Coxsackievirus

Coxsackievirus

Coxsackieviruses belong to the family Picornavirus and the genus Enterovirus, which also includes polioviruses, echovirus and hepatitis A virus, that live in the human digestive tract. Coxsackieviruses can spread from person to person, usually on unwashed hands and surfaces contaminated by feces (poop), where they can live for several days.

In most cases, coxsackievirus infections cause mild flu-like symptoms and go away without treatment. But in some cases, coxsackievirus can lead to more serious infections.

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 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 central nervous system (CNS) disease similar to poliomyelitis 2). Systemic neonatal disease is often associated with group B coxsackieviruses 3).

The development of insulin-dependent diabetes (type 1 diabetes) has recently been associated with recent enteroviral infection, particularly coxsackievirus B infection. This relationship is currently being studied further.

Death due to coxsackievirus infection is uncommon. Neonates and immunocompromised individuals are at most risk for complications secondary to all enteroviral infections.

When you should see a medical professional

See your doctor immediately if you or your child has any of these symptoms:

  • fever higher than 100.4°F (38°C) for infants younger than 6 months and higher than 102°F (38.8°C) for older kids
  • poor appetite
  • trouble feeding
  • vomiting
  • diarrhea
  • difficulty breathing
  • convulsions
  • unusual sleepiness
  • pain in the chest or abdomen
  • sores on the skin or inside the mouth
  • severe sore throat
  • severe headache, especially with vomiting, confusion, or unusual sleepiness
  • neck stiffness
  • red, swollen, and watery eyes
  • pain in one or both testicles

Is coxsackievirus contagious?

Coxsackieviruses are very contagious. They can be passed from person to person on unwashed hands and surfaces contaminated by feces. Coxsackievirus also can be spread through droplets of fluid sprayed into the air when someone sneezes or coughs.

When an outbreak affects a community, risk for coxsackievirus infection is highest among infants and children younger than 5. Coxsackievirus spreads easily in group settings like schools, childcare centers, and summer camps. People are most contagious the first week they’re sick.

In cooler climates, outbreaks most often happen in the summer and fall, but tropical parts of the world have them year-round in.

How long do coxsackievirus infections last?

How long the coxsackievirus infection lasts can vary. People who only have a fever may see their temperature return to normal within 24 hours, although the average fever lasts 3 days. Hand, foot, and mouth disease usually lasts for 2 or 3 days; viral meningitis can take 3 to 7 days to clear up.

Coxsackievirus causes

Coxsackieviruses are transmitted primarily via the fecal-oral route and respiratory aerosols, although transmission via fomites (objects or materials which are likely to carry infection, such as clothes, utensils, and furniture) is possible. Coxsackieviruses initially replicate in the upper respiratory tract and the distal small bowel. Coxsackieviruses have been found in the respiratory tract up to 3 weeks after initial infection and in feces up to 8 weeks after initial infection. Coxsackieviruses 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 4).

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 5). 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 6). Those due to coxsackievirus B4 were associated with a higher mortality rate than any other serotype.

Aseptic meningitis

Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.

Exanthems

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 hand, foot, and mouth disease, in which viruses are isolated directly from the lesions. Hand, foot, and mouth disease 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.

Acute hemorrhagic conjunctivitis

Coxsackievirus serotype A24 generally causes acute hemorrhagic conjunctivitis. 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.

Coxsackievirus prevention

There is no vaccine to prevent coxsackievirus infection. Hand washing is the best protection. Remind everyone in your family to wash their hands well and often, especially after using the toilet, after changing a diaper, before meals, and before preparing food. Shared toys in childcare centers should be cleaned often with a disinfectant because the virus can live on these objects for days.

Adults and children who are sick with a coxsackievirus infection should be kept out of school or childcare for a few days to avoid spreading the infection.

Coxsackievirus symptoms

Coxsackievirus can produce a wide variety of symptoms. More than 90% of coxsackieviruses infections have no symptoms or cause nonspecific febrile illnesses. Others suddenly get a high fever, headache, and muscle aches, and some also develop a sore throat, abdominal discomfort, or nausea. A person with a coxsackievirus infection may simply feel hot but have no other symptoms. In most people, the fever lasts about 3 days, then disappears.

In babies, coxsackievirus infections 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.

Coxsackieviruses can cause symptoms that affect different body parts, including:

  • Hand, foot, and mouth disease, a type of coxsackievirus syndrome that mainly affects children under 5 years old, but can sometimes affect older children and adults, causes painful red blisters in the throat and on the tongue, gums, hard palate, inside of the cheeks, and the palms of hands and soles of the feet. Hand-foot-and-mouth disease may cause all of the following signs and symptoms or just some of them. They include:
    • Fever
    • Sore throat
    • Feeling of being unwell (malaise)
    • Painful, red, blister-like lesions on the tongue, gums and inside of the cheeks
    • A red rash, without itching but sometimes with blistering, on the palms, soles and sometimes the buttocks
    • Irritability in infants and toddlers
    • Loss of appetite
  • Herpangina, an infection of the throat, causes red-ringed blisters and ulcers on the tonsils and soft palate, the fleshy back portion of the roof of the mouth.
  • Hemorrhagic conjunctivitis, an infection that affects the whites of the eyes, usually begins as eye pain, followed quickly by red, watery eyes with swelling, light sensitivity, and blurred vision.

Occasionally, coxsackieviruses can cause more serious infections that may need to be treated in a hospital, including:

  • Viral meningitis, an infection of the meninges (membranes that surround the brain and spinal cord)
  • Encephalitis, a brain infection
  • Myocarditis, an infection of the heart muscle

Mothers can pass an coxsackievirus infection to their newborns during or just after birth. Babies are more at risk for a serious coxsackievirus infection, including myocarditis, hepatitis, and meningoencephalitis (an inflammation of the brain and meninges). In newborns, symptoms can develop within 2 weeks after birth.

Aseptic meningitis

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.

On examination, patients may have signs of nuchal rigidity and other evidence of meningeal irritation, photophobia, pharyngitis, and rash.

Encephalitis

Encephalitis is an unusual manifestation of central nervous system (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.

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 electroencephalogram (EEG) may be helpful in localizing and characterizing the seizure focus.

Neurologic diseases

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

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.

Electrocardiography (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.

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 may be displaced, pericardial friction rub may be heard, and signs of heart failure (eg, S3 gallop, pulmonary edema) may be present.

Diabetes

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.

Exanthems

Two of the more distinctive exanthems caused by coxsackievirus hand-food-and-mouth disease and herpangina.

Hand-food-and-mouth disease 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 hand-food-and-mouth disease caused by coxsackievirus A6 were reported between 2004 and 2011 in several Asian and European countries 7). Additionally, between 2011 and 2012 in the United States, several cases of severe hand-food-and-mouth disease were reported, with 74% of those cases testing PCR positive for coxsackievirus A6; about 25% of reported cases were in adults 8).

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.

Epidemic pleurodynia

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.

On physical examination, edema of the involved muscles and tenderness to palpation may occur.

All patients recover completely within 1 week.

Acute hemorrhagic conjunctivitis

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.

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 diagnosis

Definitive diagnosis can be made based on isolation of the coxsackievirus 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 (polymerase chain reaction) is also available, with a sensitivity of 66-90%.

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.

An EEG can be used to detect the presence of and localize seizure activity.

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.

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.

Aseptic meningitis

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%) 9).

Encephalitis

Diagnostic workup requires CSF evaluation, which yields findings similar to those of aseptic meningitis.

Myopericarditis

Diagnosis is generally circumstantial, with evidence of infection from the oropharynx, feces, or on serology.

Echocardiography can be used to evaluate overall cardiac function and valvular disease in patients with myopericarditis and heart failure.

Electrocardiography (ECG) changes in myopericarditis include ST-segment elevations or nonspecific ST segment, T-wave abnormalities, arrhythmia, and heart block.

Acute hemorrhagic conjunctivitis

Diagnosis requires conjunctival swabs or scrapings, which are 90% successful. A rising antibody titer can be demonstrated.

Coxsackievirus treatment

Depending on the type of coxsackievirus infection and symptoms, your doctor may prescribe medicines to make you or your child feel more comfortable. Because antibiotics only work against bacteria, they can’t be used to fight a coxsackievirus infection.

You can give acetaminophen (paracetamol) or ibuprofen to relieve minor aches and pains. If the fever lasts for more than 24 hours or if you or your child has any symptoms of a more serious coxsackievirus infection, call your doctor.

Most people with a simple coxsackievirus infection recover completely after a few days without needing any medical treatment. An adult or child who has a fever without any other symptoms should rest in bed or play quietly indoors. Offer plenty of fluids to prevent dehydration.

Aseptic meningitis

Treatment is mainly supportive.

Pleconaril, an enteroviral capsid-stabilizing drug, appeared to reduce symptoms in a randomized double-blind study (N = 33) 10), 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.

Myopericarditis

Intravenous immunoglobulin (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 11). 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 12).

Epidemic pleurodynia

Analgesics, narcotics, and heating pads are the mainstays of therapy. All patients recover completely within 1 week.

Acute hemorrhagic conjunctivitis

Treatment is symptomatic, and no antimicrobial agent is necessary in the absence of bacterial superinfection.

Immunodeficiency

Both IVIG (intravenous immunoglobulin) and pleconaril have been used in immunocompromised patients with enteroviral infections (neonates and B-cell immunodeficient) with varying success.

Test tube 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 13).

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