SARS-CoV-2 pandemic infection caused thousands of deaths and the vaccination was the life-saving tool but some adverse effects have been also described among patients such as redness at the injection site, fever, fatigue, headache, chills, vomiting, and urticaria. Although rare, some cases of systemic hyperinflammation after vaccination have been reported, highlighting the need for a precocious identification and treatment of severe clinical manifestation [1].

AOSD is a rare autoinflammatory disorder of unknown etiology characterized by a severe hyperinflammatory state. The characteristic symptoms of the AOSD are spiking fever, hyperferritinemia, arthritis, evanescent rash, sore throat, hepatomegaly, splenomegaly, lymphadenopathy, and serositis [2].

A potential life-threating complication of AOSD, reported in up to 23% of cases, is MAS, an acute systemic inflammatory syndrome, which is characterized by a massive cytokine “storm”, whose occurrence can be related to a poor prognosis [2].

The etiology of AOSD is still unclear, it is a multifactorial disease: in case of genetically susceptible patients, an immunogenic stimulus, such as an infection (viral or bacterial), a solid or hematological cancer, could trigger a hyperinflammatory state [3].

We described here two cases of AOSD that developed after vaccination with mRNA COVID-19 vaccine. The pathogenetic mechanism underlying the occurrence of an autoimmune or autoinflammatory disease after a vaccination has not been yet clarified: a viral infection can trigger autoimmune or autoinflammatory diseases through the mechanisms of the molecular mimicry and the bystander activation [4]. The former represents a shared immunological epitope with a pathogen and the host, the latter is the activation of an antigen-presenting cell which can activate a pre-primed autoreactive T cell. In our first case, the relapse of MAS has been probably driven by SARS-CoV-2 infection itself [5]. The same mechanisms of cross reactivity could be elicited by a vaccination.

In the case of persistent elevated fever, especially in the appearance of an evolving hyperinflammatory state, the clinician should precociously consider the diagnostic hypothesis of an autoinflammatory syndrome which could also evolve into MAS, a rare and rapidly progressing fatal complication which, therefore, needs to be intercepted early, even if it is associated with significant morbidity and mortality.