Diagnostic Utility of Serum Krebs von den Lungen-6 (KL-6) and Surfactant Protein-D (SP-D) Levels in Hypersensitivity Pneumonitis
Contenuto principale dell'articolo
Keywords
Abstract
Background: This study aimed to investigate the diagnostic and prognostic values of serum Krebs von den Lungen-6 (KL-6) and ve Surfactant Protein-D (SP-D) levels in patients with hypersensitivity pneumonitis (HP). Methods: Serum samples were collected from patients diagnosed with HP and from a healthy control group. KL-6 and SP-D levels were measured using the ELISA method. HP cases were further compared according to fibrotic and non-fibrotic subgroups, as well as whether they were receiving treatment or not. The relationships between respiratory function tests (DLCO, FEV₁, FVC) and biomarker levels were examined. Results: Both KL-6 (median 5.95 ng/ml vs 5.4 ng/ml, p<0.001) and SP-D (median 14.87 ng/ml vs 14.72 ng/ml, p<0.05) levels were significantly higher in HP patients than in the control group. In non-fibrotic HP patients, KL-6 levels were higher than in the fibrotic group (median 6.07 ng/ml vs 5.62 ng/ml, p<0.05), while no significant difference was observed for SP-D (p=0.71). KL-6 levels were significantly higher in untreated cases compared to treated cases (median 6.30 ng/ml vs 5.65 ng/ml, p<0.01), while the difference in SP-D was not significant (p=0.26). Conclusion: KL-6 emerges as a sensitive biomarker in the diagnosis of HP, assessing of disease activity, and monitoring treatment response. SP-D, although reflecting inflammatory processes, seems to be have limitations in evaluating fibrotic progression.
Riferimenti bibliografici
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5. Hanzawa S, Tateishi T, Ishizuka M, et al. Changes in serum KL-6 levels during short-term strict anti-gen avoidance are associated with the prognosis of patients with fibrotic hypersensitivity pneumon-itis caused by avian antigens. Respir Investig. 2020;58(6):457-464. doi:10.1016/j.resinv.2020.05.007
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11. Quaresma M, Coleman MP, Rachet B. 40-year trends in an index of survival for all cancers combined and survival adjusted for age and sex for each cancer in England and Wales, 1971-2011: a popula-tion-based study. Lancet. 2015;385(9974):1206-1218. doi:10.1016/S0140-6736(14)61396-9
12. Walters GI, Mokhlis JM, Moore VC, et al. Characteristics of hypersensitivity pneumonitis diagnosed by interstitial and occupational lung disease multi-disciplinary team consensus. Respir Med. 2019;155:19-25. doi:10.1016/j.rmed.2019.06.026
13. Barnes H, Troy L, Lee CT, Sperling A, Strek M, Glaspole I. Hypersensitivity pneumonitis: Current concepts in pathogenesis, diagnosis, and treatment. Allergy. 2022;77(2):442-453. doi:10.1111/all.15017
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17. d'Alessandro M, Bergantini L, Cameli P, et al. Serum KL-6 levels in pulmonary Langerhans' cell histio-cytosis. Eur J Clin Invest. 2020;50(8):e13242. doi:10.1111/eci.13242
18. Ohnishi H, Miyamoto S, Kawase S, Kubota T, Yokoyama A. Seasonal variation of serum KL-6 concen-trations is greater in patients with hypersensitivity pneumonitis. BMC Pulm Med. 2014;14:129. doi:10.1186/1471-2466-14-129
19. Dyhr JJ, Linderoth IR, Hansen DN, et al. Confined placental mosaicism: placental size and function evaluated on magnetic resonance imaging. Ultrasound Obstet Gynecol. 2023;62(1):130-136. doi:10.1002/uog.26174
20. Okamoto T, Fujii M, Furusawa H, Tsuchiya K, Miyazaki Y, Inase N. The usefulness of KL-6 and SP-D for the diagnosis and management of chronic hypersensitivity pneumonitis. Respir Med. 2015;109(12):1576-1581. doi:10.1016/j.rmed.2015.10.005
21. Nukui Y, Yamana T, Masuo M, et al. Serum CXCL9 and CCL17 as biomarkers of declining pulmonary function in chronic bird-related hypersensitivity pneumonitis. PLoS One. 2019;14(8):e0220462. doi:10.1371/journal.pone.0220462
22. Rai M, Parthasarathi A, Beeraka NM, et al. Circulatory Serum Krebs von Den Lungen-6 and Surfactant Protein-D Concentrations Predict Interstitial Lung Disease Progression and Mortality. Cells. 2023;12(9):1281. doi:10.3390/cells12091281
23. Chung C, Kim J, Cho HS, Kim HC. Baseline serum Krebs von den Lungen-6 as a biomarker for the dis-ease progression in idiopathic pulmonary fibrosis. Sci Rep. 2022;12(1):8564. doi:10.1038/s41598-022-12399-8
24. Letellier A, Rolland-Debord C, Luque-Paz D, et al. Prognostic value of serum Krebs von den Lungen-6 (KL-6) levels in COVID-19 pneumonia. Respir Med Res. 2023;84:101054. doi:10.1016/j.resmer.2023.101054
25. Cambier M, Henket M, Frix AN, et al. Increased KL-6 levels in moderate to severe COVID-19 infec-tion. PLoS One. 2022;17(11):e0273107. doi:10.1371/journal.pone.0273107
26. Bonella F, Volpe A, Caramaschi P, et al. Surfactant protein D and KL-6 serum levels in systemic sclero-sis: correlation with lung and systemic involvement. Sarcoidosis Vasc Diffuse Lung Dis. 2011;28(1):27-33.
27. Yazawa S, Suzuki Y, Tanaka Y, et al. 3D-CT-derived lung volumes and mortality risk in patients with fibrotic hypersensitivity pneumonitis. Allergol Int. 2025;74(1):78-85. doi:10.1016/j.alit.2024.07.002
28. Zhu C, Zhao YB, Kong LF, Li ZH, Kang J. Zhonghua Jie He He Hu Xi Za Zhi. 2016;39(2):93-97. doi:10.3760/cma.j.issn.1001-0939.2016.02.004
29. Chung JH, Montner SM, Adegunsoye A, et al. CT findings associated with survival in chronic hyper-sensitivity pneumonitis. Eur Radiol. 2017;27(12):5127-5135. doi:10.1007/s00330-017-4936-3
30. Zhao X, Chen J, Sun H, Zhang Y, Zou D. New insights into fibrosis from the ECM degradation perspec-tive: the macrophage-MMP-ECM interaction. Cell Biosci. 2022;12(1):117. doi:10.1186/s13578-022-00856-w
31. d'Alessandro M, Bergantini L, Cameli P, et al. Krebs von den Lungen-6 as a biomarker for disease se-verity assessment in interstitial lung disease: a comprehensive review. Biomark Med. 2020;14(8):665-674. doi:10.2217/bmm-2019-0545
32. Sánchez-Díez S, Munoz X, Ojanguren I, et al. YKL-40 and KL-6 Levels in Serum and Sputum of Patients Diagnosed With Hypersensitivity Pneumonitis. J Allergy Clin Immunol Pract. 2022;10(9):2414-2423. doi:10.1016/j.jaip.2022.06.031
33. Waseda Y, Yasui M, Kurokawa K, et al. Surfactant protein D: a useful marker for differentiation of drug-induced pneumonia and bacterial pneumonia. Pneumonia (Nathan). 2021;13(1):11. doi:10.1186/s41479-021-00087-6
34. Jiang Y, Luo Q, Han Q, et al. Sequential changes of serum KL-6 predict the progression of interstitial lung disease. J Thorac Dis. 2018;10(8):4705-4714. doi:10.21037/jtd.2018.07.76
35. Miyazaki Y, Tsutsui T, Inase N. Treatment and monitoring of hypersensitivity pneumonitis. Expert Rev Clin Immunol. 2016;12(9):953-962. doi:10.1080/1744666X.2016.1182426
36. Ji Y, Bourke SJ, Spears M, et al. Krebs von den Lungen-6 (KL-6) is a pathophysiological biomarker of early-stage acute hypersensitivity pneumonitis among pigeon fanciers. Clin Exp Allergy. 2020;50(12):1391-1399. doi:10.1111/cea.13744
37. Mostafa AI, Salem AE, Ahmed HAM, Bayoumi AI, Halim RMA, Samie RMA. Role of Krebs von den Lungen-6 (KL-6) in Assessing Hypersensitivity Pneumonitis. Tuberc Respir Dis (Seoul). 2021;84(3):200-208. doi:10.4046/trd.2020.0122
38. Wakamatsu K, Nagata N, Kumazoe H, et al. Prognostic value of serial serum KL-6 measurements in pa-tients with idiopathic pulmonary fibrosis. Respir Investig. 2017;55(1):16-23. doi:10.1016/j.resinv.2016.09.003
39. Kang J, Kim YJ, Choe J, Chae EJ, Song JW. Acute exacerbation of fibrotic hypersensitivity pneumonitis: incidence and outcomes. Respir Res. 2021;22(1):152. Published 2021 May 20. doi:10.1186/s12931-021-01748-2
40. Ejima M, Okamoto T, Suzuki T, Miyazaki Y. Role of serum surfactant protein-D as a prognostic pre-dictor in fibrotic hypersensitivity pneumonitis. Respir Investig. 2022;60(3):369-378. doi:10.1016/j.resinv.2021.12.003
41. Yokoyama A, Kohno N, Hamada H, et al. Circulating KL-6 predicts the outcome of rapidly progressive idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;158(5 Pt 1):1680-1684. doi:10.1164/ajrccm.158.5.9803115
2. Morell F, Villar A, Ojanguren I, Muñoz X, Cruz MJ. Hypersensitivity Pneumonitis: Challenges in Diag-nosis and Management, Avoiding Surgical Lung Biopsy. Semin Respir Crit Care Med. 2016;37(3):395-405. doi:10.1055/s-0036-1580692
3. Lanzarone N, Gentili F, Alonzi V, et al. Bronchoalveolar lavage and serum KL-6 concentrations in chronic hypersensitivity pneumonitis: correlations with radiological and immunological fea-tures. Intern Emerg Med. 2020;15(7):1247-1254. doi:10.1007/s11739-020-02281-8
4. Vasakova M, Morell F, Walsh S, Leslie K, Raghu G. Hypersensitivity Pneumonitis: Perspectives in Di-agnosis and Management. Am J Respir Crit Care Med. 2017;196(6):680-689. doi:10.1164/rccm.201611-2201PP
5. Hanzawa S, Tateishi T, Ishizuka M, et al. Changes in serum KL-6 levels during short-term strict anti-gen avoidance are associated with the prognosis of patients with fibrotic hypersensitivity pneumon-itis caused by avian antigens. Respir Investig. 2020;58(6):457-464. doi:10.1016/j.resinv.2020.05.007
6. Cottin V, Hirani NA, Hotchkin DL, et al. Presentation, diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases. Eur Respir Rev. 2018;27(150):180076. doi:10.1183/16000617.0076-2018
7. Hilberg O, Hoffmann-Vold AM, Smith V, et al. Epidemiology of interstitial lung diseases and their pro-gressive-fibrosing behaviour in six European countries. ERJ Open Res. 2022;8(1):00597-2021. doi:10.1183/23120541.00597-2021
8. Pereira JO, Fernandes V, Alfaro TM, Freitas S, Cordeiro CR. Diagnosis of Fibrotic Hypersensitivity Pneumonitis: Is There a Role for Biomarkers?. Life (Basel). 2023;13(2):565. Published 2023 Feb 17. doi:10.3390/life13020565
9. He J, Zhang J, Ren X. Krebs von den lungen-6 as a clinical marker for hypersensitivity pneumonitis: A meta-analysis and bioinformatics analysis. Front Immunol. 2022;13:1041098. doi:10.3389/fimmu.2022.1041098
10. Nasser M, Larrieu S, Boussel L, et al. Estimates of epidemiology, mortality and disease burden associ-ated with progressive fibrosing interstitial lung disease in France (the PROGRESS study). Respir Res. 2021;22(1):162. Published 2021 May 24. doi:10.1186/s12931-021-01749-1
11. Quaresma M, Coleman MP, Rachet B. 40-year trends in an index of survival for all cancers combined and survival adjusted for age and sex for each cancer in England and Wales, 1971-2011: a popula-tion-based study. Lancet. 2015;385(9974):1206-1218. doi:10.1016/S0140-6736(14)61396-9
12. Walters GI, Mokhlis JM, Moore VC, et al. Characteristics of hypersensitivity pneumonitis diagnosed by interstitial and occupational lung disease multi-disciplinary team consensus. Respir Med. 2019;155:19-25. doi:10.1016/j.rmed.2019.06.026
13. Barnes H, Troy L, Lee CT, Sperling A, Strek M, Glaspole I. Hypersensitivity pneumonitis: Current concepts in pathogenesis, diagnosis, and treatment. Allergy. 2022;77(2):442-453. doi:10.1111/all.15017
14. Pereira CAC, Soares MR, Boaventura R, et al. Squawks in interstitial lung disease prevalence and causes in a cohort of one thousand patients. Medicine (Baltimore). 2019;98(29):e16419. doi:10.1097/MD.0000000000016419
15. Churg A. Hypersensitivity pneumonitis: new concepts and classifications. Mod Pathol. 2022;35(Suppl 1):15-27. doi:10.1038/s41379-021-00866-y
16. Fernández Pérez ER, Travis WD, Lynch DA, et al. Diagnosis and Evaluation of Hypersensitivity Pneu-monitis: CHEST Guideline and Expert Panel Report. Chest. 2021;160(2):e97-e156. doi:10.1016/j.chest.2021.03.066
17. d'Alessandro M, Bergantini L, Cameli P, et al. Serum KL-6 levels in pulmonary Langerhans' cell histio-cytosis. Eur J Clin Invest. 2020;50(8):e13242. doi:10.1111/eci.13242
18. Ohnishi H, Miyamoto S, Kawase S, Kubota T, Yokoyama A. Seasonal variation of serum KL-6 concen-trations is greater in patients with hypersensitivity pneumonitis. BMC Pulm Med. 2014;14:129. doi:10.1186/1471-2466-14-129
19. Dyhr JJ, Linderoth IR, Hansen DN, et al. Confined placental mosaicism: placental size and function evaluated on magnetic resonance imaging. Ultrasound Obstet Gynecol. 2023;62(1):130-136. doi:10.1002/uog.26174
20. Okamoto T, Fujii M, Furusawa H, Tsuchiya K, Miyazaki Y, Inase N. The usefulness of KL-6 and SP-D for the diagnosis and management of chronic hypersensitivity pneumonitis. Respir Med. 2015;109(12):1576-1581. doi:10.1016/j.rmed.2015.10.005
21. Nukui Y, Yamana T, Masuo M, et al. Serum CXCL9 and CCL17 as biomarkers of declining pulmonary function in chronic bird-related hypersensitivity pneumonitis. PLoS One. 2019;14(8):e0220462. doi:10.1371/journal.pone.0220462
22. Rai M, Parthasarathi A, Beeraka NM, et al. Circulatory Serum Krebs von Den Lungen-6 and Surfactant Protein-D Concentrations Predict Interstitial Lung Disease Progression and Mortality. Cells. 2023;12(9):1281. doi:10.3390/cells12091281
23. Chung C, Kim J, Cho HS, Kim HC. Baseline serum Krebs von den Lungen-6 as a biomarker for the dis-ease progression in idiopathic pulmonary fibrosis. Sci Rep. 2022;12(1):8564. doi:10.1038/s41598-022-12399-8
24. Letellier A, Rolland-Debord C, Luque-Paz D, et al. Prognostic value of serum Krebs von den Lungen-6 (KL-6) levels in COVID-19 pneumonia. Respir Med Res. 2023;84:101054. doi:10.1016/j.resmer.2023.101054
25. Cambier M, Henket M, Frix AN, et al. Increased KL-6 levels in moderate to severe COVID-19 infec-tion. PLoS One. 2022;17(11):e0273107. doi:10.1371/journal.pone.0273107
26. Bonella F, Volpe A, Caramaschi P, et al. Surfactant protein D and KL-6 serum levels in systemic sclero-sis: correlation with lung and systemic involvement. Sarcoidosis Vasc Diffuse Lung Dis. 2011;28(1):27-33.
27. Yazawa S, Suzuki Y, Tanaka Y, et al. 3D-CT-derived lung volumes and mortality risk in patients with fibrotic hypersensitivity pneumonitis. Allergol Int. 2025;74(1):78-85. doi:10.1016/j.alit.2024.07.002
28. Zhu C, Zhao YB, Kong LF, Li ZH, Kang J. Zhonghua Jie He He Hu Xi Za Zhi. 2016;39(2):93-97. doi:10.3760/cma.j.issn.1001-0939.2016.02.004
29. Chung JH, Montner SM, Adegunsoye A, et al. CT findings associated with survival in chronic hyper-sensitivity pneumonitis. Eur Radiol. 2017;27(12):5127-5135. doi:10.1007/s00330-017-4936-3
30. Zhao X, Chen J, Sun H, Zhang Y, Zou D. New insights into fibrosis from the ECM degradation perspec-tive: the macrophage-MMP-ECM interaction. Cell Biosci. 2022;12(1):117. doi:10.1186/s13578-022-00856-w
31. d'Alessandro M, Bergantini L, Cameli P, et al. Krebs von den Lungen-6 as a biomarker for disease se-verity assessment in interstitial lung disease: a comprehensive review. Biomark Med. 2020;14(8):665-674. doi:10.2217/bmm-2019-0545
32. Sánchez-Díez S, Munoz X, Ojanguren I, et al. YKL-40 and KL-6 Levels in Serum and Sputum of Patients Diagnosed With Hypersensitivity Pneumonitis. J Allergy Clin Immunol Pract. 2022;10(9):2414-2423. doi:10.1016/j.jaip.2022.06.031
33. Waseda Y, Yasui M, Kurokawa K, et al. Surfactant protein D: a useful marker for differentiation of drug-induced pneumonia and bacterial pneumonia. Pneumonia (Nathan). 2021;13(1):11. doi:10.1186/s41479-021-00087-6
34. Jiang Y, Luo Q, Han Q, et al. Sequential changes of serum KL-6 predict the progression of interstitial lung disease. J Thorac Dis. 2018;10(8):4705-4714. doi:10.21037/jtd.2018.07.76
35. Miyazaki Y, Tsutsui T, Inase N. Treatment and monitoring of hypersensitivity pneumonitis. Expert Rev Clin Immunol. 2016;12(9):953-962. doi:10.1080/1744666X.2016.1182426
36. Ji Y, Bourke SJ, Spears M, et al. Krebs von den Lungen-6 (KL-6) is a pathophysiological biomarker of early-stage acute hypersensitivity pneumonitis among pigeon fanciers. Clin Exp Allergy. 2020;50(12):1391-1399. doi:10.1111/cea.13744
37. Mostafa AI, Salem AE, Ahmed HAM, Bayoumi AI, Halim RMA, Samie RMA. Role of Krebs von den Lungen-6 (KL-6) in Assessing Hypersensitivity Pneumonitis. Tuberc Respir Dis (Seoul). 2021;84(3):200-208. doi:10.4046/trd.2020.0122
38. Wakamatsu K, Nagata N, Kumazoe H, et al. Prognostic value of serial serum KL-6 measurements in pa-tients with idiopathic pulmonary fibrosis. Respir Investig. 2017;55(1):16-23. doi:10.1016/j.resinv.2016.09.003
39. Kang J, Kim YJ, Choe J, Chae EJ, Song JW. Acute exacerbation of fibrotic hypersensitivity pneumonitis: incidence and outcomes. Respir Res. 2021;22(1):152. Published 2021 May 20. doi:10.1186/s12931-021-01748-2
40. Ejima M, Okamoto T, Suzuki T, Miyazaki Y. Role of serum surfactant protein-D as a prognostic pre-dictor in fibrotic hypersensitivity pneumonitis. Respir Investig. 2022;60(3):369-378. doi:10.1016/j.resinv.2021.12.003
41. Yokoyama A, Kohno N, Hamada H, et al. Circulating KL-6 predicts the outcome of rapidly progressive idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;158(5 Pt 1):1680-1684. doi:10.1164/ajrccm.158.5.9803115
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2026-04-22
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Come citare
1.
Aslan Kara A, Koyuncu A, Sarı G, Şahin Özdemirel T, Akıncı Özyürek B, Şimşek C. Diagnostic Utility of Serum Krebs von den Lungen-6 (KL-6) and Surfactant Protein-D (SP-D) Levels in Hypersensitivity Pneumonitis. Med Lav. 2026;117(2):18283. doi:10.23749/mdl.2026.18283
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Biografie autore
Asuman Aslan Kara, Ankara Atatürk Sanatorium Training and Research Hospital, Ankara, Turkey
Occupational Diseases
Adem Koyuncu, Ankara Atatürk Sanatorium Training and Research Hospital, Ankara, Turkey
Occupational Diseases
Gülden Sarı, Yenimahalle Training and Research Hospital, Ankara,Turkey
Occupational disease
Tuğçe Şahin Özdemirel, Yenimahalle Training and Research Hospital, Ankara, Turkey
Pulmonology
Berna Akıncı Özyürek, Yenimahalle Training and Research Hospital, Ankara, Turkey
Pulmonology
Cebrail Şimşek, Ankara Atatürk Sanatorium Training and Research Hospital, Ankara, Turkey
Occupational Diseases
Come citare
1.
Aslan Kara A, Koyuncu A, Sarı G, Şahin Özdemirel T, Akıncı Özyürek B, Şimşek C. Diagnostic Utility of Serum Krebs von den Lungen-6 (KL-6) and Surfactant Protein-D (SP-D) Levels in Hypersensitivity Pneumonitis. Med Lav. 2026;117(2):18283. doi:10.23749/mdl.2026.18283
