Herpangina and hand-foot-and-mouth disease (HFMD) are 2 common related clinical syndromes. They are often seen in the pediatric population, with occasional outbreaks among adult patients. They are both caused primarily by enteroviral infections. Herpangina presents as a stereotypical vesicular/ulcerative enanthem on the oropharyngeal mucosa. HFMD is identified by a similar rash on the oral mucous membranes, with additional characteristic exanthem on hands and feet. Both syndromes are highly contagious. Although these syndromes are usually benign, their symptoms can cause significant temporary discomfort for patients and distress for their parents. Rarely, they can present as a more severe disease, and patients develop long-term sequelae.
Herpangina and HFMD are both caused by enteroviral infection. The genus Enterovirus belongs to the Picornaviridae family. Within the genus, there are 12 species, which contain the coxsackievirus, echovirus, human rhinovirus, and poliovirus serotypes. The main strains which cause HFMD are coxsackievirus A16 and enterovirus A71. Coxsackievirus A1-6, 8, 10, and 22 are frequently associated with herpangina. Echoviruses have also been implicated in both syndromes. Enteroviruses are small, non-enveloped, single positive-strand RNA viruses. They are capable of surviving in a wide pH range and retain infectivity in temperatures up to 50 C. These characteristics make them capable of surviving in the environment for relatively extended periods. Humans are the only natural host of these viruses.
HFMD and herpangina most frequently occur in the pediatric population in patients younger than 7 to 10 years of age. Children are often infected via exposures at childcare centers or schools. Adolescents and adults are less frequently affected. Older patients are most commonly infected via interfamilial spread or sporadic outbreaks in close communities such as military barracks. Very young, elderly, immunocompromised, and pregnant patients can develop the more severe disease. Neither gender is more commonly infected.
In temperate climates, these syndromes are primarily associated with seasonal outbreaks in the summer and early fall. However, sporadic outbreaks have been documented at all times of the year. In tropical climates, these diseases usually occur during the rainy seasons.
The Asian region has been subject to several major outbreaks of HFMD and herpangina. Most notable was a 1998 outbreak in Taiwan that caused infection in over 1.5 million patients. Multiple enteroviruses were circulating during this outbreak, but enterovirus A71 was isolated in nearly half of these cases. This epidemic caused 78 deaths and severe disease in more than 400 patients. This outbreak was thought to be due to poor sanitation and contamination of potable water.
There have been several subsequent major documented outbreaks in Japan, Hong Kong, China, and Europe. Since 2008, coxsackievirus A6 has been implicated in large-scale outbreaks in addition to the more common enterovirus A71 and coxsackievirus A16. HFMD and herpangina are not reportable diseases in the United States, so it is unclear if there are frequent large-scale outbreaks in that country. Per the United States Center for Disease Control (CDC), “large outbreaks of hand, foot, and mouth disease are not common in the United States.”
Enteroviruses are typically spread via the fecal-oral route. Transmission can additionally result from the ingestion of infected saliva, respiratory droplets, or direct contact with fluid from vesicles. The incubation period ranges from 3 to 5 days. Viral shedding can occur even in asymptomatic patients. Respiratory viral shedding can persist for up to 3 weeks and in the stool for up to 8 weeks. Patients are most contagious in the first 1 to 2 weeks of infection.
Herpangina is associated with a painful enanthem that typically occurs on the soft palate, tonsils, and posterior pharynx. It is usually characterized by vesicles that eventually transition to tiny yellow or white ulcers with red rims. Ulceration usually occurs within 24 hours after the appearance of vesicles. These ulcers are generally 3 to 4 mm in diameter. The rash is commonly preceded by an abrupt onset of fever that can be as high as 105 F. Uncontrolled fevers may be high enough to provoke febrile seizures. Young children will likely exhibit fussiness and poor feeding or anorexia. Older children may complain of a headache, malaise, odynophagia, or a sore throat.
The oral lesions of HFMD are similar to those seen in herpangina, although ulcers may be larger. HFMD is also accompanied by an exanthema of macules and papules on the palms of hands and soles. These lesions are generally non-painful, and usually, develop after the appearance of oral ulcers. The exanthem will less commonly be vesicular and can additionally be seen on the buttocks. HFMD can be associated with a prodrome of flu-like symptoms. The fevers associated with HFMD are usually less severe than those seen in herpangina. Enterovirus A71 and coxsackievirus A16 are usually associated with more severe disease and epidemics.
A complete history should include questions regarding exposure to sick contacts, duration, and progression of symptoms. Dehydration is the most common complication of HFMD and herpangina. It is important to inquire about anorexia or signs of dehydration such as decreased urine output. Careful attention should be paid to the neurologic and cardiac exams, as the severe and long-term sequelae of HFMD and herpangina most frequently affect these organ systems. History and physical exam should also focus on ruling out other more serious, life-threatening febrile exanthemas. For example, Kawasaki disease, bacterial endocarditis, Rocky Mountain spotted fever, eczema herpeticum, and toxic shock syndrome can all present with fevers and lesions similar to those seen in HFMD and herpangina.
The diagnoses of HFMD and herpangina are usually made clinically. In mild cases, no imaging or laboratory testing is required. Laboratory studies are usually obtained to gain additional information about complications such as dehydration or to rule out alternative diagnoses. Confirmatory testing is usually required only in complicated disease, for the collection of epidemiological data during epidemics, or to differentiate herpangina or HFMD from more serious diseases such as eczema herpeticum. Viral culture is the “gold standard” for confirmatory testing. Unfortunately, it can often take longer than 1 week to obtain culture results. This makes it an impractical test for clinical practice. Polymerase chain reaction (PCR) testing is fast and highly sensitive for enteroviruses. Samples may be obtained from the stool, mucocutaneous ulcers, vesicular fluid, or cerebrospinal fluid. Enzyme-linked immunosorbent assays (ELISA) are also available. ELISA testing for enteroviruses is generally less sensitive than PCR and should be utilized only in cases where PCR is not available.
There is no prophylaxis for either HFMD or herpangina, nor is there specific management. Treatment is primarily supportive. The pain associated with these diseases is usually brief. Ibuprofen and acetaminophen are the mainstays of treatment, in conjunction with adequate oral hydration. Lidocaine or topical therapies are generally not recommended due to the risks for toxicity associated with these medications. Some small reports showed more rapid symptomatic improvement and decreased the duration of symptoms after treatment with acyclovir. Unfortunately, there has been no proven benefit reported in subsequent studies. Intravenous immunoglobulin (IVIG) has also been used to treat these diseases during major outbreaks in Asia, but no prospective data has been collected about the utility of this drug. For very severe cases the potential benefits of IVIG outweigh any risks, and this drug may still be administered even without hard evidence regarding its efficacy. Patients with more serious presentations such as encephalitis or myocarditis should be admitted to the intensive care unit (ICU) for aggressive treatment and monitoring. Additionally, patients who are dehydrated or refuse to drink secondary to pain should be admitted for intravenous (IV) fluid therapy.
Both HFMD and herpangina are generally mild and self-limited. The more serious complications of these syndromes are caused almost exclusively by enterovirus A71. Acute complications include flaccid paralysis, meningitis/encephalitis, and myocarditis. More rarely these syndromes can cause fetal loss or conjunctival ulceration. Overall mortality rates for childhood myocarditis and encephalitis are both approximately 7%. Long-term sequelae include cardiomyopathy and persistent neurologic symptoms.
Herpangina and HFMD are both highly contagious viral infectious diseases. While these syndromes are most often mild and brief, they can have rare serious complications. Early diagnosis of these diseases is important. If an individual or a family member are diagnosed, the treatment is supportive with acetaminophen, ibuprofen, and plenty of liquids to avoid dehydration. Antibiotics will not treat HFMD or herpangina. The best way to prevent the spread of this disease among people is frequent hand washing, disinfecting of hard surfaces, and avoidance of shared drinks and food. If a person believes that he or she may have contracted herpangina or HFMD, they should contact their primary care provider or local emergency room as soon as possible for evaluation.
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