Background: Corticosteroids are the cornerstone of the treatment of patients with COVID-19 admitted to hospital. However, whether corticosteroids can prevent respiratory worsening in hospitalized COVID-19 patients without oxygen requirements is currently unknown.
Aims: To assess the efficacy of methylprednisolone pulses (MPP) in hospitalized COVID-19 patients with increased levels of inflammatory markers not requiring oxygen at baseline.
Methods: Multicenter, parallel, randomized, double-blind, placebo-controlled trial conducted in Spain. Patients admitted for confirmed SARS-CoV-2 pneumonia with raised inflammatory markers (C-reactive protein >60 mg/L, interleukin-6 >40 pg/ml, or ferritin >1,000 µg/L) but without respiratory failure after the first week of symptom onset were randomized to receive a 3-day course of intravenous MPP (120 mg/day) or placebo. The primary outcome was treatment failure at 14 days, a composite variable including mortality, the need for ICU admission or mechanical ventilation, and clinical worsening, this last parameter defined as a PaO2/FiO2 ratio below 300; or a 15% decrease in the PaO2 from baseline, together with an increase in inflammatory markers or radiological progression. If clinical worsening occurred, patients received tocilizumab and unmasked corticosteroids. The secondary outcomes were 28-day mortality, adverse events, need for ICU admission or high-flow oxygen, length of hospital stay, SARS-CoV-2 clearance, and changes in laboratory parameters.
Results: A total of 72 patients were randomized and 71 patients were analyzed (34 in the MPP group and 37 in the placebo group). Twenty patients presented with treatment failure (29.4 in the MPP group vs. 27.0% in the placebo group, p = 0.82), with no differences regarding the time to treatment failure between groups. There were no cases of death or mechanical ventilation requirements at 14 days post-randomization. The secondary outcomes were similar in MPP and placebo groups.
Conclusions: A 3-day course of MPP after the first week of disease onset did not prevent respiratory deterioration in hospitalized COVID-19 patients with an inflammatory phenotype who did not require oxygen.
The WHO has issued a “strong recommendation” for baricitinib, in combination with corticosteroids, in the treatment of patients with severe or critical COVID-19.
The new recommendation comes as part of the seventh update to the WHO’s Guideline on Drugs for COVID-19. The update also includes a conditional recommendation against ruxolitinib (Opzelura, Incyte) and tofacitinib (Xeljanz, Pfizer) for patients with severe or critical COVID-19, and a conditional recommendation for the monoclonal antibody sotrovimab (VIR-7831, GlaxoSmithKline) in patients with non-severe COVID-19 who are at highest risk for hospitalization.
The WHO has issued a “strong recommendation” for baricitinib, in combination with corticosteroids, in the treatment of patients with severe or critical COVID-19.
According to the WHO, which published its guidelines in The BMJ, baricitinib (Olumiant, Eli Lilly & Co.) should be used as an alternative to interleukin-6 inhibitors in patients with severe or critical COVID-19.
“The strong recommendation for baricitinib in those with severe or critical illness reflects moderate certainty evidence for benefits on mortality, duration of mechanical ventilation, and hospital length of stay, with no observed increase in adverse events leading to drug discontinuation,” Arnav Agarwal, BHSc, MD, of McMaster University, in Hamilton, Canada, and colleagues in the WHO Guideline Development Group, wrote. “Baricitinib and IL-6 receptor blockers have similar effects; when both are available, choose one based on issues including cost and clinician experience.”
The FDA in July authorized emergency use of baricitinib alone for the treatment of patients aged 2 years and older who are hospitalized with COVID-19. That authorization applies to infected patients who require supplemental oxygen, mechanical ventilation or extracorporeal membrane oxygenation.
Meanwhile, the WHO experts advised against the use of two other JAK inhibitors — ruxolitinib and tofacitinib — for patients with severe or critical COVID-19 due to low certainty of evidence from small trials, which failed to demonstrate benefit.
According to the updated guidelines, the evidence suggests a possible increase in serious side effects with tofacitinib.
Lastly, the new guidelines include a conditional recommendation for the sotrovimab in patients with non-severe COVID-19, but only in those at highest risk for hospitalization, as data suggest “trivial benefits in those at lower risk,” according to Agarwal and colleagues.
“A conditional recommendation for the monoclonal antibody sotrovimab in patients with non-severe illness reflects substantial reduction in risk of hospitalization in those at higher risk, and trivial benefits in those at lower risk,” Agarwal and colleagues wrote. “There were insufficient data to recommend one monoclonal antibody treatment over another, and evidence on their efficacy for emerging variants is likely to influence future recommendations.”
The FDA in June issued an emergency use authorization for sotrovimab to treat mild-to-moderate COVID-19 in patients at risk for progressing to severe disease. The authorization is specifically targeted to adults and children aged 12 years and older who weigh at least 40 kg, or approximately 88 pounds. It is not intended for patients who are hospitalized or require oxygen due to COVID-19.
The WHO based its new recommendations on evidence from seven trials with more 4,000 participants with non-severe, severe and critical COVID-19.
They add to previous WHO recommendations for the use of IL-6 receptor blockers and systemic corticosteroids for patients with severe or critical COVID-19; conditional recommendations for the use of the monoclonal antibody cocktail casirivimab-imdevimab (Regeneron Pharmaceuticals) in selected patients; and against the use of convalescent plasma, ivermectin and hydroxychloroquine in patients with COVID-19 regardless of disease severity.
“They are part of a living guideline, developed by the [WHO] with the methodological support of MAGIC Evidence Ecosystem Foundation, to provide trustworthy guidance on the management of COVID-19 and help doctors make better decisions with their patients,” read a WHO press release. “Living guidelines are useful in fast moving research areas like COVID-19 because they allow researchers to update previously vetted and peer reviewed evidence summaries as new information becomes available.”
BACKGROUND: Inflammation and oedema of the facial nerve are implicated in causing Bell’s palsy. Corticosteroids have a potent anti-inflammatory action that should minimise nerve damage. This is an update of a review first published in 2002 and last updated in 2010.
OBJECTIVES: To determine the effectiveness and safety of corticosteroid therapy in people with Bell’s palsy.
SEARCH METHODS: On 4 March 2016, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and LILACS. We reviewed the bibliographies of the randomised trials and contacted known experts in the field to identify additional published or unpublished trials. We also searched clinical trials registries for ongoing trials.
SELECTION CRITERIA: Randomised trials and quasi-randomised trials comparing different routes of administration and dosage schemes of corticosteroid or adrenocorticotrophic hormone therapy versus a control group receiving no therapy considered effective for this condition, unless the same therapy was given in a similar way to the experimental group.
DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. The main outcome of interest was incomplete recovery of facial motor function (i.e. residual facial weakness). Secondary outcomes were cosmetically disabling persistent sequelae, development of motor synkinesis or autonomic dysfunction (i.e. hemifacial spasm, crocodile tears) and adverse effects of corticosteroid therapy manifested during follow-up.
MAIN RESULTS: We identified seven trials, with 895 evaluable participants for this review. All provided data suitable for the primary outcome meta-analysis. One of the trials was new since the last version of this Cochrane systematic review. Risk of bias in the older, smaller studies included some unclear- or high-risk assessments, whereas we deemed the larger studies at low risk of bias. Overall, 79/452 (17%) participants allocated to corticosteroids had incomplete recovery of facial motor function six months or more after randomisation; significantly fewer than the 125/447 (28%) in the control group (risk ratio (RR) 0.63, 95% confidence interval (CI) 0.50 to 0.80, seven trials, n = 895). The number of people who need to be treated with corticosteroids to avoid one incomplete recovery was 10 (95% CI 6 to 20). The reduction in the proportion of participants with cosmetically disabling sequelae six months after randomisation was very similar in the corticosteroid and placebo groups (RR 0.96, 95% CI 0.40 to 2.29, two trials, n = 75, low-quality evidence). However, there was a significant reduction in motor synkinesis during follow-up in participants receiving corticosteroids (RR 0.64, 95% CI 0.45 to 0.91, three trials, n = 485, moderate-quality evidence). Three studies explicitly recorded the absence of adverse effects attributable to corticosteroids. One trial reported that three participants receiving prednisolone had temporary sleep disturbances and two trials gave a detailed account of adverse effects occurring in 93 participants, all non-serious; the combined analysis of data from these three trials found no significant difference in adverse effect rates between people receiving corticosteroids and people receiving placebo (RR 1.04, 95% CI 0.71 to 1.51, n = 715).
AUTHORS’ CONCLUSIONS: The available moderate- to high-quality evidence from randomised controlled trials showed significant benefit from treating Bell’s palsy with corticosteroids.
Adding this immunosuppressive agent to prednisone did not improve GVHD survival.
Allogeneic hematopoietic stem-cell transplantation (AHSCT) is often complicated by acute graft-versus-host disease (GVHD) and is generally treated with corticosteroids. Because these agents induce durable remissions in fewer than half of patients with GVHD, they are often combined with immunosuppressive agents. In a previous phase II study, the immunosuppressor mycophenolate mofetil (MMF), when combined with corticosteroids, appeared to improve disease-free interval and overall survival (Blood 2009; 114:511).
To confirm these preliminary results, investigators conducted a phase III trial involving 235 eligible adult and pediatric AHSCT recipients with newly diagnosed acute GVHD. Patients were randomized to receive prednisone with either MMF or placebo. The primary endpoint was GVHD-free survival at day 56 of treatment.
The trial was discontinued because of futility when no significant difference in the primary endpoint was seen between patients receiving MMF or placebo (59.5% and 50.4%, respectively) and the corticosteroid doses at day 28 and 56 did not differ between treatment groups. Patients receiving MMF had a higher incidence of leucopenia (52.7% vs. 34.8%; P=0.01) but similar cumulative incidence of severe infection and similar rates of hospital readmission. In addition, no significant between-group differences were seen in quality of life at day 56 or overall survival at 1 year.
Comment
This phase III study shows that adding MMF to corticosteroids provides no benefit for patients with acute GVHD and is consistent with previous reports indicating that broad-based immunosuppressive agents are ineffective in this disorder. Another treatment approach is to target pro-inflammatory cytokines; recently it was reported that the Janus-kinase inhibitor ruxolitinib demonstrated activity in a small number of patients with steroid-resistant acute GVHD (NEJM JW Oncol Hematol Jun 24 2014).
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