Continuing Education Activity

Idiopathic pulmonary fibrosis (IPF) is a lung disorder where there is scarring of the lungs from an unknown cause. It is usually a progressive disease with a poor long-term prognosis. The classic features of the disorder include progressive dyspnea and a nonproductive cough. Pulmonary function tests usually reveal restrictive impairment and diminished carbon monoxide diffusing capacity. The diagnosis is clinically aided with imaging tests and a biopsy. This activity reviews the etiology, presentation, evaluation, and management of idiopathic pulmonary fibrosis and reviews the role of the interprofessional team in evaluating, diagnosing, and managing the condition.

Objectives:

• Identify the presentation and pathological progression of idiopathic pulmonary fibrosis.
• Review the typical examination findings, including laboratory and diagnostic imaging results, expected when evaluating a patient with idiopathic pulmonary fibrosis.
• Outline the treatment and management options available for idiopathic pulmonary fibrosis, including the newer antifibrotic pharmacologic agents.
• Explain possible interprofessional team strategies for improving care coordination and communication to advance the evaluation and treatment of idiopathic pulmonary fibrosis and improve outcomes.

Introduction

Idiopathic pulmonary fibrosis (IPF) is a lung disorder where there is scarring of the lungs from an unknown cause. It is usually a progressive disease with a poor long-term prognosis. The classic features of the disorder include progressive dyspnea and a nonproductive cough. Pulmonary function tests usually reveal restrictive impairment and diminished carbon monoxide diffusing capacity. The diagnosis can be made without biopsy if there are compatible imaging tests, appropriate clinical history, and exclusion of other conditions.  The classic pattern of imaging on computed tomography (CT) scan will show a peripheral distribution of bilateral fibrosis, more pronounced at the bases.[1] If there is diagnostic uncertainty, IPF can also be diagnosed by lung biopsy.[2][3][4] The treatment includes supportive measures, oxygen supplementation when needed, anti-fibrotic drugs, and lung transplants for severe disease.

Etiology

The exact etiology for the development of IPF is unknown, but risk factors like exposure to tobacco smoke, metal, wood, dust, and gastroesophageal reflux have been implicated. The current theory on the etiology of IPF is that recurrent injury to the alveolar epithelium triggers a cascade of signaling by the immune system leading to fibrosis. A dysregulated response to the injury can cause tissue remodeling.  The onset is likely caused by multiple mechanisms.  While inflammation is present, there is debate about whether this is the cause or an effect of fibrosis.[5] While the majority of cases are idiopathic, some genetic factors that contribute to familial cases have been identified. Mutations in the telomerase genes (e.g., TERT), surfactant genes (e.g., SFTPA2), and mucin genes (e.g., MUC5B) have been known to lead to pulmonary fibrosis. Hermansky Pudlak syndrome is another rare autosomal recessive condition with defects in lysosome-related organelles that lead to albinism, platelet defects, and, in many of the affected individuals, pulmonary fibrosis.[6][7]

Epidemiology

IPF usually presents after the fifth or sixth decade of life and is more common with older age. There is a global distribution, and the incidence appears to be increasing. This could be related to an aging population or increased recognition.[8] Prevalence in the United States is estimated to range from 10 to 60 cases per 100,000.[9] 

Pathophysiology

Environmental factors like smoking, chronic aspiration, or viral infections, along with advancing age, can lead to respiratory alveolar epithelial injury and are thought to be the likely driving factors for the pathogenesis of IPF. With an epithelial injury, there is an activation of fibroblasts and dysregulated repair of the alveolar epithelium. When this leads to increased matrix deposition in the lung interstitium and scarring, there is a destruction of lung architecture that results in pulmonary fibrosis.[7] The destruction of lung architecture impairs gas exchange and will progress to hypoxic respiratory failure, a hallmark of advanced disease.

Histopathology

The histology usually is non-specific and reveals heterogeneous zones of the normal and affected lung. Interstitial inflammation, honeycomb change, and fibrosis are common, though these changes can be seen with other forms of advanced lung disease.

To make the diagnosis histologically, the following should be present:

• Presence of foci of fibroblasts
• Evidence of honeycombing and or disruption of lung architecture
• Patchy involvement of the lung by fibrosis
• Absence of other features suggests an alternative diagnosis [10]

History and Physical

The most common presenting symptoms of IPF are dyspnea on exertion and cough, followed by fatigue. The diagnosis is often delayed, as most patients are diagnosed more than a year after symptom onset. Since symptoms are nonspecific and the disease is idiopathic, other conditions must be excluded before diagnosis. History of exposure to inhaled dust, metals, asbestos, mold, or birds should be elicited to exclude other interstitial lung diseases. Medication and drug history are important to exclude drug toxicities. A careful history should be elicited to exclude autoimmune conditions like rheumatoid arthritis, scleroderma, Sjogren disease, or poly/dermatomyositis should also be elicited since these conditions can all lead to interstitial lung disease.  The cough is most commonly dry and non-productive.

The physical exam should be focused on evaluating lung involvement, extent and severity of the disease, and excluding another diagnosis. The classic pulmonary exam usually reveals fine bibasilar “velcro” crackles during inspiration. Clubbing may also be present. To exclude autoimmune conditions, evaluate for skin rashes, joint swelling, sclerodactyly, Raynaud phenomenon, and muscle weakness.  In advanced cases of IPF, patients may be exercise intolerance with minimal exertion or even resting hypoxemia.[11] 

Evaluation

Pulmonary function tests should be performed to assess for restrictive lung disease, which is characterized by decreased lung volumes (especially decreased forced vital capacity, total lung capacity, and functional residual capacity) and decreased diffusion capacity. When IPF is suspected, laboratory tests to exclude autoimmune disease should be performed. Antinuclear antibodies and rheumatoid factors are commonly indicated, but if there is a high suspicion, then antisynthetase antibodies, aldolase, Sjogren, and scleroderma antibodies should also be sent.[12][13][14]

Chest imaging is essential for diagnosis, but chest x-rays are not detailed enough to confirm IPF. High-resolution CT (HRCT) of the chest should be performed. The characteristic feature on HRCT is a “usual interstitial pneumonia” (UIP) pattern, which on imaging consists of bilateral subpleural basal predominant honeycombing or traction bronchiectasis or bronchiectasis. Peripheral reticular opacities are usually most notable in the lower lobes. Ground glass opacities and consolidation are atypical for a UIP pattern and, when present on imaging, should lead to suspicion for conditions other than IPF.

Histopathologic confirmation for IPF is not always necessary but should be considered if there are conflicting factors.  Such factors could include imaging with an atypical UIP pattern or suspicion for connective tissue disease causing the lung findings.  Many transplant centers often want confirmation by surgical lung biopsy prior to transplant as well. Additionally, if the patient is young, a biopsy may be warranted as most cases of IPF are later in life.  Bronchoscopic biopsy has a very low yield and is more useful when done to exclude other processes.  More recently, bronchoscopic cryo-biopsies have been used for pathologic diagnosis, but surgical lung biopsy remains the gold standard.[15] If the patient has an advanced disease state with functional impairment and respiratory failure, the risks of lung biopsy may be significant.

Characteristic histopathologic features for IPF is a UIP pattern which indicates the presence of temporal and spatial heterogeneity, the presence of fibroblastic foci, areas of subpleural honeycombing, and interstitial inflammation. There should also be an absence of other features like granulomas or giant cells.

Treatment / Management

Pulmonary function tests every 3 to 6 months should be performed based on symptoms and the disease's progression. However, serial chest imaging is not always necessary. Tools like GAP (gender, age physiology) score issue points for the male gender, advanced age, forced vital capacity, and diffusing capacity or transfer factor of the lung for carbon monoxide and can be used to assess long-term prognosis, with a high GAP score indicating worse mortality. This is mainly used when considering a patient for a lung transplant referral.[16][17][18] It is also important to assess the patient's functional status objectively and screen for hypoxic respiratory failure.  Most Interstitial Lung Disease specialty centers use the 6-minute walk test to accomplish both.

There are two antifibrotic agents approved for use in IPF. These are pirfenidone and nintedanib (tyrosine kinase inhibitors). Both drugs have been shown to slow the disease progression but not significantly impact mortality. For this reason, early initiation of therapy is recommended. Further studies have also shown decreased exacerbations of IPF with these drugs. Serial monitoring of liver function tests is recommended while on either drug. The most common side effect reported with nintedanib is diarrhea and with pirfenidone rash, photosensitivity, and gastrointestinal discomfort.  Gastrointestinal side effects are the most common reason for discontinuing both drugs.[19]

Recommended supportive measures include tobacco cessation, oxygen supplementation, and control of gastroesophageal reflux with proton pump inhibitors. Influenza and pneumococcal vaccination are recommended. Corticosteroids, immunosuppressants like azathioprine, and N-acetyl cysteine, have been used in the past, but now the recommendation is against the use of these agents in IPF following the publication of the PANTHER-IPF trial.[20]

Referral for a lung transplant is recommended early in the course of the disease, especially in a patient with a progressive decline in lung function. Survival benefit has been shown for patients with IPF who undergo a lung transplant.[21]

IPF is mainly confined to the lungs, and other organ involvement has not been seen. The progression of the disease is variable in patients. Some patients remain stable for several years after diagnosis, some patients decline rapidly after diagnosis, and some patients have periodic exacerbations during their course, which leads to declining lung function and increased mortality. Baseline lung function at diagnosis, the presence of comorbidities (especially co-existing emphysema and pulmonary hypertension), smoking history, low body mass index, and older age are associated with a worse prognosis. 

Acute exacerbations can occur in IPF, which can lead to rapid decline. Factors like heart failure must be excluded, and potential infections and thromboembolic disease must also be considered and promptly treated when an acute exacerbation is suspected. Imaging during acute exacerbations may show ground-glass opacities and consolidations.[22]

Differential Diagnosis

• Occupational lung diseases including pneumoconiosis and asbestosis
• Aspiration pneumonitis
• Bacterial and viral pneumonia
• Farmer's lung and other forms of hypersensitivity pneumonitis
• Fungal infection
• Lung cancer
• Pneumocystis jiroveci pneumonia
• Sarcoidosis
• Pulmonary edema
• Connective tissue diseases like rheumatoid arthritis

Complications

• Pulmonary hypertension
• Thromboembolic disease
• Adverse effects of medications 
• Superimposed lung infections
• Acute coronary syndrome
• Hypoxic respiratory failure

Deterrence and Patient Education

There are no specific recommendations for screening or deterrence.  Patients diagnosed with IPF should:

• Maintain a healthy weight and exercise regularly.  Pulmonary rehabilitation can be utilized for formal exercise training.
• Stop smoking where applicable.
• Avoid any environmental or occupational exposure that could exacerbate lung disease.
• Control acid reflux where applicable.
• Follow up with a specialist for disease-specific therapies and transplant referrals.

Pearls and Other Issues

1. Since IPF is a challenging disease with a poor prognosis, early diagnosis is essential. Interdisciplinary management can involve a pulmonologist, chest radiologist, thoracic surgeon, rheumatologist, and pathologist.
2. Patients with IPF will benefit from referral to an Interstitial Lung Disease (ILD) specialty clinic for discussion of anti-fibrotic drug therapies and timely referral for a lung transplant.
3. Because lung disease is progressive and fatal, it is important to address advanced care plans and end-of-life issues. 

Enhancing Healthcare Team Outcomes

Once a diagnosis of idiopathic pulmonary fibrosis is made, the management is interprofessional. The goal is to improve the quality of life. A physical therapy consult is recommended because evidence shows that regular physical activity or an exercise program can result in a marked improvement in the symptoms and the quality of life. Nursing will chart and assess the patient's condition along with the pulmonologist. The pharmacist should educate the patient on refraining from smoking and alcohol. The patient may benefit from the use of bronchodilators. To improve nutrition, a dietary consult should be sought. The nurse should educate the patient on the benefits of vaccination as many patients with pulmonary fibrosis do not tolerate lung infections well. [12][23][24] Interprofessional coordination of this type can increase patient quality of life. [Level 5]

Outcomes

Idiopathic pulmonary fibrosis has a median survival rate of IPF reported in the range of two to five years. The actual range of survival of individual patients is quite large. Up to 20 to 25 percent of patients live beyond 10 years. Most patients have continued dyspnea and limited exercise tolerance with a resultant poor quality of life. Deaths are most common in the winter, even in the absence of any lung infection. Many of these patients develop pulmonary hypertension and are at an increased risk of pulmonary embolism and sudden cardiac death. The prognosis is usually worse for those with severe changes noted on imaging and a lack of response to oxygen. [25][26] [Level 5]