Report of the Association Between Multisystem Inflammatory Syndrome and Severe Myocarditis

Introduction: The people worldwide have been affected by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection since its appearance in December, 2019. Kawasaki disease-like hyperinflammatory shock associated with SARS-CoV-2 infection in previously healthy children has been reported in the literature, which is now referred to as a multisystem inflammatory syndrome in children (MIS-C). Some aspects of MIS-C are similar to those of Kawasaki disease, toxic shock syndrome, secondary hemophagocytic syndrome, and macrophage activation syndrome. Case Presentation: This study reported an 11-year-old boy with MIS-C presented with periorbital and peripheral edema, abdominal pain, elevated liver enzymes, severe right pleural effusion, moderate ascites, and severe failure of right and left ventricles. Conclusion(s): Due to the increasing number of reported cases of critically ill patients afflicted with MIS-C and its life-threatening complications, it was recommended that further studies should be carried out in order to provide screening tests for myocardial dysfunction. Adopting a multidisciplinary approach was found inevitable.Copyright © 2023, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

Italian Association of Clinical Endocrinologists (AME) 20th National Congress

The proceedings contain 9 papers. The topics discussed include: dulaglutide and NAFLD risk reduction;correlation between plasmatic long pentraxin PTX3 and nodular thyroid disease: a preliminary report;the fructose-bisphosphate aldolase a act as autoantigen in primary autoimmune hypophysitis;cortisol deficiency in Lenvatinib treatment;side effects of mitotane treatment: a retrospective study in 35 patients with adrenocortical carcinoma in adjuvant therapy;non-functioning pituitary adenoma: do predictor factors exist?;incidence and features of adrenal crisis in a series of 133 patients with Addison's disease;serological evidence and self-reported outcomes in patients with adrenal insufficiency during the first waves of COVID-19 in the North-East Italy;and persistent effects of spironolactone after its withdrawal in patients with hyperandrogenic skin disorders.

Characterization of the Immune Reaction to Covid-19 Treatment with Dexamethasone: A Narrative Review

Purpose of Study: The spread of SARS-CoV-2 and the resulting Coronavirus Disease 2019 (COVID-19) continues to manifest in individuals in varying severity with limited treatment options available. Despite research efforts put forth in developing therapeutic options for treatment of COVID-19 disease, effective and well understood mechanisms remain limited. Corticosteroid treatment with dexamethasone was shown to be beneficial for those with severe illness early in the pandemic with little understanding of its beneficial mechanism. This narrative review describes the current findings regarding the mechanism of action of dexamethasone treatment in the setting of SARS-CoV-2 infection. Methods Used: A comprehensive search of Embase and PubMed was conducted in consultation with a health sciences librarian. Search terms included (1) COVID-19 (2) dexamethasone (3) animal model and (4) immune response. No limits were used on the search and other reviews were excluded. Search results were screened based on titles and s before being selected for full text review. Outcomes recorded included characterization of the microenvironment of lung tissue following SARS-CoV-2 through cytokine measurement, histopathological staining and analysis of lung tissue, and clinical outcomes such as survival time. Summary of Results: The search resulted in 100 articles. Of these, 8 articles were identified that met the inclusion criteria. Three conducted experiments with Syrian hamsters, two with mice, two with alveolar macrophages, and one study was conducted with human subjects. Dexamethasone treatment was found to diminish inflammatory cytokine levels and preserve the integrity of lung tissue in several animal models and in vitro experiments in the setting of SARS-CoV-2 infection. Dexamethasone treatment was also found to reduce inflammatory cell infiltration of lung tissue infected with SARS-CoV-2. In humans, combination therapy of low dose dexamethasone with spironolactone proved more effective at lowering inflammatory markers than high dose dexamethasone alone. Conclusion(s): Collectively, the articles included in this review support the use of dexamethasone treatment in SARS-CoV-2 infection. Protective effects exhibited with dexamethasone treatment suggest that its action may be linked to the inflammatory nature of COVID-19 disease. Macrophage regulation and diminished inflammatory cytokine levels were hypothesized as possible mechanistic features of dexamethasone action but lacked exact characterization. Further exploration of combination treatment with dexamethasone and its mechanism of action is needed to identify specific and effective therapeutic strategies in the future.

Phase 2 randomised placebo-controlled trial of spironolactone and dexamethasone versus dexamethasone in COVID-19 hospitalised patients in Delhi.

BACKGROUND: In this phase 2 randomised placebo-controlled clinical trial in patients with COVID-19, we hypothesised that blocking mineralocorticoid receptors using a combination of dexamethasone to suppress cortisol secretion and spironolactone is safe and may reduce illness severity. METHODS: Hospitalised patients with confirmed COVID-19 were randomly allocated to low dose oral spironolactone (50 mg day 1, then 25 mg once daily for 21 days) or standard of care in a 2:1 ratio. Both groups received dexamethasone 6 mg daily for 10 days. Group allocation was blinded to the patient and research team. Primary outcomes were time to recovery, defined as the number of days until patients achieved WHO Ordinal Scale (OS) category ≤ 3, and the effect of spironolactone on aldosterone, D-dimer, angiotensin II and Von Willebrand Factor (VWF). RESULTS: One hundred twenty patients with PCR confirmed COVID were recruited in Delhi from 01 February to 30 April 2021. 74 were randomly assigned to spironolactone and dexamethasone (SpiroDex), and 46 to dexamethasone alone (Dex). There was no significant difference in the time to recovery between SpiroDex and Dex groups (SpiroDex median 4.5 days, Dex median 5.5 days, p = 0.055). SpiroDex patients had significantly lower D-dimer levels on days 4 and 7 (day 7 mean D-dimer: SpiroDex 1.15 µg/mL, Dex 3.15 µg/mL, p = 0.0004) and aldosterone at day 7 (SpiroDex 6.8 ng/dL, Dex 14.52 ng/dL, p = 0.0075). There was no difference in VWF or angiotensin II levels between groups. For secondary outcomes, SpiroDex patients had a significantly greater number of oxygen free days and reached oxygen freedom sooner than the Dex group. Cough scores were no different during the acute illness, however the SpiroDex group had lower scores at day 28. There was no difference in corticosteroid levels between groups. There was no increase in adverse events in patients receiving SpiroDex. CONCLUSION: Low dose oral spironolactone in addition to dexamethasone was safe and reduced D-dimer and aldosterone. Time to recovery was not significantly reduced. Phase 3 randomised controlled trials with spironolactone and dexamethasone should be considered. TRIAL REGISTRATION: The trial was registered on the Clinical Trials Registry of India TRI: CTRI/2021/03/031721, reference: REF/2021/03/041472. Registered on 04/03/2021.

Antiandrogens for the treatment of COVID-19 patients: A meta-analysis of randomized controlled trials.

Antiandrogens may carry a potential benefit as a therapeutic agent against COVID-19. However, studies have been yielding mixed results, thus hindering any objective recommendations. This necessitates a quantitative synthesis of data to quantify the benefits of antiandrogens. We systematically searched PubMed/MEDLINE, Cochrane Library, clinical trial registers, and reference lists of included studies to identify relevant randomized controlled trials (RCTs). Results from the trials were pooled using a random-effects model and outcomes were reported as risk ratios (RR) and mean differences (MDs) with 95% confidence intervals (CIs). Fourteen RCTs with a total sample size of 2593 patients were included. Antiandrogens yielded a significant mortality benefit (RR 0.37; 95% CI; 0.25-0.55). However, on subgroup analysis, only proxalutamide/enzalutamide and sabizabulin were found to significantly reduce mortality (RR 0.22, 95% CI: 0.16-0.30 and RR 0.42, 95% CI: 0.26-0.68, respectively), while aldosterone receptor antagonists and antigonadotropins did not show any benefit. No significant between-group difference was found in the early or late initiation of therapy. Antiandrogens also reduced hospitalizations and the duration of hospital stay, and improved recovery rates. Proxalutamide and sabizabulin may be effective against COVID-19, however, further large-scale trials are needed to confirm these findings.

The clinical effectiveness and validity of home spirometry in children with cystic fibrosis

Introduction: During the COVID-19 pandemic, home spirometry became essential for continued monitoring of cystic fibrosis patients, however, the clinical effectiveness was unknown. Aim(s): The aims of this study were to assess the success rate of testing patients at home and to compare the home spirometry and lab spirometry results Methods: 147 home spirometry devices (Air Next, NuvoAir, USA) were given out to cystic fibrosis patients (M:F 67:80;mean age 11.8 [4.7 - 17.3]) who had previous experience of spirometry and deemed to be competent to perform spirometry at home. Patients were asked to perform 4 tests in the first month, then 1 test per month unless clinically requested. When Lab spirometry resumed, 28 (M:F 12:16;mean age 13.1 [8.0-17.0]) patients tested on NuvoAir within 5 days (mean 0.7 days (1.0)) of Lab spirometry (Vyntus Spiro, Vyaire Medical, USA). Correlation between spirometry indices were analysed using linear regression. Result(s): 142 patients (96.6%) successfully onboarded onto the NuvoAir platform. Between July 2020 and Jan 2022, 1854 tests were performed, with 1711 (92.3%) tests over-read to be valid. 54 patients (36.7%) performed >=15 tests requested. FEV1 (R2 = 0.93, p = <0.00), FVC (R2 = 0.91, p = <0.00), MMEF (R2 = 0.87, p = <0.00) and PEF (R2 = 0.88, p = <0.00) all showed significant correlation between Lab spirometry and Home spirometry. Conclusion(s): Our results show that home spirometry is well adopted by cystic fibrosis patients and they are able to perform valid loops on this device. Continual encouragement may be required to achieve good trend data. There is also close agreements between this home spirometry device and the gold standard of laboratory spirometry.

Effect of spironolactone therapy on the activity of the matrix metalloproteinase system in patients with heart failure after COVID-19

Aim. To assess the change in the activity of the matrix metalloproteinase (MMP) system after 6-month spironolactone therapy in patients with heart failure (HF) with preserved (HFpEF) and mildly reduced ejection fraction (HFmrEF) after coronavirus disease 2019 (COVID-19). Material and methods. The study included 90 patients treated at the University Clinical Hospital 4 of the I. M. Sechenov First Moscow State Medical University with a laboratory-confirmed COVID-19. There were following inclusion criteria: age of 18-85 years;the presence of HFpEF and HFmrEF. The patients were randomized into two groups: group I (n=60) - patients with 6-month spironolactone therapy (25 mg/day) in addition to the standard therapy for HF, spironolactone was taken at a dose of 25 mg/day;Group II (comparison group, n=30) - patients who received standard therapy without spironolactone. All patients were determined plasma MMP concentrations. Results. There were no significant differences in the levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) between the groups when included in the study. A repeated investigation revealed a significant decrease in the concentrations of MMP-9 and TIMP-1 only in group I. In patients of group II, there were no significant changes in the plasma concentrations of MMP-9 and TIMP-1. The MMP-9/TIMP-1 ratio during the initial examination of patients did not have significant differences. After 6-months therapy, a significant decrease in the ratio of MMP-9/TIMP-1 was observed only in patients taking spironolactone. Conclusion. The results obtained confirm a significant decrease in MMP system activity after 6-month spironolactone therapy in patients with HFpEF and HFmrEF after COVID-19. The described antifibrotic effects of spironolactone make it possible to recommend the use of this drug in this category of patients to reduce the negative effect of MMPs on cardiovascular system. Copyright © 2022 Vserossiiskoe Obshchestvo Kardiologov. All rights reserved.

The Clinical Effectiveness and Validity of Home Spirometry in Children with Cystic Fibrosis

Aims During the COVID-19 pandemic, home spirometry became essential for continued monitoring of cystic fibrosis patients, however, the clinical effectiveness was unknown.The aims of this study were to assess the success rate of testing patients at home and to compare the results to the gold standard testing (in lab spirometry). Methods 147 home spirometry devices (Air Next, NuvoAir, USA) were given out to cystic fibrosis patients (M:F 67:80;mean age 11.8 [4.7 - 17.3]) who had previous experience of spirometry and deemed to be competent to perform spirometry at home. Patients were asked to perform 4 tests in the first month, then 1 test per month unless clinically requested. When Lab spirometry resumed, 28 (M:F 12:16;mean age 13.1 [8.0-17.0]) patients tested on NuvoAir within 5 days (mean 0.7 days (1.0)) of Lab spirometry (Vyntus Spiro, Vyaire Medical, USA). Correlation between spirometry indices were analysed using linear regression. Results 142 patients (96.6%) successfully onboarded onto the NuvoAir platform. Between July 2020 and Jan 2022, 1854 tests were performed, with 1711 (92.3%) tests over-read to be valid. 54 patients (36.7%) performed >=15 tests requested. FEV1 (R2 = 0.93, p = <0.00), Ratio (R2 = 0.70, p = <0.00), FVC (R2 = 0.91, p = <0.00), MMEF (R2 = 0.87, p = <0.00) and PEF (R2 = 0.88, p = <0.00) all showed significant correlation between Lab spirometry and Home spirometry. Conclusion Our results show that home spirometry is well adopted by cystic fibrosis patients, however, continual encouragement may be required. We have also shown that valid spirometry loops can be performed by cystic fibrosis patients on this device. There is also close agreement between this home spirometry device and the gold standard of lab spirometry and therefore, results can be deemed valid and reliable.

SARS-Cov-2 infection in patients with univentricular heart after fontan operation

Background and Aim: COVID-19 pandemic caused by SARS-Cov-2 coronavirus affects all groups of patients. Although pediatric pop-ulation seems to be less affected with milder or asymptomatic course of SARS-CoV-2 infection, there are few groups of patients with potential high risk of severe or fatal course of coronavirus dis-ease. These include children with congenital heart defects. The aim of this study was to evaluate the course of SARS-Cov-2 infection in patients with univentricular heart after Fontan operation. Method(s): From September 2020 to May 2021 (before vccination started in pediatric population in Poland) we screen all 38 Fontan patients admitted to Cardiology Department, Polish Mother's Memorial Hospital Research Institute for SARS-Cov2 antibodies. Result(s): We found positive SARS-Cov-2 antibodies in 21 unvac-cinated Fontan patients (55% of all hospitalized Fontan patients), 15 boys (71%) and 6 girls in the age 3-22 years (mean 11 years). 14 patients (67%) had hypoplastic left heart syndrome. Course of SARS-CoV-2 infection: asymptomatic course in 11(52%) patients, fever in 7 (33%) patients, cough 4 (19%) patients, diar-rhoea in 2 patients, loss of smell and taste-1 patient. One, 18 years old patient suffered from Covid fog symptoms (impairment of sus-tained attention and memory problems), he hasn't notice any SARS-Cov-2 symptoms but the level of antiobodies was high. Only 3 patients were hospitalized in acute SARS Cov2 infection: 2 due beacause of need for intravenous rehydratation during severe diarrhoea, 1 because of JET (junctional ectopic tachycardia) during fever. There was no case of PIMS (pediatric inflammatory multi-system syndrome) in study group. Medications used in study group: aspirin in 19 (90 %), warfarin in 2, spironolactone in 18 (86%), sildenafil in 9 (43%), angiotensyn-converting enzyme inhibitors in 17 (81%), beta-blockers in 4 (19%) of patients. Conclusion(s): 1. In our study severe congenital heart defect such as univentricular heart was not a risk factor of severe course of SARS-Cov-2 infection. 2. Absence of PIMS in analized group of patients may be connected with changed immunologic response in Fontan patients and chronic use of ASA (acetylsalicylic acid). 3. The impact of SARS CoV 2 infection on patients with congenital heart defects needs further studies.

The RELIEHF registry & clinical trial design (Relieving Increasing Oedema due to Heart Failure)

Background: Water retention leading to worsening congestion is a common reason for heart failure (HF) hospitalisation. Increases in aldosterone, due to increased secretion (driven by angiotensin and hyperkalaemia) and reduced degradation (due to hepatic dysfunction), contribute to congestion. Mineralocorticoid receptor antagonists (MRA) reduce morbidity and mortality in advanced HF. However, use of MRA is often limited by hyperkalaemia, renal dysfunction and hypotension. Hyperkalaemia can be corrected by potassium binding agents. Methods: An open-label, randomised, multi-centre (up to 100 UK sites) trial investigating the use of a potassium binding agent, patiromer, to facilitate higher doses of MRA for HF with worsening congestion requiring treatment with ≥80mg/day of furosemide (or equivalent). Patients are first entered on an unconsented screening-log (approved by the UK Health Research Authority) and then asked to consent to a registry (no exclusion criteria). If they agree, and are eligible (systolic blood pressure ≥90mmHg, eGFR ≥30mL/min/1.73 m2, no other terminal disease, no active infection or myocardial ischaemia), they are invited to participate in a randomised trial. Patients who consent for the trial enter a run-in phase of ≤35 days, when they receive ≤100mg/day of spironolactone. If serum potassium rises to >5.0mmol/L, the patient is randomised either to receive an MRA at guideline recommended doses or to have spironolactone increased ≤200mg/day, using patiromer to manage hyperkalaemia, providing eGFR remains ≥30mL/min and the patient does not become hypotensive. The primary outcome of the first phase of the trial (n = 400) is severity of congestion at 60-days but patients will be followed The RELIEHF Registry & Randomised Trial long-term for morbidity and mortality. An adaptive trial design allows recruitment to be increased up to 2.000 patients. Results: The conduct of the trial has been disrupted by COVID. As of January 2022, from 10 sites, >300 patients (40% women;median age 76 (65-83) years have been screened, >100 (37% women;median age 72 (62-80) years) have consented for the registry and >25 for the randomised trial. Of patients screened, about 50% were asked for registry-consent, of whom one third refused. The main reason for not asking was that the care-team considered it inappropriate due to patient frailty and/or cognitive dysfunction. Most patients who consented for the registry agreed, in principle, to participate in a randomised trial. Most patients have tolerated 100mg of spironolactone during the run-in period. Conclusions: For a high proportion of patients admitted to hospital with worsening HF, research staff do not deem it appropriate to approach them to ask for research consent. Most patients with HF who were asked to participate in research were willing to do so and to participate in a randomised trial, although a substantial proportion were not eligible for this trial. Of those who were, the majority tolerated spironolactone at a dose of 100mg/day.

CLINICAL IMPROVEMENT IN PATIENTS WITH ME/CFS WITH SYNERGISTIC EFFECT OF COLCHICINE AND SPIRONOLACTONE TARGETING INHIBITION OF INFLAMMASOME ACTIVITY

Background: Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) has been associated to Epstein Bar Virus (EBV), Coxsakie virus and Ross River virus infections. Recently a similar condition to ME/CFS has been described as 'Long Covid' associated to SARS-CoV-2. Patients with positive EBV serology and ME/CFS may be carriers of a chronic latent infection that translates in a chronic systemic inflammation with neuroinflammation. The activation of the immunologic cascade after a viral infection or vaccination can trigger the formation of Anti-idiotype antibodies (Ab2) and an activation of pyrin domain containing protein3 (NRLP3) inflammasome. The NRLP3 inflammasome is the pattern of activation for interleukin (IL1-beta) cytokine complex which is activated in inflammatory conditions (1). Colchicine is postulated to work by inhibiting tubulin polymerization and microtubule formation blocking inflammasome activation (2). Spironolactone increased the activity and number of macrophage angiotensin converting enzyme 2 (ACE2) receptors. In the microglia this effect may represent a reduction of neuro-inflammation (3). In this we present ME/CFS patients treated with the synergetic effect of Colchicine and Spironolactone to inhibit Inflammasome and decrease inflammation. Population and Method: 23 patients (19 females) with positive serology for EBV infection and ME/CFS were included. All the patients were treated with multivitamins. Patients were educated about benefit and adverse effects of spironolactone and colchicine before treatment. The starting dose of Spironolactone was 12.5 mg a day increased to 25 mg a day (during years 2019 to 2021). The introduction of Colchicine 0.5 mg/day on treatment plan was during year 2021. Patient follow-up was in the outpatient clinic and GP clinic. Results: Total 23 Patients 19 were Females age 37.3+28 and 4 were Males age 61+9. Two patients stop colchicine after 4 weeks. Improvement in cognitive skills was the early manifestation of spironolactone benefit. Patients reported to be less brain foggy, more alert, and they found it easier to focus when doing normal everyday activities. They were also less irritable by noise and light and described themselves to be able to multi-task again. There was an improvement in general condition and everyday activities four weeks after Colchicine started. Conclusion: Patients with ME/CFS improve their cognitive skills and everyday physical activity tolerance when treated with Colchicine and Spironolactone.

WORSENING OF LETHARGY POST SARS-COV-2 VACCINATION IN A PATIENT WITH ME/CFS

Introduction: Since the SARS-CoV-2 (severe acute respiratory syndrome coronavirus2) vaccination started there have been multiple reports of different off target adverse effects related to the vaccination, such as myocarditis, immune mediated thrombosis, thrombocytopenia and allergic reactions. W Murphy and Dan Longo in the NEJM November 2021 reported these adverse effects associated with Anti-idiotype antibodies (Ab2) in SARS-CoV-2 vaccination. The pathologic cascade of Ab2 is described in several ways as the antibodies can bind to the protective normal antibodies (Ab1) resulting in immune complex formation and clearance thus impairing Ab1 efficacy. Another action of the Ab2 could be inhibiting normal ligands affecting interaction with angiotensin converting enzyme 2 (ACE2) receptors or stimulating the ACE2 receptor and downregulating the ACE2 function. There is also a description of complementmediated and immune cell attack on ACE2 expressing cells (1). The case reported in this manuscript is related to a severe deterioration in a male with previous diagnose of ME/CFS with worsening lethargy and cognitive skills after SARS-CoV-2 vaccination. The outstanding clinical improvement after starting oral Colchicine is the reason for this paper. Case Report: A 46-year-old male with a previous history of Sarcoidosis and Haemochromatosis had ME/CFS since 2016. He was followed up at Noosa Hospital clinic related to his ME/CFS. His general symptoms related to this condition were under control and he was able to work and study at the University. After the second dose of his SARS-CoV-2 (Pfizer -BioNTech COVID-19) vaccination in August 2021 his general condition deteriorated. During September-October 2021 his cognitive skills declined and he had to stop his university studies. The patient also stopped driving his car because of lethargy and could not do any sport recreational activity. Because of ME/CFS he was on treatment with multivitamins and low dose Naltrexone and Spironolactone before vaccination. After the ME/CFS clinical deterioration the decision was to start Colchicine 0.5 mg a day (November 2021). After four weeks of Colchicine plus his previous medication, his level of energy and cognitive skills recovered to pre vaccination status. Discussion: The immunologic cascade after SARS-CoV-2 vaccination triggered by Ab2 ended in activation of pyrin domain containing protein3 (NRLP3 Inflammasome). This is the pattern of activation for interleukin (IL-1beta). This may determine a general increase in the systemic and microglia inflammation as described in ME/CFS. The clinical manifestation in the present case was worsening in the symptoms of the ME/CFS. The patient was already on Spironolactone targeting the increase on number of macrophages ACE2 receptors as immune modulation. An anti-inflammatory synergy between Colchicine and Spironolactone is currently the focus of research in atherosclerosis. Colchicine has a direct effect on phagocytes leading to inflammasome inhibition and impaired production of IL-1 beta. Conclusion: The Colchicine had a beneficial effect in recovering this patient from an exacerbation of his ME/CFS induced by SARS-CoV-2 vaccination.

Concomitant Treatment of Severe Acute Respiratory Failure and Cardiac diastolic dysfunction due to Covid 19: A Case Report

Background and Aim: Although pulmonary involvement is common in Covid 19 disease, sometimes concomitant cardiac involvement is seen as diastolic dysfunction. This case report describes a patient who received simultaneous treatment for severe acute respiratory failure and cardiac diastolic dysfunction due to Covid 19. Case report: A 40-year-old woman was transferred to the internal ICU of Ayatollah Rouhani Hospital in Babol because of severe respiratory distress. The patient was anxious, restless,and cyanotic. There was respiratory distress, hypoxia (72% oxygen saturation), and cardiac involvement as diastolic dysfunction. Heart rate was 134/min, blood pressure 122/78 mm Hg, and respiratory rate 38/min. The patient underwent non-invasive ventilation, and received beta-interferon, low-dose furosemide, bisoprolol, and spironolactone. During the course of treatment, despite receiving a prophylactic dose of subcutaneous heparin, the patient developed deep vein thrombosis of the left lower extremity and was treated with intravenous heparin. After two weeks, the patient was discharged in relatively good condition with non-invasive ventilation, spironolactone, and oral rivaroxaban. After three months, CT scan of the lungs and echocardiography became normal. Conclusion: Examination of the patients for cardiac diastolic dysfunction as a concomitant disease is recommended. In case of occurrence of this disorder in Covid 19 patients, treatment of cardiac diastolic dysfunction in addition to severe pulmonary involvement should be taken into concideation.

Damage to the Cardiovascular System in Patients with SARS-CoV-2 Coronavirus Infection. Part 2: Correction of Myocardial Systolic Dysfunction

Aim. To study changes in myocardial contractile function when prescribing mineralocorticoid receptor antagonists of spironolactone in patients after coronavirus infection SARS-CoV-2 with symptoms of chronic heart failure (CHF). Materials and methods. The study included 90 hospitalized patients with a diagnosis of SARS-CoV-2 coronavirus infection. The inclusion criteria were: age from 18 to 85 years;the presence of CHF with a preserved or mildly reduced left ventricular ejection fraction (LVEF). The patients were randomized into two groups: group I (n=60) included patients who, for 6 months after discharge from the hospital, in addition to standard drug therapy for CHF, took spironolactone at a dose of 25 mg per day;group II (comparison group;n=30) included patients who received standard drug therapy without additional prescription of spironolactone. The study groups were comparable in age, gender, prevalence of hypertension, coronary heart disease, diabetes mellitus, obesity and severity of CHF;the drug therapy given to the patients had no significant differences. Assessment of LV systolic function, exercise tolerance (six-minute walk test, TSW), quality of life (questionnaire EQ-5D-5L) were performed. Results. When repeated echocardiography was performed after 6 months of treatment, there was a significant improvement in LV systolic function in group I patients. In group I, after 6 months of treatment, there was a significant decrease in the proportion of patients with moderately reduced LVEF (from 30 [50%] to 12 [20%];p<0.001), and a significant increase in the number of patients with preserved LVEF (from 30 [50%] to 48 [80%], p=0.002). In group II, the number of patients with moderately reduced LVEF did not significantly change. After 6 months of treatment, all patients showed an increase in exercise tolerance. During the test with a six-minute walk, group I patients showed an increase in the index from 316.8±63.5 to 432.9±41.3 meters;group II patients from 337.6±42.7 to 407.6±38.9 meters. The values of the six-minute walking test after 6 months of treatment were significantly higher in group I patients when compared with group II patients. When assessing the quality of life using the EQ-5D-5L questionnaire, it was found that at the time of inclusion of patients in the study, all patients noted the presence of any health problems in one or more components. The average indicator of health status, measured by a 100-point visual analog scale, after 6 months was 71.8±9.2 in patients of group I and was significantly higher than the same indicator in group II – 63.7±9.1. There were no adverse events in the study groups during the entire observation period. Conclusion. A significantly more pronounced improvement in systolic and diastolic left ventricle function, as well as quality of life, was found in the group of CHF patients with preserved or moderately reduced LVEF, who received spironolactone for 6 months after the SARS-CoV-2 infection in addition to standard therapy, compared with patients without aldosterone antagonists. © 2022 Stolichnaya Izdatelskaya Kompaniya. All rights reserved.

Association between Mineralocorticoid Receptor Antagonist and Mortality in SARS-CoV-2 Patients: A Systematic Review and Meta-Analysis.

Since the onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, various potential targeted therapies for SARS-CoV-2 infection have been proposed. The protective effects of mineralocorticoid receptor antagonists (MRA) against tissue fibrosis, pulmonary and systemic vasoconstriction, and inflammation have been implicated in potentially attenuating the severity of SARS-CoV-2 infection by inhibiting the deleterious effects of aldosterone. Furthermore, spironolactone, a type of MRA, has been suggested to have a beneficial effect on SARS-CoV-2 outcomes through its dual action as an MRA and antiandrogen, resulting in reduced transmembrane protease receptor serine type 2 (TMPRSS2)-related viral entry to host cells. In this study, we sought to investigate the association between MRA antagonist therapy and mortality in SARS-CoV-2 patients via systematic review and meta-analysis. The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE and EMBASE databases were searched for studies that reported the incidence of mortality in patients on MRA with SARS-CoV-2 infection. Pooled odds ratio (OR) and 95% confidence interval (CI) of the outcome were obtained using the random-effects model. Five studies with a total of 1,388,178 subjects (80,903 subjects receiving MRA therapy) met the inclusion criteria. We included studies with all types of MRA therapy including spironolactone and canrenone and found no association between MRA therapy and mortality in SARS-CoV-2 infection (OR = 0.387, 95% CI: 0.134-1.117, p = 0.079).

Erratum: Follow Your Nose: A Key Clue to Understanding and Treating COVID-19.

[This corrects the article DOI: 10.3389/fendo.2021.747744.].

Spironolactone effect on the blood pressure of patients at risk of developing heart failure: an analysis from the HOMAGE trial.

AIMS: Uncontrolled blood pressure (BP) increases the risk of developing heart failure (HF). The effect of spironolactone on BP of patients at risk of developing HF is yet to be determined. To evaluate the effect of spironolactone on the BP of patients at risk for HF and whether renin can predict spironolactone's effect. METHODS AND RESULTS: HOMAGE (Heart OMics in Aging) was a prospective multicentre randomized open-label blinded endpoint (PROBE) trial including 527 patients at risk for developing HF randomly assigned to either spironolactone (25-50 mg/day) or usual care alone for a maximum of 9 months. Sitting BP was assessed at baseline, Months 1 and 9 (or last visit). Analysis of covariance (ANCOVA), mixed effects models, and structural modelling equations was used. The median (percentile25-75) age was 73 (69-79) years, 26% were female, and >75% had history of hypertension. Overall, the baseline BP was 142/78 mmHg. Patients with higher BP were older, more likely to have diabetes and less likely to have coronary artery disease, had greater left ventricular mass (LVM), and left atrial volume (LAV). Compared with usual care, by last visit, spironolactone changed SBP by -10.3 (-13.0 to -7.5) mmHg and DBP by -3.2 (-4.8 to -1.7) mmHg (P < 0.001 for both). A higher proportion of patients on spironolactone had controlled BP <130/80 mmHg (36 vs. 26%; P = 0.014). Lower baseline renin levels predicted a greater response to spironolactone (interactionP = 0.041). CONCLUSION: Spironolactone had a clinically important BP-lowering effect. Spironolactone should be considered for lowering blood pressure in patients who are at risk of developing HF.

Damage to the Cardiovascular System in Patients with SARS-CoV-2 Coronavirus Infection. Part 1: Predictors of the Development of an Unfavorable Prognosis

Aim. To evaluate the effect of sinus tachycardia and reduced left ventricular ejection fraction (LVEF) on the prognosis of patients with a verified diagnosis of a new coronavirus infection SARS-CoV-2. Material and methods. The study included 1,637 patients with a verified diagnosis of a new coronavirus infection SARS-CoV-2. The average age of the patients was 58.8±16.1 years. More than half of the patients admitted to the hospital had a history of cardiovascular diseases: hypertension was diagnosed in 915 (56%) patients, coronary artery disease – in 563 (34%), chronic heart failure – in 410 (25%). 294 (17.9%) patients suffered from diabetes mellitus. The unfavorable course of new coronavirus infection was assessed by the fact of being in the intensive care unit (ICU), the use of mechanical ventilation and death. Results. An unfavorable course of coronavirus infection was observed in 160 (9.8%) patients. Statistical analysis revealed that 341 (20.8%) patients with COVID-19 were diagnosed with sinus tachycardia, which required the appointment of pulse-reducing therapy. The occurrence of sinus tachycardia in patients with COVID-19 significantly increased the risk of death (odds ratio [OR] 1.248, confidence interval [CI] 1.038-1.499, p=0.018), increased the likelihood of mechanical ventilation use (OR 1.451, CI 1.168-1.803, p<0.001) and stay in the ICU (OR 1.440, CI 1.166-1.778, p<0.001). In 97 (5.9%) patients during hospital stay during echocardiography, a decrease in LVEF of less than 50% was diagnosed. A decrease in myocardial contractile function in patients with COVID-19 with high reliability increased the risk of death (OR 1.744, CI 1.348-2.256, p<0.001), increased the likelihood of using the mechanical ventilation (OR 1.372, CI 1.047-1.797, p=0.022) and stay in the ICU (OR 1.360, CI 1.077-1.716, p=0.010). Conclusion. The appearance of sinus tachycardia and reduced LVEF are in dependent predictors of the unfavorable course of COVID-19 in relation to factors such as death, the use of mechanical ventilation and the stay of patients in the ICU. Early pharmacological correction of cardiovascular lesions should be one of the goals of the management theese patients. © 2021 Stolichnaya Izdatelskaya Kompaniya. All rights reserved.

Metainflammation in COVID-19.

A new coronavirus pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been on the rise. This virus is fatal for broad groups of populations, including elderly, men, and patients with comorbidities among which obesity is a possible risk factor. The pathophysiologic connections between obesity/metainflammation and COVID-19 may be directly related to increasing soluble ACE2 (angiotensin-converting enzyme 2) levels which potentiate the viral entrance into the host cells, or indirectly related to dysregulation of immune system, microvascular injury and hypercoagulability. The SARS-CoV-2 S-glycoprotein interacts mainly with ACE2 or possibly DPP4 receptors to enter into the host cells. The host proteases, especially TMPRSS2 (transmembrane protease serine 2), support the fusion process and virus entry. While membranous ACE2 is considered a port of entry to the cell for SARSCoV- 2, it seems that soluble ACE2 retains its virus binding capability and enhances its entry into the cells. Interestingly, ACE2 on cell membrane may have protective roles by diminishing cytokine storm-related injuries to the organs. Applying medications that can reduce soluble ACE2 levels, antagonizing TMPRSS2 or blocking DPP4 can improve the outcomes of COVID-19. Metformin and statins through immunomodulatory activities, Orlistat by reducing viral replication, and thiazolidinediones by upregulating ACE2 expression have potential beneficial effects against COVID-19. However, the combination of dipeptidyl peptidase-4 (DPP4) inhibitors and spironolactone/ eplerenone seems to be more effective by reducing soluble ACE2 level, antagonizing TMPRSS2, maintaining ACE2 on cell membrane and reducing risk of viral entry into the cells.

Can aldosterone increase Interleukin-6 levels in CoViD-19 pneumonia

Background: Several evidence have identified the role of Interleukin- 6 (IL-6) in the cytokine storm induced by CoViD-19 pneumonia. Interestingly, the correlation between the serum levels of IL-6 and the plasma aldosterone has already been demonstrated in patients affected by primary aldosteronism (PA). Therefore, we suppose that aldosteronism may increase IL-6 levels in CoViD-19. Presentation of the case:We report a case of a 47-year-old female CoViD-19 patient who had developed severe pneumonia complicated by Guillain-Barre syndrome (GBS). The blood test revealed high levels of IL-6 (serum IL-6: 402 pg/mL) and of its soluble receptor (soluble IL-6 receptor >1900pg/mL) and she required mechanical ventilation for severe hypoxemia. Furthermore, evidence of right adrenal adenoma, resistant hypertension, severe hypokalemia and high serum levels of aldosterone with high aldosterone/renin ratio were also consistent with diagnosis of PA. Thus, tocilizumab and spironolactone were administered with rapid improvement in clinical condition. Finally, she was diagnosed with acute motor sensitive neuropathy and began the rehabilitation phase. Conclusions: Increased aldosterone levels in PA may be associated with more severe forms of CoViD-19 by stimulating IL-6 production. This association could have a synergic effect in development of complications such as GBS. Increased aldosterone activity/levels could be involved in CoViD-19 patients with secondary aldosteronism. Further studies are needed to.