Hand, Foot, and Mouth Disease Clinical Presentation and Progression

Initial Symptoms

Fever is usually the first symptom, typically low-grade but can exceed 102.2°F (39°C), in infants and toddlers with Hand, Foot, and Mouth Disease 1
General discomfort, malaise, and irritability are common early manifestations in infants and toddlers with Hand, Foot, and Mouth Disease 1
Respiratory symptoms such as cough and rhinitis may occur, especially in younger children with Hand, Foot, and Mouth Disease 1
The American Academy of Pediatrics recommends considering Hand, Foot, and Mouth Disease in the differential diagnosis of infants and toddlers presenting with fever, malaise, and irritability, followed by the development of characteristic vesicular lesions 1

Characteristic vesicular rash typically appears 1-2 days after fever onset in infants and toddlers with Hand, Foot, and Mouth Disease 2
Oral lesions develop first, appearing as small red spots that progress to painful vesicles and ulcers in the mouth, particularly on the tongue, gums, and inside of the cheeks in infants and toddlers with Hand, Foot, and Mouth Disease 2
Fever usually subsides within 3-4 days in infants and toddlers with Hand, Foot, and Mouth Disease 2
Oral ulcers may persist for 7-10 days and can cause significant discomfort, leading to decreased oral intake in infants and toddlers with Hand, Foot, and Mouth Disease 2

Warning signs of complications in Hand, Foot, and Mouth Disease include persistent high fever, lethargy, severe headache, stiff neck, or unusual irritability 2
Neurological complications such as meningitis, encephalitis, and acute flaccid paralysis can occur, particularly with Enterovirus 71 infections in infants and toddlers with Hand, Foot, and Mouth Disease 2
Respiratory distress may indicate rare but serious complications like neurogenic pulmonary edema in infants and toddlers with Hand, Foot, and Mouth Disease 3

The Centers for Disease Control and Prevention recommends considering Hand, Foot, and Mouth Disease in the differential diagnosis of infants and toddlers presenting with fever, malaise, and irritability, followed by the development of characteristic vesicular lesions 1
HFMD may be confused with other vesicular rashes such as chickenpox, but HFMD lesions are typically concentrated on hands, feet, and mouth rather than being widely distributed 1
Unlike Kawasaki disease, HFMD presents with vesicular lesions rather than diffuse erythema and does not typically have the persistent high fever characteristic of Kawasaki disease 1

The Centers for Disease Control and Prevention recommends considering Kawasaki disease in the differential diagnosis due to its potential for cardiac complications, characterized by persistent high fever, diffuse erythema, conjunctival injection, strawberry tongue, cervical lymphadenopathy, and extremity changes 4, 5
The American Academy of Pediatrics suggests that erythema multiforme can be distinguished from Hand, Foot, and Mouth Disease by its target lesions with central clearing, typically on extensor surfaces, and may have oral involvement but lacks the characteristic vesicular pattern of HFMD 4
Drug reactions should be considered if there is recent medication exposure, with a rash pattern that is usually more diffuse and maculopapular rather than vesicular, and timing correlates with medication initiation 4, 5

A thorough history should include recent medications to exclude drug reactions, with the Centers for Disease Control and Prevention recommending consideration of medication exposure as a potential cause of symptoms 4, 5