Yoshihito Ogihara

Corticosteroid Pulse Combination Therapy for Refractory Kawasaki Disease: A Randomized Trial

Objective: This study examined the clinical efficacy and safety of intravenous methylprednisolone-pulse plus intravenous immunoglobulin (IVIG) combination therapy (IVMP+IVIG) for the initial treatment of patients predicted to have refractory Kawasaki disease (KD). Methods: One hundred twenty-two patients with KD were studied at Kitasato University. Refractory KD was predicted at diagnosis using the Egami score, and the patients were randomly divided to receive either IVMP+IVIG or IVIG alone. The Egami score is used to predict refractory KD patients before treatment using the patient’s age, days of illness, platelet count, C-reactive protein, and alanine aminotransferase level (cutoff: ≥3 points; 78% sensitivity and 76% specificity). Results: Forty-eight patients (39.3%) were predicted to have refractory KD on the basis of the Egami score. The predicted IVIG responders (n = 74) received the standard therapy. The 48 predicted refractory KD patients were randomly assigned to a single-IVIG group (n = 26) or an IVMP+IVIG group (n = 22). Nineteen of the 22 patients (86.4%) in the IVMP+IVIG group had a prompt defervescence compared with 6 of the 26 patients (23.1%) in the single-IVIG group. The number of patients who had a z score ≥2.5 at 1 month was significantly higher in the single-IVIG group than in the IVMP+IVIG group. No serious adverse events were observed in either treatment group. Conclusions: This study demonstrated that IVMP+IVIG therapy is safe and effective for KD patients predicted as refractory.

The strategy of immune globulin resistant Kawasaki disease: A comparative study of additional immune globulin and steroid pulse therapy

BACKGROUND We compared the clinical utility of additional intravenous immune globulin (IVIG) therapy with the clinical utility of steroid pulse therapy in patients with IVIG-resistant Kawasaki disease. METHODS We enrolled 164 patients with Kawasaki disease who were treated with a single dose of IVIG (2 g/kg) and aspirin (30 mg/kg per day). Twenty-seven of these patients (16%) were resistant to the initial IVIG treatment. We compared the effectiveness of treatment strategies for the initial IVIG-resistant 27 patients, 14 of these patients were treated with additional IVIG therapy, and the other 13 patients were treated with steroid pulse therapy (methylprednisolone 30 mg/kg per day for 3 days). RESULTS Three patients in the group receiving additional IVIG treatment had coronary artery aneurysms (21.4%), no patients had coronary artery aneurysm in the steroid pulse therapy group; the difference in the incidence of coronary artery aneurysm was not statistically significant. The duration of high fever after additional treatment in the steroid pulse therapy group (1 ± 1.3 days) was significantly shorter than that in the additional IVIG treatment group (3 ± 2.4 days; P < 0.05). The medical costs were significantly lower in the steroid pulse therapy group than in the additional IVIG treatment group. CONCLUSION Steroid pulse therapy was useful to reduce the fever duration and medical costs for patients with Kawasaki disease. Steroid pulse therapy and additional IVIG treatment were not significantly different in terms of preventing the development of coronary artery aneurysm.

Coronary artery outcomes among children with Kawasaki disease in the United States and Japan.

OBJECTIVE It has been claimed that the aneurysm rate for Kawasaki disease (KD) patients in Japan is lower than in the U.S. However it has been difficult to compare coronary artery (CA) outcomes between the two countries because of different definitions for CA abnormalities. Therefore, we compared CA internal diameters between Japanese and U.S. KD patients using standard definitions and methods. STUDY DESIGN We retrospectively reviewed CA outcomes in 1082 KD patients from 2 centers in the U.S. and 3 centers in Japan and compared Z-max scores (maximum internal diameter for the left anterior descending or right coronary artery expressed as standard deviation units from the mean (Z-score) normalized for body surface area) obtained within 12 weeks after onset and calculated using two different regression equations from Canada (Dallaire) and Japan (Fuse). We defined a Z-max of < 2.5 as normal and a Z-max of ≥ 10 as giant aneurysm. RESULT The median Z-max for the U.S. and Japanese subjects was 1.9 and 2.3 SD units, respectively (p < 0.001). There was no significant difference in rates of patients with Z-max ≥ 5.0 between the countries. In a multivariable model adjusting for age, sex, and treatment response, being Japanese was still associated with a higher Z-max score. CONCLUSION Previously reported differences in aneurysm rates between Japan and the U.S. likely resulted from use of different definitions and nomenclature. Adoption of Z-scores as a standard for reporting CA internal diameters will allow meaningful comparisons among different countries and will facilitate international, collaborative clinical trials.

Clinical score and transcript abundance patterns identify Kawasaki disease patients who may benefit from addition of methylprednisolone.

Intravenous immunoglobulin (IVIG) treatment-resistant patients are high risk of developing coronary artery lesions with Kawasaki disease. The IVIG-responsive (Group A; n = 6) and IVIG-resistant patients (Group B) were predicted before starting the initial treatment using the Egami scoring system and randomly allocated as a single-IVIG treatment group (group B1; n = 6) or as a IVIG-plus-methylprednisolone (IVMP) combined therapy group (group B2; n = 5). We investigated the transcript abundance in the leukocytes of those patients using a microarray analysis. Five patients in group A and one patient in group B1 responded to initial IVIG treatment. All group B2 patients responded to IVIG-plus-IVMP combined therapy. Before performing these treatments, those transcripts related to IVIG resistance and to the development of coronary artery lesions, such as IL1R, IL18R, oncostatin M, suppressor of cytokine signaling-3, S100A12 protein, carcinoembryonic antigen-related cell adhesion molecule-1, matrix metallopeptidase-9, and polycythemia rubra vera-1, were more abundant in group B patients in comparison with group A patients. Moreover, those transcripts in group B2 patients were more profoundly and broadly suppressed than group B1 patients after treatment. This study elucidated the molecular mechanism of the effectiveness of IVIG-plus-IVMP combined therapy.

Transcriptional regulation by infliximab therapy in Kawasaki disease patients with immunoglobulin resistance.

Background:Infliximab (IFX), a known monoclonal antibody against tumor necrosis factor-α (TNF-α), is used to treat Kawasaki disease (KD) patients with intravenous immunoglobulin (IVIG) resistance. The transcriptional modulation of inflammation following IFX therapy has not been reported in KD patients.Methods:We investigated the transcript abundance profiles in whole blood obtained from eight IVIG-resistant KD subjects treated with IFX therapy using microarray platforms and compared them with those in initially IVIG-responsive subjects. A pathway analysis was performed using WikiPathways to search for the biological pathways of the transcript profiles. Four transcripts changed by IFX therapy were subsequently validated using quantitative real-time polymerase chain reaction.Results:The pathway analysis showed the reduced abundance of transcripts in the nucleotide-binding oligomerization domain, matrix metalloproteinase (MMP), and inflammatory cytokine pathways and the increased abundance of transcripts in the T-cell receptor, apoptosis, TGF-β, and interleukin-2 pathways. Additionally, the levels of four transcripts (peptidase inhibitor-3, MMP-8, chemokine receptor-2, and pentraxin-3) related to KD vasculitis and IVIG resistance decreased after IFX therapy.Conclusion:The administration of IFX was associated with both the signaling pathways of KD inflammation and several transcripts related to IVIG resistance factors. These findings provide strong theoretical support for the use of IFX in KD patients with IVIG resistance.Pediatric Research (2014); 76 3, 287–293. doi:10.1038/pr.2014.92

The Clinical Utility and Safety of a New Strategy for the Treatment of Refractory Kawasaki Disease

Objective To assess the clinical utility and safety of a strategy for refractory Kawasaki disease, defined by Egami score ≥3. Study design First‐line treatment was with intravenous methylprednisolone (30 mg/kg, 2 hours, 1 dose) plus intravenous immunoglobulin (2 g/kg, 24 hours) treatment. Patients resistant to first‐line treatment received additional intravenous immunoglobulin as a second‐line treatment. Patients resistant to second‐line treatment who had received Bacillus Calmette‐Guérin vaccination 6 months earlier were treated with infliximab; otherwise, plasma exchange was performed. A total of 71 refractory patients with Kawasaki disease (median age: 2.4 years) of 365 patients with Kawasaki disease were treated according to our strategy from April 2007 to April 2016. Treatment resistance was defined as a persistent fever at 36 hours after treatment. We evaluated coronary artery lesions at the time of the diagnosis, at 1 month, and at 1 year after the diagnosis in accordance with the American Heart Association guidelines and the criteria of the Japanese Ministry of Health, Labour, and Welfare. Results First‐line therapy was effective for 58 of 71 patients (81.6%), and second‐line therapy was effective for 9 of 13 patients (69.2%). At third line, 3 patients were treated by infliximab, and 1 was treated with plasma exchange. Of the 18 patients with coronary artery abnormalities at diagnosis, 13 patients at 1 month and 6 patients at 1 year had coronary artery dilatation (median z score 3.0, 2.6, and 1.4, respectively). There were no patients with coronary artery aneurysm (CAA). Conclusions Our strategy for refractory Kawasaki disease was safe and effective in preventing CAA.