Definition

Myocarditis is an inflammatory disease of the myocardium that can have greatly varying clinically courses and a variety of causes. The World Health Organization grouped these diseases under the term “inflammatory cardiomyopathy.” The most common form of myocarditis in childhood is viral myocarditis.

Epidemiology

The incidence in children is unknown. Since many children are asymptomatic, the frequency is probably underestimated. Histological evidence of myocarditis is found in autopsies in up to 40% of children who died suddenly and were not killed by trauma. The clinical significance of these findings is unclear. There is myocardial involvement in 1 to 4% of enterovirus infections (especially Coxsackie virus type B).

Pathogenesis

In myocarditis, interstitial inflammation or myocardial damage leads to decreased myocardial function. The damage to the myocardium that is associated with myocardial cell death is probably due not only to direct damage to the myocardium from the pathogens, but also to immunological mechanisms. The result is dilatation of the ventricles with an increase in end-diastolic volume. Normally, the heart responds to an increase in end-diastolic volume with an increase in contractility (Frank–Starling mechanism), but this is not possible in myocarditis due to damage to the myocardium.

Histology

The histopathological classification is based on the Dallas criteria:

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  Active myocarditis: inflammatory infiltration of the myocardium and myocytolysis; the infiltrates are mostly monocytic, less often neutrophilic, occasionally also eosinophilic

  
  
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  Borderline myocarditis: lymphocytic infiltration of the myocardium without myocytolysis

Etiology

Infectious, immunological, and toxic triggers are possible causes of myocarditis (Table 16.1). Infections, especially viral infections, are the most common causes in childhood. The most important pathogens are enteroviruses (especially Coxsackie virus type B) and adenoviruses.

Symptoms

The clinical course of acute myocarditis ranges from asymptomatic cases to fulminant, fatal courses with severe dyspnea, pulmonary edema, cardiogenic shock, and even death. Signs of acute heart failure are usually the major symptoms. Arrhythmias can also be the leading symptom of myocarditis.

In myocarditis following a viral infection, the patient typically develops fatigue, reduced physical capacity, tachycardia, and tachypnea.

The symptoms vary in different age groups. Especially in neonates and infants, the symptoms can be very nonspecific (restlessness, vomiting, cough, increased crying or whimpering). In older children, the major symptoms are reduced physical capacity and a general malaise.

Typical symptoms are:

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  Tachycardia, extrasystoles: In principle, any type of arrhythmia is possible in connection with myocarditis, including AV conduction disturbance and ventricular tachycardia

  
  
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  Tachypnea/dyspnea

  
  
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  Chest pain: This can be the result of myocardial ischemia or concomitant pericarditis

  
  
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  Gray-cyanotic skin tone, pallor, cool extremities, slow recapillarization

  
  
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  Hepatomegaly, edema

  
  
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  Hypotension, oliguria

  
  
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  Lethargy, somnolence, increased irritability, cerebral seizures

  
  
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  Fever, hypothermia

Laboratory

The following are the typical laboratory findings in myocarditis. It should be noted, however, that there are no laboratory parameters that can prove or rule out myocarditis. This also applies to the myocardial enzymes. Detection of pathogens in a culture, which is best done in an endomyocardial biopsy, is crucial.

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  Inflammatory markers (CRP, ESR): The inflammatory markers are usually elevated in myocarditis, but inconspicuous inflammatory parameters do not rule out myocarditis.

  
  
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  Lymphocytosis and neutropenia indicate a viral genesis.

  
  
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  Anemia

  
  
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  Elevated myocardial enzymes: Increases in CK-MB, LDH and especially troponin I are signs of myocardial damage. But normal myocardial enzyme levels do not rule out myocarditis.

  
  
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  Metabolic acidosis: Metabolic acidosis can be a sign of congestive heart failure.

  
  
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  Elevated transaminases: An increase in transaminases may be the result of a viral-induced hepatopathy, liver congestion, or liver failure associated with congestive heart failure.

  
  
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  Increase in urinary metabolites (creatinine, urea) with oliguria/renal failure

  
  
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  Autoantibodies: ANA, double-stranded DNA antibodies, Sm antibodies, RNP antibodies, SSA antibodies, SSB antibodies, and antimitochondrial antibodies can indicate an autoimmune cause.

  
  
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  Antimyocardial antibodies: Antimyolemmal antibodies (AMLA) and/or antisarcolemmal antibodies (ASA) can often be detected after 4 weeks and are typical but not specific for viral myocarditis.

  
  
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  Virus serology: The virus serology is indicative only if there is a substantial increase in the titer over time, making a follow-up about 3 weeks after the onset of the disease useful. Serology tests are therefore not suitable for making a rapid diagnosis.

  
  
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  Virus isolation in smears and cultures (e.g., throat urine, stool)

  
  
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  PCR / in situ hybridization: Direct evidence of the virus genome or RNA in a myocardial biopsy is the method of choice for virus detection.

Auscultation

It may be possible to hear a mitral regurgitation murmur—blowing systolic murmur with point of maximum impulse (PMI) at the cardiac apex. A gallop rhythm occurs in congestive heart failure. In pulmonary edema, there are fine crackles over the lungs.

ECG

In some patients, changes in the ECG are the only evidence suggestive of myocarditis. In theory, all types of arrhythmias may be associated with myocarditis. Especially feared are ventricular tachycardias. A new onset of cardiac arrhythmia always suggests myocarditis. Typical ECG findings of myocarditis include:

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  Sinus tachycardia: Sinus tachycardia is the most common ECG finding in myocarditis. If fever is present simultaneously, the tachycardia is usually more rapid than expected from the fever alone.

  
  
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  Ventricular tachycardia: Ventricular tachycardia may be the first symptom of myocarditis.

  
  
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  Extrasystoles

  
  
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  AV block grade I to III, bundle branch block, prolonged QT interval.

  
  
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  ST segment depression. However, if there is simultaneous pericardial effusion, ST segment elevation is more likely.

  
  
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  T wave flattening or inversion, often with small or absent Q waves in V₅/V₆

  
  
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  Occasionally low voltage

Echocardiography

An indicative finding in echocardiography is an enlarged, poorly contractile left ventricle. However, the echocardiography cannot distinguish reliably between acute myocarditis and dilated cardiomyopathy. Typical findings are:

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  end-diastolic and diastolic enlargement of the left ventricle (and possibly enlarged right ventricle),

  
  
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  poor ventricular function with reduced fractional shortening and ejection fraction,

  
  
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  regional wall motion abnormalities,

  
  
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  mitral and/or tricuspid regurgitation as a result of a dilatation of the valve annulus,

  
  
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  possibly pericardial effusion.

The coronary anatomy should be visualized if possible to rule out a coronary anomaly, especially Bland–White–Garland syndrome, which should be considered as a differential diagnosis.

Chest X-ray

Cardiomegaly is a typical radiological finding. There may be signs of pulmonary congestion up to pulmonary edema.

Cardiac Catheterization

The hemodynamic measurements show a decreased cardiac index, increased left ventricular end-diastolic pressure, and increased left atrial pressure. Left ventricular function is reduced. A coronary anomaly should be ruled out by a coronary angiography.

The main indication for cardiac catheterization is to conduct an endomyocardial biopsy, which is the gold standard for diagnosing myocarditis. The biopsy is usually taken from the right ventricular septum. Aside from confirming the diagnosis, it can aid in the classification according to the Dallas criteria (see Histology, Chapter 16.1.1). The immunohistological examination of the specimens reduces the incidence of false negative results. Molecular biological methods (PCR, in situ hybridization) can be used to identify the pathogen. The risk of myocardial perforation during the biopsy is increased in critically ill and younger children.

MRI

Using contrast medium and the late-enhancement technique in addition to other imaging methods, the location and the extent of inflammation can be determined, but the changes are not specific for myocarditis.

Differential Diagnoses

Differential diagnoses of myocarditis are:

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  Decompensated heart failure

  
  
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  Coronary anomaly (in particular Bland–White–Garland syndrome)

  
  
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  Dilated cardiomyopathy

  
  
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  Endocardial fibroelastosis

  
  
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  Myocardial infarction

  
  
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  Metabolic disorders associated with cardiac involvement (e.g., carnitine deficiency, glycogenosis)

General Measures

Patients with suspected myocarditis should be admitted to hospital and be monitored by ECG. Bed rest during the acute phase of the disease probably reduces viral replication.

Treatment of congestive heart failure

The following measures are used in the treatment of congestive heart failure:

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  Diuretics: Diuretics should initially be dosed with caution, because sufficient preload is often necessary to ensure adequate cardiac output.

  
  
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  Digoxin: Due to increased digoxin toxicity in myocarditis, patients should be started at half the dosage.

  
  
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  Beta blockers: If blood pressure is sufficiently high, start at a low dosage (not for severe heart failure).

  
  
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  ACE inhibitors: For afterload reduction if blood pressure high enough.

  
  
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  Catecholamines (e.g., dobutamine) and phosphodiesterase inhibitors (e.g., milrinone): For severe heart failure under intensive care monitoring.

  
  
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  Sedation, intubation and mechanical ventilation for cardiogenic shock or pulmonary edema.

  
  
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  Mechanical circulatory support for circulatory failure not manageable by conventional methods: Extracorporeal membrane oxygenation (ECMO) or left ventricular assist device (VAD), possibly as an interim measure until heart transplant.

Antiarrhythmic Treatment

Cardiac arrhythmias can lead to a significant deterioration of symptoms. However, it should be noted that most antiarrhythmic drugs have negative inotropic effects. Amiodarone is often used.

Supraventricular and ventricular tachycardias, which can lead to hemodynamic instability, should be treated rapidly with cardioversion. If there is a complete AV block and low ventricular rate, a temporary transvenous pacemaker may have to be placed. In most cases, AV conduction recovers.

Hemodynamically relevant, treatment-refractory arrhythmias can be an indication for temporary mechanical circulatory support with ECMO or VAD.

Immunosuppressive Treatment

The use of immunosuppressive drugs is still controversial. A large United States multicenter study showed no benefit of immunosuppressive therapy with prednisone in combination with azathioprine or cyclosporine A in comparison with purely symptomatic treatment. Steroids are therefore used in most centers only for myocarditis based on a confirmed autoimmune disease.

Immunoglobulins

There is evidence that immunoglobulins administered at a dosage of 2 g/kg IV over 24 hours improve left ventricular function in acute myocarditis.

Interferon α

Interferon is currently being investigated in studies to verify whether it is useful in viral myocarditis. No reliable evidence is available to date. On the other hand, interferon itself can lead to drug-induced myocarditis.

Specific Treatment

Specific treatment is possible for a few forms of myocarditis. A selection is listed below:

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  Bacterial myocarditis: antibiotics, depending on the pathogen

  
  
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  Fungal myocarditis: antifungals depending on the pathogen

  
  
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  Kawasaki disease: ASA, immunoglobulins, possibly steroids

  
  
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  Rheumatic carditis: penicillin, NSAIDs, possibly steroids

  
  
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  Diphtheria: fastest possible treatment with diphtheria antitoxin and high-dose penicillin

  
  
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  Borrelia: intravenous ceftriaxone for 4 weeks

  
  
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  Giant cell myocarditis: This rare but severe disease that affects mainly young people is verified by histological evidence of giant cells in the myocardium. An association with inflammatory bowel disease or autoimmune disease is suspected. Some studies have shown a positive effect of immunosuppression in giant cell myocarditis (cyclosporine in combination with steroids, azathioprine, or muromonab-CD3).

  
  
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  Eosinophilic myocarditis: steroids

Heart Transplant

If there is no improvement of left ventricular function or if there is a transition to dilated cardiomyopathy, a heart transplant is the last treatment option.

Definition

Endocarditis is an acute or subacute infection of the endocardial structures of the heart—the heart valves, the mural endocardium, or the endothelium of major vessels in the vicinity of the heart. Endocarditis may also involve foreign material such as a surgical patch, shunt connections (e.g., aortopulmonary shunts) or artificial vascular conduits, and artificial heart valves. Endocarditis can destroy the valves and lead to septic emboli.

Epidemiology

The lifetime risk for endocarditis in the general population is 5 to 7:100,000 patient-years, but increases significantly if there are risk factors such as congenital heart disease, prosthetic valves, or previous endocarditis. Some 90% of affected children have a congenital heart defect. Overall, the incidence is increasing among children, but neonates are rarely affected. In 80 to 90% of cases, endocarditis affects the valves of systemic circulation (aortic/mitral valve). Endocarditis of the pulmonary and tricuspid valves is more frequent in intravenous drug users.

Pathogenesis

In many congenital or acquired heart defects, turbulent blood flow causes a lesion of the adjacent endothelium or endocardium, where deposits of platelets and fibrin form. If there is transient bacteremia (e.g., simple infectious diseases, surgical or dental procedures), this thrombotic vegetation is colonized with bacteria, which have a tendency to adhere to the thrombotic deposits where they are well protected from the body’s immune system and from antibiotics. As a result of fibrin and platelet aggregation as well as due to bacterial growth, a typical endocarditis vegetation develops. Direct progression of the process can lead to the development of abscesses, for example, in the myocardium or in the valve annulus.

Embolization of vegetation can cause tissue infarction and septic colonization in the rest of the body. In addition, extracardiac manifestations may be caused by immune complex deposits (e.g., glomerulonephritis, vasculitis).

Highly virulent pathogens (e.g., staphylococci) can invade previously undamaged valves and usually lead to a fulminant course of the disease (acute endocarditis). Less virulent pathogens (e.g., viridans group streptococci, enterococci) settle on previously damaged valves and lead to a more gradual course of the disease (subacute endocarditis, endocarditis lenta).

Etiology

Bacteria in particular, less often fungi, are decisive in causing infectious endocarditis (Table 16.2). Viridans group streptococci and enterococci are the most common pathogens of subacute endocarditis. Staphylococcus aureus, enterobacteria, pneumococci, and hemolytic streptococci are typical pathogens of acute endocarditis. In 5 to 25% of cases, the pathogen is not identified.

Medical History

The medical history must include risk factors for bacteremia such as surgery, dental procedures, infections, toothaches, and previous endocarditis.

Forms

Acute endocarditis

Dramatic history of fever, chills, congestive heart failure, decreased consciousness up to multiple organ failure. Acute endocarditis is usually caused by highly virulent pathogens (e.g., staphylococci, beta-hemolytic streptococci, pneumococci) that can destroy even previously intact heart valves.

Subacute endocarditis (endocarditis lenta)

This form occurs practically only in patients with an existing cardiac defect. It is caused by less virulent pathogens (viridans streptococci, enterococci, gram-negative bacteria of the intestinal flora, fungi) and almost always affects previously damaged heart valves. The course is often very non-specific, particularly in the early stages, with intermittent fever or low-grade fever and fatigue.

Symptoms

There are various clinical symptoms of endocarditis including not only general symptoms such as fever and fatigue, but also cardiac symptoms and immunological phenomena and the consequences of bacterial micro-emboli. Typical symptoms are:

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  Fever with tachycardia, and possibly chills (caution: In patients previously treated with antibiotics these symptoms may be partially obscured), in subacute endocarditis also low-grade fever

  
  
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  General symptoms:

  
  
  
  
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    Headache, fatigue, decrease in physical capacity

    
    
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    Weight loss, loss of appetite

    
    
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    Night sweats

    
    
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    Myalgia, arthralgia

  
  
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  Cardiac symptoms:

  
  
  
  
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    Murmur: new occurrence or increase of an already existing murmur (in infections of prosthetic valves often a sign of perivalvular spread)

    
    
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    Valve perforation, avulsion

    
    
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    Myocardial abscesses

  
  
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  Skin symptoms:

  
  
  
  
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    Petechiae

    
    
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    Osler nodes: lentil-sized, painful, reddish nodules, mainly on the fingers and toes (sign of immune complex vasculitis)

    
    
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    Janeway lesions: hemorrhagic, painless skin lesions on the hands and feet

    
    
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    Splinter hemorrhages: subungual hemorrhages at the tips of the fingers and toes

  
  
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  Bacterial microemboli:

  
  
  
  
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    CNS: acute loss of consciousness, focal neurological deficits

    
    
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    Spleen infarction

    
    
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    Pulmonary infarction involving the right heart

  
  
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  Renal involvement:

  
  
  
  
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    Hematuria, proteinuria

    
    
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    Glomerulonephritis

    
    
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    Renal infarction

  
  
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  Eye involvement:

  
  
  
  
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    Roth spots: retinal hemorrhages

  
  
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  Splenomegaly

Duke criteria

The Duke criteria (Table 16.3) are based on clinical findings and are divided into major and minor criteria.

Laboratory

The detection of pathogens in a culture and resistance testing are of major importance. Other typical laboratory findings in endocarditis are:

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  Elevated inflammation markers (CRP, ESR): a normal ESR value practically rules out endocarditis.

  
  
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  Anemia

  
  
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  Leukocytosis with left shift

  
  
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  Thrombocytopenia

  
  
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  Detection of the pathogen in culture and resistance testing: Prior to initiating antibiotic therapy, several (preferably 6–8) blood samples each are taken for aerobic and anaerobic blood cultures. Blood cultures should be taken from different veins if possible. The samples may be taken independently of the fever profile (continuous bacteremia). During the acute course, blood cultures should be taken within 1 to 2 hours if possible so antibiotic therapy can be initiated quickly. In subacute courses, additional cultures can be taken within 1 to 2 days. The cultures are incubated for at least 3 weeks.

  
  
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  Immunological markers: Rheumatoid factors, ANA, circulating immune complexes, or cryoglobulins can sometimes be detected in endocarditis.

  
  
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  Urine: Hematuria or proteinuria can be signs of renal infarction or glomerulonephritis.

ECG

The ECG changes found in endocarditis are non-specific and can be interpreted only retrospectively. Possible abnormalities are:

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  AV block

  
  
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  Bundle branch blocks

  
  
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  Repolarization disturbances

Echocardiography

Echocardiography is very valuable for diagnosing endocarditis. If the findings from transthoracic echocardiography are not sufficient, transesophageal echocardiography is required. Echocardiography can be used for the following:

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  Detection of bacterial vegetation: Bacterial vegetations with a size of 2 to 3 mm can be detected. Detection is difficult in previously severely damaged valves and artificial valves. There is a particularly high risk of emboli if there is mobile vegetation on the mitral valve larger than 10 mm.

  
  
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  Assessment of valve regurgitation

  
  
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  Detection of complications such as abscesses, paravalvular leak, prosthetic dehiscence, leaflet perforations, tendinous cord avulsions, “kissing lesions”

  
  
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  Assessment of ventricular function

  
  
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  Assessment of treatment: verification of the regression of vegetation under antibiotic therapy

The following structures may resemble vegetation in echocardiography and must therefore be considered as a differential diagnosis: valve calcifications, healed vegetations, cardiac tumors, thrombotic deposits (especially at the edge of prostheses or at sutures), avulsions of tendinous cords or papillary muscles, prominent Eustachian valve.

Differential Diagnoses

Endocarditis should always be considered as the differential diagnosis of unexplained fever. The following are possible differential diagnoses:

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  Sepsis

  
  
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  Pneumonia

  
  
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  Kawasaki syndrome

  
  
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  Rheumatic fever

  
  
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  Collagenosis and rheumatic diseases

  
  
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  Chronic inflammatory diseases (Crohn disease)

  
  
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  Noninfectious endocarditis, such as rheumatic endocarditis in rheumatic fever, Libman–Sacks endocarditis in systemic lupus erythematosus, Loeffler syndrome (eosinophilic endomyocarditis)

  
  
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  Cardiac tumors (e.g., atrial myxoma)

  
  
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  Myocarditis

  
  
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  Malignant diseases (e.g., leukemia)

  
  
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  Vasculitis

In febrile patients with cyanotic heart defects and neurological deficits, brain abscesses should also be considered.

Surgical Treatment

In severe cases, antibiotic therapy alone is not sufficient and surgical intervention is required, usually in the form of a valve replacement.

Indications for surgical treatment are:

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  Acute aortic or mitral regurgitation with cardiac pump failure / pulmonary edema

  
  
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  Perivalvular abscess, fistula

  
  
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  Difficult to treat pathogens (e.g., MRSA, fungi)

  
  
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  Severe sepsis and septic shock for more than 48 hours

  
  
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  Persistent fever despite adequate antibiotic treatment after 5 to 10 days (caution: drug-induced fever)

  
  
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  Persistent bacteremia/fungemia despite adequate antibiotic therapy

  
  
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  New mobile vegetation over 10 mm in diameter at the mitral valve

  
  
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  Increase in size of vegetation or spread to previously normal valves

  
  
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  Local destructive course of vegetation

  
  
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  Acute cerebral embolism (after ruling out a cerebral hemorrhage)

  
  
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  Prosthetic valve endocarditis (initially conservative treatment if penicillin-sensitive streptococci are detected)