An in-depth investigation of serum Krebs von den Lungen-6 and other biomarkers in COVID-19 severity and mortality

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 vs. non-severe) and mortality (non-survivor vs. 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 in 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