A linear prognostic score based on the ratio of interleukin-6 to interleukin-10 predicts outcomes in COVID-19

Abstract

Background Prognostic tools are required to guide clinical decision-making in COVID-19. Methods We studied the relationship between the ratio of interleukin (IL)-6 to IL-10 and clinical outcome in 80 patients hospitalized for COVID-19, and created a simple 5-point linear score predictor of clinical outcome, the Dublin-Boston score. Clinical outcome was analysed as a three-level ordinal variable (“Improved”, “Unchanged”, or “Declined”). For both IL-6:IL-10 ratio and IL-6 alone, we associated clinical outcome with a) baseline biomarker levels, b) change in biomarker level from day 0 to day 2, c) change in biomarker from day 0 to day 4, and d) slope of biomarker change throughout the study. The associations between ordinal clinical outcome and each of the different predictors were performed with proportional odds logistic regression. Associations were run both “unadjusted” and adjusted for age and sex. Nested cross-validation was used to identify the model for incorporation into the Dublin-Boston score. Findings The 4-day change in IL-6:IL-10 ratio was chosen to derive the Dublin-Boston score. Each 1 point increase in the score was associated with a 5.6 times increased odds for a more severe outcome (OR 5.62, 95% CI -3.22–9.81, P = 1.2 × 10 −9 ). Both the Dublin-Boston score and the 4-day change in IL-6:IL-10 significantly outperformed IL-6 alone in predicting clinical outcome at day 7. Interpretation The Dublin-Boston score is easily calculated and can be applied to a spectrum of hospitalized COVID-19 patients. More informed prognosis could help determine when to escalate care, institute or remove mechanical ventilation, or drive considerations for therapies. Funding Funding was received from the Elaine Galwey Research Fellowship, American Thoracic Society, National Institutes of Health and the Parker B Francis Research Opportunity Award.

COVID-19 convalescent plasma composition and immunological effects in severe patients

“…CP decreased the IL-6/IL-10 and IL-6/IFN-γ ratios on day 28 post-transfusion. Recent reports have shown that an increase in the IL-6/IL-10 ratio is related to a poor prognosis in COVID-19 [ 59 ]. IL-10 is an immunoregulatory cytokine that can attenuate inflammatory responses through its Th2 activity and by blocking NF-κB, which negatively regulates IL-6 production [ 60 , 61 ].…”

IL-6 and IL-10 as predictors of disease severity in COVID-19 patients: results from meta-analysis and regression

“…Results revealed best prognostic performance for IL-6 (AUC = 0.83), followed by IL-10 (AUC = 0.73) as individual covariates whereas the model with all cytokines showed marginally better performance (AUC 0.86, sensitivity 80.0%, specificity 75.9%). A more recent study with 80 COVID-19 patients established a prognostic score with the slope of IL-6:IL-10 ration over the study period of 7 days predicting decline in condition of patients at an improved classifier performance (AUC > 0.95) than using IL-6 level alone for prognosis [ 88 ]. All of these results support our finding of both IL-6 and IL-10 as prognosticator for severe COVID-19 disease.…”

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

“…Although IL-6 release is an immunodefensive action, inflammatory disorders and cytokine storms are often marked by hyperelevated concentrations of this cytokine ( Narazaki et al., 2017 ; Tanaka et al., 2016 , 2018 ) and can signify terminal states, as in COVID-19 ( McElvaney et al., 2020 ; Mehta et al., 2020 ). Defects in the human IL-6R gene are also linked to elevated IL-6 ( Spencer et al., 2019 ).…”

“…Interleukin-6 (IL-6) is a potent pro-inflammatory cytokine released following immune challenge or tissue injury, where it broadly stimulates innate and adaptive immune reactions ( Kishimoto, 2010 ; Tanaka et al., 2014 ). Overexpression of IL-6 can lead to chronic inflammatory disorders ( Spencer et al., 2019 ; Tanaka et al., 2016 ) and potentially fatal hyperinflammation, such as seen during advanced coronavirus disease 2019 (COVID-19) ( McElvaney et al., 2020 ; Mehta et al., 2020 ). Hyperinflammatory states can be treated by antibody blockade therapies targeting the IL-6 receptor (IL-6R) and its soluble circulating form (sIL-6R) ( Tanaka et al., 2016 , 2018 ), and some early clinical studies have reported successful application to treat COVID-19 ( Biran et al., 2020 ; Somers et al., 2020 ; Xu et al., 2020 ), underscoring the importance of defining the homeostatic factors that regulate immune signaling though IL-6.…”