Comparison of the efficacy of equivalent doses of dexamethasone, methylprednisolone, and hydrocortisone for treatment of COVID-19-related acute respiratory distress syndrome: a prospective three-arm randomized clinical trial.

BACKGROUND: This prospective controlled clinical trial aimed to compare the efficacy of methylprednisolone, dexamethasone, and hydrocortisone at equivalent doses in patients with severe COVID-19. METHODS: In total, 106 patients with mild to moderate COVID-19-related acute respiratory distress syndrome (ARDS) were randomized to receive either dexamethasone (6 mg once a day), methylprednisolone (16 mg twice a day), or hydrocortisone (50 mg thrice a day) for up to 10 days. All participants received a standard of care for COVID-19. The primary and secondary efficacy outcomes included all-cause 28-day mortality, clinical status on day 28 assessed using the World Health Organization (WHO) eight-category ordinal clinical scale, number of patients requiring mechanical ventilation and intensive care unit (ICU) care, number of ventilator-free days, length of hospital and ICU stay, change in PaO2:FiO2 ratios during the first 5 days after treatment, and incidence of serious adverse events. P-values below 0.008 based on Bonferroni's multiple-testing correction method were considered statistically significant. RESULTS: According to the obtained results, there was a trend toward more favorable clinical outcomes in terms of needing mechanical ventilation and ICU care, number of ventilator-free days, change in PaO2:FiO2 ratios during the first 5 days after treatment, clinical status score at day 28, length of ICU and hospital stay, and overall 28-day mortality in patients receiving dexamethasone compared to those receiving methylprednisolone or hydrocortisone; however, likely due to the study's small sample size, the difference between groups reached a significant level only in the case of clinical status score on day 28 (p-value = 0.003). There was no significant difference in the incidence of serious adverse events between the study groups. CONCLUSION: Based on the results, severe cases of COVID-19 treated with dexamethasone might have a better clinical status at 28-day follow-up compared to methylprednisolone and hydrocortisone at an equivalent dose. Larger multicenter trials are required to confirm our findings.

Safety and efficacy of corticosteroids in ARDS patients: a systematic review and meta-analysis of RCT data.

PURPOSE: Acute respiratory distress syndrome (ARDS) is an acute and critical disease among children and adults, and previous studies have shown that the administration of corticosteroids remains controversial. Therefore, a meta-analysis of randomized controlled trials (RCTs) was performed to evaluate the safety and efficacy of corticosteroids. METHODS: The RCTs investigating the safety and efficacy of corticosteroids in ARDS were searched from electronic databases (Embase, Medline, and the Cochrane Central Register of Controlled Trials). The primary outcome was 28-day mortality. Heterogeneity was assessed using the Chi square test and I2 with the inspection level of 0.1 and 50%, respectively. RESULTS: Fourteen RCTs (n = 1607) were included for analysis. Corticosteroids were found to reduce the risk of death in patients with ARDS (relative risk (RR) = 0.78, 95% confidence interval (CI): 0.70-0.87; P < 0.01). Moreover, no significant adverse events were observed, compared to placebo or standard support therapy. Further subgroup analysis showed that variables, such as adults (RR = 0.78; 95% CI: 0.70-0.88; P < 0.01), non-COVID-19 (RR = 0.71; 95% CI: 0.62-0.83; P < 0.01), methylprednisolone (RR = 0.70; 95% CI: 0.56-0.88; P < 0.01), and hydrocortisone (RR = 0.79; 95% CI: 0.63-0.98; P = 0.03) were associated with 28-day mortality among patients who used corticosteroids. However, no association was found, regarding children (RR = 0.21; 95% CI: 0.01-4.10; P = 0.30). CONCLUSION: The use of corticosteroids is an effective approach to reduce the risk of death in ARDS patients. However, this effect is associated with age, non-COVID-19 diseases, and methylprednisolone and hydrocortisone use. Therefore, evidence suggests patients with age ≥ 18 years and non-COVID-19 should be encouraged during the corticosteroid treatment. However, due to substantial differences in the use of corticosteroids among these studies, questions still remain regarding the dosage, optimal corticosteroid agent, and treatment duration in patients with ARDS.

A retrospective comparative analysis of factors affecting the decision and outcome of initial intravenous immunoglobulin alone or intravenous immunoglobulin plus methylprednisolone use in children with the multisystem inflammatory syndrome.

BACKGROUND: For children with the multisystem inflammatory syndrome(MIS-C), intravenous immunoglobulins (IVIG) with or without methylprednisolone are the most effective treatment. In this study, IVIG combined with methylprednisolone was compared to IVIG used alone in children with MIS-C. METHODS: This retrospective cohort study was carried out between April 1, 2020, and November 1, 2021. This study covered all children with MIS-C. According to whether they received IVIG alone or IVIG with methylprednisolone as an initial treatment for MIS-C, the patients were split into two groups. The IVIG dosage for the patients in group I was 2 gr/kg, whereas the IVIG dosage for the patients in group II was 2 gr/kg + 2 mg/kg/day of methylprednisolone. These two groups were contrasted in terms of the frequency of fever, length of hospital stay, and admission to the pediatric intensive care unit. RESULTS: The study comprised 91 patients who were diagnosed with MIS-C and were under the age of 18. 42 (46.2%) of these patients were in the IVIG alone group (group I), and 49 (53.8%) were in the IVIG + methylprednisolone group (group II). Patients in group II had a severe MIS-C ratio of 36.7%, which was substantially greater than the rate of severe MIS-C patients in group I (9.5%) (p 0.01). When compared to group I (9.5%), the rate of hypotension was considerably higher in group II (30.6%) (p = 0.014). Additionally, patients in group II had considerably higher mean serum levels of C-reactive protein. The incidence of fever recurrence was 26.5% in group II and 33.3% in group I, however the difference was not statistically significant (p > 0.05). CONCLUSIONS: The choice of treatment for patients with MIS-C should be based on an individual evaluation. In MIS-C children with hypotension and/or with an indication for a pediatric intensive care unit, a combination of IVIG and methylprednisolone may be administered. For the treatment modalities of children with MIS-C, however, randomized double-blind studies are necessary.

Drug-drug interaction between remdesivir and immunosuppressant agents in a kidney transplant recipient.

A 60-year-old man was treated with a regimen of controlled-release tacrolimus (2 mg once daily), everolimus (0.5 mg twice daily), methylprednisolone (4 mg once daily), and mizoribine (100 mg twice daily) as an anti-rejection regimen following living-donor kidney transplantation. One year after transplantation, the recipient was admitted to Mie University Hospital (day X; admission date) to treat coronavirus disease 2019 pneumonia. The latest trough concentrations of tacrolimus and everolimus before admission (day X-65) were 4.5 ng/mL and 4.4 ng/mL, respectively. Since tacrolimus concentration was 4.2 ng/mL on day X+3, the dose was adjusted to 1.5 mg once daily to reach the target concentration of 3.0 ng/mL due to the introduction of remdesivir. After starting remdesivir on day X+4, the increased trough concentrations of tacrolimus on day X+6 (6.9 ng/mL) and everolimus on day X+7 (9.2 ng/mL) were observed, which resulted in dose reduction of tacrolimus (0.5 mg once daily) and discontinuation of everolimus. After discontinuation of remdesivir on day X+9, dose titration of controlled-release tacrolimus and restart of everolimus (0.5 mg twice daily) were performed from day X+15. The dose of controlled-release tacrolimus was titrated and fixed to 2 mg once daily at discharge (day X+21). There was no toxicity due to immunosuppressive agents during hospitalization. This case report indicated that remdesivir might interact with cytochrome P450 3A4 substrates, such as tacrolimus and everolimus, and elevate their blood concentrations under high inflammatory conditions.

Effects of different doses of methylprednisolone on clinical outcomes in patients with severe community-acquired pneumonia: a study protocol for a randomized controlled trial.

BACKGROUND: The specific use of methylprednisolone in severe community-acquired pneumonia (SCAP) has not yet formed a consensus. It is not clear whether the clinical efficacy of methylprednisolone in SCAP is dose-dependent, and how to balance the best efficacy with the least complications. The aim of this study is to evaluate the efficacy and safety of different doses of methylprednisolone in the adjuvant treatment for patients with SCAP. METHODS/DESIGN: This is a prospective, randomized, double-blind, parallel group, placebo-controlled trial to evaluate the efficacy and safety of different doses of methylprednisolone in the adjuvant treatment for patients with SCAP. Patients with diagnosed SCAP are randomized to the following four groups at a 1:1:1:1 ratio: group 1 (control group)-standard ICU patient care+100ml of normal saline once a day for 5 days; group 2-standard ICU patient care+40mg of methylprednisolone (dissolved in normal saline with a final volume of 100ml) once a day for 5 days; group 3-standard ICU patient care+80mg of methylprednisolone (dissolved in normal saline with a final volume of 100ml) once a day for 5 days; and group 4-standard ICU patient care+120mg of methylprednisolone (dissolved in normal saline with a final volume of 100ml) once a day for 5 days. The primary outcome is PaO2/FiO2 ratio at day 5 following randomization. The secondary outcomes are 28-day mortality, ventilator-free days at 28 days, mechanical ventilation duration at 28 days, endotracheal intubation rate, time for temperature recovery, duration of vasopressors use, serum CRP and interleukin-6 level at day 5 following randomization, hospital stay, frequency of nosocomial infections, gastrointestinal hemorrhage, and hyperglycemia. DISCUSSION: The results of our study may find the optimal dose of glucocorticoid in the adjuvant treatment of SCAP and provide evidence-based proof for clinicians to treat patients with SCAP. Since coronavirus disease 2019 (COVID-19) also belongs to community-acquired pneumonia, perhaps the results of our study will help to determine the appropriate dose of methylprednisolone in COVID-19 treatment. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100045056 . Registered on 4 April 2021.

Comparing efficacy and safety of tocilizumab and methylprednisolone in the treatment of patients with severe COVID-19.

OBJECTIVES: This study was designed to compare the efficacy and safety of methylprednisolone and tocilizumab in the treatment of patients with severe COVID-19. METHODS: During a prospective cohort study, hospitalized patients with severe COVID-19 received intravenous methylprednisolone (250-500 mg daily up to three doses), weight-based tocilizumab (maximum 800 mg, one or two doses as daily interval) or dexamethasone (8 mg daily). The primary outcome was time to onset of clinical response. Secondary outcomes were improvement rate of oxygen saturation and CRP, need for ICU admission, duration of hospitalization and 28-day mortality. During study, adverse events of the treatments were recorded. RESULTS: Although the difference was not statistically significant (p = 0.090), clinical response occurred faster in the tocilizumab group than other groups (10 vs. 16 days). Clinical response was detected in 74.19%, 81.25%, and 60% of patients in the methylprednisolone, tocilizumab, and dexamethasone groups respectively (p = 0.238). Based on the Cox regression analysis and considering dexamethasone as the reference group, HR (95% CI) of clinical response was 1.08 (0.65-1.79) and 1.46 (0.89-2.39) in the methylprednisolone and tocilizumab groups respectively. Improvement rate of oxygen saturation and CRP was not significantly different between the groups (p = 0.791 and p = 0.372 respectively). Also need for ICU admission and 28-day mortality was comparable between the groups (p = 0.176 and p = 0.143 respectively). Compared with methylprednisolone, tocilizumab caused more sleep disturbances (p = 0.019). Other adverse events were comparable among patients in the groups. CONCLUSION: When or where access to tocilizumab is a problem, methylprednisolone may be considered as an alternative for the treatment of patients with severe COVID-19.

A rare case of drug-induced bradycardia associated with the just low dose use of methylprednisolone in a child with COVID-19.

Methylprednisolone (MP) is usually used to reduce inflammation reaction and tissue damage, which may have a beneficial treatment effect on coronavirus disease 2019 (COVID-19). However, we present the case of a child who manifests significant bradycardia with the use of just low dose MP on the premise of the long-term use of arbidol. Arbidol can affect the activity of CYP3A4, which is also a key metabolic enzyme of MP by competitive inhibition, and which is easy to aggravate the side effects of MP. Therefore, more attention should be paid to bradycardia occurrence in the patient with COVID-19 when MP is considered in COVID-19.

Systemic corticosteroids for management of COVID-19: Saving lives or causing harm?

The underlying cause of many complications associated with severe COVID-19 is attributed to the inflammatory cytokine storm that leads to acute respiratory distress syndrome (ARDS), which appears to be the leading cause of death in COVID-19. Systemic corticosteroids have anti-inflammatory activity through repression of pro-inflammatory genes and inhibition of inflammatory cytokines, which makes them a potential medical intervention to diminish the upregulated inflammatory response. Early in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the role of corticosteroids was unclear. Corticosteroid use in other indications such as ARDS and septic shock has proven benefit while its use in other respiratory viral pneumonias is associated with reduced viral clearance and increased secondary infections. This review article evaluates the benefits and harms of systemic corticosteroids in patients with COVID-19 to assist clinicians in improving patient outcomes, including patient safety. Dexamethasone up to 10 days is the preferred regimen to reduce mortality risk in COVID-19 patients requiring oxygen support, mechanical ventilation, or extracorporeal membrane oxygenation. If dexamethasone is unavailable, other corticosteroids can be substituted at equivalent doses. Higher doses of corticosteroids may be beneficial in patients who develop ARDS. Corticosteroids should be avoided early in the disease course when patients do not require oxygen support because of potential harms.

Effectiveness of methylprednisolone therapy in patients with a high-risk common type of COVID-19 pneumonia: a retrospective cohort study.

The optimal timing of glucocorticoid treatment for coronavirus disease 2019 (COVID-19) pneumonia is uncertain. We evaluated the clinical outcomes of methylprednisolone therapy (MPT) for patients with a high-risk common type (HRCT) COVID-19 pneumonia. We conducted a multicenter retrospective cohort study in Northeast China. A comparison was performed between the standard treatment (SDT) group and the SDT + MPT group to determine the efficacy of methylprednisolone in treating HRCT COVID-19 pneumonia. We collected the medical records of 403 patients with HRCT COVID-19 pneumonia (127 in the SDT + MPT group and 276 in the SDT group). None of the patients had received mechanical ventilation or died. Furthermore, there were no side effects associated with MPT. Patients in the SDT + MPT group treated with methylprednisolone received an intravenous injection for a median interval of five days (interquartile range of 3 to 7 days). The trends in lymphocyte count, C-reactive protein, interleukin 6, lactic acid dehydrogenase, respiratory rate, SpO2, PaO2, D-dimer and body temperature were similar between the SDT + MPT and SDT groups. The results for the SDT + MPT group seemed to improve faster than those for the SDT group; however, the results were not statistically significant. Clinical outcomes revealed that the average hospitalized days and the rate of progression to severe type COVID-19 pneumonia in both the SDT + MPT group and the SDT group were 14.56 ± 0.57 days versus 16.55 ± 0.3 days (p = 0.0009) and 21.26% (27/127) versus 32.4% (89/276) (p = 0.0247), respectively. The 16-day nucleic acid negative rate was higher in the SDT + MPT group than in the SDT group, 81.73% (104/127) versus 65.27% (180/276) (p = 0.0006). MPT effectively prevents patients with HRCT COVID-19 pneumonia from progressing to the severe stage.

Comparison of pulse-dose and high-dose corticosteroids with no corticosteroid treatment for COVID-19 pneumonia in the intensive care unit.

Corticosteroid dosing in the range of 0.5-2 mg/kg/day of methylprednisolone equivalents has become a standard part of the management of intensive care unit (ICU) patients with COVID-19 pneumonia based on positive results of randomized trials and a meta-analysis. Alongside such conventional dosing, administration of 1 gm of methylprednisolone daily (pulse dosing) has also been reported in the literature with claims of favorable outcomes. Comparisons between such disparate approaches to corticosteroids for Coronavirus disease 2019 (COVID-19) pneumonia are lacking. In this retrospective study of patients admitted to the ICU with COVID-19 pneumonia, we compared patients treated with 0.5-2 mg/kg/day in methylprednisolone equivalents (high-dose corticosteroids) and patients treated with 1 gm of methylprednisolone (pulse-dose corticosteroids) to those who did not receive any corticosteroids. The endpoints of interest were hospital mortality, ICU-free days at Day 28, and complications potentially attributable to corticosteroids. Pulse-dose corticosteroid therapy was associated with a significant increase in ICU-free days at Day 28 compared to no receipt: adjusted relative risk (aRR): 1.45 (95% confidence interval [CI]: 1.05-2.02; p = 0.03) and compared with high-dose corticosteroid administration (p = 0.003). Nonetheless, receipt of high-dose corticosteroids-but not of pulse-dose corticosteroids-significantly reduced the odds of hospital mortality compared to no receipt: adjusted Odds ratio (aOR) 0.31 (95% CI: 0.12-0.77; p = 0.01). High-dose corticosteroids reduced mortality compared to pulse-dose corticosteroids (p = 0.04). Pulse-dose corticosteroids-but not high-dose corticosteroids-significantly increased the odds of acute kidney injury requiring renal replacement therapy compared to no receipt: aOR 3.53 (95% CI: 1.27-9.82; p = 0.02). The odds of this complication were also significantly higher in the pulse-dose group when compared to the high-dose group (p = 0.05 for the comparison). In this single-center study, pulse-dose corticosteroid therapy for COVID-19 pneumonia in the ICU was associated with an increase in ICU-free days but failed to impact hospital mortality, perhaps because of its association with development of severe renal failure. In line with existing trial data, the effect of high-dose corticosteroids on mortality was favorable.

Clinical efficacy and safety of combination therapy of tocilizumab and steroid pulse therapy for critical COVID-19 in HD patients.

BACKGROUND: Critical coronavirus disease 2019 (COVID-19) has a high fatality rate, especially in hemodialysis (HD) patients, with this poor prognosis being caused by systemic hyperinflammation; cytokine storms. Steroid pulse therapy or tocilizumab (TCZ) have insufficient inhibitory effects against cytokine storms in critical cases. This study evaluated the clinical effects and safety of combining steroid pulse therapy and TCZ. METHODS: From September 2020 to May 2021, 201 patients with COVID-19 were admitted to our hospital. Before February 2021, patients with an oxygen demand exceeding 8 L/min were intubated and treated with standard therapy (dexamethasone and antiviral therapy). After February 2021, patients underwent high-flow nasal cannula oxygen therapy and were treated with TCZ (8 mg/kg) and methylprednisolone (mPSL) (500 mg/day [≤ 75 kg], 1000 mg/day [> 75 kg]) for 3 days. We compared background characteristics, laboratory findings, and prognosis between non-HD and HD patients and between patients who received and did not receive TCZ and mPSL pulse therapy. RESULTS: Among non-HD patients, the TCZ + mPSL pulse group had significantly higher survival rates and lower secondary infection rates (p < 0.05), than the standard therapy group. All HD patients in the standard therapy group with oxygen demand exceeding 8 L/min died. Contrastingly, all patients in the TCZ + mPSL pulse group survived, with their oxygen demand decreasing to 0-1 L/min within 3 weeks post-administration. CONCLUSION: TCZ combined with mPSL pulse therapy improved the survival rate without significant adverse events in critical HD and non-HD patients with COVID-19 by strongly suppressing systemic hyperinflammation.

Does methylprednisolone reduce the mortality risk in hospitalized COVID-19 patients? A meta-analysis of randomized control trials.

Objectives: The question remained if mortality benefits with dexamethasone seen in patients with coronavirus disease 2019 (COVID-19) also extend to other systemic corticosteroids such as methylprednisolone. This article presents a meta-analysis of randomized controlled trials (RCTs) to ascertain if methylprednisolone can be recommended for use in patients with COVID-19 to prevent deaths.Methods: Systematic literature search was performed in PubMed, Scopus, Cochrane Central Register of Controlled Trials, and preprint servers until 13 April 2021. The outcome of interest was all-cause mortality. The random-effects model for the meta-analysis was utilized to estimate the pooled odds ratio (OR) at 95% confidence intervals (CI).Results: Five RCTs were included in the meta-analysis. The pooled OR for all-cause mortality was 0.64 (95% CI: 0.29 - 1.43, n = 652) comparing methylprednisolone with the control, indicating no mortality benefits. A similar finding was noted with a sub-group analysis including four trials that used low-dose methylprednisolone. However, the only trial that administered high dose methylprednisolone indicated a statistically significant mortality benefit (OR 0.08, 95% CI: 0.02-0.42).Conclusions: In determining equipotent doses for an acute short-course pulse therapy of corticosteroids, the biological half-life of steroids should also be accounted for besides the potency factor. A short duration (3-5 days) pulse therapy of high-dose methylprednisolone can be a promising alternative to the low-dose dexamethasone therapy in severely ill patients with COVID-19 to prevent deaths.

Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children.

Importance: Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown. Objective: To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C. Design, Setting, and Participants: Retrospective cohort study drawn from a national surveillance system with propensity score-matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021. Exposures: IVIG and methylprednisolone vs IVIG alone. Main Outcomes and Measures: The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1. Results: Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females [52%]; median age, 8.6 years [interquartile range, 4.7 to 12.1]). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, -0.28 [95% CI, -0.48 to -0.08]; odds ratio [OR], 0.25 [95% CI, 0.09 to 0.70]; P = .008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, -0.22 [95% CI, -0.40 to -0.04]; OR, 0.19 [95% CI, 0.06 to 0.61]; P = .004), hemodynamic support (absolute risk difference, -0.17 [95% CI, -0.34 to -0.004]; OR, 0.21 [95% CI, 0.06 to 0.76]), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, -0.18 [95% CI, -0.35 to -0.01]; OR, 0.20 [95% CI, 0.06 to 0.66]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, -2.4 [95% CI, -4.0 to -0.7]). Conclusions and Relevance: Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design.

Corticosteroid therapy in critically ill patients with COVID-19: a multicenter, retrospective study.

BACKGROUND: Corticoid therapy has been recommended in the treatment of critically ill patients with COVID-19, yet its efficacy is currently still under evaluation. We investigated the effect of corticosteroid treatment on 90-day mortality and SARS-CoV-2 RNA clearance in severe patients with COVID-19. METHODS: 294 critically ill patients with COVID-19 were recruited between December 30, 2019 and February 19, 2020. Logistic regression, Cox proportional-hazards model and marginal structural modeling (MSM) were applied to evaluate the associations between corticosteroid use and corresponding outcome variables. RESULTS: Out of the 294 critically ill patients affected by COVID-19, 183 (62.2%) received corticosteroids, with methylprednisolone as the most frequently administered corticosteroid (175 accounting for 96%). Of those treated with corticosteroids, 69.4% received corticosteroid prior to ICU admission. When adjustments and subgroup analysis were not performed, no significant associations between corticosteroids use and 90-day mortality or SARS-CoV-2 RNA clearance were found. However, when stratified analysis based on corticosteroid initiation time was performed, there was a significant correlation between corticosteroid use (≤ 3 day after ICU admission) and 90-day mortality (logistic regression adjusted for baseline: OR 4.49, 95% CI 1.17-17.25, p = 0.025; Cox adjusted for baseline and time varying variables: HR 3.89, 95% CI 1.94-7.82, p < 0.001; MSM adjusted for baseline and time-dependent variants: OR 2.32, 95% CI 1.16-4.65, p = 0.017). No association was found between corticosteroid use and SARS-CoV-2 RNA clearance even after stratification by initiation time of corticosteroids and adjustments for confounding factors (corticosteroids use ≤ 3 days initiation vs no corticosteroids use) using MSM were performed. CONCLUSIONS: Early initiation of corticosteroid use (≤ 3 days after ICU admission) was associated with an increased 90-day mortality. Early use of methylprednisolone in the ICU is therefore not recommended in patients with severe COVID-19.

SARS-CoV-2 and Aspergillus section Fumigati coinfection in an immunocompetent patient treated with corticosteroids.

BACKGROUND: Patients with severe viral pneumonia are likely to receive high-dose immunomodulatory drugs to prevent clinical worsening. Aspergillus species have been described as frequent secondary pneumonia agents in severely ill influenza patients receiving steroids. COVID-19 patients admitted to Intensive Care Unit (ICU) are receiving steroids as part of their treatment and they share clinical characteristics with other patients with severe viral pneumonias. COVID-19 patients receiving steroids should be considered a putative risk group of invasive aspergillosis. CASE REPORT: We are reporting a SARS-CoV-2/Aspergillus section Fumigati coinfection in an elderly intubated patient with a history of pulmonary embolism treated with corticosteroids. The diagnosis was made following the ad hoc definitions described for patients admitted to ICU with severe influenza, including clinical criteria (fever for 3 days refractory to the appropriate antibiotic therapy, dyspnea, pleural friction rub, worsening of respiratory status despite antibiotic therapy and need of ventilator support), a radiological criterion (pulmonary infiltrate) and a mycological criterion (several positive galactomannan tests on serum with ratio ≥0.5). In addition, Aspergillus section Fumigati DNA was found in serum and blood samples. These tests were positive 4 weeks after the patient was admitted to the ICU. The patient received voriconazole and after two month in ICU his respiratory status improved; he was discharged after 6 weeks of antifungal treatment. CONCLUSIONS: Severely ill COVID-19 patients would be considered a new aspergillosis risk group. Galactomannan and Aspergillus DNA detection would be useful methods for Aspergillus infection diagnosis as they allow avoiding the biosafety issues related to these patients.

COVID-19 in a lung transplant recipient: Exploring the diagnostic role of circulating exosomes and the clinical impact of advanced immunosuppression.

Exosomes isolated from plasma of lung transplant recipients with allograft injury contain donor-derived lung self-antigens (collagen V and Kα1 tubulin) and human leukocyte antigen (HLA) molecules. We present a case of a 76-year-old, female lung transplant recipient treated for acute cellular rejection with methylprednisolone and anti-thymocyte globulin, who subsequently contracted SARS-CoV-2 and developed a sharp increase in the mean fluorescent intensity of anti-HLA antibodies. Analysis of circulating exosomes during rejection, but before SARS-CoV-2 infection, revealed the presence of lung self-antigens and HLA class II molecules. After the patient contracted SARS-CoV-2, exosomes with the SARS-CoV-2 spike protein were also found. After resolution of infectious symptoms, exosomes with SARS-CoV-2 spike protein were no longer detected; however, exosomes with lung self-antigens and HLA class II molecules persisted, which coincided with a progressive decline in spirometric flows, suggesting chronic lung allograft dysfunction. We propose that the analysis of circulating exosomes may be used to detect allograft injury mediated by both rejection and infection. Furthermore, the detection of exosomes containing viral proteins may be helpful in identifying allograft injury driven by viral pathogens.

Corticosteroid therapy is associated with the delay of SARS-CoV-2 clearance in COVID-19 patients.

The impact of corticosteroid treatment on virological course of coronavirus disease 2019 (COVID-19) patients remains unclear. This study aimed to explore the association between corticosteroid and viral clearance in COVID-19. The clinical data of COVID-19 patients from 10 hospitals of Jiangsu, China, were retrospectively collected. Cox regression and Kaplan-Meier analysis were used to analyze the adverse factors of virus clearance. Of the 309 COVID-19 patients, eighty-nine (28.8%) patients received corticosteroid treatment during hospitalization. Corticosteroid group showed higher C-reactive protein (median 11.1 vs. 7.0 mg/l, P = 0.018) and lower lymphocytes (median 0.9 vs. 1.4 × 109/l, P < 0.001) on admission. Fever (93.3% vs. 65.0%, P < 0.001) and cough (69.7% vs. 57.3%, P = 0.043) were more common in corticosteroid group. The proportions of patients with severe illness (34.8% vs. 1.8%, P < 0.001), respiratory failure (25.8% vs. 1.4%, P < 0.001), acute respiratory distress syndrome (4.5% vs. 0%, P = 0.002), and admission to ICU (20.2% vs. 0.9%, P < 0.001) were significantly higher in corticosteroid group than non-corticosteroid group. The duration of virus clearance (median 18.0 vs. 16.0 days, P < 0.001) and hospitalization (median 17.0 vs. 15.0 days, P < 0.001) were also significantly longer in corticosteroid group than non-corticosteroid group. Treated with corticosteroid (Hazard ratio [HR], 0.698; 95% confidence interval [CI], 0.512 to 0.951; P = 0.023) was an adverse factor of the clearance of SARS-CoV-2, especially for male patients (HR, 0.620; 95% CI, 0.408 to 0.942; P = 0.025). The cumulative probability of SARS-CoV-2 clearance was lower in corticosteroid group (P < 0.001). Corticosteroid treatment may delay the SARS-CoV-2 clearance of COVID-19 patients and should be used with cautions.

Multi-centre, three arm, randomized controlled trial on the use of methylprednisolone and unfractionated heparin in critically ill ventilated patients with pneumonia from SARS-CoV-2 infection: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: To assess the hypothesis that an adjunctive therapy with methylprednisolone and unfractionated heparin (UFH) or with methylprednisolone and low molecular weight heparin (LMWH) are more effective in reducing any-cause mortality in critically-ill ventilated patients with pneumonia from SARS-CoV-2 infection compared to LMWH alone. TRIAL DESIGN: The study is designed as a multi-centre, interventional, parallel group, superiority, randomized, investigator sponsored, three arms study. Patients, who satisfy all inclusion criteria and no exclusion criteria, will be randomly assigned to one of the three treatment groups in a ratio 1:1:1. PARTICIPANTS: Inpatients will be recruited from 8 Italian Academic and non-Academic Intensive Care Units INCLUSION CRITERIA (ALL REQUIRED): 1. Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material) 2. Positive pressure ventilation (either non-invasive or invasive) from > 24 hours 3. Invasive mechanical ventilation from < 96 hours 4. PaO2/FiO2 ratio lower than 150 mmHg 5. D-dimer level > 6 times the upper limit of normal reference range 6. C-reactive Protein > 6-fold upper the limit of normal reference range EXCLUSION CRITERIA: 1. Age < 18 years 2. On-going treatment with anticoagulant drugs 3. Platelet count < 100.000/mm3 4. History of heparin-induced thrombocytopenia 5. Allergy to sodium enoxaparin or other LMWH, UFH or methylprednisolone 6. Active bleeding or on-going clinical condition deemed at high risk of bleeding contraindicating anticoagulant treatment 7. Recent (in the last 1 month prior to randomization) brain, spinal or ophthalmic surgery 8. Chronic assumption or oral corticosteroids 9. Pregnancy or breastfeeding or positive pregnancy test. In childbearing age women, before inclusion, a pregnancy test will be performed if not available 10. Clinical decision to withhold life-sustaining treatment or "too sick to benefit" 11. Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition) 12. Lack or withdrawal of informed consent INTERVENTION AND COMPARATOR: • LMWH group: patients in this group will be administered enoxaparin at standard prophylactic dosage. • LMWH + steroid group: patients in this group will receive enoxaparin at standard prophylactic dosage and methylprednisolone. • UFH + steroid group: patients in this group will receive UFH at therapeutic dosages and methylprednisolone. UFH will be administered intravenously in UFH + steroid group at therapeutic doses. The infusion will be started at an infusion rate of 18 UI/kg/hour and then modified to obtain aPTT Ratio in between the range of 1.5-2.0. aPTT will be periodically checked at intervals no longer than 12 hours. The treatment with UFH will be administered up to ICU discharge. After ICU discharge anticoagulant therapy may be interrupted or switched to prophylaxis with LMWH in the destination ward up to clinical judgement of the attending physician. Enoxaparin will be administered in both LMWH group and LMWH + steroid group at standard prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients weighting more than 90 kg). The treatment will be administered subcutaneously once a day up to ICU discharge. After ICU discharge it may be continued or interrupted in the destination ward up to clinical judgement of the attending physician. Methylprednisolone will be administered in both LMWH + steroid group and UHF + steroid group intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5 mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2 times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14. MAIN OUTCOMES: Primary Efficacy Endpoint: All-cause mortality at day 28 Secondary Efficacy Endpoints: - Ventilation free days (VFDs) at day 28, defined as the total number of days that patient is alive and free of ventilation (either invasive or non-invasive) between randomization and day 28 (censored at hospital discharge). - Need of rescue administration of high-dose steroids or immune-modulatory drugs; - Occurrence of switch from non-invasive to invasive mechanical ventilation during ICU stay; - Delay from start of non-invasive ventilation to switch to invasive ventilation; - All-cause mortality at ICU discharge and hospital discharge; - ICU free days (IFDs) at day 28, defined as the total number of days between ICU discharge and day 28. - Occurrence of new infections from randomization to day 28; including infections by Candida, Aspergillus, Adenovirus, Herpes Virus e Cytomegalovirus - Occurrence of new organ dysfunction and grade of dysfunction during ICU stay. - Objectively confirmed venous thromboembolism, stroke or myocardial infarction; Safety endpoints: - Occurrence of major bleeding, defined as transfusion of 2 or more units of packed red blood cells in a day, bleeding that occurs in at least one of the following critical sites [intracranial, intra-spinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal], bleeding that necessitates surgical intervention and bleeding that is fatal (defined as a bleeding event that was the primary cause of death or contributed directly to death); - Occurrence of clinically relevant non-major bleeding, defined ad acute clinically overt bleeding that does not meet the criteria for major and consists of any bleeding compromising hemodynamic; spontaneous hematoma larger than 25 cm2, intramuscular hematoma documented by ultrasonography, haematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after invasive procedures; haemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other medical intervention or any other bleeding requiring temporary cessation of a study drug. RANDOMIZATION: A block randomisation will be used with variable block sizes (block size 4-6-8), stratified by 3 factors: Centre, BMI (<30/≥30) and Age (<75/≥75). Central randomisation will be performed using a secure, web-based, randomisation system with an allocation ratio of 1:1:1. The allocation sequence will be generated by the study statistician using computer generated random numbers. BLINDING (MASKING): Participants to the study will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The target sample size is based on the hypothesis that the combined use of UHF and steroid versus the LMWH group will significantly reduce the risk of death at day 28. The overall sample size in this study is expected to be 210 with a randomization 1:1:1 and seventy patients in each group. Assuming an alpha of 2.5% (two tailed) and mortality rate in LMWH group of 50%, as indicated from initial studies of ICU patients, the study will have an 80% power to detect at least a 25 % absolute reduction in the risk of death between: a) LMHW + steroid group and LMWH group or b) UHF + steroid group and LMWH group. The study has not been sized to assess the difference between LMHW + steroid group and UHF + steroid group, therefore the results obtained from this comparison will need to be interpreted with caution and will need further adequately sized studies confirm the effect. On the basis of a conservative estimation, that 8 participating sites admit an average of 3 eligible patients per month per centre (24 patients/month). Assuming that 80 % of eligible patients are enrolled, recruitment of 210 participants will be completed in approximately 10 months. TRIAL STATUS: Protocol version 1.1 of April 26th, 2020. Recruitment start (expected): September 1st, 2020 Recruitment finish (expected): June 30th, 2021 TRIAL REGISTRATION: EudraCT number 2020-001921-30 , registered on April 15th, 2020 AIFA approval on May 4th, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Clinical efficacy of glucocorticoid on the treatment of patients with COVID-19 pneumonia: A single-center experience.

The aim of the present study was to identify the clinical efficacy of glucocorticoid therapy on the treatment of patients with Coronavirus Disease 2019 (COVID-19) pneumonia. Clinical and laboratory parameters were collected from 308 patients with COVID-19 pneumonia from the fever clinic of Wuhan Pulmonary Hospital (Wuhan City, Hubei Province, China) between January 14, 2020 and February 9, 2020, of which 216 patients received low-dose (equivalent of methylprednisolone 0.75-1.5 mg/kg/d) glucocorticoid treatment. The effect of glucocorticoid on imaging progress, adverse events, nucleic acid results and the outcomes were investigated. Lymphocyte count and C-reactive protein (CRP) significantly differed between the glucocorticoid therapy and non-glucocorticoid therapy groups. Compared with the non-glucocorticoid therapy group, glucocorticoid therapy did not significantly influence the clinical course of COVID-19 pneumonia, including imaging progress and the time duration for negative transformation of nucleic acid. Glucocorticoid therapy did not significantly influence the outcomes nor the adverse events of COVID-19 pneumonia. For the treatment of COVID-19 pneumonia, systemic and in-depth investigation is needed to determine the timing and dosage of glucocorticoids needed to inhibit overwhelming inflammatory response and not the protective immune response to COVID-19 pneumonia.