Lower Serum Angiotensin-Converting Enzyme Level in Relation to Hyperinflammation and Impaired Antiviral Immune Response Contributes to Progression of COVID-19 Infection

Abstract

Introduction: As a homologue of the angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2) has been identified as the main receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invasion. We aimed to investigate the role of serum ACE in predicting the coronavirus disease 2019 (COVID-19) disease progression and the underlying mechanisms.

Methods: We retrospectively enrolled 120 patients with confirmed COVID-19 who underwent serum ACE detection on admission. The clinical characteristics and laboratory findings during hospitalization were evaluated dynamically to identify the potential risk factors for disease progression.

Results: ACE level was demonstrated as one of the independent risk factors. Patients with ACE level ≤ 33.5 U/L showed a higher cumulative virus RNA detection rate, elevated pro-inflammatory mediators levels, declined lymphocyte count, and decreased SARS-CoV-2-specific antibodies than those with ACE level > 33.5 U/L.

Conclusion: Lower serum ACE levels in relation to delayed virus elimination, hyperinflammatory condition, and impaired host antiviral immune responses contribute to disease progression of COVID-19.

Keywords: COVID-19; Disease progression; Immune response; Serum angiotensin-converting enzyme; Virus clearance.

Fig. 1

Serum ACE level, diabetes, and lymphocyte count on admission are predictors of COVID-19 disease progression. a ROC curve analysis of ACE, diabetes, lymphocyte count, and their combination in patients with COVID-19 to predict the disease progression. b Optimal ACE cutoff value to distinguish disease progression cases from non-progressive cases. ACE angiotensin-converting enzyme, ROC receiver operating characteristic. ****P < 0.0001, ***P < 0.001, **P < 0.01, and *P < 0.05

Fig. 2

Kaplan–Meier survival curve for statistical analysis. Patients with ACE ≤ 33.5 U/L showed a higher cumulative detection rate of positive viral RNA (33.74% vs. 17.46%, 9.71% vs. 0% at days 20 and 30 post illness onset, respectively)

Fig. 3

Comparisons of the proinflammatory cytokines and inflammatory mediators between patients with ACE ≤ 33.5 U/L (n = 91) and patients with ACE > 33.5 U/L (n = 29) during hospitalization. The comparison of IL-2R, IL-6, IL-10 (a); CRP, PCT, ESR, and ferritin (b) between patients with ACE ≤ 33.5 U/L and patients with ACE > 33.5 U/L on admission and days 7, 14, and 21

Fig. 4

Comparisons of the immune status between patients. The comparison of lymphocyte count in patients during hospitalization. The change in total T lymphocytes and CD4⁺ T, CD8⁺ T, B, and NK cells (a), specific antibody IgM, and IgG against SARS-CoV-2 (b) between two consecutive detections with an interval of 7 ± 3 days in patients. ****P < 0.0001, ***P < 0.001, **P < 0.01, and *P < 0.05

Fig. 5

Schematic outline of low serum ACE level in relation to inflammation, immune status, and clinical outcome