Circulating angiotensin-(1-7) is decreased in patients with isolated nocturnal hypertension.

Isolated nocturnal hypertension (INHT), defined as nighttime elevated blood pressure (BP) with normal daytime BP assessed by ambulatory BP monitoring, is associated with higher cardiovascular morbidity and mortality. We hypothesized that an alteration in the circulating renin-angiotensin system (RAS) contributes to INHT development. We examined circulating levels of angiotensin (Ang) (1-7) and Ang II and ACE2 activity in 26 patients that met the INHT criteria, out of 50 that were referred for BP evaluation (62% women, 45 ±â€Š16 years old). Those with INHT were older, had a higher BMI, lower circulating Ang-(1-7) (P = 0.002) and Ang II levels (P = 0.02) and no change in ACE2 activity compared to those normotensives. Nighttime DBP was significantly correlated with Ang-(1-7) and Ang II levels. Logistic regression showed significant association in Ang-(1-7) and Ang II levels with INHT. Our study reveals differences in circulating RAS in individuals with INHT.

Evaluation of angiotensin converting enzyme 2 (ACE2), angiotensin II (Ang II), miR-141-3p, and miR-421 levels in SARS-CoV-2 patients: a case-control study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious virus that uses angiotensin converting enzyme 2 (ACE2), a pivotal member of the renin-angiotensin system (RAS), as its cell-entry receptor. Another member of the RAS, angiotensin II (Ang II), is the major biologically active component in this system. There is growing evidence suggesting that serum miRNAs could serve as prognostic biomarkers for SARS-CoV-2 infection and regulate ACE2 expression. Therefore, the aim of this study is to evaluate the changes in the serum levels of sACE2 and Ang II, as well as the expression level of miR-141-3p and miR-421 in SARS-CoV-2 positive and negative subjects. METHODS: In the present study, the serum levels of sACE2 and Ang II were measured in 94 SARS-CoV-2 positive patients and 94 SARS-CoV-2 negative subjects with some symptoms similar to those of SARS-CoV-2 positive patients using the ELISA method. In addition, the expression level of miR-141-3p and miR-421 as ACE2 regulators and biomarkers was evaluated using quantitative real-time PCR (qRT-PCR) method. RESULTS: The mean serum sACE2 concentration in the SARS-CoV-2-positive group was 3.268 ± 0.410 ng/ml, whereas in the SARS-CoV-2 negative group, it was 3.564 ± 0.437 ng/ml. Additionally, the mean serum Ang II level in the SARS-CoV-2 positive and negative groups were 60.67 ± 6.192 ng/L and 67.97 ± 6.837 ng/L, respectively. However, there was no significant difference in the serum levels of sACE2 (P value: 0.516) and Ang II (P value: 0.134) between the SARS-CoV-2 positive and negative groups. Meanwhile, our findings indicated that the expression levels of miR-141-3p and miR-421 in SARS-CoV-2 positive group were significantly lower and higher than SARS-CoV-2 negative group, respectively (P value < 0.001). CONCLUSIONS: Taken together, the results of this study showed that the serum levels of sACE2 and Ang II in SARS-CoV-2 positive and negative subjects were not significantly different, but the expression levels of miR-141-3p and miR-421 were altered in SARS-CoV-2 positive patients which need more investigation to be used as biomarkers for COVID-19 diagnosis.

Intronic Variants of the Angiotensin-Converting Enzyme 2 Gene Modulate Plasma ACE2 Levels and Possibly Confer Protection against Severe COVID-19.

Membrane-bound angiotensin-converting enzyme 2 (ACE2) receptor acts as the entry point for the novel coronavirus, SARS-CoV-2. Polymorphisms in the ACE2 gene may alter viral binding, regulate the expression of ACE2, and thus, affect disease severity. In this study, 68 COVID-19 patients with varying degrees of severity and 40 healthy controls were enrolled. The genetic landscape of the ACE2 gene was explored by whole exome sequencing of 29 individuals, and specific regions of ACE2 were analyzed for the rest of the participants via PCR, followed by barcode-tagged sequencing. The mean soluble ACE2 level in the plasma of healthy controls and patients did not vary significantly but was higher in the patient group (3.77 ± 1.55 ng/mL vs. 3.94 ± 1.42 ng/mL). Analysis of exon 1, exon 2, and exon 8 of the ACE2 gene revealed that these regions are highly conserved in our population. Investigation of exon 11 and its flanking intronic region revealed that deletions in a stretch of 18T nucleotides in the noncoding region significantly decrease ACE2 levels in plasma, as individuals harboring wild-type variants had higher plasma ACE2 levels compared to those harboring T1del, T2del, and T3del variants. However, the intronic variants were not found to be significantly associated with disease severity.

Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause lethal pulmonary damage in humans. It contains spike proteins on its envelope that bind to human angiotensin-converting enzyme 2 (hACE2) expressed on airway cells, enabling entry of the virus, and causing infection. The soluble form of hACE2 binds SARS-CoV-2 spike protein, prevents viral entry into target cells, and ameliorates lung injury; however, its short half-life limits therapeutic utilities. Here, synthetic mRNA is engineered to encode a soluble form of hACE2 (hsACE2) to prevent viral infection. A novel lipid nanoparticle (LNP) is used for packaging and delivering mRNA to cells to produce hsACE2 proteins. Intravenously administered LNP delivers mRNA to hepatocytes, leading to the production of circulatory hsACE2 initiated within 2 h and sustained over several days. Inhaled LNP results in lung transfection and secretion of mucosal hsACE2 to lung epithelia, the primary site of entry and pathogenesis for SARS-CoV-2. Furthermore, mRNA-generated hsACE2 binds to the receptor-binding domain of the viral spike protein. Finally, hsACE2 effectively inhibits SARS-CoV-2 and its pseudoviruses from infecting host cells. The proof of principle study shows that mRNA-based nanotherapeutics can be potentially deployed to neutralize SARS-CoV-2 and open new treatment opportunities for coronavirus disease 2019 (COVID-19).

Children With Short Stature Display Reduced ACE2 Expression in Peripheral Blood Mononuclear Cells.

Background: The cause of short stature remains often unknown. The renin-angiotensin system contributes to growth regulation. Several groups reported that angiotensin-converting enzyme 2 (ACE2)-knockout mice weighed less than controls. Our case-control study aimed to investigate if children with short stature had reduced ACE2 expression as compared to controls, and its significance. Materials and Methods: children aged between 2 and 14 years were consecutively recruited in a University Hospital pediatric tertiary care center. Cases were children with short stature defined as height SD ≤ -2 diagnosed with growth hormone deficiency (GHD) or idiopathic short stature (ISS), before any treatment. Exclusion criteria were: acute diseases, kidney disease, endocrine or autoimmune disorders, precocious puberty, genetic syndromes, SGA history. ACE and ACE2 expression were measured in peripheral blood mononuclear cells, angiotensins were measured by ELISA. Results: Children with short stature displayed significantly lower ACE2 expression, being 0.40 fold induction (0.01-2.27) as compared to controls, and higher ACE/ACE2, with no differences between GHD and ISS. ACE2 expression was significantly and inversely associated with the risk of short stature, OR 0.26 (0.07-0.82), and it had a moderate accuracy to predict it, with an AUC of 0.73 (0.61-0.84). The cutoff of 0.45 fold induction of ACE2 expression was the value best predicting short stature, identifying correctly 70% of the children. Conclusions: Our study confirms the association between the reduction of ACE2 expression and growth retardation. Further studies are needed to determine its diagnostic implications.

ACE2 and ANGII levels in patients with COVID-19 based on thoracic tomography findings and PCR test results.

INTRODUCTION: Reverse transcriptase polymerase chain reaction tests and thoracic tomography have been widely employed in the diagnosis of the disease, but doubts about their sensitivity still persist. Also there are controversial results about ACE2 and AngII levels according to the severity of disease. In this study, we aimed to analyze the ACE2 and AngII levels in patients with suspected COVID-19 based on polymerase chain reaction test results and thoracic tomography findings and to examine their relationship with disease severity. METHODOLOGY: Patients with suspected COVID-19 in the emergency department were divided into 4 groups according to thoracic tomography findings and PCR test results. The in-hospital mortality of patients was recorded. ACE2 and AngII levels in patients were analyzed according to groups and severity of the disease. RESULTS: ACE2 levels for the patients with suspected COVID-19 were significantly lower than in the control group, but AngII levels were higher (not statistically significant). The mean age and male sex ratio of patients who developed acute respiratory distress syndrome (ARDS) and died were significantly higher than those who survived. Whereas there was no difference in ACE2 levels in patients with severe diseases such as ARDS and mortality, their AngII levels were significantly lower. CONCLUSIONS: It can be suggested that decreased ACE2 levels combined with increased AngII levels are determinative at disease onset and in the development of lung damage. However, decreased AngII levels are more determinative in patients with severe diseases such as ARDS and mortality.

Elevated mid-pregnancy plasma levels of angiotensin-converting enzyme 2 in women prior to the development of preeclampsia.

Preeclampsia and cardiovascular disease (CVD) share multiple features and risk factors. Circulating angiotensin-converting enzyme 2 (ACE2) is increased in CVD and mediates SARS-CoV-2 entry into host cells, causing COVID-19 infection. The role of ACE2 in preeclampsia pathophysiology is unknown. We hypothesized that circulating ACE2 is increased in mid-pregnancy in women later developing preeclampsia. We included 296 women later developing preeclampsia (cases) and 333 women with a continuous healthy pregnancy (controls). Circulating ACE2 was measured with an immunoassay based on proximity extension assay technology, with levels being expressed as relative quantification on a log2 scale. Median (interquartile range) ACE2 levels were higher in cases than in controls; 3.84 (3.50-4.24) vs. 3.72 (3.45-4.04), p = 0.002. Adjusted logistic regression models showed a 60% increased risk for later development of preeclampsia with one unit elevation of ACE2 (adjusted odds ratio (aOR) 1.60, 95% confidence intervals (CI) 1.17-2.18). Preterm preeclampsia (diagnosis before 37 gestational weeks, n = 97) seemed to have a stronger ACE2 association than term preeclampsia, n = 199 (aORs, 95% Cis 2.14, 1.15-3.96 and 1.52, 1.04-2.23, respectively). Circulating ACE2 is increased at mid-pregnancy in women later developing preeclampsia, particularly preterm preeclampsia. Thus, our finding indicates a partly shared pathophysiological pathway between preeclampsia and CVD.

Neutrophils predominate the immune signature of cerebral thrombi in COVID-19 stroke patients.

Coronavirus disease 2019 (COVID-19) is associated with an increased risk of thrombotic events. Ischemic stroke in COVID-19 patients entails high severity and mortality rates. Here we aimed to analyze cerebral thrombi of COVID-19 patients with large vessel occlusion (LVO) acute ischemic stroke to expose molecular evidence for SARS-CoV-2 in the thrombus and to unravel any peculiar immune-thrombotic features. We conducted a systematic pathological analysis of cerebral thrombi retrieved by endovascular thrombectomy in patients with LVO stroke infected with COVID-19 (n = 7 patients) and non-covid LVO controls (n = 23). In thrombi of COVID-19 patients, the SARS-CoV-2 docking receptor ACE2 was mainly expressed in monocytes/macrophages and showed higher expression levels compared to controls. Using polymerase chain reaction and sequencing, we detected SARS-CoV-2 Clade20A, in the thrombus of one COVID-19 patient. Comparing thrombus composition of COVID-19 and control patients, we noted no overt differences in terms of red blood cells, fibrin, neutrophil extracellular traps (NETs), von Willebrand Factor (vWF), platelets and complement complex C5b-9. However, thrombi of COVID-19 patients showed increased neutrophil density (MPO+ cells) and a three-fold higher Neutrophil-to-Lymphocyte Ratio (tNLR). In the ROC analysis both neutrophils and tNLR had a good discriminative ability to differentiate thrombi of COVID-19 patients from controls. In summary, cerebral thrombi of COVID-19 patients can harbor SARS-CoV2 and are characterized by an increased neutrophil number and tNLR and higher ACE2 expression. These findings suggest neutrophils as the possible culprit in COVID-19-related thrombosis.

Soluble ACE2 and TMPRSS2 Levels in the Serum of Asthmatic Patients.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2) are key proteins mediating viral entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although gene expressions of ACE2 and TMPRSS2 have been analyzed in various organs and diseases, their soluble forms have been less studied, particularly in asthma. Therefore, we aimed to measure circulating ACE2 and TMPRSS2 in the serum of asthmatics and examine their relationship with clinical characteristics. METHODS: Clinical data and serum samples of 400 participants were obtained from an asthma cohort. The soluble ACE2 (sACE2) and soluble TMPRSS2 (sTMPRSS2) level was measured by enzyme-linked immunosorbent assay, and the values underwent a natural log transformation. Associations between sACE2 and TMPRSS2 levels and various clinical variables were analyzed. RESULTS: The patients younger than 70 years old, those with eosinophilic asthma (eosinophils ≥ 200 cells/µL), and inhaled corticosteroids (ICS) non-users were associated with higher levels of sACE2. Blood eosinophils and fractionated exhaled nitric oxide levels were positively correlated with serum ACE2. In contrast, lower levels of sTMPRSS2 were noted in patients below 70 years and those with eosinophilic asthma, while no association was noted between ICS use and sTMPRSS2. The level of sTMPRSS2 also differed according to sex, smoking history, coexisting hypertension, and forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio. The proportion of sputum neutrophils was positively correlated with sTMPRSS2, while the FEV1/FVC ratio reported a negative correlation with sTMPRSS2. CONCLUSION: The levels of ACE2 and TMPRSS2 were differently expressed according to age, ICS use, and several inflammatory markers. These findings suggest variable susceptibility and prognosis of SARS-CoV-2 infection among asthmatic patients.

Could serum ACE2 levels predict infarct size in acute phase of ST-segment elevation myocardial infarction: a comparative study with classical biomarkers.

OBJECTIVE: Serum ACE2 level in the acute phase of ST-segment elevation myocardial infarction may be an indicator of heart failure, however, limited studies have reported conflicting results. Therefore, in our study, we aimed to evaluate the relationship between serum ACE2 level and infarct size in the acute phase of ST-segment elevation myocardial infarction and compare the predictive value of ACE2 level with classical biomarkers. PATIENTS AND METHODS: Sixty-six patients after the primary percutaneous coronary intervention were included in the study. For the measurement of serum ACE2 levels, blood samples were taken twice from the patients: in the first 24 hours and on the 5th day of the infarction, and once from 30 healthy volunteers. hs-cTnT, BNP, and CRP levels were measured daily, and their peak values were taken. On the 7th day of ST-segment elevation myocardial infarction, gSPECT was used with the 99mTc-MIBI method for assessment of infarct size. RESULTS: Baseline ACE2 values were found to be higher in patients compared to controls, and ACE2 values obtained on the 5th day were found to be higher than the baseline values in the patients. There was no significant correlation between serum ACE2 levels and the RSS (%), while peak levels of hs-cTnT, BNP, and CRP were assessed as predictive factors for the RSS (%). CONCLUSIONS: Although serum ACE2 levels increased in the acute phase of ST-segment elevation myocardial infarction, this increase was not associated with infarct size. Serum ACE2 level did not provide additional benefit to classical biomarkers for infarct size-related prognosis prediction.

Whole Exome Sequencing Identifies a Rare Mutation in NACAD as a Possible Cause of COVID Orchitis in Brothers.

COVID orchitis (testicular pain) is reported in 10-15% of men with long COVID. We identified 2 siblings with COVID orchitis and hypothesized that genetic mutations are associated with susceptibility. Blood samples from 5 COVID-19 (+) men, three of whom had orchitis were evaluated by whole-exome-sequencing. A rare deletion on chromosome 7 was found in NACAD among the 3 men with orchitis. Interestingly, circulating ACE2 levels was decreased in men with COVID orchitis. This pilot study generated the hypothesis that men who develop COVID orchitis could have underlying genetic variants and altered levels in circulating ACE2 that may increase their risk.

Upregulated miR-200c is associated with downregulation of the functional receptor for severe acute respiratory syndrome coronavirus 2 ACE2 in individuals with obesity.

Obesity is a risk factor for coronavirus disease 2019 (COVID-19) infection, with studies demonstrating the prevalence of individuals with obesity admitted with COVID-19 ranging between 30 and 60%. We determined whether early changes in microRNAs (miRNAs) are associated with dysregulation of angiotensin-converting enzyme 2 (ACE2), the specific functional receptor for severe acute respiratory syndrome coronavirus 2. ACE2 is a membrane-bound enzyme that catalyzes the conversion of angiotensin II to angiotensin 1-7 the latter having cardioprotective and vasorelaxation effects. Quantitative real-time PCR analysis of plasma samples for circulating miRNAs showed upregulation of miR-200c and miR-let-7b in otherwise healthy individuals with obesity. This was associated with significant downregulation of ACE2, a direct target for both miRNAs, in individuals with obesity. Correlation analysis confirmed a significant negative correlation between ACE2 and both the miRNAs. Studies showed that despite being the functional receptor, inhibition/downregulation of ACE2 did not reduce the severity of COVID-19 infection. In contrast, increased angiotensin II following inhibition of ACE2 may increase the severity of the disease. Taken together, our novel results identify that upregulation of miR-200c may increase the susceptibility of individuals with obesity to COVID-19. Considering miRNA are the earliest molecular regulators, the level of circulating miR-200c could be a potential biomarker in the early identification of those at the risk of severe COVID-19.

Oral manifestations of Covid-19-A literature review.

Initially, it was reported that coronavirus 2019 disease (Covid-19) affects respiratory, gastrointestinal and neurological systems, but the oral, olfactory and integumentary systems are also involved. This review discusses various oral manifestations of Covid-19 reported in the literature along with possible underlying mechanisms. The reported manifestations include taste impairment, oral mucosal changes (petechiae, ulcers, plaque-like lesions, reactivation of herpes simplex virus 1(HSV1), geographical tongue and desquamative gingivitis) and dry mouth. The prominent location for mucosal lesions are tongue, palate and labial mucosa. The exact pathogenesis of these oral symptoms is not known. Angiotensin-converting enzyme 2 (ACE2) cell receptors are expressed in abundance on oral mucosa allowing severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) to infect them. Gustatory impairment along with olfactory changes is now listed as a symptom of Covid-19 by the World Health Organization, but further research is needed to confirm a link between reported additional oral symptoms and Covid-19. Dental professionals may encounter individuals with Covid-19 and be called upon to identify various oral manifestations of this disease.

Determinants of soluble angiotensin-converting enzyme 2 concentrations in adult patients with complex congenital heart disease.

BACKGROUND: Angiotensin-converting enzyme (ACE) 2 is known to be a functional receptor for SARS-CoV-2 in the current pandemic. Soluble ACE2 (sACE2) concentrations are elevated in patients with various cardiovascular disorders including heart failure. METHODS: In a total of 182 consecutive adult patients with complex congenital heart disease (CHD) and 63 healthy controls, sACE2 concentrations were measured in serum using the Human ACE2® assay by Cloud-Clone Corporation and associated with clinical, laboratory and echocardiographic parameters. RESULTS: Median sACE2 levels were increased in patients with complex CHD as compared to healthy controls (761.9 pg/ml vs 365.2 pg/ml, p < 0.001). Moreover, sACE2 concentrations were significantly elevated in patients with a higher NYHA class ≥ III (1856.2 pg/ml vs 714.5 pg/ml in patients with NYHA class I/II, p < 0.001). Using linear regression analysis, higher sACE2 levels were associated with a higher NYHA class ≥ III, more severe CHD, a morphological left systemic ventricle, higher creatinine and the use of mineralocorticoid receptor antagonists (MRA) in the univariable model. The use of ACE inhibitors or angiotensin receptor blockers (ARB) was associated with lower sACE2 levels. In the multivariable model, higher sACE2 levels were independently associated with a higher NYHA class ≥ III (p = 0.002) and lower sACE2 levels with the use of ACE inhibitors or ARB (p = 0.001). CONCLUSION: Soluble ACE2 concentrations were significantly increased in all types of complex CHD with highest levels found in patients with NYHA class ≥ III. Moreover, a higher NYHA class ≥ III was the most significant determinant that was independently associated with elevated sACE2 concentrations.

Dysregulation of ACE (Angiotensin-Converting Enzyme)-2 and Renin-Angiotensin Peptides in SARS-CoV-2 Mediated Mortality and End-Organ Injuries.

ACE (angiotensin-converting enzyme)-2 as the target for SARS-CoV-2 also negatively regulates the renin-angiotensin system. Pathological activation of ADAM17 (A disintegrin and metalloproteinase-17) may potentiate inflammation and diminish ACE2-mediated tissue protection through proteolytic shedding, contributing to SARS-CoV-2 pathogenesis. We aim to examine plasma soluble ACE2 and angiotensin profiles in relation to outcomes by enrolling consecutive patients admitted for COVID-19 with baseline blood collection at admission and repeated sampling at 7 days. The primary outcome was 90-day mortality, and secondary outcomes were the incidence of end-organ injuries. Overall, 242 patients were included, the median age was 63 (52-74) years, 155 (64.0%) were men, and 57 (23.6%) patients reached the primary end point. Baseline soluble ACE2 was elevated in COVID-19 but was not associated with disease severity or mortality. In contrast, an upward trajectory of soluble ACE2 at repeat sampling was independently associated with an elevated risk of mortality and incidence of acute myocardial injury and circulatory shock. Similarly, an increase in soluble tumor necrosis factor receptor levels was also associated with adverse outcomes. Plasma Ang I, Ang 1-7 (angiotensin 1-7) levels, and the Ang 1-7/Ang II (angiotensin II) ratio were elevated during SARS-CoV-2 infection related to downregulation of ACE activity at baseline. Moreover, patients having an upward trajectory of soluble ACE2 were characterized by an imbalance in the Ang 1-7/Ang II ratio. The observed dysregulation of ACE2 and angiotensin peptides with disease progression suggest a potential role of ADAM17 inhibition and enhancing the beneficial Ang 1-7/Mas axis to improve outcomes against SARS-CoV-2 infection.

A low aldosterone/renin ratio and high soluble ACE2 associate with COVID-19 severity.

BACKGROUND: The severity of COVID-19 after SARS-CoV-2 infection is unpredictable. Angiotensin-converting enzyme-2 (ACE2) is the receptor responsible for coronavirus binding, while subsequent cell entry relies on priming by the serine protease TMPRSS2 (transmembrane protease, serine 2). Although renin-angiotensin-aldosterone-system (RAAS) blockers have been suggested to upregulate ACE2, their use in COVID-19 patients is now considered well tolerated. The aim of our study was to investigate parameters that determine COVID-19 severity, focusing on RAAS-components and variation in the genes encoding for ACE2 and TMPRSS2. METHODS: Adult patients hospitalized due to SARS-CoV-2 infection between May 2020 and October 2020 in the Haga Teaching Hospital were included, and soluble ACE2 (sACE2), renin, aldosterone (in heparin plasma) and polymorphisms in the ACE2 and TMPRSS2 genes (in DNA obtained from EDTA blood) were determined. MEASUREMENTS AND MAIN RESULTS: Out of the 188 patients who were included, 60 were defined as severe COVID-19 (ICU and/or death). These patients more often used antidiabetic drugs, were older, had higher renin and sACE2 levels, lower aldosterone levels and a lower aldosterone/renin ratio. In addition, they displayed the TMPRSS2-rs2070788 AA genotype less frequently. No ACE2 polymorphism-related differences were observed. Multivariate regression analysis revealed independent significance for age, sACE2, the aldosterone/renin ratio, and the TMPRSS2 rs2070788 non-AA genotype as predictors of COVID-19 severity, together yielding a C-index of 0.79. Findings were independent of the use of RAAS blockers. CONCLUSION: High sACE2, a low aldosterone/renin ratio and having the TMPRSS2 rs2070788 non-AA genotype are novel independent determinants that may help to predict COVID-19 disease severity. TRIAL REGISTRATION: retrospectively registered.

Circulating ACE2 activity predicts mortality and disease severity in hospitalized COVID-19 patients.

OBJECTIVES: Angiotensin-converting enzyme 2 (ACE2) represents the primary receptor for SARS-CoV-2 to enter endothelial cells. Here we investigated circulating ACE2 activity to predict the severity and mortality of COVID-19. METHODS: Serum ACE2 activity was measured in COVID-19 (110 critically ill and 66 severely ill subjects at hospital admission and 106 follow-up samples) and in 32 non-COVID-19 severe sepsis patients. Associations between ACE2, inflammation-dependent biomarkers, pre-existing comorbidities, and clinical outcomes were studied. RESULTS: Initial ACE2 activity was significantly higher in critically ill COVID-19 patients (54.4 [36.7-90.8] mU/L) than in severe COVID-19 (34.5 [25.2-48.7] mU/L; P<0.0001) and non-COVID-19 sepsis patients (40.9 [21.4-65.7] mU/L; P=0.0260) regardless of comorbidities. Circulating ACE2 activity correlated with inflammatory biomarkers and was further elevated during the hospital stay in critically ill patients. Based on ROC-curve analysis and logistic regression test, baseline ACE2 independently indicated the severity of COVID-19 with an AUC value of 0.701 (95% CI [0.621-0.781], P<0.0001). Furthermore, non-survivors showed higher serum ACE2 activity vs. survivors at hospital admission (P<0.0001). Finally, high ACE2 activity (≥45.4 mU/L) predicted a higher risk (65 vs. 37%) for 30-day mortality (Log-Rank P<0.0001). CONCLUSIONS: Serum ACE2 activity correlates with COVID-19 severity and predicts mortality.

Microfluidic characterisation reveals broad range of SARS-CoV-2 antibody affinity in human plasma.

The clinical outcome of SARS-CoV-2 infections, which can range from asymptomatic to lethal, is crucially shaped by the concentration of antiviral antibodies and by their affinity to their targets. However, the affinity of polyclonal antibody responses in plasma is difficult to measure. Here we used microfluidic antibody affinity profiling (MAAP) to determine the aggregate affinities and concentrations of anti-SARS-CoV-2 antibodies in plasma samples of 42 seropositive individuals, 19 of which were healthy donors, 20 displayed mild symptoms, and 3 were critically ill. We found that dissociation constants, K d, of anti-receptor-binding domain antibodies spanned 2.5 orders of magnitude from sub-nanomolar to 43 nM. Using MAAP we found that antibodies of seropositive individuals induced the dissociation of pre-formed spike-ACE2 receptor complexes, which indicates that MAAP can be adapted as a complementary receptor competition assay. By comparison with cytopathic effect-based neutralisation assays, we show that MAAP can reliably predict the cellular neutralisation ability of sera, which may be an important consideration when selecting the most effective samples for therapeutic plasmapheresis and tracking the success of vaccinations.

COVID-19 and Diabetes: A Comprehensive Review of Angiotensin Converting Enzyme 2, Mutual Effects and Pharmacotherapy.

The potential relationship between diabetes and COVID-19 has been evaluated. However, new knowledge is rapidly emerging. In this study, we systematically reviewed the relationship between viral cell surface receptors (ACE2, AXL, CD147, DC-SIGN, L-SIGN and DPP4) and SARS-CoV-2 infection risk, and emphasized the implications of ACE2 on SARS-CoV-2 infection and COVID-19 pathogenesis. Besides, we updated on the two-way interactions between diabetes and COVID-19, as well as the treatment options for COVID-19 comorbid patients from the perspective of ACE2. The efficacies of various clinical chemotherapeutic options, including anti-diabetic drugs, renin-angiotensin-aldosterone system inhibitors, lipid-lowering drugs, anticoagulants, and glucocorticoids for COVID-19 positive diabetic patients were discussed. Moreover, we reviewed the significance of two different forms of ACE2 (mACE2 and sACE2) and gender on COVID-19 susceptibility and severity. This review summarizes COVID-19 pathophysiology and the best strategies for clinical management of diabetes patients with COVID-19.

Predicting respiratory failure in patients infected by SARS-CoV-2 by admission sex-specific biomarkers.

BACKGROUND: Several biomarkers have been identified to predict the outcome of COVID-19 severity, but few data are available regarding sex differences in their predictive role. Aim of this study was to identify sex-specific biomarkers of severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19. METHODS: Plasma levels of sex hormones (testosterone and 17ß-estradiol), sex-hormone dependent circulating molecules (ACE2 and Angiotensin1-7) and other known biomarkers for COVID-19 severity were measured in male and female COVID-19 patients at admission to hospital. The association of plasma biomarker levels with ARDS severity at admission and with the occurrence of respiratory deterioration during hospitalization was analysed in aggregated and sex disaggregated form. RESULTS: Our data show that some biomarkers could be predictive both for males and female patients and others only for one sex. Angiotensin1-7 plasma levels and neutrophil count predicted the outcome of ARDS only in females, whereas testosterone plasma levels and lymphocytes counts only in males. CONCLUSIONS: Sex is a biological variable affecting the choice of the correct biomarker that might predict worsening of COVID-19 to severe respiratory failure. The definition of sex specific biomarkers can be useful to alert patients to be safely discharged versus those who need respiratory monitoring.