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The list of infectious agents that have been associated with myocarditis include DNA and RNA viruses, bacteria, fungi, protozoa, and helminthes.22,23,24 Viral infections are the most common causes of myocarditis in both children and adults (Table 63–1).22 Nonviral cardiotropic infections, such as Trypanosoma cruzi in Chagas disease25 and Borrelia burgdorferi in Lyme disease,26 in immunocompetent individuals constitute special subgroups of myocarditis. In immunocompromised patients (eg, immunosuppressed, immunodepressed, malignancy, postsurgical, human immunodeficiency virus [HIV] infected), myocarditis is associated with different infectious agents, such as human cytomegalovirus (HCMV) or Toxoplasma gondii. In pregnancy, HCMV infection could cause fetal malformations wherein the maternal infection remains clinically subtle partly because of delayed lymphoproliferative response in primary infection27 and lower viral load.28 Myocardial infection is diagnosed when the infectious agent is detected in myocardial tissue by pathologic and genomic studies.29
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The diagnostic workup of myocardial infection should begin with timely sampling of informative tissue and paired samples of peripheral blood. The diagnostic processes include cell culture, antibody detection, antigen detection, hemagglutination assay, nucleic acid detection, and gene sequencing. Specific antibodies are always produced when adaptive immune system encounters a virus. As a general rule, immunoglobulin (Ig) Ms are highly effective at neutralizing viruses, are produced only for the initial few weeks, and are indicative of acute infections. IgGs are produced indefinitely and are tested to demonstrate prior infection. Antigens are detected by enzyme-linked immunosorbent assay (ELISA) in biologic fluids with immunofluorescence and immunoperoxidase as the alternative methods. Quantitative assays for measuring the viral genome copy number and nucleic acid sequencing establish the viral presence and the viral load. In the appropriate diagnostic workup, the serology is systematically performed, routine inflammatory markers are tested, and markers of myocardial damage are monitored. Neutralizing antibodies in serum can be tested by the neutralization test based on the enzyme-linked immunospot assay.30
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EMB is the gold standard for the confirmation of viral infection.4,31 Inflammatory cells are detected with routine pathology stains such as hematoxylin and eosin. The immunophenotyping of inflammatory cells for prevalent subtypes of T lymphocytes including CD4+ and CD8+, B lymphocytes, natural killer cells, or macrophages may add information on the presence of effector and regulatory pathogenetic pathways. Immunohistochemical detection of the infective pathogen and molecular transcription signature from the affected myocardium can contribute to the diagnosis of inflammatory heart diseases.32
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Enteroviruses belong to the family of Picornaviridae and are grouped into 12 species: enteroviruses A to H and J and rhinoviruses A to C. The disease in humans is caused by poliovirus, coxsackievirus, rhinovirus, enterovirus, and echovirus serotypes. The clinical presentation may be relatively mild (eg, fever, herpangina, conjunctivitis, hand-foot-mouth disease, tonsillitis, pharyngitis, lower respiratory tract infection, acute gastroenteritis) or, uncommonly, also severe (eg, pneumonia, meningitis, encephalitis, myocarditis, pericarditis, hepatic necrosis, coagulopathy).33 The cardiotropic coxsackievirus B3 (CV-B3) is one of the most common causes of myocarditis.33 The myocardial infection is initiated by the transmembrane coxsackievirus-adenovirus receptor (CAR); the ablation of CAR blocks viral affliction of myocardial cells and inflammation in the myocardium in experimental models.34 Similarly, increased cardiac expression of CAR may partially explain increased susceptibility to myocarditis.35 In CV-B3–infected myocytes, the cell damage is induced by direct cytotoxicity and mediated by viral proteinases.36 CV-B3 replicates on the surface of autophagosomes37,38 and enhances replication by employing microRNA (miRNA)39,40; CV-B3–induced differential expression of miRNA modulates expression of both host and viral genes.
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Patients with defects of dystrophin and dysferlin demonstrate increased susceptibility to myocardial CV-B3 infection by enhancing viral propagation to adjacent cardiomyocytes and disrupting membrane repair function.41,42,43 The history of a recent flu episode in patients with X-linked DCM caused by defects of dystrophin could mislead the clinical diagnosis, but the possibility that a viral flu triggered the onset of a pre-existing asymptomatic disease cannot be excluded. Although myocarditis and viral genome may not be found in the EMB from patients with X-linked DCM,44 the myocardium with dystrophin defects could sustain greater damage from coxsackievirus proteases known to affect host cell proteins such as dystrophin.45
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In viral infections, the early innate immune response provides the first defense mechanism and is mediated by cytokines. The virus is recognized by specific receptors (toll-like, retinoic acid inducible gene-I–like, nucleotide-binding oligomerization domain-like, and C-type lectin receptors) through pathogen-specific molecules.46,47 This interaction induces the production of proinflammatory cytokines (eg, tumor necrosis factor-α and interleukin-1) to recruit T cells (including regulatory T cells and interleukin-17–producing cells) and modulate immune response.48 The late adaptive immune response contributes to the myocardial lymphocyte infiltration that must clear virus-infected cardiac myocytes in CV-B3 myocarditis and endothelial cells in parvovirus B19 myocarditis. Although this mechanism clears the virus, it also results in myocyte injury. Depletion or ablation of T lymphocytes, both CD4+ and CD8+, decreases the mortality and reduces cardiac inflammation and injury after CV-B3 infection.49 In addition, a molecular mimicry between viral and host antigens has been proposed as a mechanism subsequently responsible for the postinfectious autoimmune-mediated damage of the myocardium.50
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Acute infections are characterized by febrile illness that commonly evolves without complications; when complicated by myocarditis, the febrile illness is commonly reported as having preceded the cardiac symptoms. The cardiac manifestations range from mild, nonspecific symptoms to life-threatening complications such as cardiogenic chock and sudden cardiac death. The pathologic features of CV-B3 myocarditis are T-lymphocyte inflammatory infiltrate and myocyte damage/necrosis (Fig. 63–2). Markers of myocardial damage and systemic inflammation can be increased. IgMs are usually missed unless the diagnosis of myocarditis is done close to the onset of the systemic illness. In the acute phase, viral particles can be recognized in infected myocytes.51,52 Polymerase chain reaction (PCR)–based demonstration of the viral genome in the affected myocardium concludes the diagnostic workup; molecular assays are paired in blood and myocardial samples.
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Human parvovirus B19 (B19V) belongs to the genus Erythroparvovirus of the Parvoviridae family, which is composed of a group of small DNA viruses with a linear single-stranded DNA genome.53 B19V usually infects human erythroid progenitor cells to cause mild-to-severe hematologic disorders,54 but may also infect nonerythroid lineage cells such as myocardial endothelial cells.55 Therefore, B19V infection typically presents clinically with erythema infectiosum, arthralgia, fetal death, transient aplastic crisis, and persistent infection in immunocompromised hosts; less common clinical manifestations include atypical skin rashes, neurologic syndromes, cardiac manifestations, and cytopenias.53,55 The cardiac manifestations of B19V infection range from mild and nonspecific symptoms (eg, fatigue, arrhythmias) to cardiogenic shock requiring mechanical support.
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Mechanistically, the B19V-antibody complex enters the cells through an endocytosis process mediated by the direct interaction of antibody-bound complement factor C1q with its receptor CD93 on the cell surface.56 B19V enters myocardial endothelial cells, but does not replicate intracellularly.57 B19V genome has been identified in the myocardial tissue of patients with myocarditis, patients with DCM, and control cases.58,59 In 72 EMBs from 35 patients with DCM, 17 patients with active myocarditis, and 20 surgical myocardial samples from patients undergoing surgery for valve disease or coronary artery disease, real-time PCR failed to identify enteroviruses, Epstein-Barr virus, or herpes simplex viruses type 1 or 2; only one DCM patient tested positive, but for adenovirus. On the other hand, 20 of 52 patients (38%) with cardiomyopathy and 8 of 20 controls (40%) tested positive for B19V, disproving the hypothesis that persistent myocardial viral infection might be a frequent cause of DCM or myocarditis.58 A possible hypothesis that could explain the role of B19V in myocarditis and cardiomyopathy is the potential role of trigger of the viral genome for innate immunity, inducing proinflammatory cytokine secretion57 and myocardial inflammation.
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EMB typically shows T-lymphocyte inflammatory infiltrates and prominent endothelial cells; myocytes may not show damage or necrosis (Fig. 63–3). B19V infection has also been associated with adult and pediatric autoimmune diseases, including systemic diseases that involve the heart, either directly or indirectly.60,61,62 Documented mechanisms in B19-associated autoimmunity include molecular mimicry (IgG antibodies to B19 proteins cross-react with human autoantigens), virus-induced apoptosis with presentation of self-antigens to T lymphocytes, and the phospholipase activity of the B19 unique VP1 protein.
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The human herpesviruses (HHV) are currently assigned to three subfamilies: α-, β-, and γ-herpesvirinae. Herpesvirus infections are characterized by their ability to establish lifelong infections with periods of latency followed by reactivation. The diagnosis of HHV myocarditis is based on the demonstration of HHV actively replicating in cardiac cells. In infected cells, HHV typically causes a morphologically manifest cytopathic effect, and commercially available antibodies can detect viral antigens expressed in the immediate/early and late phases of viral replication. PCR can selectively detect genes expressed by replicating viruses, and quantitative PCR measures the number of copies of viral genomes in the affected tissues compared to the peripheral blood. HHV6, adenovirus, and Epstein-Barr virus of the herpesvirinae family are associated with myocarditis, which may occur both in immunocompetent and immunocompromised hosts, as well as in children and adults.63,64,65,66,67,68,69 In immunocompromised patients, the HHV6 myocarditis can be fatal.66,67 The myocarditis is pathologically characterized by T-lymphocyte infiltration and myocyte injury.
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Myocardial infection with HCMV is more commonly observed in immunocompromised hosts. The myocardial pathology is characterized by T-cell inflammatory infiltrate and by the presence of typical intranuclear amphophilic inclusion bodies that specifically immune-stain with anti-HCMV antibodies. The virus infects both myocytes and endothelial cells. Seroepidemiologic studies suggest HCMV infection to be widespread and influenced by age, geography, and cultural and socioeconomic status. Children become infected early in life in developing countries. Up to 80% of the adult population is infected in developed nations. The course of primary infection is usually mild or asymptomatic in immunocompetent hosts as HCMV establishes a latent but persistent infection, reflecting the inability of the immune system to clear the infection; immune evasion mechanisms allow infected cells to escape both innate and adaptive effector immunity.70 In immunosuppressed patients (eg, solid organ or bone marrow transplantation recipients), the infection can be reactivated to result in systemic and organ infection; the heart is a possible target for tissue infection, especially in heart transplant recipients. The diagnosis and treatment of viral infections in transplanted patients are managed by pre-emptive or prophylactic therapy, and antiviral treatment is based on established protocols.71 Antiviral treatments can be administered when the viral diagnosis is established. For herpes simplex virus types 1 and 2 and for varicella-zoster virus, acyclovir (or its prodrug valacyclovir) and famciclovir have greatly reduced the burden of disease and have demonstrated a remarkable safety record. Drug resistance, in the otherwise healthy population, has remained below 0.5% after more than 20 years of antiviral use. Resistance is more common in immunocompromised patients, and alternative drugs with good safety profiles are needed. Ganciclovir and valganciclovir remain the drugs of choice for HCMV infection in immunocompromised hosts.72,73
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Postacute Phase of Viral Myocarditis
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Evolution of Myocarditis
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Myocarditis can have a fulminant course (rare), can heal spontaneously (common) or, in a minority of cases, can evolve into a chronic, low-grade inflammatory myocardial disease (Fig. 63–4). The diagnosis of chronic myocarditis is ideally established by biopsy-proven evidence of the acute phase and demonstration of the persistent myocardial inflammation. Different terms are currently found in the literature describing the latter pathologic substrate, including chronic myocarditis, subacute myocarditis, inflammatory cardiomyopathy, and myocarditis-induced DCM. Each term incorporates the demonstration of myocardial inflammation. The term inflammatory cardiomyopathy was introduced in 1995 by the World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies, and was defined as myocarditis associated with cardiac dysfunction.2 The term and the definition were adopted by the ESC Working Group for Myocardial and Pericardial Diseases.3 The term inflammatory cardiomyopathy does not describe the phenotype (dilated or arrhythmogenic) and does not specify the cause. Most available clinical series have rarely included both baseline and follow-up biopsies74,75,76 and have only reported the initial EMB performed at onset of the symptoms. The non-EMB series inferred the diagnosis of chronic myocarditis on the basis of clinical presentation suggestive of a recent-onset, flu-like syndrome shortly preceding the onset of cardiac symptoms, elevated inflammatory markers, and imaging characterization in patients with angiographically proven normal coronary arteries.77 Past studies estimated that 30% of DCM evolved from myocarditis.75,76,78,79 In a recent study, 82 patients with biopsy-proven active myocarditis were consecutively enrolled and followed-up for 147 ± 107 months. At 6 months, improvement or normalization of LVEF was observed in 53% of patients.78 In another study including 174 patients with either active or borderline myocarditis, 124 patients were alive without being transplanted, 26 were dead or transplanted, and 24 (14%) were lost at a median follow-up of 23.5 months (interquartile range, 10-54 months).79 A subsequent study included 181 consecutive patients with clinically suspected viral myocarditis; 69 patients fulfilled Dallas criteria for the diagnosis of myocarditis, 91 showed immunohistologic markers of inflammation, and 79 had a positive PCR-based genome search in the EMB. Twenty-two percent of the patients (n = 40) either died or underwent heart transplantation at a mean of 59 ± 42 months.80 In another series of 222 consecutive patients with biopsy-proven viral myocarditis, mortality was 19.2% at a median follow-up of 4.7 years.81 Overall, about one-fourth of patients with biopsy-proven myocarditis evolve through worsening of cardiac function and either undergo heart transplantation or die.
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Predictors of Outcome
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Predictors of outcome vary in different myocardial biopsy studies. Persistence of New York Heart Association (NYHA) classes III to IV, left atrium enlargement, and improvement in LVEF at 6 months emerged as independent predictors of long-term outcome in one study.78 Biventricular dysfunction at diagnosis was the main predictor of death/transplantation in another study.79 Advanced NYHA functional class, immunohistologic signs of inflammation, and lack of β-blocker therapy (but not histologic characteristics [positive Dallas criteria] or detectability of viral genome) were found to relate to poor outcome80; high rates of cardiomyocyte apoptosis were associated with functional recovery at 1 year.82 The presence of late gadolinium enhancement (LGE) emerged as the best independent predictor of all-cause and cardiac mortality, whereas the initial presentation with heart failure was a predictor of incomplete long-term recovery.81 Similarly, a high LV end-diastolic dimension Z-score on admission in children also was a predictor of worse outcomes, with higher mortality and incomplete recovery.83 In 203 consecutive patients with an initial cardiac magnetic resonance (CMR)–based diagnosis of acute myocarditis (typical LGE) and a mean follow-up of 18.9 ± 8.2 months, an initial alteration of LVEF was the only independent CMR predictor of adverse clinical outcome.84
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Therefore, the most consistent predictors of worse outcome included NYHA functional class and presence of heart failure or LV dilation and dysfunction, and suggest little added value to myocarditis or postmyocarditis substrate.
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Evolution of Acute Myocarditis to a Dilated Cardiomyopathy–Like Phenotype
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Three pathogenetic hypotheses support the evolution from acute to chronic myocarditis or chronic inflammatory heart disease.
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Immunopathogenic Hypothesis
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It has been proposed that immunopathogenic or inflammatory reactions could lead to tissue damage uncoupled from the original viral injury.33 The original myocyte damage induced by the acute inflammation might trigger an abnormal immune response that could subsequently smolder into a subacute and chronic phase of myocardial inflammation and myocyte damage. Few studies have reported the presence of anticardiac autoantibodies and immunoglobulins in blood samples.85 This hypothesis supports the potential benefit of immunosuppression.
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However, it has also been suggested that the infectious agent, or virus in particular, could persist and induce chronic inflammation and myocyte damage.33 Based on this hypothesis, antiviral agents could help cleanse the infected myocardium from the persistent viral infection. However, the pertinent issues include how to detect viral persistence, demonstrate its virulence, and implicate it as the basis of myocardial dysfunction. Several studies have questioned the validity of PCR-based detection of viral genome in myocardial tissue as cause of the underlying myocardial disease, because many nonmyocarditis and noncardiomyopathy controls also test positively for the viral genome load.86,87,88,89
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It is reasonable to propose that both mechanisms—viral persistence and the autoimmune reaction—might contribute to the progression of myocardial damage, chronic myocardial remodeling, and dysfunction. Both mechanisms, although biologically plausible, have been variably demonstrated and lend importance to the antiviral and immunosuppressive interventions. However, the major missing link in patients with poor clinical outcome is the systematic evaluation of the family to exclude underlying genetic causes that can either cause or contribute to the eventual phenotype.90
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Treatment of Viral Myocarditis
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Treatment of myocarditis consists of supportive care with heart failure guideline–directed medical therapy and diuretics to relieve congestion.91 The use of positive inotropic agents is reserved for patients with reduced cardiac output and impaired organ perfusion. Temporary or implantable mechanical support devices are frequently employed in patients with refractory cardiogenic shock.92
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Immunosuppressive Therapy
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Current clinical guidelines do not support the use of immunosuppressive therapy in the routine management of acute myocarditis.3 A study of 102 patients with acute-onset DCM classified as either reactive or nonreactive (based on the biopsy or other evidence of inflammation) failed to resolve LVEF after 9 months of prednisone treatment, even after an early transient improvement in reactive patients.93 The multicenter Myocarditis Treatment Trial randomized 111 patients with biopsy-proven myocarditis of unknown etiology and an LVEF less than 45% to conventional therapy versus immunosuppressive therapy consisting of prednisone together with azathioprine or cyclosporine. Both groups experienced an average LVEF increase of 9% over 28 weeks, but immunosuppressive therapy failed to attenuate clinical disease or improve survival.8 Reserving immunosuppressive therapy for only those patients with ongoing inflammation has met with mixed success. A randomized study of 84 patients with unexplained DCM and increased human leukocyte antigen expression in biopsy specimens compared guideline-directed medical therapy of heart failure alone or in combination with prednisone and azathioprine.94 The addition of immunosuppressive therapy was associated with an increase in LVEF and NYHA functional class at 3 and 24 months, but failed to reduce a primary composite end point of death, transplantation, or hospitalization. The favorable response to immunosuppressive therapy has been reported predominantly in virus-negative, autoimmune forms of myocarditis. In a study of 41 patients with active myocarditis and chronic heart failure treated with prednisone and azathioprine,95 21 patients were considered responders, experiencing an increase in LVEF from an average of 25.7% at baseline to 47.4% following treatment. Cardiac autoantibodies were present in 91% of these patients and in none of the nonresponders. Interestingly, viral genomes were detectable in 85% of the nonresponders and only 14% of responders. The Tailored Immunosuppression in Inflammatory Cardiomyopathy study was a randomized, placebo-controlled trial of prednisone and azathioprine in virus-negative myocarditis96; immunosuppressive therapy of 85 patients was associated with an increase in LVEF, reduction in LV volumes, and improved NYHA functional class.
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Immunomodulatory Therapies
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High-dose intravenous immunoglobulin (IVIG) has both immunomodulatory and antiviral effects. Clinical trial results of its use in myocarditis have been mixed. In an open-label study, 9 of 10 adult patients with new-onset heart failure treated with IVIG had a significant improvement in LV function.97 The Intervention in Myocarditis and Acute Cardiomyopathy trial was a randomized, placebo-controlled trial of IVIG that enrolled 62 patients with recent-onset DCM and LVEF < 40%.98 Of these, 15% of patients had biopsy-proven myocarditis. No benefit of immunomodulation was demonstrated in terms of ejection fraction or survival at 6 and 12 months. Direct removal of circulating cardiac autoantibodies through the use of immunoadsorption has also been reported in a small, single-center study of patients with recent-onset cardiomyopathy.99 In the absence of positive results from randomized controlled trials, it is not possible to make a recommendation for the use of IVIG or immunoadsorption.3
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In patients with enterovirus myocarditis and viral persistence, treatment with interferon-β (IFN-β) has been reported to produce hemodynamic and clinical improvement.76,100 Twenty-two patients with adenoviral or enteroviral genomes from EMBs and heart failure refractory to guideline-directed medical therapy were treated for 6 months with IFN-β. Treatment produced structural and functional LV improvement, and a majority of patients showed an improvement in NYHA functional class; viral genome was successfully eliminated in all patients, and myocardial inflammation was substantially reduced. Long-term follow-up of this cohort and others who spontaneously cleared enterovirus infection showed improved survival as compared to those with viral persistence.76 Elevated levels of IFN-β, either through spontaneous production or exogenous administration over 6 months, were associated with effective enterovirus clearance and improved outcome. Conversely, the lack of spontaneous IFN-β production was associated with enterovirus persistence and reduced long-term survival. In a recent phase II study, 143 patients with symptoms of heart failure and biopsy-based confirmation of the enterovirus, adenovirus, and/or B19V genomes in their myocardial tissue were randomly assigned to double-blind treatment with either placebo (n = 48) or 4 × 106 IU (n = 49) or 8 × 106 IU (n = 46) of IFN-β-1b for 24 weeks, in addition to standard heart failure treatment. Compared to placebo, virus elimination and/or virus load reduction was higher in the IFN-β-1b groups (odds ratio 2.33, P = .048; similarly in both IFN groups). IFN-β-1b treatment was associated with favorable effects on NYHA functional class and improvement in quality of life and patient global assessments. The frequency of adverse cardiac events was similar in the IFN-β-1b groups compared to the placebo group.74 Results of major clinical trials are listed in Table 63–2.
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Nonviral Infectious Myocarditis
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Bacterial Myocarditis
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Although the list of the causes of infective myocarditis (see Table 63–1) may include several different bacteria, the proportion of bacterial myocarditis in immunocompetent hosts is low. Recent reports suggest a changing epidemiologic scenario of myocarditis-causing bacterial infections (eg, Corynebacterium diphtheriae infection is increasing worldwide, particularly in the developing countries).101,102,103,104 Uncommon pathogens with atypical clinical presentation such as Listeria monocytogenes and Leptospira are rare causes of myocarditis, and Legionella typically associated with pneumonia may occasionally present with fulminant myocarditis.105,106,107 Warning messages come from single case reports or small clinical series demonstrating myocarditis in both immunocompetent and immunodeficient patients with multidrug-resistant infectious agents.108 Typhoid infection from H58 lineage is one of the numerous reports on the re-emergence of typhoid in southern and eastern Africa, particularly from in Blantyre since 2011, highlighting the need for identifying the reservoirs and transmission of disease.108 Recently, nontyphoid Salmonella, most commonly Salmonella enteritidis, was reported to inflict an overall mortality of 24%, wherein 42% of patients required intensive care and myocarditis was associated with poor prognosis and affected young adults.109 In immunocompromised hosts, myocarditis can complicate meningococcal infection with an extremely poor prognosis and high mortality.110,111,112
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Bacterial coinfections with prevalent Staphylococcus aureus and Streptococcus pneumoniae in patients with influenza can cause myocarditis.113 Children with pre-existing neurologic conditions and immunocompromise are at increased risk of pH1N1-associated death after intensive care unit admission. Secondary complications of pH1N1, including myocarditis, encephalitis, and clinical diagnosis of early presumed methicillin-resistant S aureus coinfection of the lung, have been reported as fatal risk factors.114 Tubercular myocarditis is still known to occur and cause sudden death.115,116 Finally, myocarditis can follow medical treatments for rare infections such as ehrlichiosis.117,118
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In immunocompetent hosts, fungal myocarditis is rare; Candida and Aspergillus may occasionally cause myocarditis and can represent hospital-acquired infections.119,120,121 Fungal infections are more commonly associated with endocarditis (see Chap. 67), in particular in postsurgical patients and in patients receiving implantable devices.
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Myocarditis Associated With Parasitic Infections
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In immunocompetent hosts, Trypanosoma cruzi is the most common parasitic infection known to be associated with myocarditis22,24,25 (described later). Between 5 and 18 million people are currently infected, and the infection is estimated to cause more than 10,000 deaths annually.22,24 Toxoplasma gondii causes a disease known as toxoplasmosis.122 While the parasite is found throughout the world, the prevalence of human Toxoplasma infection varies in different parts of the world and has been reported with rates up to 75%.123,124 Few infected individuals have symptoms. However, in pregnant women and individuals who have compromised immune systems, Toxoplasma infection can cause severe consequences. The implementation of prophylaxis with trimethoprim-sulfamethoxazole in transplanted patients has significantly contributed to prevent post-transplantation myocarditis.124
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A rare infection is sarcocystosis, which typically affects muscle but rarely involves the heart125; it can be suspected in travelers returning ill from high-risk areas complaining of myalgia with or without fever. Acute muscular sarcocystosis shows an apparent biphasic course with fever and acute myalgia followed subsequently by elevated creatine phosphokinase, eosinophilia, and possible relapses.126
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Helminthic Infections
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Helminthic infections rarely affect the heart. They can be suspected in endemic areas with trichinosis and echinococcal infections. Cases of cardiac involvement in leishmaniasis127 or toxocariasis128 are exceptional.
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Trichinellosis or Trichinosis
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Eosinophilic myocarditis is a possible complication in patients with trichinosis, a zoonosis caused by nematodes of the genus Trichinella. The most common species affecting humans is Trichinella spiralis, which has a global distribution and is most commonly found worldwide in carnivorous and omnivorous animals.129,130 The burden of annual infection worldwide is estimated around 10,000 cases. Trichinella is endemic in the areas with unregulated slaughter of pigs and particularly in areas where these are in contact with wild animals.131,132 A systematic analysis of six international databases with 494 studies and 65,818 cases reported 42 deaths in 41 countries from 1986 through 2009. The World Health Organization European Region accounted for 87% of cases; 50% of those occurred in Romania during 1990 to 1999. With a prevalence of 1.1 to 8.5 infected cases per 100,000 population,133 cardiac involvement continues to be a major complication in Romania.134 The myocardial involvement occurs in the second phase of the infection cycles, and humans are affected when consuming raw or undercooked meat infected with the Trichinella parasite; high temperatures (> 77°C) and freezing (–25°C) are known to kill the larvae of the parasite. After exposure to gastric acid, the larvae are released from the cysts (after 1 week of the infection) and invade the small bowel mucosa where they develop into adult worms. Then the larvae migrate through peripheral blood and may reach striated muscles where the encystment is completed in 4 to 5 weeks, and the encysted larvae may remain viable for several years. When informative, muscle biopsy shows inflammatory infiltrates, collagen capsule of the “nurse cell,” and intersected muscle larva.132,133,134,135
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The clinical presentation depends on the stage of infection, number of invading larvae, infected tissues, and general physical condition of the patient. The course of the infection can remain asymptomatic. Symptoms of trichinosis occur in two stages. Intestinal infection is the first stage and develops 1 to 2 days after consuming contaminated meat. The most common symptoms are nausea, diarrhea, abdominal cramps, and fever. The second stage corresponds to larval invasion of muscles and starts after about 7 to 15 days. The most common symptoms are muscle pain and tenderness, weakness, fever, headache, and swelling of the face, particularly periorbital swelling. The pain is pronounced in the respiratory, masticatory, retropharyngeal, and orbicular muscles and tongue. It may be accompanied by skin rash and ocular involvement.132,133,134,135 Eosinophilic myocarditis may occur in the second stage of the disease; it can be life-threatening and may manifest with heart failure and arrhythmias; right ventricular outflow tract obstruction is rarely reported.132,135 The diagnosis of trichinellosis should be based on clinical findings; pathology findings of muscle and/or EMB detecting larvae; laboratory findings of specific antibody response by indirect immunofluorescence, ELISA, or Western blot; hypereosinophilia (1000 eosinophils/mL) and/or increased total IgE levels; increased levels of muscle enzymes; and investigation of the possible source and origin of infection129,130,131,132 (Table 63–3). When the diagnosis is proven, the treatment is based on antihelminthic drugs, such as albendazole or mebendazole, and supportive therapy in patients with heart failure.132
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Echinococcosis is endemic in several geographic areas such as North Africa, South America (Argentina), New Zealand, Greece, and Iceland. In infected patients, cardiac involvement is uncommon (< 2%), and even in patients with cardiac involvement, signs and symptoms are rare (< 10%). The host of Echinococcus granulosus is the dog; humans could serve as the intermediate host if they accidentally ingest ova from contaminated dog feces. Hydatid cysts more commonly affect liver and lungs and are usually solitary. Combined liver and extraliver cysts are observed in 25% of cases; cardiac cysts comprise 0.5% to 2% of all cases. Within the heart, hydatid cysts are usually located in the left ventricle (up to 60%) or right ventricle (up to 20%) and rarely found in the pericardium (10%-15%).136 Pericardial cysts usually do not cause symptoms and remain silent until they grow large and result in cardiac compression, atrial fibrillation, and even sudden death. Myocardial cysts localized in the interventricular septum or LV wall remain segregated and undergo calcification or generate daughter cysts and undergo rupture.137,138
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Depending on the localization, the effects of the ruptured hydatid cysts vary. It could result in pericarditis and may evolve to chronic constrictive pericarditis when ruptured in the pericardium; cardiac tamponade is uncommon.139,140 When the cyst ruptures in right cardiac chambers, possible complications include pulmonary embolism and pulmonary hypertension.141,142,143 Syncope can occasionally be the first manifestation of the disease.144 The rupture of the hydatid cysts with release of the fluid may cause severe anaphylactic reaction. Symptoms may occur in patients with pericardial involvement or with mass-induced right-sided obstruction. Echocardiography and CMR may localize the myocardial cysts.145 When present, eosinophilia may contribute to the diagnostic suspicion. Serologic tests such as the Casoni test demonstrate false-positive and false-negative results in up to 30% of cases; ELISA test has a sensitivity of 91% and specificity of 82%.146
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Medical treatment is based on albendazole and mebendazole; surgical resection is the treatment of choice for the prevention of rupture of cysts. Novel application of the cardiac stabilizer (Octopus IV) was reported to safely lift the heart up and excise a hydatid cyst that was firmly adherent to the posterior surface of the heart.147
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Toxocariasis occurs worldwide. The highest prevalence is reported from tropical and subtropical countries.130 Myocarditis is the most frequent clinical presentation (58%), followed by pericarditis (25%) with or without tamponade. Cardiac involvement in Toxocara infection is a potentially life-threatening complication. The cardiac workup is based on electrocardiography (ECG), chest x-ray, echocardiography, and laboratory tests. ECG may show nonspecific abnormalities, including peripheral and thoracic low-voltage and nonspecific ST-T alterations. The chest x-ray shows cardiomegaly and signs of pulmonary congestion. Echocardiography shows wall thickening, hypokinesia, and a reduced LVEF with possible pericardial effusion or endomyocardial fibrosis and restrictive cardiomyopathy. Thrombotic complications may occur. The therapeutic regimens vary widely, especially with regard to the duration of therapy, and the combination of an anthelmintic drug and corticosteroids appears to be a valuable option. Clinical manifestation of the tissue infection by parasites should be considered in cases of nonspecific organ manifestations (ie, heart, lungs, liver) accompanied by fever and eosinophilia, with or without allergic skin rash.148,149
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Myocardial Transmission of Infections in Heart Transplantation
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Organ transplant recipients can develop infections as a result of transmission through the graft, reactivation of silent infection, reinfection in a healthy graft, or de novo infection. Infections can manifest in the post-transplant period as a consequence of immunosuppression.
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In 2004, the United Network for Organ Sharing introduced the label of “high-risk donor” to identify donors who meet the Centers for Disease Control and Prevention criteria for high-risk behavior for infection.150 In a recent single-center series including 55 recipients of heart transplants from high-risk donors, survival was excellent (short-term survival [1 year] 94%; long-term survival [3 years] 80%), and there was no increased incidence of perioperative or postoperative complications; the risk of transmission of infection from donors in this subgroup seemed to be minimal; only 1 of 55 patients (1.9%) had hepatitis C seroconversion at 105 days after receiving the transplant. After antiviral treatment, the patient had undetectable viral loads. All other patients (n = 54) had undetectable plasma viral loads of HIV, hepatitis C, and hepatitis B.151 These data encourage revision of criteria for declining grafts from high-risk donors.
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Some infectious diseases, such as Chagas disease, endemic fungal infections, tuberculosis (which could be drug resistant), leishmaniasis, and other viral and parasitic diseases, should be considered in the differential diagnosis of post-transplant infections in foreign-born recipients.152