Myocarditis and Pericarditis

50 

SECTION 2 Syndromes by Body System: Bloodstream, Heart and Vessels

Myocarditis and Pericarditis ADAM Z. BANKS  |  G. RALPH COREY

KEY CONCEPTS Myocarditis • Chronic myocarditis can cause subacute deterioration of cardiac function predating development of idiopathic dilated cardiomyopathy. • Parvovirus B19 and HHV-6 are the most frequently isolated viruses in patients with viral myocarditis; enteroviruses are found less commonly than previously expected. • Immunocompromised patients are at higher risk for clinically significant myocarditis and are uniquely at risk for opportunistic pathogens. • Diagnosis is now made with a multidisciplinary approach incorporating cardiac magnetic resonance imaging and endomyocardial biopsy. • Treatment is currently focused on supportive care and heart failure management; ongoing trials are examining immunosuppressive regimens.

Pericarditis • The most prevalent noninfectious causes of pericardial disease are malignancies, uremia and connective tissue disorders (SLE, rheumatoid arthritis). • Pain is usually retrosternal with radiation to the trapezius ridge; it is exacerbated by lying supine and relieved by leaning forward. • A pericardial friction rub is the pathognomonic physical exam finding, characterized by a scratchy or grating sound best appreciated along the left sternal border with respirations suspended and the patient leaning forward. • Echocardiography is the first-line imaging modality; computed tomography and cardiac magnetic resonance imaging can be considered for evaluation of complex disease, extracardiac disease and when echocardiography is limited by body habitus. • Myopericarditis may be present if there is evidence of cardiac dysfunction or elevation of cardiac biomarkers.

arrhythmias occur in the setting of a systemic febrile illness or after an upper respiratory tract infection. The incidence of infectious myocarditis in the general population is unknown. In a prospective study of Finnish military recruits conducted over several years, a mean annual incidence of 0.02% was found.2 The prevalence of clinically significant myocarditis is higher in children and young adults, and is thought to be a major cause of sudden cardiac death in adults under the age of 40 years.3–5 Within immunosuppressed patients, myocarditis is more prevalent, affecting approximately 50% of acquired immunodeficiency syndrome (AIDS) patients at autopsy.6

Pathogenesis and Pathology In myocarditis, damage to cardiac myocytes appears to involve four possible mechanisms: • direct cytopathic effects of an infectious agent • cellular injury secondary to circulating exogenous or bacterial toxins • cell-mediated or humoral immunologic response to the inciting agent or induced neoantigens • cellular injury caused by generalized inflammation. Histologically, both myocyte necrosis and infiltration by inflammatory cells (including neutrophils, lymphocytes, macrophages, plasma cells, eosinophils and/or giant cells) in the absence of ischemia are patho­ gnomonic of the disease (Figure 50-1).The pathologic abnormalities associated with myocarditis vary depending on the etiologic agent and host response. Coxsackievirus, for example, appears to infect myocytes directly while infection with parvovirus B19 involves the vascular endothelium. The time after infection influences the histologic appearance. In addition, analysis of endomyocardial biopsy (EMB) specimens obtained during infection with different agents shows considerable overlap. Thus, a histologic diagnosis of myocarditis usually does not indicate the agent responsible.

BACTERIA Bacteria may cause myocarditis by several mechanisms. Bacteremia caused by a variety of species may result in metastatic foci within the

Myocarditis Epidemiology The term myocarditis applies to a variety of disease states that produce inflammation of the myocardium. Acutely, myocarditis ranges from an asymptomatic illness with reversible changes to fulminant myocardial necrosis and death. In chronic myocarditis, lymphocytic infiltration of the myocardium, may cause subacute deterioration of cardiac function; indeed, chronic myocarditis may predate the development of ‘idiopathic’ dilated cardiomyopathy. Approximately 10% of new onset unexplained cardiomyopathy is attributable to myocarditis.1 Although frequently ascribed to inflammation caused by infection, myocarditis may be seen in allergic reactions, drug reactions and in association with systemic inflammatory disease. Acute infectious myocarditis is suggested when unexplained heart failure or malignant

446

Figure 50-1  Acute viral myocarditis, with a characteristic mononuclear infiltrate.



Chapter 50  Myocarditis and Pericarditis

myocardium. These include streptococcal and staphylococcal bacteremia, meningococcemia, brucellosis, salmonellosis, listeriosis, Whipple’s disease, etc. However, the resulting myocardial dysfunction is only clinically significant in a subset of patients with overwhelming infections. In contrast, myocardial involvement in bacterial endocarditis is more common and is often clinically significant. Bacteria (especially Staphylococcus aureus) may directly invade the myocardium from infected valves to cause abscesses, valvular failure and conduction abnormalities, or may embolize throughout the myocardium to cause global ventricular dysfunction. Cardiac infections caused by salmonellae are particularly serious; mural involvement responds poorly to antibiotics and, without surgical therapy, mortality nears 100%.7 Bacterial toxin production can also be clinically significant. Subtle evidence of toxin-mediated myocarditis can be detected in as many as two-thirds of patients who have diphtheria, occurring 1–2 weeks after the onset of illness, often when the oropharyngeal manifestations are improving.8 Patients who have electrocardiographic (ECG) changes consistent with myocarditis have a mortality rate three to four times that of patients who have normal tracings, with atrioventricular nodal and left bundle branch block carrying mortality rates of 60–90%.9 Finally, cardiac involvement (including myocarditis) occurs in up to 50% of cases of acute rheumatic fever. ‘Molecular mimicry’ (e.g. immunologic cross-reactivity to cardiac antigens elicited by streptococcal products) underlies the postulated pathogenesis of this disease, as group A streptococci have not been identified in myocytes.

SPIROCHETES Spirochetes, such as Borrelia burgdorferi, the etiologic agent of Lyme disease, are an important cause of myocarditis with cardiac manifestations occurring in approximately 8% of patients.10 The cardiac manifestations of Lyme disease may occur in an isolated manner, or coincident with other features such as erythema chronicum migrans or neurologic abnormalities. The most prevalent abnormality is atrioventricular block, but some patients have evidence of diffuse myopericardial involvement. Myocardial involvement is also common in cases of fatal leptospirosis (Weil’s disease), where arrhythmias or cardiogenic shock may occur in conjunction with hepatorenal or central nervous system syndromes. At autopsy, myocardial inflammation, coronary arteritis and aortitis are common. During late syphilis, gummatous involvement of the myocardium is a rare cause of myocarditis. Cardiac manifestations include conduction abnormalities and myocardial infarction usually involving the left ventricle at the base of the interventricular septum.11 Rickettsiae produce systemic vasculitis by endothelial invasion, which can involve

TABLE 50-1 

447

the myocardium. Rocky Mountain spotted fever (caused by Rickettsia rickettsii) and scrub typhus (caused by R. tsutsugamushi ) infections may cause transient cardiac dysfunction in severe illness, which clears with disease resolution. Coxiella burnetii (the agent of Q fever), an important cause of endocarditis in selected locations (e.g. France), is a rare cause of myocarditis, but may progress to congestive heart failure (CHF) and death.12

PARASITES Several parasites are known to cause chronic myocarditis and myocardial dysfunction, primarily in the developing world. Chagas disease (American trypanosomiasis), distributed in Central and South America, is caused by the protozoan Trypanosoma cruzi. The organism enters the human host via the bite of the reduviid bug. Rarely, patients develop myocarditis during acute infection, when myocardial parasites are abundant. More common is biventricular failure from chronic myocarditis, which occurs in 30% of infected individuals. Trichinella spiralis is another parasite with worldwide distribution that has been linked to fatal myocarditis. Myocarditis generally develops in severe infections, in which the cardinal features of periorbital edema, myositis, fever and eosinophilia are present. Recent consumption of poorly cooked pork enhances the likelihood of this diagnosis. Other parasites and/or their ova, including Ascaris, Schistosoma and Taenia solium, may lodge in the myocardium during their systemic phase. Eosinophilia in acute CHF should prompt a search for their presence.

VIRUSES Viral infections are the most common cause of myocarditis in the Western world (Table 50-1). Molecular techniques have shown enteroviruses to be less common than expected. Parvovirus B19 and human herpesvirus 6 (HHV-6) were the most frequently isolated viruses in patients with viral myocarditis in 2005, accounting for 56% and 18% of infections, respectively.13 The following viruses were also identified: enterovirus (9.4%), adenovirus (1.6%), Epstein–Barr virus (2%), and cytomegalovirus (CMV) (0.8%). Cases of myocarditis from influenza A, particularly H1N1, and influenza B have recently been identified after the 2009 H1N1 epidemic.14 Until recently, evidence of a causal link between enterovirus infection and myocarditis was primarily circumstantial, since many patients report an antecedent viral syndrome.15 Increased enteroviral antibody titers or a fall in convalescent titers have been offered as evidence that enteroviruses are the causative agents, but these infections are common in the general population and positive serologies are nonspecific.

Infectious Causes of Myocarditis

Occurrence/Importance

Normal Host

Immunocomprised Host

Common and/or important

Viruses: Parvovirus B19, human herpesvirus 6, coxsackieviruses (A and B), influenza echovirus, cytomegalovirus (CMV), Epstein–Barr virus (EBV), influenza viruses (A and B), adenovirus, hepatitis B virus, hepatitis C virus Bacteria: Corynebacterium diphtheriae, Borrelia spp., any organism associated with infective endocarditis Parasites: Trichinella spiralis, Trypanosoma cruzi

Viruses: HIV, CMV, EBV, varicella-zoster virus (VZV), adenovirus, parvovirus Fungi: Candida, Aspergillus, Cryptococcus Parasites: Toxoplasma gondii, Trypanosoma cruzi

Uncommon

Viruses: adenovirus, respiratory syncytial virus, hepatitis B virus, ?hepatitis C virus Bacteria: staphylococci, streptococci, meningococci, Salmonella, Listeria, Clostridium, Rickettsia, Bartonella, Ehrlichia, Campylobacter jejunii

Fungi: Histoplasma, Blastomyces, Coccidioides imitis, zygomyces

LOW- AND MIDDLE-INCOME COUNTRIES

Viruses: poliovirus, mumps virus, rubella virus, arenaviruses, dengue virus, rabies virus, chikungunya virus, Ebola virus, yellow fever virus Bacteria: Leptospira spp. Parasites: Trypanosoma cruzi, Trypanosoma gambiense

INDUSTRIALIZED COUNTRIES

448

SECTION 2  Syndromes by Body System: Bloodstream, Heart and Vessels

IMMUNOCOMPROMISED PATIENTS Immunocompromised patients are subject to the same infections as the immunocompetent; however, their risk for clinically significant myocarditis is high and they are uniquely at risk for opportunistic pathogens. Prior to highly active antiretroviral therapy (HAART) cardiac disease in the human immunodeficiency virus (HIV) population was primarily related to myocardial and pericardial disease with up to 40% demonstrating cardiac abnormalities. The increasing use of HAART therapy, however, has led to a significant decrease in the incidence of myocarditis or pericarditis. Coronary artery disease has become the leading cause of heart disease in the HIV population in higher-income countries related to lipodystrophy and the metabolic syndrome caused by HAART.16 Although HIV itself has been cultured from heart tissue17 and shown to be present by in situ hybridization,18 it is only rarely present in myocytes. Thus, whether the virus causes heart failure, sets the stage for other cardiotropic pathogens (e.g. CMV), or is a correlate for the causative nutritional wasting present in late-stage AIDS is unknown. While uncommon in the United States, in sub-Saharan Africa opportunistic pathogens are still a common cause of myocardial disease. In an autopsy study of 16 patients with cardiomyopathy, myocytes were infected with Toxoplasma gondii in 19%, Mycobacterium avium– intracellulare in 13% and Cryptococcus neoformans in 19%.19 Other disseminated fungal infections (such as disseminated candidiasis, aspergillosis and histoplasmosis) or viral infections such as herpes simplex virus or varicella-zoster virus may also present with myocarditis in the immunocompromised patient, but can usually be identified by associated findings. CMV is an important pathogen in organ and hematopoietic stem cell transplant recipients. In heart transplant recipients, CMV infection is a risk factor for a form of immune-mediated cardiac rejection that presents as accelerated coronary atherosclerosis; importantly, prophylactic ganciclovir significantly reduces the incidence of this complication.20–21 Important noninfectious causes of myocarditis are listed in Table 50-2. Considering these noninfectious sources is a key step in the diagnosis of myocarditis, as the treatment and prognosis will differ.

Clinical Features Acute myocarditis ranges from an asymptomatic state to rapidly progressive myocardial dysfunction and death. Complaints on presentation may include fever, fatigue, malaise, chest pain, dyspnea and palpitations. Chest pain may be vague, pleuritic (suggesting pericardial involvement) or angina-like. The majority of patients have no precordial discomfort.

TABLE 50-2 

Noninfectious Causes of Myocarditis

Connective tissue disorders

Systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, dermatomyositis, polymyositis

Idiopathic inflammatory/infiltrative disorders

Kawasaki disease, sarcoidosis, giant cell myocarditis

Insect and arachnid stings

Wasp, scorpion, spider stings

Medications

Cocaine, ethanol, arsenic, cyclophosphamide, daunorubicin, adriamycin, sulfonamides, tetracycline, methyldopa

Post-irradiation myocarditis Peripartum myocarditis Pheochromocytoma Thrombotic thrombocytopenic purpura Thyrotoxicosis

Physical examination may reveal tachycardia out of proportion to the height of fever or degree of heart failure. Cardiac auscultation may demonstrate muffled heart sounds, transient murmurs or ventricular gallops; friction rubs are uncommon and indicate pericardial involvement. In severe cases, signs of CHF are present. The electrocardiographic manifestations of myocarditis are usually transient and occur more frequently than clinical myocarditis. ST elevations and T wave inversions may be seen acutely, and reflect the focal nature of the myocardial inflammation. These changes usually return to normal within 2 months. Atrial and ventricular arrhythmias are common in severe cases. Atrioventricular nodal or intraventricular conduction defects denote involvement of the conduction system and suggest more widespread disease or specific etiologies (e.g. Lyme carditis).

Diagnosis The diagnosis of myocarditis is often difficult and requires a high index of suspicion. When unexplained CHF or malignant arrhythmias occur in the setting of an acute febrile illness, the clinical diagnosis of infectious myocarditis is suggested. CHF of recent onset mandates that the physician first consider ischemic, valvular, or congenital disease in the differential diagnosis. Other causes of acute myocardial dysfunction, such as rheumatologic disease, endocrinopathies, electrolyte disturbances and toxin exposure (e.g. ethanol, cocaine and heavy metals), must also be ruled out. Viral serologies or polymerase chain reaction (PCR) are not indicated for routine management as they have a high prevalence in the population with a low specificity for myocarditis. In a study of 124 patients with clinically suspected myocarditis the serum serology was only concordant with the nested PCR from the endomyocardial biopsy (EMB) in 5 of 124 cases.22 ECG changes are important, but given the high incidence of nonspecific ST segment and T wave changes seen in acute viral syndromes, they alone are nondiagnostic. Similarly, laboratory abnormalities such as leukocytosis and an elevated erythrocyte sedimentation rate are also nonspecific. Serum creatinine phosphokinase (CPK), CPK-MB and troponin T (a cardiac contractile protein) do signify myocardial injury and are important, but do not differentiate the cause of that injury. However, in contrast to ischemic necrosis, in which CPK levels return to normal within 72 hours, elevated CPK levels may persist for 6 days in myocarditis.23 Echocardiograms in myocarditis commonly show variable degrees of cardiac dysfunction, often with striking focal wall motion abnormalities. Dyskinesia or akinesia is most often biventricular. Echocardiographic changes generally resolve within a few days in parallel with the clinical course; if progressive ventricular dysfunction is demonstrated, chronic myocarditis may be suggested. Many other imaging modalities for diagnosing acute myocarditis have been studied. However, validation of these diagnostic tools has been challenging in the absence of a reliable gold standard. Cardiac magnetic resonance imaging (CMR) is able to distinguish between the different etiologies of myocardial damage, including myocarditis, ischemia and other cardiomyopathies.24 The high spatial resolution and contrast used in CMR allows for small areas of injury to be identified, which is useful for diagnosis of myocarditis since it often presents as focal or patchy inflammation of the ventricles. Despite advances in imaging techniques, EMB is still considered the reference technique for diagnosis of myocarditis. Rarely, a biopsy will identify specific disease processes (i.e. toxoplasmosis, CMV, giant cell myocarditis, trichinosis, sarcoidosis, amyloidosis) for which therapy is available or for which a prognosis can be given. However, it remains limited by the lack of sensitivity and specificity along with its invasive nature. A working standard, termed the Dallas criteria, has been used since 1986 to define the histologic findings consistent with myocarditis. Even in post-mortem specimens with proven myocarditis, the probability of diagnosing myocarditis based on the Dallas criteria with one biopsy was only 17–28%, which increased to

approximately 67% with more than five biopsies.25–28 Recently efforts have focused on improving the yield of EMB with the use of immunohistochemical staining and nested PCR for viral genomes. In experienced hands the procedure is relatively safe, although deaths have occurred. Biopsy studies have generally been carried out in cases of fulminant myocarditis. Late biopsy is unhelpful as histologic evidence of myocarditis resolves in 3–4 weeks. In recent years the use of the Dallas criteria as the sole diagnostic modality for myocarditis has fallen out of favor. Currently a multidisciplinary approach is advocated which includes histologic appearance, immunohistochemical staining, nested PCR for viral genomes, as well as CMR imaging.29 The use of molecular techniques (nested PCR) in conjunction with EMB has increased the ability to detect viral genomes.30–32 However, due to the uncertainty regarding the number of biopsy specimens required to attain high clinical sensitivity, a positive PCR result is diagnostic while a negative PCR does not exclude viral disease.33 In 2009, guidelines on CMR for myocarditis were published. CMR was recommended for a subset of patients with new-onset CHF where viral myocarditis was a likely etiology and standardized diagnostic criteria based on CMR were proposed.34–35 Fortunately, most cases of myocarditis are mild and resolve spontaneously. With this said, EMB should be performed only when results will potentially change management. Current guidelines published in 2007 recommend against routine EMB in new onset-CHF, but do recommend its use in 14 distinct scenarios where EMB would alter management.33 Transplant recipients and immunosuppressed patients represent exceptions where routine biopsy may be warranted. A thorough history (with attention to epidemiologic detail) and physical examination will diagnose most nonviral etiologies, in which signs and symptoms other than CHF frequently dominate the presentation. A complete blood count with differential should be performed to rule out eosinophilia (which may suggest parasitic infection or hypersensitivity myocarditis). In the febrile patient, blood cultures should be obtained. Testing for HIV should always be performed given the high prevalence of myocarditis in patients with AIDS; testing for Lyme disease, Chagas disease and autoimmune diseases should be performed in the appropriate clinical context. Testing for CMV in blood is unlikely to be helpful because CMV reactivation in the presence of unrelated acute febrile illnesses is common. EMB should also be considered in the setting of progressive clinical deterioration. Unfortunately the historical, physical examination, laboratory and imaging findings remain largely nonspecific in myocarditis with overlap of other CHF syndromes. The diagnosis requires a high degree of suspicion as well as exclusion of common etiologies of CHF.

Management The natural history of acute infectious myocarditis is variable, although the majority of cases run a benign course. Acute cardiac dysfunction does not predict chronic impairment, as most of these individuals demonstrate normalization of cardiac function within 1 month. General measures target cardiac dysfunction and arrhythmias associated with myocarditis. Animal models have demonstrated that exercise during viral myocarditis is associated with more extensive histologic damage; thus, bed rest may be important. Conventional therapy has included diuretics, angiotensin-converting enzyme (ACE) inhibitors and beta-blockade, as for any CHF patient. Rarely, fulminant myocarditis requires the use of inotropic support, intra-aortic balloon pumps or ventricular assist devices as a bridge to the resumption of cardiac function.36 Unfortunately, there are no clinical or laboratory indicators to identify those patients who will recover; indeed, patients who have fulminant myocarditis may have a better prognosis than those with nonfulminant myocarditis.37 As arrhythmias are probably associated with the majority of deaths in acute myocarditis, all hospitalized patients should be monitored on telemetry. Care should be exercised with any antiarrhythmic agent but sustained arrhythmias should be treated aggressively. Complete heart block can occur and serial ECGs should be followed. If a specific

Chapter 50  Myocarditis and Pericarditis

449

infection is identified antimicrobial therapy should be directed at the causative pathogen. As noted above, viruses are the most likely cause of myocarditis, but patients with viral myocarditis most commonly present after viral replication has ceased. Most studies of immunosuppressive therapy have not influenced outcome. Randomized controlled trials of both immunosuppressive therapy (prednisone + cyclosporine or azathioprine) and intravenous immunoglobulin failed to show any benefit.38–39 In contrast, the BICC trial in 2008 randomized viral myocarditis patients to interferonbeta-1b (Betaferon) versus placebo. At 6 months patients treated with Betaferon had improved NYHA functional status and 100% of the patients receiving Betaferon had no evidence of virus within the myocardium. This was documented by EMB at eight sites evaluated by both the Dallas Criteria and PCR. At 10-year follow up patients who had demonstrated viral clearance by EMB at 6 months, either spontaneously or with Betaferon, had a statistically lower rate of mortality.40-42

Pericarditis Epidemiology Interest in the pericardium dates to antiquity. Homer and Maximus relate the history of the ‘hairy hearts of heroes’ such as Aristomenes, the legendary Messinian warrior; his heart was cut out in battle and found to be ‘stuffed with hair’, probably the first recorded case of fibrinous pericarditis. Medical advances in antibiotics, surgery, antineoplastic therapy and hemodialysis have altered the spectrum and prognosis of pericardial disease. Imaging has also made an impact; since the advent of echocardiography pericardial effusions are now readily diagnosed. The incidence of pericardial inflammation detected in several autopsy series ranges from 2% to 6%, whereas clinically apparent pericarditis is diagnosed in only about 1 out of 1000 hospital admissions. The frequency of each etiologic process depends upon the clinical setting.

Pathogenesis and Pathology The pericardium forms a strong, flask-shaped sac that encloses the heart and the origins of the great vessels. It is composed of a fibrous outer layer and an inner serous membrane formed by a single layer of mesothelial cells. This membrane is attached to the epicardium to form the visceral pericardium; it reflects upon itself, lining the inside of the collagen-based fibrous layer to form the parietal pericardium. The visceral pericardium continuously produces a clear pericardial fluid, which serves as a lubricant; it is also the source of excess fluid in disease states. The human pericardium normally contains up to 50 mL of this fluid, which drains via the thoracic and right lymphatic ducts into the circulation. Pericardial effusions develop in response to pericardial injury or secondary to other processes that alter the secretion and drainage of pericardial fluid. The pathologic changes seen in acute pericarditis are those of nonspecific inflammation with cellular infiltration, fibrin deposition and the outpouring of pericardial fluid. These changes may resolve spontaneously, or may organize with fibrous adhesions between the epicardium and visceral pericardium, the visceral and parietal pericardium, or the pericardium and adjacent sternum and pleura (Figure 50-2). Thus, inflammation, fluid exudation and fibrin organization account for the cardinal manifestations of pericarditis: chest pain, pericardial effusion and constriction. The causes of this pericardial inflammation are numerous, including both noninfectious (Box 50-1) and infectious (Table 50-3) etiologies.

NONINFECTIOUS AGENTS The three most prevalent noninfectious causes of pericardial disease are malignancies, uremia and connective tissue disorders. It is imperative to rule out these diagnoses before presuming a diagnosis of acute infectious pericarditis.

450

SECTION 2  Syndromes by Body System: Bloodstream, Heart and Vessels

VIRUSES The most common etiologies of viral pericarditis have been thought to include coxsackie A and B, echovirus type 8, adenovirus and HIV (see Table 50-3). These viruses have only rarely been isolated from pericardial fluid or tissue; as such, evidence for viral causation of pericardial inflammation is based upon isolation of virus from other sites, such as stool, and by demonstration of a fourfold rise in serum antibody titers. Most recently, PCR testing has found evidence of adenovirus, enterovirus, HHV-6 and CMV in pericardial fluid and tissue from patients with acute pericarditis.43

BACTERIA AND OTHER INFECTIOUS AGENTS

Figure 50-2  Heart at autopsy of a patient who had acute suppurative pericarditis. The parietal pericardium has been stripped from the specimen, revealing a ‘bread and butter’ appearance.

BOX 50-1  NONINFECTIOUS CAUSES OF PERICARDITIS Idiopathic Connective tissue disorders Acute rheumatic fever, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, mixed connective tissue disease, Wegener’s granulomatosis, polyarteritis nodosa, temporal arteritis Metabolic Uremia, hypothyroidism Malignancies Lung cancer, breast cancer, leukemia, lymphoma, melanoma, others Acute myocardial infarction Post-myocardial infarction syndrome (Dressler syndrome) Dissecting aortic aneurysm Traumatic Chest trauma, postsurgical hemopericardium, pacemaker insertion, cardiac catheterization, esophageal rupture, pancreatic–pericardial fistula Post-irradiation Sarcoidosis, amyloidosis, inflammatory bowel disease, Behçet’s disease, familial Mediterranean fever, tumor necrosis factor-associated periodic syndrome (TRAPS), cryopryin-associated periodic syndrome (CAPS) Medications Procainamide, hydralazine, isoniazid, phenylbutazone, dantrolene, doxorubicin, dilantin, methysergide, minoxidil

• Neoplasms may cause pericarditis or effusions by direct involve-

ment of the pericardium or by obstruction of the pericardial lymphatic drainage. • Uremic pericarditis is characterized by the appearance of a shaggy, fibrinous exudate without cellular infiltration. • Collagen vascular diseases (most commonly systemic lupus erythematosus and rheumatoid arthritis) have a propensity to involve the pericardium; immune complex deposition is thought to be primary in the pathogenesis of autoimmune pericardial disease.

INFECTIOUS AGENTS A variety of microbes have been reported to cause pericarditis. Chief among these are viruses, which can produce a clinical syndrome of myopericarditis, but other infectious agents are also implicated.

Bacteria cause pericarditis by a number of different mechanisms. Hematogenous seeding of the pericardium may occur during the course of bacteremia caused by a variety of organisms. In the preantibiotic era, most cases of purulent pericarditis were seen as complications of bacteremia or pneumonia. Today, extension of infection from a contiguous focus within the chest is seen as a postoperative or post-traumatic complication. Highly invasive bacterial infections within the heart, such as staphylococcal endocarditis, may erode into the pericardium from a perivalvular abscess to cause purulent pericarditis. The microbiology of bacterial pericarditis continues to evolve (see Table 50-3). Before antibiotics, uncontrolled pneumococcal, streptococcal or staphylococcal pulmonary infections were most frequently implicated. Streptococci and staphylococci remain important pathogens today (particularly in traumatic and post-thoracotomy pericarditis), with gram-negative bacilli, atypical bacteria and Candida also assuming important roles. Pericardial involvement has also been documented in the course of such illnesses as tularemia, brucellosis, salmonellosis, legionellosis, meningococcal disease and Q fever.44 Pericarditis caused by Mycoplasma deserves mention, but has proved difficult to identify in pericardial fluid. Therefore, autoimmune phenomena have been invoked to explain the association. In one report, Mycoplasma pneumoniae, M. hominis and Ureaplasma urealyticum were isolated from pericardial fluid and/or tissue cultures in five patients with large pericardial effusions.45 Treatment with doxycycline after drainage of the effusions resulted in resolution in all cases. Pericarditis caused by Mycoplasma spp. is thus more common than previously recognized, and fluid obtained for culture should be analyzed for these organisms. Mycobacteria continue to be important causes of acute pericarditis, pericardial effusion and constrictive pericarditis, particularly in lowand middle-income countries. The incidence of tuberculous pericarditis among patients who have pulmonary tuberculosis ranges from 1% to 8%.46 While the overall incidence of tuberculous pericarditis has significantly declined in the USA, countries with a high prevalence of tuberculosis and HIV such as South Africa continue to have a higher burden of disease. In a study from the Western Cape province of South Africa, tuberculous pericarditis was the most common cause of pericardial effusions and accounted for 69.5% of the 233 cases of pericardial effusion. Of note, 50% of patients were HIV-positive.47 Despite the advent of HAART, extrapulmonary tuberculosis does still have to be considered in the USA in at-risk patients. Data from the North Carolina Division of public health from 1993 to 2006 identified over 6000 cases of tuberculosis, with extrapulmonary involvement in 1299.48 However, a minority of these cases had pericardial involvement. Histoplasma capsulatum is the most common cause of fungal pericarditis; in large outbreaks, pericarditis was noted in 6% of patients who had symptomatic histoplasmosis. It most commonly develops as a noninfectious inflammatory response that resolves without therapy. Occasionally, seeding of the pericardium occurs in the course of disseminated infection. In contrast, pericarditis has only rarely been reported in cases of severe coccidioidomycosis. In the immunosuppressed or post-thoracotomy patient, infection caused by Candida spp., Aspergillus fumigatus or Cryptococcus has occasionally resulted from fungemia or direct inoculation.



Chapter 50  Myocarditis and Pericarditis

TABLE 50-3 

451

Infectious Causes of Pericarditis

Cause of Acute Pericarditis

Incidence (%) in Western Countries

Predisposition

IDIOPATHIC

Frequent 50–70%

Unknown

Diagnostic Approaches

INFECTIOUS Viruses Enterovirus, echovirus

Common 30%

PCR

Cytomegalovirus, influenzavirus

Frequent 1-10%

Serology, PCR

Human immunodeficiency virus

Rare

Serology

Miscellaneous (adenovirus, parvovirus B19, varicella-zoster virus, Ebstein–Barr virus, mumps, hepatitis A, B, C)

Rare <1%

Serology, PCR

Coxiella burnetii

7%

Serology

Tuberculosis

4% (7% of tamponade)

Chronic alcohol use, HIV

Culture, PCR

Gram-negative rods, staphylococci, Streptococcus pneumoniae

Rare <1%

Chronic alcohol use, immunosuppression

Culture, PCR

Miscellaneous (e.g. Chlamydia, Mycoplasma, Legionella, Leptospira , Borrelia bugdorferi, Listeria)

Rare <1%

Bacteria

Serology

Fungal Candida species, histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis

Rare <1%

Immunosuppression

Culture, PCR

Parasitic Toxoplasma gondii

Rare <1%

Serology, PCR

Entamoeba histolytica

Rare <1%

Serology

Echinococcus granulosus

Rare <1%

Serology

Schistosoma spp.

Rare <1%

Serology, histology

Frequent

Creatinine, urea

NONINFECTIOUS Metabolic Disorders Uremic, dialysis-related Hypothyroidism

TSH

Vasculitis and connective tissue disease

Estimated from specific population:

Rheumatoid arthritis

Frequent

Systemic lupus erythematosus, scleroderma

Frequent 20%

Rheumatic fever

20–50%

Miscellaneous: Sjögren’s syndrome, Reiter syndrome, ankylosing spondylitis, Wegener’s granulomatosis, giant-cell arteritis, polymyositis, Behçet’s syndrome, familial Mediterranean fever, other autoinflammatory syndromes, dermatomyositis, polyarteritis, Churg–Strauss syndrome, thrombotic thrombocytopenic purpura

Rare <1%

Neoplastic Disorders

Estimated from specific population:

Primary: mesothelioma, sarcoma, fibroma, lipoma, carcinoma, lymphoma, carcinoid

Rare <1%

Pericardiocentesis

Secondary (metastatic or direct spread)

Frequent

Pericardiocentesis

Radiation

Rare <1%

20–30% rheumatoid factor Specific antibodies Children Specific antibodies

Post-injury Syndrome Myocardial infarction, and postmyocardial syndrome

5–10% cases

Pericardial perforation (cardiac, surgery, percutaneous procedures)

1–3%

Esophageal perforation, aortic dissection, pneumonia, pulmonary embolism, empyema

Rare <1%

CT scan

Continued on following page

452 TABLE 50-3 

SECTION 2  Syndromes by Body System: Bloodstream, Heart and Vessels

Infectious Causes of Pericarditis (Continued)

Cause of Acute Pericarditis

Incidence (%) in Western Countries

Predisposition

Diagnostic Approaches

Association with Other Syndromes Inflammatory bowel disease, Loffler syndrome, Stevens– Johnson syndrome, giant-cell aortitis, hypereosinophilic syndromes, acute pancreatitis

Rare <1%

Drugs Procainamide, hydralazine, methyldopa, reserpine, minoxidil, phenylbutazone, bromocriptine, amiodarone etc.

Rare <1%

Post-irradiation

Rare <1%

PERICARDITIS IN AIDS In contrast to other immunocompromised states, pericardial disease in patients who have AIDS is quite common. Effusions are frequently noted in end-stage AIDS (occurring in 16–40% of patients) and are associated with a poor prognosis. Etiologies include a variety of pathogens (including viruses, bacteria, fungi and mycobacteria), although in the majority of cases no causative agent can be defined. Malignant effusions secondary to lymphomatous involvement of the pericardium have also been noted. Although extrapericardial disease suggested specific infectious or malignant etiologies in 55% of patients who had pericardial effusions in one trial, these assumptions proved incorrect for all those in whom pericardiocentesis was performed.49 As a result, in HIV pericardiocentesis is often necessary for accurate diagnosis.

Clinical Features Acute pericarditis is most often recognized by presentation with chest pain. The pain is usually precordial or retrosternal, often with radiation to the trapezius ridge or neck; it is exacerbated by lying supine, coughing or by deep inspiration, with relief upon sitting upright or forward. The discomfort may be caused by inflammation of the adjacent pleura, accounting for the pleuritic component of the pain. This pain is distinguished from the pain of ischemia by its quality, its duration (may last for days without therapy) and the absence of associated factors. A pericardial friction rub is the pathognomonic physical finding of pericarditis. Characterized as scratchy or grating, it is best appreciated along the left sternal border with respirations suspended and the patient leaning forward. The classic friction rub has three components, corresponding to atrial systole, ventricular systole and the rapid ventricular filling phase of early diastole, although one or more of these phases are usually absent. Of note, the friction rub frequently waxes and wanes in intensity and may disappear altogether with the accumulation of fluid. The pericardial rub may again become prominent in tamponade, in which the pericardium rubs against the adjacent pleura. Pericardial effusions range from the asymptomatic to those causing cardiac tamponade. The rate of fluid accumulation is a major determinant in physiologic manifestations. When the effusion develops slowly, the pericardium may stretch to accumulate as much as 2 liters of fluid. The normal pericardium, however, can accommodate the rapid accumulation of only 100–200 mL of fluid before signs and symptoms of tamponade develop. Examination will reveal jugular venous distension, the most common physical finding in tamponade. A fall of 10 mmHg or more in systolic blood pressure during inspiration (pulsus paradoxus) is recognized as a hallmark of tamponade, although it may be absent if hypotension is already present. Enlargement of the cardiac silhouette on routine radiography does not usually occur until at least 250 mL of fluid has accumulated in the pericardium. Other findings on chest radiogram, such as a ‘water bottle’ heart (Figure 50-3) or a prominent fat stripe sign, are found only in large pericardial effusions.

Figure 50-3  Cardiomegaly in a patient who has pericarditis. The presence of a ‘water-bottle’ heart on this plain film suggests a large pericardial effusion.

ECG changes in acute pericarditis imply inflammation of the pericardium. Thus, in uremic or neoplastic pericardial effusions, characteristic ECG changes are often absent. Cardiac arrhythmias are uncommon in isolated pericardial disease; their presence implies myocardial involvement. The ECG typically evolves through four stages during acute pericarditis. • Diffuse ST-segment elevation (usually concave up) with reciprocal ST depression in aVR and V1 accompanies the onset of chest pain and is virtually diagnostic of pericarditis; these findings are present in 50% of patients who have acute pericarditis.50 PR depression in the inferolateral leads is frequently seen in this stage (Figure 50-4). • ST and PR segments normalize, typically several days later. • Diffuse T wave inversions develop, generally after ST segments become isoelectric. • ECG changes normalize; long-term inversion of T waves suggests ‘chronic’ pericarditis.

Diagnosis Several studies have established the utility of using a stepped approach.51 One study prospectively evaluated 231 consecutive patients who had acute pericardial disease of unknown cause.52 Pericardiocentesis was performed in patients who had tamponade, suspicion of purulent pericarditis or symptoms and/or effusion persisting for more than 1 week after initiation of nonsteroidal anti-inflammatory drug (NSAID) therapy. Pericardial biopsy was undertaken if clinical activity persisted



Chapter 50  Myocarditis and Pericarditis

453

Figure 50-4  Electrocardiogram of a patient who has early acute pericarditis. Note the presence of diffuse ST segment elevation and PR depression in the inferolateral leads (arrows). 25 mm/s; 10.0 mm/mV; F–W 0.05–100.

at 3 weeks and the etiology was unknown. Despite this extensive evaluation, a diagnosis was confirmed in only 32 patients: neoplasia in 13, tuberculosis in 9, rheumatic disease in 4, purulent pericarditis in 2, toxoplasmosis in 2 and viral pericarditis in 2. Diagnostic yield was substantial when pericardiocentesis or biopsy was performed to relieve tamponade, but poor when used solely for diagnostic purposes. We undertook a prospective nonrandomized trial of all patients who had large pericardial effusions hospitalized at our institution in the early 1990s. These patients underwent a similar stepped approach, with subsequent subxiphoid pericardial biopsy and drainage of their effusions.53 Microbiologic analysis of pericardial fluid and tissue allowed diagnoses to be established in 53 out of 57 patients, confirming prior reports of high diagnostic yield when stepped algorithms are used for large effusions. More than one-third of the patients had malignancy or a history of irradiation to the thorax for malignancy. Infections (mostly viral), noninfectious inflammatory disease and uremia were also frequently implicated (Table 50-4). Unexpected pathogens included CMV in three patients, herpes simplex virus 1 in one, M. pneumonia in two, Mycobacterium avium complex in one and Mycobacterium chelonei (see Table 50-3 ) in one patient. No patients showed evidence of coxsackievirus A or B infection. A comparison of diagnostic yield between pericardial fluid and biopsy demonstrated that fluid analysis was far more sensitive for malignancy; tissue provided additional information only in infected patients in whom fluid was not available for analysis. In summary, acute pericarditis is most often viral or idiopathic in etiology; as such, invasive workups are usually unnecessary. Early intervention will often yield diagnosis and therapeutic benefits in large effusions, tamponade, or presentation concerning for purulent pericarditis. A wide variety of infectious and noninfectious agents can cause acute pericarditis and/or pericardial effusions (Tables 50-1 and 50-2). For acute chest pain, initial evaluation should focus on conditions that may be rapidly fatal. Thus, myocardial infarction, aortic dissection, purulent pericarditis and cardiac tamponade should be systematically ruled out. An appropriate workup includes a thorough history and

TABLE 50-4 

Etiology of Large Pericardial Effusions

Etiology

% of 75 Diagnoses

Malignancy

27

Viral

16

Collagen vascular disease

14

Radiation

11

Uremia

11

Mycobacterial

5

Mycoplasma

3

Bacterial

1

Idiopathic

5

Other

8

From Corey G.R., et al., Am J Med 1993; 95:209-213.

physical examination, ECG and chest radiograph (to rule out intrathoracic malignancy, tuberculosis or a widened mediastinum suggestive of aortic dissection), an echocardiogram, and routine laboratory studies including complete blood counts, serum chemistries, serial cardiac enzymes, thyroid function tests; blood cultures should be obtained for the febrile patient. If the suspicion for pericarditis is high an anti-nuclear antibody should be sent to risk-stratify for autoimmune pericarditis. The diagnosis of tuberculous pericarditis should always be considered and if there is any suspicion a tuberculin skin test should be placed. A specific etiology will not be apparent in most patients, and a diagnosis of viral or idiopathic pericarditis will be made. Because either entity typically follows a brief and benign course, a full diagnostic evaluation is not appropriate. The confirmation of a specific virus is unnecessary, as serologic titers are quite nonspecific.

454

SECTION 2  Syndromes by Body System: Bloodstream, Heart and Vessels

Figure 50-5  Chest CT scan of a patient who has a large crescent-shaped pericardial effusion.

However, since significant pericardial effusion may accumulate even in idiopathic disease, all patients should be carefully evaluated and monitored for evidence of hemodynamic compromise on physical examination. If found, it can be confirmed by echocardiogram and treated with fluid aspiration or surgery. Echocardiography has replaced other methods for the detection of pericardial fluid and evaluation for tamponade. With experience, operators can detect as little as 20 mL of excess fluid posterior to the left ventricle. Echocardiography can also provide ancillary data in assessing the patient who has an effusion. Increased respiratory flow variation across the mitral valve with Doppler echocardiography is characteristic of tamponade. In addition, other etiologies of myocardial dysfunction can be ruled out. Finally, the echocardiogram can direct attempts at pericardiocentesis by identifying the location of pericardial fluid. Computed tomography (CT) scans of the chest are primarily helpful in the diagnosis of pericardial thickening though significant effusions are also readily demonstrated (Figure 50-5). In addition, CT scans are more sensitive for the demonstration of small parenchymal nodules and mediastinal lymphadenopathy than is conventional radio­­graphy, and thus have clinical utility in the diagnosis of malignant or tuberculous pericarditis. Recently published guidelines for the use of CT and CMR in pericardial disease state that echocardiography is still the first-line imaging modality for pericardial disease, but CT/CMR should be considered in the setting of complex disease, extracardiac disease, operative planning and when echocardiography is limited by body habitus.54

Management Randomized controlled trials in the treatment of pericarditis are limited, and management at this point is driven by expert opinion. In 2004 the European Society of Cardiology published the first set of guidelines for management of pericardial disease. Medical therapy is tailored to the cause of pericarditis and the co-morbidities of the patient. Aspirin or NSAIDs are effective in reducing symptoms of pericarditis and are the agents of choice for idiopathic or viral pericarditis.55 The most frequent cause of recurrence or disease persistence is inadequate dosages or duration of anti-inflammatory agents. While corticosteroids relieve symptoms, they have been demonstrated to increase the risk of side effects, recurrences and duration of

hospitalization.56 Prednisone, however, is the drug of choice in pericarditis associated with connective tissue disease. Idiopathic or viral pericarditis generally follows a benign, selflimited course but the occasional patient will present with recurrent pericarditis. Colchicine has shown promise in reducing recurrences in several recent randomized controlled trials. The COPE and CORE trial demonstrated that colchicine, in addition to aspirin or NSAIDs, reduced disease recurrence and symptom duration in both primary and recurrent pericarditis, respectively. A multicenter randomized controlled trial, ICAP, confirmed these results.57 Based on these trials colchicine should be used as first-line therapy for disease recurrence, rather than corticosteroids.58–59 Anakinra, a recombinant human interleukin-1β receptor antagonist, has recently been shown to have a potential benefit for both adult and juvenile patients with treatmentrefractory idiopathic pericarditis.60 Pericardiectomy is reserved for those with constrictive pericarditis or failure of intensive medical therapy.61 Intravenous antibiotics and surgical drainage of the pericardium remain the mainstays of therapy for purulent pericarditis. Pericardiocentesis urgently performed for the critically ill patient does not obviate the need for complete drainage and irrigation; fluid may reaccumulate rapidly and sequelae such as constriction may develop in hours. There is no rationale for intrapericardial antibiotic administration, as pericardial penetration of antibiotics is excellent. Tuberculous pericarditis remains a diagnostic and therapeutic challenge. Clinical features are nonspecific, the disease course is confusing and laboratory evaluation is often nondiagnostic, particularly in low prevalence settings and in patients who have localized disease. Although large effusions are more likely to be tuberculous, up to 50% of tuberculous effusions resolve spontaneously despite ongoing tissue infection. The tuberculin skin test may be negative in up to 30% of patients as a result of cutaneous anergy yet may be positive in the patient who has acute idiopathic pericarditis. Suggestive findings include a recent history of pulmonary tuberculosis, a positive sputum smear or culture or a high pericardial fluid adenosine deaminase level.62 Even granulomatous inflammation of the pericardium is not diagnostic, as this may be demonstrated in pericardial disease from other causes, such as histoplasmosis, sarcoidosis and rheumatoid arthritis. Additionally, a negative biopsy of the pericardium does not rule out tuberculous pericarditis, as removal of the entire pericardium may be necessary to demonstrate clear-cut evidence of tuberculosis.63 Definitive diagnosis rests upon the demonstration of the tubercle bacillus in pericardial fluid and/or tissue. However, the need for early therapy demands that treatment often be undertaken based upon a presumptive diagnosis. Initial treatment should consist of four drugs including isoniazid and rifampin until sensitivities are known. The use of concomitant prednisone to reduce pericardial inflammation has been shown to lower mortality, reduce symptom duration and need for pericardiectomy,64 however a recent large randomized trial suggested that adjunctive steroids do not reduce the risk of tamponade or death.65 Complete pericardiectomy is advocated for those who have recurrent effusions or cardiac compression with constrictive physiology after 4–6 weeks of therapy as early pericardiectomy is associated with reduced morbidity and mortality.66,67 Myopericarditis also deserves special mention since the diagnosis changes management. Myopericarditis occurs when the primary process is pericarditis. Elevation of cardiac biomarkers, ECG changes and wall motion abnormalities by echocardiogram are evidence of some degree of myocardial injury. If there is a suspicion of myopericarditis, CMR should be performed as myocardial involvement changes pharmacologic management, follow-up and advice on physical activity. Myopericarditis mandates serial echocardiograms to ensure the return of cardiac function, avoidance of physical activity, and dose-reduction of NSAIDS.68–70 References available online at expertconsult.com.



Chapter 50  Myocarditis and Pericarditis

455

KEY REFERENCES Cooper L.T., Baughman K.L., Feldman A.M., et al.: The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J Am Coll Cardiol 2007; 50:1914-1931. Felker G.M., Thompson R.E., Hare J.M., et al.: Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000; 342(15):1077.

Fowler N.O.: Tuberculous pericarditis. JAMA 1991; 266(1):99-103. Friedrich M.G., Sechtem U., Schulz-Menger J., et al.: Cardiovascular magnetic resonance in myocarditis: a JACC White Paper. J Am Coll Cardiol 2009; 53(17):1475. Imazio M., Cooper L.T.: Management of myopericarditis. Expert Rev Cardiovasc Ther 2013; 11(2):193-201. Kindermann I., Kindermann M., Kandolf R., et al.: Predictors of outcome in patients with suspected myocarditis. Circulation 2008; 118:639-648. Klein A., Chair S., White R., et al.: American Society of Echocardiography clinical recommendations for multi-

modality cardiovascular imaging of patient with pericardial disease. J Am Soc Echocardiogr 2013; 26:965-1012. Mahfoud F., Gartner B., Kindermann M., et al.: Virus serology in patients with suspected myocarditis: utility or futility? Eur Heart J 2012; 32:897-903. McCarthy R.E. III, Boehmer J.P., Hruban R.H., et al.: Long term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med 2000; 342:690-695. Reuter H., Burgess L.J., Doubell A.F.: Epidemiology of pericardial effusions at a large academic hospital in South Africa. Epidemiol Infect 2005; 133:393-399.



Chapter 50  Myocarditis and Pericarditis 455.e1

REFERENCES 1. Felker G.M., Thompson R.E., Hare J.M., et al.: Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000; 342(15):1077. 2. Sahi T., Karjalainen J., Viitasalo M.T., et al.: Myocarditis in connection with viral infections in Finnish conscripts. Ann Med Milit Fenn 1982; 57:198-203. 3. Corrado D., Basso C., Thiene G.: Sudden cardiac death in young people with apparently normal heart. Cardiovasc Res 2001; 50:399-408. 4. Drory Y., Turetz Y., Hiss Y., et al.: Sudden unexpected death in persons less than 40 years of age. Am J Cardiol 1991; 68:1388-1392. 5. McCaffrey F.M., Braden D.S., Strong W.B.: Sudden cardiac death in young athletes: a review. Am J Dis Child 1991; 145:177-183. 6. Friman G., Wesslen L., Fohlman J., et al.: The epidemiology of infectious myocarditis, lymphocytic myocarditis and dilated cardiomyopathy. Eur Heart J 1995; 16:36-41. 7. Hibbert B., Costiniuk C., Hibbert R., et al.: Cardiovascular complications of Salmonella enteritidis infection. Can J Cardiol 2010; 26(8):323-325. 8. Morgan B.C.: Cardiac complications of diphtheria. Pediatrics 1963; 32:549-557. 9. Lebetter M.K., Cannon A.B., Costa A.F.: The electrocardiogram in diphtheric myocarditis. Am Heart J 1964; 68:599-611. 10. Steere A.C., Batsford W.P., Weinberg M., et al.: Lyme disease carditis: cardiac manifestations of Lyme disease. Ann Intern Med 1980; 93:8-16. 11. Resnick J.W., Baunstein D.B., Walsch R.L.: Lyme carditis. Electrophysiologic and histopathologic study. Am J Med 1986; 81:923. 12. Landais C., Florence F., Raolt D., et al.: From acute Q fever to endocarditis: serological follow up strategy. Clin Infect Dis 2007; 44:1337-1340. 13. Mahrholdt H., Wagner A., Deluigi C.C., et al.: Presentation, patterns of myocardial damage, and clinical course of viral myocarditis. Circulation 2006; 114:15811590. 14. Kumar K., Guirgis M., Zieroth S., et al.: Influenza myocarditis and myositis: case presentation and review of the literature. Can J Cardiol 2011; 27(4):514-522. 15. Muir P., Nicholson F., Tilzey A.J., et al.: Chronic relapsing pericarditis and dilated cardiomyopathy: serological evidence of persistent enterovirus infection. Lancet 1989; 1(8642):804-807. 16. Nitsekhe M., Mayosi B.M.: Cardiac manifestations of HIV infection: an African perspective. Nat Clin Pract Cardiovasc Med 2009; 6:120-127. 17. Calabrese L.H., Proffitt M.R., Yen-Lieberman B., et al.: Congestive cardiomyopathy and illness related to the acquired immunodeficiency syndrome (AIDS) associated with isolation of retrovirus from myocardium. Ann Intern Med 1987; 107:691-692. 18. Currie P.F., Jacob A.J., Foreman A.R., et al.: Heart muscle disease related to HIV infection: prognostic implications. BMJ 1994; 309:1605-1607. 19. Shaboodien G., Maske C., Wainwright H., et al.: Prevalence of myocarditis and cardiotropic virus infection in Africans with HIV-associated cardiomyopathy, idiopathic dilated cardiomyopathy and heart transplant recipients: a pilot study. Cardiovasc J Africa 2013; 24:218-223. 20. Valantine H.A., Gao S.Z., Menon S.G., et al.: Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis. Circulation 1999; 100:61-66. 21. Maisch B., Schonian U., Crombach M., et al.: CMVassociated inflammatory heart muscle disease. Scand J Infect Dis Suppl 1993; 88:135-148. 22. Mahfoud F., Gartner B., Kindermann M., et al.: Virus serology in patients with suspected myocarditis: utility or futility? Eur Heart J 2012; 32:897-903. 23. Karjalainen J.: Clinical diagnosis of myocarditis and dilated cardiomyopathy. Scand J Infect Dis Suppl 1993; 88:33-43. 24. Assomull R.G., Lyne J.C., Keenan N., et al.: The role of cardiovascular magnetic resonance in patients

presenting with chest pain, raised troponin, and unobstructed coronary arteries. Eur Heart J 2007; 28:12421249. 25. Liu P.P., Schultheiss H.P.: Myocarditis. In: Braunwald F., ed. Heart disease: a textbook of cardiovascular medicine. 8th ed. Philadelphia, PA: WB Saunders; 2006:16991705. 26. Wynne J., Braunwald E.: Cardiomyopathy and myocarditis: Harrison’s principles of internal medicine. 16th ed. New York: McGraw–Hill; 2004:1471-1472. 27. Akkad M.Z., O’Connell J.B.: Myocarditis. In: Crawford M.H., ed. Current diagnosis and treatment in cardiology. 2nd ed. New York: McGraw–Hill; 2003:671-678. 28. Aretz H.T., Billingham M.E., Edwards W.D., et al.: Myocarditis: a histopathological definition and classification. Am J Cardiovasc Pathol 1987; 1:3-14. 29. Baughman K.L.: Diagnosis of myocarditis: death of Dallas criteria. Circulation 2006; 113:5935. 30. Kindermann I., Barth C., Mahfoud F., et al.: Update on myocarditis. J Am Coll Cardiol 2012; 59(9):779-792. 31. Kindermann I., Kindermann M., Kandolf R., et al.: Predictors of outcome in patients with suspected myocarditis. Circulation 2008; 118:639-648. 32. Schultheiss H.P.: Dilated cardiomyopathy – a chronic myocarditis? New aspects on diagnosis and therapy. Z Kardiol 1993; 82(Suppl. 4):25-32. 33. Cooper L.T., Baughman K.L., Feldman A.M., et al.: The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J Am Coll Cardiol 2007; 50:19141931. 34. Baccouche H., Mahrholdt H., Meinhardt G., et al.: Diagnostic synergy of non-invasive cardiovascular magnetic resonance and invasive endomyocardial biopsy in troponin-positive patients without coronary artery disease. Eur Heart J 2009; 30:2869-2879. 35. Friedrich M.G., Sechtem U., Schulz-Menger J., et al.: Cardiovascular magnetic resonance in myocarditis: a JACC White Paper. J Am Coll Cardiol 2009; 53(17):1475. 36. Chandra D., Kar B., Idelchik G., et al.: Usefulness of percutaneous left ventricular assist device as a bridge to recovery from myocarditis. Am J Cardiol 2007; 99:17551756. 37. McCarthy R.E. III, Boehmer J.P., Hruban R.H., et al.: Long term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med 2000; 342:690-695. 38. Mason J., O’Connell J., Herskowicz A., et al.: A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med 1995; 333:269-275. 39. McNamara D.M., Holubkov R., Starling R.C., et al.: Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation 2001; 103:2254-2259. 40. Kuhl U., Lassner D.: Interferon-beta improves survival in enterovirus-associated cardiomyopathy. J Am Coll Cardiol 2012; 1295-1296. 41. Kuhl U., Pauschinger M., Schwimmbeck P.L., et al.: Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 2003; 107:2793-2798. 42. Kuhl U., Pauschinger M., Seeberg B., et al.: Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation 2005; 112:1965-1970. 43. Maisch B., Ristic A.D., Rupp H., et al.: Pericardial access using the PerDUCER and flexible percutaneous pericardioscopy. Am J Cardiol 2001; 88:1323-1326. 44. Raoult D., Tissot-Dupont H., Foucault C., et al.: Q fever 1985–1988. Clinical and epidemiologic features of 1,383 infections. Medicine 2000; 79:109-123. 45. Kenney R.T., Li J.S., Clyde W.A., et al.: Mycoplasmal pericarditis: evidence of invasive disease. Clin Infect Dis 1993; 58-62.

46. Fowler N.O.: Tuberculous pericarditis. JAMA 1991; 266(1):99-103. 47. Reuter H., Burgess L.J., Doubell A.F.: Epidemiology of pericardial effusions at a large academic hospital in South Africa. Epidemiol Infect 2005; 133:393-399. 48. Kipp A.M., Stout J.E., Hamilton C.D.: Extrapulmonary tuberculosis, human immunodeficiency virus, and foreign birth in North Carolina, 1993–2006. BMC Public Health 2008; 8:107. 49. Hsia J., Ross A.M.: Pericardial effusion and pericardiocentesis in HIV infection. Am J Cardiol 1994; 74:94-96. 50. Lorell B.H., Braunwald E.: Pericardial disease. In: Braunwald F., ed. A textbook of cardiovascular medicine. 4th ed. Philadelphia, PA: WB Saunders; 1992:14651515. 51. Zayas R., Anguita M., Torres F., et al.: Incidence of specific etiology and role of methods for specific etiologic diagnosis of primary acute pericarditis. Am J Cardiol 1995; 75:378-382. 52. Permanyer-Miralda G., Sagrista-Salueda J., Soler-Soler J.: Primary acute pericardial disease: prospective series of 231 consecutive patients. Am J Cardiol 1985; 56:623630. 53. Corey G.R., Campbell P.T., Van Tright P., et al.: Etiology of large pericardial effusions. Am J Med 1993; 95:209-213. 54. Klein A., Chair S., White R., et al.: American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patient with pericardial disease. J Am Soc Echocardiogr 2013; 26:965-1012. 55. Imazio M.A., Spodick D.H., Brucato A.N., et al.: Controversial issues in the management of pericardial diseases. Circulation 2010; 121:916-928. 56. Imazio M., Brucato A., Cumetti D., et al.: Corticosteroids for recurrent pericarditis: high versus low doses: a nonrandomized observation. Circulation 2008; 118:667-671. 57. Imazio M., Bobbio M., Cecchi E.: Colchicine in addition to conventional therapy for acute pericarditis: results of the colchicine for acute pericarditis (COPE) trial. Circulation 2005; 112(13):2012-2016. 58. Imazio M., Bobbio M., Cecchi E., et al.: Colchicine as first choice therapy for recurrent pericarditis. Arch Intern Med 2005; 165:1987-1991. 59. Imazio M., Brucato A., Cemin R., et al.: A randomized trial of colchicine for acute pericarditis. N Engl J Med 2013; 369:1522-1528. 60. Lazaros G., Vasileiou P., Koutsianas C., et al.: Anakinra for the management of resistant idiopathic recurrent pericarditis: initial experience in 10 adult cases. Ann Rheum Dis 2014; 73(12):2215-2217. 61. Fowler N.O.: Pericardial disease. Heart Dis Stroke 1992; 2:85-94. 62. Martinez Vasquez J.M., Ocaña I., Ribera E., et al.: Adenosine deaminase activity in tuberculous pericarditis. Thorax 1986; 41:888-889. 63. Cheitlin M.D., Serfos L.J., Sbar S.S., et al.: Tuberculous pericarditis: is limited pericardial biopsy sufficient for diagnosis? Am Rev Respir Dis 1968; 98:287-291. 64. Strang J.I., Gibson D.G., Mitchinson D.A., et al.: Controlled clinical trial of complete open surgical drainage and of prednisone in treatment of tuberculous pericardial effusion in Transkei. Lancet 1988; 2:759-763. 65. Mayosi B.M., Ntsekhe M., Bosch J., et al.: Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis. N Engl J Med 2014; 371:1121-1130. 66. Fennell W.M.P.: Surgical treatment of constrictive tuberculous pericarditis. S Afr Med J 1982; 62:353-355. 67. Trautner B.W., Darouiche R.O.: Tuberculous pericarditis: optimal diagnosis and management. Clin Infect Dis 2001; 33:954-961. 68. Imazio M., Cooper L.T.: Management of myopericarditis. Expert Rev Cardiovasc Ther 2013; 11(2):193-201. 69. Imazio M., Trinchero R.: Myopericarditis: etiology, management, and prognosis. Int J Cardiol 2008; 127(1):17-26. 70. Friedrich M.G., Sechtem U., Schulz-Menger J., et al.: International Consensus Group on Cardiovascular Magnetic Resonance in Myocarditis. J Am Coll Cardiol 2009; 53(17):1475.