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. 2020 Oct;146(4):799-807.e9.
doi: 10.1016/j.jaci.2020.07.009. Epub 2020 Jul 22.

IL-6-based mortality risk model for hospitalized patients with COVID-19

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IL-6-based mortality risk model for hospitalized patients with COVID-19

Rocio Laguna-Goya et al. J Allergy Clin Immunol. 2020 Oct.

Abstract

Background: Coronavirus disease 2019 (COVID-19) has rapidly become a global pandemic. Because the severity of the disease is highly variable, predictive models to stratify patients according to their mortality risk are needed.

Objective: Our aim was to develop a model able to predict the risk of fatal outcome in patients with COVID-19 that could be used easily at the time of patients' arrival at the hospital.

Methods: We constructed a prospective cohort with 611 adult patients in whom COVID-19 was diagnosed between March 10 and April 12, 2020, in a tertiary hospital in Madrid, Spain. The analysis included 501 patients who had been discharged or had died by April 20, 2020. The capacity of several biomarkers, measured at the beginning of hospitalization, to predict mortality was assessed individually. Those biomarkers that independently contributed to improve mortality prediction were included in a multivariable risk model.

Results: High IL-6 level, C-reactive protein level, lactate dehydrogenase (LDH) level, ferritin level, d-dimer level, neutrophil count, and neutrophil-to-lymphocyte ratio were all predictive of mortality (area under the curve >0.70), as were low albumin level, lymphocyte count, monocyte count, and ratio of peripheral blood oxygen saturation to fraction of inspired oxygen (SpO2/FiO2). A multivariable mortality risk model including the SpO2/FiO2 ratio, neutrophil-to-lymphocyte ratio, LDH level, IL-6 level, and age was developed and showed high accuracy for the prediction of fatal outcome (area under the curve 0.94). The optimal cutoff reliably classified patients (including patients with no initial respiratory distress) as survivors and nonsurvivors with 0.88 sensitivity and 0.89 specificity.

Conclusion: This mortality risk model allows early risk stratification of hospitalized patients with COVID-19 before the appearance of obvious signs of clinical deterioration, and it can be used as a tool to guide clinical decision making.

Keywords: COVID-19; IL-6; mortality risk; predictive model.

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Figures

Fig 1
Fig 1
Flowchart of patients included in the study.
Fig 2
Fig 2
The mortality risk model accurately classified patients at risk of dying. A, The area under the curve (AUC) of the model was 0.94 (95% CI = 0.89-1.00); the optimal cutoff of 0.07 had a sensitivity of 0.88 and a specificity of 0.89. B, Kaplan-Meier analysis based on Youden index optimal cutoff showed a very different survival rate between the groups with low and high risk of death (P < .0001). Color shades represent the 95% CI. Time is indicated in days. C, The score obtained from the model in nonsurvivors (red) was significantly higher than that in survivors who required intensive care (blue) (P = .0001) and in survivors who did not require intensive care (gray) (P = .0001). Dashed line indicates the optimal cutoff for mortality (0.07).
Fig 3
Fig 3
Comparison of variables for survivors who did not require ICU admission, survivors who required ICU admission, and nonsurvivors. There were significant differences in most of the variables between the patient groups. The ICU survivors (blue) were similar to the nonsurvivors (red) for some variables such as CRP level and neutrophil count. For other variables, however, ICU survivors had values intermediate between those for survivors who did not require ICU admission (gray) and those for nonsurvivors.
Fig 4
Fig 4
The mortality risk model could also be applied to other severity estimates such as ICU requirement and length of hospital stay. A, The model was an acceptable predictor of ICU requirement, with an area under the curve (AUC) of 0.82 (95% CI = 0.74-0.91) and optimal cutoff of 0.03, with 0.77 sensitivity and 0.77 specificity. The risk score was significantly higher for patients who required ICU admission than the score for those who did not (P < .0001). Dashed line represents the optimal cutoff for ICU admission (0.03). B, There was a positive correlation between the model and length of hospital stay by survivors (P < .0001).
Fig E1
Fig E1
Laboratory values and SpO2/FiO2 ratio did not correlate with the time from onset of illness to the measurement. Most variables did not correlate, and for those that did, the impact of days from onset of illness was minimal (very low R2). This implied that the values obtained depended not on the number of days with symptoms until the measurement but rather on the severity of each particular patient.
Fig E2
Fig E2
ROC and Kaplan-Meier analysis of individual variables with an area under the curve (AUC) greater than 0.70 and with a P value less than .05 in univariate logistic regression. Color shades represent the 95% CI. Time is indicated in days.
Fig E2
Fig E2
ROC and Kaplan-Meier analysis of individual variables with an area under the curve (AUC) greater than 0.70 and with a P value less than .05 in univariate logistic regression. Color shades represent the 95% CI. Time is indicated in days.
Fig E3
Fig E3
Determination of the importance of each significant variable in the multivariate logistic regression by random forest analysis. The relative weights of each variable, from highest to lowest, were as follows: SpO2/FiO2 ratio, N/L ratio, LDH level, IL-6 level, and age.
Fig E4
Fig E4
Contribution of the model to prediction of patient mortality in addition to their initial respiratory function assessment. SpO2/FiO2 ratio and mortality score are represented for every deceased patient in the cohort, except for 3 of 36 patients who died (1 indicates no ARDS, and 2 indicates severe ARDS), and no score was available. Of the 11 patients without severe ARDS who died, 8 (73%) had a high mortality score in the beginning of their hospitalization. The lower limit of the color shade corresponds to the model cutoff 0.07.
Fig E5
Fig E5
Correlation plot of all the variables assessed as potential predictive biomarkers of mortality due to COVID-19. Positive correlations appear in blue, and negative correlations appear in red. The size of the circle corresponds to the magnitude of the correlation. The cross indicates no correlation.

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