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ZayFlex Results

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Asher Cooper
Asher Cooper

Multiple Studies Find Steroids Fight Severe COVID

The guideline panel suggests baricitinib in addition to standard of care for patients hospitalized with severe COVID-19. The guideline panel suggests baricitinib with remdesivir for persons for whom corticosteroids are indicated but who cannot receive them due to a contraindication. Baricitinib plus remdesivir should be reserved for patients who cannot take corticosteroids because dexamethasone has been proven to reduce mortality in patients hospitalized with COVID-19 who require supplemental oxygen or mechanical ventilation and, for this reason, dexamethasone is recommended by the panel for this group. It is uncertain whether baricitinib plus remdesivir will have the same benefit as dexamethasone. As of the time of this narrative, there are no head-to-head trials evaluating either the combination of baricitinib plus tocilizumab or evaluating baricitinib compared to tocilizumab. A post hoc subgroup analysis in the RECOVERY trial showed no difference in measured outcomes with concomitant baricitinib and tocilizumab, but further well-done studies are needed [200].

Multiple Studies Find Steroids Fight Severe COVID

The apparent discordance between bacterial and fungal co-infection in patients with COVID-19 at presentation and the use of antibacterial therapy has potential negative effects, namely in antimicrobial resistance. Several studies have attempted to differentiate patients with and without concomitant bacterial infections using laboratory data. The use of procalcitonin in a group of hospitals was not effective as tool to encourage antibiotic discontinuation compared to clinical judgment [276]. Mason and colleagues compared hospitalized cohorts of 619 patients with COVID-19 and 106 with community-acquired bacterial pneumonia (CABP) to determine if inflammatory markers could be used to rule out bacterial co-infection [277]. They found marked differences in white blood cell counts between groups (6.78 COVID-19 vs. 12.48 CABP), and that CRP declined in 48-72 hours with antibiotic therapy in the CABP cohort but not the COVID-19 group, suggesting that these can be used to guide antibiotic discontinuation when initiated empirically in COVID-19 patients. Initiating and continuing empiric antibiotics at the time of admission may lead to superinfections that are antibiotic resistant; one study found antibiotic use in the first two days of admission for COVID-19 to be a risk factor for superinfection [273]. Immunomodulatory therapies are recommended for many patients with severe and critical illness from COVID-19, including corticosteroids, IL-6 antagonists, JAK inhibitors, and others [278]. Most of the prospective studies that support these recommendations have not reported higher rates of infection in patients receiving immunomodulators, but follow-up is limited in most cases and late infections may be missed.

The goal of vaccination is to prevent serious illness. This is achieved by generating immune memory cells, such as B cells and T cells. These cells are typically long-lived and reside in the bone marrow, bloodstream, and lymph glands to monitor for exposure to a pathogen. If the pathogen is detected, these memory cells quickly become activated and stimulate the immune response to efficiently fight the infection before the infection can get out of control and cause serious illness. In the case of COVID-19 mRNA vaccines, studies demonstrated that high levels of memory cells are generated, and as the delta and omicron variants emerged, we have seen that the levels of memory cells generated by both the mRNA (Pfizer and Moderna) and adenovirus-based (J&J/Janssen) vaccines have been sufficient to prevent serious illness in most cases. As such, these findings would not warrant a booster dose.

That advance was great news, but those findings created a conundrum for Angus and other researchers who were running their own studies of steroids in COVID-19 patients. It no longer felt appropriate to be giving some people steroids and others a placebo.

Our findings from both observational studies and RCTs confirm a beneficial effect of corticosteroids on short-term mortality and a reduction in need for mechanical ventilation. And although data in the studies were too sparse to draw any firm conclusions, there might be a signal of delayed viral clearance and an increase in secondary infections.

Though many therapies aiming at mitigation of the inflammatory response are being evaluated, strong evidence of benefit is lacking. Corticosteroids might have beneficial effects in overcoming both hyperinflammation and ARDS [4, 15,16,17]. Furthermore, they could serve as an easily accessible and affordable treatment option. On the other hand, there are known adverse effects of corticosteroid use, such as delayed viral clearance, opportunistic infections and suppression of the hypothalamic-pituitary-adrenal axis [2, 18, 19]. Earlier studies done in MERS-CoV and SARS-CoV showed delayed viral clearance, opportunistic infections and hyperglycemia [20,21,22]. Therefore, a high number of observational studies and randomized controlled trials (RCT) on corticosteroids for COVID-19 have been initiated and reported, and the signal is a beneficial effect. The RECOVERY trial was the first to report that the use of dexamethasone as opposed to usual care reduced 28-day mortality in patients requiring oxygen therapy or mechanical ventilation [23]. And a prospective meta-analysis of seven randomized clinical trials showed that administration of corticosteroids was associated with lower 28-day all-cause mortality [24]. And while initially the World Health Organization (WHO) recommended against corticosteroid treatment, as of September 2, 2020, the WHO recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of patients with severe and critical COVID-19 [15, 25]. Also, the Surviving Sepsis Guideline on management of COVID-19 recommends administration of steroids in patients with severe COVID-19 on mechanical ventilation with ARDS and in patients with COVID-19 and refractory shock [26].

Our findings from both observational studies and RCTs confirm a beneficial effect of corticosteroids on short-term mortality and a reduction in the need for mechanical ventilation. And although data in the studies were too sparse to draw any firm conclusions, there might be a signal of delayed viral clearance and an increase in secondary infections related to corticosteroid use. Optimal timing, dose and duration of corticosteroids, in relation to safety, remain subject for further investigation. Since corticosteroids are affordable and easily accessible in healthcare systems quivering under the pressure of the global outbreak of this rapidly spreading coronavirus, this field of research should be a universal priority.

Main results: Inhaled corticosteroids plus standard care versus standard care (with/without placebo) - People with a confirmed diagnosis of moderate-to-severe COVID-19 We found no studies that included people with a confirmed diagnosis of moderate-to-severe COVID-19. - People with a confirmed diagnosis of asymptomatic SARS-CoV-2 infection or mild COVID-19 We included three RCTs allocating 3607 participants, of whom 2490 had confirmed mild COVID-19. We analysed a subset of the total number of participants recruited to the studies (2171, 52% female) as some trials had a platform design where not all participants were allocated to treatment groups simultaneously. The included studies were community-based, recruiting people who were able to use inhaler devices to deliver steroids and relied on remote assessment and self-reporting of outcomes. Most people were older than 50 years and had co-morbidities such as hypertension, lung disease, or diabetes. The studies were conducted in high-income countries prior to wide-scale vaccination programmes. A total of 1057 participants were analysed in the inhaled corticosteroid arm (budesonide: 860 participants; ciclesonide: 197 participants), and 1075 participants in the control arm. No studies included people with asymptomatic SARS-CoV-2 infection. With respect to the following outcomes, inhaled corticosteroids compared to standard care: - may result in little to no difference in all-cause mortality (at up to day 30) (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.22 to 1.67; 2132 participants; low-certainty evidence). In absolute terms, this means that for every nine deaths per 1000 people not receiving inhaled corticosteroids, there were six deaths per 1000 people who did receive the intervention (95% CI 2 to 16 per 1000 people); - probably reduces admission to hospital or death (at up to 30 days) (RR 0.72, 95% CI 0.51 to 0.99; 2025 participants; moderate-certainty evidence); - probably increases resolution of all initial symptoms at day 14 (RR 1.19, 95% CI 1.09 to 1.30; 1986 participants; moderate-certainty evidence); - may reduce the duration to symptom resolution (at up to day 30) (by -4.00 days, 95% CI -6.22 to -1.78 less than control group rate of 12 days; 139 participants; low-certainty evidence); - the evidence is very uncertain about the effect on serious adverse events (during study period) (RR 0.51, 95% CI 0.09 to 2.76; 1586 participants; very low-certainty evidence); - may result in little to no difference in adverse events (at up to day 30) (RR 0.78, 95% CI 0.47 to 1.31; 400 participants; low-certainty evidence); - may result in little to no difference in infections (during study period) (RR 0.88, 95% CI 0.30 to 2.58; 400 participants; low-certainty evidence). As studies did not report outcomes for subgroups (e.g. age, ethnicity, sex), we did not perform subgroup analyses.

Authors' conclusions: In people with confirmed COVID-19 and mild symptoms who are able to use inhaler devices, we found moderate-certainty evidence that inhaled corticosteroids probably reduce the combined endpoint of admission to hospital or death and increase the resolution of all initial symptoms at day 14. Low-certainty evidence suggests that corticosteroids make little to no difference in all-cause mortality up to day 30 and may decrease the duration to symptom resolution. We do not know whether inhaled corticosteroids increase or decrease serious adverse events due to heterogeneity in the way they were reported across the studies. There is low-certainty evidence that inhaled corticosteroids may decrease infections. The evidence we identified came from studies in high-income settings using budesonide and ciclesonide prior to vaccination roll-outs. We identified a lack of evidence concerning quality of life assessments, serious adverse events, and people with asymptomatic infection or with moderate-to-severe COVID-19. The 10 ongoing and four completed, unpublished RCTs that we identified in trial registries address similar settings and research questions as in the current body of evidence. We expect to incorporate the findings of these studies in future versions of this review. We monitor newly published results of RCTs on inhaled corticosteroids on a weekly basis and will update the review when the evidence or our certainty in the evidence changes. 041b061a72


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