Current management of patients with idiopathic pulmonary fibrosis (IPF) requires attention to the exclusion of other causes of interstitial lung disease and either a definitive pattern on high-resolution computed tomography (HRCT) or a suggestive HRCT plus surgical lung biopsy. The main differential considerations include chronic hypersensitivity pneumonitis and connective tissue disease-associated interstitial lung disease (CTILD). Treatment includes smoking cessation, anti-reflux therapy, and the therapeutic option of one of two recently approved drugs, pirfenidone or nintedanib. IPF remains a deadly disease despite these drugs; thus the greatest emphasis should be on exclusion of alternative, potentially favorable diagnoses, continued option for enrollment in ongoing clinical trials, and, for eligible patients, early lung transplant evaluation.
Fibrosis, idiopathic, interstitial, IPF, nintedanib, pirfenidone
Randall S Schwartz, MD, has nothing to disclose in relation to this article. Marilyn Glassberg, MD, FACP, FCCP, serves as a consultant/advisory board member for Boehringer Ingelheim, Genentech, and Mesoblast. This article is a short opinion piece and has not been submitted to external peer reviewers. No funding was received in the publication of this article.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.
October 16, 2015 Accepted
December 01, 2015
Marilyn Glassberg, MD, FACP, FCCP, Jackson Memorial Hospital, University of Miami, Miami, Florida, US. E: MGlassbe@med.miami.edu
Diagnosis Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias1 and accounts for about 20 % of all interstitial lung diseases (ILD).2 IPF should be considered in all adult patients with unexplained chronic exertional dyspnea,3 though it is rare in patients less than 50 years of age.4,5 The latest guidelines for diagnosis require exclusion of other known causes of ILD and presence of either a characteristic pattern on high-resolution computed tomography (HRCT) or specific combinations of HRCT and surgical lung biopsy with the pattern of usual interstitial pneumonia (UIP).3 Other disease processes that may cause UIP include collagen vascular disease (CT-ILD), drug toxicity, chronic hypersensitivity pneumonitis (cHP), asbestosis, and Hermansky–Pudlak syndrome.6 Diagnosis of an underlying cause, if known, is of great significance in terms of treatment and survival. For instance, in one study, patients with UIP secondary to CT-ILD lived 63 % longer than those with idiopathic UIP.7
Classic HRCT patterns seen in IPF include a basilar and subpleural predominant distribution of reticulation and honeycombing, commonly with, though not requiring, traction bronchiectasis.8 Presence of ground glass does not exclude UIP so long as there is a greater degree of reticulation.8 Emphysematous changes may complicate HRCT interpretation and has been shown to result in mistaking UIP for chronic pulmonary emphysema with fibrosis (CPEF) as well as nonspecific interstitial pneumonia (NSIP).9 Appearance of the UIP distribution may be asymmetrical in up to 25 % of cases.10
The most common differential diagnoses for IPF are cHP, CT-ILD, and pneumoconiosis with particular emphasis on asbestosis.3 Concomitant features such as centrilobular nodules, air trapping, and relative sparing of the bases may be suggestive of hypersensitivity pneumonitis; pleural plaques suggest asbestosis; and septal or bronchovascular nodules may be present in sarcoidosis.11 CT-ILD should be considered in the presence of pleural effusion and/or pleural thickening, as well as esophageal dilation.11
1. King TE Jr, Schwarz MI, Brown K, et al., Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality, Am J Respir Crit Care Med, 2001;164:1025–32.
2. Karakatsani A, Papakosta D, Rapti A, et al., Epidemiology of interstitial lung diseases in Greece, Respir Med, 2009;103:1122–9.
3. Raghu G, Collard HR, Egan JJ, et al., ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis, An official ATS/ ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management, Am J Respir Crit Care Med, 2011;183:788.
4. Raghu G, Weycker D, Edelsberg J, et al., Incidence and prevalence of idiopathic pulmonary fibrosis, Am J Respir Crit Care Med, 2006;174:810–6.
5. Nadrous HF, Myers JL, Decker PA, Ryu JH, Idiopathic pulmonary fibrosis in patients younger than 50 years, Mayo Clin Proc, 2005;80:37–40.
6. American Thoracic Society, European Respiratory Society, American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification 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;165:277–304.
7. Park JH, Kim DS, Park IN, et al., Prognosis of fibrotic interstitial pneumonia, Am J Resp Crit Care Med, 2007;175:705–11.
8. Lynch DA, Godwin JD, Safrin S, et al., Idiopathic Pulmonary Fibrosis Study Group, High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis, Am J Respir Crit Care Med, 2005;172:488–93.
9. Akira M, Inoue Y, Kitaichi M, et al., Usual interstitial pneumonia and nonspecific interstitial pneumonia with and without concurrent emphysema: thin-section CT findings, Radiology, 2009;251:271–9.
10. Tcherakian C, Cottin V, Brillet PY, et al., Progression of idiopathic pulmonary fibrosis: lessons from asymmetrical disease, Thorax, 2011;66:226–31.
11. Sverzellati N, Highlights of HRCT imaging in IPF, Respir Res, 2013;14(Suppl. 1): S3.
12. Vourlekis JS, Schwarz MI, Cherniack RM, et al., The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis, Am J Med, 2004;116:662–8.
13. Selman M, Pardo A, Barrera L, et al., Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis, Am J Respir Crit Care Med, 2006;173:188–98.
14. Ohshimo S, Bonella F, Cui A, et al., Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis, Am J Respir Crit Care Med, 2009;179:1043–7.
15. Lee JS, Kim EJ, Lynch KL, et al., Prevalence and clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis, Respir Med, 2013;107:249–55.
16. Fischer A, Antoniou KM, Brown KK, et al., ERS/ATS Task Force on Undifferentiated Forms of CTD-ILD, An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features, Eur Respir J, 2015;46:976–87.
17. Noth I, Anstrom KJ, Calvert SB, et al., Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet), A placebocontrolled randomized trial of warfarin in idiopathic pulmonary fibrosis, Am J Respir Crit Care Med, 2012;186:88–95.
18. Raghu G, Anstrom KJ, King TE Jr, et al., Idiopathic Pulmonary Fibrosis Clinical Research Network, Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis, N Engl J Med, 2012;366:1968–77.
19. Jackson RM, Glassberg MK, Ramos CF, et al., Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis, Lung, 2010;188:115–23.
20. Zisman DA, Schwarz M, Anstrom KJ, et al., Idiopathic Pulmonary Fibrosis Clinical Research Network, A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis, N Engl J Med, 2010;363:620–8.
21. Raghu G, Behr J, Brown KK, et al., ARTEMIS-IPF Investigators, Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial, Ann Intern Med, 2013;158:641–9.
22. King TE Jr, Behr J, Brown KK, et al., BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis, Am J Respir Crit Care Med, 2008;177:75–81.
23. King TE Jr, Brown KK, Raghu G, et al., BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis, Am J Respir Crit Care Med, 2011;184:92–9.
24. Raghu G, Million-Rousseau R, Morganti A, et al., MUSIC Study Group, Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial, Eur Respir J, 2013;42:1622–32.
25. Raghu G, Freudenberger TD, Yang S, et al., High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis, Eur Respir J, 2006;27:136–42.
26. Tobin RW, Pope CE II, Pellegrini CA, et al., Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis, Am J Respir Crit Care Med, 1998;158:1804–8.
27. Patti MG, Tedesco P, Golden J, et al., Idiopathic pulmonary fibrosis: how often is it really idiopathic?, J Gastrointest Surg, 2005;9:1053–6.
28. Lee JS, Ryu JH, Elicker BM, et al., Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis, Am J Respir Crit Care Med, 2011;184:1390–4.
29. Raghu G, Meyer KC, Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy?, Eur Respir J, 2012;39:242–5.
30. Janssen W, Pullamsetti SS, Cooke J, et al., The role of dimethylarginine dimethylaminohydrolase (DDAH) in pulmonary fibrosis, J Pathol, 2013;229:242–9.
31. Ghebremariam YT, Cooke JP, Gerhart W, et al., Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis, J Transl Med, 2015;13:249.
32. Taniguchi H, Ebina M, Kondoh Y, et al., Pirfenidone in idiopathic pulmonary fibrosis, Eur Respir J, 2010;35:821–9.
33. Noble PW, Albera C, Bradford WZ, et al., CAPACITY Study Group, Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials, Lancet, 2011;377:1760.
34. King TE Jr, Bradford WZ, Castro-Bernardini S, et al., ASCEND Study Group, A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis, N Engl J Med, 2014;370:2083.
35. Lederer DJ, Bradford WZ, Fagan EA, et al., Sensitivity analyses of the change in FVC in a Phase 3 trial of pirfenidone for idiopathic pulmonary fibrosis, Chest, 2015;148:196–201.
36. Costabel U, Albera C, Bradford WZ, et al., Analysis of lung function and survival in RECAP: an open-label extension study of pirfenidone in patients with idiopathic pulmonary fibrosis, Sarcoidosis Vasc Diffuse Lung Dis, 2014;31:198–205.
37. Nathan S, Albera C, Bradford W, et al., Effect Of pirfenidone on Ipf-related mortality outcome measures in patients with idiopathic pulmonary fibrosis (Ipf): Pooled data analysis from the ascend and capacity trials [Abstract], Chest, 2015; Montreal, Canada;148:391A.
38. Gotink KJ, Verheul HM, Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action?, Angiogenesis, 2010;13:1–14.
39. Lo Re S, Lecocq M, Uwambayinema F, et al., Platelet-derived growth factor-producing CD4+ Foxp3+ regulatory T lymphocytes promote lung fibrosis, Am J Respir Crit Care Med, 2011;184:1270–81.
40. Inoue Y, King TE Jr, Barker E, et al., Basic fibroblast growth factor and its receptors in idiopathic pulmonary fibrosis and lymphangioleiomyomatosis, Am J Respir Crit Care Med, 2002;1665:765–73.
41. Richeldi L, Costabel U, Selman M, et al., Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis, N Engl J Med, 2011;365:1079–87.
42. Richeldi L, du Bois RM, Raghu G, et al., INPULSIS Trial Investigators, Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis, N Engl J Med, 2014;370:2071–82.
43 Raghu G, Rochwerg B, Zhang Y, et al., An official 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:e3–e19.
44. Kistler KD, Nalysnyk L, Rotella P, Esser D, Lung transplantation in idiopathic pulmonary fibrosis: a systematic review of the literature, BMC Pulm Med, 2014;14:139.
45. Toonkel RL, Hare JM, Matthay MA, Glassberg MK, Mesenchymal stem cells and idiopathic pulmonary fibrosis potential for clinical testing, Am J Resp Crit Care, 2013;188:133–40.
Fibrosis, idiopathic, interstitial, IPF, nintedanib, pirfenidone