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

Abstract

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

Application of Monoclonal Antibody Drugs in Treatment of COVID-19: a Review

“…Moreover, there is a number of studies [105][106][107] confirming that anakinra may be effective in the treatment of COVID-19 patients that show signs of macrophage activation syndrome, especially those with persistent high fever and elevated plasma ferritin levels [108].…”

The role of interleukin 1 in the development of human diseases: focus on Anakinra (IL-1 receptor antagonist)

“…Болезнь Кавасаки Ретроспективное исследование, клинические наблюдения [226][227][228][229][230][231][232][233][234][235][236][237][238] Вторичный синдром активации макрофагов/ГЛГ при ИВЗ Клинические наблюдения [239][240][241][242][243][244] COVID-19 ассоциированный гипервоспалительный синдром РПКИ (CORIMUNO, SAVE-MORE) [245,246], наблюдательные исследования [247][248][249][250][251][252][253][254], метаанализы [255,256]…”

“…Примечательно, что in vitro ИЛ-1Ra отменяет синтез ИЛ-6 и ФНО-α моноцитами, инфицированными SARS-CoV-2 [326], а увеличение его концентрации в сыворотке рассматривается как сурогатный лабораторный биомаркер гиперпродукции ИЛ-1, коррелирующий с тяжестью СOVID-19 [327]. По данным рандомизированных плацебо-контролируемых исследований (CORIMUNO, SAVE-MORE) [245,246], наблюдательных исследований [247][248][249][250][251][252][253][254], мета-анализов [255,256,328,329], у пациентов с COVID-19 ассоциированным гипервоспалительным синдромом применение анакинры позволяет снизить летальность (на 50%) и потребность в искусственной вентиляции легких. Имеются данные о том, что раннее назначение анакинры (в среднем через 9 дней после появления симптомов COVID-19) более эффективно, чем позднее (в среднем через 15 дней) (отношение рисков (HR, hazard ration) -0,33 против HR=0,82 соответственно), но эти различия были статистически не значимы.…”

COVID-19 Myocarditis: An Emerging Clinical Conundrum

“…Given the known association between cytokine activation and COVID 19 mediated inflammatory response, various cytokine inhibitors have been studied including Toclizumab, Siltuximab and Sarilumab. 57 These are all interleukin 6 inhibitors and may have a potential therapeutic role in COVID 19 induced myocarditis. 57 In the REMAP- CAP study, 58 Toclizumab and Sarilumab were shown to have some efficacy with improved outcomes, including mortality in critically ill patients.…”