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►► Additional material is
published online only. To view,
please visit the journal online
(http://d​ x.​doi.o​ rg/​10.​1136/​
archdischild-​2019-​318245).
1
School of Medicine, Faculty
of Medicine, Taipei Medical
University, Taipei, Taiwan
2 ►► To prevent cardiac complications, intravenous
Graduate Institute of Clinical
Medicine, Collage of Medicine,
Taipei Medical University, Taipei,
Taiwan
3
Division of Hematology
Oncology, Department of
Pediatrics, Wan Fang Hospital,
Taipei Medical University, Taipei,
Taiwan
4
Department of Pediatrics,
School of Medicine, College
of Medicine, Taipei Medical
University, Taipei, Taiwan
Correspondence to
Dr Jinn-­Li Wang, Pediatrics, Wan
Fang Hospital, No.111, Sec3,
Xinglong Rd, Wenshan Dist,
Taipei city 116, Taiwan;
​jlwang@​w.​tmu.​edu.​tw
Received 19 September 2019
Revised 8 September 2020
Accepted 3 October 2020
© Author(s) (or their
employer(s)) 2020. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Chiang M-­H, Liu HE,
Wang J-­L. Arch Dis Child
Epub ahead of print: [please
include Day Month Year].
doi:10.1136/
archdischild-2019-318245
Low-­dose or no aspirin administration in acute-­phase
Kawasaki disease: a meta-­analysis and
systematic review
Ming-­Hsiu Chiang,1 Hsingjin Eugene Liu,2 Jinn-­Li Wang  ‍ ‍3,4
ABSTRACT
Objective  To compare the efficacy of low-­dose or no
aspirin with conventional high-­dose aspirin for the initial
treatment in the acute-­phase of Kawasaki disease (KD).
Design  A meta-­analysis and systematic review of
randomised control trials and cohort studies.
Methods  All available articles that compared different
dosage of aspirin in the acute-­phase of KD published
until 20 September 2019 were included from the
databases of PubMed, Embase and Cochrane Central
Register of Controlled Trials Central without language
restrictions. Extracted data from eligible studies were
reviewed by two authors independently and analysed by
using RStudio software.
Results  Nine cohorts with a total of 12 182 children
were enrolled. We found that low-­dose (3–5 mg/kg/
day) or no aspirin in the acute-­phase KD was associated
with reducing the risk of coronary artery lesions (CALs,
OR=0.81, 95% CI 0.69 to 0.95). No differences were
observed in intravenous immunoglobulin resistance,
length of hospital stay and fever days after admission
(OR=1.35, 95% CI 0.91 to 1.98; standard mean
difference (SMD)=0.17, 95% CI −1.07 to 1.4; SMD=0.3,
95% CI −1.51 to 2.11) in the low-­dose/no aspirin
subgroup compared with the high-­dose (≥30 mg/kg/
day) aspirin subgroup. We did not identify any potential
factors affecting the homogeneity of CAL risk as well as
clinical important effects in all included studies.
Conclusions  Prescribing low-­dose or no aspirin in
the acute-­phase of KD might be associated with a
decreased incidence of CAL. However, additional well-­
designed prospective trials are required to support the
theory.
INTRODUCTION
Kawasaki disease (KD) is a paediatric systematic
vasculitis which predominantly affects children
under 5 years of age. Coronary artery lesions
(CALs), which account for most acquired paedi-
atric cardiac diseases in developed countries, is
the major complication of KD.1 Neutrophil infil-
tration from the intima into the adventitia of the
coronary artery wall and destruction are observed
within 2 weeks of disease onset. This acute necro-
tising arteritis and subsequent subacute chronic
vasculitis might play a pivotal role in causing CAL
and increasing the risk of thrombosis.2 Therefore,
anti-­inflammatory and antiplatelet therapies are
considered as primary treatments for the preven-
tion of KD-­induced CAL.
Chiang M-­H, et al. Arch Dis Child 2020;0:1–7. doi:10.1136/archdischild-2019-318245
Original research
What is already known on this topic?
►► Kawasaki disease (KD) is a systematic
vasculitis with unclear pathogenesis, which
predominantly occurs in children, particularly
those under 5 years of age.
immunoglobulin (2 g/kg) and high-­dose aspirin
(≥30 mg/kg/day) have been the standard
treatment in acute-­phase KD for decades.
What this study adds?
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►► No increased risk of coronary artery lesions is
identified in the acute-­phase KD with low-­dose
(3–5 mg/kg/day) or no aspirin treatment.
►► Low-­dose or no aspirin in the acute-­phase KD
does not show differences regarding the length
of hospital stay and fever duration.
►► The adjustment in the dosage of aspirin during
acute-­phase KD is warranted to prevent the side
effects of high-­dose aspirin.
To prevent coronary artery complications, the
2017 American Heart Association recommended
intravenous immunoglobulin (IVIG) with 2 g/kg
plus high-­ dose aspirin with 80–100  mg/kg/day
during the acute febrile phase of KD3; otherwise,
IVIG administration plus aspirin with 30–50 mg/
kg/day was suggested in Japanese Society of
Paediatric Cardiology and Cardiac Surgery as
the initial treatment of KD.4 High-­dose aspirin
might exert an anti-­inflammatory effect by inhib-
iting the cyclooxygenase pathway of arachidonic
acid metabolism, while IVIG possesses both anti-­
inflammatory and immunomodulatory functions
by blocking activating Fc (fragment crystalliz-
able) receptors, neutralising the aetiological agent
and modulating T cells.5–7 However, concerns
regarding the adverse effects of high-­dose aspirin
therapy, such as gastrointestinal bleeding, anaemia
or Reye syndrome in paediatric patients have been
reported.8–10 A recent study has shown that low-­
dose aspirin (3–5 mg/kg/day) might be as effective
as high-­dose aspirin for the acute phase of KD in
reducing the incidence of CAL.11 Therefore, based
on the aforementioned concepts, this study aimed
to evaluate the efficacy of low-­dose or no aspirin
in the acute-­phase of KD by using meta-­analysis
and systematic review.
   1

Original research
METHODS
Study protocol
We conducted this meta-­analysis by strictly following a prede-
termined protocol from the recommendations of the Cochrane
Handbook of Systematic Reviews.12 Data collection and
reporting were conducted following the Preferred Reporting
Items for Systematic Reviews and Meta-­Analyses Statement.13
This meta-­analysis with systematic review described herein has
been accepted by PROSPERO, an online international prospec-
tive register of systematic reviews, curated by the National Insti-
tute for Health Research (CRD42019137001).
Inclusion and exclusion criteria
The eligibility criteria were met in the comparison of the
outcomes of low-­dose (3–5 mg/kg/day) or no aspirin with those
of high-­dose aspirin (≥30 mg/kg/day) in the acute-­phase of KD
with standard IVIG treatment in enrolled randomised controlled
trials (RCTs), prospective cohort and retrospective cohort
studies.11 The acutephase of KD was defined as the period that
started at the febrile phase after KD diagnosed and ended when
defervescence occurred according to American Heart Associa-
tion.14 Studies that involved the use of aspirin in combination
with steroid, or other anti-­inflammatory drugs or that did not
involve the use of standard IVIG in the acute phase of KD were
excluded, as well as review articles or case reports. The eligible
study designs could be prospective or retrospective.
Outcome of interest
The primary outcome was the incidence of CAL, which was
assessed through echocardiograph using either the Japanese
Ministry of Health criteria15 or the coronary artery z-­ score
system.16 All coronary artery abnormalities were summarised as
CAL, using the two designated assessment tools in this study.
Secondary outcomes were as follows: (1) the incidence of
patients with IVIG resistance defined in each included study, (2)
the length of hospital stay, (3) the fever duration and (4) the
adverse effects caused by aspirin described in enrolled studies.
Search strategy
Multiple databases, including PubMed, Embase and the Cochrane
Library, were searched by using the following keywords: (Kawa-
saki disease OR Mucocutaneous Lymph Node Syndrome
(Medical Subject Headings (MeSH) terms) OR Kawasaki
syndrome) AND (Aspirin (MeSH terms) OR Salicylates (MeSH
terms)) AND (coronary artery disease OR hospitalisation). This
search included the literature published until September 2019
with no starting publication date or language restrictions. The
‘related articles’ function was used and was supplemented with a
manual search of the reference lists of included studies and rele-
vant review articles to identify potentially eligible papers.
Study selection
The relevance of studies was initially assessed using titles and
abstracts. Full manuscripts of potentially relevant titles or
abstracts were obtained and assessed according to the prede-
signed selection criteria. We did not contact the trial authors for
eligibility classification since the inclusion criteria were clear in
all included studies. A predesigned form was adopted to assess
the eligibility by the two authors (MHC and JLW), independently.
After reviewing the methodology in each research, the authors
would independently decide whether to include the study into
meta-­analysis and the final inclusion lists were compared. Any
2 Chiang M-­H, et al. Arch Dis Child 2020;0:1–7. doi:10.1136/archdischild-2019-318245
Arch Dis Child: first published as 10.1136/archdischild-2019-318245 on 10 November 2020. Downloaded from http://adc.bmj.com/ on November 11, 2020 at Librarian Ferriman Information &
Table 1  PICO worksheet (aspirin dosage and KD)
Population Paediatric patients who had been diagnosed with KD
Intervention Standard IVIG treatments (2 g/kg) combined with high-­dose aspirin
(≥30 mg/kg/day)
Comparison Standard IVIG treatments (2 g/kg) combined with low-­dose (3–5 mg/
kg/day) or no aspirin
Outcome The primary outcome was the incidence of coronary artery lesions
detected through echocardiography. Secondary outcomes were as
follows: (1) incidence of IVIG resistance defined in each included
study, (2) the duration of fever, (3) the length of hospital stay and (4)
any adverse effects that were described in enrolled studies.
IVIG, intravenous immunoglobulin; KD, Kawasaki disease; PICO, population,
intervention, comparison and outcome.
discrepancies that occurred in this process were resolved by the
senior author (HEL).
Data extraction
Data extraction depended on the type of outcome data of
enrolled trials. Data of included studies were extracted through
a predesigned data extraction form, including (1) first author’s
name, (2) publication year, (3) sample size, (4) type of study,
(5) patient inclusion criteria, (6) KD treatment protocols, (7)
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demographics of participants and (8) clinical outcomes in each
trial. For dichotomous data, the number of patients with events
and the total number of patients in each group were analysed;
for continuous data, the mean and SD of the total number of
patients in each group were used to be examined.
Quality assessment
The Cochrane Collaboration tool was applied to assess the
quality of RCT.17 In terms of cohort studies, the methodological
quality was determined by using the Newcastle-­Ottawa Quality
Assessment Scale (NOS).18 This scoring system was used to assess
studies based on the participant selection process, comparability
of the two arms and outcome measurement. An article was rated
from 0 to 9 stars by using the NOS, but the total rating might
differ, depending on study characteristics. Briefly, studies were
graded as high quality, requiring 3–4 stars in the selection, 1–2
stars in comparability and 2–3 stars in outcomes; ‘moderate’
quality score, requiring 2–3 stars in the selection, 1 star in
comparability and 1–2 stars in outcomes; and a ‘low’ quality
score, requiring 0–1 star in the selection, 0 star in compara-
bility or 0 star in outcomes using the population, intervention,
comparison and outcome worksheet in table 1.19
Statistical analyses
Data from RCTs and cohort studies were analysed separately
using the software programme RStudio.20 The analytical
models were random-­effect meta-­analysis models rather than
fixed-­effect models with two-­sided 95% CIs.21 OR was used to
compare dichotomous outcomes and mean differences (MDs)
were used to compare continuous outcomes. Estimates for OR
and MD from multiple studies were pooled and weighted using
the inverse variance model.12 If there were any missing data,
different accounting approaches would be taken, depending on
the missing data mechanism.22 A two-­tailed p value of less than
0.05 was considered statistically significant. Adverse effects are
presented descriptively based on the information provided in
each included study.
 Arch Dis Child: first published as 10.1136/archdischild-2019-318245 on 10 November 2020. Downloaded from http://adc.bmj.com/ on November 11, 2020 at Librarian Ferriman Information &
Original research
p<0.10 because of the lower power of the test to detect hetero-
geneity.23 The I2 statistic was used to indicate the proportion
of heterogeneity among study estimates. I2 values of 0%–25%,
25%–50% and >50% were considered to exhibit low, moderate
and high heterogeneity, respectively. In terms of publication bias,
funnel plots were illustrated and Egger’s regression asymmetry
test was used.24

Figure 1  PRISMA flow diagram of search history to compare
between the effects of low-­dose or no aspirin and those of high-­dose
aspirin inacute phase of KD (adapted from Moher et al.13) (for more
information, visit www.prisma-statement.org). PRISMA, Preferred
RESULTS
Characteristics of included studies
Figure 1 represents the flowchart of the screening and selec-
tion of included studies. In brief, 437 records were identified
after removing duplicates. We had excluded 404 records at the
initial stage and left 33 records for full-­text review. Afterward,
10 studies for being irrelevant, 3 review articles, 2 comments,
1 clinical trial protocol, 2 single-­arm studies and 6 studies of
inappropriate interventions such as the absence of IVIG treat-
ment or steroid usage, and moderate-­dose aspirin (10–30 mg/kg/
day) prescription even during the follow-­up period were iden-
tified and excluded. Finally, there were two prospective cohort
studies and seven retrospective cohort studies that fulfilled the
inclusion criteria with 12 182 participants in total. The nine
enrolled studies with sample sizes ranged from 69 to 8456
patients between 1992 and 2018.25–33 There were six studies
with comparison for the efficacy of low-­ dose and high-­ dose

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Reporting Items for Systematic Reviews and Meta-­Analyses.
Heterogeneity and publication bias
Heterogeneity was assessed using the χ2 statistic and associated
p value to evaluate the dispersion of the true effect among the
recruited studies. The level of statistical significance was set at
aspirin,25–27 30 32 33 two studies with comparison for the efficacy
of no aspirin and high-­dose aspirin,28 29 and one study for the
assessment of the treatment efficacy in low-­dose/no aspirin and
high-­dose aspirin.31 The basic characteristics of the studies are
presented in table 2.
The assessment of the methodological quality of the nine
included studies is summarised in table 3. Because the initial

Table 2  Characteristics of the included studies

Study Patient number, n Age, months, Complete IVIG
Study type Inclusion criteria (male, %) mean±SD KD (%) CAL criteria dosage Interventions
Low-­dose versus high-­dose aspirin in the acute phase of KD
 Amarilyo et al26 RCS Complete or H: 315 (63.5) H: 28.8±22.8 L: H: 61.9 Z score 2 g/kg H: 80–100 mg/kg/day
incomplete KD L: 43 (65.1) 34.8±37.2 L: 53.5 L: 3–5 mg/kg/day
 Dallaire et al25 RCS Complete or H: 848 (59.4) H: 40.8±28.8 L: H: 69 Z score NA H: 80 mg/kg/day
incomplete KD L: 365 (58.4) 38.4±26.4 L: 76.2 L: 3–5 mg/kg/day
 Dhanrajani et al30 RCS Complete or H: 127 (58.3) H: 36 (18-64)* H: 66.9 NA 2 g/kg H: 80–100 mg/kg/day
incomplete KD L: 122 (59) L: 33 (17-56) L: 69.7 L: 3–5 mg/kg/day
 Huang et al31 RCS KD H: 86 (69) H: 25.8±19.4 L: NA Japanese criteria 2 g/kg H: 30–50 mg/kg/day
L: 672 (63) 23.7±11.3 L: 3–5 mg/kg/day
 Kim et al27 RCS Complete or H: 7947 (58.3) H: 32.6 H: 71.6 Z score & 2 g/kg H:≥30 mg/kg/day
incomplete KD L: 509 (57.4) L: 30.8 L: 80.4 Japanese criteria L: 3–5 mg/kg/day
 Melish et al32 PCS KD H: 40 NA NA NA 2 g/kg H: 100 mg/kg/day
L: 45 L: 3–8 mg/kg/day
 Rahbarimanesh et RCS KD H: 27 NA NA NA 2 g/kg H: 80–100 mg/kg/day
al33 L: 42 L: 3–5 mg/kg/day
Non-­use versus high-­dose aspirin in the acute phase of KD
 Huang et al31 RCS KD H: 86 (69) H: 25.8±19.4 NA Japanese criteria 2 g/kg H: 30–50 mg/kg/day
N: 152 (67) N: 22.8±17.1 N: no aspirin usage
 Kuo et al28 RCS KD H: 305 (65.9) NA NA Japanese criteria NA H:≥30 mg/kg/day
N: 546 (61.9) N: 3–5 mg/kg/day after
defervescence
 Lee et al29 PCS KD H: 129 (55.8) H: 30.2±22.3 N: NA Japanese criteria 2 g/kg H: 80–100 mg/kg/day
N: 51 (58.8) 30.7±25.1 N: 3–5 mg/kg/day after
defervescence
*Medium (IQR).
CAL, coronary artery lesion; H, high-­dose aspirin group; IVIG, intravenous immunoglobulin; KD, Kawasaki disease; L, low-­dose aspirin group; N, no aspirin group; NA, not
available; PCT, prospective cohort study; RCS, retrospective cohort study.

Chiang M-­H, et al. Arch Dis Child 2020;0:1–7. doi:10.1136/archdischild-2019-318245 3

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Original research

Table 3  Quality assessment of the included studies

Selection of Outcome was Adequacy
Representativeness non-­exposed Ascertainment not present at Assessment Length of of follow-­
Study of exposed cohort cohort of exposure start of study Comparability of outcomes follow-­up up Total
The Newcastle-­Ottawa Quality Assessment Scale
 Amarilyo et al26 ✷ ✷ NA ✷ ✷ ✷ 5/8
 Dallaire et al25 ✷ ✷ NA ✷ ✷ ✷ ✷ 6/8
 Dhanrajani et al30 ✷ ✷ NA ✷✷ ✷ ✷ ✷ 7/8
 Huang et al31 ✷ ✷ ✷ NA ✷ ✷ ✷ 6/8
 Kim et al27 ✷ ✷ NA ✷ ✷ ✷ 5/8
 Kuo et al28 ✷ ✷ ✷ NA ✷ ✷ ✷ 6/8
 Lee et al29 ✷ ✷ NA ✷ ✷ ✷ ✷ 6/8
 Melish et al32 ✷ ✷ ✷ NA ✷ ✷ 5/8
 Rahbarimanesh et ✷ ✷ ✷ NA ✷ ✷ ✷ 6/8
al33
>6 stars means high quality; 5–6 stars means medium quality; <5 stars means low quality.
NA, not applicable.

ascertainment for the absence of CAL was not applicable due
to retrospective studies, the total score was 8 points instead of
the original 9 points. Overall, two studies were ranked as high
quality25 29; four studies scored as moderate quality26 30 32 33; and
three studies scored as low quality.27 28 31
Figure 2 shows the detail information. No significant publication
bias was detected using Egger’s regression test with the p=0.71 and
t-­value= −0.38. (online supplemental figure 1A).
IVIG resistance

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Coronary artery lesions
All included studies with a total of 12 182 participants reported
the incidence of CAL. Three studies used the Japanese Ministry
of Health criteria,28 29 31 three used the coronary artery z score
system,25 26 30 one used both,27 and one did not state the criteria of
CAL in the methodology.32 Due to less anti-­inflammatory effects
in low-­dose aspirin, we grouped with low-­ dose and no-­ aspirin
subgroups to increase the sample size since there was a trend with
a lower CAL incidence in both (low-­dose vs high-­dose, OR=0.82,
95%  CI=0.61  to 1.09; no aspirin vs high-­ dose, OR=0.85,
95% CI=0.60  to 1.20, respectively). Interestingly, patients with
low-­dose or no aspirin in the acute phase of KD had a signifi-
cantly lower incidence of CAL than those with high-­dose aspirin
(OR=0.81, 95% C=0.69–0.95, P=0.01). After the pooled meta-­
analysis the overall heterogeneity was low (I2=0%, χ2 P=0.46).
IVIG resistance was assessed in seven studies with 11 392 partic-
ipants by using different predefined criteria as three studies for
patients with additional IVIG treatment,25 27 30 two studies for
patients with persistent fever for >72 hours after IVIG adminis-
tration,26 32 and two studies for patients with fever for >48 hours
after IVIG administration.28 29 The overall result revealed that
there were no differences in IVIG resistance between patients
with low-­ dose/no aspirin and high-­ dose aspirin (OR=1.35,
95% CI 0.91 to 1.98, figure 3). The overall heterogeneity was
high (I2=73%, chi-­ square p<0.01). However, the incidence
of IVIG resistance was higher in patients with low-­dose than
high-­dose aspirin (OR=1.66, 95% CI 1.13 to 2.45, heteroge-
neity p=0.02); therefore, we performed the subgroup analyses
and found the effects of different definition of IVIG resistances
(using additional IVIG treatment, OR=1.65, 95% CI 1.09 to

Figure 2  Forest plot comparing the risk of coronary artery lesions in the nine included studies using a random-­effects model.
4 Chiang M-­H, et al. Arch Dis Child 2020;0:1–7. doi:10.1136/archdischild-2019-318245

Figure 3  Forest plot comparing the risk of intravenous immunoglobulin resistance in the seven included studies using a random-­effects model. IV,
intravenous.
2.5; using fever duration >48 hours (>72 hours included due
to the smaller size), OR=1.02, 95% CI 0.52 to 2.02, (online
supplemental figure 2). In terms of the funnel plot, no signifi-
cant asymmetry was detected by Egger’s regression test (p=0.88,
t-­value= −0.16), but three dots were out from the 95% CI area
(online supplemental figure 1B).
Length of hospitalisation and fever duration
Five studies with a total of 1612 participants reported the dura-
tion of hospital stay. No significant differences were observed
in the length of hospital stay between low-­dose/no-­aspirin and
high-­dose aspirin treatment group (MD=0.17, 95% CI −1.07 to
1.40; figure 4). Four studies reported the fever duration as two
studies with total fever days after admission and the other two
with fever days after IVIG administration.29 33 We did not find
any differences between the two groups (MD=0.30, 95% CI
−1.51 to 2.11; MD=0.28, 95% CI −0.09 to 0.65, respectively).
However, it is noteworthy to mention that high heterogeneity
was observed in the first outcome; hence, the result should be
interpreted with caution (I2=78%, χ2 p<0.01; I2=52%, χ2
p=0.15; and I2=0%, χ2 p=0.75, respectively; figure 5).
Figure 4  Forest plot comparing the length of hospital stay in the five included studies using a random-­effects model.
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Original research
Adverse effects
Four studies reported adverse effects as one of their outcomes of
interests, and no significant differences were observed between the
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two treatment groups. Amarilyo et al stated that almost all side
effects were intermittent and categorised as mild.26 One patient
had abdominal pain and two patients had epistaxis in the high-­
dose aspirin subgroup. Huang et al reported two cases of mild
epistaxis with self-­recovery.31 Melish et al reported that side effects
were similar and mild in both the treatment groups.32 Additionally,
Kuo et al analysed the difference in haemoglobin levels between
no-­aspirin and high-­dose aspirin treatment groups and discovered
that high-­dose aspirin may be related to anaemia.28
DISCUSSIONS
This meta-­analysis has provided evidence that prescribing low-­
dose or no aspirin was associated with the reduced risk of CAL
compared with high-­dose aspirin in the acute phase of KD with
IVIG treatment. Furthermore, no differences regarding length of
hospital stay, and fever duration were identified in the different
dosage of aspirin subgroups. Therefore, low-­dose aspirin plus
IVIG treatment or IVIG treatment alone might be enough to
5

Original research
Figure 5  Forest plot comparing fever duration after admission and IVIG therapy in the four included studies using a random-­effects model. IVIG,
intravenous immunoglobulin.
prevent coronary artery complications in paediatric patients
with KD.
The role of high-­dose aspirin in the acute phase of KD has
been fully investigated comprehensively, but few studies evalu-
ated the efficacy of low-­dose or no aspirin in the acute phase
of KD. In the comparison with the results in a previous study,
which showed that using low-­dose aspirin does not increase the
risk of CAL,11 this study showed that low-­dose or no aspirin
in the acute phase of KD was associated with lowering CAL
incidence. This result might indicate that high-­dose aspirin has
fewer effects in reducing CAL risk for patients with KD. IVIG
administration provides the major effects to prevent CAL occur-
rence in paediatric patients with KD.7 34 To clarify this concern,
a prospective RCT is suggested to address the role of low-­dose
or no aspirin in the acute phase of KD.
Approximately 10% of patients with IVIG resistance were
those who received the standard treatment with IVIG 2 g/kg
single infusion.35 Inconsistent with the results of a previous
study,11 we also no differences for IVG resistance in the pooled
low-­dose or no-­aspirin subgroup. In our results, high-­dose aspirin
was preferred in reducing IVIG resistance in three studies using
additional IVIG treatment, but high heterogeneity was noted; on
the contrary, no differences were observed between low-­dose/
no aspirin in those using fever >48 hours. The fever duration
>48 hours might be more appropriate for IVIG resistance since
the timing of additional IVIG treatment is unclear. Perhaps, IVIG
resistance could be defined according to the clinical implication.
However, this study has several limitations. First, most of the
included studies were retrospective designs, which were prone to
reverse causation bias. Second, the results should be treated with
caution because the included studies were small-­scale studies,
and the numbers of patients in the high-­dose group and the low-­
dose/no-­aspirin subgroups were highly unbalanced. Third, the
basic information was limited because few laboratory data were
obtained.
CONCLUSIONS
Since the dosage of aspirin in the acute-­phase of KD has different
recommendations, this current meta-­analysis has demonstrated
the association of low-­dose or no-­aspirin administration with
CAL development in children with KD. Additional well-­designed
RCTs are required to provide more concrete evidence for the
effects of low-­dose or no aspirin in the acute phase of KD.
Contributors  MHC and JLW designed the study. The two authors conducted
the searches and data extraction independently. MHC conducted the statistical
6 Chiang M-­H, et al. Arch Dis Child 2020;0:1–7. doi:10.1136/archdischild-2019-318245
Arch Dis Child: first published as 10.1136/archdischild-2019-318245 on 10 November 2020. Downloaded from http://adc.bmj.com/ on November 11, 2020 at Librarian Ferriman Information &
analysis and JLW contributed to data interpretation as well as manuscript revision.
HEL revised the final data interpretation. All authors had full access to all the data
collected in this meta-­analysis, checked for accuracy and approved the final version
of this article.
Funding  This study was supported by a grant from Wan Fang Hospital (grant
number 105-­wf-­eva-18). This article was edited by Wallace Academic Editing.
Competing interests  None declared.
Patient consent for publication  Not required.
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Provenance and peer review  Not commissioned; externally peer reviewed.
Data availability statement  Data sharing is not applicable as no datasets were
generated and/or analysed for this study.
Supplemental material  This content has been supplied by the author(s).
It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not
have been peer-­reviewed. Any opinions or recommendations discussed are
solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all
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