Severe Multisystem Inflammatory Symptoms in 2 Adults After Short Interval Between COVID-19 and Subsequent Vaccination

Elizabeth R. Jenny-Avital; Ruth A. Howe


Emerging Infectious Diseases. 2022;28(5):1017-1020. 

In This Article


Although case 1 fulfilled the initial 5-criteria surveillance CDC definition for MIS-A,[1] which included acute liver injury, it does not fulfill the updated CDC definition,[2] illustrating the dynamic and competing objectives of surveillance and precision. A broader Brighton Collaboration definition of MIS[3] was developed in part to be used in the evaluation of vaccine adverse events.

Case 2, by contrast, unequivocally fulfills MIS-A criteria and occurred within the usual time frame for post–COVID-19 MIS-A; its occurrence after vaccine might have been coincidental. Because MIS is overwhelmingly a disease of children and young adults, these 2 rare events, both occurring soon after vaccination in older adults, raised our concern that vaccination soon after COVID-19 infection might provoke MIS-A (case 2) or some similar vaccine-related multisystem inflammatory illness (case 1) consistent with the broader Brighton definition.[3]

Some vaccine-triggered inflammatory symptoms, such as fever and myocarditis, occur disproportionately after a second vaccination, except in persons with previous COVID-19 infection, in whom reactions occur after a first vaccination, which suggests priming by a first antigenic exposure. The mRNA vaccine trials excluded participants with previous COVID-19, but antibody tests indicated previous infection in 2.5% of participants <65 years of age in the mRNA-1273 trial.[4] Fever after first vaccination occurred in 9.4% of participants with previous COVID-19, compared with only 0.5% in COVID-19–naive participants and increased to 15.7% in the initially COVID-19–naive after the second vaccination.[4] Similarly, myocarditis, a well-recognized vaccine adverse reaction in adolescents and young adults, almost invariably follows a second mRNA vaccine dose.[5,6] However, a well-characterized report of 23 members of the US military identified myocarditis after the first vaccination only in 3 persons who had previous COVID-19.[6] By analogy, vaccine-associated multisystem inflammation, including MIS-A, might occur differentially between COVID-19–naive and COVID-19–experienced persons, such as suggested by the Brighton Collaboration document.[3]

MIS, initially described in children who were SARS-CoV-2–negative by PCR but had plausible COVID-19 exposure or NP antibodies,[7,8] was interpreted as a postviral syndrome caused by a deleterious hyper-inflammatory immune response.[7] Although subsequent MIS cases reported in adults and children had concurrently positive PCR results in more than half,[1,9,10] this finding was attributed to prolonged SARS-CoV-2 shedding, which has been noted in up to 19% of asymptomatic convalescent outpatients,[11] rather than to a second infection in a sensitized host. Of 6 cases of MIS-A reported by Kaiser Permanente, 3 (50%) occurred in persons who were vaccinated after natural infection, despite the fact that only 7% of the cohort was vaccinated.[12] Of 20 MIS-A cases collected by CDC during December 2020–April 2021, 7 (35%) occurred after vaccination after natural infection.[2] The interval from infection to MIS-A was the same regardless of intervening vaccination, suggesting that vaccination was coincidental. Miyazato et al.[13] reported MIS-A 5 days after vaccination in a person with severe inflammatory illness that followed unrecognized previous COVID-19 infection confirmed only by positive NP antibody. Nune et al.[14] coined the term MIS-V to describe a case of MIS that began as progressive local injection-site inflammation 2 days after vaccination and demonstrated evolving systemic features, without evidence of antecedent COVID-19 infection.

COVID-19 vaccination during high periods of transmission increases the likelihood of vaccination following soon after infection. Further epidemiologic observations are needed to confirm a clear causal relationship, but our results indicate that vaccination soon after natural infection may result in the occurrence of strictly defined MIS-A or of other vaccine-triggered systemic inflammatory disorders.