Research

JAMA | Original Investigation

Association of Intravenous Immunoglobulins Plus Methylprednisolone

vs Immunoglobulins Alone With Course of Fever
in Multisystem Inflammatory Syndrome in Children
Naïm Ouldali, MD, PhD; Julie Toubiana, MD, PhD; Denise Antona, MD; Etienne Javouhey, MD, PhD;
Fouad Madhi, MD; Mathie Lorrot, MD, PhD; Pierre-Louis Léger, MD, PhD; Caroline Galeotti, MD, PhD;
Caroline Claude, MD; Arnaud Wiedemann, MD, PhD; Noémie Lachaume, MD; Caroline Ovaert, MD, PhD;
Morgane Dumortier, MD; Jean-Emmanuel Kahn, MD, PhD; Alexis Mandelcwajg, MD; Lucas Percheron, MD;
Blandine Biot, MD; Jeanne Bordet, MD; Marie-Laure Girardin, MD; David Dawei Yang, MD; Marion Grimaud, MD;
Mehdi Oualha, MD, PhD; Slimane Allali, MD, PhD; Fanny Bajolle, MD; Constance Beyler, MD;
Ulrich Meinzer, MD, PhD; Michael Levy, MD, PhD; Ana-Maria Paulet, MD; Corinne Levy, MD; Robert Cohen, MD;
Alexandre Belot, MD, PhD; François Angoulvant, MD, PhD; for the French Covid-19 Paediatric Inflammation Consortium

Supplemental content
IMPORTANCE Multisystem inflammatory syndrome in children (MIS-C) is the most severe
pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection,
potentially life-threatening, but the optimal therapeutic strategy remains unknown.

OBJECTIVE To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG

alone as initial therapy in MIS-C.

DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study drawn from a national
surveillance system with propensity score–matched analysis. All cases with suspected MIS-C
were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling
the World Health Organization definition were included. The study started on April 1, 2020,
and follow-up ended on January 6, 2021.

EXPOSURES IVIG and methylprednisolone vs IVIG alone.

MAIN OUTCOMES AND MEASURES The primary outcome was persistence of fever 2 days after
the introduction of initial therapy or recrudescence of fever within 7 days, which defined
treatment failure. Secondary outcomes included a second-line therapy, hemodynamic
support, acute left ventricular dysfunction after first-line therapy, and length of stay in the
pediatric intensive care unit. The primary analysis involved propensity score matching with a
minimum caliper of 0.1.

RESULTS Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization
definition (58 females [52%]; median age, 8.6 years [interquartile range, 4.7 to 12.1]). Five
children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and
methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to
treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with
lower risk of treatment failure (absolute risk difference, −0.28 [95% CI, −0.48 to −0.08];
odds ratio [OR], 0.25 [95% CI, 0.09 to 0.70]; P = .008). IVIG and methylprednisolone
therapy vs IVIG alone was also significantly associated with lower risk of use of second-line
therapy (absolute risk difference, −0.22 [95% CI, −0.40 to −0.04]; OR, 0.19 [95% CI, 0.06 to
0.61]; P = .004), hemodynamic support (absolute risk difference, −0.17 [95% CI, −0.34 to
−0.004]; OR, 0.21 [95% CI, 0.06 to 0.76]), acute left ventricular dysfunction occurring after
initial therapy (absolute risk difference, −0.18 [95% CI, −0.35 to −0.01]; OR, 0.20 [95% CI, Author Affiliations: Author
0.06 to 0.66]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; affiliations are listed at the end of this
article.
difference in days, −2.4 [95% CI, −4.0 to −0.7]).
Group Information: A list of the
CONCLUSIONS AND RELEVANCE Among children with MIS-C, treatment with IVIG and members of the French Covid-19
methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study Paediatric Inflammation Consortium
is in Supplement 2.
interpretation is limited by the observational design.
Corresponding Author: François
Angoulvant, MD, PhD, Paediatric
Emergency Department,
Necker-Enfants Malades University
Hospital, 149 Rue de Sèvre, 75015
JAMA. 2021;325(9):855-864. doi:10.1001/jama.2021.0694 Paris, France (francois.angoulvant@
Published online February 1, 2021. Corrected on July 6, 2021. aphp.fr).

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 Research Original Investigation Association of IVIG Plus Methylprednisolone With Persistent or Recurrent Fever in Children With MIS-C

C
hildren account for only 1% to 2% of hospitalized patients
with coronavirus disease 2019 (COVID-19).1 However, in Key Points
April 2020, severe systemic hyperinflammatory disease
Question Is there an association between treatment with
was reported in children in Europe and the United States, occur- intravenous immunoglobulins (IVIG) plus methylprednisolone vs
ring 2 to 4 weeks after severe acute respiratory syndrome coro- IVIG alone and course of fever in multisystem inflammatory
navirus 2 (SARS-CoV-2) infection.2-6 This novel entity, named mul- syndrome in children (MIS-C) associated with severe acute
tisystem inflammatory syndrome in children (MIS-C)7 or pediat- respiratory syndrome coronavirus 2?
ric multisystem inflammatory syndrome temporally associated Findings This retrospective cohort study included 111 children with
with COVID-19,8 is associated with a wide range of clinical fea- MIS-C. After propensity score matching, the rate of treatment failure
tures including persistent fever, digestive symptoms, rash, bilat- (defined by the persistence of fever 2 days after the introduction of
eral nonpurulent conjunctivitis, mucocutaneous inflammation first-line therapy or recrudescence of fever within 7 days) for those
signs, and frequent cardiovascular involvement.2,4-6,9 MIS-C is who received IVIG plus methylprednisolone vs IVIGs alone was 9%
vs 51%, a difference that was statistically significant.
often associated with hemodynamic failure, with acute cardiac
dysfunction requiring hemodynamic support in 60% to 75% of Meaning Combined treatment with methylprednisolone vs IVIG
cases,5,6 sometimes associated with death.2-6 alone was associated with a better course of fever in MIS-C.
Many children with MIS-C have received empirical treat-
ment based on Kawasaki disease guidelines, with intrave- All children with confirmed MIS-C associated with SARS-
nous immunoglobulin (IVIG) alone or combined with CoV-2 infection fulfilling WHO criteria up to October 22, 2020,
corticosteroids.2-4,6,10 In some studies, children have re- were included in the study. The final date of follow-up was
quired second-line treatment, such as tumor necrosis factor January 6, 2021.
inhibitor or interleukin 1 inhibitor, which underscores the im-
portance of defining optimal initial therapy.11,12 Outcome Measure
However, evidence for the most effective therapies for The primary outcome was treatment failure, defined as persis-
MIS-C is still lacking.10,13 In the absence of evidence, a British tence of fever for 2 days (48 hours) after the introduction of ini-
Delphi consensus study proposed treating MIS-C with IVIG as tial therapy or recrudescence of fever within 7 days after the ini-
initial therapy.14 tial therapy in children who received IVIG and methylpredniso-
The goal of this retrospective cohort study was to com- lone vs IVIG alone as first-line therapy. Time was measured from
pare the outcomes of children with MIS-C associated with the start of administration of IVIG or methylprednisolone. This
SARS-CoV-2 infection treated with IVIG and methylpredniso- outcome was similar to the primary outcome used in therapeu-
lone vs IVIG alone. tic studies of Kawasaki disease19-21 and has been associated in Ka-
wasaki disease with increased risk of further cardiovascular
complications.20,21 IVIG and methylprednisolone was considered
initial therapy when the beginning of administration of the 2
Methods
therapies occurred within 24 hours of one another. Fever was de-
Ethical Review of Study and Informed Consent fined as a temperature of 38 °C (ie, ≥100.4 °F) or greater.22
of Study Participants Secondary outcomes were second-line therapy, defined by
The study was approved by the INSERM ethics committee for a secondary treatment, such as steroids or biological agents,
evaluation (IRB00003888). A written information form vali- for MIS-C prescribed at least 24 hours after the initial therapy14;
dated by the ethics committee was given to all participants. hemodynamic support after first-line therapy; occurrence of
Oral consent was obtained from study participants; no family acute left ventricular dysfunction, defined by left ventricular
members or participants refused to participate. ejection fraction less than 55% after first-line therapy; and du-
ration of stay in the pediatric intensive care unit (PICU). For
Patients and Settings hemodynamic support and acute left ventricular dysfunc-
The reporting of all suspected MIS-C cases in France became man- tion, only outcomes occurring at least 1 day after the initia-
datory since the first descriptions of this entity in April 2020. This tion of first-line therapy were considered. Hemodynamic sup-
reporting was coordinated by the French National Public Health port was defined as vasoactive or inotropic amine but not the
Agency, with a methodology previously published.5,15 All French escalation of a previously prescribed drug.
pediatric hospitals were mandated to report any suspected case
of MIS-C to the French National Public Health Agency, without Sample Size Calculation
waiting for the SARS-COV-2 antibody test result.16 An electronic From available data, and prior to any data collection, assuming
case report form for each patient was stored in a secure database a risk of treatment failure of 50% in the IVIG alone group11,12 and
based on clinical and biological files and shared by each pediat- that the risk with IVIG and methylprednisolone would be reduced
ric hospital. The following data were recorded: demographic char- to 20%, with a total of 76 patients, the study was estimated to have
acteristics, comorbidities, initial symptoms and clinical signs, bio- 80% power to detect such a difference, assuming 2-sided tests.
logical and microbiological parameters, radiography findings,
treatments, and course during hospitalization.17 Then 2 research Statistical Analysis
members (N. O. and F. A.) classified each case as confirmed MIS-C The main analysis involved propensity score matching.23,24 The
or not following World Health Organization (WHO) criteria (Box).18 propensity score was calculated with a multivariable logistic

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 Association of IVIG Plus Methylprednisolone With Persistent or Recurrent Fever in Children With MIS-C Original Investigation Research

regression model to establish each patient’s probability of re-

ceiving combination therapy with corticosteroids according to Box. WHO Criteria for MIS-Ca
baseline characteristics. The following baseline characteris-
Children and adolescents 0 to 19 years old with fever >3 days
tics were used to generate the propensity score: age, sex, co-
AND 2 of the following:
morbidities, hospital center, gastrointestinal symptoms, lower
Rash or bilateral nonpurulent conjunctivitis or mucocutaneous
respiratory tract symptoms, neurological symptoms, initial inflammation signs (oral, hands, or feet)
acute left ventricular dysfunction (left ventricular ejection frac-
Hypotension or shock
tion <55%), intensity of inflammatory syndrome (C-reactive
Features of myocardial dysfunction, pericarditis, valvulitis, or
protein level > or ≤150 mg/L), positive SARS-CoV-2 antibody
coronary abnormalities (including echocardiographic findings or
test result, initial PICU care before first-line MIS-C therapy, and elevated troponin/NT-proBNP)
initial hemodynamic support before first-line MIS-C therapy
Evidence of coagulopathy (by prothrombin time, partial throm-
(eTable 1 in Supplement 1). All of these variables, except the boplastin time, elevated D-dimer levels)
SARS-CoV-2 antibody test result, were assessed at the initial
Acute gastrointestinal symptoms (diarrhea, vomiting, or ab-
presentation (ie, before the start of the first-line MIS-C therapy). dominal pain)
Patients who received IVIG and methylprednisolone were
AND elevated markers of inflammation such as erythrocyte sedi-
matched to those who received IVIG alone by their propen- mentation rate, C-reactive protein level, or procalcitonin level
sity score using nearest-neighbor matching, with a minimum
AND no other obvious microbial cause of inflammation, including
caliper of 0.1. The ratio was 1 patient receiving IVIG and meth- bacterial sepsis, staphylococcal, or streptococcal shock syndromes
ylprednisolone matched with 2 patients receiving IVIG alone.
AND evidence of COVID-19 (RT-PCR, antigen test, or serology posi-
The balance between the 2 treatment groups for each covari- tive) or likely contact with patients with COVID-19
ate was assessed with a standardized difference less than 0.1,
Abbreviations: COVID-19, coronavirus disease 2019; MIS-C, multisystem
which was considered acceptable.23 Conditional logistic re- inflammatory syndrome in children; NT-proBNP, N-terminal pro–brain
gression analysis was performed with the matched cohort to natriuretic peptide; RT-PCR, reverse transcriptase–polymerase chain
test the association between treatment groups and each out- reaction; WHO, World Health Organization.
come, with findings expressed as absolute risk differences, a
Based on WHO criteria.18
odds ratios (ORs), and 95% CIs. The analysis was also ad-
justed for center by using random-effects modeling, which in-
volved fitting a mixed-effects logistic regression model.25 mary outcomes included presence or absence of initial acute
ix sensitivity analyses were performed to assess the robust- left ventricular dysfunction, defined by left ventricular ejec-
ness of the study findings. First, the data were analyzed using in- tion fraction less than 55%, and age 10 years and older or
verse probability of treatment weighting, an alternative to pro- younger than 10 years. This age categorization was based on
pensity score matching to account for indication bias in nonran- the receiver operating characteristic curve to define the opti-
domized design.23,24 Unlike propensity score matching, this mized cut-off value. To test for significant differences in ef-
strategy has the advantage of including all the patients in the fi- fect size among subgroups, an interaction term was included
nal analysis.24 Second, a propensity score–matched analysis was in the main propensity score model for each subgroup.28
conducted with center as a fixed effect.25 Third, a propensity A 2-sided P < .05 was considered statistically significant.
score–matched analysis was conducted with double adjustment Because of the potential for type I error due to multiple com-
onthemostlikelyconfoundingvariables26 ofinitialhemodynamic parisons, findings for analyses of secondary end points should
support and initial left ventricular dysfunction. This strategy has be interpreted as exploratory. All analyses were performed with
been proposed to remove residual confounding after propensity R version 3.6.1 (http://www.R-project.org).
score matching for the main potential confounders and adjusts
for these variables both for propensity score calculation and in
the final conditional logistic regression analysis with the matched
cohort.26 Fourth, a propensity score–matched analysis was con-
Results
ducted including the duration of fever before first-line MIS-C Among the 181 pediatric patients reported to the French Na-
therapy and the delay between hospital admission and start of tional Public Health Agency with suspected MIS-C, 111 fulfilled
first-line MIS-C therapy as an additional baseline covariate to ac- WHO criteria for MIS-C associated with SARS-CoV-2 infection
count for potential differences in the delay between disease on- (Figure 1); 70 did not meet the criteria and were not included
set and the start of first-line therapy between the 2 treatment (eTable 2 in Supplement 1). Five children who met the criteria
groups. Fifth, a propensity score–matched analysis was conducted were not included because they did not receive either of the 2
including mechanical ventilation and the vasoactive inotropic treatments (eTable 3 in Supplement 1). The median age of the
score27 as additional baseline covariates to account for potential remaining 106 children was 8.6 years (interquartile range, 4.7 to
remaining differences in the initial severity of illness. Sixth, a lo- 12.1), and 58 (52%) were female. Most children (n = 104; 94%)
gistic multivariable regression analysis adjusted on the variables had gastrointestinal manifestations, and 52 (47%) had initial left
included in the propensity score was conducted. ventricular dysfunction. In total, 74 children (67%) were ini-
Because of the small sample size, subgroup analyses were tially admitted to a PICU, 46 (41%) received hemodynamic sup-
conducted with the inverse probability of treatment weight- port, and 29 (26%) received ventilatory support. No deaths were
ing approach. Prespecified subgroups for analyzing the pri- recorded. Among the 111 children, 100 had positive results from

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 Research Original Investigation Association of IVIG Plus Methylprednisolone With Persistent or Recurrent Fever in Children With MIS-C

Figure 1. Study Flowchart and Propensity Score Matching of Children With Suspected Multisystem Inflammatory Syndrome in Children (MIS-C)

181 Children with suspected MIS-C reported to

the French National Public Health Agencya

70 Excluded
38 Lacking sufficient clinical detail for
classification
32 Without WHO criteria for MIS-Cb
22 No evidence of COVID-19
4 Bacterial sepsis
4 No multisystemic WHO criteriac
1 No elevated inflammatory parameters
1 Older than 19 y

111 With confirmed MIS-C

5 Received neither IVIG nor steroidsd

106 With confirmed MIS-C

34 Received IVIG and methylprednisolone 72 Received IVIG alone

2 Not matchede 8 Not matchede

32 Included in the primary analysis 64 Propensity score–matched children

included in the primary analysis

COVID-19 indicates coronavirus disease 2019; IVIG indicates intravenous evidence of coagulopathy (by prothrombin time, partial thromboplastin time,
immunoglobulins; and WHO, World Health Organization. elevated D-dimers); and (5) acute gastrointestinal problems (diarrhea,
a
The reporting of all suspected MIS-C cases in France became mandatory since vomiting, or abdominal pain).
d
the first descriptions of this entity in April 2020. All French pediatric hospital Details about the 5 patients are provided in eTable 3 in the Supplement.
centers were contacted by the French National Public Health Agency in April e
Patients who received IVIG alone were then matched to those who received
2020 to electronically report any case of suspected MIS-C in French IVIG and methylprednisolone by their propensity score by using 1:2
children.5,16 nearest-neighbor matching, with a minimum caliper of 0.1. The following
b
Details of the characteristics of excluded patients are provided in eTable 2 in baseline characteristics were used to generate the propensity score: age, sex,
the Supplement. comorbidities, hospital center, gastrointestinal symptoms, lower respiratory
c
Multisystemic WHO criteria (2 of the following): (1) rash or bilateral tract symptoms, neurological symptoms, positive severe acute respiratory
nonpurulent conjunctivitis or mucocutaneous inflammation signs (oral, hands, syndrome coronavirus 2 antibody test result, initial acute left ventricular
or feet); (2) hypotension or shock; (3) features of myocardial dysfunction, dysfunction, initial pediatric intensive care unit care, initial hemodynamic
pericarditis, valvulitis, or coronary abnormalities (including echocardiographic support, and intensity of inflammatory syndrome (C-reactive protein level > or
findings or elevated troponin/N-terminal pro–brain natriuretic peptide); (4) ⱕ150 mg/L).

SARS-CoV-2 antibody testing or nasopharyngeal reverse tran- methylprednisolone had a more severe initial presentation with
scriptase–polymerase chain reaction and 11 had contact with an more frequent initial acute left ventricular dysfunction (22/34
individual with SARS-CoV-2 infection. Other baseline charac- [65%] vs 28/72 [39%]), initial PICU care (31/34 [91%] vs 42/72
teristics not included in the propensity score are reported in [58%]), and initial hemodynamic support requirement (21/34
eTable 4 in Supplement 1. [62%] vs 23/72 [32%]).
Among the 111 children, 34 received IVIG and methylpred- Among the 34 children who received IVIG and methyl-
nisolone and 72 received IVIG alone as first-line therapy. Dis- prednisolone, 3 (9%) did not respond to treatment; among the
tribution of children by participating centers is reported in 72 children who received IVIG alone, 37 (51%) did not re-
eTable 5 in Supplement 1. Among the 106 children who re- spond to treatment.
ceived IVIG and methylprednisolone or IVIG alone, none re- Among the 34 children who received IVIG and methyl-
ceived any other immunomodulatory treatment before the ini- prednisolone, 3 (9%) received a second-line therapy (a sec-
tial therapy. The dosage of IVIG was 2 g/kg for all patients. A ond IVIG course in 2 children and an interleukin 1 inhibitor in
total of 30 of 34 patients in the IVIG and methylprednisolone 1 child) (eTables 6 and 7 in Supplement 1). Two children had
group received methylprednisolone at 0.8 to 1 mg/kg every 12 acute left ventricular dysfunction after initial therapy, and 2
hours (maximum of 30 mg for 12 hours) for 5 days; the 4 re- required hemodynamic support.
maining children received a bolus of 15 to 30 mg/kg/d of meth- Among the 72 children who received IVIG alone, 33 (46%,
ylprednisolone for 3 days. As compared with children who re- all of whom had treatment failure) received second-line thera-
c e ive d I V I G a l o n e , t h o s e w h o re c e ive d I V I G a n d pies: a second IVIG course alone in 14, IVIG and methylpred-

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 Association of IVIG Plus Methylprednisolone With Persistent or Recurrent Fever in Children With MIS-C Original Investigation Research

nisolone in 11, methylprednisolone alone in 2, and a biologi- A recent research letter29 reported a single-center experi-
cal agent in 6 (an interleukin 1 inhibitor in 4 and an interleukin ence of cardiac evolution in 40 children with MIS-C and sug-
6 inhibitor in 2). Sixteen children showed acute left ventricu- gested that receiving IVIG plus corticosteroids was associ-
lar dysfunction after initial therapy, and hemodynamic sup- ated with a shorter cardiac recovery than receiving IVIG alone.
port was introduced or added for 17 (24%) (eTables 6 and 7 in Another single-center study reported that following the imple-
Supplement 1). mentation of a new local protocol including corticosteroids for
MIS-C treatment, hospital length of stay decreased.30 Recent
Primary Outcome UK guidelines for MIS-C management,14 developed using a Del-
Among the 106 treated children, 32 in the IVIG and methyl- phi method and in the absence of comparative studies, sug-
prednisolone group and 64 in the IVIG group were matched gested IVIG alone as first-line therapy, or no therapy in some
based on the propensity score (Figure 1). The treatment groups cases. The findings in the current study may warrant recon-
differed in several baseline characteristics, but after match- sidering these recommendations.
ing, the balance was satisfactory (Table 1 and the eFigure in A recent prospective surveillance of COVID-19 in children
Supplement 1). There were no missing data for all baseline co- suggested that older children may be at increased risk of de-
variates included in the propensity score. veloping severe disease.17 This may reflect an overlap in young
IVIG and methylprednisolone compared with IVIG alone children between the classification of MIS-C and Kawasaki
was associated with a lower rate of treatment failure (3/32 [9%] disease,31 which seems less severe than MIS-C.2,11 In the cur-
vs 24/64 [38%]; absolute risk difference, −0.28 [95% CI, −0.48 rent study, there were no significant interactions in sub-
to −0.08]; OR, 0.25 [95% CI, 0.09 to 0.70]; P = .008; Table 2). groups based on age 10 years as a cut point. While the sub-
group analyses are limited by a small sample size and should
Secondary Outcomes be interpreted with caution, they suggest that the association
Treatment with IVIG and methylprednisolone vs IVIG alone of IVIG and methylprednisolone with better outcomes may be
was associated with a lower rate of second-line treatment similar in older and younger children. Further studies are re-
(3/32 [9%] vs 20/64 [31%]; absolute risk difference, −0.22 quired to confirm these findings.
[95% CI, −0.40 to −0.04]; OR, 0.19 [95% CI, 0.06 to 0.61]; Some recent preliminary mechanistic studies also suggested
P = .004), secondary acute left ventricular dysfunction (ab- similarities between MIS-C and acute respiratory distress syn-
solute risk difference, −0.18 [95% CI, −0.35 to −0.01]; OR, drome related to SARS-CoV-2 infection in adults.32 Corticosteroid
0.20 [95% CI, 0.06 to 0.66]), and hemodynamic support use is currently one of the few validated therapeutics in severe
(absolute risk difference, −0.17 [95% CI, −0.34 to −0.004]; respiratory adult forms of COVID-19.33,34 The findings in the cur-
OR, 0.21 [95% CI, 0.06 to 0.76]) (Table 2). The duration of rent study suggest that corticosteroids may also be beneficial in
PICU stay was also significantly shorter (median, 4 vs 6 MIS-C,possiblyactingsystematicallyasapotentinhibitorofSARS-
days; difference in days, −2.4 [95% CI, −4.0 to −0.7]; CoV-2–induced inflammation. Combined with findings of stud-
P = .005) (Table 2). ies reporting MIS-C cases in young adults, there may be common
pathways between severe respiratory adult forms of COVID-19 and
Sensitivity Analyses and Subgroup Analyses MIS-C.32,35 Additional studies are warranted to understand the
All sensitivity analyses gave similar results (eTable 8 in Supple- mechanisms underlying a possible corticosteroid effect in MIS-C
ment 1), including the inverse probability of treatment weight- and in severe forms of COVID-19.
ing that included all 106 treated children. The association be- The main strength of this study was the use of data from
tween IVIG and methylprednisolone treatment and lower rate a national surveillance system, propensity score–matched
of treatment failure compared with IVIG alone remained simi- analysis to limit selection bias, and consistency of findings
lar for children older and younger than 10 years and with or using other statistical approaches to control for potential bias.
without initial acute left ventricular dysfunction (Figure 2, in-
teraction test: P = .78 for age and P = .74 for initial acute left Limitations
ventricular dysfunction). This study has several limitations. First, it was not a random-
ized trial. While propensity score matching and inverse prob-
Follow-up ability of treatment weighting were used to address limita-
No long-term cardiovascular complication or persistent in- tions in the observation design, confounding by indication due
flammatory syndrome was reported in patients up to January to unmeasured covariates may remain. However, given the rar-
6, 2021. ity and severity of MIS-C, conducting randomized trials may
be highly challenging, and observational methods such as these
may provide the best level of evidence.
Second, it is not certain that all patients had MIS-C. Pa-
Discussion tients with Kawasaki disease could have been infected with
AmongchildrenwithMIS-C,treatmentwithIVIGandmethylpred- SARS-CoV-2 given the high prevalence of the pandemic in the
nisolone vs IVIG alone was associated with a more favorable fe- general population. To limit this risk, study inclusion was based
ver course. The combination therapy was also associated with less on WHO criteria for MIS-C.18 Furthermore, population base-
severe acute complications, including acute left ventricular dys- line characteristics, including median age, rate of gastrointes-
function and hemodynamic support requirement. tinal symptoms, rash, bilateral nonpurulent conjunctivitis, or

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 860
Table 1. Baseline Characteristics of Children With Multisystem Inflammatory Syndrome in Children (MIS-C) According to First-line Therapy Group

Before propensity score matching, %b After propensity score matching, %b,c

IVIG and methylprednisolone IVIG and methylprednisolone
Baseline characteristica (n = 34) IVIG alone (n = 72) Standard difference (n = 32) IVIG alone (n = 64) Standard difference
Sex
Male 53 44 0.17 53 48 0.09
Female 47 56 0.17 47 52 0.09
Age, median (IQR), y 9.0 (5.1-12.9) 8.1 (4.6-11.9) 0.14 9.1 (4.7-13.1) 8.7 (4.6-12.0) 0.09
Research Original Investigation

Comorbiditiesd 26 19 0.18 28 23 0.10

Clinical features
Gastrointestinal manifestations 97 92 0.19 97 97 0.00
Abdominal pain 79 72 0.17

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Vomiting 59 54 0.09
Diarrhea 50 65 0.31
Neurological symptoms 50 50 0.00 53 48 0.09

JAMA March 2, 2021 Volume 325, Number 9 (Reprinted)

Headache 35 42 0.13
Altered mental status 8 15 0.20
Meningeal syndrome 15 4 0.37
Initial cardiac involvement
Left ventricular ejection fraction <55% 65 39 0.53 63 58 0.04
Pericarditis 16 15 0.14
Coronary dilatatione 6 4 0.08
Lower respiratory symptoms 21 28 0.16 22 20 0.04
Dyspnea 15 19 0.13
Increased work of breathf 9 15 0.20
Oxygen saturation <95% 6 7 0.04
Duration of fever before first-line therapy, median 5 (4-6) 6 (5-7) 0.35 5 (4-6) 5.5 (5-6) 0.06
(IQR), d

© 2021 American Medical Association. All rights reserved.

Delay between admission and start of first-line 1 (1-1) 1 (1-1) 0.33 1 (1-1) 1 (1-1) 0.02
therapy, median, d
Laboratory results at admission
C-reactive protein >150 mg/L (normally <10 62 49 0.26 70 59 0.23
mg/L)
SARS-CoV-2 identificationg
Positive antibody testing 85 72 0.29 84 89 0.10
Positive SARS-CoV-2 RT-PCR 41 36 0.10
Positive antibody testing or RT-PCR 90 88 0.08
Contact with an individual with coronavirus 46 62 0.06
disease 2019

(continued)

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Association of IVIG Plus Methylprednisolone With Persistent or Recurrent Fever in Children With MIS-C
 Table 1. Baseline Characteristics of Children With Multisystem Inflammatory Syndrome in Children (MIS-C) According to First-line Therapy Group (continued)

Before propensity score matching, %b After propensity score matching, %b,c

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IVIG and methylprednisolone IVIG and methylprednisolone
Baseline characteristica (n = 34) IVIG alone (n = 72) Standard difference (n = 32) IVIG alone (n = 64) Standard difference
PICU care
PICU care at any time during MIS-C hospitalization 94 69 0.67
PICU care before first-line therapy 91 58 0.66 91 89 0.05
Mechanical ventilation 3 11 0.32 3 5 0.07
Hemodynamic support at any time during MIS-C 68 56 0.12
hospitalizationh
Hemodynamic support before first-line therapyh 62 32 0.64 59 56 0.06
Vasoactive inotropic score, median (IQR) (n = 61)i 7.5 (5.0-15.0) (n = 23) 10 (5.0-15.8) 0.24 10 (5.0-15.0) (n = 22) 10 (5.0-16.0) (n = 35) 0.09
(n = 38)

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Abbreviations: IVIG, intravenous immunoglobulins; IQR, interquartile range; PICU, pediatric intensive care unit; propensity score using nearest-neighbor matching, with a minimum caliper of 0.1. The ratio was 1 patient
RT-PCR, reverse transcriptase–polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome receiving IVIG and methylprednisolone matched with 2 patients receiving IVIG alone. The balance between the 2
coronavirus 2. treatment groups for each covariate was assessed with a standardized difference less than 0.1.
a d
For additional baseline characteristics not included in propensity score matching, see eTable 4 in the Included chronic respiratory disease (n = 13), obesity (n = 6), chronic cardiac disease (n = 3), chronic liver
Supplement. disease (n = 1), heterozygous sickle cell disease (n = 1), and diabetes (n = 1).
b e
Variables included in the propensity score: age, sex, comorbidities, hospital center, lower respiratory tract Defined by a Z score of 2.5 or greater. The maximal Z score for the coronary dilation observed in this population
symptoms, gastrointestinal manifestations, neurological symptoms, left ventricular ejection fraction less than was 3.
55%, duration of fever before first-line therapy, delay between admission and start of first-line therapy, f
Grunting, nasal flaring, retractions, or indrawing.
C-reactive protein level greater than 150 mg/L, positive SARS-CoV-2 antibody test result, pediatric intensive care g
SARS-CoV-2 diagnostics are not mutually exclusive. SARS-CoV-2 identification occurred at any time during
unit care before first-line therapy, mechanical ventilation, and hemodynamic support before first-line therapy. All
hospitalization.
variables included in the propensity score analysis except SARS-CoV-2 antibody test result were recorded at
h
hospital admission (ie, before first-line MIS-C therapy). Duration of fever before first-line therapy, delay between Hemodynamic support defined by vasoactive or inotropic amine requirement.
admission and start of first-line therapy, mechanical ventilation, and vasoactive inotropic score were included i
Following the vasoactive-inotropic score defined by McIntosh et al27 combining dopamine, dobutamine,
only in sensitivity analyses. All clinical features were reported at admission by the physicians. epinephrine, milrinone, vasopression, and norepinephrin doses. The score ranges from 0 (no drug used) without
c an upper limit. The higher the dosage, the higher the score.
Patients who received IVIG and methylprednisolone were matched to those who received IVIG alone by their
Association of IVIG Plus Methylprednisolone With Persistent or Recurrent Fever in Children With MIS-C

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Original Investigation Research

861
 Research Original Investigation Association of IVIG Plus Methylprednisolone With Persistent or Recurrent Fever in Children With MIS-C

Abbreviations: IQR, interquartile

Table 2. Primary and Secondary Analyses in the Propensity Score–Matched Cohorts range; IVIG, intravenous
After propensity score matching immunoglobulins; LVEF, left
ventricular ejection fraction; PICU,
No. (%) pediatric intensive care unit.
a
IVIG and Absolute risk difference Treatment failure defined by the
methylpred- between groups Odds ratio (95% CI) persistence of fever 2 days after the
nisolone IVIG alone (95% CI) [reference: [reference: IVIG introduction of first-line therapy or
Outcomes (n = 32) (n = 64) IVIG alone] alone] P value
recrudescence of fever within 7
Primary outcome days after the first-line therapy.
b
Treatment failurea 3 (9) 24 (38) −0.28 (−0.48 to −0.08) 0.25 (0.09 to 0.70) .008 Second-line therapy, defined by a
treatment, such as steroids or
Secondary outcomes biological agents, for multisystem
Second-line treatmentb 3 (9) 20 (31) −0.22 (−0.40 to −0.04) 0.19 (0.06 to 0.61) .004 inflammatory syndrome in children
prescribed at least 24 hours after
c,d
Hemodynamic support 2 (6) 15 (23) −0.17 (−0.34 to −0.004) 0.21 (0.06 to 0.76) .01 the initial therapy.
c
LVEF <55%c 2/12 (17) 14/40 (35) −0.18 (−0.35 to −0.01) 0.20 (0.06 to 0.66) .007 Hemodynamic support defined by the
use of a vasoactive or inotropic amine.
Duration of PICU stay, 4 (2 to 5) 6 (4 to 8.5) Reduction of days: .005 d
median (IQR), d −2.4 (−4.0 to −0.7) Occurring at least 1 day after
first-line therapy introduction.

Figure 2. Association Between First-line Therapy Group and Treatment Failure Depending on Age and Acute Left Ventricular Dysfunction

Risk of treatment failure

Before PS weighting,
Absolute risk
No. of events/patients (%) After PS weighting, %
difference Favors Favors
IVIG and IVIG IVIG and IVIG between groups IVIG and IVIG P
methylprednisolone alone methylprednisolone alone (95% CI) Odds ratio (95% CI) methylprednisolone alone value
Age, y
<10 2/17 (12) 22/39 (56) 12 52 –0.41 (–0.75 to –0.07) 0.12 (0.02 to 0.62) .02
≥10 1/17 (6) 15/33 (45) 6 40 –0.34 (–0.66 to –0.03) 0.08 (<0.01 to 0.57) .03
Ventricular dysfunction
Absent 1/12 (8) 26/44 (59) 8 45 –0.37 (–0.73 to –0.02) 0.12 (0.01 to 0.93) .05
Present 2/22 (9) 11/28 (39) 9 28 –0.19 (–0.46 to 0.08) 0.27 (0.04 to 1.35) .14
All patients 3/34 (9) 37/72 (51) 9 38 –0.27 (–0.49 to –0.05) 0.17 (0.04 to 0.61) .01

0.05 0.1 1 2
Odds ratio (95% CI)

Shown are subgroup-specific odds ratios for all patients and those older or probability of treatment weighting approach. Age was transformed into a binary
younger than 10 years of age and with or without acute left ventricular variable using the receiver operating characteristic curve to define the
dysfunction (defined by left ventricular ejection fraction <55%) at baseline. optimized cut-off value. The interaction test P value for age ⱖ or <10 years was
Odds ratios are plotted as squares; the horizontal lines represent 95% CIs. All P = .78 and for presence or absence of initial acute left ventricular dysfunction
analyses displayed involved using the propensity score analysis with the inverse was P = .74. IVIG indicates intravenous immunoglobulins.

mucocutaneous inflammation signs, were similar to those in Fifth, patients with initial MIS-C may show symptoms
other reports of MIS-C.2,4,6 The clinical features of some pa- of septic shock, and initial treatment with IVIG and methyl-
tients included in this study have been prev iously prednisolone has a theoretical risk of worsening an unrecog-
described3,5,9,11,36 and are consistent with the literature.2,4 nized bacterial infection. Empirical antibiotic therapy might
Third, there was variation in the dosage and routes of ste- be initiated until the diagnosis is established to avoid
roid treatment used among the 34 children who received IVIG the risk of an untreated infection with corticosteroid expo-
and methylprednisolone as first-line therapy, and the study de- sure.
sign did not allow for comparing regimens. In the same way, Sixth, although no deaths occurred in the study popula-
because no patient received methylprednisolone alone or bio- tion and despite mandatory reporting by the French National
logical therapy as first-line therapy, other potential therapeu- Public Health Agency, underascertainment is a possibility.
tic approaches were not assessed. Further studies are needed
to answer these questions.
Fourth, patients in each treatment group may have tended
to present to the hospital at a different time in the natural course
Conclusions
of this disease. However, the duration of fever before first-line Among children with MIS-C, treatment with IVIG and meth-
therapy was similar between the 2 groups, and a sensitivity analy- ylprednisolone vs IVIG alone was associated with a more fa-
sis including the duration of fever before first-line therapy as an vorable fever course. Study interpretation is limited by the ob-
additional baseline covariate had consistent results. servational design.

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 Association of IVIG Plus Methylprednisolone With Persistent or Recurrent Fever in Children With MIS-C Original Investigation Research

ARTICLE INFORMATION Boulogne-Billancourt, France (Kahn); Paediatric and personal fees from Pfizer and Merck. Dr Cohen
Accepted for Publication: January 19, 2021. Department, Hôpital Delafontaine, Saint Denis, reported receiving personal fees from
France (Mandelcwajg); Hôpital des Enfants, GlaxoSmithKline, Pfizer, Sanofi, and Merck Sharp &
Published Online: February 1, 2021. Paediatric Nephrology Department, Purpan Dohme. No other disclosures were reported.
doi:10.1001/jama.2021.0694 University Hospital, Toulouse, France (Percheron); Funding/Support: This study received an
Correction: This article was corrected on July 6, Paediatric Department, Hôpital de Valence, unrestricted grant from Pfizer; the French Covid-19
2021, to add the list of nonauthor collaborators as a Valence, France (Biot); Strasbourg University Paediatric Inflammation Consortium received an
supplement. Hospital, Paediatric Cardiology Department, unrestricted grant from the Square Foundation
Author Affiliations: Assistance Publique–Hôpitaux Hautepierre University Hospital, Strasbourg, France (Grandir–Fonds de Solidarité Pour L’enfance).
de Paris, Department of General Paediatrics, (Bordet); Paediatric Intensive Care Unit, Strasbourg
University Hospital, Hautepierre University Role of the Funder/Sponsor: The funders had no
Paediatric Infectious Disease and Internal Medicine, role in the design and conduct of the study;
Robert Debré University Hospital, Université de Hospital, Strasbourg, France (Girardin); Assistance
Publique–Hôpitaux de Paris, Paediatric Emergency collection, management, analysis, and
Paris, Paris, France (Ouldali, Meinzer); ACTIV, interpretation of the data; preparation, review, or
Association Clinique et Thérapeutique Infantile du Department, Necker-Enfants Malades University
Hospital, Université de Paris, Paris, France (Yang, approval of the manuscript; and decision to submit
Val-de-Marne, Créteil, France (Ouldali, C. Levy, the manuscript for publication.
Cohen); Université de Paris, INSERM UMR 1123, Angoulvant); Assistance Publique–Hôpitaux de
ECEVE, Paris, France (Ouldali); Assistance Paris, Paediatric Intensive Care Unit, Group Information: A list of members in the
Publique–Hôpitaux de Paris, Department of General Necker-Enfants Malades University Hospital, French Covid-19 Pediatric Inflammation Consortium
Paediatrics and Paediatric Infectious Diseases, EA7323, Université de Paris, Paris, France (Grimaud, is in Supplement 2.
Necker-Enfants-Malades University Hospital, Oualha); Assistance Publique–Hôpitaux de Paris, Additional Contributions: We are grateful to Santé
Université de Paris, Paris, France (Toubiana, Allali); M3C Department, Necker-Enfants Malades Publique France, Société Française de Pédiatrie,
Institut Pasteur, Biodiversity and Epidemiology of University Hospital, Université de Paris, Paris, Groupe de Paediatrie Generale, Groupe de
Bacterial Pathogens, Paris, France (Toubiana); France (Bajolle); Assistance Publique–Hôpitaux de Pathologie Infectieuse Pédiatrique, Groupe
Santé Publique France, Agence Nationale de Santé Paris, Cardiopaediatric Unit, Robert Debré Francophone de Réanimation et d’Urgences
Publique, Saint-Maurice, France (Antona); Hospices University Hospital, Université de Paris, Paris, Pédiatriques, Société Française de Cardiologie,
Civils de Lyon, Paediatric Intensive Care Unit, France (Beyler); Centre for Research on Filiale de Cardiologie Pédiatrique et Congénitale,
Hopital Femme, Mère Enfant, University of Lyon, Inflammation, UMR1149, INSERM, Paris, France Société Francophone Dédiée à L’étude des Maladies
Bron, France (Javouhey); EA 7426 Pathophysiology (Meinzer); Assistance Publique–Hôpitaux de Paris, Inflammatoires Pédiatriques, and Filière de Santé
of Injury-Induced Immunosuppression, University Paediatric Intensive Care Unit, Robert Debré des Maladies Auto-immunes et
Claude Bernard Lyon 1, Hospices Civils of Lyon, University Hospital, Université de Paris, Paris, Auto-inflammatoires Rares for their participation in
Lyon, France (Javouhey); Centre Hospitalier France (M. Levy); Hôpital Nord Franche-Comté, the French Covid-19 Paediatric Inflammation
Intercommunal, Paediatric Department, Université Paediatric Department, Trévenans, France (Paulet); Consortium study. We thank Isabelle Ramay, BSc,
Paris Est, IMRB-GRC GEMINI, Créteil, France Centre Hospitalier Intercommunal, Research Claire Prieur, BSc, Marine Borg, Aurore Prieur, BSc,
(Madhi); Assistance Publique–Hôpitaux de Paris, Centre, Université Paris Est, IMRB-GRC GEMINI, Laura Meyet, LLM, Jéremy Levy, BSc, Stéphane
Department of General Paediatric, Armand Créteil, France (C. Levy, Cohen); Hospices Civils de Bechet, MSc, and Sofia Abbou, LLM, from ACTIV
Trousseau University Hospital, Sorbonne Lyon, Paediatric Nephrology, Rheumatology, (Association Clinique et Thérapeutique Infantile du
Université, Paris, France (Lorrot); Assistance Dermatology, Hopital Femme, Mère Enfant, Centre Val-de-Marne), Créteil, France; Cecile Hoffart, MSc,
Publique–Hôpitaux de Paris, Paediatric Intensive International de Recherche en Infectiologie/ and Maxime Brussieux, BSc, from Clinical Research
Care Unit, Armand Trousseau University Hospital, INSERM U1111, Bron, France (Belot); INSERM, Centre, Centre Hospitalier Intercommunal de
Sorbonne Université, Paris, France (Léger); Centre de Recherche des Cordeliers, UMRS 1138, Créteil, Créteil, France; Daniel Levy-Bruhl, MD,
Assistance Publique–Hôpitaux de Paris, Sorbonne Université, Université de Paris, Paris, Mireille Allemand, Scarlett Georges, BSc, Valerie
Department of Paediatric Rheumatology, Reference France (Angoulvant). Olie, PhD, Nolween Regnault, PhD, and Jerome
Centre for Autoinflammatory Diseases and Author Contributions: Drs Ouldali and Angoulvant Naud, PharmD, from Santé Publique France,
Amyloidosis (CEREMAIA), Bicêtre University had full access to all of the data in the study and Agence Nationale de Santé Publique,
Hospital, Université de Paris Saclay, Le take responsibility for the integrity of the data and Saint-Maurice; Murielle Herasse, PhD, from Filière
Kremlin-Bicêtre, France (Galeotti); Assistance the accuracy of the data analysis. de Santé Des Maladies Auto-immunes et
Publique–Hôpitaux de Paris, Paediatric Intensive Concept and design: Ouldali, Lachaume, M. Levy, C. Auto-inflammatoires Rares (FAI2R), Lyon, France;
Care Unit, Bicêtre University Hospital, Université de Levy, Angoulvant. and David Skurnik, PhD, from INSERM U1151-Equipe
Paris Saclay, Le Kremlin-Bicêtre, France (Claude); Acquisition, analysis, or interpretation of data: 11. We are grateful to every microbiological
Children’s Hospital, University Hospital of Nancy, Ouldali, Toubiana, Antona, Javouhey, Madhi, Lorrot, laboratory staff member who performed severe
Paediatric Department, Université de Lorraine, Léger, Galeotti, Claude, Wiedemann, Ovaert, acute respiratory syndrome coronavirus 2 reverse
Vandoeuvre les Nancy, France (Wiedemann); Dumortier, Kahn, Mandelcwajg, Percheron, Biot, transcriptase–polymerase chain reaction and
INSERM UMRS 1256 NGERE, Nutrition, Genetics, Bordet, Girardin, Yang, Grimaud, Oualha, Allali, antibody testing in each center. None of the
and Environmental Risk Exposure, National Center Bajolle, Beyler, Meinzer, M. Levy, Paulet, C. Levy, persons listed here received compensation for their
of Inborn Errors of Metabolism, Université de Cohen, Belot, Angoulvant. role in the study.
Lorraine, Vandoeuvre les Nancy, France Drafting of the manuscript: Ouldali, Mandelcwajg,
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