Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk.
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ABSTRACT: Background
Severe hypoxic respiratory failure from COVID-19 pneumonia carries a high mortality risk. There is uncertainty surrounding which patients benefit from corticosteroids in combination with tocilizumab and the dosage and timing of these agents. The balance of controlling inflammation without increasing the risk of secondary infection is difficult. At present, dexamethasone 6 mg is the standard of care in COVID-19 hypoxia; whether this is the ideal choice of steroid or dosage remains to be proven.Objectives
The primary objective was to assess the impact on mortality of tocilizumab only, corticosteroids only, and combination therapy in patients with COVID-19 respiratory failure.Methods
A multihospital, retrospective study of adult patients with severe respiratory failure from COVID-19 who received supportive therapy, corticosteroids, tocilizumab, or combination therapy were assessed for 28-day mortality, biomarker improvement, and relative risk of infection. Propensity-matched analysis was performed between corticosteroid alone and combination therapies to further assess mortality benefit.Results
The steroid-only, tocilizumab-only, and combination groups showed hazard reduction in mortality at 28 days when compared with supportive therapy. In a propensity-matched analysis, the combination group (daily equivalent dexamethasone 10 mg and tocilizumab 400 mg) had an improved 28-day mortality compared with the steroid-only group (daily equivalent dexamethasone 10 mg; hazard ratio (95% CI) = 0.56 (0.38-0.84), P = 0.005] without increasing the risk of infection.Conclusion and relevance
Combination of tocilizumab and corticosteroids was associated with improved 28-day survival when compared with corticosteroids alone. Modification of steroid dosing strategy as well as steroid type may further optimize therapeutic effect of the COVID-19 treatment.
SUBMITTER: Brosnahan SB
PROVIDER: S-EPMC8250585 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeTocilizumab has been shown to decrease mortality when used concomitantly with steroids in COVID-19 with 8 mg/kg (max 800 mg) being the standard dose. Our study sought to assess whether a low dose (400 mg) shows similar benefit compared to a high dose for COVID patients concurrently on the same median dose of steroids.Materials/methodsA retrospective, multihospital observational study of COVID-19 patients who received tocilizumab in conjunction with steroids between March 2020 and August 2021 was conducted.ResultsA total of 407 patients were analyzed with low dose group being significantly more ill at baseline as a higher percentage of patients received vasopressors, were admitted to the ICU and on mechanical ventilation. In the propensity-matched analysis, both groups receiving a median dexamethasone equivalent dose of 10 mg showed no difference in 28-day mortality (p = 0.613). The high dose group had a higher rate of fungal and viral infections.ConclusionCompared to low dose tocilizumab, the high dose did not provide additional efficacy and mortality benefit but resulted in higher fungal and viral infections. This study illustrates that low dose tocilizumab can be an alternative to high dose during a drug shortage of tocilizumab without compensating for efficacy and safety, conserving resources for more patients.
| S-EPMC10084735 | biostudies-literature
Project description:IntroductionThe aim of this study was to determine the efficacy of early tocilizumab treatment for hospitalized patients with COVID-19 disease.MethodsOpen-label randomized phase II clinical trial investigating tocilizumab in patients with proven COVID-19 admitted to the general ward and in need of supplemental oxygen. The primary endpoint of the study was 30-day mortality with a prespecified 2-sided significance level of α = 0.10. A post-hoc analysis was performed for a combined endpoint of mechanical ventilation or death at 30 days. Secondary objectives included comparing the duration of hospital stay, ICU admittance and duration of ICU stay and the duration of mechanical ventilation.ResultsA total of 354 patients (67% men; median age 66 years) were enrolled of whom 88% received dexamethasone. Thirty-day mortality was 19% (95% CI 14%-26%) in the standard arm versus 12% (95% CI: 8%-18%) in the tocilizumab arm, hazard ratio (HR) = 0.62 (90% CI 0.39-0.98; p = 0.086). 17% of patients were admitted to the ICU in each arm (p = 0.89). The median stay in the ICU was 14 days (IQR 9-28) in the standard arm versus 9 days (IQR 5-14) in the tocilizumab arm (p = 0.014). Mechanical ventilation or death at thirty days was 31% (95% CI 24%-38%) in the standard arm versus 21% (95% CI 16%-28%) in the tocilizumab arm, HR = 0.65 (95% CI 0.42-0.98; p = 0.042).ConclusionsThis randomized phase II study supports efficacy for tocilizumab when given early in the disease course in hospitalized patients who need oxygen support, especially when concomitantly treated with dexamethasone.Trial registrationhttps://www.trialregister.nl/trial/8504.
| S-EPMC9374226 | biostudies-literature
Project description:BackgroundCorticosteroids are the cornerstone of the treatment of patients with COVID-19 admitted to hospital. However, whether corticosteroids can prevent respiratory worsening in hospitalized COVID-19 patients without oxygen requirements is currently unknown.AimsTo assess the efficacy of methylprednisolone pulses (MPP) in hospitalized COVID-19 patients with increased levels of inflammatory markers not requiring oxygen at baseline.MethodsMulticenter, parallel, randomized, double-blind, placebo-controlled trial conducted in Spain. Patients admitted for confirmed SARS-CoV-2 pneumonia with raised inflammatory markers (C-reactive protein >60 mg/L, interleukin-6 >40 pg/ml, or ferritin >1,000 μg/L) but without respiratory failure after the first week of symptom onset were randomized to receive a 3-day course of intravenous MPP (120 mg/day) or placebo. The primary outcome was treatment failure at 14 days, a composite variable including mortality, the need for ICU admission or mechanical ventilation, and clinical worsening, this last parameter defined as a PaO2/FiO2 ratio below 300; or a 15% decrease in the PaO2 from baseline, together with an increase in inflammatory markers or radiological progression. If clinical worsening occurred, patients received tocilizumab and unmasked corticosteroids. The secondary outcomes were 28-day mortality, adverse events, need for ICU admission or high-flow oxygen, length of hospital stay, SARS-CoV-2 clearance, and changes in laboratory parameters.ResultsA total of 72 patients were randomized and 71 patients were analyzed (34 in the MPP group and 37 in the placebo group). Twenty patients presented with treatment failure (29.4 in the MPP group vs. 27.0% in the placebo group, p = 0.82), with no differences regarding the time to treatment failure between groups. There were no cases of death or mechanical ventilation requirements at 14 days post-randomization. The secondary outcomes were similar in MPP and placebo groups.ConclusionsA 3-day course of MPP after the first week of disease onset did not prevent respiratory deterioration in hospitalized COVID-19 patients with an inflammatory phenotype who did not require oxygen.
| S-EPMC8919087 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19) is characterized by dysregulated hyperimmune response and steroids have been shown to decrease mortality. However, whether higher dosing of steroids results in better outcomes has been debated. This was a retrospective observation of COVID-19 admissions between March 1, 2020, and March 10, 2021. Adult patients (≥18 years) who received more than 10 mg daily methylprednisolone equivalent dosing (MED) within the first 14 days were included. We excluded patients who were discharged or died within 7 days of admission. We compared the standard dose of steroids (<40 mg MED) versus the high dose of steroids (>40 mg MED). Inverse probability weighted regression adjustment (IPWRA) was used to examine whether higher dose steroids resulted in improved outcomes. The outcomes studied were in-hospital mortality, rate of acute kidney injury (AKI) requiring hemodialysis, invasive mechanical ventilation (IMV), hospital-associated infections (HAI), and readmissions. Of the 1379 patients meeting study criteria, 506 received less than 40 mg of MED (median dose 30 mg MED) and 873 received more than or equal to 40 mg of MED (median dose 78 mg MED). Unadjusted in-hospital mortality was higher in patients who received high-dose corticosteroids (40.7% vs. 18.6%, p < 0.001). On IPWRA, the use of high-dose corticosteroids was associated with higher odds of death (odds ratio [OR] 2.14; 95% confidence interval [CI] 1.45-3.14, p < 0.001) but not with the development of HAI, readmissions, or requirement of IMV. High-dose corticosteroids were associated with lower rates of AKI requiring hemodialysis (OR 0.33; 95% CI 0.18-0.63). In COVID-19, corticosteroids more than or equal to 40 mg MED were associated with higher in-hospital mortality.
| S-EPMC8661573 | biostudies-literature
Project description:Acute hypoxic respiratory failure (AHRF) is associated with significant acute mortality. It is unclear whether later mortality is predominantly driven by pre-existing comorbid disease, the acute inciting event or is the result of AHRF itself.Observational cohort study of elderly US Health and Retirement Study (HRS) participants in fee-for-service Medicare (1998-2012). Patients hospitalised with AHRF were matched 1:1 to otherwise similar adults who were not currently hospitalised and separately to patients hospitalised with acute inciting events (pneumonia, non-pulmonary infection, aspiration, trauma, pancreatitis) that may result in AHRF, here termed at-risk hospitalisations. The primary outcome was late mortality-death in the 31 days to 2 years following hospital admission.Among 15?075?HRS participants, we identified 1268 AHRF and 13?117 at-risk hospitalisations. AHRF hospitalisations were matched to 1157 non-hospitalised adults and 1017 at-risk hospitalisations. Among patients who survived at least 30 days, AHRF was associated with a 24.4% (95%CI 19.9% to 28.9%, p<0.001) absolute increase in late mortality relative to adults not currently hospitalised and a 6.7% (95%CI 1.7% to 11.7%, p=0.01) increase relative to adults hospitalised with acute inciting event(s) alone. At-risk hospitalisation explained 71.2% of the increased odds of late mortality, whereas the development of AHRF itself explained 28.8%. Risk for death was equivalent to at-risk hospitalisation beyond 90?days, but remained elevated for more than 1?year compared with non-hospitalised controls.In this national sample of older Americans, approximately one in four survivors with AHRF had a late death not explained by pre-AHRF health status. More than 70% of this increased risk was associated with hospitalisation for acute inciting events, while 30% was associated with hypoxemic respiratory failure.
| S-EPMC5799038 | biostudies-literature
Project description:ObjectivesUse of corticosteroids is common in the treatment of coronavirus disease 2019, but clinical effectiveness is controversial. We aimed to investigate the association of corticosteroids therapy with clinical outcomes of hospitalized COVID-19 patients.MethodsIn this single-centre, retrospective cohort study, adult patients with confirmed coronavirus disease 2019 and dead or discharged between 29 December 2019 and 15 February 2020 were studied; 1:1 propensity score matchings were performed between patients with or without corticosteroid treatment. A multivariable COX proportional hazards model was used to estimate the association between corticosteroid treatment and in-hospital mortality by taking corticosteroids as a time-varying covariate.ResultsAmong 646 patients, the in-hospital death rate was higher in 158 patients with corticosteroid administration (72/158, 45.6% vs. 56/488, 11.5%, p < 0.0001). After propensity score matching analysis, no significant differences were observed in in-hospital death between patients with and without corticosteroid treatment (47/124, 37.9% vs. 47/124, 37.9%, p 1.000). When patients received corticosteroids before they required nasal high-flow oxygen therapy or mechanical ventilation, the in-hospital death rate was lower than that in patients who were not administered corticosteroids (17/86, 19.8% vs. 26/86, 30.2%, log rank p 0.0102), whereas the time from admission to clinical improvement was longer (13 (IQR 10-17) days vs. 10 (IQR 8-13) days; p < 0.001). Using the Cox proportional hazards regression model accounting for time varying exposures in matched pairs, corticosteroid therapy was not associated with mortality difference (HR 0.98, 95% CI 0.93-1.03, p 0.4694).DiscussionCorticosteroids use in COVID-19 patients may not be associated with in-hospital mortality.
| S-EPMC7524527 | biostudies-literature
Project description:Hypoxemia is associated with worse outcomes in COPD. The aim of the study was to investigate the prevalence, incidence, and risk factors of hypoxic respiratory failure (HRF) in COPD.This was a longitudinal analysis of data from the Swedish National Register of COPD. HRF was defined as resting saturation ≤88% or long-term oxygen therapy. Risk factors for developing HRF were analyzed using multiple logistic regression and receiver operating characteristic curve analysis.A total of 3,061 patients were included; mean forced expiratory volume in 1 second was 1.47 L; mean age was 70 years; and 54% were females. Median follow-up time was 1.8 years (interquartile range 1.3-2.4 years). HRF was present in 43 (1.4%) patients at baseline and 74 (2.4%) patients at follow-up. Among patients without HRF at baseline, 49 (1.6%) developed HRF during follow-up. The risk was highest for patients in Global initiative for Chronic Obstructive Lung Disease (GOLD) 2017 stage IV or groups C or D at baseline. Developing HRF was independently predicted by lower forced expiratory volume in 1 second and lower COPD Assessment Test score, with a c-statistic of 0.84 (95% CI, 0.70-0.91). When the multivariable model used the GOLD 2017 variables stages I-IV and the dichotomized variables frequent exacerbations and COPD Assessment Test ≥10; the c-statistic increased slightly to 0.86 (95% CI, 0.80-0.92; P<0.0001).In patients with COPD, the prevalence and incidence of HRF was low and was predicted well by more severe air flow limitation and worse health status. The risk is highest in patients with GOLD stage IV and GOLD groups C or D.
| S-EPMC5530070 | biostudies-other
Project description:Hospitalized patients with heart failure (HF) undergoing bedside glucose monitoring with subcutaneous insulin orders were retrospectively identified over 2 years. Hypoglycaemia was defined as any glucose value <3.9 mmol/L (70 mg/dL) within 24 hours of admission (Hypo1day ) or throughout the hospitalization (HypoT ) or any glucose value <2.2 mmol/L (40 mg/dL) throughout the hospitalization (HypoSevere ). A total of 13 424 patients were included, of whom 2484 had HF. Patients with HF were more likely to have Hypo1day (9.1% vs 7.0%, P = .0003), HypoT (28% vs 18.5%, P < .0001), or Hypo Severe (3.4% vs 2.1%, P = .0001). After controlling for other variables, the odds of Hypo1day were similar between the HF and non-HF groups (odds ratio [OR] 1.14, 95% CI 0.94-1.39, P = .18, fully adjusted model), slightly lower for HypoT (OR 0.85, 95% CI 0.73-0.99, P = .03, fully adjusted model), and similar for HypoSevere (OR 1.25, 95% CI 0.91-1.70, P = .17). Hypo1day , HypoT and HypoSevere were all associated with increased mortality; there was no evidence of an interaction by HF status. Hypoglycaemia occurred at a similar or lower frequency in hospitalized patients with HF compared to those without HF. Hypoglycaemia was associated with increased hospital mortality, regardless of HF status.
| S-EPMC6625647 | biostudies-literature
Project description:ObjectivesTo evaluate the survival and neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants at 18 to 26 months with early hypoxemic respiratory failure (HRF). We also assessed whether African American infants with early HRF had improved outcomes after exposure to inhaled nitric oxide (iNO).MethodsELBW infants ≤1000 g and gestational age ≤26 weeks with maximal oxygen ≥60% on either day 1 or day 3 were labeled as "early HRF" and born between 2007 and 2015 in the Neonatal Research Network were included. Using a propensity score regression model, we analyzed outcomes and effects of exposure to iNO overall and separately by race.ResultsAmong 7639 ELBW infants born ≤26 weeks, 22.7% had early HRF. Early HRF was associated with a mortality of 51.3%. The incidence of moderate-severe NDI among survivors was 41.2% at 18 to 26 months. Mortality among infants treated with iNO was 59.4%. Female sex (adjusted odds ratio [aOR]: 2.4, 95% confidence interval [CI]: 1.8-3.3), birth weight ≥720 g (aOR: 2.3, 95% CI: 1.7-3.1) and complete course of antenatal steroids (aOR: 1.6, 95% CI: 1.1-2.2) were associated with intact survival. African American infants had a similar incidence of early HRF (21.7% vs 23.3%) but lower exposure to iNO (16.4% vs 21.6%). Among infants with HRF exposed to iNO, intact survival (no death or NDI) was not significantly different between African American and other races (aOR: 1.5, 95% CI: 0.6-3.6).ConclusionsEarly HRF in infants ≤26 weeks' gestation is associated with high mortality and NDI at 18 to 26 months. Use of iNO did not decrease mortality or NDI. Outcomes following iNO exposure were not different in African American infants.
| S-EPMC7546092 | biostudies-literature
Project description:ImportanceA World Health Organization (WHO) meta-analysis found that tocilizumab was associated with reduced mortality in hospitalized patients with COVID-19. However, uncertainty remains concerning the magnitude of tocilizumab's benefits and whether its association with mortality benefit is similar across respiratory subgroups.ObjectiveTo use bayesian methods to assess the magnitude of mortality benefit associated with tocilizumab and the differences between respiratory support subgroups in hospitalized patients with COVID-19.Design, setting, and participantsA bayesian hierarchical reanalysis of the WHO meta-analysis of tocilizumab studies published in 2020 and 2021 was performed. Main results were estimated using weakly informative priors to exert little influence on the observed data. The robustness of these results was evaluated using vague and informative priors. The studies featured in the meta-analysis were randomized clinical tocilizumab trials of hospitalized patients with COVID-19. Only patients receiving corticosteroids were included.InterventionsUsual care plus tocilizumab in comparison with usual care or placebo.Main outcomes and measuresAll-cause mortality at 28 days after randomization.ResultsAmong the 5339 patients included in this analysis, most were men, with mean ages between 56 and 66 years. There were 2117 patients receiving simple oxygen only, 2505 receiving noninvasive ventilation (NIV), and 717 receiving invasive mechanical ventilation (IMV) in 15 studies from multiple countries and continents. Assuming weakly informative priors, the overall odds ratios (ORs) for survival were 0.70 (95% credible interval [CrI], 0.50-0.91) for patients receiving simple oxygen only, 0.81 (95% CrI, 0.63-1.03) for patients receiving NIV, and 0.89 (95% CrI, 0.61-1.22) for patients receiving IMV, respectively. The posterior probabilities of any benefit (OR <1) were notably different between patients receiving simple oxygen only (98.9%), NIV (95.5%), and IMV (75.4%). The posterior probabilities of a clinically meaningful association (absolute mortality risk difference >1%) were greater than 95% in patients receiving simple oxygen only and greater than 90% in patients receiving NIV. In contrast, the posterior probability of this clinically meaningful association was only approximately 67% in patients receiving IMV. The probabilities of tocilizumab superiority in the simple oxygen only subgroup compared with the NIV and IMV subgroups were 85% and 90%, respectively. Predictive intervals highlighted that only 72.1% of future tocilizumab IMV studies would show benefit. The conclusions did not change with different prior distributions.Conclusions and relevanceIn this bayesian reanalysis of a previous meta-analysis of 15 studies of hospitalized patients with COVID-19 treated with tocilizumab and corticosteroids, use of simple oxygen only and NIV was associated with a probability of a clinically meaningful mortality benefit from tocilizumab. Future research should clarify whether patients receiving IMV also benefit from tocilizumab.
| S-EPMC8886529 | biostudies-literature