5. Iron depletion therapy
As a consequence of the abovementioned pathogenic scenario linking iron,
inflammation and infections, there is the need to find a possible
therapeutic strategy to prevent CRS and onset of fibrosis occurring
particularly in patients with COVID-19. The progress in understanding
the critical role of pro-inflammatory cytokines in the pathogenesis of
other hyperferritinemic syndromes such as MAS and AOSD has led to pilot
use of anti-cytokine agents, resulting in an increasing number of
successful case reports in patients who were unresponsive to
conventional treatments (85). The inhibition of IL-1 (with the use of
anakinra and canakinumab) and IL-6 (mainly with tocilizumab) showed a
strong efficacy compared to placebo in several cohorts and randomized
controlled trials in MAS and AOSD. In a post hoc analysis of data from
MEASURE, a randomised, multicentre, double-blind, 24-week, phase 3B
trial of tocilizumab in RA, authors depicted a rapid decrease of
ferritin, hepcidin and haptoglobin following tocilizumab administration.
This is consistent with the idea that IL-6 signalling is a common
stimulus to production of these molecules (86). An indirect confirmation
of the greater relevance of the IL-6 axis on ferritin levels derives
from a recent systematic literature review, performed on patients with
MAS while being treated with IL-1 and IL-6 blocking agents. In this
review, patients who developed MAS while treated with canakinumab
trended towards lower ferritin at MAS onset than the historical cohort.
In comparison, patients who developed MAS while treated with tocilizumab
were less likely febrile and had notably lower ferritin levels (87). The
anti-IL-6 effect on ferritin could explain part of the emerging
successful reports on tocilizumab treatment in SARS-CoV-2 infection.
Nonetheless, the rapidity of the onset of inflammation in the acute
phase of SARS-CoV-2 infection may provoke increased ferritin production
to permit adequate storage of iron and to deprive pathogen of iron. If
the binding capacity of transferrin in the blood is exceeded, iron may
be found in the plasma as non-transferrin bound iron that changes to its
redox active form termed labile plasma iron (LPI) (88). LPI correlates
with ferritin levels and contributes to the formation of reactive oxygen
species (ROS) resulting in tissue damage and subsequent fibrosis (89)
(figure 1). Thus, a novel approach to COVID-19 treatment can be
represented by iron chelation therapy that can interrupt these steps.
Iron chelation represents a pillar
in the treatment of iron overload due to a wide spectrum of diseases and
multiple chelating agents are currently registered and routinely used in
clinical practice. Indeed, deferoxamine (DFO) has a direct effect on
ferritin since promotes ferritin degradation in lysosomes by inducing
autophagy, while both deferiprone and deferasirox are likely to chelate
cytosolic iron and iron which is extracted from ferritin prior to
ferritin degradation by proteasomes (90) (Figure 1). Moreover, several
studies have been performed on the potential anti-viral effect of iron
chelating therapy. Indeed, iron overload can contribute to human
immunodeficiency virus (HIV) replication in vitro by increasing
reverse transcriptase activity and reducing the viability of infected T
cells. Iron chelation by DFO has
shown beneficial effects on HIV infection (91) probably through multiple
mechanisms such as: 1) restriction of DNA synthesis through the
inhibition of ribonucleotide reductase, which requires iron to exert its
enzymatic activity, 2) inhibition of T cell proliferation that is
essential for HIV replication, 3) direct toxic effect on viral DNA and
RNA via oxidative stress and 4) inhibition of NF-kB pathway. These
effects may not be universal for all iron chelating agents. In fact,
DFO and deferiprone (DFP) can both
inhibit T cell proliferation and DNA synthesis, while bleomycin can
directly bind to viral DNA with no effect on host T cells (92, 93).
A potential anti-viral effect has also been demonstrated with other
pathogens, such as HSV-1 (94) and CMV. More specifically, CMV requires
iron in order to induce the increase in size of infected cells, so that
increased in vitro levels of free iron have been demonstrated
before the occurrence of this phenomenon, which can be effectively
limited by iron chelation therapy (95). DFO is also capable to further
enhance the therapeutic effect of IFN on hepatitis B virus (HBV)
infection (96). Fewer data are available on the effect of iron chelation
on other infective agents, though Mateos et al. (97) reported increased
levels of free iron in the bronchoalveolar lavage (BAL) fluid of HIV
patients with Pneumocystis jiroveci pneumonia compared to
controls, suggesting a potential pathogenic role of iron. Similarly, a
beneficial effect of DFO treatment was demonstrated in a murine model ofTrypanosoma cruzi infection, independently from the iron
metabolism of the host cell (98).
However, it should be carefully
considered that iron chelators may actually be exploited by pathogens as
sources of iron (99), thus a careful analysis of the pharmacodynamic
mechanisms of the single chelating agents available is warranted.
One of the main mechanisms through
which iron can promote inflammation is mediated by an increased
production of free oxygen radicals via Haber-Weiss reaction. As an
example, iron is able to increase the in vitro production of IL-6
by endothelial cells following infection with Chlamydia
pneumoniae and Influenza A virus, which can be effectively controlled
by DFO (100). Interestingly, similar processes, including IL-6 and free
oxygen radical production, take place during septic shock. Thus, it is
not surprising that iron chelation is effective in decreasing mortality
in murine models of septic shock via NO scavenging (101) and inhibition
of MAP kinases and NF-kB pathways, eventually leading to reduced
production of pro-inflammatory cytokines (102).
One of the most severe complications of diseases leading to iron
overload is liver damage, characterised by progressive fibrosis and,
eventually, irreversible cirrhosis. In fact, the prevention of liver
damage is the main indication for iron chelation in these
conditions. Although the reduction
of free iron levels and, consequently, of oxygen radicals, is the main
mechanism preventing progressive damage, some authors suggested iron
chelating agents may exert an independent anti-fibrotic effect. This
evidence comes from studies showing reduction of liver fibrosis in the
absence of a significant decline in liver iron content (103).
Deferasirox (DFX) and DFO seem able to reduce damage and fibrosis in
multiple rat models of concavalin A and CCl4-induced
liver injury by inhibiting the production of free radicals (104–106),
though other studies did not confirm this evidence (107). Anti-fibrotic
effects in kidney disease have also been demonstrated in rat and mouse
models of renal damage, again via a reduction of oxidative stress,
macrophage tissue infiltration and production of pro-fibrotic cytokines
such as TGF-β (108, 109). Other authors showed that DFO can provoke a
remarkable decrease of IL-6 levels and have a potent anti-fibrotic
effect in HCV infection (110).
Whether these phenomena share common aspects with COVID-19 is currently
not known. It is, however, reasonable to speculate that iron chelation
may influence free radicals and pro-inflammatory cytokines production
that are strongly involved in the late phase of COVID-19, eventually
leading to acute lung injury and ARDS. It has been shown that mechanical
ventilation, often required in COVID-19 patients, may induce lung injury
that is known to be associated with the release of inflammatory factors,
apoptosis, endothelial dysfunction, and activation of the coagulation
system (111, 112). Interestingly, pre-conditioning with DFO showed a
lung protective effect against mechanical ventilation through effective
reduction of ROS formation in macrophages and mitochondria in a mouse
model (113).
Additionally, preliminary data seem to suggest that residual lung damage
may be present in a subset of severe COVID-19 patients following the
acute phase of the disease (114). If these data were to be confirmed,
the anti-fibrotic effect of iron chelating agents may represent an
additional mechanism of action deserving careful consideration.
To conclude, the abovementioned considerations lead to the idea that
COVID-19 may be part of the hyperferritinemic syndrome spectrum (115).
Possible iron acute overload caused by rapid synthesis of ferritin
exceeding its iron incorporation rate, and the beneficial effects of
iron chelation therapy on the inflammatory status as well as on the
fibrogenesis occurring in the lungs suggest that, in appropriate setting
of critically ill patients with COVID-19, iron chelation therapy could
be considered to improve survival and overall long-term outcome.