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.
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).[1, 2] Enterovirus 71 has emerged as an important public problem, causing severe clinical illness, encephalomyelitis, and potentially death in young children.[3] . 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).
A distinct phenotype of Enterovirus 71 causes herpangina. This is in contrast to the phenotype of Enterovirus 71 that causes encephalitis, aseptic meningitis, myocarditis, poliomyelitis-like paralysis, and neonatal sepsis. 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.[4, 5, 6]
While herpangina is generally a mild disease in adults, infection during pregnancy has been associated with a herpangina associated with a 2.29- (95% confidence interval [CI], 1.42-3.69), 1.67- (95% CI, 1.04-2.68), and 1.63-fold (95% CI, 1.14-2.33) increased risk of low birth weight, preterm delivery, and small-for-gestational-age infants, respectively.[7]
Viruses that cause herpangina are typically spread via the fecal-oral route, although they may spread via the respiratory route or through fomites. Freshwater sources (eg, lakes) may act as a reservoir 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.
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 in at least 5 parts of the world, the most recent being described in Kanagawa Prefecture, Japan, in 2007.[8]
Mortality/Morbidity
Herpangina is typically a mild and self-limited illness. Although most children who develop herpangina recover, the disease is occasionally complicated by CNS lesions 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. 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.[9]
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.
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 precedes the development of the enanthem by a few hours to one 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
Epidemics of enterovirus 71 complicated by encephalomyelitis, nonpolio paralytic disease, and central nervous system sequelae emerged in the late 1990s, especially affecting Southeast Asia.[5, 4] In addition to the above, history may include the following:
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 are typically 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 one 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....
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.[10]
Encephalitis, meningitis, and myelitis associated with enterovirus 71: In addition to herpangina, altered sensorium, muscular weakness, poliolike paralysis, and seizures have been recorded.
Brainstem encephalomyelitis with Enterovirus 71: Rare sudden cardiopulmonary collapse with noncardiogenic pulmonary edema has been reported with Enterovirus 71 in Southeast Asia, associated with minimal neurologic symptoms. Extensive damage to medulla and pons has been found on postmortem examination.
Herpangina is a clinical diagnosis. Laboratory studies are generally 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 is usually within the reference range.
Isolation of enterovirus in cell culture remains the criterion standard for diagnosis.[11] 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.
Herpangina is a self-limited illness. As such, no specific therapy is indicated.
Currently, 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,[12] as well as viral proteases and proteins involved in enteroviral RNA replication.[11]
Treatment is generally supportive and includes the following:
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 is also helpful.
There is no commercially available vaccine for the prevention of herpangina or hand-foot-and-mouth disease.
Because symptoms associated with herpangina are usually short-lived and resolve within one week, patients generally do not need outpatient follow-up care.
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.[13]
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.[14]
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.
Except for rare cases in which herpangina is accompanied by more severe manifestations of enterovirus infection, herpangina carries an excellent prognosis.
What is herpangina?What is the pathophysiology of herpangina?In what climates is herpangina most prevalent?Where do herpangina epidemics occur?What is the mortality and morbidity associated with herpangina?How does the prevalence of herpangina vary by sex?In which age groups is herpangina most prevalent?What are the signs and symptoms of herpangina?How is rash characterized in herpangina?What are the signs and symptoms of enterovirus 71-related herpangina?Which physical findings are characteristic of herpangina?What are causes of herpangina?How is herpangina differentiated from herpes simplex virus (HSV) and hand-foot-and-mouth disease?What are the differential diagnoses for Herpangina?What is the role of lab studies in the workup of herpangina?Which histologic findings are characteristic of herpangina?What are the treatment options for herpangina?Which dietary modifications are needed during the treatment of herpangina?Which activity modifications are needed during the treatment of herpangina?What is included in long-term monitoring following treatment for herpangina?How is herpangina prevented?What are complications of herpangina?What is the prognosis of herpangina?
Sandra G Gompf, MD, FACP, FIDSA, Associate Professor of Infectious Diseases and International Medicine, University of South Florida College of Medicine; Chief, Infectious Diseases Section, Director, Occupational Health and Infection Control Programs, James A Haley Veterans Hospital
Disclosure: Nothing to disclose.
Coauthor(s)
Beata Catherine Casanas, DO, FACP, FIDSA, Associate Professor, Director of Infectious Disease Fellowship Program, Department of Internal Medicine, Division of Infectious Diseases and International Medicine, University of South Florida Morsani College of Medicine; Executive Medical Director, Hillsborough County Health Department
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Pfizer, Allergan.
Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London
Disclosure: Nothing to disclose.
Additional Contributors
Thomas E Herchline, MD, Professor of Medicine, Wright State University, Boonshoft School of Medicine; Medical Consultant, Public Health, Dayton and Montgomery County (Ohio) Tuberculosis Clinic
Disclosure: Nothing to disclose.
References
Chapter 174: Coxsackieviruses, Echoviruses, and Numbered Enteroviruses (EV-D68). Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, PA: Saunders, an imprint of Elsevier, Inc.; 2015. Vol 1: 2080-89.
Cherry JD, et al. Herpangina. Textbook of Pediatric Infectious Diseases. 6th ed. 2009. Vol 1: Chap 11.
Christie AB. Enteroviral infections (Coxsackieviruses and echoviruses). Infectious Diseases: Epidemiology and Clinical Practice. 1987. 753-81.
Delaney JE, Keels, MA. Soft tissue lesions of the oral cavity in children. UpToDate. Available at http://www.uptodate.com. Accessed: November 10, 2009.
Modlin JF. Clinical manifestation and diagnosis of enterovirus infections. UpToDate. Available at http://www.uptodate.com. Accessed: November 10, 2009.
Coxsackievirus B4 virions under electron microscopy. Courtesy of Centers for Disease Control and Prevention (CDC).
Typical ulcerative enanthem of herpangina on the soft palate and posterior oropharynx. The lesions are usually exquisitely painful and make swallowing difficult. Ensuring adequate hydration in children is thus important. Courtesy of Wikimedia Commons/shawn c (https://commons.wikimedia.org/wiki/File:HFMD_soft_palete_oropharynx.jpg).
Typical flat vesicular exanthem of hand, foot, and mouth disease on a child's feet. The lesions may be slightly tender, and the rash often desquamates as it resolves. Courtesy of Wikimedia Commons/Ngufra (https://commons.wikimedia.org/wiki/File:Hand_foot_and_mouth_disease_on_child_feet.jpg).
Typical flat vesicular lesions of hand, foot, and mouth disease that may be associated with herpangina. The lesions may or may not be tender, and often resolve with desquamation. Courtesy of Wikimedia Commons/KlatschmohnAcker (https://commons.wikimedia.org/wiki/File:Hand_Foot_Mouth_Disease_Adult_36Years.jpg).
Typical ulcerative enanthem of herpangina on the soft palate and posterior oropharynx. The lesions are usually exquisitely painful and make swallowing difficult. Ensuring adequate hydration in children is thus important. Courtesy of Wikimedia Commons/shawn c (https://commons.wikimedia.org/wiki/File:HFMD_soft_palete_oropharynx.jpg).
Coxsackievirus B4 virions under electron microscopy. Courtesy of Centers for Disease Control and Prevention (CDC).
Typical ulcerative enanthem of herpangina on the soft palate and posterior oropharynx. The lesions are usually exquisitely painful and make swallowing difficult. Ensuring adequate hydration in children is thus important. Courtesy of Wikimedia Commons/shawn c (https://commons.wikimedia.org/wiki/File:HFMD_soft_palete_oropharynx.jpg).
Typical flat vesicular exanthem of hand, foot, and mouth disease on a child's feet. The lesions may be slightly tender, and the rash often desquamates as it resolves. Courtesy of Wikimedia Commons/Ngufra (https://commons.wikimedia.org/wiki/File:Hand_foot_and_mouth_disease_on_child_feet.jpg).
Typical flat vesicular lesions of hand, foot, and mouth disease that may be associated with herpangina. The lesions may or may not be tender, and often resolve with desquamation. Courtesy of Wikimedia Commons/KlatschmohnAcker (https://commons.wikimedia.org/wiki/File:Hand_Foot_Mouth_Disease_Adult_36Years.jpg).
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