NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

Hand Foot And Mouth Disease

Authors
Amanda M. Guerra; Emily Orille1; Muhammad Waseem2.

Affiliations
1 Michigan State University, McLaren Macomb
2 Weill Cornell Medicine New York and New York Medical College, Valhalla NY

Last Update: October 9, 2022.

Continuing Education Activity

Hand, foot, and mouth disease (HFMD) is a common viral illness usually
affecting infants and children but can affect adults. The infection usually
involves the hands, feet, mouth, and sometimes, even the genitals and
buttocks. The cause of hand, foot, and mouth disease is coxsackievirus A
type 16 in most cases, but the infection can also be caused by many other
strains of coxsackieviruses and Enteroviruses. The coxsackievirus is a
member of the Picornaviridae family, which includes non-enveloped
single-stranded RNA viruses. This activity reviews the pathophysiology
and clinical presentation of HFMD and highlights the role of the
interprofessional team in managing patients with this disease.
Objectives:
• Identify the etiology of HFMD.
• Describe the presentation of a patient with HFMD.
• Outline the management options available for HFMD.
• Describe interprofessional team strategies for improving care
coordination and communication to advance the management of
HFMD and improve outcomes.
Access free multiple choice questions on this topic.

Introduction
Hand, foot, and mouth disease (HFMD) is a common viral illness usually
affecting infants and children but can affect adults. The infection usually
involves the hands, feet, mouth, and sometimes, even the genitals and
buttocks. The cause of hand, foot, and mouth disease is coxsackievirus A
type 16 in most cases, but the infection can also be caused by many other
strains of coxsackievirus. In the western Pacific, hand, foot, and mouth
disease has been linked to enterovirus. The coxsackievirus is a member of
the Picornaviridae family, which includes non-enveloped single-stranded
RNA viruses.[1][2][3]

Etiology
Hand, foot, and mouth disease is a viral exanthem, and it is most
commonly caused by the coxsackievirus of the Enterovirus family.
Coxsackievirus A16 and enterovirus A71 are the serotypes most
commonly implicated as causative agents.[4][5][6] Coxsackievirus A6 has
recently emerged as another cause of HFMD in the USA and
worldwide.[7] Coxsackievirus A10 has been implicated in severe
disease.[8] Coxsackievirus A4 to A7, A9, B1 to B3, and B5 have also been
less commonly associated with HFMD.[9]

Epidemiology
This viral infection is not indigenous to one area in particular but occurs
worldwide. As children (particularly those younger than seven years of
age) tend to be infected at a higher rate than adults, you can see outbreaks
in daycares, summer camps, or within the family. Large-scale surveillance
from China demonstrated that more than 90% of HFMD cases occurred in
children less than five years of age, mortality was around 0.03%, and that
cases tended to occur more frequently during late spring and early
summer.[10] A study from Vietnam showed a positive correlation between
an increase in environmental temperature and humidity and an increase in
the incidence of HFMD.[11]
In 2021, French surveillance found a rapid increase in HFMD cases, with
more than 3400 cases. Although more than 90% of sequenced cases were
found to be linked to Enterovirus, atypical cases were found to be
associated with Coxsackievirus A6 and A16.[12] Coxsackievirus A6
remains the dominant cause of HFMD in the United States.[7]

Pathophysiology
The spread of the human enterovirus is mediated by oral ingestion of the
shed virus from the gastrointestinal or upper respiratory tract of infected
hosts or via vesicle fluid or oral secretions.[13] Patients tend to be most
infectious in the first week of the disease, with an incubation period
ranging between 3 to 6 days.[13] After ingestion, the virus replicates in the
lymphoid tissue of the lower intestine and the pharynx and spreads to the
regional lymph nodes. This can be spread to multiple organs, including the
central nervous system, heart, liver, and skin.

History and Physical

Hand, foot, and mouth disease can start with a low-grade fever, reduced
appetite, and general malaise. The most common hand, foot, and mouth
disease presenting symptom is usually mouth or throat pain secondary to
the enanthem. The presence of vesicles is surrounded by a thin halo of
erythema, eventually rupturing and forming superficial ulcers with a grey-
yellow base and erythematous rim. The exanthem can be macular, papular,
or vesicular. The lesions are about 2 mm to 6 mm in size, are non-pruritic,
and are typically not painful. They last about ten days, tend to rupture, and
result in painless and shallow ulcers that do not leave a scar. The exanthem
can involve the dorsum of the hand, feet, buttocks, legs, and arms. Oral
lesions commonly involve buccal and tongue ulcers but may also involve
the soft palate.[13]
HFMD can also present with atypical features like concomitant aseptic
meningitis. Enterovirus infections that cause hand, foot, and mouth disease
are notorious for involving the central nervous system (CNS) and may
cause encephalitis, polio-like syndrome, acute transverse myelitis,
Guillain-Barre syndrome, benign intracranial hypertension, and acute
cerebellar ataxia.[13]

Evaluation
The diagnosis of hand, foot, and mouth disease is usually made clinically.
The virus can be detected in the stool for about six weeks after infection;
however, shedding from the oropharynx is generally less than four weeks.
Light microscopy of biopsies or scrapings of vesicles will differentiate
HFMD from varicella-zoster virus and herpes simplex virus. While
serology is not sensitive to making a diagnosis of HFMD, levels of IgG
can be used to monitor recovery.
In some centers, serology is used to differentiate enterovirus 71 from
coxsackievirus, as this has prognostic significance. Today, polymerase
chain reaction assays are available in most centers to confirm the diagnosis
of coxsackievirus. A swab of the lesion can detect coxsackievirus or
enterovirus using real-time PCR assays.[14][7]

Treatment / Management
Hand, foot, and mouth disease is a mild clinical syndrome and will resolve
within 7 to 10 days. Treatment is primarily supportive. Pain and fever can
be managed with NSAIDs and acetaminophen. Making sure the patient
remains well-hydrated is important. Additionally, a mixture of liquid
ibuprofen and liquid diphenhydramine can be used to gargle, which helps
coat the ulcers, easing the pain.[15][16] Steroids were found to increase
the risk of severe HFMD.[17]
Over the past decade, researchers have developed specific treatments to
manage enterovirus 71-induced hand, foot, and mouth disease because of
its severe neurological complications. So far, no drug has been approved,
but promising novel agents include molecular decoys, translation
inhibitors, receptor antagonists, and replication inhibitors. An antiviral
agent that has shown promise in the treatment of enterovirus 71 is
pleconaril, an anti-picornaviral agent. However, there are currently no
licensed antivirals for the treatment of HFMD.[18] Anecdotal reports have
shown some clinical response to acyclovir, but large-scale trials have not
established this.[19]
Several vaccine candidates have been developed against HFMD and
Enteroviruses. Currently, strain-specific inactivated whole-virus
aluminum-adjuvant vaccines have been developed in China and are
approved for widespread use.[10] In a study with 10,077 participants, a
three-dose regimen of the EV71 C4a vaccine showed an overall efficacy of
94.7% (95% CI 87.8–97.6), with protection lasting for around two
years.[20] virus-like particles (VLPs) vaccines, DNA vaccines, peptide
vaccines, and subunit vaccines have been developed but are in various
stages of clinical trials.[21]

Differential Diagnosis
The differential diagnosis for HFMD should include conditions that
present with maculopapular or vesicular rashes with or without oral
lesions.[13] These conditions include:
 • Erythema multiforme
• Herpangina
• Herpes simplex
• Herpes zoster
• Kawasaki disease
• Toxic epidermal necrolysis(TEN)
• Viral pharyngitis
• Rocky Mountain spotted fever
• Varicella zoster infection (chickenpox)
• Steven-Johnson syndrome
• Monkeypox - In the context of an ongoing outbreak, it becomes
important to consider the difficulty in clinically differentiating
between monkeypox and HFMD[22]

Prognosis
The prognosis for most patients with hand, foot, and mouth disease is
excellent. Most patients recover within a few weeks without any residual
sequelae. Acute illness usually lasts 10 to 14 days, and the infection rarely
recurs or persists. However, some patients with hand, foot, and mouth
disease may develop serious complications, which include the following:
• Persistent stomatitis is associated with painful ulcers. The pain can
be severe enough to limit food intake, and dehydration can result,
especially in young children.
• Aseptic meningitis can occur, but this is more common with
enterovirus 71. This particular virus is associated with a higher rate
of neurological involvement compared to coxsackievirus. The
individual may develop acute cerebellar ataxia, polio-like syndrome,
encephalitis, benign intracranial hypertension, and Guillain-Barre
syndrome. The virus is believed to induce damage to the gray matter,
resulting in motor dysfunction.[23]
• Coxsackievirus can rarely cause interstitial pneumonia, myocarditis,
pancreatitis, and pulmonary edema.[24]
 • Some studies indicate that coxsackievirus infections may also be
associated with spontaneous abortions.[25]

Complications
Pneumonia, myocarditis, pancreatitis, and pulmonary edema, as well as
serositis involving other major organs, are rarely associated with
HFMD.[24] A large meta-analysis of children with HFMD suggested that
lethargy, pneumo-edema/pneumorrhagia, seizures, dyspnoea, and coma
were risk factors for death in HFMD.[26] The case fatality rate associated
with enterovirus 71 was found to be 1.7% in a systematic review and
meta-analysis.[27]

Deterrence and Patient Education

Patient/parental education is paramount in reducing the transmission of
HFMD among children and also between children and adults.
Handwashing has been proven to be an effective strategy in the prevention
of HFMD transmission.[28] A community intervention study showed that
intensive education on hand hygiene techniques led to an improvement in
the personal hygiene of both parents and children. This subsequently
reduced the incidence of HFMD in the study population.[29] The parents
should also be advised to keep the child away from immunosuppressed
individuals due to the potential risk of serious illness.

Pearls and Other Issues

The majority of patients with coxsackievirus-induced hand, foot, and
mouth disease are treated as outpatients, but those who have CNS
involvement may require admission for close monitoring. These patients
often require imaging studies of the brain to guide treatment and recovery.
Infants may develop dehydration, especially if they develop painful oral
ulcers and may require Intravenous hydration. Admission is highly
recommended for any infant with hand, foot, and mouth disease who
shows signs of severe disease and lethargy. The virus is shed in the stools
for a few weeks; hence, patients should be educated about hand washing
and maintenance of good personal hygiene.

Enhancing Healthcare Team Outcomes

Cases of HFMD are on the rise, and clinicians need to know how to make
the diagnosis. Because many recent cases have involved the brain,
a neurological consult may be necessary. An interprofessional team that
includes clinicians (MDs, DOs, NPs, or PAs), specialists (neurologist,
pediatrician, internist, infectious disease expert), nursing staff, and a
pharmacist should be involved. Clinicians will diagnose and initiate
therapy and decide which referrals may be necessary. Pharmacists can
assist with medication management, perform medication reconciliation,
and answer questions about the agents used. Nurses will coordinate
activities with other interprofessional team members, help with patient
examination, and counsel patients and/or parents. Everyone on the team
must communicate openly with the rest of the care team to ensure the best
care leading to optimal outcomes. [Level 5]
The outcomes for most patients with HFMD are excellent, with full
recovery occurring within 7 to 21 days. [Level 1]

Review Questions
• Access free multiple choice questions on this topic.
• Comment on this article.

References
1.
Woodland DL. Hand, Foot, and Mouth Disease. Viral
Immunol. 2019 May;32(4):159. [PubMed: 31038400]
2.
Zhu L, Yin H, Sun H, Qian T, Zhu J, Qi G, Wang Y, Qi B. The
clinical value of aquaporin-4 in children with hand, foot, and mouth
disease and the effect of magnesium sulfate on its expression: a
prospective randomized clinical trial. Eur J Clin Microbiol Infect
Dis. 2019 Jul;38(7):1343-1349. [PubMed: 31028503]
3.
Wu CY, Lin FL. Hand-foot-and-mouth-disease-induced Koebner
phenomenon in psoriasis. J Dtsch Dermatol Ges. 2019
May;17(5):549-551. [PubMed: 30994243]
4.
Muzumdar S, Rothe MJ, Grant-Kels JM. The rash with
maculopapules and fever in children. Clin Dermatol. 2019 Mar -
Apr;37(2):119-128. [PubMed: 30981292]
5.
Nelson BR, Edinur HA, Abdullah MT. Compendium of hand, foot
and mouth disease data in Malaysia from years 2010-2017. Data
Brief. 2019 Jun;24:103868. [PMC free article: PMC6441719]
[PubMed: 30976640]
6.
Tsai YH, Huang SW, Hsieh WS, Cheng CK, Chang CF, Wang YF,
Wang JR. Enterovirus A71 Containing Codon-Deoptimized VP1 and
High-Fidelity Polymerase as Next-Generation Vaccine Candidate. J
Virol. 2019 Jul 01;93(13) [PMC free article: PMC6580961]
[PubMed: 30996087]
7.
Kimmis BD, Downing C, Tyring S. Hand-foot-and-mouth disease
caused by coxsackievirus A6 on the rise. Cutis. 2018
Nov;102(5):353-356. [PubMed: 30566537]
8.
Bian L, Gao F, Mao Q, Sun S, Wu X, Liu S, Yang X, Liang Z.
Hand, foot, and mouth disease associated with coxsackievirus A10:
more serious than it seems. Expert Rev Anti Infect Ther. 2019
Apr;17(4):233-242. [PubMed: 30793637]
9.
Sarma N. Hand, foot, and mouth disease: current scenario and Indian
perspective. Indian J Dermatol Venereol Leprol. 2013 Mar-
Apr;79(2):165-75. [PubMed: 23442455]
10.
Esposito S, Principi N. Hand, foot and mouth disease: current
knowledge on clinical manifestations, epidemiology, aetiology and
prevention. Eur J Clin Microbiol Infect Dis. 2018 Mar;37(3):391-
398. [PubMed: 29411190]
11.
Nguyen HX, Chu C, Tran QD, Rutherford S, Phung D. Temporal
relationships between climate variables and hand-foot-mouth
disease: a multi-province study in the Mekong Delta Region,
Vietnam. Int J Biometeorol. 2020 Mar;64(3):389-396. [PubMed:
31720856]
12.
Mirand A, Cohen R, Bisseux M, Tomba S, Sellem FC, Gelbert N,
Béchet S, Frandji B, Archimbaud C, Brebion A, Chabrolles H,
Regagnon C, Levy C, Bailly JL, Henquell C. A large-scale outbreak
of hand, foot and mouth disease, France, as at 28 September
2021. Euro Surveill. 2021 Oct;26(43) [PMC free article:
PMC8555367] [PubMed: 34713796]
13.
Saguil A, Kane SF, Lauters R, Mercado MG. Hand-Foot-and-Mouth
Disease: Rapid Evidence Review. Am Fam Physician. 2019 Oct
01;100(7):408-414. [PubMed: 31573162]
14.
Broccolo F, Drago F, Ciccarese G, Genoni A, Porro A, Parodi A,
Chumakov K, Toniolo A. Possible long-term sequelae in hand, foot,
and mouth disease caused by Coxsackievirus A6. J Am Acad
Dermatol. 2019 Mar;80(3):804-806. [PubMed: 30661911]
15.
Rasti M, Khanbabaei H, Teimoori A. An update on enterovirus 71
infection and interferon type I response. Rev Med Virol. 2019
Jan;29(1):e2016. [PMC free article: PMC7169063] [PubMed:
30378208]
16.
Coates SJ, Davis MDP, Andersen LK. Temperature and humidity
affect the incidence of hand, foot, and mouth disease: a systematic
review of the literature - a report from the International Society of
Dermatology Climate Change Committee. Int J Dermatol. 2019
Apr;58(4):388-399. [PubMed: 30187452]
17.
He Y, Yang J, Zeng G, Shen T, Fontaine RE, Zhang L, Shi G, Wang
Y, Li Q, Long J. Risk factors for critical disease and death from
hand, foot and mouth disease. Pediatr Infect Dis J. 2014
Sep;33(9):966-70. [PubMed: 24577041]
18.
Kim B, Moon S, Bae GR, Lee H, Pai H, Oh SH. Factors associated
with severe neurologic complications in patients with either hand-
foot-mouth disease or herpangina: A nationwide observational study
in South Korea, 2009-2014. PLoS One. 2018;13(8):e0201726. [PMC
free article: PMC6086402] [PubMed: 30096160]
19.
Velástegui J, Cova L, Galarza Y, Fierro P, León Baryolo L, Bustillos
A. [A case report of hand, foot, and mouth disease with necrotizing
mucocutaneous lesions]. Medwave. 2019 Aug
14;19(7):e7683. [PubMed: 31442216]
20.
Li JX, Song YF, Wang L, Zhang XF, Hu YS, Hu YM, Xia JL, Li J,
Zhu FC. Two-year efficacy and immunogenicity of Sinovac
Enterovirus 71 vaccine against hand, foot and mouth disease in
children. Expert Rev Vaccines. 2016;15(1):129-37. [PubMed:
26460695]
21.
Nayak G, Bhuyan SK, Bhuyan R, Sahu A, Kar D, Kuanar A. Global
emergence of Enterovirus 71: a systematic review. Beni Suef Univ J
Basic Appl Sci. 2022;11(1):78. [PMC free article: PMC9188855]
[PubMed: 35730010]
22.
Lewis A, Josiowicz A, Hirmas Riade SM, Tous M, Palacios G,
Cisterna DM. Introduction and Differential Diagnosis of Monkeypox
in Argentina, 2022. Emerg Infect Dis. 2022 Oct;28(10):2123-
2125. [PMC free article: PMC9514367] [PubMed: 35960545]
23.
Gonzalez G, Carr MJ, Kobayashi M, Hanaoka N, Fujimoto T.
Enterovirus-Associated Hand-Foot and Mouth Disease and
Neurological Complications in Japan and the Rest of the World. Int J
Mol Sci. 2019 Oct 20;20(20) [PMC free article: PMC6834195]
[PubMed: 31635198]
24.
Park B, Kwon H, Lee K, Kang M. Acute pancreatitis in hand, foot
and mouth disease caused by Coxsackievirus A16: case
report. Korean J Pediatr. 2017 Oct;60(10):333-336. [PMC free
article: PMC5687981] [PubMed: 29158768]
25.
Ogilvie MM, Tearne CF. Spontaneous abortion after hand-foot-and-
mouth disease caused by Coxsackie virus A16. Br Med J. 1980 Dec
06;281(6254):1527-8. [PMC free article: PMC1714960] [PubMed:
6254606]
26.
Ni XF, Li X, Xu C, Xiong Q, Xie BY, Wang LH, Peng YH, Li XW.
Risk factors for death from hand-foot-mouth disease: a meta-
analysis. Epidemiol Infect. 2020 Feb 27;148:e44. [PMC free article:
PMC7058831] [PubMed: 32102711]
27.
Zhao YY, Jin H, Zhang XF, Wang B. Case-fatality of hand, foot and
mouth disease associated with EV71: a systematic review and meta-
 analysis. Epidemiol Infect. 2015 Oct;143(14):3094-102. [PMC free
article: PMC9151022] [PubMed: 25721492]
28.
Zhang D, Li Z, Zhang W, Guo P, Ma Z, Chen Q, Du S, Peng J, Deng
Y, Hao Y. Hand-Washing: The Main Strategy for Avoiding Hand,
Foot and Mouth Disease. Int J Environ Res Public Health. 2016 Jun
18;13(6) [PMC free article: PMC4924067] [PubMed: 27322307]
29.
Guo N, Ma H, Deng J, Ma Y, Huang L, Guo R, Zhang L. Effect of
hand washing and personal hygiene on hand food mouth disease: A
community intervention study. Medicine (Baltimore). 2018
Dec;97(51):e13144. [PMC free article: PMC6320109] [PubMed:
30572426]

Figures

Hand and Mouth. Contributed by DermNetNZ

Copyright © 2022, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution 4.0 International License

(http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution, and reproduction

in any medium or format, as long as you give appropriate credit to the original author(s) and the source, a link is

provided to the Creative Commons license, and any changes made are indicated.

Bookshelf ID: NBK431082PMID: 28613736