eMedicine Specialties > Pulmonology > Interstitial Lung Diseases
Pulmonary Fibrosis, Idiopathic: Treatment & Medication
Updated: Jun 30, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
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.
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
Increased risk of peptic ulcer disease in patient taking aspirin, indomethacin, and other NSAIDs; barbiturates, phenytoin, and rifampin decrease effects
Documented hypersensitivity; viral, fungal, connective-tissue, and tubercular skin infections; peptic ulcer disease; hepatic dysfunction
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.
Adult
2-3 mg/kg/d PO as single dose; not to exceed 150 mg/d
Pediatric
Not established
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
Documented hypersensitivity
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.
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
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
Documented hypersensitivity; severely depressed bone marrow function
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.
Adult
200 mcg SC 3 times/wk with 7.5 mg of prednisolone PO qd for 12 mo
Pediatric
Not established
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
Documented hypersensitivity; arrhythmias; congestive heart failure; seizure disorder; patients on myelosuppressive agents
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.
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
None reported
Documented hypersensitivity
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.
Adult
600 mg PO tid (1800 mg/d)
Pediatric
Not established
None reported
Documented hypersensitivity
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
More on Pulmonary Fibrosis, Idiopathic |
| Overview: Pulmonary Fibrosis, Idiopathic |
| Differential Diagnoses & Workup: Pulmonary Fibrosis, Idiopathic |
 Treatment & Medication: Pulmonary Fibrosis, Idiopathic |
| Follow-up: Pulmonary Fibrosis, Idiopathic |
| Multimedia: Pulmonary Fibrosis, Idiopathic |
| References |
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References
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Further Reading
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
