Hand, foot, and mouth disease: Identifying and managing an acute viral syndrome
ABSTRACTHand, foot, and mouth disease (HFMD) is a common, typically self-limited viral syndrome in children and adults. It is marked by fever, oral ulcers, and skin manifestations affecting the palms, soles, and buttocks, with symptoms usually lasting less than 1 week. Because it has the potential to reach epidemic levels in the United States, general practitioners need to be aware of it.
KEY POINTS
- In Asian and Pacific nations, HFMD has been a significant public health concern since 1997, with recurrent epidemics and, in some cases, severe complications, including central nervous system disease, pulmonary edema, and death.
- Coxsackievirus A16 and enterovirus 71 are the most common agents of HFMD. In addition, coxsackievirus A6 seems to be emerging.
- Neurologic and cardiopulmonary involvement are more often associated with enterovirus 71 infection.
- In March 2012, 63 cases of severe HFMD were reported in Alabama, California, Connecticut, and Nevada. Fifteen of the patients were adults, and more than half had positive sick contacts. Of the 34 patients who underwent serologic testing, 25 were positive for coxsackievirus A6, an unusual pathogen for HFMD in the United States, associated with more severe skin findings.
- Treatment focuses on supportive care and prevention.
DIAGNOSIS IS USUALLY CLINICAL
Most enteroviral infections are asymptomatic, but HFMD is a possibility if a patient has mild illness, fever, and a maculopapular or vesicular rash on the palms of the hands and soles of the feet, sometimes associated with oral ulcers (herpangina). Skin lesions can also be found on the legs, face, buttocks, and trunk.
In the United States, HFMD most commonly occurs in children under age 4 and is usually caused by coxsackievirus A16. Adults can also be affected, especially if they were in contact with children in child care, which was the case in approximately half of nonpediatric patients who tested positive for HFMD during an outbreak in several states between November 2011 and February 2012.3
The clinical characteristics of HFMD caused by enterovirus 71 may be somewhat different, with smaller vesicles, diffuse erythema of the trunk and limbs, and higher fever (temperature ≥ 39°C [102.2°F] for more than 3 days).27 However, the rash of coxsackievirus A16 HFMD may be more extensive and severe.
Other clinical manifestations of HFMD include nail dystrophies such as Beau lines and nail shedding, hyperglycemia, dehydration, and more serious and potentially life-threatening complications such as pulmonary edema28 and viral meningoencephalitis.29
Laboratory testing
In mild cases of HFMD, particularly in patients with a high probability of having the disease based on their clinical characteristics and sick contacts, laboratory testing is not necessary. Testing is usually reserved for severe cases and public health investigation of outbreaks.
Viral culture is the gold standard for diagnosing HFMD, but the final results can take nearly a week.
Polymerase chain reaction testing is faster, with a turnaround time of less than 1 day. It identifies viral RNA and is highly sensitive for detecting central nervous system infection.30
Where should samples be collected? Serum viremia precedes invasion of the skin and mucous membranes, so plasma can be tested. Inside the body, enteroviruses initially replicate in the gastrointestinal tract, although collecting a rectal swab or a stool sample is somewhat invasive. Further, in an enterovirus 71 epidemic in Taiwan, 93% of the patients had positive throat swabs, but only 30% tested positive by rectal swabs or analysis of the feces.27 At present, throat and vesicle specimens are considered to be the most useful sources for diagnostic purposes.16
ELISAs. Newly developed IgM-capture enzyme-linked immunosorbent assays (ELISAs) for coxsackievirus A16 and enterovirus 71 appear quite promising for diagnosing HFMD. These tests are inexpensive and detect IgM antibodies early and in a high percentage of patients. In the first week of the disease, the IgM detection rate was found to be 90.2% for enterovirus 71 and 68% for coxsackievirus A16.31
Cross-reactivity between these two viruses was a problem with ELISA testing in the past, causing false-positive results for enterovirus 71 in patients who in fact had coxsackievirus A16. The problem appears to be resolved in new versions that use specific enterovirus 71 proteins, eg, VP1.32
RECOGNITION AND PREVENTION ARE THE BEST MEDICINE
Recognizing HFMD early is crucial, because making the clinical diagnosis can identify patients who have signs of severe disease and can help protect future contacts and decrease the risk of an epidemic.
Infected patients continue to shed the virus for a long time, making hand hygiene and environmental control measures in health care settings and daycare centers of vital importance, to prevent spread of the infection.
Enteroviruses are stable in the environment and therefore capable of fecal-oral and oral-oral transmission. Humans are the only known natural hosts. No chemoprophylaxis or vaccination has been established to prevent HFMD. The recurrence of large-scale epidemics in the developing world is perhaps explained by ineffective sewage treatment and limited access to clean drinking water, especially in light of the fecal-oral spread of the virus. Intrafamilial spread of HFMD has been shown to be an important means of disease transmission, and asymptomatic adult carriers of these viruses may spread it to young children.33
The different viruses that cause HFMD result in a similar clinical presentation in most patients. Therefore, identifying HFMD caused by enterovirus 71, which carries a risk of severe and even fatal disease in young children vs a virus such as coxsackievirus A16, can be very difficult in practice without virologic testing. Thus, when diagnosed with HFMD, patients should be counseled to control all variables that could lead to further spread of the disease.
An analysis of epidemics in Asia suggested that public health awareness may have averted deaths in successive epidemics, highlighting the need to identify HFMD epidemics in communities and to educate patients and families about measures to prevent further spread of the virus in addition to standard supportive care.34
The CDC recommends35:
- Frequent hand-washing after toileting and changing diapers
- Disinfecting frequently used surfaces and objects, including toys
- Avoiding close contact with infected individuals and sharing of personal items such as utensils and cups.
These measures should be recommended to all affected patients.35
NO PROVEN ANTIVIRAL TREATMENT
No proven antiviral treatment exists for HFMD. Thus, the goals of treatment are typically supportive, as for any self-limited viral syndrome.16
Does acyclovir help? Shelley et al36 treated 13 patients (12 children and 1 adult) with acyclovir within 1 to 2 days of the onset of the HFMD rash and reported that it was beneficial, with significant relief of fever and skin lesions within 24 hours of starting therapy. These anecdotal results have not been replicated, and acyclovir is not an established treatment for HFMD.
If acyclovir does help, how does it work? Acyclovir, like other common antiviral medications, inactivates thymidine kinase, an enzyme produced by herpesviruses but not by HFMD-causing viruses like coxsackievirus A16. Shelley et al proposed that acyclovir may enhance the antiviral effect of the patient’s own interferon.36
Intravenous immunoglobulin has been used in severe cases during outbreaks in Asia, with retrospective data showing a potential ability to halt disease progression if used before the development of cardiopulmonary failure. However, this has not been studied prospectively and is not currently recommended.16
Acknowledgment: We would like to thank Dr. Salvador Alvarez of the Mayo Clinic Department of Infectious Disease and Dr. Donald Lookingbill of the Mayo Clinic Department of Dermatology for their collaboration.
