IL-6 signalling pathway inactivation with siltuximab in patients with COVID-19 respiratory failure: an observational cohort study

Abstract

COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SAR-CoV-2), resulting in symptoms, such as fever, cough, and shortness of breath. The SARS-CoV-2 virus has also been suggested to initiate a cytokine storm in patients with COVID-19 evidenced by elevated cytokines, such as interleukin-6 (IL-6) and Creactive protein (CRP).We report preliminary data from 21 patients with COVID-19 who developed pneumonia/acute respiratory distress syndrome (ARDS) and participated in a compassionate-use program at Papa Giovanni XXIII hospital in Bergamo, Italy.All 21 patients received intravenous siltuximab -a chimeric mAb that binds to and blocks the effect of IL-6 -at a dose ranging between 700 to 1,200 mg (median 900 mg). The median age of patients treated was 64 years, and all patients were followed for a median of eight days. Serum CRP levels reduced in all 16 patients with available . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages

“…A study from China reported a clear benefit in 15 of 20 (75%) patients treated with IL-6 blockade 21 , leading the FDA to approve trials of IL-6 blockade in patients with COVID-19. A more recent study from Italy reported a benefit in only 7 of 21 (33%) patients 22 . Neither of these studies had control arms and very few data are available on the exact clinical and inflammatory status of patients who responded versus those who did not.…”

The many faces of the anti-COVID immune response

“…These elevations in innate immune cytokines have led to the hypothesis that an innate immune-mediated "cytokine storm," similar to the cytokine release syndrome (CRS) observed in patients receiving treatment with chimeric antigen receptortransduced T cells (CAR-T), is primarily responsible for the toxicity and end-organ damage mediated by COVID-19 infections (Grupp et al, 2013;Mehta et al, 2020). A role for cytokinedriven neutrophil mobilization in COVID-associated lung toxicity may explain why neutrophilia, despite the absence of secondary bacterial infections, is associated with mortality (Lagunas-Rangel, 2020), and why administration of monoclonal antibodies targeting IL-6 has shown initial clinical promise (Gritti et al, 2020).…”

“…Perhaps most importantly, the clinical results of therapeutic blockade of circulating IL-6 with tocilizumab or siltuximab are thus far mixed; one clinical trial showed evidence of improvement in 33% of patients, at least suggesting that in many cases, a hyperinflammatory response is not primarily responsible for COVID-19-associated morbidity and mortality (Gritti et al, 2020). This may be in part due to ongoing IL-6 production that overcomes direct targeting and may explain the more favorable early data with IL-6 receptor blockade (Xu et al, 2020a Preprint).…”

Beneficial effect of corticosteroids in severe COVID-19 pneumonia: a propensity score matching analysis

“…Multiple antiviral treatment options have been evaluated in vitro, but demonstration of their convincing efficacy in vivo needs yet to be done [14][15][16][17][18][19][20][21][22][23]. Similarly, several anti-inflammatory drugs, especially corticosteroids and tocilizumab, are candidates to treat patients with COVID-19 pneumonia [9,12,13,[24][25][26][27][28].…”