Echovirus

Author: Jorge M Quinonez, MD, Medical Director of Pediatrics, Chief Medical Officer, Family Health Centers of South West Florida, Inc

 

Introduction

Background

Echoviruses (EVs) are RNA viruses of the genus Enterovirus and the family Picornaviridae. EVs were first isolated from the feces of asymptomatic children early in the 1950s, soon after the development of cell culture techniques. EVs cause cytopathic effects in primate cell cultures, although not initially associated with any disease condition. These orphan viruses were initially termed ECHO, an acronym for enteric cytopathic human orphan virus, which was later simplified to echovirus.
A committee sponsored by the National Foundation for Infantile Paralysis categorized EVs and other enteroviruses (ie, coxsackievirus group A and group B, polioviruses) together in 1957. They are grouped together and distinguished from other viruses on the basis of physicochemical characteristics and because they share common epidemiology, clinical manifestations, and pathogenesis. Enterovirus groups are differentiated based on host specificity. To date, 67 serotypes of enterovirus have been identified, 32 of which belong to the echovirus group.
EVs cause a wide range of common and uncommon clinical presentations. These agents and other members of the Enterovirus group are among the leading causes of acute febrile illness in infants and young children; they are the most common cause of aseptic meningitis. Infection in the first 2 weeks of life is particularly troublesome because it can cause severe systemic disease and is associated with high fatality rates. Another significant concern with enteroviral infections is that they can mimic symptoms caused by other common bacteria and viral infections; thus, enteroviral infections are often treated with therapies aimed for other infections.
EVs are small, measuring 24-30 nanometers (nm) under electron microscopy. They are composed of a naked protein capsid, constituting about 75% of the particle and enclosing a dense central core of single-stranded RNA. This RNA is approximately 7.5 kilobase (kb) long and contains an RNA replicase, viral-coded proteases, a single polyprotein that is responsible for forming structural polypeptides, and other proteins necessary for cellular replication. All EVs contain polypeptide chains (eg, virus protein 1 [VP1], virus protein 4 [VP4]). These structural proteins are important to determine host range and tropism, and they play a crucial role in delivering the RNA genome into the cytoplasm of new host cells.
Although EVs originally were classified into 34 serotypes, EV-10 later was reclassified as a reovirus and EV-28 as rhinovirus type 1; EV-9 now is considered the same as coxsackievirus A23.
At least 2 cellular receptors for EV have been identified: a subunit of the integrin molecule VLA-2 that binds types 1 and 8, and a complement regulatory protein (ie, a decay accelerating factor) that binds types 6, 7, 12, and 21.

Pathophysiology

Some viral replication occurs in the nasopharynx after exposure, with spread to regional lymph nodes. However, most inoculum is swallowed and reaches the lower GI tract, where the virus presumably binds to specific receptors on enterocytes. The virus traverses the intestinal epithelium, probably undergoing replication in the process but without causing any cellular effects, and reaches the Peyer patches in the lamina propria mucosae. Here, the virus undergoes substantial multiplication. A minor viremia develops on about the third day, seeding many secondary infection sites, including the CNS, liver, spleen, bone marrow, heart, and lungs. Additional replication at these sites causes a major viremia that coincides with onset of clinical disease, usually 4-6 days after exposure. The delayed appearance of CNS disease symptoms suggests viral spread can develop during both the minor and the major viremia.
Enteroviruses can infect all tissues of the human body. The tropism of each virus for certain tissues is not well understood and is neither unique nor specific. Infections involving a single serotype may vary widely in their presentation; multiple serotypes can produce the same clinical syndrome.
The incubation period for EV is difficult to establish because both symptomatic and healthy individuals spread the virus. Incubation is believed to range between 2 days and 2 weeks. EV is communicable over a long period of time. The virus can be shed from the upper respiratory tract for 1-3 weeks and in stools for more than 8 weeks after primary infection.

Frequency

United States

Several studies confirm enteroviruses account for more than 50% of spring and fall emergency department visits by infants and young children for fever without a source. EV infections only sporadically develop in other seasons. In addition to this seasonality, EV types vary strikingly in their contribution to human disease. Some EVs remain endemic in patterns that vary from area to area each year in the United States. Other serotypes (eg, EV-9, EV-11, EV-30) can cause widespread outbreaks in which the responsible strain can account for more than 90% of all isolated strains of enterovirus.
Infections by this group of viruses are most prevalent among lower socioeconomic groups, a fact easily explained by overcrowded living conditions and poor hygiene.

International

EV infections occur in all human populations. Transmission and infection occur throughout the year in the tropics and predominantly during summer and fall in temperate regions, with sporadic cases in other seasons. A few epidemics have been nearly global, such as one caused by EV-9 at the end of the 1950s and another by EV-11 in 1979 and 1980. More recently, an outbreak of EV-13 and EV-30 was reported in Germany,¹ and outbreaks of EV-13 were reported in Lithuania and Israel.^2,3 An outbreak of EV-11 has also been reported in neonates in Taiwan.⁴ Particular serotypes are endemic or epidemic for unknown reasons. One hypothesis is that some epidemic strains such as EV-9 may spread rapidly in a "critical mass" of susceptible patients necessary for continuous transmission, whereas endemic strains may not be as contagious.

Mortality/Morbidity

EV infections during the first 2 weeks of life can cause severe systemic disease associated with high fatality rates. EV and other enteroviruses account for 10-20% of documented viral causes of encephalitis. Neonates with disseminated encephalitis have a poor prognosis and many die. Infant death rates from perinatal EV infection are unknown, although some studies report high numbers. Neonatal mortality is usually caused by either overwhelming liver failure or myocarditis, rather than CNS involvement.
Children and older patients with disseminated encephalitis have a better prognosis, but fatalities occasionally occur. Acute myopericarditis, resulting from the well-established tropism of enterovirus for the heart, can be fatal in approximately 5% of cases, although most patients recover without major sequelae.

Sex

For unknown reasons, forms of EV disease such as meningitis and neonatal sepsis are far more common among male patients.

Age

Although EV infections can occur in all age groups, incidence inversely relates to age; specific antibodies directly increase with time. Several studies performed during epidemics and for surveillance show that infants become infected at significantly higher rates than older children and adults.

Clinical

History

Because echovirus (EV) has been found in the stools of healthy individuals, most children with EV and other enteroviral infections are assumed to be asymptomatic. Finding the virus in the stools of healthy individuals, however, may be misleading because enterovirus can be excreted in feces for a long time, and no clear indication exists of what happened during the initial infection. Patients may have symptoms with infection, but the symptoms may be trivial and not recognized.

• Nonfocal, acute febrile illness is the most common presentation of symptomatic enteroviral infection in young infants and children.
• Enteroviral infections are the most common cause of hospital admission for suspected sepsis in children aged 2-3 months during summer and fall.

Physical

EV causes a remarkable range of diseases. Benign forms of disease are well recognized by clinicians (eg, nonspecific exanthems, herpangina) and do not warrant major diagnostic or therapeutic actions. Severe forms of disease, such as meningitis, encephalitis, neonatal sepsis, myocarditis, and chronic infection with meningoencephalitis in patients with altered immunity, are strong reasons for concern.

• Nonspecific, acute febrile illness: Several studies have shown enterovirus can account for more than 50% of summer and fall emergency department visits for fever of unknown origin in infants and young children.
  • Fever onset is usually abrupt and without a prodrome, often exceeding 39° C. Fever, which may be the sole presentation, often is accompanied by irritability. High temperatures, irritability, and the nonspecific nature of the illness prompt the hospitalization of many infants for suspected bacterial sepsis. At least 50% of these patients have a history of poor feeding, and 25% of infants have vomiting or diarrhea. Affected infants resume feeding within 2 days of initial symptoms, and their GI manifestations are not the reason for hospital admission.
  • A large number of these patients have had thorough evaluations that included blood, urine, and cerebrospinal fluid (CSF) cultures and have received antibiotics for 48-72 hours while awaiting culture results. Differentiating patients infected with enterovirus from those with bacterial infections is impossible based solely on clinical findings.
  • Most young patients recover from the febrile episode in 2-10 days without complications.
• Exanthems
  • Skin rashes are more common with EV infections than with infections from other enteroviruses. The first exanthematous disease induced by an enterovirus was linked to EV-16.
  • Exanthems may be maculopapular, morbilliform, macular, petechial, or papulopustular in nature.
  • Likelihood of an exanthem being present appears directly related to the EV type causing infection. For example, EV-6, which has been among the most prevalent serotypes causing infection during the past 25 years, is associated only sporadically with skin manifestations. Conversely, infections with EV-5, EV-9, and EV-25 are associated with skin rashes in as many as 35% of patients.
  • Skin findings with EV infections are self-limited and without sequelae.
• Viral meningitis
  • As many as 90% of community-acquired viral meningitis cases result from EVs or coxsackie B viruses. CNS involvement is most likely with infections by EV serotypes 4, 6, 9, 11, 13, 16, and 30. More than 10,000 cases of enteroviral meningitis are reported annually to the Centers for Disease Control and Prevention (CDC), and actual numbers probably are 10 times higher.
  • Infants younger than 3 months have the highest incidence of recognized meningitis. This diagnosis is not based on specific neurological findings; instead, young infants are more likely to undergo a lumbar puncture for evaluation of a fever. Most young children with meningitis present with fever and irritability.
  • Older children with meningitis typically present with fever and severe headache. Headaches in older children and adults can be sufficiently severe to require narcotics for pain control.
  • Nuchal rigidity occurs in less than two thirds of patients and does not occur in infants.
  • Patients can have symptoms of photophobia, nausea, and vomiting.
  • About 10% of hospitalized infants with echoviral meningitis have neurologic manifestations (eg, seizures, altered mental status, increased intracranial pressure).
  • The classic results of CSF analysis are a mononuclear pleocytosis (100-300 cells/mm3), mildly elevated protein levels, and glucose concentrations within reference ranges. Higher WBC counts with a predominance of neutrophils occur early in the course of disease.
  • Illness duration typically is less than a week.
  • Despite current studies of antiviral drug therapies, standard treatments are limited to alleviating symptoms. Although the short-term prognosis appears good for young children with echoviral and other enteroviral meningitis, controversy continues about long-term cognitive, developmental, and language abnormalities among children who suffered meningitis in early life. Some prospective reports have indicated virtually no measurable long-term effects, even among patients who had neurologic findings during their illness.
• Encephalitis
  • Clearly distinguishing encephalitis from enteroviral meningitis is important. Encephalitis is more rare, is a more devastating acute disease, and has long-term sequelae.
  • EV and other enteroviruses account for 10-20% of documented viral-caused encephalitis. Common serotypes that cause encephalitis include EV types 4, 6, 9, 11, and 30. EVs are more commonly associated with a global encephalitis and generalized neurological depression.
  • Clinical manifestations range from altered mental status to coma and decerebration. Some patients manifest with focal disease (eg, partial motor seizures, hemichorea, cerebellar ataxia), symptoms that may suggest a diagnosis of herpes simplex encephalitis. Brain imaging by CT scan or MRI and electroencephalography usually show the extent of involvement. The results of CSF analysis in patients with encephalitis are similar to the results from patients with only aseptic meningitis.
  • The prognosis for neonates with disseminated encephalitis is poor, and many die. The prognosis for similarly affected children and older patients is better, but fatalities sometimes occur.
• Other neurological syndromes
  • Although rare, EV can cause a syndrome of acute motor weakness and paralysis indistinguishable from poliomyelitis. Sporadic cases of acute paralysis have been reported with EV-6 and EV-9. The myelitis caused by EV usually is less severe than that caused by poliovirus.
  • Guillain-Barré syndrome has been associated with EV-6 and EV-22 infections. Acute cerebellar ataxia has been related to infection with EV-6 and EV-9. Acute transverse myelitis has occurred in patients with EV-5 infection.
  • Chronic meningoencephalitis can occur in association with coxsackievirus or EV in patients who have acquired or congenital B-lymphocyte function defects. These patients present with an insidious course, manifested by headache, lethargy, motor dysfunction, or seizures. Symptoms may fluctuate in severity, wane, or gradually progress. Persistent pleocytosis and high protein levels in CSF are typical. Recovery of the virus from several other tissues suggests the possibility of disseminated disease. Prognosis for these patients generally is poor. The results of using intravenous immunoglobulin (IVIG) to treat these patients have been inconsistent.
• Muscle and joint infections
  • EV infections sporadically involve muscles; both focal and generalized myositis has been described. Patients usually present with myalgia associated with elevated levels of skeletal muscle enzymes in serum. The course is self-limited and hastily resolves.
  • In patients with B-lymphocyte dysfunction, skeletal muscles can become chronically infected, manifested by a dermatomyositislike syndrome. Although other enteroviruses can be the cause, EV infection is most common.
  • EV-9 is associated with both acute and subacute arthritis.
• Pleurodynia (ie, Bornholm disease)
  • First described more than 2 centuries ago, pleurodynia is characterized by fever and spasmodic pain in the chest wall or upper abdomen. The hallmark of pleurodynia is its paroxysmal nature.
  • Spasmodic periods persist from a few minutes to half an hour or longer. Pain can be severe, and patients often appear pale and diaphoretic, sometimes leading physicians treating older adults to consider the possibility of a myocardial infarction. Patients present with shallow, frequent respirations that usually suggest pleural inflammation or pneumonia. Physical examination rarely reveals pleural friction rubs; pleural effusions occur in fewer than 10% of patients. Pain usually is more severe at presentation and gradually wanes over 4-6 days, although pain occasionally persists 3 weeks. Analgesics and restricted physical activity usually suffice to reduce pain. Abdominal wall involvement occurs almost exclusively in children and often mimics appendicitis or peritonitis.
  • Pleurodynia can occur in epidemics involving adults and children, or in sporadic form. EV-1 and EV-6 are associated with epidemics of pleurodynia, and almost all other EV types have been linked to sporadic cases.
• Myopericarditis
  • EV's tropism for the heart is well established. Group B coxsackieviruses 2 and 5 traditionally have been linked to acute myopericarditis; however, many other enterovirus types, including EV, have been related to acute heart disease. Although enterovirus-induced myocarditis occurs in all age groups, the highest risk is among physically active adolescents and young adults.
  • Myopericarditis is clinically indistinguishable from diseases caused by other viruses (eg, adenoviruses, influenza A, mumps) that can infect the myocardium. Approximately 65% of patients report an upper respiratory infection preceding manifestations of substernal chest pain, fever, dyspnea, and exertion intolerance. Physical examination reveals a pericardial friction rub in as many as 80% of these patients and a gallop rhythm in 20%.
  • Electrocardiography (ECG) invariably reveals abnormal findings; ECG also can reveal acute ventricular dilatation and diminished ventricular ejection fraction. Cardiac enzyme serum levels are often high.
  • Although the acute course of myopericarditis can be complicated by arrhythmias and congestive heart failure (CHF), most patients recover without major sequelae. About 5% of cases are fatal. Approximately 10-30% of cases continue to show ECG abnormalities; about the same percentage of patients present with recurrent CHF that indicates permanent myocardial damage. Most affected patients need supportive care.
  • Corticosteroid use is controversial for cases of acute myocarditis; experts disagree about the benefits and potential adverse effects of systemic use. Some have reported benefits from administering high-dose IVIG, but this therapy remains far from the standard of care.
• Neonatal infections
  • Neonates during their first 2 weeks of life are particularly susceptible to potentially lethal diseases caused by an EV infection. Vertical transmission from an infected mother or, more rarely, a nosocomial source is the most likely mechanism for acquiring infection.
  • Passive acquisition of immunoglobulin G (IgG) antibodies from the mother appears to determine the outcome of a neonatal infection more than any other factor. The critical issue is the amount of time between maternal infection and the delivery.
  • Neonates who are infected present with a sepsislike syndrome, with fever, irritability, lethargy, respiratory distress, and an exanthem. Many patients show radiographic evidence of pulmonary involvement, and CSF analysis provides evidence of meningitis. Major systemic manifestations can develop as the disease progresses, such as hepatic necrosis, myocarditis, and disseminated intravascular coagulation. CNS disease may progress to encephalitic characteristics with seizures and focal abnormalities. Because clinical features can imitate neonatal sepsis by bacterial agents and either disseminated or localized herpes simplex infection, patients are often treated for both possibilities.
  • EV-11 specifically has been linked to a clinical syndrome of disseminated sepsis in which the dominant feature is neonatal hepatitis, accompanied by extensive necrosis of the liver and overwhelming hepatic failure. Other serotypes able to cause neonatal liver disease include EV serotypes 6, 7, 9, 14, 17, 19, and 21. In addition, EV-6, EV-9, and EV-11 have been linked to a severe form of perinatal pneumonitis with a high mortality rate. Incidence of infant death due to perinatal EV infection is unknown, although some studies report high numbers. Mortality usually results from either overwhelming liver failure or myocarditis rather than CNS involvement.
• Other infections
  • EV-4 and EV-11 have been reported as sporadic causes of mild cases of croup.
  • EVs have sporadic associations with bronchitis and bronchiolitis.
  • Pneumonia in children has been associated with infections with EV serotypes 6, 7, 9, 11, 12, 19, 20, and 30.
  • Conjunctivitis, whether alone or in conjunction with other symptoms, has been reported with EV serotypes 1, 6, 9, 20, and 30.
  • Several reports link echovirus and enterovirus infection to a risk of developing type 1 diabetes.

Causes

Overcrowded conditions and poor hygiene easily explain the high prevalence of EV infections among lower socioeconomic groups.

• EV is transmitted person-to-person; the fecal-oral route is the predominant mode, and transmission sometimes occurs via respiration of oral secretions.
• Indirect transmission occurs through numerous routes, including contaminated water, food, and fomites. Contaminated swimming and wading pools can transmit the virus. Well-documented reports detail transmission via the contaminated hands of hospital personnel.
• EV is communicable over a long period of time. The virus can be shed from the upper respiratory tract for 1-3 weeks and in stools for more than 8 weeks after primary infection.

Differential Diagnoses

Neonatal Sepsis

Other Problems to Be Considered

Bacterial sepsis
Bacterial meningitis
Neonatal herpes simplex infection
Herpes simplex virus encephalitis
Arbovirus encephalitis
Fever without localizing signs
Viral exanthems
Pharyngoconjunctival fever

Workup

Laboratory Studies

Until recently, the criterion standard laboratory procedure to diagnose echovirus (EV) and other enterovirus infections was to isolate the virus in cell culture. An etiologic diagnosis is confirmed when virus is isolated from blood, CSF, tissue, or pericardial fluid. EV can also be isolated from stool or oropharynx, although these findings are less indicative of disease because asymptomatic shedding from these sites can occur for several weeks after acute infection.

• Enteroviruses grow rapidly in cell culture, yet viral recovery occurs too slowly to provide data for decisions about treatment. Virus detection in cell culture typically takes 3-8 days, requires multiple cell lines for optimal recovery, is labor intensive and costly, and is not readily available in all clinical facilities. Antiviral therapy for enterovirus requires a faster and more efficient mechanism for diagnosis.
• Enterovirus polymerase chain reaction (EV-PCR), based on amplification of conserved genetic sequences, has been thoroughly studied and is superior to viral culture for revealing many enteroviral infections, particularly enteroviral meningitis.^5,6,7
  • EV-PCR can be used in samples other than CSF, although experience is not as extensive. EV-PCR has been successfully used in urine and serum to document neonatal infection and on throat swabs to document common outpatient illnesses.
  • Quality control from laboratory to laboratory is necessary because no commercial kit is available. Because of its extreme sensitivity, EV-PCR is subject to false-positive results from contamination within the laboratory. The greatest benefit of EV-PCR is that the test can provide results in 5-24 hours, which can expedite patient management decisions (eg, decrease length of hospitalization, antibiotic use, overall costs).
• Serologic tests for enteroviral infection diagnosis have limited value because they are slow, require acute and convalescent titers, and are not type-specific.

Treatment

Medical Care

No antiviral therapy has been available except IVIG therapy, which reportedly has some success in patients who are immunocompromised and have persistent enterovirus infections. The role of IVIG therapy for acute infections is unproven. A study evaluating its use in enteroviral infection in neonates failed to demonstrate a clear benefit. Another study evaluating the use of IVIG in 21 patients with myocarditis showed improved left ventricular function and survival when compared with 25 control patients. However, additional studies are needed.
Corticosteroid use to treat viral myopericarditis remains controversial at best. Several antiviral agents have in vitro activity against a broad range of enterovirus types, and several clinical trials have been conducted on their use.

• The first of these agents to be studied was pleconaril, a drug that interferes with the binding of enterovirus to the cell membrane and the uncoating of virions by attaching to the virus protein capsid.^8,9 Several clinical trials have demonstrated a benefit in children and adults with enterovirus meningitis.¹⁰ Pleconaril apparently may be on the verge of becoming readily available for clinical use as a new therapy option for echovirus (EV) and other enteroviral infections.
  • Pleconaril at concentrations of 0.1 mg/mL has activity against more than 90% of the most common circulating enteroviruses. The drug has good bioavailability and a prolonged half-life, allowing oral administration 3 times a day. Adequate levels can be achieved in serum and CSF.
  • Pleconaril has been studied in enteroviral meningitis, in respiratory tract infections, and in a limited number of patients who are immunocompromised and have viral myocarditis.
  • Phase III clinical trials are underway, and initial results are promising. In the first placebo-controlled double-blind study, 221 children (aged 4-14 years) with signs and symptoms of viral meningitis, most confirmed as enterovirus with EV-PCR, received 2.5 or 5 mg/kg of pleconaril or placebo 3 times a day for 7 days.¹⁰ Initial findings showed a 38-50% improvement among treated patients when compared with patients receiving a placebo. Improvement was seen as early as 24 hours after therapy initiation. Similar results have been obtained in studies of adolescents and adults with enteroviral meningitis. Pleconaril is currently under investigation in a multicenter collaborative study of therapy for neonatal enteroviral sepsis sponsored by the National Institutes of Health.
  • Schering-Plough lists pleconaril nasal spray as having completed phase II trials for preventing asthma exacerbation and common cold symptoms in asthmatic patients exposed to picornavirus.⁹
  • As of spring 2008, pleconaril is not approved by the US Food and Drug Administration (FDA).

Follow-up

Further Outpatient Care

• The specific type of infection caused by echovirus (EV) should dictate follow-up care.

Prognosis

• Neonates with disseminated encephalitis have a poor prognosis and many die. Children and older patients have a better prognosis, but the disease is occasionally fatal.
• Acute myopericarditis is fatal in approximately 5% of cases; most patients recover without major sequelae.
• The short-term prognosis for children with EV and enteroviral meningitis early in life appears to be good. The long-term prognosis for similarly affected children is controversial in regard to cognitive, developmental, and language abnormalities. Some recent prospective reports have indicated virtually no measurable long-term effects, even among patients with neurologic findings during their illness.
• The prognosis is generally poor for patients with chronic meningoencephalitis who have coxsackievirus or EV infections and acquired or congenital B-lymphocyte function defects.