Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study

Dear Editor,

Toubiana et al investigated a cluster of 21 children with features of Kawasaki disease admitted to a regional reference center in Paris between April and May 2020.(1) The authors propose that their study objective is to describe the population and to report on the temporal association of SARS-CoV-2 infection with the paediatric inflammatory multisystem syndrome. A major focus of the authors, however, is the ethnicity of the cases, positioned as an etiologic factor of the pathophysiology of the syndrome, a predictor for the evolution of the pandemic and a basis to inform policy making. Twelve (57%) of the cases are reported to have at least one parent born in sub-Saharan Africa or the Caribbean.

While surveillance of racial disparities is an important public health function, the careless use of ethnicity or race in etiologic research is dangerous, whether in relation to infection and disease in the context of the COVID-19 pandemic, or in biomedical research generally.(2) At a time when our understanding of the risk factors for SARS-CoV-2 transmission, infection and disease all remain limited, these crude observations are prone to misinterpretation.

Firstly, the observations in Toubiana et al are based on those tested for SARS-CoV-2 and confirmed as COVID-19 cases. This group is highly selected from the infected population based on symptom presentation, as well as on innumerable barriers of access including language, neighborhood, socioeconomic and demographic factors. Investigation of risk factors for infection and disease among a selected and unrepresentative subgroup of the population leads to distorted inferences.(3) While we are rather confident that all the children with the inflammatory syndrome are counted, the denominator of children at risk having been infected with SARS-CoV-2 is unknown.

In both France and the UK, and even more widely discussed in the US, exposure to SARS-CoV-2 infection and COVID-19 disease disproportionally affect people of color, a pattern that is clearly understandable in terms of socio-economic differences and inequalities in occupation and housing.(4) Given that exposure and infection by SARS-CoV-2 are dependent on race and ethnicity for social reasons, even if the incidence of the inflammatory syndrome is randomly distributed and independent of race, one would still observe an overrepresentation of ethnic minority children with the syndrome. This observation alone is therefore no evidence of increased severity of COVID-19 in children by ethnicity.

Toubiana et al offer two explanations for greater susceptibility of these children for the syndrome: social environment and genetics. Some crude markers for socio-economic status were collected by the authors (residence in “unhealthy” or subsidized housing), but these measures are quite limited and once again, there is no information on the socio-economic characteristics of all infected children, only the ascertained cases. As long as there is no representative testing data to reflect the prevalence of exposed and infected cases by ethnicity, the association between these variables in the dataset cannot provide valid evidence regarding the reliable markers for developing the inflammatory syndrome nor the underlying etiology of the disease.(5)

The second proffered explanation, ethnicity as a proxy for genetic differences, will doubtlessly be explored aggressively. To successfully explore this hypothesis, one must collect and analyze the genotypes of cases and a representative sample of non-cases, but ethnicity is a misleading distraction in this endeavor. The facile connection of race and ethnicity to genetics reveals a common misunderstanding, but it will not solve this medical mystery, nor has it solved any in the past.(6) The recurrent misguided use of race or ethnicity as a facile proxy for genetic predisposition rests on the long-outdated presumption that these social categories mark important genetic differences.(7) With the human genome now mapped, it is abundantly clear that almost all human genetic variation occurs within racial groups, not between them.(8)

A plethora of conflicting definitions are applied to ethnicity in medical studies.(9) Toubiana et al. define ethnicity based on the country of birth of one of the parents, a definition that is obviously prone to misclassification with respect to both identity and biological ancestry.(10) This measure clearly corresponds more to recent immigration than it does to any biological information. It is a practical definition for these authors because the French have opted to forbid the collection of racialized data for official purposes, exactly to avoid this kind of biological myth-making.(11) So the authors are left categorizing paediatric cases in terms of social history, specifically being children of recent immigrants from certain regions, and should therefore likewise interpret the variable as such.

No matter which arbitrary definition is used for race, however, research consistently shows that while genetic differences between human beings do exist, broad phenotypical groupings like “black” and “white”, or vast continental agglomerations like “Africans” are terrible proxies for these differences.(12) Moreover, now that DNA is routinely extracted and patients can be inexpensively genotyped, it is a proxy that is completely irrelevant, because if you want to know something about genetics, you measure genes. There is no longer any excuse for 19th century proxies based on quaint myths and outdated stereotypes.

Race and ethnicity are social constructs and the collection and reporting of these variables need to be understood within a perspective of social epidemiology and not misinterpreted as biological constructs.(2) The current pandemic, more than being a puzzle only for virologists, immunologists and rheumatologists, is also fundamentally a social and political phenomenon. Diseases happen to individuals, but epidemics happen to whole societies. Hence the critical determining role of social factors such as nativity, occupation and race in shaping its evolution and providing the context for every observation and potential intervention.

The authors’ conclusion to call children living in the African continent a high risk population for this rare complication based on this study is therefore completely misguided. Even worse, the primary action recommended is that African countries should prepare with a sufficient supply of immunoglobulins. A continued and even strengthened immunization program as well as improvements in the quality and access to basic health care would undoubtedly contribute much more to the health of children worldwide through this pandemic.

1) Toubiana J, Poirault C, Corsia A, Bajolle F, Fourgeaud J, Angoulvant F, Debray A, Basmaci R, Salvador E, Biscardi S, Frange P. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study. BMJ. 2020 Jun 3;369.
2) Cooper RS, Nadkarni GN, Ogedegbe G. Race, ancestry, and reporting in medical journals. JAMA 2018;320:1531-2.
3) Griffith G, Morris TT, Tudball M, Herbert A, Mancano G, Pike L, Sharp GC, Palmer TM, Smith GD, Tilling K, Zuccolo L. Collider bias undermines our understanding of COVID-19 disease risk and severity. medRxiv. 2020
4) Kirby T. Evidence mounts on the disproportionate effect of COVID-19 on ethnic minorities. The Lancet Respiratory Medicine. 2020 May 8
5) Kaufman JS, Cooper RS. Seeking causal explanations in social epidemiology. American journal of epidemiology. 1999 Jul 15;150(2):113-20.
6) Saini A. Stereotype threat. The Lancet. 2020 May 23;395(10237):1604-5.
7) Barr DA. The practitioner's dilemma: Can we use a patient's race to predict genetics, ancestry, and the expected outcomes of treatment?. Annals of Internal Medicine. 2005 Dec 6;143(11):809-15.
8) Rosenberg NA, Pritchard JK, Weber JL, Cann HM, Kidd KK, Zhivotovsky LA, Feldman MW. Genetic structure of human populations. science. 2002 Dec 20;298(5602):2381-5.
9) Bokor-Billmann T, Langan EA, Billmann F. The reporting of race and/or ethnicity in the medical literature: a retrospective bibliometric analysis confirmed room for improvement. Journal of clinical epidemiology. 2020 Mar 1;119:1-6.
10) Stronks K, Kulu-Glasgow I, Agyemang C. The utility of ‘country of birth’for the classification of ethnic groups in health research: the Dutch experience. Ethnicity & health. 2009 Jun 1;14(3):255-69.
11) Simon P. The choice of ignorance: The debate on ethnic and racial statistics in France. In Social Statistics and ethnic diversity 2015 (pp. 65-87). Springer, Cham
12) Cooper RS, Kaufman JS, Ward R. Race and genomics. N Engl J Med. 2003;348(12):1166‐1170. doi:10.1056/NEJMsb022863