Hand-Foot-and-Mouth Disease (HFMD)

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Practice Essentials

Hand-foot-and-mouth disease (HFMD) is an acute viral illness that presents as a vesicular eruption in the mouth, but it also can involve the hands, feet, buttocks, and/or genitalia. Hand-foot-and-mouth disease is common and potentially but infrequently fatal in children younger than 5 years.[1]  Coxsackievirus A type 16 (CVA16) is the etiologic agent involved in most cases of HFMD, but the illness also is associated with coxsackievirus A5, A7, A9, A10, B2, and B5 strains. Coxsackievirus A6 may have become the commonest enterovirus in seasonal outbreaks of hand-foot-and-mouth disease in children in France and Finland.[2]

Enterovirus 71 (EV-71) has caused outbreaks of HFMD with associated neurologic involvement in the western Pacific region and Southeast Asia.



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The lower lip has an ulcer with an erythematous halo.

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:

Physical findings include the following:

Atypical clinical features include concomitant aseptic meningitis in HFMD caused by coxsackievirus strains (rare).[3] HFMD caused by EV-71 has a higher incidence of neurologic involvement, including the following[4] :

Diagnosis

The diagnosis of HFMD is typically based on clinical grounds. Laboratory studies usually are unnecessary, but the following may be done:

Management

There is no antiviral agent specific for the etiologic agents of HFMD. Instead, the treatment is mainly supportive, as follows:

 

Background

Hand-foot-and-mouth disease (HFMD) is an acute viral illness first evident 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. Coxsackievirus A6 may have become the commonest enterovirus in seasonal outbreaks of hand-foot-and-mouth disease in children in parts of Europe.[2]  

Enterovirus 71 (EV-71) has also caused outbreaks of HFMD with associated neurologic involvement in the western Pacific region and Southeast Asia.

Pathophysiology

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.

Frequency

United States

Epidemics of HFMD generally occur in the summer to early fall months, although cases can occur sporadically all year.

International

Hand-foot-and-mouth disease (HFMD) has become a societal burden in parts of Asia with pandemic potential[9] , particularly in Vietnam.[10]   HFMD epidemics associated with EV-71 have been more frequent in Southeast Asia in recent years, including the Republic of China (1998) and Singapore (2000). Risk factors in these epidemics include attendance at childcare centers, contact with HFMD, large family number, and rural residence.[11] Seasonal trends and climate factors may be evident and were delineated in Guangzhou (Canton) China.[1]  The incidence of HFMD is increasing despite current preventive efforts in Singapore.[12]

 

Mortality/Morbidity

Hand-foot-and-mouth disease caused by coxsackievirus is generally a mild self-limited illness that resolves in 7-10 days; rarely, HFMD may recur or persist. Serious complications also are 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.

Hand-foot-and-mouth disease 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 neurologic complications have been attributed to either immunopathology or virus-induced damage to gray matter.[3, 13] There appears to be a strong association between severe illness and coxsackievirus A6 and enterovirus -A71 infections.[10]

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.[14] 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.[4]

Sex

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.

Age

Children younger than 10 years are most commonly affected with HFMD; subsequent outbreaks among family members and close contacts may develop.[15]

History

The incubation period of hand-foot-and-mouth disease (HFMD) lasts approximately 1 week; patients then report a sore mouth or throat. Malaise may develop. Rarely, vomiting occurs in HFMD cases caused by EV-71.

Physical

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, as shown in the image below. Skin lesions, which present as tender macules or vesicles on an erythematous base, develop in approximately 75% of patients with HFMD. Their dermoscopic features at various stages of cutaneous lesional development have been described.[16] A fever of 38-39°C may be present for 24-48 hours.



View Image

The lower lip has an ulcer with an erythematous halo.

Atypical clinical features may be present. HFMD caused by coxsackievirus strains rarely presents with concomitant aseptic meningitis.[3] 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.[4]

Causes

HFMD is most commonly caused by coxsackievirus A16, but it is also caused by coxsackieviruses A5, A7, A9 A10, B2, and B5 and EV-71. Two major genotypes of EV-71, EV-71 B and C, have been identified as the strains principally involved in the EV-71 HFMD epidemics in Australia, Malaysia, Singapore, Republic of China, and Japan since 1997. These genotypes are considered particularly neurovirulent, accounting for the severe neurologic complications seen in EV-71 HFMD epidemics.[17]  

A 2023 outbreak of severe HFMD in southern Vietnam was traced to enterovirus A71 subgenogroup B5.[18]

Laboratory Studies

The diagnosis of hand-foot-and-mouth disease (HFMD) is typically based on clinical grounds. Laboratory studies usually are unnecessary. However, when it mimics Stevens-Johnson Syndrome[20]  or erythema multiforme,[21]  a skin biopsy specimen would be desirable.

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 also are a good source for viral collection. In patients without vesicles, rectal swabs can be collected. For viral isolation, two swab collections are recommended—one from the throat and the other from either vesicles or the rectum.

Serologic testing (eg, acute and convalescent antibody levels) may be obtained.

Differentiating coxsackie-associated from EV-71–associated HFMD may have prognostic significance. Polymerase chain reaction (PCR) and microarray technology are among the various ways of identifying the causative virus. Specific assays vary between hospitals.[5]

Medical Care

The treatment of hand-foot-and-mouth disease (HFMD) is supportive.[22] In fact, there is no antiviral agent specific for the etiologic agents. 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. Intravenous immunoglobulin (IVIG) and milrinone have shown some efficacy in a few reports.[6, 7, 8]

There is a relative dearth of treatment options for enterovirus-associated HFMD cases. Recent research has yielded several promising novel and existing therapeutics targeting specific viral mechanisms of action. These include molecular decoys, receptor antagonists, uncoating and translation inhibitors, polyprotein processing inhibitors, and replication inhibitors. Pleconaril is an uncoating inhibitor that shows promise in enterovirus 71–associated infections.

Amantadine and quinacrine, both translation inhibitors, and ribavirin, a replication inhibitor, are also being investigated as treatment options.[23]

Prevention

A vaccine would be desirable, especially against the Enterovirus A71 (EV-A71).[24]  EV71 vaccine in China was found effective in prevention, with CA16 and EV71 proportions found inversely related to the vaccination rate in Canton (Guangzhou), China.[1]  It may have a protective effect on the occurrence of encephalitis, which still may develop.[25]  Bivalent enterovirus 71 (EV71) and coxsackievirus A16 (CA16) vaccines may be advantageous.[26] An enterovirus A71 vaccination approach utilized in part of China has been credited with HFMD reduction.[27] There is no vaccine available in American or the European Union.

A suitable mitigation strategy to minimize enterovirus transmission among children with HFMD to control severe EV epidemics may be case isolation and class suspension if more than two having an onset of HFMD in one classroom within 1 week.[28] Hand washing and mask-wearing should substantially lower the transmission of HFMD.[29, 30]

Care with sample collection is desirable, as puncture with a contaminated lancet may produce severe HFMD.[31]

As a disease often involving children under 5 years of age, wastewater monitoring for HFMD-associated serotypes of Enterovirus and Coxsackievirus in selected Asian countries would be desirable.[32] .

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Acetaminophen (Tylenol, Aspirin Free Anacin, Feverall)

Clinical Context:  Reduces fever by acting directly on hypothalamic heat-regulating centers, which increases dissipation of body heat via vasodilation and sweating.

Ibuprofen (Motrin, Ibuprin)

Clinical Context:  One of the few NSAIDs indicated for reduction of fever.

Class Summary

These agents are used to control fever and pain.

Lidocaine anesthetic (Dermaflex)

Clinical Context:  Decreases permeability to sodium ions in neuronal membranes. This results in the inhibition of depolarization, blocking the transmission of nerve impulses.

Class Summary

These agents can be applied to ulcerations to control pain.

Diphenhydramine hydrochloride (Benadryl, Benylin)

Clinical Context:  For symptomatic relief of symptoms caused by release of histamine in allergic reactions.

Class Summary

These agents act by competitive inhibition of histamine at the H1 receptor.

Further Outpatient Care

Closely observe infants with HFMD for development of dehydration.

Clinical improvement is observed after approximately 3-5 days; cutaneous and mucosal lesions resolve in 7-10 days. The patient may continue to shed virus through the stool for weeks.

Further Inpatient Care

Patients with CNS manifestations of hand-foot-and-mouth disease (HFMD; eg, encephalitis, aseptic meningitis) may require hospitalization.

Complications

Rarely, aseptic meningitis and other neurological complications accompany HFMD. More commonly, oral ulcerations can interfere with fluid intake and cause dehydration, the most common complication of HFMD.

Rare case reports show spontaneous abortions associated with HFMD.

Prognosis

The prognosis of HFMD is excellent. The vast majority of patients with this infection are expected to recover fully.  Age greater than 3 years, enterovirus 71 autonomic nervous system dysregulation, pulmonary edema/hemorrhage, C-reactive protein greater than 40 mg/L, and cardiac troponin more than 0.04 ng/ml were risk factors for fatality in a study from Guangzhou (Canton), China.[22]

What is hand-foot-and-mouth disease (HFMD)?What are the signs and symptoms of hand-foot-and-mouth disease (HFMD)?Which neurological conditions are associated with hand-foot-and-mouth disease (HFMD)?How is hand-foot-and-mouth disease (HFMD) diagnosed?How is hand-foot-and-mouth disease (HFMD) managed?What is hand-foot-and-mouth disease (HFMD)?What is coxsackievirus?What is the pathogenesis of hand-foot-and-mouth disease (HFMD)?At what time of the year are hand-foot-and-mouth disease (HFMD) epidemics most likely to occur?What are the risk factors for developing hand-foot-and-mouth disease (HFMD)?How long does hand-foot-and-mouth disease (HFMD) normally last?What are common complications of hand-foot-and-mouth disease (HFMD)?Which etiologic factor increases the risk of neurological involvement in hand-foot-and-mouth disease (HFMD)?Which complications are more likely to occur with hand-foot-and-mouth disease (HFMD) caused by enterovirus 71 (EV-71)?Is hand-foot-and-mouth disease (HFMD) more common in males or females?Which age groups are most affected by hand-foot-and-mouth disease (HFMD)?What is the incubation period for hand-foot-and-mouth disease (HFMD)?Which physical findings suggest hand-foot-and-mouth disease (HFMD)?What are atypical physical findings of hand-foot-and-mouth disease (HFMD)?Which viruses cause hand-foot-and-mouth disease (HFMD)?Which disorders should be included in the differential diagnoses of hand-foot-and-mouth disease (HFMD)?What are the differential diagnoses for Hand-Foot-and-Mouth Disease (HFMD)?How is hand-foot-and-mouth disease (HFMD) diagnosed?What is the treatment for hand-foot-and-mouth disease (HFMD)?Are there any treatment options for enterovirus-associated hand-foot-and-mouth disease (HFMD)?Is there a vaccine available to help prevent the spread of hand-foot-and-mouth disease (HFMD) in humans?What is the goal of pharmacotherapy for hand-foot-and-mouth disease (HFMD)?Which medications in the drug class Antipyretics/analgesics are used in the treatment of Hand-Foot-and-Mouth Disease (HFMD)?Which medications in the drug class Topical anesthetics are used in the treatment of Hand-Foot-and-Mouth Disease (HFMD)?Which medications in the drug class Antihistamines are used in the treatment of Hand-Foot-and-Mouth Disease (HFMD)?What is the standard outpatient care for hand-foot-and-mouth disease (HFMD)?When is hospitalization indicated in the treatment of hand-foot-and-mouth disease (HFMD)?What are possible complications of hand-foot-and-mouth disease (HFMD)?What is the prognosis of hand-foot-and-mouth disease (HFMD)?

Author

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Specialty Editors

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.

Thomas M Kerkering, MD, FACP, FIDSA, Professor of Medicine with Tenure, Division of Infectious Diseases, Virginia Tech Carilion School of Medicine; Adjunct Professor, Department of Population Studies, Masters of Public Health Program, Virginia Tech University, School of Veterinary Medicine

Disclosure: Nothing to disclose.

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

Gary L Gorby, MD, Associate Professor, Departments of Internal Medicine and Medical Microbiology and Immunology, Division of Infectious Diseases, Creighton University School of Medicine; Associate Professor of Medicine, University of Nebraska Medical Center; Associate Chair, Omaha Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

Rajendra Kapila, MD, MBBS, † Professor, Department of Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Stephen J Nervi, MD, Staff Physician, Department of Dermatology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Disclosure: Nothing to disclose.

Acknowledgements

Diane H Johnson, MD Assistant Director, Assistant Professor, Department of Internal Medicine, Division of Infectious Diseases, Winthrop-University Hospital, State University of New York at Stony Brook School of Medicine

Diane H Johnson, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Medical Women's Association, American Society for Microbiology, and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

References

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  2. Tomba Ngangas S, Bisseux M, Jugie G, Lambert C, Cohen R, Werner A, et al. Coxsackievirus A6 Recombinant Subclades D3/A and D3/H Were Predominant in Hand-Foot-And-Mouth Disease Outbreaks in the Paediatric Population, France, 2010-2018. Viruses. 2022 May 17. 14 (5):[View Abstract]
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  14. 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. [View Abstract]
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  19. Soylu A, Yıldız G, Torun Bayram M, Kavukçu S. IL-1β blockade in periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: case-based review. Rheumatol Int. 2021 Jan. 41 (1):183-188. [View Abstract]
  20. No TH, Jo KM, Jung SY, Kim MR, Kim JY, Park CS, et al. Coxsackievirus A6-induced Hand-Foot-and-Mouth Disease Mimicking Stevens-Johnson Syndrome in an Immunocompetent Adult. Infect Chemother. 2020 Dec. 52 (4):634-640. [View Abstract]
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  26. Liu D, Leung K, Jit M, Yu H, Yang J, Liao Q, et al. Cost-effectiveness of bivalent versus monovalent vaccines against hand, foot and mouth disease. Clin Microbiol Infect. 2020 Mar. 26 (3):373-380. [View Abstract]
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The lower lip has an ulcer with an erythematous halo.

The lower lip has an ulcer with an erythematous halo.

The lower lip has an ulcer with an erythematous halo.

Illness Etiologic Agent Usual Severity of Clinical Illness Appearance of Lesions Locations of Lesions Other Features
HFMDCoxsackie-virus A16 (most common), A5, A7, A9, A10, B2, B5



Enterovirus 71



MildPapules →



Vesicles → ulcerations on an erythematous base



Usually 2-6 mm



Gingiva



Buccal mucosa



Tongue



Pharynx



Lesions may also be found on hands, feet, buttocks, and genitalia.



Low-grade fever



HerpanginaCoxsackie-virus A1-A10, A16, A22



Echovirus 3, 6, 9, 16, 17, 25, 30



Moderate; can be severePapules →



Vesicles → ulcerations on an erythematous base



Usually 2-4 mm



Posterior oral cavity



Tonsils, soft palate, uvula



Temperature generally high
Herpetic gingivostomatitisHerpes simplex virus-1Moderate to severeVesicles



ulcerations



Anterior oral cavity



Lips, gingiva, buccal mucosa



Temperature generally high



Lymphadenopathy



Aphthous stomatitisUnknownMild to severeUlcerations; larger than in viral enanthemsLips, tongue, buccal mucosa; generally not diffuseAfebrile



May be recurrent



Stevens-Johnson syndromeImmunologicModerate to severeCoalescent vesicles, which then ulcerateLips, gingiva, buccal mucosa, tongue, pharynxTargetlike cutaneous lesions



Diffuse mucous membrane involvement