WORKUP

Lab Studies:

• Blood tests show normal hemoglobin, leukocyte, and differential counts.

• Approximately 50% of patients have an elevated erythrocyte sedimentation rate.

• Serologic tests are nonspecific, with the presence of antinuclear antibodies, rheumatoid factor, or circulating immune complex without a history of connective tissue disorder.

• The presence of a high titer would suggest the presence of connective tissue diseases.

• Rarely, a patient with the initial diagnosis of IPF may develop frank manifestations of an underlying connective tissue disease later, such as polymyositis or vasculitis.

Imaging Studies:

• Chest radiograph

• No pathognomic features are present.

• Findings are abnormal in 95% of patients.

• Bilateral diffuse reticular or reticulonodular infiltrates are observed, predominately at the periphery.

• High-resolution computed tomography

• A pattern on high-resolution computed tomography (HRCT) provides more information than plain chest radiograph and conventional CT scan. HRCT also provides information to determine the site for surgical lung biopsy.

• Presence of pleural effusion, hilar adenopathy, and localized parenchymal densities on chest radiographs or conventional CT scans is unlikely and suggests another disease.

• A few small mediastinal lymph nodes may be detected by chest CT scans.

• A pattern of coarse, reticular, linear opacities; cystic air spaces; and distortion of lung architecture suggests a fibrotic histopathologic process.

• A pattern of ground-glass opacities is highly predictive of a cellular inflammatory process, which responds well to corticosteroids or immunosuppressive agents.

• Ground-glass opacities correlate with a cellular biopsy but may represent fibrosis of intralobular and alveolar space. Similarly, a reticular pattern could reflect fibrosis or inflammation within alveolar ducts, septa, or spaces.

Other Tests:

• Pulmonary function tests

• Typical findings are a reduction in the lung volumes, with no airflow obstruction.

• PFTs assess the extent of restrictive impairment but cannot distinguish between alveolitis and fibrosis.

• Forced vital capacity and single-breath diffusing capacity for carbon monoxide best reflect the global extent of disease.

• Diffusing capacity for carbon monoxide less than 45% predicted or a forced vital capacity less than 50% predicted are associated with higher mortality.

• Arterial blood gas measurements reveal hypoxia with increased alveolar-arterial partial pressure of oxygen gradient at rest.

• Exercise fall in PaO₂ is evident in a patient with normal resting PaO₂.

• Bronchoalveolar lavage

• Bronchoalveolar lavage (BAL) is not required for diagnosis; however, it does help exclude infection, alveolar proteinosis, eosinophilic pneumonia, and malignancy.

• Results reveal an increase in polymorphonuclear leukocytes, alveolar macrophages, and cytokines.

• Radionuclide scans

• Scans with gallium 67 citrate detect an active alveolar process.

• However, results are nonspecific, and the scan is inconvenient, expensive, utilizes a radionucleotide, and is inferior to HRCT for providing information on the extent of the disease process.

Procedures:

• Biopsy: Tissue biopsy is important for ruling out granuloma, vasculitis, infection, and malignancy.

• Transbronchial biopsy

• Transbronchial biopsy (TBB) is less invasive and, along with BAL, can exclude some forms of diffuse interstitial disease.

• This procedure often is limited because tissue samples may be inadequate.

• Surgical lung biopsy

• Open lung biopsy (OLB) and video-assisted thoracoscope (VAT) lung biopsy are the criterion standard modalities. They reveal the extent of cellular inflammation and fibrosis.

• The combination of HRCT and VAT lung biopsy provides adequate information regarding the extent of cellular inflammation and fibrosis, with relatively minimal risk.

• VAT lung biopsy may be deferred if clinical presentation and HRCT findings are typical of IPF, especially in an elderly patient with extensive honeycombing and fibrosis. Treatment with corticosteroids and immunosuppressive agents is unlikely to benefit these patients.

• The diagnosis of IPF remains uncertain in the absence of diagnostic tissue evidence. According to the 2000 international consensus statement, a correct clinical diagnosis of IPF includes all of the major criteria and at least 3 of the 4 minor criteria, as follows:

• Major criteria

   

  • Exclusion of other known causes of intersitial lung diseases (eg, drug toxicities, environmental exposures, connective tissue diseases)

     

  • Restrictive ventilatory impairment, decreased diffusion capacity, and increased alveolar-arterial oxygen gradient at rest or exercise

     

  • Bibasilar reticular abnormalities with minimal ground-glass opacities on HRCT

     

  • TBB or BAL 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 30 years

     

  • Bibasilar inspiratory crackles (dry or Velcro type in quality)

TREATMENT

Medical Care: Emergency department care

• Patient may present with acute onset of dyspnea, with or without hypoxic respiratory failure.

• Initial arterial blood gases should be obtained if pulse oximetry suggests hypoxia. Supportive care that includes correction of hypoxia should be considered.

• Chest radiograph should be obtained to exclude pneumothorax, infection, and congestive heart failure.

Consultations:

• Pulmonary consultation should be obtained in a patient with known IPF to assist with further management with corticosteroids and cytotoxic or antifibrotic agents.

• Critical care consultation should be obtained in patients with known IPF who have acute respiratory failure that requires mechanical ventilation.

MEDICATION

The goals are to suppress the alveolitis and to prevent continued destruction of lung parenchyma and fibrosis. Corticosteroids are the drugs of choice. Cytotoxic and/or antifibrotic agents are considered, either alone or in combination with corticosteroids, in patients who continue to have clinical deterioration despite corticosteroid therapy or who experience serious adverse effects from corticosteroids. Complete remission is rare.

Drug Category: Glucocorticoids -- These are the initial drugs of choice; however, only 20% of patients are responsive. Response is favorable in patients with a histopathology pattern consistent with alveolitis. These agents are unlikely to benefit those with extensive honeycombing and/or UIP histology.

Discontinuation of the drug should be considered during follow-up if the following occur: (1) a fall in forced vital capacity or total lung capacity of 10% or more; (2) worsening of radiographic infiltrates, especially with development of honeycombing or signs of pulmonary hypertension; (3) decreased gas exchange at rest or with exercise; and (4) untoward effect from corticosteroids.

Patients should have a skin test for tuberculosis. Patients with a positive purified protein derivative (PPD) test should be considered for tuberculosis prophylaxis.

Drug Name	Prednisone (Deltasone) -- Used as an immunosuppressant in the treatment of autoimmune disorders. By reversing increased capillary permeability and suppressing PMN activity, may decrease inflammation.
Adult Dose	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: IV corticosteroids (eg, methylprednisolone [Solu-Medrol]) at 250 mg q6h Once stabilized, continue therapy as outlined under chronic progressive disease
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; viral infections, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections
Interactions	Increased risk of peptic ulcer disease in patient taking aspirin, indomethacin, and other NSAIDs Barbiturates, phenytoin, and rifampin decrease effects of corticosteroids
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hypertension, hyperkalemia, metabolic alkalosis, Cushing syndrome, and myopathy Some adverse effects include gastrointestinal irritation, osteoporosis, cataracts, psychotic behavior, and delayed wound healing

Drug Category: Immunosuppressive agents -- These agents suppress B-lymphocyte and T-lymphocyte function. Can be used alone or in combination with corticosteroids.

Drug Name	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 Dose	2 mg/kg/d PO as single dose; not to exceed 200 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
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
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Gastrointestinal disturbances (eg, nausea, vomiting, diarrhea, abdominal pain, pancreatitis) may occur Some adverse effects include leukopenia, anemia, thrombocytopenia, hepatotoxicity, and increased risk of neoplasm Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur

Drug Name	Cyclophosphamide (Cytoxan) -- Alkylating agent of the nitrogen mustard group. Metabolite inhibits the crosslink of DNA strands, leading to cell death. Has anti-inflammatory effect.
Adult Dose	Starting dose of 25-50 mg/d; increase dose gradually by increments of 25 mg, not to exceed 200 mg/d, aiming to reduce and maintain WBC count at 4000-7000/mcL
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, severely depressed bone marrow function
Interactions	Condominant use with barbiturates, phenytoin, or chloral hydrate increases the rate of metabolism of cyclophosphamide Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects of cyclophosphamide; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones Chloramphenicol may increase half-life of cyclophosphamide while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity of cyclophosphamide; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in impaired renal or hepatic function, leukopenia, or thrombocytopenia Monitor WBC count frequently and adjust dose to maintain count of 4000-7000/mcL Hemorrhagic cystitis and bladder carcinoma have been associated with cyclophosphamide

Drug Category: Antifibrotic agents -- Inhibit collagen synthesis by disrupting hydroxylation, glycosylation, and cross-linking. Colchicine has anti-inflammatory properties.

Drug Name	Colchicine -- Decreases leukocyte motility and phagocytosis observed in inflammatory responses.
Adult Dose	0.6 mg PO qd/bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe renal, hepatic, GI, or cardiac disorders; blood dyscrasias
Interactions	Alcohol consumption and loop diuretics impair efficacy; impairs absorption of oral vitamin B-12
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Some adverse effects include peripheral neuritis, gastrointestinal disturbances (eg, nausea and vomiting), aplastic anemia, thrombocytopenia, agranulocytosis, dermatitis, and reversible azoospermia Patients are at risk for possible renal failure, hepatic failure, permanent hair loss, bone marrow suppression and anemia, numbness or tingling in hands and feet, disseminated intravascular coagulopathy, and decreased sperm count (in males)

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 animals and in humans. Efficacy of interferon-gamma has shown promising result in a small group of patients. A multicenter, double-blind, placebo-controlled study using interferon-beta and involving approximately 167 patients with IPF is in progress.

Drug Name	Interferon-gamma-1b (Actimmune) -- Class-II interferon produced by T cells and natural killer cells. Effects are similar to those of class-I interferons but differ in having strong stimulating effects on the immune system. Ziesche et al reported that their 9 patients treated with interferon-gamma-1b and low-dose steroids over 12 months showed improvement in oxygenation and lung function.
Adult Dose	200 mcg SC 3 times/wk with 7.5 mg of prednisolone PO qd for a period of 12 mo
Pediatric Dose	Not established.
Contraindications	Documented hypersensitivity, arrhythmias, congestive heart failure, seizure disorder, patients on myelosuppressive agents
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
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Flulike symptoms may be minimized by administering at bedtime 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 enzymes, skin rash, erythema, and tenderness

FOLLOW-UP

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, PFTs, chest radiographs, and HRCT should be monitored frequently following the initiation of treatment.

• Patients incapacitated with dyspnea should be evaluated for pulmonary rehabilitation.

• Encourage cessation of cigarette smoking.

• Recommend an annual Haemophilus influenzae vaccination.

In/Out Patient Meds:

• Treat patients with corticosteroids or cytotoxic or antifibrotic agents.

Transfer:

• Transfer to transplant center is considered in younger patients who are not responding to corticosteroids or cytotoxic or antifibrotic agents. Consider lung transplantation for an otherwise healthy patient younger than 60 years who has experienced progressive pulmonary dysfunction and deterioration despite maximal medical and supportive care. The single-lung transplant 2-year survival rate is approximately 70% for patients with IPF.

• Transfer to pulmonary rehabilitation center is considered for incapacitated patients with dyspnea.

Complications:

• Adverse drug effects (closely monitor)

• Cor pulmonale

• Pneumothorax

• Infection

• Carcinoma

• Thromboembolism diseases

Prognosis:

• The following factors are associated with a more favorable outcome:

• Younger age

• Female sex

• Short duration of symptoms

• Less severe degree of physiological or radiological impairment

• Increased lymphocytes in BAL fluids

• HRCT consistent with a ground-glass pattern

Patient Education:

• Compliance with medications

• Awareness of adverse effects of corticosteroids and cytotoxic or antifibrotic agents

MISCELLANEOUS

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