Hyperinflammation after anti-SARS-CoV-2 mRNA/DNA vaccines successfully treated with anakinra: Case series and literature review

Abstract

The current SARS-CoV-2 pandemic diffused worldwide has encouraged the rapid development of vaccines to counter the spread of the virus. At present in Italy, 75.01% of the population completed the vaccination course (AIFA.gov.it) and very few adverse events have been recorded by now. Side-effects related to a theoretical over-reaction of the immune system in response to vaccines administration have been described, and the possibility that an autoimmune or a hyperinflammatory condition may occur was recently observed. Herein, we report four cases of hyperinflammatory syndrome with features indicative of Adult-onset Still’s disease (AOSD) and macrophage activation syndrome (MAS), occurred after anti-SARS-CoV-2 vaccine injection and seen at our Unit between March and May 2021. Since interleukin (IL)-1 is one of the pivotal cytokines involved in AOSD pathogenesis, the inhibition of IL-1 is crucial in ameliorating the clinical symptoms of those patients. Moreover, it has been highlighted the central role of IL-1 as a hallmark of the hyperinflammatory status elicited by SARS-CoV-2 infection. In this case series, we successfully employed the IL-1 receptor antagonist anakinra to curb the cytokine release likely unleashed by the vaccine stimulation in potentially predisposed subjects. We also made a literature search to detect other patients with hyperinflammation temporally related to vaccines injection who benefited from IL-1 inhibition, while other AOSD/MAS-like described syndromes improved with other immunomodulatory strategies.

Idiopathic Multicentric Castleman Disease Occurring Shortly after mRNA SARS-CoV-2 Vaccine

“…Though rare systemic inflammatory and immune-mediated adverse events have been reported following SARS-CoV-2 immunizations [ 8 , 9 , 10 , 11 ], we report here the first case of biopsy-confirmed iMCD that appears to be associated with SARS-CoV-2 immunizations. The clinical picture of our patient fulfilled the proposed consensus criteria for iMCD [ 7 ].…”

“…Of the 11 proposed minor criteria, 6 were present, including elevated CRP, thrombocytopenia, hypoalbuminemia, constitutional symptoms, hepatosplenomegaly and effusions. The patient also fulfilled the proposed international definition for the TAFRO syndrome, which is considered as an aggressive subtype of iMCD, requiring four clinical criteria (thrombocytopenia, anasarca, fever/hyperinflammatory status, organomegaly), renal dysfunction or characteristic bone marrow findings [ 12 ] and a lymph node with features consistent with iMCD [ 8 ]. Of note, reticulin fibrosis in the bone marrow was mild in our case.…”

Comparative Analysis of Antibody Titers against the Spike Protein of SARS-CoV-2 Variants in Infected Patient Cohorts and Diverse Vaccination Regimes

“…The participants in our study reported common and mild side effects like pain at the site of vaccination, headache or fatigue, and in rare cases fever, which were temporary and disappeared after one day. Severe hyper-inflammatory reactions are rare but have also been reported after inoculation with mRNA and DNA vaccines against COVID-19 [ 50 ]. As abnormal cytokine concentrations are the driving factor behind hyper-inflammatory reactions, Arunchalam et al [ 51 ] investigated cytokine titers following BT vaccination and found that especially IFNγ was increased after the second inoculation with BT.…”

“…Cytokine concentrations were reduced back to normal ranges two days after the inoculation, suggesting that mRNA- and vector-based COVID-19 vaccines cause a temporal, short-lived inflammatory immune reaction in healthy participants. In case of hyper-inflammatory reactions due to COVID-19 vaccination, treatment with the IL1 receptor antagonist Anakinra was able to restrain the overshooting immune response to the vaccination [ 50 ]. COVID-19 vaccination has been associated with adverse reactions in response to certain treatments, e.g., dermal fillers, like hyaluronic acid, polymethyl-methacrylate and fluid silicone, in the facial region [ 52 ].…”

Non‐allergic nature of vast majority of cutaneous adverse reactions to mRNA COVID‐19 vaccines: implications on treatment and re‐vaccination

“…Thirdly, there are also several reports of severe systemic inflammatory symptoms occurring after COVID‐19 vaccination, such as arthralgias, fever and rashes, that were successfully treated with IL‐1 antagonists. 7 While these reactions may be similar in severity to drug‐induced hypersensitivity syndrome, the shorter latency of a few days from vaccination to symptom onset is a helpful differentiating feature. The successful treatment with IL‐1 antagonists indicates over‐reactivity of the innate immunity as the underlying pathology, rather than allergic reactions which are mediated by the adaptive immunity.…”