Home Diagnostic performance of specific biomarkers for interstitial lung disease: a single center study
Article
Licensed
Unlicensed Requires Authentication

Diagnostic performance of specific biomarkers for interstitial lung disease: a single center study

  • Anu S. Maharjan , Sogol S. Amjadi , Troy D. Jaskowski , Sonia L. La’ulu , Dorota Lebiedz-Odrobina , Tracy M. Frech and Anne E. Tebo EMAIL logo
Published/Copyright: November 29, 2024
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 63 Issue 4

Abstract

Objectives

This study aimed to determine the clinical significance of Krebs von den Lungen-6 (KL-6), surfactant proteins A (SP-A) and D (SP-D) in the evaluation and management of interstitial lung disease (ILD).

Methods

Serum KL-6, SP-A, SP-D levels were measured in 122 unique consecutive patients referred for connective tissue disease (CTD) associated ILD (CTD-ILD) autoantibodies and 120 “healthy” controls. Patients’ charts were retrospectively reviewed and categorized as ILD and non-ILD or CTD-ILD and other ILD. All biomarkers were evaluated for diagnosis and moderate vs. severe ILD based on high-resolution computed tomography (HRCT).

Results

ILD was diagnosed in 52 % (n=64) and non-ILD in 48 % (n=58). ILD patients were categorized as other ILD (61 %, n=39) or CTD-ILD (39 %, n=25). Patients with ILD had significantly elevated levels of SP-A (p<0.02), KL-6 or SP-D (both p<0.0001) when compared to those with non-ILD. The mean levels of all biomarkers were significantly elevated levels in the ILD compared to non-ILD group (p<0.0001). No significant difference in biomarker levels between CTD-ILD and other ILD groups (p≥0.900). Biomarkers had comparable specificities (89–93 %) however; sensitivities were variable at 75 , 77 and 17 % for KL-6, SP-D and SP-A, respectively. Combination of KL-6 and SP-D yielded comparable diagnostic accuracy to all biomarkers with median levels significantly higher in patients with severe vs. mild disease.

Conclusions

KL-6 and SP-D levels are elevated in ILD and therefore contribute to the diagnosis and risk stratification for patient management.

Keywords: SP-A; SP-D; KL-6; test performance
Corresponding author: Anne E. Tebo, PhD, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA; and ARUP Laboratories, Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA, E-mail:
Anu S. Maharjan and Sogol S. Amjadi contributed equally to this work and share first authorship. Current affiliations: Anu S. Maharjan, PhD, Department of Pathology and Laboratory Medicine, UConn Health, Farmington, CT, USA; Sogol S. Amjadi, DO, Department of Internal Medicine, Arrowhead Regional Medical Center, Colton, CA, USA; Dorota Lebiedz-Odrobina, GE Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA; and Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA; Tracy M. Frech, MD, Vanderbilt University Medical Center, Nashville, TN, USA; and Anne E. Tebo, PhD, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

  1. Research ethics: The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and approved by the the Institutional Review Board (IRB #00029507) of the University of Utah.

  2. Informed consent: Not applicable

  3. Author contributions: Jaskowski TD and La’ulu SL performed the experimental work, Amjadi SS, Lebiedz-Odrobina O and Frech TM extracted clinical data, Amjadi SS and Maharjan AS analyzed the data, Tebo AET conceived and supervised the study and co-wrote the first draft with Maharjan AS. All authors contributed to revising the draft manuscript, have accept responsibility for the entire content and approve its submission.

  4. Use of Large Language Models, AI and Machine Learning Tools: None declared.

  5. Conflict of interest: The authors state no conflict of interest.

  6. Research funding: Not applicable.

  7. Data availability: The raw data can be obtained on request from the corresponding author.

References

1. Inoue, Y, Kaner, RJ, Guiot, J, Maher, TM, Tomassetti, S, Moiseev, S, et al.. Diagnostic and prognostic biomarkers for chronic fibrosing interstitial lung diseases with a progressive phenotype. Chest 2020;158:646–59. https://doi.org/10.1016/j.chest.2020.03.037.Search in Google Scholar PubMed

2. Podolanczuk, AJ, Wong, AW, Saito, S, Lasky, JA, Ryerson, CJ, Eickelberg, O. Update in interstitial lung disease 2020. Am J Respir Crit Care Med 2021;203:1343. https://doi.org/10.1164/rccm.202103-0559up.Search in Google Scholar PubMed PubMed Central

3. Lee, JS, Lee, EY, Ha, YJ, Kang, EH, Lee, YJ, Song, YW. Serum KL-6 levels reflect the severity of interstitial lung disease associated with connective tissue disease. Arthritis Res Ther 2019;21:58. https://doi.org/10.1186/s13075-019-1835-9.Search in Google Scholar PubMed PubMed Central

4. Ohnishi, H, Yokoyama, A, Kondo, K, Hamada, H, Abe, M, Nishimura, 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;165:378–81. https://doi.org/10.1164/ajrccm.165.3.2107134.Search in Google Scholar PubMed

5. Zhang, T, Shen, P, Duan, C, Gao, L. KL-6 as an immunological biomarker predicts the severity, progression, acute exacerbation, and poor outcomes of interstitial lung disease: a systematic review and meta-analysis. Front Immunol 2021;12:745233. https://doi.org/10.3389/fimmu.2021.745233.Search in Google Scholar PubMed PubMed Central

6. Takahashi, H, Kuroki, Y, Tanaka, H, Saito, T, Kurokawa, K, Chiba, 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;162:258–63. https://doi.org/10.1164/ajrccm.162.1.9903014.Search in Google Scholar PubMed

7. Yamakawa, H, Hagiwara, E, Kitamura, H, Yamanaka, Y, Ikeda, S, Sekine, A, et al.. Serum KL-6 and surfactant protein-D as monitoring and predictive markers of interstitial lung disease in patients with systemic sclerosis and mixed connective tissue disease. J Thorac Dis 2017;9:362–71. https://doi.org/10.21037/jtd.2017.02.48.Search in Google Scholar PubMed PubMed Central

8. Bonella, F, Costabel, U. Biomarkers in connective tissue disease-associated interstitial lung disease. Semin Respir Crit Care Med 2014;35:181–200. https://doi.org/10.1055/s-0034-1371527.Search in Google Scholar PubMed

9. Wang, K, Ju, Q, Cao, J, Tang, W, Zhang, J. Impact of serum SP-A and SP-D levels on comparison and prognosis of idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Medicine (Baltim) 2017;96:e7083. https://doi.org/10.1097/md.0000000000007083.Search in Google Scholar PubMed PubMed Central

10. Skemp-Dymond, G, Lebiedz-Odrobina, D, Zuromski, LM, Rhoads, JLW, Tebo, AE. Assessment of a line immunoassay for the detection of Mi-2 antibodies: results from a single academic center investigation. Am J Clin Pathol 2022;157:506–9. https://doi.org/10.1093/ajcp/aqab150.Search in Google Scholar PubMed

11. Goh, NS, Desai, SR, Veeraraghavan, S, Hansell, DM, Copley, SJ, Maher, TM, et al.. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med 2008;177:1248–54. https://doi.org/10.1164/rccm.200706-877oc.Search in Google Scholar

12. 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;271:589–97. https://doi.org/10.1111/j.1365-2796.2011.02459.x.Search in Google Scholar PubMed

13. Hu, Y, Wang, LS, Jin, YP, Du, S, Du, Y, He, X, et al.. Serum Krebs von den Lungen-6 level as a diagnostic biomarker for interstitial lung disease in Chinese patients. Clin Res J 2017;11:337–45. https://doi.org/10.1111/crj.12341.Search in Google Scholar PubMed

14. Larsson, J. Eulerr: area-proportional Euler and Venn diagrams with ellipses. R package version 6.1.1; 2021. https://CRAN.R-project.org/package=eulerr [Accessed 25 Jan 2024].Search in Google Scholar

15. Conway, JR, Lex, A, Gehnlenborg, N. An R package for the visualization of intersecting sets and their properties. https://doi.org/10.1093/bioinformatics/btx364 [Accessed 22 Jan 2024].Search in Google Scholar PubMed PubMed Central

16. Bowman, WS, Echt, GA, Oldham, JM. Biomarkers in progressive fibrosing interstitial lung disease: optimizing diagnosis, prognosis, and treatment response. Front Med 2021;8:680997. https://doi.org/10.3389/fmed.2021.680997.Search in Google Scholar PubMed PubMed Central

17. White, ES, Thomas, M, Stowasser, S, Tetzlaff, K. Challenges for clinical drug development in pulmonary fibrosis. Front Pharmacol 2022;13:823085. https://doi.org/10.3389/fphar.2022.823085.Search in Google Scholar PubMed PubMed Central

18. Bowman, WS, Newton, CA, Linderholm, AL, Neely, ML, Pugashetti, JV, Kaul, B, et al.. Proteomic biomarkers of progressive fibrosing interstitial lung disease: a multicentre cohort analysis. Lancet Respir Med 2022;10:593–602. https://doi.org/10.1016/s2213-2600(21)00503-8.Search in Google Scholar

19. Stock, CJW, Hoyles, RK, Daccord, C, Kokosi, M, Visca, D, De Lauretis, A, et al.. Serum markers of pulmonary epithelial damage in systemic sclerosis-associated interstitial lung disease and disease progression. Respirology 2021;26:461–8. https://doi.org/10.1111/resp.13988.Search in Google Scholar PubMed

20. Zheng, M, Lou, A, Zhang, H, Zhu, S, Yang, M, Lai, W. Serum KL-6, CA19-9, CA125 and CEA are diagnostic biomarkers for rheumatoid arthritis-associated interstitial dung disease in the Chinese population. Rheumatol Ther 2021;8:517–27. https://doi.org/10.1007/s40744-021-00288-x.Search in Google Scholar PubMed PubMed Central

21. d’Alessandro, M, Bergantini, L, Cameli, P, Curatola, G, Remediani, L, Bennett, D, et al.. Serial KL-6 measurements in COVID-19 patients. Intern Emerg Med 2021;16:1541–5. https://doi.org/10.1007/s11739-020-02614-7.Search in Google Scholar PubMed PubMed Central

22. He, Q, Tang, Y, Huang, J, Rao, Y, Lu, Y. The value of KL-6 in the diagnosis and assessment of interstitial lung disease. Am J Transl Res 2021;13:9216–23.Search in Google Scholar

23. Xue, M, Guo, Z, Cai, C, Sun, B, Wang, H. Evaluation of the diagnostic efficacies of serological markers KL-6, SP-A, SP-D, CCL2, and CXCL13 in idiopathic interstitial pneumonia. Respiration 2019;98:534–45. https://doi.org/10.1159/000503689.Search in Google Scholar PubMed

Received: 2024-05-24
Accepted: 2024-11-01
Published Online: 2024-11-29
Published in Print: 2025-03-26

© 2024 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Beyond test results: the strategic importance of metadata for the integration of AI in laboratory medicine
  4. Reviews
  5. Reference, calibration and referral laboratories – a look at current European provisions and beyond
  6. How has the external quality assessment/proficiency testing of semen analysis been developed in the past 34 years: a review
  7. Opinion Papers
  8. Data flow in clinical laboratories: could metadata and peridata bridge the gap to new AI-based applications?
  9. A comprehensive survey of artificial intelligence adoption in European laboratory medicine: current utilization and prospects
  10. Guidelines and Recommendations
  11. Guidelines for the correct use of the nomenclature of biochemical indices of bone status: a position statement of the Joint IOF Working Group and IFCC Committee on Bone Metabolism
  12. Candidate Reference Measurement Procedures and Materials
  13. Absolute quantitation of human serum cystatin C: candidate reference method by 15N-labeled recombinant protein isotope dilution UPLC-MS/MS
  14. General Clinical Chemistry and Laboratory Medicine
  15. Performance evaluation of the introduction of full sample traceability system within the specimen collection process
  16. Pre-analytical stability of haematinics, lactate dehydrogenase and phosphate in whole blood at room temperature up to 24 h, and refrigerated serum stability of lactate dehydrogenase, folate and vitamin B12 up to 72 h using the CRESS checklist
  17. Comparison of capillary finger stick and venous blood sampling for 34 routine chemistry analytes: potential for in hospital and remote blood sampling
  18. Performance evaluation of enzymatic total bile acid (TBA) routine assays: systematic comparison of five fifth-generation TBA cycling methods and their individual bile acid recovery from HPLC-MS/MS reference
  19. Clinical performance of a new lateral flow immunoassay for xylazine detection
  20. Evaluation of revised UK-NEQAS CSF-xanthochromia method for subarachnoid hemorrhage: outcome data provide evidence for clinical value
  21. Strategies to verify equimolar peptide release in mass spectrometry-based protein quantification exemplified for apolipoprotein(a)
  22. Evaluation of the clinical performance of anti-mutated citrullinated vimentin antibody and 14-3-3 eta testing in rheumatoid arthritis
  23. Diagnostic performance of specific biomarkers for interstitial lung disease: a single center study
  24. Reference Values and Biological Variations
  25. Neonatal reference intervals for serum steroid hormone concentrations measured by LC-MS/MS
  26. Paediatric reference intervals for haematology parameters analysed on Sysmex XN-9000: a comparison of methods in the framework of indirect sampling
  27. Cardiovascular Diseases
  28. Analytical characteristics and performance of a new hs-cTnI method: a multicenter-study
  29. Diabetes
  30. Use of labile HbA1c as a screening tool to minimize clinical misinterpration of HbA1c
  31. Letters to the Editor
  32. Current trends and future projections in the clinical laboratory test market: implications for resource management and strategic planning
  33. Particulate matter in water: an overlooked source of preanalytical error producing erroneous chemistry test results
  34. “Activation” of macro-AST by pyridoxal-5-phosphate in the assay for aspartate aminotransferase
  35. The correlation of albumin with total protein concentrations in cerebrospinal fluid across three automated analysers – relevance to the diagnosis of subarachnoid haemorrhage in clinical chemistry practice
  36. Adult reference intervals for serum thyroid‐stimulating hormone using Abbott Alinity i measuring system
  37. Cell population data in venous thrombo-embolism and erysipelas: a potential diagnostic tool?
  38. Diagnostic performances and cut-off verification of blood pTau 217 on the Lumipulse platform for amyloid deposition in Alzheimer’s disease
  39. The first case of Teclistamab interference with serum electrophoresis and immunofixation
  40. Congress Abstracts
  41. Annual meeting of the Royal Belgian Society of Laboratory Medicine (RBSLM): “A Neurological Journey: Brain Teasers for Laboratory Medicine”
https://doi.org/10.1515/cclm-2024-1048
Keywords for this article
SP-A; SP-D; KL-6; test performance

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Beyond test results: the strategic importance of metadata for the integration of AI in laboratory medicine
  4. Reviews
  5. Reference, calibration and referral laboratories – a look at current European provisions and beyond
  6. How has the external quality assessment/proficiency testing of semen analysis been developed in the past 34 years: a review
  7. Opinion Papers
  8. Data flow in clinical laboratories: could metadata and peridata bridge the gap to new AI-based applications?
  9. A comprehensive survey of artificial intelligence adoption in European laboratory medicine: current utilization and prospects
  10. Guidelines and Recommendations
  11. Guidelines for the correct use of the nomenclature of biochemical indices of bone status: a position statement of the Joint IOF Working Group and IFCC Committee on Bone Metabolism
  12. Candidate Reference Measurement Procedures and Materials
  13. Absolute quantitation of human serum cystatin C: candidate reference method by 15N-labeled recombinant protein isotope dilution UPLC-MS/MS
  14. General Clinical Chemistry and Laboratory Medicine
  15. Performance evaluation of the introduction of full sample traceability system within the specimen collection process
  16. Pre-analytical stability of haematinics, lactate dehydrogenase and phosphate in whole blood at room temperature up to 24 h, and refrigerated serum stability of lactate dehydrogenase, folate and vitamin B12 up to 72 h using the CRESS checklist
  17. Comparison of capillary finger stick and venous blood sampling for 34 routine chemistry analytes: potential for in hospital and remote blood sampling
  18. Performance evaluation of enzymatic total bile acid (TBA) routine assays: systematic comparison of five fifth-generation TBA cycling methods and their individual bile acid recovery from HPLC-MS/MS reference
  19. Clinical performance of a new lateral flow immunoassay for xylazine detection
  20. Evaluation of revised UK-NEQAS CSF-xanthochromia method for subarachnoid hemorrhage: outcome data provide evidence for clinical value
  21. Strategies to verify equimolar peptide release in mass spectrometry-based protein quantification exemplified for apolipoprotein(a)
  22. Evaluation of the clinical performance of anti-mutated citrullinated vimentin antibody and 14-3-3 eta testing in rheumatoid arthritis
  23. Diagnostic performance of specific biomarkers for interstitial lung disease: a single center study
  24. Reference Values and Biological Variations
  25. Neonatal reference intervals for serum steroid hormone concentrations measured by LC-MS/MS
  26. Paediatric reference intervals for haematology parameters analysed on Sysmex XN-9000: a comparison of methods in the framework of indirect sampling
  27. Cardiovascular Diseases
  28. Analytical characteristics and performance of a new hs-cTnI method: a multicenter-study
  29. Diabetes
  30. Use of labile HbA1c as a screening tool to minimize clinical misinterpration of HbA1c
  31. Letters to the Editor
  32. Current trends and future projections in the clinical laboratory test market: implications for resource management and strategic planning
  33. Particulate matter in water: an overlooked source of preanalytical error producing erroneous chemistry test results
  34. “Activation” of macro-AST by pyridoxal-5-phosphate in the assay for aspartate aminotransferase
  35. The correlation of albumin with total protein concentrations in cerebrospinal fluid across three automated analysers – relevance to the diagnosis of subarachnoid haemorrhage in clinical chemistry practice
  36. Adult reference intervals for serum thyroid‐stimulating hormone using Abbott Alinity i measuring system
  37. Cell population data in venous thrombo-embolism and erysipelas: a potential diagnostic tool?
  38. Diagnostic performances and cut-off verification of blood pTau 217 on the Lumipulse platform for amyloid deposition in Alzheimer’s disease
  39. The first case of Teclistamab interference with serum electrophoresis and immunofixation
  40. Congress Abstracts
  41. Annual meeting of the Royal Belgian Society of Laboratory Medicine (RBSLM): “A Neurological Journey: Brain Teasers for Laboratory Medicine”
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 10.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/cclm-2024-1048/html
Scroll to top button