key: cord-0792559-9s1ze1es
authors: Carbajal, Ricardo; Lorrot, Mathie; Levy, Yael; Grimprel, Emmanuel; Lecarpentier, Thibault; Heritier, Sebastien; Faivre, Judith; Schnuriger, Aurélie; Parisot, Pauline; Blondiaux, Eléonore; Loschi, Solene; Rivière, Simon; Guilbert, Julia; Romain, Anne‐Sophie; Leger, Pierre‐Louis; Guedj, Romain
title: Multisystem inflammatory syndrome in children rose and fell with the first wave of the COVID‐19 pandemic in France
date: 2020-12-21
journal: Acta Paediatr
DOI: 10.1111/apa.15667
sha: 1c5a3b03285a0aa0b0254eb1a334f25c342e48fa
doc_id: 792559
cord_uid: 9s1ze1es

AIM: This study determined the influence of the COVID‐19 pandemic on the occurrence of multisystem inflammatory syndrome in children (MIS‐C) and compared the main characteristics of MIS‐C and Kawasaki disease (KD). METHODS: We included patients aged up to 18 years of age who were diagnosed with MIS‐C or KD in a paediatric university hospital in Paris from 1 January 2018 to 15 July 2020. Clinical, laboratory and imaging characteristics were compared, and new French COVID‐19 cases were correlated with MIS‐C cases in our hospital. RESULTS: There were seven children with MIS‐C, from 6 months to 12 years of age, who were all positive for the virus that causes COVID‐19, and 40 virus‐negative children with KD. Their respective characteristics were as follows: under 5 years of age (14.3% vs. 85.0%), paediatric intensive care unit admission (100% vs. 10.0%), abdominal pain (71.4% vs. 12.5%), myocardial dysfunction (85.7% vs. 5.0%), shock syndrome (85.7% vs. 2.5%) and mean and standard deviation C‐reactive protein (339 ± 131 vs. 153 ± 87). There was a strong lagged correlation between the rise and fall in MIS‐C patients and COVID‐19 cases. CONCLUSION: The rise and fall of COVID‐19 first wave mirrored the MIS‐C cases. There were important differences between MIS‐C and KD.

More than one million people have died since the start of the COVID-19 pandemic, 1 but children have been relatively spared, in terms of both the incidence of the disease and the severity. Patients under 20 years of age have been reported to represent less than 2.0% of patients. 2 However, on 27 April 2020, the UK National Health Service issued an alert after a small number of children presented with an inflammatory syndrome related to COVID-19. These children were extremely ill and had similar features to atypical Kawasaki disease (KD), toxic shock syndrome 3 and KD shock syndrome. 4 The UK Royal College of Paediatrics and Child Health defined these cases as paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS-TS). 3 The US Centers for Disease Control and Prevention immediately defined it as multisystem inflammatory syndrome in children (MIS-C) 5 

World Health Organization (WHO) named it multisystem inflammatory syndrome in children and adolescents, temporally related to COVID-19. 6 In May and June 2020, reports from Italy, 7 the UK, 4, 8 France, 9, 10 Spain, 11 It has not been clearly demonstrated that this inflammatory condition is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in COVID-19. However, the temporal associations described in different countries, and the confirmation of the SARS-CoV-2 infection in most patients presenting with this inflammatory condition, provide a strong argument that they are linked. 17, 18 The reports from different countries have described some differences, but they have also pointed out some similarities between these patients and patients with KD. Relatively, few patients have been reported to date and that is why more data are needed on this syndrome, for a deeper insight into this condition and to better understand the local kinetics of the evolution of the COVID-19 pandemic and the occurrence of MIS-C.

We observed an outbreak of MIS-C in our paediatric university hospital in Paris, as in many other centres, during the first wave of the COVID-19 pandemic. This study had two aims. The first was to describe the kinetics of the MIS-C cases and the COVID-19 pandemic in France, in order to determine whether they were related and what influence the pandemic had on MIS-C cases. The second was to describe the clinical, laboratory, echocardiographic and imaging characteristics of the children involved in this MIS-C outbreak, who were all tested positive for SARS-CoV-2, to patients with KD.

We retrospectively reviewed the records of all patients up to 18 years of age who had been admitted to the University Pediatric Hospital Armand Trousseau in Paris with a diagnosis of KD or Kawasaki-like disease from 1 January 2018 to 15 July 2020. The paediatric emergency department in this tertiary paediatric hospital is visited by 55,000 patients a year. Children and adolescents fulfilling the MIS-C, 5 PIMS-TS 3 or WHO 6 definitions of an inflammatory multisystem syndrome were also included. KD is an acute vasculitis of unknown origin that presents as a febrile illness and predominantly affects children under 5 years of age. Diagnosis was based on the clinical criteria described in the 2017 guidelines issued by the American Heart Association. 19 Patients who meet the case definition are said to have complete KD, namely typical or classic KD, whereas those who do not have sufficient principal clinical findings may be diagnosed with incomplete or atypical KD. 19 The diagnosis of classic KD is based on fever for five or more days, together with at least four of the five principal clinical features. These are as follows: (a) oral changes, including erythema, cracked lips, a 'strawberry tongue' and diffuse erythema of the oropharyngeal mucosa, (b) a bilateral bulbar conjunctival infection, (c) erythematous rash, (d) erythema and oedema of the hands and feet and (e) cervical lymphadenopathy of at least 1.5 cm in diameter. If coronary artery abnormalities are detected, the diagnosis of KD is considered to be confirmed in most cases. 19 these patients may fulfil all, or some, of the criteria for Kawasaki disease. 5 The comparisons of the MIS-C, PIMS-TS and WHO definitions are shown in Table S1.

Data on patient demographics, clinical, laboratory, echocardiographic, imaging, therapeutic, and outcomes were collected for patients seen from 1 January 2018 to 15 July 2020. We collected data using a standardised form from both the hospital's electronic health record system and paper health records. For patients seen from 1 April 2020 to 15 July 2020, we collected data on SARS-CoV-2 infections and close COVID-19 contacts and determined whether patients fulfilled the MIS-C, 5 PIMS-TS, 3 WHO 6 definitions or the classic or incomplete KD criteria. 19 Since data collection on race and ethnicity are not allowed in France, these were not available. Although the above definitions are very similar, we chose to use the definition for MIC-S in our hospital because we felt that the link suggested with a SARS-CoV-2 infection was more straightforward, Table S1.

As MIS-C is a new syndrome, patients who were affected were treated according to our hospital protocol for KD. The first-line treatment was intravenous immunoglobulins at 2 g/kg as a single infusion given over 10-12 hours. If apyrexia was not obtained within 36 hours, or fever reappeared <7 days after initial treatment, the treating physician could decide on a second dose of intravenous immunoglobulins and/or the use of corticosteroids. 19 

We identified SARS-CoV-2 ribonucleic acid using reverse-transcriptase polymerase chain reaction (RT-PCR) on nasopharyngeal swabs or stool samples. Samples were obtained within the first 48 hours of admission. We used the Allplex nCoV assay (Seegene Inc, Seoul, South Korea) and the Bosphore v2 nCoV assay (Anatolia Geneworks, Istanbul, Turkey). We identified SARS-Cov-2 IgG antibodies using the Alinity-i SARS-CoV-2 IgG (Abbott Molecular, Illinois, USA). Serology was performed during hospitalisation for patients admitted from 1 April to 15 July 2020. Positive RT-PCR or serology results defined patients with a proven SARS-CoV-2 infection.

All the MIS-C patients had the SARS-CoV-2 infection. They were compared to KD patients, including those who did not have the viral infection during the pandemic phase of the study.

To determine the relationship between the occurrence of MIS-C and the evolution of the COVID-19 pandemic in France, which had 66.5 million inhabitants in January 2020, 21 we obtained official French COVID-19 data from Public Health France. The cumulative con- 

The characteristics of the two groups were compared using the Student t test for continuous variables and the chi-square test or Fisher's exact test, as necessary, for categorical variables. 

This study was approved by the Ethics Committee for Research of the Sorbonne University. Parents were informed that their children's data would be anonymously used and could ask for them to be excluded from the analysis; none of them did so.

The study comprised 47 patients admitted to the hospital from 1 January 2018 to 15 July 2020. These included seven patients diagnosed with MIS-C and 40 diagnosed with KD. Kawasaki disease (no SARS-CoV-2 infecƟon) MIS-C definition. All seven MIS-C patients were admitted to the PICU: the two boys stayed for 2 days and the five girls for three to 12 days. None of them had coronary aneurisms. An abnormal echocardiography was found in six of the seven MIS-C patients, mainly due to a low ejection fraction or mitral regurgitation. All seven children received intravenous immunoglobulins and four also received corticosteroids. The outcomes were favourable in all seven children (Table 1 ). 

Symptoms between contact and MIS_C diagnosis

Day 1 of contact Setting 

This study showed a strong lagged correlation between the rise and fall of the number of children and adolescents with MIS-C and the rise and fall of the first wave of the COVID-19 pandemic in France.

To the best of our knowledge, this has not been reported before.

The correlation was highest for the number of new COVID-19 cases It is notable that 87.3% of those who tested positive in that study had confirmed or suspected COVID-19 contacts. 23 We do not know the role played by lockdowns on the MIS-C outbreaks. It has been reported that many children are infected by their parents, so it is possible that these restrictions may have enhanced close contact and eventually increase the viral load from adults to susceptible children.

While MIS-C has been reported in several countries in Europe and in the United States, it has not been reported in China or Japan 22 where KD is more frequent. A series of KD patients in a paediatric Japanese hospital, published online in this journal in August 2020, found no increase in the incidence of KD or changes in its clinical features during the local COVID-19 pandemic. 24 It could be that MIS-C is such a rare condition that it has only been observed in countries with a very large number of COVID-19

cases, such as Italy, Spain, France, the UK and the United States. 22 The fact that the MIS-C cases in our report occurred during a shorter period than the first wave of the COVID-19 pandemic in France, and that the cases correlated with the peak of this pandemic, is consistent with this hypothesis. Figure S1 suggests that 16 We did not collect racial or ethnic data, as this is not permitted in France. Previous case series have suggested that MIS-C primarily affects people of African or Caribbean ancestry. 8, 9 However, one case series from New York reported that twelve out of seventeen patients they studied were white. 13 Although predisposing genetic factors have been described for KD, caution is necessary when interpreting the current racial or ethnic data for MIS-C. An alternative explanation may be that there is a higher prevalence of SARS-CoV-2

in some groups, with the spread of infection driven by decreased opportunities for social distancing because of dense housing. Some groups with a higher prevalence of SARS-CoV-2 are also more likely to be essential key workers or have to work for economic reasons. 25 Social disparities have been reported for COVID-19.

This study had some limitations. Its retrospective design meant 

The authors have no conflicts of interest to declare. 

COVID-19 cases, three weeks before (R 2 = 0.806) COVID-19 cases, four weeks before (R 2 = 0.544) COVID-19 cases, two weeks before (R 2 = 0.335) COVID-19 cases, one week before (R 2 = 0.079) COVID-19 cases, same week (R 2 = 0.012) New weekly COVID-19 cases reported in emergency departments sentinel centers in the Paris region

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