Coxsackieviruses belong to the family Picornaviridae and the genus Enterovirus, which also includes poliovirus and echovirus. Enteroviruses are among the most common and important human pathogens. Coxsackieviruses share many characteristics with poliovirus. With control of poliovirus infections in much of the world, more attention has been focused on understanding the nonpolio enteroviruses such as coxsackievirus.
Coxsackieviruses are nonenveloped viruses with linear single-stranded RNA. Coxsackieviruses are divided into group A and group B viruses based on early observations of their pathogenicity in mice. Group A coxsackieviruses were noted to cause a flaccid paralysis, which was caused by generalized myositis, while group B coxsackieviruses were noted to cause a spastic paralysis due to focal muscle injury and degeneration of neuronal tissue. At least 23 serotypes (1-22, 24) of group A and 6 serotypes (1-6) of group B are recognized.
In general, group A coxsackieviruses tend to infect the skin and mucous membranes, causing herpangina, acute hemorrhagic conjunctivitis (AHC), and hand-foot-and-mouth (HFM) disease. Group B coxsackieviruses tend to infect the heart, pleura, pancreas, and liver, causing pleurodynia, myocarditis, pericarditis, and hepatitis.[1] Both group A and group B coxsackieviruses can cause nonspecific febrile illnesses, rashes, upper respiratory tract disease, and aseptic meningitis.
Numerous group A coxsackieviruses are responsible for causing CNS disease similar to poliomyelitis.[2] Systemic neonatal disease is often associated with group B coxsackieviruses.[2]
The development of insulin-dependent diabetes (IDDM) has recently been associated with recent enteroviral infection, particularly coxsackievirus B infection. This relationship is currently being studied further.
Coxsackieviruses are transmitted primarily via the fecal-oral route and respiratory aerosols, although transmission via fomites is possible. The viruses initially replicate in the upper respiratory tract and the distal small bowel. They have been found in the respiratory tract up to 3 weeks after initial infection and in feces up to 8 weeks after initial infection. The viruses have been found to replicate in the submucosal lymph tissue and disseminate to the reticuloendothelial system. Further dissemination to target organs occurs following a secondary viremia. Immunity is thought to be chiefly humoral.[2]
United States
Approximately 10 million symptomatic enteroviral infections are estimated to occur annually in the United States. From 2002-2004, an estimated 16.4-24.3% of these illnesses were attributed to coxsackievirus serotypes. For 2 of the 3 years, coxsackievirus B1 was the predominant serotype. Enteroviruses are responsible for approximately 30,000-50,000 hospitalizations per year.[3] The Centers for Disease Control and Prevention (CDC) found that coxsackievirus infections accounted for approximately 25% of all neonatal enterovirus infections (26,737) from 1983 to 2003.[4] Those due to coxsackievirus B4 were associated with a higher mortality rate than any other serotype.
International
Coxsackievirus infections have worldwide distribution. They can be isolated year-round in tropical climates, with a decreasing incidence of disease and seasonality in areas of higher latitude.
Mortality due to coxsackievirus infection is uncommon. Neonates and immunocompromised individuals are at most risk for complications secondary to all enteroviral infections.
During the first decade, enteroviral infections are more common in males, with a male-to-female ratio of 2:1. The reason for this increased incidence is not well known.
Coxsackievirus infection occurs in all age groups but is more common in young children and infants. Children are at higher risk of infection during the first year of life. The rate of illness decreases greatly following the first decade of life.
More than 90% of coxsackieviruses infections are asymptomatic or cause nonspecific febrile illnesses. In neonates, they are the most common cause of febrile illnesses during the summer and fall months. Thirteen percent of newborns with fever in the first month of life were noted to have an enteroviral infection. In addition to nonspecific illnesses, various well-described illnesses have been associated with coxsackievirus infections.
Patients with aseptic meningitis may have rapid or gradual onset of fever and chills, nausea and vomiting, malaise, headaches, neck pain, light sensitivity, and upper respiratory symptoms. Infants younger than 3 months have been noted to have the highest incidence of clinically recognized aseptic meningitis, partly because lumbar punctures are often performed for the evaluation of fever in this age group. These infants often present with only a febrile illness characterized by irritability and anorexia. Meningismus occurs in only approximately 50% of infants with enteroviral meningitis.
Coxsackievirus B infection is more likely than coxsackievirus A to be associated with meningitis.
Seizures, lethargy, and movement disorders occur early in the course of disease and have been reported in 5-10% of patients with enteroviral meningitis. No long-term neurologic deficits appear to exist in infants with aseptic meningitis. Adults may experience a more prolonged period of fever and headache compared with infants and children.
Encephalitis is an unusual manifestation of CNS infection, although it is sometimes observed in association with aseptic meningitis. Enteroviruses accounts for approximately 5% of all cases of encephalitis. Coxsackievirus types A9, B2, and B5 have been linked with encephalitis. In rare cases, it mimics encephalitis secondary to herpes simplex virus.
Rarely, coxsackieviruses have been implicated in additional neurologic diseases such as sporadic cases of flaccid motor paralysis that closely mimic poliovirus infection. Additionally, cases of Guillain-Barré syndrome have been described with coxsackievirus serotypes A2, A5, and A9.
Myopericarditis can occur at any age although has a predilection for adolescents and young adults. Enteroviruses account for half of all cases of acute viral myopericarditis.
Manifestations of myopericarditis range from an asymptomatic presentation to heart failure and death. Between the two extremes, most patients report dyspnea, chest pain, fever, and malaise.
Symptoms may be preceded by an upper respiratory infection within the preceding 7-14 days.
Presenting signs include pericardial friction rub, gallop rhythm, and cardiomegaly and/or pericardial effusion on chest radiography.
ECG abnormalities may range from ST-segment elevations to heart block. Echocardiography may show diminished ejection fractions and left ventricular wall abnormalities. Myocardial enzyme levels in the serum are frequently elevated.
The male-to-female ratio is 2:1. The mortality rate is low, and the prognosis in children is believed to be better than that in adults. Complications include pericardial effusion, arrhythmia, heart block, valvular dysfunction, and dilated cardiomyopathy.
Although principally correlative, data suggest that type-1 insulin-dependent diabetes may result from group B coxsackievirus infections. Epidemiologic data note that clustering of newly onset diabetes mellitus occurs 1-3 months following infection with the virus. Similarly, animal models noted infection of pancreatic islet cells.
Two of the more distinctive exanthems caused by coxsackievirus hand-food-and-mouth disease (HFMD) and herpangina.
HFMD often affects children and spreads easily to other family members. Patients present with a sore throat and mouth. Vesicles that coalesce, form bullae, and then ulcerate form on the buccal mucosa and tongue. Seventy-five percent of patients have peripheral cutaneous lesions at approximately the same time. Biopsy reveals intracytoplasmic viral particles. The most common virus isolated is coxsackievirus A16. Numerous cases of a more severe HFMD caused by coxsackievirus A6 were reported between 2004 and 2011 in several Asian and European countries.[5] Additionally, between 2011 and 2012 in the United States, several cases of severe HFMD were reported, with 74% of those cases testing PCR positive for coxsackievirus A6; about 25% of reported cases were in adults.[5]
Herpangina is a vesicular enanthem of the posterior oropharynx with fever, sore throat, occasional throat exudate, odynophagia, and dysphagia, which is observed more often in young children than in adolescents and adults. Prompt recovery is typical, with almost all patients recovering completely. Group A coxsackieviruses are the most common viruses isolated from herpangina patients.
This is a muscular disease, and viral invasion of muscles, causing inflammation, is suspected; however, direct histologic evidence is lacking. Epidemic pleurodynia is usually associated with outbreaks of group B coxsackievirus infection.
Patients present with fever and sharp, paroxysmal, spasmodic pain in the chest and upper abdomen.
All patients recover completely within 1 week.
Pain and edema of the eyelids and subconjunctival hemorrhage are present.
Patients may also report photophobia, foreign body sensation, fever, malaise, and headache. These symptoms usually resolve spontaneously within one week.
Rare complications include keratitis and motor paralysis.
This condition is highly contagious and has resulted in epidemics and pandemics.
On examination, patients may have signs of nuchal rigidity and other evidence of meningeal irritation, photophobia, pharyngitis, and rash.
In contrast to patients with aseptic meningitis, whose brain function is normal, patients with encephalitis may present with cerebral dysfunction that manifests as altered mental status, personality changes, and neurologic deficits (eg, motor, sensory, speech impairment). An EEG may be helpful in localizing and characterizing the seizure focus.
The presentation in patients with myopericarditis ranges from asymptomatic to critical illness secondary to severe heart failure. Most patients report fever, malaise, upper respiratory tract symptoms, dyspnea, and chest pain. Chest pain increases when the patient is lying down and improves when the patient sits up and leans forward.
On examination, the point of maximal pulse (PMI) may be displaced, pericardial friction rub may be heard, and signs of heart failure (eg, S3 gallop, pulmonary edema) may be present.
Physical examination findings include vesicular lesions that may appear on the tongue or buccal mucosa, as well as the hands and feet, including the palms and soles. Uncommonly, the buttocks and genitalia are involved. The vesicles are tender and may ulcerate. However, the vesicles are usually not pruritic, which helps to distinguish them from chickenpox lesions.
On physical examination, edema of the involved muscles and tenderness to palpation may occur.
Physical examination findings include subconjunctival hemorrhage. Eye pain, edema of the eyelids, photophobia, and a serous discharge may be present. Slit lamp examination may reveal keratitis.
Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.
Coxsackieviruses cause many different types of rashes. Whether the viruses directly cause the rashes or immunologic mechanisms are responsible for the rashes is not known. An exception is HFM, in which viruses are isolated directly from the lesions. HFM is predominantly caused by coxsackievirus A16. In most other instances, rashes can be attributed to coxsackieviruses only if findings on concurrent polymerase chain reaction (PCR) or serology are positive.
Coxsackievirus serotype A24 generally causes AHC. Transmission usually occurs via contact of contaminated fingers or fomites with the eyes. To prevent further transmission, strict handwashing should be encouraged and sharing of towels should be avoided.
Definitive diagnosis can be made based on isolation of the virus in cell culture. Cytopathic effect can usually be seen within 2-6 days. Samples are normally taken from the stool or rectal swabs but may be isolated from the oropharynx early in the disease course. False-positive culture results are possible, as excretion can occur for up to 8 weeks after initial infection. Serology can be difficult to interpret. Traditionally, enteroviral infections have been noted after a rise in neutralizing antibodies titer (at least a 4-fold rise in titer between acute and convalescent phase). PCR is also available, with a sensitivity of 66-90%.
The workup needs to rule out bacterial meningitis, and appropriate antibiotics should be administered until the workup is complete. Diagnosis requires cerebrospinal fluid (CSF) evaluation, which tends to show a lymphocytic predominance, normal-to-decreased glucose levels, and normal-to-slightly elevated protein levels. The virus can be isolated via cell culture (sensitivity, 30-35%) or PCR (sensitivity, 66-90%). A recent study in infants reported that routine CSF PCR for enteroviruses resulted in shorter hospital stays (by 1.54 days) and a decreased duration of antibiotic use (by 33%).[6]
Diagnostic workup requires CSF evaluation, which yields findings similar to those of aseptic meningitis.
Diagnosis is generally circumstantial, with evidence of infection from the oropharynx, feces, or on serology.
Diagnosis requires conjunctival swabs or scrapings, which are 90% successful. A rising antibody titer can be demonstrated.
Head CT scanning without contrast may be obtained upon initial presentation of meningitis and/or encephalitis to rule out hemorrhage, increased intracranial pressure, or mass lesions.
Echocardiography can be used to evaluate overall cardiac function and valvular disease in patients with myopericarditis and heart failure.
Obtain a throat culture to rule out streptococcal pharyngitis and/or tonsillitis.
HIV testing is always appropriate in patients who present with nonspecific febrile illness or rashes.
An EEG can be used to detect the presence of and localize seizure activity.
ECG changes in myopericarditis include ST-segment elevations or nonspecific ST segment, T-wave abnormalities, arrhythmia, and heart block.
Lumbar puncture is crucial in the evaluation of meningitis and/or encephalitis.
Skin biopsy may be helpful in the evaluation of nonspecific exanthems.
Obtain a Tzank smear to rule out herpes virus infection.
Intracytoplasmic viral particles may be observed, especially with skin lesions and/or rashes of HFM.
Medical care is generally supportive and can be offered on an outpatient basis. More severe symptoms may require inpatient admission for further workup and intervention.
Treatment is mainly supportive.
Pleconaril, an enteroviral capsid-stabilizing drug, appeared to reduce symptoms in a randomized double-blind study (N = 33),[7] but has not been licensed by the Food and Drug Administration (FDA).
Not all patients require hospitalization, but consider admission for patients with changes in mental status or neurologic deficits.
IVIG has been of anecdotal benefit, but no randomized trials have been conducted. A large prospective trial of prednisone with cyclosporine or azathioprine showed no difference compared to supportive treatment alone.[8] Recent experiments have shown that carvedilol, a nonselective beta-blocker, attenuates myocardial lesions and decreases myocardial virus replication in a murine model. However, this intervention has not been evaluated in humans.[9]
Analgesics, narcotics, and heating pads are the mainstays of therapy. All patients recover completely within 1 week.
Treatment is symptomatic, and no antimicrobial agent is necessary in the absence of bacterial superinfection.
Both IVIG and pleconaril have been used in immunocompromised patients with enteroviral infections (neonates and B-cell immunodeficient) with varying success.
In vitro studies have suggested that arbidol may have potential as a future antiviral agent with activity against coxsackievirus, but no trials in humans have yet been performed.[10]
No surgical intervention is necessary unless patients develop complications such as meningitis and/or encephalitis with increased intracranial pressure, which requires ventriculostomy, or heart failure, which requires valve repair or cardiac transplant.
Consultations play an important role in patients with complex presentations.
A neurologist may help to evaluate patients who present with abnormal neurologic symptoms or to manage rare complications associated with meningitis.
A neurosurgeon may be needed to assist with obtaining brain biopsies or placing a ventriculostomy tube because of increased intracranial pressure.
A cardiologist helps with diagnosis and management of arrhythmia, heart failure, and heart block associated with myocarditis.
No FDA-approved therapy exists for the treatment of enteroviral infections. IVIG and pleconaril have been used in severe illness. Supportive use of analgesics and antipyretics are usually necessary.
No outpatient care, other than usual follow-up care, is required for patients with mild symptoms.
Severe aseptic meningitis and/or encephalitis, seizures, myopericarditis, and heart failure require admission for workup and treatment. Antibiotics may be used until bacterial meningitis is ruled out. Supportive inpatient or intensive care may be necessary for severe cases.
Inpatient medications indicated are based on the patient's presentation at admission (eg, phenytoin for seizure prophylaxis and/or suppression in patients with aseptic meningitis/encephalitis, digoxin in patients with heart failure).
Antipyretics (eg, acetaminophen) for fever and NSAIDs for pain should be adequate in patients with mild symptoms who do not require hospital admission.
Transfer to a tertiary facility may be necessary for specialized consultations or surgeries.
Minimize respiratory contact with the infected patient if possible.
To prevent further transmission, strict handwashing should be encouraged and sharing of towels should be avoided.
See History and Physical, which discuss the many presentations of coxsackievirus infections.
Complications of aseptic meningitis include lethargy, seizures, coma, and movement disorders (5-10%).
Complications of myopericarditis include pericardial effusion, arrhythmia, heart block, valvular dysfunction, and dilated cardiomyopathy.
Rare complications of acute hemorrhagic conjunctivitis (AHC) include keratitis and motor paralysis.
In general, the prognosis is very good, with 90% of patients having no symptoms or experiencing mild, self-limited, nonspecific febrile illnesses or rashes.
Patients should be aware of the need for good hygiene practices to avoid transmission.
Patients need to be reassured that they have a self-limited viral illness that does not require any antibiotics for treatment.