Annals of the American Thoracic Society

Interstitial lung disease (ILD) represents a varied group of conditions for which diagnosis is often challenging. Although international guidelines would suggest that a substantial proportion of individuals should be biopsied to obtain a confident diagnosis (1, 2), few patients actually undergo this procedure (3). Central to this paradox are concerns over the safety of biopsy (4) and the value added by biopsy, especially given unease around interobserver variability in interpretation of histopathology (5). Although retrospective studies have previously hinted at a change in therapy following biopsy ranging from 40% to 60%, these often did not specifically detail how therapy changed, did not do so in the context of multidisciplinary discussion (MDD), and were commonly performed before antifibrotic drugs were widely implemented (6, 7). No robust studies have examined how lung biopsy affects management in the post-antifibrotic era and in the setting of the most recent clinical practice guidelines.

In this issue of AnnalsATS, Tomassetti and colleagues (pp. 737–745) examine the impact of biopsy findings on the management of patients with ILD without a definite usual interstitial pneumonia (UIP) pattern on radiology (8). A substudy of a single-center, retrospective initiative designed to evaluate the prognostic value of transbronchial lung cryobiopsy (TBLC) (9), this work included 426 consecutive patients from Italy who underwent TBLC or surgical lung biopsy (SLB) for suspected ILD, of which nearly 80% had fibrotic disease. Each case was reviewed in MDD to establish a diagnosis and management plan based on clinical and radiologic information. Pathology information was then introduced by a pathologist blinded to clinical and radiologic information, with subsequent reevaluation of the diagnosis and plan. A change in therapy was judged as conversion from expectant management to initiation of treatment or vice versa, or a change in choice of therapy between immunosuppressive and antifibrotic therapy.

Tomassetti and colleagues found that biopsy led to a meaningful change in management in approximately one-third of cases, a finding that remained consistent in the major subgroup limited to patients with fibrotic disease. Among cases where there was a change in management, approximately 40% were in the setting of an altered diagnosis, whereas 60% were associated with a more confident diagnosis. In addition, the percentage of cases where treatment changed was similar regardless of whether TBLC or SLB was used.

Although the authors defined a change in treatment strategy among 20% of biopsied cases as being clinically meaningful, clinicians may disagree on what threshold is worthwhile when balanced against the risk of lung biopsy. The current findings imply that two-thirds of individuals undergoing biopsy do so without significant change in therapy, all while being subjected to procedural complications including up to approximately 10% risk of moderate or severe airway bleeding and 20% risk of pneumothorax in TBLC, as well as a relatively small but nonzero risk of death with both TBLC and SLB (4, 10). In addition, the cost of biopsy must be considered as well as the added strain of this procedure on the healthcare system.

Despite this, there are several strong arguments to support the ongoing pursuit of lung biopsy and pathologic confirmation of disease in less than definite cases. Reclassification from non–idiopathic pulmonary fibrosis (IPF) to IPF, representing approximately 7% of cases in the current study, is crucial in a minority of patients to avoid the harm of immunosuppressive therapy in this condition (11). Similarly, diagnostically challenging cases of mild disease that are identified as IPF may lead to early initiation of antifibrotic therapy, which yields benefit even in those with mild or preserved lung function (12). Finally, the endpoint of the current study does not capture those individuals with mild disease where biopsy may not change management immediately but may do so at a later date if there is progression that demands therapy.

In addition to changes in pharmacologic treatment, biopsy yields information that is beneficial to a patient’s care and should not be discounted. Histopathology provides meaningful prognostic information, especially in the setting of an unfavorable UIP pattern (13). Recognition of a UIP pattern also identifies those individuals more likely to progress, who may benefit more from aggressive treatment and close follow-up, and who may be better served by early referral for lung transplantation. Finally, a confirmed diagnosis in a minority of patients may lead to other treatment recommendations apart from pharmacotherapy, such as a renewed search for an antigen and redoubled efforts for antigen remediation in cases of fibrotic hypersensitivity pneumonitis. These arguments, in addition to treatment change in one-third of cases, may be enough to convince many clinicians of the merits of seeking lung biopsy.

The authors describe using antifibrotics only in cases of IPF at the time this study was conducted, which does not incorporate new indications for antifibrotics in progressive fibrotic disease (14), systematic sclerosis-associated ILD (15), and unclassifiable progressive ILD (16). Although the progressive fibrotic phenotype should more easily lend itself to antifibrotic therapy, it does not obviate the need for biopsy and ongoing efforts to diagnose ILD subtypes (17). In addition to identifying patterns more prone to progression and potentially leading to earlier initiation of appropriate therapy, biopsy findings may help clinicians decide between starting antifibrotic or immunosuppressive therapy in cases where both might be indicated, such as fibrotic hypersensitivity pneumonitis.

The current study has several strengths and constitutes the first robust examination of how lung biopsy leads to change in therapy in a large, relevant population that is reflective of current clinical practice. However, the findings are based on experience at a single center and require external validation, especially in the setting of the expanding role of antifibrotic therapy in ILD. Moreover, the study was not specifically designed to evaluate a difference in change in management following TBLC as compared with SLB; although no statistically significant difference was detected (31.5% change in treatment with TBLC compared with 38% with SLB), this represents an underpowered analysis and cannot be used to equate TBLC with SLB in its ability to alter management decisions.

In addition, although incorporation of histopathology findings in MDD clearly helped determine treatment, there is, nonetheless, some suggestion in the data from the underlying paper from which the present substudy is derived (9) that the biopsy results may not be entirely accurate, particularly with respect to UIP suggestive of IPF. In patients undergoing SLB who ultimately received a diagnostic label of IPF, most of whom were biopsied in the pre-antifibrotic era, the 5-year survival was 53% and median survival was 5 years, whereas in those who underwent TBLC during a timeframe that coincides with the use of antifibrotics, the 5-year survival was 68% and median survival was 7 years. These numbers are considerably better than those reported by most investigators (18) and suggest that UIP and MDD diagnosis of IPF were being overcalled, particularly by TBLC. Arguably, this finding might not matter if the miscalls are other forms of progressive fibrosing interstitial pneumonias for which antifibrotic therapy is probably the preferred therapeutic approach, but this is not true of other ILD subtypes where immunosuppressive therapy is often the recommended starting point. This whole issue emphasizes the need for specific pathologic criteria for different types of fibrosing interstitial pneumonias in TBLC, something that is largely lacking or controversial (19).

Despite some concern around diagnostic accuracy, Tomassetti and colleagues provide a much-needed study that adds valuable data to guide clinicians when considering the practical utility of lung biopsy in ILD. Although the findings need to be confirmed in geographically diverse settings, the current study offers reassurance that lung biopsy is not an antiquated diagnostic tool to be avoided, but plays an ongoing and important role that meaningfully changes the course of treatment in a significant subgroup of patients.

1. Raghu G, Remy-Jardin M, Ryerson CJ, Myers JL, Kreuter M, Vasakova M, et al. Diagnosis of hypersensitivity pneumonitis in adults. An official ATS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 2020;202:e36e69.
2. Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al.; American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 2018;198:e44e68.
3. Hopkins RB, Burke N, Fell C, Dion G, Kolb M. Epidemiology and survival of idiopathic pulmonary fibrosis from national data in Canada. Eur Respir J 2016;48:187195.
4. Hutchinson JP, Fogarty AW, McKeever TM, Hubbard RB. In-hospital mortality after surgical lung biopsy for interstitial lung disease in the United States. 2000 to 2011. Am J Respir Crit Care Med 2016;193:11611167.
5. Nicholson AG, Fulford LG, Colby TV, du Bois RM, Hansell DM, Wells AU. The relationship between individual histologic features and disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2002;166:173177.
6. Blackhall V, Asif M, Renieri A, Civitelli S, Kirk A, Jilaihawi A, et al. The role of surgical lung biopsy in the management of interstitial lung disease: experience from a single institution in the UK. Interact Cardiovasc Thorac Surg 2013;17:253257.
7. Qureshi RA, Ahmed TA, Grayson AD, Soorae AS, Drakeley MJ, Page RD. Does lung biopsy help patients with interstitial lung disease? Eur J Cardiothorac Surg 2002;21:621626, discussion 626.
8. Tomassetti S, Ravaglia C, Puglisi S, Ryu JH, Colby TV, Cavazza A, et al. Impact of lung biopsy information on treatment strategy of patients with interstitial lung diseases. Ann Am Thorac Soc 2022;19:737745.
9. Tomassetti S, Ravaglia C, Wells AU, Cavazza A, Colby TV, Rossi G, et al. Prognostic value of transbronchial lung cryobiopsy for the multidisciplinary diagnosis of idiopathic pulmonary fibrosis: a retrospective validation study. Lancet Respir Med 2020;8: 786794.
10. Ravaglia C, Wells AU, Tomassetti S, Gurioli C, Gurioli C, Dubini A, 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;19:16.
11. Raghu G, Anstrom KJ, King TE Jr., Lasky JA, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012;366:19681977.
12. Kolb M, Richeldi L, Behr J, Maher TM, Tang W, Stowasser S, et al. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax 2017;72:340346.
13. Daniil ZD, Gilchrist FC, Nicholson AG, Hansell DM, Harris J, Colby TV, et al. A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 1999;160:899905.
14. Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al.; INBUILD Trial Investigators. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med 2019;381:17181727.
15. Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD, et al.; SENSCIS Trial Investigators. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med 2019;380: 25182528.
16. Maher TM, Corte TJ, Fischer A, Kreuter M, Lederer DJ, Molina-Molina M, et al. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir Med 2020;8: 147157.
17. Ravaglia C, Nicholson AG. Biopsy in interstitial lung disease: specific diagnosis and the identification of the progressive fibrotic phenotype. Curr Opin Pulm Med 2021;27:355362.
18. Ryerson CJ, Kolb M. The increasing mortality of idiopathic pulmonary fibrosis: fact or fallacy? Eur Respir J 2018;51:1702420.
19. Churg A, Ryerson CJ, Wright JL. Fibroblast foci and patchy fibrosis do not separate usual interstitial pneumonia from fibrotic hypersensitivity pneumonitis in transbronchial cryobiopsies. Arch Pathol Lab Med 2021;145:13251326.

Author disclosures are available with the text of this article at www.atsjournals.org.

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