Are You Confident of the Diagnosis?
What you should be alert for in the history
Enteroviral exanthems are common in the pediatric population and follow a seasonal distribution, with most cases occurring in warmer months. The exanthem is usually accompanied by fever, which may precede the rash. Other associated symptoms include cough, sore throat, myalgias, malaise, mild abdominal pain, nausea, vomiting, and diarrhea. Oral lesions can be painful and may cause diminished appetite or refusal to eat or drink.
Characteristic findings on physical examination
A generalized morbilliform eruption resembling other nonspecific viral exanthems is the most common skin presentation. This generalized eruption is usually nonpruritic. Hand, foot, and mouth disease has small, tender, gray-white, ovoid papules, papulovesicles and vesicles on the hands and feet, classically on the palms and soles. Dorsal and lateral surfaces of the hands, feet, and digits may also be involved (Figure 1, Figure 2, Figure 3). The vesicles may appear deep-seated and are surrounded by an erythematous border
An eruption of erythematous macules, papules, and vesicles may be observed on the buttocks, thighs, and genitalia (Figure 4).Rarely, erythematous or violaceous vesicles arise on the trunk and extremities (Figure 5). Petechial, urticarial, and generalized pustular eruptions are occasionally reported, primarily with echovirus infection. Echovirus 6 infection may present with a dermatomal vesicular eruption. There are also reports of echovirus-associated eruptive psuedoangiomatosis, with acute onset and spontaneous resolution over days of multiple hemangioma-like papules with peripheral blanching.
Hand, foot, and mouth disease has tender or asymptomatic 1-2 mm vesicles and ulcerations with a yellow-gray base on the soft palate, tonsillar pillars, uvula, tongue, and posterior oropharynx. Herpangina is characterized by similar 1-2 mm vesicles and punched-out ulcers on the soft palate, tonsillar pillars, uvula, tongue, and posterior oropharynx.
Aseptic meningitis can present as fever and irritability in infants and as fever with headache, nuchal rigidity, nausea, vomiting, lethargy, or rarely seizure in older children. In very rare cases, paralysis can occur.
Acute hemorrhagic conjunctivitis presents with eye pain, lid edema, excessive lacrimation, and subconjunctival hemorrhage.
Expected results of diagnostic studies
Diagnostic studies are rarely needed in outpatient practice but can be useful in the setting of more severe disease, particularly when there is concern for bacterial meningitis. Polymerase chain reaction (PCR) is highly sensitive and specific for identifying enteroviral pathogens and can be performed with a rapid turn-around time. PCR of cerebrospinal fluid is helpful in the workup of meningitis. PCR of other body fluids (vesicular fluid, blood, urine, respiratory secretions, stool) is less commonly performed but can offer confirmation of suspected infection when cerebrospinal fluid PCR is negative (as can occur in infection with enterovirus 71)
Viral culture has lower sensitivity, longer turn-around time, and higher cost than PCR. If performed, viral culture of the pharynx is most likely to yield pathogen during the acute infection, while culture of the stool is most likely to be positive during the shedding period after acute infection. There are no specific histopathologic findings on skin biopsy.
Differential diagnosis includes the following:
Adenovirus – Infection is usually associated with no rash or with a nonspecific morbilliform eruption. Vesicular lesions are uncommon. Conjunctivitis, sore throat, cough, and gastroenteritis are frequently seen.
Epstein-Barr virus – The rash, which is usually morbilliform, often follows administration of ampicillin. Exudative pharyngitis and lymphadenopathy are commonly seen. The complete blood count can show an elevated number of atypical lymphocytes.
Group A streptococcus – The rash of scarlet fever classically has a sandpaper texture. There is often an exudative pharyngitis. Presentation is uncommon in children under 3 years of age.
Herpes simplex virus – Herpes stomatitis classically has single or grouped vesicles on the lips and anterior tongue with prominent gingivitis. By contrast, vesicles in herpangina and hand, foot, and mouth disease more commonly affect the posterior structures of the mouth, and gingivitis is rare.
Human herpesvirus 6 (roseola) – An eruption of numerous blanchable pink macules and papules with a peripheral halo of vasoconstriction classically appears abruptly after 3-7 days of high fever. Cervical and suboccipital lymphadenopathy can be seen.
Measles – The prototypical morbilliform eruption consists of innumerable, often confluent, erythematous macules and papules that begin on the head and progress downward, and which fade in that same sequence. Rarely seen in immunized children. Coryza and conjunctivitis are prominent, along with Koplik spots (white or yellow papules on the buccal mucosa).
Meningococcemia – Patients appear severely ill with petechiae/purpura and neurologic symptoms. This entity may be clinically indistinguishable from a severe enteroviral infection, and, when suspected, laboratory confirmation and empiric treatment are indicated.
Parvovirus B19 (erythema infectiosum, fifth disease) – Classic “slapped cheek” rash with circumoral palor. There are occasionally painful and pruritic papules with petechiae on the hands and feet.
Rubella – The eruption consists of innumerable “rose pink” confluent macules and papules that spread from the head downward and fade in the same sequence and may resolve with fine desquamation. Rarely seen in immunized children. There is often significant lymphadenopathy involving the posterior auricular and suboccipital lymph nodes.
Who is at Risk for Developing this Disease?
Infants and young children have the highest rate of infection, although all age groups can be affected. During seasonal peaks, approximately 7/1000 newborns will be hospitalized during their first 4 weeks of life due to enteroviral infection. Males more commonly develop disease than females for unknown reasons.
Transmission is by fecal-oral route primarily, so persons involved in diaper changing and young children with poor toilet hygiene are at risk. Some serotypes (such as group A coxsackievirus, causing hand, foot, and mouth disease) are also easily transmitted via respiratory secretions and vesicle fluid. Infection can occur year-round but peaks in the summer and fall in the United States (May-October).
What is the Cause of the Disease?
Enteroviruses are members of the picornavirus family that are stable at a wide range of pH (3-10), and are thus able to survive the acid environment of the stomach. There are more than 70 known serotypes of enterovirus, which are divided among five subgenera: poliovirus, group A coxsackievirus, group B coxsackievirus, echovirus, and enterovirus (the last group contains all newly identified, consecutively-ordered serotypes starting with enterovirus 68).
Hand, foot, and mouth disease is caused by group A coxsackievirus, particularly serotypes A16, A5, and A10. Enterovirus 71 can cause a similar illness with more severe neurologic symptoms. Herpangina is caused by group A coxsackieviruses. Petechial, purpuric, and urticarial enteroviral exanthems can be caused by echovirus 9 and coxsackievirus A9. Meningoencephalitis, in infants, is most commonly caused by group B coxsackieviruses, less commonly by echovirus serotypes. Enterovirus 71 can cause severe neurologic symptoms including paralysis. Acute hemorrhagic conjunctivitis is most commonly caused by enterovirus 70 and coxsackievirus A24.
After ingestion of viral particles, the virus first infects cells of the pharynx and terminal ileum, from which it spreads to the lymph nodes. The virus replicates in the lymphoid tissue and then spreads throughout the body to target organs, coinciding with the onset of symptoms, typically 3-6 days after initial infection. Virus is shed from the upper respiratory tract for 1-3 weeks and from the feces for 3-8 weeks.
Patients are most contagious in the first 1-2 weeks of illness, when the rash is typically present. Immunity develops in a serotype-specific fashion: re-infection with the same serotype will be asymptomatic.
Systemic Implications and Complications
Dehydration issecondary to pain and oral aversion when oral vesicles are present, and may also be secondary to fever. Work-up can include urine specific gravity and serum electrolyte analysis. Management includes oral and intravenous fluid replacement.
Meningitis and meningoencephalitis are due to group B coxsackievirus, echovirus, and enterovirus 71. Work-up can include cerebrospinal fluid analysis, including viral PCR. Bacterial meningitis must be ruled out. Management is supportive, though in some cases intravenous immunoglobulin (IVIG) can be considered.
-1:1 mixture of liquid diphenhydramine and Maalox (aluminum hydroxide and magnesium hydroxide), for a “swish-and-spit” or small-volume “swish-and-swallow.”
-AVOID topical viscous lidocaine in young children due to risk of toxicity with gingival absorption or ingestion.
-Therapy is usually not needed. Luke-warm soaks and bland emollients may be soothing.
-Ibuprofen 10mg/kg orally every 6 hours for pain or fever.
-Acetaminophen 15mg/kg orally every 6 hours for pain or fever.
-Intravenous immune globulin (IVIG) 0.4-2 g/kg, for severe disease with systemic complications.
-Pieconaril 2.5-5mg/kg orally three times a day, as an experimental agent for severe disease in high-risk populations.
Optimal Therapeutic Approach for this Disease
Most patients will require supportive care only. Adequate fluid intake is paramount, especially when drinking is limited by oral pain. Topical analgesia with 1:1 mixture of diphenhydramine:Maalox instilled in the buccal vestibule with a syringe can provide immediate temporary symptom relief. In cases where oral intake cannot be maintained or symptomatic dehydration is suspected, intravenous fluid administration is indicated.
Fever and pain can be controlled with oral ibuprofen and/or acetaminophen. The rash is self-resolving over a period of days and requires no specific therapy. In the setting of severe disease or in patients with humoral immunodeficiency, IVIG may be administered, though the benefit is often limited.
Pleconaril is still in clinical trials but may be indicated in the future for disease in neonates, patients with humoral immunodeficiencies, or other high-risk populations.
Patients should be monitored based on symptom severity. Caregivers should be instructed to bring the patient back to medical attention if there is concern for dehydration or mental-status change, or if symptoms do not improve in 3-5 days.
Patients, caregivers, and family members should practice good hand hygiene to avoid disease spread. Alcohol-based hand sanitizers may provide better anti-viral activity than standard soap and water, but the latter is preferable when hands are visibly soiled. Hospitalization should be considered for any patient with signs or symptoms of meningitis, encephalitis, or other internal organ involvement.
Hospitalized patients should be placed under contact precautions. Pregnant women near term should avoid contact with patients when possible, to decrease the likelihood of potential vertical transmission.
Unusual Clinical Scenarios to Consider in Patient Management
Neonates who acquire infection in the perinatal period via vertical transmission may develop severe systemic disease. Symptoms can include sudden onset listlessness, anorexia, vomiting, and respiratory distress, which can resemble pneumonia. Affected neonates may develop a morbilliform, macular, or petechial rash, occasionally with herpangina-like ulcers on the soft palate.
Potentially fatal complications can include myocarditis, heart failure, and fulminant hepatitis with hypotension, profound coagulopathy, and multi-system organ failure. Seizures have been reported as a late sequela of neonatal infection, but less commonly as a presenting symptom.
Patients with defects in B lymphocyte function, such as X-linked agammaglobulinemia and common variable immunodeficiency, may develop more severe disease or persistent infection.
Complications include headache, recurrent encephalitis, and progressive neurologic deterioration. A dermatomyositis-like syndrome can occasionally develop, sometimes after years of illness. Treatment with intravenous immunoglobulin may be beneficial.
What is the Evidence?
Pickering, LK. “Enterovirus (nonpoliovirus) infections”. Red Book: 2009 Report of the Committee on Infectious Diseases. 2009. pp. 267-8. (Authoritative reference discussing the presentation, epidemiology, and management of enterovirus, including infection control precautions.)
Friedlander, SF, Bradley, JS, Eichenfield, LF, Frieden, IJ, Esterly, NB. “Viral infections”. Textbook of Neonatal Dermatology. 2001. pp. 201-22. (Review of the presentation of enterovirus and other viral agents in the neonatal period.)
Ho, M, Chen, E, Hsu, K, Twu, S, Chen, K, Tsai, S. “An epidemic of enterovirus 71 infection in Taiwan”. N Engl J Med. vol. 341. 1999. pp. 929-35. (Report of 405 patients with severe disease (out of greater than 129,000 cases), including 78 deaths, during an outbreak of hand, foot, and mouth disease caused by a particularly virulent enteroviral serotype. Reinforces the importance of monitoring patients for the development of neurologic deterioration or other signs of systemic illness.)
Paller, AS, Mancini, AJ, Paller, AS, Mancini, AJ. “The exanthematous diseases of childhood”. Hurwitz clinical pediatric dermatology. 2006. pp. 423-48. (A thorough discussion of viral and bacterial exanthems in the pediatric population, with a particular focus on the differential diagnosis and distinguishing features.)
Ramsay, M, Reacher, M, O’Flynn, C, Buttery, R, Hadden, F, Cohen, B. “Causes of morbilliform rash in a highly immunized Enligh population”. Arch Dis Child. vol. 87. 2002. pp. 202-6. (A prospective study investigating the etiologies of morbilliform exanthem seen in a primary care setting. Enterovirus accounted for 9% of cases; more prevalent causes included parvovirus B19 [17%], group A streptococcus [15%] and HHV 6 and 11 [6%].)
Rotbart, HA, Rudolph, CD, Rudolph, AM. “Enteroviruses”. Rudolph’s pediatrics. 2003. pp. 1020-23. (Very thorough review of enterovirus infection in children, with a particular focus on microbiology and pathophysiology.)
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