Interstitial Lung Disease

Diagnosis and Overview

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;188:744-748. Written to standardize and update the diagnostic criteria and terminology for idiopathic interstitial pneumonias, this article nicely summarizes the clinical, radiologic, and histologic features of the ILD alphabet soup. Discusses recently described rare entities.

PMID: 24032382

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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;185:1004-14. This article offers some help in selecting patients most suitable for bronchoalveolar lavage. Arguably the greatest strength of the guideline is how it nicely pulls together clinical presentation and typical BAL findings for a wide spectrum of interstitial lung diseases, which is difficult to find assembled in one place.

PMID: 22550210

Larsen BT, Smith ML, Elicker BM, et al. Diagnostic approach to advanced fibrotic interstitial lung disease: bringing together clinical, radiologic, and histologic clues. Arch Pathol Lab Med. Epub 2016 Sep 15. doi: 10.5858/arpa.2016-0299-SA. A multidisciplinary review that provides overview of how to differentiate IPF from other progressive fibrotic lung disease such as chronic hypersensitivity pneumonitis and connective tissue disease-associated ILD.

PMID: 27628326

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Raj R,  Raparia K, Lynch DA,  et al. Surgical lung biopsy for interstitial lung diseases. Chest. 2017; 151:1131-40. Reviews the role of surgical lung biopsy in the diagnosis and treatment of interstitial lung disease with specific focus on when a biopsy can be diagnostic as well as when it should be avoided.

PMID: 27471113

Idiopathic Pulmonary Fibrosis

An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2018; 198:e44-e68. Updated guidelines on the diagnosis of IPF with an emphasis on high resolution CT scan patterns helping dictate clinical decision making.

PMID: 30168753

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Martinez FJ, Safrin S, Weycker D, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med 2005;142:963-7. This retrospective study of 168 patients with mild to moderate disease from the placebo arm of the IFN-gamma 1b study found minimal change in physiologic variables among survivors during the 72 weeks of follow-up. 19% of patients died of IPF-related causes, of whom 47% experienced rapid clinical deterioration. These results indicate IPF exacerbations in patients with milder disease are not uncommon, which has implications for listing for lung transplantation.

PMID: 15968010

IPF Treatment

The following studies of pirfenidone and nintedanib are the first to clearly establish treatment benefit  for patients with mild to moderate disease. Whether patients with severe IPF or usual interstitial pneumonia pathology associated with collagen vascular disease will also benefit remains to be seen.

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;370:2083-92. Year-long RCT of 555 patients with FVC 50 – 90% and DLCO 30 – 90% found pirfenidone slowed the rate of decline in FVC (23% vs. 9.7% placebo for no decline in FVC; 17% vs. 32% placebo for > 10% decline). Pirfenidone also improved the decline in 6-minute walk distance.

PMID: 24836312

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Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014; 370:2071-82. Year-long RCT of 515 patients with FVC > 50% and DLCO 30 – 79% found nintedanib slowed the rate of decline in FVC (- 115 ml vs – 240 ml for placebo over 1 year). Over 60% of nintedanib subjects experienced diarrhea vs. 19% in placebo group but < 5% discontinued study drug.

PMID: 24836310

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Other ILDs

Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung disease. N Engl J Med. 2019;381(18):1718-1727. RCT of 663 included patients with fibrosing lung disease affecting > 10% of  lung volume with progression in the past 24 months despite treatment. Randomization was stratified by UIP vs other fibrotic pattern. Overall adjusted rate of decline in FVC was -80.8 ml/year with nintedanib vs -187.8 ml/year with placebo (p<0.001). In patients with UIP pattern, adjusted rate of FVC decline was -82.9 ml/year with nintedanib vs -211.1 ml/year with placebo. Diarrhea was the most common side effect.

PMID: 31566307

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Wijsenbeek MS, Culver DA. Treatment of sarcoidosis. Clin Chest Med. 2015;36:751-67. A review addressing a number of questions related to the treatment of sarcoidosis, including when to initiate treatment, treatment strategies, and the use of collaborative decision making.

PMID: 26593147

Hypersensitivity Pneumonitis

Salisbury ML,  Myers JL, Belloli EA, et al. Diagnosis and treatment of fibrotic hypersensitivity pneumonia. where we stand and where we need to go. Am J Respir Crit Care Med. 2017; 196:690-9. A review of hypersensitivity pneumonitis that focuses on manifestations and phenotypes along with diagnostic and treatment strategies with a specific focus on fibrotic HP.

PMID: 28002680

Cryptogenic Organizing Pneumonia

Lazor R, Vandevenne A, Pelletier A, et al. Cryptogenic organizing pneumonia: characteristics of relapses in a series of 48 patients. Am J Respir Crit Care Med 2000; 162:571-7. This retrospective case series provides insight on the clinical course of COP and has had a large influence on the way corticosteroids are used to treat COP.

PMID: 10934089


Tashkin DP,  Roth MD, Clements PJ, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016; 4:708-19. Randomized controlled trial in 126 patients with scleroderma-related lung disease found 2 years of mycophenolate mofetil (MMF) treatment vs 1 year of cyclophosphamide treatment yielded similar small improvements in percent predicted FVC (2.19 vs 2.88 points, respectively, p = 0.24). MMF was better tolerated, suggesting it may be the preferred agent for scleroderma related ILD.

PMID: 27469583

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Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019; 380:2518-2528. RCT randomized 576 patients with systemic sclerosis and fibrosis affecting at least 10% of the lungs to nintedanib vs placebo. 48% of patients were on mycophenolate at baseline. The adjusted annual rate of change in FVC was -52.4 ml/year in nintedanib group vs -93.3 ml/year in placebo group (p=0.04). No difference in Rodnan skin score or SGRQ at 52 weeks. Most common side effect was diarrhea.

PMID: 31112379

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Travis WD, Hunninghake G, King TE, et al. Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project. Am J Respir Crit Care Med; 2008; 177:1338-47. Based on review by a panel of experts, idiopathic NSIP does exist as a distinct clinical entity. However, diagnosis appears challenging, as only 67 of 193 previously reported cases of NSIP were determined to have NSIP by the panel using a combination of clinical, radiologic, pathologic assessment.

PMID: 18388353