Risk factors for ILD progression 

A proportion of patients with non-IPF ILDs may develop progressive pulmonary fibrosis1–4

Three patients holding lung scan results in their hands.


The progressive fibrosing phenotype is characterized by increased extent of fibrosis, worsening respiratory symptoms and lung function decline2–5


Patients with extensive fibrotic lung disease are at the greatest risk of ILD progression6

Generalizable risk factors for progression of ILD6


UIP pattern

Extensive traction bronchiectasis

Treatment response

No disease regression or stablization with initial therapy

Other conditions

Short telomere syndrome




Older patients with a UIP pattern of pulmonary fibrosis on HRCT decline at the greatest rate6



In patients with HP, risk factors associated with ILD progression, or acute exacerbation of ILD, include antigen identification, fibrosis on HRCT, DLCO % predicted, pulmonary hypertension, and serum KL-6, YKL-40 and CCL177

Continued exposure to an inciting antigen causes disease progression and development of fibrosis in HP8

  • In patients with cHP, the inability to identify the inciting antigen is a significant predictor of shortened survival9
  • In patients with HP, an inciting antigen should be screened for, identified and removed9
  • All patients with HP should be encouraged to avoid potential sources of antigen exposure9

The nature and quantity of the inhaled antigen, intensity and frequency of exposure, environmental cofactors, and interaction of the offending antigens with the immune response can influence development and progression of HP7


In patients with iNSIP, male sex, initial TLC, decline in FVC at 3 months and the presence of honeycombing on HRCT are predictors of progressive deterioration.10


Risk factors for ILD progression in CTD-ILDs11–21


  • Extent of ILAs11,12

  • UIP pattern13

  • Lower baseline FVC or DLco13,14

  • High baseline concentration of KL-615


  • Male Sex16

  • Older age17

  • dcSSc18

  • GER19

  • High baseline mRSS19,20

  • Elevated KL-6 level21

           How can you monitor and manage your patients at risk of ILD progression?

  • CCL17, chemokine ligand 17; cHP, chronic hypersensitivity pneumonitis; CTD-ILD, connective tissue disease-associated interstitial lung disease; dsSSc, diffuse cutaneous systemic sclerosis; DLCO, diffusing capacity of the lung for carbon; FVC, forced vital capacity; GER, gastroesophageal reflux; HP, hypersensitivity pneumonitis; HRCT, high-resolution computed tomography; ILA, interstitial lung abnormality; ILD, interstitial lung disease; iNSIP, idiopathic non-specific interstitial pneumonia; IPF, idiopathic pulmonary fibrosis; KL-6, Krebs von den Lungen-6; mRSS, modified Rodnan skin score; RA-ILD, rheumatoid arthritis-associated interstitial lung disease; SSc-ILD, systemic sclerosis-associated interstitial lung disease; TLC, total lung capacity; UIP, usual interstitial pneumonia; YKL-40, chitinase-3-like protein 1.

  1. Wijsenbeek M, Kreuter M, Olson A, et al. Progressive fibrosing interstitial lung diseases: current practice in diagnosis and management. Curr Med Res Opin. 2019;35(11):2015–2024.

  2. Cottin V, Hirani N, Hotchkin D, et al. Presentation, diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases. Eur Respir Rev. 2018;27(150):180076.

  3. Kolb M, Vašáková M. The natural history of progressive fibrosing interstitial lung diseases. Respir Res. 2019;20(1).

  4. Cottin V, Wollin L, Fischer A, et al. Fibrosing interstitial lung diseases: knowns and unknowns. Eur Respir Rev. 2019b;28(151):pii:180100.

  5. Flaherty KR, et al. Design of the PF-ILD trial: a double-blind, randomised, placebo-controlled phase III trial of nintedanib in patients with progressive fibrosing interstitial lung disease. BMJ Open Respir Res. 2017;4(1):e000212.

  6. George PM, Spagnolo P, Kreuter M, et al. Progressive fibrosing interstitial lung disease: clinical uncertainties, consensus recommendations, and research priorities. Lancet Respir Med. 2020;8:925–954.

  7. Costabel U, Miyazaki Y, Pardo A, et al. Hypersensitivity pneumonitis. Nat Rev Dis Primers. 2020;6:65. 

  8. Varone F, Iovene B, Sgalla G, et al. Fibrotic Hypersensitivity Pneumonitis: Diagnosis and Management. Lung. 2020; https://doi.org/10.1007/s00408-020-00360-3. 

  9. Fernández Pérez ER, Swigris JJ, Forssén AV, et al. Identifying an inciting antigen is associated with improved survival in patients with chronic hypersensitivity pneumonitis. Chest. 2013;144:1644–1651.

  10. Park IN, Jegal Y, Kim DS, et al. Clinical course and lung function change of idiopathic nonspecific interstitial pneumonia. Eur Respir J. 2009;33:68–76.

  11. Dawson JK, Fewins HE, Desmond J, et al. Predictors of progression of HRCT diagnosed fibrosing alveolitis in patients with rheumatoid arthritis. Ann Rheum Dis. 2002;61:517–521.

  12. Kawano-Dourado L, Doyle TJ, Bonfiglioli K, et al. Baseline characteristics and progression of a spectrum of interstitial lung abnormalities and disease in rheumatoid arthritis. Chest. 2020:S0012-3692(20)31412-4. doi: 10.1016/j.chest.2020.04.061.

  13. Zamora-Legoff JA, Krause ML, Crowson CS, et al. Progressive decline of lung function in rheumatoid arthritis associated interstitial lung disease. Arthritis Rheumatol. 2017;69(3):542–549.

  14. Esposito AJ, Chu SG, Madan R, et al. Thoracic manifestations of rheumatoid arthritis. Clin Chest Med. 2019;40(3):545–560.

  15. Avouac J, Cauvet A, Steelandt A, et al. Improving risk-stratification of rheumatoid arthritis patients for interstitial lung disease. PLoS One. 2020;15(5):e0232978. doi:10.1371/journal.pone.0232978.

  16. Winstone TA, Assayag D, Wilcox PG, et al. Predictors of mortality and progression in scleroderma-associated interstitial lung disease: a systematic review. Chest. 2014;146:422–436.

  17. Cappelli S, Bellando Randone S, Camiciottoli G, et al. Interstitial lung disease in systemic sclerosis: where do we stand? Eur Respir Rev. 2015;24:411–419.

  18. Nihtyanova SI, Schreiber BE, Ong VH, et al. Prediction of pulmonary complications and long–term survival in systemic sclerosis. Arthritis Rheumatol. 2014;66: 1625–1635.

  19. Hoffmann-Vold AM, Allanore Y, Alves M, et al. Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis. 2020;217455.

  20. Wu W, Jordan S, Becker MO, et al. Prediction of progression of interstitial lung disease in patients with systemic sclerosis: the SPAR model. Ann Rheum Dis. 2018;77:1326–1332.

  21. Volkmann, Elizabeth R, Tashkin DP, et al. Progression of interstitial lung disease in systemic sclerosis: the importance of pneumoproteins Krebs von den Lungen 6 and CCL18. Arthritis Rheumatol. 2019b;71:2059–2067.

  22. Maher TM, Molina-Molina M, Russell AM, et al. Unmet needs in the treatment of idiopathic pulmonary fibrosis-insights from patient chart review in five European countries. BMC Pulm Med. 2017;17(1):124.

  23. Molina-Molina M, Aburto M, Acosta O, et al. Importance of early diagnosis and treatment in idiopathic pulmonary fibrosis. Exp Rev Resp Med. 2018;12(7):537–539.

  24. Robalo-Cordeiro C, Campos P, Carvalho L, et al. Idiopathic pulmonary fibrosis in the era of antifibrotic therapy: Searching for new opportunities grounded in evidence. Rev Port Pneumol. 2017;23(5):287–293.

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