Echovirus Infection 

Updated: Jun 14, 2019
Author: Madhu Chhanda Choudhary, MD; Chief Editor: Michael Stuart Bronze, MD 

Overview

Background

Echoviruses are members of the Enterovirus genus in the Picornaviridae family. They make up the largest Enterovirus subgroup, consisting of 29 serotypes. Echoviruses are common human pathogens that cause a range of illnesses, from minor febrile illness to severe, potentially fatal conditions (eg, aseptic meningitis, encephalitis, paralysis, myocarditis).[1] Individual serotypes have different temporal patterns of circulation and cause different clinical manifestations. Changes in circulating serotypes and variations in the genotype of the same subtype can be associated with large-scale outbreaks.[1, 2]

Enteroviruses are divided into 5 subgenera: polioviruses, group A coxsackieviruses, group B coxsackieviruses, echoviruses, and the newer enteroviruses. Each subgenus contains numerous unique enterovirus serotypes differentiated based on neutralization of specific antisera.[3]

The term enterovirus reflects enteric transmission of the virus via person-to-person spread. ECHO is an acronym for enteric cytopathic human orphan.[4]

Echoviruses were first isolated from the feces of asymptomatic children in the context of epidemiological studies of polioviruses. The viruses produced cytopathic effects in cell cultures but failed to cause detectable pathologic lesions in suckling mice.[5] Most echoviruses are no longer considered orphans.

Echoviruses were originally classified into 34 serotypes. Echovirus 10 has been reclassified as reovirus 1 and echovirus 28 as rhinovirus 1. Echovirus 9 is now recognized as the same as coxsackievirus A23. Echovirus 22 and 23 have been reclassified as members of the Parechovirus genus, and echovirus 34 is a variant of coxsackievirus A24.[6]

Echoviruses are small nonenveloped viruses with an icosahedral configuration. A capsid composed of 60 subunits is formed from 4 proteins—VP1 to VP4. These proteins play important roles in terms of determining host range and tropism and in delivering the RNA genome into the cytoplasm of the host's cells.[7] Echoviruses are infective over a wide range of pH (3-10) and are resistant to ether and alcohol.

Pathophysiology

Human echoviral infection occurs via fecal-oral transmission. Host susceptibility depends on the presence of specific cellular membrane receptor proteins that bind different enteroviral types along taxonomic lines. Decay-accelerating factor (DAF) appears to be a major echovirus receptor, binding many echovirus serotypes, including 6, 7, 11, 12, 20, 21, 29, and 33. Echovirus serotypes 1 and 8 bind to the α2 subunit of the very late antigen (VLA) integrin molecule.

The neonatal Fc receptor (FcRn) has recently been recognized as a pan-echovirus receptor expressed on intestinal enterocytes (primary site of infection) and liver hepatocytes and microvascular endothelial cells lining the blood-brain barrier (secondary sites of infection), potentially explaining enhanced susceptibility of neonates to echovirus infection.[8]

Following ingestion of fecally contaminated material, viral replication begins in the pharynx or gut. The precise site of viral entry and initial replication in the GI tract is not well established, but researchers have demonstrated the presence of enteroviruses in mucosal M cells. Ileal lymphoid tissue demonstrates enteroviral replication within 1-3 days after ingestion. The maximal duration of viral excretion is 3-4 weeks in the pharynx and 5-6 weeks in stool.

Following replication, enteroviruses spread to regional lymph nodes and cause subclinical transient viremia. During this low-grade viremia, the virus spreads to reticuloendothelial tissues, including the liver, spleen, bone marrow, and distant lymph nodes. Secondary sites of infection include the CNS, liver, spleen, bone marrow, heart, and lungs. More than 90% of echoviral infections are asymptomatic. When disease occurs, symptoms vary from undifferentiated febrile illness to severe illness, depending on the age, gender, and immune status of the host and the subgroup, serotype, and enteroviral strain.[9]

For additional information, please also refer to Medscape Reference's Enteroviruses topic.

Epidemiology

Frequency

United States

Echoviruses are common and are associated with both epidemic and endemic patterns of infection in individuals of all ages. The voluntary and passive nature of viral illness reporting complicates the true estimate of disease.[1] Serologic surveys are not feasible because of the large number of nonpoliovirus serotypes.

In temperate climates, enteroviral activity peaks during the summer and early fall. Serotype-based surveillance provides a mechanism for determining patterns of circulation and for identifying predominant serotypes.[1] Changes in predominant serotypes can be associated with large-scale outbreaks of enteroviral illnesses. The National Enterovirus Surveillance System (NESS) reported that, from 2014-2016, enterovirus D68 was the most frequently reported enterovirus type, followed by echovirus 30, coxsackievirus A6, echovirus 18, and coxsackievirus B3.[10]

In the United States, peaks in nationwide hospitalization for aseptic meningitis have been observed in years when echovirus 9 was predominant. Echovirus 9 was the most commonly reported enterovirus from 1970-2005 and accounted for 11.8% of reports with known serotypes.[1]

International

Echoviruses are found worldwide and affect people of all races and cultures. Infection rates vary with the season, geography, and the age and socioeconomic status of the population sampled. Infection among lower socioeconomic groups is attributed to overcrowded living conditions and poor hygiene. Infections occur throughout the year in tropical climates. In temperate climates, infections are more prevalent during the summer and early fall.

Epidemics have been reported in Panama, Mexico, Switzerland, Cuba, the United States, and Turkey. Asian-Pacific countries have reported major enteroviral epidemics with significant morbidity and mortality.[11, 12] A Thai hospital reported the first nosocomial outbreak of hand-foot-and-mouth disease due to echovirus type 11, underscoring the importance of strict infection control and hand washing in preventing disease.[13]

Race

Echovirus infection has no racial predilection.

Sex

For unclear reasons, males are at greater risk for clinical illness following infection, by as much as 50%.[14] Aseptic meningitis is nearly twice as common in boys as in girls. After puberty, the reverse appears to be true, perhaps because women tend to have more exposure to children who are shedding the virus. Echovirus infection in pregnancy is common; case reports have described vertical transmission or transmission shortly after birth, with potentially serious outcomes.[15, 16]

Age

Three quarters of enteroviral infections, including echoviral infections, reported to the World Health Organization occur in children younger than 15 years. In the United States, attack rates in infants younger than 1 year greatly exceed those in older children and adults.[17, 18] Children younger than one year accounted for 44.2% of reported cases. A male predominance was noted among patients younger than 20 years, but not among patients aged 20 years or older.[1]

Prognosis

Chronic meningoencephalitis in hosts who are agammaglobulinemic and other hosts who are immunocompromised may end in death.

Patient Education

Inform patients that, even if person-to-person transmission of an echovirus occurs, any complication that occurs in one person and is related to the particular type will not necessarily occur in other people.

 

Presentation

History

Fifty to eighty percent of patients with echoviral infections are asymptomatic. The most common presentation is a nonfocal, asymptomatic febrile illness. Illnesses may be caused by virtually any enteroviral serotype and are indistinguishable clinically from infection with many other viral agents. Disease syndromes characteristic of enteroviral infections (eg, aseptic meningitis, pericarditis) are, in fact, unusual manifestations of infection. Severe hepatitis, hepatic failure, and disseminated enteroviral infections have been reported in neonates, hematolymphoid malignancies, and hematopoietic transplant recipients.[19, 20]

Acute aseptic meningitis

Acute aseptic meningitis manifests as signs and symptoms of meningeal irritation and cerebrospinal fluid (CSF) pleocytosis in the absence of bacteria or fungi. CSF cell counts are typically 10-500/µL and may show neutrophil predominance early but invariably shift to a lymphocyte predominance.[9]

The onset may be gradual or abrupt. Echoviral meningitis may have a biphasic pattern. Fever and myalgias with clinical defervescence followed by reappearance of fever and headache herald the onset of meningitis, similar to what is observed in poliomyelitis.

Meningismus, when present, varies from mild to severe. Only about one third of patients demonstrate Kernig and Brudzinski signs. Pharyngitis and other symptoms of upper respiratory tract infection are often present.[9]

Complications such as febrile seizures, lethargy, coma, and movement disorders are reported in 5%-10% of cases and may overlap with an encephalitis-type illness. Adults may experience a longer period of fever and illness than younger patients, and those with severe cases may be incapacitated for 1-2 weeks.

Encephalitis

Encephalitis is a well-described, but rare, manifestation of coxsackievirus and echovirus CNS infection.

Symptoms include lethargy, drowsiness, personality changes, seizures, paresis, and coma.

Although quite rare, enteroviral CNS infections have been reported to cause an encephalitis lethargica–type picture with oculogyric crisis, cranial nerve palsies, and a parkinsonism-like picture.

Rash

Skin rashes are more common with echoviral infections than with other enteroviral infections. Exanthems may be maculopapular, morbilliform, macular, petechial, or papulopustular.

Respiratory illness

Echovirus, similar to many enteroviruses, may be associated with pyrexial illness (the so-called summer grippe), with sore throat, cough, or coryza.

Echovirus 11 can be associated with croup.

Herpangina

Herpangina is a well-characterized, vesicular, oral mucosal process involving the tonsillar fossa and soft palate. Symptoms include elevated temperature, pharyngitis, and dysphagia.

It is commonly observed in summer outbreaks involving younger children, often younger than 10 years, and less common in adolescents and young adults.

Herpangina begins abruptly with fevers as high as 104°F and is associated with nonpersistent vomiting, myalgia, and headache. Sore throat and dysphagia are the prominent symptoms and precede the appearance of the oral lesions.

Epidemic pleurodynia (Bornholm disease)

First described by William Cooper, MD, in 1888, the term "devil's grip" was used to describe cases from an outbreak of fever and chest pain. The illness is characterized by an abrupt onset of fever and sharp spasms of pain involving the intercostal muscles. Pain may also involve abdominal muscles and mimic acute abdomen.

Major epidemics have occurred at infrequent 10- to 20-year intervals. It typically affects older adults, with children having a milder course.

The illness is usually self-limited, with resolution in most individuals within 1 week. The first episode of pain is usually the most symptomatic. Subsequent episodes tend to be shorter in duration and accompanied by lower temperature elevation. Dull aching of involved muscles may be reported between episodes, but the patient usually appears well between the paroxysms.

Most patients recover within a week, but about 25% may experience relapses up to a month after the first attack.

Paralysis and other neurologic complications of echovirus infection

Paralytic disease caused by nonpolio enteroviruses is usually less prominent than poliovirus-associated paralysis. Muscle weakness is more common than flaccid paralysis and is usually not permanent. Cranial nerve involvement has been reported and usually manifests as oculomotor palsy. Cases of fatal bulbar involvement have been reported.

Guillain-Barré syndrome has been reported rarely in patients infected with echovirus serotypes 6, 7,[21] and 22.

Transverse myelitis has been reported with echovirus 2, 5, 11,[22] 18,[23] 19, 25, and 30[24] .

Myocardial/pericardial disease

Enteroviral myocarditis is often associated with an upper respiratory tract illness and may occur at any age, but seems to be particularly prominent in adolescents and young adults. Males are affected twice as often as females. In many cases, an upper respiratory tract illness is reported within 2 weeks prior to the onset of cardiac manifestations.

Common symptoms include shortness of breath, chest pain, fever, and weakness.

Orchitis

Orchitis has been rarely reported with echovirus 6[25] and 30[26] , in both cases in association with aseptic meningitis.

Physical

Acute aseptic meningitis

The highest rates of clinically recognized aseptic meningitis are reported in infants younger than 3 months. This observation may, in part, be related to the practice of performing lumbar punctures for pyrexia in this age group.

Only a small number of the infants have clinical evidence of neurologic disease.

Adults with acute aseptic meningitis demonstrate signs and symptoms of meningeal irritation and typically have a brief prodrome of fever and chills. Headache is usually a predominant complaint and may be accompanied by neck stiffness, pharyngitis, and symptoms of upper respiratory tract infections.[9]

Encephalitis

This primarily affects children and young adults.

Encephalitis can complicate aseptic meningitis or may occur in the absence of meningitis.

Focal encephalitis can manifest as a spectrum of signs, including partial motor seizures, hemichorea, and/or acute cerebellar ataxia.

Paralysis (and other neurologic complications) of echoviral infections

Paralysis caused by nonpolio enteroviruses is usually less severe than that caused by polioviruses.

Muscle weakness is more common than flaccid paralysis.

Cranial nerve involvement has occasionally been associated with unilateral oculomotor palsy.

Guillain-Barré syndrome and transverse myelitis are extremely rare complications of enteroviral infection.[9]

Vesicular rashes

Vesicular rashes are similar to lesions of hand-foot-and-mouth disease but occur in crops on the head, trunk, and extremities.

Unlike chickenpox, these vesicles do not progress to pustules and scabs. Herpetiform rash caused by echovirus 11 has been reported in immunocompromised adult patients.

Petechial and purpuric rashes have been reported with echovirus 9 and coxsackievirus A9 infections. When these rashes have a hemorrhagic component, the illness can be confused with meningococcal disease, particularly when aseptic meningitis occurs.

Acute respiratory disease

Enteroviral upper respiratory tract illness is clinically similar to diseases caused by other agents, including rhinovirus, adenovirus, respiratory syncytial virus, and mycoplasma.

Herpangina

This is characterized by pharyngeal erythema and mild tonsillar exudate.

Painful lesions originate as small macules and evolve over a day to erythematous centrally ulcerated papules that are 2-4 mm in diameter. Palatal lesions number no more than 10-12. Pyrexia resolves over 2-4 days, but the enanthem may persist for as long as a week.

Pleurodynia

Despite its name, pleurodynia is a disease of muscle, not of the pleura or peritoneum. It likely results from direct viral invasion of muscles. In many cases, the pain can be reproduced by pressure on the affected muscles. Palpable, sometimes visible, muscle swelling can be found.

It begins abruptly with spasmodic pain, usually involving the lower part of the rib cage or adjacent abdominal area. Pyrexia as high as 39.5°C occurs within 1 hour after the onset of the spasm, subsiding with the pain. Sore throat and headache can occur, but cough and rhinitis are absent.

The pain is often poorly localized, and its severity varies substantially. It is described as sticking, lancinating, stabbing, constricting, or viselike. Most commonly, the pain occurs at the costovertebral angle and can be unilateral or bilateral. Adults tend to have more thoracic pain involving the intercostal muscles. Pain may also occur in the upper abdomen or the epigastrium. Periumbilical pain and pain in the lower abdomen is more common in children.

Spasmodic pain is characteristic. Chest pain may produce thoracic splinting with shallow rapid respiration.

Chronic meningoencephalitis

This may develop in hosts who are agammaglobulinemic or otherwise immunocompromised.

Enteroviral infections can be associated with considerable morbidity and mortality in immunocompromised hosts. Persistent and sometimes fatal CNS infections have been associated with defective B-lymphocyte function. Most cases occur in children with X-linked agammaglobulinemia.[27, 28]

Nervous system manifestations may be totally absent or may present as meningismus, headache, lethargy, papilledema, seizure disorders, motor weakness, tremors, or ataxia. These abnormalities may fluctuate in severity, disappear, or progress steadily.

Myopericarditis

Enteroviral infections can produce myopericarditis, with severity ranging from asymptomatic disease to intractable heart failure. Sudden death may occur in apparently healthy adults who are later found to have evidence of viral myocarditis at autopsy.

Epidemic enteroviral myopericarditis appears to be rare. Most cases have been sporadic, even during enteroviral epidemics.

Chest pain occurs in as many as 90% of cases and often is dull in nature. A transient friction rub has been observed in 35%-80% of cases.

Causes

Acute aseptic meningitis

More than 90% of community-acquired cases of viral meningitis are caused by group B coxsackieviruses or echoviruses. The most common serotypes are group B coxsackievirus serotypes 2-5 and echovirus serotypes 4, 6, 9, 11, 16, and 30.

Aseptic meningitis is most commonly associated with echovirus 30.[1]

Encephalitis

Enteroviruses, including poliovirus, account for 10%-20% of proven cases of viral encephalitis. This ranks behind arboviruses, herpes simplex virus, and lymphocytic choriomeningitis viruses.

Many serotypes have been implicated as causes of encephalitis; coxsackievirus types A9, B2, and B5 and echovirus types 6 and 9 are the serotypes reported most often. The evidence linking each of these serotypes to encephalitis is quite variable.

Paralysis and other neurologic complications of echovirus infections

Sporadic cases of flaccid motor paralysis are associated with echoviruses 6 and 9.

Less frequently implicated serotypes include echoviruses 1-4, 7, 11, 14, 16-18, and 30.[29]

Rash

The virus can be isolated from the vesicular lesions of patients with hand-foot-and-mouth disease; therefore, these lesions appear to be a direct result of viral invasion of the skin after viremia.

Serotypes associated with rubellalike rash include coxsackievirus A9 and echoviruses 2, 4, 11, 19, and 25.

Vesicular herpetiform eruptions have been linked to coxsackievirus A9 and echovirus 11.

Respiratory tract infection

Among the echoviruses, serotype 11 is the most firmly established cause of respiratory disease, although serotypes 4, 8, 9, 20, 22, and 25 may also be causal agents.

In volunteers infected experimentally and, occasionally, in patients with naturally acquired disease, some coxsackieviruses and echoviruses may be linked with pneumonia. The role of enteroviruses in lower respiratory illness is not clearly defined; at present, they should be thought of as rare causes of pneumonia.

Herpangina

Group A coxsackieviruses (serotypes 1-10, 16, and 22) most commonly are recovered from patients with herpangina. Other less commonly isolated serotypes from herpangina include group B coxsackieviruses 1-5 and echoviruses 3, 6, 9, 16, 17, 25, and 30.

Epidemic pleurodynia

Group B coxsackievirus is the most important cause of epidemic pleurodynia. Less common agents implicated as a cause of pleurodynia include some group A coxsackieviruses and echoviruses 1, 6, 9, 16, and 19.[30]

Chronic meningoencephalitis

This is seen in agammaglobulinemic and immunocompromised hosts.

Echoviruses (and polioviruses) can cause persistent and even fatal CNS infections in immunocompromised patients. Picornaviruses require an extracellular phase for cell-to-cell transfer, providing an opportunity for the virus to be inactivated by antibody-mediated mechanisms.

Most cases have been caused by echoviruses, including types 5, 6, 7, 11, and 27.

Myopericarditis

Enteroviruses appear to be the most common viral etiology of acute myopericarditis. In older children and adults, the disease can range from asymptomatic cardiac involvement to intractable heart failure and death.

Experimental studies in murine models strongly suggest that viral replication occurs in myocytes and results in myocyte necrosis and focal infiltration by inflammatory cells.

A chronic inflammatory process can persist, with variable degrees of fibrosis and loss of myocytes.[9]

Hepatitis 

Fulminant hepatitis has been reported with echovirus 9, 18, and 25 in persons receiving anti-CD 20 antibody.[31]

Complications

Acute aseptic meningitis

Complications (eg, febrile seizures, complex seizures, lethargy, coma, movement disorders) occur early in the course of aseptic meningitis in 5-10% of patients.

Adults may experience a more prolonged period of fever and headache than infants and children; some adult patients may require weeks to return to normal activity.

Paralysis and other neurologic complications

Paralytic disease caused by nonpolio enteroviruses characteristically is less severe than poliovirus-associated paralysis. In fact, muscle weakness is more common than flaccid paralysis, and the paresis is usually not permanent.

Cranial nerve involvement occasionally has resulted in complete unilateral oculomotor palsy. Cases of fatal bulbar involvement are rare.

Guillain-Barré syndrome and transverse myelitis have been reported in a small number of patients in association with echovirus.

 

DDx

Differential Diagnoses

  • Adenoviruses

  • Aseptic meningitis

  • Cardiomyopathy

  • Coxsackieviruses

  • Enteroviruses

  • Herpes simplex virus

  • Poliovirus infections

  • Respiratory syncytial viruses

  • Rhinoviruses

 

Workup

Laboratory Studies

Viral isolation through cell culture

Until recently, echoviral infections were diagnosed via isolation of the virus in cell culture. The diagnosis can be proven by isolating the virus in blood, CSF, tissue, or pericardial fluid. Pharyngeal and stool cultures may be helpful but are not diagnostic, as asymptomatic shedding can persists for several weeks after acute infection.

Polymerase chain reaction

Reverse transcriptase polymerase chain reaction (RT-PCR) and nucleic acid sequence–based amplification are rapid, sensitive, and specific methods of detecting echoviral RNA in clinical specimens. The quick turnaround time offers advantages in terms of patient management decisions.

RT-PCR has detected echoviral RNA from CSF, throat swabs, serum, and stool samples.[32] Quality control is essential to minimize laboratory cross-contamination and false-positive results.

Serology

Serologic testing for echoviral infection has limited value. The results are slow, depend on acute and convalescent titers, and are not type-specific. Regardless of titer, a single antibody result is most often useless.

Imaging Studies

Radiography

Myopericarditis produces enlargement of the cardiac silhouette on chest radiography in approximately 50% of cases, due to either pericardial effusion or cardiac dilatation.

Echocardiography

Echocardiography may confirm the presence of acute ventricular dilatation, decreased cardiac ejection fraction, or pericardial effusion.

Other Tests

Electrocardiography

Pericarditis and myocarditis produce electrocardiographic changes ranging from ST-segment elevation or nonspecific ST-segment and T-wave abnormalities. Severe myocardial disease may lead to the development of Q waves, ventricular tachyarrhythmias, and all degrees of heart block.

Histologic Findings

In enteroviral myopericarditis, viruses reach the heart during the viremia that follows replication in the GI or respiratory tract. Experimental studies in a murine model strongly suggest that virus replication occurs in the myocytes. A chronic inflammatory response persists for weeks to months when the replicating virus is no longer present in the heart, and this lingering response is the subject of keen interest. Some investigators consider the late-phase inflammatory response to be due to virus-induced, cytotoxic T-lymphocyte destruction of myocytes. Others postulate the development of a myocardial neoantigen or cross-reactivity between viral and myocardial cell antigens. A variable degree of interstitial fibrosis and evidence of myocyte loss accompany healing.

 

Treatment

Medical Care

Most echoviral infections are self-limited and require no specific therapy. Medical treatment is supportive and symptomatic. Pleconaril, an experimental agent with in vitro activity against most enteroviruses, was evaluated in clinical trials but has not been approved by the FDA for use as an antiviral agent.[33]

Intravenous gamma globulin (IVIG) therapy has been used to treat immunocompromised patients with persistent echoviral infection. The role of IVIG in serious infections has not been subjected to adequate clinical trials. Nonrandomized trials in neonates and children with myocarditis treated with IVIG showed improved recovery in ventricular function compared with children treated without IVIG.[34]

Prevention

The ubiquitous nature of echoviruses, and of enteroviruses in general, and the ease of person-to-person transmission complicate prevention of echoviral infections. As in other enteroviral infections, good overall public health, including adequate clean and potable water, sanitation, and clean living conditions, can act as deterrents.

No vaccines are available for echovirus infections.

 

Medication

Medication Summary

Pleconaril belongs to a class of compounds that interact with the picornaviral capsids and impair viral attachment and uncoating. In a study of 79 patients, those treated with the agent demonstrated modest benefit. However, pleconaril is not FDA approved and is currently unavailable.[33]