Interleukin-8 as a Biomarker for Disease Prognosis of Coronavirus Disease-2019 Patients

Lili Li, Jie Li, Meiling Gao, Huimin Fan, Yanan Wang, Xin Xu, Chunfeng Chen, Junxiao Liu, Jocelyn Kim, Roghiyh Aliyari, Jicai Zhang, Yujie Jin, Xiaorong Li, Feng Ma, Minxin Shi, Genhong Cheng, Heng Yang, Lili Li, Jie Li, Meiling Gao, Huimin Fan, Yanan Wang, Xin Xu, Chunfeng Chen, Junxiao Liu, Jocelyn Kim, Roghiyh Aliyari, Jicai Zhang, Yujie Jin, Xiaorong Li, Feng Ma, Minxin Shi, Genhong Cheng, Heng Yang

Abstract

The widespread prevalence of coronavirus disease-2019 (COVID-19) which is caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has resulted in a severe global public health emergency. However, there are no sensitive biomarkers to predict the disease prognosis of COVID-19 patients. Here, we have identified interleukin-8 (IL-8) as a biomarker candidate to predict different disease severity and prognosis of COVID-19 patients. While serum IL-6 become obviously elevated in severe COVID-19 patients, serum IL-8 was easily detectible in COVID-19 patients with mild syndromes. Furthermore, lL-8 levels correlated better than IL-6 levels with the overall clinical disease scores at different stages of the same COVID-19 patients. Thus, our studies suggest that IL-6 and IL-8 can be respectively used as biomarkers for severe COVID-19 patients and for COVID-19 disease prognosis.

Keywords: biomarker; coronavirus disease-2019 prognosis; cytokine serum profile; cytokine storm; interleukin-6; interleukin-8; respiratory syndrome coronavirus 2.

Conflict of interest statement

Authors YW and CC were employed by the company Suzhou Func Biotech Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Li, Li, Gao, Fan, Wang, Xu, Chen, Liu, Kim, Aliyari, Zhang, Jin, Li, Ma, Shi, Cheng and Yang.

Figures

Figure 1
Figure 1
Multiple cytokine profile from different clinical outcomes of SARS-CoV-2 infected patients. (A) Clinical outcomes and nucleic acid test results of four SARS-CoV-2 infected patients. The patients were divided into two groups by clinical outcomes: severe and recovered. Patient 4# died in the hospital. (B) Heatmap of cytokines in sera from COVID-19 patients during different clinical stages. Because of the death, we did not get recovered serum from patient 4#. We then added normal serum as a control. Cytokine levels were detected using Quantibody® Human Inflammation Array-3.
Figure 2
Figure 2
Cytokine levels in COVID-19 severe and recovered patients’ sera. Cytokine levels of IL-6 (A), IL-8 (B), BLC (C), MIG (D), MIP-1b (E), Eotaxin-1 (F), TNF RI (G), and MCP-1(H) in COVID-19 severe and recovered patients’ sera. Every column represents one serum sample of COVID-19 patients.
Figure 3
Figure 3
IL-8 performed better in distinguishing COVID-19 patients from healthy people. (A, B) Scatter plot of IL-6 (A) and IL-8 (B) levels detected by ELISA in healthy and COVID-19 patients’ sera. (C, D) The detectability performance of IL-6 (C) and IL-8 (D) in COVID-19 patients was estimated using ROC curve analysis and compared with the AUC. ELISA data (A, B) are shown as Mean±SEM, ****p<0.0001, unpaired Student t test.
Figure 4
Figure 4
While IL-6 represents for COVID-19 patients with severe disease conditions, IL-8 is a better indicator of overall COVID-19 diseases. (A) Heatmap of IL-6 and IL-8 levels from COVID-19 patients during different clinical stages. (B, C) The IL-6 (B) and IL-8 (C) levels among different COVID-19 patient groups. (D) Distribution of IL-6 and IL-8 levels among different COVID-19 patient groups. Dashed lines indicate the lower limit of detection for the ELISA. ELISA data (B, C) are shown as Mean±SEM, *p<0.05, ****p<0.0001, unpaired Student t test.
Figure 5
Figure 5
IL-8 may serve as a biomarker to indicate the COVID-19 disease prognosis. (A–E) IL-6 and IL-8 levels were compared with different patients’ clinical scores at multiple time points. Left Y-axis displays the concentration of cytokines: IL-6 in orange and IL-8 in green. Right Y-axis displays the clinical scores depicted in blue. X-axis displays the day numbers of COVID-19 diagnosis from the first positive PCR test.

References

    1. Matheson NJ, Lehner PJ. How does SARS-CoV-2 cause COVID-19? Science (2020) 369(6503):510–1. 10.1126/science.abc6156
    1. Song F, Shi N, Shan F, Zhang Z, Shen J, Lu H, et al. Emerging 2019 Novel Coronavirus (2019-nCoV) Pneumonia. Radiology (2020) 295:210–7. 10.1148/radiol.2020200274
    1. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature (2020) 579(7798):270–3. 10.1038/s41586-020-2012-7
    1. Sheahan TP, Frieman MB. The continued epidemic threat of SARS-CoV-2 and implications for the future of global public health. Curr Opin Virol (2020) 40:37–40. 10.1016/j.coviro.2020.05.010
    1. Meo SA, Alhowikan AM, Al-Khlaiwi T, Meo IM, Halepoto DM, Iqbal M, et al. Novel coronavirus 2019-nCoV: prevalence, biological and clinical characteristics comparison with SARS-CoV and MERS-CoV. Eur Rev Med Pharmacol Sci (2020) 24:2012–9. 10.26355/eurrev_202002_20379
    1. The L. Emerging understandings of 2019-nCoV. Lancet (2020) 395(10221):311. 10.1016/S0140-6736(20)30186-0
    1. Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci (2020) 63(3):457–60. 10.1007/s11427-020-1637-5
    1. Li X, Wang W, Zhao X, Zai J, Zhao Q, Li Y, et al. Transmission dynamics and evolutionary history of 2019-nCoV. J Med Virol (2020) 92(5):501–11. 10.1002/jmv.25701
    1. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med (2012) 367(19):1814–20. 10.1056/NEJMoa1211721
    1. Drosten C, Gunther S, Preiser W, van der Werf S, Brodt HR, Becker S, et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med (2003) 348(20):1967–76. 10.1056/NEJMoa030747
    1. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA (2020) 323:1239–42. 10.1001/jama.2020.2648
    1. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet (2020) 395:507–13. 10.1016/S0140-6736(20)30211-7
    1. Ravi N, Cortade DL, Ng E, Wang SX. Diagnostics for SARS-CoV-2 detection: A comprehensive review of the FDA-EUA COVID-19 testing landscape. Biosens Bioelectron (2020) 165:112454. 10.1016/j.bios.2020.112454
    1. Qiu X, Xiang Y, Sun J, Wang X, Chen G, Xu X, et al. Dynamic changes of throat swabs RNA and serum antibodies for SARS-CoV-2 and their diagnostic performances in patients with COVID-19. Emerg Microbes Infect (2020) 9(1):1974–83. 10.1080/22221751.2020.1810133
    1. Holborow A, Asad H, Porter L, Tidswell P, Johnston C, Blyth I, et al. The clinical sensitivity of a single SARS-CoV-2 upper respiratory tract RT-PCR test for diagnosing COVID-19 using convalescent antibody as a comparator. Clin Med (Lond) (2020) 20:e209–11. 10.7861/clinmed.2020-0555
    1. De Smet K, De Smet D, Ryckaert T, Laridon E, Heremans B, Vandenbulcke R, et al. Diagnostic Performance of Chest CT for SARS-CoV-2 Infection in Individuals with or without COVID-19 Symptoms. Radiology (2020) 202708. 10.1148/radiol.2020202708
    1. Kelleni MT. SARS CoV-2 viral load might not be the right predictor of COVID-19 mortality. J Infect (2020) S0163-4453(20)30552-1. 10.1016/j.jinf.2020.08.018
    1. Hagman K, Hedenstierna M, Gille-Johnson P, Hammas B, Grabbe M, Dillner J, et al. SARS-CoV-2 RNA in serum as predictor of severe outcome in COVID-19: a retrospective cohort study. Clin Infect Dis (2020) ciaa1285 ciaa1285. 10.1093/cid/ciaa1285
    1. Pujadas E, Chaudhry F, McBride R, Richter F, Zhao S, Wajnberg A, et al. SARS-CoV-2 viral load predicts COVID-19 mortality. Lancet Respir Med (2020) 8(9):e70. 10.1016/S2213-2600(20)30354-4
    1. Tan C, Li S, Liang Y, Chen M, Liu J. SARS-CoV-2 viremia may predict rapid deterioration of COVID-19 patients. Braz J Infect Dis (2020) 24(6):565–9. 10.1016/j.bjid.2020.08.010
    1. Fu Y, Cheng Y, Wu Y. Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools. Virol Sin (2020) 35:266–71. 10.1007/s12250-020-00207-4
    1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (2020) 395:497–506. 10.1016/S0140-6736(20)30183-5
    1. Tomasiewicz K, Piekarska A, Stempkowska-Rejek J, Serafinska S, Gawkowska A, Parczewski M. Tocilizumab for patients with severe COVID-19: a retrospective, multi-center study. Expert Rev Anti Infect Ther (2020) 1:1–7. 10.1080/14787210.2020.1800453
    1. Wang J, Jiang M, Chen X, Montaner LJ. Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts. J Leukoc Biol (2020) 108:17–41. 10.1002/JLB.3COVR0520-272R
    1. Gubernatorova EO, Gorshkova EA, Polinova AI, Drutskaya MS. Drutskaya, IL-6: Relevance for immunopathology of SARS-CoV-2. Cytokine Growth Factor Rev (2020) 53:13–24. 10.1016/j.cytogfr.2020.05.009
    1. Weatherhead JE, Clark EH, Vogel TP, Atmar RL, Kulkarni PA. Inflammatory syndromes associated with SARS-CoV-2 infection: dysregulation of the immune response across the age spectrum. J Clin Invest (2020) 130(12):6194–7. 10.1172/JCI145301
    1. Honore PM, Barreto Gutierrez L, Kugener L, Redant S, Attou R, Gallerani A. Inhibiting IL-6 in COVID-19: we are not sure. Crit Care (2020) 24:463. 10.1186/s13054-020-03177-x
    1. Maeda T, Obata R, Rizk DD, Kuno T. The Association of Interleukin-6 value, Interleukin inhibitors and Outcomes of Patients with COVID-19 in New York City. J Med Virol (2020). 10.1002/jmv.26365
    1. Solis-Garcia Del Pozo J, Galindo MF, Nava E, Jordan J. A systematic review on the efficacy and safety of IL-6 modulatory drugs in the treatment of COVID-19 patients. Eur Rev Med Pharmacol Sci (2020) 24:7475–84. 10.26355/eurrev_202007_21916
    1. Amezcua-Guerra LM. Brief annotations on cytokine release syndrome and interleukin-6 therapeutic blockage in SARS-CoV-2/COVID-19. Arch Cardiol Mex (2020) 90(Supl):84–7. 10.24875/ACM.M20000067
    1. Palanques-Pastor T, Lopez-Briz E, Poveda Andres JL. Involvement of interleukin 6 in SARS-CoV-2 infection: siltuximab as a therapeutic option against COVID-19. Eur J Hosp Pharm (2020) 27(5):297–8. 10.1136/ejhpharm-2020-002322
    1. Hou H, Zhang B, Huang H, Luo Y, Wu S, Tang G, et al. Using IL-2R/lymphocytes for predicting the clinical progression of patients with COVID-19. Clin Exp Immunol (2020) 201:76–84. 10.1111/cei.13450
    1. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA (2020) 323(11):1061–9. 10.1001/jama.2020
    1. Chakraborty C, Sharma AR, Sharma G, Bhattacharya M, Lee SS. SARS CoV-2 causing pneumonia-associated respiratory disorder (COVID-19): diagnostic and proposed therapeutic options. Eur Rev Med Pharmacol Sci (2020) 24:4016–26. 10.26355/eurrev_202004_20871
    1. Lupia T, Scabini S, Mornese Pinna S, Di Perri G, De Rosa FG, Corcione S. novel coronavirus (2019-nCoV) outbreak: A new challenge. J Glob Antimicrob Resist (2020) 21:22–7. 10.1016/j.jgar.2020.02.021
    1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. China Novel Coronavirus, T. Research, A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med (2020) 382:727–33. 10.1056/NEJMoa2001017
    1. Corman VM, Landt O, Kaiser M, Molenkamp R, Meijer A, Chu DK, et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill (2020) 25:3. 10.2807/1560-7917.ES.2020.25.3.2000045
    1. Tang EW, Bobenchik AM, Lu S. Testing for SARS-CoV-2 (COVID-19): A General Review. R I Med J (2020) 103(5):20–3. 10.1136/ejhpharm-2020-002322
    1. Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci (2020) 63:364–74. 10.1007/s11427-020-1643-8
    1. Laguna-Goya R, Utrero-Rico A, Talayero P, Lasa-Lazaro M, Ramirez-Fernandez A, Naranjo L, et al. IL-6-based mortality risk model for hospitalized patients with COVID-19. J Allergy Clin Immunol (2020) 20:31027–7. 10.1016/j.jaci.2020.07.009
    1. Luo M, Liu J, Jiang W, Yue S, Liu H, Wei S. IL-6 and CD8+ T cell counts combined are an early predictor of in-hospital mortality of patients with COVID-19. JCI Insight (2020) 5:13.e139024. 10.1172/jci.insight.139024
    1. Lipworth B, Chan R, Lipworth S, RuiWen Kuo C. Weathering the Cytokine Storm in Susceptible Patients with Severe SARS-CoV-2 Infection. J Allergy Clin Immunol Pract (2020) 8:1798–801. 10.1016/j.jaip.2020.04.014
    1. Prete M, Favoino E, Catacchio G, Racanelli V, Perosa F. SARS-CoV-2 Inflammatory Syndrome. Clinical Features and Rationale for Immunological Treatment. Int J Mol Sci (2020) 21(9):3377. 10.3390/ijms21093377
    1. Masia M, Fernandez-Gonzalez M, Padilla S, Ortega P, Garcia JA, Agullo V, et al. Impact of interleukin-6 blockade with tocilizumab on SARS-CoV-2 viral kinetics and antibody responses in patients with COVID-19: A prospective cohort study. EBioMedicine (2020) 60:102999. 10.1016/j.ebiom.2020.102999

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