Herpangina

Etiology

Herpangina is primarily caused by viruses belonging to the genus Enterovirus within the family Picornaviridae. The most common causative agents are coxsackievirus A, particularly serotypes A1 to A10 and A16, although other enteroviruses such as coxsackievirus B and echovirus have also been implicated. An enterovirus strain, EV-A71, has been associated with neurologic complications.

These viruses are nonenveloped, single-stranded RNA viruses that replicate in the gastrointestinal tract and are transmitted primarily through fecal–oral and respiratory routes. Following entry into the host, viral replication occurs in the lymphoid tissues of the oropharynx and intestinal mucosa, leading to viremia and the development of the characteristic vesicular lesions in the posterior oropharynx.[4] Enterovirus B group serotypes, including B3, have also been implicated in epidemic clusters, demonstrating that multiple enterovirus lineages can produce the characteristic vesicular pharyngitis seen in herpangina.[5]

Epidemiology

Herpangina occurs worldwide and is most commonly reported among infants and young children, particularly children younger than 10. In the United States, enterovirus infections generally follow a seasonal pattern, with cases peaking during the summer and early fall. Transmission occurs through the fecal-oral route, respiratory droplets, and direct contact, facilitating outbreaks in childcare centers, schools, and other community settings. Results from surveillance studies conducted in the US and other countries identified several circulating serotypes, including coxsackievirus A serotypes 2, 4, 6, and 10, coxsackievirus B serotypes 2 and 4, and other nonpolio enteroviruses, with patterns varying by year and geographic region.[6] Recent surveillance data suggest that patterns of enterovirus circulation fluctuated after changes in public health measures during the COVID-19 pandemic.[7][8][9]

Pathophysiology

Herpangina is caused by nonpolio enteroviruses, primarily coxsackievirus A serotypes, although other enteroviruses, echoviruses, and parechoviruses may cause similar clinical findings. The viruses enter the host via the oral or respiratory route. Viral replication then occurs in the lymphoid tissue of the oropharynx and intestinal mucosa, leading to viremia and the subsequent formation of characteristic vesicular or ulcerative lesions in the posterior oropharynx. Infection also triggers a host immune response, resulting in systemic symptoms such as fever, malaise, and sore throat.[7][8][9] Because viremia contributes to the pathophysiology, more severe disease may occur, particularly in individuals with immunocompromised conditions.

The viruses causing herpangina likely attach to heparan sulfate glycosaminoglycans on host cell surfaces.[10] After attachment, the virus binds to functional cellular receptors, including the scavenger receptor B2 (SCARB2) or the coxsackie-adenovirus receptor (CAR), triggering viral membrane penetration and subsequent uncoating within the cell. These steps facilitate viral entry and intracellular replication. Herpangina has an incubation period of 4 to 14 days. After inoculation and local viral replication, viremia occurs, leading to involvement of secondary sites and the development of typical clinical features, including bilateral cervical lymphadenopathy and characteristic posterior pharyngeal lesions. The resulting clinical presentation reflects both local mucosal infection and systemic viral spread.

History and Physical

History

Children with herpangina usually present with a sudden onset of fever, sore throat, irritability, and decreased appetite. Preverbal children may push away a bottle containing an acidic liquid, such as orange juice, or refuse to drink altogether because of oral ulcerations. Verbal children may also report headache, malaise, or mild abdominal discomfort. The illness often develops rapidly over 1 to 2 days, and outbreaks commonly occur during the summer and early fall.

A recent history of exposure to other children with similar symptoms in childcare or school settings is common. Older children may report back pain and headache, and some patients may develop anorexia, dehydration, or abdominal pain. Depending on disease severity and organ system involvement, patients may also report headache, neck stiffness, confusion, seizures, muscle weakness, or difficulty breathing. Severe manifestations are rare. Adults generally have immunity from past infections but may occasionally present with more severe disease because of immunocompromised status or genetic susceptibility.[11][12]

Physical Examination

On physical examination, herpangina is generally straightforward to diagnose. The examiner will find small vesicles or shallow ulcers in the posterior oropharynx, including the soft palate, tonsillar pillars, and uvula, while the anterior oral cavity is usually spared. Cervical lymphadenopathy may be mild, and patients may appear irritable or lethargic because of fever. Other findings are generally minimal, and systemic involvement is rare, making the diagnosis largely clinical and based on the characteristic lesions and seasonal presentation.[11]

Even with the classic features of herpangina, the clinician should be aware that severe disease can occur in individuals without immunocompromised status. A persistently high fever accompanied by circulatory or neurologic abnormalities and elevated white blood cell counts, blood glucose levels, and lactate levels may signal the onset of more severe disease that can lead to pulmonary edema and death within 1 to 5 days. Severe disease is most often associated with enterovirus A71.[12]

The occurrence and characteristics of the rash may vary by viral subtype. Neurologic findings, such as neck stiffness or paralysis, may be present in patients with complications such as meningitis, acute flaccid paralysis, encephalitis, or encephalomyelitis. Dehydration is a common complication, with signs such as dry mouth and decreased skin turgor. The history and physical examination should also focus on excluding other serious febrile exanthems, including Kawasaki disease, Rocky Mountain spotted fever, eczema herpeticum, and toxic shock syndrome, which can present similarly but may evolve over time.

Evaluation

The diagnosis of herpangina is primarily clinical, based on the medical history and characteristic posterior oropharyngeal vesicular or ulcerative lesions; routine laboratory tests are often unnecessary in uncomplicated cases. Laboratory evaluation may include a complete blood count and basic metabolic panel to assess for dehydration or alternative diagnoses, but test results are usually normal. Confirmatory testing is reserved for complicated cases, outbreaks, or epidemiologic purposes; reverse transcription polymerase chain reaction testing for nonpolio enteroviruses using throat swabs, stool, cerebrospinal fluid, or vesicular fluid is the preferred method because of its high sensitivity and rapid turnaround time. Viral culture and paired serology, which demonstrate a 4-fold rise in antibody titers, are used less commonly. Imaging and additional studies (eg, lumbar puncture or central nervous system imaging) may be indicated if clinicians are concerned about complications such as aseptic meningitis, encephalitis, or acute flaccid paralysis, although these complications are rare.

Treatment / Management

Herpangina is typically a self-limited viral illness, and treatment is primarily supportive, focusing on symptom relief, hydration, and prevention of complications. Treatment can be broadly categorized into general care, symptomatic treatment, and antiviral therapy considerations.

General

Patients should have access to a well-ventilated, clean environment to reduce the risk of transmission. General supportive care includes maintaining adequate hydration and proper nutrition. Children should be encouraged to consume light, soft, or semiliquid foods to ensure adequate caloric intake, while avoiding hot, spicy, or irritating foods that may aggravate oral lesions.

Maintaining good oral hygiene is also important. Patients may rinse their mouths with normal saline after meals, while younger children who are unable to rinse may have their oral cavity gently wiped with saline-soaked gauze. If normal saline is unavailable, mildly salted water can be used as an alternative. Adequate oral fluid intake should be emphasized, particularly in children with fever or reduced oral intake. For those with significant feeding difficulties or at risk of dehydration, electrolyte-containing oral rehydration solutions are recommended. Patients should be monitored for signs of dehydration or worsening symptoms during the illness.[13](B3)

Symptomatic

Fever is one of the most common symptoms associated with herpangina. For children with temperatures of 38.5 °C (101.3 °F) or higher, antipyretic medications such as acetaminophen or ibuprofen may be administered according to age-appropriate dosing recommendations. Adequate hydration should be maintained while using these medications. Patients should avoid acidic or spicy foods and beverages until the lesions heal.

Nonpharmacologic measures such as cool compresses or tepid sponging may also provide additional comfort. Topical anesthetic preparations containing lidocaine or diphenhydramine are generally not recommended for the treatment of oral lesions in herpangina because of limited evidence of benefit and the potential risk of systemic toxicity in young children. In rare cases, younger children with high fever may develop febrile seizures, which require prompt treatment according to standard pediatric seizure protocols. Benzodiazepines such as intravenous midazolam may be used when clinically indicated.[13](B3)

Antiviral

Currently, no specific antiviral therapy is recommended for the routine treatment of herpangina. Supportive care remains the primary treatment approach. Results from some studies suggested that interferon alfa spray may provide benefit through local immunomodulatory and antiviral effects on mucosal immunity. However, its routine use remains limited, and the United States Food and Drug Administration has not approved this treatment for herpangina.[7][14](A1)

Differential Diagnosis

Herpangina may present with symptoms that overlap with those of several infectious and inflammatory pediatric conditions. Careful clinical evaluation, including the distribution of oral lesions, associated systemic findings, and rash characteristics, is important for distinguishing herpangina from other illnesses (see Image. Differential Diagnoses for Pediatric Oral Lesions). Diseases and conditions that should be considered in the differential diagnosis include:

• Eczema herpeticum
• Toxic shock syndrome
• Measles
• Varicella
• Kawasaki disease
• Insect bites or hypersensitivity reactions
• Rocky Mountain spotted fever
• Drug eruption or medication-related hypersensitivity reactions
• Erythema multiforme major

These conditions may present with fever, mucocutaneous lesions, or a rash resembling herpangina. However, distinguishing features, such as lesion distribution, systemic involvement, epidemiologic exposure, and laboratory findings, help establish the correct diagnosis. A large review of oral ulcerations lists more than 48 entities, including herpangina, and may serve as a useful diagnostic reference. In addition to infectious causes, noninfectious etiologies include rheumatologic, gastrointestinal, and autoimmune disorders, as well as medication and toxin ingestion.[15]

Prognosis

Herpangina is usually a mild illness that resolves spontaneously. With proper care, appropriate infection-control measures, good nutrition, and adequate hydration, most children recover within about 10 days. Treatment mainly focuses on relieving fever and oral pain, and young children with high fever should be monitored closely for febrile seizures. In rare cases, serious complications, such as acute flaccid paralysis, meningitis, encephalitis, or myocarditis, can occur, so patients should be monitored carefully for warning signs of severe disease.

Complications

Cases of herpangina generally resolve spontaneously without complications. However, clinicians should recognize the potential clinical overlap with other enterovirus-associated illnesses, including coxsackieviruses. Herpangina is usually mild, but some causative viruses, particularly enterovirus A71, can lead to serious complications. Complications may include brainstem encephalitis, acute flaccid paralysis, aseptic meningitis, and myocarditis. Patients who develop these complications can become critically ill and may require hospitalization, including admission to an intensive care unit.