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Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention

Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention
Author:
John F Modlin, MD
Section Editors:
Martin S Hirsch, MD
Morven S Edwards, MD
Deputy Editor:
Milana Bogorodskaya, MD
Literature review current through: Apr 2022. | This topic last updated: May 19, 2022.

INTRODUCTION — The human enteroviruses and parechoviruses are ubiquitous picornaviruses found throughout the world and are transmitted from person to person through fecal-oral contact and, less commonly, respiratory secretions [1].

Polioviruses, the prototypic enteroviruses, are the cause of paralytic poliomyelitis, a disease that has been eradicated in most high-income countries and targeted for worldwide eradication. The non-polio enteroviruses (comprising the group A and B coxsackieviruses, echoviruses, and “newer” enteroviruses) and the parechoviruses are responsible for a wide spectrum of disease in persons of all ages, although infection and illness disproportionately affect infants and young children.

The clinical manifestations, laboratory diagnosis, treatment, and prevention of non-polio enterovirus and parechovirus infections are reviewed in this topic. The microbiology, epidemiology, and pathogenesis of these infections are discussed separately. (See "Enterovirus and parechovirus infections: Epidemiology and pathogenesis".)

Poliovirus infection and prevention are discussed in detail elsewhere. (See "Poliomyelitis and post-polio syndrome" and "Poliovirus vaccination".)

ENTEROVIRUS NOMENCLATURE — Enterovirus taxonomy based on ribonucleic acid (RNA) sequence now specifies that the serotypes designated as "newer enteroviruses" under the original classification scheme include the letter (A, B, C, or D) that identifies the species to which the serotype belongs (eg, enterovirus D68). The terminology for the other serotypes in the original classification scheme remains unchanged (eg, polioviruses, coxsackie A viruses, coxsackie B viruses, and echoviruses). (See "Enterovirus and parechovirus infections: Epidemiology and pathogenesis", section on 'Classification'.)

The parechoviruses share many biological, clinical, and epidemiologic characteristics with the enteroviruses, but differ sufficiently in genomic sequence to be classified as a separate genus.

CLINICAL FEATURES OF ENTEROVIRUS INFECTIONS

Spectrum of disease — More than 90 percent of infections caused by the non-polio enteroviruses are asymptomatic or result only in an undifferentiated febrile illness [2,3]. When more serious disease occurs, the clinical spectrum and disease severity vary with the age, sex, and immune status of the host. Some clinical syndromes (viral meningitis and some exanthema) are caused by numerous enterovirus serotypes, while others appear limited to specific enterovirus subgroups (eg, hand, foot, and mouth disease [HFMD] with enterovirus A71 and some group A coxsackieviruses, and pleurodynia and myocarditis with the group B coxsackieviruses).

Incubation period and period of infectivity — The incubation period for enterovirus infections is difficult to measure and varies with different clinical syndromes. Careful studies during polio outbreaks showed that fever and other nonspecific clinical manifestations developed three to five days after exposure [4]. A similar incubation period was observed following a common source outbreak of nonpolio enterovirus infections acquired from swimming in contaminated water [5].

Infectious virus is shed from the upper respiratory tract for one to three weeks and from the feces for three to eight weeks. Maximum communicability occurs during the first two weeks of infection [6].

Exanthema and enanthems — Coxsackieviruses and echoviruses cause a variety of exanthema, which are sometimes associated with enanthems. Except for HFMD, these eruptions may mimic other known causes of rash illness and are not sufficiently distinctive in appearance to permit reliable etiologic diagnosis on clinical grounds alone.

Hand, foot, and mouth disease – HFMD is a common acute illness affecting mostly children and 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 1A-E) [7]. HFMD caused by enterovirus A71 is uncommonly associated with severe central nervous system (CNS) disease, including brainstem encephalitis, pulmonary edema and hemorrhage, and heart failure [8-12]. An atypical presentation of HFMD caused by coxsackievirus A6 and characterized by vesiculobullous lesions with wider cutaneous distribution and a higher risk of onychomadesis (nail shedding) has been observed in the United States and elsewhere [13-15]. HFMD is discussed in detail elsewhere. (See "Hand, foot, and mouth disease and herpangina", section on 'Hand, foot, and mouth disease'.)

Herpangina – The group A coxsackieviruses are the principal cause 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 [16]. This is discussed in detail elsewhere. (See "Hand, foot, and mouth disease and herpangina", section on 'Herpangina'.)

Maculopapular eruptions – Generalized maculopapular eruptions commonly occur with enterovirus infections, particularly those due to echoviruses [17-19]. Most cases are nonspecific and cause the patient little or no distress. The prototypic "Boston exanthem" is characteristic of these rash illnesses, in which multiple cases of mild illness occur sequentially in households with young children [18]. 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 [20,21].

Petechiae and purpura – Petechial and purpuric rashes have been described with echovirus 9 [16,19] and coxsackievirus A9 [22] infections. When these rashes have a hemorrhagic component, the illness may be confused with meningococcal disease, especially if aseptic meningitis occurs simultaneously. (See "Fever and rash in the immunocompetent patient", section on 'Selected fever and rash emergencies'.)

Urticaria-like eruptions – Occasionally, cutaneous eruptions of coxsackievirus A9 disease have an urticarial appearance [23]. (See "New-onset urticaria".)

Central nervous system infections — Acute enterovirus infection of the CNS occurs at all ages. Meningitis is the most common CNS manifestation. Both generalized and focal encephalitis occur less frequently. Certain enteroviruses (ie, polioviruses, enterovirus D68, enterovirus A71) preferentially target motor nuclei within the brainstem and spinal cord, causing acute paresis of cranial and spinal nerves. These are discussed in further detail in the following sections.

Viral (aseptic) meningitis — Viral meningitis, commonly referred to as “aseptic meningitis”, affects persons of all ages but is most commonly observed in infants less than one year of age [24,25]. The enteroviruses cause more than 90 percent of viral meningitis cases in infants; the majority are due to species B enteroviruses, which include the group B coxsackieviruses and most echoviruses [26]. 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 [27].

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 [28]. In practice, viral meningitis is often encountered during the clinical evaluation of febrile infants without an apparent source of fever. (See "Viral meningitis in children: Clinical features and diagnosis", section on 'Clinical features'.)

In the older child and adult, viral meningitis presents with fever, headache, photophobia, stiff neck, nausea, and vomiting [29] (see "Aseptic meningitis in adults"). Pharyngitis and other upper respiratory symptoms are common. Signs and symptoms of encephalitis complicate the course of viral meningitis in as many as 5 to 10 percent of patients who develop diminished consciousness or seizures. (See 'Encephalitis' below.)

Complete recovery from viral meningitis without neurologic sequelae is the rule [30]. Most infants and children recover completely within three to seven days of symptom onset, but symptoms often persist longer in adults [29].

Encephalitis — Enteroviruses cause approximately 5 percent of all cases of acute encephalitis that have undergone comprehensive diagnostic testing [31]. 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. Clinical manifestations are generally indistinguishable from other causes of acute encephalitis and range from mild to fatal illness. However, 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, herpes simplex viruses, arboviruses) [31]. (See "Viral encephalitis in adults".)

Acute paralysis and brainstem encephalitis — The syndrome of acute motor neuron weakness (also known as acute flaccid paralysis or acute flaccid myelitis [AFM], among other terms) has been reported with many enterovirus serotypes, but only a small number are associated with endemic and epidemic paralysis: poliovirus types 1, 2, and 3, enterovirus D68, and enterovirus A71. These viruses target motor neurons in the brainstem and spinal cord.

Most patients experience a prodromal illness with fever, pharyngitis, or other respiratory symptoms followed by an interval of up to 10 days during which the initial symptoms often subside. Subsequent onset of weakness may be accompanied by recurrent fever, headache, meningismus, and discomfort in the back and limbs. The weakness is characteristically asymmetric and affects proximal more than distal muscles; loss of deep tendon reflexes is characteristic, and about one-third of patients experience cranial nerve weakness. The paresis may progress over one to three days, becoming more severe and involving additional limbs. Recovery of muscle function is generally slow and often incomplete, leaving challenging residual motor deficits that require long-term management.

Poliovirus – Disease due to wild-type poliovirus infection is now limited to Afghanistan and Pakistan and is close to complete eradication. However, outbreaks of type 2 vaccine-derived polioviruses have emerged in these two countries and across sub-Saharan Africa following the discontinuation of type 2 oral poliovirus vaccine (OPV) in 2016 [32]. Additionally, rare cases of vaccine-associated paralytic polio continue to occur in countries that continue to use live attenuated oral polio vaccine for routine infant immunization and for control of wild-type polio. (See "Poliomyelitis and post-polio syndrome", section on 'Poliomyelitis'.)

Enterovirus A71 – Motor neuron disease caused by enterovirus A71 is associated with HFMD in some locations [8,33]. Large outbreaks involving hundreds of cases, mostly in children younger than six years old were initially reported in Eastern Europe and Russia [34,35] and occur regularly in Taiwan, Thailand, and China [33,36]. Sporadic smaller outbreaks have also been observed in the United States [8,37,38]. Enterovirus 71-associated acute flaccid myelitis is distinguished by a common association with concurrent HFMD and occasional myoclonus, ataxia, and autonomic instability that may represent brainstem encephalitis [39]. In young children, a severe form of enterovirus 71 brainstem encephalitis accompanied by noncardiogenic pulmonary edema and leading to a rapidly fatal course may occur [40-42].

Enterovirus D68 – Enterovirus D68 has been implicated in rare cases of AFM in the United States, Europe, and other locations [43-46]. Concurrent with a 2014 surge of respiratory illnesses due to enterovirus D68 in the United States, there were reports of children who presented with fever, gait disturbance, and neck, back, and limb pain who progressed to acute focal limb weakness and/or cranial nerve dysfunction. These children had mild to moderate lymphocytic pleocytosis in the cerebrospinal fluid (CSF) and non-enhancing gray matter spinal cord lesions on magnetic resonance imaging [47,48]. Enterovirus D68 was identified in nasopharyngeal specimens of a subset of these patients, but rarely from the CSF [45]. Episodic increases in AFM have since occurred in 2016 and 2018 in the United States and elsewhere, with a majority of cases associated with enterovirus D68 [49]. (See "Acute flaccid myelitis", section on 'Enterovirus D68'.)

Other enterovirus serotypes rarely cause sporadic acute paralysis disease [50]. Such cases are usually milder than those associated with the polioviruses and enterovirus serotypes A71 and D68, and permanent paralysis is uncommon [51].

Ocular infections — Acute hemorrhagic conjunctivitis (AHC) is a highly contagious ocular infection characterized by pain, lid edema, and subconjunctival hemorrhage. It is self-limited and rarely leads to permanent visual impairment. A pathogenic variant of coxsackievirus A24 that emerged in Southeast Asia as the main cause of AHC in 1970 is responsible for extensive outbreaks in tropical coastal areas and worldwide pandemic spread [52]. 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 enteroviral illness characterized by fever and paroxysmal spasms of the chest and abdominal muscles [53]. Most cases occur during localized summer outbreaks among adolescents and adults. Regional and nationwide outbreaks involving 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 [54,55]. Other agents rarely implicated in pleurodynia include echovirus serotypes 1, 6, 9, 16, and 19 and group A coxsackievirus serotypes 4, 6, 9, and 10 [56].

Pleurodynia can mimic 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, affecting both the subepicardial myocardium in addition to the pericardium [57]. Clinically, however, the signs of either myocarditis or pericarditis can predominate [58]. (See "Acute pericarditis: Clinical presentation and diagnosis" and "Clinical manifestations and diagnosis of myocarditis in children", section on 'Clinical manifestations' and "Clinical manifestations and diagnosis of myocarditis in adults", section on 'Clinical manifestations'.)

The severity of enterovirus myopericarditis varies from asymptomatic infection to fulminant disease with intractable heart failure and death [59]. The group B coxsackieviruses are the most frequently implicated viral cause of myocarditis in the United States and Western Europe. (See "Etiology of pericardial disease" and "Myocarditis: Causes and pathogenesis".)

Respiratory disease — Enterovirus infections have been associated with a wide spectrum of respiratory illness. Various enterovirus serotypes can cause upper respiratory tract infections that are generally clinically indistinguishable from other infectious etiologies, with sore throat, cough, and/or coryza. (See "The common cold in children: Clinical features and diagnosis" and "The common cold in adults: Diagnosis and clinical features".)

Enterovirus D68, first isolated in 1962 from children with bronchiolitis and pneumonia, has emerged to cause periodic regional outbreaks of upper and lower respiratory infections, sometimes complicated by respiratory failure or acute flaccid myelitis [60-64]. Typical symptoms and signs include low-grade or absent fever, wheezing, dyspnea, hypoxia, and perihilar infiltrates on chest radiograph. Children with asthma are disproportionately affected [61].

Acute noncardiogenic pulmonary edema has also been associated with severe enterovirus A71 encephalitis, predominately in infants and young children. It is thought to result from destruction of medullary vasomotor and respiratory centers with subsequent sympathetic activation, vasoconstriction, and overload of the pulmonary vascular bed [65]. (See 'Acute paralysis and brainstem encephalitis' above.)

Infections in special populations

Pregnant females — Other than an increased risk of paralytic poliomyelitis reported in the 1950s, enterovirus infections have not generally been associated with severe outcomes in pregnant females. Although rare cases of intrauterine fetal death are reported [66], experimental data suggest that the placental barrier reduces risk of fetal infection. This finding may explain the paucity of evidence linking developmental abnormalities to maternal enterovirus infection [67,68].

The risk of complications of pregnancy are greatest when infection occurs near term. Sudden onset of fever and severe abdominal pain mimicking abruptio placentae and attributed to mesenteric adenitis as well as intrauterine fetal death have been reported with maternal echovirus late in pregnancy [66,69]. In addition, there is a substantial risk of vertical transmission to the newborn infant when maternal infection occurs in the peripartum period [70].

Neonates — Neonates are uniquely susceptible to enterovirus disease, which can be self-limited (eg, viral meningitis, exanthema) or fulminant and life-threatening. The group B coxsackievirus serotypes 2 to 5 and echovirus 11 have most frequently been associated with overwhelming systemic neonatal infections.

Newborns presenting with serious enterovirus disease typically acquire the infection from a symptomatic mother in the perinatal period [71,72]; up to 60 percent of mothers of infected infants report a febrile illness during the last week of pregnancy [71,73]. However, infection may also be acquired via nosocomial transmission and spread through nurseries by caregivers engaged in mouth care, gavage feeding, and other activities requiring direct contact [74].

Onset of perinatally acquired group B coxsackievirus and echovirus disease occurs between three and seven days of life [71,75]. Early clinical manifestations 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.

Systemic enterovirus disease in the newborn typically 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 [76,77]. Fulminant hepatitis presenting with hypotension, profuse bleeding, jaundice, and multiple organ failure has been documented with infection with echovirus serotypes 4, 6, 7, 9, 11, 12, 14, 19, 20, 21, and 31 [71,78-82].

The outcome of neonatal infection is strongly influenced by the presence or absence of passively acquired maternal neutralizing antibody [68,83,84]. Thus, the timing of maternal infection in relation to development of maternal IgG antibody and delivery of the infant is a critical factor in determining the outcome of neonatal enterovirus infection.

Immunocompromised patients — Enteroviruses cause persistent, often fatal infections in patients with hereditary or acquired defects in B lymphocyte function; most reported patients are children with X-linked agammaglobulinemia or severe combined immunodeficiency and adults with common variable immunodeficiency [85]. Disseminated enterovirus infections contributing to fatal outcomes have also been described in hematopoietic cell allograft recipients in the post-transplant period [86-88]. Most cases have been attributed to echoviruses; single cases caused by group A coxsackievirus serotypes 4, 11, and 15, by group B coxsackievirus serotypes 2 and 3, and by enterovirus D68 are also reported [85,89,90].

In these patients, persistent CNS enterovirus infection may manifest as chronic meningitis, lethargy, papilledema, seizures, motor weakness, tremors, and ataxia. Persistent infection of skeletal muscle, the liver, and other soft tissues may lead to a dermatomyositis-like syndrome and/or chronic hepatitis. Signs and symptoms of chronic infection may fluctuate in severity, resolve spontaneously, or steadily progress to a fatal outcome.

Enteroviruses can be repeatedly recovered from the CSF over a period of months to years and have been recovered from many other sites, including brain, lung, liver, spleen, kidney, myocardium, pericardial fluid, skeletal muscle, and bone marrow [85]. Postmortem findings include meningitis and encephalitis with lymphocytic perivascular cuffing, focal loss of neurons, and gliosis of both gray and white matter.

CLINICAL FEATURES OF PARECHOVIRUS INFECTIONS — Parechoviruses are associated with a spectrum of disease similar to the echoviruses (ie, febrile syndromes, respiratory tract infections, exanthema, viral meningitis, encephalitis, myocarditis, and serious neonatal infections) [91-97]. Parechovirus serotypes 1 and 3 are most commonly associated with disease [95,98,99].

Commonly reported, self-limited presentations include prolonged high fever in infants younger than six months of age leading to a clinical evaluation for bacterial sepsis [91,94,100-103] and a distinctive exanthem of the extremities, with palmar and plantar erythema associated with serotype 3 infection [104,105]. Laboratory abnormalities may include leukopenia and mild elevation in hepatic transaminases [93,106].

More serious infections have been observed in neonates with parechovirus serotype 3 infection, including meningoencephalitis and fulminant hepatitis [93,106]. A distinctive form of neonatal encephalitis with white matter abnormalities that mimic hypoxic-ischemic encephalopathy has been described in association with parechovirus serotype 3 infection [10,107].

LABORATORY DIAGNOSIS

Indications and test selection — Most enterovirus and parechovirus infections are diagnosed on clinical manifestations alone and are self-limited, reducing the need for laboratory testing. A laboratory diagnosis is warranted for more severe infections when identification of the causative organism has management implications, as for some central nervous system infections, myopericarditis, neonatal infection, and infections in immunocompromised patients. Laboratory diagnosis is also important to assist a public health response during disease outbreaks.

Detection of virus in blood, cerebrospinal fluid (CSF), pericardial fluid, lacrimal fluid, or tissue by reverse transcriptase polymerase chain reaction (RT-PCR) is diagnostic of infection. A positive RT-PCR test from stool is supportive but less definitive because detection may represent prolonged carriage from a previous infection. In countries where oral poliovirus vaccine (OPV) is used, OPV viruses are widely transmitted and may confound positive results in both cell culture and PCR assays.

Molecular methods, such as RT-PCR, are typically used for enterovirus or parechovirus detection [108-110]. They are rapid, sensitive, and widely available in hospital and commercial laboratories, but most assays do not identify the serotype. (See 'Reverse transcriptase polymerase chain reaction' below.)

Cell culture-based methods (eg, virus isolation, neutralizing antibody titers) may not be available in many hospital laboratories but may be required when typing of the isolate is important (eg, for public health purposes). Serology is not useful for the diagnosis of acute infection. (See 'Viral isolation (cell culture)' below and 'Serology' below.)

Reverse transcriptase polymerase chain reaction — Enterovirus RNA can be detected by RT-PCR in respiratory secretions, urine, and serum in many enterovirus syndromes, and submission of specimens from multiple sites may enhance the likelihood of detection [3,111]. Viral RNA is also readily detected in CSF by RT-PCR in most cases of enterovirus meningitis, for which RT-PCR is more rapid and more sensitive than cell culture. Viral RNA is more difficult to identify in CSF in cases of meningitis and brainstem encephalitis caused by enterovirus D68 and enterovirus A71 [38,112,113]. As above, a positive PCR from stool can represent acute or prior infection. (See 'Indications and test selection' above.)

Commercially available molecular methods are rapid, sensitive, and economical. However, they are generally limited to identifying viral RNA at the species (eg, enterovirus) level and not by serotype, as most rely on primers derived from the highly conserved 5'-noncoding region (NCR) of the enterovirus genome. Enteroviruses are also not distinguished from rhinoviruses in commercial multiplex respiratory virus PCR assays due to sequence homology in the 5'-NCR. When serotype identification is required, specimens should be submitted to a reference laboratory where an isolate can be amplified in cell culture and identified at the serotype level with the use of special PCR primers or genomic sequencing [114-116]. (See 'Viral isolation (cell culture)' below.)

Parechoviruses are not detected by conventional enterovirus RT-PCR primers. However, primers that identify all known parechovirus serotypes can be synthesized, and combined enterovirus-parechovirus RT-PCR assays have been developed [117,118].

Viral isolation (cell culture) — Cell culture is labor intensive and expensive, and culture in multiple cell lines is required for optimal sensitivity [119]. However, recovery of an isolate in cell culture permits typing of the isolate for clinical, epidemiologic, and research purposes.

The characteristic enterovirus cytopathic effect (CPE) typically requires two to six days to develop in primary cell culture [119-121]. Indirect immunofluorescence with a broadly reactive monoclonal antibody may be used to confirm the virus causing the CPE [122].

Serology — In general, serology is not used for the diagnosis of acute enteroviral disease except when infection with a specific serotype is suspected. In such cases, both acute and convalescent serum specimens separated by a minimum of four weeks are required. The diagnosis of acute infection can be made retrospectively with a fourfold or greater increase in antibody titers between acute and convalescent specimens. Serum IgM antibody to the group B coxsackieviruses can often be detected early in the course of illness, but positive test results are not serotype specific [123,124].

The microneutralization test is the most widely employed method for the determination of antibodies to enteroviruses. Because microneutralization is serotype specific, it has limited utility in the routine diagnosis of non-polio enterovirus and parechovirus infections. Type-specific immunoassays are offered by commercial laboratories for measurement of antibodies against the more common enterovirus serotypes, but these assays are rarely used or useful due to cross reactivity and poor standardization.

TREATMENT

Supportive care — Symptomatic and supportive care of patients with syndromes associated with enterovirus infections are discussed elsewhere.

(See "Hand, foot, and mouth disease and herpangina", section on 'Management'.)

(See "Viral meningitis in children: Management, prognosis, and prevention" and "Aseptic meningitis in adults".)

(See "Acute viral encephalitis in children: Treatment and prevention" and "Viral encephalitis in adults", section on 'Empiric therapy'.)

(See "Poliomyelitis and post-polio syndrome", section on 'Management and prognosis'.)

(See "Acute flaccid myelitis", section on 'Treatment'.)

(See "Treatment and prognosis of myocarditis in children" and "Treatment and prognosis of myocarditis in adults".)

Antiviral therapy for severe cases — Most enterovirus and parechovirus infections are self-limited and do not require specific therapy. Potential life-threatening exceptions include fulminant neonatal infection, severe myocarditis, chronic infection in B cell-immunodeficient patients, and disseminated infections in patients with hematologic malignancies. Unfortunately, therapeutic options, even for these indications, are limited. In such cases, an expert in treating enterovirus infections should be consulted for assistance with management, including potential procurement of experimental antiviral drugs and decisions about intravenous immunoglobulin (IVIG) use.

Antiviral drugs — Antiviral drugs with activity against enteroviruses have limited clinical availability; in the United States, there are none that are US Food and Drug Administration approved. For patients with life-threatening infections, we explore whether an experimental antiviral drug or drugs (such as capsid inhibitors) are available under an investigational new drug (IND) application. Availability through IND is not consistent, however, and depends on the manufacturer; as of 2021, an antiviral drug for enteroviruses was not available through IND in the United States.

Capsid inhibitors, which impair viral attachment and uncoating, have activity against many enteroviruses, but their limited availability minimize their clinical utility. One capsid inhibitor, pocapavir (V-073, formerly SCH 48973), an orally administered drug under development to treat chronic enterovirus infections, reduced the duration of poliovirus vaccine virus excretion in a placebo-controlled randomized trial of healthy adults given an oral poliovirus vaccine challenge, although resistant virus developed in many during the trial [125]. Pocapavir is available only for poliovirus infections in B cell-deficient patients.

Pleconaril, an orally administered capsid inhibitor with a favorable pharmacokinetic profile, has been tested clinically against a spectrum of enterovirus and rhinovirus infections, including serious enterovirus infections. However, pleconaril is not currently available for systemic administration. In a trial of 61 neonates with suspected enterovirus disease who were randomly assigned to seven days of pleconaril or placebo, there was a trend toward more rapid viral clearance and lower overall mortality among pleconaril-treated infants (23 versus 44 percent with placebo) [126]. Limitations of this study included early termination related to slow enrollment and allowance of concomitant use of IVIG at the discretion of the clinician, both of which may have attenuated the observed efficacy of pleconaril. Other clinical trials with pleconaril include two combined studies of approximately 200 patients with enterovirus meningitis who were randomly assigned to pleconaril or placebo; patients in the treatment group had a modest benefit (shorter duration of headache by one to two days among participants with more severe symptoms) [127].

Intravenous immunoglobulin — We suggest not routinely using IVIG for enteroviral infections. However, for life-threatening infections, given the risk of death and the lack of other options, it is reasonable to administer IVIG on a case-by-case basis with the understanding that there is no clear evidence of benefit.  

Infection in B cell-immunodeficient patients – Although IVIG replacement therapy appears to prevent enterovirus infection in patients with B-cell immunodeficiency, use of IVIG for treatment of chronic enterovirus infections in these patients has had only limited success, even when using IVIG lots with relatively high concentrations of specific neutralizing antibody [85,128]. Some patients with chronic meningoencephalitis 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. Very limited experience suggests that antiviral therapy, if available, may be more successful in these patients [129,130]. (See 'Antiviral drugs' above.)

Neonatal infection – Evidence for IVIG efficacy in neonatal enterovirus infection is also mixed. Favorable outcomes attributed to IVIG have been described in individual case reports [131]. Additionally, in a retrospective study of 67 cases of culture-confirmed neonatal enterovirus infection, in which 41 infants received IVIG, receipt of IVIG within the first three days of illness was independently associated with survival [132]. However, a randomized, placebo-controlled trial of IVIG given at a dose of 750 mg/kg found neither clinical benefit nor reduction in viremia among the 16 enterovirus-infected infants ≤14 days of age enrolled in the study [133].

Acute myocarditis – One study relying on historical controls and another prospective, nonblinded study have each suggested a benefit of IVIG in acute myocarditis in children [134,135]. However, a single randomized trial of IVIG in adults with acute cardiomyopathy or myocarditis, which may have included only a small proportion of patients with acute enterovirus infection, showed no clinical benefit [136]. Furthermore, a systematic review of IVIG for patients of all ages with acute myocarditis, also with multiple possible etiologies, did not find sufficient evidence to recommend IVIG use [137]. (See "Treatment and prognosis of myocarditis in adults", section on 'Overview of therapy for lymphocytic myocarditis' and "Treatment and prognosis of myocarditis in children", section on 'Intravenous immune globulin'.)

PREVENTION

General measures — Simple hygienic measures, such as hand washing, are important to prevent the spread of enteroviruses and parechoviruses [138]. As with other nonenveloped viruses, alcohol-based hand sanitizers may not be optimally effective for enteroviruses [139].

In hospitalized patients, standard precautions are indicated, except in diapered or incontinent children, among whom contact precautions should be used for duration of illness and to control institutional outbreaks [140].

In outbreak settings, as in the surge of enterovirus D68 respiratory cases in the United States in 2014, standard, contact, and droplet precautions for suspect cases in health care settings have been recommended to try to prevent spread of the infection [61].

Pregnant women — Pregnant women near term should be advised to avoid contact with individuals suspected of having an enterovirus illness due to a risk of perinatal complications, including severe neonatal disease. (See 'Pregnant females' above.)

Vaccines — Vaccines against poliovirus and enterovirus are available.

Poliovirus − Poliovirus vaccines are administered worldwide. Only inactivated poliovirus vaccine is US Food and Drug Administration approved in the United States. (See "Poliovirus vaccination".)

Enterovirus − Three inactivated enterovirus A71 vaccines are licensed in China; as demonstrated in randomized clinical trials and other studies, these have high protective efficacy against the predominant C4 genotype circulating in that country [141-145]. The efficacy of these vaccines in other parts of the world, where other genotypes predominate, is unknown. Other inactivated enterovirus A71 vaccines are under investigation. In a randomized, multicenter, phase III trial of 3663 children aged 2 to 71 months, those who received the B4 genotype-based enterovirus A71 vaccine had zero infections at 14 months of follow-up compared with 22 infections in the placebo group (adjusted vaccine efficacy 96.8 percent) [146]. Many of the infections in the unvaccinated group were due to non-B4 genotypes (eg, B5 and C4), suggesting cross-protective efficacy against other genotypes. Although serious adverse events were reported by 15.5 percent of participants, only two were deemed possibly vaccine related: one case of fever and one case of urticaria.

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Basics topics (see "Patient education: Hand, foot, and mouth disease and herpangina (The Basics)" and "Patient education: Enterovirus D68 (The Basics)")

SUMMARY AND RECOMMENDATIONS

Clinical features of enteroviruses − The human enteroviruses include polioviruses, group A and B coxsackieviruses, echoviruses, and enteroviruses. Most infections caused by the nonpolio enteroviruses are asymptomatic or result in an undifferentiated febrile illness. Other clinical manifestations of infection include exanthems and enanthems, central nervous system (CNS) involvement, paralysis, ocular infection, pleurodynia, and myopericarditis. (See 'Clinical features of enterovirus infections' above.)

Enteroviruses cause a variety of exanthema, which are sometimes associated with enanthems. Hand, foot, and mouth syndrome, due to the group A coxsackieviruses and enterovirus A71, is characterized by oral vesicles on the buccal mucosa and tongue, and small tender lesions on the hands, feet, and other areas (picture 1A and picture 1B). Herpangina is a vesicular enanthem of the tonsillar fauces and soft palate caused by several different enterovirus serotypes. Maculopapular, petechial, and purpuric, and urticarial eruptions have also been described. (See 'Exanthema and enanthems' above and "Hand, foot, and mouth disease and herpangina".)

Viral meningitis is the most common manifestation of enteroviral CNS disease. Among infants, meningitis is most frequently due to species B enteroviruses (group B coxsackieviruses and most echoviruses). Encephalitis occurs less frequently. Certain enteroviruses (ie, polioviruses, enterovirus D68, enterovirus A71) cause acute paresis of cranial and spinal nerves. Ocular infections are associated with serotype enterovirus D70 and coxsackie A24 viruses. (See 'Central nervous system infections' above and 'Ocular infections' above.)

Pleurodynia is an acute illness characterized by fever and paroxysmal spasms of the chest and abdominal muscles.

Cardiac involvement of enterovirus infection typically occurs in the form of myopericarditis. The group B coxsackieviruses are the most important cause of pleurodynia and myopericarditis. (See 'Pleurodynia' above and 'Myopericarditis' above.)

The risks of pregnancy complication are greatest when infection occurs near term. Neonates are uniquely susceptible to enterovirus infection and may develop myocarditis or fulminant hepatitis following perinatal exposure.

In individuals with B lymphocyte dysfunction, enteroviruses can cause persistent disseminated infection. (See 'Infections in special populations' above.)

Clinical features of parechoviruses − Parechoviruses are associated with a spectrum of disease similar to the echoviruses (ie, febrile syndromes, respiratory tract infections, exanthema, viral meningitis, encephalitis, myocarditis, and serious neonatal infections). Serotypes 1 and 3 are most commonly causes of parechovirus infection. (See 'Clinical features of parechovirus infections' above.)

Diagnosis − Laboratory diagnosis is warranted when identification of the causative organism has management implications, as for some CNS infections, myopericarditis, neonatal infection, and infections in immunocompromised patients, or when there are public health implications. Reverse transcriptase polymerase chain reaction is typically used for enterovirus or parechovirus detection. Cell culture-based methods are useful when isolate serotyping is important. (See 'Laboratory diagnosis' above.)

Treatment − Most enterovirus infections are self-limited and do not require specific therapy apart from symptomatic and supportive care. For life-threatening infections, such as fulminant neonatal infection, severe myocarditis, chronic infection in B cell-immunodeficient patients, and disseminated infections in patients with hematologic malignancies, therapeutic approaches are limited and an expert in managing enteroviral infections should be consulted. Antiviral drugs with activity against enteroviruses may be intermittently available under an investigational new drug application (but as of 2021, were not available). We suggest not routinely using intravenous immunoglobulin (IVIG) (Grade 2C). A clear clinical benefit has not been demonstrated. However, it is reasonable to administer IVIG for life threatening infections on a case by case basis, given the high potential for mortality and lack of other options. (See 'Treatment' above.)

General preventive measures − Hand washing is important to prevent the spread of infection. Pregnant women near term should be advised to avoid contact with individuals suspected of having an enteroviral illness, if possible. (See 'Prevention' above.)

Vaccines − Effective vaccines against nonpolio enteroviruses are not yet clinically available outside of China. Several inactivated genotype C4 enterovirus A71 vaccines appear effective and are licensed in China, although the efficacy of these vaccines in other parts of the world, where other genotypes predominate, is unknown. (See 'Prevention' above.)

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