Successful treatment of severe COVID-19 with subcutaneous anakinra as a sole treatment.
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ABSTRACT:
SUBMITTER: Gonzalez-Garcia A
PROVIDER: S-EPMC7337866 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
Publications
Successful treatment of severe COVID-19 with subcutaneous anakinra as a sole treatment.
González-García Andrés A García-Sánchez Isabel I Lopes Vanessa V Moreno-Arrones Oscar Muñoz OM Tortosa-Cabañas Marina M Elías-Sáenz Isabel I Hernández-Rodríguez José J
Rheumatology (Oxford, England) 20200801 8
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Project description:BackgroundCoronaviruses 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.MethodsThe 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.InterpretationAnakinra 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 controlled trials.FundingGroupe Hospitalier Paris Saint-Joseph.
| S-EPMC7259909 | biostudies-literature
Project description:SARS-CoV-2 infection may result in a severe pneumonia associated to 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-CoV2 virus trigger such an extensive inflammation remain unexplained. A pivotal cytokine driving inflammatory phenotypes is IL-1β, whose maturation and secretion is regulated by NLRP3 inflammasome. In the present report we provide a mechanistic explanation for the strong inflammatory manifestations associated to COVID-19 and further evidence that NLRP3 and IL-1β targeting could be an effective strategy in this disease.
2022-12-23 | GSE163317 | GEO
Project description:Dysregulation of inflammation is hypothesized to play a crucial role in the severe complications of COVID-19, with the IL-1/IL-6 pathway being central. Here, we report on the treatment of eight severe COVID-19 pneumonia patients-seven hospitalized in intensive care units (ICUs) in Greece and one non-ICU patient in the Netherlands-with the interleukin-1 receptor antagonist Anakinra. All patients scored positive for the hemophagocytosis score (HScore) and were diagnosed with secondary hemophagocytic lymphohistocytosis (sHLH) characterized by pancytopenia, hyper-coagulation, acute kidney injury, and hepatobiliary dysfunction. At the end of treatment, ICU patients had less need for vasopressors, significantly improved respiratory function, and lower HScore. Although three patients died, the mortality was lower than historical series of patients with sHLH in sepsis. These data suggest that administration of Anakinra may be beneficial for treating severe COVID-19 patients with sHLH as determined by the HScore, and they support the need for larger clinical studies to validate this concept.
| S-EPMC7221383 | biostudies-literature
Project description: Not available
| S-BSST416 | biostudies-other
Project description:ObjectiveTo report the clinical experience with anakinra in preventing mechanical ventilation in patients with coronavirus disease 2019 (COVID-19), symptoms of cytokine storm syndrome, and acute hypoxemic respiratory failure.MethodsTo be included in this retrospective case series, patients must have had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), fever, ferritin levels >1,000 ng/ml with 1 additional laboratory marker of hyperinflammation, and acute hypoxemic respiratory failure. Acute hypoxemic respiratory failure was defined as requiring 15 liters of supplemental oxygen via a nonrebreather mask combined with 6-liter nasal cannula or use of ≥95% oxygen by high-flow nasal cannula. We excluded patients in whom there was suspicion of bacterial infection or who were receiving immunosuppressants. Subcutaneous anakinra was initiated at 100 mg every 6 hours and gradually tapered off completely. The primary outcome was the prevention of mechanical ventilation.ResultsOf the 14 patients who met the criteria, 11 patients received anakinra for a maximum of 19 days. Seven of the patients who started anakinra treatment ≤36 hours after onset of acute hypoxemic respiratory failure did not require mechanical ventilation, and all were discharged home. Four patients who started anakinra ≥4 days after onset of acute hypoxemic respiratory failure required mechanical ventilation. Of those, 3 patients were extubated (2 discharged home and 1 remained hospitalized), and 1 died. All 3 patients who met the criteria but did not receive anakinra required mechanical ventilation. Two patients were extubated (1 discharged home and 1 remained hospitalized), and 1 remained on mechanical ventilation.ConclusionOur data suggest that anakinra could be beneficial in treating COVID-19 patients with evidence of cytokine storm syndrome when initiated early after onset of acute hypoxemic respiratory failure. Our patient selection and treatment approach should be considered for investigation in a clinical trial to determine the safety and efficacy of anakinra in treating patients with COVID-19 and symptoms of cytokine storm syndrome.
| S-EPMC7361793 | biostudies-literature
Project description:BackgroundSevere 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.ObjectivesTo dissect the mechanisms underlying SARS-CoV-2-associated inflammation in patients with severe coronavirus disease 2019 (COVID-19), we studied the role of IL-1β, a pivotal cytokine driving inflammatory phenotypes, whose maturation and secretion are regulated by inflammasomes.MethodsWe 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.ResultsWe 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-1β 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.ConclusionsThese results provide further evidence that IL-1β targeting could represent an effective strategy in this disease and suggest a mechanistic explanation for the strong inflammatory manifestations associated with COVID-19.
| S-EPMC9272569 | biostudies-literature
Project description: Not available
| S-EPMC7256545 | biostudies-literature
Project description:BackgroundA subset of critically ill COVID-19 patients develop a hyperinflammatory state. Anakinra, a recombinant interleukin-1 receptor antagonist, is known to be effective in several hyperinflammatory diseases. We investigated the effects of anakinra on inflammatory parameters and clinical outcomes in critically ill, mechanically ventilated COVID-19 patients with clinical features of hyperinflammation.MethodsIn this prospective cohort study, 21 critically ill COVID-19 patients treated with anakinra were compared to a group of standard care. Serial data of clinical inflammatory parameters and concentrations of multiple circulating cytokines were determined and aligned on start day of anakinra in the treatment group, and median start day of anakinra in the control group. Analysis was performed for day - 10 to + 10 relative to alignment day. Clinical outcomes were analyzed during 28 days. Additionally, three sensitivity analyses were performed: (1) using propensity score-matched groups, (2) selecting patients who did not receive corticosteroids, and (3) using a subset of the control group aimed to match the criteria (fever, elevated ferritin) for starting anakinra treatment.ResultsBaseline patient characteristics and clinical parameters on ICU admission were similar between groups. As a consequence of bias by indication, plasma levels of aspartate aminotransferase (ASAT) (p = 0.0002), ferritin (p = 0.009), and temperature (p = 0.001) were significantly higher in the anakinra group on alignment day. Following treatment, no relevant differences in kinetics of circulating cytokines were observed between both groups. Decreases of clinical parameters, including temperature (p = 0.03), white blood cell counts (p = 0.02), and plasma levels of ferritin (p = 0.003), procalcitonin (p = 0.001), creatinine (p = 0.01), and bilirubin (p = 0.007), were more pronounced in the anakinra group. No differences in duration of mechanical ventilation or ICU length of stay were observed between groups. Sensitivity analyses confirmed these results.ConclusionsAnakinra is effective in reducing clinical signs of hyperinflammation in critically ill COVID-19 patients. A randomized controlled trial is warranted to draw conclusion about the effects of anakinra on clinical outcomes.
| S-EPMC7726611 | biostudies-literature
Project description: Not available
| S-EPMC7211718 | biostudies-literature
Project description:BackgroundPatients with severe coronavirus disease 2019 (COVID-19) have elevated levels of acute phase reactants and inflammatory cytokines, including interleukin-6, indicative of cytokine release syndrome (CRS). The interleukin-6 receptor inhibitor tocilizumab is used for the treatment of chimeric antigen receptor T-cell therapy-induced CRS.MethodsPatients aged 18 years or older with laboratory-confirmed COVID-19 admitted to the Annunziata Hospital in Cosenza, Italy, through March 7, 2020, who received at least one dose of tocilizumab 162 mg subcutaneously for the treatment of COVID-19-related CRS in addition to standard care were included in this retrospective observational study. The primary observation was the incidence of grade 4 CRS after tocilizumab treatment. Chest computed tomography (CT) scans were evaluated to investigate lung manifestations.FindingsTwelve patients were included; all had fever, cough, and fatigue at presentation, and all had at least one comorbidity (hypertension, six patients; diabetes, five patients; chronic obstructive lung disease, four patients). Seven patients received high-flow nasal cannula oxygen therapy and five received non-invasive mechanical ventilation for lung complications of COVID-19. No incidence of grade 4 CRS was observed within 1 week of tocilizumab administration in all 12 patients (100%) and within 2 days of tocilizumab administration in 5 patients (42%). The predominant pattern on chest CT scans at presentation was ground-glass opacity, air bronchograms, smooth or irregular interlobular or septal thickening, and thickening of the adjacent pleura. Follow-up CT scans 7 to 10 days after tocilizumab treatment showed improvement of lung manifestations in all patients. No adverse events or new safety concerns attributable to tocilizumab were reported.InterpretationTocilizumab administered subcutaneously to patients with COVID-19 and CRS is a promising treatment for reduction in disease activity and improvement in lung function. The effect of tocilizumab should be confirmed in a randomised controlled trial.
| S-EPMC7329292 | biostudies-literature