures.34 In recent years, TBCB has gained increasing popularity among interventional pulmonologists, marking significant progress in this field. However, despite these advancements, there appears to be some differing opinions regarding the efficacy and especially the safety of TBCB compared to TBFB for post-lung transplantation monitoring. The incidence rates of moderate to severe bleeding and pneumothorax associated with TBCB and TBFB vary considerably across different studies. Therefore, a systematic review and meta-analysis to provide a comprehensive evaluation of the diagnostic efficacy and safety of TBCB for ACR after lung transplantation could potentially be of significant clinical value. A previous meta-analysis included only four studies and did not specifically examine the role of TBCB in diagnosing ACR, which suggests the necessity for a more thorough and updated meta-analysis.

In our systematic review and meta-analysis, we carefully evaluated the potential effectiveness and safety of TBCB in comparison to TBFB for monitoring patients after lung transplantation. The findings suggest that TBCB may be more effective in diagnosing ACR than TBFB. Additionally, for chronic rejection diagnosis post-transplantation, TBCB appears to have a higher likelihood of effectiveness compared to TBFB. The generally superior quality of TBCB samples, characterized by their larger size and deeper extraction, along with fewer artifacts, might facilitate earlier and more accurate detection of rejection, potentially leading to better patient outcomes following a transplant. In terms of safety, our gathered data on complications following TBCB and TBFB procedures showed no significant differences in terms of moderate to severe bleeding and pneumothorax events between the groups. Based on these findings, TBCB might be considered a potentially safe and effective alternative to TBFB for postoperative monitoring in lung transplant patients.

The present study has gathered a thorough selection of relevant literature for quality evaluation and meta-analysis, with the intention of delivering a more comprehensive and objective assessment of the diagnostic role of TBCB in ACR. To the best of our understanding, our meta-analysis concerning TBCB for post-lung transplant surveillance possibly represents the most substantial sample size to date. Given the growing interdisciplinary interest in cryo-technology within pulmonology and thoracic surgery, and the current lack of multicenter randomized trial data on this subject, our study is both timely and crucial for advancing our understanding of the role of TBCB in post-transplant lung tissue sampling.

It should be noted that although the data incorporated into the meta-analysis suggest promising progress in the effectiveness and safety of TBCB for detecting rejection after lung transplantation, further issues may need to be clarified before it is considered a routine monitoring method for lung transplant patients. In clinical practice, thorough preoperative examinations (including echocardiography, coagulation function tests, blood routine tests, etc.) are advisable to identify risk factors such as bleeding tendency and pulmonary hypertension before performing TBCB under bronchoscopy.29,35 Additionally, enhancing formal training for bronchoscopists could help reduce the incidence of adverse events, given that the diagnostic accuracy and safety of TBCB appear to be closely related to professional expertise and the standardization of technical procedures.36 It is also worth considering whether the current research results from a few large centers are applicable to other centers, especially those with fewer resources and less experience.

We should also recognize the limitations of this meta-analysis. Firstly, the number of existing studies on this topic is somewhat limited, and the heterogeneity among them might affect the statistical power and generalizability of our findings, suggesting a cautious interpretation of the results. Additionally, as most of the included studies are observational, there could be selection bias and confounding factors influencing the outcomes. Furthermore, since all the studies were conducted at single centers, the lack of standardization and multicenter data may pose challenges to the reliability of our meta-analysis results. Therefore, we advocate for the initiation of multicenter studies and the establishment of standardized protocols to more robustly validate the efficacy of TBCB in post-lung transplantation applications.

In conclusion, our analysis of the limited available studies suggests that TBCB enhances the diagnostic rate of ACR and chronic rejection following lung transplantation when compared to TBFB. Moreover, there appears to be no significant difference in the incidence of complications between TBCB and TBFB. However, further research and the development of standardized procedures are warranted to ensure the safe and effective application of TBCB in broader clinical practice.

In this meta-analysis, the research process didn’t involve new human subject data since it is based on an aggregation and analysis of existing published studies. As a result, ethics committee approval was deemed unnecessary.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Yan Luo was tasked with the acquisition, analysis, and interpretation of data, as well as drafting the initial manuscript. Sheng-ping Li handled the development of the conceptual framework and the bibliographic review, and critically revised vital intellectual content. All co-authors were actively involved in revising and giving their final approval to the manuscript.

The authors declare no competing interests.

All relevant data can be found within the articles included in this study and in the supplementary materials.

This study was conducted without the aid of any artificial intelligence software or tools.