key: cord-348392-e35cd9sg
authors: Moraleda, Cinta; Serna-Pascual, Miquel; Soriano-Arandes, Antoni; Simó, Silvia; Epalza, Cristina; Santos, Mar; Grasa, Carlos; Rodríguez, Maria; Soto, Beatriz; Gallego, Nerea; Ruiz, Yolanda; Urretavizcaya-Martínez, María; Pareja, Marta; Sanz-Santaeufemia, Francisco José; Fumadó, Victoria; Lanaspa, Miguel; Jordan, Iolanda; Prieto, Luis; Belda, Sylvia; Toral-Vázquez, Belén; Rincón, Elena; Gil-Villanueva, Nuria; Méndez-Echevarría, Ana; Castillo-Serrano, Ana; Rivière, Jacques G; Soler-Palacín, Pere; Rojo, Pablo; Tagarro, Alfredo
title: Multi-Inflammatory Syndrome in Children related to SARS-CoV-2 in Spain
date: 2020-07-25
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa1042
sha: 
doc_id: 348392
cord_uid: e35cd9sg

Some clusters of children with a multisystem inflammatory syndrome associated with SARS-CoV-2 infection (MIS-C) have been reported. We describe the epidemiological and clinical features of children with MIS-C in Spain. MIS-C is a potentially severe condition that presents in children with recent SARS-CoV-2 infection.

In the last weeks, some clusters of children with a multisystem inflammatory syndrome (MIS-C) linked to SARS-CoV-2 infection have been described in the United Kingdom, France, Italy and USA, among other countries. 1,2 This syndrome shares features of Kawasaki disease, toxic shock syndrome and macrophage activation syndrome. 3 Some of these children tested positive for SARS-CoV-2 real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and/or had a positive serological response for this infection. The specific link with SARS-CoV-2 remains unclear.

In Spain, this phenomenon has also been observed.

In this case series, we intended to describe the epidemiological and clinical features of children with MIS-C in Spain.

This is a case series of children with MIS-C associated with SARS-CoV-2 enrolled in the Epidemiological Study of COVID-19 in Children of the Spanish Society of Pediatrics (EPICO-AEP), from March 1 st to June 1 st, 2020. EPICO-AEP is a multicenter national study aiming to describe the COVID-19 in Spanish children. Children younger than 18 years with infection due to SARS-CoV-2 and attended at 49 hospitals were included in this registry. Inclusion criteria included positivity in real-time polymerase chain reaction (RT-PCR) positive, IgM or IgG in lateral-flow rapid test, ELISA or immuno chemiluminescence serology (see Table 1 ), or severe disease suggestive of MIS-C and recent household contact with a confirmed patient with COVID-19. M a n u s c r i p t 6

By June 1st, 312 patients had been attended in the 49 hospitals, and 252 participants were hospitalized. Of them, 181 (72%) were admitted due to causes directly or likely related to SARS-CoV-2. The remaining 71 (28%) were admitted due to causes not related with SARS-CoV-2, but were screened and found to be infected with SARS-CoV-2. A total of 31/252 (12%) children were diagnosed as MIS-C and/or Kawasaki disease by their physicians.

Weekly admissions of children with MIS-C and children with other clinical presentations associated with COVID-19 were recorded ( Figure 1 ). The peak of MIS-C cases was one month after the peak of admissions for other COVID-19 related reasons and decreased afterward.

Median age and interquartile range were 7. 6 [4.5;11.5] A c c e p t e d M a n u s c r i p t 7 Rash or bilateral non-purulent conjunctivitis, or muco-cutaneous inflammation signs were found in 21/31 (67%) patients; hypotension or shock in 15/31 (48%), features of myocardial dysfunction 25/31 (80%) consisting of pericarditis, valvulitis, arrhythmias or coronary abnormalities in 19/31 (61%); 6 (19%) additional children had only an elevation of a biochemical marker of heart dysfunction (NT-proBNP); evidence of coagulopathy (specifically, elevated D-dimers) was found in 29/30 (97%), and acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain), in 27/31 (87%). No other apparent microbial cause of inflammation as sepsis or staphylococcal or streptococcal shock syndrome was found.

The patient who does not include WHO criteria was a 12-month old girl. The criterion she did not meet was the elevation of inflammatory markers. She was cohousing with a COVID-19 patient.

She was on chronic oral treatment with steroids due to a chronic idiopathic interstitial lung disease. She presented with 6 days of fever, shortness of breath and cardiogenic shock (pH=7.2).

She had lymphopenia (1,100 cells/mm 3 ). She was diagnosed with cardiogenic shock.

Echocardiography showed left ventricle dilatation above +2.6 Z-score for age and sex, and ejection fraction of 55%. Enterovirus infection was ruled out with PCR in nasopharyngeal aspirate. She received 10 days of remdesivir. Although she had low inflammatory markers, this fact was attributed to the long-term immunosuppressive therapy with steroids. She had a coinfection with human metapneumovirus (hMPV). She was treated for MISC with intravenous immunoglobulin (IVIG) and steroids. She was on long-term oral steroids due to pulmonary interstitial disease, which may avoid the rising of acute-phase reactants. A c c e p t e d M a n u s c r i p t 8 Twenty (65%) patients needed admission to the Pediatric Intensive Care Unit, and 6/31 (19%) invasive mechanical ventilation. Cardiac complications consisted of myocardial dysfunction (15/31; 48%), pericardial effusion (6/31; 19%) ; valvular dysfunction (9/31; 29%), arrhythmias (7/31; 23%) and coronary abnormalities (3/31; 10%, among them 1 aneurysm). Four patients (13%) had renal failure.

Two (6%) patients received remdesivir and 7/31 (23%) lopinavir/ritonavir. A total of 21/31 (68%) children received corticosteroids: 19 of these received methylprednisolone (13 patients received doses of 1 to 2.5 mg/kg/day; 2 patients boluses of 8 and 30 mg/kg/day for 3 days; 4 had dosing not available), 20/31 (65%) patients received 2 gr/kg of intravenous immunoglobulin (IVIG) and 13/31 (42%) patients received both IVIG and corticosteroids. All but three patients received broadspectrum antibiotics.

One patient with acute leukemia and bone marrow transplant died, and one 6-month-old patient developed anterior-descendant coronary aneurysm (z-score +9). This patient was an infant with Down syndrome, who presented with 5 days of fever, shortness of breath and shock due to myocardial dysfunction. He had a a positive RT-PCR for SARS-CoV-2 at diagnosis and coinfection with hMPV, proBNP=9,968 pg/mL and troponin I=34.1 ngr/mL. He developed valve insufficiency, renal failure, coronary aneurysm, and eventually had 50 days of fever despite treatment for infection (antiviral treatment with 2 days with lopinavir/ritonavir, hydroxychoroquine, cefotaxime, vancomycin and meropenem, micafungine) and for Kawasaki disease (IGIV and steroids). The rest of the patients recovered without sequels.

A c c e p t e d M a n u s c r i p t 9

In this registry, entry criteria was COVID-19 disease, differently from the previous reports that include patient without SARS-CoV-2 1,3 . Previous reports raised discussion as some children with MIS-C or Kawasaki disease lacked evidence of infection with SARS-CoV-2. Disease triggered by other causes may have been included within those reports. Our data strongly support the idea that not only there is a temporal association with SARS-CoV-2, but also a microbiological association.

In this report, only 1 patient without microbiological or serological evidence of SARS-CoV-2 was included, but he had a strong epidemiological link. There is a possibility that not all MIS-C cases are microbiologically related to SARS-CoV-2, because RT-PCR and serology do not have 100% sensitivity and specificity. That is why we have included a patient with negative tests and with recent contact with a patient with COVID-19, according to WHO definition of MIS-C. Limitations of this study include that some cases without microbiological, serological or epidemiological link may not have been included in this registry.

A c c e p t e d M a n u s c r i p t 10 SARS-CoV-2 could be a relevant trigger for a delayed cytokine storm and an inflammatory condition, with potentially severe consequences. 6 Coinfections as hMPV may be present and might play a role in triggering the immune response. It is possible that some particular patients with special features -as chronic immunosuppressive treatment influencing inflammatory markersmay have MISC but not fulfill all WHO criteria.

MIS-C is a potentially severe condition that presents in some children after SARS-CoV-2 infection.

Until herd immunity or a vaccine are available, physicians should be aware of this severe condition in children during COVID-19 epidemics. More studies are necessary to clarify the physiopathology of this syndrome and its adequate treatment. [Sp]=100%), n=4; Immunochemoluminescence Diasorin TM SARS-CoV-2 S1/S2 IgG, S=97%, E=98%, n=1; ELISA in-house total antibody test, included within Solidarity II trial, ongoing and results pending, n=6; Rapid Test BioZek TM , IgM (S=85%, Sp=96%), IgG (S=99.9%, Sp=88%), n=3;

Immunoassays Elecsys SARS-CoV-2 Cobas TM , total antibodies, S=84%, Sp=100%, n=2.

Demographic Male 18/31 (58%)

A c c e p t e d M a n u s c r i p t M a n u s c r i p t A c c e p t e d M a n u s c r i p t 20 Figure 1 

Enrique Otheo (Hospital Ramón y Cajal)

Sara Guillén (Hospital de Getafe)

Julia Jensen (Hospital Infanta Cristina), Paula Vidal (Hospital Infanta Elena)

Hyperinflammatory shock in children during COVID-19 pandemic. The Lancet

European Centre for Disease Prevention and Control. Paediatric inflammatory multisystem syndrome and SARS-CoV-2 infection in children system syndrom ECDC: Stockholm

An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. The Lancet

Primera ronda estudio nacional de seroprevalencia COVID-19

An insertion unique to SARS-CoV-2 exhibits superantigenic character strengthened by recent mutations. bioRxiv

Hemoglobin (g/dL), worst value 31/31 (100%)

We thank all the patients and families for their participation in this cohort, the staff members who cared for them at their personal risk in this time of epidemic and gathered data from them in the Pediatrics wards, Pediatric Intensive Care Units, Cardiology Units, and all the involved Units. We acknowledge the rest of the EPICO Team: Rut del Valle, Ana Barrios (Hospital Infanta Sofia), Sara

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