, Volume 42, Issue 2, pp 463–470 | Cite as

Calgranulin B and KL-6 in Bronchoalveolar Lavage of Patients with IPF and NSIP

  • David BennettEmail author
  • Martina Salvini
  • Annalisa Fui
  • Giuseppe Cillis
  • Paolo Cameli
  • Maria Antonietta Mazzei
  • Antonella Fossi
  • Rosa Metella Refini
  • Paola Rottoli


Idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP) are the most frequent idiopathic interstitial pneumonias. The aim of this study was to evaluate concentrations of calgranulin B and Krebs von den Lungen 6 (KL-6) in bronchoalveolar lavage (BAL) fluid of patients with IPF and idiopathic NSIP (i-NSIP) with fibrotic pattern. Thirty patients with IPF (68.73 ± 8.63 years), 30 with i-NSIP (68.33 ± 7.45 years), and healthy controls were included in the study. Calgranulin B and KL-6 both proved to be significantly higher in BAL of IPF and i-NSIP patients than in healthy controls (p < 0.05). Calgranulin B showed several significant correlations with functional parameters (oxygen demand at rest, 6-min walking test (6MWT), and PFTs); KL-6 was correlated with oxygen demand at rest and during 6MWT. Patients with higher concentrations of both biomarkers (> 75th percentile) had more advanced disease with lower values of FEV1%, FVC%, RV%, TLC%, DLCO% of predicted, distance walked in 6MWT, and BAL neutrophil percentage. Calgranulin B and KL-6 in BAL proved to be reliable biomarkers of IPF and i-NSIP and to have prognostic meaning, discriminating severe and advanced patients. The combination of the two biomarkers can facilitate the stratification of severity.

Key Words

biomarkers bronchoalveolar lavage calgranulin B KL-6 idiopathic pulmonary fibrosis non-specific interstitial pneumonia 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

10753_2018_955_MOESM1_ESM.docx (68 kb)
ESM 1 (DOCX 67 kb)


  1. 1.
    Travis, W.D., U. Costabel, D.M. Hansell, T.E. King Jr., D.A. Lynch, A.G. Nicholson, C.J. Ryerson, J.H. Ryu, M. Selman, A.U. Wells, J. Behr, D. Bouros, K.K. Brown, T.V. Colby, H.R. Collard, C.R. Cordeiro, V. Cottin, B. Crestani, M. Drent, R.F. Dudden, J. Egan, K. Flaherty, C. Hogaboam, Y. Inoue, T. Johkoh, D.S. Kim, M. Kitaichi, J. Loyd, F.J. Martinez, J. Myers, S. Protzko, G. Raghu, L. Richeldi, N. Sverzellati, J. Swigris, D. Valeyre, and ATS/ERS Committee on Idiopathic Interstitial Pneumonias. 2013. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. American Journal of Respiratory and Critical Care Medicine 188 (6): 733–748.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Raghu, G., H.R. Collard, J.J. Egan, F.J. Martinez, J. Behr, K.K. Brown, T.V. Colby, J.F. Cordier, K.R. Flaherty, J.A. Lasky, D.A. Lynch, J.H. Ryu, J.J. Swigris, A.U. Wells, J. Ancochea, D. Bouros, C. Carvalho, U. Costabel, M. Ebina, D.M. Hansell, T. Johkoh, D.S. Kim, T.E. King Jr., Y. Kondoh, J. Myers, N.L. Müller, A.G. Nicholson, L. Richeldi, M. Selman, R.F. Dudden, B.S. Griss, S.L. Protzko, H.J. Schünemann, and ATS/ERS/JRS/ALAT committee on idiopathic pulmonary fibrosis. 2011. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. American Journal of Respiratory and Critical Care Medicine 183 (6): 788–824.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Katzenstein, A.L., and R.F. Fiorelli. 1994. Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. The American Journal of Surgical Pathology 18: 136–147.CrossRefPubMedGoogle Scholar
  4. 4.
    Tzouvelekis, A., J. Herazo-Maya, K. Sakamoto, and D. Bouros. 2016. Biomarkers in the evaluation and management of idiopathic pulmonary fibrosis. Current Topics in Medicinal Chemistry 16 (14): 1587–1598.CrossRefPubMedGoogle Scholar
  5. 5.
    Yokoyama, A., K. Kondo, M. Nakajima, T. Matsushima, T. Takahashi, M. Nishimura, M. Bando, Y. Sugiyama, Y. Totani, T. Ishizaki, H. Ichiyasu, M. Suga, H. Hamada, and N. Kohno. 2006. Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis. Respirology 11 (2): 164–168.CrossRefPubMedGoogle Scholar
  6. 6.
    Sakamoto, K., H. Taniguchi, Y. Kondoh, T. Johkoh, H. Sumikawa, T. Kimura, O. Nishiyama, K. Kato, K. Kataoka, K. Ono, M. Kitaichi, and Y. Hasegawa. 2010. Serum KL-6 in fibrotic NSIP: correlations with physiologic and radiologic parameters. Respiratory Medicine 104 (1): 127–133.CrossRefPubMedGoogle Scholar
  7. 7.
    Bonella, F., X. Long, S. Ohshimo, Y. Horimasu, M. Griese, J. Guzman, N. Kohno, and U. Costabel. 2016. MUC1 gene polymorphisms are associated with serum KL-6 levels and pulmonary dysfunction in pulmonary alveolar proteinosis. Orphanet Journal of Rare Diseases 11: 48.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bonella, F., A. Volpe, P. Caramaschi, C. Nava, P. Ferrari, K. Schenk, S. Ohshimo, U. Costabel, and M. Ferrari. 2011. Surfactant protein D and KL-6 serum levels in systemic sclerosis: correlation with lung and systemic involvement. Sarcoidosis, Vasculitis, and Diffuse Lung Diseases 28 (1): 27–33.PubMedGoogle Scholar
  9. 9.
    Wakamatsu, K., N. Nagata, H. Kumazoe, K. Oda, H. Ishimoto, M. Yoshimi, S. Takata, M. Hamada, Y. Koreeda, K. Takakura, M. Ishizu, M. Hara, S. Ise, M. Izumi, T. Akasaki, S. Maki, M. Kawabata, H. Mukae, and M. Kawasaki. 2017. Prognostic value of serial serum KL-6 measurements in patients with idiopathic pulmonary fibrosis. Respiratory Investigation 55 (1): 16–23.CrossRefPubMedGoogle Scholar
  10. 10.
    Ohshimo, S., N. Ishikawa, Y. Horimasu, N. Hattori, N. Hirohashi, K. Tanigawa, N. Kohno, F. Bonella, J. Guzman, and U. Costabel. 2014. Baseline KL-6 predicts increased risk for acute exacerbation of idiopathic pulmonary fibrosis. Respiratory Medicine 108 (7): 1031–1039.CrossRefPubMedGoogle Scholar
  11. 11.
    Zhu, C., Y.B. Zhao, L.F. Kong, Z.H. Li, and J. Kang. 2016. The expression and clinical role of KL-6 in serum and BALF of patients with different diffuse interstitial lung diseases. Zhonghua Jie He He Hu Xi Za Zhi 39 (2): 93–97.PubMedGoogle Scholar
  12. 12.
    Bargagli, E., C. Olivieri, A. Prasse, N. Bianchi, B. Magi, R. Cianti, L. Bini, and P. Rottoli. 2008. Calgranulin B (S100A9) levels in bronchoalveolar lavage fluid of patients with interstitial lung diseases. Inflammation 31 (5): 351–354.CrossRefPubMedGoogle Scholar
  13. 13.
    Bargagli, E., C. Olivieri, M. Cintorino, R.M. Refini, N. Bianchi, A. Prasse, and P. Rottoli. 2011. Calgranulin B (S100A9/MRP14): a key molecule in idiopathic pulmonary fibrosis? Inflammation 34 (2): 85–91.CrossRefPubMedGoogle Scholar
  14. 14.
    Hara, A., N. Sakamoto, Y. Ishimatsu, T. Kakugawa, S. Nakashima, S. Hara, M. Adachi, H. Fujita, H. Mukae, and S. Kohno. 2012. S100A9 in BALF is a candidate biomarker of idiopathic pulmonary fibrosis. Respiratory Medicine 106 (4): 571–580.CrossRefPubMedGoogle Scholar
  15. 15.
    Korthagen, N.M., M.M. Nagtegaal, C.H. van Moorsel, K.M. Kazemier, J.M. van den Bosch, and J.C. Grutters. 2010. MRP14 is elevated in the bronchoalveolar lavage fluid of fibrosing interstitial lung diseases. Clinical and Experimental Immunology 161 (2): 342–347.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Miller, M.R., R. Crapo, J. Hankinson, V. Brusasco, F. Burgos, R. Casaburi, A. Coates, P. Enright, C.P. van der Grinten, P. Gustafsson, R. Jensen, D.C. Johnson, N. MacIntyre, R. McKay, D. Navajas, O.F. Pedersen, R. Pellegrino, G. Viegi, J. Wanger, and ATS/ERS Task Force. 2005. General considerations for lung function testing. The European Respiratory Journal 26 (1): 153–161.CrossRefPubMedGoogle Scholar
  17. 17.
    Holland, A.E., M.A. Spruit, T. Troosters, M.A. Puhan, V. Pepin, D. Saey, M.C. McCormack, B.W. Carlin, F.C. Sciurba, F. Pitta, J. Wanger, N. MacIntyre, D.A. Kaminsky, B.H. Culver, S.M. Revill, N.A. Hernandes, V. Andrianopoulos, C.A. Camillo, K.E. Mitchell, A.L. Lee, C.J. Hill, and S.J. Singh. 2014. An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease. The European Respiratory Journal 44 (6): 1428–1446.CrossRefPubMedGoogle Scholar
  18. 18.
    Meyer, K.C., G. Raghu, R.P. Baughman, K.K. Brown, U. Costabel, R.M. du Bois, M. Drent, P.L. Haslam, D.S. Kim, S. Nagai, P. Rottoli, C. Saltini, M. Selman, C. Strange, B. Wood, and American Thoracic Society Committee on BAL in interstitial lung disease. 2012. An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. American Journal of Respiratory and Critical Care Medicine 185 (9): 1004–1014.CrossRefPubMedGoogle Scholar
  19. 19.
    Lim, S.Y., A.E. Yuzhalin, A.N. Gordon-Weeks, and R.J. Muschel. 2016. Tumor-infiltrating monocytes/macrophages promote tumor invasion and migration by upregulating S100A8 and S100A9 expression in cancer cells. Oncogene 35 (44): 5735–5745.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Nunes, H., K. Schubel, D. Piver, E. Magois, S. Feuillet, Y. Uzunhan, Z. Carton, A. Tazi, P. Levy, P.Y. Brillet, A.G. Nicholson, M. Kambouchner, and D. Valeyre. 2015. Nonspecific interstitial pneumonia: survival is influenced by the underlying cause. The European Respiratory Journal 45 (3): 746–755.CrossRefPubMedGoogle Scholar
  21. 21.
    Hamai, K., H. Iwamoto, N. Ishikawa, Y. Horimasu, T. Masuda, S. Miyamoto, T. Nakashima, S. Ohshimo, K. Fujitaka, H. Hamada, N. Hattori, and N. Kohno. 2016. Comparative study of circulating MMP-7, CCL18, KL-6, SP-A, and SP-D as disease markers of idiopathic pulmonary fibrosis. Disease Markers 2016: 4759040.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • David Bennett
    • 1
    Email author
  • Martina Salvini
    • 1
  • Annalisa Fui
    • 1
  • Giuseppe Cillis
    • 1
  • Paolo Cameli
    • 1
  • Maria Antonietta Mazzei
    • 2
  • Antonella Fossi
    • 1
  • Rosa Metella Refini
    • 1
  • Paola Rottoli
    • 1
  1. 1.Respiratory Diseases and Lung Transplantation Unit, AOUS - Department of Medical, Surgical and Neurological SciencesUniversity of SienaSienaItaly
  2. 2.Diagnostic Imaging Unit, AOUS - Department of Medical, Surgical and Neurological SciencesUniversity of SienaSienaItaly

Personalised recommendations