Myocarditis - PEDIATRICS

CARDIOLOGY

Myocarditis

PEDIATRICS II

FACILITATOR: Regente Imperial Lapak, MD, FPPS, DPCC OBJECTIVES

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Understand what is Myocarditis Know the causes, pathophysiology, clinical signs and symptoms, treatment, and prognosis of Myocarditis Get updates on the diagnosis of Myocarditis

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MYOCARDITIS 

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An inflammatory disorder of the myocardium with necrosis of the myocytes and associated inflammatory infiltrate Considered in all patients with recent onset of congestive heart failure No obvious structural or functional etiology According to the Dallas criteria: o Inflammatory infiltrate of the myocardium with necrosis and/or degeneration of the adjacent myocytes not typical of ischemic damage” due to coronary artery or other disease

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Acute or chronic inflammation of the myocardium is characterized by inflammatory cell infiltrates, myocyte necrosis, or myocyte degeneration May be associated systemic manifestations of the disease and on occasion, the endocardium or pericardium is involved Patients may be asymptomatic, have nonspecific prodromal symptoms, or present with overt congestive heart failure, compromising arrhythmias, or sudden death Viral infections: Most common etiology

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ETIOLOGY  Infectious  Hypersensitivity drug reactions  Autoimmune or collagen-vascular diseases  Idiopathic Infectious causes:  Viral o Most common: echovirus, adenovirus types 2 and 5 o Bacterial o Rickettsial o Fungal o Parasitic

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EPIDEMIOLOGY 

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Myocarditis is listed as a “rare disease: by the office of the rare diseases (OrD) of the National Institutes of Health (NIH). This means myocarditis, or a subtype of Myocarditis affects less than 200,000 people in the US population Incidence (WHO) after an enterovirus infection: 1-4% Incidence related to: hygiene and socioeconomic conditions Availability of medical service/immunizations Presence of epidemics 0.1/1000 people each year The exact incidence of myocarditis is unknown. However, in series of routine autopsies, 1-9% of all patients had evidence of myocardial inflammation. In young adults, up to 20% of all cases of sudden death are due to myocarditis Among patients with HIV, myocarditis is the most common cardiac pathological finding at autopsy, with a prevalence of 50% or more The incidence of myocarditis is similar between males and females, although young males are particularly susceptible Susceptible groups include immunocompromised individuals, pregnant women, and children (particularly neonates) No particular race predilection is noted for myocarditis except for a peripartum cardiomyopathy (a specific form of myocarditis that appears to have high incidence

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patients of African descent) The population that is at the highest risk for serious disease is newborns The mortality rate is as high as 50 to 70%. When this is the case, there is a high risk of sudden death and some children may need a heart transplant urgently This severity of disease is rare and therefore represents a very small number of children

Viral Infections manifestations are age-dependent Neonates and Young infants: Fulminant Children: Acute, myopericarditis with heart failure Older children and Adolescents: Acute or chronic heart failure or chest pain Bacterial Myocarditis - less common Dipththeric Myocarditis produces circulatory collapse and toxic myocarditis (AV block, Bundle-branch Block, or ventricular ectopy) Systemic bacterial infection - circulatory collapse, shock and myocardial dysfunction (tachycardia, gallop rhythm, and low cardiac output)

offending agent, which causes cell-mediated cytotoxicity and cytokine release, contributing to myocardial damage and dysfunction; detection of the causal agent is uncommon during this stage 

Chronic phase (> 2 weeks) o Continuing myocyte destruction is autoimmune in nature, with associated abnormal expression of human leukocyte antigen (HLA) in myocytes (and in the case of viral myocarditis, persistence of the viral genome in myocardium)

NELSON Enteroviruses: Coxsackie. Echoviruses: predominant causative agent in children –Grist NR, Reid D, 1991 Enteroviruses  Increased isolation from hearts of young patients compared with adults – Kaplan MH, 1988  Highest direct pathogenicity of enteroviruses in children’s hearts –Mc Manus BM, 1991

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CLASSIFICATIONS OF MYOCARDITIS 

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Chronic Active Myocarditis o Less distinct onset of illness, with clinical and histological relapses o Development of ventricular dysfunction associated with chronic inflammatory changes (including giant cells) Chronic Persistent Myocarditis o Less distinct onset of illness; persistent histologic infiltrate with foci of myocyte necrosis but without ventricular dysfunction (despite symptoms, eg. Chest pain, palpitations) Fulminant Myocarditis o Follows a viral prodrome; distinct onset of illness consisting of severe cardiovascular compromise with ventricular dysfunction and multiple foci of active myocarditis; either resolves spontaneously or results in death Acute Myocarditis o Less distinct onset of illness, with established ventricular dysfunction; may progress to dilated cardiomyopathy

PATHOPHYSIOLOGY Mechanism of Damage:  Direct viral cytopathic effect  Immunologically mediated cellular injury in response to cardiotropic virus  Toxins  Aberrant induction of apoptosis 1. 2. 3. 4.

Direct cytotoxic effect of the causative agent Secondary immune response, which can be triggered by the causative agent Cytokine expression in the myocardium (eg. Tumor necrosis factor [TNF]- alpha, nitric oxide synthase Aberrant induction of apoptosis

Pathology  The inflamed myocardium is soft, flabby, and pale, with areas of scarring on gross examination  Microscopic examination reveals PATCHY INFILTRATIONS BY PLASMA CELLS, mononuclear leukocytes, and some eosinophils during the acute phase and giant cell infiltration in the later stages Phases of Myocardial Damage  Acute Phase (first 2 weeks) o Myocyte destruction is a direct consequence of the

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Characterized by myocardial inflammation, injury or necrosis, and ultimately fibrosis. Cardiac enlargement and diminished systolic function occur as a direct result of the myocardial damage Typical signs of congestive heart failure occur and may progress rapidly to shock, atrial or ventricular arrhythmias, and sudden death Viral myocarditis may also become a chronic process with persistence of viral nucleic acid in the myocardium, and the perpetuation of chronic inflammation secondary to altered host immune response including activated T lymphocytes (cytotoxic and natural killer cells) and antibody-dependent cell mediated damage Persistent viral infection may alter the expression of major histocompatibility complex antigens with resultant exposure of neoantigens to the immune system Some viral proteins share antigenic epitopes with host cells, resulting in autoimmune damage to the antigenically-related myocyte Cytokines such as tumor necrosis factor-α and interleukin-1 are inhibitors of myocyte response to adrenergic stimuli and result in diminished cardiac function The final result of viral-associated inflammation can be DCM

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CLINICOPATHOLOGIC COURSE OF MYOCARDITIS

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Heart Failure o Common in all ages o Neonates and younger children at risk Chest Pain o Rare in young children o Initial presentation in older children, adolescents and adults due to myocardial ischemia or concurrent pericarditis Arrythmia o Sinus tachycardia typical with rate faster than expected for fever o Tachycardia: difficult medical treatment Dilated Cardiomyopathy o Believed to result from previously burned out myocardial episode

SIGNS AND SYMPTOMS Infants  Irritability  Lethargy  Periodic episodes of pallor  Fever  Hypothermia  Anorexia Neonates  Respiratory distress  Signs of sepsis  Somnolence, hypotonia, seizures if CNS involvement  Hypothermia/hyperthermia  Oliguria- elevated BUN, creatinine (direct viral damage or low CO)  Elevated enzymes Older children  Lack of energy  Generalized malaise  Recent flu-like symptoms  GIT upset  Poor feeding  Rapid breathing Adolescents  More prominent decrease in exercise tolerance  Lack of energy/malaise  Chest pain/cough  Low-grade fever Arrhythmia  End organ damage  Low cardiac output

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Mild forms o Few or no symptoms Severe o Acute cardiac decompression and death

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Ranges from asymptomatic or nonspecific generalized illness to acute cardiogenic shock and sudden death. Infants and Young children: Fulminant Presentation (fever, respiratory distress, tachycardia, hypotension, gallop rhythm, and cardiac murmur)  Associated findings may include a rash or evidence of end-organ involvement (hepatitis or aseptic meningitis) Patients with Acute or Chronic Myocarditis may present with chest discomfort, fever, palpitations, easy fatigability, or syncope/near syncope. Cardiac findings:  Overactive precordial impulse  Gallop rhythm  Apical systolic murmur of mitral insufficiency Patients with associated pericardial disease: Rub may be noted Patients with decompensated heart failure:  Hepatic enlargement  Peripheral edema  Pulmonary findings (wheezes or rales)

Symptoms in infants and toddlers tend to be more non-specific with general malaise, poor appetite, abdominal pain, and/or chronic cough

Chest X-ray  Cardiomegaly  Early course: little or no cardiac enlargement

Later stages of the illness will present with RESPIRATORY SYMPTOMS with increased work of breathing, and is often mistaken for asthma     

Fever (especially when infectious, e.g. in rheumatic fever) Chest pain (often described as “stabbing in character) Congestive Heart Failure (leading to edema, breathlessness and hepatic congestion) Palpitations (due to arrhythmias) Sudden death (in young adults, myocarditis causes up to 20% of all cases of sudden death)

NELSON DIAGNOSTIC WORK-UPS

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In severe cases:  Cardiomegaly  Pulmonary vascular prominence  Overt pulmonary edema  Pleural effusions

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Diffuse T wave inversions Saddle-shaped ST-segment elevations may be present (these are also seen in pericarditis)

NELSON ECG - non-specific  Sinus tachycardia  Atrial or ventricular arrhythmias  Heart block  Diminished QRS voltages  Nonspecific ST and T-wave changes *Suggestive of acute ischemia

Cardiac enzymes  Cardiac troponin o Elevated in at least 50% of patients with biopsy-

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proven myocarditis Cardiac enzymes may also help to identify patients with resolution of viral myocarditis CPK MB- elevated most commonly when associated with ST segment elevation on ECG o CK-MB: Poor diagnostic yield  CK= 8%  CK-MB = 2% LDH- elevated in idiopathic myocarditis Troponin I- elevated up to a month after an infection but is non-specific for disease

The Dallas Classification  Myocarditis – myocardial necrosis, degeneration or both, in the absence of significant coronary artery disease with adjacent inflammatory infiltrate with or without fibrosis  Borderline myocarditis – inflammatory infiltrate too sparse or myocyte damage not apparent  No myocarditis  Ongoing (persistent) myocarditis with or without fibrosis  Resolving (healing) myocarditis with or without fibrosis  Resolved (healed) myocarditis with or without fibrosis

Cardiac troponin: 50% elevated in proven myocarditis, ongoing myocardial cell damage: 89% specificity, 34% sensitivity – Wilsong Tang WH, 2006 

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Cardiac troponin o Elevated in at least 50% of patients with biopsyproven myocarditis Cardiac enzymes may also help identify patients with resolution of viral myocarditis

Viral Antibody Titers  Common viral antibody titers available for clinical evaluation include coxsackievirus group B, human immunodeficiency virus (HIV), cytomegalovirus, EbsteinBarr virus, hepatitis virus family, and influenza viruses  Rarely indicated in the diagnoses of viral myocarditis or ny dilated cardiomyopathies, owing to its low specificity and the delayed rising of viral titers, which would have no impact on therapeutic decisions  Titers increase 4-fold or greater, with a gradual fall during convalescence phase  In situ hybridization: identifies viral RNA in myocardial tissue but has high incidence of false negative results

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Viral genome o The presence of viral genome in endomocardial biopsy samples is considered the criterion standard for viral persistence o Lacks specificity, because the presence of viral genome can be present in healthy controls. The most common viral genomes found include those of parvovirus and herpes simplex

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2D- ECHO o Exclude other causes of heart failure (e.g. amyloidosis or valvular or congenital causes) o Evaluate the degree of cardiac dysfunction (usually diffuse hypokineses and diastolic dysfunction) o Localization of the extent of inflammation (ie. Wall motion abnormalities, wall thickening, pericardial effusion) o Distinguish between fulminant and acute myocarditis by identifying near-normal left ventricular diastolic dimensions and increased septal thickness in fulminant myocarditis

Biopsy  GOLD STANDARD  Rarely helpful clinically since histologi diagnosis seldom has an impact on therapeutic strategies, unless giant cell myocarditis is suspected  Biopsy specimens from EMB should reveal the simultaneous findings of lymphocyte infiltration and myocyte necrosis

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Echocardiography findings include:  Diminished ventricular systolic function  Cardiac chamber enlargement  Mitral insufficiency  Pericardial infusion

Endomyocardial biopsy  Useful in identifying inflammatory cell infiltrates or myocyte damage and performing molecular viral analysis using polymerase chain reaction techniques

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MRI o Cardiovascular magnetic resonance image

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Sensitivity of endomyocardial biopsy: o 50% = 1 biopsy o 70% = 7 biopsies o False-negative result: 55% -Wilson Tang WH, 2006

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Cardiac MRI  Standard imaging modality for the diagnosis of myocarditis  Information on the presence and extent of edema, gadolinium-enhanced hyperemic capillary leak, myocyte necrosis, left ventricular dysfunction, and evidence of an associated pericardial effusion

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candidates for bridge therapy with left ventricular assist devices Heart transplantation is reserved for patients who fail to improve with conventional therapy

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Primary therapy for Acute Myocarditis: Supportive Use of inotropic agents (Milrinone) - entertained but used with caution because of their proarrhythmic potential If in extremis, mechanical ventilatory support and mechanical circulatory support with ventricular assist device implantation or extracorporeal membrane oxygenation to stabilize the patient’s hemodynamic status and serve as a bridge to recovery or cardiac transplantation Diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers – compensated congestive heart failure in the outpatient setting  Contraindication: Fulminant heart failure and cardiovascular collapse In patients manifesting with significant atrial or ventricular arrhythmias, specific antiarrhythmic agents (Amiodarone) should be administered and implantable cardioverter defibrillator placement considered Immunomodulation of patients with myocarditis is controversial. Intravenous immune globulin may have a role in the treatment of acute or fulminant myocarditis and corticosteroids have been reported to improve cardiac function, but the data are not convincing in children. Relapse has been noted in patients receiving immunosuppression who have been weaned from support. There are no studies to recommend specific antiviral therapies for myocarditis.

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Short-axis cardiac magnetic resonance imaging of a patient with acute myocarditis T2-weighted image, showing regional edema of the lateral left ventricle predominantly subepicardial involvement

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Others o CBC- leukocytosis (may demonstrate eosinophilia) o Elevated ESR (and other acute phase reactants, such as C-reactive protein, ESR) o Rheumatologic screening- to rule out systemic inflammatory diseases

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Nonspecific tests:  Sedimentation rate  Creatine phosphokinase  Isoenzymes  Cardiac troponin I brain natriuretic peptide levels.

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NELSON

TREATMENT  

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Bed rest and limitation in activities are recommended during the acute phase Anti-congestive measures are the following: o Rapid-acting diuretics (furosemide 1 mg/kg, 1-3 times a day) o Rapid acting inotropic agents, such as dobutamine or dopamine are useful in critically ill patients o Oxygen and bed rest are recommended Beneficial effects of high-dose gamma globulin (2g/kg) have been reported o Myocardial damage in myocarditis is mediated in part by immunologic mechanisms, and high dose of gamma globulin is an immunomodulatory agent shown to be effective in myocarditis secondary to Kawasaki disease Angiotensin-converting enzyme inhibitors such as captopril is beneficial in the acute phase Arrhythmias should be treated aggressively and may require the use of IV amiodarone

Symptomatic patients  Digoxin and diuretics provide clinical improvement. For patients with moderate to severe dysfunction, cardiac function can be supported by the use of inotropes such as Milrinone in the acute phase, followed by oral therapy with ACE inhibitors (captopril, Lisinopril) when tolerated  People who do not respond to conventional therapy are

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As most viral infections cannot be treated with directed therapy, symptomatic treatment is the only form of therapy for those forms of myocarditis In the acute phase, supportive therapy, including bed rest is indicated Patients should consume a low-sodium diet similar to that for heart failure management Bed rest and avoidance of athletic activities are recommended for a period of 3 months (with lower incidence of arrhythmia) Physical activity should be restricted to reduce the work of the heart during the acute phase of myocarditis, especially when there is fever, active systemic infection or heart failure PROGNOSIS Approximately 2/3 of the children, with appropriate medical management, will have a complete recovery If untreated, only 10-20 percent will have spontaneous recovery and 80% will develop chronic heart disease. For

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most children, recovery usually occurs within 2-3 months from onset of the illness Of the remaining 1/3 who are treated, 10-20% will improve but have chronic residual heart problems called “dilated cardiomyopathy” o Dilated Cardiomyopathy  Long term follow-up by a cardiologist because sometimes these children will develop progressive heart failure and need a heart transplant Older children may experience problems with the electrical conduction system within the heart and at risk for rhythm problems. These can often be treated with medication The population that is at the highest risk for serious disease is newborns. The mortality rate is as high as 50-70%. When this is the case, there is a high risk of sudden death and some children may need a heart transplant urgently. This severity of disease is rare and therefore represents a very small number of children

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Symptomatic acute myocarditis in newborns: POOR prognosis 75% mortality reported Prognosis is better for children and adolescents Patients who have persistent evidence of DCM often progress to need for cardiac transplantation Recovery of ventricular function has been reported in 1050%

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