eMedicine Specialties > Pulmonology > Interstitial Lung Diseases

Pulmonary Fibrosis, Idiopathic

Javier I Diaz, MD, Fellow in Pulmonary and Critical Care Medicine, Henry Ford Hospital
Daniel R Ouellette, MD, FCCP, Associate Professor of Medicine, Wayne State University School of Medicine; Consulting Staff, Pulmonary Disease and Critical Care Medicine Service, Henry Ford Health System

Updated: Jun 30, 2009

Introduction

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.

Idiopathic pulmonary fibrosis 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 idiopathic pulmonary fibrosis is called usual interstitial pneumonia (UIP), making idiopathic pulmonary fibrosis 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 idiopathic pulmonary fibrosis. However, lung transplantation is the therapy with the most data supporting survival benefit.

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

Pathophysiology

The pathogenesis of idiopathic pulmonary fibrosis (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 idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis 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 idiopathic pulmonary fibrosis 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 involved1 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 idiopathic pulmonary fibrosis 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 idiopathic pulmonary fibrosis 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 idiopathic pulmonary fibrosis is the disease itself.³ New evidence suggests that pulmonary hypertension and gastroesophageal reflux disease contribute to morbidity and mortality in idiopathic pulmonary fibrosis.^4,5

Race

Not enough data have shown any particular racial predilection for idiopathic pulmonary fibrosis.

Sex

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

Age

Idiopathic pulmonary fibrosis 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

History

Clinical features of idiopathic pulmonary fibrosis (IPF) are variable. Onset is insidious, and the condition follows a progressive course. The median duration of symptoms before the diagnosis of idiopathic pulmonary fibrosis is 1-2 years. Among asymptomatic patients with idiopathic pulmonary fibrosis (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 idiopathic pulmonary fibrosis is diagnosed. Patients become disabled with dyspnea and are oxygen-dependent. Some patients stabilize after initially declining.

Acute exacerbation of idiopathic pulmonary fibrosis (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 idiopathic pulmonary fibrosis.

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

Cigarette smoking has been associated with increased severity and mortality in persons with idiopathic pulmonary fibrosis.¹⁰ Wood and metal dust exposure are more common in patients with idiopathic pulmonary fibrosis than in age-matched control subjects. The risk of developing idiopathic pulmonary fibrosis 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.

Differential Diagnoses

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

Laboratory Studies

Blood test results are not specific for idiopathic pulmonary fibrosis (IPF); however, some abnormal values can be related to the pathophysiology of idiopathic pulmonary fibrosis. Normal hemoglobin and leukocyte values are found in persons with idiopathic pulmonary fibrosis; however, an elevated hemoglobin value may reflect chronic hypoxemia secondary to idiopathic pulmonary fibrosis. 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 idiopathic pulmonary fibrosis. At the time of diagnosis of idiopathic pulmonary fibrosis, almost all patients have abnormal chest radiography findings. Bilateral diffuse reticular or reticulonodular infiltrates are observed, predominately at the periphery and the bases.

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

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

Patient with a diagnosis of usual interstitial pneumonia. Note the reticular opacities (red circle) distributed in both lung bases, with minimal ground-glass opacities (blue circles).

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

Other Tests

Pulmonary function tests ¹⁵   

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 idiopathic pulmonary fibrosis 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 idiopathic pulmonary fibrosis.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 idiopathic pulmonary fibrosis 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 idiopathic pulmonary fibrosis.18

Echocardiography  

Patients with severe and advanced idiopathic pulmonary fibrosis 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 idiopathic pulmonary fibrosis 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 idiopathic pulmonary fibrosis. Surgical lung biopsy is not required in all patients with suspected idiopathic pulmonary fibrosis, such as those with a highly suggestive clinical presentation and typical findings after HRCT scanning. If the clinical features are inconsistent with idiopathic pulmonary fibrosis 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 idiopathic pulmonary fibrosis 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 idiopathic pulmonary fibrosis 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 idiopathic pulmonary fibrosis.

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 idiopathic pulmonary fibrosis and can also be seen in patients with other underlying conditions or etiologies such as autoimmune diseases.

During the period of accelerated idiopathic pulmonary fibrosis, 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.

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

Medical Care

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

Consultations

For a patient with known idiopathic pulmonary fibrosis (IPF), consult a pulmonary specialist to assist with further management with corticosteroids and cytotoxic or antifibrotic agents. Additionally, for patients with known idiopathic pulmonary fibrosis 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 idiopathic pulmonary fibrosis is important for quality of life.

Activity

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

Medication

Traditionally, idiopathic pulmonary fibrosis was thought to be a disease of chronic parenchymal inflammation (alveolitis) leading to fibrosis. Thus, the treatment of idiopathic pulmonary fibrosis 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.

Several years have passed since that publication. Our understanding of the pathogenesis of idiopathic pulmonary fibrosis has increased, and multiple clinical trials have been conducted using novel therapeutic agents (eg, pirfenidone, N -acetylcysteine [NAC]). However, optimal therapy for idiopathic pulmonary fibrosis remains elusive and has yet to be identified.

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.

Prednisone (Deltasone, Orasone, Sterapred)

Used as an immunosuppressant for autoimmune disorders. By reversing increased capillary permeability and suppressing PMN activity, may decrease inflammation.
Initial response usually occurs within 3 mo of high dose of steroids. Objective parameter (chest radiograph, CT scan, PFT, dyspnea scores) and nonsubjective improvement should be used for subsequent steroid therapy because of placebo effects or mood-enhancement effects of steroids.
Most pulmonologists continue low-dose prednisone (approximately 15-20 mg) as maintenance therapy in steroid-responsive patients for 1-2 y and occasionally indefinitely.
Relapse or progression of disease after an initial response suggests need for prolonging treatment or addition of an immunosuppressive agent.

Dosing

Adult

Chronic progressive disease: 1-1.5 mg/kg/d PO, not to exceed 100 mg/d, for 8-12 wk; in a responsive patient, taper dose to 0.5-1 mg/kg/d and maintain for 12 wk; further taper dose to 0.25 mg/kg/d over next 12 wk if patient shows improvement
Acute or rapidly progressive disease: 250 mg q6h IV (ie, with methylprednisolone [Solu-Medrol]); once stabilized, continue therapy as outlined under chronic progressive disease

Pediatric

Not established

Interactions

Increased risk of peptic ulcer disease in patient taking aspirin, indomethacin, and other NSAIDs; barbiturates, phenytoin, and rifampin decrease effects

Contraindications

Documented hypersensitivity; viral, fungal, connective-tissue, and tubercular skin infections; peptic ulcer disease; hepatic dysfunction

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hypertension, hyperkalemia, metabolic alkalosis, Cushing syndrome, and myopathy; adverse effects include GI irritation, osteoporosis, cataracts, psychotic behavior, and delayed wound healing

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.

Azathioprine (Imuran)

Inhibits mitosis and cellular metabolism by antagonizing purine metabolism and inhibiting synthesis of DNA, RNA, and proteins. Effects may decrease proliferation of immune cells and result in lower autoimmune activity.

Dosing

Adult

2-3 mg/kg/d PO as single dose; not to exceed 150 mg/d

Pediatric

Not established

Interactions

Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

GI disturbances (eg, nausea, vomiting, diarrhea, abdominal pain, pancreatitis) may occur; adverse effects include leukopenia, anemia, thrombocytopenia, hepatotoxicity, and increased risk of neoplasm; increases risk of neoplasia; caution in liver disease and renal impairment; hematologic toxicities may occur

Cyclophosphamide (Cytoxan)

Alkylating agent of the nitrogen mustard group. Metabolite inhibits the crosslinking of DNA strands, leading to cell death. Has anti-inflammatory effect.

Dosing

Adult

25-50 mg/d PO initially; increase dose gradually in 25-mg increments q7-14d, not to exceed 150 mg/d, with goal of reducing and maintaining WBC count at 4000-7000/µL

Pediatric

Not established

Interactions

Condominant use with barbiturates, phenytoin, or chloral hydrate increases rate of metabolism; allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones
Chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in impaired renal or hepatic function, leukopenia, or thrombocytopenia; monitor WBC count frequently and adjust dose to maintain count of 4000-7000/µL; associated with hemorrhagic cystitis and bladder carcinoma

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.

In an international multicenter, randomized, placebo-controlled trial, King et al studied 826 patients with idiopathic pulmonary fibrosis. Patients were assigned to receive either interferon gamma-1b (n = 551) or placebo (n = 275) subcutaneously 3 times per week. The second interim analysis (median treatment duration of 64 wk) showed no benefit on mortality for patients treated with interferon gamma-1b compared with placebo. Mortality in the interferon group included 80 (15%) patients compared with 35 (13%) patients in placebo group. Because treatment with interferon gamma-1b did not improve survival of patients with idiopathic pulmonary fibrosis, King et al do not recommend this treatment.²⁰

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

Interferon gamma-1b (Actimmune)

Class II interferon produced by T cells and natural killer cells. Effects similar to those of class I interferons but differ by having strong stimulating effects on immune system.

Dosing

Adult

200 mcg SC 3 times/wk with 7.5 mg of prednisolone PO qd for 12 mo

Pediatric

Not established

Interactions

Can decrease hepatic microsomal cytochrome P-450 concentrations, which could lead to decreased metabolism of drugs that use this metabolic degradation pathway; caution in patients on myelosuppressive agents

Contraindications

Documented hypersensitivity; arrhythmias; congestive heart failure; seizure disorder; patients on myelosuppressive agents

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Flulike symptoms may be minimized by hs administration and may be treated with acetaminophen; if acute hypersensitivity reaction occurs, discontinue immediately and institute symptomatic and supportive treatment; adverse reactions include flulike symptoms, fatigue, dyspepsia, neutropenia, thrombocytopenia, elevated liver enzyme levels, rash, erythema, and tenderness

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 IPF21 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.

Pirfenidone

Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone).
Inhibits transforming growth factor beta–stimulated collagen synthesis, decreases extracellular matrix, and blocks fibroblast proliferation in vitro.

Dosing

Adult

40 mg/kg/d PO; not to exceed 3600 mg/d
Dose used in study showing decreased acute exacerbations of IPF was 1800 mg/d

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Rash (photosensitivity); GI symptoms (abdominal discomfort, dyspepsia, anorexia, nausea, diarrhea); fatigue and lethargy; other adverse effects include dry skin, hyperpigmentation, headache, and weakness

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 azathioprine22 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.

N-acetylcysteine (Acetadote)

Precursor of the antioxidant glutathione. Has been shown to restore glutathione levels in lung tissue and bronchoalveolar lavage fluid.

Dosing

Adult

600 mg PO tid (1800 mg/d)

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

PO administration may cause GI distress; caution with asthma; IV administration may cause anaphylaxis (discontinue IV and administer antihistamine, epinephrine, then follow local anaphylaxis protocol); IV administration may also cause acute flushing or erythema within 30-60 min after initiating infusion, which typically resolves spontaneously despite continued infusion; adjust total fluid volume for IV in patients <40 kg

Follow-up

Further Inpatient Care

• Idiopathic pulmonary fibrosis (IPF) 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.²³
• 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

Medicolegal 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

Multimedia

Media file 1: Chest radiograph of a patient with idiopathic pulmonary fibrosis showing bilateral lower-lobe reticular opacities (red circles).

Media file 2: Classic honeycombing (red circle) in a patient with a diagnosis of idiopathic pulmonary fibrosis

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

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

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.

References

1. Verma S, Slutsky AS. Idiopathic pulmonary fibrosis--new insights. N Engl J Med. Mar 29 2007;356(13):1370-2. [Medline].

2. Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. Oct 1 2006;174(7):810-6. [Medline].

3. Olson AL, Swigris JJ, Lezotte DC, Norris JM, Wilson CG, Brown KK. Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003. Am J Respir Crit Care Med. Aug 1 2007;176(3):277-84. [Medline].

4. Patel NM, Lederer DJ, Borczuk AC, Kawut SM. Pulmonary hypertension in idiopathic pulmonary fibrosis. Chest. Sep 2007;132(3):998-1006. [Medline].

5. Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. Jan 2006;27(1):136-42. [Medline].

6. Kim DS, Collard HR, King TE Jr. Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc. Jun 2006;3(4):285-92. [Medline].

7. Hyzy R, Huang S, Myers J, Flaherty K, Martinez F. Acute exacerbation of idiopathic pulmonary fibrosis. Chest. Nov 2007;132(5):1652-8. [Medline].

8. Loyd JE. Pulmonary fibrosis in families. Am J Respir Cell Mol Biol. Sep 2003;29(3 Suppl):S47-50. [Medline].

9. Lawson WE, Loyd JE. The genetic approach in pulmonary fibrosis: can it provide clues to this complex disease?. Proc Am Thorac Soc. Jun 2006;3(4):345-9. [Medline].

10. Antoniou KM, Hansell DM, Rubens MB, Marten K, Desai SR, Siafakas NM, et al. Idiopathic pulmonary fibrosis: outcome in relation to smoking status. Am J Respir Crit Care Med. Jan 15 2008;177(2):190-4. [Medline].

11. Silva CI, Müller NL, Lynch DA, Curran-Everett D, Brown KK, Lee KS, et al. Chronic hypersensitivity pneumonitis: differentiation from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section CT. Radiology. Jan 2008;246(1):288-97. [Medline].

12. Misumi S, Lynch DA. Idiopathic pulmonary fibrosis/usual interstitial pneumonia: imaging diagnosis, spectrum of abnormalities, and temporal progression. Proc Am Thorac Soc. Jun 2006;3(4):307-14. [Medline].

13. Thannickal VJ, Horowitz JC. Evolving concepts of apoptosis in idiopathic pulmonary fibrosis. Proc Am Thorac Soc. Jun 2006;3(4):350-6. [Medline].

14. Flaherty KR, Thwaite EL, Kazerooni EA, Gross BH, Toews GB, Colby TV, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax. Feb 2003;58(2):143-8. [Medline].

15. Erbes R, Schaberg T, Loddenkemper R. Lung function tests in patients with idiopathic pulmonary fibrosis. Are they helpful for predicting outcome?. Chest. Jan 1997;111(1):51-7. [Medline].

16. Jegal Y, Kim DS, Shim TS, Lim CM, Do Lee S, Koh Y, et al. Physiology is a stronger predictor of survival than pathology in fibrotic interstitial pneumonia. Am J Respir Crit Care Med. Mar 15 2005;171(6):639-44. [Medline].

17. Martinez FJ, Flaherty K. Pulmonary function testing in idiopathic interstitial pneumonias. Proc Am Thorac Soc. Jun 2006;3(4):315-21. [Medline].

18. Kinder BW, Brown KK, Schwarz MI, Ix JH, Kervitsky A, King TE Jr. Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis. Chest. Jan 2008;133(1):226-32. [Medline].

19. Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med. Jan 8 2004;350(2):125-33. [Medline].

20. [Best Evidence] King TE, Albera C, Bradford WZ, et al. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet. Jun 2009;[Full Text].

21. Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Nakata K, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. May 1 2005;171(9):1040-7. [Medline].

22. Demedts M, Behr J, Buhl R, Costabel U, Dekhuijzen R, Jansen HM, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. Nov 24 2005;353(21):2229-42. [Medline].

23. Orens JB, Estenne M, Arcasoy S, Conte JV, Corris P, Egan JJ, et al. International guidelines for the selection of lung transplant candidates: 2006 update--a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. Jul 2006;25(7):745-55. [Medline].

24. Daniels CE, Ryu JH. Treatment of idiopathic pulmonary fibrosis. Semin Respir Crit Care Med. Dec 2006;27(6):668-76. [Medline].

25. Flaherty KR, Andrei AC, King TE Jr, Raghu G, Colby TV, Wells A, et al. Idiopathic interstitial pneumonia: do community and academic physicians agree on diagnosis?. Am J Respir Crit Care Med. May 15 2007;175(10):1054-60. [Medline].

26. Gay SE, Kazerooni EA, Toews GB, Lynch JP 3rd, Gross BH, Cascade PN, et al. Idiopathic pulmonary fibrosis: predicting response to therapy and survival. Am J Respir Crit Care Med. Apr 1998;157(4 Pt 1):1063-72. [Medline].

27. Gharaee-Kermani M, Gyetko MR, Hu B, Phan SH. New insights into the pathogenesis and treatment of idiopathic pulmonary fibrosis: a potential role for stem cells in the lung parenchyma and implications for therapy. Pharm Res. May 2007;24(5):819-41. [Medline].

28. Hunninghake GW, Kalica AR. Approaches to the treatment of pulmonary fibrosis. Am J Respir Crit Care Med. Mar 1995;151(3 Pt 1):915-8. [Medline].

29. Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med. Apr 1998;157(4 Pt 1):1301-15. [Medline].

30. King TE Jr. Idiopathic pulmonary fibrosis. In: Schwarz MI, King TE Jr, eds. Interstitial Lung Disease. St. Louis, Mo: Mosby; 1993:367-403.

31. Martinez FJ, Safrin S, Weycker D, Starko KM, Bradford WZ, King TE Jr, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. Jun 21 2005;142(12 Pt 1):963-7. [Medline].

32. Noth I, Martinez FJ. Recent advances in idiopathic pulmonary fibrosis. Chest. Aug 2007;132(2):637-50. [Medline].

33. Visscher DW, Myers JL. Histologic spectrum of idiopathic interstitial pneumonias. Proc Am Thorac Soc. Jun 2006;3(4):322-9. [Medline].

Keywords

IPF, cryptogenic fibrosing alveolitis, usual interstitial pneumonitis, UIP, interstitial disease, intersitial lung disease, desquamative interstitial pneumonitis, DIP, cor pulmonale, pneumothorax, thromboembolism disease, thromboembolic disease, chronic fibrosing alveolitis, fibrosing alveolitis, Hamman-Rich syndrome, collagen-vascular disease, collagen vascular disease, alveolar injuries, alveolar injury, inflammation of the lung parenchyma, fibrosis of the lung parenchyma, Ebstein-Barr virus, chronic aspiration secondary to gastroesophageal reflux

Contributor Information and Disclosures

Author

Javier I Diaz, MD, Fellow in Pulmonary and Critical Care Medicine, Henry Ford Hospital
Disclosure: Nothing to disclose.

Coauthor(s)

Daniel R Ouellette, MD, FCCP, Associate Professor of Medicine, Wayne State University School of Medicine; Consulting Staff, Pulmonary Disease and Critical Care Medicine Service, Henry Ford Health System
Daniel R Ouellette, MD, FCCP is a member of the following medical societies: American College of Chest Physicians and American Thoracic Society
Disclosure: Boehringer Ingleheim Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching

Medical Editor

Stephen P Peters, MD, PhD, Professor, Department of Medicine, Wake Forest University
Stephen P Peters, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Thoracic Society, and Sigma Xi
Disclosure: See below for list of all activities None None

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Daniel R Ouellette, MD, FCCP, Associate Professor of Medicine, Wayne State University School of Medicine; Consulting Staff, Pulmonary Disease and Critical Care Medicine Service, Henry Ford Health System
Daniel R Ouellette, MD, FCCP is a member of the following medical societies: American College of Chest Physicians and American Thoracic Society
Disclosure: Boehringer Ingleheim Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Zab Mosenifar, MD, Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center; Professor of Medicine, David Geffen School of Medicine at UCLA
Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, and American Thoracic Society
Disclosure: Nothing to disclose.

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.

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