Transcriptional response modules characterize IL-1β and IL-6 activity in COVID-19

Abstract

Dysregulated IL-1β and IL-6 responses have been implicated in the pathogenesis of severe Coronavirus Disease 2019 (COVID-19). Innovative approaches for evaluating the biological activity of these cytokines in vivo are urgently needed to complement clinical trials of therapeutic targeting of IL-1β and IL-6 in COVID-19. We show that the expression of IL-1β or IL-6 inducible transcriptional signatures (modules) reflects the bioactivity of these cytokines in immunopathology modelled by juvenile idiopathic arthritis (JIA) and rheumatoid arthritis. In COVID-19, elevated expression of IL-1β and IL-6 response modules, but not the cytokine transcripts themselves, is a feature of infection in the nasopharynx and blood, but is not associated with severity of COVID-19 disease, length of stay or mortality. We propose that IL-1β and IL-6 transcriptional response modules provide a dynamic readout of functional cytokine activity in vivo , aiding quantification of the biological effects of immunomodulatory therapies in COVID-19.

Tocilizumab in Treatment for Patients With COVID-19

“…Recently, early results released from the Randomised, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) international platform trial showed that tocilizumab was effective in critically ill patients. 3 In an observational study 4 in the Reggio Emilia area, considering 172 patients consecutively treated with tocilizumab, the percentage of patients who died after tocilizumab therapy was similar to that of patients with COVID-19 hospitalized in the same time period and not treated with tocilizumab after a follow-up of more than 1 month. However, when some of our researchers considered the subgroup of patients undergoing noninvasive ventilation, tocilizumab reduced the risk of being intubated or dying.…”

“…Third, IL-6 is a pleiotropic cytokine with both pro-inflammatory and anti-inflammatory properties and is also involved in antiviral responses. 4 According to pharmacokinetic studies, lower-dose tocilizumab blocks IL-6 binding to its soluble receptor, and thus inhibits pro-inflammatory response, while high-dose tocilizumab may bind to both soluble and membrane-bound IL-6 receptors and inhibit both pro-inflammatory and anti-inflammatory pathways. 5 Taken together, low-dose tocilizumab may be a better option to reduce IL-6-related cytokine storm and mortality in patients with COVID-19.…”

“…In addition, no data are available about the diffusion and concentration of tocilizumab in the lungs. A recent study 4 points out that IL-6 concentration in bronchoalveolar lavage fluid (BALF) of patients with COVID-19 may rise until it reaches 10 ng/mL, with a ratio of BALF:plasma of IL-6 significantly higher in nonsurviving patients having acute respiratory distress syndrome than in survivors. Such huge local IL-6 concentrations could be hardly inhibited by tocilizumab since 100 μg/mL tocilizumab (usual concentrations in treated patients) cannot block IL-6 concentration higher than 1 ng/mL in vitro.…”

“…3 Therefore, it is imperative that we apply novel immunophenotyping approaches to measure changes in IL-6 functional activity induced by tocilizumab in COVID-19, verifying adequate pathway suppression, and enabling correlation between clinical outcomes and levels of IL-6 activity. 4,5 Only by understanding tocilizumab's mechanistic correlates of clinical activity can we more confidently determine its therapeutic role in treating COVID-19.…”

Exclusion of bacterial co-infection in COVID-19 using baseline inflammatory markers and their response to antibiotics

“…Unfortunately, we could not investigate PCT as it was not measured routinely in our CAP cohorts. Future studies should assess the discriminatory capacity of PCT, D-dimers, 9 , 24 , 34 and other novel biomarkers, such as transcriptional signatures that quantify inflammatory cytokine activity 35 or those that discriminate bacterial from viral infections. 36 …”