Erythema multiforme- and not erythema multiforme-like rashes in Kawasaki disease.

Kawasaki disease (KD) is an acute, febrile systemic vasculitis that primarily occurs in infants and young children.1, 2 Patients with KD mostly present with “polymorphic and nonspecific” skin eruption.2 The most common form is a diffuse maculopapular eruption but the rash could present in various forms.2 These skin lesions generally disappear with convalescence from the disease. Erythema multiforme (EM) is an acute, self-limiting disease characterized by targetoid erythematous lesions with predominant acral localization.3 It is typically associated with hypersensitive reactions to infectious agents.3 The second most frequent cause of EM is drugs like allopurinol, antiepileptic agents, and antibiotics.3 Here, we report a case of a 3-year-old boy who presented with EM as an initial manifestation of KD. The EM continued to worsen, which was followed by pigmentation all over the body despite successful intravenous immunoglobulin (IVIG) treatment. The 3-year-old boy was transferred to our hospital due to febrile convulsions. The patient was born to non-consanguineous healthy parents as a full-term infant. He had a history of being prescribed levocetirizine for rashes on his lower limbs on the day before his hospitalization. On admission he showed a high fever of 40 °C, conjunctival hyperemia, red lips, strawberry tongue, cervical lymphadenopathy, erythema of the trunk of the body, and erythema and edema of the hands and feet. Although the rashes on the trunk of the body were observed to be erythematous papules, those on his extremities were targetoid (Fig. 1a,b). Furthermore, the rash was visible on the palms, soles, and even auricle of the ear (Fig. 1c). Laboratory tests showed compatible data for complete KD (Fig. S1): leukocyte count of 10.6 × 109/L with 85% neutrophils and 2.85 mg/dL of C-reactive protein. Antibody titers and genetic amplification tests for herpes simplex virus and Mycoplasma pneumoniae, and rapid diagnostic tests for Streptococcus pyogenes and adenovirus were all negative. Echocardiography indicated no evidence of coronary artery lesion (CAL). Fulfillment of the diagnostic criteria of KD prompted us to start 2 g/kg of IVIG and oral aspirin. The patient showed complete defervescence along with the improvement of clinical manifestations after the second course of IVIG. However, the skin lesions continued to deteriorate with intense pruritus. Furthermore, the skin lesions in the present case left pigmentation (Fig. 1d,e) although EM-like rashes in KD generally do not leave pigmentation during the convalescent phase.4, 5 Hence, we considered the skin lesions as “true” EM but not EM-like rashes. We started intravenous prednisolone and d-chlorpheniramine for the treatment of EM and stopped oral aspirin under suspicion of drug hypersensitivity reactions. Active skin lesions disappeared on the 14th day of the illness and periungual desquamation emerged (Fig. S1). Bullous or mucous membrane involvement was not observed. Drug lymphocyte stimulation tests for levocetirizine and aspirin were both negative (they were performed before the patient started prednisolone). The patient was discharged from our hospital on the 16th day of the illness without CAL. An EM-like rash as an initial skin manifestation of KD was first reported in a 22-month-old girl in 1979.4 To date, several similar cases have been reported.4, 5 The American Heart Association describes these EM-like rashes as a relatively common form of KD skin manifestation.2 Although the histopathological findings of EM-like lesions in KD vary from case to case, several cases show similar findings comparable to EM.4, 5 We did not perform a skin biopsy in our patient, which is a limitation of this study. In previously reported cases, KD with EM-like rashes did not leave skin pigmentation during the convalescent phase.4, 5 In the present case, the rashes continued to worsen and left pigmentation even after complete defervescence, which was a cause for major concern. These findings appeared to be “true” EM rather than EM-like rashes in KD.2-5 Recently, innate immune activity, triggered by certain factors, was shown to play a role in the development of KD vasculitis.1 Innate immunity activation, including Toll-like receptor activation, was also shown to be a possible pathogenesis mechanism for EM.3 From this viewpoint, duplicated clinical conditions of KD and EM may exist in the present case. Although controlled studies are missing with respect to acute EM treatment, systemic steroids have regularly been administered.3 However, IVIG only has a limited effect on EM.3 Hence, EM continued to worsen even after successfully treating KD with IVIG in the present patient. In conclusion, the possibility of true EM in an acute phase of KD presenting EM-like rashes should be taken into consideration because it may lead to Stevens–Johnson syndrome.3 Moreover, steroids, and not IVIG, may be effective in treating skin lesions in such cases. The authors thank Dr Yusuke Okada and Dr Akiko Miyake (Department of Pediatrics, Saiseikai Shimonoseki General Hospital) for assistance in data collection. We also thank Dr Komei Shirabe (Yamaguchi Prefectural Institute of Public Health and Environment, Yamaguchi, Japan) and Dr Shoji Kawano (Department of Pediatrics, Shimonoseki City Hospital, Yamaguchi, Japan) for conducting the polymerase chain reaction. Written informed consent was obtained from the patient’s parents. There are no conflicts of interest to declare. This research received no specific grant from any funding agency, commercial or not-for-profit sectors. S.O. led conceptualization and design of the analysis, analyzed and interpreted data, and drafted the initial manuscript. R.H. led conceptualization and design of the analysis, analyzed and interpreted data, and critically reviewed the manuscript. S.O.E., S.F., and Y.I. contributed to data collection and critically reviewed the manuscript. Each author listed on the manuscript has seen and approved the submission of this version of the manuscript and takes full responsibility for the manuscript. This manuscript has not been published or presented elsewhere in part or in entirety, and is not under consideration by another journal. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.