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Enteroviruses: Clinical Syndromes

The clinical syndromes of the enteroviruses are determined by several factors, including the viral serotype, infecting dose, tissue tropism, portal of entry, age, sex, pregnancy status, and state of health (Box 1).

Enteroviruses: Clinical Syndromes

POLIOVIRUS INFECTION

Polio vaccines and global eradication efforts have eliminated poliomyelitis from the Western Hemisphere and are expected to eliminate “wild” polio infections from the world in the near future. However, vaccine-associated cases of polio do occur.

Clinical Findings

Signs and Symptoms

Poliovirus may cause one of four outcomes, depending on the progression of the infection:

  • Asymptomatic illness results if the virus is limited to infection of the oropharynx and the gut. At least 90% of poliovirus infections are asymptomatic.
  • Abortive poliomyelitis, the minor illness, is a nonspecific febrile illness occurring in ~5% of infected individuals. Symptoms of fever, headache, malaise, sore throat, and vomiting occur within 3-4 days of exposure.
  • Nonparalytic poliomyelitis or aseptic meningitis occurs in 1-2% of patients with poliovirus infections. The virus progresses into the central nervous system and the meninges, causing stiff neck and back pain in addition to the symptoms of minor illness.
  • Paralytic polio, the major illness, occurs in 0.1-2.0% of persons with poliovirus infections and is the most severe outcome. Major illness follows 3-4 days after minor illness has subsided, thereby producing a biphasic illness. In this disease the virus spreads from the blood to the anterior horn cells of the spinal cord and the motor cortex of the brain. The severity of the paralysis is determined by the extent of the neuronal infection and the neurons affected. Spinal paralysis may involve one or more limbs, whereas bulbar (cranial) paralysis may involve a combination of cranial nerves and even the medullary respiratory center.

Paralytic poliomyelitis is characterized by an asymmetric flaccid paralysis with no sensory loss. The degree of paralysis may vary from involving only a few muscle groups (eg, one leg) to complete flaccid paralysis of all four extremities. The paralysis may progress over the first few days and may result in complete recovery, residual paralysis, or death. Most recovery occurs within 6 months.

Bulbar poliomyelitis can be more severe and may involve the muscles of the pharynx, vocal cords, and respiratory system, resulting in death in 75% of patients.

Laboratory Findings

The peripheral blood white blood cell (WBC) level is only moderately elevated with a relative lymphopenia. The CSF WBC count is elevated with a lymphocytosis, and the protein level is > 35 mg/100 mL.

Differential Diagnosis

With the disappearance of poliomyelitis from the Western Hemisphere, it is more likely that a patient presenting with febrile flaccid paralysis is suffering from the Guillain-Barre syndrome, whose etiology is unknown. The CSF examination shows elevation of protein but no pleocytosis. Alternatively there are rare instances of paralytic illness associated with entero-, echo-, or coxsackieviruses. Rheumatic fever, cytomegalovirus (CMV) polyradiculopathy, bacterial meningitis, and infectious mononucleosis are other illnesses that may be mistaken for poliomyelitis.

Complications

Pneumonia, urinary tract infections, and decubiti are early complications, whereas the post-polio syndrome is a late complication. This entity is characterized by a recrudescence of increased fatigue and impaired motor function many years after the acute poliomyelitis illness.

COXSACKIEVIRUS & ECHOVIRUS INFECTIONS

Several clinical syndromes may be caused by either coxsackievirus or echovirus (eg, aseptic meningitis) (see Box 1), but certain illnesses are especially associated with coxsackieviruses. For example, coxsackie A viruses are highly associated with herpangina, whereas myocarditis and pleurodynia are more frequently caused by coxsackie B serotypes.

HERPANGINA

Clinical Findings

Signs and Symptoms

This syndrome is inappropriately named because it has no relation to herpesvirus. Rather, it is caused by several types of coxsackie A virus. Fever, sore throat, pain on swallowing, anorexia, and vomiting characterize herpangina. The classic finding is vesicular, ulcerated lesions around the soft palate and uvula. Less typically the lesions may affect the hard palate.

Laboratory Findings

The coxsackie A virus can be recovered from throat, feces, or vesicular lesions. There are no consistent blood abnormalities.

Differential Diagnosis

Primary herpes simplex virus (HSV) stomatitis may resemble herpangina, but the latter is usually confined to the posterior pharynx, whereas HSV also affects the anterior mouth, gums, and lips.

Course

The disease is self-limited and requires only symptomatic management.

PLEURODYNIA (BORNHOLM DISEASE)

Clinical Findings

Signs and Symptoms

This syndrome, also known as the devil’s grip, is an acute illness caused by coxsackie B virus. Patients have sudden onset of fever and unilateral low thoracic, pleuritic chest pain, which may be excruciating. Abdominal pain and even vomiting may also occur. Although a pleural friction rub may be heard, the physical findings of pneumonia are not present. Muscles on the involved side may be extremely tender. The pain tends to appear and disappear abruptly and repeatedly, for example, hourly, and can be very severe.

Laboratory Findings

Chest x-ray films are almost always normal, as are blood leukocyte counts. The virus can be recovered from throat samples, stool samples, or both.

Course

Pleurodynia lasts an average of 4 days and may relapse after the patient has been asymptomatic for several days. High fever and the waxing and waning of the pain help to distinguish pleurodynia from other pleuritic processes, for example, pulmonary embolism. The absence of lung abnormalities eliminates pneumonia as a diagnosis.

MENINGITIS

Clinical Findings

Signs and Symptoms

Viral, or aseptic, meningitis is an acute febrile illness accompanied by headache and signs of meningeal irritation, including nuchal rigidity, Kernig’s or Brudzinski’s sign, or both. Petechiae or skin rash may occur in patients with enteroviral meningitis. Both echo- and coxsackieviruses cause viral “aseptic” meningitis.

Laboratory Findings

Examination of the CSF reveals a predominantly lymphocytic pleocytosis, but very early in the disease, polymorphonuclear leukocytes (PMNs) may be more numerous. CSF glucose levels are usually normal but may be slightly low. CSF protein levels are normal to slightly elevated. Blood counts and chemistry examinations are normal. The causative virus can be recovered from throat, stool, and CSF, but culture of enteroviruses requires an average of 5 days. Polymerase chain reaction of CSF is becoming a most useful rapid diagnostic test.

Differential Diagnosis

The major differential diagnosis is bacterial meningitis, which is characterized by more severe illness and prostration. The CSF reveals elevated PMNs, low glucose, high protein, and a positive Gram stain. Other viruses, for example, mumps, Epstein-Barr (EB), and lymphocytic choriomeningitis (LCM) viruses, may cause an indistinguishable meningitis, but associated clinical features help to identify these etiologies.

Course

Unless associated encephalitis (meningoencephalitis) exists, recovery is uneventful. If encephalitis is present, permanent neurologic sequelae may ensue.

ENTEROVIRAL EXANTHEMS

Clinical Findings

Signs and Symptoms

This syndrome may occur in patients infected with either echo- or coxsackieviruses and is usually accompanied by fever. The rash is usually maculopapular but occasionally may appear as petechial or even vesicular.

Laboratory Findings

The virus can be recovered from throat samples, stool samples, or both.

Differential Diagnosis

The petechial type of eruption must be differentiated from that of meningococcemia. The child with enteroviral infection is not as ill and does not usually have a PMN leukocytosis in blood like the child with meningococcemia.

HAND-FOOT-AND-MOUTH DISEASE

Clinical Findings

Signs and Symptoms

This syndrome is a vesicular exanthem usually caused by coxsackievirus A16. The name is descriptive, since the main features of this infection are vesicular lesions of the hands, feet, mouth, and tongue. The oral lesions are identical to those of herpangina.

Laboratory Findings

There are no consistent laboratory abnormalities, but the virus can be recovered from throat and stool samples in an average of 5 days.

Course

The patient is mildly febrile, and the illness subsides in a few days.

ACUTE BENIGN PERICARDITIS

Clinical Findings

Signs and Symptoms

The chest pain, pericardial friction rub, and clinical illness often follow a preceding febrile illness, which may have been associated with a rash.

Laboratory Findings

EKG reveals changes characteristic of pericarditis, but there are no consistent blood abnormalities. Pericardial fluid cultures may be positive for virus, but throat and stool cultures are often negative due to the time lag between the viral illness and the development of this late complication.

Differential Diagnosis

Pericarditis is usually a disease of young adults but may be seen in older individuals, in whom the distinction from myocardial infarction may be difficult. Usually the symptoms are similar, but in pericarditis, fever may greater and more prolonged than in a patient with myocardial infarction. Other causes of pericarditis, for example, bacterial causes, must be considered, including complications of pneumonia and tuberculosis.

MYOCARDITIS

Clinical Findings

Signs and Symptoms

Myocarditis is caused by coxsackie B virus and occurs in older children and adults but is most threatening in newborns. Neonates with these infections have febrile illnesses and the sudden, unexplained onset of heart failure. Cyanosis, tachycardia, cardiomegaly, and hepatomegaly occur. In older children or adults the cardiac involvement is usually late, ie, days to weeks after initial symptoms.

Laboratory Findings

Electrocardiographic changes are those found in patients with myocarditis, but there are no characteristic blood abnormalities. Viral culture of pericardial fluid or myocardial biopsy may be positive but is often negative due to the late-onset nature of this complication.

Course

Myocarditis is usually self-limited but may be fatal due to arrhythmia or heart failure, especially in newborns.

Complications

Myocarditis may progress to chronic myocardiopathy.

OTHER SYNDROMES

Echoviruses may also produce severe disseminated infection in infants. Enterovirus 70 and a variant of coxsackie A24 have recently been associated with an extremely contagious ocular disease, acute hemorrhagic conjunctivitis. The infection causes subconjunctival hemorrhages and conjunctivitis. The disease has a 24-h incubation period and resolves within 1 or 2 weeks.

Respiratory disease, hepatitis, and diabetes are some additional syndromes attributed to enteroviruses. Coxsackieviruses A21 and A24 and echoviruses 11 and 20 can cause coldlike symptoms if the upper respiratory tract becomes infected. Enterovirus 72, or hepatitis A virus, causes hepatitis A (see site). Coxsackie B infections of the pancreas have been suspected to cause insulin-dependent diabetes because of the destruction of the islets of Langerhans.

Diagnosis

Poliovirus. Poliovirus grows well in monkey kidney tissue culture, and the virus may be isolated from the pharynx during the first few days of illness and from the feces for = 30 days. The CSF is rarely positive for the virus, although a pleocytosis of 25-300 leukocytes usually occurs. Neutrophils may predominate early, especially in aseptic meningitis. Protein and glucose levels in CSF are usually normal or only slightly abnormal. Serologic tests can document seroconversion to one of the three poliovirus serotypes.

Coxsackievirus and Echovirus. Coxsackievirus and echovirus can usually be isolated from the throat and stool during acute infection and often from CSF in patients with meningitis. Virus is rarely isolated in pericarditis or myocarditis, since the symptoms occur several weeks after the initial infection. The coxsackie B viruses can be grown on primary monkey or human embryo kidney cells. Many coxsackie A virus strains do not grow in tissue culture and must be grown in suckling mice.

Polymerase chain reaction analysis of CSF appears to be more sensitive than culturing and is becoming the diagnostic procedure of choice for documenting enteroviral meningitis.

Serologic confirmation of poliovirus infection can be made by detection of specific immunoglobulin M (IgM) or a fourfold increase in antibody titer between acute illness and convalescence; however, the many serotypes for echo- and coxsackieviruses make this approach impractical.

Treatment

No specific antiviral therapy is approved for enterovirus infections, but pleconaril, a drug active against picornaviruses in vitro, is being evaluated for the treatment of enteroviral meningitis and viremia. Immune globulin has been used in immunocompromised patients with chronic enteroviral infection of the central nervous system (Box 2) and can diminish viral titers in body fluids.

Prevention & Control

Poliovirus. The prevention of paralytic poliomyelitis is one of the triumphs of modern medicine. In the western world, complete control has been achieved by the use of vaccines, and worldwide eradication of poliomyelitis is expected soon.

Two types of poliovirus vaccine exist: a formalin-inactivated product known as the inactivated, killed, or Salk vaccine, and an attenuated one known as the live, oral, or Sabin vaccine (Box 27-3). Both vaccines can induce a protective antibody response.

Oral vaccine is attenuated (ie, rendered less virulent) by passage in cell cultures. Attenuation yields a virus capable of replicating in the oropharynx and intestinal tract and of being shed in feces for weeks, but not of being invasive. The remote potential for reverting to virulence and causing paralytic disease is the major drawback of the live vaccine and is estimated to occur in 1 per 4 million doses administered (versus 1 in 100 of those infected with “wild” poliovirus).

The risk of vaccine-associated paralytic poliomyelitis is increased in immunocompromised individuals and is more likely to occur in susceptible adults than susceptible children. Since the live vaccine strain may spread to close, especially household, contacts (a virtue in achieving mass immunization), vaccine-associated poliomyelitis may occur in those contacted by the original recipient, rather than the actual vaccine recipient. Because of the above considerations, killed vaccine is now the recommended prophylaxis, and oral live polio vaccine is used only for those refusing injections or for those traveling to areas with endemic poliomyelitis.

Coxsackievirus and Echovirus. No vaccines exist for these viruses (see Box 3). Transmission can presumably be reduced by improvements in hygiene and living conditions.

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