https://doi.org/10.4081/monaldi.2024.2848
An in-depth investigation of serum Krebs von den Lungen-6 and other biomarkers in COVID-19 severity and mortality
Submitted: November 14, 2023
Accepted: June 3, 2024
Published: July 26, 2024
Accepted: June 3, 2024
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SUPPLEMENTARY MATERIAL: 32
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
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Krebs von den Lungen-6 (KL-6) is a glycoprotein mainly expressed by type II pneumocytes and recently known as a lung injury biomarker. However, the number of studies is still limited, especially in Indonesian COVID-19 populations. Therefore, we aim to provide correlation, sensitivity, and specificity analyses of KL-6 and other biomarkers in Indonesian COVID-19 severity and mortality. We conducted a cross-sectional study involving adult COVID-19 patients at Universitas Airlangga Hospital, Surabaya, East Java, Indonesia, between March 26, 2021, and August 25, 2021. KL-6 and other biomarker levels were compared according to severity (severe versus non-severe) and mortality (non-survivor versus survivor). We also included the receiver operating characteristic analysis to define the optimal cut-off, sensitivity, and specificity of KL-6 to determine COVID-19 severity and mortality. We enrolled 78 COVID- 19 patients (23 non-survivors), including 39 non-severe and 39 severe patients. There was no significant difference in serum KL-6 levels, neither in severity nor mortality groups. KL-6 had the strongest positive correlations with ferritin in severe patients (r=0.313) and non-survivors (r=0.467). We observed that the best sensitivity was KL-6 combined with platelet-to- lymphocyte ratio (PLR) (0.818) in severe patients and with neutrophil-to-lymphocyte ratio (NLR)/PLR/ferritin/C-reactive protein (0.867) in non-survivors. In contrast, the best specificity was found when KL-6 was combined with NLR/D-dimer (0.750) in severe patients and with D-dimer (0.889) in non-survivors. Serum KL-6 is a useful auxiliary laboratory evaluation index for COVID-19 lung injury to depict its severity and mortality.
World Health Organization. WHO COVID-19 dasboard. Available from: https://covid19.who.int. Accessed on: 30/05/2022.
Ni W, Yang X, Yang D, et al. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Crit Care 2020;24:422.
DOI: https://doi.org/10.1186/s13054-020-03120-0
Sensusiati AD, Amin M, Nasronudin N, et al. Age, neutrophil lymphocyte ratio, and radiographic assessment of the quantity of lung edema (RALE) score to predict in-hospital mortality in COVID-19 patients: a retrospective study. F1000Res 2020;9:1286.
DOI: https://doi.org/10.12688/f1000research.26723.1
Zou X, Chen K, Zou J, et al. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med 2020;14:185-92.
DOI: https://doi.org/10.1007/s11684-020-0754-0
Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: a review. Clin Immunol 2020;215:108427.
DOI: https://doi.org/10.1016/j.clim.2020.108427
Bonella F, Long X, Ohshimo S, et al. MUC1 gene polymorphisms are associated with serum KL-6 levels and pulmonary dysfunction in pulmonary alveolar proteinosis. Orphanet J Rare Dis 2016;11:48.
DOI: https://doi.org/10.1186/s13023-016-0430-2
Ma H, Lu J, Song Y, et al. The value of serum Krebs von den lungen-6 as a diagnostic marker in connective tissue disease associated with interstitial lung disease. BMC Pulm Med 2020;20:6.
DOI: https://doi.org/10.1186/s12890-019-1043-z
Tanaka S, Hattori N, Ishikawa N, et al. Krebs von den Lungen-6 (KL-6) is a prognostic biomarker in patients with surgically resected nonsmall cell lung cancer. Int J cancer 2012;130:377-87.
DOI: https://doi.org/10.1002/ijc.26007
Samukawa T, Hamada T, Uto H, et al. The elevation of serum napsin A in idiopathic pulmonary fibrosis, compared with KL-6, surfactant protein-A and surfactant protein-D. BMC Pulm Med 2012;12:55.
DOI: https://doi.org/10.1186/1471-2466-12-55
Zheng P, Liu X, Huang H, et al. Diagnostic value of KL-6 in idiopathic interstitial pneumonia. J Thorac Dis 2018;10:4724-32.
DOI: https://doi.org/10.21037/jtd.2018.07.54
Ishikawa N, Hattori N, Yokoyama A, et al. Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases. Respir Investig 2012;50:3-13.
DOI: https://doi.org/10.1016/j.resinv.2012.02.001
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;50:1391-9.
DOI: https://doi.org/10.1111/cea.13744
Peng D-H, Luo Y, Huang L-J, et al. Correlation of Krebs von den Lungen-6 and fibronectin with pulmonary fibrosis in coronavirus disease 2019. Clin Chim Acta 2021;517:48-53.
DOI: https://doi.org/10.1016/j.cca.2021.02.012
Witarto AP, Witarto BS, Putra AJE, et al. Serum Krebs von den Lungen-6 for predicting the severity of COVID-19 lung injury: a systematic review and meta-analysis. Iran Biomed J 2021;25:381-9.
DOI: https://doi.org/10.52547/ibj.25.6.381
Scotto R, Pinchera B, Perna F, et al. Serum KL-6 could represent a reliable indicator of unfavourable outcome in patients with COVID-19 pneumonia. Int J Environ Res Public Health 2021;18:2078.
DOI: https://doi.org/10.3390/ijerph18042078
Soraya GV, Ulhaq ZS. Crucial laboratory parameters in COVID-19 diagnosis and prognosis: an updated meta-analysis. Med Clin (Engl Ed) 2020;155:143-51.
DOI: https://doi.org/10.1016/j.medcli.2020.05.017
Zeng F, Huang Y, Guo Y, et al. Association of inflammatory markers with the severity of COVID-19: a meta-analysis. Int J Infect Dis 2020;96:467-74.
DOI: https://doi.org/10.1016/j.ijid.2020.05.055
Chen H, Qin R, Huang Z, et al. Clinical relevance of serum Krebs von den Lungen-6 levels in patients with coronavirus disease 2019. Cytokine 2021;148:155513.
DOI: https://doi.org/10.1016/j.cyto.2021.155513
PDPI, PERKI, PAPDI, et al. Pedoman tatalaksana COVID-19. 3rd ed. 2020. Available from: https://www.papdi.or.id/pdfs/983/Buku%20Pedoman%20Tatalaksana%20COVID-19%205OP%20Edisi%203%202020.pdf.
Rahman A, Munir SM, Yovi I, et al. The relationship of chest X-ray in COVID-19 patients and disease severity in Arifin Achmad General Hospital Riau. J Respirasi 2021;7:114-21.
DOI: https://doi.org/10.20473/jr.v7-I.3.2021.114-121
Azur MJ, Stuart EA, Frangakis C, et al. Multiple imputation by chained equations: what is it and how does it work?. Int J Methods Psychiatr Res 2011;20:40-9.
DOI: https://doi.org/10.1002/mpr.329
Madley-Dowd P, Hughes R, Tilling K, et al. The proportion of missing data should not be used to guide decisions on multiple imputation. J Clin Epidemiol 2019;110:63-73.
DOI: https://doi.org/10.1016/j.jclinepi.2019.02.016
Horimasu Y, Hattori N, Ishikawa N, et al. Different MUC1 gene polymorphisms in German and Japanese ethnicities affect serum KL-6 levels. Respir Med 2012;106:1756-64.
DOI: https://doi.org/10.1016/j.rmed.2012.09.001
Remuzgo-Martínez S, Atienza-Mateo B, Ocejo-Vinyals JG, et al. Role of MUC1 rs4072037 polymorphism and serum KL-6 levels in patients with antisynthetase syndrome. Sci Rep 2021;11:22574.
DOI: https://doi.org/10.1038/s41598-021-01992-y
Xue M, Zheng P, Bian X, et al. Exploration and correlation analysis of changes in Krebs von den Lungen-6 levels in COVID-19 patients with different types in China. Biosci Trends 2020;14:290-6.
DOI: https://doi.org/10.5582/bst.2020.03197
Menon B, Tiwari M, Gopi A, et al. Serum krebs von den lungen-6 (KL-6): a promising biomarker in sarcoidosis. MOJ Curr Res Rev 2018;1:44-7.
DOI: https://doi.org/10.15406/mojcrr.2018.01.00009
Suryananda TD, Yudhawati R. Association of serum KL-6 levels on COVID-19 severity: a cross-sectional study design with purposive sampling. Ann Med Surg 2021;69:102673.
DOI: https://doi.org/10.1016/j.amsu.2021.102673
King W, Toler K, Woodell-May J. Role of white blood cells in blood- and bone marrow-based autologous therapies. Biomed Res Int 2018;2018:6510842.
DOI: https://doi.org/10.1155/2018/6510842
Chen W, Wang J-B, Abnet CC, et al. Association between C-reactive protein, incident liver cancer, and chronic liver disease mortality in the Linxian Nutrition Intervention Trials: a nested case-control study. Cancer Epidemiol Biomarkers Prev 2015;24:386-92.
DOI: https://doi.org/10.1158/1055-9965.EPI-14-1038
Lee J, Park HK, Kwon M-J, et al. Decreased lung function is associated with elevated ferritin but not iron or transferrin saturation in 42,927 healthy Korean men: a cross-sectional study. PLoS One 2020;15:e0231057.
DOI: https://doi.org/10.1371/journal.pone.0231057
Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics 2014;6:748-73.
DOI: https://doi.org/10.1039/C3MT00347G
Alroomi M, Rajan R, Omar AA, et al. Ferritin level: a predictor of severity and mortality in hospitalized COVID-19 patients. Immun Inflamm Dis 2021;9:1648-55.
DOI: https://doi.org/10.1002/iid3.517
Nugroho J, Wardhana A, Maghfirah I, et al. Relationship of D-dimer with severity and mortality in SARS-CoV-2 patients : a meta-analysis. Int J Lab Hematol 2021;43:110-5.
DOI: https://doi.org/10.1111/ijlh.13336
Fogarty AW, Lewis SA, McKeever TM, et al. The association between blood coagulation activity and lung function: a population-based study. PLoS One 2010;5:e15014.
DOI: https://doi.org/10.1371/journal.pone.0015014
Ruta VM, Man AM, Alexescu TG, et al. Neutrophil-to-lymphocyte ratio and systemic immune-inflammation index-biomarkers in interstitial lung disease. Medicina (Kaunas) 2020;56:381.
DOI: https://doi.org/10.3390/medicina56080381
Ye G-L, Chen Q, Chen X, et al. The prognostic role of platelet-to-lymphocyte ratio in patients with acute heart failure: a cohort study. Sci Rep 2019;9:10639.
DOI: https://doi.org/10.1038/s41598-019-47143-2
Demir M, Duyuler PT, Guray U, et al. Platelet to lymphocyte ratio on admission and prognosis in patients with acute cardiogenic pulmonary edema. J Emerg Med 2018;55:465-71.
DOI: https://doi.org/10.1016/j.jemermed.2018.06.021
Bernstein D, Coster D, Berliner S, et al. C-reactive protein velocity discriminates between acute viral and bacterial infections in patients who present with relatively low CRP concentrations. BMC Infect Dis 2021;21:1210.
DOI: https://doi.org/10.1186/s12879-021-06878-y
Ngwa DN, Agrawal A. Structure-function relationships of C-reactive protein in bacterial infection. Front Immunol 2019;10:166.
DOI: https://doi.org/10.3389/fimmu.2019.00166
Kreiner FF, Kraaijenhof JM, von Herrath M, et al. Interleukin 6 in diabetes, chronic kidney disease, and cardiovascular disease: mechanisms and therapeutic perspectives. Expert Rev Clin Immunol 2022;18:377-89.
DOI: https://doi.org/10.1080/1744666X.2022.2045952
Grund B, Baker J V, Deeks SG, et al. Relevance of interleukin-6 and D-dimer for serious non-AIDS morbidity and death among HIV-positive adults on suppressive antiretroviral therapy. PLoS One 2016;11:e0155100.
DOI: https://doi.org/10.1371/journal.pone.0155100
Zella D, Giovanetti M, Cella E, et al. The importance of genomic analysis in cracking the coronavirus pandemic. Expert Rev Mol Diagn 2021;21:547-62.
DOI: https://doi.org/10.1080/14737159.2021.1917998
Deng K, Fan Q, Yang Y, et al. Prognostic roles of KL-6 in disease severity and lung injury in COVID-19 patients: a longitudinal retrospective analysis. J Med Virol 2021;93:2505-12.
DOI: https://doi.org/10.1002/jmv.26793
D’Alessandro M, Cameli P, Refini RM, et al. Serum KL-6 concentrations as a novel biomarker of severe COVID-19. J Med Virol 2020;92:2216-20.
DOI: https://doi.org/10.1002/jmv.26087
Awano N, Inomata M, Kuse N, et al. Serum KL-6 level is a useful biomarker for evaluating the severity of coronavirus disease 2019. Respir Investig 2020;58:440-7.
DOI: https://doi.org/10.1016/j.resinv.2020.07.004
Bergantini L, Bargagli E, d’Alessandro M, et al. Prognostic bioindicators in severe COVID-19 patients. Cytokine 2021;141:155455.
DOI: https://doi.org/10.1016/j.cyto.2021.155455
Wang X, Cheng Z. Cross-Sectional studies: strengths, weaknesses, and recommendations. Chest 2020;158:S65-71.
DOI: https://doi.org/10.1016/j.chest.2020.03.012
Austin PC, White IR, Lee DS, et al. Missing data in clinical research: a tutorial on multiple imputation. Can J Cardiol 2021;37:1322-31.
DOI: https://doi.org/10.1016/j.cjca.2020.11.010
Wang J, Zheng P, Huang Z, et al. Serum SP-A and KL-6 levels can predict the improvement and deterioration of patients with interstitial pneumonia with autoimmune features. BMC Pulm Med 2020;20:315.
DOI: https://doi.org/10.1186/s12890-020-01336-y
Choi MG, Choi SM, Lee JH, et al. Blood Krebs von den Lungen-6 levels predict treatment response to antifibrotic therapy in patients with idiopathic pulmonary fibrosis. Respir Res 2022;23:334.
DOI: https://doi.org/10.1186/s12931-022-02273-6
Hoashi T, Miyazaki S, Ozaki S, et al. Change in serum KL-6 level during biologic treatment for psoriasis. J Nippon Med Sch 2023;90:194-201.
DOI: https://doi.org/10.1272/jnms.JNMS.2023_90-207
Ethics Approval
This study was approved by the ethics committee of Universitas Airlangga Hospital (ethics number 121/KEP/2021).How to Cite
Witarto, Andro Pramana, Alfian Nur Rosyid, Bendix Samarta Witarto, Shidi Laras Pramudito, and Achmad Januar Er Putra. 2024. “An in-Depth Investigation of Serum Krebs Von Den Lungen-6 and Other Biomarkers in COVID-19 Severity and Mortality”. Monaldi Archives for Chest Disease, July. https://doi.org/10.4081/monaldi.2024.2848.
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