The Safety and Efficacy of Anakinra, an Interleukin-1 Antagonist in Severe Cases of COVID-19: A Systematic Review and Meta-Analysis

In December 2019, an outbreak of emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease or coronavirus disease 2019 (COVID-19) in China was brought to international notice and declared a pandemic by the World Health Organization (WHO) on March 11, 2020 [1]. As of January 2021, there are a total of 24,876,261 cases and 416,010 deaths attributed to COVID-19 in the United States of America [2]. The ongoing pandemic has presented a devastating effect on people's social and economic well-being by infecting over four million people worldwide. The alarmingly rising fatality rates demand an early intervention to guard and safeguard the vulnerable population. The need for innovative and effective treatment modalities is crucial as more people succumb to the virus [3]. Presently, there are no specific treatments or measures recommended to prevent or treat COVID-19. Clinical management is currently limited to supportive care [3]. Understanding the disease pathophysiology and targeting therapy towards the molecular processes is key in identifying effective therapeutic interventions. Coronaviruses are a group of RNA viruses with envelopes commonly present in mammals and birds, causing respiratory or gastrointestinal diseases with a few neurological debilities or hepatitis [4]. Infections are transmitted mainly via respiratory and fecal‐oral routes and manifest [5].

The inflammatory response in COVID-19 plays a fundamental role in the high mortality seen in patients. The virus is recognized by the innate immune system leading to the recruitment of immune cells and the production of various cytokines. Excessive production of these inflammatory cytokines causes a phenomenon termed the cytokine storm, which leads to the development and exacerbation of acute respiratory distress syndrome (ARDS) or extrapulmonary multiple organ failure. Many cytokines and chemokines have been implicated in the pathogenesis of this hyperinflammatory response [6]. This cytokine profile resembles secondary hemophagocytic lymphohistiocytosis (sHLH), a hyperinflammatory syndrome resulting in fulminant multiorgan failure. The underlying etiologies of sHLH include viral infections and sepsis [7]. The H-score is a good valid indicator of hemophagocytic syndromes including sHLH. Measurements include immunosuppression status, temperature, organomegaly, number of cytopenias, ferritin levels, triglycerides, fibrinogen, serum aspartate aminotransaminase, and hemophagocytosis features on bone marrow aspirate [8]. It has been suggested that all severe COVID-19 patients should have their H-score evaluated and used as a tool to guide therapeutics. When elevated and indicative of reactive HLH, immunosuppressives may be an option including steroids, intravenous immunoglobulin, selective cytokine inhibitors (i.e anakinra, tocilizumab) and medications inhibiting Janus kinase (JAK) pathways [7].

This systematic review and meta-analysis aims to identify the role of anakinra, an interleukin-1 receptor antagonist (IL-1Ra) in the treatment of COVID-19. Multiple studies have been performed on this drug, but the direct effects have not been reviewed in a large-scale study. We will be reviewing currently available evidence and methodology to determine the safety and efficacy of anakinra therapy in COVID-19 patients. We will analyze how anakinra modifies the disease duration and determine if it prolongs, reduces, or has no effect on viremia. Since anakinra is suspected of inhibiting a key cytokine in the pathogenesis of the hyper inflammation, the study will evaluate its therapeutic role in disease severity and secondary outcomes (i.e., the need and duration of mechanical ventilation, respiratory failure, death, etc.). Furthermore, this review will determine what dosage of the drug has shown optimal efficacy and safety in the treatment of COVID-19.

Respiratory failure and ARDS have been reported to be the main cause of death in COVID-19 patients followed by sepsis and multiorgan failure [20, 21]. Prior to the development of ARDS, COVID-19 patients without clinical manifestations become hypoxic through preliminary endothelial damage through inflammatory cytokine release and unusually large von Willebrand factor multimers coexisting with platelet over-activation. This asymptomatic hypoxemia can be a determining feature of prognosis. Furthermore, endotheliitis through venous thromboembolism and microthrombi leads to the characteristic coagulation overactivation, coagulopathy and elevated permeability of the blood vessels due to endothelial damage in COVID-19, as seen in parallel with the H1N1 molecular pathogenesis and is also characteristic of sHLH, ARDS and multiple organ dysfunction syndrome (MODS) [21]. Delving into the molecular biology of this pathway, ARDS is primarily caused by a cytokine storm, an unregulated systemic release of inflammatory cytokines [22]. Cytokine release syndrome (CRS), also ubiquitously referred to as cytokine storm syndrome, is the process by which an elevation of inflammation and damage to the endothelium occurs and precipitates the excessive activation of the coagulation pathways as well as disrupts the integrity of the vascular permeability. A characteristic set of markers determine cytokine storm intensity, a mortality marker composed of elevated G cerebrospinal fluid, platelet-activating factor, thrombin-induced MIF, TNF, cystatin C, IL-1, IL-6, ferritin leading to immune dysregulation injury that causes endothelial damage [21, 23]. CRS induced dysregulation of immune responses cause epithelial and endothelial cell apoptosis and vascular leakage, suboptimal T cell responses, dysfunctional and overactive macrophages infected with SARS-CoV-2 and dysfunctional tissue homeostasis, all of which contribute to the pathogenesis and severity of macrophage activation storm (MAS) leading to ARDS and MODS [21, 22, 23, 24, 25].

MAS is indirectly induced by IL-1 [25]. This may be the target point to prevent ARDS development by inhibition of IL-1 and resultant MAS and ARDS. Additionally, increased IL-1 release in viral infections results in lung and tissue inflammation, fever and fibrosis. An over-expression of IL-1 is pathognomonic of SARS-CoV-2 by activating transcription factor, nuclear factor, activator protein 1 and activating factor 2. This virus binds to Toll-like receptors (TLRs) to stimulate pro-IL-1 production and inflammasome activation regulating cells of both the innate and adaptive immune system and produces specific immune responses. IL1-b, thus produced, results in the inflammation of the lungs, fever and fibrosis to lead to respiratory complications in the infected host [26].

Anakinra is a recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist (Recombinant human IL-1Ra [27]. It is produced by recombinant DNA technology by using an Escherichia coli bacterial expression system. It is different from native human IL-1Ra, as it has an additional single methionine residue at its amino terminus [27]. It acts by blocking the biological activity of IL-1α and IL-1β (pro-inflammatory cytokines) by competitive inhibition of IL-1 binding to the interleukin-1 type I receptor (IL-1R1). Currently, intravenous and subcutaneous routes are available with a 95% bioavailability and a half-life of 3 - 7 hours [28]. It has been used successfully in treating macrophage activation syndrome caused by various inflammatory conditions, including Still's disease, HLH, and active rheumatoid arthritis. IL-1 is produced as a result of physiological response to inflammatory stimulus and immunological conditions [29]. IL-1α and IL-1β are activated through inflammasome and pro-inflammatory cytokines that mediate many cellular responses. They also increase nitric oxide production, prostaglandin, adhesion molecules, thromboxane, and histamine [29]. These factors also contribute to the "cytokine storm" implicated in the pathogenesis of COVID-19. This mechanism of action may be helpful in COVID-19, according to previous studies. Various clinical trials are being conducted that support this rationale for targeting hyper inflammation in COVID-19 with anakinra. Outcomes are promising, but varied use and dosage and outcomes have been noticed in the various trials [27].

The impact of methylprednisolone and low dose anakinra combination therapy in patients with hyperinflammatory syndrome revealed a great statistical significance toward the treatment group in term of mortality rate as it decreases the number of deaths at day 28 by 13.9% vs. 35.6% in control group with a P-value = 0.004 and hazard ratio (HR) of 0.33 (95% CI, 0.15 - 0.47) [13]. The same effect on mortality rate demonstrated by the RECOVERY trial in dexamethasone arm for patients receiving invasive mechanical ventilation as the incidence found to be lower when compared to the control (29.3% vs. 41.4%) and rate ratio of 0.64 (95% CI, 0.51 - 0.81), while no significant impact shown on group of patients without respiratory support [30]. However, Bozzi et al. concluded a better outcome than patients in the dexamethasone group of the RECOVERY study (16.7% vs. 29.3%) [13].

Borie et al. also supported the efficacy of short term immunosuppressants in severe COVID 19 patients as it observed a lower incidence death rate (22.2%) in 180 patients treated with glucocorticoids vs. (33.3%) in 63 patients enrolled to the control group [31] but Anomar-Millan et al. was in agreement with above reported data, the 60 day mortality rate was similar between two groups received corticosteroid solely or as a combination with tocilizumab as a first line but when 10 patients received anakinra; clinical improvement noticed and that explained by a possible synergistic effects of steroid and its role in controlling the hyperinflammatory state [32].

To the best of our knowledge, this is the first meta-analysis investigating the effect of anakinra on clinical outcomes of patients with severe COVID-19 which includes an RCT. A previously published meta-analysis of non-randomized cohort studies by Pasin et al. confirm our findings. The meta-analysis included four studies with a total of 184 patients and showed significantly lower mortality and risk for mechanical ventilation in anakinra group. Furthermore, no difference in adverse events was observed between the treatment and control groups [33]. Our study includes 15 articles in both qualitative and quantitative analysis, therefore providing stronger evidence in favor of anakinra.

Based on the analysis of five retrospective studies [9, 10, 12, 13, 14], it was found that anakinra could provide additional benefit for improving the mortality outcome of severe COVID-19. However, it was found that anakinra could not provide any additional benefit for other clinical outcomes of severe COVID-19. In the study by Huet et al., of 96 patients, the mortality was 25% (13/52) compared to 73% (32/44) in control, demonstrating that overall mortality favors anakinra administration. This was further demonstrated in the study by Cavalli et al., where mortality was 10% (3/29) in the anakinra group compared to 44% (7/16) in the control group [9, 12]. In a smaller size study of Dimopoulos et al. and Navarro-Millan et al., the mortality was reported to be 37.5% (3/8) and 9.09% (1/11), respectively [15, 16]. In contrast, the mortality rate favored the control group in Narain et al with an HR at 95% CI 2.12 (1.68 - 2.66) [14]. In the study by Huet et al, of the 96 patients, the need for mechanical ventilation was 25% (13/52) than 73% (32/44) in control, demonstrating that the overall need for mechanical ventilation favors anakinra administration [9]. Cavalli et al noted similar findings with 17% (5/29) in the anakinra group and 6% (1/16) in the control group [12]. In a smaller size study of Dimopoulos et al. and Navarro-Millan et al., the need for mechanical ventilation was reported to be 87.5% (7/8) and 36.4% (4/11), respectively [15, 16]. Several studies reported an overall decrease in the inflammatory marker levels, such as C- reactive protein (CRP) levels, ferritin levels, and NOD-like receptor protein-3 (NLRP-3) inflammasome [9, 12, 29, 34]. Multiple other studies also supported decreased oxygen requirements at the end of the treatment period [1, 3, 10]. Huet et al showed that oxygen supply decreased to 2 L/min from 7 L/min [9].

Two studies noticed a significant decrease in temperature reaching normalcy in 2 - 10 days, improving oxygen requirements and respiratory function [16, 17]. Two studies noticed a significant improvement in the modified WHO ordinal scale [12, 15]. Cavalli et al reported improved survival in patients receiving anakinra compared to standard therapy; however, mechanical ventilation-free survival was not significantly improved in the anakinra group than the standard treatment group [12]. Navarro-Millan et al. noted that early initiation before requiring supplemental O₂ therapy prevented worsening in clinical status (i.e., need for mechanical ventilation). The study also included four mechanically ventilated patients who received anakinra; two patients were discharged, and one patient died [15]. The H-score used to diagnose HLH was noted to significantly decrease at the end of the treatment period (of anakinra administration to COVID-19 patients) in the studies by Dimopoulos et al. and Day et al. [16, 17]. Although both studies reported high sensitivity and specificity for diagnosing HLH, this tool has certain limitations in stratifying between moderate and severe COVID-19 patients, so severity may be underreported [35].

In our review, the therapeutic efficacy of anakinra for COVID-19 pneumonia was assessed by the need of IMV and the rate of mortality. The need for mechanical ventilation was reduced in patients treated with anakinra as compared to patients receiving SOC (OR of 0.68 [95% CI 0.49 - 0.59, P = 0.02]). However, with the therapeutic use of anakinra in patients with COVID-19 the risk of mortality was reduced by almost 20% (P <0.00001). This latter finding suggests that Anakinra is efficacious and although it may not change the course of the disease, it does increase the risk of survival. Furthermore, the utility of anakinra in the treatment of COVID-19 was found to be safe, as measured by the incidence of thromboembolic events and elevation in hepatic transaminases. There were no significant differences between these adverse events in patients treated with anakinra and those receiving SOC.

Anakinra use in COVID-19 patients has shown to have a similar safety profile with the control group without any other significant increase in adverse effects. Cavalli et al., 10 patients in the anakinra group experienced thromboembolic events than five in the control group. This was consistent in Huet et al., which showed three patients in the anakinra group than two in control having thromboembolic events. Cavalli et al., seven patients in the anakinra group had increased liver transaminase levels than four in the control group [9, 12]. This was consistent in Huet et al., which showed three patients in the anakinra group than five in control [9]. Cavalli et al. identified four patients with bacteremia in the anakinra group and two in the control group [12]. Drug adverse reactions as the clinical outcome were noticed in a retrospective cohort study by Cavalli et al. in seven (24%) patients after a median treatment duration of nine days (interquartile range [IQR] 8 - 10) with high dose anakinra; four of the patients had bacteremia with the isolation of staphylococcus epidermidis and three had raised serum enzyme levels. This event led to drug discontinuation among patients with a median age of 62 years (IQR 55 - 71) with at least one comorbidity (arterial hypertension, diabetes, chronic obstructive pulmonary disease, and tobacco) [11]. No significant adverse events, including bacterial infections, were noted in the study of Huet et al. superimposed infections were most likely seen in mechanically ventilated patients due to respiratory failure [9]. Raise in procalcitonin and transaminase levels were seen in many patients. In another cohort study, raised serum liver aminotransferases were seen [9]. Other complications included injection site reaction and leukopenia in one patient. No drug allergic reactions were seen in any of the patients in the studies.

In conclusion, based on the current evidence, our analysis demonstrated that the use of anakinra for patients with COVID-19 was associated with the significantly low mortality rate and mechanical ventilation compared with standard care alone. Other outcomes such as thromboembolism risk and rise in liver enzymes are not significantly affected with the treatment. More extensive studies (RCTs) with long term follow-up of patients are required to provide conclusive evidence on the most effective dosing strategies and adverse effects.

Supplementary Table 1

Risk of bias for case series (Joanna Briggs Institute Appraisal Tool)

Supplementary Figure 1

Subgroup analysis based on gender, survival outcome, comorbidities such as hypertension, diabetes and cardiovascular disease.