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1.
Front Immunol ; 14: 1185716, 2023.
Article in English | MEDLINE | ID: covidwho-20232537

ABSTRACT

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.


Subject(s)
COVID-19 , Humans , Male , Aged , SARS-CoV-2 , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Propensity Score , Retrospective Studies , COVID-19 Drug Treatment , Oxygen
2.
Drugs Today (Barc) ; 59(3): 107-112, 2023 Mar.
Article in English | MEDLINE | ID: covidwho-2309855

ABSTRACT

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.


Subject(s)
COVID-19 , Interleukin 1 Receptor Antagonist Protein , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Receptors, Interleukin-1 , SARS-CoV-2 , United States
3.
J Interferon Cytokine Res ; 43(4): 147-163, 2023 04.
Article in English | MEDLINE | ID: covidwho-2295509

ABSTRACT

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.


Subject(s)
COVID-19 , Humans , Interleukin-6 , Cytokines , SARS-CoV-2 , Interleukin-1 , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Cytokine Release Syndrome , Biomarkers , C-Reactive Protein
4.
JAMA Netw Open ; 6(4): e237243, 2023 04 03.
Article in English | MEDLINE | ID: covidwho-2294863

ABSTRACT

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.


Subject(s)
COVID-19 , Adult , Male , Humans , Middle Aged , Interleukin 1 Receptor Antagonist Protein/therapeutic use , SARS-CoV-2 , Standard of Care , Respiration, Artificial
5.
Arthritis Rheumatol ; 75(5): 664-672, 2023 05.
Article in English | MEDLINE | ID: covidwho-2291189

ABSTRACT

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.


Subject(s)
COVID-19 , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , SARS-CoV-2 , Pandemics , Glucocorticoids/therapeutic use
6.
PLoS One ; 18(3): e0283529, 2023.
Article in English | MEDLINE | ID: covidwho-2250026

ABSTRACT

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.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Male , Aged , Female , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Retrospective Studies , Adrenal Cortex Hormones/therapeutic use , Treatment Outcome
7.
PLoS One ; 18(4): e0273202, 2023.
Article in English | MEDLINE | ID: covidwho-2280393

ABSTRACT

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.


Subject(s)
COVID-19 , Respiratory Insufficiency , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Receptors, Urokinase Plasminogen Activator , Retrospective Studies , Urokinase-Type Plasminogen Activator , Plasminogen , RNA, Viral , SARS-CoV-2 , Disease Progression , Respiratory Insufficiency/chemically induced , Biomarkers
8.
Clin Exp Immunol ; 207(2): 218-226, 2022 04 04.
Article in English | MEDLINE | ID: covidwho-2278276

ABSTRACT

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.


Subject(s)
COVID-19 Drug Treatment , Interleukin 1 Receptor Antagonist Protein , Aged , Female , Humans , Intensive Care Units , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Male , Middle Aged , Respiration, Artificial , Retrospective Studies
10.
Joint Bone Spine ; 90(2): 105524, 2023 03.
Article in English | MEDLINE | ID: covidwho-2165494

ABSTRACT

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.


Subject(s)
COVID-19 , Macrophage Activation Syndrome , Still's Disease, Adult-Onset , Adult , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Still's Disease, Adult-Onset/complications , Still's Disease, Adult-Onset/diagnosis , Still's Disease, Adult-Onset/drug therapy , Macrophage Activation Syndrome/diagnosis , Macrophage Activation Syndrome/drug therapy , Macrophage Activation Syndrome/etiology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/complications , Pandemics , COVID-19/complications , SARS-CoV-2
12.
Turk J Med Sci ; 52(5): 1486-1494, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2091802

ABSTRACT

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.


Subject(s)
COVID-19 Drug Treatment , Interleukin 1 Receptor Antagonist Protein , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Retrospective Studies , Cross-Sectional Studies , Cohort Studies
13.
Eur Rev Med Pharmacol Sci ; 26(19): 7297-7304, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2081434

ABSTRACT

OBJECTIVE: Pneumonia and hyperinflammatory state related to COVID-19 infection are fatal clinical conditions without definite treatment modalities. Interleukin-6 and Interleukin-1 targeted therapies have been proposed as treatment options. This study was conducted to investigate the efficacy of anakinra and tocilizumab added to corticosteroids in patients with COVID-19-associated pneumonia and hyper-inflammatory syndrome in our tertiary clinical center. PATIENTS AND METHODS: Patients with COVID-19-associated pneumonia and hyperinflammatory state who did not respond to initial treatments, including corticosteroids, were included in the study. The patients' electronic records were reviewed retrospectively and recorded according to a standardized data table. Univariate and multivariate regression analyses were used to identify risk factors associated with intubation. RESULTS: 388 patients were included in the study. 197 patients were intubated and most of them died (n=194/197, 98%). 67 patients received tocilizumab, and 97 patients received anakinra. Anakinra [OR: 0.440, 95% CI=0.244-0.794, p=0.006] and tocilizumab [OR: 0.491, 95% CI=0.256-0.943, p=0.033] were both associated with a decreased risk for intubation. However, having a neutrophil/lymphocyte ratio ≥ 10 [OR: 2.035, 95% CI=1.143-3.623, p=0.016], serum lactate dehydrogenase (LDH) level ≥ 400 [OR: 3.160, 95% CI=1.937-5.156, p<0.001] and age ≥ 50 [OR: 4.048, 95% CI=2.037-8.043, p < 0.001] was associated with an increased risk for intubation. CONCLUSIONS: Both anakinra and tocilizumab, added to initial standard COVID-19 treatments (including glucocorticoids) reduced the need for intubation in patients with COVID-19-associated severe pneumonia and hyperinflammatory syndrome. Given the high mortality rate of intubated patients with COVID-19, both treatments may have added benefits on mortality.


Subject(s)
COVID-19 Drug Treatment , Humans , SARS-CoV-2 , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-6 , Retrospective Studies , Treatment Outcome , Adrenal Cortex Hormones/therapeutic use , Interleukin-1 , Lactate Dehydrogenases
14.
J Allergy Clin Immunol ; 150(4): 796-805, 2022 10.
Article in English | MEDLINE | ID: covidwho-1991092

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may result in a severe pneumonia associated with elevation of blood inflammatory parameters, reminiscent of cytokine storm syndrome. Steroidal anti-inflammatory therapies have shown efficacy in reducing mortality in critically ill patients; however, the mechanisms by which SARS-CoV-2 triggers such an extensive inflammation remain unexplained. OBJECTIVES: To dissect the mechanisms underlying SARS-CoV-2-associated inflammation in patients with severe coronavirus disease 2019 (COVID-19), we studied the role of IL-1ß, a pivotal cytokine driving inflammatory phenotypes, whose maturation and secretion are regulated by inflammasomes. METHODS: We analyzed nod-like receptor protein 3 pathway activation by means of confocal microscopy, plasma cytokine measurement, cytokine secretion following in vitro stimulation of blood circulating monocytes, and whole-blood RNA sequencing. The role of open reading frame 3a SARS-CoV-2 protein was assessed by confocal microscopy analysis following nucleofection of a monocytic cell line. RESULTS: We found that circulating monocytes from patients with COVID-19 display ASC (adaptor molecule apoptotic speck like protein-containing a CARD) specks that colocalize with nod-like receptor protein 3 inflammasome and spontaneously secrete IL-1ß in vitro. This spontaneous activation reverts following patient's treatment with the IL-1 receptor antagonist anakinra. Transfection of a monocytic cell line with cDNA coding for the ORF3a SARS-CoV-2 protein resulted in ASC speck formation. CONCLUSIONS: These results provide further evidence that IL-1ß targeting could represent an effective strategy in this disease and suggest a mechanistic explanation for the strong inflammatory manifestations associated with COVID-19.


Subject(s)
COVID-19 Drug Treatment , Inflammasomes , Anti-Inflammatory Agents , Cytokine Release Syndrome/drug therapy , Cytokines/metabolism , DNA, Complementary , Humans , Inflammasomes/metabolism , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-1beta/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Proteins , Receptors, Interleukin-1 , SARS-CoV-2
15.
PLoS One ; 17(8): e0269065, 2022.
Article in English | MEDLINE | ID: covidwho-1974304

ABSTRACT

OBJECTIVE: We aimed to investigate whether anakinra, an interleukin-1receptor inhibitor, could improve outcome in moderate COVID-19 patients. METHODS: In this controlled, open-label trial, we enrolled adults with COVID-19 requiring oxygen. We randomly assigned patients to receive intravenous anakinra plus optimized standard of care (oSOC) vs. oSOC alone. The primary outcome was treatment success at day 14 defined as patient alive and not requiring mechanical ventilation or extracorporeal membrane oxygenation. RESULTS: Between 27th April and 6th October 2020, we enrolled 71 patients (240 patients planned to been enrolled): 37 were assigned to the anakinra group and 34 to oSOC group. The study ended prematurely by recommendation of the data and safety monitoring board due to safety concerns. On day 14, the proportion of treatment success was significantly lower in the anakinra group 70% (n = 26) vs. 91% (n = 31) in the oSOC group: risk difference-21 percentage points (95% CI, -39 to -2), odds ratio 0.23 (95% CI, 0.06 to 0.91), p = 0.027. After a 28-day follow-up, 9 patients in the anakinra group and 3 in the oSOC group had died. Overall survival at day 28 was 75% (95% CI, 62% to 91%) in the anakinra group versus 91% (95% CI, 82% to 100%) (p = 0.06) in the oSOC group. Serious adverse events occurred in 19 (51%) patients in the anakinra group and 18 (53%) in the oSOC group (p = 0·89). CONCLUSION: This trial did not show efficacy of anakinra in patients with COVID-19. Furthermore, contrary to our hypothesis, we found that anakinra was inferior to oSOC in patients with moderate COVID-19 pneumonia.


Subject(s)
COVID-19 Drug Treatment , Adult , Humans , Interleukin 1 Receptor Antagonist Protein/adverse effects , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Respiration, Artificial , SARS-CoV-2 , Treatment Outcome
16.
Int Immunopharmacol ; 111: 109075, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-1936581

ABSTRACT

Despite the progressing knowledge in COVID-19 management, remdesivir is the only agent that got approval to inhibit viral replication. However, there are limited data about effective immunomodulatory agents to prevent cytokine release in COVID-19. Cytokine release syndrome in COVID-19 resembles secondary hemophagocytic lymphohistiocytosis, in which interleukin-1 (IL-1) plays a key role. Anakinra is the first recombinant IL-1 receptor antagonist studied for off-label use in COVID-19 treatment. This study reviews the current clinical evidence on the role of interleukin-1 in COVID-19-related cytokine storm, therapeutic effects, significant clinical concerns, and pros and cons of anakinra administration in the management of COVID-19 patients. In this review, four items are shown to be important for achieving the optimal therapeutic effects of anakinra in COVID-19 patients. These items include duration of treatment ≥ 10 days, doses ≥ 100 mg, intravenous administration, and early initiation of therapy. Also, anakinra might be more beneficial in the early stages of the disease when higher levels of cytokines are yet to be observed, which could prevent progression to severe illness and mechanical ventilation. Further studies are required to address the SARS-CoV-2 induced cytokine release syndrome and the role of anakinra in identifying ideal treatment approaches for COVID-19 patients based on their clinical status.


Subject(s)
COVID-19 Drug Treatment , Cytokine Release Syndrome/drug therapy , Cytokines , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-1 , SARS-CoV-2
17.
Int J Mol Sci ; 23(14)2022 Jul 19.
Article in English | MEDLINE | ID: covidwho-1938840

ABSTRACT

Coronavirus disease 2019 (COVID-19) is characterized by immune activation in response to viral spread, in severe cases leading to the development of cytokine storm syndrome (CSS) and increased mortality. Despite its importance in prognosis, the pathophysiological mechanisms of CSS in COVID-19 remain to be defined. Towards this goal, we analyzed cytokine profiles and their interrelation in regard to anti-cytokine treatment with tocilizumab in 98 hospitalized patients with COVID-19. We performed a multiplex measurement of 41 circulating cytokines in the plasma of patients on admission and 3-5 days after, during the follow-up. Then we analyzed the patient groups separated in two ways: according to the clusterization of their blood cytokines and based on the administration of tocilizumab therapy. Patients with and without CSS formed distinct clusters according to their cytokine concentration changes. However, the tocilizumab therapy, administered based on the standard clinical and laboratory criteria, did not fully correspond to those clusters of CSS. Furthermore, among all cytokines, IL-6, IL-1RA, IL-10, and G-CSF demonstrated the most prominent differences between patients with and without clinical endpoints, while only IL-1RA was prognostically significant in both groups of patients with and without tocilizumab therapy, decreasing in the former and increasing in the latter during the follow-up period. Thus, CSS in COVID-19, characterized by a correlated release of multiple cytokines, does not fully correspond to the standard parameters of disease severity. Analysis of the cytokine signature, including the IL-1RA level in addition to standard clinical and laboratory parameters may be useful to define the onset of a cytokine storm in COVID-19 as well as the indications for anti-cytokine therapy.


Subject(s)
COVID-19 Drug Treatment , Antibodies, Monoclonal, Humanized , Cytokine Release Syndrome/drug therapy , Cytokines , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-6 , SARS-CoV-2
18.
J Transl Med ; 20(1): 270, 2022 06 15.
Article in English | MEDLINE | ID: covidwho-1902395

ABSTRACT

BACKGROUND: Heart failure (HF) is a global leading cause of mortality despite implementation of guideline directed therapy which warrants a need for novel treatment strategies. Proof-of-concept clinical trials of anakinra, a recombinant human Interleukin-1 (IL-1) receptor antagonist, have shown promising results in patients with HF. METHOD: We designed a single center, randomized, placebo controlled, double-blind phase II randomized clinical trial. One hundred and two adult patients hospitalized within 2 weeks of discharge due to acute decompensated HF with reduced ejection fraction (HFrEF) and systemic inflammation (high sensitivity of C-reactive protein > 2 mg/L) will be randomized in 2:1 ratio to receive anakinra or placebo for 24 weeks. The primary objective is to determine the effect of anakinra on peak oxygen consumption (VO2) measured at cardiopulmonary exercise testing (CPX) after 24 weeks of treatment, with placebo-corrected changes in peak VO2 at CPX after 24 weeks (or longest available follow up). Secondary exploratory endpoints will assess the effects of anakinra on additional CPX parameters, structural and functional echocardiographic data, noninvasive hemodynamic, quality of life questionnaires, biomarkers, and HF outcomes. DISCUSSION: The current trial will assess the effects of IL-1 blockade with anakinra for 24 weeks on cardiorespiratory fitness in patients with recent hospitalization due to acute decompensated HFrEF. TRIAL REGISTRATION: The trial was registered prospectively with ClinicalTrials.gov on Jan 8, 2019, identifier NCT03797001.


Subject(s)
Heart Failure , Adult , Double-Blind Method , Humans , Interleukin 1 Receptor Antagonist Protein/pharmacology , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-1 , Quality of Life , Stroke Volume/physiology , Treatment Outcome
19.
BMJ Case Rep ; 15(6)2022 Jun 09.
Article in English | MEDLINE | ID: covidwho-1891770

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C) is a newly described syndrome related to the COVID-19, resembling other known aetiologies, including Kawasaki disease. Cardiovascular involvement is common; left ventricle dysfunction and coronary artery aneurysm (CAA) are also observed. Many treatment guidelines recommend using intravenous immunoglobulin (IVIG) alone or with glucocorticoids as the first-line therapy. Biological agents, such as anakinra, are recommended for refractory cases, but the evidence is still accumulating. Moreover, the use of other treatment agents can be beneficial, especially when anakinra is unavailable. Here, we report the case of a 9-year-old girl who presented with MIS-C with CAAs. She received cyclosporine because two rounds of IVIG treatment were ineffective and the use of anakinra is not approved in Japan. Her cytokine profile showed that cyclosporine prevented exacerbation. The case highlights that cyclosporine therapy can be an option for the treatment of refractory MIS-C with CAA.


Subject(s)
COVID-19 , Coronary Aneurysm , Mucocutaneous Lymph Node Syndrome , COVID-19/complications , Child , Coronary Aneurysm/complications , Coronary Aneurysm/drug therapy , Coronary Vessels , Cyclosporine/therapeutic use , Female , Humans , Immunoglobulins, Intravenous , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Mucocutaneous Lymph Node Syndrome/complications , Mucocutaneous Lymph Node Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/complications , Systemic Inflammatory Response Syndrome/drug therapy
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