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Multisystem inflammatory syndrome in children related to COVID-19: a systematic review

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An association between a novel pediatric hyperinflammatory condition and SARS-CoV-2 was recently published and termed pediatric inflammatory multisystem syndrome, temporally associated with SARS-CoV-2 (PIMS-TS) or multisystem inflammatory syndrome (in children) (MIS(-C)). We performed a systematic review and describe the epidemiological, clinical, and prognostic characteristics of 953 PIMS-TS/MIS(-C) cases in 68 records. Additionally, we studied the sensitivity of different case definitions that are currently applied. PIMS-TS/MIS(-C) presents at a median age of 8 years. Epidemiological enrichment for males (58.9%) and ethnic minorities (37.0% Black) is present. Apart from obesity (25.3%), comorbidities are rare. PIMS-TS/MIS(-C) is characterized by fever (99.4%), gastrointestinal (85.6%) and cardiocirculatory manifestations (79.3%), and increased inflammatory biomarkers. Nevertheless, 50.3% present respiratory symptoms as well. Over half of patients (56.3%) present with shock. The majority of the patients (73.3%) need intensive care treatment, including extracorporal membrane oxygenation (ECMO) in 3.8%. Despite severe disease, mortality is rather low (1.9%). Of the currently used case definitions, the WHO definition is preferred, as it is more precise, while encompassing most cases. Conclusion: PIMS-TS/MIS(-C) is a severe, heterogeneous disease with epidemiological enrichment for males, adolescents, and racial and ethnic minorities. However, mortality rate is low and short-term outcome favorable. Long-term follow-up of chronic complications and additional clinical research to elucidate the underlying pathogenesis is crucial.What is Known: • A novel pediatric inflammatory syndrome with multisystem involvement has been described in association with SARS-CoV-2. • To date, the scattered reporting of cases and use of different case definitions provides insufficient insight in the full clinical spectrum, epidemiological and immunological features, and prognosis. What is New: • This systematic review illustrates the heterogeneous spectrum of PIMS-TS/MIS(-C) and its epidemiological enrichment for males, adolescents, and racial and ethnic minorities. • Despite its severe presentation, overall short-term outcome is good. • The WHO MIS definition is preferred, as it is more precise, while encompassing most cases.
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REVIEW
Multisystem inflammatory syndrome in children related to COVID-19:
a systematic review
Levi Hoste
1,2
&Ruben Van Paemel
3,4,5
&Filomeen Haerynck
1,2
Received: 27 August 2020 /Revised: 2 February 2021 /A ccepted: 10 February 2021
#The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature 2021
Abstract
An association between a novel pediatric hyperinflammatory condition and SARS-CoV-2 was recently published and termed
pediatric inflammatory multisystem syndrome, temporally associated with SARS-CoV-2 (PIMS-TS) or multisystem inflamma-
tory syndrome (in children) (MIS(-C)). We performed a systematic review and describe the epidemiological, clinical, and
prognostic characteristics of 953 PIMS-TS/MIS(-C) cases in 68 records. Additionally, we studied the sensitivity of different
case definitions that are currently applied. PIMS-TS/MIS(-C) presents at a median age of 8 years.Epidemiological enrichment for
males (58.9%) and ethnic minorities (37.0% Black) is present. Apart from obesity (25.3%), comorbidities are rare. PIMS-TS/
MIS(-C) is characterized by fever (99.4%), gastrointestinal (85.6%) and cardiocirculatory manifestations (79.3%), and increased
inflammatory biomarkers. Nevertheless, 50.3% present respiratory symptoms as well. Over half of patients (56.3%) present with
shock. The majority of the patients (73.3%) need intensive care treatment, including extracorporal membrane oxygenation
(ECMO) in 3.8%. Despite severe disease, mortality is rather low (1.9%). Of the currently used case definitions, the WHO
definition is preferred, as it is more precise, while encompassing most cases.
Conclusion: PIMS-TS/MIS(-C) is a severe, heterogeneous disease with epidemiological enrichment for males, adolescents,
and racial and ethnic minorities. However, mortality rate is low and short-term outcome favorable. Long-term follow-up of
chronic complications and additional clinical research to elucidate the underlying pathogenesis is crucial.
Hoste Levi and Van Paemel Ruben contributed equally to this work.
Communicated by Nicole Ritz
*Levi Hoste
levi.hoste@ugent.be
Ruben Van Paemel
ruben.vanpaemel@ugent.be
Filomeen Haerynck
filomeen.haerynck@ugent.be
1
Department of Pediatric Pulmonology, Infectious Diseases and
Immunology, Ghent University Hospital, Ghent, Belgium
2
Primary Immunodeficiency Research Lab, Center for Primary
Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research
Center, Ghent University Hospital, Ghent, Belgium
3
Center for Medical Genetics, Ghent University Hospital,
Ghent, Belgium
4
Cancer Research Institute Ghent (CRIG), Ghent, Belgium
5
Department of Pediatric Hematology, Oncology and Stem Cell
Transplantation, Ghent University Hospital, Ghent, Belgium
European Journal of Pediatrics
https://doi.org/10.1007/s00431-021-03993-5
Keywords PIMS-TS .MIS-C .COVID-19 .SARS-CoV-2
Abbreviations
ARDS Acute respiratory distress syndrome
COVID-19 Coronavirus disease 2019
ECMO Extracorporal membrane oxygenation
IVIG Intravenous immunoglobulins
KD Kawasaki disease
KDSS Kawasaki disease shock syndrome
LVEF Left ventricular ejection fraction
MAS Macrophage activation syndrome
MIS(-C) Multisystem inflammatory
syndrome (in children)
PIMS-TS Pediatric inflammatory multisystem
syndrome temporally associated
with COVID-19
RT-PCR Reverse transcriptase-polymerase
chain reaction
SARS-CoV-2 Severe acute respiratory syndrome
coronavirus 2
TSS Toxic shock syndrome
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2), causing coronavirus disease 2019 (COVID-19), led
to a pandemic health crisis within a few monthstime [13].
Severe COVID-19 and associated mortality has been highest
in elderly and patients with comorbidities, such as cardiovas-
cular disease, diabetes mellitus, and chronic lung disease
[46]. Since the outbreak, COVID-19 was generally described
as asymptomatic or mild in children, causing few pediatric
hospitalizations and minimal mortality [710].
Since April 2020, several countries from Europe and North
America reported on young patients with a severe multisystem
inflammatory syndrome associated with SARS-CoV-2. The
initial descriptions exposed important clinical heterogeneity,
partially overlapping with features of Kawasaki disease (KD)
or toxic shock syndrome (TSS), but nevertheless distinct from
these known inflammatory conditions [11,12]. In contrast
with (acute) COVID-19 respiratory disease, a significant pro-
portion of children were reported with severe or fatal disease
[11,1317]. Since its description, this novel disease is mostly
referred to as pediatric inflammatory multisystem syndrome
temporally associated with SARS-CoV-2 infection (PIMS-
TS) [18,19] or multisystem inflammatory syndrome in chil-
dren (MIS(-C)) [18,19].
At present, it is pivotal to optimize the characterization and
the diagnostic criteria of this inflammatory syndrome related
to COVID-19. To date, the scattered case reporting provides
insufficient insight in the full clinical, epidemiological, immu-
nological, and prognostic spectrum. Hence, we performed a
systematic review, the most extensive to date to our knowl-
edge, to describe the diagnostic criteria and clinical manifes-
tations of this novel pediatric COVID-19-associated
phenotype.
Methods
Original studies describing cases meeting the definition of
PIMS-TS or MIS(-C) by the Royal College of Paediatrics
and Child Health (RCPCH) [20], World Health Organization
(WHO) [19], or Centers for Disease Control and Prevention
(CDC) [18], were eligible for inclusion (Supplementary
information 1). Primary outcome analysis focused on epide-
miological, clinical, and outcome parameters.
A search strategy was designed with keywords combining
the pediatric population, COVID-19, and hyperinflammatory
presentations (Table 1), including articles published from
December 31, 2019, to August 13, 2020. Electronic databases
were searched (PubMed, Embase), including pre-print
(bioRxiv, medRxiv) and COVID-19-specific repositories
(Cochrane COVID-19 Study Register and WHO COVID-19
Global Research Database). The reference lists of included
studies were considered additional sources.
After duplicate removal, two reviewers (LH/RVP) inde-
pendently applied the inclusion and exclusion criteria, first,
by screening titles and abstracts and, second, by examining
What is Known:
A novel pediatric inflammatory syndrome with multisystem involvement has been described in association with SARS-CoV-2.
To date, the scattered reporting of cases and use of different case definitions provides insufficient insight in the full clinical spectrum, epidemiological
and immunological features, and prognosis.
What is New:
This systematic review illustrates the heterogeneous spectrum of PIMS-TS/MIS(-C) and its epidemiological enrichment for males, adolescents, and
racial and ethnic minorities.
Despite its severe presentation, overall short-term outcome is good.
The WHO MIS definition is preferred, as it is more precise, while encompassing most cases.
Eur J Pediatr
full texts. LH extracted data using a standardized form, while
RVP cross-checked for correctness and completeness. Any
disagreement was resolved by FH. The Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA)
checklist guided study selection and extraction. Risk for bias
[21] and levels of evidence [22] were assessed (LH) with
verification (RVP). Prior to conducting the review, the proto-
col was published (PROSPERO CRD42020189248). Data
was analyzed with R v3.6.3 (Supplementary information 4).
Cohort studies and studies reporting single-case data were
analyzed separately. To report on most variables, we used the
sum of cases of only the records reporting on the variable. As
such, the denominator in the proportions varies depending on
the publications reporting on a given variable. Rare conditions
(e.g., death), however, were calculated on the total group of
cases. Severe coursewas defined as the presence of one or
more of following conditions: coronary dilatation/aneurysm,
shock, death, need for mechanical ventilation, extracorporeal
membrane oxygenation (ECMO), renal replacement therapy,
inotropes, or PICU admission. Data was extracted from pre-
print publications for 4 records [2326]. During the process of
conducting this systematic review, 3 of these manuscripts
[2729] were published in peer-reviewed literature. The data
extracted in this review was left unchanged and is thus based
on the pre-print publications.
Results
Study characteristics
The search strategy yielded 918 records. After removing du-
plicates, 567 unique publications were screened on title and
abstract of which 409 were excluded, mostly because it
concerned editorial or review articles (n = 139), non-clinical
case studies (n = 84), or articles on PIMS-TS/MIS(-C) diag-
nostics, epidemiology, or management (n = 70). One hundred
and fifty-eight full-text articles were assessed for eligibility.
Finally, 68 studies were included (Fig. 1). In general, risk of
bias was low (Supplementary information 2), despite short
follow-up in all studies.
All studies were published after May 9, 2020, and present-
ed observational data from single case reports [24,3057]or
case series (2186 cases per publication) [1117,23,25,26,
5886](Fig.2- Supplementary 3). Four manuscript published
on pre-print servers were included [2326]. Most studies were
non-controlled, although three publications used historical
KD [15,64,81], MAS [81], or TSS [15] cohorts as a reference
population. Limited studies prospectively included control co-
horts of non-PIMS-TS/MIS(-C) pediatric COVID-19 [23,26,
83], KD [26], (adult) COVID-19-associated acute respiratory
distress syndrome (ARDS) [25], or convalescent plasma do-
nors [25]. Studies were mostly conducted in the USA (n = 28),
the UK (n = 10), or France (n = 6) and India (n = 6).
Demographics
In total, 953 patients with PIMS-TS/MIS(-C) were reported,
with individual patient information (single-case data) avail-
able for 138 patients (14.5%). Fifty-five patients (5.8%) were
reported in duplicate, although the corresponding manuscripts
[13,16,17,78,83] did not provide sufficient information to
filter for unique data.
Among single cases, a median age of 8.4 years (IQR 5
12.6) was found (Fig. 3a), corresponding with a median age of
at least 8 years noted in 14/20 cohorts (586/716 cohort pa-
tients) [13,14,16,17,23,25,26,59,6365,78,81,86].
Remarkably, age was substantially higher compared to non-
COVID-19 KD cases (median age 2.02.7y) [15,64]ornon-
PIMS-TS/MIS(-C) pediatric COVID-19 (median age 2.0
years) [23]. Additionally, a male predominance (561/953;
58.9%; Fig. 3b) was found, comparable to historic KD groups
[64] and non-PIMS-TS/MIS(-C) pediatric COVID-19 [23].
PIMS-TS/MIS(-C) cases were frequent Black (240/647;
37.0%), followed by patients of Caucasian (189/647; 29.2%)
or Asian origin (56/647; 8.7%) [11,1315,17,2326,30,35,
58,61,63,6567,70,71,76,7881,83,86]. However, many
mixed/other/unknown origins (144/647; 22.3%) were report-
ed. Hispanic/Latino was reported in 97/332 (29.2%).
Overweight (BMI > 25 kg/m
2
or >85th percentile for age/
sex) was found in 147/581 (25.34%). Other comorbidities
were infrequent, and mainly consisted of respiratory diseases,
including asthma (39/953; 4.1%) or chronic lung disease (14/
953; 1.5%), cardiovascular diseases (12/953; 1.3%) and im-
munodeficiencies (10/953; 1.0%) [1315,17,23,25,55,59,
60,63,64,66,68,70,81,82,86].
Table 1 Search strategy criteria
Inclusion criteria
1 Study population: hyperinflammatory syndrome meeting the case
definitions of PIMS-TS [19]orMIS(-C)[20,21]inchildren(021
years of age) with a temporal association with confirmed or probable
COVID-19
2 Outcome: clinical, epidemiological, and immunological descriptions;
therapeutic management and clinical effect; and prognosis of
individuals or cohorts of patients.
3 Types of study designs: RCT, observational studies, case-control
studies, cross-sectional studies, case reports, and case series
Exclusion criteria
1 Studies on adult patients with SARS-CoV-2 infection and/or
SARS-CoV-2 associated hyperinflammatory syndromes
2 Studies on pediatric patients with other coronavirus infections
(SARS-CoV-1 and Middle East Respiratory Syndrome Coronavirus
(MERS-CoV) infection or other respiratory infections.
3 Studies with incomplete or lacking necessary data
4 Duplicate studies
5 Studies without accessible full-text versions
6 Studies not in English language
Eur J Pediatr
Clinical presentation
Fever was documented in nearly all patients (922/928; 99.4%)
[1117,23,24,3085], commonly during at least 5 days (258/
928; 27.0%). The majority (598/699; 85.6%) presented gastroin-
testinal symptoms, mostly abdominal pain (315/539; 58.4%),
vomiting (306/532; 57.5%), and diarrhea (268/532; 50.4%)
[1114,16,24,26,3037,39,40,4345,47,4952,5477,
79,80,82,8486]. Cardiovascular manifestations were found in
79.3% of patients (307/387) [1117,24,3037,3941,4449,
5186]. Tachycardia (194/253; 76.7%), hemodynamic shock or
hypotension (416/695; 59.9%), myocarditis (128/309; 41.4%)
and mild or moderate decreased left ventricular ejection fraction
(LVEF between 30 and 55%; 211/522; 40.4%) were frequently
observed cardiovascular abnormalities. Severe complications
such as LVEF less than 30% (36/506; 7.1%), coronary dilatation
(z-score between 2.0 and 2.5; 74/638; 11.6%) or aneurysms (z-
score above 2.5; 59/572; 10.3%) were found in a minority of
cases. Pericardial effusion was frequently found (114/511;
22.3%). Half of cases (295/587; 50.3%) showed respiratory
symptoms, including upper respiratory tract symptoms (95/397;
23.9%), dyspnea (101/378; 26.7%) and (multiple) radiological
infiltrates (114/321; 35.5%) [14,15,23,33,35,37,38,40,44,
45,47,52,59,60,66,68,71,73,77,82]. Thirteen cases (1.4%)
revealed thrombotic complications [11,13,16,17,74,78], in-
cluding 2 splenic infarctions [16]. (Hemorrhagic) Cerebral strokes
during ECMO (n= 5), a recognized complication, contributed
substantially to thrombotic complications [11,16,17,74,75].
A quarter of patients (130/557; 23.3%) fulfilled criteria for
complete KD [12,13,15,30,35,37,41,45,46,50,53,56,59,
Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram
Eur J Pediatr
61,63,64,68,69,72,73,77,79,81,83,85,86] (criteria in
Supplementary information 1). A similar proportion (99/411;
24.1%) fulfilled 2 or 3 of the KD criteria in combination with
prolonged fever, resembling incomplete KD [1113,32,36,
39,44,47,48,52,54,57,6163,6569,77,79,81,83].
Polymorphous exanthema (466/849; 54.9%) and non-
purulent conjunctivitis (423/849; 49.8%) occurred the most.
Although shock was frequently reported in single cases (103/
138; 74.6%), shock only presented in half of single cases with
complete KD (11/24; 45.8%) [12,30,35,41,45,46,53,68,
69,72,77].
Biological markers
Increased inflammatory markers were frequently documented
(Fig. 4)[11,12,24,3057,60,62,64,6673,7577,80,84],
including C-reactive protein (CRP; median 249 mg/l
[IQR 173322] in single cases), ferritin (910 μg/l [457
1521]), and interleukin-6 (244.5 pg/ml [107379]). Notably,
patients exhibited substantially higher inflammation com-
pared to historical KD [15,64] or non-PIMS-TS/MIS(-C)
[23]cohorts.
Although white blood cell counts were frequently in-
creased (12,800/μl [915020,075]), lymphocytopenia was
common (831.5/μl [5101157.5]) [12,24,3036,3941,
4346,4850,5257,60,62,6773,75,77,80,84], contrast-
ing with historical KD cohorts [15,64] (median lymphocytes
28003080/μl) or non-PIMS-TS/MIS(-C) (median 2100/μl)
[23]. Most PIMS-TS/MIS(-C) presented reduced to normal
thrombocytes (platelets below 150,000/μl in 44/104; 42.3%)
[11,12,24,30,3236,38,40,41,4346,48,50,5256,62,
6668,70,71,77,80,84]. Thrombocytosis (platelets above
450,000/μl), a typical KD sign and a laboratory criterium for
incomplete KD [87], occurred in only 5/104 (4.8%).
Besides inflammatory parameters, coagulation markers
were substantially upregulated, including D-dimers (3750
ng/ml [19466896]) and fibrinogen (640 mg/dl [504800])
[11,12,3135,38,40,4347,49,51,5557,60,62,6668,
70,71,7577,80,84]. Furthermore, myocardial injury
markers such as troponins (188 ng/l [60614]) and brain na-
triuretic peptide (BNP)(median 1619pg/ml [4243325]) were
often elevated [11,12,30,3236,39,40,4649,5457,60,
62,6671,75,77,80,84,87,88]. Hyponatremia (130 mmol/l
[128133]) [12,24,30,32,35,37,41,4446,4850,52,54,
Fig. 2 Cumulative number of published PIMS-TS/MIS(-C) cases (bars) in relation to total worldwide reported COVID-19 cases, according to data from
Johns Hopkins Coronavirus Resource Center (lines; 7-day rolling average)
Eur J Pediatr
55,62,67,69,76,84] was frequent, contrasting with KD
controls (135 mmol/l [134137]) [64] or non-PIMS-TS/
MIS(-C) COVID-19 (137 mmol/l [136139]) [23].
SARS-CoV-2 testing and diagnostic criteria
Current or recent SARS-CoV-2 infection was assessed with
RT-PCR (nasopharyngeal or fecal swab) and/or serological
assays (IgG/IgM/IgA) [1217,25,26,3034,3653,55,
5772,7582,8486]. Two-thirds of patients were IgG-
positive (362/569; 63.6%). IgM (substantial variation between
5.7 and 100%) [16,26,59,82] and IgA positivity (25/35;
71.4%) [59] were documented in only four and one cohort(s),
respectively. All single patients being IgA-positive (19/138;
13.8%) [36,62,70] or IgM-positive (8/138; 5.8%) [12,34,46,
47,69,72], had detectable IgG as well. Only338/901 (37.5%)
had positive respiratory RT-PCR. Positive fecal RT-PCR was
rare (7/268; 2.6%) [16,39,40,45,58,59,62,64,79]. Close
contacts with COVID-19 were registered in 168/598 (28.1%)
[1113,17,24,34,36,40,44,47,48,53,59,61,6365,70,
72,73,75,77,78,8082]. Of single cases, 115/138 (83.3%)
had a microbiologically confirmed SARS-CoV-2 infection
(PCR and/or serology-positive). Of the 23 cases negative (or
missing) for both techniques [11,12,24,35,50,54,56,62,
73,77,79], 15 additionally had no known COVID-19 contact
[11,12,35,50,54,56,62,79].
As an inclusion criterium, all cases in this review
corresponded to at least one of the recognized case definitions
[1820]. The RCPCH definition, not requiring proven or
probable SARS-CoV-2 infection, was most comprehensive,
and subsequently comprised all single cases. Although more
stringent concerning clinical manifestations and the relation-
ship with SARS-CoV-2, the WHO definition nevertheless in-
cluded 97% (18 not assessable), missing only4 mild cases that
did not present multisystem dysfunction (criterium 3). In con-
trast, the CDC definition comprised only 62% (8 not assess-
able) of single cases and neglected on 31 cases with severe
course, all failing to achieve the CDC criterium concerning the
multi-organ (2 organ systems) dysfunction. Of single cases,
the WHO definition missed 1 out of 5 patients needing ECMO
Fig. 3 Demographic characteristics of all included studies. aAge
distribution. bFraction of males and females in each study. IQR,
interquartile range. Controlcorresponds to the control populations
with Kawasaki disease as described by Pouletty et al. [64]and
Whittaker et al. [15] and non-PIMS-TS/MIS(-C) pediatric COVID-19
by Swann et al. [23]. Data from Swann et al. [23], Rostad et al. [26],
and Weisberg et al. [25] was extracted from pre-print publications and
these references and have subsequently been published in the peer-
reviewed literature [2729]
Eur J Pediatr
because of insufficient data reported to assess [74], while the
CDC definition not included 2/5 ECMO cases [11,52,66,74,
75] and 2/6 deaths [11,24,66,74,75,79].
Therapeutic management
Three quarter of patients (662/872; 75.9%) received intrave-
nous immunoglobulins (IVIG) [1115,17,25,30,35,37,39,
41,4348,50,5254,5669,7173,7586]. Only few papers
report IVIG dosages, which were mainly immunomodulatory.
Multiple IVIG doses were needed in 73/662 (11.0%).
Systemic corticosteroids were prescribed in 516/908 (56.8%)
[1115,17,23,25,31,3335,43,46,47,50,54,5767,69,
71,72,7686]. Acetylsalicylic acid was reported in 171/327
(52.3%) of which 39/171 (22.8%) received high, anti-
inflammatory dosages (80100mg/kg/day) [11,12,30,35,
37,39,44,45,47,48,50,5254,56,61,6367,69,71,
7779,81,85,86]. Heparin (259/563; 46.0%) was a frequent
anti-thrombotic [11,13,17,33,34,43,51,52,55,59,60,63,
65,66,68,74,75,78,80,81,84,86].
One hundred and fifty-five cases (155/953; 16.3%) were
treated with biopharmaceuticals, including IL-1R antagonist
(anakinra) (72/953; 7.6%), interleukin-6 inhibitors (toci-
lizumab/siltuximab; 64/953; 6.7%), and to a lesser extent,
TNFα-inhibitors (infliximab) (22/953; 2.3%) [11,13,15,
17,25,33,38,4143,45,46,51,5760,63,64,6668,70,
75,76,7881,8486]. Remdesivir (22/953; 2.3%) was rarely
prescribed [17,25,57,60,66,78,81,82].
Inotropics were given to 477/863 (55.3%) [1117,23,26,
3133,35,39,4547,52,54,57,5972,75,77,78,80,81,
8386]. Mechanical and non-invasiveventilation was initiated
in 219/928 (23.6%) and 130/503 (25.8%), respectively [11,
1317,23,30,31,33,39,41,46,47,52,54,5862,6472,
74,75,78,8086]. A relative high rate of ECMO (36/953;
3.8%) [11,1317,52,59,66,74,75,78] was reported.
Prognosis and outcomes
Intensive care admission was common (564/769; 73.3%) with
median duration of 4 days (IQR 3.758) in single cases and 4
7daysincohorts[11,13,14,16,17,23,26,33,45,47,54,
5967,70,71,79,8183,85,86].Themediantimeofhospi-
talization was 8 days (IQR 712) in single cases and 412
days in cohorts [13,17,30,54,55,59,63,6567,70,71,
86]. A majority of single cases (118/138; 86%) experienced
severe course. Such patients were substantially older and pre-
sented more gastrointestinal and cardiovascular symptoms as
compared to mild PIMS-TS/MIS(-C) (Table 2). They present-
ed however less respiratory symptoms, exanthema, or com-
plete KD. Laboratory measurements in patients with severe
disease showed lower WBC counts and more lymphopenia,
higher CRP, and ferritin (but lower IL-6), and higher platelet
counts, D-dimer, and troponin. There were no differences in
sex, microbiology, or medical treatment.
Eighteen deaths were described (18/953; 1.9%) [11,1317,
24,66,74,75,78,79,82]. Of deaths with reported ages, 2/12
(16.7%) patients were less than 1 year old [14,79], 6/12 (50%)
were aged 512 [13,14,17,66,74,75], and 4/12 (33.3%)
were older than 13 years [11,13]. The majority was male
(8/11; 72.3%) and Black (5/8; 62.5%), although race/
ethnicity was underreported. All reported deaths but one
[79] presented with shock and/or myocardial dysfunction,
needing inotropics, and/or mechanical circulatory support
[11,1317,24,66,74,75]. ECMO was initiated in 10/15
(66.7%) of fatal cases, of which 5 died of (hemorrhagic) ce-
rebral infarction [11,16,17,74,75]. Comorbidities among
fatal cases were obesity (n = 4) [11,13], acute leukemia (n =
1) [82], glucose-6-phosphate dehydrogenase deficiency (n =
1) [24], asthma (n=1)[13], and multiple neurological condi-
tions (n = 1) [13]. Residual cardiac dysfunction, often reported
as decreased LVEF at discharge or follow-up, was present in
21/287 (7.3%) [17,59,6365,75,86]. Two patients showed
persistent neurological damage after PIMS-TS/MIS(-C) [76].
No other residual morbidity was reported.
Discussion
Overall, children with COVID-19 exhibit mild or asymptom-
atic disease. Only limited reports of complicated or fatal
COVID-19 in children are published [7,10,89,90].
Although some immunological hypotheses are presented
[9194], hitherto, obvious elucidation on why children dis-
play a milder COVID-19 phenotype is lacking.
At the end of April 2020, while over 3 million SARS-CoV-
2 infections were reported worldwide, a relative sudden
emerge of children presenting a severe hyperinflammatory
disorder with multisystem involvement, prompted an interna-
tional alert. Noteworthy, during the first 4 months after the
initial reports, more than 950 individual cases with PIMS-
TS/MIS(-C) have been reported in scientific literature, and,
subsequently, systematically reviewed herein. Currently, sev-
eral countries are still struggling with widespread SARS-
CoV-2, requiring continuous and evidence-based updates on
the COVID-19 spectrum, in particular concerning complicat-
ed disease courses. In this context, we performed the most
extensive PIMS-TS/MIS(-C) systematic review to appropri-
ately characterize its presentation and prognosis.
The findings in this review confirm the heterogeneous clin-
ical spectrum. The majority of PIMS-TS/MIS(-C) patients
present gastrointestinal symptoms. Despite SARS-CoV-2
displaying respiratory tract tropism [95], a large proportion
of cases does not exhibit respiratory symptoms, as typically
seen in adults. Eventually, in 50.3% respiratory manifestations
are noted, although critical illness might have contributed to
Eur J Pediatr
Eur J Pediatr
secondary respiratory failure and ventilator-associated pneu-
monia. Considering the high rate of ICU admission (73.3%),
we conclude that a relevant proportion of critical cases does
not exhibit initial respiratory manifestations. In contrast with
typical adult COVID-19, PIMS-TS/MIS(-C) predominantly
affects cardiovascular, gastrointestinal, and/or neurological
organ systems and only occasionally the respiratory system.
Cardiovascular manifestations, including severe circulatory
failure and myocardial involvement requiring intensive care,
burdens PIMS-TS/MIS(-C) substantially, and was dominantly
present in all deceased patients. Nevertheless, the majority of
patients (98.1%) survived the acute phase of PIMS-TS/MIS(-
C). Noteworthy, an overrepresentation of males and minori-
ties (Black, Hispanic/Latino), as well as the paucity of reports
from Asian countries, is observed in this review. Apart from
obesity, significant co-morbidities are missing, also among
fatal cases. So far, underlying factors such as genetic predis-
position, prior infections, or immunizations contributing to
PIMS-TS/MIS(-C) vulnerability are unclear.
Comparing with historical KD cohorts [15,64] or non-
PIMS-TS/MIS(-C) COVID-19 children [23], PIMS-TS/
MIS(-C) patients are substantially older, and represent more
systemic inflammation (higher WBC counts and drastically
increased CRP and IL-6), more lymphocytopenia and throm-
bocytopenia, and higher markers of myocardial injury (tropo-
nin and NT-pro-BNP) and coagulopathy (D-dimers). Of the
PIMS-TS/MIS(-C) cases fulfilling complete KD criteria, half
presented with shock, contrasting with non-COVID-19-
associated KD shock syndrome with an incidence rate of only
3.37% of KD cases [96,97]. Moreover, coronary dilatation
(11.6%) and aneurysm formation (10.3%) are more prevalent
than in appropriately treated KD (~5%), as well as mortality
rates, typically less than 0.1% in KD (1.9% in PIMS-TS/
MIS(-C)) [98]. Despite some overlapping features, this review
confirms that PIMS-TS/MIS(-C) is a distinct entity from KD,
KD shock syndrome, or (acute) COVID-19 in children.
Epidemiological enrichment for adolescents is present, but
clinicians should remain vigilant with other age categories as
similar disease also presents in series of infants [33,37,48,
53,79], and recently, even in a 36-year-old [99]. Despite the
international recognition of this novel disease entity, none of
the clinical variables presented in this review seems to be
neither sensitive nor specific for PIMS-TS/MIS(-C). Thus, it
remains challenging to recognize this heterogeneous disease
in daily clinical practice. Prompt recognition is pivotal to
insure a good individual prognosis. Knowledge of the dis-
ease spectrum (summarized in Fig. 5)andthecombination
of a detailed medical history, clinical examination, and rou-
tine laboratory markers in a child presenting with prolonged
fever should allow an experienced clinician to differentiate
against diseases with overlapping presentations. In either
case, its frequent association with end-organ damage re-
quires the accessibility of a pediatric intensive care unit.
Severe COVID-19 might be related to host immune over-
drive and unbounded cytokine release [100,101]. In contrast
with adult COVID-19, respiratory symptoms are less common
in PIMS-TS/MIS(-C), and primary respiratory failure does not
seem a dominant cause for ICU admission. Moreover, the
clinical presentation of PIMS-TS/MIS(-C) is mainly charac-
terized by systemic vasculitis, multisystem involvement, and
hypercoagulation. However, although abnormal coagulation
parameters are frequently reported, thrombotic or embolic
events were rare, in contrast with adult COVID-19 [102]. To
date, the molecular pathophysiological mechanisms in PIMS-
TS/MIS(-C) are insufficiently studied, although publications
measuring serological and inflammatory responses have
shown some initial insights [28,103,104]. Further research
efforts are however required as understanding of the involved
pathways might contribute to appropriate therapeutics that
interfere with these dysregulated immune responses.
With a seroconversion rate of two-thirds, this review con-
firms the probable association with recent SARS-CoV-2 in-
fection and possibility of antibody-driven pathogenesis in
PIMS-TS/MIS(-C). In this review, a proportion of patients
are, however, included without microbiological evidence for
(past) SARS-CoV-2 infection, which is an important caveat in
the current case definitions. The true incidence of PIMS-TS/
MIS(-C) remains moreover unknown and a notification bias
might be present. In absence of comprehensive pediatric sur-
veillance studies, the proportion of SARS-CoV-2-infected
children subsequently suffering from PIMS-TS/MIS(-C) can
only be estimated. A better understanding of affected age
groups and associated risk factors is thus necessary.
The appropriate use of case definitions should prospective-
ly be assessed. This review currently favors the WHO MIS
definition. In contrast with the RCPCH definition, both CDC
and WHO case descriptions are more precise (e.g., requiring a
proven association with SARS-CoV-2 and multisystem in-
volvement), while the WHO definition comprised 97% of
cases, and CDC only 62%.
Fig. 4 Laboratory tests values and distribution for each study. Error bars
correspond to the interquartile range. Dashed vertical line equals the
upper limit of normal (CRP, white blood cells, ferritin, D-dimers, IL6,
and troponin) or the lower limit of normal (sodium, lymphocytes, and
platelets). For studies that report multiple values for the same test, the
maximum (CRP, white blood cells, ferritin, D-dimers, IL6, and troponin)
or the minimum (sodium, lymphocytes, platelets) was used. Covid(red
line) equals values corresponding to the COVID-19-related
hyperinflammatory syndrome; control(gray line) equal values corre-
sponding to the control populations with Kawasaki disease described by
Pouletty et al. [64] and Whittaker et al. [15] and (orange line) non-PIMS-
TS/MIS(-C) pediatric COVID-19 by Swann et al. [23]. Data from Swann
et al. [23], Rostad et al. [26], and Weisberg et al [25]. was extracted from
pre-print publications and these references have subsequently been pub-
lished in the peer-reviewed literature [2729]
Eur J Pediatr
Ultimately, this review has some limitations. In particular,
we were unable to collect individual data of all patients. We
did not contact authors of included studies for insights in their
data as we believed this would significantly delay the
reporting of this pressing data. Due to the nature of included
studies, these reports are moreover enriched for severe disease
Table 2 Characteristics of
patients with mild versus severe
PIMS-TS/MIS(-C) of reported
single cases (n= 138). Severe
course was defined as presence of
coronary dilatation/aneurysm,
shock, death, need for mechanical
ventilation, extracorporal
membrane oxygenation (ECMO),
renal replacement therapy,
inotropes, or PICU admission.
Abbreviations used: ECMO,
extracorporal membrane
oxygenation; IL, interleukin;
IVIG, intravenous
immunoglobulins; KD, Kawasaki
disease; RRT, renal replacement
therapy; WBC, white blood cells
PIMS-TS/MIS(-C)
Variable Severe course Mild course
Count, n(%) 118 (100) 20 (100)
Age (year), median (IQR) 9 (612.7) 6.5 (39.75)
Male, n(%) 70(59) 13(65)
Symptoms, n(%)
Respiratory 56 (47) 12 (60)
Gastrointestinal 103 (87) 10 (50)
Cardiovascular 117 (99) 7 (35)
Shock 103 (87) NA
Coronary dilatation 13 (11) NA
Aneurysm formation 12 (10) NA
Neurological 38 (32) 9 (45)
Dermatological 59 (50) 14 (70)
Fever 5days 64(54) 12(60)
Complete KD 16 (14) 8 (40)
Incomplete KD 29 (25) 4 (20)
SARS-CoV-2, n(%)
RT-PCR-positive 54 (45) 9 (45)
Serology-positive 65 (55) 11 (55)
Critical care interventions, n(%)
PICU admission 64 (54) NA
Inotropics 77 (65) NA
Mechanical ventilation 35 (30) NA
ECMO 5 (4) NA
RRT 2 (2) NA
Medical treatment, n(%)
IVIG once 90 (76) 14 (70)
IVIG multiple 9 (8) 2 (10)
Systemic corticoids 49 (42) 9 (45)
Anakinra 8 (7) 1 (5)
Tocilizumab 22 (19) 3 (15)
Infliximab 9 (8) 1 (5)
Laboratory markers, median (IQR)
WBC (/μl) 12,735 (8602.520,075) 14,950 (1002518,827.5)
Lymphocytes (/μl) 800 (5101190) 920 (7001030)
Platelets (/μl) 181,000 (123,000254,000) 121,000 (104000151,000)
CRP (mg/l) 251 (183328) 197 (132.25258.7)
Ferritin (ng/ml) 966.5 (482.51569.25) 752.5 (3431286.5)
IL-6 (pg/ml) 2197.15 (23.1259927.5) 3689 (0.7512,193.75)
Sodium (mmol/l) 130 (128133) 132 (129.35133)
D-Dimer (ng/ml) 3917 (2105.758218) 2818 (633.54379)
Troponin (ng/l) 2020.5 (1119660) 193.5 (1910,949.2)
Outcome, n(%)
Death 6 (5) NA
Eur J Pediatr
course. Furthermore, only 7 studies contain a control popula-
tion, of which3 use historical data [15,64,81], 1 uses an adult
control population [25] and 2 others report on 15 or less con-
trol cases [26,83]. Additionally, the association with COVID-
19 could have triggered a reporting bias, which might result in
overdiagnosis of PIMS-TS/MIS(-C). This phenomenon could
have affected the in-depth analysis of the case definitions as
well, as the truefalse positivity rate remains unknown. To
partly overcome this issue, we excluded cases with insuffi-
cient data in our sensitivity analysis. As this review was con-
ducted while PIMS-TS/MIS(-C) has only been described
since a few months, inevitably, delayed complications or
long-term effects were not yet assessed.
Because the relatively small number in the single-case co-
hort and many lacking data in larger cohorts, formal statistical
testing was not conducted. As such, the findings of this review
should be interpreted as descriptive and exploratory. Due to
the retrospective nature of included studies, and not all studies
reporting all variables, we were unable to collect sufficient
data for prediction modeling for disease course or treatment
response. To date, there is lack of randomized controlled trials
concerning PIMS-TS/MIS(-C) and additional prospective co-
hort studies including control populations are needed. As a
surrogate, systematic reviewing of observational data might
contribute to the expertise required and identify gaps in
knowledge. Updating the dataset of this review, might con-
secutively provide answers to these ongoing needs.
Conclusions
A novel hyperinflammatory condition with severe multisys-
tem involvement has been described in children and adoles-
cents during the COVID-19 pandemic (PIMS-TS/MIS(-C)).
This review systematically assesses this novel syndrome and,
as such, illustrates an epidemiological enrichment for males,
adolescents, and racial minorities; a clinical heterogeneous
presentation with frequent gastrointestinal manifestations
and circulatory failure including myocardial injury; and lastly,
an overall good prognosis with absence of short-term compli-
cations despite frequent critical care interventions. Further ep-
idemiological, clinical, immunological, and genetic research
is needed, as well as long-term follow-up studies of PIMS-TS/
MIS(-C) patients.
Supplementary Information The online version contains supplementary
material available at https://doi.org/10.1007/s00431-021-03993-5.
Fig. 5 Summary figure
presenting the findings of this
systematic review on the clinical
spectrum of PIMS-TS/MIS(-C).
Comparison of the clinical picture
is made, based on relevant
differences with control
populations such as published on
Kawasaki disease (KD) by
Pouletty et al. [64] and Whittaker
et al. [15] (*), and non-PIMS-TS/
MIS(-C) pediatric COVID-19 by
Swann et al. [23] (°). For each
variable, the percentage denoting
the fraction of included cases is
displayed. PIMS-TS/MIS(-C)
disease severity is assessed as de-
scribed in the Methodssection.
Arrows pointing upwards mean
that a higher proportion of cases
display one of the mentioned
symptoms or that higher values
for the laboratory markers are
found. Arrows pointing down
denote lower values or
frequencies
Eur J Pediatr
Acknowledgements This research effort was conducted as part of the
pediatric COVID<19 research consortium of the Ghent University
Hospital.
Authors contributions LH contributed to study conception and design
and drafted the review protocol. LH independently carried out the review
selection process, extracted data from the included records, and assessed
risk of bias and level of evidence. LH drafted the initial manuscript, and
has read, contributed to and approved the final version of the manuscript.
RVP contributed to study conception and design, independently carried
out the review selection process. RVP cross-checked extracted data, ver-
ified risk of bias and level of evidence, and carried out the data analysis.
RVP has read, contributed to and approved the final version of the
manuscript.FH supervised the full study conception, design, data extrac-
tion, data analysis and interpretation, and manuscript drafting. FH re-
solved any disagreement in the record selection process. FH has read,
contributed to and approved the final version of the manuscript.
Funding LH was funded by the VIB Grand Challenge Programs. RVP
was funded by a predoctoral fellowship from the Research Foundation
Flanders (FWO). FH is supported by Ghent University research grant
(BOF-UGent), VIB Grand Challenges Programs and Jeffrey Modell
Foundation.
Data availability/Code availability All code, additional supporting data,
and the full data analysis have been made publicly accessible (url
provided in Supplementary information)
Code availability N/A
Declarations
Ethics approval/consent to participate/consent for publication This
article does not contain any studies with human participants or animals
performed by any of the authors.
Competing interests The authors declare no competing interests.
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Eur J Pediatr
... The presence of rash and conjunctival congestion were proportionately higher with the increasing age of children. Gastrointestinal system involvement was seen in 62% of our study population which was lower than global data of 86% as reported by recent systematic reviews [14,17]. ...
... Nine percent of our patients had serositis (5.4% had pleural effusion, 1.4% had ascites, and 2.7% had polyserositis). One systematic review revealed the incidence of pericardial effusion to be 22% [14]. ...
... Fifty-eight (74.3%) of children presented with shock out of which 28 (35.9%) were fluid refractory requiring inotropes. Similar results were reported by Hoste et al. [14]. In studies from New York by Kaushik et al., 51% required vasopressor support [16]. ...
Article
Full-text available
Background Multisystem inflammatory syndrome in children (MIS-C) is a post-infectious sequelae of acute COVID-19 infection affecting children. This study was done over a period of 12 months from December 2020 to November 2021 to describe the clinical presentation, laboratory abnormalities, and outcome of children with MIS-C. Methods Seventy-eight children below 12 years of age who satisfied the WHO diagnostic criteria for MIS-C were included in the study. Clinical parameters were recorded at admission. Relevant laboratory investigations, radiological studies, and outcome were documented. Results The most commonly affected age group was 6–12 years with a female predominance. COVID RTPCR was negative in all patients. Most cases presented 2–6 weeks after the onset of acute COVID-19 infection. Lethargy, poor feeding, vomiting, abdominal pain, loose stools, cough, and cold are common symptoms of MIS-C syndrome in children and the common signs were rash, conjunctival congestion, hypotension, tachycardia, tachypnea, and hypoxemia. Gastrointestinal system was the commonly affected followed by the hepatic, renal, and cardiovascular systems. Coronary artery abnormalities were seen in 20% of cases. IVIg was the mainstay of therapy used in 95% of patients. Mortality was 1.3%. Cases responded we