CLASSIFICATION AND CHARACTERIZATION
Enteroviruses, members of the family Picornaviridae, are so designated because of their ability to multiply in the gastrointestinal tract. Despite their name, these viruses are not a prominent cause of gastroenteritis. Enteroviruses encompass more than 100 human serotypes: 3 serotypes of poliovirus, 21 serotypes of coxsackievirus A, 6 serotypes of coxsackievirus B, 28 serotypes of echovirus, enteroviruses 68–71, and multiple new enteroviruses (beginning with enterovirus 73) that have been identified by molecular techniques. Human enteroviruses have been reclassified into four species designated A–D. Echoviruses 22 and 23 have been reclassified as parechoviruses 1 and 2 on the basis of low nucleotide homology and differences in viral proteins. Enterovirus surveillance conducted in the United States by the Centers for Disease Control and Prevention (CDC) in 2007–2008 showed that the most common enterovirus serotype, coxsackievirus B1, was followed in frequency by echoviruses 18, 9, and 6; together, these four viruses accounted for 52% of all isolates.
Human enteroviruses contain a single-stranded RNA genome surrounded by an icosahedral capsid comprising four viral proteins. These viruses have no lipid envelope and are stable in acidic environments, including the stomach. They are susceptible to chlorine-containing cleansers but resistant to inactivation by standard disinfectants (e.g., alcohol, detergents) and can persist for days at room temperature.
PATHOGENESIS AND IMMUNITY
Much of what is known about the pathogenesis of enteroviruses has been derived from studies of poliovirus infection. After ingestion, poliovirus is thought to infect epithelial cells in the mucosa of the gastrointestinal tract and then to spread to and replicate in the submucosal lymphoid tissue of the tonsils and Peyer’s patches. The virus next spreads to the regional lymph nodes, a viremic phase ensues, and the virus replicates in organs of the reticuloendothelial system. In some cases, a second episode of viremia occurs and the virus replicates further in various tissues, sometimes causing symptomatic disease.
It is uncertain whether poliovirus reaches the central nervous system (CNS) during viremia or whether it also spreads via peripheral nerves. Since viremia precedes the onset of neurologic disease in humans, it has been assumed that the virus enters the CNS via the bloodstream. The poliovirus receptor is a member of the immunoglobulin superfamily. Poliovirus infection is limited to primates, largely because their cells express the viral receptor. Studies demonstrating the poliovirus receptor in the end-plate region of muscle at the neuromuscular junction suggest that, if the virus enters the muscle during viremia, it could travel across the neuromuscular junction up the axon to the anterior horn cells. Studies of monkeys and of transgenic mice expressing the poliovirus receptor show that, after IM injection, poliovirus does not reach the spinal cord if the sciatic nerve is cut. Taken together, these findings suggest that poliovirus can spread directly from muscle to the CNS by neural pathways.
Poliovirus can usually be cultured from the blood 3–5 days after infection, before the development of neutralizing antibodies. While viral replication at secondary sites begins to slow 1 week after infection, it continues in the gastrointestinal tract. Poliovirus is shed from the oropharynx for up to 3 weeks after infection and from the gastrointestinal tract for as long as 12 weeks; hypogammaglobulinemic patients can shed poliovirus for >20 years. During replication in the gastrointestinal tract, attenuated oral poliovirus can mutate, reverting to a more neurovirulent phenotype within a few days; however, additional mutations are probably required for full neurovirulence. One patient with hypogammaglobulinemia who had been infected 12 years earlier and was receiving IV immune globulin suddenly developed quadriplegia and respiratory muscle paralysis and died; analysis showed that the virus had reverted to a more wild-type sequence.
Humoral and secretory immunity in the gastrointestinal tract is important for the control of enterovirus infections. Enteroviruses induce specific IgM, which usually persists for <6 months, and specific IgG, which persists for life. Capsid protein VP1 is the predominant target of neutralizing antibody, which generally confers lifelong protection against subsequent disease caused by the same serotype but does not prevent infection or virus shedding. Enteroviruses also induce cellular immunity whose significance is uncertain. Patients with impaired cellular immunity are not known to develop unusually severe disease when infected with enteroviruses. In contrast, the severe infections in patients with agammaglobulinemia emphasize the importance of humoral immunity in controlling enterovirus infections. Disseminated enterovirus infections have occurred in hematopoietic cell transplant recipients. IgA antibodies are instrumental in reducing poliovirus replication in and shedding from the gastrointestinal tract. Breast milk contains IgA specific for enteroviruses and can protect humans from infection.
Enteroviruses have a worldwide distribution. More than 50% of nonpoliovirus enterovirus infections and more than 90% of poliovirus infections are subclinical. When symptoms do develop, they are usually nonspecific and occur in conjunction with fever; only a minority of infections are associated with specific clinical syndromes. The incubation period for most enterovirus infections ranges from 2 to 14 days but usually is <1 week.
Enterovirus infection is more common in socioeconomically disadvantaged areas, especially in those where conditions are crowded and in tropical areas where hygiene is poor. Infection is most common among infants and young children; serious illness develops most often during the first few days of life and in older children and adults. In developing countries, where children are infected at an early age, poliovirus infection has less often been associated with paralysis; in countries with better hygiene, older children and adults are more likely to be seronegative, become infected, and develop paralysis. Passively acquired maternal antibody reduces the risk of symptomatic infection in neonates. Young children are the most frequent shedders of enteroviruses and are usually the index cases in family outbreaks. In temperate climates, enterovirus infections occur most often in the summer and fall; no seasonal pattern is apparent in the tropics.
Most enteroviruses are transmitted primarily by the fecal-oral or oral-oral route. Patients are most infectious shortly before and after the onset of symptomatic disease, when virus is present in the stool and throat. The ingestion of virus-contaminated food or water also can cause disease. Certain enteroviruses (such as enterovirus 70, which causes acute hemorrhagic conjunctivitis) can be transmitted by direct inoculation from the fingers to the eye. Airborne transmission is important for some viruses that cause respiratory tract disease, such as coxsackievirus A21. Enteroviruses can be transmitted across the placenta from mother to fetus, causing severe disease in the newborn. The transmission of enteroviruses through blood transfusions or insect bites has not been documented. Nosocomial spread of coxsackievirus and echovirus has taken place in hospital nurseries.
Most infections with poliovirus are asymptomatic. After an incubation period of 3–6 days, ~5% of patients present with a minor illness (abortive poliomyelitis) manifested by fever, malaise, sore throat, anorexia, myalgias, and headache. This condition usually resolves in 3 days. About 1% of patients present with aseptic meningitis (nonparalytic poliomyelitis). Examination of cerebrospinal fluid (CSF) reveals lymphocytic pleocytosis, a normal glucose level, and a normal or slightly elevated protein level; CSF polymorphonuclear leukocytes may be present early. In some patients, especially children, malaise and fever precede the onset of aseptic meningitis.
The least common presentation is that of paralytic disease. After one or several days, signs of aseptic meningitis are followed by severe back, neck, and muscle pain and by the rapid or gradual development of motor weakness. In some cases the disease appears to be biphasic, with aseptic meningitis followed first by apparent recovery but then (1–2 days later) by the return of fever and the development of paralysis; this form is more common among children than among adults. Weakness is generally asymmetric, is proximal more than distal, and may involve the legs (most commonly); the arms; or the abdominal, thoracic, or bulbar muscles. Paralysis develops during the febrile phase of the illness and usually does not progress after defervescence. Urinary retention may also occur. Examination reveals weakness, fasciculations, decreased muscle tone, and reduced or absent reflexes in affected areas. Transient hyperreflexia sometimes precedes the loss of reflexes. Patients frequently report sensory symptoms, but objective sensory testing usually yields normal results. Bulbar paralysis may lead to dysphagia, difficulty in handling secretions, or dysphonia. Respiratory insufficiency due to aspiration, involvement of the respiratory center in the medulla, or paralysis of the phrenic or intercostal nerves may develop, and severe medullary involvement may lead to circulatory collapse. Most patients with paralysis recover some function weeks to months after infection. About two-thirds of patients have residual neurologic sequelae.
Paralytic disease is more common among older individuals, pregnant women, and persons exercising strenuously or undergoing trauma at the time of CNS symptoms. Tonsillectomy predisposes to bulbar poliomyelitis, and IM injections increase the risk of paralysis in the involved limb(s).
The risk of developing poliomyelitis after oral vaccination is estimated at 1 case per 2.5 million doses. The risk is ~2000 times higher among immunodeficient persons, especially in persons with hypo- or agammaglobulinemia. Before 1997, an average of eight cases of vaccine-associated poliomyelitis occurred—in both vaccinees and their contacts—in the United States each year. With the change in recommendations first to a sequential regimen of inactivated poliovirus vaccine (IPV) and oral poliovirus vaccine (OPV) in 1997 and then to an all-IPV regimen in 2000, the number of cases of vaccine-associated polio declined. From 1997 to 1999, six such cases were reported in the United States; no cases have been reported since 1999.
The postpolio syndrome presents as a new onset of weakness, fatigue, fasciculations, and pain with additional atrophy of the muscle group involved during the initial paralytic disease 20–40 years earlier. The syndrome is more common among women and with increasing time after acute disease. The onset is usually insidious, and weakness occasionally extends to muscles that were not involved during the initial illness. The prognosis is generally good; progression to further weakness is usually slow, with plateau periods of 1–10 years. The postpolio syndrome is thought to be due to progressive dysfunction and loss of motor neurons that compensated for the neurons lost during the original infection and not to persistent or reactivated poliovirus infection.
An estimated 5–10 million cases of symptomatic disease due to enteroviruses other than poliovirus occur in the United States each year. Among neonates, enteroviruses are the most common cause of aseptic meningitis and nonspecific febrile illnesses. Certain clinical syndromes are more likely to be caused by certain serotypes (Table 228-1).
TABLE 228-1Manifestations Commonly Associated with Enterovirus Serotypes ||Download (.pdf) TABLE 228-1Manifestations Commonly Associated with Enterovirus Serotypes
| ||Serotype(s) of Indicated Virus |
|Manifestation ||Coxsackievirus ||Echovirus (E) and Enterovirus (Ent) |
|Acute hemorrhagic conjunctivitis ||A24 ||E70 |
|Aseptic meningitis ||A2, 4, 7, 9, 10; B1–5 ||E4, 6, 7, 9, 11, 13, 16, 18, 19, 30, 33; Ent70, 71 |
|Encephalitis ||A9; B1–5 ||E3, 4, 6, 7, 9, 11, 18, 25, 30; Ent71 |
|Exanthem ||A4, 5, 9, 10, 16; B1, 3–5 ||E4–7, 9, 11, 16–19, 25, 30; Ent71 |
|Generalized disease of the newborn ||B1–5 ||E4–7, 9, 11, 14, 16, 18, 19 |
|Hand-foot-and-mouth disease ||A5–7, 9, 10, 16; B1, 2, 5 ||Ent71 |
|Herpangina ||A1–10, 16, 22; B1–5 ||E6, 9, 11, 16, 17, 25, 30; Ent71 |
|Myocarditis, pericarditis ||A4, 9, 16; B1–5 ||E6, 9, 11, 22 |
|Paralysis ||A4, 7, 9; B1–5 ||E2–4, 6, 7, 9, 11, 18, 30; Ent70, 71 |
|Pleurodynia ||A1, 2, 4, 6, 9, 10, 16; B1–6 ||E1–3, 6, 7, 9, 11, 12, 14, 16, 19, 24, 25, 30 |
|Pneumonia ||A9, 16; B1–5 ||E6, 7, 9, 11, 12, 19, 20, 30; Ent-D68, 71 |
NONSPECIFIC FEBRILE ILLNESS (SUMMER GRIPPE)
The most common clinical manifestation of enterovirus infection is a nonspecific febrile illness. After an incubation period of 3–6 days, patients present with an acute onset of fever, malaise, and headache. Occasional cases are associated with upper respiratory symptoms, and some cases include nausea and vomiting. Symptoms often last for 3–4 days, and most cases resolve in a week. While infections with other respiratory viruses occur more often from late fall to early spring, febrile illness due to enteroviruses frequently occurs in the summer and early fall.
GENERALIZED DISEASE OF THE NEWBORN
Most serious enterovirus infections in infants develop during the first week of life, although severe disease can occur up to 3 months of age. Neonates often present with an illness resembling bacterial sepsis, with fever, irritability, and lethargy. Laboratory abnormalities include leukocytosis with a left shift, thrombocytopenia, elevated values in liver function tests, and CSF pleocytosis. The illness can be complicated by myocarditis and hypotension, fulminant hepatitis and disseminated intravascular coagulation, meningitis or meningoencephalitis, or pneumonia. It may be difficult to distinguish neonatal enterovirus infection from bacterial sepsis, although a history of a recent virus-like illness in the mother provides a clue.
ASEPTIC MENINGITIS AND ENCEPHALITIS
In children and young adults, enteroviruses are the cause of up to 90% of cases of aseptic meningitis in which an etiologic agent can be identified. Patients with aseptic meningitis typically present with an acute onset of fever, chills, headache, photophobia, and pain on eye movement. Nausea and vomiting also are common. Examination reveals meningismus without localizing neurologic signs; drowsiness or irritability may also be apparent. In some cases, a febrile illness may be reported that remits but returns several days later in conjunction with signs of meningitis. Other systemic manifestations may provide clues to an enteroviral cause, including diarrhea, myalgias, rash, pleurodynia, myocarditis, and herpangina. Examination of the CSF invariably reveals pleocytosis; the CSF cell count shows a shift from neutrophil to lymphocyte predominance within 1 day of presentation, and the total cell count does not exceed 1000/μL. The CSF glucose level is usually normal (in contrast to the low CSF glucose level in mumps), with a normal or slightly elevated protein concentration. Partially treated bacterial meningitis may be particularly difficult to exclude in some instances. Enteroviral meningitis is more common in summer and fall in temperate climates, while viral meningitis of other etiologies is more common in winter and spring. Symptoms ordinarily resolve within a week, although CSF abnormalities can persist for several weeks. Enteroviral meningitis is often more severe in adults than in children. Neurologic sequelae are rare, and most patients have an excellent prognosis.
Enteroviral encephalitis is much less common than enteroviral aseptic meningitis. Occasional highly inflammatory cases of enteroviral meningitis may be complicated by a mild form of encephalitis that is recognized on the basis of progressive lethargy, disorientation, and sometimes seizures. Less commonly, severe primary encephalitis may develop. An estimated 10–35% of cases of viral encephalitis are due to enteroviruses. Immunocompetent patients generally have a good prognosis.
Patients with hypogammaglobulinemia, agammaglobulinemia, or severe combined immunodeficiency may develop chronic meningitis or encephalitis; about half of these patients have a dermatomyositis-like syndrome, with peripheral edema, rash, and myositis. They may also have chronic hepatitis. Patients may develop neurologic disease while receiving immunoglobulin replacement therapy. Echoviruses (especially echovirus 11) are the most common pathogens in this situation.
Paralytic disease due to enteroviruses other than poliovirus occurs sporadically and is usually less severe than poliomyelitis. Most cases are due to enterovirus 70 or 71 or to coxsackievirus A7 or A9. Guillain-Barré syndrome is also associated with enterovirus infection. While earlier studies suggested a link between enteroviruses and chronic fatigue syndrome, most recent studies have not demonstrated such an association.
PLEURODYNIA (BORNHOLM DISEASE)
Patients with pleurodynia present with an acute onset of fever and spasms of pleuritic chest or upper abdominal pain. Chest pain is more common in adults, and abdominal pain is more common in children. Paroxysms of severe, knifelike pain usually last 15–30 min and are associated with diaphoresis and tachypnea. Fever peaks within an hour after the onset of paroxysms and subsides when pain resolves. The involved muscles are tender to palpation, and a pleural rub may be detected. The white blood cell count and chest x-ray results are usually normal. Most cases are due to coxsackievirus B and occur during epidemics. Symptoms resolve in a few days, and recurrences are rare. Treatment includes the administration of nonsteroidal anti-inflammatory agents or the application of heat to the affected muscles.
MYOCARDITIS AND PERICARDITIS
Enteroviruses are estimated to cause up to one-third of cases of acute myocarditis. Coxsackievirus B and its RNA have been detected in pericardial fluid and myocardial tissue in some cases of acute myocarditis and pericarditis. Most cases of enteroviral myocarditis or pericarditis occur in newborns, adolescents, or young adults. More than two-thirds of patients are male. Patients often present with an upper respiratory tract infection that is followed by fever, chest pain, dyspnea, arrhythmias, and occasionally heart failure. A pericardial friction rub is documented in half of cases, and the electrocardiogram shows ST-segment elevations or ST- and T-wave abnormalities. Serum levels of myocardial enzymes are often elevated. Neonates commonly have severe disease, while most older children and adults recover completely. Up to 10% of cases progress to chronic dilated cardiomyopathy. Chronic constrictive pericarditis may also be a sequela.
Enterovirus infection is the leading cause of exanthems in children in the summer and fall. While exanthems are associated with many enteroviruses, certain types have been linked to specific syndromes. Echoviruses 9 and 16 have frequently been associated with exanthem and fever. Rashes may be discrete or confluent, beginning on the face and spreading to the trunk and extremities. Echovirus 9 is the most common cause of a rubelliform (discrete) rash. Unlike the rash of rubella, the enteroviral rash occurs in the summer and is not associated with lymphadenopathy. Roseola-like rashes develop after defervescence, with macules and papules on the face and trunk. The Boston exanthem, caused by echovirus 16, is a roseola-like rash. A variety of other rashes have been associated with enteroviruses, including erythema multiforme (see Fig. 25e-25) and vesicular, urticarial, petechial, or purpuric lesions. Enanthems also occur, including lesions that resemble the Koplik’s spots seen with measles (see Fig. 25e-2).
(Fig. 228-1) After an incubation period of 4–6 days, patients with hand-foot-and-mouth disease present with fever, anorexia, and malaise; these manifestations are followed by the development of sore throat and vesicles (see Fig. 25e-23) on the buccal mucosa and often on the tongue and then by the appearance of tender vesicular lesions on the dorsum of the hands, sometimes with involvement of the palms. The vesicles may form bullae and quickly ulcerate. About one-third of patients also have lesions on the palate, uvula, or tonsillar pillars, and one-third have a rash on the feet (including the soles) or on the buttocks. The disease is highly infectious, with attack rates of close to 100% among young children. The lesions usually resolve in 1 week. Most cases are due to coxsackievirus A16 or enterovirus 71.
Vesicular eruptions of the hand (A), foot (B), and mouth (C) of a 6-year-old boy with coxsackievirus A6 infection. (Images reprinted courtesy of Centers for Disease Control and Prevention/Emerging Infectious Diseases.)
An epidemic of enterovirus 71 infection in Taiwan in 1998 resulted in thousands of cases of hand-foot-and-mouth disease or herpangina (see below). Severe complications included CNS disease, myocarditis, and pulmonary hemorrhage. About 90% of those who died were children ≤5 years old, and death was associated with pulmonary edema or pulmonary hemorrhage. CNS disease included aseptic meningitis, flaccid paralysis (similar to that seen in poliomyelitis), and rhombencephalitis with myoclonus and tremor or ataxia. The mean age of patients with CNS complications was 2.5 years, and MRI in cases with encephalitis usually showed brain-stem lesions. Follow-up of children at 6 months showed persistent dysphagia, cranial nerve palsies, hypoventilation, limb weakness, and atrophy; at 3 years, persistent neurologic sequelae were documented, with delayed development and impaired cognitive function.
Another epidemic of enterovirus 71 infection occurred in China in 2008–2010, with nearly 500,000 infections and 126 deaths. Infections were associated with fever, rash, brain-stem encephalitis with myoclonic jerks, and limb trembling; some cases progressed to seizures and coma. Lung findings included pulmonary edema and hemorrhage; while the level of creatine kinase MB was sometimes elevated, myocardial necrosis was generally not found.
Cyclic epidemics occur every 2–3 years in other Asian countries. However, the virus circulates at lower rates in the United States, Europe, and Africa. In the United States, hand-foot-and-mouth disease is most commonly associated with coxsackievirus A16. Between November 2011 and February 2012, outbreaks of hand-foot-and-mouth disease due to coxsackievirus A6 occurred in several U.S. states, and 19% of the affected persons were hospitalized.
Herpangina is usually caused by coxsackievirus A and presents as acute-onset fever, sore throat, odynophagia, and grayish-white papulovesicular lesions on an erythematous base that ulcerate. The lesions can persist for weeks; are present on the soft palate, anterior pillars of the tonsils, and uvula; and are concentrated in the posterior portion of the mouth. In contrast to herpes stomatitis, enteroviral herpangina is not associated with gingivitis. Acute lymphonodular pharyngitis associated with coxsackievirus A10 presents as white or yellow nodules surrounded by erythema in the posterior oropharynx. The lesions do not ulcerate.
ACUTE HEMORRHAGIC CONJUNCTIVITIS
Patients with acute hemorrhagic conjunctivitis present with an acute onset of severe eye pain, blurred vision, photophobia, and watery discharge from the eye. Examination reveals edema, chemosis, and subconjunctival hemorrhage and often shows punctate keratitis and conjunctival follicles as well (Fig. 228-2). Preauricular adenopathy is often found. Epidemics and nosocomial spread have been associated with enterovirus 70 and coxsackievirus A24. Systemic symptoms, including headache and fever, develop in 20% of cases, and recovery is usually complete in 10 days. The sudden onset and short duration of the illness help to distinguish acute hemorrhagic conjunctivitis from other ocular infections, such as those due to adenovirus and Chlamydia trachomatis. Paralysis has been associated with some cases of acute hemorrhagic conjunctivitis due to enterovirus 70 during epidemics.
Acute hemorrhagic conjunctivitis due to entero-virus 70. (Image reprinted with permission from Red Book 2012: Committee on Infectious Diseases, 29th ed. Used with permission of the American Academy of Pediatrics.)
Enteroviruses are an infrequent cause of childhood pneumonia and the common cold. In the fall of 2014, enterovirus D68 infection was confirmed in more than 500 persons with mild to severe respiratory illnesses in 43 U.S. states. Nearly all reported cases were in children, many of whom had asthma. Enterovirus D68 was detected in upper respiratory tract specimens from some patients with unexplained acute neurologic disease during outbreaks of infection with this virus; however, the virus was not detected in the CSF, and at present the link between the virus and neurologic disease is uncertain. Coxsackievirus B has been isolated at autopsy from the pancreas of a few children presenting with type 1 diabetes mellitus; however, most attempts to isolate the virus have been unsuccessful. Other diseases that have been associated with enterovirus infection include parotitis, bronchitis, bronchiolitis, croup, infectious lymphocytosis, polymyositis, acute arthritis, and acute nephritis.
Isolation of enterovirus in cell culture is the traditional diagnostic procedure. While cultures of stool, nasopharyngeal, or throat samples from patients with enterovirus diseases are often positive, isolation of the virus from these sites does not prove that it is directly associated with disease because these sites are frequently colonized for weeks in patients with subclinical infections. Isolation of virus from the throat is more likely to be associated with disease than is isolation from the stool since virus is shed for shorter periods from the throat. Cultures of CSF, serum, fluid from body cavities, or tissues are positive less frequently, but a positive result is indicative of disease caused by enterovirus. In some cases, the virus is isolated only from the blood or only from the CSF; therefore, it is important to culture multiple sites. Cultures are more likely to be positive earlier than later in the course of infection. Most human enteroviruses can be detected within a week after inoculation of cell cultures. Cultures may be negative because of the presence of neutralizing antibody, lack of susceptibility of the cells used, or inappropriate handling of the specimen. Coxsackievirus A may require inoculation into special cell-culture lines or into suckling mice.
Identification of the enterovirus serotype is useful primarily for epidemiologic studies and, with a few exceptions, has little clinical utility. It is important to identify serious infections with enterovirus during epidemics and to distinguish the vaccine strain of poliovirus from the other enteroviruses in the throat or in the feces. Stool and throat samples for culture as well as acute- and convalescent-phase serum specimens should be obtained from all patients with suspected poliomyelitis. In the absence of a positive CSF culture, a positive culture of stool obtained within the first 2 weeks after the onset of symptoms is most often used to confirm the diagnosis of poliomyelitis. If polio-virus infection is suspected, two or more fecal and throat swab samples should be obtained at least 1 day apart and cultured for enterovirus as soon as possible. If poliovirus is isolated, it should be sent to the CDC for identification as either wild-type or vaccine virus.
Reverse-transcriptase polymerase chain reaction (PCR) has been used to amplify viral nucleic acid from CSF, serum, urine, stool, conjunctiva, throat swabs, and tissues. A pan-enterovirus PCR assay can detect all human enteroviruses. With the proper controls, PCR of the CSF is highly sensitive (70–100%) and specific (>80%) and is more rapid than culture. PCR of the CSF is less likely to be positive when patients present ≥3 days after the onset of meningitis or with enterovirus 71 infection; in these cases, PCR of throat or rectal swabs—although less specific than PCR of CSF—should be considered.
PCR of serum is also highly sensitive and specific in the diagnosis of disseminated disease. PCR may be particularly helpful for the diagnosis and follow-up of enterovirus disease in immunodeficient patients receiving immunoglobulin therapy, whose viral cultures may be negative. Antigen detection is less sensitive than PCR.
Serologic diagnosis of enterovirus infection is limited by the large number of serotypes and the lack of a common antigen. Demonstration of seroconversion may be useful in rare cases for confirmation of culture results, but serologic testing is usually limited to epidemiologic studies. Serum should be collected and frozen soon after the onset of disease and again ~4 weeks later. Measurement of neutralizing titers is the most accurate method for antibody determination; measurement of complement-fixation titers is usually less sensitive. Titers of virus-specific IgM are elevated in both acute and chronic infection.
TREATMENT Enterovirus Infections
Most enterovirus infections are mild and resolve spontaneously; however, intensive supportive care may be needed for cardiac, hepatic, or CNS disease. IV, intrathecal, or intraventricular immunoglobulin has been used with apparent success in some cases for the treatment of chronic enterovirus meningoencephalitis and dermatomyositis in patients with hypogammaglobulinemia or agammaglobulinemia. The disease may stabilize or resolve during therapy; however, some patients decline inexorably despite therapy. IV immunoglobulin often prevents severe enterovirus disease in these patients. IV administration of immunoglobulin with high titers of antibody to the infecting virus has been used in some cases of life-threatening infection in neonates, who may not have maternally acquired antibody. In one trial involving neonates with enterovirus infections, immunoglobulin containing very high titers of antibody to the infecting virus reduced rates of viremia; however, the study was too small to show a substantial clinical benefit. The level of enteroviral antibodies varies with the immunoglobulin preparation. A phase 2 trial of pleconaril for severe neonatal enterovirus disease has been completed; however, as of this writing, the results have not been reported and the drug is not available on a compassionate-use basis. Glucocorticoids are contraindicated.
Good hand-washing practices and the use of gowns and gloves are important in limiting nosocomial transmission of enteroviruses during epidemics. Enteric precautions are indicated for 7 days after the onset of enterovirus infections. Enterovirus 71 vaccine candidates are under development.
PREVENTION AND ERADICATION OF POLIOVIRUS
(See also Chap. 148) After a peak of 57,879 cases of poliomyelitis in the United States in 1952, the introduction of IPV in 1955 and of OPV in 1961 ultimately eradicated disease due to wild-type poliovirus in the Western Hemisphere. Such disease has not been documented in the United States since 1979, when cases occurred among religious groups who had declined immunization. In the Western Hemisphere, paralysis due to wild-type poliovirus was last documented in 1991.
In 1988, the World Health Organization adopted a resolution to eradicate poliomyelitis by the year 2000. From 1988 to 2001, the number of cases worldwide decreased by >99%, with only 496 confirmed cases reported in 2001. Wild-type poliovirus type 2 has not been detected in the world since 1999. The Americas were certified free of indigenous wild-type poliovirus transmission in 1994, the Western Pacific Region in 2000, and the European Region in 2002. However, in 2002, there were 1922 cases of polio, with 1600 cases reported in India. In fact, after the nadir of 496 cases in 2001, 21 countries that had previously been free of polio reported cases imported from 6 polio-endemic countries in 2002–2005. By 2006, polio transmission had been reduced in most of these 21 countries. In 2012, 293 cases of polio were reported (the lowest number ever in a 1-year period); 85% were from Nigeria, Pakistan, and Afghanistan, the only countries where polio remains endemic (Table 228-2). As of November 2013, there had been 390 cases of polio in 2013 compared with 293 cases in 2012. The increase was associated with a marked rise in imported cases, including more than 180 cases in Somalia, more than 10 cases each in Kenya and Syria, and cases in Cameroon and Ethiopia. Also in 2013, wild-type poliovirus was detected in sewage in Israel, prompting a massive vaccination campaign with OPV. As of November 2013, India had not reported a case of polio since January 2011. Polio is a source of concern for unimmunized or partially immunized travelers. Importation of poliovirus accounted for ~50% of cases in 2013. Clearly, global eradication of polio is necessary to eliminate the risk of importation of wild-type virus. Outbreaks are thought to have been facilitated by suboptimal rates of vaccination, isolated pockets of unvaccinated children, poor sanitation and crowding, improper vaccine-storage conditions, and a reduced level of response to one of the serotypes in the vaccine. While the global eradication campaign has markedly reduced the number of cases of endemic polio, doubts have been raised as to whether eradication is a realistic goal, given the large number of asymptomatic infections and the political instability in developing countries.
TABLE 228-2Laboratory-Confirmed Cases of Poliomyelitis in 2012 ||Download (.pdf) TABLE 228-2Laboratory-Confirmed Cases of Poliomyelitis in 2012
|Country ||Type of Transmission ||No. of Cases |
|Nigeria ||Endemic ||130a |
|Pakistan ||Endemic ||74b |
|Afghanistan ||Endemic ||46c |
|Chad ||Imported ||17d |
|Democratic Republic of the Congo ||Vaccine-derived ||17 |
|Kenya ||Vaccine-derived ||3 |
|Yemen ||Vaccine-derived ||2 |
|China ||Vaccine-derived ||2 |
|Niger ||Imported ||1 |
|Somalia ||Vaccine-derived ||1 |
|Total || ||293 |
The occurrence of outbreaks of poliomyelitis due to circulating vaccine-derived poliovirus of all three types has been increasing, especially in areas with low vaccination rates. In Egypt, 32 cases of vaccine-derived polio occurred in 1983–1993; in the Dominican Republic and Haiti, 21 cases occurred in 2000–2001; in Indonesia, 46 cases were reported in 2005; in Nigeria, 385 cases occurred in 2005–2012; in the Democratic Republic of the Congo, 64 cases were reported in 2008–2012; in Pakistan, 16 cases occurred in 2012, and at least 30 cases occurred in 2013. These OPV-derived viruses reverted to a more neurovirulent phenotype after undetected circulation (probably for >2 years). The epidemic in Hispaniola was rapidly terminated after intensive vaccination with OPV. In 2005, a case of vaccine-derived polio occurred in an unvaccinated U.S. woman returning from a visit to Central and South America. In the same year, an unvaccinated immunocompromised infant in Minnesota was found to be shedding vaccine-derived poliovirus; further investigation identified 4 of 22 infants in the same community who were shedding the virus. All 5 infants were asymptomatic. These outbreaks emphasize the need for maintaining high levels of vaccine coverage and continued surveillance for circulating virus.
IPV is used in most industrialized countries and OPV in most developing countries, including those in which polio still is or recently was endemic. While IM injections of other vaccines (live or attenuated) can be given concurrently with OPV, unnecessary IM injections should be avoided during the first month after OPV vaccination because they increase the risk of vaccine-associated paralysis. Since 1988, an enhanced-potency inactivated poliovirus vaccine has been available in the United States.
After several doses of OPV alone, the seropositivity rate for individual poliovirus serotypes may still be suboptimal for children in developing countries; one or more supplemental doses of IPV can increase the rate of seropositivity for these serotypes. Against a given serotype, monovalent OPV containing only that serotype is more immunogenic than trivalent vaccine because of a lack of interference from other serotypes. With eradication of wild-type poliovirus type 2, bivalent OPV (types 1 and 3), which was shown to be superior to trivalent OPV, has been the vaccine of choice to eliminate polio and has markedly reduced rates of polio in Nigeria. As the frequency of wild-type polio declines and reports of polio associated with circulating vaccine-derived viruses increase, the World Health Organization is investigating whether IPV can be produced from OPV strains that require less biocontainment, ultimately replacing OPV.
OPV and IPV induce antibodies that persist for at least 5 years. Both vaccines induce IgG and IgA antibodies. Compared with recipients of IPV, recipients of OPV shed less virus and less frequently develop reinfection with wild-type virus after exposure to poliovirus. Although IPV is safe and efficacious, OPV offers the advantages of ease of administration, lower cost, and induction of intestinal immunity resulting in a reduction in the risk of community transmission of wild-type virus. Because of progress toward global eradication of polio and the continued occurrence of cases of vaccine-associated polio, an all-IPV regimen was recommended in 2000 for childhood poliovirus vaccination in the United States, with vaccine administration at 2, 4, and 6–18 months and 4–6 years of age. The risk of vaccine-associated polio should be discussed before OPV is administered. Recommendations for vaccination of adults are listed in Table 228-3.
TABLE 228-3Recommendations for Poliovirus Vaccination of Adults ||Download (.pdf) TABLE 228-3Recommendations for Poliovirus Vaccination of Adults
Most adults in the United States have been vaccinated during childhood and are at little risk of exposure to wild-type virus in the United States. Immunization is recommended for those with a higher risk of exposure than the general population, including:
travelers to areas where poliovirus is or may be epidemic or endemic;
members of communities or population groups with disease caused by wild-type polioviruses;
laboratory workers handling specimens that may contain wild-type polioviruses; and
health care workers in close contact with patients who may be excreting wild-type polioviruses.
Three doses of IPV are recommended for adults who need to be immunized. The second dose should be given 1–2 months after the first dose; the third dose should be given 6–12 months after the second dose.
Adults who are at increased risk of exposure to wild-type poliovirus and who have previously completed primary immunization should receive a single dose of IPV. Adults who did not complete primary immunization should receive the remaining required doses of IPV.
There are concerns about discontinuing vaccination in the event that endemic spread of poliovirus is eliminated. Among the reasons for these concerns are that poliovirus is shed from some immunocompromised persons for >10 years, that vaccine-derived poliovirus can circulate and cause disease, and that wild-type poliovirus is present in research laboratories.