Pathogenesis

Underlying endothelial injury combined with bacteremia leads to the development of vegetations. Heart lesions with high-velocity jets predispose to endothelial injury. The resulting platelet–fibrin coagulum creates a rich environment for the deposition of bacteria and the growth of a vegetation. The bacteria often become fully enveloped by fibrin, allowing the pathogens to evade the host defenses (Figure 94-1). Congenital heart lesions most at risk include unrepaired cyanotic heart disease (including palliative shunts and conduits), any repaired congenital heart defect with prosthetic material or device in the first 6 months after the procedure, and repaired heart defects with residual defects at the site or adjacent to the site of the prosthesis.

Figure 94-1 Bacterial endocarditis.

Procedures at highest risk for bacteremia involve manipulation of gingival tissue or perforation of oral mucosa. Frequent exposures to random bacteremia from daily activities such as brushing teeth and chewing are more likely to cause endocarditis than are medical procedures. Intravascular catheters also predispose patients to bacteremia. Bacterial colonization of the catheter may prolong periods of bacteremia and creates a risk factor for IE. Nosocomial infections are on the rise. This is troubling because nosocomial infections frequently affect patients without underlying heart conditions, the organisms tend to be more resistant, and there is a high case fatality rate.

The bacteria implicated in IE tend to be those with greatest ability to adhere to damaged tissue. Staphylococcus and Streptococcus spp. have certain surface adhesins, which facilitate attachment to the endocardium. Staphylococcus aureus is the most common pathogen in IE, accounting for more than 50% of cases, especially in those with indwelling catheters, prosthetic valves, and IV drug use. Staphylococcus epidermidis, oral streptococci, and enterococci are also common. In cases of culture-negative endocarditis, the HACEK organisms (a group of fastidious, oral gram-negative bacilli including Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) along with Brucella spp. and fungus must be considered.

Clinical Presentation

Symptoms of IE range from being asymptomatic, to congestive heart failure, to end-organ involvement with septic emboli. History taking should focus on fever, predisposing heart conditions, recent procedures at risk for bacteremia, the existence of indwelling catheters, and symptoms from end-organ involvement. The organs most commonly involved with septic emboli from left-sided IE include the central nervous system, eyes, kidneys, spleen, and skin. Septic pulmonary emboli are seen in cases of right-sided IE. Neurologic complications, which can occur in up to 33% of cases, include stroke, hemorrhage, seizure, abscess, and meningoencephalitis. The physical examination should include a thorough cardiac examination and a search for splenomegaly and for emboli of the fundus, conjunctiva, skin, and digits. Cardiac findings that are most likely to be present include new regurgitant murmurs and signs of congestive heart failure. Physical examination findings that support the diagnosis of IE but are not diagnostic include splinter hemorrhages, Janeway’s lesions, Osler’s nodes, and Roth’s spots (Figure 94-2). These peripheral stigmata of IE are less common in acute IE because patients often present at an earlier stage of disease than those with subacute IE. IE remains a disease with high morbidity and mortality. Cardiac complications occur in up to 30% to 50% of cases. Heart failure is the most common complication and the leading cause of death.

Figure 94-2 Bacterial endocarditis: remote embolic effects.

Evaluation and Management

The Duke classification remains the most reliable way to diagnose IE (Box 94-1). A definitive diagnosis of IE requires direct histologic evidence of IE, culture of specimens from surgery or autopsy, two major criteria, one major criteria and three minor criteria, or five minor criteria. Blood culture results may be negative in up to 15% of cases. The most common reason for a negative culture result is pretreatment with antibiotics, but one must also consider organisms that are difficult to isolate such as nutritionally variant streptococci, HACEK organisms, fungi, and intracellular bacteria (Coxiella burnetii, Bartonella spp., Chlamydia spp., and Tropheryma whippelii). If blood culture results are negative but clinical suspicion remains high, specific culture media or adsorbent resins may be used to isolate these organisms. Cultures should be maintained for up to 2 weeks to allow slower growing organisms to replicate. Serologic testing may be useful for detecting C. burnetii and Bartonella spp. and should be performed if cultures are negative. Polymerase chain reaction (PCR) testing from the blood or infected tissue may also prove useful in cases of culture negative IE. Transesophageal echocardiography (TEE) remains more sensitive than transthoracic echocardiography (TTE) and should be used in high-risk groups. For routine screening in low-risk patients, TTE is acceptable, but if clinical suspicion remains high despite a normal finding, TEE may be required.

Antimicrobial therapy for IE should be directed against the isolated organism, with special attention paid to susceptibility testing. In recent years, the development of resistant organisms poses a particular challenge. A full discussion of antibiotic treatments is beyond the scope of this chapter but can be found in the Suggested Readings. Bactericidal IV treatments should be used, usually for a minimum of 4 weeks. An adequate response to therapy can be ascertained by the absence of fever, normalization of inflammatory markers, negative blood culture results, and echocardiography. Surgical intervention is required in up to 20% to 40% of cases of IE. The indications for surgery include refractory cardiac failure from valvular insufficiency, persistent sepsis, abscess, and persistent life-threatening embolization.

The recommendations for antibiotic prophylaxis for procedures have recently changed. Current recommendations for prophylaxis focus on conditions at the highest risk for an adverse outcome, not an overall increased lifetime risk of IE (Box 94-2). Prophylaxis is only recommended for certain dental procedures and is no longer recommended for respiratory, gastrointestinal, or genitourinary procedures unless contact with infected tissue is expected.

Future Directions

Research is underway to evaluate potential vaccines and therapies against bacterial adhesins, which may prevent bacterial adhesion to damaged endocardium. Because IE is increasingly becoming a nosocomial disease in patients with indwelling catheters, modified biomaterials with antiadherence properties are under development. Despite advances and the development of newer antimicrobial therapies, antibiotic resistance will continue to pose a problem in the treatment of IE.

Pathogenesis

IM is mainly caused by viruses, although bacteria, fungi, protozoa, and parasites have been implicated as well (Box 94-3). The most common causes include enteroviruses, adenovirus, human herpes virus-6 (HHV-6), Epstein-Barr virus (EBV), cytomegalovirus (CMV), parvovirus B19, and HIV. Coxsackievirus B was initially the most commonly discovered virus associated with myocarditis, but this shifted to include other enteroviruses and adenovirus in the late 1990s and more recently to HHV-6 and parvovirus B19. Borrelia burgdorferi (Lyme disease) should be considered in patients with a history of tick bite, especially if conduction abnormalities are present. Myocarditis is commonly seen in HIV infection—by some reports, up to 50% at autopsy. It is unknown if this is solely because of the viral infection or the effects of long-term antiretroviral therapy.

It is believed that viral pathogens enter cardiac myocytes via specific receptors, and the ensuing immunologic response and inflammation is responsible for much of the damage. However, direct killing from viruses likely takes place because viral genomes have been found in cases of dilated cardiomyopathy in the absence of inflammation or myocarditis. Whether IM is purely an infectious process or also involves an autoimmune component is still under debate.

Clinical Presentation

IM can present with a wide range of symptoms, from none at all to sudden death. Patients often have a history of a viral prodrome such as fever, malaise, myalgias, and rash. These symptoms usually precede the cardiac symptoms by several weeks and are often resolved at the time of diagnosis. Typically, cardiac symptoms have only been present for a few weeks before diagnosis. Patients may present with chest pain, dyspnea, exercise intolerance, symptoms of congestive heart failure, arrhythmias, or an acute myocardial infarction–like syndrome. The physical examination should focus on a detailed cardiac examination and stigmata of other diseases known to be associated with myocarditis. Skeletal muscle weakness, dysmorphic facies, hepatosplenomegaly, or multiple organ anomalies may indicate underlying genetic or metabolic causes. History or physical examination findings for particular viral etiologies may help guide the diagnosis. Risk factors for HIV should always be assessed. A history of pharyngitis may point toward EBV or adenovirus, hand or feet lesions may indicate coxsackievirus B, and a history of a “slapped cheek” appearance may implicate parvovirus B19.

Evaluation and Management

There is much debate on how to accurately diagnose myocarditis. Historically, diagnosis has relied on endomyocardial biopsy and the Dallas criteria, which state that an inflammatory cell infiltrate with associated myocyte necrosis be present (Figure 94-3). The sensitivity of the Dallas criteria is reported to be as low as 10% to 22%, and to increase sensitivity to 80%, an estimated 17 ventricular biopsy specimens are needed. The low sensitivity can be explained by a number of reasons. The inflammation in myocarditis is often patchy, leading to endomyocardial biopsy sampling error. There is also much variability in the interpretation of histopathologic samples, with differences in opinion among pathologists in interpreting the same specimen. Often, biopsy is not performed because it is thought to be too invasive, and the diagnosis of myocarditis is made on clinical grounds after other cardiac processes are ruled out.

Figure 94-3 Viral myocarditis.

Echocardiographic findings of myocarditis are often nonspecific and are most useful in ruling out other causes of heart failure. Echocardiography may show segmental wall motion abnormalities, thrombus, right ventricular involvement, pericardial effusion, or transient increases in left ventricular thickness as a measure of edema. More recently, cardiac magnetic resonance (CMR) imaging has proven a useful tool in the diagnosis of acute myocarditis, with high sensitivity and specificity. It has been used to select endomyocardial biopsy sites, with proven success. Cardiac biomarkers, including creatine kinase and troponins, may or may not be elevated in acute myocarditis. Electrocardiography (ECG) may show nonspecific ST-segment and T-wave abnormalities. If the pericardium is involved, the ECG would show changes consistent with pericarditis.

The search for a viral cause of IM includes testing for specific virus serology as well as viral genomes. Any biopsy specimen should be tested by PCR for coxsackievirus B, echoviruses, parvovirus B19, adenovirus, CMV, EBV, and HHV-6. If an endomyocardial biopsy is not performed, these tests can be sent from the blood. Serologies may also be useful in identifying acute infection. If the history is suggestive of HIV infection, the patient should undergo HIV testing.

Treatment of IM is mainly supportive. Because most patients with viral myocarditis improve over time, therapy is focused on medical management of heart failure until the inflammation improves. This usually includes angiotensin-converting enzyme inhibitors, β-blockers, and diuretics. There may be a need for mechanical circulatory support such as left ventricular assist devices or extracorporeal membrane oxygenation in cases of fulminant myocarditis with profound left ventricular dysfunction. Studies on immunosuppressive therapies for treatment of acute myocarditis have not shown any benefit. Treatment with IV immunoglobulin (IVIG) has proven equally disappointing. A Cochrane review concluded that there was no benefit from the use of IVIG for the management of presumed viral myocarditis in children and adults. Interferon-α and -β have shown some promise in small, single-center studies, but the results need to be confirmed in larger randomized studies. Because the diagnosis of IM often happens weeks after the onset of acute viral infection, it is unlikely that specific viral treatments would significantly alter the course of the disease. Although there is a high rate of spontaneous improvement in IM, the late sequela of chronic dilated cardiomyopathy has significant morbidity, with some patients progressing to a need for cardiac transplantation.

Future Directions

CMR is becoming increasingly useful in the diagnosis and management of patients with myocarditis. It is likely to become integral in the diagnosis and follow-up of all patients with myocarditis, perhaps even making biopsies unnecessary. Better understanding of viral pathogenesis and the immune response should help guide therapies in the future, whether it is to halt viral replication or alter the body’s immune destruction to minimize damage.