Background Coronaviruses can induce the production of interleukin (IL)-1β, IL-6, tumour necrosis factor, and other cytokines implicated in autoinflammatory disorders. It has been postulated that anakinra, a recombinant IL-1 receptor antagonist, might help to neutralise the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related hyperinflammatory state, which is considered to be one cause of acute respiratory distress among patients with COVID-19. We aimed to assess the off-label use of anakinra in patients who were admitted to hospital for severe forms of COVID-19 with symptoms indicative of worsening respiratory function.Methods The Ana-COVID study included a prospective cohort from Groupe Hospitalier Paris Saint-Joseph (Paris, France) and a historical control cohort retrospectively selected from the Groupe Hospitalier Paris Saint-Joseph COVID cohort, which began on March 18, 2020. Patients were included in the prospective cohort if they were aged 18 years or older and admitted to Groupe Hospitalier Paris Saint-Joseph with severe COVID-19-related bilateral pneumonia on chest x-ray or lung CT scan. The other inclusion criteria were either laboratory-confirmed SARS-CoV-2 or typical lung infiltrates on a lung CT scan, and either an oxygen saturation of 93% or less under oxygen 6 L/min or more, or aggravation (saturation ≤93% under oxygen 3 L/min) with a loss of 3% of oxygen saturation in ambient air over the previous 24 h. The historical control group of patients had the same inclusion criteria. Patients in the anakinra group were treated with subcutaneous anakinra (100 mg twice a day for 72 h, then 100 mg daily for 7 days) as well as the standard treatments at the institution at the time. Patients in the historical group received standard treatments and supportive care. The main outcome was a composite of either admission to the intensive care unit (ICU) for invasive mechanical ventilation or death.The main analysis was done on an intention-to-treat basis (including all patients in the anakinra group who received at least one injection of anakinra). FindingsFrom March 24 to April 6, 2020, 52 consecutive patients were included in the anakinra group and 44 historical patients were identified in the Groupe Hospitalier Paris Saint-Joseph COVID cohort study. Admission to the ICU for invasive mechanical ventilation or death occurred in 13 (25%) patients in the anakinra group and 32 (73%) patients in the historical group (hazard ratio [HR] 0•22 [95% CI 0•11-0•41; p<0•0001). The treatment effect of anakinra remained significant in the multivariate analysis (HR 0•22 [95% CI 0•10-0•49]; p=0•0002). An increase in liver aminotransferases occurred in seven (13%) patients in the anakinra group and four (9%) patients in the historical group.Interpretation Anakinra reduced both need for invasive mechanical ventilation in the ICU and mortality among patients with severe forms of COVID-19, without serious side-effects. Confirmation of efficacy will require con trolled trials.
Background Anakinra might improve the prognosis of patients with moderate to severe COVID-19 (ie, patients requiring oxygen supplementation but not yet receiving organ support). We aimed to assess the effect of anakinra treatment on mortality in patients admitted to hospital with COVID-19. Methods For this systematic review and individual patient-level meta-analysis, a systematic literature search was done on Dec 28, 2020, in Medline (PubMed), Cochrane, medRxiv, bioRxiv, and the ClinicalTrials.gov databases for randomised trials, comparative studies, and observational studies of patients admitted to hospital with COVID-19, comparing administration of anakinra with standard of care, or placebo, or both. The search was repeated on Jan 22, 2021. Individual patient-level data were requested from investigators and corresponding authors of eligible studies; if individual patient-level data were not available, published data were extracted from the original reports. The primary endpoint was mortality after 28 days and the secondary endpoint was safety (eg, the risk of secondary infections). This study is registered on PROSPERO (CRD42020221491). Findings 209 articles were identified, of which 178 full-text articles fulfilled screening criteria and were assessed. Aggregate data on 1185 patients from nine studies were analysed, and individual patient-level data on 895 patients were provided from six of these studies. Eight studies were observational and one was a randomised controlled trial. Most studies used historical controls. In the individual patient-level meta-analysis, after adjusting for age, comorbidities, baseline ratio of the arterial partial oxygen pressure divided by the fraction of inspired oxygen (PaO 2 /FiO 2 ), C-reactive protein (CRP) concentrations, and lymphopenia, mortality was significantly lower in patients treated with anakinra (38 [11%] of 342) than in those receiving standard of care with or without placebo (137 [25%] of 553; adjusted odds ratio [OR] 0·32 [95% CI 0·20–0·51]). The mortality benefit was similar across subgroups regardless of comorbidities (ie, diabetes), ferritin concentrations, or the baseline PaO 2 /FiO 2 . In a subgroup analysis, anakinra was more effective in lowering mortality in patients with CRP concentrations higher than 100 mg/L (OR 0·28 [95% CI 0·17–0·47]). Anakinra showed a significant survival benefit when given without dexamethasone (OR 0·23 [95% CI 0·12–0·43]), but not with dexamethasone co-administration (0·72 [95% CI 0·37–1·41]). Anakinra was not associated with a significantly increased risk of secondary infections when compared with standard of care (OR 1·35 [95% CI 0·59–3·10]). Interpretation Anakinra could be a safe, anti-inflammatory treatment option to reduce the mortality risk in patients admitted to hospital with moderate t...
Background Anakinra may represent an important therapy to improve the prognosis of COVID-19 patients. This meta-analysis using individual patient data was designed to assess the efficacy and safety of anakinra treatment in patients with COVID-19. Methods Based on a pre-specified protocol (PROSPERO: CRD42020221491), a systematic literature search was performed in MEDLINE (PubMed), Cochrane, medRxiv.org, bioRxiv.org and clinicaltrials.gov databases for trials in COVID-19 comparing administration of anakinra with standard-of-care and/or placebo. Individual patient data from eligible trials were requested. The primary endpoint was the mortality rate and the secondary endpoint was safety. Findings Literature search yielded 209 articles, of which 178 articles fulfilled screening criteria and were full-text assessed. Aggregate data on 1185 patients from 9 studies were analyzed and individual patient data on 895 patients from 6 studies were collected. Most studies used historical controls. Mortality was significantly lower in anakinra-treated patients (38/342 [11.1%]) as compared with 137/553 (24.8%) observed in patients receiving standard-of-care and/or placebo on top of standard-of-care (137/553 [24.8%]); adjusted odds ratio (OR), 0.32; 95% CI, 0.20 to 0.51; p <0.001. The mortality benefit was similar across subgroups regardless of diabetes mellitus, ferritin concentrations, or baseline P/F ratio. The effect was more profound in patients exhibiting CRP levels >100 mg/L (OR 0.28,95%CI 0.27-1.47). Safety issues, such as increase of secondary infections, did not emerge. Interpretation Anakinra may be a safe anti-inflammatory treatment option in patients hospitalized with moderate-to-severe COVID-19 pneumonia to reduce mortality, especially in the presence of hyperinflammation signs such as CRP>100mg /L. Funding Sobi.
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