Skip to main content
SpringerLink
Log in

Biomarkers in interstitial lung disease: moving towards composite indexes and multimarkers?

  • Interstitial Lung Disease (E Alhamed, Section Editor)
  • Published:
Current Pulmonology Reports Aims and scope Submit manuscript

Abstract

Interstitial lung disease (ILD) covers a large spectrum of lung disorders that affects the parenchyma and is often associated with inflammation and/or fibrosis. Clinically, there is a great need for biomarker development for these disorders, to help diagnosis, treatment selection and assessment of efficacy as well as to predict progression. Thus far, no broadly validated biomarker exists for ILD, due to the existence of a very large number of disorders of often-unknown etiology, overlapping symptoms and disorders associated with a spectrum of multi-morbidities involving similar chronic inflammatory and fibrotic biochemical processes. We discuss here the development of biomarkers in IPF, sarcoidosis, connective tissue disease-associated ILD (CTD-ILD), and chronic hypersensitivity pneumonitis. We further discuss the need and opportunity to develop a multimarker approach that would be clinically meaningful for patients with ILD. Such composite index could include clinical symptoms, pathological assessment, and lung physiology measurements added to molecular information derived from bronchoalveolar lavage and serum. We also discuss the increased opportunity for patients to be involved in research as recent technological advances now allow the serial measurement of lung function using handheld spirometers, combined with handheld devices allowing measurement of patient reported outcomes, mobility, exercise, and sleep.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Travis WD, Costabel U, Hansell DM, King Jr TE, Lynch DA, Nicholson AG, 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;188:733–48.

    Article  PubMed  Google Scholar 

  2. Antoniou KM, Margaritopoulos GA, Tomassetti S, Bonella F, Costabel U, Poletti V. Interstitial lung disease. Eur Respir Rev. 2014;23:40–54.

    Article  PubMed  Google Scholar 

  3. Meyer KC. Diagnosis and management of interstitial lung disease. Transl Respir Med. 2014;2:4.

    Article  PubMed Central  PubMed  Google Scholar 

  4. King Jr TE, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083–92.

    Article  PubMed  Google Scholar 

  5. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071–82.

    Article  PubMed  Google Scholar 

  6. Hambly N, Chimbori C, Kolb M. Molecular classification of IPF: personalized medicine, genetics, and biomarkers. Respirology. 2015. doi:10.1111/resp.12569.

    PubMed  Google Scholar 

  7. Yang G, Yang L, Wang W, Wang J, Wang J, Xu Z. Discovery and validation of extracellular/circulating microRNAs during idiopathic pulmonary fibrosis disease progression. Gene. 2015;562:138–44.

    Article  CAS  PubMed  Google Scholar 

  8. Ten Klooster L, van Moorsel CH, Kwakkel-van Erp JM, van Velzen-Blad H, Grutters JC. IgA in serum: an old acquaintance as a new prognostic biomarker in Idiopathic Pulmonary Fibrosis. Clin Exp Immunol. 2015.

  9. Tajiri M, Okamoto M, Fujimoto K, Johkoh T, Ono J, Tominaga M, et al. Serum level of periostin can predict long-term outcome of idiopathic pulmonary fibrosis. Respir Investig. 2015;53:73–81.

    Article  PubMed  Google Scholar 

  10. Schiza S, Mermigkis C, Margaritopoulos GA, Daniil Z, Harari S, Poletti V, et al. Idiopathic pulmonary fibrosis and sleep disorders: no longer strangers in the night. Eur Respir Rev. 2015;24:327–39.

    Article  PubMed  Google Scholar 

  11. Saini G, Porte J, Weinreb PH, Violette SM, Wallace WA, McKeever TM, et al. alphavbeta6 integrin may be a potential prognostic biomarker in interstitial lung disease. Eur Respir J. 2015.

  12. Matsuzawa Y, Kawashima T, Kuwabara R, Hayakawa S, Irie T, Yoshida T, et al. Change in serum marker of oxidative stress in the progression of idiopathic pulmonary fibrosis. Pulm Pharmacol Ther. 2015.

  13. Lee RN, Kelly E, Nolan G, Eigenheer S, Boylan D, Murphy D, et al. Disordered breathing during sleep and exercise in idiopathic pulmonary fibrosis and the role of biomarkers. QJM. 2015;108:315–23.

    Article  CAS  PubMed  Google Scholar 

  14. Kim HJ, Brown MS, Chong D, Gjertson DW, Lu P, Kim HJ, et al. Comparison of the quantitative CT imaging biomarkers of idiopathic pulmonary fibrosis at baseline and early change with an interval of 7 months. Acad Radiol. 2015;22:70–80.

    Article  PubMed  Google Scholar 

  15. Kaarteenaho R, Lappi-Blanco E. Tissue is an issue in the search for biomarkers in idiopathic pulmonary fibrosis. Fibrogenesis Tissue Repair. 2015;8:3.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Jenkins RG, Simpson JK, Saini G, Bentley JH, Russell AM, Braybrooke R, et al. Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study. Lancet Respir Med. 2015;3:462–72. This important paper shows that patients with IPF have increased levels of extracellular matrix degradation protein fragments in serum, associated with disease progression and survival.

  17. DePianto DJ, Chandriani S, Abbas AR, Jia G, N’Diaye EN, Caplazi P, et al. Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis. Thorax. 2015;70:48–56.

    Article  PubMed  Google Scholar 

  18. Ley B, Brown KK, Collard HR. Molecular biomarkers in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2014;307:L681–91.

    Article  CAS  PubMed  Google Scholar 

  19. Seibold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364:1503–12.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Lee MG, Lee YH. A meta-analysis examining the association between the MUC5B rs35705950 T/G polymorphism and susceptibility to idiopathic pulmonary fibrosis. Inflamm Res. 2015;64:463–70.

    Article  CAS  PubMed  Google Scholar 

  21. Peljto AL, Zhang Y, Fingerlin TE, Ma SF, Garcia JG, Richards TJ, et al. Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. JAMA J Am Med Assoc. 2013;309:2232–9.

    Article  CAS  Google Scholar 

  22. Rosas IO, Richards TJ, Konishi K, Zhang Y, Gibson K, Lokshin AE, et al. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med. 2008;5:e93.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Ishikawa N, Hattori N, Yokoyama A, Kohno N. Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases. Respir Investig. 2012;50:3–13.

    Article  PubMed  Google Scholar 

  24. Durheim MT, Collard HR, Roberts RS, Brown KK, Flaherty KR, King Jr TE, et al. Association of hospital admission and forced vital capacity endpoints with survival in patients with idiopathic pulmonary fibrosis: analysis of a pooled cohort from three clinical trials. Lancet Respir Med. 2015;3:388–96. This paper identifies hospital admissions as an appropriate component of a meaningful composite endpoint.

    Article  PubMed  Google Scholar 

  25. Shigemitsu H, Azuma A. Sarcoidosis and interstitial pulmonary fibrosis; two distinct disorders or two ends of the same spectrum. Curr Opin Pulm Med. 2011;17:303–7.

    Article  PubMed  Google Scholar 

  26. Wessendorf TE, Bonella F, Costabel U. Diagnosis of sarcoidosis. Clin Rev Allergy Immunol. 2015.

  27. Ragusa F. Sarcoidosis and Th1 chemokines. Clin Ter. 2015;166:e72–6.

    CAS  PubMed  Google Scholar 

  28. Ahmadzai H, Loke WSJ, Huang S, Herbert C, Wakefield D, Thomas PS. Biomarkers in sarcoidosis: a review. Curr Biomark Find. 2014;4.

  29. Haggmark A, Hamsten C, Wiklundh E, Lindskog C, Mattsson C, Andersson E, et al. Proteomic profiling reveals autoimmune targets in sarcoidosis. Am J Respir Crit Care Med. 2015;191:574–83.

    Article  PubMed  Google Scholar 

  30. Castelino FV, Varga J. Interstitial lung disease in connective tissue diseases: evolving concepts of pathogenesis and management. Arthritis Res Ther. 2010;12:213.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Stone KB, Oddis CV, Fertig N, Katsumata Y, Lucas M, Vogt M, et al. Anti-Jo-1 antibody levels correlate with disease activity in idiopathic inflammatory myopathy. Arthritis Rheum. 2007;56:3125–31.

    Article  CAS  PubMed  Google Scholar 

  32. Saketkoo LA, Mittoo S, Huscher D, Khanna D, Dellaripa PF, Distler O, et al. Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials. Thorax. 2014;69:428–36.

    Article  PubMed  Google Scholar 

  33. Selman M, Pardo A, King Jr TE. Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am J Respir Crit Care Med. 2012;186:314–24.

    Article  CAS  PubMed  Google Scholar 

  34. Myers JL. Hypersensitivity pneumonia: the role of lung biopsy in diagnosis and management. Mod Pathol. 2012;25 Suppl 1:S58–67.

    Article  PubMed  Google Scholar 

  35. Akashi T, Takemura T, Ando N, Eishi Y, Kitagawa M, Takizawa T, et al. Histopathologic analysis of sixteen autopsy cases of chronic hypersensitivity pneumonitis and comparison with idiopathic pulmonary fibrosis/usual interstitial pneumonia. Am J Clin Pathol. 2009;131:405–15.

    Article  PubMed  Google Scholar 

  36. de Garcia Alba C, Buendia-Roldan I, Salgado A, Becerril C, Ramirez R, Gonzalez Y, et al. Fibrocytes contribute to inflammation and fibrosis in chronic hypersensitivity pneumonitis through paracrine effects. Am J Respir Crit Care Med. 2015;191:427–36.

    Article  Google Scholar 

  37. Moeller A, Gilpin SE, Ask K, Cox G, Cook D, Gauldie J, et al. Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009;179:588–94.

    Article  PubMed  Google Scholar 

  38. Sterclova M, Vasakova M, Paluch P, Paulik M. Surfactant protein A in chronic extrinsic allergic alveolitis. Eur Respir J. 2012;39:1543–4.

    Article  PubMed  Google Scholar 

  39. Ohnishi H, Miyamoto S, Kawase S, Kubota T, Yokoyama A. Seasonal variation of serum KL-6 concentrations is greater in patients with hypersensitivity pneumonitis. BMC Pulm Med. 2014;14:129.

    Article  PubMed Central  PubMed  Google Scholar 

  40. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007;117:524–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. De Lauretis A, Renzoni EA. Molecular biomarkers in interstitial lung diseases. Mol Diagn Ther. 2014;18:505–22. An excellent review on current lung and serum derived biomarkers tested in patients diagnosed with IPF and other ILD’s.

    Article  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Dr. Ask declares that they have no conflicts of interests.

Dr. Hambly reports grants from Intermune Canada Clincal Fellowship, personal fees from Boehringer Ingelheim, personal fees from Intermune Canada, grants from Intermune Canada, outside the submitted work.

Dr. Kolb reports grants from Canadian Institute for Health Research.

Human and Animal Rights and Informed Consent

This article contains no studies with human or animal subjects performed by the author.

Author information

Authors and Affiliations

  1. Department of Medicine, Department of Pathology and Molecular Medicine, Firestone Institute for Respiratory Health, The Research Institute of St Joe’s, McMaster University, Hamilton, ON, Canada

    Kjetil Ask & Martin R. J. Kolb

  2. Department of Medicine, Firestone Institute for Respiratory Health, The Research Institute of St Joe’s, McMaster University, Hamilton, ON, Canada

    Nathan Hambly

Authors
  1. Kjetil Ask
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nathan Hambly
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin R. J. Kolb
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kjetil Ask.

Additional information

This article is part of the Topical Collection on Interstitial Lung Disease

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ask, K., Hambly, N. & Kolb, M.R.J. Biomarkers in interstitial lung disease: moving towards composite indexes and multimarkers?. Curr Pulmonol Rep 4, 125–129 (2015). https://doi.org/10.1007/s13665-015-0123-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13665-015-0123-7

Keywords

Search

Navigation