Enterovirus Infections

Enteroviruses (polioviruses, coxsackieviruses, echoviruses)are among the most common and significant causes of infectious illness in infants and children. They are associated with a broad spectrum of clinical syndromes, including aseptic meningitis, herpangina, hand-foot-mouth disease,conjunctivitis, pleurodynia, myopericarditis, poliomyelitis, various exanthems, and nonspecific febrile illness. In the neonate, enteroviral infection can cause a sepsis-like picture or meningoencephalitis, either of which can be severe. Newer technologies such as polymerase chain reaction(PCR) may provide rapid and sensitive testing methods for diagnosis of enteroviral infections, which may expand the list of diseases attributable to this group of pathogens. Although treatment of enteroviral infections remains unsatisfactory, immunization against poliovirus has been remarkably successful, and new immunization regimens using live and killed virus vaccines have been developed. A role has been postulated for enteroviruses in the pathogenesis of diabetes mellitus.In 1920, soon-to-be president Franklin Delano Roosevelt developed a febrile illness during his summer vacation that was followed by paralysis. Although this is one of the most publicly recognized cases of paralytic poliomyelitis, polio has been described as early as 1580 B.C. An Egyptian stone tablet shows a young priest who has a withered, shortened leg, the characteristic deformity of poliomyelitis. The virus was not isolated until 1949 when John Enders grew it in tissue culture. Following the isolation and identification of this prototypic enterovirus, other members of the enteroviral family were studied and their properties elucidated.The enteroviruses are a subgroup of single-stranded RNA, non-enveloped viruses belonging to the Picornaviradae family (pico=small, RNA=ribonucleic acid). They include the polioviruses, coxsackieviruses, echoviruses (echo=enteric cytopathogenic human orphan), and unclassified enteroviruses. Early classification of enteroviruses involved groupings based on cytopathologic effect in tissue culture. Newly discovered enteroviruses are now simply assigned enterovirus type numbers. The enteroviruses currently recognized to infect humans are outlined in Table 1. Enterovirus 72 is hepatitis A virus,which differs from the other enteroviruses by having only one serotype and replicating only in liver cells. It will not be included in this review.The virion consists of an icosohedron-shaped protein capsid and an RNA core. Although the capsid proteins determine antigenicity, there are no significant antigens common to all members of this group of viruses. The virus can withstand the acidic pH of the human gastrointestinal tract and can survive at room temperature for several days. These features enable the fecal-oral mode of transmission. Most enteroviruses can grow in primate(human or non-human) cell cultures, exhibiting cytopathic effect in 3 to 7 days.Enteroviruses are commonly referred to as “summer viruses” because resulting infections occur primarily during the warmer,summer months (May through October) in temperate northern hemisphere climates such as in the United States. In tropical climates, enteroviral infection is seen all year without seasonal variation.Humans are the only known natural hosts for enteroviruses. The fecal-oral route is the most common mode of transmission, but oral-oral and respiratory spread also are possible. Risk factors for infection include poor sanitation, crowded living conditions, and low socioeconomic class. Children younger than 5 years of age are the most susceptible to infection, due in part to a lack of prior immunity and to the poor hygienic habits associated with this age group.Sixty-eight enteroviral serotypes have been identified, but most infections are caused by a small number of these. During annual epidemics of clinical disease, certain serotypes predominate. In the past 25 years, approximately 15 serotypes have been responsible for the majority of infections and include echoviruses 4, 6, 9, 11, and 30; coxsackieviruses A9, A16, and B2 through B5; and enteroviruses 70 and 71. A given serotype may decrease in prevalence following an epidemic only to reemerge in subsequent outbreaks,when a new group of susceptible hosts becomes available.The pattern of enteroviral epidemics occurring each season has not included the polioviruses since the use of vaccination virtually eliminated paralytic poliomyelitis from developed nations.The incubation period for most enteroviral infections ranges from 3 to 10 days. The virus enters the host via the oral cavity and/or respiratory tract, then invades and replicates in the upper respiratory tract and small intestine, with a predilection for lymphoid tissues in these regions (Peyer patches,mesenteric nodes, tonsils, and cervical nodes). Virus then enters the bloodstream, resulting in a minor viremia and dissemination to a variety of target organs, including the central nervous system (CNS), heart, liver,pancreas, adrenal glands, skin, and mucous membranes. A major viremia results from viral replication at and dissemination from these secondary sites, which provide additional opportunities for seeding the CNS (Table 2). The minor and major viremia may correlate with the biphasic appearance of fever and symptoms commonly described in enteroviral infections (Fig 1).Viremia is the most common source of CNS infection, with some enteroviral serotypes exhibiting increased neurotropism or neurovirulence. These include all three serotypes of poliovirus, numerous echovirus strains, and coxsackieviruses B3 through B5. In paralytic polio infection, the virus replicates in the motor neurons in the anterior horn of the spinal cord and brainstem, leading to death of the neuronal cells and paralysis of the innervated muscles.The immune response in enteroviral infections involves an early immunoglobulin M (IgM) antibody response at 7 to 10 days,followed by a rise in IgG and intestinal IgA neutralizing antibodies. There is relative immunity to reinfection with the same serotype, but if reinfection does occur, the symptoms are ameliorated and the illness may be subclinical.Nonpolio enteroviruses are estimated to cause 10 to 15 million symptomatic infections in the United States annually. They cause a wide spectrum of disease that can involve almost any organ system (Table 3). Disease severity can range from life-threatening with significant morbidity to mild or subclinical. It is believed that approximately 50% of nonpolio enterovirus infections are asymptomatic. The more common syndromes include nonspecific febrile illness, aseptic meningitis, herpangina,hand-foot-mouth syndrome, and exanthems. The clinical manifestations of infection in the neonate can be distinct and will be discussed separately.The most common clinical presentation of nonpolio enterovirus infection is a nonspecific febrile illness. Typically, fever develops suddenly, without a prodrome, and temperatures range from 38.5°to 40°C (101° to 104°F) and last for an average of 3 days. Occasionally, a biphasic pattern of symptoms can be seen, with an initial fever for 1 day, followed by 2 to 3 days of normal temperatures and recurrence of fever for an additional 2 to 4 days. Accompanying symptoms are nonspecific and include malaise, myalgia, headache, and sore throat, as well as gastrointestinal symptoms of nausea, vomiting, mild abdominal discomfort,and mildly loose stools. Findings on the physical examination are usually unremarkable, but mild conjunctivitis, lymphadenitis, or pharyngeal erythema may be present. If a white blood cell count is obtained, there is usually little to no elevation and no shift in the differential. Knowledge that the fever can last for up to 1 week may prevent unnecessary diagnostic evaluations and ease parental fears.Nonpolio enteroviruses are the leading causes of aseptic meningitis, accounting for 80% to 90% of all cases from which an etiologic agent is identified. The most common enterovirus types associated with aseptic meningitis are coxsackievirus B5 and echoviruses 4, 6, 9, and 11. These have occurred in epidemic outbreaks as well as sporadic cases.The initial presentation is similar to that of nonspecific febrile illness. Commonly, a biphasic pattern of symptoms is seen, with signs of CNS involvement developing in addition to recurrence of fever. Evidence for meningeal irritation commonly includes headache and photophobia, with 50% of children older than 1 to 2 years of age also developing nuchal rigidity. Approximately one third of these older children will have a positive Kernig and/or Brudzinski sign. Children younger than 1 year of age usually have no specific meningeal signs, but exhibit increased irritability. Rash is often present and is usually nonspecific. However, on occasion it is petechial and may be confused with the rash of meningococcemia. Examination of the cerebrospinal fluid (CSF) reveals a mildly elevated white blood cell count that typically is less than 500/mm3but can be as high as 2,000/mm3. In the first 1 to 2 days of the illness,polymorphonuclear cells predominate, but they are replaced rapidly by mononuclear cells. Because bacterial meningitis usually produces a persistent granulocytosis in the CSF, sequential lumbar punctures can be useful in differentiating bacterial from viral infection. The CSF glucose level tends to be normal, but it has been reported to be low in some patients, and the CSF protein concentration may be normal or mildly elevated(80 to 100 mg/dL). The differential diagnosis for aseptic meningitis is extremely broad and includes the tick-borne illnesses (ie, Rocky Mountain spotted fever, Lyme disease, and ehrlichiosis) as well as arbovirus infections. These all occur more commonly during the summer/autumn months,which corresponds to the peak season for enteroviral infection. The distribution and character of the rash and blood count findings may help distinguish these different entities. Partially treated bacterial meningitis may present with similar clinical and CSF findings; this possibility should be considered in every patient presenting with aseptic meningitis. The presence of other identifiable enteroviral syndromes in the community, such as herpangina and hand-foot-mouth disease, can be useful in diagnosis because outbreaks tend to be epidemic and seasonal.The course of enteroviral meningitis usually is self-limited and benign, but there has been ongoing debate about the occurrence of long-term sequelae. Recent large studies have shown that there are no long-term neurologic, cognitive, or developmental abnormalities from this infection in older children. However,several investigations have documented that 10% of children younger than 3 months of age who have aseptic meningitis may suffer long-term sequelae,especially speech and language delay.CNS infection by nonpolio enteroviruses less commonly is manifested as encephalitis, which is often severe and, unlike meningitis, can result in long-term sequelae. The encephalitis is typically global, which can differentiate it from the focal presentation often seen with herpes simplex encephalitis.Herpangina is an enanthemous (mucous membrane) disease characterized by a painful vesicular eruption of the oral mucosa associated with fever, sore throat, and pain on swallowing. It is seen most commonly in children ages 3 to 10 years. Group A coxsackieviruses are the most common etiologic agents, but group B coxsackieviruses and echoviruses also have been isolated from patients.Fever, usually mild, develops suddenly, but higher temperatures up to 41°C (105.8°F) can be seen,particularly in younger patients. Nonspecific early symptoms may include headache, vomiting, and myalgia. Sore throat and pain with swallowing are the most prominent symptoms and precede the characteristic enanthem by approximately 1 day. The enanthem consists of punctate macules that vesiculate and ulcerate. The vesicles and ulcers are surrounded by an erythematous ring and are found on the anterior tonsillar pillars, soft palate, and posterior pharynx. There are typically two to six lesions, but there can be as many as 12 to 16. The posterior oropharynx usually is minimally erythematous. Herpangina is self-limited, and symptoms resolve within 1 week. Young children are at risk for dehydration because of refusal to eat or drink.Lymphonodular pharyngitis, a variant of herpangina,presents similarly but differs in the appearance of the oral lesions, which are tiny, firm, white nodules (packed with lymphocytes) in the same distribution.The differential diagnosis for herpangina is discussed in the next section.HFM disease is characterized clinically by a vesicular eruption on the hands and feet and in the oral cavity. Toddlers and school-age children are most is the etiologic but other enteroviruses have been as present with fever of to to that 1 to 2 sore or throat, and the characteristic The oral vesicles usually are on the mucosa and and are only mildly They are surrounded by erythematous and 2). The involves vesicles on the and of the hands and feet (Fig 3). be seen on the and Most children within 1 differential diagnosis for disease includes infection by herpes simplex or and In to are more are more and usually the and of involves vesicles resolve by of In usually more may have erythema or present with higher and exhibit significant cervical and to the oral cavity without These findings may help distinguish from Herpangina also may but the herpangina oral usually are in the posterior of the are is characterized by of the and mucosa that are It is seen most commonly in older children and and is not associated with enteroviruses are the leading cause of in children during the summer and The most common serotype is echovirus The enteroviral consists of a this rash usually is not associated with the rash can or The rash may be the of infection or may present in with febrile illness or aseptic meningitis. It also can be seen fever are seen most commonly in children younger than 5 years of age and decrease in prevalence with The rash is self-limited and in 3 to 5 enterovirus can cause a wide range of symptoms that are clinically from of other viral These include upper or respiratory tract infections, and gastrointestinal symptoms such as vomiting, and abdominal pain are common in children who have enteroviral infections, but are the are associated with enteroviral or epidemic is characterized by an of severe pain in the and by fever. B3 and B5 are the major causes of epidemic sporadic cases have been described with other nonpolio pain is and with typically 15 to they can last up to several During may signs of respiratory or with and to the in young children may or The illness usually 1 to 2 but a biphasic pattern is seen, with several the initial signs and symptoms include headache, nausea, and The are to and a is on In to many other enteroviral is more common in older children and and/or is associated with group B coxsackievirus most in up to 50% of present with on or more symptoms of or involvement is usually self-limited, with but associated with is that coxsackievirus infection can be have been found in who have and enteroviral has been from of who have studies also have described an group B coxsackievirus infection and in epidemic described in in and is now found It is more common in tropical and The majority of outbreaks have been caused by enterovirus serotype but coxsackievirus has been isolated during is characterized by of severe photophobia, and of the and are bacterial infection is symptoms are usually and within 7 to 10 days. is by the route in to the fecal-oral route seen with most enteroviral infections. it is more common in but it also does school-age with nonpolio enteroviruses are at high risk for developing significant illness, including a sepsis-like and/or and group B coxsackieviruses for the majority of enterovirus infections. is usually during or by with an is but less has for outbreaks in in to 50% of infants in there is a of illness in the week The severity of the illness is to the severity of illness at the of as well as to the age of the at of infection. younger than 10 days of age are at higher risk for severe disease because of their relative to a significant immune response and their lack of infection is but one documented that up to of infants developed symptomatic disease during an enterovirus symptoms include fever, poor abdominal and The sepsis-like clinical picture often is from bacterial and, at disease as and In a enterovirus infection in the first 2 of of infants developed Although was other studies have that CNS may be a long-term infections also significant risk to children who have in the most common of which is other viruses that are by immune enteroviruses are eliminated from the host by immune An response is believed to be to viral the who have may enteroviral infection, most commonly present with motor and may and for years, but there is an in CNS and elevation of protein concentration in CSF, and virus can be from the CSF for months to years. A of enteroviral infection is a in which virus is present in many is in most children who are has been the most common cause of infection, but cases caused by other and coxsackieviruses have been Children who have are at risk for developing paralytic poliomyelitis from oral polio or from virus from infections caused by poliovirus are or only about clinically the three serotypes of poliovirus, type 1 causes the majority of clinical syndromes are to poliovirus poliomyelitis, aseptic meningitis, and paralytic poliomyelitis. poliomyelitis is characterized by a nonspecific febrile illness that includes headache, sore throat, and no CNS These symptoms last 2 to 3 days infection also can be manifested as aseptic meningitis, from the same caused by other poliomyelitis with a minor febrile illness that is followed by a period of 2 to 3 days. A of paralysis with no significant is the characteristic of paralytic within a days. is but some results from other cells some of the The most of within the first little or no is 1 poliomyelitis the and of the and can cause death by paralysis of the respiratory muscles.The role of group B coxsackieviruses, in the pathogenesis of type 1 diabetes has been studied A of and a type 1 diabetes in with a seasonal pattern that 1 to 2 months the enteroviral studies have the presence of to coxsackieviruses in who have type 1 diabetes and most have an increased prevalence of the in with have been isolated from tissue of children who have of and to cells by coxsackievirus has been in cell The by which viral infection cause type 1 diabetes is not the are an response due to antigens found in the and the viral or a of these and other infection usually is clinically without isolation and identification of the specific that in diagnosis include of characteristic of physical findings and In certain clinical such as meningitis or and/or identification of the virus may be methods for enterovirus infections include cell developed The for diagnosis has been isolation of enterovirus in cell culture. Virus can be isolated from and CSF of but most clinical are from blood is not common because viremia is usually by the symptoms Virus can be isolated from the throat for 2 days to approximately 2 infection. of virus from be with because can virus for up to 4 to diagnosis is by a or in neutralizing antibody and of a is not useful because there is a wide range of to different serotypes in The more than different serotypes that have no common group antigens and most in diagnostic for enteroviral infections is The is against a that is among almost all enteroviral such has been against serotypes and found to of The has been almost in CSF and found to be more sensitive than cell and using methods that can be in 5 have been shown to be 90% sensitive and testing of and from in infection was was as sensitive as cell and may sensitive and rapid currently is for enteroviral treatment is symptomatic and have been of some in the treatment of but their use is not because in has of enteroviral infections on immune immune has been in and children. Most on are from A in that of high neutralizing to the specific viral was associated with of viremia and seen in The of in children who have has been only enterovirus for which a is is of poliovirus vaccines has polio from the and the The first poliovirus developed by in was an poliovirus In developed an live poliovirus that all three vaccines are with than among was rapidly as the of include ease of secondary immunization of and of immunity in the gastrointestinal Because the pathogenesis of polio infection on intestinal high of neutralizing (ie, in intestinal are for live virus replicates in the small intestine, high of IgA at this In the presence of intestinal immunity may help prevent spread of poliovirus within an is believed to occur by of the poliovirus within the of secondary immunization may an additional of It has been estimated that 10% to of children in are by with virus by in developing is less as by factors are responsible for this including of the poor among and of the gastrointestinal tract with other all of which may cause risk associated with is of paralytic The last of poliomyelitis in the United States was seen in there have been to 10 cases year of paralytic poliomyelitis, all to the live virus corresponds to approximately 4 cases 10 million of The risk for of is seen the initial of with about 1 in children or developing paralytic virus can in the intestinal tract of and these have a for replication in the and may increased serotype 3 for of because it is more followed by serotype 2 and then is a live virus and live virus is by should be to or to living in that includes who have human virus infection, immunoglobulin or due to for other should be in these because there is no live virus and, no risk of It is not to but if against polio is not is or are not to initial was replaced in the by an poliovirus higher with It has been in several and as the mode of polio have been it of and and, are a possibility in who are sensitive to these to the was in However, with the of polio from the United States and many other developed and the ongoing about the small number of each other for were The of any one of three polio vaccination an a or an 4 The for Disease and and the for the of followed by which the of intestinal and immunity associated with the risk of by with studies and immunity and neutralizing with all but higher IgA with the The that and are in of immunity against has and ease of risk of (Table Because nonpolio enteroviral serotypes are responsible for clinical illness, by vaccination will not be in the such as who have and from because infection among these children significant morbidity and are on of to enteroviral infections.