Multisystem inflammatory syndrome in children rare after COVID-19 vaccination in adolescents

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been marked by severe or critical disease in a minority of patients as well as delayed complications after apparent recovery.

Study: Reported Cases of Multisystem Inflammatory Syndrome in Children (MIS-C) Aged 12–20 Years in the United States Who Received COVID-19 Vaccine, December 2020 through August 2021. Image Credit: Prostock-studio/Shutterstock

The multisystem inflammatory syndrome in children (MIS-C), also known as pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), is among the complications of this infection. A recent preprint describes MIS-C incidence following COVID-19 vaccination in the pediatric age group of 12-20 years in the USA.  


MIS-C is a rare but potentially fatal complication in which a generalized hyperinflammatory state prevails following infection with this virus. Both dysregulated immunity and genetic factors are thought to be implicated in the pathogenesis of this condition.

It generally occurs two to six weeks after infection in children and adolescents. Besides generalized inflammation, its presenting features include fever, shock, and the involvement of multiple organs.

Over the period from May 14, 2020, through November 30, 2021, there were almost 6,000 reported cases in the national database linked to the Centers for Disease Control and Prevention (CDC). Due to the link with SARS-CoV-2, it is considered an adverse event of special interest (AESI) and is expected to be notified as a part of vaccine safety monitoring post-COVID-19 vaccine administration.

The diagnosis of MIS-C is difficult due to the vague and generalized symptoms, often mimicking those of COVID-19 itself, Kawasaki disease, or toxic shock syndrome. It is also challenging to discriminate between MIS-C following COVID-19 vs. that following vaccination against the disease. In some cases, the vaccine may be administered during asymptomatic infection, falsely appearing to be associated with subsequent MIS-C secondly, some cases may occur in relation to breakthrough infection.

The current study, published on the medRxiv* preprint server, was based on merged results using the CDD’s surveillance database coupled with the Vaccine Adverse Event Reporting System (VAERS), along with reports from health departments or physicians to the CDC. All seropositive results were accepted as a possible link to MIS-C.

What did the study show?

The scientists found 21 MIS-C post-vaccine cases, the median age being 16 years, with almost two-thirds being male. Over 70% had a positive nucleic acid amplification test (NAAT), rapid antigen, or serology test either before features of MIS-C appeared or during the evaluation of the illness. A third had no laboratory evidence of infection, of which six developed MIS-C after the second dose of the vaccine.

Of the 21, 15 showed evidence of infection at the time of MIS-C. Five of them were negative by NAAT or viral antigen tests at the time of illness. All 15 had got the Pfizer mRNA vaccine, ten having got one dose and five two doses before MIS-C set in.

Six of these were negative for anti-nucleocapsid antibodies during the illness and had no history of a positive test for the virus beforehand. They had antibodies to the viral spike but negative NAAT. Three were 12-15 years, and three 18-20 years. All had cardiac symptoms, including shock, at presentation, and most had hematologic issues.

All the patients recovered and were discharged home after a median of six days in hospital.

What are the implications?

By August 31, 2021, over 21 million people aged 12-20 years had received one or more doses of a COVID-19 vaccine, with 18 million and 2.6 million having taken the Pfizer and Moderna messenger ribonucleic acid (mRNA) vaccines, respectively. The median time to onset of MIS-C symptoms was five days after one dose and five days after two overall, but in the six patients without a prior history of infection, MIS-C set in at a median of 14 days from the second dose.

The majority of the 21 MIS-C cases among the vaccinated population had a history of prior COVID-19 infection. in three, the positive test appeared to be too far back in time to be related to the illness. In four others, a history of exposure was lacking though they were positive for anti-nucleocapsid antibodies.

The overall reporting rate for MIS-C was thus 1 per million vaccine recipients in the 12-20 years population, including all those who had received one or more doses. In comparison, among unvaccinated people with COVID-19, the rate of MIS-C was 224 and 164 per million infections, among those aged 11-15 and 16-20 years, respectively.

When the six cases that showed no evidence of prior infection are considered, the incidence of MIS-C is 0.3 per million vaccine recipients in this age group. It is impossible with currently available data to link vaccination to this outcome or rule out the prior occurrence of SARS-CoV-2 infection since many such infections in children are asymptomatic, and the anti-nucleocapsid antibody titer induced by such infections wanes with time, more so with mild infection.

As more infections occur among children, it will be necessary to rule out other conditions before attributing similar symptoms to the vaccination to provide appropriate treatment. However, all suspected cases should be reported to VAERS to enable continuous data assessment and arrive at a definitive consensus.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Yousaf, A. et al. (2022) "Reported Cases of Multisystem Inflammatory Syndrome in Children (MIS-C) Aged 12–20 Years in the United States Who Received COVID-19 Vaccine, December 2020 through August 2021". medRxiv. doi: 10.1101/2022.01.03.22268681.

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Adolescents, Antibodies, Antibody, Antigen, Children, Coronavirus, Coronavirus Disease COVID-19, covid-19, Fever, Genetic, Hospital, immunity, Inflammation, Kawasaki Disease, Laboratory, Nucleic Acid, Pandemic, Respiratory, Ribonucleic Acid, SARS, SARS-CoV-2, Serology, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Toxic Shock Syndrome, Vaccine, Virus

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Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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