AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease of unknown etiology characterized by a poor prognosis and no proven effective treatment. Of interest may be Medscape's CME course High-Resolution Chest Tomography in Idiopathic Pulmonary Fibrosis and Nonspecific Interstitial Pneumonia: Utility and Challenges.

IPF is the most common of the 7 idiopathic interstitial pneumonias classified by the American Thoracic Society/European Respiratory Society (ATS/ERS) consensus in 2002. Its pathogenesis remains unknown, but disordered fibroproliferation and alveolar epithelial cell function has been identified. The most common histologic pattern found in surgical lung biopsy specimens from patients with IPF is called usual interstitial pneumonia (UIP), making IPF and UIP interchangeable terms in most patients. See Table 1 below.

Clinical features consist of progressive dyspnea and/or nonproductive cough, diffuse interstitial infiltrates on chest radiographs, honeycombing on high-resolution  CT (HRCT) scans, and a restrictive impairment with reduced gas exchange on pulmonary function test results.

The definitive diagnosis should be made after a clinical, radiological, and pathological evaluation of the patient, and only after excluding other causes of interstitial lung disease.

Treatment with systemic corticosteroids, other immunosuppressants, or both may benefit patients with IPF. However, lung transplantation is the therapy with the most data supporting survival benefit. See Lung Transplantation for more information. Additionally, see Medscape's Lung & Heart Transplant Resource Center and Transplantation page. 

Table 1. Classification of Idiopathic Interstitial Pneumonias From the ATS/ERS 2002 Consensus

Pathophysiology

The pathogenesis of IPF remains unknown. Intra-alveolar inflammation was believed to play a big role; however, anti-inflammatory agents and immune modulators have proven to be minimally effective in the treatment of IPF.

IPF is characterized by diffuse interstitial fibrosis with only mild inflammation, honeycomb cysts, and fibroblastic foci (areas of accumulation of fibroblasts and connective tissue).

A disruption in the homeostasis of alveolar epithelial cells caused by unknown endogenous or environmental stimuli is thought to occur. Some of the factors associated with IPF include cigarette smoking, infections, environmental pollutants, gastroesophageal reflux disease, and drugs.

This disruption in the homeostasis results in diffuse epithelial cell activation and aberrant epithelial repair, in which cytokines (eg, tumor necrosis factor-alpha, transforming growth factor beta-1) and dysfunctional apoptosis are involved.¹ This process leads to the overproduction of collagen and fibronectin by fibroblasts. A vicious cycle of injury and abnormal epithelial healing sets the stage for progressive fibrosis and architectural distortion of the lung parenchyma.

Frequency

United States

The prevalence of IPF ranges from 14-42.7 cases per 100,000 persons depending on the criteria used for diagnosis. Meanwhile, the incidence ranges from 6.8-16.3 cases per 100,000 persons based on recent estimates.²

International

Worldwide, the reported prevalence and incidence are estimated at 10-20 and 7-10 cases per 100,000 persons, respectively.

Mortality/Morbidity

From 1992-2003, the average age- and sex-adjusted mortality rate associated with IPF was estimated at 50.8 deaths per million persons.³ Mortality increases with age, and rates are higher in men than in women. Median survival  is 2-4 years once the diagnosis is made, and the 5-year survival rate ranges from 20-40%. The most common cause of death in patients with IPF is the disease itself.³ New evidence suggests that pulmonary hypertension and gastroesophageal reflux disease contribute to morbidity and mortality in IPF.^{4, 5}

Race

Not enough data have shown any particular racial predilection for IPF.

Sex

The prevalence of IPF is higher in men than in women, predominantly those older than 55 years.

Age

IPF mainly affects elderly persons, with more than two thirds of patients being older than 60 years at the time of presentation. A  US study estimated the prevalence at 4 cases per 100,000 persons aged 18-34 years and 227.2 cases per 100,000 persons older than 75 years.²

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

Clinical features are variable. Onset is insidious, and the condition follows a progressive course. The median duration of symptoms before the diagnosis of IPF is 1-2 years. Among asymptomatic patients with IPF (diagnosed by radiographic abnormalities found on routine chest radiographs and after lung biopsy specimens show UIP), symptoms developed approximately 1000 days after the recognition of the radiologic abnormality.⁶

Dyspnea upon exertion is the most common symptom. Most patients have a nonproductive cough in the early part of the disease. Approximately 5% have no presenting symptoms when IPF is diagnosed. Patients become disabled with dyspnea and are oxygen-dependent. Some patients stabilize after initially declining.

Acute exacerbation of IPF (defined most often by worsening dyspnea, new radiologic pulmonary infiltrates, deterioration in pulmonary function measurements or gas exchange, and the absence of an identifiable cause) is an indicator of disease progression.⁷ Extrapulmonary (eg, articular, muscular, skin) involvement may indicate a collagen-vascular disease with pulmonary fibrosis. In addition, fever and wheezing are not features of IPF.

A thorough history of occupational (eg, silica, asbestos, heavy metals, moldy foliage), environmental (eg, pigeon breeding, contaminated ventilation system), and drug (eg, amiodarone) exposure is essential to exclude other causes of diffuse interstitial disease.

Physical

End-inspiratory velcrolike rales can be heard at the lung bases. Clubbing of the fingers is noted in 20-50% of patients. Signs of pulmonary hypertension and right-sided heart failure (eg, a loud second heart sound, right ventricular heave, pedal edema) may be observed as the disease progresses.⁴

Causes

The etiology of IPF remains undefined. Familial pulmonary fibrosis represents 20% of all cases of IPF.⁸ Only one genetic mutation, which involves surfactant protein C, has been clearly associated with IPF.⁹

Cigarette smoking has been associated with increased severity and mortality in persons with IPF.¹⁰ Wood and metal dust exposure are more common in patients with IPF than in age-matched control subjects. The risk of developing IPF increases with the number of work-years of exposure. Chronic aspiration secondary to gastroesophageal reflux disease has been implicated in the development of pulmonary fibrosis.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Chronic aspiration pneumonia
Collagen-vascular diseases
Granulomatosis (sarcoidosis, histoplasmosis)
Lung cancer (especially bronchoalveolar carcinoma)
Radiation pneumonitis
Recurrent intra-alveolar hemorrhage
Recurrent pulmonary edema

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

Blood test results are not specific for IPF; however, some abnormal values can be related to the pathophysiology of IPF. Normal hemoglobin and leukocyte values are found in persons with IPF; however, an elevated hemoglobin value may reflect chronic hypoxemia secondary to IPF. The erythrocyte sedimentation rate is elevated in 50% of patients. Serologic test results (eg, antinuclear antibodies, rheumatoid factor, circulating immune complexes) are nonspecific; however, high titers should raise the possibility of connective-tissue disorders.

Imaging Studies

Chest radiography

Radiographic findings are not specific for IPF. At the time of diagnosis of IPF, almost all patients have abnormal chest radiography findings. Bilateral diffuse reticular or reticulonodular infiltrates are observed, predominately at the periphery and the bases.

Media File 1. Chest radiograph of a patient with IPF showing bilateral lower-lobe reticular opacities (red circles). 

HRCT scanning 

A typical pattern on HRCT scans that correlates with histologic UIP is characterized by reticular opacities, traction bronchiectasis, honeycombing, and architectural distortion with basal and peripheral distribution. Ground-glass opacity, if present, is less extensive than the reticular abnormality. 

The term reticular opacities refers to the fine network of lines that sometimes include interlobular thickening or intralobular lines. Honeycombing is recognized by the presence of one or more rows of clustered cysts (<5 mm in diameter), which are almost always subpleural. Reticular opacities and honeycombing (seen on HRCT scans) correlate histologically with fibrosis and honeycombing, respectively. See Media Files 2-3 below. 

The presence of pleural effusions, hilar adenopathy, and localized parenchymal densities are unlikely, and these findings suggest a different disease. Other entities that can have similar HRCT scan findings include nonspecific interstitial pneumonia and chronic hypersensitivity pneumonitis.¹¹ See Media File 4 and Table 2 below. 

HRCT scanning has improved the ability to make a definitive diagnosis (in 50-90% of cases, depending on the experience of the observer) without performing a biopsy in patients with IPF.¹² The higher extent of honeycombing found on HRCT scans is an independent predictor of mortality.¹³ Patients with typical IPF changes on HRCT scans have a worse prognosis than patients with atypical IPF findings (but biopsy-proven diagnosis).¹⁴


Media File 2. Classic honeycombing (red circle) in a patient with a diagnosis of IPF.



Media File 3. Patient with a diagnosis of UIP. Note the reticular opacities (red circle) distributed in both lung bases, with minimal ground-glass opacities (blue circles).

Table 2. Radiologic Characteristics Seen on HRCT Scans of Different Types of Pneumonitis

	Usual Interstitial Pneumonia	Nonspecific Interstitial Pneumonitis	Hypersensitivity Pneumonitis
Hallmark Findings	Honeycombing and reticular opacities	Ground-glass and reticular opacities	Nodules and mosaic attenuation
Other findings	Ground-glass opacities typically absent	Honeycombing typically absent (except in fibrotic nonspecific interstitial pneumonitis)	Ground-glass and reticular opacities
Location	Lower-lobe predominance (subpleural)	Peribronchovascular  predominance	Throughout the lungs

Media File 4. Patient with nonspecific interstitial pneumonitis. Note the predominance of ground-glass opacities (blue circle) and some reticular lines (red arrow).

Other Tests

Pulmonary function tests¹⁵  

The typical finding is a restrictive ventilatory defect with a reduced diffusing capacity; however, these findings are nonspecific and should be used in conjunction with clinical, radiographic, and histologic information to ensure an accurate diagnosis.

Obstructive ventilatory defect is unusual and, if present, should raise the possibility of a different diagnosis. The most common abnormality found in patients with IPF is a decreased diffusing capacity. Diffusing capacity also correlates with the extent of disease as indicated on HRCT scans. Different studies have shown that a decreased baseline diffusing capacity is associated with high mortality in patients with IPF.¹⁶

Serial forced vital capacity and diffusing capacity measurements provide valuable information in determining disease progression and response to therapy. Oxygen desaturation during exercise of less than 88% at baseline over the course of short-term follow-up identifies patients at particularly high risk of mortality.¹⁷ 

Bronchoalveolar lavage   

Bronchoalveolar lavage is not required for diagnosis; however, findings help exclude other diseases such as infection, alveolar proteinosis, eosinophilic pneumonia, and malignancy. Most patients with IPF have an increase in macrophages, polymorphonuclear cells, and cytokines, with a paucity of lymphocytes. An increased neutrophil percentage could be a predictor of early mortality in patients with IPF.¹⁸

Echocardiography   

Patients with severe and advanced IPF show signs of pulmonary hypertension on echocardiograms (pulmonary artery systolic pressure >30 mm Hg at rest with dilated right-sided chambers).

Procedures

Bronchoscopy with transbronchial biopsy and bronchoalveolar lavage can help to exclude some forms of diffuse interstitial disease. However, this procedure is often of limited value to diagnose IPF because tissue samples may be inadequate.

Surgical lung biopsy (open lung biopsy or video-assisted thoracoscopic lung biopsy) is much more sensitive to show histologic findings related to IPF. Surgical lung biopsy is not required in all patients with suspected IPF, such as those with a highly suggestive clinical presentation and typical findings after HRCT scanning. If the clinical features are inconsistent with IPF or if atypical HRCT scan features are present, consider performing a surgical lung biopsy.

According to the 2000 ATS/ERS international consensus statement, a correct clinical diagnosis (in the absence of surgical lung biopsy findings) of IPF must include all of the major criteria and at least 3 of the 4 minor criteria.  

• Major criteria  
• • Exclusion of other known causes of intersitial lung diseases (eg, drug toxicities, environmental exposures, connective-tissue diseases)
  • Abnormal pulmonary function study results that include evidence of restriction (reduced vital capacity often with an increased ratio of forced expiratory volume in 1 second to forced vital capacity) and impaired gas exchange
  • Bibasilar reticular abnormalities with minimal ground-glass opacities on HRCT scan images
  • Transbronchial lung biopsy or bronchoalveolar lavage findings showing no features to support an alternative diagnosis
• Minor criteria 
• • Patient older than 50 years
  • Insidious onset of otherwise unexplained dyspnea upon exertion
  • Duration of illness longer than 3 months
  • Bibasilar, inspiratory crackles

Histologic Findings

Lung biopsy of patients with IPF shows a histologic pattern of UIP characterized by a heterogeneous, variegated appearance with alternating areas of normal lung, interstitial inflammation, fibrosis, and honeycomb change (patchwork appearance).

Fibroblast foci (ie, the combination of fibroblasts and myofibroblasts arranged in a linear fashion within pale-staining matrix) are not specific for UIP, but they are an important diagnostic criterion that is associated with poor survival in patients with IPF.

Honeycomb change is defined as cystic, dilated bronchioles (containing mucous and leukocytes) lined by columnar respiratory epithelium in scarred, fibrotic lung tissue.

Fibrotic scars (dense eosinophilic collagen without associated honeycomb change) are also characteristic for UIP.

UIP is not specific for IPF and can also be seen in patients with other underlying conditions or etiologies such as autoimmune diseases.

During the period of accelerated IPF, lung biopsy typically shows a combination of UIP with superimposed diffuse alveolar damage, characterized by fibroblast proliferation of the alveoli septa, hyperplasia of type 2 pneumocytes, and hyaline membrane remnants.

Media File 5. Patchwork distribution of abnormalities in a classic example of usual interstitial pneumonitis (low-magnification photomicrograph; hematoxylin and eosin stain; original magnification, X4). Courtesy of Chad Stone, MD.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

Oxygen therapy should be prescribed for patients with documented hypoxemia; this may improve exercise tolerance.

Consultations

For a patient with known IPF, consult a pulmonary specialist to assist with further management with corticosteroids and cytotoxic or antifibrotic agents. Additionally, for patients with known IPF who have acute respiratory failure that requires mechanical ventilation, consult a critical care specialist.

Diet

Maintaining adequate nutritional intake and immunizations (ie, pneumonia vaccine, influenza vaccine) in patients with IPF is important for quality of life.

Activity

Deconditioning is a common problem in patients with IPF and can exacerbate functional impairment and psychosocial aspects. Thus, participation in a pulmonary rehabilitation program should be encouraged.

MEDICATION

Section 7 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Traditionally, IPF was thought to be a disease of chronic parenchymal inflammation (alveolitis) leading to fibrosis. Thus, the treatment of IPF was focused on immunosuppressive therapy using high-dose corticosteroids with or without cytotoxic drugs (eg, azathioprine, cyclophosphamide), as was recommended in the ATS/ERS 2000 consensus.

Drug Category: Glucocorticoids

In older studies in which the definition of IPF was less specific, corticosteroids alone improved physiologic and radiographic findings in 15-30% of patients. However, many investigators now suspect that the subgroup of responders did not have IPF, but instead had nonspecific interstitial pneumonitis.

The use of corticosteroids is associated with significant morbidity in patients with IPF, which sometimes outweighs any potential benefits. However, in select patients, a trial of corticosteroid therapy may be indicated, particularly those patients for whom the diagnosis of IPF is not certain (eg, those with atypical HRCT scan features who decline surgical lung biopsy or atypical HRCT scan features with UIP in lung biopsy specimens).

Latent tuberculosis should be excluded before patients begin corticosteroid therapy.

Drug Category: Immunosuppressive agents

Azathioprine and cyclophosphamide have been the most common second-line drugs used in patients in whom corticosteroid therapy fails. Azathioprine plus corticosteroids is the most commonly used combination therapy in patients with IPF.

Cytotoxic drugs suppress B- and T-lymphocyte function. Can be used alone or in combination with corticosteroids, especially among patients whose conditions are nonresponsive to steroids; patients experiencing serious adverse effects from steroids; patients at high risk, such as elderly patients, for serious adverse effects of steroid complications; or patients with poorly controlled diabetes, hypertension, severe osteoporosis, or peptic ulcer disease.

Drug Category: Antiviral cytokines

Two classes (I and II) of interferons have an important role in cell growth regulation and modulation of the immune system. Interferon gamma and interferon beta have been demonstrated to inhibit proliferation of fibroblasts and suppress the production of connective-tissue matrix protein in both animals and humans.

The 2004 study by Raghu et al¹⁹ was a multicenter, prospective, randomized, double-blind, placebo-controlled trial of subcutaneous interferon gamma-1b in 330 patients with IPF whose conditions were unresponsive to corticosteroid therapy. The investigators remarked that over a 1-y period, patients with IPF showed no significant delay in disease progression with interferon gamma-1b treatment. No significant effects were detected in the primary outcome measure of progression-free survival (disease progression or death) or in conventional measures of lung function and gas exchange at rest. Of note, a trend toward increased overall survival was observed in the interferon gamma-1b group.

Although interferon gamma is one of the best-studied drugs in the treatment of IPF, its role remains uncertain for patients with this disorder.

Drug Category: Antifibrotic agents

Pirfenidone has previously been studied for treatment of various fibrotic diseases, including IPF and extrapulmonary disorders.

A multicenter, randomized, double-blind, placebo-controlled study of pirfenidone versus placebo was performed in 107 Japanese patients with IPF.²⁰ Although no difference was noted in mortality or in the lowest oxygen saturation during a 6-min walk test between both groups, it showed a significant difference in the decline of forced vital capacity at 9 mo and in the rate of acute exacerbations of IPF in favor of the pirfenidone group.

Despite these results, pirfenidone has not yet been approved by the FDA for the treatment of IPF.

Drug Category: Antioxidant drug

NAC is a form of antioxidant therapy used for acetaminophen overdose and prevention of radiocontrast-induced nephropathy.

A double-blind, controlled, multinational, randomized trial investigated the use of NAC versus placebo in 155 patients with IPF treated with corticosteroids and azathioprine.²¹ The study showed benefit in the NAC group for change from baseline in forced vital capacity and diffusing capacity at 12 mo, but no mortality benefit was demonstrated. Moreover, the NAC group had a lower overall number of myelotoxic effects compared with the placebo group, reflecting a protective effect of NAC from azathioprine-induced myelotoxicity.

A placebo-controlled trial investigating the efficacy of NAC monotherapy in the treatment of IPF is needed.

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• Patients with pneumothorax should be admitted.
• Patients with severe hypoxemia should be admitted.
• Use diuretics judiciously in patients who develop right-sided heart failure as a consequence of cor pulmonale.

Further Outpatient Care

• Closely monitor for adverse drug effects and complications.
• Complete history and physical examination, pulmonary function tests, chest radiographs, and HRCT scans should be performed frequently following initiation of treatment.
• Patients incapacitated by dyspnea should be evaluated for pulmonary rehabilitation.
• Encourage patients to quit smoking.
• Recommend annual influenza vaccinations.

Transfer

• Referral to a lung transplantation center should be instituted early in patients with histologic or radiographic evidence of UIP, irrespective of vital capacity.²²
• Consider lung transplantation for otherwise healthy patients younger than 65 years who have experienced progressive pulmonary dysfunction and deterioration despite maximal medical and supportive care.
• Referral to a pulmonary rehabilitation center should be considered for patients incapacitated by dyspnea.
• Patients should be referred to a specialized center for any ongoing clinical trials for new treatments that can offer new hope for patients with IPF

Complications

• Adverse drug effects (closely monitor)
• Cor pulmonale
• Pneumothorax
• Infection
• Carcinoma
• Thromboembolic diseases

Prognosis

The following factors are associated with worse prognosis:  

• Older age
• Male sex
• Cigarette smoking
• Higher predominance of honeycombing on the lung HRCT scan
• Lower diffusing capacity on pulmonary function test results at the time of diagnosis
• Higher rate of acute exacerbations of IPF
• Presence of pulmonary hypertension

Patient Education

Educate patients about the importance of compliance with medication therapy. Additionally, patients must be made aware of the adverse effects of cytotoxic or antifibrotic agents and corticosteroids. For excellent patient education resources, see eMedicine's Lung and Airway Center.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to exclude other causes of interstitial lung disease
• Failure to disclose to patients the adverse effects of medications used to treat this disorder

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Rajesh G. Patel, MD, to the development and writing of this article.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  Chest radiograph of a patient with idiopathic pulmonary fibrosis showing bilateral lower-lobe reticular opacities (red circles).
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Media file 2:  Classic honeycombing (red circle) in a patient with a diagnosis of idiopathic pulmonary fibrosis
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Media file 3:
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Media file 4:  Patient with nonspecific interstitial pneumonitis. Note the predominance of ground-glass opacities (blue circle) and some reticular lines (red arrow).
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Media file 5:  Patchwork distribution of abnormalities in a classic example of usual interstitial pneumonitis (low-magnification photomicrograph; hematoxylin and eosin stain; original magnification, X4). Courtesy of Chad Stone, MD.
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Media type:  Photo

REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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