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. 2022 Apr 1;12(4):886.
doi: 10.3390/diagnostics12040886.

Soluble Angiotensin-Converting Enzyme 2 as a Prognostic Biomarker for Disease Progression in Patients Infected with SARS-CoV-2

Noelia Díaz-Troyano  1   2   3 , Pablo Gabriel-Medina  1   2   3 , Stephen Weber  4 , Martin Klammer  4 , Raquel Barquín-DelPino  1   2 , Laura Castillo-Ribelles  1   2   3 , Angels Esteban  1 , Manuel Hernández-González  2   3   5 , Roser Ferrer-Costa  1   2 , Tomas Pumarola  2   3   6 , Francisco Rodríguez-Frías  1   2   3
Affiliations

Soluble Angiotensin-Converting Enzyme 2 as a Prognostic Biomarker for Disease Progression in Patients Infected with SARS-CoV-2

Noelia Díaz-Troyano et al. Diagnostics (Basel). .

Abstract

Predicting disease severity in patients infected with SARS-CoV-2 is difficult. Soluble angiotensin-converting enzyme 2 (sACE2) arises from the shedding of membrane ACE2 (mACE2), which is a receptor for SARS-CoV-2 spike protein. We evaluated the predictive value of sACE2 compared with known biomarkers of inflammation and tissue damage (CRP, GDF-15, IL-6, and sFlt-1) in 850 patients with and without SARS-CoV-2 with different clinical outcomes. For univariate analyses, median differences between biomarker levels were calculated for the following patient groups (classified by clinical outcome): RT-PCR-confirmed SARS-CoV-2 positive (Groups 1−4); RT-PCR-confirmed SARS-CoV-2 negative following previous SARS-CoV-2 infection (Groups 5 and 6); and ‘SARS-CoV-2 unexposed’ patients (Group 7). Median levels of CRP, GDF-15, IL-6, and sFlt-1 were significantly higher in hospitalized patients with SARS-CoV-2 compared with discharged patients (all p < 0.001), whereas levels of sACE2 were significantly lower (p < 0.001). ROC curve analysis of sACE2 provided cut-offs for predicting hospital admission (≤0.05 ng/mL (positive predictive value: 89.1%) and ≥0.42 ng/mL (negative predictive value: 84.0%)). These findings support further investigation of sACE2, as a single biomarker or as part of a panel, to predict hospitalization risk and disease severity in patients with SARS-CoV-2 infection.

Keywords: COVID-19; SARS-CoV-2; SARS-CoV-2 spike protein; angiotensin-converting enzyme 2; biomarkers; disease severity; inflammation.

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Conflict of interest statement

S.W. and M.K. are employees of Roche Diagnostics GmbH and hold shares in F. Hoffmann-La Roche Ltd. The other authors report no potential conflict of interest.

Figures

Figure 1
Figure 1
Levels of (a) CRP, (b) GDF-15, (c) IL-6, (d) sACE2, and (e) sFlt-1 by disease severity in patients with SARS-CoV-2 who were admitted to hospital (Groups 2–4) and patients with SARS-CoV-2 who were discharged (Group 1). Thick black line = median; yellow cross = mean; upper/lower limits and whiskers = interquartile range and maximum/minimum values excluding outliers.
Figure 1
Figure 1
Levels of (a) CRP, (b) GDF-15, (c) IL-6, (d) sACE2, and (e) sFlt-1 by disease severity in patients with SARS-CoV-2 who were admitted to hospital (Groups 2–4) and patients with SARS-CoV-2 who were discharged (Group 1). Thick black line = median; yellow cross = mean; upper/lower limits and whiskers = interquartile range and maximum/minimum values excluding outliers.
Figure 2
Figure 2
Bivariate analysis performed in patients with SARS-CoV-2 infection who were admitted to hospital (Groups 2–4) versus patients with SARS-CoV-2 infection who were discharged (Group 1). Data are shown as ROC curves for (a) sFlt-1 + IL-6, (b) GDF-15 + IL-6, and (c) sACE2 + IL-6.
Figure 3
Figure 3
ROC curve analysis used to calculate lower and upper cut-off values of sACE2 for the prediction of hospitalization in patients with SARS-CoV-2. Blue dotted lines = upper and lower limits of the 95% CI for AUC.
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