Herpangina

Practice Essentials

Herpangina is a very contagious acute viral infection characterized by small ulcerative or vesicular lesions in the posterior oropharynx. It primarily is seen in children but also affects newborns, adolescents, and young adults. Herpangina mostly occurs during the summer months. It is caused by 22 enterovirus serotypes, and most often is linked to the Coxsackie B virus serotype in the United States. Herpangina may occur along with an enteroviral exanthem and a number of neurological conditions, including aseptic meningitis, acute flaccid paralysis, and encephalitis.^[1]

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Background

Herpangina is an acute febrile illness associated with small vesicular or ulcerative lesions on the posterior oropharyngeal structures (enanthem). Herpangina typically occurs during the summer and usually develops in children, occasionally occurring in newborns, adolescents, and young adults. Herpangina is one of many manifestations of enterovirus infection and can occur in association with enteroviral exanthem, aseptic meningitis, encephalitis, acute flaccid paralysis, and other clinical syndromes.

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Pathophysiology

Herpangina is a pharyngeal infection typically caused by various enteroviruses. In recent years, coxsackievirus A16, enterovirus 71, and coxsackievirus B have been implicated most often. Less-common causes include echovirus, parechovirus 1, adenovirus, and herpes simplex virus (HSV).^{[2, 3]} Enterovirus 71 has emerged as an important public problem, causing severe clinical illness, encephalomyelitis, and potentially death in young children, particularly in Southeast Asia.^{[4, 5, 40, 41]}  Enteroviruses that cause herpangina belong to the Picornaviridae family.

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Coxsackievirus B4 virions under electron microscopy. Courtesy of Centers for Disease Control and Prevention (CDC).

EV-71 genotypes B4, B5, and C4 in Southeast Asia emerged in the early 2000s as causing pediatric encephalitis, aseptic meningitis, myocarditis, poliomyelitis-like paralysis, and neonatal sepsis with neurogenic cardiopulmonary collapse.

The severity of hand-food-and-mouth-disease (HFMD) can be graded from 1 to 4 based on a Taiwanese system.^{[40, 41]}  Grades 2b-4 are indicators of severe disease warranting hospitalization:

• Grade 1 - Uncomplicated illness with fever, vesicles in the oral mucosa, and vesicles or papules on hands, feet, and buttocks.
• • Grade 2a - Myoclonus reported by the caregiver.
  • Grade 2b - Myoclonus is observed by a physician. 

   

  

   
• Grade 3 - Autonomic dysfunction manifesting with fever unresponsive to antipyretics, hypertension, and persistent tachycardia.
• Grade 4 - Cardiopulmonary dysfunction manifesting with pulmonary edema or hemorrhage, cytokine storm, and cardiorespiratory collapse.

Risk factors for postinfectious neurologic sequelae appear to include myoclonic jerks over 4 times per night. Age younger than 3 years and fever lasting 3 days or longer have been associated with encephalitis in enterovirus 71 infection.^{[6, 7, 8]}

Although herpangina generally is a mild disease in adults, infection during pregnancy has been associated with a herpangina associated with a 2.29-, 1.67-, and 1.63-fold increased risk for low birth weight, preterm delivery, and small-for-gestational-age infants, respectively.^[9]

Viruses that cause herpangina typically are spread via the fecal-oral route, although they may spread via the respiratory route or through fomites. Freshwater sources (eg, lakes) may act as reservoirs for transmission.

Herpangina typically has an incubation period of 4-14 days. Viremia occurs after inoculation and subsequently results in distant sites of infection. Viral replication at these secondary sites leads to characteristic clinical symptoms and oropharyngeal lesions. Bilateral, anterior, cervical lymphadenopathy may occur, resulting from infection of the posterior oropharynx. Coxsackievirus A may be recovered from the nasopharynx, feces, blood, urine, and cerebrospinal fluid (CSF). After clinical symptoms have resolved, asymptomatic enteroviral infection may persist in the gastrointestinal tract.

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Epidemiology

Frequency

United States

Enteroviral infections are most common during the summer and fall in temperate climates and occur year-round in tropical climates.

International

Enteroviral infections occur worldwide. Acute fatal epidemics have been reported predominantly in Asia.^[10]

Mortality/Morbidity

Herpangina typically is a mild and self-limited illness.^[5] Although most children who develop herpangina recover, the disease sometimes is complicated by central nervous system involvement and cardiopulmonary failure. Fatalities associated with herpangina have been reported, primarily in infants aged 6-11 months.

Notably, herpangina has been associated with the potential for adverse pregnancy outcomes.^[5] A Taiwanese population-based study of 242 pregnant women with herpangina found an associated 2.29-fold greater risk for low birth weight, 1.67-fold greater risk for preterm delivery, and 1.63-fold greater risk for small-for-gestational-age infants, after adjustment for income, maternal, and fetal characteristics.^[11]

Sex

Herpangina does not have a sexual predilection.

Age

Herpangina most commonly affects infants and young children aged 3-10 years. Herpangina is less common in adolescents and adults.

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History

Approximately 50% of enteroviral infections are asymptomatic. Clinical manifestations may vary, depending on the strain of the virus.

All enteroviral infections may cause fever, which may be the first apparent symptom. Patients with enteroviral infection typically develop a temperature of 101-104°F.

Most symptomatic patients report malaise.

Sore throat and pain upon swallowing may develop and precede the development of the enanthem by a few hours to 1 day.

Older children frequently report headache and backache.

Persons with enteroviral infection may experience anorexia, emesis, or abdominal pain, which may mimic appendicitis.

Infants with enteroviral infection may appear listless.

Exanthem: Characteristics and occurrence rates vary, depending on the viral subtype. Persons with enteroviral infection may develop a rash that is not pruritic and that does not cause skin desquamation. The following are other rash characteristics:

• Macular
• Maculopapular
• Papulopustular
• Papulovesicular
• Vesicular
• Morbilliform
• Urticarial
• Petechial
• Hemangiomalike
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Epidemics of enterovirus 71 complicated by encephalomyelitis, nonpolio paralytic disease, and central nervous system sequelae emerged in the late 1990s, especially affecting Southeast Asia.^{[6, 7]}  In addition to the above, history may include the following:

• Headache
• Neck stiffness with anterior flex

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Physical

Herpangina may have the following characteristics:

• Hyperemia of the pharynx is associated with lesions that characteristically appear as discrete erythematous-based macules. These evolve into papules that vesiculate and then ulcerate centrally, creating an erythematous halo.
• In most cases, these lesions are the first physical finding of herpangina. The lesions typically are smaller than 5 mm in diameter. Most cases of herpangina involve 2-12 lesions.
• Uninvolved portions of the pharynx usually appear normal. The most commonly affected structures include the anterior pillars of the fauces, soft palate, uvula, tonsils, and posterior pharyngeal wall.
• Occasionally, lesions caused by herpangina appear on the tongue and posterior buccal mucosa (see Table for differential diagnoses of oral lesions).
• The ulcers may persist for up to 1 week, even after the fever has subsided.

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Typical ulcerative enanthem of herpangina on the soft palate and posterior oropharynx. The lesions are usually exquisitely painful and make swallowing....

Other characteristics of herpangina include the following:

• Pharyngitis: Erythema of the pharynx may range from mild to severe. Pharyngitis in enteroviral infections may be associated with pleurodynia, meningitis, and/or exanthem.
• Bilateral, anterior, cervical lymphadenopathy may develop.
• Acute lymphonodular pharyngitis is a variant of herpangina associated with coxsackievirus A10 infection. Tiny nodules of packed lymphocytes develop in the same distribution as herpangina oropharyngeal lesions. However, unlike the lesions of herpangina, these recede without vesiculation or ulceration.^[12]
• Encephalitis, meningitis, and myelitis associated with enterovirus 71: In addition to herpangina, altered sensorium, muscular weakness, poliolike paralysis, and seizures have been recorded.
• Systemic inflammatory response syndrome, neurogenic cardiopulmonary collapse:

  • Sudden cardiopulmonary collapse with noncardiogenic pulmonary edema has been reported with Enterovirus 71 in Southeast Asia, associated with neurologic symptoms. Extensive damage to medulla and pons has been found on postmortem examination.
  • Encephalitis, cardiopulmonary collapse, and severe pulmonary hemorrhage has been described with Coxsackievirus A2 in China, with survival after extracorporeal membrane oxygenation. ^[39]

   

  

   

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Causes

Coxsackieviruses A 1-10, 12, 16, and 22 represent the most common pathogens that cause herpangina.

Less-common causes of herpangina include the following:

• Coxsackievirus B 1-5
• Echovirus 3, 6, 9, 11, 16, 17, 22, 25, and 30
• Enterovirus 71 (see Pathophysiology)
• Parechovirus 1
• Herpes simplex virus
• Adenovirus

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Complications

Complications most commonly are associated with hand-foot-and-mouth disease due to younger age and EV-71 infection, most often manifesting as meningitis or encephalitis. Less often, poliolike illness (acute flaccid paralysis) may be seen, with prolonged recovery. The most severe complications and mortality have been associated with EV-71 infections, with cardiopulmonary failure due to neurogenic pulmonary edema and/or hemorrhage related to severe encephalitis; the latter is associated with high mortality.^{[13, 14]}

The Asia Pacific region has been most significantly impacted by EV-71. Longterm sequelae of severe disease may include need for chronic oxygen supplemention or mechanical ventilation, dysphagia requiring enteric feeding, and chronic cognitive and musculoskeletal impairments.^{[13, 14, 15]}

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Laboratory Studies

Herpangina is a clinical diagnosis. Laboratory studies generally are not indicated because herpangina is a mild and self-limited illness.

Investigate the salient features of the history and physical examination, including the following:

• Season (depending on the latitude)
• Age
• Exposure history
• Clinical symptoms

The WBC count usually is within the reference range.

Isolation of enterovirus in cell culture remains the criterion standard for diagnosis.^[16] To isolate the virus, obtain cultures from swabs of the nasopharynx. Other specimens that may produce an isolate include stool and rectal swabs, urine, serum, and CSF.

Serum antibodies to coxsackievirus may be measured after the onset of clinical symptoms. The antibody titer should show a 4-fold rise in serial samples performed 2-3 weeks apart.

Polymerase chain reaction can be performed for enteroviral RNA of the throat, blood, CSF, urine, feces, and tissue specimens.

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Histologic Findings

No histopathologic findings are specific to herpangina.

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Medical Care

Herpangina is a self-limited illness. As such, no specific therapy is indicated.

No antiviral therapy is effective against herpangina. Antibacterial therapy is of no benefit.

Recently, considerable efforts have been made in the development of antiviral compounds targeting the capsid protein of enterovirus, as well as viral proteases and proteins involved in enteroviral RNA replication.^{[16, 17, 18, 19]}

Treatment generally is supportive and includes the following:

• Hydration
• Antipyretics (eg, acetaminophen, ibuprofen)
• Topical analgesics (eg, topical lidocaine)

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Diet

Ensure that patients with herpangina maintain adequate hydration and caloric intake during the illness.

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Activity

Limit patient activity as tolerated.

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Prevention

Prevention of herpangina is difficult, especially in childcare settings, as children can shed the viruses associated with herpangina without symptoms. Close attention to frequent hand hygiene with soap and water and ethanol-based hand sanitizers, especially after diapering activities or contact with nasal or oral secretions, may limit spread of infection. Frequent washing or sanitizing of surfaces and toys also is helpful.

A case-control study in Guangdong, China suggests that caregivers who have herpangina may be a significant source of transmission, especially in the case of shared eating utensils; hand hygiene before eating reduced the likelihood.^[20]

There is no commercially available vaccine in the United States for the prevention of herpangina or hand-foot-and-mouth disease.

Owing to the high regional prevalence and severity of childhood hand-foot-and-mouth-disease due to EV-71, much of the effort to develop vaccines has been concentrated in Asia. Inactivated whole virus vaccines have been the most successful and demonstrate high neutralization titers and cross-genotype neutralizing antibody response. Three, based on the C4 genotype most prevalent in China, have been licensed by the China NMPA (National Medical Products Administration). The Sinovac product has shown broad, long-term persistence of immunogenicity within 5 years. Given Sinovac's high production capacity, WHO suggested the potential for its global use. A Taiwanese vaccine, EV71vac, has shown safety and efficacy against B4, B5, and C4 genotypes for at least 1 year. Recombinant EV-A71 VP1 capsid protein, synthetic peptide, and VLP vaccines remain in development stages. Given successful deployments during the COVID-19 pandemic, mRNA approaches may offer additional alternatives in the future.^{[18, 19, 41, 42]}

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Further Outpatient Care

Because symptoms associated with herpangina usually are short-lived and resolve within 1 week, patients generally do not need outpatient follow-up care.

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Deterrence/Prevention

Enteroviruses are spread through the fecal-oral route; therefore, emphasis is placed on measures that may help reduce this mode of spread, especially hand hygiene. A Chinese study of risk factors for herpangina found increased risk posed by playing with neighborhood children, visiting an outpatient clinic within the week before onset of illness, and exposure to crowded public spaces. The same study found significant correlation of good hand hygiene practices with reduced incidence of disease. Low hand hygiene scores were found in 50% of cases versus 2.5% of controls; on the other hand, high hand hygiene scores were found in 12% of cases versus 78% of controls.^[21]

The development of a vaccine to eradicate enterovirus 71 has been a priority. Recently, preliminary results of several in vitro and animal studies are encouraging. In particular, VP1 capsid protein of enterovirus 71, identified as a potent inducer of neutralizing antibody titer, shows promise in the development of a potential vaccine.^[22]

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Complications

Herpangina is a self-limited viral illness. Most cases resolve without complications. However, more severe enteroviral manifestations such as aseptic meningitis and neurological manifestations occur in very rare cases. Note a possible association of herpangina during pregnancy with low birth weight, small-for-gestational-age infants, or preterm delivery. See Mortality/Morbidity.

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Prognosis

Except for rare cases in which herpangina is accompanied by more severe manifestations of enterovirus infection, herpangina carries an excellent prognosis.

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