Familial Mediterranean Fever and COVID-19: Friends or Foes?

Abstract

Familial Mediterranean Fever (FMF) and COVID-19 show a remarkable overlap of clinical symptoms and similar laboratory findings. Both are characterized by fever, abdominal/chest pain, elevation of C-reactive protein, and leukocytosis. In addition, colchicine and IL-1 inhibitors treatments that are effective in controlling inflammation in FMF patients have recently been proposed for off-label use in COVID-19 patients. Thus, FMF may resemble a milder recapitulation of the cytokine storm that is a hallmark of COVID-19 patients progressing to severe disease. We analyzed the sequence of the MEFV-encoded Pyrin protein-whose mutations cause FMF-in mammals, bats and pangolin. Intriguingly, although Pyrin is extremely conserved in species that are considered either a reservoir or intermediate hosts for SARS-CoV-2, some of the most common FMF-causing variants in humans are present as wildtype residues in these species. We propose that in humans, Pyrin may have evolved to fight highly pathogenic infections.

COVID-19 outcomes in patients with familial Mediterranean fever: a retrospective cohort study

“…Activation of inflammasomes by viral proteins and release of proinflammatory cytokines is a natural response of innate immunity to viral infections however, a dysregulated inflammasome activity may also result in an aberrant inflammatory response. Likewise, in Familial Mediterranean fever (FMF), a hereditary innate immunity disorder due to gain of function mutations in Mediterranean fever gene ( MEFV) encoding pyrin protein, a hyperactive pyrin inflammasome leads to febrile inflammatory episodes sharing similarities with COVID-19-associated cytokine storm [ 4 , 5 ]. As mentioned before, an already hyperresponsive innate immune system may increase susceptibility developing cytokine storm and severe symptoms in COVID-19.…”

Genetics of symptom remission in outpatients with COVID-19

“…It is possible that the genetic variant at 9q33.1 may act in a biological pathway that is shared with that of colchicine, which acts on multiple inflammatory pathways including the NLRP3 inflammasome 33 , 34 . A recent report by Stella and colleagues 35 on familial Mediterranean Fever (FMF) in the context of COVID-19 argues that there could be a finely regulated competition between the NLRP3 inflammasome and pyrin that is necessary to maintain protective inflammation levels. FMF is an inherited monogenic autoinflammatory disorder caused by excess activity of the pyrin protein and which is typically treated with colchicine to prevent fever attacks.…”

The impact of COVID-19 on familial Mediterranean fever: a nationwide study

“…The first antiviral response is initiated by the innate immune system. Secretion of type 1 interferons and proinflammatory cytokines occurs in this response [ 8 ]. The inflammatory phase may cause rapid deterioration.…”

“…It was suggested that impairment in the regulation of NLRP3 inflammasome could lead to a complex immune response in viral infections [ 20 ]. Stalla et al hypothesized that the dysregulation between Pyrin and NLRP3 inflammasome might alter the balance between protective inflammation against virus and hyperinflammation [ 8 ]. Therefore, the frequency and severity of SARS-CoV-2 infection in FMF are intriguing.…”

“…Most patients are from the Eastern Anatolia and the Eastern Black Sea Region [ 7 ]. The innate immune system that plays a critical role in the pathogenesis of FMF is also essential in antiviral defense [ 8 ]. It is thought that some viral protein particles increase COVID-19 severity via prolonged and excessive activation of the innate immune system.…”