Tocilizumab versus anakinra in COVID-19: results from propensity score matching.

Background: Tocilizumab and anakinra are anti-interleukin drugs to treat severe coronavirus disease 2019 (COVID-19) refractory to corticosteroids. However, no studies compared the efficacy of tocilizumab versus anakinra to guide the choice of the therapy in clinical practice. We aimed to compare the outcomes of COVID-19 patients treated with tocilizumab or anakinra. Methods: Our retrospective study was conducted in three French university hospitals between February 2021 and February 2022 and included all the consecutive hospitalized patients with a laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection assessed by RT-PCR who were treated with tocilizumab or anakinra. A propensity score matching was performed to minimize confounding effects due to the non-random allocation. Results: Among 235 patients (mean age, 72 years; 60.9% of male patients), the 28-day mortality (29.4% vs. 31.2%, p = 0.76), the in-hospital mortality (31.7% vs. 33.0%, p = 0.83), the high-flow oxygen requirement (17.5% vs. 18.3%, p = 0.86), the intensive care unit admission rate (30.8% vs. 22.2%, p = 0.30), and the mechanical ventilation rate (15.4% vs. 11.1%, p = 0.50) were similar in patients receiving tocilizumab and those receiving anakinra. After propensity score matching, the 28-day mortality (29.1% vs. 30.4%, p = 1) and the rate of high-flow oxygen requirement (10.1% vs. 21.5%, p = 0.081) did not differ between patients receiving tocilizumab or anakinra. Secondary infection rates were similar between the tocilizumab and anakinra groups (6.3% vs. 9.2%, p = 0.44). Conclusion: Our study showed comparable efficacy and safety profiles of tocilizumab and anakinra to treat severe COVID-19.

Unbalanced networks and disturbed kinetics of serum soluble mediators associated with distinct disease outcomes in severe COVID-19 patients.

The present study applied distinct models of descriptive analysis to explore the integrative networks and the kinetic timeline of serum soluble mediators to select a set of systemic biomarkers applicable for the clinical management of COVID-19 patients. For this purpose, a total of 246 participants (82 COVID-19 and 164 healthy controls - HC) were enrolled in a prospective observational study. Serum soluble mediators were quantified by high-throughput microbeads array on hospital admission (D0) and at consecutive timepoints (D1-6 and D7-20). The results reinforce that the COVID-19 group exhibited a massive storm of serum soluble mediators. While increased levels of CCL3 and G-CSF were associated with the favorable prognosis of non-mechanical ventilation (nMV) or discharge, high levels of CXCL10 and IL-6 were observed in patients progressing to mechanical ventilation (MV) or death. At the time of admission, COVID-19 patients presented a complex and robust serum soluble mediator network, with a higher number of strong correlations involving IFN-γ, IL-1Ra and IL-9 observed in patients progressing to MV or death. Multivariate regression analysis demonstrates the ability of serum soluble mediators to cluster COVID-19 from HC. Ascendant fold change signatures and the kinetic timeline analysis further confirmed that the pairs "CCL3 and G-CSF" and "CXCL10 and IL-6" were associated with favorable or poor prognosis, respectively. A selected set of systemic mediators (IL-6, IFN-γ, IL-1Ra, IL-13, PDGF and IL-7) were identified as putative laboratory markers, applicable as complementary records for the clinical management of patients with severe COVID-19.

Anakinra as a potential treatment for COVID-19.

On November 8, 2022, the United States Food and Drug Administration (FDA) issued an emergency use authorization for the interleukin-1 (IL-1) inhibitor anakinra for the treatment of patients with COVID-19 pneumonia. The authorization was specifically intended for patients requiring supplemental oxygen who are at risk of progression to respiratory failure and are likely to have an elevated plasma soluble urokinase plasminogen activator receptor. Anakinra is a modified, recombinant human IL-1 receptor antagonist used to treat rheumatoid arthritis, neonatal-onset multisystem inflammatory disease and other inflammatory diseases. This manuscript examines what is known about the role of IL-1 receptor antagonism in the treatment of patients with COVID-19 and examines how anakinra may be used in the future to address the SARS-CoV-2 infection pandemic.

Criteria for Hyperinflammation Developing in COVID-19: Analysis of 2 Cohorts From Different Periods of the Pandemic.

OBJECTIVE: Hyperinflammation (HI) that develops in week 2 of COVID-19 contributes to a worse outcome. Because week 2 laboratory findings can be relatively mild, the available criteria for classification of hemophagocytic lymphohistiocytosis or macrophage activation syndrome are not helpful. METHODS: Our study included a discovery cohort of patients from Turkey with symptomatic COVID-19 who were followed up while hospitalized during the initial wave and a replication cohort of hospitalized patients from a later period, all of whom required oxygen support and received glucocorticoids. Diagnosis of HI was made by an expert panel; most patients with COVID-19-associated HI (HIC) received tocilizumab or anakinra. Clinical and laboratory data from start day of treatment with tocilizumab or anakinra in HIC patients were compared with the data from day 5-6 in patients without HIC. Values maximizing the sensitivity and specificity of each parameter were calculated to determine criteria items. RESULTS: The discovery cohort included 685 patients, and the replication cohort included 156 patients, with 150 and 61 patients receiving treatment for HI, respectively. Mortality rate in HI patients in the discovery cohort (23.3%) was higher than the rate in patients without HI (3.7%) and the rate in patients in the overall replication cohort (10.3%). The 12-item criteria that we developed for HIC showed that a score of 35 provided 85.3% sensitivity and 81.7% specificity for identification of HIC. In the replication cohort, the same criteria resulted in 90.0% sensitivity for HIC; however, lower specificity values were observed because of the inclusion of milder cases of HIC responding only to glucocorticoids. CONCLUSION: The use of the 12-item criteria for HIC can better define patients with HIC with reasonable sensitivity and specificity and enables an earlier treatment start.

The Role of Inflammatory Cytokines (Interleukin-1 and Interleukin-6) as a Potential Biomarker in the Different Stages of COVID-19 (Mild, Severe, and Critical).

Cytokine storm refers to the overproduction of immune and inflammatory cells and their proteins (cytokines) [interleukin (IL)-1 and IL-6] causing acute respiratory distress syndrome in COVID-19. COVID-19 causes inflammatory reactions, and patients with COVID-19 had categorized as mild, severe, and critical after reviewing previous studies. Then, it is crucial to find immune-inflammatory indicators that might predict the disorder severity and the prognosis primarily for guiding medical therapy in the face of this unexpectedly developing unique infectious disease. Higher levels of IL-6 and IL-1 levels might be seen in patients with COVID-19 at each stage. In addition, IL-1-induced IL-6 assists in the synthesis of liver C-reactive protein (CRP) in acute phase responses. Recent studies suggested that IL-6 levels are an independent predictor of COVID-19 illness because they were significantly higher in patients with severe than with mild COVID-19 symptoms. Anakinra and tocilizumab (TCZ) are beneficial in lowing mortality in COVID-19 patients; however, information on their safety and efficacy is scarce. The aim of this study was to investigate the role of inflammatory cytokines (IL-1 and IL-6) as potential biomarkers in the different stages (mild, severe, and critical) of COVID-19. A systematic search during the years 2021-2022 using the keywords SARS-CoV-2, COVID-19, IL-6, IL-1, CRP, mild stage, severe stage, critical stage, cytokine storm, tocilizumab, and anakinra was performed in PubMed and Google Scholar databases. This study reviews studies that have investigated the role of high levels of these cytokines in the severity of the disease in patients with COVID-19 and the inhibitory function of TCZ and anakinra in preventing mechanical ventilation and patient mortality. According to the result, studies suggest that decreased innate immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in association with the production of inflammatory cytokines is the determining and driving function of COVID-19.

Efficacy and Safety of Anakinra Plus Standard of Care for Patients With Severe COVID-19: A Randomized Phase 2/3 Clinical Trial.

Importance: COVID-19 pneumonia is often associated with hyperinflammation. The efficacy and safety of anakinra in treating patients with severe COVID-19 pneumonia and hyperinflammation are still unclear. Objective: To assess the efficacy and safety of anakinra vs standard of care alone for patients with severe COVID-19 pneumonia and hyperinflammation. Design, Setting, and Participants: The Clinical Trial of the Use of Anakinra in Cytokine Storm Syndrome Secondary to COVID-19 (ANA-COVID-GEAS) was a multicenter, randomized, open-label, 2-group, phase 2/3 clinical trial conducted at 12 hospitals in Spain between May 8, 2020, and March 1, 2021, with a follow-up of 1 month. Participants were adult patients with severe COVID-19 pneumonia and hyperinflammation. Hyperinflammation was defined as interleukin-6 greater than 40 pg/mL, ferritin greater than 500 ng/mL, C-reactive protein greater than 3 mg/dL (rationale, ≥5 upper normal limit), and/or lactate dehydrogenase greater than 300 U/L. Severe pneumonia was considered if at least 1 of the following conditions was met: ambient air oxygen saturation 94% or less measured with a pulse oximeter, ratio of partial pressure O2 to fraction of inspired O2 of 300 or less, and/or a ratio of O2 saturation measured with pulse oximeter to fraction of inspired O2 of 350 or less. Data analysis was performed from April to October 2021. Interventions: Usual standard of care plus anakinra (anakinra group) or usual standard of care alone (SoC group). Anakinra was given at a dose of 100 mg 4 times a day intravenously. Main Outcomes and Measures: The primary outcome was the proportion of patients not requiring mechanical ventilation up to 15 days after treatment initiation, assessed on an intention-to-treat basis. Results: A total of 179 patients (123 men [69.9%]; mean [SD] age, 60.5 [11.5] years) were randomly assigned to the anakinra group (92 patients) or to the SoC group (87 patients). The proportion of patients not requiring mechanical ventilation up to day 15 was not significantly different between groups (64 of 83 patients [77.1%] in the anakinra group vs 67 of 78 patients [85.9%] in the SoC group; risk ratio [RR], 0.90; 95% CI, 0.77-1.04; P = .16). Anakinra did not result in any difference in time to mechanical ventilation (hazard ratio, 1.72; 95% CI, 0.82-3.62; P = .14). There was no significant difference between groups in the proportion of patients not requiring invasive mechanical ventilation up to day 15 (RR, 0.99; 95% CI, 0.88-1.11; P > .99). Conclusions and Relevance: In this randomized clinical trial, anakinra did not prevent the need for mechanical ventilation or reduce mortality risk compared with standard of care alone among hospitalized patients with severe COVID-19 pneumonia. Trial Registration: ClinicalTrials.gov Identifier: NCT04443881.

Anakinra for the treatment of COVID-19 patients: a systematic review and meta-analysis.

BACKGROUND: At the end of 2021, the European Medicines Agency (EMA) expanded its approval for the recombinant human interleukin-1 (IL-1) receptor antagonist Anakinra for the treatment of COVID-19 patients with elevated soluble urokinase plasminogen activator receptor (suPAR). However, the role of Anakinra in COVID-19 remains unanswered, especially in patients receiving different forms of respiratory support. Therefore, the objective of this systematic review is to assess the safety and effects of Anakinra compared to placebo or standard care alone on clinical outcomes in adult hospitalized patients with SARS-CoV-2 infection. METHODS: We searched the Cochrane COVID-19 Study Register (comprising MEDLINE, Embase, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, medRxiv, and the Cochrane Central Register of Controlled Trials (CCSR)) and the WHO COVID-19 Global literature on coronavirus disease database to identify completed and ongoing studies from inception of each database to December 13, 2021. Since then, we monitored new published studies weekly up to June 30, 2022 using the CCSR. We included RCTs comparing treatment with Anakinra to placebo or standard care alone in adult hospitalized patients with SARS-CoV-2 infection. RESULTS: We included five RCTs with 1,627 patients (nAnakinra = 888, ncontrol = 739, mean age 59.63 years, 64% male). Random-effects meta-analysis was used to pool data. We found that Anakinra makes little or no difference to all-cause mortality at up to day 28 compared to placebo or standard care alone (RR 0.96, 95% CI 0.64-1.45; RD 9 fewer per 1000, 95% CI 84 fewer to 104 more; 4 studies, 1593 participants; I2 = 49%; low certainty of evidence). CONCLUSIONS: Anakinra has no effect on adult hospitalized patients with SARS-CoV-2 infection regarding mortality, clinical improvement and worsening as well as on safety outcomes compared to placebo or standard care alone. TRIAL REGISTRATION: PROSPERO Registration Number: CRD42021257552.

Anakinra-An Interleukin-1 Receptor Antagonist for COVID-19.

BACKGROUND: Coronavirus disease (COVID-19) caused by SARS-CoV-2 virus caused a global pandemic in 2019. There are limited pharmacologic options available. The Food and Drug Administration initiated an emergency use authorization process to expedite pharmacologic agents to treat COVID-19. There are several agents available through the emergency use authorization process, ritonavir-boosted nirmatrelvir, remdesivir, and baricitinib. Anakinra is an interleukin (IL)-1 receptor antagonist that exhibits properties in fighting against COVID-19. MECHANISM OF ACTION, PHARMACODYNAMICS, AND PHARMACOKINETICS: Anakinra is a recombinant IL-1 receptor antagonist. The epithelial cell damage that may occur with COVID-19 enhances the release of IL-1, which plays a central role in severe cases. Thus, drugs that inhibit the IL-1 receptor may be beneficial in the management of COVID-19. Anakinra has good bioavailability after subcutaneous injection and a half-life of up to 6 hours. CLINICAL TRIALS: The SAVE-MORE, double-blind, randomized controlled trial, phase 3 evaluated the efficacy and safety of anakinra. Anakinra 100 mg was given subcutaneously daily for up to 10 days in patients with moderate and severe COVID-19 and plasma suPAR ≥6 ng/mL. Anakinra group had a 50.4% fully recovered with no viral RNA detected on day 28 versus 26.5% for placebo, and more than 50% of relative decrease in mortality. A significantly decreased risk of worse clinical outcome was observed. THERAPEUTIC ADVANCE: COVID-19 causes global pandemic and a serious viral disease. There are limited therapy options to combat this deadly disease. Anakinra is an IL-1 receptor antagonist and shown to be effective for the treatment of COVID-19 in some trials but not others. Anakinra, the first in this class, seems to have a mix result for the treatment of COVID-19.

Characteristics and clinical outcome in 312 patients with moderate to severe pneumonia due to SARS-COV-2 and hyperinflammation treated with anakinra and corticosteroids: A retrospective cohort study.

OBJECTIVE: To assess the clinical outcome (death and/or Intensive Care Unit (ICU) admission) based on the time from hospital admission to the administration of anakinra and the possible usefulness of a "simplified" SCOPE score to stratify the risk of worse prognosis in our cohort of patients with moderate/severe SARS-CoV-2 pneumonia, both vaccinated and unvaccinated, that received anakinra and corticosteroids. In addition, the clinical, analytical, and imaging characteristics of patients at admission are described. METHODS: Retrospective cohort study of 312 patients admitted to Hospital Clínico San Cecilio in Granada for moderate/severe pneumonia caused by SARS-CoV-2 that received anakinra and corticosteroids between March 2020 and January 2022. Clinical and analytical data were collected as well as the patient outcome at 30 and 60 days after admission. Three treatment groups were established according to the time from hospital admission to administration of anakinra: early (1st-2nd day), intermediate (3rd-5th day), and late (after the 5th day). RESULTS: The median age was 67.4 years (IQR 22-97 years) and 204 (65.4%) were male. The most common comorbidity was hypertension (58%). The median time from the start of symptoms to anakinra administration was 6 days (IQR 5-10) and the SaFi (SaO2/FiO2) was 228 (IQR 71-471). The cure rate was higher in the early-onset anakinra group versus the late-onset group (73% vs 56.6%). The latter had a higher percentage of deaths (27.4%) and a greater number of patients remained hospitalized for a month (16%). On admission, the patients had elevated C-reactive protein (CRP), ferritin, and D-dimer values and decreased total lymphocytes. Analytical improvement was observed at both 72 hours and one month after treatment. 42 (13.5%) required ICU admission, and 23 (7.3%) orotracheal intubation. At 60 days, 221 (70.8%) were discharged, 87 (27.8%) had died and 4 (1.4%) remained hospitalized. The mean dose of anakinra was 1000 mg (100-2600 mg) with differences found between the dose administered and the clinical outcome. There were no differences in the primary outcome based on vaccination. A simplified SCOPE score at the start of anakinra administration was lower in patients with better clinical evolution. CONCLUSIONS: Early treatment with anakinra and corticosteroids was associated with a better outcome regardless of vaccination status. A simplified SCOPE was found to be a good prognostic tool.

Anakinra in hospitalized COVID-19 patients guided by baseline soluble urokinase plasminogen receptor plasma levels: A real world, retrospective cohort study.

BACKGROUND: In patients with COVID-19 and baseline soluble urokinase plasminogen receptor plasma (suPAR) levels ≥ 6ng/mL, early administration of anakinra, a recombinant interleukin-1 receptor antagonist, may prevent disease progression and death. In case of suPAR testing unavailability, the Severe COvid Prediction Estimate (SCOPE) score may be used as an alternative in guiding treatment decisions. METHODS: We conducted a monocenter, retrospective cohort study, including patients with SARS-CoV2 infection and respiratory failure. Patients treated with anakinra (anakinra group, AG) were compared to two control groups of patients who did not receive anakinra, respectively with ≥ 6 ng/mL (CG1) and < 6 ng/mL (CG2) baseline suPAR levels. Controls were manually paired by age, sex, date of admission and vaccination status and, for patients with high baseline suPAR, propensity score weighting for receiving anakinra was applied. Primary endpoint of the study was disease progression at day 14 from admission, as defined by patient distribution on a simplified version of the 11-point World Health Organization Clinical Progression Scale (WHO-CPS). RESULTS: Between July, 2021 and January, 2022, 153 patients were included, among which 56 were treated with off-label anakinra, 49 retrospectively fulfilled prescriptive criteria for anakinra and were assigned to CG1, and 48 presented with suPAR levels < 6ng/mL and were assigned to CG2. At day 14, when comparing to CG1, patients who received anakinra had significantly reduced odds of progressing towards worse clinical outcome both in ordinal regression analysis (OR 0.25, 95% CI 0.11-0.54, p<0.001) and in propensity-adjusted multiple logistic regression analysis (OR 0.32, 95% CI 0.12-0.82, p = 0.021) thus controlling for a wide number of covariates. Sensitivities of baseline suPAR and SCOPE score in predicting progression towards severe disease or death at day 14 were similar (83% vs 100%, p = 0.59). CONCLUSION: This real-word, retrospective cohort study confirmed the safety and the efficacy of suPAR-guided, early use of anakinra in hospitalized COVID-19 patients with respiratory failure.

Patients diagnosed with COVID-19 and treated with anakinra: a real-world study in the USA.

Anakinra, a recombinant, non-glycosylated human interleukin (IL)-1 receptor antagonist, has been used in real-world clinical practice to manage hyperinflammation in coronavirus disease 2019 (COVID-19). This retrospective, observational study analyses US hospital inpatient data of patients diagnosed with moderate/severe COVID-19 and treated with anakinra between 1 April and 31 August 2020. Of the 119 patients included in the analysis, 63.9% were male, 48.6% were of black ethnicity, and the mean (standard deviation [SD]) age was 64.7 (12.5) years. Mean (SD) time from hospital admission to anakinra initiation was 7.3 (6.1) days. Following anakinra initiation, 73.1% of patients received antibiotics, 55.5% received antithrombotics, and 91.0% received corticosteroids. Overall, 64.7% of patients required intensive care unit (ICU) admittance, and 28.6% received mechanical ventilation following admission. Patients who did not require ICU admittance or who were discharged alive experienced a significantly shorter time between hospital admission and receiving anakinra treatment compared with those admitted to the ICU (5 vs. 8 days; P = 0.002) or those who died in hospital (6 vs. 9 days; P = 0.01). Patients with myocardial infarction or renal conditions were six times (P < 0.01) and three times (P = 0.01), respectively, more likely to die in hospital than be discharged alive. A longer time from hospital admission until anakinra treatment was associated with significantly higher mortality (P = 0.01). Findings from this real-world study suggest that a shorter time from hospital admission to anakinra treatment is associated with significantly lower ICU admissions and mortality among patients with moderate/severe COVID-19.

Clinical and biochemical short-term effects of hyperbaric oxygen therapy on SARS-Cov-2+ hospitalized patients with hypoxemic respiratory failure.

BACKGROUND: Hyperbaric oxygen therapy (HBOT) has been proposed to address COVID-19- associated respiratory failure. However, its biochemical effects are poorly known. METHOD: 50 patients with hypoxemic COVID-19 pneumonia were divided into C group (standard care) and H group (standard care plus HBOT). Blood was obtained at t = 0 and t = 5 days. Oxygen saturation (O2 Sat) was followed up. White blood cell (WC) count, lymphocytes (L) and platelets (P) and serum analysis (glucose, urea, creatinine, sodium, potassium, ferritin, D dimer, LDH and CRP) were carried out. Plasma levels of sVCAM, sICAM, sPselectin, SAA and MPO, and of cytokines (IL-1ß, IL-1RA, IL-6, TNFα, IFNα, IFNγ, IL-15, VEGF, MIP1α, IL-12p70, IL-2 and IP-10) were measured by multiplex assays. Angiotensin Converting Enzyme 2 (ACE-2) levels were determined by ELISA. RESULTS: The average basal O2 Sat was 85 ± 3%. The days needed to reach O2 Sat >90% were: H: 3 ± 1 and C: 5 ± 1 (P < 0,01). At term, H increased WC, L and P counts (all, H vs C: P < 0,01). Also, H diminished D dimer levels (H vs C, P < 0,001) and LDH concentration (H vs C, P < 0.01]. At term, H showed lower levels of sVCAM, sPselectin and SAA than C with respect to basal values (H vs C: ΔsVCAM: P < 0,01; ΔsPselectin: P < 0,05; ΔSAA: P < 0,01). Similarly, H showed diminished levels of TNFα (ΔTNFα: P < 0,05) and increased levels of IL-1RA and VEGF than C respect to basal values (H vs C: ΔIL-1RA and ΔVEGF: P < 0,05). CONCLUSION: Patients underwent HBOT improved O2 Sat with lower levels of severity markers (WC and platelets count, D dimer, LDH, SAA). Moreover, HBOT reduced proinflammatory agents (sVCAM, sPselectin, TNFα) and increased anti-inflammatory and pro-angiogenic ones (IL-1RA and VEGF).

High-dose intravenous anakinra treatment is safe and effective in severe and critical COVID-19 patients: a propensity score-matched study in a single center.

BACKGROUND: In COVID-19, severe disease course such as need of intensive care unit (ICU) as well as development of mortality is mainly due to cytokine storm. In this study, we aimed to evaluate the high-dose intravenous anakinra treatment response and outcome in patients with severe and critically ill COVID-19 compared to standard of care. METHODS: This retrospective observational study was carried out at a tertiary referral center. The study population consisted of two groups as follows: the patients receiving high-dose intravenous anakinra (anakinra group) between 01.09.2021 and 01.02.2022 and the patients treated with standard of care (SoC, control group) as historical control group who were hospitalized between 01.07.2021 and 01.09.2021. RESULTS: After the propensity score 1:1 matching, 79 patients in anakinra and 79 patients in SoC matched and were included into the analysis. Mean ± SD patient age was 67.4 ± 16.7 and 67.1 ± 16.3 years in anakinra and SoC groups, respectively (p = 0.9). Male gender was 38 (48.7%) in anakinra and 36 (46.2%) in SoC (p = 0.8). Overall, ICU admission was in 14.1% (n = 11) and 30.8% (n = 24) (p = 0.013; OR 6.2), intubation in 12.8% (n = 10) and 16.7% (n = 13) patients (p = 0.5), and 14.1% (n = 11) and 32.1% (n = 25) patients died in anakinra and control groups, respectively (p = 0.008; OR 7.1). CONCLUSION: In our study, mortality was lower in patients receiving anakinra compared to SoC. Intravenous high-dose anakinra is safe and effective treatment in patients with severe and critical COVID-19.

Anakinra was not associated with lower mortality in hospitalised COVID-19 patients: A systematic review and meta-analysis of randomized controlled trials.

The Coronavirus disease-2019 (COVID-19) pandemic continues, and the death toll continues to surge. This meta-analysis aimed to determine the efficacy of anakinra on mortality in patients with COVID-19. A systematic search was made of PubMed, Embase, Cochrane Library, and clinicaltrials.gov, without language restrictions. Randomized controlled trials on treatment of COVID-19 with anakinra, compared with placebo or blank, were reviewed. Studies were pooled to risk ratios (RRs), with 95% confidence intervals (CIs). Five Randomized controlled trials (enrolling 1859 participants) met the inclusion criteria. There was no statistically significant difference in 14-day mortality (RR 0.78, 95% CI 0.43-1.39; P = 0.40), 28-day mortality (RR 1.06, 95% CI 0.89-1.26; P = 0.51), and 90-day mortality (RR 1.01, 95% CI 0.73-1.39; P = 0.97) between the two groups. Sensitivity analyses further confirmed these results. Anakinra was not associated with reduced mortality in hospitalised patients with COVID-19. Anakinra probably should not be used routinely in COVID-19 patients.

Intravenous anakinra to curb cytokine storm in adult-onset Still's disease and in macrophage activation syndrome: A case series.

OBJECTIVE: Adult-onset Still's disease (AOSD) is an auto-inflammatory polygenic disorder, for which the diagnosis is essentially clinical. The exclusion of mimickers [such as common bacterial and viral infections, hematologic malignancies, and, more recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] is necessary to confirm the diagnosis. Anti-interleukin (IL)-1 therapy is considered a treatment milestone for AOSD. Herein, we present a short series of newly-diagnosed AOSD or upcoming macrophage activation syndrome (MAS) cases who received intravenous (IV) anakinra, an IL-1 receptor blocker. METHODS: Four patients with newly-diagnosed AOSD or upcoming MAS were treated with IV anakinra at the Rheumatology Unit of Padova University Hospital, Italy. We obtained informed consent from the patients for use of their cases and medical images for publication purposes. RESULTS: All patients presented with AOSD or MAS during the COVID-19 pandemic, making diagnosis challenging due to similar immunological and clinical characteristics across both pathologies. All patients presented with hyperpyrexia and elevated inflammatory markers; two patients had a skin rash typically seen in AOSD. IV anakinra slowed down AOSD progression in all patients, prevented severe outcomes and mitigated the risk of multiorgan failure. All cases improved within 24hours of anakinra administration. CONCLUSION: We found that administration of anakinra in patients with newly-diagnosed AOSD and/or upcoming MAS reduced hyperinflammation and prevented life-threatening complications. The IV route appears to be preferable in the hospital setting, where comorbidities such as coagulopathies and thrombocytopenia can complicate the use of other routes of administration.

Interferon gamma-induced protein 10 (IP-10) for the early prognosis of the risk for severe respiratory failure and death in COVID-19 pneumonia.

OBJECTIVES: Elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) predict progression to severe respiratory failure (SRF) or death among patients with COVID-19 pneumonia and guide early anakinra treatment. As suPAR testing may not be routinely available in every health-care setting, alternative biomarkers are needed. We investigated the performance of C-reactive protein (CRP), interferon gamma-induced protein-10 (IP-10) and TNF-related apoptosis-inducing ligand (TRAIL) for predicting SRF or death in COVID-19. METHODS: Two cohorts were studied; one discovery cohort with 534 patients from the SAVE-MORE clinical trial; and one validation cohort with 364 patients from the SAVE trial including also 145 comparators. CRP, IP-10 and TRAIL were measured by the MeMed Key® platform in order to select the biomarker with the best prognostic performance for the early prediction of progression into SRF or death. RESULTS: IP-10 had the best prognostic performance: baseline concentrations 2000 pg/ml or higher predicted equally well to suPAR (sensitivity 85.0 %; negative predictive value 96.6 %). Odds ratio for poor outcome among anakinra-treated participants of the SAVE-MORE trial was 0.35 compared to placebo when IP-10 was 2,000 pg/ml or more. IP-10 could divide different strata of severity for SRF/death by day 14 in the validation cohort. Anakinra treatment decreased this risk irrespective the IP-10 concentrations. CONCLUSIONS: IP-10 concentrations of 2,000 pg/ml or higher are a valid alternative to suPAR for the early prediction of progression into SRF or death the first 14 days from hospital admission for COVID-19 and they may guide anakinra treatment. CLINICALTRIALS: gov, NCT04680949 and NCT04357366.

Comparison of anakinra and tocilizumab in management of severe COVID-19: a retrospective cohort study.

BACKGROUND: Studies regarding effectiveness of anakinra and tocilizumab treatments in coronavirus disease 2019 (COVID-19) have contradictory results. Furthermore, there is scarce comparative data regarding superiority of any agent. To further elucidate any superiority between these two agents, we retrospectively investigated and compared outcomes in hospitalized COVID-19 patients of our inpatient cohort who received anakinra or tocilizumab. METHODS: This study was designed as a single-center, retrospective, cross-sectional cohort study. Hospitalized patients with confirmed diagnosis of COVID-19 who had Brescia-COVID respiratory severity scale score ≥3 and hyperinflammation (defined as elevation of C reactive protein ≥50 g/L or ferritin ≥700 ng/mL) and received anakinra or tocilizumab in addition to standard care were enrolled in the study. Length of hospital stay after initiation of antiinflammatory treatment, need for mechanical ventilation, need for intensive care unit admission, mortality were set as primary outcomes and compared between tocilizumab and anakinra recipients after propensity score matching. RESULTS: One hundred and six patients were placed in each group after propensity score matching. In the anakinra group, relative risk reduction for intensive care unit admission was 50% when compared to the tocilizumab group and the number needed to treat to avert an intensive care unit admission was 3 (95% CI, 2-5). In terms of mortality, a 52% relative risk reduction was observed with anakinra treatment and the number needed to treat to avert an intensive care unit admission was 8 (95% CI, 4-50). Significantly more patients were observed to receive glucocorticoids in the anakinra group. DISCUSSION: Anakinra administration in severe COVID-19 patients was significantly associated with better survival and greater clinical improvement compared to the tocilizumab administration in our study. Increased rate of glucocorticoid use in the anakinra group might have contributed to better outcomes.