- Author: Stephen J Nervi, MD; Chief Editor: Michael Stuart Bronze, MD more...
Hand-foot-and-mouth disease (HFMD) is an acute viral illness that presents as a vesicular eruption in the mouth (see the image below), but it can also involve the hands, feet, buttocks, and/or genitalia. Coxsackievirus A type 16 (CVA16) is the etiologic agent involved in most cases of HFMD, but the illness is also associated with coxsackievirus A5, A7, A9, A10, B2, and B5 strains. Enterovirus 71 (EV-71) has caused outbreaks of HFMD with associated neurologic involvement in the western Pacific region.
See Clues in the Oral Cavity: Are You Missing the Diagnosis?, a Critical Images slideshow, to help identify the causes of abnormalities of the oral cavity.
Also, see the 15 Rashes You Need to Know: Common Dermatologic Diagnoses slideshow to help identify and treat various rashes and the 15 Back-to-School Illnesses You Should Know slideshow to help identify conditions that may occur in young patients after they return to the classroom.
Signs and symptoms
The history in patients with HFMD is as follows:
Sore mouth or throat
Rarely, vomiting occurs in HFMD cases caused by EV-71
Physical findings include the following:
Initially, macular lesions appear on the buccal mucosa, tongue, and/or hard palate
These mucosal lesions rapidly progress to vesicles that erode and become surrounded by an erythematous halo
Lesions may also be found on the hands, feet, buttocks, and genitalia
A fever of 38-39°C may be present for 24-48 hours
Atypical clinical features include concomitant aseptic meningitis in HFMD caused by coxsackievirus strains (rare). HFMD caused by EV-71 has a higher incidence of neurologic involvement, including the following :
A poliolike syndrome
Acute cerebellar ataxia
Acute transverse myelitis
Benign intracranial hypertension
See Clinical Presentation for more detail.
The diagnosis of HFMD is typically based on clinical grounds. Laboratory studies are usually unnecessary, but the following may be done:
The virus can be isolated and identified via culture and immunoassay from cutaneous lesions, mucosal lesions, or stool samples; oral specimens have the highest isolation rate
In patients with vesicles, vesicle swabs are also a good source for viral collection
In patients without vesicles, rectal swabs can be collected
For viral isolation, 2 swab collections are recommended: From the throat and from either vesicles or the rectum
Serologic testing (eg, acute and convalescent antibody levels) may be obtained
Differentiating coxsackievirus-associated HFMD from EV-71–associated HFMD may have prognostic significance
PCR and microarray technology are among the various ways of identifying the causative virus 
See Workup for more detail.
There is no antiviral agent specific for the etiologic agents of HFMD. Instead, the treatment is supportive, as follows:
Ensure adequate fluid intake to prevent dehydration; cold liquids are generally preferable
Spicy or acidic substances may cause discomfort
Intravenous hydration may be necessary if the patient has moderate-to-severe dehydration or if discomfort precludes oral intake
Fever may be treated with antipyretics
Pain may be treated with standard doses of acetaminophen or ibuprofen
Direct analgesia may also be applied to the oral cavity via mouthwashes or sprays
IVIG and milrinone have shown some efficacy in a few reports [4, 5, 6]
Hand-foot-and-mouth disease (HFMD) is an acute viral illness that presents as a vesicular eruption in the mouth. HFMD can also involve the hands, feet, buttocks, and/or genitalia. Coxsackievirus A type 16 (CV A16) is the etiologic agent involved in most cases of HFMD, but the illness is also associated with coxsackievirus A5, A7, A9, A10, B2, and B5 strains. Enterovirus 71 (EV-71) has also caused outbreaks of HFMD with associated neurologic involvement in the western Pacific region.
Coxsackievirus is a subgroup of the enteroviruses and is a member of the family Picornaviridae. This family consists of small, nonenveloped, single-stranded RNA viruses.
Infection generally occurs via the fecal-oral route or via contact with skin lesions and oral secretions. Viremia develops, followed by invasion of the skin and mucous membranes. Widespread apoptosis likely results in the characteristic lesion formation.
Epidemics of HFMD generally occur in the summer to early fall months, although cases can occur sporadically all year.
HFMD epidemics associated with EV-71 have been more frequent in Southeast Asia in recent years, including Taiwan (1998) and Singapore (2000). Risk factors in these epidemics include attendance at child care centers, contact with HFMD, large family number, and rural residence.
HFMD caused by coxsackievirus is generally a mild self-limited illness that resolves in 7-10 days; rarely, HFMD may recur or persist. Serious complications are also rare.
Severe oral ulcerations can create painful stomatitis. This may interfere with oral intake and cause dehydration, the most common complication of HFMD. Rarely, aseptic meningitis accompanies coxsackievirus-induced HFMD.
HFMD caused by EV-71 has a higher incidence of neurologic involvement, including a poliolike syndrome, aseptic meningitis, encephalitis, encephalomyelitis, acute cerebellar ataxia, acute transverse myelitis, Guillain-Barré syndrome, opsomyoclonus syndrome, and benign intracranial hypertension. These neurological complications have been attributed to either immunopathology or virus-induced damage to gray matter.[1, 8]
Rarely, cardiopulmonary complications such as myocarditis, interstitial pneumonitis, and pulmonary edema may occur. Neurologic involvement with sequelae is less likely to occur in patients with HFMD caused by coxsackievirus strains than with HFMD caused by EV-71. Chang et al analyzed the Taiwan HFMD epidemic of 1998 and revealed that 68% of the EV-71 cases were uncomplicated. Thirty-two percent of the cases had complications; 7.3% involved aseptic meningitis, 10% involved encephalitis, 2.3% involved poliolike syndrome, 4.5% involved encephalomyelitis, and 6.8% involved fatal pulmonary edema (7.9% of patients died and 4% of patients had sequelae). In the coxsackievirus A16 group, 94% of the cases of were uncomplicated; only 6.3% cases were complicated by aseptic meningitis; no fatalities or sequelae were reported.
Chong et al observed vomiting, leukocytosis, and an absence of mouth ulcers as predictive risk factors for fatal cases of EV-71 HFMD during the Singapore epidemic in 2000.
Most reports indicate that HFMD has no sexual predilection. Some epidemic data observe a slight male-to-female predominance ratio of 1.2-1.3:1.
Children younger than 10 years are most commonly affected with HFMD, and subsequent outbreaks among family members and close contacts may develop.
Chan KP, Goh KT, Chong CY, Teo ES, Lau G, Ling AE. Epidemic hand, foot and mouth disease caused by human enterovirus 71, Singapore. Emerg Infect Dis. 2003 Jan. 9(1):78-85. [Medline].
Chong CY, Chan KP, Shah VA, Ng WY, Lau G, Teo TE, et al. Hand, foot and mouth disease in Singapore: a comparison of fatal and non-fatal cases. Acta Paediatr. 2003 Oct. 92(10):1163-9. [Medline].
Chen TC, Chen GW, Hsiung CA, Yang JY, Shih SR, Lai YK, et al. Combining multiplex reverse transcription-PCR and a diagnostic microarray to detect and differentiate enterovirus 71 and coxsackievirus A16. J Clin Microbiol. 2006 Jun. 44(6):2212-9. [Medline].
Thomas I, Janniger CK. Hand, foot, and mouth disease. Cutis. 1993 Nov. 52(5):265-6. [Medline].
Toida M, Watanabe F, Goto K, Shibata T. Usefulness of low-level laser for control of painful stomatitis in patients with hand-foot-and-mouth disease. J Clin Laser Med Surg. 2003 Dec. 21(6):363-7. [Medline].
Wang SM, Liu CC. Enterovirus 71: epidemiology, pathogenesis and management. Expert Rev Anti Infect Ther. 2009 Aug. 7(6):735-42. [Medline].
Saeed A, Khan QM, Waheed U, Arshad M, Asif M, Farooq M. RT-PCR evaluation for identification and sequence analysis of foot-and-mouth disease serotype O from 2006 to 2007 in Punjab, Pakistan. Comp Immunol Microbiol Infect Dis. 2011 Mar. 34(2):95-101. [Medline].
Chen SC, Chang HL, Yan TR, Cheng YT, Chen KT. An eight-year study of epidemiologic features of enterovirus 71 infection in Taiwan. Am J Trop Med Hyg. 2007 Jul. 77(1):188-91. [Medline].
Chang LY, Lin TY, Huang YC, Tsao KC, Shih SR, Kuo ML, et al. Comparison of enterovirus 71 and coxsackie-virus A16 clinical illnesses during the Taiwan enterovirus epidemic, 1998. Pediatr Infect Dis J. 1999 Dec. 18(12):1092-6. [Medline].
Chen KT, Chang HL, Wang ST, Cheng YT, Yang JY. Epidemiologic features of hand-foot-mouth disease and herpangina caused by enterovirus 71 in Taiwan, 1998-2005. Pediatrics. 2007 Aug. 120(2):e244-52. [Medline].
Ahmad K. Hand, foot, and mouth disease outbreak reported in Singapore. Lancet. 2000 Oct 14. 356(9238):1338. [Medline].
Tan CW, Lai JK, Sam IC, Chan YF. Recent developments in antiviral agents against enterovirus 71 infection. J Biomed Sci. 2014. 21:14. [Medline].
Boughton B. EV71: Vaccine Prevents Hand-Foot-Mouth, Associated Disease. Medscape Medical News. Available at http://www.medscape.com/viewarticle/804983. Accessed: June 4, 2013.
Chan YF, AbuBaker S. Recombinant human enterovirus 71 in hand, foot and mouth disease patients. Emerg Infect Dis. 2004 Aug. 10(8):1468-70. [Medline].
Chang LY, King CC, Hsu KH, Ning HC, Tsao KC, Li CC, et al. Risk factors of enterovirus 71 infection and associated hand, foot, and mouth disease/herpangina in children during an epidemic in Taiwan. Pediatrics. 2002 Jun. 109(6):e88. [Medline].
Cherry JD. Contemporary infectious exanthems. Clin Infect Dis. 1993 Feb. 16(2):199-205. [Medline].
Faulkner CF, Godbolt AM, DeAmbrosis B, Triscott J. Hand, foot and mouth disease in an immunocompromised adult treated with aciclovir. Australas J Dermatol. 2003 Aug. 44(3):203-6. [Medline].
Frydenberg A, Starr M. Hand, foot and mouth disease. Aust Fam Physician. 2003 Aug. 32(8):594-5. [Medline].
Hooi PS, Chua BH, Lee CS, Lam SK, Chua KB. Hand, foot and mouth disease: University Malaya Medical Centre experience. Med J Malaysia. 2002 Mar. 57(1):88-91. [Medline].
Kuo RL, Kung SH, Hsu YY, Liu WT. Infection with enterovirus 71 or expression of its 2A protease induces apoptotic cell death. J Gen Virol. 2002 Jun. 83(Pt 6):1367-76. [Medline].
McMinn P, Stratov I, Nagarajan L, Davis S. Neurological manifestations of enterovirus 71 infection in children during an outbreak of hand, foot, and mouth disease in Western Australia. Clin Infect Dis. 2001 Jan 15. 32(2):236-42. [Medline].
McMinn PC. An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev. 2002 Mar. 26(1):91-107. [Medline].
Miller GD, Tindall JP. Hand-foot-and-mouth disease. JAMA. 1968 Mar 4. 203(10):827-30. [Medline].
Modlin JF. Enterovirus deja vu. N Engl J Med. 2007 Mar 22. 356(12):1204-5. [Medline].
Modlin JF. Coxsachie Virus, Echoviruses, and Newer Enteroviruses. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Disease. 5th ed. 2000. 1904-17.
Ooi MH, Solomon T, Podin Y, Mohan A, Akin W, Yusuf MA, et al. Evaluation of different clinical sample types in diagnosis of human enterovirus 71-associated hand-foot-and-mouth disease. J Clin Microbiol. 2007 Jun. 45(6):1858-66. [Medline].
Ooi MH, Wong SC, Clear D, Perera D, Krishnan S, Preston T, et al. Adenovirus type 21-associated acute flaccid paralysis during an outbreak of hand-foot-and-mouth disease in Sarawak, Malaysia. Clin Infect Dis. 2003 Mar 1. 36(5):550-9. [Medline].
Prager P, Nolan M, Andrews IP, Williams GD. Neurogenic pulmonary edema in enterovirus 71 encephalitis is not uniformly fatal but causes severe morbidity in survivors. Pediatr Crit Care Med. 2003 Jul. 4(3):377-81. [Medline].
Scott LA, Stone MS. Viral exanthems. Dermatol Online J. 2003 Aug. 9(3):4. [Medline].
Shekhar K, Lye MS, Norlijah O, Ong F, Looi LM, Khuzaiah R, et al. Deaths in children during an outbreak of hand, foot and mouth disease in Peninsular Malaysia--clinical and pathological characteristics. Med J Malaysia. 2005 Aug. 60(3):297-304. [Medline].
Shimizu H, Okuyama K, Hirai Y. Epidemic of hand, foot and mouth disease in Kawasaki City, Japan. Jpn J Infect Dis. 2005 Oct. 58(5):330-1. [Medline].
Shimizu H, Utama A, Onnimala N, Li C, Li-Bi Z, Yu-Jie M, et al. Molecular epidemiology of enterovirus 71 infection in the Western Pacific Region. Pediatr Int. 2004 Apr. 46(2):231-5. [Medline].
Singh S, Poh CL, Chow VT. Complete sequence analyses of enterovirus 71 strains from fatal and non-fatal cases of the hand, foot and mouth disease outbreak in Singapore (2000). Microbiol Immunol. 2002. 46(11):801-8. [Medline].
Solomon T. Exotic and emerging viral encephalitides. Curr Opin Neurol. 2003 Jun. 16(3):411-8. [Medline].
Sutton-Hayes S, Weisse ME, Wilson NW, Ogershok PR. A recurrent presentation of hand, foot, and mouth disease. Clin Pediatr (Phila). 2006 May. 45(4):373-6. [Medline].
Tsao KC, Chang PY, Ning HC, Sun CF, Lin TY, Chang LY, et al. Use of molecular assay in diagnosis of hand, foot and mouth disease caused by enterovirus 71 or coxsackievirus A 16. J Virol Methods. 2002 Apr. 102(1-2):9-14. [Medline].
Tsao LY, Lin CY, Yu YY, Wang BT. Microchip, reverse transcription-polymerase chain reaction and culture methods to detect enterovirus infection in pediatric patients. Pediatr Int. 2006 Feb. 48(1):5-10. [Medline].
Tseng FC, Huang HC, Chi CY, Lin TL, Liu CC, Jian JW, et al. Epidemiological survey of enterovirus infections occurring in Taiwan between 2000 and 2005: Analysis of sentinel physician surveillance data. J Med Virol. 2007 Dec. 79(12):1850-60. [Medline].
Wang CY, Li Lu F, Wu MH, Lee CY, Huang LM. Fatal coxsackievirus A16 infection. Pediatr Infect Dis J. 2004 Mar. 23(3):275-6. [Medline].
Zhu FC, Meng FY, Li JX, Li XL, Mao QY, Tao H, et al. Efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in China: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2013 May 28. [Medline].
Zhu Z, Xu WB, Xu AQ, Wang HY, Zhang Y, Song LZ, et al. Molecular epidemiological analysis of echovirus 19 isolated from an outbreak associated with hand, foot, and mouth disease (HFMD) in Shandong Province of China. Biomed Environ Sci. 2007 Aug. 20(4):321-8. [Medline].
|Illness||Etiologic Agent||Usual Severity of Clinical Illness||Appearance of Lesions||Locations of Lesions||Other Features|
|HFMD||Coxsackie-virus A16 (most common), A5, A7, A9, A10, B2, B5
Vesicles → ulcerations on an erythematous base
Usually 2-6 mm
|Lesions may also be found on hands, feet, buttocks, and genitalia.
|Herpangina||Coxsackie-virus A1-A10, A16, A22
Echovirus 3, 6, 9, 16, 17, 25, 30
|Moderate; can be severe||Papules →
Vesicles → ulcerations on an erythematous base
Usually 2-4 mm
|Posterior oral cavity
Tonsils, soft palate, uvula
|Temperature generally high|
|Herpetic gingivostomatitis||Herpes simplex virus-1||Moderate to severe||Vesicles
|Anterior oral cavity
Lips, gingiva, buccal mucosa
|Temperature generally high
|Aphthous stomatitis||Unknown||Mild to severe||Ulcerations; larger than in viral enanthems||Lips, tongue, buccal mucosa; generally not diffuse||Afebrile
May be recurrent
|Stevens-Johnson syndrome||Immunologic||Moderate to severe||Coalescent vesicles, which then ulcerate||Lips, gingiva, buccal mucosa, tongue, pharynx||Targetlike cutaneous lesions
Diffuse mucous membrane involvement