Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk

Brosnahan, Shari B.; Chen, Xian Jie Cindy; Chung, Juri; Altshuler, Diana; Islam, Shahidul; Thomas, Sarun; Winner, Megan; Greco, Allison; Divers, Jasmin; Spiegler, Peter; Sterman, Daniel H.; Parnia, Sam

doi:10.1177/10600280211028882

Cited by 9 publications

(10 citation statements)

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“…Following the elimination of duplicates and screening of titles and abstracts, we evaluated 244 articles in full text. Among these, we found 43 eligible articles (5 RCTs, 16 cohort studies, 2 case-control studies, and 20 case reports) (Figure 1) (Salvarani et al, 2021;REMAP-CAP Investigators et al, 2021;Canziani et al, 2020;Menzella et al, 2020;Fisher et al, 2021;Campochiaro et al, 2020;Vazquez Guillamet et al, 2021;Rajendram et al, 2021;Huang et al, 2021;Galván-Román et al, 2021;Saffo et al, 2021;Somers et al, 2021;Brosnahan et al, 2021;Corominas et al, 2021;Cavalli et al, 2021;Abe et al, 2021;Patel et al, 2020;Mady et al, 2020;Bernardo et al, 2020;Morillas et al, 2020;Cascella et al, 2020;Al-Kaf et al, 2021;Eroglu et al, 2021;Kataoka et al, 2021;Kishaba et al, 2021;Leelayuwatanakul et al, 2021;McKenzie et al, 2021;Nourié et al, 2021;Ladna et al, 2021;Senegaglia et al, 2021;Thammathiwat et al, 2021;Lescure et al, 2021;Della-Torre et al, 2020;Gremese et al, 2020;Kyriazopoulou et al, 2021a;Bozzi et al, 2021;Franzetti et al, 2021;…”

Section: Search Resultsmentioning

confidence: 99%

“…The results are shown in Supplementary Figure S1 (Supplementary Material S2, Appendix p1). Some studies reported only one outcome, and we assessed the risk of bias for the results-for instance, bias in the measurement of outcomes was not available for safety for the study of Brosnahan et al (2021) because they did not report it. For mortality outcomes, the methodological quality of 16 cohorts was moderate to high, and those of 2 case-control studies were moderate.…”

Section: Risk Of Bias Assessmentmentioning

confidence: 99%

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Specific Interleukin-1 Inhibitors, Specific Interleukin-6 Inhibitors, and GM-CSF Blockades for COVID-19 (at the Edge of Sepsis): A Systematic Review

et al. 2022

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Sepsis is a syndrome with high mortality, which seriously threatens human health. During the pandemic of coronavirus disease 2019 (COVID-19), some severe and critically ill COVID-19 patients with multiple organ dysfunction developed characteristics typical of sepsis and met the diagnostic criteria for sepsis. Timely detection of cytokine storm and appropriate regulation of inflammatory response may be significant in the prevention and treatment of sepsis. This study evaluated the efficacy and safety of specific interleukin (IL)-1 inhibitors, specific IL-6 inhibitors, and GM-CSF blockades in the treatment of COVID-19 (at the edge of sepsis) patients through systematic review and meta-analysis. Methodology: A literature search was conducted on PubMed, EMBASE, Clinical Key, Cochrane Library, CNKI, and Wanfang Database using proper keywords such as “SARS-CoV-2,” “Corona Virus Disease 2019,” “COVID-19,” “anakinra,” “tocilizumab,” “siltuximab,” “sarilumab,” “mavrilimumab,” “lenzilumab,” and related words for publications released until August 22, 2021. Other available resources were also used to identify relevant articles. The present systematic review was performed based on PRISMA protocol. Results: Based on the inclusion and exclusion criteria, 43 articles were included in the final review. The meta-analysis results showed that tocilizumab could reduce the mortality of patients with COVID-19 (at the edge of sepsis) [randomized controlled trials, RCTs: odds ratio (OR) 0.71, 95%CI: 0.52–0.97, low-certainty evidence; non-RCTs: risk ratio (RR) 0.68, 95%CI: 0.55–0.84, very low-certainty evidence) as was anakinra (non-RCTs: RR 0.47, 95%CI: 0.34–0.66, very low-certainty evidence). Sarilumab might reduce the mortality of patients with COVID-19 (at the edge of sepsis), but there was no statistical significance (OR 0.65, 95%CI: 0.36–1.2, low-certainty evidence). For safety outcomes, whether tocilizumab had an impact on serious adverse events (SAEs) was very uncertain (RCTs: OR 0.87, 95%CI: 0.38–2.0, low-certainty evidence; non-RCTs 1.18, 95%CI: 0.83–1.68, very low-certainty evidence) as was on secondary infections (RCTs: OR 0.71, 95%CI: 0.06–8.75, low-certainty evidence; non-RCTs: RR 1.15, 95%CI: 0.89–1.49, very low-certainty evidence). Conclusions: This systematic review showed that tocilizumab, sarilumab, and anakinra could reduce the mortality of people with COVID-19 (at the edge of sepsis), and tocilizumab did not significantly affect SAEs and secondary infections. The current evidence of the studies on patients treated with siltuximab, mavrilimumab, and lenzilumab is insufficient. In order to establish evidence with stronger quality, high-quality studies are needed.Systematic Review Registration: PROSPERO (https://www.crd.york.ac.uk/prospero/), identifier CRD42020226545

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Section: Search Resultsmentioning

confidence: 99%

Section: Risk Of Bias Assessmentmentioning

confidence: 99%

Specific Interleukin-1 Inhibitors, Specific Interleukin-6 Inhibitors, and GM-CSF Blockades for COVID-19 (at the Edge of Sepsis): A Systematic Review

et al. 2022

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“…Low dose methylprednisolone has been defined as 40 mg IV daily for 5 days [ 5 ] and 80 mg IV daily for 8 days [ 6 , 7 ]. High dose methylprednisolone has been defined as 120–180 mg IV daily for 10 days [ 8 ], 250 mg IV every day for 3 days [ 9 ], 250–500 mg IV daily for 3 days followed by prednisone 50 for 10 days [ 10 ], and 1 mg/kg IV for ≥ 3 days [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…We found that LDMP (< 1.36 mg/kg of absolute body weight/day), administered > 7 days from onset of symptoms was associated with prolonged survival compared to no methylprednisolone and no additional benefit with HDMP (≥ 1.36 mg/kg of absolute body weight/day) [ 12 ]. Interestingly, the studies with varying definitions of high dose and showed mortality benefit fit our actual weight-based definition of low dose [ 8 – 11 ].…”

Section: Introductionmentioning

confidence: 99%

Methylprednisolone, venous thromboembolism, and association with heparin to 30 days in hospital survival in severe Covid-19 pneumonia

Nyirenda

Bojarian

et al. 2022

BMC Pulm Med

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Background Mortality in severe COVID-19 pneumonia is associated with thrombo-inflammation. Corticosteroids are given to attenuate the inflammation, but they are associated with thrombosis. The aims of this study were to determine the risk of venous thromboembolism between no methylprednisolone and methylprednisolone (dose versus duration) and to evaluate any synergistic dose-dependent association of heparin and methylprednisolone to 30 days in hospital survival. Methods This was a secondary analysis of a retrospective cohort. Patients included in this study were ≥ 18 years of age and admitted for severe COVID-19 pneumonia between March and June 2020 in 13 hospitals in New Jersey, United States. A propensity score analysis between administration of methylprednisolone and no methylprednisolone was fitted for 11 variables and Youden Index Method was used to determine cut-off between low dose and high dose methylprednisolone. Multivariate cox regression was to assess risk. Results In 759 patients, the incidence of venous thromboembolism was 9% of patients who received methylprednisolone and 3% of patients who did not receive methylprednisolone with a [RR 2.92 (95% CI 1.54, 5.55 P < 0.0001)]. There was a higher incidence of mechanical ventilation in the methylprednisolone group. The median d-dimer between patients with venous thromboembolism was higher compared to those without (P < 0.0003). However, the d-dimer was not statistically significant between those who had venous thromboembolism between methylprednisolone and no methylprednisolone groups (P = 0.40). There was no higher risk in high dose versus low dose [RR = 0.524 (95% CI 0.26, 1.06 P 0.4)]; however, the risk for venous thromboembolism between methylprednisolone for > 7 days and ≤ 7 days was statistically significant (RR 5.46 95% CI 2.87, 10.34 P < 0.0001). Patients who received low dose methylprednisolone and therapeutic heparin had a trend towards higher risk of mortality compared to prophylactic heparin (HR 1.81 95% CI 0.994 to 3.294) (P = 0.0522). There was no difference in 30 days in hospital survival between high dose methylprednisolone with prophylactic or therapeutic heparin (HR 0.827 95% CI 0.514 to 1.33) (P = 0.4335). Conclusion Methylprednisolone for > 7 days had a higher association of venous thromboembolism. There was no added benefit of therapeutic heparin to methylprednisolone on mechanically ventilated patients.

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“…We read with interest the recent publication by Brosnahan et al 1 regarding the impact of tocilizumab with high-dose corticosteroids in COVID-19 hypoxic respiratory failure.…”

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confidence: 99%

Comment: Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk

Bissell¹,

Mefford²,

Donaldson³

2021

Ann Pharmacother

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Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk

Cited by 9 publications

References 30 publications

Specific Interleukin-1 Inhibitors, Specific Interleukin-6 Inhibitors, and GM-CSF Blockades for COVID-19 (at the Edge of Sepsis): A Systematic Review

Specific Interleukin-1 Inhibitors, Specific Interleukin-6 Inhibitors, and GM-CSF Blockades for COVID-19 (at the Edge of Sepsis): A Systematic Review

Methylprednisolone, venous thromboembolism, and association with heparin to 30 days in hospital survival in severe Covid-19 pneumonia

Comment: Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk

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