Infective and nonbacterial thrombotic endocarditis in patients with post-COVID-19 viral-immune myocarditis

The possibility of heart inflammation (both myocardial and endocardial) months after a coronavirus disease 2019 (COVID-19) has not been practically studied, especially since approaches to the treatment of myocarditis in combination with various endocarditis forms have not been developed. Aim. To study the prevalence and mechanisms of SARS-CoV-2-associated endocardial injury in patients with morphologically verified post-COVID-19 myocarditis, as well as to develop approaches to comprehensive therapy. Material and methods. The study included 18 patients with severe morphologically verified post-COVID-19 myocarditis (men, 9;51,1+/-9,4 years;35 to 66 years). Patients with prior verified myocarditis/myocardial infarction, rheumatic heart disease, and systemic immune diseases were excluded. The average time after COVID-19 was 6,5 [3.5;10] months The diagnosis of myocarditis was confirmed by endomyocardial biopsy (including immunohistochemical examination with antibodies to CD3, CD20, CD45, CD68, and to SARS-CoV-2 antigens;polymerase chain reaction for SARS-CoV-2 RNA, DNA of cardiotropic viruses). The blood level of anticardiac antibodies was determined by indirect immunofluorescence. In addition, echocardiography, magnetic resonance imaging (n=8), cardiac multislice tomography (n=1), and coronary angiography (n=14) were performed. Results. Biopsy revealed active (n=12) and borderline (n=3) lymphocytic myocarditis, eosinophilic (n=2) and giant cell (n=1) myocarditis. In 4 patients, nonbacterial thrombotic endocarditis (NBTE) with parietal and intravascular thrombosis was diagnosed, and in one patient - infective endocarditis (IE) of the bicuspid aortic valve. Myocardial persistence of SARS-CoV-2 was detected in 72% of cases (in 3 patients - with NBTE;in 1 - with IE;in 9 - without endocarditis). Titers of anticardiac antibodies increased by 3-4 times in 94% of patients. Patients with endocarditis were characterized by larger heart chambers, lower ejection fraction (27,5+/-6,6 vs 36,0+/-13,4%), more severe pulmonary hypertension, and valvular regurgitation. Intraventricular thrombosis according to echocardiography/magnetic resonance imaging and cardiac embolism was not observed. Treatment in all patients included methylprednisolone at an average dose of 24 mg a day. In 10 patients, the result was monitored for at least 3 months as follows: the ejection fraction was 46,0+/-12,7% and 44,3+/-7,3% in patients with and without endocarditis, respectively. Conclusion. Endocarditis in patients with post-COVID-19 myocarditis was detected in 28% (1 patient - IE;4 - NBTE). The key mechanisms of post-COVID-19 myocarditis and NBTE are long-term (up to 18 months) myocardial persistence of SARS-Cov-2 and the development of an autoimmune reaction. Endocarditis was diagnosed in more severe patients, including those with giant cell and eosinophilic myocarditis. The effectiveness of steroid therapy in combination with anticoagu-lants in patients with NBTE requires further study. In case of IE, steroids can also be used in the treatment of myocarditis (in combination with antibiotics and im-munoglobulin). Copyright © 2022, Silicea-Poligraf. All rights reserved.

Clinical and morphological characteristics of COVID-19-associated myocarditis

Background: COVID-19 is accompanied by the development of a wide range of cardiovascular lesions. The goal: to study the clinical and morphological features of SARS-CoV-2-associated myocarditis (SCM), determining the presence of viral RNA and proteins in myocardial tissue. Methods: The study was based on 32 autopsies with a confirmed diagnosis of myocarditis. The average age of the patients was 72.7±15.5 years. Men predominated in the group (53%). The immunohistochemical determination of the surface markers of CD45, CD3, CD20, CD 68 inflammatory infiltrates and SARS-CoV-2 nucleocapsid and spike protein has been done. Detection of coronavirus RNA was performed. Results: The clinical manifestations SCM included heart failure and variety of rhythm disturbances. Increased level of anticardiac antibodies was detected. Lymphomacrophage infiltrates (more than 7 CD3+ T-lymphocytes, more than 14 CD45+ lymphocytes and more than 7 CD68+ macrophages per 1 mm2) were found in 100% of cases. RNA of the virus was detected in myocardial tissue. Virus proteins were identified in macrophages of the inflammatory infiltrate and cardiomyocytes. Conclusion: The results suggest persistence of the virus.

Post-COVID myocarditis diagnosed by endomyocardial biopsy and/or magnetic resonance imaging 2-9 months after acute COVID-19

Purpose: To study clinical features of myocarditis and its possible mechanisms (including persistence of SARS-Cov-2 in the myocardium) in the long-term period after acute COVID-19. Methods: Fifteen patients (8 male and 7 female, mean age 47.8±13.4, 24-65 years) diagnosed with postcovid myocarditis were included in the study. The diagnosis of COVID-19 was confirmed by positive PCR results in 40%, and seroconversion in all patients. The average time of admission after COVID-19 was 4 [3;7] months, from 2 to 9 months. The diagnosis of myocarditis was confirmed by cardiac MRI in 10 patients and by right ventricular endomyocardial biopsy (EMB) in 6 patients. The PCR for cardiotropic viruses and PCR with immunohistochemical study for SARSCov2 detection were used. All patients had study for anti-heart antibodies (AHA), EchoCG, and Holter ECG. Coronary atherosclerosis was excluded in all patients over 40 years (7 coronary angiography, 4 cardiac CT). Results: A clear association of the cardiac symptoms with a previous new coronavirus infection was noted in all patients. The symptoms started 1-5 months following COVID-19. MRI showed subepicardial and intramyocardial LGE, signs of hyperemia, increased T1 relaxation time, edema. AHA levels were increased 3-4-fold in 73%. Two variants of postcovid myocarditis were observed. 1. Arrhythmic variant (n=6) - newly developed frequent supraventricular or ventricular extrasystole, recurrent atrial fibrillation in the absence of systolic dysfunction. 2. Decompensated variant with biventricular heart failure (n=9): the mean LV EF was 34.1±7.8% (23 to 46%), LV EDD 5.8±0.7 cm, EDV 153.8±46.1 ml, pulmonary artery systolic pressure 40.7±11.2 mmHg. In one case, myocarditis was accompanied by IgG4- and ANCA-negative aortitis. SARS-Cov-2 RNA was detected in 4 of 5 myocardial biopsies (in one case the material in the study). The longest period of virus persistence after COVID-19 was 9 months. By using spike and nucleocapsid antibodies, coronavirus was detected in cardiomycytes and macrophages. Data of patients with morphologically proved myocarditis are presented in Table 1. Lymphocytic myocarditis was diagnosed and confirmed immunohistochemically (n=5);giant cell myocarditis with atrial standstill was detected in one more case (Fig. 1). Three patients had also signs of endocarditis, in two cases with parietal thrombosis. Conclusions: COVID-19 can lead to the subacute and chronic myocarditis of varying severity. Post-COVID myocarditis manifests itself in two main clinical forms - isolated arrhythmias and systolic dysfunction with heart failure. Post-COVID myocarditis is characterized by prolonged persistence of coronavirus (up to 9 months in this study, in most patients with decompensated variant) in combination with high immune activity (high titers of AHA), which should be considered as the main mechanisms of its longterm course. Treatment approaches for such myocarditis require investigation. (Figure Presented).

[Pathogenesis and morphological changes in the lung in COVID-19]. / Patogenez i morfologicheskie izmeneniya v legkikh pri COVID-19.

The novel coronavirus infection is a rapidly spreading infectious disease that primarily affects the respiratory system and vascular endothelium and has a serious negative impact on healthcare economy and system around the world. To effectively combat the virus, there is a need for a full understanding of the pathogenesis of this infectious disease, and every day there are more and more works that shed light on certain mechanisms of SARS-CoV-2 penetration, replication, and spread. One of these works is studies showing the role of extracellular vesicles (ECVs). The latter are the membrane-enclosed vesicles with a different composition, which are involved in many physiological processes and various diseases, including infectious ones. This review gives the available data on the pathomorphogenesis of COVID-19 and on the possible role of ECVs.

Subacute and chronic post-covid myoendocarditis: clinical presentation, role of coronavirus persistence and autoimmune mechanisms.

Aim    To study clinical features of myoendocarditis and its possible mechanisms, including persistence of SARS-Cov-2 in the myocardium, in the long-term period following COVID-19.Material and methods    This cohort, prospective study included 15 patients aged 47.8±13.4 years (8 men) with post-COVID myocarditis. The COVID-19 diagnosis was confirmed for all patients. Median time to seeking medical care after COVID-19 was 4 [3; 7] months. The diagnosis of myocarditis was confirmed by magnetic resonance imaging (MRI) of the heart (n=10) and by endomyocardial biopsy of the right ventricle (n=6). The virus was detected in the myocardium with PCR; immunohistochemical (IHC) study with antibody to SARS-Cov-2 was performed; anticardiac antibody level was measured; and echocardiography and Holter monitoring were performed. Hemodynamically significant coronary atherosclerosis was excluded for all patients older than 40 years.Results    All patients showed a clear connection between the emergence or exacerbation of cardiac symptoms and COVID-19. 11 patients did not have any signs of heart disease before COVID-19; 4 patients had previously had moderate arrhythmia or heart failure (HF) without myocarditis. Symptoms of myocarditis emerged at 1-5 months following COVID-19. MRI revealed typical late gadolinium accumulation, signs of hyperemia, and one case of edema. The level of anticardiac antibodies was increased 3-4 times in 73 % больных. Two major clinical variants of post-COVID myocarditis were observed. 1. Arrhythmic (n=6), with newly developed extrasystole or atrial fibrillation without systolic dysfunction. 2. Decompensated variant with systolic dysfunction and biventricular HF (n=9). Mean left ventricular ejection fraction was 34.1±7.8 %, and left ventricular end-diastolic dimension was 5.8±0.7 cm. In one case, myocarditis was associated with signs of IgG4­negative aortitis. SARS-Cov-2 RNA was found in 5 of 6 biopsy samples of the myocardium. The longest duration of SARS-Cov-2 persistence in the myocardium was 9 months following COVID-19. By using antibody to the Spike antigen and nucleocapsid, SARS-Cov-2 was detected in cardiomyocytes, endothelium, and macrophages. Five patients were diagnosed with lymphocytic myocarditis; one with giant-cell myocarditis; three patients had signs of endocarditis (infectious, lymphocytic with mural thrombosis).Conclusion    Subacute/chronic post-COVID myocarditis with isolated arrhythmias or systolic dysfunction is characterized by long-term (up to 9 months) persistence of SARS-Cov-2 in the myocardium in combination with a high immune activity. Endocarditis can manifest either as infectious or as nonbacterial thromboendocarditis. A possibility of using corticosteroids and anticoagulants in the treatment of post-COVID myoendocarditis should be studied.

[Clinical and morphological characteristics of SARS-CoV-2-related myocarditis proven by the presence of viral RNA and proteins in myocardial tissue]. / Kliniko-morfologicheskaya kharakteristika SARS-CoV-2-assotsiirovannogo miokardita, podtverzhdennogo nalichiem RNK i belkov virusa v tkani miokarda.

OBJECTIVE: To investigate the clinical and morphological features of SARS-CoV-2-related myocarditis, by determining the presence of viral RNA and proteins in myocardial tissue. MATERIAL AND METHODS: The study was conducted to examine the material of 32 autopsies with a confirmed diagnosis of myocarditis. There were data of a morphological study, including a standard histological study, as well as immunohistochemical determination of the surface markers CD45, CD3, CD20, and CD68 cells of an inflammatory infiltrate and virus proteins (SARS-CoV-2 nucleocapsid protein and spike protein). Positive and negative control tests were carried out. In addition, coronavirus RNA was detected in the myocardium using a polymerase chain reaction. RESULTS: Polymerase chain reaction (PCR) revealed viral RNA in myocardial tissue. Viral proteins were identified in the macrophages of an inflammatory infiltrate and cardiomyocytes. CONCLUSION: The findings may suggest that the virus persists in the myocardium and chronic myocarditis develops.

Effect of sars-cov-2 infections on the male and female reproductive system (meta-analysis)

In view of current pandemic situation with COVID-19, certain questions reasonably arise: what are the main ways of SARS-CoV-2 penetration into the organs of the male and female reproductive system;can this virus have a damaging effect on spermatogenesis;what are the possible complications? The identification of the mechanisms of COVID-19 pathogenesis will be helpful for further investigations and understanding of this disease. The results of the PCR to scRNA-seq revealed a high level of expression of TMPRSS-2 in spermatogonia and spermatids, and ACE-2 in spermatogonia, Sertoli and Leydig cells, seminiferous tubule epithelial cells, which was confirmed by Gene Ontology. ACE-2 receptors is detected at all stages of folliculogenesis, as confirmed by the results of the PCR, therefore, they are potential viral targets in the presence of viremia. In the endometrial epithelium, ACE-2 concentration varies depending on the phase of the menstrual cycle: high values are observed in the secretory phase, so can disrupt local angiotensin II homeostasis and endometrial regeneration. Thus, during the viremia period, the targets for SARS-CoV-2 can be Leydig cells, follicular and stromal cells of the ovary, since they are ACE-2 positive, although they do not have perfect co-expression of TMPRSS-2 or Furin protease.

[Miocarditis in Patients with COVID-19 Confirmed by Immunohistochemical].

Aim      Despite the regular heart damage in patients with coronavirus pneumonia caused by SARS-Cov-2, a possibility of developing lymphocytic myocarditis as a part of COVID-19 remains unsubstantiated. The aim of this study was to demonstrate a possibility of lymphocytic myocarditis and to study its morphological features in patients with the novel coronavirus infection (COVID-19) with a severe course.Material and methods   Postmortem data were studied for 5 elderly patients (74.8±4.4 years; 3 men and 2 women) with the novel coronavirus infection and bilateral, severe polysegmental pneumonia (stage 3-4 by computed tomography). COVID-19 was diagnosed based on the typical clinical presentation and positive polymerase chain reaction test in nasopharyngeal swabs. All patients were treated in different hospitals repurposed for the treatment of patients with COVID-19. A standard histological study was performed with hematoxylin and eosin, toluidine blue, and van Gieson staining. Serial paraffin slices were studied immunohistochemically with antibodies to CD3, СD68, CD20, perforin, and toll-like receptors (TLR) 4 and 9.Results In none of the cases, myocarditis was suspected clinically, added to the diagnosis or indicated as a possible cause of death. IHD and acute myocardial infarction were mentioned as error diagnoses not confirmed by the postmortem examination. The morphological examination of the heart identified signs of lymphocytic myocarditis consistent with Dallas criteria for this diagnosis. Myocardial infiltrate was characterized in detail, and a combined inflammatory damage of endocardium and pericardium was described. The immunohistochemical study with cell infiltrate typing confirmed the presence of CD3-positive Т lymphocytes and the increased expression of TLR-4. A picture of coronaritis, including that with microvascular thrombosis, was found in all cases.Conclusion      A possibility for development of lymphocytic viral myocarditis in COVID-19 was confirmed morphologically and immunohistochemically. Specific features of myocarditis in COVID-19 include the presence of coronaritis and a possible combination of myocarditis with lymphocytic endo- and pericarditis.

[Lymphocytic myocarditis in patients with COVID-19 (4 autopsy cases)]. / Limfotsitarnyi miokardit u patsientov s COVID-19 (4 autopsiinykh nablyudeniya).

The paper describes 4 autopsy cases of myocarditis in elderly patients with confirmed coronavirus infection. It gives the data of a morphological study of heart specimens and a detailed characterization of a myocardial infiltrate. An immunohistochemical study with cellular infiltrate typing was performed. The fact that lymphocytic viral myocarditis can develop in COVID-19 was morphologically and immunohistochemically confirmed. The features of myocarditis in COVID-19 are the development of the former in the presence of coronaritis and the possibility of its concurrence with lymphocytic endo- and pericarditis.

COVID-19 Pneumonia in Patients with Chronic Myocarditis (HBV-Associated with Infarct-Like Debute): Specifics of the Diseases Course, the Role of the Basic Therapy (Part II)

Chronic infectious-immune myocarditis of severe course can potentially be considered as a factor that aggravates the course of new coronavirus disease (COVID-19) and increases the risk of adverse outcomes. The interaction of chronic myocarditis and COVID-19 during long-term immunosuppressive therapy has not been studied. We present a description of a 35-year-old female patient with chronic infectious-immune myocarditis (morphologically confirmed, with a history of infarction-like onset and thromboembolic complications), who had continuous immunosuppressive therapy with methylprednisolone and mycophenolate mofetil. The patient also received new oral anticoagulants and tenofovir (for chronic HBV infection). COVID-19 (SARS-Cov-2 RNA+) was diagnosed in May 2020. Risk factors for the adverse course of coronavirus infection included severe obesity, heart failure, and life-threatening ventricular arrhythmias. Correction of immunosuppressive therapy (withdrawal of the cytostatic agent, administration of hydroxychloroquine) and therapy with levofloxacin, an interleukin-17 inhibitor (netakimab) were performed. The severity of pneumonia and respiratory failure was moderate despite high fever and high levels of inflammatory markers in the blood (including interleukin-6). Signs of exacerbation of myocarditis, increased levels of troponin T and anticardial antibodies (compared with the initial ones) were not found. It can be assumed that supportive immunosuppressive therapy for myocarditis has a positive effect on the course of coronavirus pneumonia and avoids exacerbation of myocarditis. Careful continuation of immunosuppressive therapy with temporary withdrawal of aggressive cytostatics can be recommended in chronic myocarditis. Further study of the features of the course of previous myocarditis and COVID-19 pneumonia is necessary. Хронический инфекционно-иммунный миокардит тяжелого течения потенциально может рассматриваться как фактор, утяжеляющий течение новой коронавирусной болезни (COVID-19) и повышающий риск неблагоприятных исходов. Вместе с тем, особенности взаимодействия хронического миокардита и COVID-19 на фоне длительной иммуносупрессивной терапии (ИСТ) не изучены. Приводим описание больной 35 лет с хроническим инфекционно-иммунным миокардитом (морфологически подтвержденным, с инфарктоподобным дебютом и тромбоэмболическими осложнениями в анамнезе), находившейся на постоянной ИСТ метилпреднизолоном и микофенолата мофетилом). Кроме того, пациентка получала также новые пероральные антикоагулянты и тенофовир (по поводу хронической HBV-инфекции). В мае 2020 г. был поставлен диагноз COVID-19, подтвержденный серологически. Из факторов риска неблагоприятного течения коронавирусной инфекции имелись выраженное ожирение, сердечная недостаточность, угрожающие жизни желудочковые аритмии. Проведены коррекция ИСТ (отмена цитостатика, назначение гидроксихлорохина), терапия левофлоксацином, ингибитором интерлейкина-17 нетакимабом. Несмотря на высокую лихорадку, резкое увеличение уровня воспалительных маркеров в крови (включая интерлейкин-6), тяжесть пневмонии и дыхательной недостаточности была умеренной. Каких-либо признаков обострения миокардита, повышения уровня тропонина Т и антикардиальных антител (по сравнению с исходным) не отмечено. Можно предположить, что поддерживающая ИСТ миокардита положительно влияет на течение коронавирусной пневмонии и позволяет избежать обострения миокардита. При хроническом миокардите можно рекомендовать осторожное продолжение ИСТ с временной отменой агрессивных цитостатиков. Необходимо дальнейшее изучение особенностей течения предшествующего миокардита и пневмонии при COVID-19.