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Treatment of idiopathic pulmonary fibrosis

Author
Talmadge E King, Jr, MD
Section Editor
Kevin R Flaherty, MD, MS
Deputy Editor
Helen Hollingsworth, MD

INTRODUCTION

Idiopathic pulmonary fibrosis (IPF, also called cryptogenic fibrosing alveolitis) is specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause, occurring in adults and limited to the lungs. It is associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP). In the past, treatment was aimed at minimizing inflammation and slowing the progression from inflammation to fibrosis. However, the underlying lesion in IPF may be more fibrotic than inflammatory, explaining why few patients respond to anti-inflammatory therapies and the prognosis remains poor [1-4].

The following questions will be discussed in this topic review, although considerable uncertainty remains about the answers [2,4-6]:

Which patients should be treated?

When should therapy be started?

What is the best therapy?

                                               

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Literature review current through: Nov 2016. | This topic last updated: Mon Sep 26 00:00:00 GMT+00:00 2016.
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References
Top
  1. Lynch DA, Godwin JD, Safrin S, et al. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med 2005; 172:488.
  2. Raghu G, Collard HR, Egan JJ, et al. 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.
  3. King TE Jr, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet 2011; 378:1949.
  4. 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.
  5. Schwartz DA, Helmers RA, Galvin JR, et al. Determinants of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1994; 149:450.
  6. Schwartz DA, Van Fossen DS, Davis CS, et al. Determinants of progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1994; 149:444.
  7. Flaherty KR, Toews GB, Lynch JP 3rd, et al. Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med 2001; 110:278.
  8. Carrington CB, Gaensler EA, Coutu RE, et al. Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 1978; 298:801.
  9. Wright PH, Heard BE, Steel SJ, Turner-Warwick M. Cryptogenic fibrosing alveolitis: assessment by graded trephine lung biopsy histology compared with clinical, radiographic, and physiological features. Br J Dis Chest 1981; 75:61.
  10. Martinez FJ, Safrin S, Weycker D, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med 2005; 142:963.
  11. Arakawa H, Honma K. Honeycomb lung: history and current concepts. AJR Am J Roentgenol 2011; 196:773.
  12. Lama VN, Flaherty KR, Toews GB, et al. Prognostic value of desaturation during a 6-minute walk test in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2003; 168:1084.
  13. King TE Jr, Tooze JA, Schwarz MI, et al. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med 2001; 164:1171.
  14. King TE Jr, Safrin S, Starko KM, et al. Analyses of efficacy end points in a controlled trial of interferon-gamma1b for idiopathic pulmonary fibrosis. Chest 2005; 127:171.
  15. Nishiyama O, Taniguchi H, Kondoh Y, et al. A simple assessment of dyspnoea as a prognostic indicator in idiopathic pulmonary fibrosis. Eur Respir J 2010; 36:1067.
  16. du Bois RM, Weycker D, Albera C, et al. Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference. Am J Respir Crit Care Med 2011; 184:1382.
  17. Lancaster LH, Mason WR, Parnell JA, et al. Obstructive sleep apnea is common in idiopathic pulmonary fibrosis. Chest 2009; 136:772.
  18. Mermigkis C, Bouloukaki I, Antoniou K, et al. Obstructive sleep apnea should be treated in patients with idiopathic pulmonary fibrosis. Sleep Breath 2015; 19:385.
  19. Stack BH, Choo-Kang YF, Heard BE. The prognosis of cryptogenic fibrosing alveolitis. Thorax 1972; 27:535.
  20. Turner-Warwick M, Burrows B, Johnson A. Cryptogenic fibrosing alveolitis: response to corticosteroid treatment and its effect on survival. Thorax 1980; 35:593.
  21. Turner-Warwick M, Burrows B, Johnson A. Cryptogenic fibrosing alveolitis: clinical features and their influence on survival. Thorax 1980; 35:171.
  22. Costabel U, Matthys H. Different therapies and factors influencing response to therapy in idiopathic diffuse fibrosing alveolitis. Respiration 1981; 42:141.
  23. Dayton CS, Schwartz DA, Helmers RA, et al. Outcome of subjects with idiopathic pulmonary fibrosis who fail corticosteroid therapy. Implications for further studies. Chest 1993; 103:69.
  24. Douglas WW, Ryu JH, Bjoraker JA, et al. Colchicine versus prednisone as treatment of usual interstitial pneumonia. Mayo Clin Proc 1997; 72:201.
  25. Douglas WW, Ryu JH, Swensen SJ, et al. Colchicine versus prednisone in the treatment of idiopathic pulmonary fibrosis. A randomized prospective study. Members of the Lung Study Group. Am J Respir Crit Care Med 1998; 158:220.
  26. Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 183:431.
  27. Collard HR, King TE Jr, Bartelson BB, et al. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003; 168:538.
  28. Alakhras M, Decker PA, Nadrous HF, et al. Body mass index and mortality in patients with idiopathic pulmonary fibrosis. Chest 2007; 131:1448.
  29. Nadrous HF, Pellikka PA, Krowka MJ, et al. Pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Chest 2005; 128:2393.
  30. du Bois RM, Weycker D, Albera C, et al. Ascertainment of individual risk of mortality for patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 184:459.
  31. Tomassetti S, Gurioli C, Ryu JH, et al. The impact of lung cancer on survival of idiopathic pulmonary fibrosis. Chest 2015; 147:157.
  32. Dalleywater W, Powell HA, Hubbard RB, Navaratnam V. Risk factors for cardiovascular disease in people with idiopathic pulmonary fibrosis: a population-based study. Chest 2015; 147:150.
  33. Kim WY, Mok Y, Kim GW, et al. Association between idiopathic pulmonary fibrosis and coronary artery disease: a case-control study and cohort analysis. Sarcoidosis Vasc Diffuse Lung Dis 2015; 31:289.
  34. Khan KA, Kennedy MP, Moore E, et al. Radiological characteristics, histological features and clinical outcomes of lung cancer patients with coexistent idiopathic pulmonary fibrosis. Lung 2015; 193:71.
  35. Panos RJ, Mortenson RL, Niccoli SA, King TE Jr. Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment. Am J Med 1990; 88:396.
  36. Fernández Pérez ER, Daniels CE, Schroeder DR, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study. Chest 2010; 137:129.
  37. Saydain G, Islam A, Afessa B, et al. Outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit. Am J Respir Crit Care Med 2002; 166:839.
  38. Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med 2012; 156:684.
  39. Ley B, Bradford WZ, Weycker D, et al. Unified baseline and longitudinal mortality prediction in idiopathic pulmonary fibrosis. Eur Respir J 2015; 45:1374.
  40. National Institute for Health and Care Excellence (NICE). Diagnosis and management of suspected idiopathic pulmonary fibrosis, 2013. http://www.nice.org.uk/nicemedia/live/14183/64119/64119.pdf (Accessed on January 27, 2014).
  41. Ryerson CJ, Arean PA, Berkeley J, et al. Depression is a common and chronic comorbidity in patients with interstitial lung disease. Respirology 2012; 17:525.
  42. Ryerson CJ, Berkeley J, Carrieri-Kohlman VL, et al. Depression and functional status are strongly associated with dyspnea in interstitial lung disease. Chest 2011; 139:609.
  43. Collard HR, Tino G, Noble PW, et al. Patient experiences with pulmonary fibrosis. Respir Med 2007; 101:1350.
  44. Daniels CE, Ryu JH. Treatment of idiopathic pulmonary fibrosis. Semin Respir Crit Care Med 2006; 27:668.
  45. Holland AE, Hill CJ, Conron M, et al. Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease. Thorax 2008; 63:549.
  46. Ferreira A, Garvey C, Connors GL, et al. Pulmonary rehabilitation in interstitial lung disease: benefits and predictors of response. Chest 2009; 135:442.
  47. Nishiyama O, Kondoh Y, Kimura T, et al. Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis. Respirology 2008; 13:394.
  48. Salhi B, Troosters T, Behaegel M, et al. Effects of pulmonary rehabilitation in patients with restrictive lung diseases. Chest 2010; 137:273.
  49. Kozu R, Senjyu H, Jenkins SC, et al. Differences in response to pulmonary rehabilitation in idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. Respiration 2011; 81:196.
  50. Huppmann P, Sczepanski B, Boensch M, et al. Effects of inpatient pulmonary rehabilitation in patients with interstitial lung disease. Eur Respir J 2013; 42:444.
  51. Jackson RM, Gómez-Marín OW, Ramos CF, et al. Exercise limitation in IPF patients: a randomized trial of pulmonary rehabilitation. Lung 2014; 192:367.
  52. Dowman L, Hill CJ, Holland AE. Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst Rev 2014; :CD006322.
  53. Lee JS, McLaughlin S, Collard HR. Comprehensive care of the patient with idiopathic pulmonary fibrosis. Curr Opin Pulm Med 2011; 17:348.
  54. Meyer KC, Danoff SK, Lancaster LH, Nathan SD. Management of Idiopathic Pulmonary Fibrosis in the Elderly Patient: Addressing Key Questions. Chest 2015; 148:242.
  55. Carlos WG, Strek ME, Wang TS, et al. Treatment of Idiopathic Pulmonary Fibrosis. Ann Am Thorac Soc 2016; 13:115.
  56. Wollin L, Wex E, Pautsch A, et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J 2015; 45:1434.
  57. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370:2071.
  58. Laurenson S, Sidhu R, Goodall M, Adler AI. NICE guidance on nintedanib for treating idiopathic pulmonary fibrosis. Lancet Respir Med 2016; 4:176.
  59. 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.
  60. Costabel U, Inoue Y, Richeldi L, et al. Efficacy of Nintedanib in Idiopathic Pulmonary Fibrosis across Prespecified Subgroups in INPULSIS. Am J Respir Crit Care Med 2016; 193:178.
  61. Wuyts WA, Kolb M, Stowasser S, et al. First Data on Efficacy and Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis and Forced Vital Capacity of ≤50 % of Predicted Value. Lung 2016; 194:739.
  62. Nintedanib. US Food and Drug Administration (FDA) approved product information. US National Library of Medicine. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=da1c9f37-779e-4682-816f-93d0faa4cfc9 (Accessed on November 10, 2014).
  63. Hunninghake GW, Kalica AR. Approaches to the treatment of pulmonary fibrosis. Am J Respir Crit Care Med 1995; 151:915.
  64. Scotton CJ, Chambers RC. Molecular targets in pulmonary fibrosis: the myofibroblast in focus. Chest 2007; 132:1311.
  65. Raghu G, Johnson WC, Lockhart D, Mageto Y. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label Phase II study. Am J Respir Crit Care Med 1999; 159:1061.
  66. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005; 171:1040.
  67. Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010; 35:821.
  68. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377:1760.
  69. Spagnolo P, Del Giovane C, Luppi F, et al. Non-steroid agents for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev 2010; :CD003134.
  70. Okuda R, Hagiwara E, Baba T, et al. Safety and efficacy of pirfenidone in idiopathic pulmonary fibrosis in clinical practice. Respir Med 2013; 107:1431.
  71. 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.
  72. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials. Eur Respir J 2016; 47:243.
  73. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014; 370:2083.
  74. Pirfenidone. US Food and Drug Administration (FDA) approved product information. US National Library of Medicine. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0ab861c2-d5ca-4f92-854c-6477971a1b38 (Accessed on October 30, 2014).
  75. Nathan SD, Albera C, Bradford WZ, et al. Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis. Thorax 2016; 71:429.
  76. Gahl WA, Brantly M, Troendle J, et al. Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome. Mol Genet Metab 2002; 76:234.
  77. Valeyre D, Albera C, Bradford WZ, et al. Comprehensive assessment of the long-term safety of pirfenidone in patients with idiopathic pulmonary fibrosis. Respirology 2014; 19:740.
  78. Walter N, Collard HR, King TE Jr. Current perspectives on the treatment of idiopathic pulmonary fibrosis. Proc Am Thorac Soc 2006; 3:330.
  79. Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2007; 176:636.
  80. Kondoh Y, Taniguchi H, Kawabata Y, et al. Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of clinical and pathologic findings in three cases. Chest 1993; 103:1808.
  81. Ambrosini V, Cancellieri A, Chilosi M, et al. Acute exacerbation of idiopathic pulmonary fibrosis: report of a series. Eur Respir J 2003; 22:821.
  82. Churg A, Wright JL, Tazelaar HD. Acute exacerbations of fibrotic interstitial lung disease. Histopathology 2011; 58:525.
  83. Song JW, Hong SB, Lim CM, et al. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J 2011; 37:356.
  84. Collard HR, Ryerson CJ, Corte TJ, et al. Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report. Am J Respir Crit Care Med 2016; 194:265.
  85. Wootton SC, Kim DS, Kondoh Y, et al. Viral infection in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 183:1698.
  86. Simon-Blancal V, Freynet O, Nunes H, et al. Acute exacerbation of idiopathic pulmonary fibrosis: outcome and prognostic factors. Respiration 2012; 83:28.
  87. Akira M, Kozuka T, Yamamoto S, Sakatani M. Computed tomography findings in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008; 178:372.
  88. Tcherakian C, Cottin V, Brillet PY, et al. Progression of idiopathic pulmonary fibrosis: lessons from asymmetrical disease. Thorax 2011; 66:226.
  89. Hyzy R, Huang S, Myers J, et al. Acute exacerbation of idiopathic pulmonary fibrosis. Chest 2007; 132:1652.
  90. Ryerson CJ, Cottin V, Brown KK, Collard HR. Acute exacerbation of idiopathic pulmonary fibrosis: shifting the paradigm. Eur Respir J 2015; 46:512.
  91. Rush B, Wiskar K, Berger L, Griesdale D. The use of mechanical ventilation in patients with idiopathic pulmonary fibrosis in the United States: A nationwide retrospective cohort analysis. Respir Med 2016; 111:72.
  92. Alalawi R, Whelan T, Bajwa RS, Hodges TN. Lung transplantation and interstitial lung disease. Curr Opin Pulm Med 2005; 11:461.
  93. Yusen RD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-second Official Adult Lung and Heart-Lung Transplantation Report--2015; Focus Theme: Early Graft Failure. J Heart Lung Transplant 2015; 34:1264.
  94. Thabut G, Mal H, Castier Y, et al. Survival benefit of lung transplantation for patients with idiopathic pulmonary fibrosis. J Thorac Cardiovasc Surg 2003; 126:469.
  95. Steinman TI, Becker BN, Frost AE, et al. Guidelines for the referral and management of patients eligible for solid organ transplantation. Transplantation 2001; 71:1189.
  96. Weill D, Benden C, Corris PA, et al. A consensus document for the selection of lung transplant candidates: 2014--an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2015; 34:1.
  97. Weiss ES, Allen JG, Merlo CA, et al. Lung allocation score predicts survival in lung transplantation patients with pulmonary fibrosis. Ann Thorac Surg 2009; 88:1757.
  98. Mason DP, Brizzio ME, Alster JM, et al. Lung transplantation for idiopathic pulmonary fibrosis. Ann Thorac Surg 2007; 84:1121.
  99. George TJ, Arnaoutakis GJ, Shah AS. Lung transplant in idiopathic pulmonary fibrosis. Arch Surg 2011; 146:1204.
  100. International Society for Heart and Lung Transplantation. Adult Lung Transplantation Statistics, 2014. https://www.ishlt.org/registries/slides.asp?slides=heartLungRegistry&year=2014 (Accessed on November 07, 2014).
  101. Unilateral lung transplantation for pulmonary fibrosis. Toronto Lung Transplant Group. N Engl J Med 1986; 314:1140.
  102. Experience with single-lung transplantation for pulmonary fibrosis. The Toronto Lung Transplant Group. JAMA 1988; 259:2258.
  103. Grossman RF, Frost A, Zamel N, et al. Results of single-lung transplantation for bilateral pulmonary fibrosis. The Toronto Lung Transplant Group. N Engl J Med 1990; 322:727.
  104. Meyers BF, Lynch JP, Trulock EP, et al. Single versus bilateral lung transplantation for idiopathic pulmonary fibrosis: a ten-year institutional experience. J Thorac Cardiovasc Surg 2000; 120:99.
  105. Meyer DM, Edwards LB, Torres F, et al. Impact of recipient age and procedure type on survival after lung transplantation for pulmonary fibrosis. Ann Thorac Surg 2005; 79:950.
  106. Neurohr C, Huppmann P, Thum D, et al. Potential functional and survival benefit of double over single lung transplantation for selected patients with idiopathic pulmonary fibrosis. Transpl Int 2010; 23:887.
  107. ten Klooster L, Nossent GD, Kwakkel-van Erp JM, et al. Ten-Year Survival in Patients with Idiopathic Pulmonary Fibrosis After Lung Transplantation. Lung 2015; 193:919.
  108. Fitton TP, Kosowski TR, Barreiro CJ, et al. Impact of secondary pulmonary hypertension on lung transplant outcome. J Heart Lung Transplant 2005; 24:1254.
  109. Nathan SD, Shlobin OA, Ahmad S, et al. Serial development of pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Respiration 2008; 76:288.
  110. Date H, Tanimoto Y, Goto K, et al. A new treatment strategy for advanced idiopathic interstitial pneumonia: living-donor lobar lung transplantation. Chest 2005; 128:1364.
  111. Miyoshi S, Schaefers HJ, Trulock EP, et al. Donor selection for single and double lung transplantation. Chest size matching and other factors influencing posttransplantation vital capacity. Chest 1990; 98:308.
  112. Borie R, Kannengiesser C, Hirschi S, et al. Severe hematologic complications after lung transplantation in patients with telomerase complex mutations. J Heart Lung Transplant 2015; 34:538.
  113. Silhan LL, Shah PD, Chambers DC, et al. Lung transplantation in telomerase mutation carriers with pulmonary fibrosis. Eur Respir J 2014; 44:178.
  114. Tokman S, Singer JP, Devine MS, et al. Clinical outcomes of lung transplant recipients with telomerase mutations. J Heart Lung Transplant 2015; 34:1318.
  115. Park SJ, Nguyen DQ, Savik K, et al. Pre-transplant corticosteroid use and outcome in lung transplantation. J Heart Lung Transplant 2001; 20:304.
  116. Schäfers HJ, Wagner TO, Demertzis S, et al. Preoperative corticosteroids. A contraindication to lung transplantation? Chest 1992; 102:1522.
  117. McAnally KJ, Valentine VG, LaPlace SG, et al. Effect of pre-transplantation prednisone on survival after lung transplantation. J Heart Lung Transplant 2006; 25:67.
  118. Hubbard RB, Smith C, Le Jeune I, et al. The association between idiopathic pulmonary fibrosis and vascular disease: a population-based study. Am J Respir Crit Care Med 2008; 178:1257.
  119. Sode BF, Dahl M, Nielsen SF, Nordestgaard BG. Venous thromboembolism and risk of idiopathic interstitial pneumonia: a nationwide study. Am J Respir Crit Care Med 2010; 181:1085.
  120. Kubo H, Nakayama K, Yanai M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005; 128:1475.
  121. Kinder BW, Collard HR, King TE Jr. Anticoagulant therapy and idiopathic pulmonary fibrosis. Chest 2006; 130:302.
  122. Noth I, Anstrom KJ, Calvert SB, et al. A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2012; 186:88.
  123. Davies HR, Richeldi L, Walters EH. Immunomodulatory agents for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev 2003; :CD003134.
  124. Raghu G, Depaso WJ, Cain K, et al. Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial. Am Rev Respir Dis 1991; 144:291.
  125. Idiopathic Pulmonary Fibrosis Clinical Research Network, Raghu G, Anstrom KJ, et al. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012; 366:1968.
  126. Cantin AM, Hubbard RC, Crystal RG. Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Am Rev Respir Dis 1989; 139:370.
  127. Commonly used three-drug regimen for idiopathic pulmonary fibrosis found harmful. NIH News October 21, 2011. http://www.nih.gov/news/health/oct2011/nhlbi-21.htm (Accessed on January 06, 2012).
  128. Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004; 350:125.
  129. Dubrawsky C, Dubravsky NB, Withers HR. The effect of colchicine on the accumulation of hydroxyproline and on lung compliance after irradiation. Radiat Res 1978; 73:111.
  130. Zhang L, Zhu Y, Luo W, et al. The protective effect of colchicine on bleomycin-induced pulmonary fibrosis in rats. Chin Med Sci J 1992; 7:58.
  131. Rennard SI, Bitterman PB, Ozaki T, et al. Colchicine suppresses the release of fibroblast growth factors from alveolar macrophages in vitro. The basis of a possible therapeutic approach ot the fibrotic disorders. Am Rev Respir Dis 1988; 137:181.
  132. Douglas WW, Ryu JH, Schroeder DR. Idiopathic pulmonary fibrosis: Impact of oxygen and colchicine, prednisone, or no therapy on survival. Am J Respir Crit Care Med 2000; 161:1172.
  133. Selman M, Carrillo G, Salas J, et al. Colchicine, D-penicillamine, and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial. Chest 1998; 114:507.
  134. Kolb M, Kirschner J, Riedel W, et al. Cyclophosphamide pulse therapy in idiopathic pulmonary fibrosis. Eur Respir J 1998; 12:1409.
  135. Johnson MA, Kwan S, Snell NJ, et al. Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis. Thorax 1989; 44:280.
  136. Baughman RP, Lower EE. Use of intermittent, intravenous cyclophosphamide for idiopathic pulmonary fibrosis. Chest 1992; 102:1090.
  137. Collard HR, Ryu JH, Douglas WW, et al. Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest 2004; 125:2169.
  138. Alton EW, Johnson M, Turner-Warwick M. Advanced cryptogenic fibrosing alveolitis: preliminary report on treatment with cyclosporin A. Respir Med 1989; 83:277.
  139. Venuta F, Rendina EA, Ciriaco P, et al. Efficacy of cyclosporine to reduce steroids in patients with idiopathic pulmonary fibrosis before lung transplantation. J Heart Lung Transplant 1993; 12:909.
  140. Moolman JA, Bardin PG, Rossouw DJ, Joubert JR. Cyclosporin as a treatment for interstitial lung disease of unknown aetiology. Thorax 1991; 46:592.
  141. Grgic A, Lausberg H, Heinrich M, et al. Progression of fibrosis in usual interstitial pneumonia: serial evaluation of the native lung after single lung transplantation. Respiration 2008; 76:139.
  142. Park SH, Saleh D, Giaid A, Michel RP. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med 1997; 156:600.
  143. 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.
  144. Raghu G, King TE Jr, Behr J, et al. Quality of life and dyspnoea in patients treated with bosentan for idiopathic pulmonary fibrosis (BUILD-1). Eur Respir J 2010; 35:118.
  145. 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.
  146. Raghu G, Million-Rousseau R, Morganti A, et al. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J 2013; 42:1622.
  147. Raghu G, Behr J, Brown KK, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med 2013; 158:641.
  148. Piguet PF, Vesin C. Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice. Eur Respir J 1994; 7:515.
  149. Raghu G, Brown KK, Costabel U, et al. Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial. Am J Respir Crit Care Med 2008; 178:948.
  150. Ziesche, R. Long-term survival in idiopathic pulmonary fibrosis patients treated with interferon gamma-1b (abstract). Chest 2002; 122:75S.
  151. Bienkowski RS, Gotkin MG. Control of collagen deposition in mammalian lung. Proc Soc Exp Biol Med 1995; 209:118.
  152. Ziesche R, Hofbauer E, Wittmann K, et al. A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med 1999; 341:1264.
  153. King TE Jr, Albera C, Bradford WZ, et al. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet 2009; 374:222.
  154. Pesci A, Bertorelli G, Manganelli P, Ambanelli U. Bronchoalveolar lavage analysis of interstitial lung disease in CREST syndrome. Clin Exp Rheumatol 1986; 4:121.
  155. Lacher MJ. Spontaneous remission or response to methotrexate in sarcoidosis. Ann Intern Med 1968; 69:1247.
  156. Lower EE, Baughman RP. The use of low dose methotrexate in refractory sarcoidosis. Am J Med Sci 1990; 299:153.
  157. Lower, EE, Baughman, RP, Winget, D. The long term use of methotrexate in patients with chronic symptomatic sarcoidosis. Sarcoidosis 1992; 9:465S.
  158. Scott DG, Bacon PA. Response to methotrexate in fibrosing alveolitis associated with connective tissue disease. Thorax 1980; 35:725.
  159. Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005; 353:2229.
  160. Cantin AM, North SL, Fells GA, et al. Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis. J Clin Invest 1987; 79:1665.
  161. Meyer A, Buhl R, Magnussen H. The effect of oral N-acetylcysteine on lung glutathione levels in idiopathic pulmonary fibrosis. Eur Respir J 1994; 7:431.
  162. Meyer A, Buhl R, Kampf S, Magnussen H. Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals. Am J Respir Crit Care Med 1995; 152:1055.
  163. Behr J, Maier K, Degenkolb B, et al. Antioxidative and clinical effects of high-dose N-acetylcysteine in fibrosing alveolitis. Adjunctive therapy to maintenance immunosuppression. Am J Respir Crit Care Med 1997; 156:1897.
  164. Behr J, Degenkolb B, Krombach F, Vogelmeier C. Intracellular glutathione and bronchoalveolar cells in fibrosing alveolitis: effects of N-acetylcysteine. Eur Respir J 2002; 19:906.
  165. Raghu G, DeAndrade J, Anstrom KJ, et al. A double blind, placebo-controlled, randomized trial of N-acetylcysteine in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2014; 189:A6601.
  166. Idiopathic Pulmonary Fibrosis Clinical Research Network, Martinez FJ, de Andrade JA, et al. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370:2093.
  167. Ward WF, Shih-Hoellwarth A, Tuttle RD. Collagen accumulation in irradiated rat lung: modification by D-penicillamine. Radiology 1983; 146:533.
  168. Ekimoto H, Aikawa M, Ohnuki T, et al. Immunological involvement in pulmonary fibrosis induced by peplomycin. J Antibiot (Tokyo) 1985; 38:94.
  169. Molteni A, Ward WF, Ts'ao CH, et al. Monocrotaline-induced pulmonary fibrosis in rats: amelioration by captopril and penicillamine. Proc Soc Exp Biol Med 1985; 180:112.
  170. Geismar LS, Hennessey S, Reiser KM, Last JA. D-penicillamine prevents collagen accumulation in lungs of rats given bleomycin. Chest 1986; 89:153S.
  171. Steen VD, Owens GR, Redmond C, et al. The effect of D-penicillamine on pulmonary findings in systemic sclerosis. Arthritis Rheum 1985; 28:882.
  172. de Clerck LS, Dequeker J, Francx L, Demedts M. D-penicillamine therapy and interstitial lung disease in scleroderma. A long-term followup study. Arthritis Rheum 1987; 30:643.
  173. Cegla UH. [Treatment of idiopathic fibrosing alveolitis. Therapeutic experiences with azathioprine-prednisolone and D-penicillamine-prednisolone combination therapy]. Schweiz Med Wochenschr 1977; 107:184.
  174. Chapela R, Zúñiga G, Selman M. D-penicillamine in the therapy of fibrotic lung diseases. Int J Clin Pharmacol Ther Toxicol 1986; 24:16.
  175. Collard HR, Anstrom KJ, Schwarz MI, Zisman DA. Sildenafil improves walk distance in idiopathic pulmonary fibrosis. Chest 2007; 131:897.
  176. Jackson RM, Glassberg MK, Ramos CF, et al. Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis. Lung 2010; 188:115.
  177. Idiopathic Pulmonary Fibrosis Clinical Research Network, Zisman DA, Schwarz M, et al. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 2010; 363:620.
  178. Han MK, Bach DS, Hagan PG, et al. Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction. Chest 2013; 143:1699.
  179. Lota HK, Wells AU. The evolving pharmacotherapy of pulmonary fibrosis. Expert Opin Pharmacother 2013; 14:79.
  180. Selman M, Pardo A, Richeldi L, Cerri S. Emerging drugs for idiopathic pulmonary fibrosis. Expert Opin Emerg Drugs 2011; 16:341.
  181. Daniels CE, Lasky JA, Limper AH, et al. Imatinib treatment for idiopathic pulmonary fibrosis: Randomized placebo-controlled trial results. Am J Respir Crit Care Med 2010; 181:604.
  182. Tabata C, Tabata R, Kadokawa Y, et al. Thalidomide prevents bleomycin-induced pulmonary fibrosis in mice. J Immunol 2007; 179:708.
  183. Horton MR, Santopietro V, Mathew L, et al. Thalidomide for the treatment of cough in idiopathic pulmonary fibrosis: a randomized trial. Ann Intern Med 2012; 157:398.
  184. Hams E, Armstrong ME, Barlow JL, et al. IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis. Proc Natl Acad Sci U S A 2014; 111:367.
  185. Tobin RW, Pope CE 2nd, Pellegrini CA, et al. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998; 158:1804.
  186. 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.
  187. Sweet MP, Hoopes C, Golden J, et al. Prevalence of delayed gastric emptying and gastroesophageal reflux in patients with end-stage lung disease. Ann Thorac Surg 2006; 82:1570; author reply 1570.
  188. Schachter LM, Dixon J, Pierce RJ, O'Brien P. Severe gastroesophageal reflux is associated with reduced carbon monoxide diffusing capacity. Chest 2003; 123:1932.
  189. Lee JS, Collard HR, Raghu G, et al. Does chronic microaspiration cause idiopathic pulmonary fibrosis? Am J Med 2010; 123:304.
  190. Pashinsky YY, Jaffin BW, Litle VR. Gastroesophageal reflux disease and idiopathic pulmonary fibrosis. Mt Sinai J Med 2009; 76:24.
  191. Bandeira CD, Rubin AS, Cardoso PF, et al. Prevalence of gastroesophageal reflux disease in patients with idiopathic pulmonary fibrosis. J Bras Pneumol 2009; 35:1182.
  192. Raghu G, Yang ST, Spada C, et al. Sole treatment of acid gastroesophageal reflux in idiopathic pulmonary fibrosis: a case series. Chest 2006; 129:794.
  193. Hershcovici T, Jha LK, Johnson T, et al. Systematic review: the relationship between interstitial lung diseases and gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2011; 34:1295.
  194. Sweet MP, Patti MG, Leard LE, et al. Gastroesophageal reflux in patients with idiopathic pulmonary fibrosis referred for lung transplantation. J Thorac Cardiovasc Surg 2007; 133:1078.
  195. 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.
  196. Lee JS, Collard HR, Anstrom KJ, et al. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med 2013; 1:369.