The antifbrotic medications pirfenidone and nintedanib are recommended in clinical practice guidelines for the treatment of IPF [59]. Both medications reduce the rate of FVC decline by approximately half and might reduce the risk for exacerbation and improve survival [5, 6]. Evidence is emerging that antifbrotic medications can be similarly effective in patients with non-IPF ILDs. Nintedanib slows progression of FVC decline in SSc-ILD, and the drug is now approved for this indication [60]. Recently a randomized controlled study demonstrated that nintedanib slows the rate of FVC decline by approximately half in patients with progressive non-IPF ILDs, similar to what was observed in the previous antifbrotic trials for IPF [46]. This effect was consistent in several subgroups including the 17% of patients with unclassifable ILD [61]. Pirfenidone seems to similarly reduce the loss in pulmonary function in patients with unclassifable ILD, as demonstrated in a phase 2 clinical trial [45].

Clinicians have been very cautious in prescribing immunosuppressive therapies to patients with an IPF-like phenotype following publication of the PANTHER trial that demonstrated increased risk of death and hospitalizations in IPF patients with the combination of prednisone, azathioprine and acetylcysteine [4]. In contrast, other fbrotic ILD subtypes beneft from immunosuppression. For example, large studies including patients with SSc-ILD have demonstrated a favourable response to cyclophosphamide and mycophenolate mofetil [2, 3], and weaker evidence of a benefcial effect of tocilizumab and rituximab [62, 63]. Patients with chronic hypersensitivity pneumonitis might beneft from treatment with mycophenolate mofetil or azathioprine with a retrospective study demonstrating an improvement of DLCO following initiation of therapy [64]. Another recent retrospective study of patients with unclassifable ILD reported a favourable treatment response to cyclophosphamide, especially when patients lacked features more consistent with an IPF diagnosis [65]. Given that undiagnosed fbrotic HP and CTD-ILD likely represent a substantial percentage of unclassifable ILD, immunosuppression is likely a valid treatment option for some of these patients, particularly when IPF has been confdently excluded.

Regardless of the specifc medication being considered, the anticipated disease behaviour can aid in management decisions. Most often, this includes prioritization of more aggressive treatment approaches in patients who are suspected to have rapidly progressive fbrosis. Conversely, active pharmacotherapy is typically avoided in patients with mild and likely non-progressive disease.

Regardless of the underlying phenotype, patient preference and the patient’s attitude towards diagnostic and therapeutic uncertainty should always be considered in the decision-making process.

Conclusion

Unclassifable ILD represents an important and challenging subgroup of patients. A meticulous ILD workup is essential to minimize the proportion of patients who cannot be provided with a confdent, specifc ILD diagnosis. A multidisciplinary discussion including clinicians, radiologists, and pathologists is frequently valuable and might reduce the proportion of patients which remains unclassifable. The term unclassifable ILD is poorly defned, resulting in a heterogeneous population with clinical features intermediate between that of IPF and other ILD subtypes.

Attempting to understand the underlying biology of individual patients can potentially help in management decisions and prognostication; however, there is no validated approach to this determination. There is a clear need for new non-­ invasive diagnostic tools, particularly since the risk–beneft ratio for SLB disqualifes many ILD patients for this invasive procedure. Molecular and genetic phenotyping by various methods of transcriptomics, proteomics, metabolomics, and epigenetics are currently being developed to advance the current approach to ILD classifcation.

Suggested Defnition for Unclassifable ILD

•\ Fibrotic interstitial lung disease.

•\ No single specifc ILD diagnosis >50% likely after:

––Gathering of all available diagnostic information.

Clinical information including exposure history.

Physical examination and pulmonary function tests.

Autoimmune serology. Chest computed tomography.

Bronchoalveolar lavage results. Histopathology: Surgical lung biopsy (or lung cryobiopsy).

––Multidisciplinary team discussion.

•\ Document availability of SLB for diagnosis and most likely differential diagnosis.

•\ Re-evaluate when new diagnostic information emerges.

References

1.\Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG, et al. An offcial American Thoracic Society/ European Respiratory Society statement: Update of the international multidisciplinary classifcation of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733–48.

2.\Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016;4(9):708–19.

3.\Tashkin DP, Elashoff R, Clements PJ, Roth MD, Furst DE, Silver RM, et al. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med. 2007;176(10):1026–34.

4.\Idiopathic Pulmonary Fibrosis Clinical Research N, Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fbrosis. N Engl J Med. 2012;366(21):1968–77.

5.\King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fbrosis. N Engl J Med. 2014;370(22):2083–92.

6.\Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Effcacy and safety of nintedanib in idiopathic pulmonary

A systematic review and meta-analysis. Ann Am Thorac Soc. 2018;15(7):854–63.

8.\Liebow AA. New concepts and entities in pulmonary diseases. In: The Lung. Baltimore: Williams Wilkins; 1968p. 332–65.

9.\American Thoracic Society/European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classifcation of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS executive committee, June 2001. Am J Respir Crit Care Med. 2002;165(2):277–304.

10.\Ryerson CJ, Urbania TH, Richeldi L, Mooney JJ, Lee JS, Jones KD, et al. Prevalence and prognosis of unclassifable interstitial lung disease. Eur Respir J. 2013;42(3):750–7.

11.\Hyldgaard C, Bendstrup E, Wells AU, Hilberg O. Unclassifable interstitial lung diseases: Clinical characteristics and survival. Respirology (Carlton, Vic). 2017;22(3):494–500.

12.\Cottin V, Wells A. Unclassifed or unclassifable interstitial lung disease: confusing or helpful disease category? Eur Respir J. 2013;42(3):576–9.

13.\Ryerson CJ, Corte TJ, Lee JS, Richeldi L, Walsh SLF, Myers JL, et al. A standardized diagnostic ontology for fbrotic interstitial lung disease. An international working group perspective. Am J Respir Crit Care Med. 2017;196(10):1249–54.

14.\Mayo JR. CT evaluation of diffuse infltrative lung disease: dose considerations and optimal technique. J Thorac Imaging. 2009;24(4):252–9.

15.\Lynch DA, Sverzellati N, Travis WD, Brown KK, Colby TV, Galvin JR, et al. Diagnostic criteria for idiopathic pulmonary fbrosis: a Fleischner society white paper. Lancet Respir Med. 2018;6(2):138–53.

16.\Jones KD. Unclassifable interstitial lung disease: a pathologist’s perspective. Eur Respir Rev. 2018;27(147):170132.

17.\Walsh SL, Wells AU, Desai SR, Poletti V, Piciucchi S, Dubini A, et al. Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: a case-cohort study. Lancet Respir Med. 2016;4(7):557–65.

18.\Jo HE, Corte TJ, Moodley Y, Levin K, Westall G, Hopkins P, et al. Evaluating the interstitial lung disease multidisciplinary meeting: a survey of expert centres. BMC Pulm Med. 2016;16:22.

19.\Esposito DB, Lanes S, Donneyong M, Holick CN, Lasky JA, Lederer D, et al. Idiopathic Pulmonary Fibrosis in United States

automated claims. Incidence, prevalence, and algorithm validation. Am J Respir Crit Care Med. 2015;192(10):1200–7.

20.\Ley B, Collard HR. House of cards? Testing fundamental assumptions in Idiopathic Pulmonary Fibrosis Epidemiology. Am J Respir Crit Care Med. 2015;192(10):1147–8.

21.\Ley B, Urbania T, Husson G, Vittinghoff E, Brush DR, Eisner MD, et al. Code-based diagnostic algorithms for Idiopathic Pulmonary Fibrosis. Case validation and improvement. Ann Am Thorac Soc. 2017;14(6):880–7.

22.\Hopkins RB, Burke N, Fell C, Dion G, Kolb M. Epidemiology and survival of idiopathic pulmonary fbrosis from national data in Canada. Eur Respir J. 2016;48(1):187–95.

23.\Singh S, Collins BF, Sharma BB, Joshi JM, Talwar D, Katiyar S, et al. Interstitial lung disease in India. Results of a prospective registry. Am J Respir Crit Care Med. 2017;195(6):801–13.

24.\Patterson KC, Shah RJ, Porteous MK, Christie JD, D’Errico CA, Chadwick M, et al. Interstitial lung disease in the elderly. Chest. 2017;151(4):838–44.

25.\Morisset J, Johannson KA, Jones KD, Wolters PJ, Collard HR, Walsh SLF, et al. Identifcation of diagnostic criteria for chronic hypersensitivity pneumonitis: an international modifed Delphi survey. Am J Respir Crit Care Med. 2018;197(8):1036–44.

26.\Kropski JA, Pritchett JM, Zoz DF, Crossno PF, Markin C, Garnett ET, et al. Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogenesis of interstitial lung disease. Am J Respir Crit Care Med. 2015;191(4):417–26.

27.\Krauss E, Gehrken G, Drakopanagiotakis F, Tello S, Dartsch RC, Maurer O, et al. Clinical characteristics of patients with familial idiopathic pulmonary fbrosis (f-IPF). BMC Pulm Med. 2019;19(1):130.

2013;143(3):814–24.

29.\Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An offcial ATS/ERS/JRS/ALAT Clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44–68.

30.\Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An offcial ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fbrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788–824.

31.\Jacob J, Bartholmai BJ, Rajagopalan S, Egashira R, Brun AL, Kokosi M, et al. Unclassifable-interstitial lung disease: outcome prediction using CT and functional indices. Respir Med. 2017;130:43–51.

32.\Meyer KC, Raghu G, Baughman RP, Brown KK, Costabel U, du Bois RM, et al. An offcial American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med. 2012;185(9):1004–14.

33.\Johannson KA, Marcoux VS, Ronksley PE, Ryerson CJ. Diagnostic yield and complications of transbronchial lung Cryobiopsy for interstitial lung disease. A systematic review and Metaanalysis. Ann Am Thorac Soc. 2016;13(10):1828–38.

34.\Romagnoli M, Colby TV, Berthet JP, Gamez AS, Mallet JP, Serre I, et al. Poor concordance between sequential transbronchial lung Cryobiopsy and surgical lung biopsy in the diagnosis of diffuse interstitial lung diseases. Am J Respir Crit Care Med. 2019;199(10):1249–56.

35.\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(10):1161–7.

36.\Hutchinson JP, McKeever TM, FogartyAW, NavaratnamV, Hubbard RB. Surgical lung biopsy for the diagnosis of interstitial lung disease in England: 1997–2008. Eur Respir J. 2016;48(5):1453–61.

37.\Pannu J, Roller LJ, Maldonado F, Lentz RJ, Chen H, Rickman OB. Transbronchial Cryobiopsy for diffuse parenchymal lung disease: 30and 90-day mortality. Eur Respir J. 2019;54(4):1900337.

38.\Guler SA, Berezowska SA, Christe A, Geiser T, Funke-Chambour M. Multidisciplinary discussion for diagnosis of interstitial lung disease in real life. Swiss Med Wkly. 2016;146:w14318.

39.\Hyldgaard C, Hilberg O, Muller A, Bendstrup E. A cohort study of interstitial lung diseases in Central Denmark. Respir Med. 2014;108(5):793–9.

40.\Raj R, Brown KK. Mortality related to surgical lung biopsy in patients with interstitial lung disease. The devil is in the denominator. Am J Respir Crit Care Med. 2016;193(10):1082–4.

41.\Thomeer MJ, Vansteenkiste J, Verbeken EK, Demedts M. Interstitial lung diseases: characteristics at diagnosis and mortality risk assessment. Respir Med. 2004;98(6):567–73.

42.\Ryerson CJ, Vittinghoff E, Ley B, Lee JS, Mooney JJ, Jones KD, et al. Predicting survival across chronic interstitial lung disease: the ILD-GAP model. Chest. 2014;145(4):723–8.

43.\Guler SA, Winstone TA, Murphy D, Hague C, Soon J, Sulaiman N, et al. Does systemic sclerosis-associated interstitial lung disease burn out? Specifc phenotypes of disease progression. Ann Am Thorac Soc. 2018;15(12):1427–33.

44.\Walsh SL, Sverzellati N, Devaraj A, Keir GJ, Wells AU, Hansell DM. Connective tissue disease related fbrotic lung disease: high resolution computed tomographic and pulmonary function indices as prognostic determinants. Thorax. 2014;69(3):216–22.

45.\Maher TM, Corte TJ, Fischer A, Kreuter M, Lederer DJ, Molina-­ Molina M, et al. Pirfenidone in patients with unclassifable progressive fbrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir Med. 2020;8(2):147–57.

46.\Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al. Nintedanib in progressive fbrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718–27.

47.\Fischer A, Antoniou KM, Brown KK, Cadranel J, Corte TJ, du Bois RM, et al. An offcial European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J. 2015;46(4):976–87.

48.\Oldham JM, Adegunsoye A, Valenzi E, Lee C, Witt L, Chen L, et al. Characterisation of patients with interstitial pneumonia with autoimmune features. Eur Respir J. 2016;47(6):1767–75.

49.\Ferri C, Manfredi A, Sebastiani M, Colaci M, Giuggioli D, Vacchi C, et al. Interstitial pneumonia with autoimmune features and undifferentiated connective tissue disease: our interdisciplinary rheumatology-pneumology experience, and review of the literature. Autoimmun Rev. 2016;15(1):61–70.

50.\Lacasse Y, Selman M, Costabel U, Dalphin JC, Ando M, Morell F, et al. Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med. 2003;168(8):952–8.

51.\Hunninghake GW, Lynch DA, Galvin JR, Gross BH, Muller N, Schwartz DA, et al. Radiologic fndings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest. 2003;124(4):1215–23.

52.\Flaherty KR, Colby TV, Travis WD, Toews GB, Mumford J, Murray S, et al. Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease. Am J Respir Crit Care Med. 2003;167(10):1410–5.

53.\Song JW, Do KH, Kim MY, Jang SJ, Colby TV, Kim DS. Pathologic and radiologic differences between idiopathic and collagen

vascular disease-related usual interstitial pneumonia. Chest. 2009;136(1):23–30.

54.\Takemura T, Akashi T, Kamiya H, Ikushima S, Ando T, Oritsu M, et al. Pathological differentiation of chronic hypersensitivity pneumonitis from idiopathic pulmonary fbrosis/usual interstitial pneumonia. Histopathology. 2012;61(6):1026–35.

55.\Walsh SLF, Lederer DJ, Ryerson CJ, Kolb M, Maher TM, Nusser R, et al. Diagnostic likelihood thresholds that defne a working diagnosis of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2019;200(9):1146–53.

56.\Dowman LM, McDonald CF, Hill CJ, Lee AL, Barker K, Boote C, et al. The evidence of benefts of exercise training in interstitial lung disease: a randomised controlled trial. Thorax. 2017;72(7):610–9.

57.\Bell EC, Cox NS, Goh N, Glaspole I, Westall GP, Watson A, et al. Oxygen therapy for interstitial lung disease: a systematic review. Eur Respir Rev. 2017;26(143):160080.

58.\Kreuter M, Bendstrup E, Russell AM, Bajwah S, Lindell K, Adir Y, Brown CE, Calligaro G, Cassidy N, Corte TJ, Geissler K, Hassan AA, Johannson KA, Kairalla R, Kolb M, Kondoh Y, Quadrelli S, Swigris J, Udwadia Z, Wells A, Wijsenbeek M. Palliative care in interstitial lung disease: living well. Lancet Respir Med. 2017;5(12):968–80. https://doi.org/10.1016/S2213- 2600(17)30383-1. Epub 2017 Oct 13. PMID: 29033267.

59.\Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, Behr J, et al. An offcial ATS/ERS/JRS/ALAT Clinical practice guideline: treatment of Idiopathic Pulmonary Fibrosis. An update of the 2011 Clinical practice guideline. Am J Respir Crit Care Med. 2015;192(2):e3–19.

60.\Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019;380(26):2518–28.

61.\Wells AU, Flaherty KR, Brown KK, Inoue Y, Devaraj A, Richeldi L, et al. Nintedanib in patients with progressive fbrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-­controlled, parallel-group trial. Lancet Respir Med. 2020;8(5):453–60.

62.\Elhai M, Boubaya M, Distler O, Smith V, Matucci-Cerinic M, Alegre Sancho JJ, et al. Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study. Ann Rheum Dis. 2019;78(7):979–87.

63.\Khanna D, Denton CP, Jahreis A, van Laar JM, Frech TM, Anderson ME, et al. Safety and effcacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016;387(10038):2630–40.

64.\Morisset J, Johannson KA, Vittinghoff E, Aravena C, Elicker BM, Jones KD, et al. Use of mycophenolate mofetil or azathioprine for the management of chronic hypersensitivity pneumonitis. Chest. 2017;151(3):619–25.

65.\Wiertz IA, van Moorsel CHM, Vorselaars ADM, Quanjel MJR, Grutters JC. Cyclophosphamide in steroid refractory unclassifable idiopathic interstitial pneumonia and interstitial pneumonia with autoimmune features (IPAF). Eur Respir J. 2018;51(4):1702519.

66.\Guler SA, Ryerson CJ. Unclassifable interstitial lung disease: from phenotyping to possible treatments. Curr Opin Pulm Med. 2018;24(5):461–8.