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 more 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

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

Troy LK, Grainge C, Corte TJ, et al. Diagnostic accuracy of transbronchial lung cryobiopsy for interstitial lung disease diagnosis (COLDICE): a prospective, comparative study. Lancet Respir Med. 2020; 8:171-181. Direct comparisons of cryobiopsy and surgical biopsy results in the same patient are scarce. This study compared diagnostic accuracy by doing sequential procedures in 65 patients with mean FVC 84% predicted. Masked pathologists examined the slides with histopathologic agreement achieved in 70.8% of patients. With incorporation of pathology into multi-disciplinary discussions, diagnostic agreement was 76.4%. Among the 40% (26 patients) with a non-diagnostic cryobiopsy, surgical biopsy provided a confident diagnosis in 26% (6 patients). Of note, the study was not designed to assess the safety of the individual procedures.
PMID 31578168

Idiopathic Pulmonary Fibrosis:

Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2022; 205:e18-e47. This guideline provides updates on IPF including diagnostic criteria, conditional recommendation for use of cryobiopsy, as well as a conditional recommendation against anti-acid therapy and surgery. Progressive pulmonary fibrosis is defined for deteriorating patients with ILD other than IPF, with a conditional recommendation for nintedanib treatment in this group. 
PMID: 35486072
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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.
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. The INBUILD RCT enrolled 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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Wells AU, Flaherty KR, Brown KK, et al. INBUILD trial investigators. Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomized, double-blind, placebo-controlled, parallel-group trial. Lancet Respir Med. 2020; 8:453-460. This subgroup analysis within the INBUILD trial suggests nintedanib slows ILD progression regardless of underlying ILD diagnosis.
PMID: 32145830
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Waxman A,Restrepo-Jaramillo R, Thenappan T,  et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. New Engl J Med. 2021; 348:325-34. RCT of 326 patients with pulmonary hypertension and ILD found inhalation of treprostinil qid resulted in a 31-meter difference in the 6 minute walk (the primary study outcome), improving by about 20 meters in the intervention group vs. 10 meter decline in controls (minimally important clinical difference is 30 meters). The accompanying editorial notes short trial duration (16 weeks), lack of improved quality of life, missing outcome data, and need to assess hospitalization and mortality as reasons for further trials.
PMID: 33440084


Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and detection of sarcoidosis. An Official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020; 201:e26-e51. This comprehensive diagnostic guideline includes recommendations on when to perform lymph node biopsy and screen for extra-pulmonary disease, as well as extensive differentials to consider based on biopsy and clinical findings. The strength of recommendations is uniformly low owing to a lack of supporting studies.
PMID: 32293205
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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:

Raghu G, Remy-Jardin M, Ryerson CJ, et al. Diagnosis of hypersensitivity pneumonitis in adults. An Official ATS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2020; 202:e36-e69. This guideline provides a detailed review of diagnostic strategies for hypersensitivity pneumonitis with a focus on potential antigens, high resolution CT findings, and histopathological criteria. Noteworthy for changing HP nomenclature to fibrosing and non-fibrosing types with recommendations tailored to these categories.
PMID: 33385222
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Fernández Pérez ER, Travis WD, Lynch DA, et al. Diagnosis and evaluation of hypersensitivity pneumonitis: CHEST guideline and expert panel report. Chest 2021; 160:e97-e156. This guideline addresses 14 PICO-based questions and offers practical guidance, although primarily comprised of weak recommendations in light of limited evidence.
PMID: 33861992

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 influenced 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. RCT of 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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Khanna D, Lin CJF, Furst DE, et al. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2020; 8:963-974. The primary outcome of improved skin score was negative in this trial of 210 patients with systemic sclerosis, but the study is noteworthy for being the basis for the FDA approval of tocilizumab for treatment of SSc-induced ILD. The mean decline in % predicted FVC was - 3.9 in the placebo group vs. – 0.6 in the tocilizumab group at 48 weeks.
PMID: 32866440

Sjögren's Lung Disease:

Lee AS, Scofield RH, Hammitt KM, et al. Consensus guidelines for evaluation and management of pulmonary disease in Sjögren's. Chest. 2021; 159: 683–698. This article provides comprehensive guidance on the evaluation and management of the full spectrum of Sjögren's patients, from at risk but disease free to those with advanced fibrotic lung disease. 
PMID: 33075377
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