Question 2: In pediatric cases of erythema multiforme (EM) minor, is herpes simplex virus (HSV) a common cause?

Traditionally, EM had been classified as part of a continuum alongside Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), but this is no longer the case. Currently, EM minor and major are believed to be separate pathological entities from SJS and TEN. EM minor typically involves cutaneous lesions alone, while EM major additionally involves mucosal surfaces. These EM lesions are immune-mediated reactions and are most commonly described as target lesions located predominantly on the extremities and less on the torso and back.

A 1992 prospective study of 20 pediatric patients (ages 1 to 16 years) by Weston et al evaluated HSV involvement in cases of EM.1 Ten patients had associated oral mucosal lesions, a history of recent preceding HSV labial lesion, or a positive HSV culture from a labial lesion that occurred after the EM rash; this group was designated “herpes-associated EM.” Ten separate EM cases involved cutaneous lesions only without a history of HSV-associated lesions, and they were designated “idiopathic EM.”

Cutaneous lesions from both groups were sampled, and polymerase chain reaction was performed. In the herpes-associated EM group, eight of 10 lesion samples were positive for HSV DNA. In the idiopathic EM group, eight of 10 cutaneous lesions demonstrated HSV DNA.

Weston further clarified, “No HSV could be detected in a biopsy of normal uninvolved skin of a child in whom HSV was present in lesional skin.”

Control specimens of bullous skin diseases were negative for HSV DNA. The study does not mention how many children had oral lesions at the time of specimen collection. The idiopathic EM group appeared to be EM minor, and these results suggest HSV might be a common cause of EM minor in children.

A 14-year study by Siedner-Weintraub published in 2017 retrospectively evaluated children (n=30) 4 to 18 years old with EM.² Of these 30 children, common etiologies included idiopathic (15 of 30), nonspecific febrile illness (11 of 30), history of past HSV infection (seven of 30), new medication (five of 30), and mycoplasma pneumonia (four of 14). In this study, a direct association with HSV was not found because no cases had a recent history of an HSV infection in the preceding weeks. However, only eight of these children were tested for HSV.

A three-year retrospective study published in 2017 by Read and Keijzers identified nine pediatric patients with EM of whom zero had mucosal involvement.³ Of these patients, the causes were designated as upper respiratory tract infection (three of nine), otitis media (three of nine), nonspecific viral illness (two of nine), and immunizations (one of nine). There was no identified HSV involvement in these cases, but blood work was drawn in only one patient, and all were treated conservatively.