[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
Purchase Options:
[Skip to Content Landing]
Views 28,793
Citations 0
Editorial
June 8, 2020

SARS-CoV-2–Related Inflammatory Multisystem Syndrome in Children: Different or Shared Etiology and Pathophysiology as Kawasaki Disease?

Author Affiliations
  • 1Labatt Family Heart Centre, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
  • 2Johns Hopkins University School of Medicine, Division of Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland
JAMA. 2020;324(3):246-248. doi:10.1001/jama.2020.10370

The pediatric inflammatory multisystem syndrome (PIMS) now described in association with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has generated considerable interest, both for its severity and delayed emergence in an age group largely spared the complications of primary infection, but also for its overlapping clinical features with Kawasaki disease (KD), the leading cause of acquired heart disease in children in high-income countries.1 This has prompted considerable discussion that the 2 conditions could have different or shared etiologic and pathophysiologic pathways.

The article in this issue of JAMA by Whittaker et al2 carefully described a case series of 58 hospitalized patients with severe presentations of PIMS temporally associated with SARS-CoV-2 (PIMS-TS), and in addition importantly compares the clinical and laboratory features with historical cohorts of patients with KD and with KD shock syndrome. Also in this issue, the Research Letter by Cheung et al3 described similar clinical characteristics for 17 patients with PIMS, 8 of whom also met criteria for typical KD and 5 for incomplete KD. As illustrated in these reports, the differences between PIMS-TS and KD are just as interesting as the similarities.

Five decades of clues have not elucidated the etiology of KD. A genetic predisposition has already been established, evidenced by a male preponderance, racial predisposition (East Asian individuals), and some increased risk in first-degree relatives of affected individuals and twins.1,4 This genetic predisposition is partially explained by known susceptibility genes that are associated with the immune system.5 The epidemiology of KD, with marked variations in incidence between countries,6 region-specific seasonality,7 periodic outbreaks, and the existence of spatiotemporal clusters,8,9 suggests that there is more to the etiology of KD than the genetic component alone. Over the years, associations between the distribution of KD and exposure to infectious agents, pollution levels, local weather conditions, concentration of atmospheric biological particles, and early childhood, habitual, or unfamiliar exposures have been documented and postulated to be implicated in the pathophysiology of KD or even to be the etiologic trigger.9-12 Conflicting studies have been published for almost all of these associations. Some factors have been shown to apply only at a local level; some are associated with the global distribution of case, but none have been shown to have a direct causal relationship with KD.

One of the most common and consistently reported factors associated with KD are infectious diseases. In addition to epidemiological associations, the involvement of infectious disease in the etiology of KD is based on the clinical observation that both infectious disease symptoms and culture-proven infections are common in KD, and specific organisms have been described with some clusters of KD. Many infectious organisms have been suggested as the primary etiology, ranging from toxin-producing Streptococcus and Staphylococcus to Mycoplasma species to a large number of viruses, including coronavirus strains NL63 (2006)13 and 229E (2014),14 but the associations have been inconsistent or not replicated.15,16

Additional clues as to the etiology of KD have come from pathology studies of fatal cases, which have shown the presence of intracytoplasmic inclusion bodies in bronchial epithelium, analyses of which have suggested the possibility of a novel virus.17 The normal flora may be involved, particularly that of the gastrointestinal tract. Gastrointestinal infections may be involved as either the trigger or altering susceptibility to the trigger. Animal models have used intraperitoneal injection of Candida albicans or Lactobacillus casei wall extract to induce a KD-like syndrome in mice. Decades of immunologic studies have suggested that KD is associated with a response to a classic antigen, with activation of the innate immune system, but also features of an adaptive immune response.1 The trigger and the etiologic and pathophysiologic pathways remain complex and elusive.

Based on a series of studies documenting the epidemiological distribution of KD in Canada,18 including the examination of spatiotemporal clusters,8 and a case-control environmental epidemiology study,19 Manlhiot et al proposed a comprehensive framework for the time and space distribution of KD. The framework ties together many clues as to the etiology and pathogenesis of the disease and addresses the numerous and apparently disjointed epidemiological associations that have been documented with KD over the years. This framework, which has recently been updated, includes 3 major components: a genetic predisposition to KD, immunomodulation through both habitual exposures and environmental factors, and contact with the disease trigger or triggers. In this framework, exposure to the still unidentified trigger(s) results in the development of KD in a genetically susceptible child, with at least a partial contribution from immune-modulating factors. These factors include those that reduce the risk of KD, such as a more abundant habitual exposure to environmental allergens, and those that increase risk, such as pollution. Multiple factors may act sequentially or simultaneously as predisposing, immune-modulating, or triggering agents, altering both individual risk as well as the incidence of KD in the population across countries or regions. Potential factors found to be associated with KD, either identified through epidemiological association studies or clinical observations, can be integrated into this framework.

PIMS, which has emerged with the SARS-CoV-2 pandemic, shares multiple clinical and laboratory features with KD, such that a substantial proportion of patients included in early reports of PIMS-TS20,21 also met the American Heart Association criteria for KD.1 Whittaker et al2 reported that 7 of the 58 children met criteria for KD and an additional 6 met criteria if coronary artery aneurysm was included. However, it also is clear that PIMS-TS and KD have substantial differences as well as similarities, as the report by Whittaker et al suggests, with age being a major difference (median age, 9 years for children with PIMS-TS vs 2.7 years for those with KD).2 These observations lead to some speculation, most importantly, the extent to which the etiology and pathophysiology of KD and PIMS-TS might overlap or share commonalities.

These early observations about the characteristics of patients with MIS have already provided some clues. While both conditions have a similar male preponderance, case series suggest that MIS in children may have a different racial/ethnic predilection, affecting primarily people of African American, Caribbean, and Hispanic ancestry, whereas KD affects primarily those of East Asian ancestry. Does this indicate that PIMS-TS might be mediated by a different set of susceptibility genes, or is this related to other factors that are associated with race/ethnicity, including environment and social factors? PIMS-TS also appears to affect an older age group than KD and has a higher prevalence of gastrointestinal symptoms and lower prevalence of classic KD clinical signs. These differences could be associated with 1 or more factors influencing immunomodulation and susceptibility. These observations suggest some areas where susceptibility and immune-modulating factors for PIMS-TS and KD may contribute differently for each condition.

Another important question is whether SARS-CoV-2 directly triggers MIS in children (or perhaps KD), or is it an intermediate primer or co-stimulatory agent or does coronavirus disease 2019 (COVID-19) provide a portal of entry or exposure for the actual trigger? Both a gastrointestinal and respiratory portal of entry, possibly related to infection, have been proposed for KD, and PIMS-TS has affected both systems. The absence of preceding symptoms of COVID-19, often negative polymerase chain reaction result but sometimes positive antibodies or familial exposure, and development of PIMS-TS after a 3- to 6-week lag suggest that SARS-CoV-2 may be acting either as the trigger or an immune-modulating factor. The response to the SARS-CoV-2 pandemic, such as quarantine and social isolation, may have affected children’s level of exposure to environmental factors and infections, providing further immune modulation. There has never been a global outbreak of KD where it might be traced to a specific trigger, but this may now be the case. It might be that this is what a specific, unique, and ubiquitous form of KD looks like, providing an important opportunity for investigations to determine factors associated with variations.

With so many questions, how will clinicians and researchers find answers? Careful determination of the unique features of SARS-CoV-2 and the epidemiology, clinical features, genetic and immunologic susceptibility, and pathophysiologic pathways of both PIMS-TS and KD may help to inform the etiologic and pathophysiologic framework for both conditions. The article by Whittaker et al2 and Research Letter by Cheung et al3 mark the beginning of an important time of focused discovery, which will likely have relevance to an entire host of inflammatory conditions.

Back to top
Article Information

Corresponding Author: Brian W. McCrindle, MD, MPH, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, 555 University Ave, Toronto, ON M5G 1X8, Canada (brian.mccrindle@sickkids.ca).

Published Online: June 8, 2020. doi:10.1001/jama.2020.10370

Conflict of Interest Disclosures: Dr McCrindle reported receiving personal fees from Janssen and serving as an investigator for Janssen and Mezzion. No other disclosures were reported.

References
1.
McCrindle  BW, Rowley  AH, Newburger  JW,  et al; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; and Council on Epidemiology and Prevention.  Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association.   Circulation. 2017;135(17):e927-e999. doi:10.1161/CIR.0000000000000484 PubMedGoogle ScholarCrossref
2.
Whittaker  E, Bamford  A, Kenny  J,  et al; PIMS-TS Study Group; EUCLIDS and PERFORM Consortia.  Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.   JAMA. Published online June 8, 2020. doi:10.1001/jama.2020.10369Google Scholar
3.
Cheung  EW, Zachariah  P, Gorelik  M,  et al.  Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York City.   JAMA. Published online June 8, 2020. doi:10.1001/jama.2020.10374Google Scholar
4.
Uehara  R, Yashiro  M, Nakamura  Y, Yanagawa  H.  Kawasaki disease in parents and children.   Acta Paediatr. 2003;92(6):694-697. doi:10.1111/j.1651-2227.2003.tb00602.x PubMedGoogle ScholarCrossref
5.
Onouchi  Y, Gunji  T, Burns  JC,  et al.  ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms.   Nat Genet. 2008;40(1):35-42. doi:10.1038/ng.2007.59 PubMedGoogle ScholarCrossref
6.
Singh  S, Vignesh  P, Burgner  D.  The epidemiology of Kawasaki disease: a global update.   Arch Dis Child. 2015;100(11):1084-1088. doi:10.1136/archdischild-2014-307536 PubMedGoogle ScholarCrossref
7.
Burns  JC, Herzog  L, Fabri  O,  et al; Kawasaki Disease Global Climate Consortium.  Seasonality of Kawasaki disease: a global perspective.   PLoS One. 2013;8(9):e74529. doi:10.1371/journal.pone.0074529 PubMedGoogle Scholar
8.
Hearn  J, McCrindle  BW, Mueller  B,  et al.  Spatiotemporal clustering of cases of Kawasaki disease and associated coronary artery aneurysms in Canada.   Sci Rep. 2018;8(1):17682. doi:10.1038/s41598-018-35848-9 PubMedGoogle ScholarCrossref
9.
Nagao  Y, Urabe  C, Nakamura  H, Hatano  N.  Predicting the characteristics of the aetiological agent for Kawasaki disease from other paediatric infectious diseases in Japan.   Epidemiol Infect. 2016;144(3):478-492. doi:10.1017/S0950268815001223 PubMedGoogle ScholarCrossref
10.
Awaya  A, Sahashi  N.  The etiology of Kawasaki disease: does intense release of pollen induce pollinosis in constitutionally allergic adults, while constitutionally allergic infants develop Kawasaki disease?   Biomed Pharmacother. 2004;58(2):136-140. doi:10.1016/j.biopha.2003.08.026 PubMedGoogle ScholarCrossref
11.
Zeft  AS, Burns  JC, Yeung  RS,  et al.  Kawasaki disease and exposure to fine particulate air pollution.   J Pediatr. 2016;177:179-183.e1. doi:10.1016/j.jpeds.2016.06.061PubMedGoogle ScholarCrossref
12.
Fujiwara  T, Shobugawa  Y, Matsumoto  K, Kawachi  I.  Association of early social environment with the onset of pediatric Kawasaki disease.   Ann Epidemiol. 2019;29:74-80. doi:10.1016/j.annepidem.2018.10.010 PubMedGoogle ScholarCrossref
13.
Esper  F, Shapiro  ED, Weibel  C, Ferguson  D, Landry  ML, Kahn  JS.  Association between a novel human coronavirus and Kawasaki disease.   J Infect Dis. 2005;191(4):499-502. doi:10.1086/428291 PubMedGoogle ScholarCrossref
14.
Shirato  K, Imada  Y, Kawase  M, Nakagaki  K, Matsuyama  S, Taguchi  F.  Possible involvement of infection with human coronavirus 229E, but not NL63, in Kawasaki disease.   J Med Virol. 2014;86(12):2146-2153. doi:10.1002/jmv.23950 PubMedGoogle ScholarCrossref
15.
Dominguez  SR, Anderson  MS, Glodé  MP, Robinson  CC, Holmes  KV.  Blinded case-control study of the relationship between human coronavirus NL63 and Kawasaki syndrome.   J Infect Dis. 2006;194(12):1697-1701. doi:10.1086/509509 PubMedGoogle ScholarCrossref
16.
Lehmann  C, Klar  R, Lindner  J, Lindner  P, Wolf  H, Gerling  S.  Kawasaki disease lacks association with human coronavirus NL63 and human bocavirus.   Pediatr Infect Dis J. 2009;28(6):553-554. doi:10.1097/INF.0b013e31819f41b6 PubMedGoogle ScholarCrossref
17.
Rowley  AH, Baker  SC, Arrollo  D,  et al.  A protein epitope targeted by the antibody response to Kawasaki disease.   J Infect Dis. Published online February 13, 2020. doi:10.1093/infdis/jiaa066 PubMedGoogle Scholar
18.
Manlhiot  C, O’Shea  S, Bernknopf  B,  et al.  Epidemiology of Kawasaki disease in Canada 2004 to 2014: comparison of surveillance using administrative data vs periodic medical record review.   Can J Cardiol. 2018;34(3):303-309. doi:10.1016/j.cjca.2017.12.009 PubMedGoogle ScholarCrossref
19.
Manlhiot  C, Mueller  B, O’Shea  S,  et al.  Environmental epidemiology of Kawasaki disease: linking disease etiology, pathogenesis and global distribution.   PLoS One. 2018;13(2):e0191087. doi:10.1371/journal.pone.0191087 PubMedGoogle Scholar
20.
Verdoni  L, Mazza  A, Gervasoni  A,  et al.  An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.   Lancet. 2020;(May):13. doi:10.1016/S0140-6736(20)31103-XPubMedGoogle Scholar
21.
Riphagen  S, Gomez  X, Gonzalez-Martinez  C, Wilkinson  N, Theocharis  P.  Hyperinflammatory shock in children during COVID-19 pandemic.   Lancet. 2020;395(10237):1607-1608. doi:10.1016/S0140-6736(20)31094-1 PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    1 Comment for this article
    EXPAND ALL
    Prescribed or OTC Acetaminophen the Common Factor?
    Richard Schmidt, BPharm PhD | [Retired pharmacist]
    COVID-19 infection appears to cause problems only where a particular tissue or organ fails to control an induced inflammatory process, this resulting in a "cytokine storm". The common factor is an underlying condition that is already known to be associated with an oxidative stress (= pro-inflammatory) condition, for example obesity, metabolic syndrome, type 2 diabetes, and cigarette smoking.[1]

    The question that no-one seems to be asking is whether the patients who do develop a cytokine storm are also taking acetaminophen / paracetamol. This has long been known to cause, when taken in high dose, hepatotoxicity [2] and lung
    toxicity [3,4] as a result of glutathione depletion, this potentially resulting in a tissue-damaging cytokine storm. Acetaminophen / paracetamol overdose is treated with N-acetylcysteine, which raises intracellular glutathione [5]. The use of oral and IV glutathione, glutathione precursors (N-acetylcysteine) and alpha lipoic acid has been explored as therapy to relieve dyspnea in 2 COVID-19 patients, with apparent success [6].

    Perhaps the COVID-19 associated pediatric inflammatory multisystem syndrome and
    Kawasaki disease are both precipitated by acetaminophen / paracetamol administration, but only in those who are already pre-disposed to developing a cytokine storm in one or more tissues / organs for other reasons?

    1. https://doi.org/10.1093/toxsci/kfaa042
    2. http://bit.ly/2QqZmvl
    3. https://doi.org/10.1289/ehp.94102s963
    4. https://doi.org/10.1164/rccm.200409-1269OC
    5. https://doi.org/10.1056/NEJM198812153192401
    6. https://doi.org/10.1016/j.rmcr.2020.101063
    CONFLICT OF INTEREST: None Reported
    READ MORE
    ×