Citations

... It's important to note that in our study, all included COVID-19 patients received corticosteroid treatment. While the immunosuppressive effect of steroids is undisputed and desirable in the context of severe COVID-19 [62], corticosteroids might increase the susceptibility to secondary bacterial or fungal infections in vulnerable patients, such as elderly, frail patients and might potentially affect the risk-benefit balance [63][64][65]. The impairment of neutrophil oxidative burst in response to bacterial formyl peptide highlighted in our COVID-19 cohort emphasizes the resulting immunosuppression due to corticosteroid treatment. ...
Article
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Background A dysregulated immune response is emerging as a key feature of critical illness in COVID-19. Neutrophils are key components of early innate immunity that, if not tightly regulated, contribute to uncontrolled systemic inflammation. We sought to decipher the role of neutrophil phenotypes, functions, and homeostasis in COVID-19 disease severity and outcome. Methods By using flow cytometry, this longitudinal study compares peripheral whole-blood neutrophils from 90 COVID-19 ICU patients with those of 22 SARS-CoV-2-negative patients hospitalized for severe community-acquired pneumonia (CAP) and 38 healthy controls. We also assessed correlations between these phenotypic and functional indicators and markers of endothelial damage as well as disease severity. Results At ICU admission, the circulating neutrophils of the COVID-19 patients showed continuous basal hyperactivation not seen in CAP patients, associated with higher circulating levels of soluble E- and P-selectin, which reflect platelet and endothelial activation. Furthermore, COVID-19 patients had expanded aged-angiogenic and reverse transmigrated neutrophil subsets—both involved in endothelial dysfunction and vascular inflammation. Simultaneously, COVID-19 patients had significantly lower levels of neutrophil oxidative burst in response to bacterial formyl peptide. Moreover patients dying of COVID-19 had significantly higher expansion of aged-angiogenic neutrophil subset and greater impairment of oxidative burst response than survivors. Conclusions These data suggest that neutrophil exhaustion may be involved in the pathogenesis of severe COVID-19 and identify angiogenic neutrophils as a potentially harmful subset involved in fatal outcome. Graphic Abstract
... Factors evaluated for association with ICU-AI are shown in Table 2. ICU-AI was associated with longer ICU length of stay (median 24 days (IQR [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] days vs 11 days (IQR 6-17) (p < 0.001), as was infection with MDRO (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43) days for MDRO vs 23 days (IQR [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] for those with non-MDRO infection (p < 0.001). ...
... Factors evaluated for association with ICU-AI are shown in Table 2. ICU-AI was associated with longer ICU length of stay (median 24 days (IQR [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] days vs 11 days (IQR 6-17) (p < 0.001), as was infection with MDRO (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43) days for MDRO vs 23 days (IQR [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] for those with non-MDRO infection (p < 0.001). ...
... Factors evaluated for association with ICU-AI are shown in Table 2. ICU-AI was associated with longer ICU length of stay (median 24 days (IQR [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] days vs 11 days (IQR 6-17) (p < 0.001), as was infection with MDRO (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43) days for MDRO vs 23 days (IQR [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] for those with non-MDRO infection (p < 0.001). ...
Article
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Background The COVID-19 pandemic presented major challenges for critical care facilities worldwide. Infections which develop alongside or subsequent to viral pneumonitis are a challenge under sporadic and pandemic conditions; however, data have suggested that patterns of these differ between COVID-19 and other viral pneumonitides. This secondary analysis aimed to explore patterns of co-infection and intensive care unit-acquired infections (ICU-AI) and the relationship to use of corticosteroids in a large, international cohort of critically ill COVID-19 patients. Methods This is a multicenter, international, observational study, including adult patients with PCR-confirmed COVID-19 diagnosis admitted to ICUs at the peak of wave one of COVID-19 (February 15th to May 15th, 2020). Data collected included investigator-assessed co-infection at ICU admission, infection acquired in ICU, infection with multi-drug resistant organisms (MDRO) and antibiotic use. Frequencies were compared by Pearson’s Chi-squared and continuous variables by Mann–Whitney U test. Propensity score matching for variables associated with ICU-acquired infection was undertaken using R library MatchIT using the “full” matching method. Results Data were available from 4994 patients. Bacterial co-infection at admission was detected in 716 patients (14%), whilst 85% of patients received antibiotics at that stage. ICU-AI developed in 2715 (54%). The most common ICU-AI was bacterial pneumonia (44% of infections), whilst 9% of patients developed fungal pneumonia; 25% of infections involved MDRO. Patients developing infections in ICU had greater antimicrobial exposure than those without such infections. Incident density (ICU-AI per 1000 ICU days) was in considerable excess of reports from pre-pandemic surveillance. Corticosteroid use was heterogenous between ICUs. In univariate analysis, 58% of patients receiving corticosteroids and 43% of those not receiving steroids developed ICU-AI. Adjusting for potential confounders in the propensity-matched cohort, 71% of patients receiving corticosteroids developed ICU-AI vs 52% of those not receiving corticosteroids. Duration of corticosteroid therapy was also associated with development of ICU-AI and infection with an MDRO. Conclusions In patients with severe COVID-19 in the first wave, co-infection at admission to ICU was relatively rare but antibiotic use was in substantial excess to that indication. ICU-AI were common and were significantly associated with use of corticosteroids. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021). Graphical abstract
... Despite evidence that supports the benefits of corticosteroids, retrospective/prospective studies have described a lack thereof in some patient subgroups. One study, for instance, reported increased mortality in patients aged > 80 years [10]. Another multicentre study in France [11] including ICU-admitted patients found elevated mortality in patients aged < 60 years without any increase in inflammation markers, [i.e., d-dimer, ferritin or C-reactive protein (C-RP)]. ...
... The RECOVERY trial [7], for instance, reported no efficacy of corticosteroid use in the subgroup of patients aged > 70 years; however, only 169 (4.74%) patients from that particular group were on mechanical ventilation. Another recently published study [10] showed that mortality rose in patients aged ≥ 80 years receiving corticosteroids. There are two primary reasons that may explain these discrepancies between our study and those prior as follows: (1) the heterogeneity of populations included in randomised controlled trials (RCTs) and observational studies (different severity and degrees of respiratory failure, different age threshold); and (2) the varying immunophenotypes (humoral immunodeficiency, hyperinflammatory and complement-dependent) recently identified in critically ill patients [33]. ...
Article
Purpose: Although there is evidence supporting the benefits of corticosteroids in patients affected with severe coronavirus disease 2019 (COVID-19), there is little information related to their potential benefits or harm in some subgroups of patients admitted to the intensive care unit (ICU) with COVID-19. We aim to investigate to find candidate variables to guide personalized treatment with steroids in critically ill patients with COVID-19. Methods: Multicentre, observational cohort study including consecutive COVID-19 patients admitted to 55 Spanish ICUs. The primary outcome was 90-day mortality. Subsequent analyses in clinically relevant subgroups by age, ICU baseline illness severity, organ damage, laboratory findings and mechanical ventilation were performed. High doses of corticosteroids (≥ 12 mg/day equivalent dexamethasone dose), early administration of corticosteroid treatment (< 7 days since symptom onset) and long term of corticosteroids (≥ 10 days) were also investigated. Results: Between February 2020 and October 2021, 4226 patients were included. Of these, 3592 (85%) patients had received systemic corticosteroids during hospitalisation. In the propensity-adjusted multivariable analysis, the use of corticosteroids was protective for 90-day mortality in the overall population (HR 0.77 [0.65-0.92], p = 0.003) and in-hospital mortality (SHR 0.70 [0.58-0.84], p < 0.001). Significant effect modification was found after adjustment for covariates using propensity score for age (p = 0.001 interaction term), Sequential Organ Failure Assessment (SOFA) score (p = 0.014 interaction term), and mechanical ventilation (p = 0.001 interaction term). We observed a beneficial effect of corticosteroids on 90-day mortality in various patient subgroups, including those patients aged ≥ 60 years; those with higher baseline severity; and those receiving invasive mechanical ventilation at ICU admission. Early administration was associated with a higher risk of 90-day mortality in the overall population (HR 1.32 [1.14-1.53], p < 0.001). Long-term use was associated with a lower risk of 90-day mortality in the overall population (HR 0.71 [0.61-0.82], p < 0.001). No effect was found regarding the dosage of corticosteroids. Moreover, the use of corticosteroids was associated with an increased risk of nosocomial bacterial pneumonia and hyperglycaemia. Conclusion: Corticosteroid in ICU-admitted patients with COVID-19 may be administered based on age, severity, baseline inflammation, and invasive mechanical ventilation. Early administration since symptom onset may prove harmful.
... Fourteen studies (16.5%) [93,102,104,111,113,116,122,137,142,151,154,155,157,162] were rated as having moderate risk of bias, with no studies receiving a rating of low risk of bias. The remaining 7 studies (8.2%) [83,123,127,148,153,159,171] were rated as 'no information' due to insufficient reporting of study methodology, treatment descriptions and baseline information. ...
... Eighty-six studies [28][29][30][83][84][85][86][87][88][89][90][91][92][93][94][96][97][98][99][101][102][103][104][105][106][107][108][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][127][128][129][131][132][133][134][135][137][138][139][140][141][142][166][167][168][169][171][172][173][174] with 40,623 patients compared the effect of corticosteroids versus control in terms of mortality incidence and were included in the metaanalysis ( Figure 6). The overall pooled OR was 1. Subgroup analyses by different corticosteroid regimens revealed significant between-group differences (p < 0.05; Supplementary Figure 35). ...
Article
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Aim: To evaluate the efficacy and safety of corticosteroids for treating hospitalized COVID-19 patients. Materials & methods: Efficacy outcomes included time to negative SARS-CoV-2 tests, length of stay, duration and incidence of intensive unit care stay, incidence of mortality and duration and incidence of mechanical ventilation. Safety outcomes included the incidence of adverse events and severe adverse events, incidence of hyperglycemia and incidence of nosocomial infections. Results: Ninety-five randomized controlled trials (RCTs) and observational studies (n = 42,205) were included. Corticosteroids were associated with increased length of stay (based on RCT only), increased time to negative tests, decreased length of mechanical ventilation and increased odds of hyperglycemia. Conclusion: Corticosteroids should be considered in patients requiring mechanical ventilation, and glycemic monitoring may be needed when administering corticosteroids.
... This selection bias towards the sickest patients could possibly explain the difference in the corticosteroid impact on outcomes compared to recent prospective trials. Of note, corticosteroids have recently been shown to exert less beneficial effects in certain patient subgroups, including elderly patients [27] and those with a hypo-inflammatory phenotype [28,29]. As expressed by De Backer et al., the beneficial effects on the Day-28 mortality endpoint, relatively short in duration, may not necessarily translate into longer-term benefits [30]. ...
Article
Full-text available
Background: The coronavirus disease 2019 (COVID-19) pandemic has put significant pressure on hospitals and in particular on intensive care units (ICU). Some patients develop acute hypoxemic respiratory failure with profound hypoxia, which likely requires invasive mechanical ventilation during prolonged periods. Corticosteroids have become a cornerstone therapy for patients with severe COVID-19, though only little data are available regarding their potential harms and benefits, especially concerning the risk of a ventilator-associated lower respiratory tract infection (VA-LRTI). Methods: This retrospective multicenter study included patients admitted in four ICUs from Belgium and France for severe COVID-19, who required invasive mechanical ventilation (MV). We compared clinical and demographic variables between patients that received corticosteroids or not, using univariate, multivariate, and Fine and Gray analyses to identify factors influencing VA-LRTI occurrence. Results: From March 2020 to January 2021, 341 patients required MV for acute respiratory failure related to COVID-19, 322 of whom were included in the analysis, with 60.6% of them receiving corticosteroids. The proportion of VA-LRTI was significantly higher in the early corticosteroid group (63.1% vs. 48.8%, p = 0.011). Multivariable Fine and Gray modeling considering death and extubation as competing events revealed that the factors independently associated with VA-LRTI occurrence were male gender (adjusted sHR:1.7, p = 0.0022) and corticosteroids (adjusted sHR: 1.44, p = 0.022). Conclusions: in our multicenter retrospective cohort of COVID-19 patients undergoing MV, early corticosteroid therapy was independently associated with VA-LRTI.
... The difference in the safety profile for dexamethasone suggests that clinicians need to weigh up the potential benefits in each patient to decide if the higher rate of dexamethasone adverse events is acceptable. [8][9][10] The adverse events in patients who received dexamethasone did not affect the efficacy comparison (primary outcome) because this trial was neither designed nor powered for that. Patients with adverse events during hospitalisations have higher hospitalisation costs 11 and quality-adjusted life year losses. ...
Article
Background Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19. Methods In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168. Findings Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI −3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012). Interpretation In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered. Funding National Institute of Allergy and Infectious Diseases.
... Data by Keller et al. showed that early CS in patients with low CRP (<10 mg/dl) was associated with significantly increased risk of mortality or MV [29]. A recently published prospective multicentric study showed an independent association of CS use in critically ill elderly (70 years and older) COVID-19 patients with increased mortality [30]. Our data included older patient population with median age of 72 years and 71.3% patients above the age of 65 years. ...
Article
Introduction: Inherent differences as well as health disparities among rural and urban populations warrant further studies focused on the characteristics and outcomes in COVID-19 patients in a rural setting. The aim of this study was to describe these elements in patients infected with SARS-CoV2, hospitalized at a single center in rural Pennsylvania. Methods: Patients with SARS-CoV2 infections hospitalized between March-December 2020 were studied. Data were obtained from electronic health records generated reports and was retrospectively analyzed. Patients were classified into three groups according to severity. Distribution of variables was studied among these three groups. Using certain variables, we ran logistic regression analysis to study the odds of death and requirement of mechanical ventilation (MV). Results: Among 335 hospitalized patients infected with SARS-CoV2, age more than 65 years increased the severity of clinical status and in-hospital mortality. Gender did not affect odds of death nor need for MV. Hypertension was the most common comorbidity, but diabetes mellitus and chronic obstructive pulmonary disease (COPD) increased the risk of death. In terms of laboratory parameters, our data suggests that maximum LDH marginally increased the risk of death and maximum WBC marginally increased the risk of need for MV and death. Conclusion: Through our basic analysis of various characteristics of SARS-CoV2 positive patients admitted in a rural hospital, we have identified certain risk factors associated with severe disease and increased in-hospital mortality. These were found to be largely similar to current literature from studies in urban populations, bolstering the reproducibility and generalizability of existing knowledge. This information lays the foundation for future studies to investigate the role of these factors in morbidity and mortality associated with COVID-19 in depth.
... However, only few data are available on the prognosis of older patients hospitalized for COVID-19 and receiving corticosteroids (9), and their results are heterogeneous. Two retrospective observational studies concluded a benefit of corticosteroids in COVID-19 for older patients (10,11), but subgroup analysis of RECOVERY trial data (7) did not find a significant difference in terms of mortality and ventilator-free days at 28 days between older adults patients (≥70 years old) who received corticosteroids and those who did not. ...
Article
Background Few data are available on the prognosis of older patients who received corticosteroids for COVID-19. We aimed to compare the in-hospital mortality of geriatric patients hospitalized for COVID-19 who received corticosteroids or not. Methods We conducted a multicentric retrospective cohort study in 15 acute COVID-19 geriatric wards in the Paris area from March to April 2020 and November 2020 to May 2021. We included all consecutive patients aged 70 years and older who were hospitalized with confirmed COVID-19 in these wards. Propensity score and multivariate analyses were used. Results Of the 1579 patients included (535 received corticosteroids), the median age was 86 (interquartile range 81-91)years, 56% of patients were female, the median Charlson Comorbidity Index (CCI) was 2.6 (interquartile range 1-4), and 64% of patients were frail (Clinical Frailty Score 5-9). The propensity score analysis paired 984 patients (492 with and without corticosteroids). The in-hospital mortality was 32.3% in the matched cohort. On multivariate analysis, the probability of in-hospital mortality was increased with corticosteroids use (odds ratio [OR]=2.61 [95% confidence interval (CI) 1.63-4.20]). Other factors associated with in-hospital mortality were age (OR=1.04[1.01-1.07], CCI (OR=1.18[1.07-1.29], activities of daily living (OR=0.85[0.75-0.95], oxygen saturation <90% on room air (OR=2.15[1.45-3.17], C-reactive protein level (OR=2.06[1.69-2.51] and lowest lymphocyte count (OR=0.49[0.38-0.63]). Among the 535 patients who received corticosteroids, 68.3% had at least one corticosteroid side effect, including delirium(32.9%), secondary infections(32.7%) and decompensated diabetes(14.4%). Conclusions In this multicentric matched-cohort study of geriatric patients hospitalized for COVID-19, the use of corticosteroids was significantly associated with in-hospital mortality.
... Despite evidence supporting the benefits of corticosteroids, retrospective/prospective studies have described a lack thereof in some patient subgroups such as patients aged >80 years. 12 Another study in France 13 including ICU-admitted patients found elevated mortality in patients aged <60 years without any increase in inflammation markers. ...
... In this cohort, corticosteroid prescription was independently associated with mortality in the multivariate analysis (Table 3). There are some previously published data suggesting similar results, as a secondary analysis of the COVIP study having found a higher 30-day-mortality in critically ill COVID-19 patients, aged 70 years or older, who received steroids as part of their treatment [41]. However, there is no recommendation yet for the differentiated treatment of elderly patients. ...
... We found that the impact of corticosteroids on mortality differs according to the period of COVID-19 surge, but we did not analyse the SARS-CoV-2 variants. A few researchers have already suggested that the natural history of the different SARS-CoV-2 variant diseases responded differently to corticosteroids [41]. ...
... Second, mortality was significantly higher in elderly patients receiving corticosteroids and corticotherapy was independently associated with increased mortality. These results are similar to previously reported data questioning the routine use of corticosteroid treatment in elderly COVID-19 patients [41]. Even though this study was not specifically designed to evaluate the effects of corticosteroids in elderly patients, the results suggest that this treatment might not be as beneficial as expected from the results in younger patients. ...
Article
Full-text available
Background: During the COVID-19 pandemic, resource allocation became a major problem in globally overwhelmed ICUs. The main goal of this study was to describe the clinical characteristics of the very elderly patients (aged ≥ 80 years) with COVID-19 admitted in Romanian ICUs. The study objectives were to evaluate and determine the factors associated with ICU mortality. Methods: We designed a national, multicentric, observational platform with prospective enrolment. This study included patients aged ≥ 80 years admitted in Romanian ICUs with SARS-CoV-2 infection from March 2020 to December 2021. Results: We included 1666 patients with a median age of 83 years and 78% ICU mortality. Male sex, dyspnoea, lower Glasgow Coma Scale and lower SpO2 at ICU admission, the need for mechanical ventilation (MV), and corticosteroid use were independently associated with mortality. A total of 886/1666 (53%) elderly patients underwent invasive mechanical ventilation, with a mortality of 97%. The age impact on mortality was confirmed by a 1:1 propensity matching with less elderly ICU patients. Conclusion: In extremely elderly patients with COVID-19 admitted in the ICU, mortality is high, particularly when requiring MV. Therapy should be directed towards the optimization of less invasive ventilatory methods and the use of MV and corticosteroids only in highly selected patients.