Pediatric Inflammatory Multisystem Syndrome: Time to Collaborate

Abstract

There is significant variability in the names and case definition of pediatric inflammatory multisystem syndrome associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Such variability leads to adverse consequences in the quest for further knowledge and management strategies. It is time to collaborate to gain consensus.

A recently described hyperinflammatory syndrome in children with overlapping features of Kawasaki disease (KD) and toxic shock syndrome associated with the coronavirus disease 2019 (COVID-19) pandemic has caused significant concern in the pediatric medical community [1]. As a newly described condition, clarity in the name and case definition is important. However, in just over 2 months of being first described, there is already significant variability in both name and case definition (Table 1) [2–6]. Although “pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 pandemic (PIMS-TS)” and “multisystem inflammatory syndrome in children (MIS-C)” are the most commonly used names; another is “SARS-CoV-2–induced Kawasaki-like hyperinflammatory syndrome (SCiKH syndrome)” [7].

Table 1.

Summary of Different Names and Case Definitions of Pediatric Inflammatory Multisystem Syndrome

Characteristics	Royal College of Paediatrics and Child Health [2]	Centers for Disease Control and Prevention [3]	World Health Organization [4]	British Paediatric Surveillance Unit [5]	Canadian Paediatric Surveillance Program [6]
Name	Paediatric multisystem inflammatory syndrome temporally associated with COVID-19	Multisystem inflammatory syndrome in children associated with COVID-19	Multisystem inflammatory syndrome in children and adolescents with COVID-19	Multisystem inflammatory syndrome, Kawasaki disease and toxic shock syndrome	Paediatric inflammation multisystem syndrome/Kawasaki disease temporally associated with COVID19
Age	Child	<21 years	0–19 years	<16 years	<18 years
Fever	Persistent (>38.5°C)	≥38°C or subjective fever for ≥24 hours	Fever ≥3 days	>38°C	>38°C ≥3 days
Blood characteristics	Neutrophilia	Elevation of 1 or more of the following:	Elevated	CRP >100 mg/L (mandatory) ferritin, D-dimers (optional, see below)	Elevated: CRP
	Elevated CRP	CRP	CRP
	Lymphopenia	ESR	ESR		ESR
		Fibrinogen	Procalcitonin		Ferritin
		Procalcitonin
		D-dimer
		Ferritin
		Lactate dehydrogenase
		Interleukin 6
		Neutrophils
		Reduced lymphocytes Low albumin
Clinical features	1 or more of the following organ dysfunctions:	Hospitalization and ≥2 organs involved	2 of following:	1 or more of the following:	Either features of KD (complete or incomplete) or toxic shock syndrome (typical or atypical)
	Shock	Cardiac	Rash or bilateral conjunctivitis, or mucocutaneous	Cardiac involvement
	Cardiac	Renal	Hypotension or shock	Gastrointestinal involvement
	Respiratory	Respiratory	Cardiac involvement	Respiratory failure: need for high-flow and humidified oxygen or continuous positive airway pressure or ventilation
	Renal	Hematologic	Coagulopathy	Raised ferritin (>500) ± raised D-dimers (>2× upper limit of normal)
	Gastrointestinal	Gastrointestinal	Acute gastrointestinal problems
	Neurological disorder	Dermatologic
		Neurological
KD	This may include children fulfilling full or partial criteria for KD	Some individuals may fulfil full or partial criteria for KD but should be reported if they meet the case definition for multisystem inflammatory syndrome in children	Not mentioned	Typical or atypical KD and/or toxic shock syndrome	Features of KD (complete or incomplete)
Toxic shock syndrome	Not mentioned	Not mentioned	Not mentioned	Typical or atypical toxic shock syndrome	Toxic shock syndrome (typical or atypical)
Exclusion of other etiologies	Exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, infections associated with myocarditis such as enterovirus	No alternative plausible diagnoses	No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes	No alternative etiology	No alternative etiology
Link to SARS-CoV-2 infection	SARS-CoV-2 PCR may be positive or negative	Positive evidence of recent SARS CoV-2 infection (PCR, antibody, exposure history in the last 4 weeks)	Evidence of COVID-19 (PCR or serology positive) or likely contact with patients with COVID-19	Regardless of SARS-CoV-2 status	Regardless of SARS-CoV-2 status

Abbreviations: COVID-19, coronavirus disease 2019; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; KD, Kawasaki disease; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Using different nomenclature and case definitions for the same condition is not only confusing for healthcare professionals and the public but also introduces significant difficulties with case ascertainment, aggregation of medical literature, comparison of management strategies, and reporting outcomes. Moreover, introduction of a term such as “likeness” of an existing disease can inadvertently raise anxiety in patients already diagnosed and their families, for example, the eponymous KD, an already rare but important cause of acquired heart disease in children. Only relatively minor variations related to age ranges, characterization of fever, number of organ systems involved, and association with SARS-CoV-2 exposure or testing are evident from the different case definitions (Table 1). However, a review of the literature highlights instances where only 58% of patients described in 1 case series would have also met an alternative case definition [8]. Hence, the differences cannot be considered trivial or insignificant. Using latent class analysis, Godfred-Cato et al were able to identify 3 distinct presentations among patients reported to have met the Centers for Disease Control and Prevention’s case definition for MIS-C [9]. They highlighted that the broad inclusive case definition may have meant that at least some patients with acute COVID-19 and KD may have been reported as MIS-C. It is clear that the existing scenario aids confusion rather than clarity.

Treatment strategies for these children have ranged from intravenous immunoglobulins, a variety of steroids, anakinra, tocilizumab, rituximab, infliximab, and antiplatelets at a variety of doses [8, 9]. In order to improve care for children with this condition, further clarity about the best treatment modality is required. While clinical trials are being planned, a comparative effectiveness study- the “best available treatment study” has been proposed [10]. However, the utility of such initiatives would be adversely impacted by the differences in case definitions as the confusion regarding case ascertainment may lead to difficulties in analyzing the utility of therapies.

The World Health Organization has identified best practices for the naming of new infectious diseases [11]. These principles were applied when SARS-CoV-2 and COVID-19 were named early in the current pandemic. With current widespread availability of both SARS-CoV-2 antigen and antibody testing compared with availability in April 2020–May 2020 when many of the definitions were originally proposed, a clearer link to SARS-CoV-2 infection, rather than merely a temporal association, is often established. However, the usefulness of SARS-CoV-2 antibodies as part of diagnostic criteria may be limited as the pandemic spreads further [9]. The majority of children may acquire the infection and therefore the antibody in the months and years to come.

We suggest that a uniform name and precise case definition are essential, urgent, and achievable immediately, perhaps using a consensus gathering process such as the Delphi. We call upon organizations, societies, clinicians, and pediatric researchers to collaborate to achieve much needed consensus.

Note

Potential conflicts of interest. Both authors: No reported conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.