An inflammatory cytokine signature predicts COVID-19 severity and survival
Open accessPublished version of a preprint
Abstract
Several studies have revealed that the hyper-inflammatory response induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of disease severity and death. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α and IL-1β in hospitalized patients with coronavirus disease 2019 (COVID-19) upon admission to the Mount Sinai Health System in New York. Patients (n = 1,484) were followed up to 41 d after admission (median, 8 d), and clinical information, laboratory test results and patient outcomes were collected. We found that high serum IL-6, IL-8 and TNF-α levels at the time of hospitalization were strong and independent predictors of patient survival (P < 0.0001, P = 0.0205 and P = 0.0140, respectively). Notably, when adjusting for disease severity, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF-α serum levels remained independent and significant predictors of disease severity and death. These findings were validated in a second cohort of patients (n = 231). We propose that serum IL-6 and TNF-α levels should be considered in the management and treatment of patients with COVID-19 to stratify prospective clinical trials, guide resource allocation and inform therapeutic options.
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Certain cytokines such as IL-1β and IL-6 have clearly emerged as key to promoting inflammaging.
“Certain cytokines, such as IL-1β and IL-6, have clearly emerged as key to promoting inflammaging.83,229–232”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [231]
The Results (Association with demographics and comorbidities; page not provided) report that IL-6 levels increased with age in hospitalized COVID-19 patients. The paper also describes IL-1 as pro-inflammatory, but it does not show that IL-1β increases with age or that either cytokine promotes inflammaging. (LLM, conf=0.84)
Experimental — accuracy not yet measuredProinflammatory cytokines and cardiac biomarkers are elevated in men with COVID-19 compared with women, including ferritin, CRP, IL-6, IL-8, and IL-18.
“Proinflammatory cytokines and cardiac biomarkers have been reported to be elevated in men with COVID-19 compared with women including ferritin, CRP (C-reactive protein), IL-6, IL-8, and IL-18. 13,121-123”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [121]
The Results section (“Association with demographics and comorbidities”; page not available) reports significantly higher IL-6 in men with COVID-19, but explicitly says there were no sex differences for the other measured cytokines, including IL-8. The cited passages do not establish higher ferritin, CRP, cardiac biomarkers, or IL-18 in men than in women; IL-18 was not among the cytokines measured. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIL-6 and TNFα serum levels are significant predictors of COVID-19 disease severity and death.
“Notably, IL-6 and TNFα serum levels are known to be significant predictors of disease severity and death (340).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [340]
Men have more neutrophils and monocytes, whereas women have more T cells, similar to autoimmune myocarditis.
“And men have more neutrophils and monocytes, whereas women have more T cells, 13,121-123 similar to autoimmune myocarditis. 124,125”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [121]
The Results section, “Association with demographics and comorbidities” (page unavailable), reports higher IL-6 in men, not higher neutrophil or monocyte counts or lower T-cell counts. Searches for sex-specific neutrophil, monocyte, and T-cell differences found no passage addressing the cited claim. The autoimmune-myocarditis comparison has separate citations and is not assessed here. (LLM, conf=0.76)
Experimental — accuracy not yet measuredHuman recovery from SARS-CoV-2 infection seems to require both antibody and cell-mediated immune responses.
“Recovery following infection with SARS-CoV-2 in humans appears to involve both humoral and cell-mediated immunity22–24.”
From Immunological mechanisms of vaccine-induced protection against COVID-19 in humans (2021) · cites this paper as [23]
In 1,484 COVID-19 patients, TNF, IL-1β, and IL-6 were elevated, and TNF and IL-6 independently predicted disease severity and death.
“four cytokines (IL-6, CXCL8, TNF, and IL-1β) were assessed in serum from 1,484 COVID-19 patients (Del Valle et al., 2020) of which TNF, IL-1β, and IL-6 were elevated in COVID-19 patients, and TNF and IL-6 turned out to be independent predictors of disease severity and fatal outcome.”
From COVID-19 and the human innate immune system (2021) · cites this paper as Del Valle et al., 2020
Higher interleukin-6 levels are strongly associated with shorter survival in Covid-19.
“Higher interleukin-6 levels are strongly associated with shorter survival.91”
From Cytokine storm (2020) · cites this paper as [91]
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- Authors
- Del Valle, D. M., Kim-Schulze, S., Huang, H.-H., Beckmann, N. D., Nirenberg, S., Wang, B., Lavin, Y., Swartz, T. H., Madduri, D., Stock, A., Marron, T. U., Xie, H., Patel, M., Tuballes, K., Van Oekelen, O., Rahman, A., Kovatch, P., Aberg, J. A., Schadt, E., Jagannath, S., Mazumdar, M., Charney, A. W., Firpo-Betancourt, A., Mendu, D. R., Jhang, J., Reich, D., Sigel, K., Cordon-Cardo, C., Feldmann, M., Parekh, S., Merad, M., & Gnjatic, S.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Tisch Cancer Institute (US)
- University of Oxford (GB)
- Corresponding author
- Gnjatic, Sacha
- ORCID
- Huang, Hsin-Hui
- Beckmann, Noam D.
- Nirenberg, Sharon
- Wang, Bo
- Lavin, Yonit
- Swartz, Talia H.
- Madduri, Deepu
- Stock, Aryeh
- Marron, Thomas U.
- Xie, Hui
- Patel, Manishkumar
- Tuballes, Kevin
- Van Oekelen, Oliver
- Rahman, Adeeb
- Kovatch, Patricia
- Aberg, Judith A.
- Schadt, Eric
- Jagannath, Sundar
- Mazumdar, Madhu
- Charney, Alexander W.
- Mendu, Damodara Rao
- Reich, David
- Sigel, Keith
- Cordon-Cardo, Carlos
- Feldmann, Marc
- Parekh, Samir
- Gnjatic, Sacha
- Venue
- Nature Medicine
- Published
- 2020-08-24
- Volume
- 26
- Issue
- 10
- Pages
- 1636-1643
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC7869028
- OpenAlex
- W3080981445
- Cited by
- 2,605
- References
- 29
- Citations by year
- 2026: 169 · 2025: 208 · 2024: 323 · 2023: 452 · 2022: 673 · 2021: 647 · 2020: 125 · 2019: 1 · 2018: 3
- FWCI
- 62.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature Medicine (publishedVersion)
- medRxiv (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- PubMed Central (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (P01 CA190174, U24 CA224319, U01 DK124165, P30 CA196521)
- U.S. Department of Health & Human Services | National Institutes of Health (K08AI120806, R01 CA244899)
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Keywords
- COVID-19 pandemic, SARS-CoV-2, cytokine signature, interleukin-6, TNF-α, interleukin-8, IL-1β, hyperinflammation, disease severity, mortality prediction, prognostic factors, hospitalized patients, multiplex cytokine assay
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