key: cord-0942930-0pzt6zum
authors: Chen, Luke Y.C.; Biggs, Catherine M.; Jamal, Shahin; Stukas, Sophie; Wellington, Cheryl L.; Sekhon, Mypinder S.
title: Soluble Interleukin-6 Receptor in the COVID-19 Cytokine Storm Syndrome
date: 2021-04-19
journal: Cell Rep Med
DOI: 10.1016/j.xcrm.2021.100269
sha: e81b24541eb60e0c41c2b8429a69d7fc734d6fd8
doc_id: 942930
cord_uid: 0pzt6zum

Data suggest that interleukin (IL)-6 blockade could reduce mortality in severe COVID-19, yet IL-6 is only modestly elevated in most patients. Chen et al. describe the role of soluble interleukin-6 receptor (sIL-6R) in IL-6 trans-signaling, and how understanding the IL-6:sIL-6R axis might help define and treat COVID-19 cytokine storm syndrome.

disease of 2019 (COVID-19) by Dr. Koutsakos and colleagues provides a fresh perspective on the 28 immune dysregulation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 29 2). 1 Their cohort included patients with a broad spectrum of severities, including 12 critically ill, 30 20 ward, 1 discharged, and 52 ambulatory patients with a mix of acute and chronic phase 31 samples. In this commentary we elaborate on their findings regarding the soluble IL-6 receptor, 32 and how further exploration of the complex checks and balances involved in IL-6 signaling may 33 be key to diagnosing and treating COVID-19 immunopathology. 34 COVID-19 is associated with remarkably heterogeneous presentations and outcomes in 35 humans. The majority of those infected are asymptomatic or have mild ambulatory disease, 36 but approximately 2-10% develop severe disease leading to hospitalization, and 25-30% of 37 hospitalized patients will require intensive care. 2 Surges of severe and critical patients have 38 overwhelmed health care systems in many countries. Some risk factors for critical illness are 39 older age, male gender and co-morbid conditions, yet a substantial proportion of severe cases 40 are driven by a maladaptive, pathological immune response known as COVID-19 cytokine storm 41 (COVID-CSS) which can afflict young, otherwise healthy adults. 3 Early in the pandemic, 42 numerous studies reported an association between elevated inflammatory cytokine levels, 43 particularly interleukin (IL)-6 and poor outcomes including respiratory failure and death. The Early reports describing COVID-CSS generated great enthusiasm for immunomodulatory 50 therapies, including corticosteroids, blockade of specific cytokines (e.g. IL-1, IL-6, TNF), 51 interferon therapy, and modulation of intra-cellular pathways (e.g. JAK inhibition). In studies of 52 prognostic biomarkers, IL-6 and C-reactive protein (which is produced by hepatocytes in 53 response to IL-6) consistently emerged as the most sensitive and specific for predicting adverse 54 outcomes such as respiratory failure and death. 3 Autopsy studies also pointed towards 55 cytokine storm as a major contributor to COVID related morbidity and mortality. While some 56 patients died with a high viral load evident in their tissues, others had profound inflammation in 57 lungs, heart, brain and other organs, but little to no evidence of SARS-CoV-2, suggesting that Studies from CAR-T cell therapeutic trials suggest that sIL-6R levels may serve as a 142 bottleneck in driving CAR-T CRS, and support evaluating the IL-6:sIL-6R ratio as a parameter for 143 CRS-mediated toxicity. In a study of 63 patients with rheumatoid arthritis, sIL-6R levels were a 144 better predictor of response to tocilizumab than IL-6. 11 Patients with high sIL6R (mean ± SD 145 J o u r n a l P r e -p r o o f 72 ng/mL) responded well to tocilizumab irrespective of their IL-6 levels. 11 Whether sIL-6R is 147 predictive of response to IL-6 blockade in COVID-19 remains to be seen. In the study by 148 Koutsakos et al. sIL-6R was higher in ICU vs. ward patients (57.9 ng/mL ICU vs 40.37 ng/mL 149 ward, p=0.002); likewise, ICU patients had higher IL-6 levels than ward patients (median 28.8 150 pg/mL vs. 11.95 pg/mL, p=0.025). However, levels of sIL-6R did not correlate with IL-6 levels; 151 some patients with very high IL-6 had low sIL-6R and vice versa. In this study, sIL-6R was more 

Integrated immune dynamics define correlates of 213 COVID-19 severity and antibody responses

Life-Threatening COVID-19: Defective Interferons Unleash 215 Excessive Inflammation

Confronting the controversy: 217 interleukin-6 and the COVID-19 cytokine storm syndrome

COVID-19 cytokine storm syndrome: a threshold concept. The Lancet 220 Microbe

Interleukin-6 Receptor Antagonists in Critically Ill 222 Patients with Covid-19

Interleukin-6 blocking agents for treating COVID-19: a 225 living systematic review

Cytokine elevation in severe and critical COVID-19: a rapid 228 systematic review, meta-analysis, and comparison with other inflammatory syndromes

Preliminary predictive criteria for COVID-19 cytokine storm

The persistence of interleukin-6 is regulated by a blood buffer 235 system derived from dendritic cells

The combination of IL-6 and its soluble receptor is 237 associated with the response of rheumatoid arthritis patients to tocilizumab. Seminars in 238 arthritis and rheumatism

Functional IL6R 358Ala allele impairs classical IL-6 240 receptor signaling and influences risk of diverse inflammatory diseases

Therapeutic IL-6 trans-signalling inhibition by 245 olamkicept (sgp130Fc) in patients with active inflammatory bowel disease

Selective blockade of interleukin-6 trans-signaling 248 improves survival in a murine polymicrobial sepsis model

Classic signaling via membrane bound IL-6 receptor is restricted to immune cells (macrophages, 254 lymphocytes, dendritic cells), hepatocytes and gut epithelium. Other organs, such as lungs, 255 myocardium, and nervous system, require soluble IL-6 receptor to initiate trans signaling. The trans 256 signaling system is buffered by soluble glycoprotein 130, which binds and inhibits the IL-6:sIL-6R 257 complex with picomolar affinity. Conventional dendritic cells overcome this buffering system by 258secreting sIL-6R directly as well as facilitating cleavage of mIL-6R to produce sIL-6R vias the membrane 259 bound sheddase ADAM17. Siltuximab (antibody against IL-6), sarilumab and tocilizumab (antibodies 260 against IL-6:IL-6R) block both classic and trans signaling. Olamkicept (sgp130Fc) specifically blocks trans 261signaling. The intracellular TYK2/JAK1/JAK2/JAK3 system leads to upregulation of IL-6 target genes and 262is inhibited by Jak inhibitors such as baricitinib, ruxolitinib and tofacitinib. The inhibition of TYK-2 (*) is 263 relatively weak relative to JAK inhibition by these molecules.