picornavirus

Picornavirus

Picornavirus is an icosahedral, nonenveloped, small (22 to 30 nm) particle 1). The term picornavirus 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 picornaviruses family 2). All members of picornaviridae 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 3). The RNA carries a covalently bound noncapsid viral protein at its 5′ end and a polyadenylated tail at its 3′ end. Most picornavirus infections are asymptomatic 4). Some picornaviruses cause mild illnesses; a few picornavirus serotypes give rise to serious conditions of the central nervous system, heart, skeletal muscles, and liver. These varied manifestations are presented under each of the five genera, namely, enteroviruses, rhinoviruses, hepatoviruses, cardioviruses, and aphthoviruses.

The enteroviruses are subdivided into human polioviruses (1–3); human coxsackieviruses A1–22, 24 (CA1–22 and CA24, CA23 = echovirus 9); human coxsackieviruses (B1–6 (CB1–6); human echoviruses 1–7, 9, 11–27, 29–33 (E1–7, 9, 11–27, 29–33; E8=E1; E10 = Reovirus; E28 = Rhinovirus 1A and E34 = CA24 prime strain); human enterovirus 68–71 (EV68–71); vilyuish virus; simian enteroviruses 1–18 (SEV1–18); porcine enteroviruses 1–11 (PEV1–11); bovine enteroviruses 1–2 (BEV1–2) 5).

Picornaviruses multiply in the cytoplasm, and their RNA acts as a messenger to synthesize viral macromolecules. Viral RNA replicates in complexes associated with cytoplasmic membranes via two distinct, partially double-stranded RNAs – the “replicative intermediates.” One complex uses the sense RNA strand, and the other uses the antisense RNA strand as template.

Picornavirus diseases

The Picornaviridae family (picornaviruses) causes a wider range of illnesses than most other, if not all, virus families 6). Infection with various picornaviruses may be asymptomatic or may cause clinical syndromes  (see Table 1) such as aseptic meningitis (the most common acute viral disease of the central nervous system), encephalitis, the common cold, febrile rash illnesses (hand-foot-and-mouth disease), conjunctivitis, herpangina, myositis and myocarditis, and hepatitis 7).

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.

Rhinoviruses are transmitted by saliva, respiratory discharge, and contaminated inanimate objects. Rhinoviruses infect and replicate mainly in nasopharyngeal epithelium and regional lymph nodes.

Hepatitis A virus replicates in the intestinal epithelium, viremia transports the virus to the liver where secondary virus multiplication in the hepatocytes and Kupffer cells results in infectious hepatitis A.

Enteroviruses

Enteroviruses are implicated in many diseases, including undifferentiated febrile illnesses, upper and lower respiratory tract infections, gastrointestinal disturbances, conjunctivitis, skin and mucous membrane lesions, and diseases of the central nervous system, muscles, heart, and liver. Less commonly, enteroviruses are associated with generalized neonatal infections, diabetes mellitus, pancreatitis, orchitis, and occasionally hemolytic-uremic syndrome and intrauterine infections. A new disease called wandering myoclonus was discovered in China. Rhinoviruses cause mainly upper (e.g. coryza) and lower respiratory tract illnesses (Table 1).

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 8).

Human enteroviral infections occur primarily via ingestion of fecally contaminated material (ie, fecal-oral route), via salivary and respiratory droplets, and in some cases via conjunctival secretions and skin lesion exudates. Cockroaches and flies may be vectors. The ingested virus replicates in susceptible tissues of the nasopharynx and regional lymphoid tissue, conjunctiva, intestines, mesenteric nodes, and the reticuloendothelial system. 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), the spinal cord, brain, meninges, heart, liver, and skin. Some chronic enterovirus infections result in postviral fatigue syndrome.

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, central nervous system, 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.

Table 1. Clinical Picornavirus syndromes

Clinical Picornavirus Syndromes

Poliovirus

Poliovirus has tropism for epithelial cells of the alimentary tract and cells of the central nervous system. Infection is asymptomatic or causes a mild, undifferentiated febrile illness. Spinal and bulbar poliomyelitis occasionally occurs. Paralytic poliomyelitis is not always preceded by minor illness. Paralysis is usually irreversible, and there is residual paralysis for life. All three poliovirus serotypes (1 to 3) can give rise to paralytic poliomyelitis.

Coxsackieviruses

Most infections are inapparent or mild. Rashes and vesicular lesions are most commonly caused by group A coxsackieviruses and pleurodynia and viral pericarditis/myocarditis by group B coxsackieviruses. The coxsackievirus A24 variant causes epidemic and pandemic outbreaks of acute hemorrhagic conjunctivitis. Occasionally, coxsackieviruses are associated with paralytic and encephalitic diseases. Coxsackieviruses are characterized by their pathogenicity for suckling mice. They are classified by antibody neutralization tests as coxsackievirus group A (A1 to A24) and coxsackievirus group B (B1 to B6).

Echoviruses

Echoviruses have been associated with febrile and respiratory illnesses, aseptic meningitis, rash, occasional conjunctivitis, and paralytic diseases.

New Enteroviruses

Enterovirus types 68 and 69 cause respiratory illnesses; type 70 causes acute hemorrhagic conjunctivitis and occasionally polio-like radiculomyelitis; type 71 can cause meningitis, encephalitis and outbreaks of hand-foot-mouth disease with or without encephalitis.

Rhinoviruses

Rhinoviruses cause mainly respiratory infections including the common cold. There are to date 115 serotypes. Immunity is type specific.

Hepatovirus

There is only one serotype of Hepatitis A virus. This virus causes gastroenteritis infections and hepatitis A.

Picornavirus 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 (CDC), regularly updates immunization recommendations for children, adolescents, and adults in the United States.

Poliomyelitis can be prevented by Salk-type (inactivated) and Sabin-type (live) attenuated poliovirus vaccines. Hepatitis A can be prevented by inactivated hepatitis A vaccine (Havrix). Control can be achieved via public education on transmission modes and personal hygiene. Adequate sewage disposal and uncontaminated water supplies are critical for prevention of enteroviral infections.

Poliomyelitis vaccine recommendations are as follows:

  • The current recommendation for inactivated polio vaccine (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 oral polio vaccine (OPV) doses.
  • Outside the United States, oral polio vaccine (OPV) is given in 4 doses, at ages 2 months, 4 months, 6-18 months, and 4-6 years. The main disadvantage of oral polio vaccine (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.
  • Oral polio vaccine (OPV) is not recommended for use in the Unites States except for certain circumstances, as follows: (1) rapid control of an outbreak, (2) inactivated polio vaccine (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.

Hepatitis A 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 hepatitis A immunoglobulin after exposure or as an alternative for hepatitis A immunization include the following:

  • Patients exposed to hepatitis A virus 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

Picornavirus symptoms

Enteroviral infection symptoms

Poliovirus

Manifestations of infection range from inapparent illness to severe paralysis and death 9).

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

  • Central nervous system (CNS): Enterovirus 71 is a prominent cause of CNS infections, including encephalitis 10).
  • 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, 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 unrelated to the foot-and-mouth disease of cattle, vesicles and ulcers develop in the anterior part of the mouth, followed by a vesicular rash on the hands and feet 11).
  • 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.

Complications of infections with enteroviruses include the following 12):

  • 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 13).
  • Fatal encephalitis has been observed in enterovirus 71 infections 14).
  • Echovirus and parechovirus infections in children treated with aspirin may lead to Reye syndrome 15)
  • A connection between pancreatitis and diabetes mellitus type 1 is still being sought 16)

Rhinoviruses

Rhinoviruses produce the common cold, which usually lasts no more than 7 days 17).

In most cases, rhinorrhea and nasal obstruction are the most prominent complaints 18).

The throat is frequently sore or scratchy. Cough and hoarseness occur in 33% of all cases 19).

Complications of infections with rhinoviruses 20) and enteroviruses include the following:

  • Superimposed bacterial sinusitis
  • Bacterial otitis media
  • Precipitation of asthma or exacerbation of chronic obstructive pulmonary disease

Hepatitis A

Hepatitis A virus has an incubation period of 2-6 weeks, with an average of 28 days. Many infections are silent, particularly in small children 21).

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.

Complications of hepatitis A virus infection include the following 22):

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

Picornavirus diagnosis

Picornaviruses must be isolated and identified in the clinical laboratory. Serology is used to confirm the virus as the cause of infection and for the assessment of immune status.

Polymerase chain reaction (PCR)

To detect enteroviral RNA in clinical specimens, use reverse-transcriptase PCR (RT-PCR), which is rapid, sensitive, and specific 23). Reverse-transcriptase PCR (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 24).

Picornavirus treatment

Poliomyelitis

No specific antiviral agents for the treatment of poliomyelitis are available; therefore, management is supportive and symptomatic 25).

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

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

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

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

Because of the lack of specific antiviral therapy, clinicians manage most enteroviral illnesses symptomatically 26).

Patients with agammaglobulinemia and echoviral meningoencephalitis have benefited from immunoglobulin therapy 27).

Hepatitis A

At present, no specific therapy is available for HAV infection, and management is supportive in nature 28).

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

Symptomatic care for fever and rhinitis 29).

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.

Picornavirus 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 hand-foot-and-mouth disease 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 hand-foot-and-mouth disease case-patients was 0.08%, which is similar to the rate of 0.06% experienced in the 1998 Taiwanese outbreak 30).

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 hepatitis A virus cases 31).

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