COVID-19 Heart Lesions in Children: Clinical, Diagnostic and Immunological Changes.

In the beginning of COVID-19, the proportion of confirmed cases in the pediatric population was relatively small and there was an opinion that children often had a mild or asymptomatic course of infection. Our understanding of the immune response, diagnosis and treatment of COVID-19 is highly oriented towards the adult population. At the same time, despite the fact that COVID-19 in children usually occurs in a mild form, there is an incomplete understanding of the course as an acute infection and its subsequent manifestations such as Long-COVID-19 or Post-COVID-19, PASC in the pediatric population, correlations with comorbidities and immunological changes. In mild COVID-19 in childhood, some authors explain the absence of population decreasing T and B lymphocytes. Regardless of the patient's condition, they can have the second phase, related to the exacerbation of inflammation in the heart tissue even if the viral infection was completely eliminated-post infectious myocarditis. Mechanism of myocardial dysfunction development in MIS-C are not fully understood. It is known that various immunocompetent cells, including both resident inflammatory cells of peripheral tissues (for example macrophages, dendritic cells, resident memory T-lymphocytes and so on) and also circulating in the peripheral blood immune cells play an important role in the immunopathogenesis of myocarditis. It is expected that hyperproduction of interferons and the enhanced cytokine response of T cells 1 and 2 types contribute to dysfunction of the myocardium. However, the role of Th1 in the pathogenesis of myocarditis remains highly controversial. At the same time, the clinical manifestations and mechanisms of damage, including the heart, both against the background and after COVID-19, in children differ from adults. Further studies are needed to evaluate whether transient or persistent cardiac complications are associated with long-term adverse cardiac events.

Features of Myocarditis: Morphological Differential Diagnosis in Post-COVID-19 Children.

Myocarditis is characterized by dysfunction and destruction of cardiomyocytes, infiltrative inflammation, and development of fibrosis. Late diagnosis of myocarditis has been a serious global health problem, especially due to the spread of a new coronavirus infection. The aim of this review is to identify differences between myocarditis of viral etiology, including SARS-CoV-2 lesions, based on instrumental and pathomorphological findings. MATERIAL AND METHODS: We analyzed publications covering the period from December 2019 to May 2023, published in publicly accessible international databases ("Medline", "PubMed", "Scopus"), with queries for the keywords "myocarditis", "children", "cardiovascular inflammation", "COVID-19", "SARS-CoV-2", "severe acute respiratory syndrome coronavirus 2", "differential diagnosis". RESULTS: It was found that no unambiguous morphological criteria for the diagnosis of myocarditis coupled to SARS-CoV-2 lesions were identified. However, the detected histopathological changes such as virus-associated degeneration, apoptosis, cardiomyocyte necrosis, moderate interstitial hyperemia, myocardial tissue oedema, and capillary endothelial cell dysfunction were the major markers of SARS-CoV-2 infection. CONCLUSION: It is necessary further reconsider morphological criteria to diagnose SARS-CoV-2-caused myocarditis, rather than solely relying on detecting viral RNA by PCR as the sole evidence-based criterion. Similar issues accompany diagnostics of myocardial lesions associated with other viral infections. Evidence for an etiological diagnosis of myocarditis can be provided by a comprehensive analysis of the diagnostic criteria obtained, confirming virus exposure, followed by development of distinct clinical symptoms, MRI and CT changes, and morphological criteria.

Circulating Regulatory T Cell Subsets in Patients with Sarcoidosis.

Over recent years, many researchers have supported the autoimmune theory of sarcoidosis. The presence of uncontrolled inflammatory response on local and system levels in patients with sarcoidosis did not define that the immunoregulatory mechanisms could be affected. The aim of this study was to evaluate the distribution and the disturbance circulating Treg cell subsets in the peripheral blood in patients with sarcoidosis. MATERIALS AND METHODS: A prospective comparative study was performed in 2016-2018 (34 patients with sarcoidosis (men (67.6%), women (32.3%)) were examined). Healthy subjects-the control group (n = 40). The diagnosis of pulmonary sarcoidosis was performed according to the standard criteria. We used two ten-color combinations of antibodies for Treg immunophenotyping. The first one contained CD39-FITC, CD127-PE, CCR4-PE/Dazzle™ 594, CD25-PC5.5, CD161-PC7, CD4-APC, CD8-APC-AF700, CD3-APC/Cy7, HLA-DR-PacBlue, and CD45 RA-BV 510™, while the second consisted of CXCR3-Alexa Fluor 488, CD25-РЕ, CXCR5-РЕ/Dazzle™ 594, CCR4-PerСP/Сy5.5, CCR6-РЕ/Cy7, CD4-АPC, CD8 АPC-AF700, CD3-АPC/Cy7, CCR7-BV 421, and CD45 RA-BV 510. The flow cytometry data were analyzed by using Kaluza software v2.3. A statistical analysis was performed with Statistica 7.0 and GraphPad Prism 8 software packages. RESULTS OF THE STUDY: Primarily, we found that patients with sarcoidosis had decreased absolute numbers of Treg cells in circulation. We noted that the level of CCR7-expressing Tregs decreased in patients with sarcoidosis vs. the control group (65.55% (60.08; 70.60) vs. 76.93% (69.59; 79.86) with p < 0.001). We noticed that the relative numbers of CD45RA-CCR7+ Tregs decreased in patients with sarcoidosis (27.11% vs. 35.43%, p < 0.001), while the frequency of CD45 RA-CCR7- and CD45RA+ CCR7- Tregs increased compared to the control group (33.3% vs. 22.73% and 0.76% vs. 0.51% with p < 0.001 and p = 0.028, respectively). CXCR3-expressing Treg cell subsets-Th1-like CCR60078CXCR3+ Tregs and Th17.1-like CCR6+ CXCR3+ Tregs-significantly increased in patients with sarcoidosis vs. the control group (14.4% vs. 10.5% with p < 0.01 and 27.9% vs. 22.8% with p < 0.01, respectively). Furthermore, the levels of peripheral blood EM Th17-like Tregs significantly decreased in the sarcoidosis group vs. the control group (36.38% vs. 46.70% with p < 0.001). Finally, we found that CXCR5 expression was increased in CM Tregs cell subsets in patients with sarcoidosis. CONCLUSIONS: Our data indicated a decrease in circulating Tregs absolute numbers and several alterations in Treg cell subsets. Moreover, our results highlight the presence of increased levels of CM CXCR5+ follicular Tregs in the periphery that could be linked with the imbalance of follicular Th cell subsets and alterations in B cell, based on the immune response. The balance between the two functionally distinct Treg cell populations-Th1-like and Th17-like Tregs-could be used in sarcoidosis diagnosis and the determination of prognosis and disease outcomes. Furthermore, we want to declare that analysis of Treg numbers of phenotypes could fully characterize their functional activity in peripherally inflamed tissues.

Severe Course of COVID-19 and Long-COVID-19 in Children: Difficulties in Diagnosis.

The question of COVID-19 and long-COVID-19 course in children remains unsolved. This infection in children, which is associated with COVID-19, can vary from asymptomatic to systemic damage of various systems. Multisystem inflammatory syndrome in children, associated with SARS-CoV-2 (MIS-C), is a serious condition in children and adolescents after experiencing COVID-19. Published data on MIS-C have indicated that the inflammation can be registered in the gastrointestinal tract (60-100%), as well as in cardiovascular (80%), nervous (29-58%), and respiratory (21-65%) systems. However, with the changing characteristics of SARS-CoV-2, the manifestations of COVID-19 and long-COVID-19 in children have also been changing. Currently, there is no clear understanding of the development of severe COVID-19 and MIS-C in children, especially after being exposed to patients with COVID-19. We presented two new clinical courses of multisystem inflammatory syndrome in children with severe multisystem damage after close contact to relatives with COVID-19 or long-COVID-19. Thus, high-risk children, who are positive for SARS-CoV-2 infection after contact with COVID-19 patients, should be clinically managed during the first few months. The identification of the disease complexity requires the involvement of neurologists, cardiologists, and other specialists.

Sarcoidosis: Progression to the chronic stage and pathogenic based treatment (narrative review).

Many factors confirm the autoimmune nature of sarcoidosis and help in determining the strategy of patient management and treatment initiation. However, the causes and the mechanisms of disease progression that result in fibrosis and insufficiency of the affected organ remain unclear. This narrative review aims to analyse the mechanisms and biomarkers of sarcoidosis progression, as well as the pathogenetic basis of sarcoidosis therapy. The following characteristics of progressive chronic sarcoidosis were revealed: the disease develops in patients with a genetic predisposition (SNP in genes GREM1, CARD15, TGF-ß3, HLA-DQB1*06:02, HLA-DRB1*07/14/15), which contributes either the decreased ability of antigen elimination or autoimmune inflammation. Various prognostic biomarkers of disease progression (decreased levels of neopterin, elastase, sIL-2R, chitotriosidase, glycoprotein Krebs von den Lungen, Th17 cell count, reduced quantity of TNF-α in peripheral blood or bronchoalveolar lavage fluid) have been described and can potentially be used to determine the group of patients who will benefit from the use of corticosteroids/cytostatic drugs/biologics.

Efficacy of Tuberculosis Treatment in Patients with Drug-Resistant Tuberculosis with the Use of Bedaquiline: The Experience of the Russian Federation.

In the conditions of the continued growth of multiple- and extensive drug-resistant tuberculosis, use of the new highly effective anti-tuberculosis drugs in this patient category is of great relevance. The aim of the study was determination the efficacy of treatment in patients with multidrug- and extensive drug-resistant tuberculosis using bedaquiline based on studies published in the Russian Federation. MATERIALS AND METHODS: The authors analyzed data published in studies from 2014 to 2022; 41 publications were included in total and 17 articles corresponded to the study design. The results of treatment of 1404 tuberculosis patients with MDR/XDR TB were described. Bedaquiline was used according to the standard scheme with a description of the treatment results after 24-26 weeks. Treatment efficacy was estimated according to accepted criteria. RESULTS OF THE STUDY: The analysis showed that the treatment efficacy on conversion was achieved in 79.5% of cases (95% Cl 76.5-82.3), and recovery was observed in 82.0% of cases (95% Cl 78.6-85.1). Departure from the therapy was observed in rare cases (9.8%; 95% Cl 7.9-12.2). Deaths were recorded in 6.5% of cases (95% Cl 4.9-8.3), which were associated with the severe disease and concomitant pathology in 74.3%. The development of adverse events was noted in half of the patients (55.7%); however, bedaquiline cancellation occurred in a few cases (7.0%; 95% Cl 3.0-13.0). From analyzing data in patients with MDR and XDR TB, the efficacy of treatment was 89.9% (95% Cl 85.9-93.2) and 71.9% (95% Cl 66.2-77.1), respectively. CONCLUSION: Use of bedaquiline in treatment makes it possible to achieve recovery of patients with MDR/XDR TB in 82.0% of cases with patients dropping out of treatment in 9.8%. At the same time, in patients with MDR TB, recovery was achieved in 89.9% of cases, while in patients with XDR TB, 71.9% of cases recovered.

Cardiac Involvement in Children Affected by COVID-19: Clinical Features and Diagnosis.

COVID-19 (Coronavirus disease 2019) in children is usually mild. However, multiple organ disorders associated with SARS-CoV-2 (severe acute respiratory syndrome-related coronavirus 2) have been detected with poor respiratory symptoms. Cardiac changes are noted in 17% to 75% of cases, which are associated with diagnostic difficulties in high-risk groups for the development of complications that are associated with myocardial damage by the SARS-CoV-2 virus. The objective of this review is to identify the most significant symptoms of cardiac involvement affected by COVID-19, which require in-depth examination. The authors analyzed publications from December 2019 to the October 2022, which were published in accessible local and international databases. According to the analysis data, the main sign of myocardial involvement was increasing as cardiomarkers in the patient's blood, in particular troponin I or troponin T. Many authors noted that the increased level of CRP (C-reactive protein) and NT-proBNP, which are accompanied by changes in the ECG (electrocardiogram) and EchoCG (echocardiography), as a rule, were nonspecific. However, the identified cardiac functional dysfunctions affected by SARS-CoV-2, required an cardiac MRI. The lack of timely diagnosis of myocardial involvements, especially in children at high risk for the development of complications associated with SARS-CoV-2 myocardial injury, can lead to death. The direct damage of the structural elements of myocardial blood vessels in patients with severe hypoxic changes resulted from respiratory failure caused by SARS-CoV-2 lung damage, with the development of severe acute diffuse alveolar damage and cell-mediated immune response and myocardial involvement affected by SARS-CoV-2 damage. In this article, the authors introduce a clinical case of a child who dead from inflammatory myocardities with COVID-19 in a background of congenital heart disease and T-cell immunodeficiency.

Tuberculosis in the Russian Federation: Dynamics of the Epidemic Indicators before and after COVID-19 Pandemic.

The measures taken against tuberculosis (TB) in recent years in the Russian Federation have been highly effective. Unfortunately, the COVID-19 pandemic may seriously undermine the progress that has been made in the fight against TB. The aim of this study was to assess changes in the epidemiological rates of tuberculosis in the Russian Federation before and after the COVID-19 pandemic. Materials and methods. The analysis was conducted by considering the main epidemiological indicators of tuberculosis, according to the federal statistics for the period from 2017 to 2021. The parameters were estimated according to the data received from 11 areas in the North-Western region. Statistical analysis was carried out using the free software computing environment R (v.3.5.1) and the commercial software package Statistical Package for the Social Sciences (SPSS Statistics for Windows, version 24.0, IBM Corp., 2016). Research results. We found a positive correlation between the incidence among the overall population and the incidence among children aged 0-17, inclusively (r = 0.55 in 2017, r = 0.60 in 2020, and r = 0.53 in 2021). Along with the received regularities, a different trend is shown in the data analysis of general incidence and health X-ray examination for tuberculosis among the general population. The correlation has decreased threefold from 2017 (r = 0.72) to 2020 (r = 0.32); this negative trend might be the result of factors such as the quality of X-ray screening examinations among the general population, and the reduced assessment objectivity of the tuberculosis incidence rate. Conclusions. In assessing the correlation between general incidence and incidence in children under 17 years of age, as well as between incidence and mortality in the Russian Federation, a positive correlation was found with an increasing trend. Such a discrepancy might be due to decreases in the occupational health examination coverage among the general population. Therefore, in the years ahead, we can expect epidemiological indicators to increase incidence and mortality, including child mortality, associated with the insufficient detection of tuberculosis among the population during the COVID-19 pandemic.

Identification of autoimmune markers in pulmonary tuberculosis.

Introduction: Pathogenesis of many autoimmune diseases is mainly promoted by poorly regulated and/or wrong targeted immune response to pathogens including M. tuberculosis. Autoimmunity is one of the processes with are characteristics of tuberculosis (Tbc). The aim was to determine the autoimmune clinical and immunological features in patients with pulmonary Tbc. Materials and methods: A prospective comparative study was performed in 2017 - 2019 with the inclusion of 46 patients with Tbc. The trigger factors and clinical manifestations, autoantibodies, peripheral blood B cell subsets were stained with fluorochrome-conjugated monoclonal antibodies. 40 healthy volunteers in the control group, were matched for age with no chronic diseases, contacts with TB patients and changes in their laboratory parameters. A statistical analysis was done with GraphPad Prism 6, Statistica 10 (Statsoft) and MedCalc - version 18.2.1 values. Results: There were no significant ASIA triggers in Tbc patients and control group. 21.1% of Tbc patients had a high level of a rheumatoid factor and in 47.4% complement system factor C3 was high; anti-MCV was detected in 60.7% of Tbc patients. Relative and absolute frequencies of "naïve" Bm1 cells and eBm5 were significantly decreased and activated pre-germinal-center Bm2' cells were significantly increased in Tbc patients. The CD24++CD38++ B cells were increased in Tbc vs control group (10.25% vs 5.42%), p < 0.001, and 19 cell/1µL (10; 290 vs 11 cell/1µL (6; 20), p = 0.029, respectively). The frequency of CXCR3+CCR4- Tfh1 cells was significantly lower in Tbc vs control one (26.52% vs. 31.00%, p = 0.004), while CXCR3-CCR4+ Tfh2 cells were increased in Tbc (20.31% vs. controls (16.56%, p = 0.030). The absolute numbers of Tfh1 cells were decreased in the Tbc vs. control (24 cell/1µL vs. 37 cell/1µL p = 0.005). Conclusion: The results of our study showed that the detection of a rheumatoid factor, the components of complement system and anti-MCV in complex with alterations in B cells and follicular Th cell subsets may indicate a presence of autoimmunity in the pathogenesis of tuberculosis, but they are not specific. The indicators of autoimmune-related provide new opportunities in the Tbc treatment.

Efficacy of Different Types of Therapy for COVID-19: A Comprehensive Review.

A new coronavirus disease (COVID-19) has already affected millions of people in 213 countries. The possibilities of treatment have been reviewed in recent publications but there are many controversial results and conclusions. An analysis of the studies did not reveal a difference in mortality level between people treated with standard therapy, such as antiviral drugs and dexamethasone, and new antiviral drugs/additional immune therapy. However, most studies describe clinical improvement and a decrease in mortality among patients with severe and critical conditions, with the early initiation of additional immune therapy. Possible new targets based on viral life cycles were considered. Unfortunately, the data analysis on the efficacy of different medicine and therapy regimens among patients with COVID-19, showed little success in decreasing the mortality rate in all treatment methods. Some efficacy has been shown with an immunosuppressive therapy in small patient samples, but when a larger number of patients were analyzed the data did not differ significantly from the control groups.

Post COVID-19 Syndrome in Patients with Asymptomatic/Mild Form.

Post COVID-19 Syndrome (PCS) is a complex of various symptoms developing a month or more after the acute phase of the disease. The cases of PCS development among patients with asymptomatic/mild forms are frequently reported; however, the pathogenesis of PCS in this group of patients is still not completely clear. The publications about COVID-19 which were published in online databases from December 2019 to September 2021 are analyzed in this review. According to the analysis, PCS develops on average in 30-60% of patients, mainly among women. Fatigue, shortness of breath, cough, and anosmia were reported as the most common symptoms. The possible association between the described PCS symptoms and brain damage was revealed. We assume the possibility of an alternative course of COVID-19, which develops in genetically predisposed individuals with a stronger immune response, in which it predominantly affects the cells of the nervous system, possibly with the presence of an autoimmune component, which might have similarity with chronic fatigue syndrome or autoimmune disautonomia. Thus, the gender (female) and the presence of anosmia during an asymptomatic or mild course of the disease can be predictive factors for the development of PCS, which can be caused by autoimmune damage to neurons, glia, and cerebral vessels.

Prevalence and correlates of asthma among children in central St. Petersburg, Russia: cross-sectional study.

AIM: To estimate the prevalence of asthma among children in central St. Petersburg and to evaluate associations between asthma and socio-demographic, biological, and environmental factors. METHODS: A cross-sectional study included 1464 children aged 0-18 years from two central districts of St. Petersburg. Parents filled out a questionnaire on children's respiratory health, characteristics at birth, socio-demographic data, housing situation, and their own history of asthma and allergies. The diagnosis of asthma was based on the results of spirometry in children aged > or =5 years and on questionnaire data as reported by parents of younger children. Independent effects of the investigated factors on asthma were assessed by multiple logistic regression analysis. Crude and adjusted odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS: The estimated prevalence of asthma was 7.4% (95% CI, 6.2-8.8). A history of allergies (OR, 1.6; 95% CI, 1.0-2.6), bronchitis, bronchiolitis, or pneumonia in infancy (OR, 12.2; 95% CI, 7.3-20.5), and self-reported parental allergies (OR, 3.6; 95% CI, 2.2-5.8 for one parent and OR, 7.1; 95% CI, 3.0-17.0 for both parents) were associated with childhood asthma. Children whose mothers were out of work also had higher prevalence of asthma than the reference group (OR, 3.4; 95% CI, 1.1-10.4). CONCLUSION: The prevalence of asthma is several times higher than what is officially reported for St. Petersburg's inner city children population. Early life events and socio-demographic and biologic factors were associated with asthma in children.