Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by a pattern of scarring of the lung interstitium, leading to a progressive decline in lung function. IPF is the most common interstitial pneumonia and has a median age of onset of 65 years. The prognosis is worse than most lung cancers, with a 5-year survival rate of 20%.1 IPF is a rare disease, with an estimated incidence of three to nine cases per 100,000 population in Europe and North America but the incidence has been increasing in the last few decades.2
Despite decades of research, IPF remains poorly understood; originally, the pathogenesis was thought to be due to chronic inflammation. Early treatments that targeted these pathways proved to be largely ineffective, and some treatment regimens were harmful. New hypotheses regarding the pathogenesis of IPF focus on three mechanisms that underlie disease progression: repeated lung injury, abnormal wound healing responses, and genetic susceptibility (Figure 1). No cure exists for IPF, and only within the last few years have two new treatments been approved by the FDA. Although these agents slow disease progression, neither has clearly demonstrated increased patient survival, and lung transplantation remains the best option. However, transplant surgery involves risks, and results in a median survival of 5.3 years.3
The exact pathophysiology of IPF is unclear but is thought to involve repeated microinjuries to the lung epithelium, followed by aberrant wound repair mechanisms.4 Microinjuries can be caused by smoking, dust, or any lung infection. Aberrant activation of signaling pathways by alveolar epithelial cells in response to stress underlies the fibrotic changes observed. Dysregulation of the cytokines transforming growth factor (TGF)-beta, platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) has been implicated in IPF pathophysiology.5 Fibroblasts are an important part of normal wound repair but problems arise when signaling is uncontrolled and fibroblasts continue to proliferate instead of die once a normal epithelium is reestablished. At the site of injury, fibroblasts proliferate and produce excessive amounts of collagen, leading to fibrotic changes to the extracellular matrix.5
Any agent that causes repeated lung injury increases IPF risk; a case-controlled study identified cigarette smoking as the most significant risk factor associated with IPF.2 Metal dust is another risk factor highly associated with IPF.6 Irritants from hairdressing, farming, wood dust, and petrochemicals have been linked to IPF.5 Clerical work was significantly associated with a reduced risk of IPF.7 Gastroesophageal reflux disease (GERD) is another source of recurrent lung injury in patients with IPF. One retrospective study demonstrated that 94% of patients with IPF had GERD, but only 24% displayed typical reflux symptoms.8
Viral infections are not only a source of lung injury but also are implicated as a risk factor for the onset of IPF. One cross-sectional study looked at the association of IPF development with hepatitis C virus (HCV) infection; development of IPF was significantly higher in patients infected with HCV.9 Interestingly, a study conducted in 2011 found herpes simplex virus-1 (HSV-1) DNA in 9% of lung samples of patients with IPF.10 Study authors showed that macrophages were permissive for HSV-1 and that infected macrophages expressed higher levels of profibrotic genes. Whether a viral agent is responsible for initiating IPF is not yet clear but the hypothesis is conceivable, especially in a genetically susceptible patient.
Over the last 20 years, a set of candidate genes has been identified that predispose a patient to develop IPF. Mutations in surfactant proteins (SFPT-C, SFPT-A2, and ABCA3) are found in a significant percentage of patients with IPF and are considered a risk factor. Mutations in the telomerase genes also are seen in patients with IPF. Up to 25% of patients were found to have shortened telomeres, which correlated with a worse prognosis in IPF.11 A genome-wide scan of patients revealed a single nucleotide change in the promoter of the mucin gene MUC5b that causes a 14-fold increase in MUC5b expression. Overproduction of mucus may impair alveolar repair. In addition, mutations in Toll-like receptors (which cause fibroblast dysregulation) have been found in patients with IPF.12 These studies and additional studies suggest a genetic component to IPF susceptibility and disease progression.
Patients in the early stages of IPF typically present with exertional dyspnea and a nonproductive cough. Dyspnea is insidious and progressive; by the time a patient seeks medical assistance, more than 6 months may have passed.13 Obtain a detailed history—part of the criteria for a diagnosis of IPF is to rule out other causes of lung injury. The initial aggravating event that preceded dyspnea usually is a respiratory infection from which the patient never fully recovered. A history of smoking is the most common factor associated with IPF, followed by professions where dust is generated, such as metalworking or mining.
The physical examination reveals fine inspiratory crackles at the base of both lungs. Associated systemic symptoms are rare in patients with early disease. Right-sided heart failure and pulmonary hypertension are seen in up to 85% of patients with IPF, although these are more commonly in the later stages of the disease.13
Patients presenting with increasing shortness of breath or cough often are referred to a pulmonologist for definitive diagnosis after their initial evaluations are either inconclusive or suggestive of IPF. Making this diagnosis requires a threefold approach: laboratory studies, pulmonary function testing, and imaging studies. Although no test is specific for IPF, much of the initial testing is performed to rule out other diseases. The diagnosis of IPF is made primarily through imaging; if imaging is ambiguous, a biopsy may be necessary (Figure 2).
Because some diseases, including rheumatoid arthritis and scleroderma, may present early with fibrotic pulmonary changes before classic rheumatologic symptoms appear, assess the following serologic markers for autoimmune diseases: antinuclear antibodies, rheumatoid factor, and anticitrullinated peptide. Any positive rheumatologic test results should be followed up with more specific markers for diseases.
Pulmonary function tests evaluate for a variety of lung diseases, and can track lung function decline over time. In patients with IPF, pulmonary function test results should be consistent with the typical pattern of a restrictive lung disease. Although the clinical progression of IPF is highly variable, forced vital capacity (FVC) decline is a good objective measure of disease status. In untreated patients, FVC has been reported to decrease 150 to 200 mL per year on average.14
High-resolution CT is essential to make the diagnosis of IPF. The usual interstitial pneumonia pattern in high-resolution CT, illustrated in Figure 3, shows reticular opacities, often with bronchiectasis and honeycombing. Lesions are characteristically bibasilar and subpleural. Ground-glass opacities are common, but extensive opacities are not characteristic of IPF. Consolidation, micronodules, discrete cysts, air trappings, and lesions in the middle or upper segments of the lungs are not characteristic of usual interstitial pneumonia.1 In patients for whom high-resolution CT results are ambiguous, lung biopsy can demonstrate a usual interstitial pneumonia pattern on histopathology. Low magnification will show areas of fibrosis, scarring, and honeycombing interspersed with areas of normal parenchyma. Fibrotic zones densely packed with collagen and fibroblasts are prominent. Areas of honeycombing consist of fibrosed airspaces surrounded by bronchial epithelial cells and smooth muscle due to rearrangement of the architecture.
Although a lung biopsy can yield a definitive diagnosis, it is not always necessary. A 2014 randomized, double-blind, placebo-controlled trial confirmed the positive predictive value of high-resolution CT to diagnose IPF in patients with possible usual interstitial pneumonia.15 Study authors defined an “appropriate clinical setting,” or a patient for whom high-resolution CT alone was sufficient to accurately diagnose IPF despite ambiguities. The appropriate patient was defined as a man over age 60 years with unexplained dyspnea on exertion and pulmonary fibrosis. In a patient who fits the above criteria, a biopsy is unnecessary, and a diagnosis of IPF can reasonably be made based on high-resolution CT, sparing patients the discomfort of a biopsy.
BEST EVIDENCE TREATMENT GUIDELINES
Lung protection and supportive care
Avoiding lung injury is the first and best defense. Offer all patients with IPF the influenza and pneumococcal vaccines. Educate patients on how to protect their lungs; for example, by wearing a surgical-type mask while traveling in airplanes, quitting smoking, and avoiding pollutants and industrial dust. For patients with GERD and IPF, taking a proton-pump inhibitor may slow the decline of their FVC values over time.16
All patients should be enrolled in a pulmonary rehabilitation program consisting of aerobic and strength training exercises. A 2014 placebo-controlled study compared patients with IPF who enrolled in a 3-month pulmonary rehabilitation program with patients who were counseled to exercise but were not given a formal exercise program.17 Although the rehabilitation group participants did not increase their FVC, they reported significant improvements in quality of life and maintained more normal physical activity; these parameters worsened in the control participants. As dyspnea worsens, virtually all patients require supplemental oxygen. Indications for oxygen therapy are chronic lung disease and an SpO2 less than 89% at rest.
Acute respiratory decline in a patient with IPF may be unexplained, or secondary to common conditions such as infection, pulmonary embolism, pneumothorax, or heart failure. Exacerbations with an identified underlying cause should be treated accordingly. When the cause cannot be explained, the term acute exacerbation of IPF is used. The clinical manifestation generally is an acute worsening of dyspnea over days to weeks. Treatment for an acute exacerbation of IPF consists of broad-spectrum antibiotics and high-dose glucocorticoids (prednisone 1 mg/kg daily).1 A recent study demonstrated that the use of high-dose sulfamethoxazole/trimethoprim during severe IPF exacerbations was significantly correlated with survival and better outcomes.18
Pirfenidone is one of two FDA-approved drugs for the treatment of IPF. In several studies, pirfenidone reduced fibroblast proliferation and inhibited production of TGB-beta. The efficacy and safety of pirfenidone for IPF was established by three multinational phase III randomized controlled clinical trials. In the CAPACITY 004 and 006 trials, FVC decline was significantly slowed in patients receiving treatment.19 A third study, ASCEND, confirmed the ability of pirfenidone to slow disease progression and increase exercise tolerance in patients with IPF.20 A follow-up sensitivity analysis calculated an approximate 50% reduction in the decline of FVC in treated patients.21 A 2016 meta-analysis of pooled data from all three clinical trials confirmed that treatment with pirfenidone resulted in a significant reduction of disease progression.22
The American Thoracic Society (ATS) 2011 Idiopathic Pulmonary Fibrosis Guidelines noted a conditional recommendation against the use of pirfenidone. However, with the availability of these recent data, the updated practice guidelines of 2015 stated a conditional recommendation for pirfenidone use.1,23 The most common adverse reactions to the drug were nausea (36%), rash (30%), and diarrhea (26%). Check the patient's liver enzymes before starting therapy, monthly for 6 months, and then every 3 months. Pirfenidone is started at 267 mg (one capsule) three times daily (for a total daily dosage of 801 mg), and increased weekly up to the maximum dose of three capsules three times daily (for a total daily dosage of 2,403 mg).24
Nintedanib, the second drug to receive FDA approval for the treatment of IPF, is a tyrosine kinase receptor blocker with activity against many of the growth factors involved in the pathogenesis of IPF, and inhibits fibroblast differentiation and reduces collagen production. Two randomized placebo-controlled clinical trials, IMPULSIS-1 and IMPULSIS-2, demonstrated a significant reduction in the rate of FVC decline and a slowing of the fibrotic disease progression. The use of nintedanib was not addressed in the 2011 ATS guidelines. The 2015 guidelines give it a conditional recommendation.23 The most frequent adverse reaction to this medication was diarrhea (62%).25 In both clinical trials, patients in the nintedanib treatment groups had elevated liver enzymes.26 FDA guidelines establish the dosing schedule at 150 mg twice daily.25 Obtain liver function tests before starting therapy, monthly for 3 months, then every 3 months. If the patient develops elevated liver enzymes between three and five times the upper limits of normal without signs or symptoms of severe liver damage, discontinue the medication or reduce the dosage to 100 mg twice daily until liver enzymes return to baseline; the drug may be increased to 150 mg twice daily thereafter as tolerated. If the patient's liver enzymes increase to greater than three times the upper limit of normal with evidence of severe liver damage, discontinue the medication.25
Pirfenidone and nintedanib target different mechanisms of the fibrotic process but overall their results are similar, reducing the rate of lung volume loss by about 100 mL per year.
For acceptable candidates, lung transplantation remains the best treatment option. Patients with IPF have the highest mortality of all categories of patients waiting for lung transplantation, making early referral an important step in the overall treatment plan.27 Single-lung transplants are the standard for patients with IPF, are more readily available than double-lung transplants, and offer similar long-term survival rates.4 Median survival rate post-transplant is 5.3 years.4 Published guidelines of indications for lung transplantation surgery are not meant to be used as absolutes; the overall clinical picture of the patient and availability of a donor lung should be the driving factors. The presentation of IPF can be variable, as can its progression to end-stage disease. The following clinical features are associated with advanced disease and higher mortality risk:
- a decline in FVC of 10% or greater within 6 months
- a decline in diffusion capacity of the lungs for carbon monoxide of 15% or greater compared with baseline
- oxygen desaturation to less than 88% on 6-minute walk test
- evidence of pulmonary hypertension
- hospitalization because of respiratory decline.1
The availability of two IPF medications, each with a unique mechanism of action, lets clinicians consider combination therapy. To date, only one randomized double-blind phase II study has been conducted to look specifically at the safety, tolerability, and pharmacokinetics of pirfenidone and nintedanib used concurrently.28 This study was not designed to assess efficacy, and combination therapy lasted only 28 days. All adverse reactions were mild or moderate in severity and were observed in 52% of the nintedanib-only group, and in 48% of the nintedanib and pirfenidone combination group.28 Vomiting and gastrointestinal disturbances were the most common adverse reactions. Although this study demonstrated that combination therapy is tolerated, additional studies are needed to further assess safety and efficacy of combination therapy.
Dozens of investigational compounds that target various aspects of the fibrotic process are being evaluated in clinical trials.29 A 2015 phase I/II study showed promising results using rituximab in patients suffering from severe acute IPF exacerbations, significantly improving recovery from the exacerbations.30 Nearly 50% of the rituximab group survived to 1 year (compared with no one in the control group), while significantly reducing their supplemental oxygen requirements and increasing their maximum walking distances.30 A 2014 phase 1b clinical trial using placental-derived mesenchymal stem cells found them to be well tolerated with only minor adverse reactions.31 Participants' lung function did not worsen, and they had no evidence of increased fibrosis during the 6-month study.31 Treatment guidelines are summarized in Table 1.
The best treatment for IPF is to avoid lung-damaging factors. Pirfenidone and nintedanib are effective treatments that reduce lung function decline. Clinicians should encourage all patients to enroll in ongoing clinical trials. With no cure, the best hope for future IPF patients lies in clinical trials that are evaluating the efficacy and safety of potential new treatments.
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18. Oda K, Yatera K, Fujino Y, et al. Efficacy of concurrent treatments in idiopathic pulmonary fibrosis
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. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med
. US Food and Drug Administration (FDA) approved product information. US National Library of Medicine. www.ncbi.nlm.nih.gov/pubmedhealth/PMH0069484
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. US Food and Drug Administration (FDA) approved product information. US National Library of Medicine. www.ncbi.nlm.nih.gov/pubmedhealth/PMH0069492
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. J Thorac Cardiovasc Surg
29. Borie R, Justet A, Beltramo G, et al. Pharmacological management of IPF. Respirology
30. Donahoe M, Valentine VG, Chien N, et al. Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis
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31. Chambers DC, Enever D, Ilic N, et al. A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis