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  • Cytokeratin 18 cell death assays as biomarkers for quantification of apoptosis and necrosis in COVID-19: a prospective, observational study

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Original research
Cytokeratin 18 cell death assays as biomarkers for quantification of apoptosis and necrosis in COVID-19: a prospective, observational study
  1. Brandon Michael Henry1,
  2. Isaac Cheruiyot2,
  3. Stefanie W Benoit3,4,
  4. Fabian Sanchis-Gomar5,6,
  5. Giuseppe Lippi7,
  6. Justin Benoit8
  1. 1 Cardiac Intensive Care Unit, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  2. 2 School of Medicine, University of Nairobi, Nairobi, Kenya
  3. 3 Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  4. 4 Department of Pediatrics, University of Cincinnati, College of Medicine, Ohio, Cincinnati, USA
  5. 5 Department of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California, USA
  6. 6 Department of Physiology, Faculty of Medicine, University of Valencia and INCLIVA Biomedical Research Institute, Valencia, Spain
  7. 7 Section of Clinical Biochemistry, Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy
  8. 8 Department of Emergency Medicine, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
  1. Correspondence to Dr Brandon Michael Henry, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Brandon.henry{at}cchmc.org

Abstract

Background The mechanism by which SARS-CoV-2 triggers cell damage and necrosis are yet to be fully elucidated. We sought to quantify epithelial cell death in patients with COVID-19, with an estimation of relative contributions of apoptosis and necrosis.

Methods Blood samples were collected prospectively from adult patients presenting to the emergency department. Circulating levels of caspase-cleaved (apoptosis) and total cytokeratin 18 (CK-18) (total cell death) were determined using M30 and M65 enzyme assays, respectively. Intact CK-18 (necrosis) was estimated by subtracting M30 levels from M65.

Results A total of 52 COVID-19 patients and 27 matched sick controls (with respiratory symptoms not due to COVID-19) were enrolled. Compared with sick controls, COVID-19 patients had higher levels of M65 (p = 0.046, total cell death) and M30 (p = 0.0079, apoptosis). Hospitalised COVID-19 patients had higher levels of M65 (p= 0.014) and intact CK-18 (p= 0.004, necrosis) than discharged patients. Intensive care unit (ICU)-admitted COVID-19 patients had higher levels of M65 (p= 0.004), M30 (p= 0.004) and intact CK-18 (p= 0.033) than hospitalised non-ICU admitted patients. In multivariable logistic regression, elevated levels of M65, M30 and intact CK-18 were associated with increased odds of ICU admission (OR=22.05, p=0.014, OR=19.71, p=0.012 and OR=14.12, p=0.016, respectively).

Conclusion Necrosis appears to be the main driver of hospitalisation, whereas apoptosis and necrosis appear to drive ICU admission. Elevated levels CK-18 levels are independent predictors of severe disease, and could be useful for risk stratification of COVID-19 patients and in assessment of therapeutic efficacy in early-phase COVID-19 clinical trials.

  • COVID-19
  • apoptosis
  • virology

Data availability statement

Data are available on reasonable request.

This article is made freely available for personal use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

https://bmj.com/coronavirus/usage

https://doi.org/10.1136/jclinpath-2020-207242

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    Data availability statement

    Data are available on reasonable request.

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    Footnotes

    • Handling editor Tony Mazzulli.

    • Contributors Study conception and design: BMH, IC; data collection: BMH; analysis and interpretation of results: BMH, IC; draft manuscript preparation: all authors. All authors reviewed the results and approved the final version of the manuscript.

    • Funding This study was funded by the University of Cincinnati College of Medicine Special Coronavirus (COVID-19) Research Pilot Grant Program.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.