Soluble angiotensin‐converting enzyme 2 is transiently elevated in COVID‐19 and correlates with specific inflammatory and endothelial markers
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Abstract
The main entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is angiotensin‐converting enzyme 2 (ACE2). SARS‐CoV‐2 interactions with ACE2 may increase ectodomain shedding but consequences for the renin‐angiotensin system and pathology in Coronavirus disease 2019 (COVID‐19) remain unclear. We measured soluble ACE2 (sACE2) and sACE levels by enzyme‐linked immunosorbent assay in 114 hospital‐treated COVID‐19 patients compared with 10 healthy controls; follow‐up samples after four months were analyzed for 58 patients. Associations between sACE2 respectively sACE and risk factors for severe COVID‐19, outcome, and inflammatory markers were investigated. Levels of sACE2 were higher in COVID‐19 patients than in healthy controls, median 5.0 (interquartile range 2.8–11.8) ng/ml versus 1.4 (1.1–1.6) ng/ml, p < .0001. sACE2 was higher in men than women but was not affected by other risk factors for severe COVID‐19. sACE2 decreased to 2.3 (1.6–3.9) ng/ml at follow‐up, p < .0001, but remained higher than in healthy controls, p = .012. sACE was marginally lower during COVID‐19 compared with at follow‐up, 57 (45–70) ng/ml versus 72 (52–87) ng/ml, p = .008. Levels of sACE2 and sACE did not differ depending on survival or disease severity. sACE2 during COVID‐19 correlated with von Willebrand factor, factor VIII and D ‐dimer, while sACE correlated with interleukin 6, tumor necrosis factor α, and plasminogen activator inhibitor 1. Conclusions: sACE2 was transiently elevated in COVID‐19, likely due to increased shedding from infected cells. sACE2 and sACE during COVID‐19 differed in correlations with markers of inflammation and endothelial dysfunction, suggesting release from different cell types and/or vascular beds.
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SciScore for 10.1101/2021.03.03.21252841: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: The only exclusion criteria for the present study was age below 18 years and inability to give informed consent.
IRB: The study was approved by the National Ethical Board (EPM 2020-01653).Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable Analyzed risk factors for severe COVID-19 infection were age, BMI, male sex, diab etes, hypertension, known CVD and chronic pulmonary disease. Table 2: Resources
Software and Algorithms Sentences Resources Statistical analyses were performed in SPSS version 26 (IBM, United States) and figure 2 generated by Prism (Graphpad Software Inc., SPSSsuggested: (SPSS, RRID:SCR_002865)SciScore for 10.1101/2021.03.03.21252841: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: The only exclusion criteria for the present study was age below 18 years and inability to give informed consent.
IRB: The study was approved by the National Ethical Board (EPM 2020-01653).Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable Analyzed risk factors for severe COVID-19 infection were age, BMI, male sex, diab etes, hypertension, known CVD and chronic pulmonary disease. Table 2: Resources
Software and Algorithms Sentences Resources Statistical analyses were performed in SPSS version 26 (IBM, United States) and figure 2 generated by Prism (Graphpad Software Inc., SPSSsuggested: (SPSS, RRID:SCR_002865)Prismsuggested: (PRISM, RRID:SCR_005375)Graphpadsuggested: (GraphPad, RRID:SCR_000306)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Limitations: The study is of moderate size and included hospital-treated patients with a limited proportion severe/fatal COVID-19. While the cohort is considered representative, it was heterogenous with respect to age and underlying conditions, which makes it potentially vulnerable to confounding. There are no standardized methods to measure sACE2 antigen. ELISA results were stable with median intra-assay CoV 1.8% (0.8-3.1%) between wells and sACE2 values were similar to those of a previous study (53). We did not have spare aliquots to rerun tests at higher dilution for patients with OD above maximum concentration on the standard curve; concentrations were therefore likely underestimated for ACE2 in 16 patients and for ACE in 10 patients. The group of healthy controls could have been larger considering that levels of sACE depend on genetic polymorphisms. However, our main conclusions are based on comparisons of values during COVID-19 compared with four months later with patients being their own controls. In conclusion, we find the plasma RAS-balance in hospital-treated Covid-19 patients to be characterized by a strong transient increase of circulation plasma sACE2 combined with marginally reduced sACE. Contributing factors to the sACE2 elevation likely include increased shedding in infected cells, and possibly also increased ACE2 membrane expression. The reduction of sACE may not be specific for COVID-19 and could be secondary to pneumonia. The relation between circulation an...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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- No protocol registration statement was detected.
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