Unclassifiable interstitial lung disease: A review

Transcription

1 bs_bs_banner INVITED REVIEW SERIES EDITORS: TAMERA J. CORTE, ATHOL U. WELLS AND HAROLD R. COLLARD Unclassifiable interstitial lung disease: A review KATE SKOLNIK 1 AND CHRISTOPHER J. RYERSON 2 1 Department of Medicine, University of Calgary, Calgary, Alberta, 2 Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada ABSTRACT Accurate classification of interstitial lung disease (ILD) requires a multidisciplinary approach that incorporates input from an experienced respirologist, chest radiologist and lung pathologist. Despite a thorough multidisciplinary evaluation, up to 15% of ILD patients have unclassifiable ILD and cannot be given a specific diagnosis. The objectives of this review are to discuss the definition and features of unclassifiable ILD, identify the barriers to ILD classification and outline an approach to management of unclassifiable ILD. Several recent studies have described the characteristics of these patients; however, there are inconsistencies in the definition and terminology of unclassifiable ILD due to limited research in this population. Additional studies are required to determine the appropriate evaluation and management of patients with unclassifiable ILD. Key words: diffuse lung disease, idiopathic interstitial pneumonia, idiopathic pulmonary fibrosis, interstitial lung disease, unclassifiable. Abbreviations: ANA, anti-nuclear antibody; ATS, American Thoracic Society; CTD, connective tissue disease; DLCO, diffusing capacity of the lung for carbon monoxide; ERS, European Respiratory Society; FVC, forced vital capacity; HP, hypersensitivity pneumonitis; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; IIP, idiopathic interstitial pneumonia; IPF, idiopathic pulmonary fibrosis; NSIP, nonspecific interstitial pneumonia; UIP, usual interstitial pneumonia. Correspondence: Christopher J. Ryerson, St. Paul s Hospital, 1081 Burrard St, Ward 8B, Vancouver, BC V6Z 1Y6, Canada. chris.ryerson@hli.ubc.ca Funding Sources: Dr. Ryerson is supported by a Career Investigator Award from the Michael Smith Foundation for Health Research. Conflict of interest: CJR has received speaking honoraria and research funding from InterMune Inc. and Boehringer Ingelheim. Invited review series: Idiopathic Interstitial Pneumonia Part 2: Specific disease entities. The Authors: Kate Skolnik is a current fellow in the University of Calgary Respirology Program. Christopher Ryerson is an Assistant Professor at the Centre for Heart Lung Innovation at the University of British Columbia in Vancouver, Canada. Received 17 November 2014; invited to revise 16 April 2015; revised 21 April 2015; accepted 21 April Article first published online: 9 June 2015 A case report illustrating this review is available in Respirology Case Reports: Leung SC, Churg AM, Leipsic JA, Levy RD, Wilcox PG, Ryerson CJ. Unclassifiable interstitial lung disease: An unresolved diagnostic dilemma. Respirology Case Reports, 2015; doi: doi: / rcr2.112 Summary at a Glance We report a case of ILD that remained unclassifiable due to discordant clinical, radiological and pathological findings despite a thorough evaluation that included examination of explanted lung tissue. This case demonstrates that ILD can remain unclassifiable even with a complete evaluation and illustrates one approach to the management of such patients. Main teaching points: ILD classification requires a thorough review by a multidisciplinary panel that includes an experienced respirologist, chest radiologist and lung pathologist. Some ILD patients cannot be confidently classified with a specific ILD despite detailed review of a complete diagnostic evaluation. Management of unclassifiable ILD should be guided by considering the most likely diagnosis and the anticipated disease behaviour. INTRODUCTION Interstitial lung disease (ILD) includes a large number of conditions that are characterized by inflammation or fibrosis of the pulmonary parenchyma. ILD can occur due to a number of specific causes or may be classified as an idiopathic interstitial pneumonia (IIP), 1 a group of well-defined ILDs that lack a clear predisposing factor or underlying pathophysiology. Accurate classification of ILD requires a multidisciplinary approach that incorporates input from an doi: /resp.12568

2 Unclassifiable interstitial lung disease 52 experienced respirologist, chest radiologist and lung pathologist. Despite this effort, a large number of patients cannot be provided a confident ILD diagnosis, and are instead assigned a label of unclassifiable ILD. This is particularly common in patients with fibrotic ILD, with a differential diagnosis that primarily includes idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (HP), idiopathic nonspecific interstitial pneumonia (NSIP) and connective tissue disease associated-ild (CTD-ILD). The objectives of this review are to discuss the definition and features of unclassifiable ILD, identify the barriers to ILD classification and outline an approach to management of unclassifiable ILD. We focus on unclassifiable fibrotic ILD (hereafter referred to as unclassifiable ILD) to distinguish this from patients with a predominantly non-fibrotic or inflammatory biology that possesses distinct clinical features. DEFINITION The 2002 American Thoracic Society (ATS) and European Respiratory Society (ERS) consensus statement on the classification of the IIPs described unclassifiable ILD as an IIP that cannot be categorized despite extensive clinical, radiological and/or pathological assessment. 2 This statement noted several specific circumstances that can preclude a specific ILD diagnosis and thus results in an unclassifiable condition: An inability to obtain a key piece of clinical, radiological or pathological information critical for diagnosis (e.g. poor patient suitability or unwillingness to pursue surgical biopsy). A major discrepancy between clinical, radiological and pathological findings. Previous therapy confounding the interpretation of radiological or pathological findings. The presence of overlapping or concurrent conditions (e.g. discrepancy between pathological findings from different lobes on surgical lung biopsy). The 2013 ATS/ERS statement update provided a similar definition, again highlighting the importance of a multidisciplinary diagnostic approach. 1 Recent studies have used two main definitions for unclassifiable ILD, differing on whether a surgical lung biopsy is required in the diagnostic work-up. Some unclassifiable ILD cohorts have been defined based on the inability to provide a confident diagnosis after multidisciplinary review of clinical, radiological and pathological findings, with a surgical lung biopsy performed in all patients. 3 Other cohort studies have not required a surgical lung biopsy, and instead defined ILD as unclassifiable if a confident diagnosis was not obtained based on the available information, even if this was considered an incomplete evaluation. 4 These inconsistent definitions indicate the importance of establishing consensus criteria for unclassifiable ILD and developing a standardized approach to describing this population. EPIDEMIOLOGY Previous studies suggest that unclassifiable ILD accounts for up to 15% of ILD (Table 1), 3 8 with most recent cohorts reporting that ILD remains unclassifiable in approximately 10% of all ILD cases. This estimate depends on the clinical setting, study design and definition of unclassifiable ILD; however, ILD remains unclassifiable in a substantial proportion of patients undergoing surgical lung biopsy, 3 demonstrating that the prevalence of unclassifiable ILD can remain high even with a thorough diagnostic evaluation. The development of new diagnostic tests will likely change both the definition and prevalence of unclassifiable ILD. In particular, cryobiopsy may allow a definitive diagnosis in unclear cases when the patient is not a candidate for a more invasive surgical biopsy. 9,10 Future peripheral blood biomarkers and genetic testing may also allow a definitive diagnosis in similar situations; however, there are currently no such tests available that can accurately classify the IIPs. CLINICAL FEATURES Unclassifiable ILD represents a heterogeneous collection of undiagnosed fibrotic ILDs, and patients therefore have clinical features typical of IPF and other Table 1 Characteristics of unclassifiable ILD patients in recent cohort studies Country Years n Unclassifiable/ total N (%) % with surgical biopsy % Male Mean age (SD), years Mean FVC (SD), % Mean DLCO (SD), % Spain /500 (14.6) (13.6) China /251 (15.1) 100 Spain /511 (5.1) 22.7 United States /1370 (9.6) (12.9) 69.0 (22.1) 47.6 (19.7) Denmark /431 (14) (14.5) 73.7 (22.8) 55.8 (21.4) Australia /232 (9.9) Blank cells represent data that were not reported. DLCO, diffusing capacity of the lung for carbon monoxide; FVC, forced vital capacity; ILD, interstitial lung disease; SD, standard deviation.

3 53 non-ipf ILDs (i.e. chronic HP, idiopathic NSIP, CTD- ILD). 4,5,7 These common features include subacute onset of dyspnoea, dry cough, auscultatory crackles and the absence of clear exposures or features of autoimmune disease. In previous cohort studies of unclassifiable ILD, the mean age at the time of presentation was years, approximately half of patients were male, and 64% of patients had a history of smoking (Table 1). 4,5,7 Lung function measurements in unclassifiable ILD are also similar to other fibrotic ILDs, typically with mild restriction and moderately reduced DLCO at presentation. 4,7 Patients with unclassifiable ILD had a mean age, sex, smoking history, forced vital capacity (FVC), DLCO and oxygen use that was intermediate between those observed in IPF and non-ipf ILDs. 4,5,7 High-resolution computed tomography (HRCT) showed that 17% of unclassifiable ILD patients had a usual interstitial pneumonia (UIP) pattern, 50% had a possible UIP pattern and 33% were inconsistent with a UIP pattern. 4 There are no studies evaluating the inheritance patterns of unclassifiable ILD. Familial pulmonary fibrosis often has atypical radiological and pathological features that make accurate classification of ILD more challenging, 11 and it is likely that some patients with unclassifiable ILD have a family history of ILD. MANAGEMENT Management of unclassifiable ILD includes smoking cessation, vaccinations, supplemental oxygen, pulmonary rehabilitation, lung transplantation and treatment of comorbidities. Pulmonary rehabilitation has been studied in multiple fibrotic ILD subtypes and can improve quality of life, dyspnoea and exercise capacity in ILD patients that have exertional dyspnoea or functional limitation Lung transplantation should be considered in patients with severe or rapidly progressive ILD, and the absence of a clear aetiology for ILD should not be a contraindication for transplantation. The remaining interventions have benefit in other chronic pulmonary conditions, 17,18 and their non-specific mechanisms of action suggest similar benefits are likely in unclassifiable ILD. There is no direct evidence to guide the pharmacologic management of unclassifiable ILD, and identifying the most appropriate therapy is particularly challenging given the diverging treatment approaches for IPF and non-ipf ILD. The PANTHER study highlighted the lack of benefit and significantly increased morbidity and mortality from prednisone and azathioprine in IPF, 19 indicating that chronic immunosuppression with these agents should be avoided if the probability of IPF is moderate or high. The INPULSIS study showed that nintedanib, an oral antifibrotic agent, slowed the rate of FVC decline in IPF; 20 however, the inclusion criteria allowed for the enrollment of patients with possible IPF that was not confirmed by surgical lung biopsy. This suggests that the benefit of antifibrotic agents may extend to some patients with unclassifiable ILD that have suspected Respirology (2016) 21, but unconfirmed IPF, although additional confirmatory data are needed. PROGNOSIS Unclassifiable ILD has a prognosis intermediate between IPF and non-ipf ILDs, with a reported 5-year mortality of 31% in a large American ILD cohort. 4 Individuals with unclassifiable ILD had significantly lower mortality compared with IPF on unadjusted analysis and with adjustment for potential confounders including age, sex, FVC and DLCO. Unclassifiable ILD had higher mortality compared with non-ipf ILD on unadjusted analysis only. Unclassifiable ILD patients at high risk of mortality can be identified using several baseline clinical, physiological and radiological features. In a large cohort study, progression and mortality of unclassifiable ILD were independently predicted by the use of chronic oxygen therapy, a high burden of radiological fibrosis and the presence of honeycombing on HRCT. 4 The ILD-GAP clinical prediction tool uses patient age, sex, FVC and DLCO to estimate the risk of death in unclassifiable ILD and in other fibrotic ILD subtypes. 21,22 DISCUSSION K Skolnik and CJ Ryerson Unclassifiable ILD is a common problem in fibrotic ILD; however, little is known about this population and these patients are a major challenge for ILD physicians. Recent studies have improved our understanding of unclassifiable ILD, but several important questions remain. What is the most appropriate definition of unclassifiable ILD? A major criticism of designating unclassifiable ILD as a distinct disease entity is that this may discourage a complete evaluation, since it is then possible to assign patients to a diagnostic category even with an incomplete workup. 8,23 Despite this possibility, a substantial percentage of patients in well-phenotyped ILD cohorts cannot be confidently diagnosed even with a thorough evaluation. 4 The need for additional research in this large group of patients highlights the importance of standardizing the definition and terminology of unclassifiable ILD. The primary difference between the major definitions of unclassifiable ILD is whether a surgical lung biopsy is considered a mandatory component of the diagnostic evaluation. While a surgical biopsy would ideally be pursued in every patient, this is often not possible for the reasons described earlier. This results in two major subgroups of patients who lack a confident ILD diagnosis, with one group having a complete diagnostic evaluation including surgical lung biopsy, and a second group having a comparable assessment with the exception of a biopsy. The term unclassifiable has been applied to both of these populations, and was similarly used in the 2013 ATS/ ERS consensus statement on the classification of the 2015 Asian Pacific Society of Respirology

4 Unclassifiable interstitial lung disease 54 Figure 1 Proposed approach to the categorization of unclassifiable ILD. Abbreviations: ILD, interstitial lung disease; MDD, multidisciplinary discussion. IIPs. 1 Others have suggested the use of unclassified ILD for ILD patients that have not undergone a surgical lung biopsy, implying that although these patients are currently unclassified, they could theoretically be diagnosed with a more complete evaluation. The designation unclassifiable IIP has also been used to describe this population; however, using IIP in this setting implies that there is a distinct population of unclassifiable IIPs that can be distinguished from other unclassifiable ILDs. There are therefore multiple terms used to describe this population, and these often have subtle differences in meaning that can cause confusion. The definition and terminology of unclassifiable ILD summarized in Figure 1 addresses these major issues. We propose that unclassifiable ILD should be the primary term for this population, as the unclassifiable label is consistent with several previous studies as well as the 2013 ATS/ERS consensus statement on the classification of the IIPs. We suggest the use of a provisional descriptor for patients with ILD of uncertain aetiology who are theoretically classifiable with a complete evaluation. This subgroup includes patients who are not surgical candidates, patients who decline surgery, patients who have mild or stable disease that does not justify a surgical biopsy and those who have undergone surgical biopsy but cannot be diagnosed due to an inadequate sample. The provisional label indicates that these patients may be classified if additional diagnostic tests are performed in the future, and suggests that additional investigations should be pursued for these patients when possible. For example, a surgical biopsy may become a future possibility if a patient changes his mind after previously declining a surgical lung biopsy, develops symptoms and disease progression that now warrant a biopsy, or has an improvement in a comorbidity that was previously a barrier to surgery. Unclassifiable ILD with a complete diagnostic evaluation includes subgroups with unclassifiable clinical radiological pathological findings and those with conflicting findings or overlapping conditions. Additional diagnostic data are unlikely for these patients, distinguishing these subgroups from those with provisional unclassifiable ILD in which a surgical lung biopsy could provide a specific diagnosis. We believe this terminology will help standardize ILD classification and facilitate across-study comparisons; however, further clarification of the definition of unclassifiable ILD is required. What evaluation is required before labelling an ILD as unclassifiable? The acceptance of unclassifiable ILD as a disease category does not diminish the need for an extensive diagnostic evaluation in these patients. All patients with ILD should undergo a thorough multidisciplinary review, including a history, physical exam, autoimmune serology, full pulmonary function tests and HRCT. Standard investigations for autoimmune disease should include anti-nuclear antibody (ANA) titre and pattern, rheumatoid factor, anti-cyclic citrullinated peptide antibody and creatinine kinase. 17 Additional serological studies should include an extractable nuclear antigen panel and antisynthetase antibodies in patients with increased likelihood of autoimmune disease (e.g. women, younger individuals, those with CTD symptoms or positive ANA). A surgical lung biopsy should be obtained in appropriate ILD patients that remain unclassifiable following the evaluation discussed earlier. The decision to pursue a biopsy should be made with the patient fol-

5 55 lowing detailed discussion of the potential benefits and risks, considering patient-specific variables that can increase post-operative complications (e.g. age, ILD severity and the presence of comorbid disease). When a surgical lung biopsy is performed, sampling should be guided by the HRCT, ideally taking three large biopsies from different areas of one lung. 24 Biopsy samples should be at least 4 cm in length and taken to a depth of 3 5 cm, with each biopsy including areas of normal, minimally diseased and severely diseased lung. 24 The role of bronchoalveolar lavage and transbronchial biopsies is controversial in patients with fibrotic ILD, but these can be helpful if there is suspicion of sarcoidosis or acute/subacute HP. The location of bronchoscopic sampling should also be based on recent imaging. 25 Cryobiopsy may have better diagnostic yield than traditional transbronchial biopsy; 9,10 however, this requires further study before widespread adoption into clinical practice. All available data should be reviewed by a multidisciplinary panel that includes a respirologist, radiologist and pathologist with expertise in ILD. 1 Patients should be referred to a specialized ILD clinic if such expertise is not available locally, and early referral may improve outcomes in some fibrotic ILD subtypes. 26 The diagnosis of ILD is a dynamic process and diagnostic classification should be revisited periodically as new information can potentially provide a definitive ILD diagnosis. Providing a clear ILD diagnosis has become more important with the diverging treatment strategies used in IPF compared with other fibrotic ILD subtypes. How should patients with unclassifiable ILD be managed? Non-pharmacological management is similar among all fibrotic ILDs (e.g. smoking cessation, vaccinations, supplemental oxygen, pulmonary rehabilitation, lung transplantation, treatment of comorbidities), and these therapies should be considered in appropriate patients with unclassifiable ILD. The choice of pharmacotherapy for unclassifiable ILD is more complicated due to the absence of direct evidence in this population, and by recent data indicating the need for different treatment strategies in IPF compared with other fibrotic ILDs. 27 It is therefore not possible to provide clear recommendations for the pharmacological management of unclassifiable ILD, and each patient must be considered on an individual basis. There are two complementary approaches that can help determine the most appropriate management of unclassifiable ILD. First, it is essential to identify the differential diagnosis in each patient, considering input derived from a multidisciplinary discussion as reviewed earlier. This information can be used to assign approximate probabilities for each potential diagnosis, and ideally can identify a first-choice diagnosis that suggests the most appropriate pharmacotherapy. It is most important to distinguish patients with a high likelihood of IPF from those with a higher likelihood of non-ipf fibrotic ILD (e.g. chronic HP, idiopathic NSIP, CTD-ILD), which will Respirology (2016) 21, determine a preference for either antifibrotic or immunosuppressive therapy. Second, the multidisciplinary discussion should determine the anticipated disease behaviour as introduced in the 2013 ATS/ERS consensus statement on the classification of the IIPs. 1 The decision of whether to proceed with therapy for a suspected diagnosis is then based upon the anticipated disease behaviour and response to therapy, balanced against the potential risks of this therapy. There are limited data to support this approach however, and additional studies are required to determine the utility of the disease behaviour classification, and to evaluate the impact of antifibrotic and immunosuppressive medications in selected patients with unclassifiable ILD. CONCLUSIONS It is now recognized that a substantial number of ILD patients cannot be definitively classified as a specific ILD subtype. Recent studies have described the clinical features of these patients; however, there is still much about unclassifiable ILD that is unknown. The terminology of unclassifiable ILD requires further clarification and supportive evidence is needed to justify the definition of unclassifiable ILD and unclassifiable ILD subgroups. Additional research is required to identify novel diagnostic studies that can be applied in unclassifiable ILD, and to validate the utility of the disease behaviour classification in the approach to management. Importantly, the label of unclassifiable ILD is not intended to create an impression of a biologically unique entity or to justify an incomplete diagnostic evaluation, but instead should highlight that a confident diagnosis is not attained in a large number of ILD patients and that additional studies are required to better characterize this population. REFERENCES K Skolnik and CJ Ryerson 1 Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG, Ryerson CJ, Ryu JH, Selman M, Wells AU et al. 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