The Role of Surgical Lung Biopsy in Antifibrotic Therapy for Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic, fibrosing lung disease with high mortality (1). The diagnosis rests upon a compatible clinical picture of insidious dyspnea, dry cough, and the exclusion of exposure to mineral or organic dusts, connective tissue disease, fibrogenic drugs, or radiation. High-resolution computed tomography (CT) is an essential part of a clinical diagnosis, with typical features of bibasilar reticular interstitial markings and a lack of atypical features such as nodularity, upper-lobe distribution, and considerable amounts of ground-glass infiltrates or emphysematous changes. The presence of honeycombing in the bases strongly adds to the confidence of a radiographic diagnosis of usual interstitial pneumonia (UIP). When necessary, a surgical lung biopsy (SLB) can be performed to identify histologic features of UIP. A confident diagnosis of IPF is believed to be critical, as it helps direct considerations for antifibrotic medications, rehabilitation, referral to lung transplantation, enrollment in clinical trials, and, in cases of advanced disease, palliative care.

Since 2014, two antifibrotic medications, nintedanib and pirfenidone, have received U.S. Food and Drug Administration approval following the publication of two parallel phase III randomized controlled trials (INPULSIS 1 and 2, and ASCEND [Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis]) that demonstrated a slowing of the rate of decline in lung function in IPF (2, 3). However, there were no significant beneficial effects in terms of mortality, respiratory symptoms, or quality of life for either medication. The 2015 American Thoracic Society (ATS) IPF clinical practice guideline statement supported a “conditional recommendation” for the use of these medications in patients with IPF (4). In a recent study, Dempsey and colleagues used data from a large U.S. insurance database to compare patients with IPF who had been treated with antifibrotics with propensity-matched control subjects who had not received such therapy, and the authors found that the use of antifibrotic medications was associated with a decreased risk of all-cause mortality over the first 2 years of treatment, as well as decreased acute hospitalization (5). No differences were noted between patients taking pirfenidone and those receiving nintedanib. However, given the high costs of these antifibrotic agents, insurers are increasingly requiring rigorous diagnostic confidence, based on either typical CT findings or lung biopsy, to approve coverage of these agents.

In a study presented in this issue of the Journal, Walsh and colleagues (pp. 1146–1153) examined the level of diagnostic likelihood at which physicians prescribe antifibrotic therapy without requesting an SLB in patients suspected of having IPF (6). The study consisted of an international cohort of respiratory physicians who evaluated 60 cases of interstitial lung disease and reported differential diagnoses along with diagnostic likelihood, whether an SLB would be requested, and recommendations for initial management. IPF was included in the differential diagnosis in 41% of all physician–patient evaluations. SLB was requested in 8%, 29%, and 48% of definite, provisional high-confidence, and provisional low-confidence diagnoses of IPF. Antifibrotic therapy was prescribed without requesting an SLB in over 60% of provisional high-confidence IPF diagnoses (6). The team concluded that most respiratory physicians prescribe antifibrotic therapy without requesting an SLB if a “working diagnosis” of IPF can be rendered with high confidence. Using this simulated real-world diagnostic approach, these investigators better define the role of clinical certainty based on clinical presentation and CT imaging in the diagnosis of IPF, and the relative desire to apply SLB to confirm such a diagnosis. They also examine the issue of whether SLB is required before initiation of therapy. The study confirms the suspicion of many experts that SLB may not be required for prescription of antifibrotic agents as long as a “working diagnosis” of IPF can be made with high confidence.

The role of SLB in clinical diagnosis of IPF remains unsettled. Specifically, opinions regarding the necessity for lung biopsy in the presence of compatible clinical features and supportive (though not definitive) CT imaging evidence are also evolving. The 2018 ATS clinical practice guideline on the diagnosis of IPF considered the issue of SLB in patients with newly detected interstitial lung disease of apparently unknown cause who are clinically suspected of having IPF and a high-resolution CT pattern of probable UIP, indeterminate for UIP, or an alternative diagnosis (7). For such patients, the guideline suggested the use of SLB as a conditional recommendation, based on very low-quality evidence. Not surprisingly, in clinical practice, the biopsy rates for suspected IPF are relatively low, ranging from ∼15% to 30% of patients who ultimately receive a diagnosis of IPF (8–10). When deciding whether or not to perform an SLB, clinicians should also consider the mortality associated with SLB, as the procedure has an associated in-hospital mortality of 1.7%, a 30-day mortality of 2.4%, and a 90-day mortality of 3.9% (11). Hence, they must balance the need to know versus the morbidity and mortality of SLB, particularly in individuals with compromised lung function. The decision to proceed with biopsy must take into account the impact of a variety of clinical factors, such as advanced age, the degree of respiratory impairment (including low DlCO), the need for supplemental oxygen, and other comorbidities (e.g., diabetes mellitus, hypertension, cardiac disease, and cerebrovascular disease).

The current study further illustrates the challenges involved in reaching agreement when diagnosing IPF even among experts. In this study, interobserver agreement about the decision to perform SLB was poor to fair among participating physicians, which may raise some concerns about applying these results to individual patients. However, such concerns regarding interobserver agreement are widely acknowledged in this field, leading to the recommendation by many experts to include multidisciplinary discussion (MDD) as a central component of diagnosis. Although MDDs can be accomplished in academic centers, they can be challenging in private practice settings. The 2018 ATS clinical practice guideline suggested the use of MDDs in diagnostic decision-making as a conditional recommendation, based on a very low quality of evidence (7).

At the end of the diagnostic process for IPF, clinicians are often left with some level of diagnostic uncertainty. Accordingly, clinicians use the best available information to make decisions to manage individual patients. In that light, the investigation by Walsh and colleagues provides reassurance that most respiratory physicians prescribe antifibrotic therapy without requesting an SLB when a “working diagnosis” of IPF can be made with high confidence (6).