Sex hormones in SARS-CoV-2 susceptibility: key players or confounders?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a clear sex disparity in clinical outcomes. Hence, the interaction between sex hormones, virus entry receptors and immune responses has attracted major interest as a target for the prevention and treatment of SARS-CoV-2 infections. This Review summarizes the current understanding of the roles of androgens, oestrogens and progesterone in the regulation of virus entry receptors and disease progression of coronavirus disease 2019 (COVID-19) as well as their therapeutic value. Although many experimental and clinical studies have analysed potential mechanisms by which female sex hormones might provide protection against SARS-CoV-2 infectivity, there is currently no clear evidence for a sex-specific expression of virus entry receptors. In addition, reports describing an influence of oestrogen, progesterone and androgens on the course of COVID-19 vary widely. Current data also do not support the administration of oestradiol in COVID-19. The conflicting evidence and lack of consensus results from a paucity of mechanistic studies and clinical trials reporting sex-disaggregated data. Further, the influence of variables beyond biological factors (sex), such as sociocultural factors (gender), on COVID-19 manifestations has not been investigated. Future research will have to fill this knowledge gap as the influence of sex and gender on COVID-19 will be essential to understanding and managing the long-term consequences of this pandemic.

Pulmonary Surfactant Proteins are Inhibited by IgA Autoantibodies in Severe COVID-19.

RATIONALE: Coronavirus disease 2019 (COVID-19) can lead to acute respiratory distress syndrome with fatal outcomes. Evidence suggests that dysregulated immune responses, including autoimmunity, are key pathogenic factors. OBJECTIVES: To assess whether IgA autoantibodies target lung-specific proteins and contribute to disease severity. METHODS: We collected 147 blood, 9 lung tissue, and 36 bronchoalveolar lavage fluid samples from three tertiary hospitals in Switzerland and one in Germany. Severe COVID-19 was defined by the need to administer oxygen. We investigated the presence of IgA autoantibodies and their effects on pulmonary surfactant in COVID-19 using the following methods: immunofluorescence on tissue samples, immunoprecipitations followed by mass spectrometry on bronchoalveolar lavage fluid samples, enzyme-linked immunosorbent assays on blood samples, and surface tension measurements with medical surfactant. MEASUREMENTS AND MAIN RESULTS: IgA autoantibodies targeting pulmonary surfactant proteins B and C were elevated in patients with severe COVID-19, but not in patients with influenza or bacterial pneumonia. Notably, pulmonary surfactant failed to reduce surface tension after incubation with either plasma or purified IgA from patients with severe COVID-19. CONCLUSIONS: Our data suggest that patients with severe COVID-19 harbor IgA against pulmonary surfactant proteins B and C and that these antibodies block the function of lung surfactant, potentially contributing to alveolar collapse and poor oxygenation. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Development and validation of a prognostic model for the early identification of COVID-19 patients at risk of developing common long COVID symptoms.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic demands reliable prognostic models for estimating the risk of long COVID. We developed and validated a prediction model to estimate the probability of known common long COVID symptoms at least 60 days after acute COVID-19. METHODS: The prognostic model was built based on data from a multicentre prospective Swiss cohort study. Included were adult patients diagnosed with COVID-19 between February and December 2020 and treated as outpatients, at ward or intensive/intermediate care unit. Perceived long-term health impairments, including reduced exercise tolerance/reduced resilience, shortness of breath and/or tiredness (REST), were assessed after a follow-up time between 60 and 425 days. The data set was split into a derivation and a geographical validation cohort. Predictors were selected out of twelve candidate predictors based on three methods, namely the augmented backward elimination (ABE) method, the adaptive best-subset selection (ABESS) method and model-based recursive partitioning (MBRP) approach. Model performance was assessed with the scaled Brier score, concordance c statistic and calibration plot. The final prognostic model was determined based on best model performance. RESULTS: In total, 2799 patients were included in the analysis, of which 1588 patients were in the derivation cohort and 1211 patients in the validation cohort. The REST prevalence was similar between the cohorts with 21.6% (n = 343) in the derivation cohort and 22.1% (n = 268) in the validation cohort. The same predictors were selected with the ABE and ABESS approach. The final prognostic model was based on the ABE and ABESS selected predictors. The corresponding scaled Brier score in the validation cohort was 18.74%, model discrimination was 0.78 (95% CI: 0.75 to 0.81), calibration slope was 0.92 (95% CI: 0.78 to 1.06) and calibration intercept was -0.06 (95% CI: -0.22 to 0.09). CONCLUSION: The proposed model was validated to identify COVID-19-infected patients at high risk for REST symptoms. Before implementing the prognostic model in daily clinical practice, the conduct of an impact study is recommended.

Sex disparities in patients with suspected COVID-19 presenting at an emergency department in Switzerland.

AIMS OF THE STUDY: In the global COVID-19 pandemic, female sex is associated with comparable infection rates but better outcome. However, most studies lacked appropriate controls. We investigated whether these sex disparity findings are specific to patients with COVID-19 or generalizable to patients presenting to the emergency room (ER) with similar symptoms but no COVID-19. METHODS: In this prospective cohort study, consecutive patients presenting with symptoms suggestive of COVID-19 were recruited at the ER of the University Hospital Basel, Switzerland from March to June 2020. Patients were categorized as SARS-CoV-2 positive (cases) or negative (controls) based on nasopharyngeal PCR swab tests. The final clinical diagnosis was determined for all patients. The primary outcome was a composite of intensive care admission, rehospitalization for respiratory distress and all-cause death within 30 days. We used Kaplan-Meier curves and Cox proportional hazards models to explore associations between sex and outcomes. RESULTS: Among 1,081 consecutive ER patients, 191 (18%) tested positive for SARS-CoV-2, with an even sex distribution (17.9% female vs. 17.5% male, p = 0.855). In COVID-19 patients, female sex was associated with lower risk of hospitalization (51% vs. 66%, p = 0.034), lower necessity of haemodynamic support (8% vs. 20%, p = 0.029), lower rates of intubation (10% vs. 21%, p = 0.037) and the primary outcome (18% vs. 31%, p = 0.045; age-adjusted HR 0.536, 95%CI 0.290-0.989, p = 0.046) compared with male sex. Sex disparities were most prominent in patients ≥55 years (HR for composite primary outcome in women 0.415, 95%CI 0.201-0.855, p = 0.017). In contrast to the COVID-19 patients, no sex-specific differences in outcomes were observed in the unselected overall control group (age-adjusted HR 0.844, 95%CI 0.560-1.273, p = 0.419) or in a subgroup of controls with upper respiratory tract infections or pneumonia (age-adjusted HR 0.840, 95%CI 0.418-1.688, p = 0.624). CONCLUSION: In this unselected, consecutive cohort study at a tertiary hospital in Switzerland, female sex is associated with better outcome in patients presenting to the ER with COVID-19. These sex disparities seem to be at least partly specific to COVID-19, as they were not observed in comparable controls.

Clinical utility of inflammatory biomarkers in COVID-19 in direct comparison to other respiratory infections-A prospective cohort study.

BACKGROUND: Inflammatory biomarkers are associated with severity of coronavirus disease 2019 (COVID-19). However, direct comparisons of their utility in COVID-19 versus other respiratory infections are largely missing. OBJECTIVE: We aimed to investigate the prognostic utility of various inflammatory biomarkers in COVID-19 compared to patients with other respiratory infections. MATERIALS AND METHODS: Patients presenting to the emergency department with symptoms suggestive of COVID-19 were prospectively enrolled. Levels of Interleukin-6 (IL-6), c-reactive protein (CRP), procalcitonin, ferritin, and leukocytes were compared between COVID-19, other viral respiratory infections, and bacterial pneumonia. Primary outcome was the need for hospitalisation, secondary outcome was the composite of intensive care unit (ICU) admission or death at 30 days. RESULTS: Among 514 patients with confirmed respiratory infections, 191 (37%) were diagnosed with COVID-19, 227 (44%) with another viral respiratory infection (viral controls), and 96 (19%) with bacterial pneumonia (bacterial controls). All inflammatory biomarkers differed significantly between diagnoses and were numerically higher in hospitalized patients, regardless of diagnoses. Discriminative accuracy for hospitalisation was highest for IL-6 and CRP in all three diagnoses (in COVID-19, area under the curve (AUC) for IL-6 0.899 [95%CI 0.850-0.948]; AUC for CRP 0.922 [95%CI 0.879-0.964]). Similarly, IL-6 and CRP ranged among the strongest predictors for ICU admission or death at 30 days in COVID-19 (AUC for IL-6 0.794 [95%CI 0.694-0.894]; AUC for CRP 0.807 [95%CI 0.721-0.893]) and both controls. Predictive values of inflammatory biomarkers were generally higher in COVID-19 than in controls. CONCLUSION: In patients with COVID-19 and other respiratory infections, inflammatory biomarkers harbour strong prognostic information, particularly IL-6 and CRP. Their routine use may support early management decisions.

The very low risk of myocarditis and pericarditis after mRNA COVID-19 vaccination should not discourage vaccination.

The benefits of vaccination - regarding COVID-19 infection and transmission, as well as COVID-associated complications - clearly outweigh the potential risk of vaccine-associated inflammation of the heart and other adverse events. Given the current state of knowledge, the outcome of myocarditis and pericarditis following vaccination is generally good. This review aims to guide physicians in the early diagnosis and management of suspected myocarditis following mRNA COVID vaccination. The initial work-up should include detailed history, a 12-lead electrocardiogram and serological biomarkers (high-sensitivity cardiac troponin T/I, natriuretic peptides and markers of inflammation) in accordance with the assessments recommended in current clinical practice guidelines for patients presenting with acute chest pain. In patients with suspected myocarditis, further assessment with transthoracic echocardiography and cardiovascular magnetic resonance imaging should be undertaken to confirm peri-/myocarditis and to distinguish the findings from other diseases with similar presentation. Patients with mRNA vaccine-associated myocarditis should be followed-up at least once to exclude chronic myocardial inflammation and deterioration of left ventricular ejection fraction. Consultation with an expert such as an immunologist with experience in vaccination regarding further mRNA vaccinations is advised in all patients with mRNA vaccine-associated perimyocarditis. Reporting of mRNA vaccine-associated myocarditis to Swissmedic is mandatory. Cohort studies prospectively follow-up on young adult and paediatric populations following immunisation with an mRNA COVID vaccine to monitor cardiac and immune parameters would generate valuable knowledge to better understand pathogenesis and risk factors for vaccine-associated perimyocarditis.

Immunoreactivity of the SARS-CoV-2 entry proteins ACE-2 and TMPRSS-2 in murine models of hormonal manipulation, ageing, and cardiac injury.

Previous work indicates that SARS-CoV-2 virus entry proteins angiotensin-converting enzyme 2 (ACE-2) and the cell surface transmembrane protease serine 2 (TMPRSS-2) are regulated by sex hormones. However, clinical studies addressing this association have yielded conflicting results. We sought to analyze the impact of sex hormones, age, and cardiovascular disease on ACE-2 and TMPRSS-2 expression in different mouse models. ACE-2 and TMPRSS-2 expression was analyzed by immunostaining in a variety of tissues obtained from FVB/N mice undergoing either gonadectomy or sham-surgery and being subjected to ischemia-reperfusion injury or transverse aortic constriction surgery. In lung tissues sex did not have a significant impact on the expression of ACE-2 and TMPRSS-2. On the contrary, following myocardial injury, female sex was associated to a lower expression of ACE-2 at the level of the kidney tubules. In addition, after myocardial injury, a significant correlation between younger age and higher expression of both ACE-2 and TMPRSS-2 was observed for lung alveoli and bronchioli, kidney tubules, and liver sinusoids. Our experimental data indicate that gonadal hormones and biological sex do not alter ACE-2 and TMPRSS-2 expression in the respiratory tract in mice, independent of disease state. Thus, sex differences in ACE-2 and TMPRSS-2 protein expression observed in mice may not explain the higher disease burden of COVID-19 among men.

Direct Comparison of Clinical Characteristics, Outcomes, and Risk Prediction in Patients with COVID-19 and Controls-A Prospective Cohort Study.

Most studies investigating early risk predictors in coronavirus disease 19 (COVID-19) lacked comparison with controls. We aimed to assess and directly compare outcomes and risk predictors at time of emergency department (ED) presentation in COVID-19 and controls. Consecutive patients presenting to the ED with suspected COVID-19 were prospectively enrolled. COVID-19-patients were compared with (i) patients tested negative (overall controls) and (ii) patients tested negative, who had a respiratory infection (respiratory controls). Primary outcome was the composite of intensive care unit (ICU) admission and death at 30 days. Among 1081 consecutive cases, 191 (18%) were tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 890 (82%) were tested negative (overall controls), of which 323 (30%) had a respiratory infection (respiratory controls). Incidence of the composite outcome was significantly higher in COVID-19 (23%) as compared with the overall control group (10%, adjusted-HR 2.45 (95%CI, 1.61-3.74), p < 0.001) or the respiratory control group (10%, adjusted-HR 2.93 (95%CI, 1.66-5.17), p < 0.001). Blood oxygen saturation, age, high-sensitivity troponin, c-reactive protein, and lactate dehydrogenase were identified as the strongest predictors of poor outcome available at time of ED presentation in COVID-19 with highly comparable prognostic utility in overall and respiratory controls. In conclusion, patients presenting to the ED with COVID-19 have a worse outcome than controls, even after adjustment for differences in baseline characteristics. Most predictors of poor outcome in COVID-19 were not restricted to COVID-19, but of comparable prognostic utility in controls and therefore generalizable to unselected patients with suspected COVID-19.

Comparison of Acute Kidney Injury in Patients with COVID-19 and Other Respiratory Infections: A Prospective Cohort Study.

Previous studies have indicated an association between coronavirus disease 2019 (COVID-19) and acute kidney injury (AKI) but lacked a control group. The prospective observational COronaVIrus-surviVAl (COVIVA) study performed at the University Hospital, Basel, Switzerland consecutively enrolled patients with symptoms suggestive of COVID-19. We compared patients who tested positive for SARS-CoV-2 with patients who tested negative but with an adjudicated diagnosis of a respiratory tract infection, including pneumonia. The primary outcome measure was death at 30 days, and the secondary outcomes were AKI incidence and a composite endpoint of death, intensive care treatment or rehospitalization at 30 days. Five hundred and seven patients were diagnosed with respiratory tract infections, and of those, 183 (36%) had a positive PCR swab test for SARS-CoV-2. The incidence of AKI was higher in patients with COVID-19 (30% versus 12%, p < 0.001), more severe (KDIGO stage 3, 22% versus 13%, p = 0.009) and more often required renal replacement therapy (4.4% versus 0.93%; p = 0.03). The risk of 30-day mortality and a composite endpoint was higher in patients with COVID-19-associated AKI (adjusted hazard ratio (aHR) mortality 3.98, 95% confidence interval (CI) 1.10-14.46, p = 0.036; composite endpoint aHR 1.84, 95% CI 1.02-3.31, p = 0.042). The mortality risk was attenuated when adjusting for disease severity (aHR 3.60, 95% CI 0.93-13.96, p = 0.062). AKI occurs more frequently and with a higher severity in patients with COVID-19 and is associated with worse outcomes.

Influence of Antihypertensive Treatment on RAAS Peptides in Newly Diagnosed Hypertensive Patients.

(1) Background: Recently, influences of antihypertensive treatment on the renin-angiotensin-aldosterone system (RAAS) has gained attention, regarding a possible influence on inflammatory and anti-inflammatory pathways. We aimed to study the effects of newly initiated antihypertensive drugs on angiotensin (Ang) II and Ang (1-7) as representers of two counter-regulatory axes. (2) Methods: In this randomized, open-label trial investigating RAAS peptides after the initiation of perindopril, olmesartan, amlodipine, or hydrochlorothiazide, Ang II and Ang (1-7) equilibrium concentrations were measured at 8 a.m. and 12 a.m. at baseline and after four weeks of treatment. Eighty patients were randomized (1:1:1:1 fashion). (3) Results: Between the four substances, we found significant differences regarding the concentrations of Ang II (p < 0.0005 for 8 a.m., 12 a.m.) and Ang (1-7) (p = 0.019 for 8 a.m., <0.0005 for 12 a.m.) four weeks after treatment start. Ang II was decreased by perindopril (p = 0.002), and increased by olmesartan (p < 0.0005), amlodipine (p = 0.012), and hydrochlorothiazide (p = 0.001). Ang (1-7) was increased by perindopril and olmesartan (p = 0.008/0.002), but not measurably altered by amlodipine and hydrochlorothiazide (p = 0.317/ 0.109). (4) Conclusion: The initiation of all first line antihypertensive treatments causes early and distinct alterations of equilibrium angiotensin levels. Given the additional AT1R blocking action of olmesartan, RAAS peptides shift upon initiation of perindopril and olmesartan appear to work in favor of the anti-inflammatory axis compared to amlodipine and hydrochlorothiazide.

Serum Neurofilament Light Chain Levels in the Intensive Care Unit: Comparison between Severely Ill Patients with and without Coronavirus Disease 2019.

There is emerging evidence for multifarious neurological manifestations of coronavirus disease 2019 (COVID-19), but little is known regarding whether they reflect structural damage to the nervous system. Serum neurofilament light chain (sNfL) is a specific biomarker of neuronal injury. We measured sNfL concentrations of 29 critically ill COVID-19 patients, 10 critically ill non-COVID-19 patients, and 259 healthy controls. After adjusting for neurological comorbidities and age, sNfL concentrations were higher in patients with COVID-19 versus both comparator groups. Higher sNfL levels were associated with unfavorable short-term outcome, indicating that neuronal injury is common and pronounced in critically ill patients. ANN NEUROL 2021;89:610-616.

Prevalence and outcome of dysnatremia in patients with COVID-19 compared to controls.

OBJECTIVE: The pandemic of coronavirus disease (COVID-19) has rapidly spread globally and infected millions of people. The prevalence and prognostic impact of dysnatremia in COVID-19 is inconclusive. Therefore, we investigated the prevalence and outcome of dysnatremia in COVID-19. DESIGN: The prospective, observational, cohort study included consecutive patients with clinical suspicion of COVID-19 triaged to a Swiss Emergency Department between March and July 2020. METHODS: Collected data included clinical, laboratory and disease severity scoring parameters on admission. COVID-19 cases were identified based on a positive nasopharyngeal swab test for SARS-CoV-2, patients with a negative swab test served as controls. The primary analysis was to assess the prognostic impact of dysnatremia on 30-day mortality using a cox proportional hazard model. RESULTS: 172 (17%) cases with COVID-19 and 849 (83%) controls were included. Patients with COVID-19 showed a higher prevalence of hyponatremia compared to controls (28.1% vs 17.5%, P < 0.001); while comparable for hypernatremia (2.9% vs 2.1%, P = 0.34). In COVID-19 but not in controls, hyponatremia was associated with a higher 30-day mortality (HR: 1.4, 95% CI: 1.10-16.62, P = 0.05). In both groups, hypernatremia on admission was associated with higher 30-day mortality (COVID-19 - HR: 11.5, 95% CI: 5.00-26.43, P < 0.001; controls - HR: 5.3, 95% CI: 1.60-17.64, P = 0.006). In both groups, hyponatremia and hypernatremia were significantly associated with adverse outcome, for example, intensive care unit admission, longer hospitalization and mechanical ventilation. CONCLUSION: Our results underline the importance of dysnatremia as predictive marker in COVID-19. Treating physicians should be aware of appropriate treatment measures to be taken for patients with COVID-19 and dysnatremia.