High-dose glucocorticoids pulse-therapy for beta-coronaviridae pneumonia: a systematic literature review and case-series of Coronavirus disease-2019.

OBJECTIVES: The results of the RECOVERY trial identified dexamethasone as the first pharmacological therapy that reduces mortality in patients with COVID-19. The aim of this paper is to conduct a systematic literature review on safety and efficacy of pulse glucocorticoid therapy for Severe Acute Respiratory Syndrome (SARS)-CoronaVirus (CoV), Middle East Respiratory Syndrome (MERS)-CoV or SARS-CoV-2 infections and describe a case-series of COVID-19 patients treated with off-label pulse doses of methylprednisolone. METHODS: We performed a systematic literature review on safety and efficacy of pulse therapy for betacoronaviridae infections as described in the protocol registered on PROSPERO (CRD42020190183). All consecutive patients admitted to Arcispedale Santa Maria Nuova di Reggio Emilia or Guastalla Hospital with COVID-19 between March 1st and April 30th, 2020 and treated with methylprednisolone 1 gram/day for at least three days were included in the case series. A retrospective review of available computed tomography (CT) scan and chest x-ray was performed independently by two radiologists blinded to clinical data, and discordances were resolved by consensus. RESULTS: Twenty papers were included for SARS, but only two were comparative and were included in the primary endpoint analysis. Likewise, eleven papers were included for COVID-19, four of which were comparative and were considered for the primary outcome analysis. Included studies for both SARS and COVID-19 are mostly retrospective and highly heterogeneous, with lethality ranging from 0% to 100% and ICU admission rate ranging from 9% to 100%. Fourteen patients were included in our case series, 7 males and 7 females. CONCLUSIONS: No randomised controlled trial is available yet for corticosteroids pulse-therapy defined as at least ≥500mg/day methylprednisolone in patients with emerging coronavirus pneumonia. Lethality among our cohort is high (4/14), but this finding should be interpreted with caution due to the fact that in our setting pulse-steroids were used in patients not eligible for other treatments because of comorbidities or as rescue therapy. The incidence of steroid-related adverse events seems low in our cohort. The quality of the evidence on glucocorticoid pulse-therapy in SARS, MERS and COVID-19 is poor. Randomised controlled trials are greatly needed.

The Combination of Tocilizumab and Methylprednisolone Along With Initial Lung Recruitment Strategy in Coronavirus Disease 2019 Patients Requiring Mechanical Ventilation: A Series of 21 Consecutive Cases.

OBJECTIVE: To describe the outcomes with use of a combination of tocilizumab and methylprednisolone administered around the time of endotracheal intubation in patients with confirmed coronavirus disease 2019-associated hypoxemic respiratory failure requiring mechanical ventilation. DATA SOURCES: Retrospective chart review. STUDY SELECTION/DATA EXTRACTION: Twenty-one consecutive patients with confirmed coronavirus disease 2019-associated hypoxemic respiratory failure requiring mechanical ventilation. Initial ventilator parameters were positive end-expiratory pressure 14 cm H2o and target plateau pressure 29 cm H2o to maximize lung recruitment. Methylprednisolone (125 mg every 6hr for 24 hr with tapering to 60 mg every 12 hr) was administered shortly after patients were intubated (median 11 hr after intubation). DATA SYNTHESIS: No patient in the cohort died while hospitalized (mortality, 0%; 95% CI, 0%-18%) and 18 patients have been discharged from the acute care setting. Twenty of 21 patients (95%) have been liberated from mechanical ventilation after a median duration of 8 days (range, 4-30 d). Following 48 hours of methylprednisolone, the A-a o2 gradient decreased from 455 ± 103 to 228 ± 109 mm Hg (difference 227 ± 108 mm Hg; p < 0.01). CONCLUSIONS: Our positive experience with tocilizumab in combination with methylprednisolone started early after endotracheal intubation may be one avenue for reducing the morbidity and mortality seen with severe coronavirus disease 2019 and merits further exploration in clinical studies.

Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS.

Current literature addressing the pharmacological principles guiding glucocorticoid (GC) administration in ARDS is scant. This paucity of information may have led to the heterogeneity of treatment protocols and misinterpretation of available findings. GCs are agonist compounds that bind to the GC receptor (GR) producing a pharmacological response. Clinical efficacy depends on the magnitude and duration of exposure to GR. We updated the meta-analysis of randomized trials investigating GC treatment in ARDS, focusing on treatment protocols and response. We synthesized the current literature on the role of the GR in GC therapy including genomic and non-genomic effects, and integrated current clinical pharmacology knowledge of various GCs, including hydrocortisone, methylprednisolone and dexamethasone. This review addresses the role dosage, timing of initiation, mode of administration, duration, and tapering play in achieving optimal response to GC therapy in ARDS. Based on RCTs' findings, GC plasma concentration-time profiles, and pharmacodynamic studies, optimal results are most likely achievable with early intervention, an initial bolus dose to achieve close to maximal GRα saturation, followed by a continuous infusion to maintain high levels of response throughout the treatment period. In addition, patients receiving similar GC doses may experience substantial between-patient variability in plasma concentrations affecting clinical response. GC should be dose-adjusted and administered for a duration targeting clinical and laboratory improvement, followed by dose-tapering to achieve gradual recovery of the suppressed hypothalamic-pituitary-adrenal (HPA) axis. These findings have practical clinical relevance. Future RCTs should consider these pharmacological principles in the study design and interpretation of findings.

Myoclonus and Cerebellar Ataxia Associated with SARS-CoV-2 Infection: Case Report and Review of the Literature.

The current SARS-CoV-2/COVID-19 pandemic has led to a global health crisis. The clinical spectrum of SARS-CoV-2 infection ranges from asymptomatic infection to critical illness affecting almost every organ including the central and peripheral nervous systems. Myoclonus, a less expected and relatively unusual neurological complication, together with ataxia, has lately been associated with SARS-CoV-2 infection. We describe the case of a 67-year-old male patient, admitted to our hospital for interstitial bilateral pneumonia due to SARS-CoV-2 infection, who progressively developed general myoclonus and later cerebellar ataxia and gait disturbance. Given the timeline from COVID-19 systemic symptoms to neurological manifestations and the normal results of extensive and non-conclusive diagnostic work-up (blood test, lumbar puncture, EEG, cerebral MRI), a para-infectious encephalopathy related to SARS-CoV-2 was contemplated and a high dose of methylprednisolone was started with prompt symptom improvement. Further investigation and neuroepidemiological studies are needed to help define the mechanism of neuroinvasion and the entire spectrum of neurological manifestations of SARS-CoV-2 infection, even in mildly affected patients, in terms of prevention, treatment and possible neurological sequelae. LEARNING POINTS: SARS-CoV-2 infection can be related to neurological symptoms and sequelae.Myoclonus, specifically when associated with ataxia, might represent the expression of COVID-19-related encephalopathy.Myoclonus associated with SARS-CoV-2 infection mostly responds to treatment with steroids.

Postinfectious Olfactory Dysfunction: Oral Steroids and Olfactory Training versus Olfactory Training Alone: Is There any Benefit from Steroids?

INTRODUCTION: There are limited treatment options for postinfectious olfactory dysfunction (PIOD). Olfactory training has recently been used in clinical practice, but no medical treatment is widely accepted. Although there is weak evidence for their value, some physicians use oral corticosteroids as first-line treatment. The aim of this study was to compare combined oral methylprednisolone and olfactory training with olfactory training alone in the management of PIOD. METHODS: This prospective cohort study included 131 patients with PIOD over a 2-year period before the COVID-19 pandemic. Seventy-eight patients who were treated with oral methylprednisolone and olfactory training (group A) were compared with 53 patients who were treated with olfactory training only (group B). Olfactory function was evaluated with "Sniffin' Sticks" at baseline and 2, 8, and 16 weeks after initial assessment. Patients who improved after steroid treatment underwent magnetic resonance imaging of the paranasal sinuses, skin prick tests, lung spirometry, and sputum eosinophil assessment. RESULTS: Oral steroids improved 19.23% of patients (n = 15) of group A. History, clinical evaluation, imaging, and laboratory tests identified an inflammatory background in half of them (n = 8). The remaining 7 had no findings of nasal inflammation, and all had a short history of olfactory dysfunction. Both groups significantly improved in olfactory testing results at the end of the olfactory training scheme without significant difference between them. CONCLUSIONS: The percentage of improved patients after oral methylprednisolone was relatively low to suggest it as first-line treatment. Half of the improved patients had an underlying upper airway inflammatory condition not related to the infection that caused the acute loss of olfactory function.

Impact of intermediate to high doses of methylprednisolone on mortality rate in patients with COVID-19 pneumonia-induced severe systemic inflammation.

INTRODUCTION: In addition to respiratory support needs, patients' characteristics to guide indication or timing of corticosteroid treatment in COVID-19 patients are not completely established. This study aimed to evaluate the impact of methylprednisolone on mortality rate in patients with COVID-19 pneumonia-induced severe systemic inflammation (PI-SSI). METHODS: Between 9 March and 5 May 2020 (final follow-up on 2 July 2020), a retrospective cohort study was conducted in hospitalised patients with COVID-19 PI-SSI (≥2 inflammatory biomarkers [IBs]: temperature ≥38℃, lymphocyte ≤800 cell/µL, C-reactive protein ≥100 mg/L, lactate dehydrogenase ≥300 units/L, ferritin ≥1000 mcg/L, D-dimer ≥500 ng/mL). Patients received 0.5-1.0 mg/kg of methylprednisolone for 5-10 days or standard of care. The primary outcome was 28-day all-cause mortality. Secondary outcomes included ≥2 points improvement on a 7-item WHO-scale (Day 14), transfer to intensive care unit (ICU) (Day 28) and adverse effects. Kaplan-Meier method and Cox proportional hazard regression were implemented to analyse the time to event outcomes. RESULTS: A total of 142 patients (corticosteroid group n = 72, control group n = 70) were included. A significant reduction in 28-day all-cause mortality was shown with methylprednisolone in patients with respiratory support (HR: 0.15; 95% CI 0.03-0.71), with ≥3 (HR: 0.17; 95% CI 0.05-0.61) or ≥4 altered IB (HR: 0.15; 95% CI 0.04-0.54) and in patients with both respiratory support and ≥3 (HR: 0.11; 95% CI 0.02-0.53] or ≥4 altered IB (HR: 0.14; 95% CI 0.04-0.51). No significant differences were found in secondary outcomes. CONCLUSION: Intermediate to high doses of methylprednisolone, initiated between 5 and 12 days after symptom onset, was associated with a significant reduction in 28-day all-cause mortality in patients with COVID-19 pneumonia and ≥3 o ≥ 4 altered IB, independently of the need of respiratory support.

Multisystemic inflammatory syndrome in children associated with COVID-19: a single center experience in Turkey.

OBJECTIVE: Multisystem inflammatory syndrome in children (MIS-C) associated with the coronavirus disease 2019 (COVID-19) is a new concern emerging as a severe presentation of COVID-19 in children. We aimed to describe the characteristics and short-term outcomes of children diagnosed with MIS-C. MATERIAL AND METHODS: A retrospective study was conducted on 24 patients who were diagnosed with MIS-C between June 1, 2020 and December 1, 2020. A total of 24 (14 male and 10 female) patients were included in the study. RESULTS: The median age at the diagnosis was 111 (10-180) months. A total of 17 patients had a history of contact with a patient with COVID-19. Among the 24 patients, the most common findings were gastrointestinal involvement (n=20), followed by conjunctivitis (n=12), erythematous rash (n=11), and oral changes (n=10). Cardiovascular involvement was detected in 12 patients, of whom six had systolic dysfunction, four had mild coronary artery involvement, four had pericardial effusion, and three had mitral insufficiency. All patients received intravenous immunoglobulin, and 14 patients were treated with methylprednisolone in addition. Anti-interleukin-1 was given to two patients. The median duration of hospitalization was 8 (5-15) days. A total of 23 patients were discharged and evaluated on the median of 68.5 (52-140) days after discharge. The remaining one patient with dilated cardiomyopathy died after 2 months in the intensive care unit. CONCLUSION: Increasing the knowledge on MIS-C will provide clinicians with information on early recognition, evaluation, and management of these patients.

Registry of patients with multiple sclerosis and COVID-19 infection in Saudi Arabia.

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) has rapidly spread and developed as a pandemic threatening global health. Patients with multiple sclerosis (MS)-an autoimmune demyelinating inflammatory disease of the central nervous system (CNS)-are predominantly treated with immunomodulatory/immunosuppressive disease-modifying therapies (DMTs), which can increase the risk of infection. Therefore, there is concern that these patients may have a higher risk of COVID-19. In response to growing concerns of neurologists and patients, this study aimed to determine the prevalence, severity, and possible complications of COVID-19 infection in patients with MS in Saudi Arabia (SA). METHODS: In this prospective cohort study, demographic and clinical data were obtained from patients residing in SA with MS who had a positive result for COVID-19 per reverse transcription-polymerase chain reaction test or viral gene sequencing, using respiratory or plasma samples. Comparison of COVID-19 severity groups was performed using one-way ANOVA or Kruskal-Wallis test for numerical variables and Chi-squared test for categorical variables. RESULTS: Seventy patients with MS and COVID-19 (71% female) were included in this analysis. Of the 53 (75.7%) patients receiving a DMT at the time of COVID-19 infection, the most frequently used DMTs were fingolimod (25%) and interferon-beta (25%). Nine (13%) patients had MS relapse and were treated with intravenous methylprednisolone in the four weeks before COVID-19 infection. The most common symptoms at the peak of COVID-19 infection were fever (46%), fatigue (37%), and headache (36%). Symptoms lasted for a mean duration of 8.7 days; all symptomatic patients recovered and no deaths were reported. COVID-19 severity was categorized in three groups: asymptomatic (n = 12), mild-not requiring hospitalization (n = 48), and requiring hospitalization (n = 10; two of whom were admitted to the intensive care unit [ICU]). Between the three groups, comparison of age, body mass index , Expanded Disability Severity Score , MS disease duration, and DMT use at the time of infection showed no significant differences. A higher percentage of patients who were admitted to hospital or the ICU (40%; p = 0.026) presented with an MS relapse within the prior four weeks compared with those who were asymptomatic or had a mild infection (both 8.3%). CONCLUSION: These findings present a reassuring picture regarding COVID-19 infection in patients with MS. However, patients with MS who have had a relapse in the preceding four weeks (requiring glucocorticoid treatment) may have an increased risk of severe COVID-19.

Magnesium supplementation alleviates corticosteroid-associated muscle atrophy in rats.

PURPOSE: Corticosteroid (CS) therapy for infectious and rheumatological diseases showed to decrease serum magnesium (Mg++) level and induce muscle atrophy in patients. The present study investigated the effects of Mg++ supplementation on preventing CS-induced muscle atrophy in an animal model, which provided experimental data for potential clinical translation. METHODS: Twelve 24-week-old male Sprague-Dawley rats were treated with lipopolysaccharide (LPS) and CS methylprednisolone (MPS) to induce muscle atrophy, with half of the rats also given daily 50 mg/kg Mg++ oral supplementation. Additional six rats without LPS + CS treatments were used as normal controls. After treatment for 6 weeks, serum was collected for Mg++ quantification, animal dual-energy X-ray absorptiometry (DXA) was performed for tissue composition, and the extensor digitorum longus (EDL) was collected for muscle functional test and histology including muscle fiber size, intramuscular fat infiltration and fiber typing. In vitro myotube atrophy model was used to study the in vitro effect associated with in vivo muscle atrophy. RESULTS: LPS + CS treatments induced hypomagnesemia while the serum Mg++ level was in normal range after Mg++ supplementation. DXA showed 53.0% lower fat percent and 29.7% higher lean mass in LPS + CS + Mg group when compared to LPS + CS group. Muscle functional test showed 22.2% higher specific twitch force and 40.3% higher specific tetanic force in LPS + CS + Mg group when compared to LPS + CS group. Histological analysis showed 4.1% higher proportion of muscle fibers area to total area and 63.6% lower intramuscular fat infiltration in EDL sections in LPS + CS + Mg group when compared to LPS + CS group. LPS + CS + Mg group had 33.0% higher area proportion and 29.4% higher cross-sectional area (CSA) of type IIb muscle fiber. Myoblast culture results showed that Mg++ supplementation group had larger myotube diameter. The mRNA expressions of the muscle atrophy marker genes MuRF1 and MAFbx were lower in Mg++ supplementation group both in vitro and in vivo. CONCLUSION: The current study demonstrated that Mg++ supplementation successfully alleviated CS-associated muscle atrophy in rats at both functional and morphology levels, indicating a translational potential for patients undergoing CS therapy. This study provided the evidence for the first time that Mg++ supplementation could prevent muscle atrophy-an adverse effect of CS therapy, currently also adopted for treating coronavirus disease 2019 (COVID-19).

Dexamethasone vs methylprednisolone high dose for Covid-19 pneumonia.

BACKGROUND: There is no effective therapy for the severe acute respiratory syndrome by coronavirus 2 (SARS-CoV2) responsible for the Coronavirus disease 2019 (Covid-19). To date, dexamethasone has shown a decrease in mortality in patients who require oxygen, especially those with invasive mechanical ventilation. However, it is unknown if another corticosteroid can be used, the optimal dose and its duration, to achieve a better clinical outcome. The objective of the study was to compare the differences in clinical outcome and laboratory results in hospitalized patients with severe SARS-CoV2 Pneumonia treated with dexamethasone at 6 mg doses versus patients treated with high-dose methylprednisolone. MATERIALS AND METHODS: Ambispective cohort study with survival analysis of 216 patients diagnosed with severe Covid-19 pneumonia confirmed by polymerase chain reaction for SARS-CoV2 by Berlin protocol, who were hospitalized in a high-complexity clinic in Medellín, Colombia. The patients should also have supplementary oxygen and radiological confirmation of Pneumonia by chest tomography. Sample size was not calculated since the total population that met the inclusion criteria was evaluated. 111 patients were treated with the institutional protocol with intravenous dexamethasone 6 mg QD for seven to 10 days if they required oxygen. Since September 15, 2020, the hospitalization protocol of the clinic was modified by the Infectious Diseases and Pulmonology service, recommending a high dose of methylprednisolone of 250 to 500 mg every day for three days with a subsequent change to oral prednisone 50 mg every day for 14 days. The protocol was not applied in the intensive care unit, where dexamethasone continued to be administered. The clinical outcome and differences in laboratory results of the patients who received dexamethasone vs. the prospective cohort that received methylprednisolone from September 15 to October 31, 2020, were evaluated. Follow-up was carried out by outpatient consultation one month after discharge or by telephone, inquiring about readmission or living-dead status. RESULTS: 216 patients had Covid-19 pneumonia documented by ground-glass imaging and alveolar pressure / inspired oxygen fraction (PaFi) less than 300. 111 patients received dexamethasone (DXM) and 105 received methylprednisolone (MTP). Patients in the DXM group evolved to severe ARDS in a higher proportion (26.1% vs 17.1% than the MTP group). Upon completion 4 days of treatment with parenteral corticosteroid, laboratory markers of severity decreased significantly in the group that received MTP, CRP 2.85 (2.3-3.8) vs 7.2 (5.4-9.8), (p-value < 0.0001), D-dimer 691 (612-847) vs 1083 (740-1565) (p-value = 0.04) and DHL 273 (244-289) vs 355 (270.6-422) (p-value = 0.01). After starting the corticosteroid, transfer to the intensive care unit (4.8% vs. 14.4%) and mortality (9,5% vs. 17.1%) was lower in the group that received MTP. Recovery time was shorter in patients treated with MTP, three days (3-4) vs. DXM 6 days (5-8) (p-value < 0.0001). At 30-day follow-up, 88 (92.6%) were alive in MTP vs 58 (63.1%) of those who received dexamethasone. CONCLUSIONS: In this study, the treatment of severe Covid-19 Pneumonia with high-dose methylprednisolone for three days followed by oral prednisone for 14 days, compared with 6 mg dexamethasone for 7 to 10 days, statistically significantly decreased the recovery time, the need for transfer to intensive care and the severity markers C-reactive protein (CRP), D-dimer and LDH. Randomized controlled studies with methylprednisolone are required to corroborate its effect, and studies in a population hospitalized in intensive care wards.

Corticosteroids for hospitalized patients with mild to critically-ill COVID-19: a multicenter, retrospective, propensity score-matched study.

Corticosteroids use in coronavirus disease 2019 (COVID-19) is controversial, especially in mild to severe patients who do not require invasive/noninvasive ventilation. Moreover, many factors remain unclear regarding the appropriate use of corticosteroids for COVID-19. In this context, this multicenter, retrospective, propensity score-matched study was launched to evaluate the efficacy of systemic corticosteroid administration for hospitalized patients with COVID-19 ranging in the degree of severity from mild to critically-ill disease. This multicenter, retrospective study enrolled consecutive hospitalized COVID-19 patients diagnosed January-April 2020 across 30 institutions in Japan. Clinical outcomes were compared for COVID-19 patients who received or did not receive corticosteroids, after adjusting for propensity scores. The primary endpoint was the odds ratio (OR) for improvement on a 7-point ordinal score on Day 15. Of 1092 COVID-19 patients analyzed, 118 patients were assigned to either the corticosteroid and non-corticosteroid group, after propensity score matching. At baseline, most patients did not require invasive/noninvasive ventilation (85.6% corticosteroid group vs. 89.8% non-corticosteroid group). The odds of improvement in a 7-point ordinal score on Day 15 was significantly lower for the corticosteroid versus non-corticosteroid group (OR, 0.611; 95% confidence interval [CI], 0.388-0.962; p = 0.034). The time to improvement in radiological findings was significantly shorter in the corticosteroid versus non-corticosteroid group (hazard ratio [HR], 1.758; 95% CI, 1.323-2.337; p < 0.001), regardless of baseline clinical status. The duration of invasive mechanical ventilation was shorter in corticosteroid versus non-corticosteroid group (HR, 1.466; 95% CI, 0.841-2.554; p = 0.177). Of the 106 patients who received methylprednisolone, the duration of invasive mechanical ventilation was significantly shorter in the pulse/semi-pulse versus standard dose group (HR, 2.831; 95% CI, 1.347-5.950; p = 0.006). In conclusion, corticosteroids for hospitalized patients with COVID-19 did not improve clinical status on Day 15, but reduced the time to improvement in radiological findings for all patients regardless of disease severity and also reduced the duration of invasive mechanical ventilation in patients who required intubation.Trial registration: This study was registered in the University hospital Medical Information Network Clinical Trials Registry on April 21, 2020 (ID: UMIN000040211).

Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With Coronavirus Disease 2019 (COVID-19; Metcovid): A Randomized, Double-blind, Phase IIb, Placebo-controlled Trial.

BACKGROUND: Steroid use for coronavirus disease 2019 (COVID-19) is based on the possible role of these drugs in mitigating the inflammatory response, mainly in the lungs, triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aimed to evaluate the efficacy of methylprednisolone (MP) among hospitalized patients with suspected COVID-19. METHODS: A parallel, double-blind, placebo-controlled, randomized, Phase IIb clinical trial was performed with hospitalized patients aged ≥18 years with clinical, epidemiological, and/or radiological suspected COVID-19 at a tertiary care facility in Manaus, Brazil. Patients were randomly allocated (1:1 ratio) to receive either intravenous MP (0.5 mg/kg) or placebo (saline solution) twice daily for 5 days. A modified intention-to-treat (mITT) analysis was conducted. The primary outcome was 28-day mortality. RESULTS: From 18 April to 16 June 2020, 647 patients were screened, 416 were randomized, and 393 were analyzed as mITT, with 194 individuals assigned to MP and 199 to placebo. SARS-CoV-2 infection was confirmed by reverse transcriptase polymerase chain reaction in 81.3%. The mortality rates at Day 28 were not different between groups. A subgroup analysis showed that patients over 60 years old in the MP group had a lower mortality rate at Day 28. Patients in the MP arm tended to need more insulin therapy, and no difference was seen in virus clearance in respiratory secretion until Day 7. CONCLUSIONS: The findings of this study suggest that a short course of MP in hospitalized patients with COVID-19 did not reduce mortality in the overall population. CLINICAL TRIALS REGISTRATION: NCT04343729.

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.

Rapid Identification of Druggable Targets and the Power of the PHENotype SIMulator for Effective Drug Repurposing in COVID-19.

The current, rapidly diversifying pandemic has accelerated the need for efficient and effective identification of potential drug candidates for COVID-19. Knowledge on host-immune response to SARS-CoV-2 infection, however, remains limited with very few drugs approved to date. Viable strategies and tools are rapidly arising to address this, especially with repurposing of existing drugs offering significant promise. Here we introduce a systems biology tool, the PHENotype SIMulator, which - by leveraging available transcriptomic and proteomic databases - allows modeling of SARS-CoV-2 infection in host cells in silico to i) determine with high sensitivity and specificity (both > 96%) the viral effects on cellular host-immune response, resulting in a specific cellular SARS-CoV-2 signature and ii) utilize this specific signature to narrow down promising repurposable therapeutic strategies. Powered by this tool, coupled with domain expertise, we have identified several potential COVID-19 drugs including methylprednisolone and metformin, and further discern key cellular SARS-CoV-2-affected pathways as potential new druggable targets in COVID-19 pathogenesis.

Corticosteroids for COVID-19 patients requiring oxygen support? Yes, but not for everyone: Effect of corticosteroids on mortality and intensive care unit admission in patients with COVID-19 according to patients' oxygen requirements.

Corticosteroids reduce mortality in hospitalized patients with coronavirus disease 2019 (COVID-19), but the response seems to vary according to the level of respiratory support needed. This retrospective cohort study included COVID-19 patients with oxygen saturation (SatO2 ) in room air <92% admitted between March 3 and April 30, 2020. Following the interim protocol, patients could receive dexamethasone or methylprednisolone, and were classified according to oxygen requirements. The primary endpoint was admission to the intensive care unit (ICU) or mortality. Kaplan-Meier and Cox hazards analyses were used. Of the 115 patients included, 38 received corticosteroids. Among requiring high-flow, noninvasive ventilation (NIV) or fraction of inspired oxygen (FiO2 ) > 0.40, the hazard ratio (HR) for death or ICU admission, between the corticosteroids and non-corticosteroids group, was 0.07 (95% CI 0.01-0.4), p = .002, and for patients requiring low-flow oxygen, the HR was 0.70 (95% CI 0.13-3.8), p = .68. Significant differences were also observed when all patients were analyzed together. A significant reduction in mortality and ICU admission frequency was observed among patients requiring high-flow oxygen or NIV, but not among those requiring low-flow oxygen. Better targeting of COVID-19 patients is needed for the beneficial use of corticosteroids.

Methylprednisolone or dexamethasone, which one is superior corticosteroid in the treatment of hospitalized COVID-19 patients: a triple-blinded randomized controlled trial.

BACKGROUND: Although almost a year has passed since the Coronavirus disease 2019 (COVID-19) outbreak and promising reports of vaccines have been presented, we still have a long way until these measures are available for all. Furthermore, the most appropriate corticosteroid and dose in the treatment of COVID-19 have remained uncertain. We conducted a study to assess the effectiveness of methylprednisolone treatment versus dexamethasone for hospitalized COVID-19 patients. METHODS: In this prospective triple-blinded randomized controlled trial, we enrolled 86 hospitalized COVID-19 patients from August to November 2020, in Shiraz, Iran. The patients were randomly allocated into two groups to receive either methylprednisolone (2 mg/kg/day; intervention group) or dexamethasone (6 mg/day; control group). Data were assessed based on a 9-point WHO ordinal scale extending from uninfected (point 0) to death (point 8). RESULTS: There were no significant differences between the groups on admission. However, the intervention group demonstrated significantly better clinical status compared to the control group at day 5 (4.02 vs. 5.21, p = 0.002) and day 10 (2.90 vs. 4.71, p = 0.001) of admission. There was also a significant difference in the overall mean score between the intervention group and the control group, (3.909 vs. 4.873 respectively, p = 0.004). The mean length of hospital stay was 7.43 ± 3.64 and 10.52 ± 5.47 days in the intervention and control groups, respectively (p = 0.015). The need for a ventilator was significantly lower in the intervention group than in the control group (18.2% vs 38.1% p = 0.040). CONCLUSION: In hospitalized hypoxic COVID-19 patients, methylprednisolone demonstrated better results compared to dexamethasone. TRIAL REGISTRATION: The trial was registered with IRCT.IR (08/04/2020-No. IRCT20200204046369N1 ).

Nintedanib treatment for pulmonary fibrosis after coronavirus disease 2019.

A 78-year-old Japanese woman with no smoking history suffered from near-fatal coronavirus disease 2019 (COVID-19) requiring four-week invasive mechanical ventilation, with subsequent radiological features of pulmonary fibrosis. Although methylprednisolone gradually improved her respiratory condition, her oxygenation and exercise tolerance had drastically deteriorated, necessitating high-flow nasal cannula oxygen therapy. In parallel with tapering systemic steroid, the patient was treated with nintedanib. Three months later, the patient was able to walk with a walking aid using oxygen at 4 L/min. The present case is an indication that nintedanib might provide a novel therapeutic approach for managing post-COVID-19 fibrosis, although further studies are warranted.

Subacute cerebellar ataxia following respiratory symptoms of COVID-19: a case report.

BACKGROUND: Severe acute respiratory syndrome virus 2 (SARS-CoV-2) is spreading globally and causes most frequently fever and respiratory symptoms, i.e. Coronavirus disease 2019 (COVID-19), however, distinct neurological syndromes associated with SARS-CoV-2 infection have been described. Among SARS-CoV-2-infections-associated neurological symptoms fatigue, headache, dizziness, impaired consciousness and anosmia/ageusia are most frequent, but less frequent neurological deficits such as seizures, Guillain-Barré syndrome or ataxia may also occur. CASE PRESENTATION: Herein we present a case of a 62-year-old man who developed a subacute cerebellar syndrome with limb-, truncal- and gait ataxia and scanning speech 1 day after clinical resolution of symptomatic SARS-CoV-2 infection of the upper airways. Apart from ataxia, there were no signs indicative of opsoclonus myoclonus ataxia syndrome or Miller Fisher syndrome. Cerebral magnetic resonance imaging showed mild cerebellar atrophy. SARS-CoV-2 infection of the cerebellum was excluded by normal cerebrospinal fluid cell counts and, most importantly, absence of SARS-CoV-2 RNA or intrathecal SARS-CoV-2-specific antibody production. Other causes of ataxia such as other viral infections, other autoimmune and/or paraneoplastic diseases or intoxication were ruled out. The neurological deficits improved rapidly after high-dose methylprednisolone therapy. CONCLUSIONS: The laboratory and clinical findings as well as the marked improvement after high-dose methylprednisolone therapy suggest a post-infectious, immune-mediated cause of ataxia. This report should make clinicians aware to consider SARS-CoV-2 infection as a potential cause of post-infectious neurological deficits with an atypical clinical presentation and to consider high-dose corticosteroid treatment in case that a post-infectious immune-mediated mechanism is assumed.

Judicious use of low-dosage corticosteroids for non-severe COVID-19: A case report.

Inflammation-mediated lung injury in severe cases of infection with SARS-CoV-2, the aetiological agent of Coronavirus disease 2019 (COVID-19), can lead to respiratory failure and death, and therapies that block or ameliorate lung injury-associated inflammatory "cytokine storms" and progression to acute respiratory distress syndrome (ARDS) are urgently needed. Therapeutic use of corticosteroids for this purpose has been controversial because of conflicting reports on their efficacy and immunosuppressive behaviour. The WHO has strongly recommended treating critical COVID-19 patients with systemic corticosteroid therapy, but recommends against corticosteroid therapy in non-severe COVID-19 disease because of a lack of strong evidence on its efficacy. This retrospective case report describing the successful treatment of a non-severe COVID-19 case in Changchun, China, by judicious administration of corticosteroids using a personalized therapeutic approach was recorded to strengthen the evidence base showing how corticosteroid use in non-severe COVID-19 cases can be safe and efficacious. Alongside supportive care and lopinavir/ritonavir antiviral drugs, a low dosage of methylprednisolone was administered over a short period to attenuate lung inflammation. Regular chest CT scans guided dosage reduction in response to lesion absorption and improved lung condition. Judicious use of corticosteroids safely attenuated disease progression and facilitated rapid and complete recovery.