Susceptibility and characteristics of infections in patients with glucocorticoid excess or insufficiency: the ICARO tool.

Objective: Registry data show that Cushing's syndrome (CS) and adrenal insufficiency (AI) increase mortality rates associated with infectious diseases. Little information is available on susceptibility to milder forms of infections, especially those not requiring hospitalization. This study aimed to investigate infectious diseases in patients with glucocorticoid disorders through the development of a specific tool. Methods: We developed and administered the InfeCtions in pAtients with endocRinOpathies (ICARO) questionnaire, addressing infectious events over a 12-month observation period, to 1017 outpatients referred to 4 University Hospitals. The ICARO questionnaire showed good test-retest reliability. The odds of infection (OR (95% CI)) were estimated after adjustment for confounders and collated into the ICARO score, reflecting the frequency and duration of infections. Results: In total, 780 patients met the inclusion criteria: 43 with CS, 32 with adrenal incidentaloma and mild autonomous cortisol secretion (MACS), and 135 with AI, plus 570 controls. Compared to controls, CS was associated with higher odds of urinary tract infections (UTIs) (5.1 (2.3-9.9)), mycoses (4.4 (2.1-8.8)), and flu (2.9 (1.4-5.8)). Patients with adrenal incidentaloma and MACS also showed an increased risk of UTIs (3.7 (1.7-8.0)) and flu (3.2 (1.5-6.9)). Post-dexamethasone cortisol levels correlated with the ICARO score in patients with CS. AI was associated with higher odds of UTIs (2.5 (1.6-3.9)), mycoses (2.3 (1.4-3.8)), and gastrointestinal infections (2.2 (1.5-3.3)), independently of any glucocorticoid replacement dose. Conclusions: The ICARO tool revealed a high prevalence of self-reported infections in patients with glucocorticoid disorders. ICARO is the first of its kind questionnaire, which could be a valuable tool for monitoring infections in various clinical settings.

How May Obesity-Induced Oxidative Stress Affect the Outcome of COVID-19 Vaccines? Lesson Learned from the Infection

Concomitantly, the reduced sources of antioxidants, including superoxide dismutase, glutathione peroxidase, catalase, vitamin A, E, C and carotenoids in obese patients promotes a vulnerability to oxidative damage and consequently increases susceptibility to infections [14]. [...]obesity is associated with a state of metaflammation—chronic low-grade inflammation—a condition that, among other factors, contributes to inducing systemic OS. Characteristic hyperlipidaemia observed in obese patients stimulates monocytes and macrophages and induces the production of pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α and interleukin (IL)-6 [16,18,19]. [...]in obese COVID-19 patients, the already pre-existing effects prompted by the lipid peroxidation-dependent OS could be further aggravated by SARS-CoV-2 infection [20], affecting the immune control system in response to infection and potentially increasing the severity of the lung disease and contributing to multiorgan failure. The results of the study demonstrated that the antibody titre was significantly higher in young and female participants compared to the male and older population. [...]the humoral response was significantly more efficient in subjects with lower and normal weight compared to overweight and obese subjects. [...]the consequence of OS on immunological functions and the evidence of weakened virus vaccine effectiveness in obese patients raise concerns about COVID-19 vaccine responsiveness in this population.

A New Clinical Model to Estimate the Pre-Test Probability of Cushing's Syndrome: The Cushing Score.

Background: Hypercortisolism accounts for relevant morbidity and mortality and is often a diagnostic challenge for clinicians. A prompt diagnosis is necessary to treat Cushing's syndrome as early as possible. Objective: The aim of this study was to develop and validate a clinical model for the estimation of pre-test probability of hypercortisolism in an at-risk population. Design: We conducted a retrospective multicenter case-control study, involving five Italian referral centers for Endocrinology (Turin, Messina, Naples, Padua and Rome). One hundred and fifty patients affected by Cushing's syndrome and 300 patients in which hypercortisolism was excluded were enrolled. All patients were evaluated, according to current guidelines, for the suspicion of hypercortisolism. Results: The Cushing score was built by multivariable logistic regression, considering all main features associated with a clinical suspicion of hypercortisolism as possible predictors. A stepwise backward selection algorithm was used (final model AUC=0.873), then an internal validation was performed through ten-fold cross-validation. Final estimation of the model performance showed an average AUC=0.841, thus reassuring about a small overfitting effect. The retrieved score was structured on a 17.5-point scale: low-risk class (score value: ≤5.5, probability of disease=0.8%); intermediate-low-risk class (score value: 6-8.5, probability of disease=2.7%); intermediate-high-risk class (score value: 9-11.5, probability of disease=18.5%) and finally, high-risk class (score value: ≥12, probability of disease=72.5%). Conclusions: We developed and internally validated a simple tool to determine pre-test probability of hypercortisolism, the Cushing score, that showed a remarkable predictive power for the discrimination between subjects with and without a final diagnosis of Cushing's syndrome.

Sex Disparities in COVID-19 Severity and Outcome: Are Men Weaker or Women Stronger?

The coronavirus disease 2019 (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health issue which has profound effects on most aspects of societal well-being, including physical and mental health. A plethora of studies globally have suggested the existence of a sex disparity in the severity and outcome of COVID-19 patients, mainly due to mechanisms of virus infection, immune response to the virus, development of systemic inflammation, and consequent systemic complications, particularly thromboembolism. Epidemiological data report a sex difference in the severity of COVID-19, with a more favorable course of the disease in women compared to men regardless of age, although the rate of SARS-CoV-2 infection seems to be similar in both sexes. Sex hormones, including androgens and estrogens, may not only impact virus entry and load, but also shape the clinical manifestations, complications, and ultimately the outcome of the disease. The current review comprehensively summarizes the current literature on sex disparities in susceptibility and outcome of COVID-19 as well as the literature underpinning the pathophysiological and molecular mechanisms, which may provide a rationale to a sex disparity. These mechanisms include sex hormone influence on factors that facilitate virus entry and priming, immune and inflammatory response, as well as coagulation and thrombosis diathesis. Based on present evidence, women appear to be relatively protected from COVID-19 because of a more effective immune response and a less pronounced systemic inflammation, with consequent moderate clinical manifestations of the disease, together with a lesser predisposition to thromboembolism. Conversely, men appear to be particularly susceptible to COVID-19 because of a less effective immune response with consequent severe clinical manifestations of the disease, together with a greater predisposition to thromboembolism. In the elderly, generally characterized by the phenomenon of inflammaging, sex disparities in overall mortality following SARS-CoV-2 infection are even more palpable as elderly men appear to be more prone to severe COVID-19 because of a greater predisposition to infections, a weaker immune defense, and an enhanced thrombotic state compared to women. The information revealed from the review highlights potential novel therapeutic approaches employing the administration of hormonal or antihormonal therapy in combination with antiviral drugs in COVID-19 patients.

Diabetes is most important cause for mortality in COVID-19 hospitalized patients: Systematic review and meta-analysis.

The presence of SARS-CoV-2 was officially documented in Europe at the end of February 2020. Despite many observations, the real impact of COVID-19 in the European Union (EU), its underlying factors and their contribution to mortality and morbidity outcomes were never systematically investigated. The aim of the present work is to provide an overview and a meta-analysis of main predictors and of country differences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-associated mortality rate (MR) in hospitalized patients. Out of 3714 retrieved articles, 87 studies were considered, including 35,486 patients (mean age 60.9 ± 8.2 years) and 5867 deaths. After adjustment for confounders, diabetes mellitus was the best predictors of MR in an age- and sex-dependent manner, followed by chronic pulmonary obstructive diseases and malignancies. In both the US and Europe, MR was higher than that reported in Asia (25[20;29] % and 20[17;23] % vs. 13[10;17]%; both p < 0.02). Among clinical parameters, dyspnea, fatigue and myalgia, along with respiratory rate, emerged as the best predictors of MR. Finally, reduced lymphocyte and platelet count, along with increased D-dimer levels, all significantly contributed to increased mortality. The optimization of glucose profile along with an adequate thrombotic complications preventive strategy must become routine practice in diseased SARS-CoV-2 infected patients.

Glucocorticoid excess and COVID-19 disease.

The pandemic of coronavirus disease (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is causing high and rapid morbidity and mortality. Immune system response plays a crucial role in controlling and resolving the viral infection. Exogenous or endogenous glucocorticoid excess is characterized by increased susceptibility to infections, due to impairment of the innate and adaptive immune system. In addition, diabetes, hypertension, obesity and thromboembolism are conditions overrepresented in patients with hypercortisolism. Thus patients with chronic glucocorticoid (GC) excess may be at high risk of developing COVID-19 infection with a severe clinical course. Care and control of all comorbidities should be one of the primary goals in patients with hypercortisolism requiring immediate and aggressive treatment. The European Society of Endocrinology (ESE), has recently commissioned an urgent clinical guidance document on management of Cushing's syndrome in a COVID-19 period. In this review, we aim to discuss and expand some clinical points related to GC excess that may have an impact on COVID-19 infection, in terms of both contagion risk and clinical outcome. This document is addressed to all specialists who approach patients with endogenous or exogenous GC excess and COVID-19 infection.