1. Background
The outbreak of the SARS-CoV-2 virus emerged as a pandemic risk in early 2020. The disease (COVID-19) is mainly characterized by fever, dry cough, fatigue, and lung involvement leading to pneumonia (1). Despite most cases have a mild behaviour, up to 14% can be severe with dyspnoea, tachypnoea with a respiratory frequency ≥30/min, hypoxemia with SpO2 ≤93%, partial pressure of arterial oxygen to fraction of inspired oxygen ratio <300, and/or pulmonary infiltrates involving more than 50% of lung parenchyma within 24 to 48 hours. The disease can be life threating in 5% of cases (i.e., respiratory failure, septic shock, and/or multiple organ dysfunction or failure) (2).
So far, no specific treatment has been approved and there is the urgent need for any agent that could either lower the rate of patients entering the critical stage and be lifesaving, especially when acute respiratory distress syndrome (ARDS) occurs. The current treatment strategy includes several anti-viral drugs and anti-rheumatic agents such as chloroquine and hydroxychloroquine, that have immunomodulant properties as well as may have a direct anti-viral activity. Nonetheless, a typical hallmark of the disease seems to be a pro-inflammatory condition with markedly high levels of interleukin (IL)-1B, IL-1RA, and tumor necrosis factor (TNF)-α in early phase and higher levels of IL-2, IL-10, and TNF-α in intensive-care-unit patients. Critically ill patients usually develop neutrophilia, lymphopenia, and strikingly elevated levels of IL-6 (3).
Indeed, such over-exuberant cytokine release (aka “cytokine storm”) (4, 5) has been already described in in SARS-CoV and MERS-CoV pneumonia suggesting that viral load precedes the peak of IL-6 concentration and subsequent radiographic severity (6). SARS-CoV-2 enters the pulmonary and intestinal cells through the angiotensin converting enzyme II (ACE2) to infect them (7, 8). The result of this excessive cytokine release is the infiltration of activated neutrophils into the alveolar space and a fibroproliferative stage leading to interstitial fibrosis (9, 10). Cytokine release syndrome (CRS) in coronaviruses infection has different causes that have been exemplified by two main mechanisms. The first one is a delayed interferon (IFN) response mediated by multiple structural and non-structural proteins harboured by both SARS-CoV and MERS-CoV that antagonize IFN. The delayed IFN signaling further orchestrates immune responses and sensitizes T cells to apoptosis. Then, inflammatory monocyte-macrophages and neutrophils accumulate in the lungs following human coronaviruses infection as demonstrated in both human and animal studies. These cells are the predominant source of cytokines and chemokines associated with fatal outcome (11). On these bases, targeted anti-cytokine treatment has been proposed and, in some cases, used successfully. Tocilizumab is a monoclonal antibody directed against IL-6. It was developed to treat rheumatoid arthritis (RA) patients as well as the CRS as possible consequence of the administration of chimeric antigen receptor engineered T cells (CAR-T) immunotherapy (12, 13). Trials to test the efficacy of tocilizumab on severe COVID-19 patients are being carried out in China and Italy (14, 15).
Nonetheless, identification and treatment of hyperinflammation is mandatory. Mehta et al. (16) have recently proposed that COVID-19 can be part of the broader spectrum of hyperinflammatory syndromes characterized by CRS, such as the secondary haemophagocytic lymphohistiocytosis (sHLH). Notably, one the cardinal features of these syndromes is hyperferritinemia. Significantly higher ferritin characterizes COVID-19 severity and worse prognosis (mean 1297.6 ng/ml in non-survivors vs 614.0 ng/ml in survivors) suggesting that mortality might be due to virally driven hyperinflammation (17). Circulating ferritin levels may not only reflect an acute phase response but rather play a critical role in inflammation (18). If moderate levels of hyperferritinemia are associated with autoimmune diseases, including systemic lupus erythematosus, RA, multiple sclerosis and antiphospholipid syndrome (APS) (19-22), typically elevated levels are described in other conditions including macrophage activation syndrome (MAS), adult onset Still’s disease (AOSD), catastrophic APS (cAPS) and septic shock. In critically ill patients, hyperferritinemia is associated with the severity of the underlying disease (23-25); moreover, extremely high levels of ferritin (>3,000 ng/ml) seem to be associated with increased mortality in a dose-response manner (26). It is very intriguing that a viral infection, specifically Chikungunya, was able to induce a hyperferritinemic syndrome with underlying AOSD and cAPS (27).