The effect of increasing corticosteroid doses on clinical outcomes and chest findings in patients with coronavirus disease (COVID-19) pneumonia and lung disease remains unknown. We aimed to investigate the effects of increasing steroid dosage on chest lesion area and clinical outcomes in patients with moderate or severe COVID-19 and progressive lung involvement on chest computed tomography (CT). A total of 105 patients with radiological progression during methylprednisolone (MP) therapy either received an increased MP dose (n = 79) or were maintained on the same MP dose (n = 26). These patients were divided into dose-increment and no-change groups according to the MP dose adjustment strategy. Clinical features, changes in CT severity scores within 7 days after steroid adjustment, and outcomes were compared between the groups. Six (7.6%) and one (3.8%) patients in the dose-increment and no-change groups, respectively, had increasing World Health Organization outcome scores 96 h after MP adjustment (P = 0.678). Length of stay [15 days (IQR: 10-24) vs. 14 days (IQR: 10-25); P = 0.994] and in-hospital death rate (7.6% vs. 3.8%; P = 0.678) showed no significant differences between the groups. Logistic regression analyses revealed that an increased MP dose was significantly associated with improvement in CT lesion area compared with no change in MP dose, but the CT lesions deteriorated subsequently (79.7% vs. 53.8%, P = 0.044). In conclusion, increasing the MP dose in patients with worsening CT findings ameliorates CT lesions but fails to prevent serious adverse outcomes.

Dexamethasone 6 mg in patients with severe COVID-19 has been shown to decrease mortality and morbidity. The effects of higher doses of corticosteroid, that would further increase anti-inflammatory effects, are uncertain. The objective of our study was to assess the effect of 20 mg dexamethasone vs. 6 mg dexamethasone intravenously in patients with moderate-to-severe acute respiratory distress syndrome (ARDS) and COVID-19.

In a multicenter, open-label, randomized trial conducted in nine hospitals in the Czech Republic, we randomized adult patients with ARDS and COVID-19 requiring high-flow oxygen, noninvasive or invasive mechanical ventilation to receive either intravenous high-dose dexamethasone (20 mg/day on days 1-5, 10 mg/day on days 6-10) or standard-dose dexamethasone (6 mg/d, days 1-10). The primary outcome was 28-day ventilator-free days. The five secondary outcomes were 60-day mortality, C-reactive protein dynamics, 14-day WHO (World Health Organization) Clinical Progression Scale score, adverse events and 90-day Barthel index. The long-term outcomes were 180- and 360-day mortality and the Barthel index. The planned sample size was 300, with interim analysis after enrollment of 150 patients.

The trial was stopped due to a lack of recruitment, and the follow-up was completed in February 2023. Among 234 randomized patients of 300 planned patients, the primary outcome was available for 224 patients (110 high-dose and 114 standard-dose dexamethasone; median [interquartile range (IQR)] age, 59.0 [48.5-66.0] years; 130 [58.0%] were receiving noninvasive or invasive mechanical ventilation at baseline). The mean number of 28-day ventilator-free days was 8.9 (± 11.5) days for high-dose dexamethasone and 8.0 (± 10.7) days for standard-dose dexamethasone, with an absolute difference of + 0.81 days (95% CI - 2.12-3.73 days). None of the prespecified secondary outcomes, including adverse events, differed between the groups.

Despite not reaching its prespecified enrollment, there was no signal to either benefit or harm high-dose dexamethasone over standard-dose dexamethasone in patients with COVID-19 and moderate-to-severe ARDS. Trial registration Trial registration: ClinicalTrials.gov Identifier: NCT04663555. Registered 10 December 2020, https://clinicaltrials.gov/study/NCT04663555?term=NCT04663555&rank=1 and EudraCT: 2020-005887-70.

Current guidelines recommend dexamethasone 6 mg/day for up to 10 days in patients with severe coronavirus disease 2019 (COVID-19) requiring supplemental oxygenation or mechanical ventilation. The practice has significant variation, however, and dexamethasone has been used for >10 days for many patients with severe COVID-19. The aim of this study was to assess the benefits and risks associated with standard versus extended use of dexamethasone in patients with severe COVID-19.

A multicenter retrospective cohort study was conducted from January 2021 to December 2021. All of the consecutive patients with severe COVID-19 receiving 6 mg/day dexamethasone were eligible for inclusion. The primary outcome was the incidence of in-hospital mortality for patients treated with dexamethasone 6 mg/day for the standard duration of 10 days versus an extended duration of >10 days.

A total of 1294 patients met the inclusion criteria: 803 received the standard duration of dexamethasone and 491 received the extended duration. The incidence of in-hospital mortality was significantly higher (P = 0.003) in the extended duration group (36.5%) compared with the standard duration group (28.5%), with no significant difference in in-hospital major adverse cardiac events (16.1% for extended vs 13.2% for the standard duration; P = 0.15).

The results show that extended duration of dexamethasone compared with standard duration is associated with a significant increase in in-hospital mortality in patients with severe COVID-19. These findings need to be confirmed in well-designed and performed randomized controlled trials.

There is lack of research on corticosteroid use for severe and critical COVID-19 patients with Omicron variant infection.

This multi-center retrospective cohort study involved 1167 patients from 59 ICUs across the mainland of China diagnosed with severe or critical SARS-CoV-2 Omicron variant infection between November 1, 2022, and February 11, 2023. Patients were segregated into two groups based on their corticosteroid treatment-usual dose (equivalent prednisone dose 30-50 mg/day) and higher dose (equivalent prednisone dose > 50 mg/day). The primary outcome was 28-day ICU mortality. Propensity score matching was used to compare outcomes between cohorts.

After propensity score matching, 520 patients in the usual dose corticosteroid group and 260 patients in the higher dose corticosteroid group were included in the analysis, respectively. The mortality was significantly higher in the higher dose corticosteroid group (67.3%, 175/260) compared to the usual dose group (56.0%, 291/520). Logistic regression showed that higher doses of corticosteroids were significantly associated with increased mortality at 28-day (OR = 1.62,95% CI 1.19-2.21, p = 0.002) and mortality in ICU stay (OR = 1.66,95% CI 1.21-2.28, p = 0.002). Different types of corticosteroids did not affect the effect.

The study suggests that higher-dose corticosteroids may lead to a poorer prognosis for severe and critical COVID-19 patients with Omicron variant infection in the ICU. Further research is needed to determine the appropriate corticosteroid dosage for these patients.

The severe respiratory manifestations observed in severe coronavirus disease 2019 (COVID-19) cases are often associated with an excessive inflammatory response. Dexamethasone, a synthetic glucocorticoid, exerts its anti-inflammatory effects by inhibiting the transcription of pro-inflammatory genes and suppressing the activity of various immune cells. This mechanism has implications for mitigating the cytokine storm observed in severe COVID-19 cases. Early on in the pandemic, the Recovery Collaborative working group showed a mortality benefit of using dexamethasone in decreasing mortality in patients with COVID-19 requiring respiratory support. However, the optimal dosage of corticosteroids remains debatable. Several studies that compare different doses of dexamethasone in COVID-19 exist, but the results are conflicting.

To review the latest evidence regarding dosage, safety, and efficacy of dexamethasone in severe COVID-19.

We followed preferred reporting items for systematic reviews and meta-analysis guidelines. A detailed literature search was conducted across PubMed, Google Scholar, and Medline to include publications up to March 2024. Our keywords included "COVID-19" "SARS-CoV-2" "dexamethasone" "corticosteroid" "steroid" and "glucocorticoid"-along with their combinations. We employed the Cochrane Risk of Bias Tool and the Newcastle-Ottawa scale to evaluate the integrity and potential of bias in the included studies. A meta-analysis was conducted using a random-effects model, assessing pooled odds ratios and mean differences, with heterogeneity gauged by the I 2 statistic and the χ 2 tests.

No statistical differences were found in 28-day all-cause mortality [pooled odds ratio (OR) = 1.109, 95%CI: 0.918-1.340], 60-day all-cause mortality (OR = 0.873, 95%CI: 0.744-1.024; I 2 = 47.29%), mean length of hospital stay (mean difference = -0.08 days, 95%CI: -0.001 to 0.161) and adverse events (OR = 0.877, 95%CI: 0.707-1.087).

Differing doses of corticosteroids have no clinical implications on mortality, mean length of hospital stay, and adverse events in COVID-19 patients. Additional research is required in patients requiring invasive or non-invasive ventilation.

Corticosteroids are commonly used to treat COVID-19 patients with hypoxemia, and clinicians have adjusted the corticosteroid intensity on the basis of clinical needs. However, neither the optimal dose nor the duration of treatment has been recommended.

To investigate whether cumulative doses of corticosteroids, measured as dexamethasone-equivalent doses over the first 14 days, impact outcomes in patients with COVID-19 pneumonia.

We conducted a retrospective cohort study of COVID-19 pneumonia patients admitted between April 1st, 2020, and September 30th, 2021. The study focused on the type and dose of corticosteroid administered during the initial 14 days, clinical outcomes, and complications. The primary outcome was in-hospital mortality.

Among 271 patients, the mean cumulative dexamethasone-equivalent dose was 158 (119.9-197.25) mg in survivors and 185 (131.7-222.0) mg in nonsurvivors. Univariate analysis revealed that the cumulative dexamethasone-equivalent dose was a risk factor for in-hospital mortality. However, this association did not hold true in the multivariate analysis. After the cumulative dexamethasone-equivalent dose was categorized into quartiles, the moderate dosage (126.01-165.00 mg) in the second quartile was found to be associated with the lowest in-hospital mortality (16.2%). Higher cumulative dexamethasone-equivalent doses were associated with longer hospital and ICU stays and fewer ventilator-free days (p < 0.001). Doses exceeding 165 mg were associated with an increased risk of hospital-acquired infections (p < 0.001).

The cumulative dexamethasone-equivalent dose during the first 14 days is not associated with in-hospital mortality in hypoxemic COVID-19 patients. However, higher cumulative doses exceeding 165 mg are associated with an increased risk of in-hospital mortality and secondary hospital-acquired infections.

Systemic corticosteroids have become the standard of care for severe to critically ill patients with coronavirus disease 2019 (COVID-19). However, the real-world efficacy and safety outcomes associated with a higher dose of corticosteroids remain uncertain.

We conducted a nationwide, population-based, matched cohort study of severe to critically ill adult patients with COVID-19 between January 2020 and June 2021 in Korea using the National Health Information Database. Patients using systemic corticosteroids were included and high-dose corticosteroid use was defined as a daily mean prescribed dose of more than 6 mg of dexamethasone. We then employed a proportional hazard regression model to identify prognostic factors for 28-day all-cause mortality and conducted a Fine and Gray regression model to assess risk factors for developing COVID-19-associated pulmonary aspergillosis (CAPA).

During the study period, 102,304 patients with COVID-19 were screened, 5,754 met the eligibility criteria, and 2,138 were successfully matched. The mean prescribed daily dose was 4.2 mg and 13.4 mg in the standard- and high-dose groups, respectively, and the mean duration of use was not different between the groups. High-dose corticosteroid use independently increased all-cause mortality at 28 days (adjusted hazard ratio [aHR], 1.48; 95% confidence interval [CI], 1.25-1.76) and 90 days (aHR, 1.63; CI, 1.44-1.85) after admission. Subgroup analysis revealed a statistically significant elevation in the risk of mortality among patients using low-flow or high-flow nasal cannulas, with aHRs of 1.41 and 1.46, respectively. No significant impact of high-dose steroids was observed, even in patients who underwent mechanical ventilation at 28 days (aHR, 1.17; CI, 0.79-1.72). As a safety outcome, high-dose corticosteroid use showed an association with the development of CAPA (aHR, 2.97; 95% CI, 0.94-9.43).

Among severe to critically ill patients with COVID-19, high-dose corticosteroid use was associated with increased 28-day all-cause mortality and showed a trend toward the development of CAPA.

The 2019 coronavirus (COVID-19) outbreak was declared a global pandemic in March 2020. It quickly spread across all continents, causing significant social, environmental, health, and economic impacts. During the pandemic, there has been consideration of repurposing and repositioning of medications, such as corticosteroids, for the treatment of hospitalised COVID-19 patients.

To assess and summarise corticosteroid regimens used for hospitalised COVID-19 patients, focusing on dosage, route of administration, and clinical outcome from clinical trials.

PubMed and Embase databases and the grey literature were searched to identify randomised controlled trials (RCTs) that evaluated the efficacy of corticosteroids in hospitalised patients with COVID-19 between January 2020 and January 2023. This scoping review was conducted in line with the PRISMA extension for scoping reviews (PRISMA-ScR) checklist.

A total of 24 RCTs were eligible for inclusion. There was variation in the steroid regimens used for treatment across COVID-19 trials. Despite the heterogeneity of included RCTs, the overall results have shown the benefits of improving lung function and a lower all-cause mortality rate in hospitalised COVID-19 patients treated with systematic corticosteroids.

Corticosteroids have proven to be an effective treatment for COVID-19 patients in critical condition. However, comparative effectiveness studies should be conducted to assess the efficacy and safety of optimal corticosteroid treatment at the population level. Moreover, the global burden of long COVID is significant, affecting millions with persistent symptoms and long-term health complications. Thus, it is also necessary to evaluate the optimal steroid regimen for long COVID treatment.

The COVID-19 pandemic has posed a major challenge to healthcare systems globally. Millions of people have been infected, and millions of deaths have been reported worldwide. Glucocorticoids have attracted worldwide attention for their potential efficacy in the treatment of COVID-19. Various glucocorticoids with different dosages and treatment durations have been studied in patients with different severities, with a suitable dosage and treatment duration not yet defined. This study aimed to investigate whether in-hospital survival differs between critically ill patients treated with low-dose glucocorticoids, high-dose glucocorticoids or no glucocorticoids. All critically ill patients admitted to the intensive care unit of the Charité Hospital-Universitätsmedizin Berlin between February 2020 and December 2021 with COVID-19 pneumonia receiving supplemental oxygen were eligible to participate in this multicenter real-world data study. Patients were retrospectively assigned to one of three groups: the high corticosteroid dose (HighC) group (receiving 6 mg parenteral dexamethasone or an equivalent corticosteroid dosage for ten days), the low corticosteroid dose (LowC) group (receiving less than 6 mg parenteral dexamethasone or an equivalent corticosteroid dosage for ten days), or the no corticosteroid (NoC) group. Overall survival and risk effects were compared among groups within the total observation period, as well as at 35 days after the onset of COVID-19 symptoms. Adjusted multivariable Cox proportional hazard regression analysis was performed to compare the risk of death between the treatment groups. Out of 1561 critically ill COVID-19 patients, 1014 were included in the baseline analysis. In the survival study, 1009 patients were assigned to the NoC (n = 346), HighC (n = 552), or LowC group (n = 111). The baseline characteristics were balanced between groups, except for age, BMI, APACHE II score, SOFA and SAPS II. While the 35-day survival did not show any differences, a landmark analysis of the patients surviving beyond 35 days revealed differences between groups. The restricted mean survival time was 112 days in the LowC group [95% CI: 97 - 128], 133 days in the HighC group [95% CI: 124 - 141] and 144 days in the NoC group [95% CI: 121 - 167]. The multivariable-adjusted Cox proportional hazard analysis indicated that, regardless of age, sex, health status or invasive oxygenation, a low-dose treatment increased the hazard of death of critically ill COVID-19 patients by a factor of 2.09 ([95% CI: 0.99, 4.4], p = 0.05) and a high-dose corticosteroid treatment increased the risk by a factor of 1.07 ([95% CI: 0.53, 2.15], p = 0.85) compared to no treatment with glucocorticoids. The analysis reveals that corticosteroid treatment does not influence the survival of critically ill COVID-19 patients in the intensive care unit within 35 days. Our evaluations further suggest that regardless of ventilation status, the decision-making process for administering corticosteroid therapy should account for the individual severity of the illness.

Since November 2019, the SARS-CoV-2 pandemic has created challenges for preventing and managing COVID-19 in children and adolescents. Most research to develop new therapeutic interventions or to repurpose existing ones has been undertaken in adults, and although most cases of infection in pediatric populations are mild, there have been many cases of critical and fatal infection. Understanding the risk factors for severe illness and the evidence for safety, efficacy, and effectiveness of therapies for COVID-19 in children is necessary to optimize therapy.

A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacology, and pediatric intensive care medicine from 21 geographically diverse North American institutions was re-convened. Through a series of teleconferences and web-based surveys and a systematic review with meta-analysis of data for risk factors, a guidance statement comprising a series of recommendations for risk stratification, treatment, and prevention of COVID-19 was developed and refined based on expert consensus.

There are identifiable clinical characteristics that enable risk stratification for patients at risk for severe COVID-19. These risk factors can be used to guide the treatment of hospitalized and non-hospitalized children and adolescents with COVID-19 and to guide preventative therapy where options remain available.

Corticosteroids have become standard of care for COVID-19 but their effect on the systemic immune-inflammatory response has been little investigated.

Multicenter prospective cohort, including critically ill COVID-19 patients between March and November 2020. C-reactive protein (CRP), lymphocyte count and fibrinogen levels were collected upon hospital admission before initiation of steroid treatment and at ICU admission, three days and seven days later, along with interleukin (IL)-6, IL-10 and tumor necrosis factor-alpha (TNF-α) plasma levels.

A hundred and fifty patients were included, 47 received corticosteroids, 103 did not. Median age was 62 [53-70], and 96 (65%) patients were mechanically ventilated. Propensity score matching rendered 45 well-balanced pairs of treated and non-treated patients, particularly on pre-treatment CRP levels. Using a mixed model, CRP (P=0.019), fibrinogen (P=0.003) and lymphocyte counts (P=0.006) remained lower in treated patients over ICU stay. Conversely, there was no significant difference over the ICU stay for Il-6 (P=0.146) and IL-10 (0.301), while TNF- α levels were higher in the treated group (P=0.013). Among corticosteroid-treated patients, CRP (P=0.012), fibrinogen (P=0.041) and lymphocyte count (P=0.004) over time were associated with outcome, whereas plasma cytokine levels were not.

Steroid treatment was associated with an early and sustained decrease in the downstream IL-6-dependent inflammatory signature but an increase in TNF-α levels. In corticosteroid-treated patients, CRP and lymphocyte count were associated with outcome, conversely to plasma cytokine levels. Further research on using these biomarker's kinetics to individualize immunomodulatory treatments is warranted.

The optimal dose of dexamethasone for severe/critical COVID-19 is uncertain. We compared higher versus standard doses of dexamethasone in adults with COVID-19 and hypoxia.

We searched PubMed and trial registers until 23 June 2023 for randomised clinical trials comparing higher (>6 mg) versus standard doses (6 mg) of dexamethasone in adults with COVID-19 and hypoxia. The primary outcome was mortality at 1 month. Secondary outcomes were mortality closest to 90 days; days alive without life support; and the occurrence of serious adverse events/reactions (SAEs/SARs) closest to 1 month. We assessed the risk of bias using the Cochrane RoB2 tool, risk of random errors using trial sequential analysis, and certainty of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE).

We included eight trials (2478 participants), of which four (1293 participants) had low risk of bias. Higher doses of dexamethasone probably resulted in little to no difference in mortality at 1 month (relative risk [RR] 0.97, 95% CI: 0.79-1.19), mortality closest to Day 90 (RR 1.01, 95% CI: 0.86-1.20), and SAEs/SARs (RR 1.00, 95% CI: 0.97-1.02). Higher doses of dexamethasone probably increased the number of days alive without invasive mechanical ventilation and circulatory support but had no effect on days alive without renal replacement therapy.

Based on low to moderate certainty evidence, higher versus standard doses of dexamethasone probably result in little to no difference in mortality, SAEs/SARs, and days alive without renal replacement therapy, but probably increase the number of days alive without invasive mechanical ventilation and circulatory support.

COVID-19 patients with severe or critical symptoms are often treated with corticosteroids, per contemporary guidelines. Due to their immunosuppressive and immunomodulatory properties, corticosteroids are associated with the development of superinfections. We aimed to retrospectively assess patterns of corticosteroid use and the profiles of bacterial blood stream infections associated with exposure to different dosing levels, in a cohort of 1558 real-life adult COVID-19 patients. A total of 1391 (89.3%) patients were treated with corticosteroids, with 710 (45.6%) patients receiving low, 539 (34.6%) high and 142 (9.1%) very high corticosteroid doses. Bacteremia developed in a total of 178 (11.4%) patients. The risk of bacteremia was of similar magnitude between the no and low-dose corticosteroid treatments (p = 0.352), whereas it progressively increased with high (OR 6.18, 95% CI (2.66-14.38), p < 0.001) and very high corticosteroid doses (OR 8.12, 95% CI (3.29-20.05), p < 0.001), compared to no corticosteroid treatment. These associations persisted after multivariate adjustments and were present independently of sex, comorbidity burden, and mechanical ventilation. The profiles of individual bacterial pathogens differed depending on the used corticosteroid doses. High and very high corticosteroid doses are frequently used for real-life COVID-19 patients with severe and critical clinical presentations and are associated with a higher risk of bacteremia independently of sex, comorbidity burden, and mechanical ventilation use.

Corticosteroids are commonly prescribed in oncology, but few studies have examined its adverse events (AEs) compared to placebo control.

Using data from a double-blind, placebo-controlled randomized trial, we evaluated the association between the dose and duration of dexamethasone and serious AEs.

This is a pre-planned secondary analysis of the Alleviating Breathlessness in Cancer Patients with Dexamethasone (ABCD) trial in which patients were randomized to dexamethasone 8 mg BID x1 week, then 4 mg BID x1 week or placebo, followed by an optional open-label phase with 4 mg BID x1 week, then 2 mg BID x1 week. The primary outcome was Grade 3+ AEs (CTCAE v4.03). We evaluated the association between AEs and dexamethasone exposure using multivariable logistic regression.

Among 119 cancer patients, 32 received intervention followed by open label (mean exposure 243 mg over 27 days), 47 received intervention with no open label, 20 received placebo followed by open label, and 20 received no dexamethasone. The most common AEs included insomnia (31%), dyspepsia (21%), neuropsychiatric symptoms (18%), and infections (17%). Overall, 38 (32%) had Grade 3+ AEs and 27 (23%) were hospitalized. Patients with the greatest exposure to dexamethasone experienced more Grade 3+ AEs compared to those with no exposure (65% vs. 15%); odds ratio of 15.1 (95% CI 1.4-160.8, P = 0.01).

Greater dexamethasone exposure, even at moderate doses, was associated with more serious AEs. Prescribers should cautiously weigh the risks and benefits of dexamethasone use, especially when considering for palliation of symptoms.

Currently, some meta-analyses on COVID-19 have suggested that glucocorticoids use can reduce the mortality rate of COVID-19 patients, utilization rate of invasive ventilation, and improve the prognosis of patients. However, optimal regimen and dosages of glucocorticoid remain unclear. Therefore, the purpose of this network meta-analysis is to analyze the efficacy and safety of glucocorticoids in treating COVID-19 at regimens.

This meta-analysis retrieved randomized controlled trials from the earliest records to December 30, 2022, published in PubMed, Embase, Cochrane Library, CNKI Database and Wanfang Database, which compared glucocorticoids with placebos for their efficacy and safety in the treatment of COVID-19, Effects of different treatment regimens, types and dosages (high-dose methylprednisolone, very high-dose methylprednisolone, Pulse therapy methylprednisolone, medium-dose hydrocortisone, high-dose hydrocortisone, high-dose dexamethasone, very high-dose dexamethasone and placebo) on 28-day all-caused hospitalization mortality, hospitalization duration, mechanical ventilation requirement, ICU admission and safety outcome were compared.

In this network meta-analysis, a total of 10,544 patients from 19 randomized controlled trials were finally included, involving a total of 9 glucocorticoid treatment regimens of different types and dosages. According to the analysis results, the 28-day all-cause mortality rate was the lowest in the treatment with pulse therapy methylprednisolone (OR 0.08, 95% CI 0.02, 0.42), but the use of high-dose methylprednisolone (OR 0.85, 95% CI 0.59, 1.22), very high-dose dexamethasone (OR 0.95, 95% CI 0.67, 1.35), high-dose hydrocortisone (OR 0.64, 95% CI 0.34, 1.22), medium-dose hydrocortisone (OR 0.80, 95% CI 0.49, 1.31) showed no benefit in prolonging the 28-day survival of patient. Compared with placebo, the treatment with very high-dose methylprednisolone (MD = -3.09;95%CI: -4.10, -2.08) had the shortest length of hospital stay, while high-dose dexamethasone (MD = -1.55;95%CI: -3.13,0.03) and very high-dose dexamethasone (MD = -1.06;95%CI: -2.78,0.67) did not benefit patients in terms of length of stay.

Considering the available evidence, this network meta‑analysis suggests that the prognostic impact of glucocorticoids in patients with COVID-19 may depend on the regimens of glucocorticoids. It is suggested that pulse therapy methylprednisolone is associated with lower 28-day all-cause mortality, very high-dose methylprednisolone had the shortest length of hospital stay in patients with COVID-19.

PROSPERO CRD42022350407 (22/08/2022).

The aim of this study is to design a population pharmacokinetic study to gain a deeper understanding of the pharmacokinetics of dexamethasone in critically ill COVID-19 patients in order to identify relevant covariates that can be used to personalize dosing regimens.

Blood samples from critically ill patients receiving fixed-dose intravenous dexamethasone (6 mg/day) for the treatment of COVID-19 were sampled in a retrospective pilot study. The data were analyzed using Nonlinear Mixed Effects Modeling (NONMEM) software for population pharmacokinetic analysis and clinically relevant covariates were selected and evaluated.

A total of 51 dexamethasone samples from 18 patients were analyzed and a two-compartment model fit the data best. The mean population estimates were 2.85 L/h (inter-individual-variability 62.9%) for clearance, 15.4 L for the central volume of distribution, 12.3 L for the peripheral volume of distribution and 2.1 L/h for the inter-compartmental distribution clearance. The covariate analysis showed a significant negative correlation between dexamethasone clearance and CRP.

Dexamethasone PK parameters in ICU COVID patients were substantially different from those from non-ICU non-COVID patients, and inflammation may play an important role in dexamethasone exposure. This finding suggests that fixed-dose dexamethasone over several days may not be appropriate for ICU COVID patients.

The impact of different doses of dexamethasone on outcomes from acute COVID-19 pneumonia is unknown.

We performed a systematic review and meta-analysis of randomised control trials comparing different doses of dexamethasone in adult patients with COVID-19. High dose dexamethasone treatment was defined as 12-24 mg daily, whereas low-dose treatment was 6-8 mg daily. Primary outcome was 28-day mortality.

Eight trials including 3469 patients were identified, with 1775 patients receiving high dose dexamethasone. There was no difference in mortality between patients receiving high dose or low-dose dexamethasone (22.0% vs. 20.2%; odds ratio 1.20 [95% confidence interval 0.86-1.67]; p = 0.29; I2 = 63%; TSA-adjusted CI [0.31-4.66]; very low QoE). Meta-regression did not demonstrate a dose-dependent effect of steroids on mortality. High dose dexamethasone was associated with an increased risk of hyperglycaemia (23.6% vs. 17.2%; 1.51 [1.19-1.92]; p = 0.0008; I2 = 0%; TSA-adjusted CI [0.90-2.54]; low QoE) but not secondary infections (14.3% vs. 15.0%; 0.87 [0.56-1.37]; p = 0.56; I2 = 72%; very low QoE). Risk of bias was low for seven of the eight studies.

The mortality of patients with acute COVID-19 receiving high-dose dexamethasone is similar to patients receiving low-dose dexamethasone, although high-dose dexamethasone is associated with an increased risk of hyperglycaemia.

Glucocorticoids as a drug class are widely used in the treatment of many conditions including more recently as one of the mainstay treatments for the SARS-CoV-2 infection. The physiological adverse effects are well described. However, less is known and understood about the potentially deleterious neuro-cognitive effects of this class of medication.

We carried out a systematic review of the literature using two separate search strategies. The first focussed on the rates of reporting of adverse cognitive effects of glucocorticoid use in randomised controlled trials. The second looked at those studies focussing directly on adverse cognitive effects associated with the use of glucocorticoids. MEDLINE, Embase and Cochrane Library was searched for randomised controlled trials utilising glucocorticoids as a part of a treatment regimen. Additionally, these databases were also used to search for articles looking directly at the adverse cognitive effects of glucocorticoids.

Of the forty-three RCTs included as a part of the first search strategy, only one (2.3%) included specific documentation pertaining to cognitive side effects. As a part of the twenty studies included in the second search strategy, eleven of the included studies (55%) were able to demonstrate a correlation between glucocorticoid use and decreased cognition. Most studies within this strategy showed that GCs predominately affected hippocampus-dependent functions such as memory, while sparing executive function and attention.

Overall, the data reporting of adverse clinical effects of glucocorticoid use is poor in recent RCTs. Given the demonstrable effect on predominately hippocampal-dependent cognitive functions evident within the literature, more thorough documentation is needed within clinical research to fully appreciate the potentially widespread nature of these effects.

For the distinct immune/inflammatory responses from Omicron variant infection, this study aimed to investigate the diagnostic efficacy of systemic inflammatory indicators and the clinical efficacy of corticosteroids on the in-hospital mortality among COVID-19 patients.

Under a retrospective cohort study, 1081 COVID-19 patients were recruited from Beijing Youan Hospital, Capital Medical University between November 16, 2022 and January 30, 2023. We chose neutrophil-to-lymphocyte ratio (NLR), CRP-to-lymphocyte ratio (CLR), and CRP-to-albumin ratio (CAR) as the systemic inflammatory indicators. Receiver operating curve (ROC) and multivariate logistic regression analysis were used to determine the diagnostic efficacy of systemic inflammatory indicators and the association between systemic inflammatory indicators and in-hospital mortality.

Among 684 patients included in analysis, 96 died during hospitalization. NLR, CLR and CAR performed well (with an area under the curve (AUC) greater than 0.75) in discriminating in-hospital mortality among COVID-19 patients. The severe status of systemic inflammation, with optimal cut-off value derived from ROC analysis, significantly associated higher risk of in-hospital mortality (OR = 3.81 for NLR ≥ 6.131; OR = 3.76 for CLR ≥ 45.455; OR = 5.10 for CAR ≥ 1.436). Corticosteroids use within 72 hours of admission increased the in-hospital mortality 2.88-fold for COVID-19 patients. In the subgroup of patients with severe systemic inflammation, corticosteroids increased the risk of in-hospital mortality (OR = 2.11 for NLR, p = 0.055; OR = 2.94 for CLR, p = 0.005; OR = 2.31 for CAR, p = 0.036).

Systemic inflammatory indicators had good diagnostic performance for in-hospital mortality. Patients with severe systemic inflammatory status should not receive corticosteroid treatment and further studies are warranted for confirmation.

A limited number of studies have described thrombotic complications in pregnant women with COVID-19. Here we report on fatal pulmonary embolism in a pregnant woman with laboratory confirmed SARS-CoV-2 infection.

A 28-year-old Kazakh woman was hospitalized with muscle pain, dry cough and a temperature of 37.5 °C at the 29th week of gestation. Upon admission, a blood test demonstrated elevated neutrophil-to-lymphocyte ratio, decreased levels of erythrocytes and hemoglobin, as well as prolonged prothrombin and activated partial thromboplastin time. Within 14 days of admission, she experienced respiratory distress and underwent transfer to the intensive care unit, intubation and a cesarean section. The patient received intravenous antibiotics, antiviral medications, systemic corticosteroids and dual anticoagulation with aspirin and enoxaparin. Death outcome was reported on day 18 of illness despite aggressive supportive care. Histological analysis demonstrated that obstruction of the main pulmonary arthery and disseminated intravascular coagulation were the causes of death.

This case demonstrates that in the management of pregnancy and childbirth in patients with suspected or confirmed COVID-19 infection, special attention should be paid to coagulation system parameters and timely appropriate prophylaxis of thromboembolic complications, which has yet to be determined.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. Its symptoms range from mild to severe, with the latter often being life-threatening. This study aims to assess the effects of low-dose dexamethasone (DEX) in mild-to-severe COVID-19 pneumonia and examine the final clinical outcomes to identify the optimal therapeutic dose.

Clinical data from 132 patients hospitalized for COVID-19 pneumonia between January and October 2021 at Yamato Municipal Hospital were retrospectively analyzed. Based on the ratio of peripheral arterial oxygen saturation (SpO2) to inspired fraction of oxygen (FiO2), patients were categorized into the mild (>450, n = 65), moderate (315-450, n = 55), and severe (<315, n = 12) pneumonia groups. The event of interest was defined as the worsening of the patient's condition during treatment (need to increase FiO2 > 0.1). Patients were treated with low-dose DEX (6.6 mg/day) for 10 days.

The event-free survival rate decreased significantly in patients with severe pneumonia compared with in those with mild and moderate pneumonia (Bonferroni-adjusted p < 0.02). A total of 16 patients were treated with high-dose corticosteroids because of severe hypoxia. Recovery was observed in all discharged patients with respiratory condition improvement. Low SpO2/FiO2 at admission was significantly associated with serum C-reactive protein levels.

For Japanese patients with COVID-19, severe pneumonia, and SpO2/FiO2 of <315, it may be necessary to administer a dose of corticosteroids of >6.6 mg DEX.

The present review critically appraised the randomized clinical trials that compared mortality outcomes between intermediate- to high-dose dexamethasone and low-dose dexamethasonein patients with COVID-19 and reported pooled mortality risk estimates associated with these two dosing regimens of dexamethasone. The systematic searching of electronic databases was limited to randomized clinical trials that compared mortality outcomes between intermediate- to high-dose dexamethasone with low-dose dexamethasone in patients with COVID-19 requiring respiratory support. The primary outcome of interest in this review was all-cause mortality. A total of eight trials with 1800 patients randomized to receive intermediate to high-dose dexamethasone and 1715 patients randomized to low-dose dexamethasone were included. The meta-analysis of six trials revealed no significant difference in the risk of 28-day all-cause mortality between intermediate- to high-dose dexamethasone and low-dose dexamethasone (odds ratio 1.16, 95% confidence interval, 0.77-1.74). Similarly, the meta-analysis of five trials revealed no significant difference between the two doses regarding 60-day all-cause mortality (odds ratio 0.96, 95% confidence interval 0.74-1.26). The results suggest intermediate- to high-dose dexamethasone to be as effective as low-dose dexamethasone in reducing the risk of mortality among patients with COVID-19 requiring respiratory support. However, higher dexamethasone doses could expose patients with COVID-19 to an increased risk of adverse events, such as hyperglycemia.

Dexamethasone (DEX) given at a dose of 6 mg once-daily for 10 days is a recommended dosing regimen in patients with coronavirus disease 2019 (COVID-19) requiring oxygen therapy. We developed a population pharmacokinetic and pharmacodynamic (PopPK/PD) model of DEX anti-inflammatory effects in COVID-19 and provide simulations comparing the expected efficacy of four dosing regimens of DEX. Nonlinear mixed-effects modeling and simulations were performed using Monolix Suite version 2021R1 (Lixoft, France). Published data for DEX PK in patients with COVID-19 exhibited moderate variability with a clearance of about half that in healthy adults. No accumulation of the drug was expected even with daily oral doses of 12 mg. Indirect effect models of DEX inhibition of TNFα, IL-6, and CRP plasma concentrations were enacted and simulations performed for DEX given at 1.5, 3, 6, and 12 mg daily for 10 days. The numbers of individuals that achieved specified reductions in inflammatory biomarkers were compared among the treatment groups. The simulations indicate the need for 6 or 12 mg daily doses of DEX for 10 days for simultaneous reductions in TNFα, IL-6, and CRP. Possibly beneficial is DEX given at a dose of 12 mg compared to 6 mg. The PopPK/PD model may be useful in the assessment of other anti-inflammatory compounds as well as drug combinations in the treatment of cytokine storms.

The wide and rapid spread of the COVID-19 pandemic has placed an unanticipated burden on the global healthcare sector. This necessitated a swift response from the international community to reach a solution. Efforts were made in parallel to develop preventative and therapeutic modalities. Since then, drug repurposing has blossomed as a potentially rapid resolution and has included various agents with anti-viral and anti-inflammatory properties. Corticosteroids, being potent anti-inflammatory agents, have been placed under extensive investigation. Various trials have recorded the beneficial outcome of corticosteroids in decreasing the mortality and morbidity of COVID-19. With the high pace of escalating events, the quality and study design of clinical trials are varied. Therefore, this study aims to explore the role of corticosteroids in COVID-19 disease. It inspects the molecular, pharmacologic, and clinical proof behind this theory.

Mucormycosis (also called black fungus) is an opportunistic serious fungal infection caused by mucormycetes. It can occur in diabetes mellitus patients and other immunosuppressive conditions with recent predisposing factors such as maxillofacial surgery and corticosteroid usage.

In this study, 14 patients were referred to the otorhinolaryngology or ophthalmology ward of Shafa Hospital (Kerman, Iran) with primary symptoms of nasal fullness and facial nerve dysfunction; they were admitted to the hospital to rule out the fungal infection. An endoscopic biopsy was taken from facial sinuses or orbit, and a microscopic evaluation was performed using hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining methods to rule out mucormycosis.

In the histopathological examination, broad-based nonseptate branching fungal hyphae were found in nasal sinuses through the endoscopic biopsy. Most of the patients had diabetes mellitus with a primary symptom of facial nerve palsy; also, most of them received corticosteroids (intravenous [IV] or intramuscular [IM] injection). All patients have recently been infected with COVID-19 (less than 1 month ago).

COVID-19 infection might be a predisposing factor for many opportunistic infections, such as fungal elements); thus, the physician should be aware of the dosage and duration of corticosteroid therapy to prevent the development of these infections.

Drug repositioning is a strategy to identify a new therapeutic indication for molecules that have been approved for other conditions, aiming to speed up the traditional drug development process and reduce its costs. The high prevalence and incidence of coronavirus disease 2019 (COVID-19) underline the importance of searching for a safe and effective treatment for the disease, and drug repositioning is the most rational strategy to achieve this goal in a short period of time. Another advantage of repositioning is the fact that these compounds already have established synthetic routes, which facilitates their production at the industrial level. However, the hope for treatment cannot allow the indiscriminate use of medicines without a scientific basis.

The main small molecules in clinical trials being studied to be potentially repositioned to treat COVID-19 are chloroquine, hydroxychloroquine, ivermectin, favipiravir, colchicine, remdesivir, dexamethasone, nitazoxanide, azithromycin, camostat, methylprednisolone, and baricitinib. In the context of clinical tests, in general, they were carried out under the supervision of large consortiums with a methodology based on and recognized in the scientific community, factors that ensure the reliability of the data collected. From the synthetic perspective, compounds with less structural complexity have more simplified synthetic routes. Stereochemical complexity still represents the major challenge in the preparation of dexamethasone, ivermectin, and azithromycin, for instance.

Remdesivir and baricitinib were approved for the treatment of hospitalized patients with severe COVID-19. Dexamethasone and methylprednisolone should be used with caution. Hydroxychloroquine, chloroquine, ivermectin, and azithromycin are ineffective for the treatment of the disease, and the other compounds presented uncertain results. Preclinical and clinical studies should not be analyzed alone, and their methodology's accuracy should also be considered. Regulatory agencies are responsible for analyzing the efficacy and safety of a treatment and must be respected as the competent authorities for this decision, avoiding the indiscriminate use of medicines.

Corticosteroid dosing in COVID-19 cases associated with early-onset and late-onset hypoxia have not been separately explored.

In this retrospective cohort study, we divided hypoxic COVID-19 cases into groups based on timing of initiation of corticosteroids relative to onset of symptoms; Group A (≤6th day), Group B (7th-9th day) and Group C (≥10th day), each group being sub-grouped into high and low-to-moderate dose corticosteroid recipients. Cox regression with propensity scoring was used to compare 28-day mortality between high and low-to-moderate dose recipients separately in Group A, Group B, Group C.

Among 505 patients included, propensity score matched Cox regression showed greater risk of all-cause mortality among high dose recipients in Group A [HR= 7.35, 95%CI 3.36-16.11, p-value<0·01, N=114] and Group B [HR=3.17, 95%CI 1.65-6.07, p-value<0·01, N=251]. In Group C, mortality was lowest [12.8% (18/140)] with no significant difference between sub-groups [HR=2.52, 95%CI 0.22-29.15, p-value=0.459, N=140]. Kruskal-Wallis Test between Group A, Group B and Group C for six pre-defined exposure variables showed significant differences for Neutrophil:Lymphocyte Ratio (NLR).

When steroids were initiated early (owing to an earlier onset of hypoxic symptoms), a high dose of corticosteroid was associated with greater overall 28-day mortality compared to a low-to-moderate dose. NLR, a marker for individual immune response, varied between treatment groups.

Data on Pakistani COVID-19 patient mortality predictors is limited. It is essential to comprehend the relationship between disease characteristics, medications used, and mortality for better patient outcomes.

The medical records of confirmed cases in the Lahore and Sargodha districts were examined using a two-stage cluster sampling from March 2021 to March 2022. Demographics, signs and symptoms, laboratory findings, and pharmacological medications as mortality indicators were noted and analyzed.

A total of 288 deaths occurred out of the 1000 cases. Death rates were higher for males and people over 40. Most of those who were mechanically ventilated perished (OR: 124.2). Dyspnea, fever, and cough were common symptoms, with a significant association amid SpO2 < 95% (OR: 3.2), RR > 20 breaths/min (OR: 2.5), and mortality. Patients with renal (OR: 2.3) or liver failure (OR: 1.5) were at risk. Raised C-reactive protein (OR: 2.9) and D-dimer levels were the indicators of mortality (OR: 1.6). The most prescribed drugs were antibiotics, (77.9%), corticosteroids (54.8%), anticoagulants (34%), tocilizumab (20.3%), and ivermectin (9.2%).

Older males having breathing difficulties or signs of organ failure with raised C-reactive protein or D-dimer levels had high mortality. Antivirals, corticosteroids, tocilizumab, and ivermectin had better outcomes; antivirals were associated with lower mortality risk.

By January of 2023, the COVID-19 pandemic had led to a reported total of 6,700,883 deaths and 662,631,114 cases worldwide. To date, there have been no effective therapies or standardized treatment schemes for this disease; therefore, the search for effective prophylactic and therapeutic strategies is a primary goal that must be addressed. This review aims to provide an analysis of the most efficient and promising therapies and drugs for the prevention and treatment of severe COVID-19, comparing their degree of success, scope, and limitations, with the aim of providing support to health professionals in choosing the best pharmacological approach. An investigation of the most promising and effective treatments against COVID-19 that are currently available was carried out by employing search terms including "Convalescent plasma therapy in COVID-19" or "Viral polymerase inhibitors" and "COVID-19" in the Clinicaltrials.gov and PubMed databases. From the current perspective and with the information available from the various clinical trials assessing the efficacy of different therapeutic options, we conclude that it is necessary to standardize certain variables-such as the viral clearance time, biomarkers associated with severity, hospital stay, requirement of invasive mechanical ventilation, and mortality rate-in order to facilitate verification of the efficacy of such treatments and to better assess the repeatability of the most effective and promising results.

Rationale: Corticosteroids are standard of care for patients with severe coronavirus disease (COVID-19). However, the optimal dose is uncertain. Objectives: To compare higher doses of corticosteroids with lower doses in patients with COVID-19. Methods: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, MedRxiv, and Web of Science from inception to August 1, 2022, for trials that randomized patients with severe-to-critical COVID-19 to corticosteroids, standard care, or placebo. Reviewers, working in duplicate, screened references, extracted data, and assessed risk of bias using a modified version of the Cochrane risk of bias 2.0 tool. We performed a dose-response meta-analysis and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to assess the certainty of evidence. We present our results both in relative risk and absolute risk difference per 1,000, with 95% confidence intervals (CIs). Results: We included 20 trials, with 10,155 patients. We show that, compared with lower-dose corticosteroids, higher-dose corticosteroids probably reduce mortality (absolute risk difference, 14 fewer deaths per 1,000 [95% CI, 26 fewer to 2 fewer]; moderate certainty) and may reduce the need for mechanical ventilation (absolute risk difference, 11.6 fewer per 1,000 [95% CI, 23.2 fewer to 6.9 more]; low certainty). The effect of corticosteroids on nosocomial infections is uncertain (16.7 fewer infections per 1,000 [95% CI, 5.4 fewer to 25.0 fewer]; very low certainty). Conclusions: Relatively higher doses of corticosteroids may be beneficial in patients with severe-to-critical COVID-19 and may not increase the risk of nosocomial infections.

Electronic circuits intuitively visualize and quantitatively simulate biological systems with nonlinear differential equations that exhibit complicated dynamics. Drug cocktail therapies are a powerful tool against diseases that exhibit such dynamics. We show that just six key states, which are represented in a feedback circuit, enable drug-cocktail formulation: 1) healthy cell number; 2) infected cell number; 3) extracellular pathogen number; 4) intracellular pathogenic molecule number; 5) innate immune system strength; and 6) adaptive immune system strength. To enable drug cocktail formulation, the model represents the effects of the drugs in the circuit. For example, a nonlinear feedback circuit model fits measured clinical data, represents cytokine storm and adaptive autoimmune behavior, and accounts for age, sex, and variant effects for SARS-CoV-2 with few free parameters. The latter circuit model provided three quantitative insights on the optimal timing and dosage of drug components in a cocktail: 1) antipathogenic drugs should be given early in the infection, but immunosuppressant timing involves a tradeoff between controlling pathogen load and mitigating inflammation; 2) both within and across-class combinations of drugs have synergistic effects; 3) if they are administered sufficiently early in the infection, anti-pathogenic drugs are more effective at mitigating autoimmune behavior than immunosuppressant drugs.

Corticosteroids (CSs), specifically dexamethasone (DEX), are the treatment of choice for severe acute respiratory distress syndrome (ARDS) due to COVID-19 pneumonia (CARDS). However, data from both ARDS and relatively small CARDS clinical trials have suggested improved outcomes with methylprednisolone (MP) versus DEX. The objective of this retrospective cohort study was to compare the safety and effectiveness of MP and DEX in critically ill CARDS patients.

The study cohort included CARDS patients admitted to a tertiary referral intensive care unit (ICU) between April and September 2020 who received at least 5 days of CSs for CARDS.

The cohort was notable for a high severity of illness (overall, 88.5% of patients required mechanical ventilation and 16% required vasopressors on admission). The DEX group (n = 62) was significantly older with a higher illness severity [Sequential Organ Failure Assessment (SOFA) 6 (4.75-8) versus 4.5 (3-7), p = 0.008], while the MP group (n = 51) received significantly more loading doses [19 (37.3%) versus 4 (6.5%), p < 0.0001]. MP was associated with a shorter time to intubation and more rapid progression to mortality [days to death: 18 (15-23) versus 27 (15-34), p = 0.026]. After correction for baseline imbalances in age and SOFA score, DEX was associated with improved mortality at 90 days compared with MP [hazard ratio (HR) = 0.43, 95% confidence interval (CI) = 0.23-0.80, p = 0.008]. However, there were no differences between rates of secondary infections during hospitalization or insulin requirements at 7 and 14 days.

In this cohort of critically ill CARDS, choice of CS was associated with mortality but not adverse event profile, and thus warrants further investigation.

Coronavirus disease 2019 (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant mortality in pandemic proportions. Inflammation in response to the infection contributes to the pathogenesis of pneumonia. This review will discuss prior studies on the use of glucocorticoids to treat respiratory infections, the rationale for the use glucocorticoids in COVID-19, and review of existing data. We will also highlight outstanding research questions for future studies.

The efficacy and safety of high versus medium doses of glucocorticoids for the treatment of patients with COVID-19 has shown mixed outcomes in controlled trials and observational studies. We aimed to evaluate the effectiveness of methylprednisolone 250 mg bolus versus dexamethasone 6 mg in patients with severe COVID-19.

A randomised, open-label, controlled trial was conducted between February and August 2021 at four hospitals in Spain. The trial was suspended after the first interim analysis since the investigators considered that continuing the trial would be futile. Patients were randomly assigned in a 1:1 ratio to receive dexamethasone 6 mg once daily for up to 10 days or methylprednisolone 250 mg once daily for 3 days.

Of the 128 randomised patients, 125 were analysed (mean age 60 ± 17 years; 82 males [66%]). Mortality at 28 days was 4.8% in the 250 mg methylprednisolone group versus 4.8% in the 6 mg dexamethasone group (absolute risk difference, 0.1% [95% CI, -8.8 to 9.1%]; p = 0.98). None of the secondary outcomes (admission to the intensive care unit, non-invasive respiratory or high-flow oxygen support, additional immunosuppressive drugs, or length of stay), or prespecified sensitivity analyses were statistically significant. Hyperglycaemia was more frequent in the methylprednisolone group at 27.0 versus 8.1% (absolute risk difference, -18.9% [95% CI, -31.8 to - 5.6%]; p = 0.007).

Among severe but not critical patients with COVID-19, 250 mg/d for 3 days of methylprednisolone compared with 6 mg/d for 10 days of dexamethasone did not result in a decrease in mortality or intubation.

The aim of this study is to compare the efficacy and safety of low-dose and high-dose dexamethasone in hospitalized coronavirus disease 2019 (COVID-19) patients. The current meta-analysis was conducted in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search was carried out using PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and Embase. Outcomes assessed in the current meta-analysis included 28-day mortality, intensive care unit (ICU) admission, mechanical ventilation, length of ICU admission (days), and length of hospital stay (days). For safety, we compared hypoglycemia and the incidence of infection between the high-dose dexamethasone group and the low-dose dexamethasone group. A total of four studies fulfilled the inclusion criteria and were included in this meta-analysis. No significant difference was found between the two groups in terms of ICU admission (risk ratio (RR): 0.72, 95% confidence interval (CI): 0.41-1.28, p-value: 0.27), length of stay in ICU in days (mean difference (MD): -0.05, 95%CI: -3.96-3.87, p-value: 0.98, I-square: 94%), length of hospital stay in days (MD: -0.94, 95%CI: -1.94-0.06, p-value: 0.07), need of mechanical ventilation (RR: 0.72, 95%CI: 0.36-1.48, p-value: 0.38), and 28-day mortality (RR: 0.90, 95% CI: 0.50-1.64, p-value: 0.74). The current study showed that higher doses of dexamethasone failed to enhance efficacy compared to low-dose dexamethasone. Thus, based on the findings of this meta-analysis, low-dose dexamethasone can be recommended for these patients.

Systemic corticosteroids are used to treat people with COVID-19 because they counter hyper-inflammation. Existing evidence syntheses suggest a slight benefit on mortality. Nonetheless, size of effect, optimal therapy regimen, and selection of patients who are likely to benefit most are factors that remain to be evaluated.

To assess whether and at which doses systemic corticosteroids are effective and safe in the treatment of people with COVID-19, to explore equity-related aspects in subgroup analyses, and to keep up to date with the evolving evidence base using a living systematic review approach.

We searched the Cochrane COVID-19 Study Register (which includes PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies to 6 January 2022.

We included randomised controlled trials (RCTs) that evaluated systemic corticosteroids for people with COVID-19. We included any type or dose of systemic corticosteroids and the following comparisons: systemic corticosteroids plus standard care versus standard care, different types, doses and timings (early versus late) of corticosteroids. We excluded corticosteroids in combination with other active substances versus standard care, topical or inhaled corticosteroids, and corticosteroids for long-COVID treatment.

We followed standard Cochrane methodology. To assess the risk of bias in included studies, we used the Cochrane 'Risk of bias' 2 tool for RCTs. We rated the certainty of the evidence using the GRADE approach for the following outcomes: all-cause mortality up to 30 and 120 days, discharged alive (clinical improvement), new need for invasive mechanical ventilation or death (clinical worsening), serious adverse events, adverse events, hospital-acquired infections, and invasive fungal infections.

We included 16 RCTs in 9549 participants, of whom 8271 (87%) originated from high-income countries. A total of 4532 participants were randomised to corticosteroid arms and the majority received dexamethasone (n = 3766). These studies included participants mostly older than 50 years and male. We also identified 42 ongoing and 23 completed studies lacking published results or relevant information on the study design. Hospitalised individuals with a confirmed or suspected diagnosis of symptomatic COVID-19 Systemic corticosteroids plus standard care versus standard care plus/minus placebo We included 11 RCTs (8019 participants), one of which did not report any of our pre-specified outcomes and thus our analyses included outcome data from 10 studies. Systemic corticosteroids plus standard care compared to standard care probably reduce all-cause mortality (up to 30 days) slightly (risk ratio (RR) 0.90, 95% confidence interval (CI) 0.84 to 0.97; 7898 participants; estimated absolute effect: 274 deaths per 1000 people not receiving systemic corticosteroids compared to 246 deaths per 1000 people receiving the intervention (95% CI 230 to 265 per 1000 people); moderate-certainty evidence). The evidence is very uncertain about the effect on all-cause mortality (up to 120 days) (RR 0.74, 95% CI 0.23 to 2.34; 485 participants). The chance of clinical improvement (discharged alive at day 28) may slightly increase (RR 1.07, 95% CI 1.03 to 1.11; 6786 participants; low-certainty evidence) while the risk of clinical worsening (new need for invasive mechanical ventilation or death) may slightly decrease (RR 0.92, 95% CI 0.84 to 1.01; 5586 participants; low-certainty evidence). For serious adverse events (two RCTs, 678 participants), adverse events (three RCTs, 447 participants), hospital-acquired infections (four RCTs, 598 participants), and invasive fungal infections (one study, 64 participants), we did not perform any analyses beyond the presentation of descriptive statistics due to very low-certainty evidence (high risk of bias, heterogeneous definitions, and underreporting). Different types, dosages or timing of systemic corticosteroids We identified one RCT (86 participants) comparing methylprednisolone to dexamethasone, thus the evidence is very uncertain about the effect of methylprednisolone on all-cause mortality (up to 30 days) (RR 0.51, 95% CI 0.24 to 1.07; 86 participants). None of the other outcomes of interest were reported in this study. We included four RCTs (1383 participants) comparing high-dose dexamethasone (12 mg or higher) to low-dose dexamethasone (6 mg to 8 mg). High-dose dexamethasone compared to low-dose dexamethasone may reduce all-cause mortality (up to 30 days) (RR 0.87, 95% CI 0.73 to 1.04; 1269 participants; low-certainty evidence), but the evidence is very uncertain about the effect of high-dose dexamethasone on all-cause mortality (up to 120 days) (RR 0.93, 95% CI 0.79 to 1.08; 1383 participants) and it may have little or no impact on clinical improvement (discharged alive at 28 days) (RR 0.98, 95% CI 0.89 to 1.09; 200 participants; low-certainty evidence). Studies did not report data on clinical worsening (new need for invasive mechanical ventilation or death). For serious adverse events, adverse events, hospital-acquired infections, and invasive fungal infections, we did not perform analyses beyond the presentation of descriptive statistics due to very low-certainty evidence. We could not identify studies for comparisons of different timing and systemic corticosteroids versus other active substances. Equity-related subgroup analyses We conducted the following subgroup analyses to explore equity-related factors: sex, age (< 70 years; ≥ 70 years), ethnicity (Black, Asian or other versus White versus unknown) and place of residence (high-income versus low- and middle-income countries). Except for age and ethnicity, no evidence for differences could be identified. For all-cause mortality up to 30 days, participants younger than 70 years seemed to benefit from systemic corticosteroids in comparison to those aged 70 years and older. The few participants from a Black, Asian, or other minority ethnic group showed a larger estimated effect than the many White participants. Outpatients with asymptomatic or mild disease There are no studies published in populations with asymptomatic infection or mild disease.

Systemic corticosteroids probably slightly reduce all-cause mortality up to 30 days in people hospitalised because of symptomatic COVID-19, while the evidence is very uncertain about the effect on all-cause mortality up to 120 days. For younger people (under 70 years of age) there was a potential advantage, as well as for Black, Asian, or people of a minority ethnic group; further subgroup analyses showed no relevant effects. Evidence related to the most effective type, dose, or timing of systemic corticosteroids remains immature. Currently, there is no evidence on asymptomatic or mild disease (non-hospitalised participants). Due to the low to very low certainty of the current evidence, we cannot assess safety adequately to rule out harmful effects of the treatment, therefore there is an urgent need for good-quality safety data. Findings of equity-related subgroup analyses should be interpreted with caution because of their explorative nature, low precision, and missing data. We identified 42 ongoing and 23 completed studies lacking published results or relevant information on the study design, suggesting there may be possible changes of the effect estimates and certainty of the evidence in the future.