Coxsackieviruses belong to the family Picornaviridae and the genus Enterovirus, which also includes poliovirus and echovirus.[1] Enteroviruses are among the most common and important human pathogens with 9 different species classified(Enterovirus A-H and I).[2] Enterovirus C includes poliovirus 1-3, whereas Enterovirus A, B, and C include the numbered coxsackieviruses. 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 coxsackieviruses.
Coxsackieviruses are nonenveloped viruses with linear single-stranded RNA.[1] 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 that was caused by generalized myositis, whereas group B coxsackieviruses were noted to cause a spastic paralysis due to focal muscle injury and degeneration of neuronal, pancreatic, and myocardial 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. 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. Systemic neonatal disease often is associated with group B coxsackieviruses.
The development of insulin-dependent diabetes (IDDM) has been associated with recent enteroviral infection, particularly coxsackievirus B infection.[3]
The Centers for Disease Control and Prevention (CDC) have rigorously evaluated cases of acute flaccid myelitis (AFM) since 2014, when an increased number of cases were reported. AFM is a CNS disease that specifically affects the spinal cord gray matter, causing muscle and reflex weakness. Most reported AFM cases do not have an identified etiologic pathogen. However, coxsackievirus A16 has been one of the viruses recovered from cerebrospinal fluid in a small number of confirmed cases.
Coxsackieviruses primarily are transmitted via the fecal-oral route and respiratory aerosols, although transmission via fomites also is possible. Viral replication initially occurs in the upper respiratory tract, particularly the tonsils, and the distal small bowel. Viremia with systemic dissemination then occurs and involves the reticuloendothelial system, which leads to further replication in other anatomic locations and organs and ultimately to development of symptoms.[4] Central nervous system (CNS) invasion is proposed to occur from viral migration along peripheral and central nerves into the CNS.[4] Coxsackieviruses have been identified in the respiratory tract up to 3 weeks after initial infection and in feces up to 8 weeks after initial infection. Innate, humoral and cell-mediated immunity all play a role in the body's response to enteroviral infection.[5] However, the infection frequently is eradicated before antibody production occurs.[5]
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 to 50,000 hospitalizations per year. The CDC found that coxsackievirus infections accounted for approximately 25% of all neonatal enterovirus infections (26,737) from 1983 to 2003. Those due to coxsackievirus B4 were associated with a higher mortality rate than any other serotype.
The CDC reports coxsackievirus A16 as the virus most frequently isolated in hand, foot, and mouth disease (HFMD). Similarly, coxsackievirus A6 was the most frequently reported enterovirus from 2009-2013.
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.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Co-infections
The COVID-19 pandemic, caused by SARS-CoV-2, has significantly impacted the epidemiology of other respiratory viral pathogens.[6] Among patients with SARS-CoV-2 co-infection, rhinoviruses and respiratory enteroviruses are the leading causative pathogens.[7] This could be attributed to their non-enveloped nature and prolonged survival, which contribute to them being less susceptible to nonpharmaceutical interventions such as mask wearing and surface cleaning.[8, 9] Additionally, the majority of these co-infections manifest as mild COVID-19.[7]
Mortality due to coxsackievirus infection is uncommon. Neonates and immunocompromised individuals are at highest risk for complications secondary to 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 disparity is not well understood.
Coxsackievirus infections occur in all age groups but are more common in young children and infants. Children are at higher risk for infection during the first year of life. The rate of incident infection decreases substantially after the first decade of life.
In general, the prognosis for coxsackievirus infection is quite good, with over 90% of patients having no symptoms or experiencing mild, self-limited, nonspecific febrile illnesses or rashes.[10, 11]
Patients should be aware of the need for good hygiene practices to avoid transmission of coxsackievruses.
Patients can be reassured that they most likely have a self-limited viral illness that does not require antibiotics.
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. As measured yearround, thirteen percent of newborns with fever in the first month of life were noted to have an enteroviral infection. In addition to nonspecific febrile illnesses, various well-described syndromes also 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 often are 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 approximately 50% of infants with enteroviral meningitis.
Coxsackievirus B infection is more likely than coxsackievirus A to be associated with meningitis.[12]
Seizures, lethargy, and movement disorders can 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 caused by coxsackievirus. 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 sometimes is observed in association with aseptic meningitis. Enteroviruses account for approximately 5% of all cases of encephalitis. Coxsackievirus types A9, B2, and B5 have been linked with encephalitis.
Rarely, coxsackieviruses have been implicated in other sporadic neurologic syndromes such as acute flaccid myelitis (AFM) that closely mimics poliovirus infection. In particular, Enterovirus D68 (EV-D68) is of prime interest as a causative agent of AFM. Initially described in the context of AFM in 2005, EV-D68 was associated with a sizable AFM outbreak in the United States in 2014, with additional outbreaks described in 2016 and 2018.[5] Enterovirus A71 and coxsackievirus A16 also have been described in cases of AFM.[5] Additionally, cases of Guillain-Barré syndrome have been described with coxsackievirus serotypes A2, A5, and A9.
Myopericarditis can occur at any age, but the condition occurs more often in 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 to 14 days.
Presenting signs include pericardial friction rub, gallop rhythm, and cardiomegaly and/or pericardial effusion on chest radiography.
ECG abnormalities range from ST-segment elevations to heart block. Echocardiography can show diminished ejection fraction and/or left ventricular wall-motion abnormalities. Myocardial enzyme levels in the serum frequently are elevated.
The male-to-female ratio of myopericardtis is 2:1. The overall mortality rate is low, and the prognosis generally is better in children than adults. Complications include pericardial effusion, arrhythmia, heart block, valvular dysfunction, and dilated cardiomyopathy.
Although principally correlative, data suggests that autoimmune insulin-dependent diabetes is associated with group B coxsackievirus infections. Viral infection alone is not thought to be sufficient to cause autoimmune insulin-dependent diabetes.[3] However, multiple factors, including viral load and type of infection along with host genetics and the pancreatic environment are thought to play significant roles in disease development.[3, 13] Epidemiologic data note that clustering of new onset diabetes mellitus occurs 1 to 3 months following infection. Similarly, animal models have described infection of pancreatic islet cells by coxsackieviruses with multiple proposed mechanisms of action. Persistent rather than acute coxsackievirus B infection of the islet cells has been demonstrated, which can lead to beta-cell destruction via interferon and T-cell-mediated autoimmune pathways.[14] Thymic dysfunction also has been implicated by means of coxsackievirus-B-induced thymic atrophy, apoptosis, and lymphocyte maturation impairment, leading to autoreactive T-cell production.[15]
Two of the most distinctive rash syndromes caused by coxsackieviruses are hand, foot, and mouth disease (HFMD) and herpangina.
HFMD often affects children and easily spreads to close contacts. Patients present with a sore throat and painful lesions in the mouth. Vesicles that coalesce, form bullae, and then ulcerate, occur on the buccal mucosa and tongue. Seventy-five percent of patients have simultaneous peripheral cutaneous lesions. HFMD also can present more atypically, including as eczema coxsackium, with erosions or bullous lesions.[16, 17] Biopsy reveals intracytoplasmic viral particles. Coxsackieviruses A16, A6, and A10 are among the most common types implicated in HFMD. Numerous cases of a more severe HFMD caused by coxsackievirus A6 were reported between 2004 and 2011 in several Asian and European countries. Additionally, between 2011 and 2012 in the United States, among cases of severe HFMD that were reported, 74% had a positive PCR test for coxsackievirus A6; about 25% of reported cases occured in adults.
Herpangina is a vesicular enanthem of the posterior oropharynx. Patients often present with fever, sore throat, occasional throat exudate, odynophagia, and dysphagia. Dysphagia 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.
Epidemic pleurodynia is a muscular disease in which viral invasion of muscle tissue causing inflammation is suspected; however, direct histologic evidence is lacking. Epidemic pleurodynia usually is associated with outbreaks of group B coxsackievirus infection.
Patients present with fever and sharp, paroxysmal, spasmodic pain in the chest and upper abdomen.
Pain and edema of the eyelids and subconjunctival hemorrhage are present.
Patients may report photophobia, foreign body sensation, fever, malaise, and headache. Symptoms usually resolve spontaneously within 1 week.
Rare complications include keratitis and motor paralysis.
This condition is highly contagious and has resulted in epidemics and pandemics.[18]
Coxsackieviruses have been identified in young pediatric patients with sepsis. Five coxsackievirus A serotypes (2, 4, 6, 10, 16) and one coxsackievirus B serotype (9) have been implicated. Coxsackievirus B9 also has been identified in neonatal sepsis.[19]
Patients may have nuchal rigidity or other signs of meningeal irritation, photophobia, pharyngitis, and rash. However, absence of one or more of these findings does not entirely exclude the diagnosis of aseptic meningitis.
Patients with encephalitis can present with cerebral dysfunction that manifests as altered mental status, neurologic deficits (eg, motor, sensory, speech impairment), or seizures.
The presentation in patients with myopericarditis ranges from asymptomatic to critical illness due to severe heart failure. Most patients report fever, malaise, upper respiratory tract symptoms, dyspnea, and chest pain. The classic description of chest pain associated with pericarditis is that it 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) might be displaced, a pericardial friction rub may be heard, and signs of heart failure (eg, S3 gallop, pulmonary edema) may be present.
Findings include vesicular lesions on the tongue or buccal mucosa and 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 not typically pruritic, which helps to distinguish the condition from chickenpox.
Edema and tenderness to palpation of the involved muscles may be present.
Findings include subconjunctival hemorrhage. Eye pain, edema of the eyelids, photophobia, and a serous discharge might be present. Slit-lamp examination might show 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 is not known. An exception is HFMD, in which viruses are isolated directly from skin lesions. In most other instances, confirmation of a coxsackievirus as the etiologic cause occurs via polymerase chain reaction (PCR) or serology. HFMD predominantly is caused by coxsackievirus A16.
AHC most often is caused by coxsackievirus serotype A24. 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.
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.
Enteroviruses can be excreted in human feces for up to 3 months after infection. However, a clinically identifiable syndrome correlates with the acute phase of infection, during which time virus can be found in the throat, blood, and various organs.
There are no confirmatory laboratory tests, procedures, or imaging that are used in routine clinical practice for HFMD or herpangina. Diagnosis for these conditions mainly is based on clinical presentation and assessment.
Definitive diagnosis of coxsackievirus infection can be made based on isolation of the virus in cell culture. Cytopathic effect usually can be seen within 2 to 6 days. Samples normally are taken from the stool or rectal swabs; the virus also can be isolated from the oropharynx early in the disease course. However, given improved sensitivity and faster turn-around time, polymerase chain reaction (PCR) has emerged as the most prominent diagnostic tool used for enteroviral detection. Serology is available as a diagnostic modality but can be difficult to interpret. Traditionally, enteroviral infections are diagnosed after a rise in neutralizing antibody titer (at least a 4-fold rise in titer between acute and convalescent phase).
Before a diagnosis of aseptic meningitis can be made, bacterial meningitis should be considered and excluded. Empiric antibiotics typically are required during this time period. 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 PCR (sensitivity, 66-90%) and, much less commonly, cell culture (sensitivity, 30-35%). 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%).
Diagnostic workup requires a lumbar puncture (LP) with CSF evaluation, which yields findings similar to those of aseptic meningitis.
Electroencephalography (EEG) can be considered in some patients, particularly for the evaluation of nonconvulsive or subclinical seizures. Enteroviral and other causes of viral encephalitis typically appear as diffuse background slowing on EEG, but epileptiform activity may be present as well.[20]
Please see section on Imaging Studies below for further recommendations
Laboratory tests generally are circumstantial, with evidence of infection based upon positive PCR tests from the oropharynx or feces, or upon serological testing.
Diagnosis requires conjunctival swabs or scrapings, which are 90% successful. A rising antibody titer also can theoretically be used to confirm a diagnosis.
Computed tomographic (CT) scanning of the brain can be obtained upon initial presentation of patients with suspected meningitis and/or encephalitis to evaluate for hemorrhage, increased intracranial pressure, or mass lesions.
Magnetic Resonance Imaging (MRI) of the brain can show hyperintense signal uptake in the posterior brain stem, substantia nigra, dentate nucleus, and anterior horns of the spinal cord.[21]
Echocardiography should be used to evaluate cardiac function and valvular disease in patients with myopericarditis and/or heart failure.
Cardiovascular Magnetic Resonance (CMR) can be used to identify imaging features characteristic of myocarditis such as necrosis, scarring, and myocardial hyperemia and edema.[22]
Depending upon the clinical presentation, a throat culture can be obtained to evaluate for possible streptococcal pharyngitis and/or tonsillitis.
HIV testing can be considered in patients who present with nonspecific febrile illness or rashes, depending on the epidemiologic history.
ECG changes in myopericarditis include ST-segment elevations or nonspecific ST segment and/or T-wave abnormalities, arrhythmia, and heart block.
In select instances in which viral myocarditis is being considered as the etiological cause for new-onset heart failure, endomyocardial biopsy might be indicated.
Lumbar puncture is crucial in the evaluation of suspected meningitis and/or encephalitis.
Skin biopsy rarely may be helpful in the evaluation of nonspecific exanthems.
Intracytoplasmic viral particles may be observed, especially with skin lesions and/or rashes of HFMD.
Viral killing may be complicated by difficult eradication and potentially prolonged survival in water and sewage in the environment.[23] Medical care generally is supportive and can be offered on an outpatient basis. More severe symptoms and clinical syndromes may require inpatient admission for further evaluation and treatment.
Antivirals and other therapies
There are no routine antiviral drugs used to treat infections caused by coxsackieviruses.[23] However, both intravenous immune globulin (IVIG) and the antiviral agent pleconaril have been investigated for possible efficacy in treating enteroviral infections, particularly in infants and immunocomprimised individuals with severe enteroviral syndromes such as encephalitis and myocarditis.
Pleconaril is an antiviral drug that has been shown to impair the function of viral capsid protein, thereby preventing viral attachment to cells necessary for proliferation. Several small trials have investigated the clinical efficacy of pleconaril in the treatment of coxsackieviruses and other viruses. These studies have shown a potential modest effect in shortening the course of illness when initiated early in the disease course.[24, 25, 26] However, given the small benefit of treatment along with potential side effects, drug-drug interactions, and potential rise in viral resistance, the US Food and Drug Administration (FDA) elected not to approve the use of pleconaril for the treatment of Picornavirus infections.
The mechanism of IVIG in inhibiting enteroviral infections is unclear but thought to involve direct viral neutralization by specific antibodies along with downregulation of inflammatory cytokines. In a literature review of IVIG use in the setting of enteroviral encephalitis, the authors noted that interleukin and interferon levels typically were elevated in severe enteroviral infection and were subsequently lowered after IVIG administration. However, it remains unclear whether reduction in cytokine levels results in improved mortality. In addition, many questions remain regarding optimal IVIG use including dosing, timing, and route of administration.[27]
Treatment mainly is supportive.
Pleconaril, an enteroviral capsid-stabilizing drug, appeared to reduce symptoms in a randomized double-blind study (N = 33),[28] but has not been licensed by the Food and Drug Administration (FDA), as noted above.
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 with supportive treatment alone.[29] 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.[30]
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 severe enteroviral infections (neonates and B-cell immunodeficient) with varying success based mainly on case reports and and small case series (see Medical Care section).
In vitro studies have suggested that arbidol may have potential as a future antiviral agent with activity against coxsackievirus, but no human trials have been performed.[31]
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 routine vaccinations are available for prevention of coxsackievirus infections. However, there has been increased interest in vaccine development for coxsackieviruses for prevention of complications such as HFMD. Multiple studies have demonstrated good tolerability and high immunogenicity in mouse models.[14, 32, 33] Trials are ongoing to investigate the safety profile in human subjects.[34]
Minimize respiratory contact with patients with active infection if possible.
To prevent further transmission, strict handwashing should be encouraged.
There is a paucity of prospective data describing the neurodevelopmental outcomes of meningitis in children (Posnakoglou). However, case series describing outcomes such as neurodevelopmental delay, diminished verbal operations, and seizure disorders suggest close developmental monitoring is appropriate in those patients.[12]
No outpatient care, other than usual follow-up care, is required for patients with mild symptoms.
Patients with aseptic meningitis and/or encephalitis, seizures, myopericarditis, and heart failure typically require hospital admission for further evaluation and treatment. Antibiotics may be needed until bacterial meningitis or another bacterial infection has been excluded as a diagnostic consideration.
Inpatient medications prescribed would be based on the patient's clinical presentation (eg, phenytoin for seizure prophylaxis and/or suppression in patients with aseptic meningitis/encephalitis, furosemide in patients with heart failure, etc.).
Antipyretics (eg, acetaminophen) for fever and non-steroidal anti-inflammatory drugs (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.
No FDA-approved therapy exists for the treatment of enteroviral infections. IVIG and pleconaril have been used on a case-by-case basis in severe illness (see section on Medical Care). Supportive use of analgesics and antipyretics frequently are necessary.