Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19

Yang Yang, Chenguang Shen, Jinxiu Li, Jing Yuan, Jinli Wei, Fengmin Huang, Fuxiang Wang, Guobao Li, Yanjie Li, Li Xing, Ling Peng, Minghui Yang, Mengli Cao, Haixia Zheng, Weibo Wu, Rongrong Zou, Delin Li, Zhixiang Xu, Haiyan Wang, Mingxia Zhang, Zheng Zhang, George F Gao, Chengyu Jiang, Lei Liu, Yingxia Liu, Yang Yang, Chenguang Shen, Jinxiu Li, Jing Yuan, Jinli Wei, Fengmin Huang, Fuxiang Wang, Guobao Li, Yanjie Li, Li Xing, Ling Peng, Minghui Yang, Mengli Cao, Haixia Zheng, Weibo Wu, Rongrong Zou, Delin Li, Zhixiang Xu, Haiyan Wang, Mingxia Zhang, Zheng Zhang, George F Gao, Chengyu Jiang, Lei Liu, Yingxia Liu

Abstract

Background: The outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 was first reported in Wuhan, December 2019, and continuously poses a serious threat to public health, highlighting the urgent need of identifying biomarkers for disease severity and progression.

Objective: We sought to identify biomarkers for disease severity and progression of COVID-19.

Methods: Forty-eight cytokines in the plasma samples from 50 COVID-19 cases including 11 critically ill, 25 severe, and 14 moderate patients were measured and analyzed in combination with clinical data.

Results: Levels of 14 cytokines were found to be significantly elevated in COVID-19 cases and showed different expression profiles in patients with different disease severity. Moreover, expression levels of IFN-γ-induced protein 10, monocyte chemotactic protein-3, hepatocyte growth factor, monokine-induced gamma IFN, and macrophage inflammatory protein 1 alpha, which were shown to be highly associated with disease severity during disease progression, were remarkably higher in critically ill patients, followed by severe and then the moderate patients. Serial detection of the 5 cytokines in 16 cases showed that continuously high levels were associated with deteriorated progression of disease and fatal outcome. Furthermore, IFN-γ-induced protein 10 and monocyte chemotactic protein-3 were excellent predictors for the progression of COVID-19, and the combination of the 2 cytokines showed the biggest area under the curve of the receiver-operating characteristics calculations with a value of 0.99.

Conclusions: In this study, we report biomarkers that are highly associated with disease severity and progression of COVID-19. These findings add to our understanding of the immunopathologic mechanisms of severe acute respiratory syndrome coronavirus 2 infection, and provide potential therapeutic targets and strategies.

Keywords: COVID-19; SARS-CoV-2; biomarkers; disease progression; prediction.

Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Figures

Fig 1
Fig 1
Comparison of the significantly elevated cytokines measured at different days after illness onset among critically ill, severe, and moderate COVID-19 patients. The expression levels of 14 cytokines measured at different days after illness onset with differential expression levels among patients with different disease severity were shown and compared among the critically ill, severe, and moderate COVID-19 patients. P values between .01 and .05, .001 and .01, and .0001 and .001 were considered statistically significant (∗), very significant (∗∗), and extremely significant (∗∗∗), respectively. ns, Not significant.
Fig 2
Fig 2
The ROC curve of plasma cytokine levels on admission for patients with and without ARDS during hospitalization. The ROC curve was calculated using SPSS. The AUC of the ROC curve for IL-1ra, IL-6, HGF, MCP-3, M-CSF, and IP-10 was estimated using the expression levels upon admission. A, The ROC curve of each cytokine. B, The ROC curves of different combination of IP-10, MCP-3, and IL-1ra. All the P values were less than .05.
Fig 3
Fig 3
IP-10, MCP-3, HGF, MIG, MIP-1α, and IL-1ra expression levels were highly correlated with Murray score. The expression levels of IL-1β, IL-1ra, IL-6, IL-13, IL-18, HGF, MCP-3, MIG, M-CSF, G-CSF, MIP-1α, MIP-1β, CTACK, and IP-10 measured from plasma samples collected on admission and thereafter and the corresponding Murray scores at the same day were analyzed using Spearman rank correlation analysis, and the results of IP-10, MCP-3, HGF, MIG, MIP-1α, and IL-1ra, which showed high association, were shown.
Fig 4
Fig 4
Dynamic changes of the IP-10, MCP-3, HGF, MIG, MIP-1α, and IL-1ra in 16 patients with COVID-19. The expression levels measured at the indicated time points of 8 critically ill (cases 1-8), 5 severe (cases 9-13), and 3 moderate patients (cases 14-16) were shown. The fatal cases (cases 1 and 2) were marked in red. Cases in critical condition at present (cases 3-6) were marked in blue, and the other patients were discharged from hospital.
Fig E1
Fig E1
Comparison of plasma cytokine concentrations between healthy volunteers and COVID-19 cases. Plasma samples from critically ill (N = 11), severe (N = 25), and moderate (N = 14) COVID-19 patients were collected at the earliest possible time point after hospitalization for assays measuring the concentrations of 48 cytokines. Eight healthy subjects were involved as control. Values were graphed on a logarithmic scale and presented in units of pg/mL. P values between .01 and .05, .001 and .01, and .0001 and .001 were considered statistically significant (∗), very significant (∗∗), and extremely significant (∗∗∗), respectively, whereas ns represents not significant.
Fig E2
Fig E2
Comparison of the significantly elevated cytokines measured at different days after illness onset among critically ill, severe, and moderate COVID-19 patients. The expression levels of 17 cytokines measured at different days after illness onset without differential expression levels among patients with different disease severity were shown and compared among the critically ill, severe, and moderate COVID-19 patients. P values between .01 and .05, .001 and .01, and .0001 and .001 were considered statistically significant (∗), very significant (∗∗), and extremely significant (∗∗∗), respectively. ns, Not significant.
Fig E3
Fig E3
The ROC curve of MIG, IL-13, MIP-1α, IL-1β, CTACK, G-CSF, IL-18, and MIP-1β expression levels upon admission for patients with and without ARDS during hospitalization. All the P values were above .05. CTACK, Cutaneous T-cell–attracting chemokine.

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