Hand-foot-mouth disease is a common, highly contagious enteroviral illness primarily affecting children under 5 years, caused most commonly by coxsackievirus A16 and enterovirus A71 (EV-A71), with coxsackievirus A6 emerging as a cause of more severe/atypical presentations. [1-2] The disease is self-limited in the vast majority of cases, resolving in 7–10 days, but rare neurologic and cardiopulmonary complications can be fatal. [1][3]
1. History
- Onset and prodrome: Low-grade fever, malaise, sore throat, and decreased appetite typically precede the rash by 1–2 days [1][4]
- Rash characterization: Painful oral ulcers (tongue, buccal mucosa, hard palate) followed by papulovesicular lesions on palms, soles, and sometimes buttocks/knees [1][4]
- Timing: Spring to fall seasonality in North America; incubation period 3–6 days [1]
- Triggers/exposures: Daycare/school attendance, sick contacts, recent outbreak in community
- Associated symptoms: Odynophagia, drooling, refusal to eat/drink (especially toddlers), irritability
- Important negatives: Ask about decreased urine output (dehydration), lethargy, vomiting, limb weakness, seizures, respiratory distress
2. Alarm Features
- High fever ≥39°C (especially sustained) [5-6]
- Neurologic signs: Lethargy, drowsiness, myoclonic jerks/limb shaking, startle reflex, seizures, acute flaccid paralysis, neck stiffness [5][7-8]
- Cardiopulmonary signs: Tachypnea, tachycardia, frothy sputum, cyanosis [5][7]
- Persistent vomiting — associated with increased mortality risk [7]
- Age <3 years with EV-A71 infection — highest risk for brainstem encephalitis and death [2][9]
- Rapid clinical deterioration over hours — suggests autonomic dysregulation/pulmonary edema
3. Medications
- Supportive analgesics/antipyretics: Acetaminophen or ibuprofen for fever and pain [1]
- Oral lidocaine is NOT recommended due to risk of aspiration and toxicity in children [1]
- No approved antiviral therapy is currently available [1][3]
- IVIG has been used in severe cases (particularly EV-A71 with CNS involvement) and may shorten illness duration, though evidence is limited [10]
- Avoid aspirin in children (Reye syndrome risk)
- Avoid antibiotics unless secondary bacterial superinfection is suspected
- Topical agents: "Magic mouthwash" (diphenhydramine/Maalox mixture) is sometimes used off-label for oral pain in older children, though evidence is limited
4. Diet
- Hydration is the priority — encourage cold fluids, popsicles, ice chips to maintain intake despite oral pain [1]
- Avoid acidic, salty, or spicy foods that exacerbate oral ulcer pain
- Soft, bland diet (yogurt, applesauce, mashed foods) is best tolerated
- Monitor for dehydration — especially in toddlers who refuse oral intake due to painful ulcers
5. Review of Systems
- Neuro: Headache, irritability, lethargy, tremor, limb weakness, gait instability
- Respiratory: Cough, tachypnea, dyspnea (pulmonary edema/pneumonia)
- GI: Vomiting, diarrhea, poor oral intake
- Derm: Distribution and morphology of rash, pruritus, nail changes (onychomadesis weeks later) [11-12]
- Cardiac: Palpitations (myocarditis, rare)
- MSK: Arthralgias (more common in CVA6 adult cases) [12]
6. Collateral History and Family History
- Daycare/school exposure: Outbreaks are common in group childcare settings
- Sick contacts: Other children or adults with febrile illness, rash, or oral ulcers
- Adult contacts: >50% of infected adults may be asymptomatic but still transmit virus [4]
- Family history of atopic dermatitis: Increases risk of atypical/severe cutaneous presentations ("eczema coxsackium") [11][13]
- Immunocompromised household members: Higher risk for severe disease
7. Risk Factors
- Age <5 years (peak incidence) [1][3]
- Daycare/school attendance and crowded living conditions
- Poor hand hygiene and diaper-changing practices
- Summer/fall season in temperate climates [1]
- Rural residence — associated with increased risk of severe disease [6]
- Atopic dermatitis — risk for eczema coxsackium [11]
- Immunocompromised state — risk for severe/prolonged disease
- EV-A71 serotype — strongest association with neurologic complications [2][8]
8. Differential Diagnosis
- Herpangina — posterior oral ulcers only (uvula, soft palate, tonsillar pillars), no hand/foot lesions [4]
- Herpes simplex (HSV) gingivostomatitis — anterior oral ulcers, gingival involvement, grouped vesicles on an erythematous base
- Varicella — centripetal distribution, lesions in various stages ("crops"), pruritic
- Erythema multiforme — target lesions, may have mucosal involvement; consider drug reaction
- Measles — Koplik spots, cephalocaudal maculopapular rash, coryza/cough/conjunctivitis
- Eczema herpeticum — punched-out erosions in atopic dermatitis distribution; distinguish from eczema coxsackium [11][13]
- Kawasaki disease — prolonged fever, conjunctival injection, strawberry tongue, extremity changes
- Stevens-Johnson syndrome — mucosal erosions, targetoid lesions, systemic toxicity
- Impetigo — honey-crusted lesions, bacterial culture positive
9. Past Medical History
- Atopic dermatitis — predisposes to eczema coxsackium and more widespread/atypical rash [11]
- Prior HFMD episodes — reinfection with different serotypes is possible
- Immunodeficiency — congenital or acquired; risk for severe/prolonged course
- Chronic cardiopulmonary disease — may worsen with HFMD-related complications
- Recent nail shedding (onychomadesis) — may indicate prior undiagnosed HFMD [11-12]
10. Physical Exam
- Vital signs: Low-grade fever typical; high fever (≥39°C), tachycardia, or tachypnea are red flags [5-6]
- Oral cavity: Vesicles and shallow ulcers on tongue, buccal mucosa, hard palate; distinguish from posterior-only herpangina [1][4]
- Skin: Papulovesicular lesions on palms, soles, dorsal hands/feet, and buttocks; may be maculopapular early. Atypical CVA6 presentations include widespread vesiculobullous, purpuric, or Gianotti-Crosti-like eruptions [12-13]
- Neuro exam: Assess for meningismus, altered consciousness, myoclonus, tremor, cranial nerve palsies, limb weakness/hypotonia [5][8]
- Hydration status: Mucous membranes, skin turgor, capillary refill, urine output
- Respiratory: Auscultate for crackles (pulmonary edema), wheezing
11. Lab Studies
- Routine labs are generally unnecessary in uncomplicated HFMD
- If severe disease suspected:
- CBC with differential — elevated WBC, neutrophilia, decreased eosinophils associated with severity [6-7]
- BMP — glucose >8.3 mmol/L, low chloride, and low sodium are predictors of severe disease [6][9]
- CRP/procalcitonin — to help exclude bacterial superinfection
- Blood glucose — hyperglycemia is an independent risk factor for severe HFMD [9]
- Cardiac enzymes (troponin, CK-MB) — if myocarditis suspected [5]
- CSF analysis — if meningitis/encephalitis suspected (mononuclear pleocytosis expected) [5]
- Viral confirmation (if needed): RT-PCR from throat swab, vesicle fluid, stool, or rectal swab for enterovirus typing [12][14]
12. Imaging
- Not indicated in uncomplicated HFMD
- Chest X-ray: If respiratory distress — look for pulmonary edema, diffuse infiltrates [5]
- Brain MRI: If encephalitis or brainstem involvement suspected — may show brainstem, cerebellar, or spinal cord signal abnormalities [4]
- Echocardiography: If myocarditis suspected — assess for decreased contractility [5]
13. Special Tests
- Enterovirus RT-PCR — gold standard for serotype identification (throat swab, vesicle fluid, stool) [12]
- Viral culture — less commonly used, slower turnaround
- CSF enterovirus PCR — for suspected CNS involvement
- Clinical scoring systems have been developed for pediatric HFMD diagnosis (incorporating age, exposure history, rash density) with AUC ~0.80 [14]
- Point-of-care: Bedside glucose (hyperglycemia as severity marker) [9]
14. ECG
- Not routinely indicated in uncomplicated HFMD
- Obtain ECG if: Tachycardia out of proportion to fever, irregular rhythm, or suspected myocarditis
- Findings in myocarditis: ST-segment changes, T-wave inversions, arrhythmias, low voltage
- Continuous monitoring warranted if autonomic dysregulation or cardiopulmonary compromise suspected [5]
15. Assessment
- Typical presentation: Brief febrile illness with characteristic oral ulcers and papulovesicular rash on hands/feet, self-limited over 7–10 days [1]
- Atypical presentations (increasingly recognized with CVA6): Widespread vesiculobullous eruptions, purpuric lesions, eczema coxsackium, Gianotti-Crosti-like rash; may affect adults [12-13]
- Severity stratification:
- Mild: Fever <39°C, oral ulcers, typical rash, adequate oral intake
- Moderate: High fever, vomiting, poor oral intake, dehydration
- Severe: Neurologic signs (lethargy, myoclonus, paralysis), cardiopulmonary compromise (tachypnea, pulmonary edema, shock) [5][9]
- Complications: Brainstem encephalitis, aseptic meningitis, acute flaccid paralysis, pulmonary edema/hemorrhage, myocarditis [2-3]
- Late sequelae: Onychomadesis (nail shedding) 1–2 months post-infection; neurologic sequelae in severe EV-A71 cases [11-12]
16. Treatment Plan
- Supportive care is the mainstay: [1][3]
- Antipyretics/analgesics: Acetaminophen 10–15 mg/kg q4–6h or ibuprofen 10 mg/kg q6–8h
- Oral hydration: Cold fluids, popsicles; consider NG or IV fluids if unable to maintain intake
- Topical oral pain relief: Diphenhydramine/antacid mixture for older children (swish and spit); avoid viscous lidocaine [1]
- Severe cases (hospitalized):
- IV fluids for dehydration
- IVIG (1–2 g/kg) considered for severe EV-A71 with CNS involvement [10]
- ICU admission for autonomic dysregulation, pulmonary edema, or shock
- Mechanical ventilation if respiratory failure
- Milrinone has been used in cases with neurogenic pulmonary edema (limited evidence)
- Infection control: Strict hand hygiene, contact precautions, surface disinfection; exclude from daycare until fever-free and vesicles have crusted [1]
- No role for antibiotics or antivirals in routine cases [1][3]
17. Disposition
- Discharge criteria (majority of cases):
- Tolerating oral fluids adequately
- No signs of dehydration
- No neurologic or cardiopulmonary red flags
- Reliable caregiver with return precautions understood
- Admission criteria:
- Inability to maintain oral hydration / clinical dehydration
- High fever (≥39°C) with systemic toxicity [5]
- Any neurologic signs: lethargy, myoclonus, seizures, limb weakness, altered consciousness [5][8]
- Cardiopulmonary compromise: tachypnea, tachycardia, cyanosis [5][7]
- Age <6 months with significant illness
- ICU admission: Brainstem encephalitis, pulmonary edema, hemodynamic instability, autonomic dysregulation
- Specialist consultation: Pediatric neurology (encephalitis/paralysis), pediatric cardiology (myocarditis), infectious disease (severe/atypical cases)
18. Follow Up / Return Precautions
- Expected course: Fever resolves in 2–3 days; oral ulcers and rash resolve in 7–10 days [1]
- Onychomadesis (nail shedding) may occur 4–8 weeks later — benign and self-resolving [11-12]
- Return immediately for:
- Persistent high fever >3 days
- Decreased responsiveness, excessive sleepiness, or irritability
- Jerking movements, tremor, or limb weakness
- Difficulty breathing or rapid breathing
- Persistent vomiting or inability to drink
- Decreased urine output (<3 wet diapers/day in infants)
- Contagion counseling: Virus shed in stool for weeks after resolution; emphasize hand hygiene, especially after diaper changes [1]
- Follow-up: PCP in 3–5 days if symptoms not improving; sooner if any red flags develop
References
1. Hand-Foot-and-Mouth Disease: Rapid Evidence Review. — Saguil A, Kane SF, Lauters R, Mercado MG. American Family Physician. 2019.
2. Changing Epidemiology of Hand, Foot, and Mouth Disease Causative Agents and Contributing Factors. — Kalam N, Balasubramaniam V. The American Journal of Tropical Medicine and Hygiene. 2024.
3. Current Status of Hand-Foot-and-Mouth Disease. — Zhu P, Ji W, Li D, et al. Journal of Biomedical Science. 2023.
4. Clinical Features, Diagnosis, and Management of Enterovirus 71. — Ooi MH, Wong SC, Lewthwaite P, Cardosa MJ, Solomon T. The Lancet. Neurology. 2010.
5. An Epidemic of Enterovirus 71 Infection in Taiwan. — Ho M, Chen ER, Hsu KH, et al. The New England Journal of Medicine. 1999.
6. Identification of Immune and Metabolic Predictors of Severe Hand-Foot-Mouth Disease. — Qin L, Dang D, Wang X, et al. PloS One. 2019.
7. Epidemiological Characteristics, Routine Laboratory Diagnosis, Clinical Signs and Risk Factors for Hand, -Foot -and -Mouth Disease: A Systematic Review and Meta-Analysis. — Yi Z, Pei S, Suo W, et al. PloS One. 2022.
8. 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. — Kim B, Moon S, Bae GR, et al. PloS One. 2017.
9. Study on Risk Factors for Severe Hand, Foot and Mouth Disease in China. — Li W, Teng G, Tong H, et al. PloS One. 2014.
10. Clinical Characteristics and Managements of Severe Hand, Foot and Mouth Disease Caused by Enterovirus A71 and Coxsackievirus A16 in Shanghai, China. — Cai K, Wang Y, Guo Z, et al. BMC Infectious Diseases. 2019.
11. Hand-Foot-and-Mouth Disease: A New Look at a Classic Viral Rash. — Nassef C, Ziemer C, Morrell DS. Current Opinion in Pediatrics. 2015.
12. Coxsackievirus A6–Induced Hand-Foot-Mouth Disease. — Stewart CL, Chu EY, Introcaso CE, Schaffer A, James WD. JAMA Dermatology. 2013.
13. Arising Concerns of Atypical Manifestations in Patients With Hand, Foot, and Mouth Disease. — Chen Y, Dai B, Han S, et al. Vaccines. 2023.
14. A Clinical Scoring System for Pediatric Hand-Foot-Mouth Disease. — Huang H, Deng L, Jia L, Zhu R. BMC Infectious Diseases. 2021.