Idiopathic Pulmonary Fibrosis

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Practice Essentials

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, primarily occurring in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP).[1]

Essential update: FDA approves two new drugs for idiopathic pulmonary fibrosis

The FDA has approved nintedanib (Ofev) and pirfenidone (Esbriet) for the treatment of IPF. Both drugs block multiple pathways that may be involved in pulmonary scarring, and both were granted approval through a triple-path process of fast track, orphan product, and breakthrough designations. In clinical trials, patients taking either drug experienced significantly reduced declines in forced vital capacity compared with patients who received placebo.[2, 3, 4]

Nintedanib is not recommended for patients with moderate to severe liver disease and may cause birth defects or stillbirth. Pirfenidone is not recommended for patients with liver disease or end-stage kidney disease, and may cause photosensitivity. Adverse effects seen with both drugs include diarrhea, nausea, abdominal pain, vomiting, decrease or loss of appetite, and headache.[2, 3, 4]

Signs and symptoms

The clinical symptoms of idiopathic pulmonary fibrosis are nonspecific and can be shared with many pulmonary and cardiac diseases. Most patients present with a gradual onset (often >6 mo) of exertional dyspnea and/or a nonproductive cough. Approximately 5% of patients have no presenting symptoms when idiopathic pulmonary fibrosis is serendipitously diagnosed.

Associated systemic symptoms that can occur but are not common in idiopathic pulmonary fibrosis include the following:

See Clinical Presentation for more detail.

Diagnosis

It is critical to obtain a complete history, including medication history, drug use, social history, occupational, recreational, and environmental respiratory exposure history, risks for the human immunodeficiency virus, and review of systems, to ensure other causes of interstitial lung disease are excluded. The diagnosis of idiopathic pulmonary fibrosis relies on the clinician to integrate and correlate the clinical, laboratory, radiologic, and/or pathologic data.[5]

Physical examination in patients with idiopathic pulmonary fibrosis may reveal the following:

Laboratory testing

Results from routine laboratory studies are nonspecific for the diagnosis of idiopathic pulmonary fibrosis. Some tests that may be helpful to exclude other causes of interstitial lung disease include the following:

A 6-minute walk test (6MWT) is often used in the initial and longitudinal clinical assessment of patients with idiopathic pulmonary fibrosis. In patients who desaturate to less than 88% during a 6MWT, a progressive decline in the DLCO (>15% after 6 mo) is a strong predictor of increased mortality.[9]

Imaging studies

Procedures

See Workup for more detail.

Management

The optimal medical therapy for the treatment of idiopathic pulmonary fibrosis has yet to be identified. Treatment strategies for idiopathic pulmonary fibrosis include the assessment and management of comorbid conditions according to current practice guidelines, including chronic obstructive pulmonary disease, obstructive sleep apnea, gastroesophageal reflux disease, and coronary artery disease.

Other management strategies include the following:

Surgery

Pharmacotherapy

See Treatment and Medication for more detail.

Background

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, primarily occurring in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP).[1]

Of the seven listed idiopathic interstitial pneumonias in the American Thoracic Society/European Respiratory Society consensus statement (ie, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial pneumonia, lymphoid interstitial pneumonia), idiopathic pulmonary fibrosis is the most common.[12] Idiopathic pulmonary fibrosis portends a poor prognosis, and, to date, no proven effective therapies are available for the treatment of idiopathic pulmonary fibrosis beyond lung transplantation.[5]

Most patients with idiopathic pulmonary fibrosis present with a gradual onset, often greater than six months, of dyspnea and/or a nonproductive cough. The symptoms often precede the diagnosis by a median of one to two years.[13] A chest radiograph typically reveals diffuse reticular opacities. However, it lacks diagnostic specificity.[14] High-resolution computed tomography (HRCT) findings are significantly more sensitive and specific for the diagnosis of idiopathic pulmonary fibrosis. On HRCT images, usual interstitial pneumonia is characterized by the presence of reticular opacities often associated with traction bronchiectasis. As idiopathic pulmonary fibrosis progresses, honeycombing becomes more prominent.[10] Pulmonary function tests often reveal restrictive impairment and reduced diffusing capacity for carbon monoxide.[14]

Available data suggest that no single etiologic agent serves as a common inciting event in the pathogenesis of idiopathic pulmonary fibrosis. During the past 15 years, the pathogenesis theory of generalized inflammation progressing to widespread parenchymal fibrosis has become less popular.[14] Rather, it is now believed that epithelial injury and activation in fibroblast foci are crucial early events that trigger a cascade of changes leading to reorganization of pulmonary tissue compartments.[15]

As mentioned above, idiopathic pulmonary fibrosis is an idiopathic interstitial pneumonitis characterized by usual interstitial pneumonia on histopathology. The hallmark pathologic feature of usual interstitial pneumonia is a heterogeneous, variegated appearance with alternating areas of healthy lung, interstitial inflammation, fibrosis, and honeycomb change. Fibrosis predominates over inflammation.[15]

The diagnosis of idiopathic pulmonary fibrosis relies on the clinician integrating the clinical, laboratory, radiologic, and/or pathologic data to make a clinical-radiologic-pathologic correlation that supports the diagnosis of idiopathic pulmonary fibrosis.[5]

Pathophysiology

The previous theory regarding the pathogenesis of idiopathic pulmonary fibrosis (IPF) was that generalized inflammation progressed to widespread parenchymal fibrosis. However, anti-inflammatory agents and immune modulators have proved to be minimally effective in modifying the natural course of the disease. It is currently believed that idiopathic pulmonary fibrosis (IPF) is an epithelial-fibroblastic disease, in which unknown endogenous or environmental stimuli disrupt the homeostasis of alveolar epithelial cells, resulting in diffuse epithelial cell activation and aberrant epithelial cell repair.[16]

In the current hypothesis regarding the pathogenesis of idiopathic pulmonary fibrosis, exposure to an inciting agent (eg, smoke, environmental pollutants, environmental dust, viral infections, gastroesophageal reflux disease, chronic aspiration) in a susceptible host may lead to the initial alveolar epithelial damage.[17] Reestablishing an intact epithelium following injury is a key component of normal wound healing. In idiopathic pulmonary fibrosis, it is believed that after injury, aberrant activation of alveolar epithelial cells provokes the migration, proliferation, and activation of mesenchymal cells with the formation of fibroblastic/myofibroblastic foci, leading to the exaggerated accumulation of extracellular matrix with the irreversible destruction of the lung parenchyma.[17]

Activated alveolar epithelial cells release potent fibrogenic cytokines and growth factors. These include, tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), platelet-derived growth factor, insulin-like growth factor-1, and endothelin-1 (ET-1).[15, 17] These cytokines and growth factors are involved in the migration and proliferation of fibroblasts and the transformation of fibroblasts into myofibroblasts. Fibroblasts and myofibroblasts are key effector cells in fibrogenesis, and myofibroblasts secrete extracellular matrix proteins.[17]

For normal wound healing to occur, wound myofibroblasts must undergo apoptosis. Failure of apoptosis leads to myofibroblast accumulation, exuberant extracellular matrix protein production, persistent tissue contraction, and pathologic scar formation.[17] TGF-β has been shown to promote an antiapoptotic phenotype in fibroblasts.[17] Additionally, myofibroblasts in fibroblastic foci of idiopathic pulmonary fibrosis have been reported to undergo less apoptotic activity in comparison to myofibroblasts in the fibromyxoid lesions of bronchiolitis obliterans organizing pneumonia.[18]

Excess alveolar epithelial cell apoptosis and fibroblast resistance to apoptosis are also believed to contribute to fibroproliferation in idiopathic pulmonary fibrosis. Research has demonstrated that prostaglandin E2 deficiency, in lung tissue of patients with pulmonary fibrosis, results in increased sensitivity of alveolar epithelial cells to FAS-ligand induced apoptosis but induces fibroblast resistance to Fas-ligand induced apoptosis.[19] Therefore, apoptosis resistance in the fibroblasts and myofibroblasts participating in the repair of the alveolar epithelium may contribute to the persistent and/or progressive fibrosis in idiopathic pulmonary fibrosis.

Evidence for a genetic basis for idiopathic pulmonary fibrosis is accumulating. It has been described that mutant telomerase is associated with familial idiopathic pulmonary fibrosis.[20] Telomerase is a specialized polymerase that adds telomere repeats to the ends of chromosomes. This helps to offset shortening that occurs during DNA replication. TGF-β negatively regulates telomerase activity.[17] It is proposed that pulmonary fibrosis in patients with short telomeres is provoked by a loss of alveolar epithelial cells. Telomere shortening also occurs with aging, and it can also be acquired. This telomere shortening could promote the loss of alveolar epithelial cells, resulting in aberrant epithelial cell repair, and therefore should be considered as another potential contributor to the pathogenesis of idiopathic pulmonary fibrosis.[20]

Additionally, a common variant in the putative promoter of the gene that encodes mucin 5B (MUC5B) has been associated with the development of both familial interstitial pneumonia and sporadic pulmonary fibrosis. MUC5B expression in the lung was reported to be 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not. Therefore, dysregulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis.[21]

Finally, caveolin-1 has been proposed as a protective regulator of pulmonary fibrosis. Caveolin-1 limits TGF-β–induced production of extracellular matrix proteins and restores the alveolar epithelial-repair process.[17] It has been observed that the expression of caveolin-1 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis and that fibroblasts, the key cellular component of fibrosis, have low levels of caveolin-1 expression in patients with idiopathic pulmonary fibrosis.[22]

The recognition of the above-mentioned factors as contributors to the pathogenesis of idiopathic pulmonary fibrosis has led to the development of novel approaches to treat idiopathic pulmonary fibrosis.

Frequency

United States

No large-scale studies of the incidence or prevalence of idiopathic pulmonary fibrosis are available on which to base formal estimates.

A population-based cohort study was completed in Olmsted County, Minnesota, between 1997 and 2005, with the intention of updating and describing the incidence and prevalence of idiopathic pulmonary fibrosis. Narrow-criteria idiopathic pulmonary fibrosis was defined by usual interstitial pneumonia on a surgical lung biopsy specimen or a definite usual interstitial pneumonia pattern on an HRCT image. Broad-criteria idiopathic pulmonary fibrosis was defined by usual interstitial pneumonia on a surgical lung biopsy specimen or a definite or possible usual interstitial pneumonia pattern on an HRCT image.[23] These criteria were obtained from the 2002 American Thoracic Society/European Thoracic Society consensus statement.[12]

The age-adjusted and sex-adjusted incidence rate of idiopathic pulmonary fibrosis among residents aged 50 years or older ranges from 8.8 cases per 100,000 person-years (narrow-case criteria) to 17.4 cases per 100,000 person-years (broad-case criteria).[23]

The age-adjusted and sex-adjusted prevalence among residents aged 50 years or older ranges from 27.9 cases per 100,000 persons (narrow-case criteria) to 63 cases per 100,000 persons (broad-case criteria).[23]

Whether the incidence and prevalence of idiopathic pulmonary fibrosis are influenced by geographic, ethnic, cultural, or racial factors is unclear.[1]

International

Worldwide, the incidence of idiopathic pulmonary fibrosis is estimated to be 10.7 cases per 100,000 person-years for males and 7.4 cases per 100,000 person years for females. The prevalence of idiopathic pulmonary fibrosis is estimated to be 20 cases per 100,000 persons for males and 13 cases per 100,000 persons for females.[14]

Mortality/Morbidity

Idiopathic pulmonary fibrosis portends a poor prognosis, with an estimated mean survival of 2-5 years from the time of diagnosis.[5] Estimated mortality rates are 64.3 deaths per million in men and 58.4 deaths per million in women.[24]

Death rates in patients with idiopathic pulmonary fibrosis increase with increasing age, are consistently higher in men than women, and experience seasonal variation, with the highest death rates occurring in the winter, even when infectious causes are excluded.[13]

Estimates are that 60% of patients with idiopathic pulmonary fibrosis die from their idiopathic pulmonary fibrosis, as opposed to dying with their idiopathic pulmonary fibrosis. Of those patients who die with idiopathic pulmonary fibrosis, most commonly it is after an acute exacerbation of idiopathic pulmonary fibrosis. When an acute exacerbation of idiopathic pulmonary fibrosis is not the cause of death, an increased cardiovascular risk and an increased venous thromboembolic disease risk contribute to the cause of death. The most common causes of death in patients with idiopathic pulmonary fibrosis include acute exacerbations of idiopathic pulmonary fibrosis, acute coronary syndromes, congestive heart failure, lung cancer, infectious causes, and venous thromboembolic disease.[5]

Race

Epidemiologic data from large, geographically diverse populations are limited, and, therefore this data cannot be used to accurately determine the existence of a racial predilection for idiopathic pulmonary fibrosis.

Sex

Using data obtained from a large US healthcare claims database, the incidence and prevalence of idiopathic pulmonary fibrosis is higher in men aged 55 years or older, compared with women of the same age.[25]

Age

Idiopathic pulmonary fibrosis mainly affects persons aged 50 years or older. Approximately two thirds of persons diagnosed with idiopathic pulmonary fibrosis are aged 60 years or older at the time of diagnosis. Using data obtained from a large US healthcare claims database, the incidence of idiopathic pulmonary fibrosis was estimated to range from 0.4-1.2 cases per 100,000 person-years for persons aged 18-34 years. However, the estimated incidence of idiopathic pulmonary fibrosis in persons aged 75 years or older was significantly higher and ranged from 27.1-76.4 cases per 100,000 person-years.[25]

History

The clinical symptoms of idiopathic pulmonary fibrosis are nonspecific. Most patients present with exertional dyspnea and a nonproductive cough. Such symptoms can be shared with a variety of pulmonary and cardiac diseases. Dyspnea, which is the most prominent symptom in idiopathic pulmonary fibrosis (IPF), usually begins insidiously and is often progressive. Associated systemic symptoms can occur but are not common. Some of these systemic symptoms include weight loss, low-grade fevers, fatigue, arthralgias, or myalgias.

The reported median duration of symptoms before the diagnosis of idiopathic pulmonary fibrosis is established is one to two years.[14] Most patients are referred to a cardiologist for evaluation of exertional dyspnea prior to being referred to a pulmonologist. Approximately 5% of patients have no presenting symptoms when idiopathic pulmonary fibrosis is diagnosed. Among asymptomatic patients with idiopathic pulmonary fibrosis (diagnosed by radiographic abnormalities found on routine chest radiograph screening and lung biopsy showing usual interstitial pneumonia), symptoms developed approximately 1000 days after the recognition of the radiographic abnormality.[14]

It is critical to obtain a complete history, including medication history, drug use, social history, occupational, recreational, and environmental respiratory exposure history, risk factors for human immunodeficiency virus infection, and review of systems, to ensure other causes of interstitial lung disease are excluded. Amiodarone, bleomycin, and nitrofurantoin are notable medications associated with pulmonary fibrosis. Oxidant stress from smoking may damage alveolar epithelial cells and contribute to the pathogenesis of idiopathic pulmonary fibrosis.[26] Any patient with idiopathic pulmonary fibrosis who is a current smoker should be encouraged to quit. Any prior exposure to asbestos, silica, heavy metals, contaminated ventilation systems, moldy foliage, and/or pigeon droppings should be investigated. Evidence of arthralgia, arthritis, photosensitivity, Raynaud phenomenon, dry eyes, and/or dry mouth on review of systems may indicate the presence of a collagen-vascular disease.

Physicians should pay attention to historical clues that may suggest the presence of obstructive sleep apnea (OSA) because a 2009 study demonstrated the high prevalence of OSA in patients with idiopathic pulmonary fibrosis. Fifty outpatients with stable idiopathic pulmonary fibrosis were prospectively evaluated for the presence of OSA. OSA was defined as an apnea-hypopnea index (AHI) of greater than 5 events per hour. Ten subjects (20%) had mild OSA (AHI of 5-15 events per hour) and 34 subjects (68%) had moderate-to-severe OSA (AHI of >15 events per hour).[27] Therefore, the prevalence of OSA in this sample was 88%, suggesting that OSA in patients with idiopathic pulmonary fibrosis may have been previously underrecognized.

Physical

In most patients with idiopathic pulmonary fibrosis, the physical examination reveals fine bibasilar inspiratory crackles (Velcro crackles). Additionally, digital clubbing is seen in 25-50% of patients with idiopathic pulmonary fibrosis (IPF).[14] Extrapulmonary involvement does not occur with idiopathic pulmonary fibrosis, and, therefore, physical examination findings do not help to confirm the diagnosis.

Pulmonary hypertension is a common comorbidity in patients with idiopathic pulmonary fibrosis, and an estimated 20-40% of patients with idiopathic pulmonary fibrosis who are evaluated or listed for lung transplantation have pulmonary hypertension at rest.[6] Physical examination findings may be suggestive of the presence of pulmonary hypertension. Patients may have a loud P2 component of the second heart sound, a fixed split S2, a holosystolic tricuspid regurgitation murmur, and pedal edema. As right ventricular hypertrophy ensues, a right ventricular heave may be palpated at the lower left sternal border and increased right atrial pressure may cause elevation of the jugular venous pressure.[7]

Causes

The etiology of idiopathic pulmonary fibrosis remains undefined; however, in the current hypothesis regarding the pathogenesis of idiopathic pulmonary fibrosis (IPF), exposure to an inciting agent (eg, smoke, environmental pollutants, environmental dust, viral infections, gastroesophageal reflux disease, chronic aspiration) in a susceptible host may lead to the initial alveolar epithelial damage.[17] This damage may lead to activation of the alveolar epithelial cells, which provokes the migration, proliferation, and activation of mesenchymal cells with the formation of fibroblastic/myofibroblastic foci, leading to the exaggerated accumulation of extracellular matrix with the irreversible destruction of the lung parenchyma.[17]

Other potential causes of idiopathic pulmonary fibrosis have been recognized through the study of familial pulmonary fibrosis. Familial pulmonary fibrosis, affecting 2 or more members of the same primary biological family, accounts for less than 5% of total patients with idiopathic pulmonary fibrosis.[28]

Genetic mutations in serum surfactant protein C have been discovered in some individuals with familial pulmonary fibrosis.[28] These mutations in serum surfactant protein C may damage type II alveolar epithelial cells.[28] Additionally, a common variant in the putative promoter of the gene encoding mucin 5B (MUC5B) has been associated with the development of both familial interstitial pneumonia and sporadic pulmonary fibrosis.[21]

Finally, mutant telomerase is associated with familial idiopathic pulmonary fibrosis.[20] Pulmonary fibrosis in patients with short telomeres is provoked by a loss of alveolar epithelial cells. Telomere shortening also occurs with aging and can also be acquired. This telomere shortening could promote the loss of alveolar epithelial cells, resulting in aberrant epithelial cell repair, and therefore should be considered as another potential contributor to the pathogenesis of idiopathic pulmonary fibrosis.[20]

Respiratory viruses have been considered a particularly likely cause of AE-IPF based on the similarities in clinical and radiologic presentation between and AE-IPF and viral pneumonitis and the poor sensitivity of standard methods of viral detection. A study by Wootton et al used genomics-based discovery methods to define the role of viral infections in AE-IPF. Initial multiplex polymerase chain reaction (PCR) revealed common respiratory viral infection in only 4 of 43 patients with AE-IPF. Pan-viral microarrays revealed torque teno virus (TTV) in 12 patients with AE-IPF. The pathogenic significance of TTV in AE-IPF is unclear. Overall, viral infection was not detected in most cases of AE-IPF.[29]

Laboratory Studies

Results from routine laboratory studies are nonspecific for the diagnosis of idiopathic pulmonary fibrosis; however, some laboratory studies may be helpful for ruling out other causes of interstitial lung disease. Reportedly, up to 30% of patients with idiopathic pulmonary fibrosis (IPF) have positive tests for antinuclear antibodies or rheumatoid factor; however, these titers are generally not high.[7] The presence of high titers of antinuclear antibodies or rheumatoid factor may suggest the presence of a connective-tissue disease. The C-reactive protein value and erythrocyte sedimentation rate can be elevated in patients with idiopathic pulmonary fibrosis; however, this finding is nondiagnostic. Although chronic hypoxemia is a common finding in patients with idiopathic pulmonary fibrosis, polycythemia is a rare finding on laboratory studies.

Imaging Studies

Chest radiography

The chest radiograph lacks diagnostic specificity for idiopathic pulmonary fibrosis. Virtually all patients with idiopathic pulmonary fibrosis (IPF) have an abnormal chest radiograph at the time of diagnosis. The typical findings are peripheral reticular opacities (netlike linear and curvilinear densities) predominantly at the lung bases (see image below). Honeycombing (coarse reticular pattern) and lower lobe volume loss can also be seen.[10]


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Chest radiograph of a patient with idiopathic pulmonary fibrosis showing bilateral lower lobe reticular opacities (red circles).

High-resolution computed tomography

High-resolution computed tomography (HRCT) findings are significantly more sensitive and specific for the diagnosis of idiopathic pulmonary fibrosis and are an essential component of the diagnostic pathway of idiopathic pulmonary fibrosis. On HRCT images, idiopathic pulmonary fibrosis is characterized by patchy, peripheral, subpleural, and bibasilar reticular opacities (see image below).


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Classic subpleural honeycombing (red circle) in a patient with a diagnosis of idiopathic pulmonary fibrosis.

Reticular opacities refer to the fine network of lines that sometimes include interlobular septal thickening and/or intralobular lines. Areas that are severely involved with reticular markings may also demonstrate traction bronchiectasis. Subpleural honeycombing (< 5-mm round translucencies with a density equal to that of air) is also a common finding (see image below).


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A patient with IPF and a confirmed histologic diagnosis of usual interstitial pneumonia. Note the reticular opacities (red circle) distributed in both....

Ground-glass opacities can be found but are less extensive than reticular abnormalities.[10] Reticular opacities and honeycombing seen on HRCT imaging correlates histologically with fibrosis and honeycombing. The presence of subpleural honeycombing, traction bronchiectasis, and thickened interlobular septae increase the specificity of HRCT for diagnosing idiopathic pulmonary fibrosis.[10] Patients with typical changes of idiopathic pulmonary fibrosis on HRCT imaging have a worse prognosis compared with patients with biopsy-proven usual interstitial pneumonia and atypical changes of idiopathic pulmonary fibrosis on HRCT imaging.[30]

Multiple studies have documented that the accuracy of a confident diagnosis of usual interstitial pneumonia made on the basis of HRCT imaging findings by an experienced observer exceeds 90%.[10] However, several clinical conditions may be associated with the histologic pattern of usual interstitial pneumonia and must therefore be considered in the differential diagnosis of usual interstitial pneumonia diagnosed on the basis of HRCT imaging.

The differential diagnosis of ground-glass opacities on HRCT imaging include heart failure, nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, and hypersensitivity pneumonitis. Fine nodules are suggestive of hypersensitivity pneumonitis, granulomatous infection, or metastatic malignancy. Upper lobe disease is the predominant pattern in hypersensitivity pneumonitis, a variety of pneumoconioses, sarcoidosis, and eosinophilic pneumonia.[7] Lymphadenopathy is associated with sarcoidosis and other granulomatous disease. Idiopathic pulmonary fibrosis and NSIP can have indistinguishable clinical presentations, and understanding how HRCT imaging can help to distinguish between these two entities is important (see image below).


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A patient with nonspecific interstitial pneumonia. Note the predominance of ground-glass opacities (blue circles) and a few reticular lines (red arrow....

The abnormalities in NSIP usually predominate in the middle and lower lungs. NSIP is less likely to have a subpleural distribution compared with usual interstitial pneumonia. Ground-glass opacities are a frequent feature of NSIP and are reported to be found in 76-100% of cases.[10] Finally, honeycombing is less common than in usual interstitial pneumonia, with the prevalence ranging from 0-30% in different series.[10] Honeycombing is mainly seen in patients with purely fibrotic NSIP.

The following are HRCT Criteria for UIP Pattern:[1]

UIP pattern requires all 4 features below.

Possible UIP pattern requires all 3 features below.

Inconsistent with UIP pattern requires any of the 7 features below.

Other Tests

Pulmonary function testing

The typical findings on pulmonary function tests in patients with idiopathic pulmonary fibrosis are a restrictive ventilatory defect and a reduced diffusion capacity for carbon monoxide.[8] These findings are nonspecific and should be used in conjunction with clinical, radiologic, and pathologic information to ensure an accurate diagnosis of idiopathic pulmonary fibrosis (IPF).

In patients with idiopathic pulmonary fibrosis, a restrictive ventilatory defect is typically present. Vital capacity, functional residual capacity, total lung capacity, and forced vital capacity (FVC) all are reduced. Additionally, the static pressure-volume curve is shifted downward and to the right as a result of decreased lung compliance.[8] Obstructive ventilatory defects are not common. However, if present, they may suggest the coexistence of chronic obstructive pulmonary disease.

Prognostication in idiopathic pulmonary fibrosis relies on serial assessments of FVC. Patients who have a greater than 10% decline in FVC (percent predicted) over 6 months, have a 2.4-fold increased risk of death. Additionally, in patients who do not desaturate to less than 88% during a 6-minute walk test (6MWT), the only strong predictor of mortality is a progressive decline in FVC (>10% after 6 mo).[31] As a result of these findings, change in FVC is being used more frequently as a primary end point in clinical trials.

A large study was completed in 2012 to estimate the minimal clinically important difference (MCID) of FVC in patients with IPF. In this study, data was used from 1,156 patients included in two clinical trials investigating IFN-γ1β. This study found that the hazard ratio for the one-year risk of death was 2.14 (1.43-3.20) in patients with a 24-week decline in FVC between 5% and 10%. The estimated MCID was 2-6%.[32]

Impaired gas exchange is demonstrated by the decreased diffusion capacity of carbon monoxide (DLCO). In idiopathic pulmonary fibrosis, the reduced DLCO may precede the development of abnormal lung volumes. Additionally, DLCO is reduced to a greater extent in idiopathic pulmonary fibrosis compared with other idiopathic interstitial pneumonias.[8] Prognostication in idiopathic pulmonary fibrosis also relies on serial assessments of DLCO. A baseline DLCO below 35% is correlated with increased mortality. Additionally, a decline in DLCO greater than 15% over 1 year is also associated with increased mortality.[31]

6-Minute walk testing

The 6MWT is a marker of functional exercise capacity that is being increasingly used in the initial and longitudinal clinical assessment of patients with idiopathic pulmonary fibrosis. Desaturation below the threshold of 88% during the 6MWT has been associated with an increased mortality.[31] Additionally, in patients with idiopathic pulmonary fibrosis who desaturate to less than 88% during a 6MWT, a progressive decline in DLCO (>15% after 6 mo) is a strong predictor of increased mortality.[9]

Heart rate recovery (HRR), specifically the failure of the heart rate to decline at 1 or 2 minutes postexercise, is associated with increased mortality. A 2009 retrospective analysis found that the failure of the heart rate to decline after exertion (by >13 beats at 1 min or by >22 beats at 2 min) is a strong predictor of increased mortality.[33]

A study by du Bois and colleagues estimated the minimal clinically important difference in the 6MWT in 822 patients with idiopathic pulmonary fibrosis. For patients who had a decline in 6MWT of 26-50 meters at 24 weeks, the hazard ratio for death at 1 year was 3.59 (1.95-6.63). For patients who had a decline in the 6MWT of more than 50 meters at 24 weeks, the hazard ratio for death at 1 year was 4.27 (2.57-7.10). The minimal clinically important difference in 6MWT was distance is 24-45 meters.[34]

Bronchoalveolar lavage

Bronchoalveolar lavage (BAL) has been an immensely useful research tool in idiopathic pulmonary fibrosis. However, the role of BAL in the clinical diagnosis of idiopathic pulmonary fibrosis remains limited. Increased numbers of neutrophils in BAL fluid are found in 70-90% of all patients with idiopathic pulmonary fibrosis, and increased numbers of eosinophils in BAL fluid are found in 40-60% of all patients with idiopathic pulmonary fibrosis. Previous studies have demonstrated that the absence of BAL fluid lymphocytosis is important for the diagnosis of idiopathic pulmonary fibrosis. A 2009 study suggests that BAL fluid analysis has an additional benefit for the diagnosis of idiopathic pulmonary fibrosis. The study demonstrated the discriminating power of a cut-off level of less than 30% lymphocytosis in BAL fluid in distinguishing idiopathic pulmonary fibrosis from nonidiopathic pulmonary fibrosis diagnoses.[35]

BAL is not required for the diagnosis of idiopathic pulmonary fibrosis. However, BAL fluid analysis can be useful to exclude other alternative diagnoses. Appropriate analysis of BAL fluid may demonstrate the presence of infection, malignancy, alveolar proteinosis, eosinophilic pneumonia, or occupational dusts.

BAL fluid neutrophilia has been demonstrated to predict early mortality. One study demonstrated a linear relationship between increasing neutrophil percentage and the risk of mortality. Each doubling in baseline BAL fluid neutrophil percentage was associated with a 30% increased risk of death or transplantation in the first year after presentation.[36] Additionally, studies of BAL matrix metalloproteinase (MMP) levels suggest that MMP1 and MMP7 are increased in patients with idiopathic pulmonary fibrosis and that MMP7 levels may correlate with disease severity.[1]

Transthoracic echocardiography

Studies have demonstrated that pulmonary hypertension is present at rest in approximately 20-40% of idiopathic pulmonary fibrosis patients who are listed for lung transplantation.[6] The US National Institutes of Health (NIH) definition of pulmonary arterial hypertension is a mean pulmonary artery pressure greater than 25 mmHg at rest with a normal pulmonary capillary wedge pressure measured by right-sided heart catheterization. Generally, transthoracic echocardiography is an excellent modality to detect pulmonary hypertension. However, in patients with chronic lung disease, including idiopathic pulmonary fibrosis, studies have shown a variable performance for transthoracic echocardiography to detect pulmonary hypertension.[6]

Procedures

Bronchoscopy

As previously stated, bronchoscopy with BAL and/or transbronchial biopsy is not required for the diagnosis of idiopathic pulmonary fibrosis. However, it can be used to ensure that alternative diagnoses are excluded. In cases requiring histopathology, the specificity and positive predictive value of UIP pattern identified by transbronchial biopsy has not been rigorously studied.[1]

Surgical lung biopsy

A surgical lung biopsy specimen can be obtained through either an open lung biopsy or video-assisted thoracoscopic surgery (VATS). A surgical lung biopsy provides the best sample for which to distinguish usual interstitial pneumonia from other idiopathic interstitial pneumonias. VATS is preferred because it is associated with less morbidity and a shorter hospital stay compared with open lung biopsy.

Given the high-quality evidence regarding HRCT specificity for the recognition of histopathologic UIP pattern, surgical lung biopsy is not essential in making the diagnosis.[1] In patients with UIP pattern on HRCT a surgical lung biopsy is not needed for the diagnosis of idiopathic pulmonary fibrosis. However, in patients with possible UIP pattern or inconsistent with UIP pattern on HRCT, a surgical lung biopsy is needed for the diagnosis of idiopathic pulmonary fibrosis.[1] The previously described major and minor criteria for the clinical diagnosis of idiopathic pulmonary fibrosis have been eliminated.[12]

The diagnosis of idiopathic pulmonary fibrosis now requires the following:[1]

Histologic Findings

The histopathological lesion associated with idiopathic pulmonary fibrosis is usual interstitial pneumonia. Usual interstitial pneumonia is characterized by a heterogeneous, variegated appearance with alternating areas of healthy lung, interstitial inflammation, fibrosis, and honeycomb change, which results in a patchwork appearance at low magnification (see image below).[15]


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Patchwork distribution of abnormalities in a classic example of usual interstitial pneumonia (low-magnification photomicrograph; hematoxylin and eosin....

Fibrosis predominates over inflammation in usual interstitial pneumonia. Fibroblastic foci represent microscopic zones of acute lung injury and are randomly distributed within areas of interstitial collagen deposition and consist of fibroblasts and myofibroblasts arranged in a linear fashion within a pale-staining matrix.[15] Although fibroblastic foci are not specific for usual interstitial pneumonia, they represent an important diagnostic criterion.

Another important diagnostic criterion for usual interstitial pneumonia is honeycomb change. Microscopically, honeycomb change is defined by cystically dilated bronchioles lined by columnar respiratory epithelium in scarred, fibrotic lung tissue.[15] Dense eosinophilic collagen without associated honeycomb change signifies fibrotic scars and is also characteristic of usual interstitial pneumonia. Interstitial inflammation, consisting of patchy alveolar septal infiltrates of mononuclear cells, is not predominant in usual interstitial pneumonia.

The usual interstitial pneumonia histologic pattern can be associated with other diseases besides idiopathic pulmonary fibrosis. These include asbestosis, collagen-vascular disease, fibronodular sarcoidosis, hypersensitivity pneumonitis, and toxic drug reactions (eg, to amiodarone, bleomycin, or nitrofurantoin). Correlation with clinical history is needed to identify these conditions.

In pathology specimens taken during acute exacerbations of idiopathic pulmonary fibrosis, microscopy reveals a combination of usual interstitial pneumonia with superimposed diffuse alveolar damage. Alveolar septa are expanded by more extensive fibroblast proliferation than is seen in conventional fibroblast foci. Additionally, marked hyperplasia of type 2 pneumocytes and hyaline membrane remnants is present.[15]

The following are histopathological criteria for UIP pattern:[1]

UIP pattern requires all 4 criteria below.

Probable UIP pattern requires the following:

OR

Possible UIP pattern requires all 3 criteria below.

Not UIP pattern requires any of the 6 criteria below.

A patient with possible UIP pattern on HRCT and UIP pattern or probable UIP pattern on surgical lung biopsy is consistent with the diagnosis of idiopathic pulmonary fibrosis. However, a patient with possible UIP pattern on HRCT and possible UIP pattern or nonclassifiable fibrosis on surgical lung biopsy is consistent with the diagnosis of probable idiopathic pulmonary fibrosis.[1]

A patient with a pattern inconsistent with UIP on HRCT and UIP pattern on surgical lung biopsy is consistent with the diagnosis of possible UIP. However, a patient with a pattern inconsistent with UIP on HRCT and probable UIP, possible UIP, or nonclassifiable fibrosis on surgical lung biopsy is not consistent with the diagnosis of idiopathic pulmonary fibrosis.[1]

Any pattern on HRCT associated with a surgical lung biopsy finding of not UIP is not consistent with the diagnosis of idiopathic pulmonary fibrosis.[1]

Multidisciplinary discussion amongst pulmonologists, radiologists, and pathologists experienced in the diagnosis of ILD is of the utmost importance to an accurate diagnosis.[1]

Medical Care

The goal of any disease management strategy should include assessment and treatment of comorbid medical conditions. Common comorbid medical conditions found in patients with idiopathic pulmonary fibrosis (IPF) include chronic obstructive pulmonary disease, obstructive sleep apnea, gastroesophageal reflux disease, and coronary artery disease. Therefore, if any of these comorbid illnesses are present, they should be managed according to current practice guidelines.

Given the high prevalence of gastroesophageal reflux (GER) in patients with IPF, a retrospective study was conducted to investigate the relationship of reflux-related variables and survival time in patients with IPF. Of the 204 included patients, 34% reported symptoms of GER, 45% had a history of GER disease, 47% reported use of medications for GER, and 5% of patients had previously undergone Nissen fundoplication. On adjusted analysis, the use of GER medications was associated with a longer survival time. Additionally, patients taking GER medications had a lower fibrosis score on HRCT.[37]

Any patient with idiopathic pulmonary fibrosis who is a current smoker should be encouraged to quit and offered pharmacologic therapy if needed.

Patients with hypoxemia (PaO2 < 55 mmHg or oxygen saturation as measured using pulse oximetry [SpO2] < 88%) at rest or with exercise should be prescribed oxygen therapy to maintain a saturation of at least 90% at rest, with sleep, and with exertion.

Vaccination against influenza and pneumococcal infection should be encouraged in all patients with idiopathic pulmonary fibrosis.

See Medication for a discussion of the various drugs, experimental and otherwise, used in the treatment of idiopathic pulmonary fibrosis.

Surgical Care

Lung transplantation for idiopathic pulmonary fibrosis has been shown to confer a survival benefit over medical therapy. In May 2005, the lung allocation score (LAS) was implemented, which dramatically changed lung allocation from a system based purely on waiting time to an algorithm based on survival probability on the waiting list and after lung transplantation.[38] Therefore, the LAS is used to prioritize patients based on the difference between post-transplant 1-year survival and pre-transplant urgency. Consequent to the use of LAS, idiopathic pulmonary fibrosis has now replaced chronic obstructive pulmonary disease as the most common indication for lung transplantation in the United States.[39]

Any patient diagnosed with idiopathic pulmonary fibrosis or probable idiopathic pulmonary fibrosis should be referred for lung transplantation evaluation, regardless of the vital capacity.[11] After a patient is referred for transplantation evaluation, the appropriate timing to list a patient on the lung transplantation list needs to be determined. Guidelines for listing a patient with idiopathic pulmonary fibrosis include a diffusion capacity of carbon monoxide (DLCO) less than 39% predicted, a 10% or greater decrement in forced vital capacity during six months of follow-up, a decrease in pulse oximetry below 88% during a 6-minute walk test (6MWT), or honeycombing on high-resolution computed tomography (HRCT) imaging (fibrosis score >2).[11]

A 2009 retrospective review of the United Network for Organ Sharing data to identify lung transplant recipients with idiopathic pulmonary fibrosis between 2005 and 2007 examined risk for 30-day, 90-day, and 1-year mortality for single lung transplant versus bilateral lung transplant. Data were examined across levels of the LAS (quartile 1, quartile 2, quartile 3, and quartile 4).

Patients in LAS quartile 4 were defined as high risk. A clear inverse relationship between wait-list times and LAS was seen, with a higher LAS score associated with shorter wait-list times.[39] Patients in the LAS quartile 4 had a 7.1% lower cumulative survival at 1 year when compared with patients in quartiles 1 to 3. Just over 21% more patients received bilateral lung transplantation in the highest LAS quartile than in the lowest LAS quartile. In the high-risk quartile, bilateral lung transplantation was associated with a 14.4% decrease in mortality 1 year after lung transplantation.[39] However, this study is limited by the retrospective nature and the need to see if these trends persist at 3 years and 5 years. The reported 5-year survival rates after lung transplantation in idiopathic pulmonary fibrosis are estimated at 50-56%.[1]

Consultations

Any patient suspected of having idiopathic pulmonary fibrosis, interstitial lung disease, or any another idiopathic interstitial pneumonia should be referred to a pulmonologist for further evaluation and management. Any patient diagnosed with idiopathic pulmonary fibrosis or probable idiopathic pulmonary fibrosis should be referred for lung transplantation evaluation, regardless of the vital capacity unless there are contraindications for transplantation.[11]

Diet

Any patient with idiopathic pulmonary fibrosis who is overweight should be encouraged to meet with a nutritionist and make dietary changes to achieve ideal body weight. Maintaining adequate nutritional intake is important for quality of life in patients with idiopathic pulmonary fibrosis.

Activity

Improving quality of life is an important goal in disease management. Deconditioning and subsequent functional impairment is a common problem in patients with idiopathic pulmonary fibrosis and negatively impacts quality of life. Two controlled trials of pulmonary rehabilitation in idiopathic pulmonary fibrosis have demonstrated an improvement in walk distance and symptoms or quality of life.[1] Therefore, patients with idiopathic pulmonary fibrosis should be evaluated for pulmonary rehabilitation and encouraged to participate in regular exercise to maintain a maximal degree of musculoskeletal conditioning.[5]

Medication Summary

The previous theory regarding the pathogenesis of idiopathic pulmonary fibrosis was that generalized inflammation progressed to widespread parenchymal fibrosis. It was believed that an unidentified insult to the alveolar wall initiated a cycle of chronic alveolar inflammatory injury (alveolitis) leading to fibrosis.[40] Based on this pathogenetic concept, anti-inflammatory agents and immune modulators were used to treat idiopathic pulmonary fibrosis (IPF). However, it is currently believed that idiopathic pulmonary fibrosis is an epithelial-fibroblastic disease, in which unknown endogenous or environmental stimuli disrupt the homeostasis of alveolar epithelial cells, resulting in diffuse epithelial cell activation and aberrant epithelial cell repair.[16] The recognition of new factors contributing to the pathogenesis of idiopathic pulmonary fibrosis has led to the development of novel approaches to treat idiopathic pulmonary fibrosis.

The optimal medical therapy for the treatment of idiopathic pulmonary fibrosis has yet to be identified. Therefore, in selecting patients for treatment, careful consideration should be paid to the risk-to-benefit ratio. Evidence-based guidelines for the diagnosis and management of idiopathic pulmonary fibrosis did not find sufficient evidence to support the use of any specific pharmacologic therapy for patients with idiopathic pulmonary fibrosis.[1] Patients should understand the risk of adverse effects from treatment along with any potential merits of therapy before deciding on a course of action. Pros, cons, risks, benefits, and alternatives must be discussed in a comprehensive fashion.

Antioxidants

An oxidant-antioxidant imbalance may contribute to the pathogenesis of idiopathic pulmonary fibrosis. Therefore, a double-blind, randomized, placebo-controlled trial in 155 subjects with idiopathic pulmonary fibrosis was completed to test the hypothesis that high dose (600 mg PO tid) N -acetylcysteine (NAC), administered over a period of 1 year in addition to prednisone and azathioprine, would slow functional deterioration in patients with idiopathic pulmonary fibrosis.[41] No true placebo group was included in that subjects in the placebo group received prednisone and azathioprine. The study showed that NAC, added to prednisone and azathioprine, significantly slowed the rate of deterioration of vital capacity and DLCO at 12 months. However, this did not translate into a survival benefit . Additionally, a significantly lower rate of myelotoxic effects was noted in the group taking NAC.[41]

The PANTHER-IPF trial was initiated by the Idiopathic Pulmonary Fibrosis Network. This blinded, randomized, placebo-controlled trial was designed to determine whether azathioprine and oral corticosteroids and/or NAC slow the rate of disease progression in idiopathic pulmonary fibrosis.[5] Patients with mild-to-moderate lung function impairment were assigned to 1 of 3 groups, receiving a combination of prednisone, azathioprine, and NAC; NAC alone; or placebo alone in a 1:1:1 ratio.[42]

In October 2011, when approximately 50% of the data had been collected, an announcement was made that 1 of the 3 arms was stopped. This arm was comparing triple-drug therapy (azathioprine, prednisone, NAC) to placebo. The interim results showed that compared with placebo, those assigned to triple-drug therapy had greater mortality (11% vs 1%), more hospitalizations (29% vs 8%), more serious adverse events (31% vs 9%), and remained on the assigned treatment at a much lower rate (78% vs 98%).[42] The other 2 study arms, comparing NAC alone to placebo alone, have continued.[43]

Evidence-based guidelines recommend that the majority of patients with IPF should not be treated with N-acetylcysteine monotherapy, however, this therapy may be a reasonable choice in a minority of patients.

Biological response modulators

Elevated levels of tumor necrosis factor (TNF)–α, a cytokine with inflammatory and fibrogenic properties, have been detected in the lungs of animals in experimental models of pulmonary fibrosis and in patients with idiopathic pulmonary fibrosis.[44] Etanercept is a recombinant soluble human TNF receptor that binds to TNF and neutralizes its activity.

To investigate the potential efficacy of etanercept as therapy for idiopathic pulmonary fibrosis, a multicenter, double-blind, randomized, placebo-controlled trial was conducted. Patients with idiopathic pulmonary fibrosis were randomized to receive subcutaneous etanercept (25 mg twice weekly) or placebo as their sole treatment for idiopathic pulmonary fibrosis.

At the conclusion of the 48-week trial, no differences were noted in the predefined endpoints between the etanercept group and the placebo group.[45] Therefore, it was a negative study. An explanation for the negative results could simply be due to the small sample size (88 patients) and inadequate power of the trial to detect a significant difference. Evidence-based guidelines recommend that patients with idiopathic pulmonary fibrosis should not be treated with etanercept.[1]

Interferon-γ is an endogenously produced cytokine with diverse properties, including antifibrotic, antiinfective, antiproliferative, and immunomodulatory effects. In vitro, exogenous interferon-γ therapy inhibits the expression of profibrotic cytokines, enhances the activation of macrophages and killing of ingested bacteria, shifts the T-cell response toward a macrophage-dominated inflammatory response, and up-regulates the expression of antimicrobial peptides by alveolar macrophages and monocytes.[44] It was hypothesized that interferon-γ1b therapy may influence the course of idiopathic pulmonary fibrosis through antifibrotic, anti-inflammatory, or antiinfective effects.

In 2004, the results of a double-blind, randomized, placebo-controlled trial that assigned 330 patients with idiopathic pulmonary fibrosis unresponsive to corticosteroid therapy to receive subcutaneous interferon-γ1b (200 µg 3 times per wk) or placebo, were reported. Over a median of 58 weeks, interferon-γ1b therapy did not significantly affect progression-free survival, pulmonary function, or quality of life.[44] However, a trend toward enhanced survival was noted in all randomized patients who were treated with interferon-γ1b, which was more pronounced in patients who adhered to treatment.[44]

In 2009, the results of a multicenter, double-blind, randomized, placebo-controlled trial, which was designed to assess the effect of interferon-γ1b on survival in patients with idiopathic pulmonary fibrosis and mild-to-moderate impairment in baseline pulmonary function, were reported.[46] Eligible patients were aged 40-79 years, had been diagnosed in the past 48 months, had a forced vital capacity of 55-90% of the predicted value, and DLCO of 35-90% of the predicted value. Patients were randomly assigned to receive 200 µg interferon-γ1b (n = 551) or equivalent placebo (n = 275) subcutaneously 3 times per week.[46]

At the second interim analysis (median treatment duration of 64 wk), 15% of patients on interferon-γ1b and 13% of patients on placebo had died. Interferon-γ1b did not improve survival in patients with mild-to-moderate idiopathic pulmonary fibrosis.[46] Therefore, treatment of idiopathic pulmonary fibrosis with interferon-γ1b is not currently recommended.[1]

Endothelin receptor antagonists

Endothelin-1 is a potent, endogenous vasoconstrictor that is implicated in the pathophysiology of pulmonary arterial hypertension. Additionally, endothelin-1 is a profibrotic molecule that can modulate matrix production and turnover, resulting in increased collagen synthesis and decreased collagenase production.[47] Bosentan, an endothelin receptor A and B antagonist is approved for the treatment of pulmonary hypertension. Bosentan has been shown to have antifibrotic effects in an animal model of pulmonary fibrosis.[5]

The BUILD-1 trial, a randomized, placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis, was designed to evaluate the efficacy, safety, and tolerability of bosentan in patients with idiopathic pulmonary fibrosis. The primary objective was to evaluate the effect of bosentan on 6-minute walk distance.[47] Patients with idiopathic pulmonary fibrosis were randomized to receive bosentan (n = 74) at 62.5 mg twice daily for 4 weeks, increased to 125 mg twice daily thereafter, or placebo (n = 84), for 12 months or longer.[47]

Bosentan showed no superiority over placebo in 6-minute walk distance up to month 12. In analyzing secondary endpoints, a trend was noted that favored the bosentan group in terms of time to disease progression, dyspnea assessments, and quality-of-life assessments. These benefits were more pronounced in the subgroup of patients that underwent surgical lung biopsy.[47]

Based on these results, investigators pursued a follow-up phase III study (BUILD-3) of greater power, with the primary objective to demonstrate that bosentan delays disease worsening or death in patients with idiopathic pulmonary fibrosis.[5] The study included 616 patients with a proven diagnosis of idiopathic pulmonary fibrosis , of less than 3 years duration, who underwent a surgical lung biopsy. The primary end-point was not met. Currently, evidence-based guidelines recommend that patients with idiopathic pulmonary fibrosis should not be treated with bosentan.[1]

Phosphodiesterase inhibitors

Sildenafil, a phosphodiesterase-5 inhibitor, leads to pulmonary vasodilatation by stabilizing cyclic guanosine monophosphate, the second messenger of nitric oxide. It is hypothesized that sildenafil, through pulmonary vasodilation, would improve ventilation-perfusion matching and thus gas exchange in patients with idiopathic pulmonary fibrosis.

To assess the potential efficacy of sildenafil in the treatment of idiopathic pulmonary fibrosis, a multicenter, double-blind, randomized, placebo-controlled trial was conducted. One hundred and eighty patients were enrolled in the study.[48] Patients with advanced idiopathic pulmonary fibrosis (diffusing capacity less than 35% of predicted value) were randomly assigned to receive sildenafil (20 mg tid) or matched placebo over 12 weeks. The primary outcome was the presence or absence of an improvement of at least 20% in the 6MWT at 12 weeks, as compared with baseline.

At the conclusion of the 12-week study period, no significant difference was noted in the proportion of patients with an improvement of 20% or more in the 6MWT in patients taking sildenafil compared with those taking placebo. However, statistically significant differences in the change in dyspnea, PaO2, diffusing capacity, and quality of life favoring sildenafil were noted. The presence of these positive secondary outcomes may stimulate further research.[48]

Tyrosine kinase inhibitors

In October 2014, the FDA approved nintedanib (Ofev) for treatment of idiopathic pulmonary fibrosis. Approval was based on conducted 2 replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2). Each trial showed a statistically significant improvement in FVC compared with placebo (P = 0.001).[49] Nintedanib was associated with the development of diarrhea; however, it led to discontinuation of the medication in less than 5% of the patients.[49]

A 12-month, phase 2 trial, completed by Richeldi and colleagues assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor nintedanib (formerly BIBF 1120) compared to placebo in patients with IPF. Nintedanib targets platelet-derived growth factor receptors α and β, vascular endothelial growth factor receptors 1, 2, and 3, and fibroblast growth factor receptors 1, 2 and 3. The primary end point was the annual rate of decline of FVC.

A total of 432 patients were randomly assigned to receive one of four doses of nintedanib (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In patients receiving 150 mg twice daily, there was a trend toward a reduction in the decline of lung function when compared to placebo. The annual rate of decline in FVC was 0.06 liters in those taking 150 mg twice daily compared to 0.19 liters in the placebo group (P = 0.06 with the closed testing for multiplicity).

In regards to secondary end points the incidence of acute exacerbations of IPF was lower in the group receiving nintedanib at 150 mg twice daily compared to placebo (2.4 versus 15.7 per 100 patient years, P = 0.02). The highest proportion of patients who discontinued the study medication because of adverse events was those subjects taking 150 mg twice daily. The adverse events most frequently leading to discontinuation include diarrhea, nausea, and vomiting. Overall, the phase 2 study revealed an acceptable safety profile and potential clinical benefits of treatment with nintedanib 150 mg twice daily thus warranting phase 3 clinical investigations.[50]

Imatinib mesylate is a tyrosine kinase inhibitor with activity against the platelet-derived growth factor receptors (PDGFRs), discoidin domain receptors, c-kit, and c-Abl. The proliferative activities of PDGFRs and other tyrosine kinases in idiopathic pulmonary fibrosis pathogenesis led to in vivo and in vitro investigations to assess imatinib as a potential inhibitor of lung fibrosis.[51] Imatinib was identified as a potent inhibitor of lung fibroblast-myofibroblast transformation and proliferation, as well as extracellular matrix production through inhibition of platelet-derived growth factor and transforming growth factor-β signaling.[51] Based on these data, a randomized, double-blind, placebo-controlled trial to investigate the safety and clinical effects of imatinib on survival and lung function in patients with mild-to-moderate idiopathic pulmonary fibrosis was conducted.

Subjects were randomized to imatinib (n = 60) at 600 mg orally once daily or placebo (n = 61) for 96 weeks. At 96 weeks, no effect from imatinib therapy was noted on change in forced vital capacity, DLCO, resting PaO2, or time to disease progression.[51] One potential limitation of the trial is that a 30%-per-year and a 51%-over-2-years placebo event rate was anticipated. The actual placebo event rate was 31.7% and suggests the study may be underpowered to detect a difference between the groups.[51]

Antifibrotic agents

The FDA approved pirfenidone (Esbriet) for the treatment of IPF in October 2014. Approval was based on the ACSEND and CAPACITY 1 and 2 trials. Pirfenidone slowed the decline and in some patients halted the decline of FVC and improved progression-free survival.[52, 53]

Experimental models of idiopathic pulmonary fibrosis revealed that pirfenidone, a novel compound with combined anti-inflammatory, antioxidant, and antifibrotic effects, had potential therapeutic benefits for idiopathic pulmonary fibrosis.[54] A randomized, double-blind, placebo-controlled trial of 10 patients with idiopathic pulmonary fibrosis evaluated the efficacy of pirfenidone. Patients were randomized to pirfenidone (n = 72) at 1800 mg orally per day or placebo (n = 35).

The primary endpoint was defined as the change in the lowest SpO2 during a 6-minute steady-state exercise test. The secondary endpoints were changes in resting pulmonary function test results, disease progression by HRCT patterns, episodes of acute exacerbations of idiopathic pulmonary fibrosis, change in serum markers of pneumocyte damage, and changes in quality-of-life measurements.[54] No significant treatment effect in the primary endpoint was noted. Positive treatment effects were demonstrated in the secondary endpoints of change in vital capacity measurement at 9 months and acute exacerbations of idiopathic pulmonary fibrosis occurring exclusively in the placebo group during 9 months.[54] This study prompted additional studies to evaluate the efficacy and safety of pirfenidone in idiopathic pulmonary fibrosis.

A phase III clinical trial in Japan, which was a multicentered, double-blind, placebo-controlled, randomized trial that examined the use of pirfenidone.[55] Two-hundred and seventy-five Japanese patients with idiopathic pulmonary fibrosis were randomized to high-dose pirfenidone (n = 108; 1800 mg/d PO), low-dose pirfenidone (n = 55; 1200 mg/d PO), or placebo (n = 104). The primary endpoint was a change in vital capacity from baseline to week 52. Secondary endpoints were progression-free survival time and the change in the lowest SpO2 during a 6-minute steady-state exercise test.[55]

Significant differences were observed in the decline of vital capacity between the placebo group (-0.16 L) and the high-dose pirfenidone group (-0.09 L). Additionally, a significant improvement was noted in progression-free survival time in the high-dose pirfenidone group compared with the placebo group.[55] The results of this study led to regulatory approval of pirfenidone in Japan for the treatment of IPF.

The Clinical Studies Assessing Pirfenidone in IPF: Research of Efficacy and Safety Outcomes (CAPACITY) program conducted 2 multinational trials to evaluate the change in percentage predicted FVC at week 72.[52] All patients enrolled in both studies had mild to moderate IPF. In study 004, 435 subjects were randomized to a pirfenidone dose of 2403 mg/d (n = 174), a pirfenidone dose of 1197 mg/d (n = 87), or placebo (n = 174). At week 72, a significant reduction in decline of FVC was noted in the group assigned to a pirfenidone dose of 2403 mg/d (-8%) compared to placebo (-12.4%).

In study 006, 344 subjects were randomized to a pirfenidone dose of 2403 mg/d (n = 171) or placebo (n = 173). At week 72, no significant reduction in decline of FVC in the pirfenidone group (-9%) was found compared with placebo (-9.6%).[52]

When data from both studies were pooled together comparing a pirfenidone dose of 2403 mg/d to placebo, a significant reduction in decline of FVC was noted in the pirfenidone group (-8.5%) compared with placebo (-11%). Additionally, in the pooled analysis, pirfenidone prolonged progression-free survival by 26% compared with placebo. Finally, in the pooled analysis, pirfenidone reduced the proportion of patients with a 10% or more decline in FVC by 30% compared with placebo.[52]

In February 2014, InterMune released preliminary data from the Phase 3 ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in IPF) trial.[56] The study was a multinational, randomized, double-blind placebo-controlled Phase 3 trial to evaluate the safety and efficacy of pirfenidone in patients with IPF. Patients (N=555) were randomly assigned 1:1 to receive oral pirfenidone (2403 mg/day) or placebo and were enrolled at 127 centers in the United States, Australia, Brazil, Croatia, Israel, Mexico, New Zealand, Peru and Singapore.

The primary endpoint was comparing the proportion of patients in the pirfenidone and placebo groups experiencing either a clinically significant change in FVC or death. At week 52, 16.5% of patients in the pirfenidone group experienced an FVC decline of 10% or more or death, compared with 31.8% in the placebo group. Additionally, at week 52 the data demonstrated that 22.7% of patients in the pirfenidone group experienced no decline in FVC, compared with 9.7% in the placebo group. Pirfenidone alos improved progression-free survival and reduced the decline in the 6-minute walk distance. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to discontinuation of treatment.[53]

Currently, evidence-based guidelines recommend that most patients with IPF should not be treated with pirfenidone and that this therapy may be a reasonable choice in a minority of patients.[1] However, with the new data available from the CAPACITY program trials and the ASCEND trial, pirfenidone has a favorable benefit-risk profile and now represents a treatment option for patients with IPF which has been approved by the FDA.[52]

Colchicine

Colchicine has been shown to inhibit fibroblast proliferation and collagen synthesis in vitro. Several prospective clinical trials have compared colchicine with various treatment regimens showing no difference in clinical outcomes. Evidence-based guidelines recommend that patients with idiopathic pulmonary fibrosis should not be treated with colchicine.[1]

Anticoagulants

Coagulation cascade is important in IPF. A study was designed to test the hypothesis that warfarin, targeting an international normalized ratio of 2-3, in patients with IPF would reduce mortality, rates of hospitalization, and decline in FVC. Patients with a current indication for, or active treatment with, warfarin were excluded.[57]

Subjects were randomized in a 1:1 ratio to receive warfarin (72 subjects) or placebo (73 subjects). Due to excess mortality in subjects randomized to warfarin (14 deaths) versus placebo (3 deaths) an independent Data and Safety Monitoring Board recommended stopping the study after 145 of the planned 256 subjects were enrolled.[57]

Nintedanib (Ofev)

Clinical Context:  Nintedanib inhibits multiple tyrosine kinases and targets growth factors, which have been shown to be potentially involved in pulmonary fibrosis (eg, vascular endothelial growth factor receptor [VEGFR], fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor [PDGF]. Binds competitively to the adenosine triphosphate (ATP)-binding pocket of these receptors and blocks the intracellular signaling, which is crucial for the proliferation, migration, and transformation of fibroblasts, representing essential mechanisms of the IPF pathology.

Class Summary

Inhibition of various tyrosine kinases decreases the proliferative activities that lead to fibrosis.

Pirfenidone (Esbriet)

Clinical Context:  Precise mechanism by which pirfenidone may work in pulmonary fibrosis has not been established. It inhibits transforming growth factor (TGF)-beta, a chemical mediator that controls many cell functions including proliferation and differentiation. It also inhibits the synthesis of TNF-alpha, a cytokine that is known to have an active role in inflammation.

Class Summary

Reduction of fibroblast proliferation may decrease formation and/or accumulation of fibrotic materials within the lungs.

Prednisone (Sterapred)

Clinical Context:  Metabolized in the liver to its active form, prednisolone. Corticosteroids, including prednisone, prevent or suppress inflammation and immune responses when administered at pharmacological doses. At a molecular level, unbound corticosteroids readily cross cell membranes and bind with high affinity to specific cytoplasmic receptors. This binding induces a response by modifying transcription and, ultimately, protein synthesis, to achieve the steroid's intended action. Such actions may include inhibition of leukocyte infiltration at the site of inflammation, interference in the function of mediators of the inflammatory response, and suppression of humoral immune responses.

Initial response should occur within 3 mo of initiating corticosteroid therapy. Improvement in objective parameters such as HRCT imaging, pulmonary function tests, 6MWT, and/or dyspnea scores should be monitored when deciding if additional therapy with prednisone is warranted.

Class Summary

In some older observational studies, in which the definition of idiopathic pulmonary fibrosis was less specific, corticosteroids alone had positive effects on spirometry and gas exchange in approximately 15-30% of patients. Many investigators believe that this subgroup of responders did not have idiopathic pulmonary fibrosis, but instead had nonspecific interstitial pneumonia.

Corticosteroids have not been evaluated in a randomized, placebo-controlled trial to determine their benefit in treating patients with idiopathic pulmonary fibrosis. Retrospective uncontrolled studies have reported no survival benefits. Latent tuberculosis should be excluded before patients are started on corticosteroid therapy.

Evidence-based guidelines recommend that patients with idiopathic pulmonary fibrosis should not be treated with corticosteroid monotherapy.

Azathioprine (Imuran)

Clinical Context:  Decreases metabolism of purines and may also inhibit DNA and RNA synthesis. Also may integrate into nucleic acids, resulting in chromosome breakage, nucleic acid malfunction, or synthesis of faulty proteins. May interfere with coenzyme functioning, thereby decreasing cellular metabolism, and may inhibit mitosis. Effects may decrease proliferation of immune cells and result in lower autoimmune activity.

Cyclophosphamide (Cytoxan)

Clinical Context:  Prodrug that requires hepatic activation in order to be cytotoxic. Phosphoramide mustard and acrolein are formed following hepatic and cellular activation. Phosphoramide mustard is the active alkylating moiety responsible for the cytotoxic effects. As with other bifunctional alkylating agents, phosphoramide mustard forms intrastrand and interstrand DNA-DNA cross-links, which are responsible for inactivation of DNA. Also has immunosuppressant effects. Causes lymphopenia (both B and T cells) and selective suppression of B-lymphocyte activity.

Class Summary

Corticosteroids and immunomodulator agents (azathioprine or cyclophosphamide) had not been previously evaluated in randomized, placebo-controlled trials to determine their benefit in treating patients with idiopathic pulmonary fibrosis.

The PANTHER-IPF trial was initiated by the Idiopathic Pulmonary Fibrosis Network. This blinded, randomized, placebo-controlled trial was designed to determine whether azathioprine and oral corticosteroids and/or NAC slow the rate of disease progression in IPF. Patients with mild-to-moderate lung function impairment were assigned to one of three groups, receiving a combination of prednisone, azathioprine, and NAC; NAC alone; or placebo alone in a 1:1:1 ratio.

In October 2011, when approximately 50% of the data had been collected, an announcement was made that one of the three arms was stopped. This arm was comparing triple-drug therapy (azathioprine, prednisone, NAC) to placebo. The interim results showed that compared with placebo, those assigned to triple-drug therapy had greater mortality (11% vs 1%), more hospitalizations (29% vs 8%), more serious adverse events (31% vs 9%), and remained on the assigned treatment at a much lower rate (78% vs 98%). The other two study arms, comparing NAC alone to placebo alone, have continued.

Further Inpatient Care

The clinical course of patients with idiopathic pulmonary fibrosis is generally marked by a decline in pulmonary function over time. Increasingly, patients have been recognized as having an acute, and often fatal, clinical deterioration, termed an acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF).

The following are diagnostic criteria for an AE-IPF:[58]

Patients with idiopathic pulmonary fibrosis who develop an acute clinical deterioration often require hospitalization. These patients should undergo HRCT imaging of the chest to document the interval development of significant ground-glass opacities, which are suggestive of an AE-IPF. Additionally, a BAL should be completed to examine the possibility of infectious etiologies. Support with supplemental oxygen should be given to alleviate hypoxemia.[58]

Once infection has been acceptably ruled out and other alternative causes of the acute deterioration have been excluded, treatment with intravenous methylprednisolone (Solu-Medrol) at 2 mg/kg/d for 2 weeks followed by a prolonged taper can be given.[58] However, no randomized controlled trials support a particular therapy for an AE-IPF. If a patient with an AE-IPF develops respiratory failure and requires invasive mechanical ventilation, plateau pressures should be maintained at less than 30 cm water.[58] Patients with idiopathic pulmonary fibrosis who require mechanical ventilation have a poor prognosis.

In a retrospective review, of 461 patients with idiopathic pulmonary fibrosis, 20.8% of all subjects experienced an AE-IPF during the median follow-up period of 22.9 months. Approximately 50% of patients hospitalized for an AE-IPF died during the hospitalization. The 1-year and 5-year survival rates from the initial diagnosis of an AE-IPF were 56.2% and 18.4%, respectively.[59] Therefore, an acute exacerbation of idiopathic pulmonary fibrosis has a serious impact on the overall survival of patients with idiopathic pulmonary fibrosis.

Further Outpatient Care

The rate of decline and progression to death in patients with idiopathic pulmonary fibrosis may take several clinical forms, including slow physiologic deterioration with worsening severity of dyspnea, rapid deterioration and progression to death, or periods of relative stability interposed with periods of acute respiratory decline sometimes manifested by hospitalizations for respiratory failure.[13] Therefore, all patients with idiopathic pulmonary fibrosis should be seen by a pulmonologist on a regular basis for a complete history and physical examination. Patients must undergo disease-specific monitoring with serial assessments of lung physiology, gas exchange, exercise performance, and HRCT to further refine prognosis and management decisions. Patients must be asked about adverse medication effects.

Any patient with idiopathic pulmonary fibrosis who is a current smoker should be encouraged to quit and offered pharmacologic therapy if needed.

Vaccination against influenza and pneumococcal infection should be encouraged in all patients with idiopathic pulmonary fibrosis.

Patients with idiopathic pulmonary fibrosis should be evaluated for pulmonary rehabilitation and should be encouraged to participate in regular exercise to maintain a maximal degree of musculoskeletal conditioning.

Transfer

Lung transplantation for idiopathic pulmonary fibrosis has been shown to confer a survival benefit over medical therapy. Any patient diagnosed with idiopathic pulmonary fibrosis or probable idiopathic pulmonary fibrosis should be referred to a lung transplantation center for lung transplant evaluation, regardless of the vital capacity unless contraindications for transplantation exist.[11]

Patients with idiopathic pulmonary fibrosis should be referred to institutions where they can be counseled regarding enrollment in a trial of an investigational agent for the treatment of idiopathic pulmonary fibrosis.

Complications

The following are complications that can be seen in patients with idiopathic pulmonary fibrosis:

Prognosis

A worse prognosis can be expected based on various clinical parameters, physiologic factors, radiographic findings, histopathologic findings, laboratory findings, and bronchoalveolar lavage findings. du Bois et al evaluated a scoring system to predict individual risk of mortality. They used a Cox proportional hazards model and data from two clinical trials (n = 1,099) to identify independent predictors of 1-year mortality among patients with IPF. The findings demonstrated that 4 readily ascertainable predictors (age, history of respiratory hospitalization within the previous 24 weeks, percent predicted FVC, and 24-week change in FVC) could be used in a scoring system to estimate 1-year mortality. However, this scoring system needs to be validated in other populations of patients with IPF.[60]

Ley et al used competing risks regression modeling to retrospectively screen potential predictors of mortality in a derivation cohort of patients with IPF (n = 228). They identified a model consisting of 4 predictors (sex, age, % predicted FVC, and % predicted DLCO). Based on these 4 predictors, they developed a simple point-score model and staging system that was retrospectively validated in a separate cohort of patients with IPF (n = 330).[61]

Table 1. Scoring for mortality risk in IPF.


View Table

See Table

Table 2. Staging and mortality risk for IPF.


View Table

See Table

The authors believe that the index and staging system provide clinicians with a framework for discussing prognosis, policy-makers with a tool for investigating stage-specific management options, and researchers with the ability to identify at-risk study populations that maximize the efficiency and power of clinical trials.[61]

Patients with idiopathic pulmonary fibrosis who have concomitant pulmonary hypertension have more dyspnea, greater impairment of their exercise capacity, and increased 1-year mortality compared with their counterparts without pulmonary hypertension.[5] Additionally, a multicenter prospective cohort study of 126 lung transplant procedures performed for idiopathic pulmonary fibrosis revealed elevated pulmonary artery pressure as a risk factor for primary graft dysfunction (PGD) following lung transplantation.[62] The mean pulmonary artery pressure (mPAP) for patients with PGD following lung transplantation was 38.5 ± 16.3 mm Hg compared with a mPAP of 29.6 ± 11.5 mm Hg in patients without PGD following lung transplantation.

Patients with IPF pattern on HRCT imaging have a worse prognosis compared with patients with biopsy-proven usual interstitial pneumonia and atypical changes of idiopathic pulmonary fibrosis on HRCT imaging.[30, 13]

Patients who have a greater than 10% decline in forced vital capacity (FVC) (percent predicted) over 6 months have a 2.4-fold increased risk of death. Additionally, in patients who do not desaturate to less than 88% during a 6-minute walk test (6MWT), the only strong predictor of mortality is a progressive decline in FVC (>10% after 6 mo).[31]

A baseline diffusion capacity of carbon monoxide (DLCO) below 35% is correlated with increased mortality. Additionally, a decline in DLCO greater than 15% over 1 year is also associated with increased mortality.[31]

Desaturation below the threshold of 88% during the 6MWT has been associated with an increased mortality.[31] Additionally, in patients with idiopathic pulmonary fibrosis who desaturate to less than 88% during a 6MWT, a progressive decline in DLCO (>15% after 6 mo) is a strong predictor of mortality.[9]

BAL fluid neutrophilia has been demonstrated to predict early mortality. One study demonstrated a linear relationship between increasing neutrophil percentage and the risk of mortality. Each doubling in baseline BAL fluid neutrophil percentage was associated with a 30% increased risk of death or transplantation in the first year after presentation.[36]

Serum surfactant protein A (SP-A) is a member of the collectin family. SP-A is secreted by type II pneumocytes, and the level of SP-A appears to be increased early after breakdown in the alveolar epithelium. SP-A has been shown to be present in abnormal amounts in the BAL fluid of patients with idiopathic pulmonary fibrosis.[63] In a cohort study, after controlling for known clinical predictors of mortality, each increase of 49 ng/mL in baseline serum SP-A level was associated with a 3.3-fold increased risk of mortality in the first year after presentation.[63] Therefore, serum SP-A is independently and strongly associated with death or lung transplantation 1 year after presentation.[63]

Author

Amanda M K Godfrey, MD, Associate Staff, Department of Internal Medicine, IHA Pulmonary, Critical Care, and Sleep Consultants; Associate Staff, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, St Joseph Mercy Ann Arbor

Disclosure: Nothing to disclose.

Coauthor(s)

Daniel R Ouellette, MD, FCCP, Associate Professor of Medicine, Wayne State University School of Medicine; Chair of the Clinical Competency Committee, Pulmonary and Critical Care Fellowship Program, Senior Staff and Attending Physician, Division of Pulmonary and Critical Care Medicine, Henry Ford Health System; Chair, Guideline Oversight Committee, American College of Chest Physicians

Disclosure: Nothing to disclose.

Specialty Editors

Stephen P Peters, MD, PhD, FACP, FAAAAI, FCCP, FCPP, Thomas H Davis Chair in Pulmonary Medicine, Chief, Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases, Professor of Internal Medicine, Pediatrics, and Translational Science, Associate Director, Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine; Executive Director of the Respiratory Service Line, Wake Forest Baptist Medical Center

Disclosure: See below for list of all activities None None

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Daniel R Ouellette, MD, FCCP, Associate Professor of Medicine, Wayne State University School of Medicine; Chair of the Clinical Competency Committee, Pulmonary and Critical Care Fellowship Program, Senior Staff and Attending Physician, Division of Pulmonary and Critical Care Medicine, Henry Ford Health System; Chair, Guideline Oversight Committee, American College of Chest Physicians

Disclosure: Nothing to disclose.

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, St Louis University School of Medicine

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Chief Editor

Ryland P Byrd Jr, MD, Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Rajesh G. Patel, MD, and Javier I. Diaz, MD, to the development and writing of this article.

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Chest radiograph of a patient with idiopathic pulmonary fibrosis showing bilateral lower lobe reticular opacities (red circles).

Chest radiograph of a patient with idiopathic pulmonary fibrosis showing bilateral lower lobe reticular opacities (red circles).

Classic subpleural honeycombing (red circle) in a patient with a diagnosis of idiopathic pulmonary fibrosis.

A patient with IPF and a confirmed histologic diagnosis of usual interstitial pneumonia. Note the reticular opacities (red circle) distributed in both lung bases and the minimal ground-glass opacities (blue circle).

A patient with nonspecific interstitial pneumonia. Note the predominance of ground-glass opacities (blue circles) and a few reticular lines (red arrow).

Patchwork distribution of abnormalities in a classic example of usual interstitial pneumonia (low-magnification photomicrograph; hematoxylin and eosin stain; original magnification, X4). Courtesy of Chad Stone, MD.

Chest radiograph of a patient with idiopathic pulmonary fibrosis showing bilateral lower lobe reticular opacities (red circles).

Classic subpleural honeycombing (red circle) in a patient with a diagnosis of idiopathic pulmonary fibrosis.

A patient with IPF and a confirmed histologic diagnosis of usual interstitial pneumonia. Note the reticular opacities (red circle) distributed in both lung bases and the minimal ground-glass opacities (blue circle).

A patient with nonspecific interstitial pneumonia. Note the predominance of ground-glass opacities (blue circles) and a few reticular lines (red arrow).

Patchwork distribution of abnormalities in a classic example of usual interstitial pneumonia (low-magnification photomicrograph; hematoxylin and eosin stain; original magnification, X4). Courtesy of Chad Stone, MD.

PredictorPoints
SexFemale0
Male1
Age (years)≥600
61-651
>652
FVC (% predicted)>750
50-751
< 502
DLCO (% predicted)>550
36-551
≤352
Cannot perform3
StageIIIIII
Points0-34-56-8
Mortality
1-year5.616.239.2
2-year10.929.962.1
3-year16.342.176.8