Evaluating the role of American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Society high-resolution CT-thorax usual interstitial pneumonitis imaging categories in selecting candidates for transbronchial lung cryobiopsy for undifferentiated interstitial lung disease, a retrospective study

Introduction

Transbronchial lung cryobiopsy (TBLC) is a less invasive method than surgical lung biopsy (SLB) for obtaining larger biopsy samples than traditional transbronchial lung biopsy (TBB). Since being introduced it has been proven to reduce hospital stays, adverse events and cost to healthcare systems, while providing a reliable diagnostic yield and improving safety for patients (1-3). Undifferentiated interstitial lung disease (ILD) often requires biopsy sampling to confirm a diagnosis. Previously SLB was needed for a tissue diagnosis in those patients whose initial investigations for ILD were inconclusive. However, post-operative mortality rates from SLB stood at 3.6% in one 2019 meta-analysis, with mortality in this instance being defined as death within 90 days of procedure (4).

Guidelines now recommend TBLC as a reasonable alternative to SLB in the investigation of ILD. TBLC sacrifices a small amount on diagnostic yield, for a lower rate of serious adverse events (5,6). While plenty is known about diagnostic rates and complications of TBLC, little is known about which patients should be selected for TBLC.

In a direct comparison between TBLC and SLB involving 447 patients, it was shown that TBLC reduced hospital stays (6.1 vs. 2.6 days, P<0.0001) and mortality (2.7% vs. 0.3%), while 20.02% suffered pneumothorax (7). TBLC allows for larger biopsy samples than traditional TBB, but with greater risk of complications. Pneumothorax and bleeding are the two most concerning commonly occurring complications.

When comparing TBLC to traditional forceps TBB in patients with diffuse parenchymal lung disease, a 2016 meta-analysis showed a diagnostic rate of 86% in TBLC vs. 56% in TBB, with a number needed to achieve an additional diagnosis of 4 (8). This highlights a significant step forward in ILD management. A 2022 meta analysis has shown that TBLC has an 80% diagnostic rate in ILD with acceptable complications, further endorsing its role in this field (9).

High-resolution computed tomography-thorax (HRCT) is the gold standard imaging modality for assessing ILD. The American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Society (ALAT) guidelines on diagnosis of idiopathic pulmonary fibrosis (IPF) were most recently updated in 2022 (2). Within the guidelines, the joint-societies designed HRCT imaging and histology categories; usual interstitial pneumonia (UIP) pattern, probable UIP, indeterminate UIP and alternative diagnosis based on the specific patterns, features and distribution of the interstitial changes on imaging and biopsy.

Our objective was to see if imaging could help guide which undifferentiated ILD patients would benefit most from TBLC, by determining which patients had a change in diagnosis and management following TBLC. As it is still a procedure that carries the risk of pneumothorax, serious bleeding and even death, selecting the correct patient and avoiding unnecessary invasive investigations is important. As with this study, most TBLC studies are retrospective, with a lack of prospective data. One review from 2017 highlighted that 73.1% of the studies referenced were retrospective (10). Guidelines have already stated that those with UIP pattern imaging do not necessarily always require SLB or TBLC, so our primary focus is on the patients who fall into the other imaging categories and whether TBLC alters their diagnosis and management. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-734/rc).

Methods

This study was carried out in our dedicated ILD specialist service in the south-west of Ireland with a catchment area of 550,000 people.

Patient selection

This was a retrospective review of all available TBLC procedures performed in Cork University Hospital over a 7-year period (2017–2023). Eighty-one patients had TBLC in this time for undifferentiated ILD, however we excluded five due to the lack of full investigations required for the parameters of this study. Seventy-six patients remained in the study. Five patients were excluded as we wanted all included patients to have the same investigations and comparable data. Patients with missing data could compromise the integrity of our findings. Retrospective studies can be affected by accuracy of reported data, however the majority of data points we collected were objective and diligently recorded. Any patient with questionable or incomplete data was excluded as explained. Exclusion criteria for TBLC in Cork University Hospital include but are not limited to forced vital capacity (FVC) <50% predicted, transfer factor for carbon monoxide (TLCO) <35% predicted, requirements for supplementary oxygen at rest or significant desaturation to <85% during 6-minute walk test, multiple co-morbidities including significant cardiac or liver co-morbidities and significant history of bleeding diathesis or use of any anticoagulant for 5 days before procedure.

To be considered for the study, patients needed to have had a clinical history and exposure history, pulmonary function testing (PFT), ILD-screening blood test panel, chart review, discussion at multi-disciplinary team meeting (MDM), HRCT and bronchoscopy with bronchoalveolar lavage (BAL) prior to TBLC. Following review of the pre-TBLC database and MDM discussion, it was determined whether the case was still undifferentiated or had a likely diagnosis. They were then discussed again at MDM post-TBLC. Both pre-TBLC and post-TBLC MDMs included dedicated radiologists (D.D., M.M.M.), a histopathologist (L.B.) with special interests in ILD and a dedicated specialist ILD respiratory physician (M.T.H.). The pre- and post-TBLC MDM findings were compared to see if the preferred pre-TBLC MDM diagnosis was confirmed, if an alternative diagnosis was provided, or whether it remained undifferentiated.

Procedure

All procedures took place in the endoscopy day unit of our tertiary university teaching hospital and were carried out by an experienced operator (M.T.H.), with assistance from a senior interventional bronchoscopy trainee and three endoscopy nurses. Anticoagulation was held prior to procedure. An initial routine airway inspection was performed in all cases. The procedures were not fluoroscopy-guided, due to lack of availability locally. The appropriate segment was selected based on computed tomography (CT) imaging. TBLC cooling was tested prior to the procedure in saline. The 2.4 mm flexible cryoprobe, length 900 mm (ERBE Elektromedizin GmbH, Tuebingen, Germany) was passed through the working channel of the bronchoscope and after positioning of the bronchoscope at the intended segment, the cryoprobe was advanced distally until resistance was met, after which the cryoprobe was retracted approximately 1–2 cm. The cryoprobe was activated for 5 to 6 seconds and then pulled firmly back. Endobronchial balloon blockade was achieved with 7fr Cook Medical (Limerick, Ireland) Arndt endobronchial balloon blocker, the management of which was designated to one endoscopy nurse. This was deployed prophylactically in all cases immediately post-biopsy.

All patients in Cork University Hospital undergoing TBLC had routine chest X-ray post-procedure to exclude pneumothorax. Conscious sedation was achieved with intravenous midazolam and fentanyl. The average fentanyl dose in our patient groups has been previously published 78.9–85.4 mcg and average midazolam dosing was 7.9–8.7 mg (11). No advanced airway equipment was used as procedures were performed under conscious sedation as described, however in cases of emergency cardiac arrest trolleys with advanced airway equipment were available in the procedure room. Oxygen saturations, heart rate, blood pressure and electrocardiogram were monitored through-out. Cork University Hospital uses endobronchial balloon blockers based on evidence previously published from Cork University Hospital in 2021. This study showed that in 25 patients, the use of endobronchial balloon blockade during the procedure had a moderate to severe airway bleeding rate of 8.3%, versus 38.5% without blockade (11). Cold saline and adrenaline were also administered if necessary.

All patients included had HRCT prior to the TBLC. These HRCTs were reviewed by a consultant specialist ILD radiologist (D.D., M.M.M.) and consultant respiratory physician (M.T.H.) prior to moving forward with TBLC, and pattern of ILD determined; UIP pattern, probable UIP, indeterminate UIP and alternative diagnosis.

Histology samples were transferred to our on-site histopathology laboratory and analysed by an experienced consultant histopathologist (L.B.) who was present at the MDM and had knowledge of patient’s clinical information and radiology. They were then categorised as per the ATS/ERS/JRS/ALAT guidelines on diagnosis of IPF (2).

Statistical analysis

Statistical analysis on change of outcome results documented below performed by Chi-squared analysis on Microsoft Excel^TM. Statistical significance determined as P value <0.05.

Ethics

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Clinical Research Ethics Committee of the Cork Teaching Hospitals, which oversees research ethics for Cork University Hospital [No. ECM 4 (aa)] and individual consent for this retrospective analysis was waived.

Results

The average number of samples taken per procedure was 2.7. The average size of the largest sample taken per procedure was 8.4 mm. Sixty-seven patients (88.2%) had their samples taken from the right lower lobe only, two from the left lower lobe only and two from right middle lobe. Four patients had samples from both right lower lobe and right middle lobe.

Overall, the presumptive pre-TBLC MDM diagnosis was changed in 43.4% (33/76) of cases post-TBLC. See Table 1 for patient demographics and characteristics. Change was most common in the indeterminate UIP group at 65% (13/20), followed by the alternative diagnosis group with 41.9% (13/31), probable UIP with 30% (6/20) and finally UIP pattern with 20% (1/5) change-detailed in Table 2. On statistical analysis, defining statistical significance as a P value <0.05, there was a statistically significant difference between the probable UIP and indeterminate UIP groups in terms of change of management or diagnosis (P=0.03). There was no statistically significant difference between the probable UIP and alternative diagnosis groups (P=0.39), or between indeterminate UIP and alternative diagnosis groups (P=0.11). Again, we did not compare with the definite UIP group due to the small sample size.

There was a limited number in the UIP pattern group as guidelines dictate that TBLC is not required in those with UIP pattern on HRCT, so TBLC was performed in this group far less often. The patients in the UIP pattern group that had TBLC had individual specific circumstances that necessitated cryobiopsy (i.e., one example where a patient had evidence of UIP but also features of sarcoidosis on imaging and other investigations. TBLC showed both UIP and granulomas, and the patient was diagnosed with IPF and sarcoidosis concurrently).

The diagnostic rate was 19/20 (95%) in probable UIP, 15/20 (75%) in indeterminate UIP and 24/31 (77.4%) in alternative diagnosis imaging groups after post-TBLC MDM discussion (see Table 2). Three out of 5 cases of UIP pattern were considered diagnostic post-MDT discussion. The overall diagnosis rate of patients having TBLC was 80.2%, in keeping with international standards. Thirty-three of the 76 (43.4%) patients had concordance between their imaging and histology category.

The presumptive pre-TBLC MDM diagnoses and post-TBLC confirmed MDM diagnoses are listed in Table 3.

Nineteen out of 76 (25%) patients studied suffered a pneumothorax during the TBLC. Only 7 (9.2%) cases required intercostal chest drain insertion, with 12 cases (15.8%) needing admission to hospital for monitoring overnight. This highlights the risk associated with TBLC. All patients having routine chest X-ray post-procedure which is not standard practice in all centres.

Prior meta-analysis shows that in centres who have performed greater than 70 TBLC, post-MDM diagnostic yield is 80.7%. In the same meta-analysis, the rate of procedure-related pneumothorax varied from 0–26%, with a pooled average of 5.3% suffering pneumothorax requiring intercostal chest drain insertion in centres with greater than 70 procedures performed (12). We did not record bleeding rates in this cohort as there was prior data released from Cork University Hospital, with this information discussed below.

There was no procedure-related mortality within 30 days.

Discussion

As per previous guidelines, TBLC is not generally indicated in patients with UIP pattern imaging on HRCT. The purpose of this study was to see how useful TBLC was in the remaining imaging categories (probable UIP, indeterminate UIP and alternative diagnosis). As mentioned, the focus of this study is not on the diagnostic rate itself, but rather whether performing TBLC changed the previous diagnosis and impacted on patient care. The less convincing HRCT imaging is for UIP, the less likely it is to provide a confident diagnosis pre-TBLC; 30% of patients with probable UIP had their likely diagnosis changed post-TBLC. It opens a discussion on the role of TBLC in patients with probable UIP imaging. Given the complication rates of the procedure and low impact on management in this group, it may lead clinicians to reconsider the risks and benefits of this procedure in patients with probable UIP imaging. When comparing indeterminate UIP and probable UIP imaging groups, TBLC was much more helpful in the indeterminate group as it changed the diagnosis and management of patients more often.

The strengths of this study include that it is an easily reproducible study in centres that perform TBLC with an easy-to-follow methodology and the relevant information should already be available to clinicians. All procedures were carried out by a very experienced operator, which may not be the cases in all centres yet. It is a novel idea for a study, in literature review no research could be found that that looked at TBLC from a similar perspective. Standardisation of local radiology services including these ATS/ERS/JRS/ALAT definitions in their HRCT reports would raise awareness of these categories and make it easier to pursue future multi-centre research in this area.

A weakness of this study is that it is a single centre study with the inherent biases which that involves. We are the only centre in Ireland that regularly perform TBLC in ILD patients. The data is also retrospective, further prospective studies would add significant weight to our findings. This study was limited in terms of demographics (primarily White European) and further research would benefit from a more racially diverse cohort of patients. Patient frailty was not factored into this study, and as TBLC is a less invasive and safer procedure than SLB, it would be interesting to see data on whether TBLC is safe and feasible in frailer patients who would have not previously been considered candidates for SLB. Also, data on multidisciplinary meeting diagnosis (MDD) diagnostic confidence was not readily available in many of our cases, and thus we are not able to include data or comment on diagnostic confidence in this study. This data would have been helpful in our study, with previous work showing inter-observer diagnostic confidence amongst pathologists is lower in TBLC than SLB (13). When diagnostic confidence was high, TBLC tended to return similar yields to SLB.

As mentioned in our methods, we have stringent criteria for inclusion and exclusion in our study, which while promoting patient safety does exclude some groups of patients from undergoing TBLC. The procedure will only be performed on patients deemed capable of tolerating a pneumothorax or severe bleeding event.

While there has been no prior studies on imaging categories in diffuse undifferentiated ILD as a means of candidate selection, one study did show that TBLC was better at establishing a diagnosis in idiopathic interstitial pneumonias (IPF, desquamative interstitial pneumonia, acute interstitial pneumonia, non-specific interstitial pneumonia, cryptogenic organising pneumonia, lymphocytic interstitial pneumonia, respiratory bronchiolitis-ILD—as per ATS/ERS guidelines) versus granulomatous ILD, drug associated, collagen vascular associated and ILD of other causes (14,15).

There are also undoubtedly risks associated with TBLC. Previously published data of 85 patients from Cork University Hospital from 2014 to 2016 showed an 18% rate of moderate bleeding, all of which was successfully controlled by cold saline or adrenaline (16); 34% suffered mild bleeding and there were no severe airway bleeding events. These bleeding risks were assessed and classified based on British Thoracic Society guidelines for flexible bronchoscopy (17). Severe bleeding events were described as events that required resuscitation, use of fibrin sealant, placement of a bronchus blocker, blood transfusion, admission to critical care or death. None of these types of events occurred in Cork University Hospital. In a study from a Danish centre of 141 patients undergoing TBLC, no procedure related mortality or severe bleeding events were recorded, again highlighting the improved safety profile of TBLC (18). A 2019 prospective randomised multi-centre study compared bleeding rates in TBLC to that of TBB, with their results showing a significant increased risk of bleeding with TBLC, 72.7% vs. 48.2% (19).

Pneumothorax is the other major safety concern when performing TBLC. In Cork University Hospital, TBLC is non-fluoroscopy guided at Cork University Hospital due to lack of availability and performed under conscious-sedation as described above. There was a high rate of pleural tissue found in our biopsy samples, this is likely related to the lack of fluoroscopy available during the procedure. The probe is inserted as distally into the airway as possible, and then we withdraw 1–2 cm before freezing, however we cannot guarantee that pleural tissue will not be taken in this sample. A 2021 study involving bedside conscious-sedation, non-fluoroscopy guided TBLC showed a pneumothorax rate of 18.8%, although in a smaller sample size of 32 patients (20). The above Danish study also reported 9.9% of patients undergoing TBLC required pleural drainage post-procedure (17). A large single centre study showed a post-MDM diagnostic rate of 82% in patients undergoing TBLC for undifferentiated ILD, with a 28% (70/250) pneumothorax rate as well (21). It would be a useful exercise to compare diagnostic rates and complications in fluoroscopy vs. non-fluoroscopy guided TBLC. Although it must also be noted conversely that fluoroscopy exposes the patients and practitioner to more radiation so both methods have their advantages and disadvantages (22). Also in many centres reporting data, it is not standard practice to routinely perform chest X-rays post-procedure on asymptomatic patients, which may be leading to lower reported rates of pneumothorax (23). The majority of pneumothoraces in our study did not require chest drainage.

Radial endobronchial ultrasound (EBUS), available only in highly specialised centres, is one method of potentially reducing complications and taking a more targeted approach to cryobiopsy—and has a role in identifying ground glass lesions also (24,25). However, research into its role is still in its infancy and larger studies are needed to confirm how useful it will be.

When it comes to pneumothorax, other factors alongside fluoroscopy and sedation have to be considered also. A newly published Japanese study commented on risk factors for bleeding in TBLC, and reported lower fentanyl dose per body weight was the only significant predictive factor for increased bleeding, likely due to its cough suppression effects. In that study however, TBLC was performed through endotracheal tube under general anaesthetic, with higher doses of fentanyl or midazolam than we use in Cork University Hospital (that study’s fentanyl average dose was 92.4 mcg, and midazolam average dose 11.8 mg per patient) (26). As mentioned earlier, previous publication from Cork University Hospital showed the average fentanyl dose in our patient groups was 78.9–85.4 mcg and average midazolam dosing was 7.9–8.7 mg (11). Further research on sedation dosing and relationship with pneumothorax would also be beneficial.

An interesting new take on approach to TBLC has been described by Salton et al., in which an uncuffed endotracheal tube is used under moderate sedation and spontaneous breathing. In Cork University Hospital we perform a similar method without the endotracheal tube, however this highlights a new means of increasing accessibility to TBLC in centres without access to anaesthesiologists or elective admission beds. Diagnostic yield was 90.1% in an albeit small sample size (27).

Finally, one more potentially useful update in this field is the advancement of genomics—albeit not yet widely available. Combining this with TBLC could help increase diagnostic confidence and yield in ILD patients. It has been shown to have 92% specificity in predicting histopathological UIP, however with lower sensitivity (28). When combined with TBLC, it has the potential to alter therapeutic management strategies. Interestingly when studied, the combination showed a significant reduction in follow-up without treatment, and had a possible role in prognosticating also (29).

The ERS/ATS/JRS/ALAT guidelines on the role of TBLC recommend it as a reasonable replacement test in patients eligible for SLB where histopathology is required, but also still recommends SLB as a follow-up test if TBLC is non-informative (1). There is no significant data available yet on whether repeating the TBLC in this scenario is beneficial. Most of these recommendations were considered ‘very-low’ confidence so it is imperative for centres to continue producing cryobiopsy data and research to provide the best standard of care for our ILD patients.

As explained, our findings show us that based on HRCT imaging, it is possible that the more likely a patient is to have UIP/IPF, the less likely TBLC is to alter their management or diagnosis. However, while we reached statistical significance between probable UIP and indeterminate UIP imaging groups, larger multi-centre data would help to corroborate our hypothesis. The overall post-MDM diagnostic rate of 80.2% is comparable to international standards for TBLC, including centres with fluoroscopy guidance performing procedures under general anaesthetic. As was to be expected, IPF was the most common diagnosis, however likely lower than usual prevalence rates as there were far less patients with UIP pattern imaging included.

We need multi-centre prospective data on this topic to investigate our hypothesis that TBLC is more useful in patients with indeterminate UIP or alternative diagnosis HRCT imaging. We cannot make a recommendation either way as the findings are not all statistically significant between groups, however we believe this is the starting point of a topic that could be investigated further. The data we have collected should be easily reproducible in other centres.

Conclusions

What our data shows us is that there is potential for the role of HRCT imaging patterns in streamlining appropriate patients for TBLC, which could improve patient safety and outcomes, with particular interest in patients with probable UIP imaging where the rate of diagnostic change was lower than indeterminate UIP patterns. As mentioned above, multi-centre prospective data would help further investigate our findings.

Acknowledgments

Parts of this study were originally presented as an abstract and poster presentation at the 2024 Irish Thoracic Society Scientific Meeting.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-734/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-734/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-734/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-2025-734/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 Clinical Research Ethics Committee of the Cork Teaching Hospitals, which oversees research ethics for Cork University Hospital [No. ECM 4 (aa)] 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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