Josefina Robertson (1,2), Bengt Nellgård (2,3), Lillemor Mattsson Hulten (2,4), Staffan Nilsson (5), Keti Dalla (2,3), Mats Börjesson (2,6,7), Henrik Zetterberg (8,9,10,11,12), Joar Svanvik (13), Magnus Gisslén (1,2)

Affiliates

1. Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 2. Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden 3. Department of Anaesthesiology and Intensive care, Institution of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 4. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden 5. Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg 6. Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 7. Department of Food and Nutrition and Sport Science, University of Gothenburg, Gothenburg, Sweden 8. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden 9. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden 10. Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK 11. UK Dementia Research Institute at UCL, London, UK 12. Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China 13. The transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden

Abstract

Introduction
Membrane-bound ACE (angiotensin-converting enzyme)-2 in epithelial cells is the main receptor for the SARS-CoV-2 virus entering the cells and then replicating in the cytoplasm causing COVID-19. The extracellular portion of ACE2 may be shedded to plasma in which process ADAM17 (A disintegrin and metalloproteinase 17) is important. Results on the relationship between blood levels of soluble ACE2 (sACE2) and disease severity are inconclusive. This study investigates the correlation between plasma sACE2 concentration and COVID-19 severity, and whether this is affected by gender.

Methods
sACE2 was analyzed in three groups: 104 patients (23 women and 81 men) with severe COVID-19 admitted to an intensive care unit (ICU), patients with moderate COVID-19 who required hospital care (n=19, 4 women and 15 men), and age and gender matched healthy controls (n=20, 4 women and 16 men). Blood samples were collected at hospital admission between March 18, 2020, and May 3, 2021, whereas blood samples at follow-up were collected between October 27, 2020, and October 19, 2021. Circulating sACE2 (µg/L) was measured in EDTA plasma with an enzyme-linked immunosorbent assay. Additionally, data on CRP, ferritin, and lymphocyte count were analyzed at hospital admission.

Results
COVID-19 patients treated in the ICU had a mean age of 63.6 (SD 11.6) years, while mean age in patients with moderate COVID-19 was 61.0 (SD 13.2) years, and in healthy controls 58.1 (SD 11.4) years. A total of 23 patients (22%) died in the ICU. We found that plasma sACE2 concentration decreased with disease severity in men (p = 0.002) but increased with severity in women (p = 0.043) (Figure 1). The interaction term was statistically significant (p = 0.002), confirming a sex-dependent difference in how COVID-19 severity is related to sACE2 concentration. Moreover, we identified a relationship between prognostic inflammatory biomarkers and sACE2 concentration during the intensive care treatment, such that higher CRP, higher ferritin concentration, and lower lymphocyte count correlated to lower sACE2 concentration (Figure 2).

Conclusions
The decrease in sACE2 concentration, selectively in men, in severe COVID-19 is of pathophysiological interest since men are affected more severely by the disease compared to women. Additionally, the inflammatory biomarkers, CRP and ferritin, correlated inversely with sACE2 concentration, suggesting a role in more severe disease. Our findings also imply that sACE2 is a possible predictor of disease severity in men.