Idiopathic Pulmonary Fibrosis
Why Family Physicians Should Know About IPF
As front-line health care providers, family physicians play an essential role in the early detection of idiopathic pulmonary ﬁbrosis (IPF) and the timely referral to a pulmonologist. The disease is rare and includes signs and symptoms that make it diﬃcult to distinguish among other interstitial lung diseases (ILDs). By identifying suspected cases of IPF at primary care visits, family physicians have an opportunity to refer patients earlier and enable diagnosis and treatment sooner. This makes education about IPF a key factor in early detection, which can potentially lead to better health outcomes.
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Introduction to IPF
Idiopathic pulmonary ﬁbrosis (IPF) is a speciﬁc form of chronic, progressive ﬁbrosing interstitial lung disease (ILD) of unknown cause.1 ILDs may be a result of a number of insults to the lungs (e.g., medication, connective tissue disease, occupational or environmental exposures).2
Idiopathic pulmonary ﬁbrosis is characterized by a progressive breathlessness and cough, as well as a decline in lung function.1 Studies suggest that patients with the disease experience a median survival period of approximately three to ﬁve years from the time of diagnosis.1
The most common symptoms of IPF are dyspnea and cough.2 Dyspnea is usually exertional and associated with walking up inclines or steps.2 The cough is typically described as “dry” and “hacking,” and may start with a tickle in the throat.3 The severity of these symptoms varies.
Other possible symptoms of IPF are fatigue and problems with sleeping.3 Symptoms that have not been associated with IPF include chest pain, fever, rash, weight loss, and myalgia or arthralgia,4 although these may be seen in various other forms of ILD.
Knowledge of a patient’s medical history and exposures is vital to diagnosing IPF and essential to excluding other ILDs. Questions should focus on the following:
- Smoking history. Cigarette smoking is strongly associated with IPF, especially individuals with a history of more than 20 pack-years.2,4
- Other medical conditions. Gastroesophageal reﬂux disease, hiatal hernia, pulmonary malignancy, coronary artery disease, obstructive sleep apnea, obesity, emphysema, and pulmonary hypertension are comorbid conditions frequently associated with IPF.2,4
- Occupational and environmental exposures. Chronic, repeated exposure to metal dusts (brass, lead, and steel), wood dust (pine), and aerosolized organic antigens (primarily, molds, bacteria, and bird antigens) have been associated with IPF. Relevant occupations with associated exposures include farming, raising birds, hair dressing, and stone cutting/polishing.2,4
- Medication history. Some medications may have pulmonary ﬁbrosis as a potential toxicity.5
The physical examination should focus on two key signs:
- Inspiratory crackles. This sign may be the earliest clinical ﬁnding and is the hallmark feature of IPF, reported in more than 90% of patients.4 These crackles sound like the ripping apart of Velcro and are heard at the posterolateral, basal aspects of the lungs.3 It is best to listen with the stethoscope applied directly to the skin.3 Inspiratory “squeaks” and wheezes are uncommon in IPF, and should prompt consideration of other diagnoses.6
- Finger clubbing. This sign occurs in 25% to 50% of patients.4
Idiopathic pulmonary ﬁbrosis is unlikely in the presence of signs of connective tissue disease, such as joint deformity, synovitis, muscle weakness, and rash.4 Instead, these signs should prompt a workup for rheumatologic disease.4
The cause of IPF is unknown, but some patients have a higher risk, including those who:
- Are older than 55 years7
- Are male7
- Have a history of smoking4
- Have been or are currently exposed to occupational or environmental antigens4
No one clinical factor indicates IPF. Rather, a patient’s entire clinical context should be considered when making a diagnosis of IPF.
While IPF is rare, a lack of large-scale studies makes it diﬃcult to estimate the incidence of the disease. We do know that the incidence of IPF increases with age, occurring most often after 55 years, and slightly more often in men.7 Among all individuals 55 to 64 years old, the incidence is 19.3 cases per 100,000 person-years.7
Misdiagnosis and delays in diagnosis of IPF are common. In one study, IPF was most often misdiagnosed as asthma (13.5%), pneumonia (13.0%), or bronchitis (12.3%).8 Delays in diagnosis have been reported to be from one year to as long as three years, with longer delays associated with an increased risk of death.4,7
Idiopathic pulmonary ﬁbrosis is diﬃcult to diagnose for several reasons, including:2
- Symptoms (breathlessness on exertion or at rest, and a dry cough) are nonspeciﬁc.
- Clinical presentation is similar to that of many other pulmonary diseases.
- Many interstitial lung diseases may mimic IPF.
- Diagnostic criteria for IPF have changed over the past few years.
- No biomarkers of the disease are available.
The diagnosis of IPF is challenging and one of exclusion. No one clinical factor indicates IPF. Rather, a patient’s entire clinical context should be considered when making a diagnosis of IPF. The diagnosis should be made according to evidence-based guidelines developed jointly by the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and the Latin American Thoracic Association (ALAT).2 Currently, the gold standard for diagnosis includes a multidisciplinary discussion (MDD) among pulmonologists, radiologists, and pathologists discussing all features of the patient’s presentation, radiographic ﬁndings, and pathologic ﬁndings (if available) to address all features of the consensus diagnosis.9
According to the ATS/ERS/JRS/ALAT guidelines, the diagnosis of IPF requires the following:9
- Exclusion of other known causes of interstitial lung disease (e.g., domestic and occupational environmental exposures, connective tissue disease, drug toxicity).
- Presence of usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) in patients who do not have surgical lung biopsy.
- Speciﬁc combinations of HRCT and surgical lung biopsy pattern (in patients who have surgical lung biopsy).
The guidelines note that an MDD enhances the accuracy of diagnosis, with family physicians playing a vital role through early detection and timely referral. Excluding other causes of disease relies on recognizing the signs and symptoms of the disease, as well as:9
- Documenting risk factors
- Taking a detailed, comprehensive history
- Carefully performing a physical examination
- Ordering appropriate diagnostic testing
Referrals should include a complete documentation of ﬁndings.10,11 Diagnosing IPF requires not only knowledge of the signs and symptoms of IPF, but also the ability to distinguish it from other diseases with similar clinical presentations.
Most objective testing is not part of the recommended diagnostic criteria. Nevertheless, the results of some tests can help exclude other diagnoses and/or add to the clinical context of IPF.
Although laboratory testing is not useful in diagnosing IPF, guidelines recommend serologic testing for most patients to exclude underlying connective tissue disease.8 Such testing should include rheumatoid factor, anti-cyclic citrullinated peptide, and anti-nuclear antibodies.8 An extractable nuclear antigen panel is often times helpful to identify other connective tissue diseases, such as Sjögren’s syndrome, systemic lupus erythematosus, and scleroderma, all of which are also associated with ILDs.12
The sensitivity of chest radiographs for the detection of subtle interstitial changes is low.4 An indication of IPF is symmetric peripheral, basilar reticular opacity with loss of volume in the lower lobe.4 However, some patients with IPF may have normal ﬁndings on chest radiographs.4
Pulmonary function tests are integral to monitoring progression of IPF and staging of disease severity.4 The results may also be helpful in establishing an initial diagnosis of IPF. The forced vital capacity (FVC), diﬀ using capacity of the lung for carbon monoxide are usually decreased, but these values may be normal early in the disease course.4
The radiographic standard for the diagnosis of IPF is an HRCT of the chest.9 An HRCT is a special, non-contrast chest computed tomography (CT) that obtains thin slice (< 2 millimeters), volumetric images of the lungs enhanced with special software algorithms. A pattern of UIP on HRCT is characterized by a subpleural, basilar predominance, reticular abnormality, and honeycombing with or without peripheral traction bronchiectasis with a relative paucity of ground-glass opacities.4,9
The UIP pattern on HRCT is highly accurate for a UIP pattern on histologic examination of a surgical lung biopsy specimen.9 Thus, surgical lung biopsy is needed only when the ﬁndings on HRCT are not “classic” for UIP.9
It is essential for HRCT images to be interpreted by a radiologist experienced with ILDs. The decision to pursue surgical lung biopsy is best left to the providers in the MDD, as many factors go into this decision.
When to Consider IPF
Idiopathic pulmonary ﬁbrosis should be considered for all patients with unexplained chronic exertional dyspnea, and those who present with a cough, bibasilar inspiratory crackles, and ﬁnger clubbing.9 The disease most often occurs in individuals older than 50, men, and smokers.4,9 The index of suspicion for connective tissue disease should be high for women younger than 50 years.9
An HRCT should be ordered for any patient who has abnormal ﬁndings on chest radiographs and clinical ﬁndings that are consistent with an ILD.4
A complete report of the family physician’s ﬁndings is an important aspect of a referral to conﬁrm IPF. A thorough referral report should include the following:11
- Symptoms and their duration
- Smoking history
- Family history
- Medication history
- Occupational history
- Environmental exposures, including hobbies, pets, and other exposures outside of work
- Results of physical examination, primarily the presence of inspiratory crackles and ﬁnger clubbing
- Findings on chest radiographs
- Description of previous treatments
- Results of pulmonary function tests
- Results of HRCT (plus images), if available
Pathogenesis and Complications
The pathogenesis of IPF is unknown.4 It was believed that IPF was caused by generalized inﬂammation that progressed to widespread parenchymal ﬁbrosis.13,14 This was questioned when IPF failed to respond to anti-inﬂammatory drugs and immune modulators.13 Studies now suggest that exposure to external stimuli (e.g., smoke, environmental agents) can lead to damage of alveolar epithelial cells, subsequent activation of mesenchymal cells, and excess accumulation of extracellular matrix.13,14 A genetic basis for IPF is still being explored.
Patients with IPF are at an increased risk for several comorbidities, including coronary artery disease, lung cancer, obstructive sleep apnea, emphysema, pulmonary hypertension, pulmonary infection, gastroesophageal reﬂux disease, hiatal hernia, and diabetes mellitus.2,4,15
The course of IPF is unpredictable, and many people experience acute exacerbations of the disease. In one study, 72% of 1,735 patients with IPF sought urgent, outpatient care because of a suspected exacerbation of the disease, and 39% of the patients had at least one all-cause hospitalization.16 These disease-related interruptions diminish patients’ quality of life.
Treatment of IPF
The goals of treatment are to slow progression of the disease, reduce symptoms, and improve the quality of life. IPF is currently treated with a combination of disease-modifying drugs and pulmonary rehabilitation.2,4,17 The need for oxygen therapy should be assessed, and lung transplantation is an option for moderate to severe disease in select patients.2,4 Clinical trials and registries may be available for patient involvement in your area.
Until 2014, no approved drugs were available for the treatment of IPF. Now, two first-in-class antifibrotic drugs are approved by the Food and Drug Administration (FDA). Studies have shown both drugs slow disease progression in patients with IPF, as measured by the decline in FVC.18-20
|Drug||ATS/ERS/JRS/ALAT Guideline Recommendations|
|Antifibrotics||Conditional recommendation for use|
|Anti-acid therapy||Conditional recommendation for use|
|Anticoagulation||Strong recommendation against use|
|Prednisone + azathioprine +|
|Strong recommendation against use|
|Selective endothelin receptor antagonist||Strong recommendation against use|
|Imatinib||Strong recommendation against use|
|Dual endothelin receptor antagonists||Conditional recommendation against use|
|Phosphodiesterase inhibitor||Conditional recommendation against use|
|N-acetylcysteine||Conditional recommendation against use|
Adapted from Raghu G, Richeldi L. Respir Med. 2017;129:24-30.22
A systematic review of nine studies demonstrated that pulmonary rehabilitation is beneﬁcial for people with interstitial lung disease, including IPF.21 According to the ﬁndings, pulmonary rehabilitation was safe and was associated with short-term improvements in functional exercise capacity, dyspnea, and quality of life.21 The quality of the evidence was low to moderate, however, and little evidence was available on the long-term eﬀects of pulmonary rehabilitation.21 A more recent systematic review and meta-analysis (ﬁve randomized controlled trials) focused on only IPF and showed that pulmonary rehabilitation was associated with increased exercise tolerance and improved quality of life.23
Patients derive the most beneﬁt from pulmonary rehabilitation early in the course of the disease.24 As such, pulmonary rehabilitation should begin immediately after diagnosis.
The 2011 ATS/ERS/JRS/ALAT guidelines strongly recommend supplemental oxygen for the treatment of hypoxemia at rest.2 This recommendation was based, in part, on the strong evidence indicating a survival beneﬁt with such use of supplemental oxygen for patients with chronic obstructive pulmonary disease (COPD).2 Patients with IPF should be assessed for the need for oxygen therapy. This is best accomplished by a six-minute walk study. If the patient’s oxygen saturation drops below 88%, then an oxygen titration component should be performed.2 This can help determine the least amount of oxygen necessary to maintain saturations above 88% with exertion.2
Management of Comorbidities
Most specialty centers advocate for aggressive management of comorbidities.
Lung transplantation is a potential option for patients with moderate to severe IPF, and it is the only treatment associated with prolonged survival.24,25 While the number of single-lung transplantation has remained steady, the number of double-lung transplantations has increased since the mid-1990s.26 There is no evidence showing the beneﬁt of single- versus double-lung transplantation.17 For the ATS/ERS/JRS/ALAT guidelines, the guideline committee recognized this lack of evidence and did not make a recommendation regarding the choice of lung transplantation.17
Living With IPF
Idiopathic pulmonary ﬁbrosis has a substantial impact on health-related quality of life, primarily attributed to a high-symptom burden and functional limitations. People with IPF have reported that the most troublesome symptoms are dyspnea, severe coughing, and persistent fatigue.27 Limited mobility is also an issue.27 One study reported that individuals with IPF were sedentary for more than nine hours per day.28 People with IPF become frustrated as they lose the ability to engage in activities they once enjoyed.27
Diﬃculty interacting with friends and family, and the ﬁnancial strain are also primary challenges.27 Depression is common and is also a substantial factor of health-related quality of life.29-31 In one study, nearly 26% of patients with IPF experienced symptoms of depression.31
Diagnosing IPF is challenging, but guidelines are available to help primary care physicians identify patients with IPF and make earlier referrals. Early referral means earlier treatment, which can help improve patient outcomes.
The Role of Family Physicians in Treatment
In addition to their vital role in early detection and referral, family physicians play an important role in the ongoing care of their patients with IPF. Family physicians can contribute to the care of patients with IPF in the following ways:
- Oversee the treatment of comorbidities
- Encourage participation in pulmonary rehabilitation and monitor progress
- Vaccinate against inﬂuenza, pneumococcus, and pertussis
- Assess emotional and mental health
- Recommend support groups for patients and their caregivers
- Monitor the need for oxygen therapy
- Discuss treatment preferences and end-of-life care
Patients value a trusted source of information and may ask their family physician for information and advice. Family physicians should provide their patients with guidance for self-management of their disease and recommend credible resources for patient education.
Resources for Patient Education on IPF
1. Torrisi SE, Pavone M, Vancheri A, Vancheri C. When to start and when to stop antiﬁ brotic therapies. Eur Respir. Rev. 2017;26(145).
2. Raghu G, Collard HR, Egan JJ, et al. An oﬃ cial ATS/ERS/JRS/ALAT statement: idiopathic pulmonary ﬁ brosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824.
3. National Jewish Health. PeerView Institute for Medical Education. Idiopathic pulmonary ﬁ brosis: a guide for providers. www.nationaljewish.org/NJH/media/pdf/FINAL-IPF-Provider-Guide.pdf. Accessed July 26, 2018.
4. Oldham JM, Noth I. Idiopathic pulmonary ﬁ brosis: early detection and referral. Respir Med. 2014;108(6):819-829.
5. Schwaiblmair M, Behr W, Haeckel T, Markl B, Foerg W, Berghaus T. Drug induced interstitial lung disease. Open Respir Med J. 2012;6:63-74.
6. Antin-Ozerkis D. Interstitial lung disease: a clinical overview and general approach. Thoracic key. Chapter 54. Section 11. www.thoracickey.com/interstitial-lung-disease-a-clinical-overview-and-general-approach. Accessed July 26, 2018.
7. Raghu G, Chen SY, Hou Q, Yeh WS, Collard HR. Incidence and prevalence of idiopathic pulmonary ﬁ brosis in US adults 18-64 years old. Eur Respir J. 2016;48(1):179-186.
8. Cosgrove GP, Bianchi P, Danese S, Lederer DJ. Barriers to timely diagnosis of interstitial lung disease in the real world: the INTENSITY survey. BMC Pulm Med. 2018;18(1):9.
9. Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44-e68.
10. Lamas DJ, Kawut SM, Bagiella E, Philip N, Arcasory SM, Lederer DJ. Delayed access and survival in idiopathic pulmonary fibrosis: a cohort study. Am J Respir Crit Care Med. 2011;184(7):842-847.
11. Purokivi M, Hodgson U, Myllarniemi M, Salomaa ER, Kaarteenaho R. Are physicians in primary health care able to recognize pulmonary ﬁ brosis? Eur Clin Respir J. 2017;4(1):1290339.
12. Hiepe F, Dorner T, Burmester G. Antinuclear antibody- and extractable nuclear antigen-related diseases. Int Arch Allergy Immunol. 2000;123(1):5-9.
13. Harari S, Caminati A. IPF: new insight on pathogenesis and treatment. Allergy. 2010;65(5):537-553.
14. Sgalla G, Iovene B, Calvello M, Ori M, Varone F, Richeldi L. Idiopathic pulmonary ﬁ brosis: pathogenesis and management. Respir Res. 2018;19(1):32.
15. Suzuki A, Kondoh Y. The clinical impact of major comorbidities on idiopathic pulmonary ﬁ brosis. Respir Investig. 2017;55(2):94-103.
16. Yu YF, Wu N, Chuang CC, et al. Patterns and economic burden of hospitalizations and exacerbations among patients diagnosed with idiopathic pulmonary ﬁ brosis. J Manag Care Spec Pharm. 2016;22(4):414-423.
17. Raghu G, Rochwerg B, Zhang Y, et al. An oﬃ cial ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary ﬁ brosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med. 2015;192(2):e3-e19.
18. Fleetwood K, McCool R, Glanville J, et al. Systematic review and network meta-analysis of idiopathic pulmonary ﬁ brosis treatments. J Manag Care Spec Pharm. 2017;23(3-b Suppl):S5-S16.
19. King TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary ﬁ brosis. N Engl J Med. 2014;370(22):2083-2092.
20. Richeldi L, duBois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082.
21. Dowman L, Hill CJ, Holland AE. Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst Rev. 2014;10:CD006322.
22. Raghu G, Richeldi L. Current approaches to the management of idiopathic pulmonary fibrosis. Respir Med. 2017;129:24-30.
23. Gomes-Neto M, Silva CM, Ezequiel D, Conceicao CS, Saquetto M, Machado AS. Impact of pulmonary rehabilitation on exercise tolerance and quality of life in patients with idiopathic pulmonary ﬁ brosis: a systematic review and meta-analysis. J Cardiopulm Rehabil Prev. 2018;Jan 18 [Epub ahead of print].
24. Holland AE, Hill CJ, Glaspole I, Goh N, McDonald CF. Predictors of beneﬁ t following pulmonary rehabilitation for interstitial lung disease. Respir Med. 2012;106(3):429-435.
25. Thabut G, Mal H, Castier Y, et al. Survival beneﬁ t of lung transplantation for patients with idiopathic pulmonary ﬁ brosis. J Thorac Cardiovasc Surg. 2003;126(2):469-475.
26. Christie JD, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report—2012. J Heart Lung Transplant. 2012;31(10):1073-1086.
27. Center for Drug Evaluation and Research. The voice of the patient. Idiopathic pulmonary ﬁ brosis. U.S. Food and Drug Administration. Washington, DC: 2015. https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM440829.pdf. Accessed April 18, 2018.
28. Atkins C, Baxer M, Jones A, Wilson A. Measuring sedentary behaviors in patients with idiopathic pulmonary ﬁ brosis using wrist-worn accelerometers. Clin Respir J. 2018;12(2):746-753.
29. Glaspole IN, Chapman SA, Cooper WA, et al. Health-related quality of life in idiopathic pulmonary ﬁ brosis: data from the Australian IPF registry. Respirology. 2017;22(5):950-956.
30. Matsuda T, Taniguchi H, Ando M, et al. Depression is signiﬁ cantly associated with health status in patients with idiopathic pulmonary ﬁ brosis. Intern Med. 2017;56(13):1637-1644.
31. Lee YJ, Choi SM, Lee YJ, et al. Clinical impact of depression and anxiety in patients with idiopathic pulmonary ﬁ brosis. PLoS One. 2017;12(9):e0184300.
This content has been supported by Boehringer Ingelheim Pharmaceuticals.