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).