Idiopathic pulmonary fibrosis (IPF), a type of interstitial lung disease and the most common type of idiopathic interstitial pneumonia, is characterized by chronic fibrosis and progressive scarring of the lung tissues.1 The disease is of clinical significance because of its misdiagnosis and high mortality rate.1 The cause of IPF remains unknown; however, alveolar epithelial injury and abnormal injury repair are thought to be the main causative agents.2 Its estimated prevalence in the US ranges from 10 to 60 cases per 100,000 people.1 As IPF progresses, patients experience increasing episodes of dyspnea, eventually leading to respiratory failure.3 The average survival rate after diagnosis is 3 to 5 years; the probability of surviving 5 years after diagnosis is estimated to be 20% to 40%.2
Table of Contents
Differential Diagnosis
A workup to diagnose IPF includes laboratory blood test, chest radiographs, high resolution computed tomography (HRCT), and lung biopsy.1 The first step in diagnosing IPF is ruling out other known causes of interstitial lung disease (ILD), with the most common being chronic hypersensitivity pneumonitis, sarcoidosis, connective tissue disease–related ILD, drug-induced ILD, and pneumoconiosis (Table 1).1 They share similar clinical and radiologic findings of the usual interstitial pneumonia (UIP) pattern.4
Making an accurate diagnosis of IPF is critical because treatments vary amongst the different types of ILD. The incorrect treatment regimen may lead to a degradation in the patient’s quality of life and shorten their lifespan.4
Another potential differential diagnosis is COVID-19 pneumonia. Findings of COVID-19 pneumonia can present in a similar way to idiopathic interstitial pneumonias on HRCT.5 An acute exacerbation of IPF will show ground-glass opacities on HRCT, comparable with findings of COVID-19 pneumonia.5 However, if the patient is presenting with the common symptoms of COVID-19 and had a known exposure to the virus, this can aid in ruling out IPF as a differential diagnosis. Radiologists play a vital role in discerning between COVID-19 pneumonia, idiopathic interstitial pneumonias, and chronic fibrosing lung diseases.5
History and Physical Exam Findings
A detailed patient history is necessary to rule out other causes of ILD. A history of co-morbidities, environmental exposures, medication use, family history, connective tissue disorders, high-risk occupations (such as those in dusty environments, including farming, hairdressing, and metal work) and history of tobacco smoking should be inquired about.6 There are more than 380 medications that are known to cause lung disease, some of the medications that are noted to cause ILD are Amiodarone, Macrobid, chemotherapy, Methotrexate, Amphotericin B, sulfonamides, biological agents, anti-inflammatories. 7 There are many environmental and occupational exposure risk factors of ILD, including, but not limited to, asbestos, silica, coal, organic and metal dusts, chemicals, mold, farm animals, and birds. 8 A history of smoking tobacco is associated with a 2-fold increase in developing IPF.8 The disease is more prevalent in people older than 50 years and in men.3 In a study by Luppi et al, an estimated 60% of patients with IPF had up to 3 of the following comorbidities: pulmonary hypertension, emphysema, obstructive sleep apnea, lung cancer, venous thromboembolism, chronic obstructive pulmonary disease, coronary artery disease, anxiety, depression, sarcopenia, osteoporosis, diabetes mellitus, hypothyroidism, and gastroesophageal reflux disease.9
Patients with IPF most commonly present with complaints of progressive dyspnea, at rest or with exertion, and a nonproductive cough.1 Positive physical examination findings for IPF include inspiratory fine crackles and clubbing.3 Crackles may be present in all lung fields, correlating with fibrotic areas.10 Cyanosis, fatigue, right-sided heart failure, and respiratory failure are associated with more advanced disease.10 Patients may also report experiencing episodes of a sudden onset of respiratory failure with new abnormalities on HRCT unexplained by other causes.1
Workup in Primary Care Setting
The primary care provider can initiate the workup for IPF with laboratory testing, chest radiographs, and HRCT until the patient is referred to a pulmonologist. If the patient’s symptoms, history, and physical examination are suggestive of ILD, the clinician may proceed with obtaining laboratory testing to further rule out diagnoses closely associated with the symptoms of IPF. An extensive laboratory panel to include in the workup for IPF is indicated in Table 2.11
Genetic testing should be included in the workup of IPF in all patients who have interstitial lung disease or those with a positive family history of interstitial lung disease.11 There are sporadic and familial forms of IPF and it is estimated that 33% of these forms can be diagnosed through genetic testing for certain genetic variants.12 A list of gene mutations is included in Table 3.12 Telomere length should also be tested when evaluating for sporadic and familial forms of IPF, as one third of patients with IPF will have short telomeres.12
A complete workup of IPF includes spirometry, serologic testing, imaging, and lung biopsy.1 Pulmonary function tests including forced vital capacity (FVC), total lung capacity and diffusion capacity of the lungs for carbon monoxide (DLCO); 6-minute walk distance should also be assessed.1 A positive finding is a reduction in FVC, total lung capacity, DLCO, and 6-minute walk distance; however, these tests are imprecise in that the results may be normal in early disease or positive in the presence of other restrictive lung diseases.1 Serologic tests commonly included in the workup of IPF aid in exclusion, rather than being specific for IPF.1 However, serum lactate dehydrogenase, though non-specific, can be used as a biomarker for the severity of acute exacerbations and activity of the disease.10
Chest radiographs are used for evaluating disease location, changes in volume loss, and the presence of pulmonary hypertension.10 The typical findings on chest radiograph are bilateral reticulonodular opacities, more commonly in the lower lobes.6 The disease presents with a UIP pattern on HRCT, consisting of heterogeneous paraseptal fibrosis.1 Peripheral, subpleural, and lower lobar reticulation, honeycombing, and single-layered clusters of cystic airspaces suggest the presence of IPF in the absence of other causes.1,10 Another feature of lung fibrosis is the presence of traction bronchiectasis and bronchiolectasis seen on HRCT.13 Findings on HRCT can be classified as typical, probable, indeterminate, or non-IPF based on the criteria shown in Table 4.10 If the pattern seen on HRCT is atypical or unclear, surgical lung biopsy or bronchoscopic lung cryobiopsy can be performed to provide a more definitive diagnosis.10 However, lung biopsies are restricted to certain patients because of potential complications.1 A patient presenting with a clinical history highly suggestive of IPF, a history of tobacco use and older than 60 years of age, with a probable UIP pattern on HRCT, does not need a lung biopsy.4
Treatment
The American Thoracic Society, European, Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax updated the IPF guidelines on diagnosis and treatment of IPF in 2022.14 The guidelines state that the treatments of IPF should include nonpharmacological and pharmacological, as discussed below.14 It is mentioned that patients’ comorbidities, most notable being pulmonary hypertension, gastroesophageal reflux, obstructive sleep apnea, and lung cancer, should be diagnosed and treated.14 However, in the treatment of gastroesophageal reflux, the updated guidelines recommend not treat patients with IPF with antacid medications or anti reflux surgery to improve respiratory outcomes.14
Shared decision making between the patients, family members and provider can be utilized to also offer palliative care to patients.14 The guidelines state that providers should monitor patients’ disease progression, utilizing pulmonary function tests and the six-minute walk test, every four to six months.14 HRCT scans can also be used to monitor progression, presence of lung cancer or acute exacerbations.14 Acute exacerbations should be treated with corticosteroids, and it is recommended to avoid mechanical ventilation for most patients with respiratory failure.14
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Making an accurate diagnosis of IPF is critical because treatments vary amongst the different types of interstitial lung disease. The incorrect treatment regimen may lead to a degradation in the patient’s quality of life and shorten their lifespan.
Nonpharmacologic and pharmacologic treatments are implemented to slow the progression of IPF, enhance quality of life, and improve symptoms and survival.1 Nonpharmacologic treatment includes supplemental oxygen, pulmonary rehabilitation, and lung transplantation.1 Supplemental oxygen therapy should be started when oxygen saturation declines to 88% or less at rest or during activity.1 Pulmonary rehabilitation enhances physical exertion capacity, thus minimizing dyspnea during activity.1
Undergoing lung transplantation can increase survival and improve quality of life; however, transplants are limited to select candidates.1 Clinicians should educate the patient about a lung transplant if they experience a sudden reduction in pulmonary function, decline in oxygen saturation, pulmonary hypertension, or need treatment in the emergency department for an acute exacerbation, respiratory deterioration, or pneumothorax.2
Pirfenidone and nintedanib are the 2 antifibrotic medications approved for the treatment of IPF.2,6 Pirfenidone, a modified pyridine, slows the rate of fibrosis by reducing the production of collagen and suppressing transforming growth factor-β (TGFβ).2 Nintedanib, a tyrosine kinase inhibitor, reduces fibroblast activity by suppressing signaling pathways of vascular endothelial, fibroblast and platelet-derived growth factor receptors.2 Both medications slow FVC decline by 50% per year and are used to prevent acute exacerbations.10
Pirfenidone and nintedanib have similar efficacy and tolerability; therefore, selecting between the 2 should be individualized to patient preference, comorbidities, and current medications.15 Side effects of pirfenidone include skin rash, weight loss, nausea, fatigue, and increased liver enzymes.2 Side effects of nintedanib include diarrhea, nausea, and hepatotoxicity; patients taking either antifibrotic therapy require liver-function monitoring.2 There are no definitive guidelines in predicting disease progression; it is recommended to initiate antifibrotic therapy early in the disease despite the patient’s baseline impairments.15
Cost-Effectiveness of Antifibrotic Therapy
The economic burden to the patient must be considered when treating patients with IPF. In the US, the annual cost of pirfenidone averages $113,193, and $112,357 for nintedanib.16 These prices were estimated from a database including patients who have commercial private insurance and those with Medicare Advantage.16 The lifetime analysis of cost and benefits demonstrates that symptom management treatment costs $79,815 with 3.78 quality-adjusted life years (QALYs), nintedanib costs $675,544 with 4.15 QALYs, and pirfenidone costs $688,778 with 4.10 QALYs.16 Though antifibrotics are clinically efficacious, there is a lower-than-expected number of patients with IPF receiving antifibrotics, possibly because of their high price.16 A potential solution to the high cost of antifibrotic therapy is assistance programs through the drug’s manufactuer; however, these programs are highly individualized and not all patients will meet inclusion criteria.16
Conclusion
The complexity of IPF makes the diagnosis challenging. More research is still needed to accurately understand the disease pathophysiology and treatment. Prevention and early detection of IPF are necessary in developing a management plan for patients since a diagnosis carries a poor prognostic outcome. A multidisciplinary approach that includes primary care providers, pulmonologists, radiologists, and pathologists is essential to accurately make the diagnosis of IPF.10