Diagnostic performance and safety of transbronchial lung cryobiopsy in the study of interstitial lung diseases: a single-center experience

Introduction

Transbronchial lung cryobiopsy (TBLC) is a valid alternative for the diagnosis of diffuse interstitial lung disease (ILD) (1). Moreover, TBLC is less invasive than surgical lung biopsy, with a high level of concordance between TBLC in terms of histological interpretation and final diagnosis established by a multidisciplinary committee (MDC) (2). The European Respiratory Society recently published its guidelines for the use of TBLC in patients with suspicion of ILD (3). TBLC provides larger, better-quality lung tissue specimens lacking the crush artifact observed in conventional transbronchial forceps lung biopsies (TBFP). The size of these samples can be sufficient to establish a final diagnosis in most ILDs, thereby reducing the need for a surgery lung biopsy (SLB).

The main objective of this study was to assess the diagnostic performance and safety of the TBLC technique in the diagnosis of ILDs in our setting. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-276/rc).

Methods

A diagnostic cross-sectional, single-center study was performed including all patients who underwent a TBLC for diagnosis of an ILD (from December 1, 2017 to November 30, 2024). All cases were discussed by a MDC following the algorithm displayed in Figure 1, composed of the departments of pathology, radiology, rheumatology, thoracic surgery and pulmonology. Radiological patterns and the most likely diagnosis according to the American Thoracic Society guidelines were collected (4). MDC recommendations were not guided by a set of predetermined criteria, but were established on a case-by-case basis following discussion of multiple factors, as it occurs in real practice. Once the TBLC had been performed, results were interpreted by the MDC, who decided whether a final diagnosis could be established or a SLB was required. The interventional pulmonologists had experience as bronchoscopists (ranging from 5 to 18 years), but not in TBLC. To ensure technique harmonization, all completed a 3-day rotation at an experienced center.

Figure 1 Diagnostic algorithm. BAL, bronchoalveolar lavage; HRCT, high-resolution computed tomography; IPF, idiopathic pulmonary fibrosis; SLB, surgical lung biopsy; TBLC, transbronchial lung cryobiopsy; TBFB, transbronchial forceps lung biopsies; UIP, usual interstitial pneumonia.

TBLCs were performed following the procedure described in the literature (5). A 1.9-mm cryoprobe (900 mm in length) was used in all cases (ERBE, Germany). The procedure was performed under general anesthesia with the patient intubated with a flexible tube and under fluoroscope guidance to ensure that the biopsy was obtained 1cm from the ribs. The biopsy site was selected prior to the procedure on the basis of the location of the abnormalities identified on high-resolution computed tomography (HRCT). Samples were obtained from one or several sites according to the radiological distribution of the disease (diffuse, homogeneous, single-site radiological pattern vs. heterogeneous interlobar, several-site, radiological pattern). The probe was cooled for 7–8 seconds, and specimens were thawed in saline solution and embedded in formalin for fixation. A Fogarty balloon was used to prevent severe bleeding.

Bleeding was defined as “mild” if it only required endoscopic aspiration; “moderate” if it subsided in 3’ after endoscopic aspiration; and “severe” if it could not be controlled endoscopically, caused hemodynamic or respiratory instability and the procedure had to be stopped (6,7). Cases of severe bleeding were managed according to the recommendations for procedure standardization (5). Within the first postoperative hours, a chest X-ray was performed to screen for the presence of pneumothorax and determine the need for a chest drain (If the size of the pneumothorax was greater than 15% of the corresponding lung).

All patients ≥18 years diagnosed with ILD between 2017 and 2024 who underwent a TBLC were included in the study. The data collected included: demographics; medical history; lung function [forced vital capacity% (FVC%) and carbon monoxide diffusion (single breath)% (DLCOsb%)]; radiological pattern on HRCT prior to the procedure; date of the procedure; lung lobe biopsied; number of specimens collected; and post-procedure histological diagnosis.

Statistical analysis

Qualitative results were expressed as absolute frequencies (percentages). Quantitative data were presented as means ± standard deviation (SD) or as median values (25th percentile, 75th percentile) for normally and non-normally distributed values, respectively. To investigate the association between the study variables, diagnostic performance and the occurrence of adverse events, Chi-squared test was used for categorical variables and Student t-test or Mann-Whitney U test for continuous variables. Finally, the variables with statistically significant differences were included in multivariate logistic regression models. For the multivariate analyses, one record that had a missing value for one variable (DLCOsb%) was removed. All statistical analyses were performed using Windows^® SPSS software package version 30.0 (SPSS, Chicago, IL, USA). The maximum error in estimating cost-effectiveness and complications for a sample size of 117 patients would be ±8.5% for maximum variance (P=q=0.5).

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Clinical University Hospital of Santiago, Santiago de Compostela (2024/493) and individual consent for this retrospective analysis was waived.

Results

During the study period, the MDC approved performing a TBLC on 133 patients. Ultimately, 117 procedures were carried out, as 7 patients had a high bleeding risk and 9 patients/families did not authorize the procedure. Table 1 details the characteristics of patients and the technique, along with the diagnostic performance and complications of TBLC. Median age was 68 years and 58.1% of patients were male (68/117). The median FVC% was within normal limits [92% (81–106%)], whereas DLCOsb% was low [58% (47–67%)].

Cryobiopsy was performed in only one lobe in 101 patients (86.3%) (87% in the lower lobe). The median number of specimens obtained was 5 [4–5]. TBLC provided a specific histological pattern in 62.4% of cases (53.0%, 71.2%) (73/117). In these 73 patients, the most common histological pattern was that of hypersensitivity pneumonitis (47.9%), followed by usual interstitial pneumonia (UIP)/probable UIP (31.5%). Final diagnosis was established by the MDC in 79 cases (67.5%) (58.2%, 75.9%) (Table 1).

Of the 44 patients who did not have a diagnosis by TBLC, 29 (65.9%) underwent video-assisted thoracic surgery (VATS). A histological diagnosis was obtained in 24 (82.8%) patients, with UIP being the most frequent diagnosis (18/24: 75%) (Table 1).

In total, 65 patients (55.6%) developed a complication. Forty-four patients (37.6%) (22.8%, 47.0%) experienced bleeding, which was clinically significant (moderate + severe) in 18 (15.4%). Twenty-one patients had a pneumothorax (17.8%) (11.5%, 26.1%) and 11 (52.4%) needed a chest drainage. Finally, only a patient needed mechanical ventilation. No 30-day mortality was observed (Table 1).

Table 2 shows associations between baseline characteristics and the likelihood of having a positive TBLC result or the occurrence of complications. The likelihood of a positive result was not associated with any of the study variables (age, sex, body mass index, FVC%, DLCOsb%, several-site biopsies, number of samples and time from first procedure). However, the occurrence of pneumothorax was associated with age (indirect relationship) [odds ratio (OR), 0.920; 95% confidence interval (CI): 0.868–0.976; P=0.006] and the number of samples obtained (OR, 2.094; 95% CI: 1.111–3.947; P=0.02). The occurrence of moderate/severe bleeding was associated with age (OR, 1.108; 95% CI: 1.021–1.202; P=0.01) and a lower number of biopsies performed (OR, 0.349; 95% CI: 0.169–0.719; P=0.004) (the same variables were analyzed as when the result was positive).

Discussion

In our study, in a relevant proportion of cases (62.4%), histological diagnosis of ILD could be established by TBLC performed by pulmonologists without previous experience. The rate of histological diagnosis increased when cases were further discussed by the MDC (67.5%). Although the frequency of complications was not negligible (pneumothorax 17.8%, mild/moderate bleeding 35%), the procedure emerges as a safe alternative to SLB. Hence, there was no 30-day mortality, only a patient needed mechanical ventilation (0.9%) and only 3 (2.6%) patients experienced severe bleeding. None of the variables correlated with a positive TBLC result. Age was associated with a higher risk for moderate/severe bleeding events and a lower risk for pneumothorax events. In addition, the number of samples was associated with a higher risk for moderate/severe bleeding and a lower risk for pneumothorax.

TBLC is a well-positioned technique for multidisciplinary discussion upon suspicion of an ILD (4). Thus, TBLC demonstrated a good concordance with SLB in our cohort of patients who sequentially underwent the two techniques [histological concordance 80% (95% CI: 55–86%); diagnostic concordance after MDC discussion 77% (95% CI: 47–78%) (2). Currently, less than 10% of patients with ILD undergo a lung biopsy (8,9). TBLC has replaced VATS for obtaining lung tissue, as it is a minimally invasive procedure with a lower rate of complications than VATS that provides a similar level of diagnostic accuracy (9).

Recommendations (5) and guidelines (3) have been developed to standardize TBLC and provide guidance about some related issues. Issues include histopathological considerations, contraindications and safety considerations, the setting where it should be performed, who should perform it and where (5). However, despite these advances, competence and safety standards have not yet been verified for this technique. Moreover, inconsistent results have been obtained in different centers for this type of patients and are hardly comparable (differences in the procedure, diagnostic performance, and complications, among other). It should also be taken into account that, even after a thorough clinical examination including a lung biopsy, up to 15% of patients with an ILD are not classifiable (10).

A recent systematic review of 38 studies including 3,762 patients was published to assess the diagnostic performance of TLBC (11). Although the quality of evidence was low due to the lack of controlled studies, consecutive patient inclusion and inconsistency of results, this review provides relevant results. In the first review, the diagnostic performance of TBLC + histological interpretation in ILD was 80% (95% CI: 76–83%), ranging from 64% (95% CI: 5–83%) (12) to 93% (95% CI: 80–100%) (13) in the literature. Following this systematic review, two new publications reported significantly discordant diagnostic performances. In one of the studies, yields for both pathological and final multidisciplinary diagnosis was low (47.1% and 61.8%, respectively) (14), as compared to 82% (IQR, 64–92%) and 89% (IQR, 73–96%), respectively, in the other study (15). Our results are in the lower limit established by Kheir et al. (11) (62.4%), despite the procedure was performed in accordance with current recommendations. The reason for such a significant difference in diagnostic performance between series is unclear, although some factors may have contributed. In two different studies, Ravaglia et al. observed that diagnostic performance was significantly influenced by the number of samples collected (1 vs. ≥2 biopsies, P<0.005) (6,16). In the same line, Maritano Furcada et al. also obtained similar results, finding an association between the number of samples and diagnostic performance in multivariate analysis (OR 2.15; 95% CI: 1.16–3.99) (17). Biopsies obtained from two different sites instead of a single site, although they are obtained from the same lobe, may also contribute to variations in diagnostic performance, especially in the fibrotic forms of the disease [performance 93.4% vs. 65.5%, respectively (P<0.001)] (6). The underlying disease may also influence results. Ribeiro Neto et al. considered that, in the series with a higher incidence of hypersensitivity pneumonitis or sarcoidosis, TBLC is expected to have a higher diagnostic performance, as compared to the series with a higher incidence of UIP, which diagnosis is more challenging (14). The decision of the MDC prior to the procedure can also contribute to the result. Thus, if the MDC recommends TBLC in a very restrictive manner, a selection bias may occur, as only the cases with a higher diagnostic complexity will be selected. Currently, some cases of ILD are exclusively diagnosed on the basis of clinical and/or radiological criteria (4,18,19). Future studies will probably report a lower diagnostic performance for TBLC, as criteria become more specific and the use of lung biopsy decreases and be reserved only for complex cases where establishing a histological diagnosis is difficult. Although cryoprobe size (1.7, 1.9 or 2.4 mm) has been suggested to influence results, this has not yet been confirmed (6,20). Finally, Ribeiro Neto et al. observed that the diagnostic performance of TBLC improved with the learning curve (28.6% the first year, 54.5% the second year, and 66.7% the third year) (14). On another note, Davidsen et al. used an innovative method to calculate learning curves for the diagnostic performance of TBLC (CUSUM score). The authors reported a satisfactory diagnostic performance for the whole period (21). In our series, the probability of having a positive result with TBLC was not associated with any of the study variables. It does not seem that parameters such as age or pulmonary function influence the obtained yield, as all of them fall within the range of previous studies (age: 61–69 years, FVC%: 71–92%, and DLCOsb: 52–63.4%) (2,6,14,20,21).

Pneumothorax and bleeding are common complications of TBLC and, to a lesser extent, the need for mechanical ventilation and death. The systematic review conducted by Kheir et al. revealed a mean incidence of pneumothorax of 8% (95% CI: 6–11%) (11) ranging from 3% (95% CI: 0–6%) (22-24) to 22% (95% CI: 13–31%) (25). In one of the largest series published to date (699 cases), pneumothorax occurred in 19.2% of patients, of whom 70% needed a chest drain (6). These authors associated pneumothorax with intubation under deep sedation with invasive jet ventilation, the number of samples, the number of biopsy sites, the presence of abnormal FVC and DLCOsb, and the use of a 2.4-mm cryoprobe. In our case, the incidence of pneumothorax fell within the reported range (17.8%: 21/117), and 11 patients (52.4%) needed a chest drain. In our experience, the occurrence of pneumothorax was associated with age (the younger the patients, the higher the number of events) and a higher number of samples, as aforementioned (6).

Thirty percent (95% CI: 20–41%) of patients who underwent a TBLC experienced bleeding (7), with incidence ranging from 3% (95% CI: 3–9%) (26) to 67% (95% CI: 52–82%) (27). In our series, bleeding occurred in 44 patients (37.6%), although moderate/severe bleeding only occurred in 15.4% (18/117). Bleeding correlated with age and had an inverse relationship with the number of samples collected. Although the latter seems to be contradictory, this probably occurs because, when bleeding occurs during the first biopsy, the bronchoscopist will probably decide to be cautious and not do many more biopsies. Severe bleeding rarely occurs. However, Ribeiro Neto et al. reported a general incidence of grade-4 bleeding of 11.8% (respiratory compromise requiring intubation) (14). Ravaglia et al. reported an incidence of 0.7% (5 patients) (6) versus 2.6% in our series (3 cases). In another study not included in the systematic review by Kheir et al. (11), the percentages of pneumothorax and moderate + severe bleeding were 13% and 19%, respectively, similar to ours (17.8% and 15.4%, respectively) (28).

Of the 38 studies included in the systematic review conducted by Kheir et al., only 20 provided information about mortality after the procedure, and the follow-up period was not reported (11). Three patients died from acute exacerbations and a death was not considered to be associated with the procedure (6). In conclusion, mortality rarely was related to the procedure and severe bleeding was infrequent.

This study is subject to some limitations. Its cross-sectional design may cause a selection bias and may have influenced results. As it is a single-center study, the generalizability of results to other populations, geographic regions or health systems may be limited. A control group was not used, and TBLC results were not compared to those of SLB. The results of this study are inconsistent with those obtained in centers with more experienced pulmonologists and MDCs (5), which may explain our poorer results.

Conclusions

In summary, multiple factors may contribute to inter-series differences in the diagnostic performance of TBLC. However, in selected patients with ILD, TBLC provides a specific diagnosis and spares a SLB in at least 2/3 of cases that need a lung biopsy, with an acceptable incidence of pneumothorax and moderate/severe bleeding. The risk-benefit balance can be improved by adopting some measures to increase the diagnostic performance of the technique (although it did not occur in our study) and reduce the rate of complications. The TBLC procedure should be further standardized for a more consistent estimation of its diagnostic performance.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-276/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-276/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-276/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-2025-276/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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the Clinical University Hospital of Santiago, Santiago de Compostela (2024/493) and individual consent for this retrospective analysis was waived.

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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