Viral Cardiac Infections

Viruses are among the commonest causes of myocarditis, defined as an inflammatory infiltrate of the heart muscle with death or degeneration of the adjacent myocytes, a picture distinct from the ischaemic damage of coronary artery disease. The inflammation may involve the myocytes, the interstitium, the small vessels and the pericardium, and it impairs cardiac function to produce ventricular dysfunction, arrhythmia, or both.

Many different viruses cause the same syndrome, and a single virus can produce a wide range of manifestations. Clinically, viral heart disease typically begins with a flu-like illness and is followed within days by congestive heart failure: breathlessness, exercise intolerance and fatigue, sometimes with chest pain, palpitations, syncope or sudden death.

The presentation is strongly age-dependent. In infancy and childhood viral myocarditis is usually fulminant, with left or right ventricular systolic dysfunction with or without dilation, whereas adults present less abruptly and resemble dilated cardiomyopathy with left ventricular dilation and systolic failure. The modern understanding is that the attack on heart muscle is one part of a systemic viral, immune and inflammatory process, and that acute viraemia can be followed by long-standing immunovirological disturbance and cardiomyopathy.

The viruses

Most community-acquired myocarditis in high-income settings is viral, but the identified agent has shifted with the diagnostic method. Isolation and serology lack sensitivity and specificity, and molecular detection of viral genomes in heart tissue has become the main means of attribution, with the caveat that a genome in the myocardium does not always equate to disease.

Group	Principal viruses	Comment
Enteroviruses	Coxsackievirus B (especially), coxsackievirus A, echoviruses, poliovirus	The classical cause; neonatal epidemics; coxsackievirus B commonest
Adenoviruses	Types 2 and 5	Common historically; share a receptor with coxsackievirus B
Parvovirus B19	Erythroparvovirus	Predominant on European biopsy series; causal role harder to prove
Herpesviruses	HHV-6, CMV, EBV, HSV, VZV	Mainly in the immunocompromised
Other	Influenza A and B, HIV, hepatitis C (notably Japan), measles, rubella, RSV, human metapneumovirus, dengue, chikungunya, CCHF	Context-dependent

Through the late 20th century the adenoviruses (serotypes 2 and 5) and the enteroviruses, particularly coxsackievirus B, were the agents most often identified; more recently parvovirus B19 has predominated in European biopsy series, though its causal role is debated because the genome persists in many hearts without disease. A shared susceptibility runs through the classical agents: coxsackievirus B (types 3 and 4) and adenoviruses (types 2 and 5) enter cells through the same coxsackievirus and adenovirus receptor (CAR), which is important in cardiac development and is expressed at higher levels in the young and in dilated cardiomyopathy.

The heart is affected across a spectrum of distinct syndromes, several of them congenital, summarised in the table below.

Syndrome	Typical virus	Setting
Myocarditis, pericarditis, cardiomyopathy	Coxsackievirus B and other enteroviruses; adenoviruses; parvovirus B19	Any age; recrudescences occur
Neonatal encephalomyocarditis	Coxsackievirus B, echovirus 11	Newborn; high case fatality
Cardiac malformations (patent ductus, pulmonary stenosis, septal defects)	Rubella (congenital rubella syndrome)	Prenatal
Hydrops fetalis	Parvovirus B19	Prenatal
Endocardial fibroelastosis	Mumps	Prenatal; now rare

Endocardial fibroelastosis, once an important cause of childhood heart failure, has all but disappeared since mumps vaccination, a natural experiment that supports a viral cause for at least that form of cardiomyopathy.

Epidemiology

Myocarditis is difficult to diagnose and is therefore underdiagnosed, so its true incidence is uncertain and every figure depends on how the diagnosis was made. Autopsy series find the usual lymphocyte-predominant myocarditis in 4% to 5% of young men dying of trauma and in 16% to 21% of children dying suddenly. Among adults with unexplained dilated cardiomyopathy the reported proportion ranges from 3% to 63%, but the large Myocarditis Treatment Trial, using the strict Dallas criteria, found a prevalence of about 9%.

Most disease is sporadic, but viral myocarditis can occur in epidemics, usually in newborns and most often with coxsackievirus B. Intrauterine myocarditis occurs both during community epidemics and sporadically. The World Health Organization estimates that the enteroviruses cause cardiovascular sequelae in under 1% of infections overall, rising to about 4% for coxsackievirus B specifically.

Transmission follows the agent: enteroviruses spread by the faecal-oral and respiratory routes, while adenoviruses and influenza spread chiefly by the respiratory route.

Pathogenesis

Myocardial and pericardial infection depends on viraemic dissemination from the initial site of entry at a respiratory or gastrointestinal mucosa. Injury then occurs in two overlapping phases: direct viral damage to myocytes, followed by immune-mediated injury, and a great deal of damage is done by the virus itself before immune cells arrive.

Animal model studies

The murine coxsackievirus B model has defined the time course. Viraemia appears 24 to 72 hours after infection, tissue viral loads peak at 72 to 96 hours, and infectivity is rarely detectable beyond 14 days as neutralising antibody rises. Macrophages, T lymphocytes and natural killer cells appear within 5 to 8 days.

Two cytolytic T-cell populations operate, one killing virus-infected cells and another, autoreactive, destroying uninfected myocytes, so the immune response both clears virus and injures the heart. Severity is modulated by age, sex, host genetics, exercise and viral strain: males run a more severe course, testosterone increases and oestradiol decreases injury, and matrix metalloproteinases shape the early inflammatory phase and later remodelling.

Human observations

Antibody-mediated cytolysis is found in about 30% of patients with suspected myocarditis and in almost all with proven coxsackievirus B or influenza A infection, and a muscle-specific antimyolemmal antibody correlates with cytolysis. Viral genome persists in the myocardium for weeks to months in healing myocarditis and cardiomyopathy while cultures stay negative, suggesting low-level or abortive replication.

Two mechanisms tie the virus directly to chronic disease. The enteroviral protease 2A cleaves dystrophin, the cytoskeletal protein whose inherited mutation causes familial dilated cardiomyopathy and the cardiomyopathy of Duchenne and Becker muscular dystrophy, and the adenoviral E1A proteins promote apoptosis and disturb interleukin-6 signalling.

Pathophysiologic consequences

Infection triggers interstitial inflammation and myocyte loss, so the ventricle dilates and end-diastolic volume rises. The failing myocardium cannot mount the normal Starling increase in contractile force, and cardiac output falls.

A cascade follows: sympathetic activation raises heart rate and afterload; congestive heart failure develops as rising left atrial pressure is transmitted to the pulmonary veins, producing breathlessness and pulmonary oedema; chamber dilation stretches the mitral annulus and causes functional mitral regurgitation, worsening the load; and during healing, fibroblast expansion lays down scar that stiffens the ventricle and creates the electrical inhomogeneity behind ventricular arrhythmias.

Pathology

Gross findings

The changes are non-specific whatever the agent. The heart is heavy with all four chambers affected, the muscle flabby and pale, and petechial haemorrhages are often seen on the epicardium, especially with coxsackievirus B. A serosanguineous pericardial effusion may accompany the common associated pericarditis. Mural thrombi can form on the inflamed endocardium and shed small emboli into the coronary and cerebral vessels.

Findings by microscopy

The hallmark is an interstitial infiltrate of mononuclear cells, predominantly lymphocytes and macrophages, with myocyte necrosis and apoptosis; polymorphs are uncommon. Effacement of the cross-striations and oedema mark severe infection, again especially with coxsackievirus. Certain agents give a more vasculocentric pattern, notably varicella-zoster virus and the rickettsiae. Giant-cell myocarditis is a distinct, aggressive entity separate from the usual lymphocytic form.

Clinical presentation

Presentation depends on age, immune status, the specific virus and host genetics. A non-specific influenza-like illness, gastroenteritis or rash commonly precedes the cardiac symptoms.

Newborns and infants

Newborns and infants present with poor feeding, fever, irritability or listlessness, pallor and diaphoresis, and sudden death may occur. The younger the child, the more likely the infection was acquired in utero, and the more severe the illness, reflecting the immature immune response to a lytic infection. Prognosis is poor: one series of suspected coxsackievirus B myocarditis reported around 75% mortality, most deaths in the first week.

Children, adolescents and adults

Older children and adults usually give a history of a non-specific respiratory or gastrointestinal illness 10 to 14 days before presentation, then lethargy, low-grade fever, pallor, exercise intolerance and the signs of congestive heart failure, with jugular venous distension and pulmonary crackles. Arrhythmias, including atrial fibrillation, supraventricular and ventricular tachycardia and atrioventricular block, may occur.

Prognosis is better than in infancy, with a mortality of about 10% to 25% in clinically manifest cases; roughly half recover completely, while a quarter retain an abnormal electrocardiogram or cardiomegaly. A dangerous subgroup masquerades as common viral respiratory illness, gastroenteritis or dehydration and deteriorates over hours to days to cardiac arrest, the diagnosis made only at autopsy. Pericarditis frequently accompanies myocardial involvement, with friction rub and pleuritic pain, and may become persistent.

Diagnosis

Myocarditis should be suspected in anyone with unexplained congestive heart failure or ventricular tachycardia, especially without predisposing cardiac disease.

Chest radiography classically shows cardiomegaly with pulmonary oedema. The electrocardiogram shows sinus tachycardia with low-voltage QRS complexes and T-wave changes, sometimes a pseudo-infarct pattern of wide Q waves and ST change, and various arrhythmias or atrioventricular block. Echocardiography shows a dilated, hypokinetic left ventricle with functional mitral regurgitation and frequent pericardial effusion, and cardiac magnetic resonance imaging with gadolinium has become a valuable non-invasive test, mapping the site and extent of inflammation.

Blood tests are supportive but non-specific: troponin and creatine kinase MB rise with myocardial injury, and inflammatory markers may be raised, but none is specific for viral myocarditis.

Endomyocardial biopsy is the tissue standard, showing the mononuclear infiltrate and myocyte damage, but its sensitivity is low (reported 3% to 63%) because the inflammation is patchy, and it carries real risk in small children (under 10 kg) and those with severe ventricular failure, so many centres have restricted its use. The Dallas criteria classify a biopsy as active, borderline or no myocarditis; they standardised trial diagnosis but are criticised for missing the low-grade inflammation that separates normal from failing hearts.

Viral studies complete the workup. Culture from myocardium was the old standard but is insensitive, and a fourfold antibody rise is non-specific because prior infection is common. Polymerase chain reaction (PCR) and in situ hybridisation on cardiac tissue detect enterovirus, adenovirus, parvovirus B19, CMV and EBV, in situ hybridisation localising the genome to injured myocytes. The central pitfall is that a genome detected in the myocardium, and still more one detected in blood or the respiratory tract, does not by itself prove the virus caused the disease.

Diagnosis	PCR-positive	Commonest genomes
Myocarditis (624 samples)	38%	Adenovirus 23%, enterovirus 14%, CMV 3%
Dilated cardiomyopathy (149 samples)	20%	Adenovirus 12%, enterovirus 8%
Controls (215 samples)	1.4%	Rare, isolated detections

Differential diagnosis

Any cause of acute circulatory failure can mimic viral myocarditis. Non-viral infectious causes include the rickettsiae, bacteria, protozoa and fungi: diphtheria toxin causes atrioventricular block, and Trypanosoma cruzi causes Chagas disease, a major cause of myocarditis in South America but rare elsewhere.

Non-infectious mimics include drugs (cytotoxics, antipsychotics, some antimicrobials), hypersensitivity and autoimmune or connective-tissue disease (systemic lupus erythematosus, rheumatic fever, rheumatoid arthritis), Kawasaki disease, sarcoidosis and giant-cell myocarditis. In many cases the cause is never identified and idiopathic myocarditis is diagnosed.

Long-term sequelae

Where cardiac function does not recover, chronic dilated cardiomyopathy results, with a dilated, poorly contracting left ventricle. Viral persistence and autoimmunity are both implicated, and the direct cleavage of dystrophin by the enteroviral protease 2A gives a mechanistic link to the inherited dilated cardiomyopathies. Arrhythmias may persist long after the acute illness, so patients who recover are monitored indefinitely.

Establishing a viral cause

Proving that a detected virus caused a given case remains difficult. Viral genome is found in up to 70% of myocarditis biopsies yet only rarely in controls, which argues for a causal role, but frank inflammation is not always present and definitive cause-and-effect data are sparse.

The clearest human evidence comes from cardiac transplant surveillance biopsies: patients with no PCR-positive result over five years had a 96% survival, against 67% for those with any positive result, and the specific virus mattered, with adenovirus provoking less inflammation than enterovirus or parvovirus B19.

Management

Care depends on the severity of involvement. Many patients have mild disease, because the common cardiotropic viruses are “high-attack, low-virulence” agents, and need only close monitoring. Bed rest is advised in the acute stage, since animal data suggest activity increases intramyocardial viral replication.

Acute heart failure is managed with hemodynamic support aimed at organ perfusion. Vasopressors (noradrenaline, adrenaline, vasopressin) maintain blood pressure; inotropes (dobutamine, dopamine, milrinone) and digoxin are used with caution because they can drive arrhythmia; and once the patient is stable, angiotensin- converting enzyme inhibitors, beta-blockers and diuretics are introduced.

Arrhythmias are treated only when they cause symptoms or compromise, with amiodarone or cardioversion, and complete atrioventricular block needs temporary pacing. When medical therapy fails, mechanical circulatory support with a ventricular assist device or extracorporeal membrane oxygenation bridges the acute phase, and transplantation is occasionally needed.

Immunomodulatory and antiviral therapy remains unproven. Immunosuppression does not improve outcomes in viral myocarditis (the Myocarditis Treatment Trial showed no benefit), though it helps in giant-cell myocarditis; intravenous immunoglobulin is used in children with uncertain evidence. Interferon has shown mixed results against enteroviral and adenoviral disease, and the picornaviral capsid inhibitors pleconaril and vapendavir remain investigational and unapproved.

Vaccination is the clearest success but is limited: only influenza vaccine is available among the principal cardiotropic agents. The elimination of mumps-associated endocardial fibroelastosis by mumps vaccination, and the success of polio vaccine, support the idea that an enteroviral or coxsackievirus B vaccine could reduce myocarditis.

References and recommended reading

• McManus BM, Seidman M, Klingel K, Luo H. Viral Heart Disease. In: Richman DD, Whitley RJ, Hayden FG, editors. Clinical Virology, 4th edition, Chapter 7. Washington: ASM Press; 2016. The backbone source for the aetiology, pathogenesis, diagnosis and management of viral myocarditis.
• Burrell CJ, Howard CR, Murphy FA. Fenner and White’s Medical Virology, 5th edition. Academic Press / Elsevier; 2017. The source for the spectrum-of-carditis table and the congenital cardiac syndromes.