Tocilizumab therapy in individuals with COVID-19 infection and hyperinflammatory state.
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ABSTRACT:
SUBMITTER: McCarthy C
PROVIDER: S-EPMC7404856 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
Publications
Tocilizumab therapy in individuals with COVID-19 infection and hyperinflammatory state.
McCarthy Cormac C Savinelli Stefano S Feeney Eoin R ER Butler Marcus W MW O'Broin Cathal C Ryan Silke S O'Neill Lorraine L Murphy David J DJ Gallagher Charles G CG McKone Edward F EF Waqas Sarmad S Cotter Aoife A Doran Peter P Keane Michael P MP Mallon Patrick W PW
Respirology (Carlton, Vic.) 20200721 10
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Project description:ObjectivesThe objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters.MethodsA cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs).ResultsIn all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001).ConclusionsTocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situation.
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Project description:Although the starting event in COVID-19 is a viral infection some patients present with an over-exuberant inflammatory response, leading to acute lung injury (ALI) and adult respiratory distress syndrome (ARDS). Since IL-6 plays a critical role in the inflammatory response, we assessed the efficacy and safety of tocilizumab (TCZ) in this single-centre, observational study in all Covid-19 in-patient with a proven SARS-CoV-2 rapidly progressing infection to prevent ALI and ARDS. 104 patients with COVID-19 treated with TCZ had a lower mortality rate (5·8%) compared with the regional mortality rate (11%), hospitalized patient's mortality (10%), and slightly lower than hospitalized patients treated with our standard of care alone (6%). We found that TCZ rapidly decreased acute phase reactants, ferritin and liver release of proteins. D-Dimer decreased slowly. We did not observe specific safety concerns. Early administration of IL6-R antagonists in COVID-19 patients with impending hyperinflammatory response, may be safe and effective treatment to prevent, ICU admission and further complications.
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Project description:A dysregulated hyperinflammatory response is a key pathogenesis of severe COVID-19, but optimal immune modulator treatment has not been established. To evaluate the clinical effectiveness of double (glucocorticoids and tocilizumab) and triple (plus baricitinib) immune modulator therapy for severe COVID-19, a retrospective cohort study was conducted. For the immunologic investigation, a single-cell RNA sequencing analysis was performed in serially collected PBMCs and neutrophil specimens. Triple immune modulator therapy was a significant factor in a multivariable analysis for 30-day recovery. In the scRNA-seq analysis, type I and II IFN response-related pathways were suppressed by GC, and the IL-6-associated signature was additionally downregulated by TOC. Adding BAR to GC and TOC distinctly downregulated the ISGF3 cluster. Adding BAR also regulated the pathologically activated monocyte and neutrophil subpopulation induced by aberrant IFN signals. Triple immune modulator therapy in severe COVID-19 improved 30-day recovery through additional regulation of the aberrant hyperinflammatory immune response.
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2024-09-26 | E-MTAB-13593 | biostudies-arrayexpress
Project description:Hydroxychloroquine has been touted as a potential COVID-19 treatment. Tocilizumab, an inhibitor of IL-6, has also been proposed as a treatment of critically ill patients. In this retrospective observational cohort study drawn from electronic health records we sought to describe the association between mortality and hydroxychloroquine or tocilizumab therapy among hospitalized COVID-19 patients. Patients were hospitalized at a 13-hospital network spanning New Jersey USA between March 1, 2020 and April 22, 2020 with positive polymerase chain reaction results for SARS-CoV-2. Follow up was through May 5, 2020. Among 2512 hospitalized patients with COVID-19 there have been 547 deaths (22%), 1539 (61%) discharges and 426 (17%) remain hospitalized. 1914 (76%) received at least one dose of hydroxychloroquine and 1473 (59%) received hydroxychloroquine with azithromycin. After adjusting for imbalances via propensity modeling, compared to receiving neither drug, there were no significant differences in associated mortality for patients receiving any hydroxychloroquine during the hospitalization (HR, 0.99 [95% CI, 0.80-1.22]), hydroxychloroquine alone (HR, 1.02 [95% CI, 0.83-1.27]), or hydroxychloroquine with azithromycin (HR, 0.98 [95% CI, 0.75-1.28]). The 30-day unadjusted mortality for patients receiving hydroxychloroquine alone, azithromycin alone, the combination or neither drug was 25%, 20%, 18%, and 20%, respectively. Among 547 evaluable ICU patients, including 134 receiving tocilizumab in the ICU, an exploratory analysis found a trend towards an improved survival association with tocilizumab treatment (adjusted HR, 0.76 [95% CI, 0.57-1.00]), with 30 day unadjusted mortality with and without tocilizumab of 46% versus 56%. This observational cohort study suggests hydroxychloroquine, either alone or in combination with azithromycin, was not associated with a survival benefit among hospitalized COVID-19 patients. Tocilizumab demonstrated a trend association towards reduced mortality among ICU patients. Our findings are limited to hospitalized patients and must be interpreted with caution while awaiting results of randomized trials. Trial Registration: Clinicaltrials.gov Identifier: NCT04347993.
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Project description:Tocilizumab (TCZ) is used for treating moderate-to-severe Covid-19 pneumonia by targeting interleukin-6 receptors (IL-6Rs) and reducing cytokine release. Yet, in spite of this therapy, patients with vs. patients without diabetes have an adverse disease course. In fact, glucose homoeostasis has influenced the outcomes of diabetes patients with infectious diseases. Of the 475 Covid-19-positive patients admitted to infectious disease departments (University of Bologna, University Vanvitelli of Napoli, San Sebastiano Caserta Hospital) in Italy since 1 March 2020, 31 (39.7%) hyperglycaemic and 47 (60.3%) normoglycaemic patients (blood glucose levels ≥140mg/dL) were retrospectively evaluated at admission and during their hospital stay. Of note, 20 (64%) hyperglycaemic and 11 (23.4%) normoglycaemic patients had diabetes (P<0.01). At admission, hyperglycaemic vs. normoglycaemic patients had fivefold higher IL-6 levels, which persisted even after TCZ administration (P<0.05). Intriguingly, in a risk-adjusted Cox regression analysis, TCZ in hyperglycaemic patients failed to attenuate risk of severe outcomes as it did in normoglycaemic patients (P<0.009). Also, in hyperglycaemic patients, higher IL-6 plasma levels reduced the effects of TCZ, while adding IL-6 levels to the Cox regression model led to loss of significance (P<0.07) of its effects. Moreover, there was evidence that optimal Covid-19 infection management with TCZ is not achieved during hyperglycaemia in both diabetic and non-diabetic patients. These data may be of interest to currently ongoing clinical trials of TCZ effects in Covid-19 patients and of optimal control of glycaemia in this patient subset.
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