The expression and clinical significance of plasma KL-6 in patients with idiopathic interstitial pneumonia and secondary interstitial pneumonia associated with connective tissue disease_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

GUO Lili ¹ ,  CAO Mengshu ² , WANG Xin ^2,3 , DING Jingjing ² , CHEN Zhiyong ⁴ , WANG Dongmei ⁵ , CAI Hourong ²

1. Department of Clinical Laboratory, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, P. R. China;
2. Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, P. R. China;
3. Department of Respiratory Medicine, Jiangning Hospital, Nanjing Medical University, Nanjing, Jiangsu 211100, P. R. China;
4. Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, P. R. China;
5. Department of Radiology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, P. R. China;

Corresponding author：

CAO Mengshu, Email: mengshucao@126.com

Keywords：

Interstitial pneumonia; Connective tissue diseases; Kerbs von den lungen-6

DOI：

10.7507/1671-6205.201806052

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Objective To compare the expressive differences of plasma Kerbs von den lungen-6 (KL-6) in patients with idiopathic interstitial pneumonia (IIP) and connective tissue disease associated secondary interstitial pneumonia (CTD-SIP), and analyze the clinical significances.Methods The clinical data and peripheral blood of 399 inpatients with interstitial pneumonia and 50 healthy controls were collected from January 2011 to December 2014 in Nanjing Drum Tower Hospital. The level of plasma KL-6 was measured by chemiluminescence immunoassay method. The subjects were divided into IIP (n=233) group and CTD-SIP (n=166) group, usual interstitial pneumonia (UIP) pattern and non-UIP pattern, and stable (S) UIP group and acute exacerbation (AE) UIP group. Statistical analyses were performed by using IBM SPSS 19.0 (SPSS, Inc., Chicago IL, USA) to compare the differences of plasma KL-6 in groups.Results There were more male subjects (61.8%) in the IIP group, and the average age of (62.3±12.5) years was significantly older (both P<0.01). Plasma KL-6 levels in the IIP ［(1 822.7±1 505.2) U/ml) and the CTD-SIP group ［(1 846.7±1 625.3) U/ml］ were significantly higher than the healthy control group ［(190.2±88.7) U/ml］ (both P<0.001). However, there was no any difference of KL-6, white blood cell count (WBC), lactate dehydrogenase (LDH), C-reactive protein (CRP) and erythrocyte sedimentation rate between the IIP and the CTD-SIP group. The level of plasma KL-6 was positively correlated to WBC, LDH and CRP in the IIP group (r=0.159, P=0.016; r=0.380, P<0.001; r=0.158, P=0.015, respectively); and it was positively correlated to LDH and CRP in the IIP group (r=0.187, P=0.016 and r=0.068, P=0.032) in the CTD-SIP group. There was no significant difference of plasma KL-6 between the UIP and non-UIP subgroups (P>0.05). The difference of plasma KL-6 between the S-UIP and AE-UIP subgroup was significant (P<0.001 and P=0.023). There was no any significant difference of plasma KL-6 among the subgroups with CTD patients (primary Sjögren’s syndrome, n=90; rheumatoid arthritis, n=20; polymyositis/dermatomyositis, n=26; undifferentiated connective tissue disease, n=10; anti-neutrophil cytoplasmic antibody associated vasculitis, n=15 and systemic sclerosis, n=5) (P=0.785 2).Conclusions Plasma KL-6 may be a useful biomarker for interstitial pneumonia. It can show the disease activities, but is not able to distinguish IIP from SIP.

Citation： GUO Lili, CAO Mengshu, WANG Xin, DING Jingjing, CHEN Zhiyong, WANG Dongmei, CAI Hourong. The expression and clinical significance of plasma KL-6 in patients with idiopathic interstitial pneumonia and secondary interstitial pneumonia associated with connective tissue disease. Chinese Journal of Respiratory and Critical Care Medicine, 2019, 18(2): 128-133. doi: 10.7507/1671-6205.201806052 Copy

1.	Kohno N, Akiyama M, Kyoizumi S, et al. Detection of soluble tumor-associated antigens in sera and effusions using novel monoclonal antibodies, KL-3 and KL-6, against lung adenocarcinoma. Jpn J Clin Oncol, 1988, 18(3): 203-216.
2.	Ohtsuki Y, Fujita J, Hachisuka Y, et al. Immunohistochemical and immunoelectron microscopic studies of the localization of KL-6 and epithelial membrane antigen (EMA) in presumably normal pulmonary tissue and in interstitial pneumonia. Med Mol Morphol, 2007, 40(4): 198-202.
3.	Ishikawa N, Hattori N, Yokoyama A, et al. Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases. Respir Investig, 2012, 50(1): 3-13.
4.	Hu Y, Wang LS, Jin YP, et al. Serum Krebs von den Lungen-6 level as a diagnostic biomarker for interstitial lung disease in Chinese patients. Clin Respir J, 2017, 11(3): 337-345.
5.	Ohshimo S, Ishikawa N, Horimasu Y, et al. Baseline KL-6 predicts increased risk for acute exacerbation of idiopathic pulmonary fibrosis. Respir Med, 2014, 108(7): 1031-1039.
6.	Travis WD, Costabel U, Hansell DM, 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(6): 733-748.
7.	American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med, 2000, 161(2 Pt 1): 646-664.
8.	Collard HR, Ryerson CJ, Corte TJ, et al. Acute Exacerbation of Idiopathic Pulmonary Fibrosis: An International Working Group Report. Am J Respir Crit Care Med, 2016, 194(3): 265-275.
9.	Rangu G, Collard HR, Egan JJ, et al. An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. Am J Respir Crit Care Med, 2011, 183(6): 788-824.
10.	Shiboski SC, Shiboski CH, Criswell L, et al. American College of Rheumatology Classification Criteria for Sjögren’s syndrome: A Data-driven, Expert Consensus Approach in the Sjögren’s International Collaborative Clinical Alliance Cohort. Arthritis Care Res (Hoboken), 2012, 64(4): 475-487.
11.	Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid Arthritis Classification Criteria: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis Rheum, 2010, 62(9): 2569-2581.
12.	Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum, 2013, 65(1): 1-11.
13.	Mosca M, Tani C, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a new frontier for rheumatology. Best Pract Res Clin Rheumatol, 2007, 21(6): 1011-1023.
14.	van den Hoogen F, Khanna D, Fransen J, et al. 2013 Classification Criteria for Systemic Sclerosis: An American College of Rheumatology/European League against Rheumatism Collaborative Initiative. Ann Rheum Dis, 2013, 72(11): 1747-1755.
15.	Fathi M, Barbasso HS, Lundberg IE. KL-6: a serological biomarker for interstitial lung disease in patients with polymyositis and dermatomyositis. J Intern Med, 2012, 271(6): 589-597.
16.	Lee YS, Kim HC, Lee BY, et al. The value of biomarkers as predictors of outcome in patients with rheumatoid arthritis-associated usual interstitial pneumonia. Sarcoidosis Vasc Diffuse Lung Dis, 2016, 33(3): 216-223.
17.	Kumánovics G, Görbe E, Minier T, et al. Follow-up of serum KL-6 lung fibrosis biomarker levels in 173 patients with systemic sclerosis. Clin Exp Rheumatol, 2014, 32(6 Suppl 86): 138-144.
18.	Oguz EO, Kucuksahin O, Turgay M, et al. Association of serum KL-6 levels with interstitial lung disease in patients with connective tissue disease: a cross-sectional study. Clin Rheumatol, 2016, 35(3): 663-666.
19.	Benyamine A, Heim X, Resseguier N, et al. Elevated serum Krebs von den Lungen-6 in systemic sclerosis: a marker of lung fibrosis and severity of the disease. Rheumatol Int, 2018, 38(5): 813-819.
20.	Xu L, Yan DR, Zhu SL, et al. KL-6 regulated the expression of HGF, collagen and myofibroblast differentiation. Eur Rev Med Pharmacol Sci, 2013, 17(22): 3073-3077.
21.	Nukiwa T. The role of biomarkers in management of interstitial lung disease: implication of biomarkers derived from type II pneumocytes. Eur Respir Mon, 2009, 46: 47-66.
22.	Jun S, Park B, Seo JB, et al. Development of a computer-aided differential diagnosis system to distinguish between usual interstitial pneumonia and non-specific interstitial pneumonia using texture- and shape-based hierarchical classifiers on HRCT images. J Digit Imaging, 2018, 31(2): 235-244.
23.	Ohnishi H, Yokoyama A, Kondo K, et al. Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases. Am J Respir Crit Care Med, 2002, 165(3): 378-381.
24.	Takahashi H, Kuroki Y, Tanaka H, et al. Serum levels of surfactant proteins A and D are useful biomarkers for interstitial lung disease in patients with progressive systemic sclerosis. Am J Respir Crit Care Med, 2000, 162(1): 258-263.
25.	Kakugawa T, Yokota S, Ishimatsu Y, et al. Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis. Cell Stress Chaperones, 2013, 18(5): 581-590.
26.	Cao MS, Swigris JJ, Wang X, et al. Plasma leptin is elevated in acute exacerbation of idiopathic pulmonary fibrosis. Mediators Inflamm, 2016: 6940480.
27.	Qiu M, Chen Y, Ye Q. Risk factors for acute exacerbation of idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Clin Respir J, 2018, 12(3): 1084-1092.
28.	Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fbrosis. Am J Respir Crit Care Med, 2007, 176(7): 636-643.
29.	任登华, 丁晶晶, 蔡后荣, 等. 血清 KL-6 水平在间质性肺疾病诊断中的价值研究. 中国呼吸与危重监护杂志, 2015, 14(5): 468-473.

1. Kohno N, Akiyama M, Kyoizumi S, et al. Detection of soluble tumor-associated antigens in sera and effusions using novel monoclonal antibodies, KL-3 and KL-6, against lung adenocarcinoma. Jpn J Clin Oncol, 1988, 18(3): 203-216.
2. Ohtsuki Y, Fujita J, Hachisuka Y, et al. Immunohistochemical and immunoelectron microscopic studies of the localization of KL-6 and epithelial membrane antigen (EMA) in presumably normal pulmonary tissue and in interstitial pneumonia. Med Mol Morphol, 2007, 40(4): 198-202.
3. Ishikawa N, Hattori N, Yokoyama A, et al. Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases. Respir Investig, 2012, 50(1): 3-13.
4. Hu Y, Wang LS, Jin YP, et al. Serum Krebs von den Lungen-6 level as a diagnostic biomarker for interstitial lung disease in Chinese patients. Clin Respir J, 2017, 11(3): 337-345.
5. Ohshimo S, Ishikawa N, Horimasu Y, et al. Baseline KL-6 predicts increased risk for acute exacerbation of idiopathic pulmonary fibrosis. Respir Med, 2014, 108(7): 1031-1039.
6. Travis WD, Costabel U, Hansell DM, 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(6): 733-748.
7. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med, 2000, 161(2 Pt 1): 646-664.
8. Collard HR, Ryerson CJ, Corte TJ, et al. Acute Exacerbation of Idiopathic Pulmonary Fibrosis: An International Working Group Report. Am J Respir Crit Care Med, 2016, 194(3): 265-275.
9. Rangu G, Collard HR, Egan JJ, et al. An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. Am J Respir Crit Care Med, 2011, 183(6): 788-824.
10. Shiboski SC, Shiboski CH, Criswell L, et al. American College of Rheumatology Classification Criteria for Sjögren’s syndrome: A Data-driven, Expert Consensus Approach in the Sjögren’s International Collaborative Clinical Alliance Cohort. Arthritis Care Res (Hoboken), 2012, 64(4): 475-487.
11. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid Arthritis Classification Criteria: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis Rheum, 2010, 62(9): 2569-2581.
12. Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum, 2013, 65(1): 1-11.
13. Mosca M, Tani C, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a new frontier for rheumatology. Best Pract Res Clin Rheumatol, 2007, 21(6): 1011-1023.
14. van den Hoogen F, Khanna D, Fransen J, et al. 2013 Classification Criteria for Systemic Sclerosis: An American College of Rheumatology/European League against Rheumatism Collaborative Initiative. Ann Rheum Dis, 2013, 72(11): 1747-1755.
15. Fathi M, Barbasso HS, Lundberg IE. KL-6: a serological biomarker for interstitial lung disease in patients with polymyositis and dermatomyositis. J Intern Med, 2012, 271(6): 589-597.
16. Lee YS, Kim HC, Lee BY, et al. The value of biomarkers as predictors of outcome in patients with rheumatoid arthritis-associated usual interstitial pneumonia. Sarcoidosis Vasc Diffuse Lung Dis, 2016, 33(3): 216-223.
17. Kumánovics G, Görbe E, Minier T, et al. Follow-up of serum KL-6 lung fibrosis biomarker levels in 173 patients with systemic sclerosis. Clin Exp Rheumatol, 2014, 32(6 Suppl 86): 138-144.
18. Oguz EO, Kucuksahin O, Turgay M, et al. Association of serum KL-6 levels with interstitial lung disease in patients with connective tissue disease: a cross-sectional study. Clin Rheumatol, 2016, 35(3): 663-666.
19. Benyamine A, Heim X, Resseguier N, et al. Elevated serum Krebs von den Lungen-6 in systemic sclerosis: a marker of lung fibrosis and severity of the disease. Rheumatol Int, 2018, 38(5): 813-819.
20. Xu L, Yan DR, Zhu SL, et al. KL-6 regulated the expression of HGF, collagen and myofibroblast differentiation. Eur Rev Med Pharmacol Sci, 2013, 17(22): 3073-3077.
21. Nukiwa T. The role of biomarkers in management of interstitial lung disease: implication of biomarkers derived from type II pneumocytes. Eur Respir Mon, 2009, 46: 47-66.
22. Jun S, Park B, Seo JB, et al. Development of a computer-aided differential diagnosis system to distinguish between usual interstitial pneumonia and non-specific interstitial pneumonia using texture- and shape-based hierarchical classifiers on HRCT images. J Digit Imaging, 2018, 31(2): 235-244.
23. Ohnishi H, Yokoyama A, Kondo K, et al. Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases. Am J Respir Crit Care Med, 2002, 165(3): 378-381.
24. Takahashi H, Kuroki Y, Tanaka H, et al. Serum levels of surfactant proteins A and D are useful biomarkers for interstitial lung disease in patients with progressive systemic sclerosis. Am J Respir Crit Care Med, 2000, 162(1): 258-263.
25. Kakugawa T, Yokota S, Ishimatsu Y, et al. Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis. Cell Stress Chaperones, 2013, 18(5): 581-590.
26. Cao MS, Swigris JJ, Wang X, et al. Plasma leptin is elevated in acute exacerbation of idiopathic pulmonary fibrosis. Mediators Inflamm, 2016: 6940480.
27. Qiu M, Chen Y, Ye Q. Risk factors for acute exacerbation of idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Clin Respir J, 2018, 12(3): 1084-1092.
28. Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fbrosis. Am J Respir Crit Care Med, 2007, 176(7): 636-643.
29. 任登华, 丁晶晶, 蔡后荣, 等. 血清 KL-6 水平在间质性肺疾病诊断中的价值研究. 中国呼吸与危重监护杂志, 2015, 14(5): 468-473.

Chinese Journal of Respiratory and Critical Care Medicine

The expression and clinical significance of plasma KL-6 in patients with idiopathic interstitial pneumonia and secondary interstitial pneumonia associated with connective tissue disease

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