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).