Picornavirus Infections 

Updated: Apr 24, 2018
Author: Shivan Shah, MD; Chief Editor: Mark R Wallace, MD, FACP, FIDSA 

Overview

Background

The Picornaviridae family (picornaviruses) causes a wider range of illnesses than most other, if not all, virus families. Infection with various picornaviruses may be asymptomatic or may cause clinical syndromes such as aseptic meningitis (the most common acute viral disease of the CNS), encephalitis, the common cold, febrile rash illnesses (hand-foot-and-mouth disease), conjunctivitis, herpangina, myositis and myocarditis, and hepatitis.[1, 2]

Poliomyelitis, caused by the enteroviral type species, was one of the first recorded infections; an Egyptian tomb carving showed a man with a foot-drop deformity typical of paralytic poliomyelitis.

Characteristics

The term Picornaviridae is derived from pico, which means small (typically, 18-30 nm), and RNA, referring to the single-stranded positive-sense RNA common to all members of the Picornaviridae family.[3] All members of this family, whose RNA molecules range from 7.2-8.5 kilobases (kb) in size, lack a lipid envelope and are therefore resistant to ether, chloroform, and alcohol. However, ionizing radiation, phenol, and formaldehyde readily inactivate picornaviruses.

The viral capsid of picornaviruses consists of a densely packed icosahedral arrangement of 60 protomers. Each protomer consists of 4 polypeptides, etoposide (VP) 1, 2, 3, and 4, which all derive from the cleavage of a larger protein. The capsid-coat protein serves multiple functions, including (1) protecting the viral RNA from degradation by environmental RNase, (2) determining host and tissue tropism by recognition of cell-specific cell-membrane receptors, (3) penetrating target cells and delivering the viral RNA into the cell cytoplasm, and (4) selecting and packaging viral RNA.[4]

Two genera of Picornaviridae— enterovirus and rhinovirus —have an identical morphology but can be distinguished based on clinical, biophysical, and epidemiological studies. Enteroviruses grow at a wide pH range (ie, 3-10). After initial replication in the oropharynx, enteroviruses survive the acidic environment of the stomach. The small intestine is the major invasion site of enteroviruses, which replicate best at 37°C. Rhinoviruses replicate at a pH of 6-8. After initial replication in the nasal passages, the acidic environment of the stomach destroys rhinoviruses. Rhinoviruses optimally replicate at 33°C and primarily infect the nasal mucosa.[5, 6]

Classification

Overall, the family Picornaviridae includes 9 genera. In addition to the major human enteroviral pathogens (poliovirus, enterovirus, coxsackievirus, echovirus), rhinoviruses (approximately 105 serotypes), the human hepatitis A virus (HAV), and several parechoviruses, Picornaviridae contains several other genera of viruses that infect nonhuman vertebrate hosts.

Enteroviruses have several subgroups: 3 serotypes of polioviruses, 23 serotypes of group A coxsackieviruses, 6 serotypes of group B coxsackieviruses, and at least 31 serotypes of echoviruses. (ECHO virus is a misnomer based on the acronym enteric cytopathic human orphan virus.) Viruses are grouped according to pathogenicity, host range, and serotype, which is based on serum neutralization. Some enteroviruses are not classified further but rather assigned a number, currently 68 to 71. Bovine, equine, simian, porcine, and rodent enteroviruses also exist.

Cardiovirus (type species, encephalomyocarditis virus) is a classic infection in mice, although it has been observed to cause disease in humans.[7] Certain strains of this virus are associated with the development of diabetes in certain strains of mice and are used as a model for virus-associated insulin-requiring diabetes in humans.

Aphthovirus (type species, foot-and-mouth disease virus [FMDV]) creates a major worldwide economic problem, particularly in South America and Australia. FMDV, which has 7 serotypes, is largely controlled by the immunization or slaughter of infected animals. Aphthoviruses are more acid-labile than other picornaviruses.

The other genera include Parechovirus, Erbovirus (equine rhinitis B virus), Kobuvirus (Aichi virus), and Teschovirus (porcine teschovirus). Arthropod-infecting viruses, including Cricket paralysis virus, Drosophila C virus, and Tussock moth virus, are additional unclassified picornaviruses.

Pathophysiology

The pathogenesis of picornaviral infection is best understood for polioviruses, whose pathophysiology is similar to other picornaviruses except for tissue tropism after viremia. Of note, not all picornaviruses spread from the initial site of infection (eg, rhinoviruses).[8]

The replication cycle of picornaviruses is approximately 8 hours, with the exact duration depending on variables such as pH, temperature, cell type, and number of viral particles that infect the cell. The cycle proceeds in host cell cytoplasm, can occur in enucleated cells, and is not inhibited by actinomycin D. Although lytic infections are the rule, HAV can cause nonlytic infections that persist indefinitely.[9, 10]

Cellular protein synthesis declines precipitously after infection, possibly because of the interference with the 5' end of eukaryotic mRNA. A virus-encoded, RNA-dependent RNA polymerase, which produces negative-sense strands, copies the genomic RNA. These strands serve as templates for the positive-sense RNA synthesis.[9, 11]

In most picornaviral infections, infected cells growing in tissue culture show characteristic morphologic changes.[12] Within an hour of infection, margination of the chromatin occurs, in which normally homogeneous nuclear material begins to accumulate on the inside of the nuclear envelope. By 2.5-3 hours, membranous vesicles appear in the cytoplasm, beginning around the nuclear membrane and spreading outward. This vesiculation is associated with changes in the permeability of the cellular plasma membrane and eventual shriveling of the cell. Crystals of virus can be observed late in the process. The cytopathic effect appears mediated, at least in part, by a redistribution of lysosomal enzymes.

The antigenic structure of each viral capsid allows it to bind to specific cell membrane components. The virus uses these membrane receptors to enter the target cell. Different viruses use different identifiable receptors, and receptors may vary even among the same genus. For example, most human rhinoviruses bind to the intracellular adhesion molecule 1 (ICAM-1), an immunoglobulinlike molecule; others use a low-density lipoprotein receptor.[8] Families among the picornaviruses may use the same receptor, which may be shared by unrelated viruses.

Enteroviruses

Human enteroviral infections occur primarily via ingestion of fecally contaminated material (ie, fecal-oral route). The ingested virus replicates in susceptible tissues of the pharynx or gut. Enteroviral replication can be observed in lymphoid tissue of the small intestine within 24-72 hours of ingestion of the virus.

After multiplication in submucosal lymphatic tissues, enteroviruses pass to regional lymph nodes and give rise to a minor viremia that is transient and usually undetectable. During this low-grade viremia, the virus can spread to reticuloendothelial tissue (eg, liver, spleen, bone marrow, distant lymph nodes).

In subclinical infections, which are the most common, viral replication ceases after minor viremia because it is contained by host defense mechanisms. In a minority of infected individuals, however, further virus replication occurs in these reticuloendothelial sites, leading to major viremia. Major viremia can result in dissemination to target organs (eg, CNS, heart, skin), where necrosis and inflammatory lesions can occur. In target organs, the degree of inflammatory change and tissue necrosis corresponds to viral titer. Exercise, cold exposure, malnutrition, pregnancy, immunosuppression, and radiation can enhance the severity of the infection; enteroviral infection in persons with HIV infection may result in chronic enteroviral meningitis.

Epidemiology

Frequency

United States

The overall incidence of picornavirus infections is unknown.

Most enteroviruses survive well in moist or wet environments and are readily transmitted via the fecal-oral route. Enteroviral infections occur not only in warmer climates, where they may be endemic year-round, but also with more seasonal periodicity in temperate climates (particularly during summer and fall months).[13]

Coxsackievirus A16 is the most common cause of hand-foot-and-mouth disease (HFMD) in the United States.

Coxsackievirus A6 was the most commonly reported type of enterovirus in United States from 2009-2013, mostly owing to a large severe HFMD outbreak in 2012. Some of the infected people developed symptoms that were more severe than usual.

Coxsackievirus A24 and enterovirus 70 have been associated with outbreaks of conjunctivitis.

Echoviruses 13, 18, and 30 have caused outbreaks of viral meningitis in the United States.

Enterovirus D68 caused a nationwide outbreak of severe respiratory illness in the United States in 2014.[14]

Rhinoviruses have a well-established seasonal pattern that differs from those of enteroviral infections. In temperate climates, rhinoviral infections have fall and spring peaks; early-fall outbreaks of rhinoviral colds characteristically herald the respiratory disease season. In tropical areas, rhinovirus outbreaks occur during the rainy season; in the arctic, outbreaks occur during colder weather.[15]

International

Enteroviruses are distributed worldwide.[16, 17, 18, 19, 20, 21, 22]

Enterovirus 71 has caused large outbreaks of HFMD worldwide, especially in children in Asia. Some enterovirus 71 infections have been associated with severe neurologic disease, such as brainstem encephalitis.

Poliomyelitis eradication projects have typically involved mass vaccine administration with secondary emphasis on hygiene measures. By 1994, poliomyelitis was considered eradicated from the Americas. As of 2008, poliomyelitis was considered endemic in only 4 countries—Nigeria, India, Pakistan, and Afghanistan—accounting for 1392 of 1491 cases reported in 2008 (as of November 14, 2008).[19]

In 1994, the WHO Region of the Americas was certified polio-free, followed by the WHO Western Pacific Region in 2000 and the WHO European Region in June 2002. On March 27, 2014, the WHO South-East Asia Region was certified polio-free, meaning that transmission of wild poliovirus has been interrupted in this bloc of 11 countries stretching from Indonesia to India. This achievement marks a significant leap forward in global eradication, with 80% of the world’s population now living in certified polio-free regions.[23]

Mortality/Morbidity

Picornaviruses cause various illnesses. Different viruses produce different clinical pictures; in addition, a given picornavirus type can cause varying manifestations in different hosts.

HAV infection may result in fatal fulminant hepatitis. Enteroviruses, particularly enterovirus 71, may cause fatal encephalitis. Infection with coxsackieviruses may lead to nonischemic cardiomyopathy, either chronic or fulminant in nature, and has been reported to cause fatal pneumonitis.[24] Parechoviruses have been observed to cause severe, even fatal, sepsis.[25] Poliomyelitis may be fatal if respiratory support is unavailable or ineffective.

Although many picornaviral infections are asymptomatic, short-term morbidity is the rule in those that do cause symptoms.[26] Gastrointestinal and upper respiratory tract symptoms are most common. Long-term morbidity is uncommon, except for persistent neurologic deficits as a consequence of meningoencephalitis,[18, 27] chronic nonischemic cardiomyopathy, or persistent paralysis (partial or complete) or postpolio syndrome.

Race

Picornaviral infections have no known racial predilection.

Sex

The vast majority of enteroviral infections in children are asymptomatic. Some enteroviral infections, particularly those of the CNS, are more common in boys than in girls. After puberty, the reverse is true, perhaps because women have greater exposure to children who shed the virus and because of the relative immunosuppression of pregnancy.

Age

Most picornavirus infections have no age predilection, although clinical manifestations may favor certain age groups. Aseptic meningitis is most common in very young infants, whereas myocarditis and pleurodynia are most prevalent in adolescents and young adults.[28]

Enteroviruses

The risk of certain enterovirus-related clinical syndromes varies with age and sex. Enteroviral infections occur predominantly in children. In enteroviral infections, antibody prevalence rates of a few serotypes indicate that, after the decline of passively acquired maternal antibodies (by age 6 mo), the fraction of immune persons in the population rises progressively with age; 15%-90% of the adult population has type-specific neutralizing antibodies. Symptomatic enteroviral infections are uncommon in elderly persons. Approximately 95% of infections caused by poliovirus and at least 50% of enteroviral infections that are not associated with polio are presumed completely asymptomatic.[29]

Rhinovirus

Prevalence studies of rhinovirus antibody show rapid acquisition of antibody during childhood and adolescence, with peak prevalence in young adults. Colds range from 1.2 infections per year in children younger than 1 year to 0.7 infections per year in young adults. Approximately 70%-88% of rhinovirus infections are associated with symptomatic respiratory illness.[30]

Prognosis

Poliovirus

Paralytic poliomyelitis occurs in less than 1% of all poliovirus infections. The case-fatality rate of paralytic poliomyelitis is generally 2%–5% among children younger than 5 years and increases with age to 10%–30% among adults, with most deaths due to complications of rapidly progressive bulbar paralysis.

Enterovirus 71

Chinese surveillance data from 2008-2012 of more than 7 million children with HFMD identified the highest incidence to be in children aged 12-23 months. Children younger than 6 months had the highest risk for severe and fatal disease, with the risk declining with increasing age. Of the 1.1% who had neurological or cardiopulmonary complications, 3% died. Overall, the case-fatality rate was 0.03% (n=2457), and 93% of the laboratory-confirmed deaths (n=1737) were associated with EV71. In a Singapore outbreak, the case-fatality rate among all reported HFMD case-patients was 0.08%, which is similar to the rate of 0.06% experienced in the 1998 Taiwanese outbreak.[31]

Hepatitis A

Fulminant hepatitis is the most severe rare complication of hepatitis A infection, with mortality estimates up to 80%. In the prevaccine era, fulminant hepatitis A caused about 100 deaths per year in the United States. The hepatitis A case-fatality rate among persons of all ages was approximately 0.3% but may have been higher among older persons (approximately 2% among persons ≥40 years). More recent case-fatality estimates range from 0.3%-0.6% for all ages and up to 1.8% among adults older than 50 years. Vaccination of high-risk groups and public health measures have significantly reduced the number of overall hepatitis A cases and fulminant HAV cases.[32]

Patient Education

For excellent patient education resources, visit eMedicineHealth's Cold and Flu Center. Also, see eMedicineHealth's patient education article Colds.

 

Presentation

History

The following summary intends to cover general clinical symptomatology for major members of the Picornaviridae family.

Enteroviral infection symptoms[33]

Poliovirus: Manifestations of infection range from inapparent illness to severe paralysis and death.

Abortive poliomyelitis virus infection is characterized by 2-3 days of fever, headache, sore throat, listlessness, anorexia, vomiting, and abdominal pain. Findings of neurologic examination are normal.

Nonparalytic poliomyelitis is similar to the abortive form but produces meningeal irritation.

Spinal paralytic poliomyelitis has a biphasic course. The minor illness coinciding with viremia corresponds to the symptoms of abortive polio and lasts 1-3 days. The patient then appears to be recovering and remains symptom-free for 2-5 days before the abrupt onset of the major illness. Meningitis is the preparalytic symptom of the major illness. Meningismus and accompanying muscle pain are generally present for 1-2 days before frank weakness and paralysis ensue. The paralysis is flaccid, asymmetric in distribution. Proximal muscles of the extremities tend to be more involved than distal muscles; the legs are more commonly involved than the arms.

Bulbar paralytic poliomyelitis consists of paralysis of muscle groups innervated by cranial nerves, especially those of the soft palate and pharynx, resulting in dysphagia, nasal speech, and some dyspnea.

Polioencephalitis is characterized by disturbances of consciousness, occurring predominantly in infants. This condition is the only type of poliomyelitis in which seizures are common.

Systemic infections caused by enteroviruses other than polioviruses[29]

CNS: Enterovirus 71 is a prominent cause of CNS infections, including encephalitis.[34]

Heart: Coxsackievirus B in particular causes acute myocarditis and pericarditis.

Skeletal muscles: Pleurodynia (Bornholm disease) is also usually caused by coxsackievirus B and is characterized by fever and severe pain in the chest. If the diaphragm is involved, severe pain develops in the abdomen. Symptoms last for a few days to 2 weeks and resolve without ill effects. Individuals who develop myalgic encephalomyelitis (ME), another syndrome, have few, if any, physical signs, but many symptoms develop. The most prominent symptoms include fatigue, following even minor physical activity, and depressive psychological illness.

Skin and mucous membranes: Enteroviral infections of these tissues are caused almost entirely by coxsackievirus A. Rashes may accompany infections of other systems. Herpangina is a painful infection of the pharynx with herpeslike features (eg, vesicles of the soft palate, fauces, uvula, posterior wall of the pharynx). The infection resolves spontaneously in a few days. In hand-foot-and-mouth disease (HFMD) unrelated to the FMD of cattle, vesicles and ulcers develop in the anterior part of the mouth, followed by a vesicular rash on the hands and feet.[35]

Conjunctiva: Infection is characterized by subconjunctival hemorrhage, severe pain in the eyes, photophobia, and occasional keratitis. Coxsackievirus A24 and echovirus 70 are the main causes of this infection.

Rhinoviruses[15, 36, 37]

Rhinoviruses produce the common cold, which usually lasts no more than 7 days.

In most cases, rhinorrhea and nasal obstruction are the most prominent complaints.

The throat is frequently sore or scratchy. Cough and hoarseness occur in 33% of all cases.

Hepatitis A[26]

HAV has an incubation period of 2-6 weeks, with an average of 28 days. Many infections are silent, particularly in small children.

Clinical illness usually starts in a few days, with symptoms of malaise, anorexia, vague abdominal discomfort, and fever. Later, the urine becomes dark and the feces appear pale.

Soon afterwards, jaundice appears, first in the sclera and then in the skin; if severe, itching may accompany these symptoms. The patient starts to feel better within the next week or so, and the jaundice disappears within a month.

Physical

Physical examination findings depend on the infection, and a given virus and strain can produce variable symptoms in different patients.[26, 15, 33, 29]

Complications

Complications of hepatitis A virus infection include the following:[26]

  • Cholestasis
  • Relapsing disease
  • Fulminant hepatitis, particularly in patients with underlying liver disease or chronic viral hepatitis
  • Chronic, active autoimmune hepatitis

Complications of infections with enteroviruses include the following:[29]

  • Respiratory compromise is caused by paralysis of the respiratory muscles, by airway obstruction due to involvement of cranial nerve nuclei, or by respiratory center lesions.
  • Postpolio syndrome (new onset weakness, fatigue, breathing or sleeping difficulty, myalgias and/or arthralgias) may affect poliomyelitis survivors months to years after recovery.
  • Gastrointestinal events (eg, hemorrhage, paralytic ileus, gastric dilatation) may complicate acute paralysis.
  • Chronic nonischemic cardiomyopathy and pneumonitis has been associated with coxsackieviruses. [24]
  • Fatal encephalitis has been observed in enterovirus 71 infections. [34, 20]
  • Echovirus and parechovirus infections in children treated with aspirin may lead to Reye syndrome. [38]
  • A connection between pancreatitis and diabetes mellitus type 1 is still being sought. [39, 40]

Complications of infections with rhinoviruses[15, 36]  and enteroviruses include the following:

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Viral isolation through cell culture

Sample multiple sites to optimize recovery.

Isolate virus from cerebrospinal fluid (CSF), pericardial fluid, tissue, or blood, depending on the clinical syndrome.[41]

Viral culture of stool late in enteroviral illnesses may be true or unrelated; pharyngeal secretion culture should be performed simultaneously.

Isolate rhinoviruses at the optimum temperature of 33-34°C.[5]

With the identification of characteristic cytopathic effect in any of 3 or 4 appropriately chosen cell lines, the laboratory can report a presumptive diagnosis of enteroviral infection within 2-5 days.

Polymerase chain reaction (PCR)[38]

To detect enteroviral RNA in clinical specimens, use reverse-transcriptase PCR (RT-PCR), which is rapid, sensitive, and specific.[42] RT-PCR can detect enteroviral RNA in CSF, throat swabs, serum, urine, and stool.

Rhinovirus can be detected on respiratory PCR testing.

Given the close genetic relationship between rhinovirus and enterovirus, they are indistinguishable on PCR testing and must be inferred based on clinical syndrome.

Serology

Acute and convalescent serum studies should, if possible, be run in parallel. A single high-antibody result can be misleading.

The microneutralization test is the most widely used method to evaluate for antibodies to enteroviruses.

During the acute stage, viral hepatitis can be diagnosed based on liver dysfunction, as indicated by raised levels of serum bilirubin and aminotransferases.

Enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay

A specific diagnosis of HAV infection is usually achieved with ELISA or radioimmunoassay for specific immunoglobulin M (IgM).

Immunohistochemistry

Immunohistochemistry can also be used to diagnose cutaneous viral infections.[43]

 

Treatment

Medical Care

Poliomyelitis[33]

No specific antiviral agents for the treatment of poliomyelitis are available; therefore, management is supportive and symptomatic.

Patients in the acute phase of paralytic poliomyelitis may require hospitalization.

Paralysis of the respiratory muscles necessitates mechanical ventilation before severe hypoventilation develops.

Severe bulbar paralysis necessitates tracheal intubation.

Weakness or paralysis of the bladder necessitates catheterization.

Applying moist hot packs to muscles can help relieve pain and muscle spasm.

Bed rest prevents the augmentation or extension of paralysis. Animal model data suggest that exercise early during infection can heighten the paresis.

Other systemic enteroviral infections[29, 44]

Because of the lack of specific antiviral therapy, clinicians manage most enteroviral illnesses symptomatically.

Patients with agammaglobulinemia and echoviral meningoencephalitis have benefited from immunoglobulin therapy.

Hepatitis A[26]

At present, no specific therapy is available for HAV infection, and management is supportive in nature.

Explain dietary recommendations to the patient, including the avoidance of other potentially hepatotoxic substances (eg, medications, ethanol).

Hospitalize and offer supportive treatment to any patient with fulminant hepatitis. Consider liver transplantation in patients who have a poor prognosis with medical management alone.

Rhinovirus[15]

Symptomatic care for fever and rhinitis.

Rest, hydration, nasal decongestants, and cough suppressants may be appropriate.

Start treatment as early as symptoms are recognized, and continue for 4-5 days.

Consider petrolatum-based ointment to nares to prevent painful maceration.

Surgical Care

Tracheotomy or tracheostomy may be required for acute paralysis that involves the respiratory muscles in patients with poliomyelitis.

Consultations

Polio survivors may require consultations with a physical, occupational, or speech therapist.

Gastric or other feeding tubes may be needed if ventilation or cranial nerve disability is prolonged.

Prevention

The importance of proper hand hygiene, cough etiquette, and safe food/beverage choices (particularly during travel) cannot be emphasized enough and are the keys to interrupting picornavirus disease transmission.

The Advisory Committee on Immunization Practices, under the Department of Health and Human Services and the Centers for Disease Control and Prevention, regularly updates immunization recommendations for children, adolescents, and adults in the United States.

Poliomyelitis vaccine recommendations are as follows:

  • The current recommendation for IPV is 4 doses, at ages 2 months, 4 months, 6-18 months, and 4-6 years. The efficacy of IPV after only 1-2 doses is lower than the equivalent number of OPV doses.
  • Outside the United States, OPV is given in 4 doses, at ages 2 months, 4 months, 6-18 months, and 4-6 years. The main disadvantage of OPV is the very rare occurrence of vaccine virus-associated poliomyelitis (ie, 8 cases annually in the United States). The mechanism by which vaccine virus strains cause paralytic disease is not fully understood.
  • OPV is not recommended for use in the Unites States except for certain circumstances, as follows: (1) rapid control of an outbreak, (2) IPV is unavailable, (3) children of parents who do not accept the recommended number of vaccine injections, and (4) unvaccinated children traveling within 4 weeks to endemic areas.

HAV vaccine is recommended for the following:

  • All children aged 12 months and older
  • Populations at increased risk of infection
  • Persons traveling to endemic countries
  • Men who have sex with men
  • Users of illegal drugs
  • Patients with chronic liver disease or clotting factor deficiencies
  • People who may have occupational risk for exposure, including sewage workers, plumbers, primate handlers, medical and nursing staff, and daycare staff

Populations recommended to receive HAV immunoglobulin after exposure or as an alternative for HAV immunization include the following:

  • Patients exposed to HAV in the past 14 days who may be susceptible to the disease
  • Household and sexual contacts of known cases
  • Staff and attendees of daycare centers or homes after 1 or more cases occur in children and employees or 2 or more cases occur in the household of attendees
  • Fellow food handlers
  • Those at risk who work in schools and hospitals or other work settings
  • Patients in outbreak situations with suspected exposure
  • Children younger than 2 years
 

Medication

Medication Summary

No medications are currently indicated for picornavirus infections, except for relief of symptoms (such as cold preparations).