27 Aug Cytokines Associated with Severity and Survival from COVID-19
MedicalResearch.com Interview with:
Sacha Gnjatic, PhD
Associate Director of the Human Immune Monitoring Center
Associate Professor of Medicine, Oncological Sciences and Pathology
Icahn School of Medicine at Mount Sinai
Member of the Precision Immunology Institute and The Tisch Cancer Institute
MedicalResearch.com: What is the background for this study? Would you explain what is meant by cytokine/cytokines?
Response: COVID-19 is a disease where inflammation is suspected to play a large role in pathogenicity, possibly more so than the tissue damage created by the virus alone. Cytokines are small soluble proteins that are produced by both immune cells and cells from tissues, and many play a role in signaling such inflammation, to alert of tissue damage or infection. Among these cytokines, interleukin-6 (IL-6), IL-8, IL-1beta, and Tumor Necrosis Factor alpha (TNF-a) have been well established as important markers of pathogenic inflammation. Drugs that counteract these cytokines are routinely use in various inflammatory disease, from rheumatoid arthritis to plaque psoriasis and Crohn’s disease. When the initial wave of SARS-CoV-2 infection hit our hospitals in New York, we therefore wondered whether these cytokines were associated with COVID-19 disease severity and outcome, and hoped that a rapid test to detect them in blood could be useful to make clinical decisions about treatment. We were able to analyze a very large number of patient samples (>1400) in a period of one month, and confirmed our findings in a second smaller cohort.
MedicalResearch.com: What are the main findings?
Response: We found that the majority of patients admitted to the hospital with confirmed SARS-CoV-2 infection had very elevated levels of IL-6, IL-8, and TNF-a compared to uninfected controls. When further categorizing patients in two groups, those with the highest levels of each cytokine vs. the rest, we found that each cytokine measured was associated with poor survival if elevated when the patient entered the hospital. This was true independently of demographics (sex, age, BMI) and comorbidities (a variety of preexisting conditions such as chronic kidney disease or diabetes). Since there are other vital and lab measurements that are related to inflammation, such as fever, D-dimer, or CRP, we asked whether the cytokine panel was still useful regardless. After adjusting for all these other variables and considering all the cytokines together, we found that high IL-6 and TNF-a still remained independently predictive of increased severity and risk of death. In other words, even within patients with the worse symptoms, such as low blood oxygen, these two cytokines could distinguish patients who will be at a survival disadvantage; and conversely, in patients seemingly with more moderate disease, we could still predict a subset of patients who would do poorly based on these cytokines. For some of the patients, we could also look at changes in cytokines with experimental treatments, and saw dynamic differences in cytokines from baseline following corticosteroids, antiviral, and anti-cytokine drugs that suggest they may be important to predict or quantify response.
MedicalResearch.com: What should readers take away from your report?
Response: Cytokines are associated with severity and survival from COVID-19, and IL-6 and TNF-a help predict patients who will fare the worst, independently of many other known risk factors.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Because it still remains to be seen if cytokines directly cause severity or are merely a secondary marker, trials assessing drugs to either directly target cytokines, alone or in combination, as well as treatments with more general immunomodulators should be investigated in the context of cytokine levels. Will patients who arrive to the hospital with the highest levels of these cytokines benefit more from certain treatment(s)? Are these cytokines predictive not only of overall outcome but also of response to treatment? Combinations targeting several cytokines have not been attempted, due to feasibility and cost, but baseline cytokine levels could be used to guide enrollment in a more rational manner. Treatments such as dexamethasone, which seem to work best in the patients with the most severe symptoms, should also investigate whether cytokines may be useful as predictive biomarkers. Finally, it is probable that many other cytokines not considered in this study could have even better predictive value, and follow-up work currently includes other proteomic approaches to measure dozens to thousands of soluble analytes, which may eventually lead to a more refined predictive pane
Disclosures from the manuscript are below, though none are related to the current work.
S.G. reports consultancy and/or advisory roles for Merck, Neon Therapeutics and OncoMed and research funding from Bristol-Myers Squibb, Genentech, Immune Design, Agenus, Janssen R&D, Pfizer, Takeda and Regeneron. S.P. reports consulting fees from Foundation Medicine and research funding from Celgene and Karyopharm. D.M. reports consultancy and/or advisory roles from Janssen, Celgene, Bristol-Myers Squibb, Takeda, Legend, GlaxoSmithKline, Kinevant and Foundation Medicine. B.W. reports a consulting role at Sanofi Genzyme. J.A.A. reports grants and personal fees from Gilead, grants and personal fees from Merck, grants and personal fees from Janssen, personal fees from Theratech, personal fees from Medicure, grants from Regeneron and grants and personal fees from ViiV, all outside of the submitted work. S.J. reports consulting and/or advisory roles from Janssen, Celgene, Bristol-Myers Squibb, Takeda, Legend and GlaxoSmithKline.
Del Valle, D.M., Kim-Schulze, S., Huang, H. et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med (2020). https://doi.org/10.1038/s41591-020-1051-9
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