Diagnostic yield and safety of transbronchial lung cryobiopsy using 1.7-mm probes in interstitial lung disease

Introduction

Interstitial lung disease (ILD) is a heterogeneous condition that is diagnosed and treated based on combination of clinical, radiological, and pathological findings. An accurate diagnosis requires a multidisciplinary discussion (MDD) among pulmonologists, radiologists, and pathologists. The integration of clinical information, computed tomography (CT) findings, bronchoalveolar lavage fluid (BALF) characteristics, and pathology enhances diagnostic confidence (1,2).

Surgical lung biopsy (SLB) can obtain large tissues and contributes to a high diagnostic yield (3), however, compared to transbronchial lung biopsy (TBLB), it cause significant complications in patients with ILD (4,5). Recently, transbronchial lung cryobiopsy (TBLC) has been showed to yield larger specimens with minimal tissue damage compared to TBLB, despite a higher incidence of complications such as pneumothorax and hemorrhage. Additionally, TBLC is considered less invasive than SLB. Reusable (1.9, 2.4 mm) probes were previously used in cryobiopsy; however, single-use cryoprobes (1.1, 1.7, 2.4 mm) have been available since January 2022 and are now mainly used. A recent single-center study indicated that 1.7-mm single-use probes offer similar diagnostic yield, adverse event rates, and sampling validity compared to the 1.9-mm reusable probes. Nevertheless, the study observed that approximately 30% of participants in both groups developed pneumothorax as a complication (6). The safety and efficacy of single-use probes are expected to be comparable to those of reusable probes with similar external sizes, however, this has not been sufficiently demonstrated. Furthermore, investigations are necessary to determine the optimal conditions for safely performing TBLC with the single-use cryoprobes.

At our institution, TBLC is performed using a 1.7-mm single-use probe with a freezing time of 5 s for patients with ILD. In the present study, we investigated the complications associated with these conditions and evaluated the usefulness of TBLC in the diagnosis of MDD. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2160/rc).

Methods

This retrospective study included 25 consecutive patients who underwent TBLC for ILD at Kyushu University Hospital in Japan between August 2023 and June 2024. Given that a definitive diagnosis or a high level of diagnostic confidence could not be established based on clinical profiles, CT scan findings, and laboratory tests, TBLC was performed in all participants. A 1.7-mm single-use cryoprobe (Flexible cryoprobe, single-use, φ 1.7 mm, length 1,150 mm) and a flexible BF-1TQ290 bronchoscope (Olympus Corporation, Tokyo, Japan) were used. TBLC was targeted to areas of abnormality seen on high-resolution CT (HRCT), and the site and side of the biopsy were chosen and decided upon before the procedure. The probe was placed approximately 1 cm away from the chest wall under X-ray fluoroscopy and frozen for 5 s in all participants. In all cases, a Fogarty™ catheter (E-080-4 F; Edwards Lifesciences, Irvine, CA, USA) was placed in the subsegmental bronchi to prevent bleeding. The balloon was deflated after 2 min to check for bleeding. BALF was collected when the balloon was inflated. These tests were performed in an endoscopic procedure room without intubation, under sedation with midazolam and fentanyl, which are commonly used in Japan.

Details of the examinations were collected from medical records. The time during examination was measured from bronchoscope insertion to removal. Bleeding was categorized as follows: mild, defined as cases in which hemorrhage was controlled with ballooning alone, with biopsy subsequently being discontinued due to bleeding; moderate, referred to cases requiring intratracheal administration of hemostatic agents such as adrenaline-containing lidocaine or thrombin; and severe, defined as the need for transfusion, surgery, or admission to the intensive care unit post-procedure. Pneumothorax was classified as follows; mild, observation only; moderate, requiring chest drainage, or severe, requiring surgery. Acute exacerbation was defined as the worsening of the respiratory status or imaging findings within 30 d post-procedure (7). After the examination, MDD was conducted using a standardized diagnostic ontology for fibrotic ILD by pulmonologists, two radiologists, and one pathologist (8). The diagnosis of idiopathic interstitial pneumonias (IIPs) and hypersensitivity pneumonitis (HP) was based on the international clinical practice guidelines (9,10). The usefulness of TBLC was assessed by analyzing the changes in diagnostic confidence caused by this procedure.

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was planned in accordance with the guidelines for research ethics of Kyushu University and approved by the Institutional Review Board and Research Ethics Committee of Kyushu University Hospital (No. 23347-01). Written informed consent for participation was not required for this retrospective study.

Results

Characteristics of study participants

Cryobiopsy was performed in 25 patients in whom a high level of diagnostic confidence could not be achieved based on clinical background and imaging findings, in order to assess the various possible etiologies of diffuse parenchymal lung disease between August 2023 and June 2024. The participants’ characteristics are shown in Table 1. The median age was 68 [29–77] years, and 64.0% of patients were men. Overall, 16 patients (64.0%) had a history of smoking. Five patients received antithrombotic medications because of comorbidities; however, TBLC was performed after discontinuation of these medications. The median forced vital capacity as a percentage of the predicted value was 83.6% (54.5–134%), whereas the median diffusion capacity of carbon monoxide as a percentage of the predicted value was 60.3% (23.6–91.7%). In accordance with idiopathic pulmonary fibrosis (IPF) guidelines (9), the most common radiological feature was an alternative diagnosis (n=12, 48.0%), followed by probable usual interstitial pneumonia (UIP) (24.0%), indeterminate for UIP (16.0%), and UIP (12.0%). Under HP guidelines (10), the most frequent radiological finding was indeterminate for HP (n=19, 76.0%). The provisional diagnoses before TBLC were IPF, HP, and other diagnoses in 6 (24%), 9 (36%) and 10 cases (40%), respectively.

TBLC operation and specimen characteristics

The details of the examinations are summarized in Table 2. The median examination time was 44 [28–90] min. The median amount of sedative administered during the examination was midazolam at 7 [4–15] mg/dL and fentanyl at 60 [30–100] µg. The average number of biopsies was 1.62, and 38 specimens (92.7%) were obtained from the lower lobes. The mean long diameter of the fragments was 5.47 mm, and the mean specimen area was 16.0 mm². At least one specimen was obtained from the lung parenchyma of the lesions in 24 cases (96%). In one case, a biopsy was not suitable for diagnosis. BAL was performed after the first biopsy in 21cases, with a median recovery rate of BALF of 50% (range, 30.6–79.3%).

TBLC complications

The adverse events are summarized in Table 3. Although Fogarty balloon occlusion was routinely performed in all cases to prevent and control bleeding, moderate bleeding occurred in three cases (12%), requiring the application of a hemostatic agent. None of the patients required interventions to control bleeding. Hemoptysis was observed in 16 patients during the average hospital stay of 5 days following TBLC, all of whom improved with follow-up, and no patients required additional hospital visits or admissions due to bleeding after discharge. Pneumothorax occurred in one case (4%), with no need for a chest drainage tube or surgical intervention. Pneumonia was observed in three cases (12%). Two cases of balloon deviation were noted during biopsy. No deaths or acute exacerbations of interstitial pneumonia occurred within 30 days post-procedure.

Diagnostic yield of TBLC

The pathologist identified histopathological criteria from adequate TBLC samples that were sufficient to establish a characteristic pattern in 24 patients (96%). MDD was performed according to the pathological findings of the TBLC specimens combined with clinical and imaging evidence. The diagnoses after MDD were as follows: six cases of IPF, eight of HP, two of connective tissue diseases (CTD)-associated ILD, one of pneumoconiosis and eight of unclassifiable IIPs. The most common reason for unclassifiable IIPs was the presence of multiple HRCT and/or pathological patterns (observed in six of eight cases) (11). One case each was classified as having significant discordance between clinical, imaging, and pathological findings, or inadequate biopsy samples (Table 4). We evaluated the diagnostic confidence levels before and after TBLC for each case using a standardized diagnostic ontology for fibrotic ILD, and assessed the changes in confidence levels specifically for IPF and HP (Figure 1). Among the six cases diagnosed with IPF in the MDD, the diagnostic confidence increased from low to high in four of the five cases initially assessed with low confidence prior to TBLC, and one case initially rated with high confidence was confirmed with a definitive diagnosis post-TBLC. Based on the diagnosis of MDD, antifibrotic therapy was initiated in five of the six IPF cases. Similarly, in the eight cases diagnosed with HP after TBLC, confidence levels improved from low to high in four of the five initially uncertain cases, and all three cases initially assessed with high confidence were definitively diagnosed. The treatment strategies for HP cases included antigen avoidance and anti-inflammatory therapies.

Figure 1 Changes in diagnostic confidence between pre-TBLC and post-TBLC. (A) Changes in diagnostic confidence in patients with IPF before TBLC. (B) Changes in diagnostic confidence in patients with HP before TBLC. HP, hypersensitivity pneumonitis; IPF, idiopathic pulmonary fibrosis; TBLC, transbronchial lung cryobiopsy.

Discussion

We analyzed the diagnostic yield and safety of TBLC using 1.7-mm single-use probes for ILD. Specimens frozen for 5 s with this probe were comparable in size to those obtained using reusable probes. Pathological findings from these samples, combined with clinical information, CT findings, and BALF characteristics in MDD, were sufficient to enhance the diagnostic reliability, even with a limited sample number. The complications observed under biopsy conditions were within the acceptable range.

The present study used a 1.7-mm single-use probe, achieving a median specimen area of 13.6 mm² and a median maximum diameter of 5.2 mm. Previous reports using a 1.9-mm reusable probe showed a median specimen area of 15.5 mm², a median maximum diameter of 5.3 mm, a median diameter of 6.8 mm, and an average specimen size of 12.4 mm² (6,12,13). The tissue sizes obtained in this study with a 5-s freezing duration using the 1.7-mm single-use probe were comparable to these previous results. A specimen with a diameter of approximately 5 mm can contain one or more thin lobules, making it suitable for ILD diagnosis (14). These findings suggest that TBLC using 1.7-mm single-use probes with a freezing time of approximately 5 s may be sufficient for obtaining diagnostic samples.

The complication rate in this study was 4% for pneumothorax, and moderate bleeding occurred in 12% of cases. Recent studies report that the incidence of complications associated with TBLC using a reusable probe ranges from 2.9% to 30% for pneumothorax and from 0.5% to 23% for moderate to severe bleeding (6,15,16). The relatively safer execution of our procedure using a 1.7-mm single-use probe can be attributed to the conditions under which the TBLC was conducted. Consistent with other studies, a biopsy was performed at the site located 1 cm from the pleura. However, our protocol involved shorter freezing times and fewer biopsies. Extending the freezing time to 9–10 seconds resulted in larger specimens with diameters of approximately 6 mm; however, pneumothorax complications were observed in 33% of patients (6). Additionally, the frequency of pneumothorax has been linked to the number of biopsies obtained from the same lobe (12,17). Previous reports have demonstrated that the freezing time was ranged from 3 to 10 s for 1.7-mm probe (6,16), whereas our study used a freezing time of 5 s based on the CHEST guidelines (18). The findings of this study indicate that a 5-s freezing duration with a 1.7-mm single-use probe, along with careful selection of biopsy locations and minimization of biopsy numbers, represents a safe approach for the execution of TBLC. Besides the 1.7-mm single-use probe, a 2.4-mm single-use probe is available. In previous studies using reusable probes, the 2.4-mm probe was associated with a higher complication rate than the 1.9-mm probe (19,20). The use of smaller diameter probes reduces the frequency of moderate bleeding and the need for hemostatic agents (21). In the present study, balloon occlusion was used in all cases, and the incidence of moderate bleeding was consistent with that reported in previous studies. The 1.7-mm single-use probe was suitably sized to conduct the examination with minimal risk of complications.

In this study, MDD improved diagnostic confidence in 5/6 (83.3%) cases of IPF and 7/8 (87.5%) cases of HP. In two cases of CTD-ILD, a definitive diagnosis was established after excluding other conditions based on pathological findings. Patients suspected of having idiopathic nonspecific interstitial pneumonia (iNSIP) or pleuroparenchymal fibroelastosis before TBLC were ultimately diagnosed with unclassifiable IIP. INSIP is considered difficult to diagnose even with SLB (22), and obtaining a definitive diagnosis from the TBLC specimens was challenging, leading to its classification as unclassifiable IIP. However, among the reasons for the lack of consensus in MDD, only one case presented diagnostic difficulties owing to poor specimen quality. The other cases exhibited overlapping histopathological patterns in the tissue samples obtained using a 1.7-mm single-use probe. Additionally, based on MDD, antifibrotic agents were administered in two cases, and immunosuppressants such as steroids were administered in three cases, demonstrating the contribution of TBLC samples to the determination of the treatment strategy. ILD diagnosis depends on the area and number of samples in the TBLC specimens and the guidelines recommend obtaining more than three specimens (18,19,23). In this study, although a maximum of only two tissue specimens of a size comparable to that obtained with reusable probes were acquired, the diagnostic accuracy was enhanced, and therapeutic agents were appropriately selected. A thorough examination of the clinical information and BALF data, along with the pathological findings, contributed to the diagnostic ontology. Diagnostic accuracy improves through the integration of various information, including clinical background, pathological and radiological findings and BALF, therefore, insights beyond the pathological findings obtained from TBLC are also important for MDD (22,24,25). In the present study, BAL was performed concurrently with TBLC under sedation. A recovery rate of >30% in BALF is diagnostically useful (26), and high recovery rates were observed in this study. While multiple biopsies from the same lobe are necessary to reduce sampling errors, a thorough examination of clinical, CT, and BALF findings enables the minimization of biopsy frequency, facilitating the safe use of TBLC.

Our study had some limitations. First, this study had a small sample size, as it was conducted over a 1-year period at a single institution. Complication rates tended to decrease as institutional experience increases (27). With increased proficiency, the incidence of complications further decreased, and the diagnostic accuracy improved. Second, the retrospective design introduced the possibility of selection bias. Third, since our institution only has experience with the 1.7-mm single-use probe, we have been unable to directly compare the treatment outcomes and safety with the 1.9-mm reusable probe under the same conditions. We compared our results with previously reported data. Fourth, the low number of biopsies performed per procedure may also have been associated with the low incidence of complications.

Conclusions

Our findings suggest that the 1.7-mm single-use probe enables the safe acquisition of diagnostically sufficient samples with a freezing time of 5 s. To further enhance diagnostic accuracy and confidence, performing MDD that integrates the pathological findings obtained with this probe and complementary insights from CT imaging and BALF analysis is imperative.

Acknowledgments

We thank all patients and their representatives who participated in this study, as well as the clinicians who collected the TBLC samples used in this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2160/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2160/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2160/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-2024-2160/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 protocol was planned in accordance with the guidelines for research ethics of Kyushu University and approved by the Institutional Review Board and Research Ethics Committee of Kyushu University Hospital (No. 23347-01). Written informed consent for participation was not required for this retrospective study.

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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