Currently Viewing:
Supplements A Managed Care Perspective:Treatment of Idiopathic Pulmonary Fibrosis
Currently Reading
Overview of Idiopathic Pulmonary Fibrosis (IPF) and Evidence-Based Guidelines
Roozbeh Sharif, MD, MEd, MSc
Strategies to Manage Costs in Idiopathic Pulmonary Fibrosis
Gary M. Owens, M
Participating Faculty
A Managed Care Perspective: Treatment of Idiopathic Pulmonary Fibrosis Post Test

Overview of Idiopathic Pulmonary Fibrosis (IPF) and Evidence-Based Guidelines

Roozbeh Sharif, MD, MEd, MSc
One of the most feared complications of IPF is an acute exacerbation. It is defined as acute decline in lung function and worsening of respiratory symptoms, with no evidence of infection and exclusion of alternative causes. It occurs in 5% to 10% of patients annually, with mortality rates as high as 85% and significant risk of recurrence.30 In addition to acute exacerbation of IPF, other causes of acute worsening of respiratory symptoms in patients with IPF, such as pneumonia, pulmonary embolism, or heart failure, have similar clinical presentation with comparable outcomes.31 Supportive care is the mainstay of therapy.7 Recently a classification of worsening of symptoms has been proposed but studies are ongoing to confirm the clinical implications and efficacy.32

Life expectancy and survival

The median survival of IPF is 2 to 3 years because diagnosis with a 5-year survival rate ranges between 20% and 40%.7,33 A recent analysis of Medicare data found that the median survival time from all-cause mortality was 3.8 years, with survival time decreasing sharply based on age at diagnosis. Patients between age 66 and 69 years had a median survival of 8 years, compared with 4.5 years in those diagnosed between age 75 and 79 years, and 2.5 years in those diagnosed at 80 years or older.13

Comorbidities in IPF

The majority of patients with IPF have multiple comorbid conditions, which, rather than fibrotic disease itself, may contribute to the high morbidity and mortality they experience.34,35 Comorbidities result in more frequent exacerbations and rapid decline in function and survival. Conversely, there is some evidence that obesity may convey a protective effect on mortality.36 Studies suggest that identifying and treating comorbidities may improve overall outcomes, including quality of life and survival.37

Table 337 summarizes some of the common comorbidities among patients with IPF: pulmonary hypertension, GERD, chronic obstructive pulmonary disease, lung cancer, pulmonary embolism, obstructive sleep apnea, ischemic heart disease, and diabetes.37

In a retrospective study of 352 patients with IPF, 79.3% of the cohort had at least 1 comorbid condition and 57.2% had 2 or more. The multivariate analysis result indicated that each additional comorbid condition increased mortality risk by nearly 10%.38 The authors suggested that the number of comorbidities relates to overall patient well-being.

The majority of patients with IPF have comorbid GERD, yet up to half may not exhibit any symptoms.8 There is some evidence that GERD may be a causative factor of IPF, with animal studies documenting worsening pulmonary parenchymal damage with exposure to decreasing pH, and damage to the lung periphery from gastric acid.39 Studies also suggest that treating GERD in IPF patients can improve survival.40,41

Guidelines for the management of IPF address the treatment of pulmonary hypertension and GERD. The updated ATS/ERS guideline on IPF treatment published in 2015 made a weak recommendation against treatment of pulmonary hypertension and weak recommendation in favor of GERD treatment.1 These are suggested due to conflicting data in this field.


The pharmacologic treatment of IPF has evolved substantially over the last 2 decades. Historically, many pulmonologists used various immunosuppressive and anti-inflammatory agents, until the results from a randomized clinical trial on the combination of prednisone, azathioprine, and N-acetylcysteine (PANTHER-IPF) showed increased harm from this approach.42 In 2014, the FDA approved 2 treatments for IPF: pirfenidone, an antifibrotic and anti-inflammatory agent, and nintedanib, a kinase inhibitor.43

The 2015 guidelines strongly recommend against the use of imatinib, a selective tyrosine kinase inhibitor, based on the results from a single randomized controlled trial that failed to show a mortality benefit or any reduction in time to disease progression.1,44 Similarly, ambrisentan, an ETA-endothelin receptor antagonist, also earned a strong recommendation against its use based on the ARTEMIS-IPF study. That study was stopped early because of an increased risk of disease progression and respiratory hospitalizations.45 The dual endothelin receptor antagonists, bosentan and macitentan, have weak recommendations against their use due to the findings of the BUILD-3 and MUSIC studies, which failed to demonstrate beneficial outcomes.46,47 The 2015 update recommends against the use of warfarin in patients with IPF, unless otherwise indicated for conditions such as atrial fibrillation; however, the panel notes that other anticoagulants including the new oral agents might be beneficial.

Pharmacologic treatment of IPF is thoroughly discussed in subsequent articles of this supplement.

Nonpharmacologic treatment

Nonpharmacologic treatment modalities of IPF include supplemental oxygen therapy, pulmonary rehabilitation, mechanical ventilation, and palliative care services.

Supplemental oxygen is typically recommended when a patient’s desaturation is below 88% during a 6MWT or its equivalent.8 Physicians should monitor patient oxygenation with pulse oximetry at rest and exertion at baseline and at 3- to 6-month intervals. Nocturnal oxygen may also be indicated in patients with IPF with concurrent obstructive sleep apnea. There is no evidence of survival benefit from supplemental oxygen therapy, but some studies suggest better patient comfort and improved function.48,49

Pulmonary rehabilitation remains a robust part of nonpharmacologic treatment of IPF. It includes aerobic conditioning, strength and flexibility training, education about the condition, nutritional counseling, and psychosocial support.7 Clinical trials have demonstrated its beneficial impact on patients’ functional status and quality of life.50,51 Its long-term impact remains unclear and requires further studies, but its implementation is a crucial part of management.

Data on the role of palliative care in management of IPF are lacking and deserve more attention. Palliative services can be beneficial, particularly in advanced stages of IPF. Symptoms such as dyspnea and cough pose high symptom burden on patients and affect quality of life.

Multidisciplinary management of IPF: unmet needs of patients

Over the last 2 decades, ATS/ERS guidelines have provided individual recommendations for the diagnosis and treatment of patients with IPF. Although the strong association of comorbid conditions and poor outcome among patients with IPF is well known, no randomized clinical trial has examined the impact of management of comorbid conditions on their survival.

Observational studies have demonstrated the ability of a bundled, multidisciplinary approach to improve transplant-free survival among patients with IPF.52 This included biannual specialized interstitial lung disease visits with pulmonary function tests, annual referral to pulmonary rehabilitation, annual timed walk test and echocardiogram, therapy for GERD, screening for sleep-related disorders, and assessment for potential referral for lung transplantation.

Better adherence to this approach was associated with significantly improved survival of patients.52 Although these results are not generalizable to the entire population of patients with IPF, given that the study was conducted at a tertiary referral academic medical center with a sicker cohort of patients, this approach could assist providers in better assessing patients’ overall prognosis.

Lung transplantation

Lung transplantation can improve survival among patients with IPF and should be considered in patients with moderate to severe IPF.8 In May 2005, the United Network for Organ Sharing implemented the Lung Allocation Score to predict the survival benefit and determine the priority of a candidate. Since then, the actual number and the rate of patients with IPF on the lung transplantation wait list has increased.53 An important criterion for receiving a lung transplant is adherence to medications, thus the pharmacist should work with patients closely to promote proper medication use.

The ideal time to refer a patient for transplantation evaluation and the choice of single or bilateral lung transplantation remain controversial, with further studies required.7,54-57 However, the consensus is in favor of earlier referral considering the unpredictable course of disease.


IPF is the most common type of idiopathic interstitial pneumonia, usually diagnosed in the sixth or seventh decade of life. The accurate and timely diagnosis of IPF remains a diagnostic challenge in clinical practice and requires a high level of clinical suspicion as well as consideration of other possible causes. Clinicians are highly encouraged to obtain a thorough history and physical examination. Serological studies, particularly in younger and female patients, are encouraged to evaluate for possible underlying autoimmune disease. Exclusion of alternative diagnosis remains the first step in diagnosis. High-resolution computed tomography of the chest with both inspiratory and expiratory images remains the pivotal component of the diagnostic work-up. A surgical lung biopsy would be necessary in a highly selected patient population, but should be obtained with careful assessment of risks and benefits.

The diagnostic assessment should involve a multidisciplinary approach among the pulmonologist, chest radiologist, and pathologist.

IPF has very high morbidity and mortality rates. Most patients rapidly progress during the last year of life and experience prolonged hospitalization.

Several aspects of IPF pathophysiology and management are not clearly understood and are the subject of ongoing research. However, advances in recent years have kept hopes high for more optimal management of and better therapies for this fatal condition.

Author affiliation: Fellow, Division of Pulmonary, Allergy and Critical Care Medicine, The University of Alabama at Birmingham, Birmingham, Alabama.
Funding source: This activity is supported by educational grants from Genentech and Boehringer Ingelheim Pharmaceuticals, Inc.
Author disclosure: Dr Sharif has no relevant financial relationships with commercial interests to disclose.
Authorship information: Concept and design, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and supervision.
Address correspondence to:
Acknowledgment: Debra Gordon, MS, provided medical writing and editorial support for this manuscript.
1. Raghu G, Rochwerg B, Zhang Y, et al; American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, Latin American Thoracic Association. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. an update of the 2011 clinical practice guideline [erratum in: Am J Respir Crit Care Med. 2015;192(5):644]. Am J Respir Crit Care Med. 2015;192(2):e3-e19. doi: 10.1164/rccm.201506-1063ST.
2. Ley B, Collard HR. Epidemiology of idiopathic pulmonary fibrosis. Clin Epidemiol. 2013;5:483-492. doi: 10.2147/CLEP.S54815.
3. British Thoracic Society Standards of Care Committee. Part 1: diagnosis and assessment of diffuse parenchymal lung disease. Thorax. 1999;54(suppl 1):S2-S14.
4. Tzouvelekis A, Bonella F, Spagnolo P. Update on the therapeutic management of idiopathic pulmonary fibrosis. Ther Clin Risk Manag. 2015;11:359-370. doi: 10.2147/TCRM.S69716.
5. Kazerooni EA, Martinez FJ, Flint A, et al. Thin-section CT obtained at 10-mm increments versus limited three-level thin-section CT for idiopathic pulmonary fibrosis: correlation with pathologic scoring. AJR Am J Roentgenol. 1997;169(4):977-983.
6. Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis. clinical relevance and pathologic classification. Am J Respir Crit Care Med. 1998;157(4 Pt 1):1301-1315.
7. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. international consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161(2 Pt 1):646-664. doi: 10.1164/ajrccm.161.2.ats3-00.
8. 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(6):788-824. doi: 10.1164/rccm.2009-040GL.
9. Travis WD, Hunninghake G, King TE Jr, et al. Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project. Am J Respir Crit Care Med. 2008;177(12):1338-1347. doi: 10.1164/rccm.200611-1685OC.
10. Martinez FJ, Safrin S, Weycker D, et al; IPF Study Group. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005;142(12 Pt 1):963-967.
11. Collard HR, Ward AJ, Lanes S, Cortney Hayflinger D, Rosenberg DM, Hunsche E. Burden of illness in idiopathic pulmonary fibrosis. J Med Econ. 2012;15(5):829-835. doi: 10.3111/13696998.2012.680553.
12. Collard HR, Chen SY, Yeh WS, et al. Health care utilization and costs of idiopathic pulmonary fibrosis in U.S. Medicare beneficiaries aged 65 years and older. Ann Am Thorac Soc. 2015;12(7):981-987. doi: 10.1513/AnnalsATS.201412-553OC.
13. Kaunisto J, Salomaa ER, Hodgson U, Kaarteenaho R, Myllärniemi M. Idiopathic pulmonary fibrosis—a systematic review on methodology for the collection of epidemiological data. BMC Pulm Med. 2013;13:53. doi: 10.1186/1471-2466-13-53.
14. Sgalla G, Biffi A, Richeldi L. Idiopathic pulmonary fibrosis: diagnosis, epidemiology and natural history. Respirology. 2016;21(3):427-437. doi: 10.1111/resp.12683.
15. Raghu G, Chen SY, Yeh WS, et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001-11 [erratum in: Lancet Respir Med. 2014;2(7):e12]. Lancet Respir Med. 2014;2(7):566-572. doi: 10.1016/S2213-2600(14)70101-8.
16. Raghu G, Chen SY, Hou Q, Yeh WS, Collard HR. Incidence and prevalence of idiopathic pulmonary fibrosis in US adults 18-64 years old. Eur Respir J. 2016;48(1):179-186. doi: 10.1183/13993003.01653-2015.
17. Padilla M. Idiopathic pulmonary fibrosis: the role of pathobiology in making a definitive diagnosis. Am J Manag Care. 2015;21(suppl 14):s276-s283.
18. Azadeh N, Limper AH, Carmona EM, Ryu JH. The role of infection in interstitial lung diseases - a review. Chest. 2017. doi: 10.1016/j.chest.2017.03.033.
19. Walsh SL, Wells AU, Desai SR, 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):557-565. doi: 10.1016/S2213-2600(16)30033-9.
20. Felício CH, Parra ER, Capelozzi VL. Idiopathic and collagen vascular disease nonspecific interstitial pneumonia: clinical significance of remodeling process. Lung. 2007;185(1):39-46. doi: 10.1007/s00408-006-0104-2.
21. Martinez FJ, Flaherty K. Pulmonary function testing in idiopathic interstitial pneumonias. Proc Am Thorac Soc. 2006;3(4):315-321. doi: 10.1513/pats.200602-022TK.
22. Lama VN, Martinez FJ. Resting and exercise physiology in interstitial lung diseases. Clin Chest Med. 2004;25(3):435-453,v. doi: 10.1016/j.ccm.2004.05.005.
23. Chetta A, Marangio E, Olivieri D. Pulmonary function testing in interstitial lung diseases. Respiration. 2004;71(3):209-213. doi: 10.1159/000077416.
24. Lynch JP 3rd, Saggar R, Weigt SS, Ross DJ, Belperio JA. Usual interstitial pneumonia. Semin Respir Crit Care Med. 2006;27(6):634-651.
25. 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(4):488-493. doi: 10.1164/rccm.200412-1756OC.
26. Fell CD, Martinez FJ, Liu LX, et al. Clinical predictors of a diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2010;181(8):832-837. doi: 10.1164/rccm.200906-0959OC.
27. Sharif R, Kulkarni T, Acosta-Lara P, et al. High resolution CT scan pattern as a predictor of disease progression and survival in idiopathic pulmonary fibrosis. Paper presented at: Annual Meeting of American Thoracic Society 2016; Presented May 15, 2016; San Francisco, CA. Accessed June 15, 2017.
28. Tomassetti S, Wells AU, Costabel U, et al. Bronchoscopic lung cryobiopsy increases diagnostic confidence in the multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2016;193(7):745-752. doi: 10.1164/rccm.201504-0711OC.
29. Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 2012;156(10):684-691. doi: 10.7326/0003-4819-156-10-201205150-00004.
30. Juarez MM, Chan AL, Norris AG, Morrissey BM, Albertson TE. Acute exacerbation of idiopathic pulmonary fibrosis—a review of current and novel pharmacotherapies. J Thorac Dis. 2015;7(3):499-519. doi: 10.3978/j.issn.2072-1439.2015.01.17.
31. Song JW, Hong SB, Lim CM, Koh Y, Kim DS. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors, and outcome. Eur Respir J. 2011;37(2):356-363. doi: 10.1183/09031936.00159709.
32. Ryerson C, Cottin V, Brown KK, Collard HR. Acute exacerbation of idiopathic pulmonary fibrosis: shifting the paradigm. Eur Respir J. 2015;46(2):512-520. doi: 10.1183/13993003.00419-2015.
33. Kim DS, Collard HR, King TE Jr. Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc. 2006;3(4):285-292. doi: 10.1513/pats.200601-005TK.
34. 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(4):396-404.
35. Collard HR, Ward AJ, Lanes S, Cortney Hayflinger D, Rosenberg DM, Hunsche E. Burden of illness in idiopathic pulmonary fibrosis. J Med Econ. 2012;15(5):829-835. doi: 10.3111/13696998.2012.680553.
36. Alkaharas M, Decker PA, Nadous HF, Collazo-Clavell M, Ryu JH. Body mass index and mortality in patients with idiopathic pulmonary fibrosis. Chest. 2007;131(5):1448-1453.
37. Raghu G, Amatto VC, Behr J, Stowasser S. Comorbidities in idiopathic pulmonary fibrosis patients: a systematic literature review. Eur Respir J. 2015;46(4):1113-1130. doi: 10.1183/13993003.02316-2014.
38. Sharif R, Zouk A, Kulkarni T, et al. The impact of comorbidities on idiopathic pulmonary fibrosis outcomes. Chest. 2016;150(4S):471A.
39. King C, Nathan S. Identification and treatment of comorbidities in idiopathic pulmonary fibrosis and other fibrotic lung diseases. Curr Opin Pulm Med. 2013;19(5):466-473. doi: 10.1097/MCP.0b013e328363f460.
40. Lee JS, Collard HR, Anstrom KJ, et al; IPFnet Investigators. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med. 2013;1(5):369-376. doi: 10.1016/S2213-2600(13)70105-X.
41. 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(12):1390-1394. doi: 10.1164/rccm.201101-0138OC.
42. Idiopathic Pulmonary Fibrosis Clinical Research Network; Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968-1977. doi: 10.1056/NEJMoa1113354.
43. Hand L. FDA approves Ofev and Esbriet for idiopathic pulmonary fibrosis [news release]. Medscape Multispecialty. October 15, 2014. Accessed May 16, 2017.
44. Daniels CE, Lasky JA, Limper AH, Mieras K, Gabor E, Schroeder DR; Imatinib-IPF Study Investigators. Imatinib treatment for idiopathic pulmonary fibrosis: randomized placebo-controlled trial results. Am J Respir Crit Care Med. 2010;181(6):604-610. doi: 10.1164/rccm.200906-0964OC.
45. Raghu G, Behr J, Brown KK, et al; ARTEMIS-IPF Investigators. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial [erratum in Ann Intern Med. 2014;160(9):658].  Ann Intern Med. 2013;158(9):641-649. doi: 10.7326/0003-4819-158-9-201305070-00003.
46. 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(1):92-99. doi: 10.1164/rccm.201011-1874OC.
47. Raghu G, Million-Rousseau R, Morganti A, Perchenet L, Behr J; MUSIC Study Group. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J. 2013;42(6):1622-1632. doi: 10.1183/09031936.00104612.
48. Douglas WW, Ryu JH, Schroeder R. Idiopathic pulmonary fibrosis: impact of oxygen and colchicine, prednisone, or no therapy on survival. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1172-1178.
49. Morrison DA, Stovall JR. Increased exercise capacity in hypoxemic patients after long-term oxygen therapy. Chest. 1992;102(2):542-550.
50. Holland AE, Hill CJ, Conron M, Munro P, McDonald CF. Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease. Thorax. 2008;63(6):549-554. doi: 10.1136/thx.2007.088070.
51. Nishiyama O, Kondoh Y, Kimura T, et al. Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis. Respirology. 2008;13(3):394-399. doi: 10.1111/j.1440-1843.2007.01205.x.
52. Kulkarni T, Willoughby J, Acosta Lara Mdel P, et al. A bundled care approach to patients with idiopathic pulmonary fibrosis improves transplant-free survival. Respir Med. 2016;115:33-38. doi: 10.1016/j.rmed.2016.04.010.
53. Valapour M, Skeans MA, Smith JM, et al. OPTN/SRTR 2015 Annual Data Report: Lung. Am J Transplant. 2017;17(suppl 1):357-424. doi: 10.1111/ajt.14129.
54. Algar FJ, Espinosa D, Moreno P, et al. Results of lung transplantation in idiopathic pulmonary fibrosis patients. Transplant Proc. 2010;42(8):3211-3213. doi: 10.1016/j.transproceed.2010.05.046.
55. Force SD, Kilgo P, Neujahr DC, et al. Bilateral lung transplantation offers better long-term survival, compared with single-lung transplantation, for younger patients with idiopathic pulmonary fibrosis. Ann Thorac Surg. 2011;91(1):244-249. doi: 10.1016/j.athoracsur.2010.08.055.
56. Mason DP, Brizzio ME, Alster JM, et al. Lung transplantation for idiopathic pulmonary fibrosis. Ann Thorac Surg. 2007;84(4):1121-1128. doi: 10.1016/j.athoracsur.2007.04.096.
57. Neurohr C, Huppmann P, Thum D, et al; Munich Lung Transplant Group. Potential functional and survival benefit of double over single lung transplantation for selected patients with idiopathic pulmonary fibrosis. Transpl Int. 2010;23(9):887-896. doi: 10.1111/j.1432-2277.2010.01071.x.
Copyright AJMC 2006-2018 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
Welcome the the new and improved, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up

Sign In

Not a member? Sign up now!