Document text
Received: 17 November 2020 |Revised: 13 December 2020 |Accepted: 23 December 2020
DOI: 10.1002/ppul.25245
ORIGINAL ARTICLE: COVID 19
COVID ‐19 and multisystem inflammatory syndrome in
children: A systematic review and meta ‐analysis
Jun Yasuhara MD1|Kae Watanabe MD2|Hisato Takagi MD, PhD3|
Naokata Sumitomo MD, PhD4|Toshiki Kuno MD, PhD5
1Center for Cardiovascular Research, The
Abigail Wexner Research Institute and The
Heart Center, Nationwide Children's Hospital,Columbus, Ohio, USA
2Division of Pediatric Cardiology, Ann &
Robert H. Lurie Children's Hospital ofChicago, Northwestern University Feinberg
School of Medicine, Chicago, Illinois, USA
3Division of Cardiovascular Surgery, Shizuoka
Medical Center, Shizuoka, Japan
4Department of Pediatric Cardiology, Saitama
Medical University International Medical
Center, Saitama, Japan
5Department of Medicine, Icahn School of
Medicine at Mount Sinai, Mount Sinai Beth
Israel, New York, New York, USA
Correspondence
Jun Yasuhara, MD, Center for Cardiovascular
Research, The Abigail Wexner Research
Institute and The Heart Center, Nationwide
Children's Hospital, 700 Children's Dr Room
WB4237, Columbus, OH 43205.Email: [email protected]
Background: Multisystem inflammatory syndrome in children (MIS C) associated
with coronavirus disease 2019 has been increasingly recognized. However, the clinical
features of MIS C and the differences from Kawasaki disease remain unknown. The
study aims to investigate the epidemiology and clinical course of MIS C.Methods: PubMed and EMBASE were searched through August 30, 2020. Ob-
servational studies describing MIS C were included. Data regarding demographicfeatures, clinical symptoms, laboratory, echocardiography and radiology findings,
treatments, and outcomes were extracted. Study specific estimates were combined
using one group meta analysis in a random effects model.Results: A total of 27 studies were identified including 917 MIS C patients. The
mean age was 9.3 (95% confidence interval [CI], 8.4 –10.1). The pooled proportions
of Hispanic and Black cases were 34.6% (95% CI, 28.3 –40.9) and 31.5% (95% CI,
24.8–38.1), respectively. The common manifestations were gastrointestinal symp-
toms (87.3%; 95% CI, 82.9– 91.6) and cardiovascular involvement such as myo-
cardial dysfunction (55.3%; 95% CI, 42.4– 68.2), coronary artery aneurysms (21.7%;
95% CI, 12.8 –30.1) and shock (65.8%; 95% CI, 51.1 –80.4), with marked elevated
inflammatory and cardiac markers. The majority of patients received intravenous
immunoglobulin (81.0%; 95% CI, 75.0– 86.9), aspirin (67.3%; 95% CI, 48.8– 85.7), and
corticosteroids (63.6%; 95% CI, 53.4– 73.8) with a variety of anti inflammatory
agents. Although myocardial dysfunction improved in 55.1% (95% CI, 33.4– 76.8) at
discharge, the rate of extracorporeal membrane oxygenation use was 6.3% (95% CI,
2.8–9.8) and the mortality was 1.9% (95% CI, 1.0 –2.8).
Conclusion: Our findings suggest that MIS C leads to multiple organ failure, including
gastrointestinal manifestations, myocardial dysfunction and coronary abnormalities,
and has distinct features from Kawasaki disease.
KEYWORDS
hyperinflammatory shock, Kawasaki disease, MIS‐C, myocarditis, PIMS ‐TS
Pediatric Pulmonology . 2021;56:837 848. wileyonlinelibrary.com/journal/ppul © 2020 Wiley Periodicals LLC |837
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1|INTRODUCTION
Coronavirus disease 2019 (COVID ‐19), caused by a novel coronavirus,
called severe acute respiratory syndrome coronavirus 2 (SARS ‐CoV ‐2),
has resulted in a global pandemic since December 2019. Initial studies
indicated that children with SARS ‐CoV ‐2 infection generally present
with mild symptoms or are asymptomatic.1–3However, in late April
2020, the United Kingdom reported a newly recognized syndrome re-lated to SARS‐ CoV ‐2 infection characterized by hyperinflammation and
multiorgan involvement in children, presenting with clinical features
similar to Kawasaki disease (KD) and toxic shock syndrome.
4This
syndrome has been named multisystem inflammatory syndrome in
children (MIS‐ C) associated with COVID ‐19 by the Centers for Disease
Control and Prevention5and pediatric inflammatory multisystem syn-
drome temporally associated with SARS ‐CoV ‐2i nE u r o p e .
Since this new syndrome was identified, several reports have
revealed the clinical features of MIS‐C, however, there is no largestudy to date which can clarify the nature and course of MIS‐C,including the epidemiology, pathogenesis, clinical spectrum, labora-
tory features, potential optimal management, and long ‐term out-
comes. Therefore, we conducted a systematic review and meta‐
analysis aimed to investigate the characteristics of MIS‐C, to provideinsights into further understanding and the clinical practice of MIS ‐C.2|METHODS
2.1 |Search strategy
All observational studies and case series reporting patients withMIS ‐C were searched using a two ‐level search strategy. First,
PubMed, and EMBASE were searched through August 10, 2020.Second, relevant studies were identified through a manual searchof secondary sources including references of initially identifiedarticles, reviews, and commentaries. All references were down-
loaded for consolidation, elimination of duplicates, and further
analyses (Figure 1).
The search terms included “COVID ‐19”OR “SARS ‐CoV ‐2”
OR “coronavirus ”,“MIS ‐C”OR “multisystem inflammatory
syndrome in children ”OR “multisystem” ,“inflammatory ”OR
“Kawasaki disease ”,“pediatrics ”OR“child ”OR“children ”.T w o
independent and blinded authors (J.Y. and T.K.) reviewed thesearch results separately to select the studies based on the in-clusion and exclusion criteria. Any discrepancies were resolved
by discussion and consensus. There were no language restric-
tions. This study was conducted in accordance with the preferredreporting items for systematic reviews and meta ‐analyses re-
porting guidelines.
6
FIGURE 1 PRISMA flow diagram for the
study selection. MIS‐C, multisystem
inflammatory syndrome in children. PRISMA,preferred reporting items for systematicreviews and meta‐analyses838 |
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2.2 |Study selection and risk of bias assessment
Studies which met the following criteria were included: (1) the study
design was an observational study or a case series, (2) the study
population included children and adolescents (age <21 years old)who met the diagnostic criteria for MIS‐C with confirmed SARS ‐CoV ‐
2 infection through a reverse transcriptase ‐polymerase chain reac-
tion or serological tests. The diagnosis of MIS‐C was confirmed usingthe case definition established by the Centers for Disease Controland Prevention and World Health Organization.
5,7Case reports in-
cluding one patient, studies not containing original data of the pa-tients such as clinical guidelines, consensus documents, clinical trials,editorials, letters, reviews, systematic reviews and meta ‐analyses,
and articles on other types of coronavirus were excluded from thesecondary review. The risk of bias in the individual studies was re-viewed using an assessment of the risk of bias in prevalence studies.
8
2.3 |Data extraction
The following information was extracted: author, year of publication,country of the study, sample size, age, sex, race/ethnicity, co-morbidities, clinical symptoms, laboratory data, echocardiography,
and chest X ‐ray findings, treatments, and outcomes. Disagreements
regarding the extracted data were resolved through discussion and
consensus of a third author (H.T.).
2.4 |Statistical analysis
We performed one ‐group meta‐analysis in a random effects model
using the DerSimonian ‐Laird method for continuous values and Wald
method for discrete values with the OpenMetaAnalyst version
12.11.14 (available from http://www.cebm.brown.edu/openmeta/).
Continuous variables are expressed as the means ± standard devia-tions or medians (interquartile range), as appropriate for the data
distribution. Categorical variables are expressed as frequencies and
percentages.
3|RESULTS
3.1 |Study characteristics
Our search identified 372 articles that were reviewed based on thetitle and abstract, and of those, 307 articles were excluded. Sixty‐five
full texts were assessed for eligibility and 38 articles were excluded
based on the article type (case reports, clinical guidelines, consensusdocuments, clinical trials, editorials, letters, reviews, systematic
reviews, and meta‐analyses), population (adult patients with COVID ‐
19, cases without meeting the case definition for MIS ‐C) and topic
(other viruses). Twenty ‐seven articles met the inclusion and
exclusion criteria and were analyzed for the systemic review andmeta ‐analysis (Figure 1).
4,9–34The study and patient characteristics
of the included studies are shown in Table S1 and Table S2. The
results of the pooled analysis are summarized in Table 1. A summary
of the risk of bias assessment for the prevalence studies for each
retrospective cohort study is shown in Table S3.
All the included articles were published between May 2020
and July 2020. Twelve studies were conducted in theUnited States,
11,12,15,17,21,22,24,27 –29,32,337 in the United
Kingdom,4,16,20,23,26,30,316 in France,10,13,14,18,19,25and 1 each in
Italy9and Spain.34Overall, the studies included 917 patients with
MIS ‐C associated with SARS ‐CoV‐2 infections.
3.2 |Demographic features
The mean age was 9.3 (95% confidence interval [CI], 8.4 10.1;
I277.6%) and males were 56.8% (95% CI, 52.1 61.5; I241.6%)
(Figure 2
). The pooled proportions of Hispanic and Black cases were
34.6% (95% CI, 28.3 40.9; I241.6%) and 31.5% (95% CI, 24.8 38.1;
I263.4%), respectively, which was higher compared to the other
race/ethnicities. In
addition, at least one comorbidity was present in
30.7% (95% CI, 24.7 36.7; I248.1%) of the population, including
obesity and
asthma or chronic lung disease (Table 1).
3.3 |Clinical symptoms
The most common symptom was fever (99.3%; 95% CI, 98.8 99.9;
804/809 patients; I20%), followed by gastrointestinal symptoms
(87.3%; 95%
CI, 82.9 91.6; 564/653 patients; I284.2%) and ab-
dominal pain
(70.1%; 95% CI, 58.4 81.7; 245/378 patients;
I265.3%). The pooled prevalence of respiratory symptoms was
40.7% (95%
CI, 23.1 58.1; 259/488 patients; I294.2%), however,
only 7
studies reported respiratory symptoms. The pooled pre-
valence of neurologic symptoms was 36.0% (95% CI, 22.8 49.2;98/459 patients; I
290.2%). Commonly reported symptoms similar
to KD
were conjunctivitis (57.0%; 95% CI, 47.3 66.6; 405/766 pa-
tients; I287.2%), rash (59.0%; 95% CI, 52.8 65.2; 436/770 patients;
I262.3%), and oral mucosal changes (42.3%; 95% CI, 31.7 53.0;
235/595 patients; I242.3%) (Table 1).
3.4 |Laboratory findings
Laboratory findings are shown in Figure 3, Table 1, and Figure S1.Inflammatory biomarkers, such as C ‐reactive protein, procalcitonin,
ferritin, erythrocyte sedimentation rate, interleukin ‐6 (IL ‐6) and
fibrinogen, were significantly elevated (Figure 3 and Figure S1).In addition, cardiac markers were elevated with marked elevations in
B‐type natriuretic peptide, N ‐terminal proB ‐type natriuretic peptide,
and troponin (Figure 3). The majority of patients had elevated levels
of
D‐dimer, elevated neutrophils, reduced lymphocytes, and low
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TABLE 1 Random‐effects estimate (95% confidence interval [CI])
of the demographics, clinical characteristics, treatment, outcomes,
laboratory, echocardiogram, and imaging findings of the patientswith MIS‐C
Random ‐effects estimate
(95% CI)
Demographics
Age, years 9.3 (8.4 10.1)
BMI, kg/m219.2 (17.7 20.6)
Male, % 56.8 (52.1 61.5)
Race/ethnicity
Hispanic, % 34.6 (28.3 40.9)
Black, % 31.5 (24.8 38.1)
White, % 18.9 (14.3 23.6)
Asian, % 18.7 (8.6 28.9)
Other, % 19.0 (10.0 28.0)
Comorbidity
Total, % 30.7 (24.7 36.7)
Obesity, % 18.0 (11.0 24.9)
Asthma/CLD, % 14.4 (11.2 17.5)
Symptoms
Fever, % 99.3 (98.8 99.9)
Any respiratory symptoms, % 40.7 (23.1 58.4)
Cough, % 35.2 (22.2 48.1)
Dyspnea, % 37.6 (22.2 53.0)
Sore throat, % 18.5 (10.6 26.3)
Any neurologic symptoms, % 36.0 (22.8 49.2)
Headache, % 25.3 (19.6 31.0)
Meningeal signs, % 14.8 (5.8 23.8)
Any gastrointestinal symptoms, % 87.3 (82.9 91.6)
Diarrhea, % 57.0 (49.3 64.7)
Vomiting, % 60.0 (52.6 67.4)
Abdominal pain, % 70.1 (58.4 81.7)
Conjunctivitis, % 57.0 (47.3 66.6)
Rash, % 59.0 (52.8 65.2)
Peripheral extremity changes, % 32.9 (20.6 45.1)Cervical lymphadenopathy, % 25.2 (15.0 35.3)
Oral mucosal changes, % 42.3 (31.7 53.0)
Myalgia, % 14.2 (8.3 20.0)
Laboratory values
Hematology
White blood cell, × 10
9/L 11.8 (10.5 13.2)
Neutrophil count, × 109/L 10.8 (9.3 12.4)
Lymphocyte count, × 109/L 0.8 (0.7 1.0)
Platelet count, × 109/L 155.1 (143.2 167.1)
Hemoglobin, g/dl 10.7 (9.9 11.5)
Inflammatory markers
C‐reactive protein, mg/L 235.5 (215.8 255.5)
Procalcitonin, ng/ml 8.5 (5.3 11.7)
Ferritin, ng/ml 711.0 (599.5 822.4)TABLE 1 (Continued)
Random ‐effects estimate
(95% CI)
ESR, mm/h 62.8 (58.9 66.6)
Interleukin ‐6, pg/ml 172.2 (137.9 206.5)
Biochemistry
Albumin, g/dl 2.7 (2.4 2.9)
Serum sodium, mEq/L 131.7 (129.6 133.8)
Serum creatinine, mg/dl 0.8 (0.7 1.0)
AST, U/L 49.1 (35.5 62.7)
ALT, U/L 44.6 (32.9 60.4)
Lactate dehydrogenase, U/L 347.7 (292.5 403.0)
Coagulation
D‐Dimer, μg/ml 3.5 (2.9 4.1)
Fibrinogen, mg/dl 643.0 (598.6 687.5)
Cardiac markers
Troponin, ng/L 100.8 (55.2 146.3)
BNP, pg/ml 2191.5 (1334.2 3048.7)
NT ‐proBNP, pg/ml 14072.0 (7975.1 20168.9)
Echocardiography findings
LV systolic dysfunction or
myocarditis, %55.3 (42.4 68.2)
LVEF, % 41.7 (36.1 47.4)
LVEF < 30%, % 7.9 (2.6 13.2)
LVEF 30 ‐50%, % 53.8 (37.0 70.5)
Coronary artery dilation or
aneurysm, %21.4 (12.8 30.1)
Pericardial effusion, % 31.7 (23.5 40.0)
Chest X ‐ray findings
infiltrates or Opacities, % 38.3 (29.7 46.9)
Treatment
Intravenous immunoglobulin, % 81.0 (75.0 86.9)
Corticosteroids, % 63.6 (53.4 73.8)
Tocilizumab (IL ‐6 receptor
antagonist), %27.7 (15.2 40.3)
Anakinra (IL ‐1 receptor
antagonist), %10.8 (8.2 13.4)
Infliximab (TNF ‐αantagonist), % 8.0 (2.9 13.1)
Remdesivir, % 8.3 (0.0 16.7)
Aspirin, % 67.3 (48.8 85.7)
Anticoagulation, % 56.5 (41.8 71.1)
Inotropes, % 62.9 (53.2 72.6)
High‐flow nasal cannula, % 16.8 (10.4 23.3)
Noninvasive ventilation, % 24.6 (14.4 34.7)
Mechanical ventilation, % 33.0 (24.5 41.5)
ECMO, % 6.3 (2.8 9.8)
Outcomes
ICU admission, % 79.1
(71.6 86.7)
Kawasaki Disease, % 44.3 (34.7 53.9)
Shock, % 65.8 (51.1 80.4)840 |
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3.5 |Echocardiography and radiology findings
According to the echocardiography findings, cardiovascular in-
volvement was common (Table 1). Left ventricular (LV) systolic
dysfunction, defined as a depressed LV ejection fraction (<50%)or myocarditis was identified in 55.3% (95% CI, 42.4 68.2; 410/
773 patients; I
294.6%). The mean LV ejection fraction at ad-
mission
was 41.7% (95% CI, 36.1 47.4; I291.4%). The pooledprevalence of
coronary artery dilation or aneurysms was 21.7%
(95% CI, 12.8 30.1). Finally, the proportion of chest X ‐ray find-
ings, such as infiltrates or opacities was 38.3% (95% CI,
29.7 46.9; 133/341 patients; I24 6 . 6 % )( T a b l e 1).
3.6 |Treatment and outcomes
The pooled proportions of the therapeutic management and
outcomes are shown in Table 1.O v e r a l l ,7 9 . 1 %( 9 5 %C I ,
71.6 86.7; 550/725 patients; I289.4%) required admission to
th
e intensive care unit. The most common therapy was in-
travenous immunoglobulin (IVIG) (81.0%; 95% CI, 75.0 86.9;
608/787 patients; I284.7%), followed by aspirin (67.3%; 95%
CI,
48.8 85.7; 147/235 patients; I293.7%), systemic corticos-
te
roids (63.6%; 95% CI, 53.4 73.8; 434/714 patients; I28 8 . 6 % ) ,
inotropes (62.9%;
95% CI, 53.2 72.6; 469/770 patients;
I287.8%), and anticoagulation (56.5%; 95% CI, 41.8 71.1; 261/
466
patients; I291.1%). A range of anti ‐inflammatory biologics
and antiviral agents were used including tocilizumab, anakinra,infliximab, and remdesivir (Table 1) .O v e r a l l ,3 3 . 0 %( 9 5 %C I ,
24.5 41.5; 252/891 patients; I
291.5%) required mechanical
ventilation. The
rate of extracorporeal membrane oxygenationTABLE 1 (Continued)
Random ‐effects estimate
(95% CI)
Recovery of LV systolic dysfunction
at discharge, %55.1 (33.4 76.8)
Death, % 1.9 (1.0 2.8)
Abbreviations: ALT, alanine aminotransferase; AST, aspartate
aminotransferase; BMI, body mass index; BNP, B ‐type natriuretic peptide;
CLD, chronic lung disease; ECMO, extracorporeal membrane
oxygenation; ESR, erythrocyte sedimentation rate; ICU, intensive care
unit; IL, interleukin; LV left ventricular; LVEF, left ventricular ejection
fraction; MIS ‐C, multisystem inflammatory syndrome in children; NA, not
available, NT ‐proBNP, N‐terminal proBNP; TNF‐α , tumor necrosis
factor ‐α.
FIGURE 2 Forrest plots of the included studies showing the pooled estimate of the age [Color figure can be viewed at
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(ECMO) use was 6.3% (95% CI, 2.8 9.8; 36/553 patients;
I260.4%). Overall, 44.3% (95% CI, 34.7 53.9; 256/590 patients;
I280.5%) received a diagnosis of KD or atypical KD and 65.8%
(95% CI,
51.1 80.4; 357/615 patients; I295.8%) developed
shock. At
time of hospital discharge, recovery of LV systolic
function, which was defined as an LV ejection fraction of more
than 60%, was observed in 55.1% (95% CI, 33.4 76.8; 79/145
patients; I288.3%). The mortality rate was 1.9% (95% CI,
1.0 2.8; 16/917
patients; I20 % )( T a b l e 1).4|DISCUSSION
This systematic review and meta ‐analysis comprehensively sum-
marized the available published literature and assessed the clinical
characteristics and management of MIS ‐C associated with COVID ‐
19. The salient findings of our study can be summarized as follows:
(1) the mean age was 9.3 years; (2) the majority of MIS ‐Cc a s e s
were Hispanic and Black children; (3) the common symptoms
were fever, gastrointestinal symptoms, and dermatologic or
FIGURE 3 Forrest plots of the included studies showing the pooled estimate of the laboratory findings. (A) C reactive protein.
(B) Ferritin. (C) Interleukin 6. (D) Ddimer. (E) Troponin. (F) B type natriuretic peptide. (G) N terminal proB type natriuretic peptide
[Color
figure can be viewed at wileyonlinelibrary.com]842 |
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mucocutaneous symptoms; (4) the inflammatory markers, D‐dimer,
and cardiac markers were significantly elevated; (5) cardiovascular
involvement was common, including shock and myocardial dys-function; (6) MIS ‐C patients were commonly treated with IVIG,
aspirin, and systemic corticosteroid; and (7) myocardial dysfunctionimproved in many cases but the rate of ECMO use and the mor-
tality rate were high.
Identification of MIS‐C is crucial as it can result in severe organ
dysfunction, including myocardial dysfunction, even leading todeath.
28,29MIS‐C has been reported to occur approximately
FIGURE 3 Continued844 |
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2 4 weeks after infection with SARS ‐CoV‐2.35The interval between
SARS ‐CoV‐2 infection and MIS‐C which may result from immune
response to infection with SARS ‐CoV‐2. Although both the Centers
for Disease Control and Prevention and World Health Organization
case definitions may apply to patients with other infectious and in-flammatory conditions, such as KD, viral infections, and juvenile
idiopathic arthritis, the findings of our study are consistent with the
current diagnostic guidelines.
5,7,36Our data indicated that MIS‐C
patients commonly present with gastrointestinal, dermatologic, ormucocutaneous symptoms, and cardiovascular manifestations, as
well as elevated inflammatory and cardiac marker levels. Further-
more, compared to acute COVID ‐19, we found that the prevalence
of neurological symptoms was higher in MIS‐C, with a lower pre-
valence of respiratory symptoms.
30,37 –39Interestingly, our study also
showed that infiltrates or opacities were less frequent in MIS‐C,
whereas these are common findings in acute COVID ‐19.40–44These
findings can be useful clues to the development of an accurate di-agnosis and case definition of MIS‐C.
MIS‐C and KD have clinical similarities and there is no definitive
diagnostic test for either MIS‐C or KD, resulting in diagnostic diffi-culty. Although MIS‐C shares clinical features with KD, we demon-strated that these syndromes have important distinct features. Aspreviously reported, we confirmed that MIS‐C affects older children
and adolescents, which is in a marked contrast to the epidemiology
of KD, occurring predominantly in children 5 years of age or youngerand with a peak incidence at 9 11 months of age.
45Interestingly, the
proportions of Hispanic and Black cases were high for MIS‐C withfew cases reported in children of Asian descent or in Asian countriesin contrast to KD.
46This might be associated with the socioeconomic
disparities as the rates of COVID ‐19 were shown to be higher among
racial/ethnic minorities and socioeconomically disadvantagedchildren.
47In addition, we noted that MIS‐C manifests with a higher
incidence of myocardial dysfunction and gastrointestinal symptoms
compared to KD.16Furthermore, the extent of the elevation of in-
flammatory biomarkers and cardiac markers in MIS‐C are sig-
nificantly higher than in KD.9,16These marked differences in the
epidemiology and clinical and laboratory findings suggest that MIS‐Cand KD are two distinct disease with overlapping clinicalcharacteristics.
Kawasaki disease shock syndrome (KDSS), a rare form of KD, has
many similarities to MIS ‐C. The incidence of KDSS is 1.5% to 7.0% of
KD patients and is higher in Western countries than Asian countries.
48
KDSS is previously found to be associated with an older age and ischaracterized as hyperinflammation with higher C ‐reactive protein,
procalcitonin, erythrocyte sedimentation rate, IL ‐6, and
D‐dimer as
compared to KD.48In addition, KDSS is often associated with
myocarditis and prolonged myocardial dysfunction.49,50Patients with
KDSS often requires intensive care in the acute phase such asintravenous fluid resuscitation and inotropes. These features of KDSS
are consistent with our findings of MIS ‐C. However, resistance to IVIG
and coronary artery abnormalities are more common in KDSS and
gastrointestinal symptoms are more common in MIS ‐C. A great
uncertainty still exists regarding the link between MIS ‐Ca n dK D S Srelated to COVID ‐19, and further research is needed to better un-
derstand MIS ‐C, KD, and KDSS.
Patients with MIS ‐C are currently managed in different ways
based on symptoms, using standard protocol for KD, or COVID ‐
19 treatment for adult patients. In this study, we report that themost common treatments were IVIG, aspirin, and corticosteroids,
extrapolated from KD management. These standard treatments
for KD were primarily used based on the known efficacy in pre-venting coronary aneurysms in this population. In addition, sev-eral MIS ‐Cp a t i e n t sr e c e i v e da n t i ‐inflammatory biologics and
antiviral therapies. Tocilizumab, an IL‐ 6 receptor antagonist, and
Anakinra, an IL ‐1 receptor antagonist, have been used for the
treatment of severe COVID ‐19 in adults, although safety and
efficacy has been controversial.
51–54Infliximab, an anti ‐human
tumor necrosis factor ‐α(TNF ‐α) monoclonal antibody, is effective
against several inflammatory di seases including KD thus maybe
an interesting agent in the MIS ‐C population.55,56Furthermore,
remdesivir, which is a nucleoside analogue that inhibits viral RNAp o l y m e r a s e s ,h a sb e e ns h o w nt ob ea s s o c i a t e dw i t ht h ec l i n i c a l
improvement in adults with COVID ‐19.
57–59Given the pre-
sentation of shock, MIS ‐C cases required inotropes and intensive
care, including mechanical ventilation and ECMO. The rate of
ECMO use and the mortality rate in MIS‐ Cw e r ee x t r e m e l y
higher than that in children with acute COVID ‐19 or KD.60,61Our
findings demonstrated heterogeneity in management of MIS ‐C.
Further studies including randomized clinical trials or global re-
gistries are required to determine what treatments are beneficial
against distinct manifestations of MIS ‐C, such as shock and
myocardial dysfunction, hopefully improving the high mortal-
ity rate.
Myocardial dysfunction is a more common cardiovascular com-
plication in MIS‐C than coronary artery dilation or aneurysms, unlike
in KD. We revealed that the majority of MIS‐C patients recovered
successfully with a relatively high rate of improvement in myocardial
dysfunction, however, the underlying mechanism of myocardialdysfunction in MIS‐C has not been fully elucidated. The pathogenesis
of myocardial injury characterized by the elevation of cardiac tro-
ponin in acute COVID ‐19 can be direct damage of myocardial cells
by the virus or a severe cytokine storm induced by inflammatory
responses, leading to myocarditis.
62–66Recent studies have identi-
fied that IL‐6 is elevated in COVID ‐19 patients with myocarditis67
and IL ‐6 plays a crucial role in a cytokine storm associated with
COVID ‐19 by forming hyperinflammation and promoting the pro-
duction of the coagulation cascade activator plasminogen activator
inhibitor ‐1.68In addition, they found that the inhibition of IL‐6 sig-
naling by tocilizumab treatment decreased plasminogen activator
inhibitor ‐1 production and resolved clinical manifestations in severe
COVID ‐19. Therefore, a potential mechanism for myocardial injury in
MIS ‐C may be a cytokine storm induced by IL ‐6, leading to the de-
velopment of fulminant myocarditis. In contrast, immunological ac-
tivation accompanied by secretion of TNF ‐αis an essential
predisposing factor to exacerbate vascular damage in KD, resulting
in coronary artery aneurysms.69Given the differences in cytokines,YASUHARA ET AL.
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anti ‐IL‐6 treatment might be a potential therapeutic option for MIS‐
C in addition to IVIG and steroids as opposed to anti ‐TNF ‐αtherapy
for KD. To date, the long ‐term morbidity and outcomes of MIS‐C,
such as sequelae of myocardial dysfunction and coronary artery
aneurysm formation remain unknown. Future research is needed tounderstand which treatment could prevent myocarditis and coronary
artery aneurysms as well as tracking long ‐term cardiac co ‐
morbidities.
Radia et al. reported a systematic review of MIS‐C.
70They
summarized the clinical, biochemical, radiological, and micro-biological features of 783 cases of MIS‐C between March to June,
2020. Compared to this systematic review, the novelty of our studylies on the examination of the pooled estimates across published
observational studies on MIS‐C using one ‐group meta‐ analysis in a
random‐effects model. We identified more cases of MIS‐C through a
longer‐term literature search and examined more variables. The
pooled estimates of a variety of clinical findings would provide novel
insights into understanding the full spectrum of MIS ‐C. In particular,
more detailed and specific data such as on the race/ethnicity, in-
flammatory and cardiac markers, infiltrates or opacities, myocardial
dysfunction, coronary artery abnormalities, and treatment would beuseful for a diagnosis and management of MIS‐C as well as the ex-ploration of the risk factors and susceptibility for MIS‐C and
COVID ‐19.
This study had several limitations to be noted. First, the available
studies were observational studies or case series, which are subjectto methodological biases or publication biases. However, only ob-
servational studies are currently available describing the clinicalfeatures of MIS‐C patients, and our study is crucial to assess the
current data on MIS‐C. Second, the data on some variables were not
available in all studies or were not reported consistently. Third, thelack of a universal case inclusion criteria or diagnostic test could leadto a misdiagnosis or underreporting of MIS‐C cases. Finally, the
studies were from the United States and European countries, which
limit generalizability of findings.
5|CONCLUSION
Our findings demonstrated MIS‐C could lead to severe multisystemdysfunction, including myocardial dysfunction and coronary arterydilation or aneurysms. MIS‐C has distinct features from KD, including
an older age at onset and higher incidence of gastrointestinal
symptoms and myocardial dysfunction with elevated inflammatoryand cardiac markers. Most cases of MIS‐C are treated by extra-polating from standard protocols for KD with a variety of anti ‐
inflammatory agents. Although myocardial injury improved in manycases at discharge, the rate of ECMO use and the mortality rate werehigher than that in children with acute COVID ‐19 or KD. These
findings provide insights into understanding the clinical character-istics and establishing specific diagnostic criteria and management ofMIS‐C. Further studies with large cohorts of MIS‐C patients arenecessary to investigate the pathophysiology, full spectrum of theclinical features, optimal treatment and long ‐term outcomes of this
population.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
AUTHOR CONTRIBUTIONS
Jun Yasuhara: conceptualization (lead); data curation (lead); formalanalysis (lead); investigation (lead); methodology (lead); project ad-
ministration (lead); resources (lead); software (lead); validation (lead);
visualization (lead); writing original draft (lead); writing review &editing (lead). Kae Watanabe: formal analysis (supporting); in-
vestigation (supporting); validation (supporting); writing review &
editing (supporting). Hisato Takagi: investigation (supporting); su-pervision (supporting); validation (supporting); writing review &
editing (supporting). Naokata Sumitomo: investigation (supporting);
supervision (equal); validation (supporting); writing review & editing(supporting). Toshiki Kuno: conceptualization (supporting); data
curation (supporting); formal analysis (supporting); investigation
(supporting); methodology (supporting); supervision (equal); valida-tion (supporting); writing review & editing (supporting).
ORCID
Jun Yasuhara
https://orcid.org/0000-0002-7937-3699
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SUPPORTING INFORMATION
Additional Supporting Information may be found online in the
supporting information tab for this article.
How to cite this article: Yasuhara J, Watanabe K, Takagi H,
Sumitomo N, Kuno T. COVID ‐19 and multisystem
inflammatory syndrome in children: A systematic review and
meta‐analysis. Pediatric Pulmonology . 2021;56:837 ‐848.
https://doi.org/10.1002/ppul.25245848 |
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