Background There is accumulating evidence for an overly activated immune response in severe COVID-19, with several studies exploring the therapeutic role of immunomodulation Through systematic review and meta-analysis, we assess the effectiveness of specific interleukin inhibitors for the treatment of COVID-19 Methods Electronic databases were searched on 7 January 2021 to identify studies of immunomodulatory agents (anakinra, sarilumab, siltuximab and tocilizumab) for the treatment of COVID-19 The primary outcomes were severity on an Ordinal Scale measured at day 15 from intervention and days to hospital discharge Key secondary endpoints included overall mortality Results 71 studies totalling 22 058 patients were included, 6 were randomised trials Most studies explored outcomes in patients who received tocilizumab (60/71) In prospective studies, tocilizumab was associated with improved unadjusted survival (risk ratio 083, 95% CI 072 to 096, I2=00%), but conclusive benefit was not demonstrated for other outcomes In retrospective studies, tocilizumab was associated with less severe outcomes on an Ordinal Scale (generalised OR 134, 95% CI 110 to 164, I2=98%) and adjusted mortality risk (HR 052, 95% CI 041 to 066, I2=766%) The mean difference in duration of hospitalisation was 036 days (95% CI −007 to 080, I2=938%) There was substantial heterogeneity in retrospective studies, and estimates should be interpreted cautiously Other immunomodulatory agents showed similar effects to tocilizumab, but insufficient data precluded meta-analysis by agent Conclusion Tocilizumab was associated with a lower relative risk of mortality in prospective studies, but effects were inconclusive for other outcomes Current evidence for the efficacy of anakinra, siltuximab or sarilumab in COVID-19 is insufficient, with further studies urgently needed for conclusive findings PROSPERO registration number CRD42020176375

https://thorax.bmj.com/content/thoraxjnl/76/9/907.full.pdf

Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19.

Background Currently, the data regarding the effectiveness and safety
of tocilizumab as treatment for COVID-19 infection is still conflicting.
This study aims to give clear evidence regarding the potential benefit and
safety of tocilizumab in improving the outcome of COVID-19 patients. Methods We systematically searched the PubMed and Europe PMC database
using specific keywords related to our aims until November 1st,
2020. All articles published on COVID-19 and tocilizumab were retrieved.
Statistical analysis was done using Review Manager 5.4 software. Results A total of 38 studies with a total of 13 412 COVID-19
patients were included in our analysis. Our meta-analysis showed that
tocilizumab treatment is associated with reduction of mortality rate from
COVID-19 [OR 0.54 (95% CI 0.42–0.71),
p<0.00001, I
 2=79%, random-effect modelling], but did not
alter the severity of COVID-19 [OR 1.05 (95% CI 0.92–1.20),
p=0.47, I
 2=84%, random-effect modelling] and length of
hospital stay [Mean Difference 1.77 days (95% CI
−0.61–4.14 days), p=0.15, I
 2=97%, random-effect modelling]. Tocilizumab also
does not associated with serious adverse events compared with standard of
care treatment [OR 0.91 (95% CI 0.71–1.15),
p=0.42, I
 2=46%, random-effect modelling]. Conclusion Our study does not support the routine use of tocilizumab
for COVID-19 patients. Future studies should focus more on other potential
therapies for COVID-19 patients.

/pdf/efficacy-and-safety-of-tocilizumab-for-coronavirus-disease-81k1s7cpha.pdf

Efficacy and Safety of Tocilizumab for Coronavirus Disease 2019 (Covid-19) Patients: A Systematic Review and Meta-analysis.

Despite the global effort to mitigate the spread, coronavirus disease 2019 (COVID-19) has become a pandemic that took more than 2 million lives There are numerous ongoing clinical studies aiming to find treatment options and many are being published daily Some effective treatment options, albeit of variable efficacy, have been discovered Therefore, it is necessary to develop an evidence-based methodology, to continuously check for new evidence, and to update recommendations accordingly Here we provide guidelines on pharmaceutical treatment for COVID-19 based on the latest evidence

https://icjournal.org/pdf/10.3947/ic.2021.0303

Revised Korean society of infectious diseases/national evidence-based healthcarea collaborating agency guidelines on the treatment of patients with COVID-19

Background There is accumulating evidence for an overly activated immune response in severe Covid-19. Several studies exploring the role of immunomodulation as a potential therapeutic strategy have been published. Through systematic review and meta-analysis, we assess the effectiveness of specific interleukin inhibitors for the treatment of Covid-19. Methods Electronic databases, preprint servers and clinical trial registries were searched on 23rd October 2020 to identify studies of immunomodulatory agents (anakinra, sarilumab, siltuximab and tocilizumab) for the treatment of Covid-19. The primary outcomes were severity on an ordinal scale measured at day 15 and days to hospital discharge. Key secondary endpoints included overall mortality. Results Sixty studies totalling 16588 patients were included, four were randomised controlled studies. Most explored outcomes in patients who received tocilizumab (50/60), followed by anakinra (5/60), sarilumab (4/60) and siltuximab (1/60). There was substantial heterogeneity in meta-analysis and pooled effect estimates should be interpreted with caution. In retrospective studies, tocilizumab was associated with less severe outcomes on an ordinal scale (Generalised odds ratio 1.23 95%CI 1.10;1.37, I2=97%) and reduced mortality (HR 0.58 95%CI 0.43;0.78, I2 =80.3%) but consistent outcome benefit was not shown in prospective studies. The mean difference with control in the duration of hospitalisation was 0.26 days (95%CI −0.10;0.62, I2 =85%). Insufficient data precluded meta-analysis for other immunomodulatory agents. Conclusion Meta-analysis revealed substantial heterogeneity in reported findings of tocilizumab and an inconclusive effect from prospective studies. Currently available evidence for the efficacy of anakinra, siltuximab or sarilumab in Covid-19 is insufficient. Results from adequately powered, high-quality randomised studies are urgently needed.

/pdf/a-systematic-review-of-anakinra-tocilizumab-sarilumab-and-2bx32v55fy.pdf

A systematic review of anakinra, tocilizumab, sarilumab and siltuximab for coronavirus-related infections

We performed a meta-analysis to determine safety and efficacy of tocilizumab in persons with coronavirus disease-2019 (COVID-19). We searched PubMed, Web of Science and Medline using Boolean operators for studies with the terms coronavirus OR COVID-19 OR 2019-nCoV OR SARS-CoV-2 AND tocilizumab. Review Manager 5.4 was used to analyze data and the modified Newcastle-Ottawa and Jadad scales for quality assessment. We identified 32 studies in 11,487 subjects including three randomized trials and 29 cohort studies with a comparator cohort, including historical controls (N = 5), a matched cohort (N = 12), or concurrent controls (N = 12). Overall, tocilizumab decreased risk of death (Relative Risk [RR] = 0.74; 95% confidence interval [CI], 0.59, 0.93; P = 0.008; I2 = 80%) but not of surrogate endpoints including ICU admission (RR = 1.40 [0.64,3.06]; P = 0.4; I2 = 88%), invasive mechanical ventilation (RR = 0.83 [0.57,1.22]; P = 0.34; I2 = 65%) or secondary infections (RR = 1.30 [0.97,1.74]; P = 0.08; I2 = 65%) and increased interval of hospitalization of subjects discharged alive(mean difference [MD] = 2 days [<1, 4 days]; P = 0.006; I2 = 0). RRs of death in studies with historical controls (RR = 0.28 [0.16,0.49; P < 0.001]; I2 = 62%) or a matched cohort (RR = 0.68 [0.53, 0.87]; P = 0.002; I2 = 42%) were decreased. In contrast, RRs of death in studies with a concurrent control (RR = 1.10 [0.77, 1.56]; P = 0.60; I2 = 85%) or randomized (RR = 1.18 [0.57,2.44]; P = 0.66; I2 = 0) were not decreased. A reduced risk of death was not confirmed in our analyses which questions safety and efficacy of tocilizumab in persons with COVID-19.

/pdf/systematic-review-and-meta-analysis-of-tocilizumab-in-51oxzihoyl.pdf

Systematic review and meta-analysis of tocilizumab in persons with coronavirus disease-2019 (COVID-19).

What is known and objective The coronavirus disease 2019 (COVID-19) associated cytokine activation can lead to a rapid progression into respiratory failure, shock and multiorgan failure. Interleukin-6 (IL-6) is a pro-inflammatory cytokine that likely contributes to the pathogenesis of cytokine release syndrome. It is hypothesized that modulating IL-6 levels or its effects with tocilizumab, a recombinant humanized anti-IL-6 receptor monoclonal antibody, may alter the course of disease. Methods We examined the association between tocilizumab use and intubation or death at a community hospital in New York City. Data were obtained regarding consecutive patients hospitalized with COVID-19. The primary end point was a composite of intubation or death in a time-to-event analysis. We compared outcomes in patients who received tocilizumab with those in patients who did not, using a multivariable Cox model with inverse probability weighting according to the propensity score. Results and discussion In this single-centre retrospective cohort study involving 1225 hospitalized patients with SARS-CoV-2 infection, the probability to respiratory failure, which was measured as intubation or death, was less frequent in patients who received tocilizumab. What is new and conclusion Tocilizumab and other IL-6 receptor monoclonal antibodies may evolve as a viable option in treating patients with moderate and severe COVID-19.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jcpt.13303

Tocilizumab use in patients with moderate to severe COVID-19: A retrospective cohort study.

This study evaluated an antibiotic stewardship program (ASP) intervention aimed at reducing inpatient fluoroquinolone (FQ) use and examined its impact on ciprofloxacin susceptibilities of gram-nega...

https://journals.sagepub.com/doi/pdf/10.1177/00368504211011876

Association between fluoroquinolone utilization rates and susceptibilities of gram-negative bacilli: Results from an 8-year intervention by an antibiotic stewardship program in an inner-city United States hospital:

Kyoung-Sil Kang

Papers

Tocilizumab use in patients with moderate to severe COVID-19: A retrospective cohort study.

Association between fluoroquinolone utilization rates and susceptibilities of gram-negative bacilli: Results from an 8-year intervention by an antibiotic stewardship program in an inner-city United States hospital:

COVID-19 preparedness: A Bronx, New York, inner-city hospital's experience with medication management and readiness for a second surge.