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.