You are about halfway through your Peds shift, when a little girl is brought in by her mother for worsening rash and swelling. You immediately notice the child is in no respiratory distress and is awake and alert. She is febrile to 102.6°F. However, other vital signs are within normal limits.
Mom tells you this started yesterday morning when she woke up with a rash along her extremities and slight facial/periorbital swelling. Her pediatrician gave her diphenydramine in the office, observed her for an hour, and then sent her home with instructions for diphenydramine every 6 hours. The rash seemed to be improving initially with some of the lesions resolving.
Despite mom continuing the advised treatment and applying hydrocortisone cream, the child woke up this morning with a diffuse rash involving the face, upper, and lower extremities. There is swelling of the hands and feet, but no change in facial swelling.
She denies any recent URI, fever at home, travel, new soaps/detergents/foods, or lotions. The only thing mom says is that her child consumed a lot of cherry vanilla ice cream before developing the rash 2 days ago. She tried only a small amount of in the past. She is otherwise a healthy girl, without significant past medical or birth history.
As you try to bribe your crying little girl with stickers during your exam, you notice her rash looks a little bit like this…
They are annular, target-like erythematous lesions with a dusky center, confluent more so on the abdomen, diffuse on extremities, trunk, and face. However, the rash spares the palms and soles without mucosal involvement. She has mild swelling of bilateral hands, tender to touch, and 1+ pitting edema of bilateral lower extremities from feet to calves. Physical exam is otherwise within normal limits. This isn’t just your typical fever and a rash now, is it? So you put your thinking hat on…1. What is your differential?
- Erythema Multiforme
- Urticaria Multiforme
- Stevens-Johnson Syndrome
- Serum Sickness-like reaction
- Kawasaki’s Disease
2. What is the most likely diagnosis and why?
Urticaria Multiforme, also known as acute, annular urticaria is the most likely diagnosis. This hypersensitivity reaction is characterized by annular wheals often with a dusky or hemorrhagic hue in the center, often fading within hours, and then reappearing. Lesions are often pruritic and can be accompanied by fever and acral edema.(1) This description seems to be very similar to our patient’s presentation.
The patient lacks the mucosal involvement seen in Stevens-Johnson syndrome and does not meet clinical criteria needed to diagnose Kawasaki’s Disease, typical or atypical/incomplete. (A diagnosis of Kawasaki’s Disease requires fever greater than or equal to 5 days along with at least 4 signs of mucocutaneous inflammation, and atypical Kawasaki Disease also requires a fever greater than or equal to 5 days.(2)) Serum sickness-like reaction may also present in a similar fashion, characterized by fever, arthralgia, and rash often 1-2 weeks after administration of drugs such as amoxicillin, trimethoprim-sulfamethoxazole, and penicillin, among others.(3)
Erythema Multiforme can appear with similar-appearing rashes, called “target lesions”, with a central dusky zone of epidermal necrosis, surrounded by an inner ring of pale edema and an outer ring of erythema.(1) The lesions of both Erythema Multiforme and Serum sickness-like reaction are fixed, however, and may be present for days to weeks. This is different from the changing and reappearing lesions of Urticaria Multiforme, such as in our patient. Erythema Multiforme also often involves the palms and soles, while our child’s rash spares the palms and soles.
3. What is Urticaria Multiforme?
Urticaria Multiforme is an acute hypersensitivity syndrome mediated mainly by histamine with or without IgE involvement. It is characterized by transient, cutaneous erythema and dermal edema.(1) It is benign, usually self-resolving, and affects children generally between 4 months and 4 years of age.(4) In a case study of 18 pediatric patients presenting with rash and diagnosed with urticarial multiforme, symptoms included pruritis in 94% of patients and hand/foot or facial edema in 61% of patients. None of the evaluated patients demonstrated arthralgias or true target lesions as in Erythema Multiforme.(1) While individual lesions usually last about 24 hours, the rash as a whole usually self-resolves in about 6-10 days.(4) A phenomenon known as dermatographism can also be present. This is an induced, transient wheal and flare reaction that occurs when rubbing the skin and represents dermal hypersensitivity. This does not commonly occur in Erythema Multiforme or serum sickness-like reactions.(1)
While no exact cause exists, Urticaria Multiforme is an allergic hypersensitivity reaction and may be triggered by various exposures. In the same case study, it was found that recent antibiotic use was reported in 44% of patients.(1) Other sources have reported vaccine administration, use of antibiotics such as amoxicillin prior to onset, and the presence of infectious agents such as mycoplasma or streptococcus.(4)
4. How is it diagnosed?
Urticaria Multiforme is diagnosed clinically, without need for specific lab tests or skin biopsy. The presence of typical annular transient lesions, angioedema, and favorable response to antihistamines are some criteria that may help distinguish Urticaria Multiforme from other disease entities. See the diagnostic criteria table below from a review and case series in the Journal of Pediatrics by Shah et al.(1)
5. What kind of diagnostic tests would you like to order in this patient?
While the diagnosis is clinical, ordering certain diagnostic tests may help narrow down your differential or rule out other potential causes.
CBC, ESR/CRP may be useful, and more specific tests such as streptococcal antibody screens and EBV and HSV titers may also be considered. While mild elevations in inflammatory markers may be seen, these are not usually at levels expected to be seen with infectious or rheumatologic conditions.(1)
6. How do you manage this condition?
Antihistamines are the mainstay of therapy for Urticarial Multiforme. While many children can show an incomplete response to oral antihistamines, combination therapy with both an H1-antagonist such as diphenydramine and an H2-antagonist such as ranitidine can be used for treatment. Systemic corticosteroids may also be used, but are rarely required.(1)
7. What is your patient's disposition?
While the disease is generally self-limited and does not require hospitalization, admission may be considered if differential diagnosis cannot be sufficiently narrowed, and there is strong suspicion for Kawasaki’s Disease, Stevens-Johnson Syndrome, or other serious systemic disease. Our patient was admitted for observation. She was treated with hydroxyzine every 6-8 hours and antipyretics with improvement in the rash the following day.
(1) Shah KN, Honig PJ, Yan AC. “Urticaria Multiforme”: A Case Series and Review of Acute Annular Urticarial Hypersensitivity Syndromes in Children. Pediatrics 2007;119(5).
(2) Incomplete (atypical) Kawasaki disease [Internet]. Incomplete (atypical) Kawasaki disease. [cited 2017 Aug 16];Available from: https://www.uptodate.com/contents/incomplete-atypical-kawasaki-disease
(3) Pediatric Serum Sickness Clinical Presentation [Internet]. Pediatric Serum Sickness Clinical Presentation: History, Physical Examination, Complications. 2017 [cited 2017 Aug 16];Available from: http://emedicine.medscape.com/article/887954-clinical
(4) Sempau L, Martín-Sáez E, Gutiérrez-Rodríguez C, Gutiérrez-Ortega MC. Urticaria Multiforme: A Report of 5 Cases and a Review of the Literature [Internet]. Actas Dermo-Sifiliográficas (English Edition). 2016 [cited 2017 Aug 16];Available from: http://www.actasdermo.org/en/urticaria-multiforme-a-report-5/articulo/S1578219015003194/