Non-polio Enterovirus Infections

Michael Kramer, M.D.

Virology A. Classification and Host Range 1. The enteroviruses comprise one class of the family Picornaviridae (table 1). They are distinguished from other picornaviruses by their acid stability. Enteroviruses are found in many mammalian and non-mammalian hosts. However, enteroviruses that infect humans represent a distinct group that are not found in other hosts. II. Most human enteroviruses are subclassified into four subclasses. A. Inactivation 1. Unlike rhinoviruses, enteroviruses maintain infectivity over a wide pH range (3-l0). 2. They are rapidly inactivated at temperatures >500C. III. Pathogenesis of Enterovirus Infections A. Transmission 1. Infection results from ingestion of fecally contaminated material or, less commonly, via contact with respiratory secretions. 2. The incubation period is characteristically 3-5 days between infection and onset of nonspecific symptoms. B. Infection and Viral Dissemination 1. Initial sites of replication include both the pharynx and terminal ilium 2. Virus is shed from the upper respiratory tract for 1-3 weeks, and from the feces for 38 weeks. The period of maximum communicability is during the first 2 weeks after infection. C. Immunity to Infection 1. Immunity to enterovirus infection is serotype specific. 2. Passive humoral antibody confers protection from disease in low titer, and from both infection and disease in high titer. 3. Humoral antibodies also have an important role in the immune response to enterovirus infection. Patients with isolated B cell immunodeficiency are at risk of prolonged, severe infections. IV. Epidemiology A. Epidemic and Endemic Behavior 1. Seasonal patterns a. Although enterovirus infections occur throughout the year, they are strikingly more prevalent between June and October in temperate climates. I.

The human enteroviruses are picornaviruses from the family Picornaviridae. They are distinguished from the other picornaviruses by the fact that they are acid stable and survive transit through the gastrointestinal tract and replicate in the intestinal tract unlike the other picornaviruses. The various subgroups of enteroviruses include polio, Coxsackie A viruses and Coxsackie B viruses, and echoviruses. The echo of course stands for enteric cytopathic human orphan virus. The echoviruses cause a large spectrum of disease. Enteroviruses are transmitted via the fecal-oral route. It is both direct and indirect transmission that can occur, but they are ingested orally. There is an initial cycle of replication that goes on both in the oropharynx, with regards to shedding from the upper respiratory tract and then a cycle of replication goes on in the ileum. Replication is probably more efficient in the lower gastrointestinal tract where more virus is shed for longer periods of time in the feces than from the upper respiratory tract. But, there is prolonged shedding after infection, particularly from the gastrointestinal tract where the virus may be shed in the feces for between three and eight weeks. After a few days, there is an asymptomatic minor viremia which seeds systemic lymphoid tissue, such as bone marrow, lymphoid tissue in the liver and spleen. There is another cycle of replication that produces a major viremia. The major viremia heralds the onset of fever and other symptoms that we see with enterovirus infections. That is what leads to seeding of the target organs such as the central nervous system or the myocardium or other target organs. The period of time between ingestion and onset of symptoms is typically somewhere between three and five days with a relatively brief intervention period before onset of symptoms. But, then there is another considerable period of time of which the onset of these so-called end-organ symptoms, such as polio and myocarditis, which may be as long as nine to twelve days. Then again, the virus is shed in stool characteristically for long periods of time. Immunity to enteroviruses. Immunity is serotype specific. Infection with the Coxsackie B1 incurs life long immunity but not to the other Coxsackie B type II, III or the others. Passive antibodies provide limited immunity to disease. The passive antibodies are clearly very protective if given during the incubation period, early on in the incubation period. Secretory IgA develops within about three weeks after infection and provides some relative protection against re-infection. Re-infection occurs readily even with the same serotype; it is just that re-infections usually are asymptomatic when they occur. Humoral and antibody and macrophage function appear to be important effectors in terms of the immune response to infection. Individuals that have profound T-cell immunodeficiency syndromes, have trouble with persistent and long progressive enterovirus infections. Macrophage function is important. Cytotoxic T-cell activity probably does not contribute to viral clearance. Epidemiology. There is a marked seasonal variation

Population immunity a. Adults usually have a seroprevalence of 30-80% against the more common, endemic enterovirus serotypes. b. Periodic epidemics may result in accumulation of a sufficient cohort of susceptibles to sustain transmission of the epidemic serotype. B. Age and Socioeconomic Status 1. Incidence rates of infection and disease are inversely proportional to age. Infants <12 months have the highest incidence of disease 2. Rates of infection and disease are also higher among children of lower socioeconomic classes. C. Transmission 1. Both direct person-to-person transmission, and indirect transmission (via contaminated fomites, food, and water) probably occurs. 2. Transmission is most efficient in households and families. Secondary attack rates for infection of 30-90% within households. V. Laboratory Diagnosis A. Virus Isolation. Cell culture is labor intensive and expensive. B. Polymerase Chain Reaction (PCR) 1. PCR has superior sensitivity compared to cell culture for identification of enteroviruses in CSF. 2. Experience with other specimens is more limited. PCR compares favorably to culture for throat and serum specimens, but may be less sensitive for urine specimens. C. Serology 1. The micro-neutralization test is the standard serologic method used for determination of immunity. a. Type specific b. Both acute and convalescent sera required c. Should not be used for diagnosis of acute disease except when a specific serotype or a small number of serotypes can be tested. VI. Prevention and Treatment of Enterovirus Infections A. Prevention 1. There are no vaccines available for non-polio enterovirus infections 2. Passive immunoglobulin treatment (IVIG) would probably prevent infection, but this would be practical only in very isolated clinical situations.

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with a late summer, early fall predominance. Both endemic and epidemic disease, the common enterovirus types, the Coxsackie B types, the more common echovirus types such a type 9 and type 11, anywhere from 30-80% of adults tend to have antibodies, so the antibody prevalence in the adult population is high. Most of these infections occurred at a very early age. We will find the highest infection rates in children who come from the most disadvantaged backgrounds. Transmission occurs both directly person to person and via indirect viral spread via fomites, and within households there are very high secondary attack rates. Secondary household attack rates are in the 50-90% among susceptibles. Seasonal occurrence of the enteroviruses. You get a peak at the beginning and in the middle of the summer, peaking in late August or early September. Then, a marked drop off at the appearance of cool weather. However, the enterovirus infections do occur at all times of the year. Marked peaks that occur in July, August, and September, there was disease activity in every calendar month of the year. The nadir for enterovirus activity is March and April while the peak time is August the early of September. The ten or twelve most common types of enteroviruses actually caused about 60-70% of all the disease. The most common types being echo 9 and 11, and then the Coxsackie B viruses are common. Of the five most common types of enterovirus, the Coxsackie viruses and echoviruses, some of these viruses seem to be endemic and occur year after year after year, very commonly. Others tend to occur very infrequently and may only show up once every seven or ten years, or in some cases even longer that. When they do appear, they tend to be dominant causes of disease as shown in the next slide. Viruses like the Coxsackie B viruses or the others are simply endemic and occur each year, year in, year out. On the regional basis these outbreaks tend to be local or regional. In this case of echo 30 here in the Northeast there are other enteroviruses such as the enterovirus 70, which can cause pandemics on a worldwide basis. The age incidence for the children under a year of age is 82 cases per 100,000 is four times that for the next age group, and then the age incidence levels off at a fairly level rate up to the second and third decades of life, and then may fall off thereafter. So, at least with respect to aseptic meningitis, this is a disease that occurs in all age groups, but there is a marked increase in incidence that is detectable in children under a year of age. Eighty percent of the disease occurred in the first twenty weeks of life. So that it is very clear that this is a disease of the very young. Enterovirus disease is a disease of extremely young children.

Nosocomial Infections a. Hospital outbreaks reported, especially in newborn nurseries b. Simple hygienic measures such as handwashing should reduce risk of transmission; special isolation procedures such as gowning and masking are not warranted. B. Treatment 1. No antiviral agents are currently licensed for treatment of enterovirus infections. VII. Infections in Infancy A. Perinatal Infections 1. Incidence a. In Nassau Co., NY, neonatal group B coxsackievirus infection was estimated to occur in 50/100,000 live births from 1970 to 1979. b. Based on cases reported to the CDC echovirus disease is slightly more common than group B coxsackievirus disease (19). 2. Age onset a. Echovirus disease onset <7 days of age (peak 3-5 days) b. Coxsackie B virus disease: onset <10 days of age (peak 3-7 days) 3. Clinical Disease a. Hepatitis (1) This is a severe hepatitis that is unique to newborns and is characterized by rapid and extensive necrosis of the liver and overwhelming hepatic failure (2) The initial signs and symptoms include lethargy, poor feeding, apnea and jaundice. It is associated with progression there marked elevation of serum transaminases and severe coagulopathy with widespread and prolonged bleeding, progressive anemia, marked prolongation of the PT and PTT (3) More than 80% of these infants die within 1-3 weeks. Survivors may develop cirrhosis and chronic hepatic insufficiency. (4) Echovirus 11 has been implicated in the majority of reports (20), but cases attributed to several other echoviruses and the coxsackie B viruses are well documented.

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Virus isolation, of course, is the gold standard by which we compare other methods. It is expensive. It takes at least two to five days to see visible cytopathic effect in most cell lines. There are some enteroviruses, particularly many of the Coxsackie A serotypes that are very difficult to isolate and culture. Type 1 and type 18 have never been isolated in cell cultures. PCR has been applied principally to detection of enterovirus RNA. The experience of PCR is very positive. Whereas we can isolate virus from about 30% of cerebrospinal fluid specimen of which we ultimately make a diagnosis of enterovirus meningitis, PCR is positive in as many as 80%. PCR will pick up enterovirus in about two-thirds of CSF specimens that are cultured negative. So that at least for CSF specimen, PCR turns out to be far more sensitive than culture and has the added advantage that there is a turn around time of only one to two days. PCR is not yet widely available commercially. It has not yet been approved by the FDA. Serology, of course, has been widely used, but is labor intensive, cumbersome, difficult to do, and relatively insensitive. Even though there are a number of tests available commercially, serology is not widely used because it requires acute and convalescent serum. Treatment of enterovirus infections. There is no currently available agent to treat any picornavirus infection or any enterovirus infection. However, there has been a lot of interest in the oxazolone compounds, which are compounds that actually interpolate on the capsid of the virus and stabilize the virus capsid and prevent uncoating once it enters the cell. These compounds are broadly reactive against many enterovirus serotypes in vitro. They have been used with impressive results in animal models and are now just entering clinical testing. One compound called Placinoral has been tested in adults with aseptic meningitis. The drug had very impressive activity in reducing the duration of signs and symptoms of aseptic meningitis in adults, in studies that were done last year. The drug is just now going into trial in children and adolescents this year and probably will be going to trial in young infants and neonates sometime within the next couple of years. You will be hearing much more about Placinoral in the future. In neonates, serious infection is relatively uncommon, but when it does occur it can often be very serious and often fatal. In the neonatal period, when echovirus is acquired intrapartum and perinatally, the onset of the echoviruses is characteristically around three, four or five days and almost always less than seven days. The onset of the Coxsackie B disease would be a little bit longer, and serious infections have been seen to last up to ten days. But, rarely, if ever, do you see serious disease in infants presenting beyond seven to ten days of life. Almost all of these are probably perinatally acquired from the mother, or in a small number of cases, there have been serious cases of serious disease reported with which viral infections have been acquired nosocomially.

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Myocarditis (1) May begin with non-specific signs such as lethargy, poor feeding, or mild respiratory distress. The onset of frank myocarditis is often abrupt with temperature instability, respiratory distress, tachycardia, cyanosis, arrhythmias, hepatomegaly, jaundice and signs of poor peripheral circulation. The ECG may show low voltage and other electrophysiologic abnormalities, and echocardiographic studies often indicate poor left ventricular or biventricular function (2) Unlike older children and adults, infants with group B coxsackievirus myocarditis often develop concomitant meningoencephalitis, pneumonia, hepatitis, pancreatitis, or adrenalitis. (3) Mortality among infants with myocarditis alone is generally reported to be 30-50%, but is higher when other organs are involved. (4) Virtually all cases are caused by the coxsackie B viruses. Meningocephalitis (1) Signs and symptoms such as extreme lethargy, seizures, hemiparesis, flaccid paralysis, and coma help to differentiate the more serious forms of CNS involvement that often accompany myocarditis or hepatitis from the far more benign disease observed with aseptic meningitis. (2) Inflammation of the brain or spinal cord can be found in about 2/3 of infants dying with myocarditis. Meningoencephalitis in the absence of other organ involvement is quite rare. Pneumonia (1) A small number of infants have been reported with severe pneumonia caused by echovirus serotypes 6, 9, and 11. Some of these cases have been characterized by onset of symptoms within hours of birth suggesting prenatal exposure, and associated with a high mortality rate. Neonatal pneumonitis of lesser severity has been described with

The echoviruses cause a very severe hepatitis syndrome, which is termed disseminated disease. The liver is the major target organ. Pneumonia is much less common. Coxsackie B viruses have been associated with myocarditis and sometimes encephalitis and hepatitis, although it is unusual to see either encephalitis or hepatitis occur in the absence of myocarditis. Peak onset is in the three, four, five day range, suggesting that most of these infections had been acquired at the time of delivery with a week incubation period and peak at an early age. Pathogenesis of neonatal enterovirus infections. Most of these are acquired from the moms. The mothers often do have symptoms late in pregnancy, particularly with echovirus disease. These symptoms characteristically are fever and onset of very intense abdominal pain. Sometimes the infants have actually been C-sectioned because of a misdiagnosis of abruptio placenta. Nosocomial transmission has been reported but most transmission is vertical, it probably occurs intrapartum, at the time of delivery. We think that the placenta actually acts as a very effective barrier. Intrauterine infections do occur but they are very uncommon. Most of the serious infections are those with infection acquired at the time of delivery as opposed to prior to delivery. The role of passively acquired maternal antibody turns out to be critical, in that, depending on the timing of the maternal infection and whether or not she transmits IgG antibody across the placenta to the newborn, the infant either gets into very serious trouble with disease or remains asymptomatic. What appears to determine whether or not that happens is whether or not the infant has acquired antibodies from the mom. So it all depends on the timing of the maternal infection and at what point she does or does not transmit antibody to the fetus or the newborn infant. The liver in echovirus disease is small, shrunken and very hemorrhagic. There are a few small nests of normal hepatocytes and the rest of this is just basically coagulation and necrosis. Very serious, overwhelming disease where presents with marked elevation of serum transaminase and a severe coagulopathy. The normal mortality unfortunately is about 80%.

echovirus serotypes 7 and 22. Management 1. Acyclovir. Many of the presenting clinical features of neonatal enteroviral disease cannot reliably be distinguished from disseminated HSV infection. Therefore, it is prudent to treat with intravenous acyclovir until laboratory studies confirm the diagnosis of enterovirus infection. 2. Intravenous Immune Globulin (IVIG) a. One infant has been reported with severe echovirus hepatitis who survived after receiving a large dose of IVIG. b. It is reasonable to give a single infusion of IVIG in a dose of 1-2 g/kg to infants with clinical features strongly suggestive of enterovirus myocarditis or hepatitis. C. Non-Specific Febrile Illness With and Without Aseptic Meningitis 1. Non-polio enteroviruses are the most commonly WBC Cell Count identified cause of fever without an apparent focus among infants under a month of age who present for emergent care. During the summer and fall months, enteroviruses account for at least 53-63% of these cases. 2. Fever is often the sole examination finding although some infants will present with other non-specific findings such as irritability, lethargy, poor feeding, vomiting, diarrhea, exanthems, and signs of upper respiratory tract infection. Upon evaluation, which for infants of this age usually includes a full "septic workup", approximately half of enterovirus infected infants will have aseptic meningitis, although there are no clinical features that distinguish those with meningitis prior to performing the lumbar puncture. VIII. Central Nervous System Infections A. Aseptic Meningitis 1. Viral meningitis is the most common infection of the CNS. It is predominantly a disease of infants less than a year of age. 2. The enteroviruses account for >90% of cases. a. A prospective study conducted at three Baltimore hospitals from 1986 to 1990 showed >90% of viruses isolated from children under 2 years old are coxsackie B viruses and echoviruses; coxsackie A B.

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viruses appear to cause <3% of cases. Clinical Presentation a. In the older child and adult aseptic meningitis presents with fever to 400 C, headache, meningismus, nausea and vomiting. Other signs of enterovirus infection, i.e., rash, are present in a minority of cases. Altered mentation, seizures, and focal neurological signs are unusual and suggest a diagnosis of meningoencephalitis. b. In infants less than a year of age, the characteristic symptoms and signs of meningitis are difficult to elicit by history and exam. The most common symptoms are fever and irritability. In practice, aseptic meningitis is often diagnosed during the clinical evaluation of febrile infants without an apparent source of fever. Diagnosis a. The peripheral WBC and differential are usually non-specific. b. CSF examination c. Virology (1) Cell culture virus isolation rates from the CSF have varied from 20% to 90% in various reports. Viruses are less often isolated from CSF than from the GI tract. Enteroviruses are often isolated from the oropharynx for 1-2 weeks after onset of symptoms, and from the feces for 3-8 weeks (2) The use of the polymerase chain reaction (PCR) to detect enterovirus RNA in CSF is likely to be more rapid and more sensitive than cell culture (41). Sawyer, et al, found that PCR detected enteroviral RNA in 97% of culture positive CSF specimens, and in 66% of culture negative CSF specimens from aseptic meningitis patients. Differential diagnosis a. Partially treated bacterial meningitis b. Parameningeal bacterial infection or brain abscess c. TB and fungal meningitis d. Spirochetal meningitis (Lyme disease, syphilis, leptospirosis) Complications and Prognosis

Complete recovery is the rule, most infants and children recover completely within 3-7 days of onset. b. 12% patients with aseptic meningitis develop signs of encephalitis during the acute illness. Specific signs include seizures (3.4%), weakness (1.0%), and coma (3.7%). Most patients are teenagers and young adults. Virtually all the complications were associated with coxsackieviruses and echoviruses. c. In a Baltimore study of aseptic meningitis among children <2 years of age, the acute illness was complicated by either complex seizures, physical evidence of increased intracranial pressure, or coma in 25 (9%) cases. However, these complications were not associated with adverse long term neurological sequelae. d. Long Term Sequelae (1) More recent studies with larger numbers of cases and more appropriate controls have found no effect of viral meningitis on cognitive development 7. Management a. Admission b. Treatment options B. Encephalitis 1. Well described, but less common manifestation of enterovirus infection. a. 5-10% of aseptic meningitis patients have symptoms or signs suggestive of encephalitis such as diminished consciousness, seizures. b. Frank enterovirus encephalitis is reported with multiple serotypes 2. Focal disease may mimic HSV encephalitis. 3. Prognosis is generally very good. Neurologic sequelae and rare deaths reported. C. Acute Myelitis (Poliomyelitis) 1. Sporadic cases of acute paralysis indistinguishable from poliomyelitis have occurred with many enterovirus serotypes. 2. Enterovirus 71 is the only non-polio serotype associated with outbreaks of paralytic disease. a. Causes coxsackie A virus-like disease in newborn mice, but neurovirulent for monkeys (unlike coxsackie A viruses). b. Clusters of paralytic cases reported from

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many locations, including the U.S. (50). Large outbreaks involving hundreds of cases, mostly children < 6 y/o, reported from eastern Europe and Russia.

IX. Exanthems A. Rubelliform and morbilliform rashes B. Hand-Foot-Mouth Syndrome 1. Hand-foot-mouth syndrome (vesicular stomatitis with exanthem) is a relatively common acute illness affecting mostly children under 10 years of age. The characteristic findings include fever, oral vesicles on the buccal mucosa and tongue, and peripherally distributed small, tender cutaneous lesions on the hands, feet, buttocks and (less commonly) genitalia. 2. The group A coxsackieviruses are recovered most often from HFM syndrome patients. Coxsackie A16 is especially common. 3. Differential diagnosis a. Varicella b. HSV stomatitis 4. Course. HFM syndrome usually resolves in 2-3 days without complication. Concomitant CNS disease may occur when HFM syndrome is caused by enterovirus 71. X. Respiratory Infections A. Acute Respiratory Disease 1. Febrile illness with URI ("summer gripe") is a very common manifestation of enterovirus infection that cannot be differentiated from "colds" caused by rhinoviruses and other respiratory viruses (54,55). 2. The role of enteroviruses in lower respiratory tract disease (i.e., pneumonia) is less certain. They can be considered rare causes of viral pneumonia. B. Herpangina 1. Herpangina is a vesicular exanthem of the tonsillar fauces and soft palate, accompanied by fever, sore throat, and pain with swallowing, that principally affects children 3-10 years of age. Most disease occurs during summer outbreaks. Sporadic herpangina is less common (56). 2. The coxsackie A viruses are the usual cause; coxsackie B viruses and echoviruses have been responsible for some outbreaks. 3. Differential diagnosis a. Herpes simplex gingivostomatitis

b. Hand-foot-mouth syndrome c. Aphthous stomatitis C. Pleurodynia 1. Pleurodynia is an acute illness characterized by fever and paroxysmal spasms of the chest and abdominal muscles. Most cases occur during summer outbreaks among adolescents and adults. 2. Major epidemics occur at infrequent intervals, typically 10-20 years apart. 3. Group B coxsackieviruses are the most important cause. Coxsackie A viruses and echoviruses are rarely implicated. 4. Differential diagnosis a. Pneumonia b. Pulmonary embolus c. Myocardial infarction d. Acute abdomen XI. Other Clinical Diseases Associated with Enteroviruses A. Myopericarditis 1. Background. Acute myopericarditis occurs at all ages, but most often among healthy, often athletic, adolescents and young adults. There is a wide range of clinical manifestations and outcomes. 2. Etiology and Pathogenesis a. The enteroviruses are among the most common identified causes of acute myocarditis. Other agents include adenoviruses, influenza A virus, EBV, VZV, and mumps virus. b. The group B coxsackieviruses are by far the most prominent among the enteroviruses, although disease due to coxsackie A viruses, echoviruses, and polioviruses is well documented. c. The role of enteroviruses in cases of dilated cardiomyopathy is uncertain. d. Animal studies suggest the exercised myocardium is at increased risk of more severe infection. 3. Clinical Manifestations a. Fever, malaise, dyspnea, chest pain, signs of CHF b. Pericardial friction rub observed in 35-80% of cases c. Cardiomegaly d. ECG: ST-T elevation, T wave abnormalities, arrhythmias e. Ejection fraction

Often misdiagnosed as myocardial infarction 4. Management a. Supportive care b. Corticosteroids are often given, although controlled studies indicate little or no long term benefit. 5. Prognosis a. Acute mortality <10% b. Persistent cardiomegaly, failure 5-20% c. Chronic constrictive pericarditis - rare B. Acute Hemorrhagic Conjunctivitis 1. Acute hemorrhagic conjunctivitis (AHC) is a highly contagious ocular infection characterized by pain, lid edema, and subconjunctival hemorrhages. It is self-limited and rarely leads to permanent visual impairment. Worldwide pandemics caused by enterovirus 70 and coxsackie A24 have occurred mostly in tropical coastal areas. 2. Transmission probably occurs via indirect routes involving eye discharge and fingers, towels, etc., rather than fecal-oral spread. 3. Differential diagnosis a. Epidemic keratoconjunctivitis (due to adenoviruses) 4. Course. AHC usually peaks in 2-3 days and resolves within 10 days without complication. In severe cases, keratitis may persist for several weeks, but does not lead to permanent scarring. Concomitant CNS disease may occur when AHC is caused by enterovirus 70. C. Pancreatitis D. Hepatitis E. Disease in Immunocompromised Persons 1. Persistent enterovirus infection a. Patients at risk are those with profound B cell immunodeficiency (X-linked agammaglobulinemia, other inherited B cell disorders, severe combined immune deficiency, common variable immunodeficiency). b. The most common clinical manifestation is chronic meningoencephalitis with slowly progressive cognitive and neurologic deterioration. More than half of patients also have a chronic dermatomyositis syndrome due to persistent infection of skeletal muscle. Some patients also develop hepatitis.

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Most infections are caused by echoviruses, but the group A coxsackieviruses and group B coxsackieviruses have also caused persistent infections. Acute, overwhelming enterovirus infection a. Neonates b. Bone marrow transplantation (1) Patients with acquired immune deficiency syndrome (AIDS) appear to have little or no increased risk from enterovirus infections.

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