Cardiovascular Manifestations of Multisystem Inflammatory Syndrome in Children: A Single-Center Bulgarian Study.

Background and objectives: Multisystem inflammatory syndrome in children (MIS-C) poses challenges to the healthcare system, especially with frequent heart involvement. The current retrospective observational study aims to summarize the type and degree of cardiovascular involvement in children with MISC and to find possible associations between laboratory, inflammatory, and imaging abnormalities and the predominant clinical phenotype using a cluster analysis. Material and methods: We present a retrospective observational single-center study including 51 children meeting the MIS-C criteria. Results: Fifty-three percent of subjects presented with at least one sign of cardiovascular involvement (i.e., arterial hypotension, heart failure, pericardial effusion, myocardial dysfunction, pericarditis without effusion, myocarditis, coronaritis, palpitations, and ECG abnormalities). Acute pericarditis was found in 30/41 of the children (73%) assessed using imaging: 14/30 (46.7%) with small pericardial effusion and 16/30 (53.3%) without pericardial effusion. The levels of CRP were significantly elevated in the children with pericarditis (21.6 ± 13 mg/dL vs. 13.9 ± 11 mg/dL, p = 0.035), and the serum levels of IL-6 were higher in the children with small pericardial effusion compared to those without (191 ± 53 ng/L vs. 88 ± 27 ng/L, p = 0.041). Pericarditis with detectable pericardial effusion was significantly more frequent in the female vs. male subjects, 72% vs. 30% (p = 0.007). The hierarchical clustering analysis showed two clusters: Cluster 1 includes the children without cardiovascular symptoms, and Cluster 2 generalizes the MIS-C children with mild and severe cardiovascular involvement, combining pericarditis, myocarditis, heart failure, and low blood pressure. Also, subjects from Cluster 2 displayed significantly elevated levels of fibrinogen (5.7 ± 0.3 vs. 4.6 ± 0.3, p = 0.03) and IL-6 (158 ± 36 ng/mL vs. 66 ± 22 ng/mL, p = 0.032), inflammatory markers suggestive of a cytokine storm. Conclusions: Our results confirm that children with oligosymptomatic MIS-C or those suspected of long COVID-19 should be screened for possible cardiological involvement.

Role of children in the Bulgarian COVID-19 epidemic: A mathematical model study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic affects all aspects of our lives, including children. With the advancement of the pandemic, children under five years old are at increased risk of hospitalization relative to other age groups. This makes it paramount that we develop tools to address the two critical aspects of preserving children's health - new treatment protocols and new predictive models. For those purposes, we need to understand better the effects of COVID-19 on children, and we need to be able to predict the number of affected children as a proportion of the number of infected children. This is why our research focuses on clinical and epidemiological pictures of children with heart damage post-COVID, as a part of the general picture of post-COVID among this age group. AIM: To demonstrate the role of children in the COVID-19 spread in Bulgaria and to test the hypothesis that there are no secondary transmissions in schools and from children to adults. METHODS: Our modeling and data show with high probability that in Bulgaria, with our current measures, vaccination strategy and contact structure, the pandemic is driven by the children and their contacts in school. RESULTS: This makes it paramount that we develop tools to address the two critical aspects of preserving children's health - new treatment protocols and new predictive models. For those purposes, we need to understand better the effects of COVID-19 on children, and we need to be able to predict the number of affected children as a proportion of the number of infected children. This is why our research focuses on clinical and epidemiological pictures of children with heart damage post-COVID, as a part of the general picture of post-Covid among this age group. CONCLUSION: Our modeling rejects that hypothesis, and the epidemiological data supports that. We used epidemiological data to support the validity of our modeling. The first summer wave in 2020 from the listed here school proms endorse the idea of transmissions from students to teachers.

Nationwide analysis of the impact of COVID-19 in patients with a cardiovascular, oncological or chronic pulmonary disease in the context of an Eastern European country with a low vaccination rate, Bulgaria: March 2020-April 2022.

OBJECTIVE: This study focused on Bulgarian patient cohorts harbouring a single documented chronic comorbidity-cardiovascular pathology, an oncological disease or a chronic pulmonary diseases (CPD) comparing the outcomes in fully vaccinated and non-vaccinated populations classified by sex and age groups in ambulatory, hospital and intensive care unit (ICU) settings at the national level. DESIGN: Retrospective analysis SETTINGS, PARTICIPANTS AND OUTCOME MEASURES: In total, 1 126 946 patients with confirmed COVID-19, on a national level, were retrospectively analysed between March 2020 and April 2022, using data from the Ministry of Health's United Information Portal, launched in March 2020. RESULTS: Of all the confirmed 247 441 hospitalised cases of COVID-19, 67 723 (27.3%) had documented cardiovascular disease (CVD), 2140 (0.9%) had confirmed solid malignancy (regardless of stage) and 3243 (1.3%) had established CPD as their only chronic pathology. The number of cumulative deaths in each subgroup was 10 165 (in-hospital=5812 and ICU=4353); 4.0% vaccinated (410/10 165, p<0.001), 344 (in-hospital=196 and ICU=148), 4.9% vaccinated (17/344, p<0.001), 494 (in-hospital=287 and ICU=207) and 5.2% vaccinated (26/494, p<0.001), respectively. Statistical significance (p<0.001) was obtained in favour of reduced ambulatory, hospitalisation and both in-hospital and ICU-related mortality in the vaccinated cohorts, and BNT162b2 was the most effective at preventing mortality in all age groups. CONCLUSIONS: This retrospective analysis shows that patients vaccinated against COVID-19 demonstrated trends of reduced hospitalisations and premature mortality in patients with CVD, solid malignancy or CPD as a single comorbidity.

Applications of time series analysis in epidemiology: Literature review and our experience during COVID-19 pandemic.

Time series analysis is a valuable tool in epidemiology that complements the classical epidemiological models in two different ways: Prediction and forecast. Prediction is related to explaining past and current data based on various internal and external influences that may or may not have a causative role. Forecasting is an exploration of the possible future values based on the predictive ability of the model and hypothesized future values of the external and/or internal influences. The time series analysis approach has the advantage of being easier to use (in the cases of more straightforward and linear models such as Auto-Regressive Integrated Moving Average). Still, it is limited in forecasting time, unlike the classical models such as Susceptible-Exposed-Infectious-Removed. Its applicability in forecasting comes from its better accuracy for short-term prediction. In its basic form, it does not assume much theoretical knowledge of the mechanisms of spreading and mutating pathogens or the reaction of people and regulatory structures (governments, companies, etc.). Instead, it estimates from the data directly. Its predictive ability allows testing hypotheses for different factors that positively or negatively contribute to the pandemic spread; be it school closures, emerging variants, etc. It can be used in mortality or hospital risk estimation from new cases, seroprevalence studies, assessing properties of emerging variants, and estimating excess mortality and its relationship with a pandemic.

Effectiveness and safety of COVID-19 vaccines in patients with oncological diseases: State-of-the-art.

Although the coronavirus disease 2019 (COVID-19) pandemic was declared to be no longer "a public health emergency of international concern" with its wide range of clinical manifestations and late complications, severe acute respiratory syndrome coronavirus 2 infection proved to be a serious threat, especially to the elderly and patients with comorbidities. Patients with oncologic diseases are vulnerable to severe infection and death. Indeed, patients with oncohematological diseases have a higher risk of severe COVID-19 and impaired post-vaccination immunity. Unfortunately, cancer patients are usually excluded from vaccine trials and investigations of post-vaccinal immune responses and the effectiveness of the vaccines. We aimed to elucidate to what extent patients with cancer are at increased risk of developing severe COVID-19 and what is their overall case fatality rate. We also present the current concept and evidence on the effectiveness and safety of COVID-19 vaccines, including boosters, in oncology patients. In conclusion, despite the considerably higher mortality in the cancer patient group than the general population, countries with high vaccination rates have demonstrated trends toward improved survival of cancer patients early and late in the pandemic.

The End or a New Era of Development of SARS-CoV-2 Virus: Genetic Variants Responsible for Severe COVID-19 and Clinical Efficacy of the Most Commonly Used Vaccines in Clinical Practice.

Although the chief of the World Health Organization (WHO) has declared the end of the coronavirus disease 2019 (COVID-19) as a global health emergency, the disease is still a global threat. To be able to manage such pandemics in the future, it is necessary to develop proper strategies and opportunities to protect human life. The data on the SARS-CoV-2 virus must be continuously analyzed, and the possibilities of mutation and the emergence of new, more infectious variants must be anticipated, as well as the options of using different preventive and therapeutic techniques. This is because the fast development of severe acute coronavirus 2 syndrome (SARS-CoV-2) variants of concern have posed a significant problem for COVID-19 pandemic control using the presently available vaccinations. This review summarizes data on the SARS-CoV-2 variants that are responsible for severe COVID-19 and the clinical efficacy of the most commonly used vaccines in clinical practice. The consequences after the disease (long COVID or post-COVID conditions) continue to be the subject of studies and research, and affect social and economic life worldwide.

Blood Coagulation and Thrombotic Disorders following SARS-CoV-2 Infection and COVID-19 Vaccination.

Although abundant data confirm the efficacy and safety profile of the developed vaccines against COVID-19, there are still some concerns regarding vaccination in high-risk populations. This is especially valid for patients susceptible to thrombotic or bleeding events and hesitant people due to the fear of thrombotic incidents following vaccination. This narrative review focuses on various inherited and acquired thrombotic and coagulation disorders and the possible pathophysiologic mechanisms interacting with the coagulation system during immunization in view of the currently available safety data regarding COVID-19 vaccines. Inherited blood coagulation disorders and inherited thrombotic disorders in the light of COVID-19, as well as blood coagulation and thrombotic disorders and bleeding complications following COVID-19 vaccines, along with the possible pathogenesis hypotheses, therapeutic interventions, and imaging for diagnosing are discussed in detail. Lastly, the lack of causality between the bleeding and thrombotic events and COVID-19 vaccines is debated, but still emphasizes the importance of vaccination against COVID-19, outweighing the minimal risk of potential rare adverse events associated with coagulation.

COVID-19 Delta Wave Caused Early Overburden of Hospital Capacity in the Bulgarian Healthcare System in 2021.

We develop and apply our methodology to estimate the overburdening of hospitals in Bulgaria during the upcoming delta surge. We base our estimations on an exponential risk model from the UK. Still, the methodology is generally applicable to all risk models, depending on age. Our hypothesis is that during the delta wave in Bulgaria, the system experienced a burden from late August due to decreased capacity. This will explain most of the excess mortality during the wave. We estimate the number of people from the active cases in need of hospitalization and intensive care.

Pandemic control - do's and don'ts from a control theory perspective.

Managing a pandemic is a difficult task. Pandemics are part of the dynamics of nonlinear systems with multiple different interactive features that co-adapt to each other (such as humans, animals, and pathogens). The target of controlling such a nonlinear system is best achieved using the control system theory developed in engineering and applied in systems biology. But is this theory and its principles actually used in controlling the current coronavirus disease-19 pandemic? We review the evidence for applying principles in different aspects of pandemic control related to different goals such as disease eradication, disease containment, and short- or long-term economic loss minimization. Successful policies implement multiple measures in concordance with control theory to achieve a robust response. In contrast, unsuccessful policies have numerous failures in different measures or focus only on a single measure (only testing, vaccines, etc.). Successful approaches rely on predictions instead of reactions to compensate for the costs of time delay, on knowledge-based analysis instead of trial-and-error, to control complex nonlinear systems, and on risk assessment instead of waiting for more evidence. Iran is an example of the effects of delayed response due to waiting for evidence to arrive instead of a proper risk analytical approach. New Zealand, Australia, and China are examples of appropriate application of basic control theoretic principles and focusing on long-term adaptive strategies, updating measures with the evolution of the pandemic.

Effectiveness and safety of COVID-19 vaccines in patients with diabetes as a factor for vaccine hesitancy.

Diabetes mellitus is one of the most common comorbid conditions encountered in patients with severe acute respiratory syndrome coronavirus 2 infection accompanied by significantly increased mortality, prolonged hospital stay, and requirement of invasive mechanical ventilation. This review aims to present the effectiveness and safety profile of available coronavirus disease 2019 (COVID-19) vaccines in people with diabetes as a potential cause of hesitancy for vaccination. Data from published research proves a robust immune response following immunization for COVID-19 in diabetic patients with substantial production of virus-neutralizing antibodies; however, the observed immune response was unequivocally weaker than that in individuals without diabetes. This observation was further enhanced by the findings that worse glycemic control was associated with more suppressed antibody production. In contrast, individuals with optimal glycemic control performed similarly to healthy controls. In addition to the need for strict glucose monitoring and adequate diabetes treatment, those findings reinforce the concept of diabetes-induced secondary immune deficiency and necessitate the application of booster doses to diabetic patients with priority. Nevertheless, after vaccination, reported adverse events were not different from those in the general population. No increase in severe adverse events was documented. While single case reports detected transient increases in blood glucose post-vaccination, more extensive trials could not replicate such a relationship.

COVID-19 in patients with gastrointestinal stromal tumors: Recommendations for management and vaccination.

The coronavirus disease 2019 (COVID-19) pandemic profoundly affected the management and treatment of patients with malignancies. Based on the progress reported in the literature, we reviewed the recommendations for treatment and vaccination in patients with gastrointestinal stromal tumor (GIST) during COVID-19. We focus on whether there is a risk and what could be the possible effects of vaccinating patients with GIST/cancer. Since the situation is quickly changing, and the health services have been severely disrupted, the diagnosis, treatment and recommendations for vaccination of these patients against COVID-19 are still not updated. The approval of vaccines in the pandemic gave hope that we would soon be able to return to a more normal life. However, the oncology community needs to adapt and provide the most effective treatment and care models for patients with rare cancer, such as GIST. Collecting data on the impact of vaccination in patients with GIST/cancer also will be beneficial in expanding knowledge about the future planning of treatment strategies and optimizing care in the event of a subsequent pandemic.

Mucosal COVID-19 vaccines: Risks, benefits and control of the pandemic.

Based on mucosal immunization to promote both mucosal and systemic immune responses, next-generation coronavirus disease 2019 (COVID-19) vaccines would be administered intranasally or orally. The goal of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines is to provide adequate immune protection and avoid severe disease and death. Mucosal vaccine candidates for COVID-19 including vector vaccines, recombinant subunit vaccines and live attenuated vaccines are under development. Furthermore, subunit protein vac-cines and virus-vectored vaccines have made substantial progress in preclinical and clinical settings, resulting in SARS-CoV-2 intranasal vaccines based on the previously successfully used nasal vaccines. Additional to their ability to trigger stable, protective immune responses at the sites of pathogenic infection, the development of 'specific' mucosal vaccines targeting coronavirus antigens could be an excellent option for preventing future pandemics. However, their efficacy and safety should be confirmed.

Gastrointestinal mucosal immunity and COVID-19.

As the gastrointestinal tract may also be a crucial entry or interaction site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the role of the gut mucosal immune system as a first-line physical and immunological defense is critical. Furthermore, gastrointestinal involvement and symptoms in coronavirus disease 2019 (COVID-19) patients have been linked to worse clinical outcomes. This review discusses recent data on the interactions between the virus and the immune cells and molecules in the mucosa during the infection. By carrying out appropriate investigations, the mucosal immune system role in SARS-CoV-2 infection in therapy and prevention can be established. In line with this, COVID-19 vaccines that stimulate mucosal immunity against the virus may have more advantages than the others.

Immunological aspects of COVID-19: What do we know?

The newly emerged coronavirus (severe acute respiratory syndrome coronavirus 2 SARS-CoV-2) and the disease that it causes coronavirus disease 2019 (COVID-19) have changed the world we know. Yet, the origin and evolution of SARS-CoV-2 remain mostly vague. Many virulence factors and immune mechanisms contribute to the deteriorating effects on the organism during SARS-CoV-2 infection. Both humoral and cellular immune responses are involved in the pathophysiology of the disease, where the principal and effective immune response towards viral infection is the cell-mediated immunity. The clinical picture of COVID-19, which includes immune memory and reinfection, remains unclear and unpredictable. However, many hopes are put in developing an effective vaccine against the virus, and different therapeutic options have been implemented to find effective, even though not specific, treatment to the disease. We can assume that the interaction between the SARS-CoV-2 virus and the individual's immune system determines the onset and development of the disease significantly.