Discussion
In the current prospective RCT with 955 KD patients and 80 IVIG-resistant KD patients, we verified thatthe medical costs of patients treated with MPT were significantly lower and the duration of fever after retreatment wassignificantly shorter than those ofpatients treated with additional IVIG treatment. In addition, the WBC, PLT, Na, and N% of patients treated with MPT returned to normal faster than those ofpatients treated with additional IVIG treatment. MPThad a higher incidence of treatment failure and CALs compared with the second IVIG treatmentgroupin long-term follow-up.To the best of our knowledge, this is the first prospective RCT to study MPTandadditionalIVIGfor patients withIVIG-resistant KD in China.
The incidence of patients with KD who do not respond to the initialtreatment with IVIGis approximately 10% to 20%.4Our research shows thatthe incidence of IVIG resistant is about 8.38%. A large amount of research suggests that the incidence of CALsin IVIG-resistant KD is as high as22%-45.8%16,17,our study shows that 33 of 80IVIG resistant patients had coronary artery lesion,the incidence of CALs is about 41.25%.Because the incidence of CALsis so high, it is important to find a more beneficial treatmentforthese children. The current retreatment options mainly include additionalIVIG,corticosteroids, infliximab, etc.18–21Several retrospective study results suggest that CPT for IVIG-resistant KD may reduce the riskfor CALs,22but there are no robust data from clinical trials to guide the clinician in the choice of therapeutic agents for the child with IVIG resistance.13
Corticosteroids were used as the initial therapy for KD long before the first report by Furusho et al in 1984.23In the past, some studies reported that steroid treatment for KD is unsafe and is contraindicated due to the high incidence of CALs.24Recently, becauseof its cost-effectiveness, corticosteroid pulse therapy in IVIG-resistant KD has increasingly attracted clinicians’ attention.25Shinohara et al.26 found that prednisolone could significantly shorten fever duration and led to a lower prevalence of coronary artery aneurysms. A recentmeta-analysis by Chen et al.27found that a combination of corticosteroids with standard-dose IVIG as an initial treatment in high-risk patients could reduce the rate of CALs.There is still no convincing research on the clinical efficacy of steroid pulse therapy on KD. In particular, the long-term effect of steroid pulse therapy onthe coronary arterieshas not been clarified.28
In ourtrial, through comparison between an IVIG retreatment group and MPT group, we found that patients in the MPT group had a shorter duration of fever after retreatment and lower medical costs, more rapid decline in CRP, N%, and PLT levels, and more rapid rise in Na, and they were not significantly different in terms of preventing the development CALs in short-term follow-up(≤6 months). But our research found that the MPT group had a higher incidence CALs compared with the second IVIG treatmentgroupin long-term follow-up(>6months).
The optimal steroid regimen is therefore not known, and both pulsed and longer-term steroid therapy remain options. Furukawa et al.27found that the incidence of CALs was similar between the intravenous methylprednisolone followed by oral methylprednisolone tapered over 7 days and a second infusion of IVIG. Kobayashi et al.19foundthat patients treated with IVIG plus prednisolonehad significantly lower rates of persistent or recrudescent fever and CALs than those whoreceived IVIG mono-therapy.In our study,we gaveintravenous methylprednisolone 15mg.kg−1.d−1 for 3 consecutive days, without asubsequent course and taper of oral prednisone.This study suggeststhat patients in the MPTgroup had a shorter duration of fever after retreatment and lower medical costs, more rapid decline in CRP, N%, and PLT levels, and more rapid rise in Na,buthad a higher incidence CALs compared with the second IVIG treatmentgroupin long-term follow-up(>6months). However,we discovered that the readmission rate in patientstreated with MPTwas significantly higher than that in patientstreated with additional IVIG treatment.We think the high readmission rate may be related to the sudden withdrawal of intravenous methylprednisolone andlack ofa subsequent course and taper of oral prednisone.
The guideline13 suggests that administration of high-dose pulse steroidsfor retreatment of patients with KD who have had recurrent or recrudescent fever after additional IVIG,butone study suggests that high-dose MPT may cause bradycardia and elevated blood pressure and blood sugar.29Therefore, clinicians are more cautious about the application of MPT to IVIG-resistant KD, and more ordinary doses are used.The dose of methylprednisolone used in ourstudy was 15mg.kg−1.d−1, and although five patients developed bradycardia, these cases improved spontaneously.
Immunoglobulin is expensive, and as a blood product posesrisks related to blood transfusion. The anti-inflammatory effect of corticosteroids is certain and their medical cost is relatively low. Acomprehensive analysis of cost-effectiveness shows that there is a bright future for IVIG-resistant KD.30Our studyshows that the MPTgroup had a shorter duration of fever after retreatment and lower medical costs, more rapid decline in CRP, N%, and PLT levels, and more rapid rise in Nain the treatment of IVIG-resistant KD.But our study shows that the readmission rate inMPT groupwas significantly higher, and had a higherincidence CALs in long-term follow-up, So the MPT used to treat IVIG-resistant KD still need to be considered carefully.
Though this study is the largest to be performed in Chinese children and the firstprospective RCT for patients with IVIG-resistant KD in China,certain limitations should be acknowledged. First, the sample size in the current study is still small, Therefore, multi-center prospective RCTs with larger sample sizesare needed to confirm whether MPTor additionalIVIGis better for patients with IVIG-resistant KD. Second, we only compared the efficacy and safety of re-treatment of IVIG therapy with MPT (15mg.kg−1.d−1 for 3 consecutive days, without a subsequent course and taper of oral prednisone)in patients with IVIG-resistant KD.Many other therapies have not been compared,such as steroid pulse therapy(20-30mg.kg−1.d−1 for 3 consecutive days, with a subsequent course and taper of oral prednisone).