Spectrum of Viral Pathogens Identified in Children with Clinical Myocarditis (Pre-Coronavirus Disease-2019, 2000-2018): Etiologic Agent Versus Innocent Bystander.

OBJECTIVE: To identify the etiologies of viral myocarditis in children in the pre-coronavirus disease 2019 era. STUDY DESIGN: This was a retrospective review of all patients (age <18 years) diagnosed with myocarditis and hospitalized at Rady Children's Hospital San Diego between 2000 and 2018. RESULTS: Twenty-nine patients met inclusion criteria. Of 28 (97%) patients who underwent testing for viruses, polymerase chain reaction was used in 24 of 28 (86% of cases), and 16 of 24 (67%) detected a virus. Pathogens were rhinovirus (6), influenza A/B (4), respiratory syncytial virus (RSV) (3), coronavirus (3), parvovirus B19 (2), adenovirus (2), and coxsackie B5 virus, enterovirus, and parainfluenza virus type 2 in one case each. Six (21%) patients had no pathogen detected but imaging and other laboratory test results were compatible with myocarditis. Age 0-2 years was associated with RSV, influenza A/B, coronavirus, and enteroviruses (P < .001). Twenty-one patients (72%) experienced full clinical recovery. Three patients (10%) required venoarterial extracorporeal membrane oxygenation (VA-ECMO), and all 3 recovered. Three others (10%) required and underwent successful cardiac transplantation without complications. Two patients (7%) died 9-10 days after hospitalization (1 had RSV and 1 had influenza A/B). Two other patients presented with complete atrioventricular block; 1 case (rhinovirus) resolved spontaneously, and 1 (coronavirus) resolved after support with VA-ECMO. Age <2 years, female sex, lower ejection fraction at admission, and greater initial and peak levels of brain natriuretic peptide were significant predictors of critical outcomes (use of VA-ECMO, listing for cardiac transplantation, and death). CONCLUSIONS: Viral nucleic acid-based testing revealed a wider spectrum of viruses that could be associated with myocarditis in children than previously reported and traditionally anticipated. A predilection of certain pathogens in the very young patients was observed. Whether the observed range of viral agents reflects an undercurrent of change in viral etiology or viral detection methods is unclear, but the wider spectrum of viral pathogens found underscores the usefulness of polymerase chain reaction testing to explore possible viral etiologies of myocarditis in children.

Th17 Cells in Viral Infections-Friend or Foe?

Th17 cells are recognized as indispensable in inducing protective immunity against bacteria and fungi, as they promote the integrity of mucosal epithelial barriers. It is believed that Th17 cells also play a central role in the induction of autoimmune diseases. Recent advances have evaluated Th17 effector functions during viral infections, including their critical role in the production and induction of pro-inflammatory cytokines and in the recruitment and activation of other immune cells. Thus, Th17 is involved in the induction both of pathogenicity and immunoprotective mechanisms seen in the host's immune response against viruses. However, certain Th17 cells can also modulate immune responses, since they can secrete immunosuppressive factors, such as IL-10; these cells are called non-pathogenic Th17 cells. Here, we present a brief review of Th17 cells and highlight their involvement in some virus infections. We cover these notions by highlighting the role of Th17 cells in regulating the protective and pathogenic immune response in the context of viral infections. In addition, we will be describing myocarditis and multiple sclerosis as examples of immune diseases triggered by viral infections, in which we will discuss further the roles of Th17 cells in the induction of tissue damage.

Adverse effects, pharmacological interactions, and cardiovascular drugs in COVID-19 treatment.

In severe coronavirus disease (COVID)-19 patients, an extraordinary systemic inflammatory response is seen. It could impact in multiple organ disorders, specially a severe myocardial injury, an acute myocarditis results in focal or global myocardial inflammation and necrosis. Those events can be present in healthy subjects or cardiovascular (CV) patients. It is clinically associated with ventricular dysfunction exacerbation or worsening and tachyarrhythmias. It is also related to a poor outcome for CV patients with ischemic heart disease, hypertensión, and heart failure. COVID-19 patients require multiple and complex treatment that alleviates symptoms, the vast variety of agents interacts with diseases and CV drugs. Our purpose is to correlate in guidance synopsis: Adverse effects, pharmacological interactions, and CV drugs in COVID-19 treatment.

En pacientes con COVID-19 grave se ha observado una extraordinaria respuesta inflamatoria sistémica. Este impacto se traduce en múltiples trastornos de órganos, especialmente cardíacos, por lesión miocárdica grave, miocarditis aguda que resulta en inflamación focal o miocárdica global, necrosis cardiaca. Estos tremendos eventos son observados en sujetos sanos como pacientes cardiovasculares. Clínicamente asociados con nueva presentación o empeoramiento de la disfunción ventricular y taquiarritmias. Relacionado a un predictor principal de malos resultado en pacientes cardiovasculares (CV), especialmente en aquellos con cardiopatía isquémica, hipertensión e insuficiencia cardíaca. Los enfermos con COVID-19 requieren múltiples y complejos tratamientos que alivien los síntomas, esta gran variedad de agentes interactúa con enfermedades y medicamentos CV. Nuestro propósito es correlacionar, en una guía sinóptica: efectos adversos, interacciones farmacológicas y fármacos cardiovasculares en el tratamiento del COVID-19.

COVID-19 myocarditis: a case report.

A male patient with flu-like symptoms and tomography and laboratory diagnosis of severe acute respiratory syndrome. He developed acute cardiac dysfunction during admission and was submitted to a cardiac magnetic resonance imaging examination, which confirmed acute myocarditis, indicating cardiac involvement by coronavirus disease 2019. A review and discussion about coronavirus disease 2019-related cardiac manifestations are reported, focusing on the imaging findings to make diagnosis.

Acute myocarditis following varicella zoster infection in an immunocompetent adolescent: An uncommon complication. / Miocarditis aguda tras una infección por el virus de la varicela-zóster en un adolescente inmunocompetente: una complicación poco frecuente.

Myocarditis is a serious complication of varicella zoster virus infection. A 15 year-old boy was admitted to the Emergency Department for chest pain, tachycardia and hypotension. An electrocardiogram showed sinus tachyicardia. Cardiac biomarkers were elevated and echocardiography revealed left ventricular apical, inferolateral, septal hypokinesis, and mitral regurgitation. Varicella zoster virus serum immunoglobulin M antibody was positive. The patient was discharged without any sequelae.

La miocarditis es una complicación grave de la infección por el virus de la varicela-zóster. Un varón de 15 años ingresó a la sala de emergencias debido a dolor torácico, taquicardia e hipotensión. En el electrocardiograma se observó taquicardia sinusal. Los biomarcadores cardíacos estaban elevados. En el ecocardiograma se notó hipocinesia apical, septal, e inferolateral del ventrículo izquierdo e insuficiencia mitral. Los anticuerpos IgM en suero para el virus de la varicela-zóster eran positivos. El paciente recibió el alta sin secuelas.

COVID-19 myocarditis: a case report / Miocardite na COVID-19: um relato de caso

ABSTRACT A male patient with flu-like symptoms and tomography and laboratory diagnosis of severe acute respiratory syndrome. He developed acute cardiac dysfunction during admission and was submitted to a cardiac magnetic resonance imaging examination, which confirmed acute myocarditis, indicating cardiac involvement by coronavirus disease 2019. A review and discussion about coronavirus disease 2019-related cardiac manifestations are reported, focusing on the imaging findings to make diagnosis.

RESUMO Paciente do sexo masculino apresentando síndrome gripal aguda com diagnóstico tomográfico e laboratorial de infecção por síndrome respiratória aguda grave. Evoluiu com disfunção cardíaca aguda durante a internação, motivo pelo qual foi submetido à ressonância magnética cardíaca, que confirmou miocardite aguda, indicando acometimento cardíaco por COVID-19. Foram realizadas revisão e discussão sobre o acometimento cardíaco na COVID-19, com ênfase nos aspectos por imagem para o diagnóstico.

Heart failure due to cytomegalovirus myocarditis in immunocompetent young adults: a case report.

BACKGROUND: Cardiac complications constitute a rare clinical manifestation of cytomegalovirus (CMV) infection. This virus is usually asymptomatic in immunocompetent individuals. We report a case of myocarditis and cardiac insufficiency due to primary CMV infection. Serological tests by using ELISA method showed positive results for the virus. CASE PRESENTATION: A 41-year-old man with no prior comorbidities presenting with dyspnoea, fever, and oedema was admitted to the cardiac emergency service. He had fever and dry cough, which aggravated into progressive respiratory distress, lower limb oedema, and orthopnoea 30 days prior to hospitalisation. The electrocardiogram revealed sinus tachycardia, first-degree right bundle branch block, and ventricular and left atrial overload as well as diffuse and nonspecific disturbances of ventricular repolarization. Serological tests were conducted, and IgM (1.54 UI/mL) and IgG (2.5 UI/mL) were found positive only for CMV by using ELISA. The patient was diagnosed with cardiac insufficiency due to CMV myocarditis. He was treated with ganciclovir for 10 days and received supportive medication. CONCLUSION: This case reaffirms the possibility of cardiac involvement in CMV infection and emphasises the importance of viral aetiologies as differential diagnoses for acute myocarditis.

[Myocarditis and complicated dengue: a case report]. / Dengue complicado y miocarditis: comunicación de un caso.

Hemorragic dengue fever is a prevalent infection in many countries around the world. Myocarditis is a severe manifestation of dengue virus infection. With prompt intervention and an early diagnosis, the outcome of this condition can be improve. We report a adult patient with complicated dengue, myocarditis, cardiac and respiratory insufficiency with acute renal injury.

Macrophages and galectin 3 play critical roles in CVB3-induced murine acute myocarditis and chronic fibrosis.

Macrophage influx and galectin 3 production have been suggested as major players driving acute inflammation and chronic fibrosis in many diseases. However, their involvement in the pathogenesis of viral myocarditis and subsequent cardiomyopathy are unknown. Our aim was to characterise the role of macrophages and galectin 3 on survival, clinical course, viral burden, acute pathology, and chronic fibrosis in coxsackievirus B3 (CVB3)-induced myocarditis. Our results showed that C3H/HeJ mice infected with CVB3 and depleted of macrophages by liposome-encapsulated clodronate treatment compared with infected untreated mice presented higher viral titres but reduced acute myocarditis and chronic fibrosis, compared with untreated infected mice. Increased galectin 3 transcriptional and translational expression levels correlated with CVB3 infection in macrophages and in non-depleted mice. Disruption of the galectin 3 gene did not affect viral titres but reduced acute myocarditis and chronic fibrosis compared with C57BL/6J wild-type mice. Similar results were observed after pharmacological inhibition of galectin 3 with N-acetyl-d-lactosamine in C3H/HeJ mice. Our results showed a critical role of macrophages and their galectin 3 in controlling acute viral-induced cardiac injury and the subsequent fibrosis. Moreover, the fact that pharmacological inhibition of galectin 3 induced similar results to macrophage depletion regarding the degree of acute cardiac inflammation and chronic fibrosis opens up the possibility of new pharmacological strategies for viral myocarditis.

Antiviral and myocyte protective effects of IL-28A in coxsackievirus B3-induced myocarditis

Objective: This study aimed to investigate whether interleukin-28A (IL-28A) plays a role in murine myocarditis induced by coxsackievirus B3 (CVB3), and to explore its possible mechanism involved. Methods: Male BALB/c mice both infected and not infected by CVB3 were randomly divided into four groups (n = 40), untreated or treated with different doses of IL-28A for 4 days, and then sacrificed on days 4 and 7 post-infection. The heart samples were collected for histopathologic examination. Cardiac viral load was determined by a plaque assay. Additionally, immunoblot analysis, TUNEL assay, and immunohistochemistry were performed to examine the expression of signal transducer, activator of transcription 1 and 2 (STAT1 and STAT2), CVB3-induced apoptosis and the expression of Bcl-2, BAX and Caspase-3. Results: Compared to uninfected mice, the CVB3 infected mice exhibited higher mortality rate (p < 0.001), apparent inflammation and myocardial lesion (p < 0.01), and higher cardiac viral load (p < 0.01). After CVB3 infection, IL-28A treated mice presented no death (p < 0.001), reduced inflammation and myocardial lesion (p < 0.01), and lower viral load (p < 0.01) compared to untreated mice. Besides, treatment with IL-28A markedly increased the expressions of STAT1 and STAT2, and inhibited CVB3-induced apoptosis in myocardial cells with increased ratio of Bcl-2/BAX. Conclusion: The antiviral and myocyte protective effects of IL-28A in CVB3-inducedmyocarditis are regulated by STAT1 and STAT2. .

Platelets interact with Coxsackieviruses B and have a critical role in the pathogenesis of virus-induced myocarditis.

BACKGROUND: To further understand the role of platelets in the pathogenesis of viral infections we explored platelet interaction with Coxsackieviruses B (CVB) 1 and 3. CVB is a group of viruses that cause the majority of human enterovirus-related viral myocarditis; their receptor (CAR) is expressed on the platelet surface and there is a well-characterized CVB3-induced myocarditis murine model. METHODS: Human platelets were infected with CVB1 and 3 and viruses were detected in pellets and in supernatants. C57BL/6J mice with or without platelet depletion were inoculated with CVB3 and peripheral blood and heart samples collected at different times post-infection. RESULTS: CVB1 and 3 RNA and a capsid protein were detected in infected platelets. Despite the fact that titration assays in Vero cells showed increasing infectivity titers over time, supernatants and pellets from infected platelets showed similar levels, suggesting that platelets were not susceptible to a replicative infectivity cycle. CVB binding was CAR-independent and resulted in P-selectin and phosphatidylserine (PS) exposure. CVB3-infected mice showed a rapid thrombocytopenia that correlated with an increase in platelet PS exposure and platelet-leukocyte aggregates without modification of platelet P-selectin expression or von Willebrand factor levels. Mortality, viremia, heart viral titers and myocarditis were significantly higher in platelet-depleted than normal animals. Type I IFN levels were not changed but IgG levels were lower in infected and platelet-depleted mice. CONCLUSIONS: Our data reveal that platelets play a critical role in host survival and immune response against CVB3 infection.

Antiviral and myocyte protective effects of IL-28A in coxsackievirus B3-induced myocarditis.

OBJECTIVE: This study aimed to investigate whether interleukin-28A (IL-28A) plays a role in murine myocarditis induced by coxsackievirus B3 (CVB3), and to explore its possible mechanism involved. METHODS: Male BALB/c mice both infected and not infected by CVB3 were randomly divided into four groups (n=40), untreated or treated with different doses of IL-28A for 4 days, and then sacrificed on days 4 and 7 post-infection. The heart samples were collected for histopathologic examination. Cardiac viral load was determined by a plaque assay. Additionally, immunoblot analysis, TUNEL assay, and immunohistochemistry were performed to examine the expression of signal transducer, activator of transcription 1 and 2 (STAT1 and STAT2), CVB3-induced apoptosis and the expression of Bcl-2, BAX and Caspase-3. RESULTS: Compared to uninfected mice, the CVB3 infected mice exhibited higher mortality rate (p<0.001), apparent inflammation and myocardial lesion (p<0.01), and higher cardiac viral load (p<0.01). After CVB3 infection, IL-28A treated mice presented no death (p<0.001), reduced inflammation and myocardial lesion (p<0.01), and lower viral load (p<0.01) compared to untreated mice. Besides, treatment with IL-28A markedly increased the expressions of STAT1 and STAT2, and inhibited CVB3-induced apoptosis in myocardial cells with increased ratio of Bcl-2/BAX. CONCLUSION: The antiviral and myocyte protective effects of IL-28A in CVB3-induced myocarditis are regulated by STAT1 and STAT2.

Fulminant myocarditis associated with the H1N1 influenza virus: case report and literature review.

A case of fulminant myocarditis associated with the H1N1 influenza virus. This case report describes the patient's clinical course and emphasizes the importance of bedside echocardiography as an aid in the early diagnosis and management of children with severe myocardial dysfunction. It also discusses aspects relevant to the treatment and prognosis of fulminant myocarditis. The patient was a female, 4 years and 8 months old, previously healthy and with a history of flu symptoms in the past two weeks. The patient was admitted to the emergency room with signs of hemodynamic instability, requiring ventilatory support and vasoactive drugs. The laboratory tests, chest X-ray and echocardiogram suggested the presence of myocarditis. The test for H1N1 in nasopharyngeal secretions was positive. The patient evolved to refractory cardiogenic shock despite the clinical measures applied and died 48 hours after admission to the intensive care unit. The H1N1 influenza virus is an etiological agent associated with acute myocarditis, but there are few reported cases of fulminant myocarditis caused by the H1N1 virus. The identification of signs and symptoms suggestive of fulminant progression should be immediate, and bedside echocardiography is a useful tool for the early detection of myocardial dysfunction and for therapeutic guidance. The use of immunosuppressive therapy and antiviral therapy in acute myocarditis of viral etiology is controversial; hence,the treatment is based on hemodynamic and ventilatory support. The use of hemodynamic support by extracorporeal membrane oxygenation emerges as a promising treatment.

Miocardite fulminante associada ao vírus influenza H1N1: relato de caso e revisão de literatura / Fulminant myocarditis associated with the H1N1 influenza virus: case report and literature review

Caso de miocardite fulminante associada ao vírus influenza H1N1, em que foi descrita a evolução clínica do paciente e enfatizada a importância do ecocardiograma à beira do leito como auxílio no diagnóstico precoce e manejo de crianças com disfunção miocárdica grave, além de terem sido discutidos aspectos relevantes relacionados à terapêutica e ao prognóstico da miocardite fulminante. Trata-se de paciente do sexo feminino, 4 anos e 8 meses, previamente hígida, com história de quadro gripal há 2 semanas. Admitida no pronto-socorro com sinais de instabilidade hemodinâmica, necessitando de suporte ventilatório e drogas vasoativas. Exames laboratoriais, radiografia de tórax e ecocardiograma sugestivos de miocardite. Pesquisa positiva para H1N1 em secreção de nasofaringe. Evoluiu com choque cardiogênico refratário a despeito das medidas clínicas, indo a óbito em 48 horas após admissão na unidade de terapia intensiva. O vírus influenza H1N1 é agente etiológico associado a quadros de miocardite aguda, porém poucos são os casos relatados de miocardite fulminante pelo vírus H1N1. A identificação de sinais e sintomas sugestivos de evolução fulminante deve ser imediata e o ecocardiograma à beira do leito é uma ferramenta útil para detecção precoce de disfunção miocárdica e orientação terapêutica. O uso de terapia imunossupressora, em casos de miocardite fulminante de etiologia viral, é controverso, bem como o de terapia antiviral, de tal forma que o tratamento baseia-se em suporte hemodinâmico e ventilatório. O uso de suporte hemodinâmico, por meio de oxigenação por membrana extracorpórea, aparece como terapia promissora.

A case of fulminant myocarditis associated with the H1N1 influenza virus. This case report describes the patient's clinical course and emphasizes the importance of bedside echocardiography as an aid in the early diagnosis and management of children with severe myocardial dysfunction. It also discusses aspects relevant to the treatment and prognosis of fulminant myocarditis. The patient was a female, 4 years and 8 months old, previously healthy and with a history of flu symptoms in the past two weeks. The patient was admitted to the emergency room with signs of hemodynamic instability, requiring ventilatory support and vasoactive drugs. The laboratory tests, chest X-ray and echocardiogram suggested the presence of myocarditis. The test for H1N1 in nasopharyngeal secretions was positive. The patient evolved to refractory cardiogenic shock despite the clinical measures applied and died 48 hours after admission to the intensive care unit. The H1N1 influenza virus is an etiological agent associated with acute myocarditis, but there are few reported cases of fulminant myocarditis caused by the H1N1 virus. The identification of signs and symptoms suggestive of fulminant progression should be immediate, and bedside echocardiography is a useful tool for the early detection of myocardial dysfunction and for therapeutic guidance. The use of immunosuppressive therapy and antiviral therapy in acute myocarditis of viral etiology is controversial; hence, the treatment is based on hemodynamic and ventilatory support. The use of hemodynamic support by extracorporeal membrane oxygenation emerges as a promising treatment.