Clinical Manifestations and Diagnosis of Enterovirus and Parechovirus Infections

Clinical manifestations and diagnosis of enterovirus and parechovirus infections

Author:

John F Modlin, MD

Section Editors:

Martin S Hirsch, MD

Morven S Edwards, MD

Deputy Editor:

Allyson Bloom, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and ourpeer review processis complete.

Literature review current through:Nov 2016.|This topic last updated:Sep 30, 2016.

INTRODUCTION—The human enteroviruses and parechoviruses are ubiquitous viruses found throughout the world, and are transmitted from person to person through fecal-oral contact [1]. Polioviruses, the prototypic enteroviruses, are the cause of paralytic poliomyelitis, a disease that has been eradicated in the United States and other developed countries (except for very rare cases that are attributable to live, attenuated polio vaccine viruses), and that is targeted for worldwide eradication.

The non-polio enteroviruses (group A and B coxsackieviruses, echoviruses, and enteroviruses) and parechoviruses continue to be responsible for a wide spectrum of disease in persons of all ages, although infection and illness occur most commonly in infants and young children.

The clinical manifestations and laboratory diagnosis of enterovirus and parechovirus infections will be reviewed here. The microbiology, epidemiology, pathogenesis, treatment, and prevention of these infections are discussed separately. (See"Epidemiology, pathogenesis, treatment, and prevention of enterovirus and parechovirus infections"and"Poliovirus vaccination".)

CLINICAL DISEASE—More than 90 percent of infections caused by the non-polio enteroviruses are asymptomatic or result only in an undifferentiated febrile illness [2]. When disease occurs, the spectrum and severity of clinical manifestations vary with the age, gender, and immune status of the host. Some clinical syndromes (viral meningitis and some exanthems) are caused by many enterovirus serotypes; others are predominantly caused by certain enterovirus subgroups (eg, pleurodynia and myocarditis due to the group B coxsackieviruses).

The spectrum of diseases attributed to parechoviruses is similar to that of the echoviruses, including fever, respiratory tract infections, exanthems, viral meningitis, encephalitis, myocarditis, and serious neonatal infections [3-10].

Exanthems and enanthems—Coxsackieviruses, echoviruses, and parechoviruses cause a variety of exanthems, which sometimes are associated with enanthems. With the exception of hand-foot-and-mouth disease, these eruptions are not sufficiently distinctive in appearance to permit reliable etiologic diagnosis on clinical grounds alone.

Maculopapular eruptions—Generalized maculopapular eruptions commonly occur with enterovirus infections, particularly those due to echoviruses [11-13]. Most cases are nonspecific and cause the patient little or no distress. The prototypic "Boston exanthem" is characteristic of these rash illnesses whereby multiple cases of mild illness occur sequentially in families, with as many as one-quarter of the children in a household developing a rash [12]. Fever lasts 24 to 36 hours, and then declines simultaneously with the appearance of discrete, nonpruritic, salmon-pink macules and papules of approximately 1 cm diameter on the face and upper chest [14,15].

Hand, foot, and mouth syndrome—The hand, foot, mouth syndrome (HFM) is a common acute illness, affecting mostly children, which is characterized by 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 (picture 1andpicture 2andpicture 3andpicture 4andpicture 5) [16]. An atypical presentation, associated with outbreaks caused by coxsackievirus A6 and characterized by vesiculobullous lesions with wider cutaneous distribution and a higher risk of onychomadesis have been reported [17-19]. HFM caused by enterovirus A71 has been associated with severe illness, with concomitant central nervous system (CNS) disease, pulmonary edema and hemorrhage, and heart failure [20-24]. This is discussed in detail elsewhere. (See"Hand, foot, and mouth disease and herpangina: An overview".)

Herpangina—Coxsackie A virus is the etiologic agent of herpangina, a vesicular enanthem of the tonsillar fauces and soft palate that principally affects children 3 to 10 years of age. Oropharyngeal symptoms of sore throat are accompanied by fever and odynophagia. Most cases of disease occur during summer outbreaks [25]. (See"Hand, foot, and mouth disease and herpangina: An overview".)

Petechiae and purpura—Petechial and purpuric rashes have been described with echovirus 9 [13,25] and coxsackievirus A9 [26] infections. When these rashes with a hemorrhagic component occur, the illness is easily confused with meningococcal disease, especially if aseptic meningitis occurs simultaneously. Occasionally, cutaneous eruptions of coxsackievirus A9 disease have an urticarial nature [27]. (See"Fever and rash in the immunocompetent patient"and"Clinical manifestations and diagnosis of Rocky Mountain spotted fever".)

Central nervous system infections—Acute infection of the CNS occurs at all ages. Meningitis is by far the most common CNS manifestation. Both generalized and focal encephalitis occur less frequently. Certain enteroviruses (ie, polioviruses, enterovirus 71) preferentially target the motor nuclei and anterior horn cells of the brain and spinal cord, causing acute paresis of cranial and spinal nerves.

Viral (aseptic) meningitis—Aseptic meningitis affects persons of all ages but is most commonly observed in infants less than one year of age [28,29]. The enteroviruses cause more than 90 percent of cases in infants; the great majority is due to the group B coxsackieviruses and echoviruses [30]. When older children and adults are included, enteroviruses remain the most common cause of viral meningitis, accounting for well over 50 percent of all cases [31].

In infants, the characteristic symptoms and signs of meningitis are difficult to elicit by history and examination. The most common clinical manifestations are fever and irritability [32]. In practice, aseptic meningitis is often diagnosed during the clinical evaluation of febrile infants without an apparent source of fever.

In the older child and adult, aseptic meningitis presents with fever to 40ºC, headache, meningismus, nausea, and vomiting [29]. Symptoms of encephalitis complicate the course of aseptic meningitis in as many as 5 to 10 percent of patients who develop diminished consciousness or seizures.

The differential diagnosis for viral meningitis includes:

●Partially treated bacterial meningitis

●Parameningeal bacterial infection

●Brain abscess

●Tuberculous or fungal meningitis

●Meningitis caused by a spirochete such asBorrelia burgdorferi,Treponema pallidum, andLeptospiraspp

Complete recovery from viral meningitis is the rule. Most infants and children recover completely within three to seven days of onset, but symptoms often persist in adults for longer [33].

Encephalitis—Enteroviruses account for about 5 percent of all cases of acute encephalitis which undergo comprehensive diagnostic testing [34]. Numerous serotypes have been implicated as causes of encephalitis; coxsackievirus types A9, B2, and B5, and echovirus types 6 and 9 are the serotypes reported most often. Typically, enteroviruses isolated from encephalitis patients are representative of the serotype(s) concurrently circulating in the community. Enterovirus encephalitis occurs in all ages with a slight predilection for children and young adults. While clinical manifestations range from mild illness to fatal encephalitis, comparative studies suggest that enterovirus encephalitis is associated with less severe disease, shorter hospitalization, and better outcomes than encephalitis commonly caused by other viruses (eg, HSV, arboviruses) [34].

Acute paralysis—Poliomyelitis is an acute, febrile illness characterized by aseptic meningitis and weakness or paralysis of one or more extremities. Disease due to wild type poliovirus infection no longer occurs in the Western hemisphere, and a World Health Organization led international eradication program is making progress in the rest of the world. Very rare cases continue to occur in developed countries as a complication of live, attenuated oral polio vaccine use.

Sporadic cases of acute paralysis similar to paralytic poliomyelitis also occur with other enterovirus serotypes, the most important of which is enterovirus A71 [20,35]. Large outbreaks of paralytic disease associated with enterovirus A71 involving hundreds of cases, mostly in children less than six years old have been reported from eastern Europe and Russia [36,37], and more recently in Taiwan, Thailand, and China [21,22,38,39]. Some children have presented with brainstem encephalitis, non-cardiogenic pulmonary edema, and a rapidly fatal course [40-42].

Enterovirus D68 has also been implicated in rare cases of acute paralysis in the United States [43-45]. In the setting of a 2014 surge of respiratory illnesses due to enterovirus D68, there were reports of children with acute focal limb weaknessand/orcranial nerve dysfunction, with a mild to moderate lymphocytic pleocytosis in the cerebrospinal fluid (CSF) and nonenhancing grey matter spinal cord lesions on magnetic resonance imaging, similar to poliomyelitis [46,47]. Enterovirus D68 was identified in nasopharyngeal specimens of a subset of these patients, but not from the CSF of any cases. (See"Polio and infectious diseases of the anterior horn", section on 'Acute flaccid myelitis'.)

Ocular infections—Acute hemorrhagic conjunctivitis (AHC) is a highly contagious ocular infection characterized by pain, lid edema, and subconjunctival hemorrhage that is self-limited and rarely leads to permanent visual impairment. Worldwide pandemics caused by enterovirus D70 and coxsackie A24 have occurred mostly in tropical coastal areas [48]. Transmission occurs via indirect routes involving eye discharge, fingers, and fomites, with rapid spread enhanced by crowding and unsanitary conditions. Symptoms peak in two to three days, and the infection 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 can occur when AHC is caused by enterovirus D70.

Pleurodynia—Pleurodynia is an acute illness characterized by fever and paroxysmal spasms of the chest and abdominal muscles [49]. Most cases occur during localized summer outbreaks among adolescents and adults. Regional and nationwide outbreaks involving a large number of older children and young adults have been reported at infrequent intervals, often separated by decades. The role of the group B coxsackieviruses, the most important cause of epidemic pleurodynia, was established in 1949 [50,51]. Other agents rarely implicated in pleurodynia include echoviruses 1, 6, 9, 16, and 19 and group A coxsackieviruses 4, 6, 9, and 10 [52]. Pleurodynia sometimes mimics more serious diseases including bacterial pneumonia, pulmonary embolus, myocardial infarction, acute surgical abdomen, and herpes zoster infection. Most patients are ill for four to six days. Children have milder disease than adults, who are often confined to bed.

Myopericarditis—Cardiac involvement during enterovirus infection typically occurs in the form of myopericarditis, as enteroviruses typically affect both the subepicardial myocardium in addition to the pericardium [53]. Clinically, however, the signs of either myocarditis or pericarditis predominate [54]. The severity of myopericarditis varies from asymptomatic cardiac involvement to fulminant disease with intractable heart failure and death [55]. The group B coxsackieviruses are the most frequently implicated viral cause of myocarditis in the United States and Western Europe. (See"Etiology and pathogenesis of myocarditis"and"Etiology of pericardial disease".)

Respiratory disease—Enteroviral infections have been associated with a wide spectrum of respiratory illness. Various enteroviral serotypes can cause upper respiratory tract infections that are generally clinically indistinguishable from other infectious etiologies, with sore throat, cough,and/orcoryza.

Enterovirus D68, first isolated in 1962 from children with bronchiolitis and pneumonia, has since been noted to cause clusters of upper and lower respiratory infections, some of which can be severe, leading to mechanical ventilation [56,57]. In a cluster of cases first reported in Missouri and Illinois in 2014 and subsequently many other states in the US, severe infections were characterized by low-grade or absent fever, wheezing, dyspnea, hypoxia, and perihilar infiltrates and occurred predominantly in children with a prior history of asthma [57].

Acute noncardiogenic pulmonary edema has also been associated with severe enterovirus A71 encephalitis, thought to result from destruction of medullary vasomotor and respiratory centers with subsequent sympathetic activation, vasoconstriction, and overload of the pulmonary vascular bed [58]. (See'Acute paralysis'above.)

Infections in pregnancy—Pregnant women are frequently exposed to enteroviruses. The risk of infection is higher among those who do not have antibodies from earlier exposure to these viruses and for those who are exposed to young children (the primary spreaders of enteroviruses). Most enterovirus infections during pregnancy cause mild or no maternal illness. Enterovirus infections in pregnant women do not readily cross the placenta and cause fetal disease, nor is there an association with miscarriage or preterm birth [59]. However, rare cases of intrauterine fetal death from enterovirus infection and severe maternal abdominal pain suggestive of abruption have been reported [60,61]. Vertical transmission is much more likely to occur in the perinatal period. Strict adherence to good hygiene practices may help to decrease the risk of infection during pregnancy and around the time of delivery.

There is no strong evidence that maternal enterovirus infections cause congenital malformation even though a few reports have suggested a possible relationship with certain anomalies [62-64].

Infections in neonates—Neonates are uniquely susceptible to enterovirus disease. Although many enterovirus serotypes cause self-limited clinical syndromes in neonates (eg, aseptic meningitis, exanthems), some serotypes are capable of producing fulminant, frequently fatal disease in the newborn infant. The group B coxsackievirus serotypes 2 to 5 and echovirus 11 are most frequently associated with overwhelming, systemic neonatal infections. Although most neonatal enterovirus infections are acquired directly from the mother, some infections are acquired via nosocomial transmission. Infant-to-infant spread within nurseries probably occurs via the hands of personnel engaged in mouth care, gavage feeding, and other activities requiring close direct contact [65].

Most newborns with life-threatening enterovirus disease acquire the infection from a symptomatic mother in the perinatal period [66,67]; approximately 60 to 70 percent of mothers of infected infants develop a febrile illness during the last week of pregnancy [66,68]. Experimental evidence indicates that the fetus is relatively protected during maternal infection by the placenta [67], but the newborn has a high risk of infection [69,70] resulting from exposure to either virus-positive cervical secretions [71,72] or viremic maternal blood [73].

The outcome of neonatal infection is strongly influenced by the presence or absence of passively acquired maternal antibody specific for the infecting enterovirus serotype [70,74,75]. Thus, the timing of maternal infection in relation to development of maternal IgG antibody and delivery of the infant may be the most critical factor in determining the outcome of neonatal enterovirus infection.

Most neonates with generalized coxsackievirus and echovirus disease develop symptoms between three and seven days of life [66,76]. Early symptoms may be mild and nonspecific, including listlessness, anorexia, and transient respiratory distress. Approximately one-third of cases have a biphasic illness with a period of one to seven days of apparent well-being interspersed between the initial symptoms and the appearance of more serious manifestations.

Generalized enterovirus disease in the newborn most often occurs in one of two characteristic clinical syndromes: myocarditis or fulminant hepatitis. Neonatal myocarditis, which is often accompanied by encephalitis and sometimes by hepatitis, is characteristically a manifestation of group B coxsackievirus infection [77,78]. Fulminant hepatitis presents with hypotension, profuse bleeding, jaundice, and multiple organ failure. Echovirus 11 is responsible for a large proportion of cases, but there are well-documented cases of severe hepatitis in neonates resulting from echovirus serotypes 4, 6, 7, 9, 12, 14, 19, 20, 21, and 31 [66,79-83].

The management of neonatal enterovirus disease is supportive. Infants in congestive heart failure require judicious fluid management and administration of inotropic agents and diuretics. The profuse bleeding and coagulopathy that result from hepatic failure necessitate frequent replacement therapy with packed red blood cells, platelets, and fresh-frozen plasma.Vitamin Kshould be administered intravenously in pharmacologic doses.

Large doses of IVIG, which have been reported to improve outcome in at least one case [84], may be justified given the extremely poor prognosis. No antiviral agent is available in the United States or Canada to treat enterovirus infections.

Infections in immunocompromised patients—The enteroviruses cause persistent, sometimes fatal, infections in patients with hereditary or acquired defects in B lymphocyte function; most reported patients are children with X-linked agammaglobulinemia or adults with common variable immunodeficiency [85].

These persons have an increased risk of vaccine associated paralytic poliomyelitis when exposed to OPV viruses by direct administration of oral vaccine, or via contact with a vaccinee [86]. In one well-documented case, OPV infection is estimated to have persisted for approximately 22 years [87]. The existence of immunodeficient persons excreting virulent vaccine derived polioviruses is a threat to global poliomyelitis eradication and justification for development of an antiviral drug.

The non-polio enteroviruses also cause persistent CNS infections in these patients, in addition to a dermatomyositis-like syndrome, and chronic hepatitis. Most cases have been caused by echoviruses; single cases caused by group A coxsackievirus serotypes 4, 11, and 15 and by group B coxsackievirus serotypes 2 and 3 are recorded [85,88]. Nervous system manifestations may be absent, or there may be mild nuchal rigidity, headache, lethargy, papilledema, seizure disorders, motor weakness, tremors, and ataxia. These neurologic abnormalities may fluctuate in severity, disappear, or steadily progress.

An enterovirus can be repeatedly recovered from the CSF over a period of months to years. Enteroviruses have been recovered from many other sites in these patients, including brain, lung, liver, spleen, kidney, myocardium, pericardial fluid, skeletal muscle, and bone marrow [85]. In many persons, possibly a majority, the disease ends fatally. Autopsy findings have included chronic meningitis and encephalitis, with lymphocytic perivascular cuffing, focal loss of neurons, and gliosis of both gray and white matter.

Intravenous immunoglobulin (IVIG) replacement therapy appears to prevent most cases of chronic enterovirus infection in these patients. Use of IVIG for treatment has met only limited success, even when using IVIG lots with relatively high concentrations of specific antibody. Some patients have experienced clinical improvement when IVIG has been injected directly into the ventricles [85], but relapse of infection may occur even after long term intraventricular IVIG therapy. Anecdotal reports suggest that pleconaril may be more successful [87,89], but this experimental drug is no longer available.