Impact of hypertension on long-term humoral and cellular response to SARS-CoV-2 infection.

It was shown that hypertension delays SARS CoV-2 viral clearance and exacerbates airway hyperinflammation in the respiratory tract. However, it is unknown whether hypertension determines the long-term cellular and humoral response to SARS Cov2. Health care workers (HCWs) after an outbreak of SARS Cov-2 infections were analyzed. Infected HCWs were not vaccinated before blood collection. 5-14 months (median 7 months) after detection of SARS CoV-2 infection, blood was taken to analyze humoral response (S1 IgG and SARS CoV-2 neutralizing antibodies) and cellular (T cell responses to SARS-CoV-2 with Lymphocyte Transformation Test). To identify clinical factors that determine the immune response, a multivariate regression analysis was done considering age, BMI, sex, diabetes, hypertension, smoking, COPD, asthma and time between PCR positivity and blood collection as confounding factors. Infected hypertensive HCWs more often needed to be hospitalized than non-hypertensive HCWs, but were less likely to develop anosmia and myalgia. The long-term humoral and cellular immune response was significantly strengthened in hypertensive versus normotensive infected HCWs. Multivariate regression analysis revealed that hypertension was independently associated with the humoral response to SARS CoV-2 infection. Multivariate regression analysis using same confounding factors for the humoral response showed a clear trend for an association with the cellular response to SARS CoV-2 infection as well. In conclusion, SARS CoV-2 infection strengthened immune response to SARS CoV-2 infection in hypertensive HCWs independent of other risk factors.

Safety of COVID-19 vaccination in women undergoing IVF/ICSI treatment - Clinical study and systematic review.

Background: It was suggested that vaccination in general might affect reproductive health. Safety of COVID-19 vaccination in women undergoing assisted reproductive techniques (ART) treatment is not well established. Methods: We performed a retrospective study including 536 women undergoing fresh embryo transfer after IVF/ICSI treatment in a huge IVF center in southern China to investigate the effect of COVID-19 vaccination on oocyte maturation, fertilization rate, blastulation rate, implantation rate, clinical pregnancy rate and miscarriage rate. In addition, we performed a systematic review of existing studies on the safety of COVID-19 vaccination in women undergoing ART treatment. Results: In our study, 268 women received inactivated or recombinant COVID-19 vaccination and 268 controls were enrolled based on propensity score matching. We observed a decreased fertilization rate and signs for impaired oocyte maturation in vaccinated women. Besides our study, there were 15 studies analyzing the safety of COVID-19 vaccination in women undergoing ART treatment. For the mRNA vaccines, no adverse signals were reported concerning oocyte maturation, fertilization rate, blastulation rate, implantation rate, clinical pregnancy rate and miscarriage rate. In women being vaccinated with an inactivated vaccine, implantation rate, clinical pregnancy rate and miscarriage rate were not affected, whereas oocyte maturation and fertilization rate were impaired. Conclusions: Vaccination against COVID-19 in women undergoing ART treatment seems to be safe especially for women getting mRNA vaccines. The effects on oocyte maturation and fertilization rate of inactivated and recombinant COVID-19 vaccinations might be a safety signal and need further investigation and independent confirmation.

Outliers Matter-Correlation between S1 IgG SARS-CoV-2 Antibodies and Neutralizing SARS-CoV-2 Antibodies.

Vaccination against the SARS-CoV-2 virus or infection with SARS-CoV-2 will lead to the development of IgG antibodies against the S1 protein of the SARS-CoV-2 virus. However, even despite having high levels of IgG antibodies against the S1 protein of the SARS-CoV-2 virus, (re-)infection may occur. We thus examined 2994 consecutive blood samples of outpatients from the Berlin-Brandenburg area in Germany in which IgG antibodies against the S1 protein of the SARS-CoV-2 virus as well as neutralizing SARS-CoV-2 virus antibodies were determined from the same sample. When analyzing the entire study population (2994 outpatients), we saw that S1 IgG antibodies (women: 223.98 ± 3.81; men: 207.80 ± 4.59; p = 0.014) and neutralizing antibodies (women: 66.65 ± 0.82; men: 62.88 ± 1.01; p = 0.021) are slightly higher in women than in men. Curve fitting revealed a good non-linear relationship between S1 IgG and neutralizing SARS-CoV-2 antibodies. However, 51 out of the 2994 blood samples from individual subjects were positive with regard to the neutralizing antibodies and at the same time negative for S1 IgG antibodies, and 112 out of the 2994 blood samples from individual subjects were negative with regard to the neutralizing antibodies and at the same time positive for S1 IgG antibodies. In conclusion, our study shows that there is a relevant number of patients who, despite developing significant titers of S1 antibodies, do not have relevant amounts of neutralizing antibody titers and are probably at high risk of (re-)infection.

Impact of Salt Intake and Renin-Angiotensin-Aldosterone System Blockade on Lung Severe Acute Respiratory Syndrome Coronavirus 2 Host Factors.

INTRODUCTION: The angiotensin-converting enzyme 2 (ACE2) as well as the transmembrane protease serine type 2 (TMPRSS2) have been found to play roles in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19). SARS-CoV-2 infection risk and severity of COVID-19 might be indicated by the expression of ACE2 and TMPRSS2 in the lung. METHODS: A high-salt diet rat model and renin-angiotensin-aldosterone system (RAAS) blockade were used to test whether these factors affect ACE2 and TMPRSS2 expression in the lung. A normal (0.3% NaCl), a medium (2% NaCl), or a high (8% NaCl) salt diet was fed to rats for 12 weeks, along with enalapril or telmisartan, before examining the lung for histopathological alteration. Using immunofluorescence and qRT-PCR, the localization as well as mRNA expression of ACE2 and TMPRSS2 were investigated. RESULTS: The findings provide evidence that both TMPRSS2 and ACE2 are highly expressed in bronchial epithelial cells as well as ACE2 was also expressed in alveolar type 2 cells. High-salt diet exposure in rats leads to elevated ACE2 expression on protein level. Treatment with RAAS blockers had no effect on lung tissue expression of ACE2 and TMPRSS2. CONCLUSIONS: These findings offer biological support regarding the safety of these drugs that are often prescribed to COVID-19 patients with cardiovascular comorbidity. High salt intake, on the other hand, might adversely affect COVID-19 outcome. Our preclinical data should stimulate clinical studies addressing this point of concern.

Impact of hypertension on long-term humoral and cellular response to SARS-CoV-2 infection

It was shown that hypertension delays SARS CoV-2 viral clearance and exacerbates airway hyperinflammation in the respiratory tract. However, it is unknown whether hypertension determines the long-term cellular and humoral response to SARS Cov2. Health care workers (HCWs) after an outbreak of SARS Cov-2 infections were analyzed. Infected HCWs were not vaccinated before blood collection. 5-14 months (median 7 months) after detection of SARS CoV-2 infection, blood was taken to analyze humoral response (S1 IgG and SARS CoV-2 neutralizing antibodies) and cellular (T cell responses to SARS-CoV-2 with Lymphocyte Transformation Test). To identify clinical factors that determine the immune response, a multivariate regression analysis was done considering age, BMI, sex, diabetes, hypertension, smoking, COPD, asthma and time between PCR positivity and blood collection as confounding factors. Infected hypertensive HCWs more often needed to be hospitalized than non-hypertensive HCWs, but were less likely to develop anosmia and myalgia. The long-term humoral and cellular immune response was significantly strengthened in hypertensive versus normotensive infected HCWs. Multivariate regression analysis revealed that hypertension was independently associated with the humoral response to SARS CoV-2 infection. Multivariate regression analysis using same confounding factors for the humoral response showed a clear trend for an association with the cellular response to SARS CoV-2 infection as well. In conclusion, SARS CoV-2 infection strengthened immune response to SARS CoV-2 infection in hypertensive HCWs independent of other risk factors.

T-cell proliferation assay for the detection of SARS-CoV-2-specific T-cells.

Both infection with and vaccination against SARS-CoV-2 trigger a complex B-cell and T-cell response. Methods for the analysis of the B-cell response are now well established. However, reliable methods for measuring the T-cell response are less well established and their usefulness in clinical settings still needs to be proven. Here, we have developed and validated a T-cell proliferation assay based on 3H thymidine incorporation. The assay is using SARS-CoV-2 derived peptide pools that cover the spike (S), the nucleocapsid (N) and the membrane (M) protein for stimulation. We have compared this novel SARS-CoV-2 lymphocyte transformation test (SARS-CoV-2 LTT) to an established ELISA assay detecting Immunoglobulin G (IgG) antibodies to the S1 subunit of the SARS-CoV-2 spike protein. The study was carried out using blood samples from both vaccinated and infected health care workers as well as from a non-infected control group. Our novel SARS-CoV-2 LTT shows excellent discrimination of infected and/or vaccinated individuals versus unexposed controls, with the ROC analysis showing an area under the curve (AUC) of > 0.95. No false positives were recorded as all unexposed controls had a negative LTT result. When using peptide pools not only representing the S protein (found in all currently approved vaccines) but also the N and M proteins (not contained in the vast majority of vaccines), the novel SARS-CoV-2 LTT can also discriminate T-cell responses resulting from vaccination against those induced by infection.

Regulation of SARS CoV-2 host factors in the kidney and heart in rats with 5/6 nephrectomy-effects of salt, ARB, DPP4 inhibitor and SGLT2 blocker.

BACKGROUND: Host factors such as angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease, serine-subtype-2 (TMPRSS2) are important factors for SARS-CoV-2 infection. Clinical and pre-clinical studies demonstrated that RAAS-blocking agents can be safely used during a SARS-CoV-2 infection but it is unknown if DPP-4 inhibitors or SGLT2-blockers may promote COVID-19 by increasing the host viral entry enzymes ACE2 and TMPRSS2. METHODS: We investigated telmisartan, linagliptin and empagliflozin induced effects on renal and cardiac expression of ACE2, TMPRSS2 and key enzymes involved in RAAS (REN, AGTR2, AGT) under high-salt conditions in a non-diabetic experimental 5/6 nephrectomy (5/6 Nx) model. In the present study, the gene expression of Ace2, Tmprss2, Ren, Agtr2 and Agt was assessed with qRT-PCR and the protein expression of ACE2 and TMPRSS2 with immunohistochemistry in the following experimental groups: Sham + normal diet (ND) + placebo (PBO); 5/6Nx + ND + PBO; 5/6Nx + high salt-diet (HSD) + PBO; 5/6Nx + HSD + telmisartan; 5/6Nx + HSD + linagliptin; 5/6Nx + HSD + empagliflozin. RESULTS: In the kidney, the expression of Ace2 was not altered on mRNA level under disease and treatment conditions. The renal TMPRSS2 levels (mRNA and protein) were not affected, whereas the cardiac level was significantly increased in 5/6Nx rats. Intriguingly, the elevated TMPRSS2 protein expression in the heart was significantly normalized after treatment with telmisartan, linagliptin and empagliflozin. CONCLUSIONS: Our study indicated that there is no upregulation regarding host factors potentially promoting SARS-CoV-2 virus entry into host cells when the SGLT2-blocker empagliflozin, telmisartan and the DPP4-inhibitor blocker linagliptin are used. The results obtained in a preclinical, experimental non-diabetic kidney failure model need confirmation in ongoing interventional clinical trials.

Comparison of infection risks and clinical outcomes in patients with and without SARS-CoV-2 lung infection under renin-angiotensin-aldosterone system blockade: Systematic review and meta-analysis.

AIMS: Angiotensin-converting enzyme-2 (ACE2) is the receptor for SARS-CoV-2. Animal studies suggest that renin-angiotensin-aldosterone system (RAAS) blockers might increase the expression of ACE2 and potentially increase the risk of SARS-CoV-2 infection. METHODS AND RESULTS: The effect of ACE inhibitor (ACEI) treatment on the pneumonia incidence in non-COVID-19 patients (25 studies, 330 780 patients) was associated with a 26% reduction of pneumonia risk (odds ratio [OR]: 0.74, P < .001). Pneumonia-related death cases in ACEI-treated non-COVID-19 patients were reduced by 27% (OR: 0.73, P = .004). However, angiotensin II receptor blockers (ARB) treatment (10 studies, 275 621 non-COVID-19 patients) did not alter pneumonia risk in patients. Pneumonia-related death cases in ARB-treated non-COVID-19 patients was analysed only in 1 study and was significantly reduced (OR, 0.47; 95% confidence interval, 0.30 to 0.72). Results from 11 studies (8.4 million patients) showed that the risk of getting infected with the SARS-CoV-2 virus was reduced by 13% (OR: 0.87, P = .014) in patients treated with ACEI, whereas analysis from 10 studies (8.4 million patients) treated with ARBs showed no effect (OR, 0.92, P = .354). Results from 34 studies in 67 644 COVID-19 patients showed that RAAS blockade reduces all-cause mortality by 24% (OR = 0.76, P = .04). CONCLUSION: ACEIs reduce the risk of getting infected with the SARS-CoV-2 virus. Blocking the RAAS may decrease all-cause mortality in COVID-19 patients. ACEIs also reduce the risk of non-COVID pneumonia. All-cause mortality due to non-COVID pneumonia is reduced by ACEI and potentially by ARBs.