Myocarditis in Malta in the COVID-19 vaccination era – a population-based study

BACKGROUND Vaccination against COVID-19 is crucial for controlling this scourge. COVID/vaccination deniers often rationalise their unfounded fears by citing rare vaccination side-effects. One of the most frequently cited side effects is myocarditis, especially in younger persons. Malta has very high vaccination rates. This study was carried out to ascertain whether admissions to hospital for myocarditis changed during the vaccination rollout, up to October 2021, when 83.4% of Malta’s population of circa half a million had had their first 1st dose. METHODS Malta is served by one large regional hospital (Mater Dei Hospital). Anonymous data for admissions with a diagnosis of myocarditis (ICD I40, I41, I51.4) were obtained for 01/2016-10/2021. Myocarditis discharges and 95% confidence intervals were plotted for 2016-2020. Myocarditis discharges for Jan-Oct 2021 were plotted separately. RESULTS There were no outlier values for myocarditis discharges in either direction for any age for either sex. CONCLUSION Myocarditis, independent of vaccination, is commonest in young males, half resolving and some developing dilated cardiomyopathy, possibly leading to transplantation or death. The ongoing mass vaccination with novel messenger RNA vaccines resulted in reports of myocarditis in male teens, this being a rare side effect. The lack of significantly increased rates of myocarditis admission in any age age/sex group in Malta confirms that only rarely, myocarditis may be temporally associated with COVID vaccination which almost invariably runs a benign course and that this risk is very low, far lower than myocarditis due to actual COVID infection.

Subjective well-being in men and women during the COVID-19 lockdown: A structural model

Introduction. As a measure for controlling COVID-19, lockdown has had a psychological impact on people. Since subjective well-being (SW) has been positively associated with mental health, the identification of its predictors in this context will enable it to be strengthened. Objective. To generate and test explanatory models for SW in men and women under lockdown due to the pandemic. Method. Four thousand seven hundred and seventy-one inhabitants of Mexico, with paid employment, under lockdown, answered a set of instruments via the Internet that evaluated positive and negative psychological factors in addition to SW. Based on correlation and multiple regression analysis, models were proposed for men and women, which were tested by path analysis. Results. Both models successfully fit the data and explained a high proportion of the SW variance. Spiritual strength was the best predictor, mainly for women, while the capacity for enjoyment was central to the models, mediating the effect of empathy and depression. Discussion and conclusion. SW is significantly predicted by the factors studied, especially spiritual strength and capacity for enjoyment, which seem to provide men and women with fortitude and meaning of life in adverse circumstances such as today's.

Origin of antiphospholipid antibodies in autoimmunity and viral infection

Background: Antiphospholipid Antibodies (aPLs) cause Antiphospholipid Syndrome (APS), a severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Beside APS, many infections have been found to be associated with elevated aPL titers. In addition to COVID-19 patients, aPLs of unknown origin were also observed in patients with Cytomegalovirus (CMV) infection. Both infections are associated with higher risk of thrombosis. Aims: We want to analyze whether the higher risk of thrombosis in the context of viral infection was due to the procoagulant properties of aPL. Moreover we want to characterize the circulating B cells producing the different types of aPL. Methods: We studied B cells of human patient EDTA plasma or EDTA plasma of CMV infected mice by flow cytometry. Antibody titers in sera were measured by ELISA technique. Human and mouse monocytic cell activation by aPL was analyzed by single stage clotting assay, gene induction and molecule tracking by confocal microscopy. Results: Purified COVID-19 or CMV aPL specifically activate the same pathogenic signaling pathway of aPL that have recently been described in the context of APS. In this pathway, lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) is the pivotal cell surface antigen recognized by aPLs that is responsible for induction of thrombosis and endosomal inflammatory signaling. These pathogenic aPLs occurring during viral infection were secreted by CD5 + CD27 + CD43 + B1a cells. The preformed B1 B-cell clones initially produce purely lipid-reactive antibodies of the IgG isotype. During the course of the disease, an MHC-dependent hypermutation process occurs in which glycoprotein-binding antibodies are generated, further increasing the risk for vascular pathologies. Conclusions: Our results demonstrate that patients suffering from viral infection, rapidly expand B1a-cells secreting pathogenic aPL with broad acute thrombotic and inflammatory effects as well as the potential for long-term autoimmune complications.

Lipid-binding antiphospholipid antibodies trigger autoimmune signaling in severe COVID-19

Background: Antiphospholipid antibodies (aPL) are causally involved in the pathogenesis of the antiphospholipid syndrome (APS), but lipid-binding aPL are also frequently found in acute infections. While lipid-binding aPL are considered irrelevant for APS we have shown that they are prothrombotic in vivo and have delineated the underlying signaling pathway. COVID-19 associated coagulopathy has many similarities to severe and catastrophic APS e.g. stroke, venous and pulmonary clots, as well as microvascular thrombosis and aPL have been described in COVID-19. However, their role in COVID-19 is still poorly understood. Aims: In this study, we aimed to elucidate the role of lipid-binding aPL in severe COVID-19. Methods: B cells were analyzed using flow cytometry. aPL were measured by immunoassays including a home-made ELISA for lipidbinding aPL. Cultured cells were stimulated with immunoglobulins isolated from COVID-19 patients. Gene expression was measured by qRT-PCR, cellular procoagulant activity was determined by a clotting assay. In vivo thrombus formation was determined in the flowrestricted inferior vena cava mouse model. Results: We identified a distinct population of circulating B1a cells producing lipid-reactive aPL of the IgG isotype in COVID-19 patients. 43 of 53 COVID-19 patients tested positive for lipid-binding aPL. Positive patients had more often a critical clinical course and a higher mortality. In vitro, COVID-19 aPL induced inflammatory and prothrombotic pathways in monocytes and endothelial cells and rapidly decrypted cell surface tissue factor. These effects were dependent on a recently described signaling pathway involving lysobisphosphatidic acid (LBPA) presented by the endothelial protein C receptor (EPCR) on the cell surface. In vivo, COVID-19 aPL induced thrombus formation by this EPCR-LBPA-dependent signaling pathway. Conclusions: COVID-19 patients develop lipid-binding aPL produced by circulating B1a cells. These aPL are associated with a more severe course and mortality and show prothrombotic and inflammatory properties by targeting the previously delineated aPL autoimmune signaling pathway dependent on EPCR-LBPA.

Blockade of COVID-19 antiphospholipid antibody-induced thrombosis by a specific inhibitor of the tf initiationcomplex

Background : Antiphospholipid antibodies (aPL) cause the antiphospholipid syndrome (APS) and promote rapid complement-and protein disulfide isomerase (PDI)-dependent tissue factor (TF) decryption on monocytes. In this context, aPL induce procoagulant phosphatidylserine exposure by a rapid thrombin-dependent translocation of acidic sphingomyelinase (ASM) to the cell surface, where ASM is specifically activated by the endosomal lysobisphosphatidic acid (LBPA) presented by the endothelial protein C receptor (EPCR). aPL are also found in COVID-19 patients and effective therapeutic approaches to prevent TF-dependent thrombosis in APS associated with viral infections are needed. Aims : Analyze the effect of rNAPc2, a hookworm-derived inhibitor of the TF initiation complex, in COVID-19 aPL immunoglobulin (Ig)-induced thrombosis in mice. Methods : Isolated Ig from hospitalized COVID-19 patients or healthy controls were injected into C57Bl/6J wild type mice to induce aPLamplified thrombosis in a flow restricted inferior vena cava (IVC) model. Labeled platelets and leukocytes were tracked over 3 h and thrombus size was quantified by intravital microscopy. Results : COVID-19 Ig accelerated thrombus formation significantly in comparison to isolated Ig from healthy controls (31528 vs 302 μm2;P < 0.0001). This increase was not impaired by non-inhibitory aEPCR injected prior to COVID-19 Ig but blocked by aEPCR which specifically inhibits EPCR-LBPA induction of ASM activity. These data showed that COVID-19 Ig triggered the same prothrombotic pathway elucidated for aPL from APS patients. Administration of the TF complex inhibitor rNAPc2 30 min prior to COVID-19 Ig-induced thrombosis markedly reduced thrombus size to levels comparable to control Ig injected mice (31527 vs 1399 μm2;P < 0.0001), demonstrating that thrombosis is induced by TF activation. Conclusions : Blockade of TF with rNAPc2 is effective to prevent COVID-19 Ig-induced thrombosis in a preclinical model of APS.

'Cocooning' the vulnerable - a main pillar of Malta's COVID-19 response

Issue Early epidemiology established higher risk of morbidity & mortality amongst infected older individuals or those having specific chronic diseases, consuming most hospital care. Also where demand exceeding supply of healthcare, mortality was very high. As an island nation with one central main hospital, not overwhelming the healthcare system whilst avoiding total lockdown was key. Description On the 27-03-2020, the Superintendent of Public Health enacted the Protection of Vulnerable Persons Order, specifying that these categories (or subcategories thereof) of persons are to be granted vulnerable status: age >65;pregnant;persons suffering from diabetes;immunosuppressed;cancer;end stage renal failure;respiratory disease;cardiac disease;heart failure. Such persons were entitled to stay at home, to be granted special leave from work, entitled to a monthly allowance by social services. One could go out only to attend to essential or urgent personal matters, e.g. groceries, medicines, medical needs, bank etc. with mitigation measures. Exemptions were only granted to special categories such as healthcare workers, farmers, or headship positions. In addition, the carers & staff of most nursing homes voluntarily decided to isolate themselves inside the homes for periods of 2/3 weeks. Thanks to a very active family support network, offspring, relatives or neighbours ran basic errands for them, or else organised deliveries. This legal status has been lifted on the 5th June 2020. Results This status was granted to 126 000 persons, including 14000 employed persons. Only 9 deaths occurred in Malta out of 664 cases in a population of 500000 up till 20th June 2020, with a case fatality rate of 1.35% - one of the lowest in Europe. Lessons Protection of vulnerable individuals can be a cornerstone of COVID-19 public health response if mobility is effectively restricted in this subpopulation. Key messages Protection of the vulnerable reduces healthcare & mortality burden. Effective legal & economic support measures, & extensive societal engagement required.

COVID-19 mortality in Mexico and metabolic diseases during a critical pandemic year br

Objective: To know the specific association of metabolic disease on COVID-19 mortality, occurred during the critical year of the pandemic, from march 2020 to march 2021. Method: The Covid-19 national base of the General Directorate of Epidemiology was used. Positive cases of metabolic diseases were analyzed: cardiovascular disease, hypertension, diabetes and obesity. A descriptive analysis was carried out to find out the distribution of deceased and non-deceased cases. The chi-square test was used for the difference in proportions. Logistic regression analysis was used to understand the association between metabolic diseases and COVID 19 mortality in people who tested positive for the SARS-CoV-2 virus. The data were adjusted for age and gender. Results: The association of metabolic diseases on mortality was observed. Diabetes had a higher percentage of lethality 18,4%. When cardiovascular disease and diabetes were combined, the fatality rate rose to 31,5%;the combination of cardiovascular diseases, with hypertension and diabetes was the highest percentage of lethality 38,7%. Obesity had the least incidence. Conclusions: Metabolic diseases in Mexico are a public health problem that affected COVID-19 mortality. It is a priority to deal with preventive and effective public policies in favor of a healthy food consumption model, in line with the nutritional needs of the population.