Discussion
It is well known that higher mortality rate and poor outcomes are mainly
associated with development of cytokine storm in patients with COVID-19
(Gustine & Jones, 2021). Cytokine storm is a hyperinflammatory state
that seen in several conditions such as hematological malignancies,
infectious diseases and rheumatological conditions including adult-onset
still disease (AOSD), systemic lupus erythematosus (Jarczak & Nierhaus,
2022). Development of cytokine storm depends on excessive production of
several cytokines including interleukin-1 (IL-1), IL-6, tumor necrosis
factor-alpha (TNF-α) and type 1 interferon (IFN) triggered by SARS-CoV-2
in COVID-19 (Chen et al., 2020). Recent studies revealed the importance
of pulmonary macrophages’ activation secondary to SARS-CoV-2 (23), which
results in inflammasome activation in COVID-19 (Junqueira et al., 2022)
(Sefik et al., 2022). Inflammasomes are essentials in the host defense
against microorganisms including viruses that are present in various
innate immune cells such as neutrophils, macrophages and dendritic
cells. Activation of inflammasomes is leading to the cleavage of
pro-IL-1β to produce active IL-1β (Vora, Lieberman, & Wu, 2021), and
responsible for development of various immune-mediated diseases such as
Familial Mediterranean Fever (FMF), gout, and AOSD (Gabay, Lamacchia, &
Palmer, 2010). Furthermore, safety and efficacy of IL-1 blockade in
these diaseases were established in these conditions (Dinarello, 2011).
Anakinra is an IL-1 receptor antagonist which is widely used in several
rheumatological diseases such as FMF, AOSD, and gout (Marko et al.,
2021) (Giacomelli et al., 2021) (Saag et al., 2021) and also several
hyperinflammatory conditions such as cancer-related hemophagocytic
syndrome, chimeric antigen receptor-modified (CAR) T cell associated
cytokine storm, and macrophage activation syndrome (Bami et al., 2020)
(Strati et al., 2020) (Grom, Horne, & De Benedetti, 2016). Safety and
efficacy of Anakinra was also established in COVID-19-associated
cytokine storm (Kyriazopoulou et al., 2021). Intravenous and high dose
anakinra is an emerging therapeutic option both in rheumatology, other
hyperinflammatory conditions, and COVID-19 (Nigrovic et al., 2011)
(Mehta, Cron, Hartwell, Manson, & Tattersall, 2020) (Phadke,
Rouster-Stevens, Giannopoulos, Chandrakasan, & Prahalad, 2021).
Intravenous administration of anakinra ensures higher and fast maximum
plasma concentration compared to subcutaneous form (Saunders, Kuijpers,
Sloan, & Gertner, 2023). Daily dose adjustment of anakinra may allow
early intervention of the cytokine storm according to daily clinical
status, also withdrawing the drug in case of infection or other
complications. Additionally, intravenous high-dose anakinra treatment
reduced mortality in our previous study (Bektaş et al., 2023a).
Thromboembolic events are common in COVID-19 which is a remarkable
finding from the beginning of pandemic (Asakura & Ogawa, 2021). In
Middeldorp et al. study overall VTE frequency was 20% which was higher
in patients in ICU (47%) than ward (3.3%). In the former study, ICU
admission, increased d-dimer and NLR levels were associated with
development of VTE which were similar with our results. In another
observational study with 3334 patients, 16% of patients experienced a
thrombotic event which 6.2% of them were VTE and 11.1% were arterial
events (1.6% stroke and 8.9% MI) (Bilaloglu et al., 2020). The former
study also revealed an association between development of thrombosis and
prior history of CHD and increased d-dimer levels which were consistent
with our results. In the former study, thrombotic events were also
higher in patients who had critical disease and/or deceased compared to
those who had not. In a study with COVID-19-related deceased patients,
although 9% of the patients had macroscopic thrombosis, most of the
patients (87%) had microscopic evidence of thrombosis accompanying
intense inflammation in autopsy specimens (Khismatullin et al., 2021).
The authors also concluded a pathologic link between inflammation and
thrombosis in the former study. In our study, higher mcHIS score and its
components such as d-dimer and CRP levels in patients experienced
thrombosis suggest that hyperinflammation is one of the key factors for
the development of thrombotic events in patients with COVID-19.
Moreover, the fact that higher values of peak levels of CRP, d-dimer,
LDH, ferritin than those baseline levels emphasize the crucial role of
hyperinflammation into the development of thrombotic events. This
finding was also consistent with our previous results regarding the
close association between peak levels of these laboratory tests and poor
outcomes (Bektaş et al., 2023a).
In our study, lower frequency of PTE in anakinra group was a remarkable
finding even though anakinra group had more severe disease before
propensity score matching (Bektaş et al., 2023b). This finding persists
after the PS matching procedure. As already known, endothelial
dysfunction, thrombophilia and stasis are the main contributors into the
development of venous thrombosis according to Virchow’s triad. In
COVID-19, endothelial dysfunction appears to be a more prominent factor
for the development of thrombosis (Ahmed, Zimba, & Gasparyan, 2020). In
our study, none of patients with PTE had clinical evident DVT which
suggests COVID-19-related pulmonary thrombosis is an in-situ thrombosis
rather than embolism which was claimed by Gabrielli et. al. study
(Gabrielli, Lamendola, Esperide, Valletta, & Franceschi, 2020). In our
study, all patients received background anticoagulant prophylaxis in two
arms but could not prevent thrombotic events. This situation is recently
called ‘inflammothrombosis’ which is similar to Behçet’s disease (BD)
associated venous thrombosis. While DVT and PT (in situ thrombosis, not
embolism) may develop in BD separately, DVT is not expected to cause
embolism due to its inflammatory nature (firmly attached to the vascular
wall). Therefore, the definition of pulmonary thrombosis may be more
accurate than pulmonary embolism in patients with COVID-19 similar to
BD. Furthermore, while anticoagulant therapy does not prevent vascular
thrombosis in BD patients, anti-inflammatory treatment improves the
vascular outcomes such as recanalization and prevention of relapses
(Bettiol et al., 2023). In the light of these data, pulmonary thrombosis
in COVID-19 may be mainly associated with pulmonary inflammatory
environment rather than stasis or other components of Virchow’s triad
and develops in situ thrombosis rather than embolism. Therefore,
anti-inflammatory treatment may reduce thrombosis risk beyond the
anticoagulant treatment in patients with severe COVID-19 which were
shown in our study. However, it should be kept in mind that there is
limited data showing the efficacy of anti-inflammatory therapy as an
anticoagulant effect in patients with COVID-19.
Inflammation is an important contributor to the development of
cardiovascular disease including acute coronary syndromes (ACS). During
the pandemic arterial thrombotic events such as CVA and MI were
increased in patients with COVID-19 (Stein, Mayman, Dhamoon, & Fifi,
2021) (Knight et al., 2022). The NLRP3 (NOD [nucleotide
oligomerization domain]-, LRR [leucine-rich repeat]-, and PYD
[pyrin domain]-containing protein 3) [NLRP3] inflammasome, an
innate immune signaling complex, is the key mediator of IL-1 family
cytokine production. Recent evidence has shown that NLRP3 inflammasome
activation has a crucial role leading higher IL-1 production for the
development of ACS (Afrasyab et al., 2016). Furthermore, colchicine, an
inflammasome inhibitor was found to be effective for the prevention of
MI in patients prior to ACS history (Tardif et al., 2019). Similarly,
canakinumab, is an IL-1β monoclonal antibody that decreases composite
cardiovascular events including MI, stroke, coronary revascularization,
and cardiovascular death in the CANTOS study (Everett et al., 2020). In
our study, decreased incidence of MI with Anakinra was consistent with
previous studies. Additionally, higher mcHIS score in patients had MI
compared with had not emphasized the crucial role of hyperinflammation
into the development of arterial events.
This study has some strengths and limitations. Retrospective
design of the study was the main limitation although controlled design
of the study adjusting potential confounders by PS matching was
important to prevent bias. We could not perform doppler USG screening in
patients who had PTE since it did not cause a change in treatment and
critical situation of the patients. Diagnosis of MI could not be
confirmed with cardiac catheterization. Having missing data is also a
limitation of the study. On the other hand, the fact that the study is
conducted in a single center enables homogeneity in terms of patient
population and treatment decisions that are made by a single physician.