> Table of Contents > Diffuse Interstitial Lung Disease
Diffuse Interstitial Lung Disease
Jacqueline L. Olin, MS, PharmD, BCPS, FASHP, FCCP
J. Andrew Woods, PharmD, BCPS
Brian Hertz, MD
image BASICS
  • Interstitial lung diseases (ILDs) represent a diverse group of chronic progressive lung diseases associated with alveolar inflammation and/or potentially irreversible pulmonary fibrosis.
  • >200 individual diseases may present with similar characteristics, making ILD difficult to classify.
  • A classification scheme proposed by the American Thoracic Society and European Respiratory Society includes these subtypes:
    • Known causes (environmental, occupational, or drug-associated disease)
    • Systemic disorders (e.g., sarcoidosis, Wegener granulomatosis, collagen vascular disease)
    • Rare lung diseases (e.g., pulmonary histiocytosis, lymphangioleiomyomatosis)
    • Idiopathic interstitial pneumonias (IIPs)
  • Based on clinical, radiologic, and histologic features, IIPs are further subclassified into the following diagnoses (1):
    • Major IIPs, including idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), respiratory bronchiolitis-associated ILD (cryptogenic organizing pneumonia [COP], etc.)
    • Rare IIPs
    • Unclassifiable IIPs
  • Classification of IIPs and relationships between the subtypes are difficult to classify due to mixed patterns of injury (1).
Pediatric Considerations
ILD in infants and children represents a heterogeneous group of respiratory disorders. Diseases result from a variety of processes involving genetic factors and inflammatory or fibrotic responses, and processes are distinct from those that cause ILD in adults (2). Some diseases result from developmental disorders and growth abnormalities in infancy (2,3). After common causes are excluded, referral of infants to a subspecialist is recommended (2).
  • Exact incidence and prevalence are difficult to determine because of differences in case definitions and procedures used in diagnosis.
  • Cited incidence of IPF in the United States: 16.3 to 17.4/100,000 (4) and pediatric ILD of 1.32/1,000,000 (3)
Cited prevalence of IPF in the United States: 42.7 to 63 cases/100,000 in the general population (4) and pediatric ILD of 3.6/1 million (3)
  • Alveolar inflammation may progress into irreversible fibrosis.
  • Varying degrees of ventilatory dysfunction occur among the ILD subtypes.
  • ILD associated with collagen vascular disease and systemic connective disorders can manifest involvement of skin, joints, muscular, and ocular systems.
  • Some types of ILD are associated with specific exposures:
    • Medications (amiodarone, antibiotics [especially nitrofurantoin], chemotherapy agents, gold, illicit drugs)
    • Inorganic dusts (silicates, asbestos, talc, mica, coal dust, graphite)
    • Organic dusts (moldy hay, inhalation of fungi, bacteria, animal proteins)
    • Metals (tin, aluminum, cobalt, iron, barium)
    • Gases, fumes, vapors, aerosols
Some subtypes of ILD may be associated with specific predisposing genes and environmental exposures; however, the role of genetic factors is unknown.
  • Environmental or occupational exposure to inorganic or organic dusts
  • 66-75% of patients with ILD have a history of smoking.
  • Due to diversity of diseases, age is not a reliable predictor of pathology:
    • Most patients with connective tissue disease-related pathology and inherited subtypes present between ages 20 and 40 years.
    • Median age of patients with IPF is 66 years. Studies of clinical predictors of survival including age, ethnicity, and smoking status have been inconsistent (5).
Avoiding environmental/occupational exposure to organic or inorganic dust and smoking cessation may reduce incidence or improve clinical course in patients with established ILD.
Many systemic disorders and primary diseases are associated with ILD. A partial list includes the following:
  • Collagen vascular disease
  • Sarcoidosis
  • Amyloidosis
  • Goodpasture syndrome
  • Churg-Strauss syndrome
  • Wegener granulomatosis
  • Accurate diagnosis is imperative, as treatment choices and prognosis can vary with pathogenesis.
  • Diagnosis of IPF requires exclusion of other known ILD causes, the presence of a UIP pattern on high-resolution computed tomography (HRCT), and/or surgical lung biopsy pattern (6).
Physical findings are usually nonspecific. Some common features includes the following:
  • Crackles (typically present on auscultation of lung bases on posterior axillary line)
  • Rales
  • Inspiratory “squeaks”
  • Clubbing of the digits and cyanosis in advanced disease
  • Acute pulmonary edema
  • Diffuse hemorrhage
  • Atypical pneumonia
  • Diffuse bronchoalveolar cell carcinoma or lymphatic spread of tumor
Initial Tests (lab, imaging)
  • O2 saturation
  • Peak expiratory flow rate
  • CBC with differential, comprehensive metabolic profile
  • CRP or sedimentation rate
  • Chest x-ray (CXR): most commonly reticular pattern, less commonly nodular or mixed patterns
Follow-Up Tests & Special Considerations
HRCT of the chest is the most useful tool for distinguishing among ILD subclasses, especially if normal CXRs:
  • If indicated, arterial blood gas (ABG), hypersensitivity pneumonitis panel, plasma ACE inhibitor concentration (sarcoidosis)
  • If a systemic disorder is suspected, consider antinuclear antibody (ANA), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and antineutrophil cytoplasmic antibodies (ANCA).
Diagnostic Procedures/Other
  • Pulmonary function testing (PFT; spirometry, lung volumes, carbon monoxide diffusing capacity)
    • Commonly demonstrates a restrictive defect (decreased vital capacity and total lung capacity)
    • Forced vital capacity (FVC) has been shown to decline 100 to 200 mL/year in the placebo arm of IPF patients in clinical trials (5).
  • Bronchoscopy
    • Bronchoalveolar lavage (BAL) cellular analysis studies may be useful in distinguishing subtypes (including sarcoidosis, hypersensitivity pneumonitis, cancer). If performed, the BAL target site should be chosen based on the HRCT finding (7).
    • Bronchoscopic transbronchial lung biopsy may help diagnose sarcoidosis and, on occasion, is sufficiently supportive of other ILD diagnoses.
  • Thoracoscopic surgery for lung biopsy has the greatest diagnostic specificity for ILDs but is less frequently used given improved specificity of HRCT. May be indicated if a diagnosis cannot be determined from transbronchial biopsy or HRCT
Test Interpretation
  • Diagnostic classifications of IIPs are based on histopathologic patterns seen on lung biopsy.
  • Major histologies include an inflammation and fibrotic and granulomatous patterns.
  • Characteristic changes on HRCT may help to distinguish between the following subtypes:
    • Reticulonodular, ground glass opacities, and, in later stages, honeycombing may be seen.
    • Associated hilar and mediastinal adenopathy are characteristic of stage I and II sarcoidosis.
  • No specific test is the gold standard, which emphasizes the importance of a multidisciplinary consensus for diagnosis with clinical, radiologic, and pathologic findings.

  • Evidence does not support the routine use of any specific therapy for ILD in general, and especially IPF (6).
  • No survival benefit of home oxygen use in ILD (8)[A].
  • Corticosteroids have a role in some ILD subtypes (9)[A].
  • Current evidence does not clearly support routine use of noncorticosteroid anti-inflammatory agents for IPF, including cyclosporine, azathioprine, colchicines, cyclophosphamide, cytokines, bosentan, etanercept, methotrexate, N-acetylcysteine, or interferon.
  • Clinical trials have indicated that anticoagulation (warfarin) and endothelin receptor antagonists (ambrisentan, bosentan) are ineffective, potentially harmful, and therefore not recommended in the treatment of IPF.
  • Lung transplant among selected IPF patients has demonstrated median survival of 4.5 years (10)[A].
  • Avoid/minimize offending environmental/occupational exposures/medications.
  • Smoking cessation
  • Supplemental oxygen, if indicated
First Line
  • Corticosteroids are most effective for certain ILDs, especially exacerbations of sarcoidosis, NSIP, COP, and hypersensitivity pneumonitis. However, response rates have been variable across and within subtypes. The optimal dose and duration of therapy are unknown.
  • Common starting dose of prednisone is 0.5 to 1 mg/kg/day for 4 to 12 weeks, with potential up-titration to 0.5 mg/kg based on patient response.
Second Line
  • Two antifibrotic agents were approved in 2014 for IPF, which have demonstrated modest slowing of FVC decline over 52 weeks compared to placebo. Both medications decreased all-cause mortality rates. Longer term studies are not yet available. It is not clear if FVC is the most conclusive meaningful efficacy variable for IPF.
    • Pirfenidone (Esbriet), an orally active antifibroblast agent has demonstrated a favorable risk-to-benefit profile in three randomized, placebo-controlled trials of IPF patients with mild-to-moderate impairment of lung function. The ASCEND trial demonstrated that pirfenidone led to a significant reduction in rate of decline in FVC compared with placebo. Notable secondary endpoints include the following: significant improvement in progression-free survival; in pooled analysis that included patients from other phase 3 trials, there was a significant reduction in all-cause death as well as death from IPF. Adverse effects from the ASCEND trial were GI related (nausea, vomiting, anorexia, weight loss, GERD, and dyspepsia), rash, insomnia, dizziness, fatigue, and aminotransferase elevation. Most were mild to moderate in nature and did not result in pirfenidone discontinuation. Pirfenidone is not recommended for patients with severe liver impairment or ESRD (requiring dialysis) (11)[A].
    • Pirfenidone is titrated over 2 weeks to 801 mg orally 3 times daily with food.
    • Nintedanib (Ofev), a tyrosine kinase inhibitor, reduced the annual rate of decline in FVC and fewer acute exacerbations occurred compared to placebo. The most common adverse effects are GI upset (nausea, vomiting, diarrhea, abdominal pain), anorexia, aminotransferase elevation, and hypertension. It is not recommended in moderate to severe liver impairment and can cause birth defects (12)[A].
    • Nintedanib is given at 150 mg orally twice daily with food.
  • The addition of tacrolimus to corticosteroids (with cyclosporine, cyclophosphamide, or no additional therapy) demonstrated improved event-free survival in patients with ILD complicated with polymyositis or dermatomyositis (13)[A].
  • Several second-line agents have been used in Wegener granulomatosis:
    • Cyclophosphamide is commonly used in treatment of Wegener granulomatosis. It is given 1.5 to 2 mg/kg/day PO for 3 to 6 months.
    • Methotrexate has been used in treatment of mild Wegener granulomatosis in combination with corticosteroids. A studied dosing regimen consisted of an initial methotrexate dose of 0.3 mg/kg (maximum dose of 15 mg) once weekly, with 2.5 mg titration each week (maximum dose of 25 mg/week).
    • Other second-line agents that have been studied include mycophenolate, mofetil, and rituximab.
Single- or double-lung transplantation may be a treatment of last resort. Some ILDs associated with systemic disease may recur in the recipient lung.
Follow-up testing should include PFTs, cardiopulmonary stress test, pulse oximetry, and CXR.
National Heart, Lung, and Blood Institute: http://www.nhlbi.nih.gov/health/health-topics/topics/ipf/
IPF confers the worst prognosis (median survival of 2.5 to 3 years) (5). A clinical prediction model to estimate the risk of death from ILD has been described (14). Other subtypes, including hypersensitivity pneumonitis, nonspecific interstitial pneumonia, and cryptogenic organizing pneumonia, have a good prognosis.
1. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733-748.
2. Kurland G, Deterding RR, Hagood JS, et al. An official American Thoracic Society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy. Am J Respir Crit Care Med. 2013;188(3):376-394.
3. Cazzato S, di Palmo E, Ragazzo V, et al. Interstitial lung disease in children. Early Hum Dev. 2013; 89(Suppl 3): S39-S43.
4. Nalysnyk L, Cid-Ruzafa J, Rotella P, et al. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev. 2012;21(126):355-361.
5. Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(4): 431-440.
6. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824.
7. Meyer KC, Raghu G, Baughman RP, et al. An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med. 2012;185(9):1004-1014.
8. Crockett A, Cranston JM, Antic N. Domiciliary oxygen for interstitial lung disease. Cochrane Database Syst Rev. 2010;(3):CD002883.
9. Richeldi L, Davies HR, Ferrara G, et al. Corticosteroids for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev. 2009;(3):CD002880.
10. Kistler KD, Nalysnyk L, Rotella P, et al. Lung transplantation in idiopathic pulmonary fibrosis: a systematic review of the literature. BMC Pulm Med. 2014;14:139.
11. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-2092.
12. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22): 2071-2082.
13. Kurita T, Yasuda S, Oba K, et al. The efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis. Rheumatology (Oxford). 2015;54(8):1536.
14. Ryerson CJ, Vittinghoff E, Ley B, et al. Predicting survival across chronic interstitial lung disease: the ILD-GAP model. Chest. 2014;145(4):723-728.
Additional Reading
  • Martinez FJ, de Andrade JA, Anstrom KJ, et al. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22): 2093-2101.
  • Noth I, Anstrom KJ, Calvert SB, et al. A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;186(1):88-95.
  • Spagnolo P, Del Giovane C, Luppi F, et al. Nonsteroid agents for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev. 2010;(9):CD003134.
  • J84.9 Interstitial pulmonary disease, unspecified
  • J84.10 Pulmonary fibrosis, unspecified
  • J84.111 Idiopathic interstitial pneumonia, not otherwise specified
Clinical Pearls
  • ILD differs from chronic obstructive pulmonary disease (COPD); anatomically, ILD involves the lung parenchyma (i.e., alveoli) and COPD involves both airways and alveoli.
  • In some cases, avoiding or minimizing offending environmental/occupational exposures, medications, and smoking may alter disease severity.