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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}


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.

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Data availability statement

Data are available on reasonable request.

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  • 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.