TBLC is widely used for ILD diagnosis (7, 9, 20–22). To the best of our knowledge, this is the first randomized controlled trial comparing the use of 1.1-mm and 1.9-mm cryoprobes for TBLC in patients with suspected ILD. Our results suggest that 1.1-mm cryoprobes significantly reduced moderate bleeding incidence and facilitated equivalent diagnostic rates of MDD and sample quality when diagnosing ILD. However, using 1.1-mm cryoprobes may increase pneumothorax incidence. We evaluated the sample weight and applied finite element analysis to analyze the corresponding phenomena.
Currently, 2.4-mm and 1.9-mm cryoprobes are used for TBLC (20, 23). Several pilot studies have described higher accessibility and reduced bleeding with a 1.1-mm cryoprobe (12, 24). However, whether the use of smaller cryoprobes results in diagnostic yields similar to those obtained using larger cryoprobes is unclear (25). Yarmus et al. (12) demonstrated no significant differences in histological accessibility scores between 1.1-mm and 1.9-mm cryoprobes using a porcine model. In our study, the sample number in the 1.1-mm group was larger than in the 1.9-mm group, which, due to the 1.1-mm cryoprobe, was easier to detach from the lung tissue during TBLC. This was also observed using finite element analysis. Although the tissue sample surface areas obtained from the 1.1-mm cryoprobe group were significantly smaller than those from the 1.9-mm cryoprobe group, no statistical difference was observed in the sample weight between the two groups. Additionally, experienced pathologists found no difference between the groups regarding pathological scores, indicating that the sample quality obtained with 1.1-mm cryoprobes was equivalent to that obtained with 1.9-mm cryoprobes. Therefore, no significant differences were observed in the final MDD scores. Regarding the effect of cryoprobe size on MDD diagnosis rate, previous studies have reported no difference in ILD diagnosis using 2.4-mm and 1.9-mm cryoprobes (10, 26). However, the sample sizes obtained using 1.1-mm cryoprobes were relatively small. As the finite element analysis showed, detachment occurs if a larger specimen (diameter ≥ 5 mm) is required, consistent with our clinical practice. Probe and tissue detachment occurred when using a 1.1-mm cryoprobe. Additionally, the lack of diagnostic rate difference may also be caused by the high disease heterogeneity of ILD. Karina et al. studied the use of TBLC in lung transplant patients and showed that the sample quality and diagnostic rate obtained using 2.4-mm cryoprobes were higher than those obtained using 1.9-mm cryoprobes (27). Therefore, the use of 1.1-mm cryoprobes may also be limited in this patient cohort. Moreover, the primary ILD type in our study was more easily targeted using cryobiopsy. While many are likely to be diagnosed using transbronchial biopsy. Only a small number of patients were diagnosed with IPF and nonspecific interstitial pneumonia, which require more distal and larger areas of sampling to make an accurate diagnosis, making it more challenging to assess the performance of the 1.1-mm cryoprobe in these ILD types, which has a limited ability to obtain larger samples. Furthermore, the identification of histopathologic patterns is an important step in evaluation the diagnostic efficiency because MDD might be based on relevant components the clinical history and the CT scan aspects. Our study also showed no difference in the detection of TBLC specimens between the two probes in terms of the histopathology patterns.
Pneumothorax is one of the main TBLC complications and may be related to cryoprobe size. Previous studies showed that pneumothorax incidence was higher with 2.4-mm cryoprobes than with 1.9-mm cryoprobes (10) (11). However, a study by Zhou et al. (26) comparing the use of 2.4-mm and 1.9-mm cryoprobes guided by cone-beam computed tomography rather than fluoroscopy demonstrated no significant differences in pneumothorax incidence. Hence, we suggest that pneumothorax risk may not only be related to cryoprobe size but also to other factors, such as the guidance method. We found that pneumothorax incidence was relatively higher in the 1.1-mm cryoprobe group than in the 1.9-mm cryoprobe group. This may be due to the greater accessibility of the 1.1-mm cryoprobe, which may be closer to the pleura during sampling. However, we could not draw any conclusions regarding this; therefore, we conducted a finite element analysis that showed that the stress generated by a 1.1-mm cryoprobe was larger than that by 1.9-mm cryoprobes, which may be the reason for the higher pneumothorax incidence in the 1.1-mm cryoprobe group. This is based only on the interpretation of mathematical models, and more clinical investigations are needed to verify this in the future. According to our study’s results, the cryoprobe size may be a factor affecting pneumothorax occurrence, and physicians need to pay attention to the role of fluoroscopy and the operative process when using 1.1-mm cryoprobes.
Bleeding is the most common TBLC complication. A systematic review reported moderate bleeding occurs in 20.9% (5.6–42.8%) of TBLC procedures (28). Hetzel et al. (29) showed that moderate or severe bleeding occurred in 15.7% of patients. No severe bleeding occurred in a porcine model using 1.1-mm cryoprobes (12). In a prospective single-arm study using 1.1-mm cryoprobes, mild bleeding (Grade ≤ 2) was observed in 25 cases (50%), indicating TBLC using a 1.1-mm cryoprobe is feasible with an acceptable safety profile (30). However, most patients had undergone lung transplantation and had suspected pulmonary parenchymal lesions. Thus, this may not represent TBLC application in ILD. In our study, moderate bleeding incidence was significantly higher in the 1.9-mm cryoprobe group than in the 1.1-mm cryoprobe group. This may be because a 1.1-mm cryoprobe produces a smaller wound; therefore, the wound closes faster after the tissue sample is retrieved, reducing the amount of bleeding. Some heterogeneity occurred in our study, and we did not analyze the relationship between the imaging features of the target lung lobes and bleeding risk. Future studies may be required in this regard. An observational study indicated lower moderate bleeding incidence with a 1.9-mm cryoprobe compared with a 2.4-mm cryoprobe (31). In combination with our findings, this suggests that smaller cryoprobes may help reduce moderate bleeding incidence.
Health economics should be considered in clinical practice. The 1.1-mm cryoprobes we used were disposable; hence, patient cost is higher than that with 1.9-mm cryoprobes, which are reusable. This may be a disadvantage of TBLC using 1.1-mm cryoprobes for ILD diagnosis.
Our study had some limitations. First, this was a single-center study. As a national medical center, our center performs > 250 TBLC procedures annually. Our team is more experienced; thus, we had lower rates of serious adverse events, which introduced some bias. This single-center design may prevent comparison of the derived data in a validation cohort and limit the possibility of generalizing these findings. Second, our study’s lower rate of adverse events may be related to relatively better lung function, contributing to the low complication incidence. Therefore, future studies are needed to compare the efficacy of different probe sizes in patients with progressive pulmonary fibrosis and critically ill patients.
In summary, we evaluated the diagnostic performance of 1.1-mm cryoprobes in TBLC. The sample quality obtained using 1.1-mm cryoprobes met the requirements for pathological diagnosis, and a diagnostic efficiency equivalent to that using 1.9-mm cryoprobes was achieved. Additionally, the use of 1.1-mm cryoprobes can significantly reduce the incidence of moderate bleeding; however, it may increase pneumothorax incidence.
Table 1. Baseline characteristics