Prognostic value of transbronchial lung cryobiopsy for the multidisciplinary diagnosis of idiopathic pulmonary fibrosis: a retrospective validation study

doi:10.1016/S2213-2600(20)30122-3

The Lancet Respiratory Medicine

Volume 8, Issue 8, August 2020, Pages 786-794

, , , , , , , , , , , , , , , , , , , …

https://doi.org/10.1016/S2213-2600(20)30122-3 Get rights and content

Summary

Background

Transbronchial lung cryobiopsy (TBLC) has been introduced recently in the diagnosis of interstitial lung diseases. We aimed to evaluate the prognostic significance of the distinction between idiopathic pulmonary fibrosis and other interstitial lung diseases with the use of TBLC data in multidisciplinary team (MDT) diagnosis.

Methods

In this single-centre, retrospective, investigator-initiated comparative study, we evaluated consecutive patients without a definite usual interstitial pneumonia pattern on high-resolution CT, who presented to the GB Morgagni Hospital (Forlì, Italy), and who underwent TBLC (Jan 1, 2011, to Dec 31, 2014) or surgical lung biopsy (SLB; Jan 1, 2002, to Dec 31, 2016). Three pathologists reviewed the specimens, masked to clinical information. MDT evaluation was done before and after biopsy. The primary endpoint was the prognostic significance of the MDT diagnostic separation between idiopathic pulmonary fibrosis and other interstitial lung diseases in patients undergoing TBLC. Mortality was evaluated by means of Cox regression analysis.

Findings

We evaluated 500 consecutive cases, 426 of which were included: 266 had TBLC and 160 had SLB. 189 patients had idiopathic pulmonary fibrosis, 143 had other fibrotic interstitial lung diseases, and 94 had non-fibrotic interstitial lung diseases. Patients undergoing TBLC had more comorbidities and better preserved lung function compared with those undergoing SLB; among patients with a final MDT diagnosis of idiopathic pulmonary fibrosis, patients undergoing TBLC were older, had more comorbidities, and had a different post-biopsy treatment profile than those who received SLB. The distinction between idiopathic pulmonary fibrosis and other interstitial lung diseases made by MDT diagnosis on the basis of TBLC biopsy had clear prognostic significance, with a 5-year transplant-free survival of 68% (95% CI 57–76) in patients with an MDT idiopathic pulmonary fibrosis diagnosis based on TBLC compared with 93% (87–96) in patients without an idiopathic pulmonary fibrosis diagnosis based on TBLC (hazard ratio 5·28, 95% CI 2·72–10·04; p<0·0001). This distinction remained statistically significant in a multivariate analysis controlling for age, sex, smoking status, comorbidities, pulmonary function, and high-resolution CT patterns (p=0·02).

Interpretation

TBLC makes an important diagnostic contribution in interstitial lung disease, on the basis of the prognostic distinction between idiopathic pulmonary fibrosis and other interstitial lung diseases when TBLC findings are included in multidisciplinary diagnosis.

Funding

None.

Introduction

Idiopathic pulmonary fibrosis is a lethal interstitial lung disease with a median survival of 2–5 years.¹ Distinguishing between idiopathic pulmonary fibrosis and other lung diseases, particularly other fibrotic interstitial lung diseases (ie, idiopathic non-specific interstitial pneumonia, hypersensitivity pneumonitis, connective tissue disease-related interstitial lung disease, and smoking-related interstitial lung diseases), is sometimes difficult but has major prognostic significance and underpins treatment decisions.² In many patients with interstitial lung disease, clinical and radiological data do not provide a confident multidisciplinary team (MDT) diagnosis and lung biopsy is advised.1, 3

Two diagnostic procedures provide meaningful histological information in the MDT diagnosis of idiopathic pulmonary fibrosis: surgical lung biopsy (SLB) and transbronchial lung cryobiopsy (TBLC);4, 5 SLB is the technique recommended in the 2018 updated idiopathic pulmonary fibrosis guidelines,¹ whereas TBLC has shown promise in several studies.4, 6, 7 The COLDICE study,⁵ a rigorous, prospective, multicentre, comparative study, reported histopathological concordance between TBLC and SLB of 70·8% (κ 0·70, 95% CI 0·55–0·86) and diagnostic agreement at multidisciplinary discussion of 76·9% (0·62, 0·47–0·78). This study provided robust information on diagnostic accuracy, not achieved in an earlier underpowered study,⁸ and supported the integration of TBLC in the interstitial lung disease diagnosis. Although the TBLC diagnostic yield falls short of that of SLB (75–90% compared with 95–100%), a confident TBLC diagnosis had strong concordance with SLB findings.⁵ Before the COLDICE study, the use of TBLC was not uniformly accepted, with scientific societies acknowledging uncertainty about its diagnostic role in interstitial lung diseases.⁹ The substantial body of literature showing that TBLC has lower mortality, fewer complications, and lower costs than SLB was offset by concerns that the technique had not been standardised, with procedural variability between centres reflecting the rapid spread of the technique; thus, the place of TBLC in interstitial lung disease diagnosis remained uncertain.¹⁰ However, the 2019 American College of Chest Physicians guidelines¹¹ recognise that TBLC is safer than SLB and endorse its use in the MDT diagnosis of interstitial lung diseases, while acknowledging that further research is required.

Research in context

Evidence before this study

Transbronchial lung cryobiopsy (TBLC) is a novel, minimally invasive technique used in many centres to obtain lung tissue for the diagnosis of interstitial lung diseases. Studies have shown reassuring safety data and a good accuracy, but studies evaluating the clinical outcome of patients who underwent TBLC have not been done, and validation of the prognostic ability of this biopsy method is still pending. We searched PubMed using the terms “transbronchial lung cryobiopsy” or “surgical lung biopsy” and “interstitial lung disease” or “diffuse parenchymal lung disease” or “idiopathic pulmonary fibrosis”, for all studies published from database inception until Oct 15, 2019, with no language restrictions. With the exception of two prospective randomised studies on diagnostic accuracy of TBLC and five systematic reviews, most of the publications were retrospective studies reporting the diagnostic yield and the complication rate of TBLC. To our knowledge, no study has compared the prognosis of patients with idiopathic pulmonary fibrosis versus those with non-idiopathic pulmonary fibrosis interstitial lung diseases diagnosed by TBLC. By contrast, the prognostic ability of surgical lung biopsy (SLB) has been validated in several large retrospective studies, with histopathology findings of usual interstitial pneumonia on SLB being predictive of significantly worse outcomes compared with non-usual interstitial pneumonia. On the basis of these findings, SLB has been accepted as the gold histopathology standard for the diagnosis of usual interstitial pneumonia, even in the absence of solid, prospective, and controlled accuracy studies. We identified only one small study that compared the survival prognostication of TBLC to SLB and to high-resolution CT diagnosis. The study evaluated 19 patients who had TBLC, 43 who had SLB, and 112 who had high-resolution CT and showed no difference in survival between TBLC and SLB.

Added value of this study

To our knowledge, this is the first large comparative study to show prognostic prediction of idiopathic pulmonary fibrosis diagnosis by TBLC. The findings for TBLC compared favourably with those based on SLB. Similarly, blinded pathological assessment using TBLC biopsies provided a good prognostic separation between usual interstitial pneumonia and non-usual interstitial pneumonia cases.

Implications of all the available evidence

Although SLB has been used for decades because it has prognostic value, TBLC yields solid prognostic information approaching that reported for SLB. Our findings suggest that TBLC is acceptable for multidisciplinary team diagnosis of idiopathic pulmonary fibrosis, and provide a rationale to integrate the use of TBLC in the diagnostic algorithm of interstitial lung diseases that do not have diagnostic clinical–radiological features of usual interstitial pneumonia or idiopathic pulmonary fibrosis. This study adds to the 2020 accuracy study by Troy and colleagues, providing strong evidence of prognostic separation between idiopathic pulmonary fibrosis and non-idiopathic pulmonary fibrosis interstitial lung diseases achieved by TBLC.

A strong rationale for the use of SLB is that it provides important prognostic information in the context of MDT diagnosis of interstitial lung diseases, with histopathological findings of usual interstitial pneumonia on SLB predictive of significantly worse outcomes compared with other patterns.12, 13 The prognostic significance of TBLC findings has never been assessed in this way, and panellists of international guidelines for idiopathic pulmonary fibrosis have raised an important argument against the use of TBLC: so far, no studies have evaluated survival outcomes for MDT diagnostic distinctions on the basis of TBLC information.¹

Using SLB as a gold standard, we aimed to evaluate the prognostic value of TBLC in the context of MDT diagnoses of idiopathic pulmonary fibrosis.

Section snippets

Study design and patient selection

In this single-centre, retrospective, investigator-initiated comparative study, we evaluated consecutive patients presenting to the pulmonary unit of the GB Morgagni Hospital (Forlì, Italy) with suspected interstitial lung disease who underwent TBLC (between Jan 1, 2011, and Dec 31, 2014) or SLB (between Jan 1, 2002, and Dec 31, 2016). Patients with incomplete clinical data and those with a definite usual interstitial pneumonia pattern on high-resolution CT (HRCT) were excluded. Patient data

Results

500 patients were evaluated: 310 received TBLC and 190 SLB (figure 1). The final study cohort consisted of 426 cases (266 TBLC and 160 SLB). 189 patients had idiopathic pulmonary fibrosis, 143 had other fibrotic interstitial lung diseases, and 94 had non-fibrotic interstitial lung diseases. 43 TBLC and 48 SLB cases reported in a previous study published by our group were included in the present study.⁴ Patients undergoing TBLC were older and had a higher comorbidity burden and relative

Discussion

This study shows that TBLC data make a robust contribution to an MDT diagnosis of idiopathic pulmonary fibrosis, as validated by the higher mortality associated with an idiopathic pulmonary fibrosis diagnosis compared both with other interstitial lung diseases and with other fibrotic interstitial lung diseases. Similarly, TBLC pathological assessment, masked to clinical and radiological information, showed that a usual interstitial pneumonia pattern was associated with higher mortality compared

References (18)

DA Lynch et al.
Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper
Lancet Respir Med
(2018)
LK Troy et al.
Diagnostic accuracy of transbronchial lung cryobiopsy for interstitial lung disease diagnosis (COLDICE): a prospective, comparative study
Lancet Respir Med
(2020)
F Maldonado et al.
Transbronchial cryobiopsy for the diagnosis of interstitial lung diseases: CHEST Guideline and expert panel report
Chest
(2020)
LJ De Sadeleer et al.
Diagnostic ability of a dynamic multidisciplinary discussion in interstitial lung diseases: a retrospective observational study of 938 cases
Chest
(2018)
SL Walsh et al.
Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: a case-cohort study
Lancet Respir Med
(2016)
G Raghu et al.
Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline
Am J Respir Crit Care Med
(2018)
DJ Lederer et al.
Idiopathic pulmonary fibrosis
N Engl J Med
(2018)
S Tomassetti et al.
Bronchoscopic lung cryobiopsy increases diagnostic confidence in the multidisciplinary diagnosis of idiopathic pulmonary fibrosis
Am J Respir Crit Care Med
(2016)
C Ravaglia et al.
Diagnostic yield and risk/benefit analysis of trans-bronchial lung cryobiopsy in diffuse parenchymal lung diseases: a large cohort of 699 patients
BMC Pulm Med
(2019)

There are more references available in the full text version of this article.

Cited by (35)

Relationship between idiopathic interstitial pneumonias (IIPs) and connective tissue disease-related interstitial lung disease (CTD-ILD): A narrative review
2024, Respiratory Investigation
While idiopathic interstitial pneumonia (IIP) centering on idiopathic pulmonary fibrosis (IPF) is the most prevalent interstitial lung disease (ILD), especially in the older adult population, connective tissue disease (CTD)-related ILD is the second most prevalent ILD. The pathogenesis of IPF is primarily fibrosis, whereas that of other ILDs, particularly CTD-ILD, is mainly inflammation. Therefore, a precise diagnosis is crucial for selecting appropriate treatments, such as antifibrotic or immunosuppressive agents. In addition, some patients with IIP have CTD-related features, such as arthritis and skin eruption, but do not meet the criteria for any CTD, this is referred to as interstitial pneumonia with autoimmune features (IPAF). IPAF is closely associated with idiopathic nonspecific interstitial pneumonia (iNSIP) and cryptogenic organizing pneumonia (COP). Furthermore, patients with iNSIP or those with NSIP with OP overlap frequently develop polymyositis/dermatomyositis after the diagnosis of IIP. Acute exacerbation of ILD, the most common cause of death, occurs more frequently in patients with IPF than in those with other ILDs. Although acute exacerbation of CTD-ILD occurs at a low rate of incidence, patients with rheumatoid arthritis, microscopic polyangiitis, or systemic sclerosis experience more acute exacerbation of CTD-ILD than those with other CTD. In this review, the features of each IIP, focusing on CTD-related signatures, are summarized, and the pathogenesis and appropriate treatments to improve the prognoses of patients with various ILDs are discussed.
Idiopathic Pulmonary Fibrosis and Progressive Pulmonary Fibrosis
2023, Immunology and Allergy Clinics of North America
Transbronchial lung cryobiopsy and pulmonary fibrosis: A never-ending story?
2023, Heliyon
The diagnostic process of pulmonary fibrosis (PF) is often challenging, requires a collaborative effort of several experts, and often requires bioptic material, which can be difficult to obtain, both in terms of quality and technique. The main procedures available to obtain such samples are transbronchial lung cryobiopsy (TBLC) and surgical lung biopsy (SLB).
The purpose of this paper is to review the evidence for the role of TBLC in the diagnostic-therapeutic process of PF.
A comprehensive review was performed to identify articles to date that addressed the role of TBLC in the diagnostic-therapeutic process of PF using the PubMed® database.
The reasoned search identified 206 papers, including 21 manuscripts (three reviews, one systematic review, two guidelines, two prospective studies, three retrospective studies, one cross-sectional study, one original article, three editorials, three clinical trials, and two unclassifiable studies), which were included in the final review.
TBLC is gaining increasing efficacy and improving safety profile; however, there are currently no clear data demonstrating its superiority over SLB. Therefore, the two techniques should be considered with careful rationalization on a case-by-case basis. Further research is needed to further optimize and standardize the procedure and to thoroughly study the histological and molecular characteristics of PF.
Transbronchial needle aspiration combined with cryobiopsy in the diagnosis of mediastinal diseases: a multicentre, open-label, randomised trial
2023, The Lancet Respiratory Medicine
Transbronchial mediastinal cryobiopsy is a novel sampling technique for mediastinal disease. Despite the possibility of lung cancer misdiagnosis, the improved diagnostic yield of this approach for non-lung-cancer lesions compared with standard endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) highlights its diagnostic potential as a complementary technique to conventional biopsy. We aimed to evaluate the safety profile and added value of the combined use of transbronchial mediastinal cryobiopsy and standard EBUS-TBNA for the diagnosis of mediastinal diseases.
We conducted an open-label, randomised trial at three hospital sites in Europe and Asia. Eligible patients were aged 15 years or older, with at least one mediastinal lesion of 1 cm or longer in the short axis that required diagnostic bronchoscopy. Participants were randomly assigned (1:1) using a block randomisation scheme generated by a computer (block size of four participants based on a random table from an independent statistician) to the combined use of EBUS-TBNA and transbronchial mediastinal cryobiopsy (combined group) or EBUS-TBNA alone (control group). Because of the nature of the intervention, neither participants nor investigators were masked to group assignment. The coprimary outcomes were differences in procedure-related complications and diagnostic yield (defined as the proportion of participants for whom mediastinal biopsy led to a definitive diagnosis), assessed in the full analysis set, including all the patients who met the eligibility criteria and had a biopsy. A fully paired, intraindividual diagnostic analysis in participants who had both needle aspiration and mediastinal cryobiopsy was conducted, in addition to interindividual comparisons. This trial is now complete and is registered with ClinicalTrials.gov, NCT04572984.
Between Oct 12, 2020, and Sept 9, 2021, 297 consecutive patients were assessed for eligibility and 271 were enrolled and randomly assigned to the combined group (n=136) or the control group (n=135). The addition of cryobiopsy to standard sampling significantly increased the overall diagnostic yield for mediastinal lesions, as shown by both interindividual (126 [93%] of 136 participants in the combined group vs 109 [81%] of 135 in the control group; risk ratio [RR] 1·15 [95% CI 1·04–1·26]; p=0·0039) and intraindividual (126 [94%] of 134 vs 110 [82%] of 134; RR 1·15 [95% CI 1·05–1·25]; p=0·0026) analyses. In subgroup analyses in the intraindividual population, diagnostic yields were similar for mediastinal metastasis (68 [99%] of 69 participants in the combined group vs 68 [99%] of 69 in the control group; RR 1·00 [95% CI 0·96–1·04]; p=1·00), whereas the combined approach was more sensitive than standard needle aspiration in benign disorders (45 [94%] of 48 vs 32 [67%] of 48; RR 1·41 [95% CI 1·14–1·74]; p=0·0009). The combined approach also resulted in an improved suitability of tissue samples for molecular and immunological analyses of non-small-cell lung cancer. The incidence of adverse events related to the biopsy procedure did not differ between trial groups, as grade 3–4 airway bleeding occurred in three (2%) patients in the combined group and two (1%) in the control group (RR 0·67 [95% CI 0·11–3·96]; p=1·00). There were no severe complications causing death or disability.
The addition of mediastinal cryobiopsy to standard EBUS-TBNA resulted in a significant improvement in diagnostic yield for mediastinal lesions, with a good safety profile. These data suggest that this combined approach is a valid first-line diagnostic tool for mediastinal diseases.
National Natural Science Foundation of China.
Diagnostic yield and safety of transbronchial lung cryobiopsy for diffuse parenchymal lung diseases diagnosis: Comparison between 1.7-mm and 1.9-mm probes
2023, Pulmonology
Purpose of the research: transbronchial lung cryobiopsy has been recently accepted as a valid and less invasive alternative to surgical lung biopsy. The purpose of this randomized controlled study was to evaluate, for the first time, the quality and safety of biopsy specimens obtained by using the new disposable 1.7-mm cryoprobe compared with the standard re-usable 1.9 mm cryoprobe in the diagnosis of diffuse parenchymal lung diseases. Methods: 60 consecutive patients were prospectively enrolled and randomly assigned to two different groups: 1.9 mm (group A) and 1.7 mm (group B); primary endpoints were pathological and multidisciplinary diagnostic yield, sample size and complication rate. Principal results: the pathological diagnostic yield of cryobiopsy was 100% in group A and 93.3% in group B (p = 0.718); cryobiopsy median diameter was 6.8 mm in group A and 6.7 mm in group B (p = 0,5241). Pneumothorax occurred in 9 patients in group A and 10 in group B (p = 0.951); mild-to-moderate bleeding in 7 cases and 9 cases in group A and B respectively (p = 0.559). No death or severe adverse events were observed. Conclusions: there was no statistically significant difference between the two groups, regarding diagnostic yield, adverse events and sampling adequacy.
Interstitial lung diseases
2022, The Lancet
Citation Excerpt :
Transbronchial lung cryobiopsy has been developed as a less invasive method than surgical lung biopsy for obtaining biopsy samples in individuals with interstitial lung disease. Studies comparing transbronchial lung cryobiopsy with surgical lung biopsy suggest a lower incidence of complications but a similar level of diagnostic accuracy when histological findings are incorporated into the multidisciplinary discussion; thus, in centres with appropriate bronchoscopic and pathological expertise, transbronchial lung cryobiopsy represents a good alternative to surgical biopsy.62–64 It is important to recognise that, given the overlap of histopathological lesions across interstitial lung diseases, biopsy is not in itself the diagnostic gold standard but should be integrated into multidisciplinary discussion of the diagnosis.65
Over 200 interstitial lung diseases, from ultra rare to relatively common, are recognised. Most interstitial lung diseases are characterised by inflammation or fibrosis within the interstitial space, the primary consequence of which is impaired gas exchange, resulting in breathlessness, diminished exercise tolerance, and decreased quality of life. Outcomes vary considerably for each of the different interstitial lung diseases. In some conditions, spontaneous reversibility or stabilisation can occur, but unfortunately in many people with interstitial lung disease, especially in those manifesting progressive pulmonary fibrosis, respiratory failure and death are a sad reality. Over the past 3 years, the field of interstitial lung disease has had important advances, with the approval of drugs to treat systemic sclerosis-associated interstitial lung disease, interstitial lung disease-associated pulmonary hypertension, and different forms of progressive pulmonary fibrosis. This Seminar provides an update on epidemiology, pathogenesis, presentation, diagnosis, disease course, and management of the interstitial lung diseases that are most frequently encountered in clinical practice. Furthermore, we describe how developments have led to a shift in the classification and treatment of interstitial lung diseases that exhibit progressive pulmonary fibrosis and summarise the latest practice-changing guidelines. We conclude with an outline of controversies, uncertainties, and future directions.

View all citing articles on Scopus

^†: Emeritus

View full text

ArticlesPrognostic value of transbronchial lung cryobiopsy for the multidisciplinary diagnosis of idiopathic pulmonary fibrosis: a retrospective validation study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and patient selection

Results

Discussion

Lancet Respir Med

Lancet Respir Med

Chest

Chest

Lancet Respir Med

Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline

Am J Respir Crit Care Med

Idiopathic pulmonary fibrosis

N Engl J Med

Bronchoscopic lung cryobiopsy increases diagnostic confidence in the multidisciplinary diagnosis of idiopathic pulmonary fibrosis

Am J Respir Crit Care Med

Diagnostic yield and risk/benefit analysis of trans-bronchial lung cryobiopsy in diffuse parenchymal lung diseases: a large cohort of 699 patients

BMC Pulm Med

Articles
Prognostic value of transbronchial lung cryobiopsy for the multidisciplinary diagnosis of idiopathic pulmonary fibrosis: a retrospective validation study