Israel Medical Association Journal

In 2013, the idea of the hyperferritinemic syndrome was introduced to suggest the possible inflammatory properties of ferritin in contributing to the pathogenesis of four diseases, namely Still’s disease, macrophage activation syndrome (MAS), septic shock, and catastrophic antiphospholipid syndrome [1]. Based on this concept, ex vivo and in vitro studies were performed reporting the inflammatory properties of the heavy subunit of ferritin (FeH) in inducing the commitment of macrophages toward an inflammatory phenotype, production of pro-inflammatory cytokines, and the direct stimulation of NLRP3 and NF-kB pathway [2,4]. In addition, recent in vivo studies have established the pathogenic role of hyperferritinemia [4-6], mainly triggering a Still’s disease-like phenotype in a wild type murine model by the aberrant activation of immune cells and production of inflammatory mediators [5]. Moreover, the hyperferritinemic syndrome arena has seen many recent developments due to the rapid accrual of knowledge in coronavirus disease 2019 (COVID-19) [6,7]. Specifically, the appearance of hyperferritinemia is increasingly recognized to be associated with a more severe patient phenotype at higher risk of poor prognosis due to the appearance of the cytokine storm syndrome [8], which is a hyper-inflammatory state due to overwhelming massive release of inflammatory mediators and rapidly evolving to multiorgan failure [9].

Background: Ferritin, the cellular protein storage for iron, has emerged as a key molecule in the immune system, orchestrating the cellular defense against inflammation. At the end of 2019, the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) rapidly spread throughout China and other countries around the world, resulting in a viral pandemic.

Objectives: To evaluate the correlation between ferritin and disease severity in coronavirus disease-2019 (COVID-19).

Methods: In this cross-sectional study, we obtained clinical and laboratory data regarding 39 hospitalized patients with confirmed COVID-19 from two hospitals in Israel.

Results: A significant increase in ferritin levels was demonstrated in patients with moderate and severe disease, compared to patients with mild disease (P = 0.006 and 0.005, respectively). Severe patients had significantly higher levels of ferritin (2817.6 ng/ml) than non-severe patients (708.6 ng/ml) P = 0.02.

Conclusions: In this preliminary cross-sectional study, elevated ferritin levels were shown to correlate with disease severity in 39 patients from Israel with confirmed COVID-19 infection. Our results further strengthen the hypothesis that severe COVID-19 disease might be due to an underlying dysregulated hyperimmune response. In order to identify these patients early and prioritized resources, we believe that all patients with COVID-19 should be screened for hyperferritinemia.

A virally-induced cytokine storm syndrome, associated with a massive and overwhelming systemic inflammation, burdens a subgroup of patients with severe coronavirus disease-2019 (COVID-19), which leads to pulmonary inflammation and extensive lung damage. These severe COVID-19 patients are characterized by high ferritin levels. These findings mirror what was previously reported about the prognostic role of this iron storage protein in other inflammatory diseases included in the hyperferritinemic syndrome. The latter suggests that ferritin could be a further pathogenic mediator in enhancing the inflammatory process, stimulating inflammatory pathways, and thus perpetuating a vicious pathogenic loop. Considering its activity as an immune activator, a therapeutic approach targeting ferritin may be also postulated in these diseases. Considering these observations, high ferritin levels characterize severe COVID-19 and other diseases included in the hyperferritinemic syndrome. Because ferritin could enhance the inflammatory process, it could be tested as a possible new therapeutic target to improve the outcome of these patients.