Aslı GÖREK DİLEKTAŞLI, Ezgi DEMİRDÖĞEN, Mehmet KARADAĞ, Ayşe Esra UZASLAN, Ahmet URSAVAŞ, Dane EDİGER, Haluk Barbaros ORAL, Nilüfer Aylin ACET ÖZTÜRK, Necmiye Funda COŞKUN, Diğdem YÖYEN ERMİŞ, Mert KARACA, Shahriyar MAHARRAMOV, Gamze YAZICI

Interleukin-21: a potential biomarker for diagnosis and predicting prognosis in COVID-19 patients

Background/aim: COVID-19 patients have a wide spectrum of disease severity. Several biomarkers were evaluated as predictors for progression towards severe disease. IL-21 is a member of common γ-chain cytokine family and creates some specific effects during programming and maintenance of antiviral immunity. We aimed to assess IL-21 as a biomarker for diagnosis and outcome prediction in patients hospitalized with COVID-19. Materials and methods: Patients with a preliminary diagnosis of COVID-19 and pneumonia other than COVID-19 admitted to a tertiary care hospital were included consecutively in this comparative study. Results: The study population consisted of 51 patients with COVID-19 and 11 patients with non-COVID-19 pneumonia. Serum IL-21 concentration was markedly higher, and serum CRP concentration was significantly lower in COVID-19 patients compared to nonCOVID-19 pneumonia patients. Within COVID-19 patients, 10 patients showed radiological and clinical progression. Patients with clinical worsening had lower lymphocyte count and haemoglobin. In addition to that, deteriorating patients had higher urea, LDH levels, and elevated concentration of both IL-6 and IL-21. The cut-off value of 106 ng/L for IL-21 has 80.0% sensitivity, %60.9 specificity for discriminating patients with clinical worsening. Multivariable analysis performed to define risk factors for disease progression identified IL-6 and IL-21 as independent predictors. Odds ratio for serum IL-6 concentrations ≥ 3.2 pg/mL was 8.07 (95% CI: 1.37- 47.50, p = 0.04) and odds ratio for serum IL-21 concentrations ≥ 106 ng/L was 6.24 (95% CI: 1.04 – 37.3, p = 0.02). Conclusion: We identified specific differences in serum IL-21 between COVID-19 and non-COVID-19 pneumonia patients. Serum IL-21 measurement has promising predictive value for disease progression in COVID-19 patients. High serum IL-6 and IL-21 levels obtained upon admission are independent risk factors for clinical worsening.Key words: COVID-19, interleukin 21, prognosis

PDF

___

1. Long QX, Tang XJ, Shi QL, Li Q, Deng HJ et al. Clinical and immunological assessment of asymptomatic SARSCoV-2 infections. Nature Medicine 2020; 26 (8): 1200-1204. doi:10.1038/s41591-020-0965-6
2. Wu YC, Chen CS, Chan YJ. The outbreak of COVID-19: An overview. Journal of the Chinese Medical Association 2020; 83 (3): 217-220. doi:10.1097/JCMA.0000000000000270
3. Wu C, Chen X, Cai Y, Xia J, Zhou X et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Internal Medicine 2020; 180 (7): 934- 943. doi:10.1001/jamainternmed.2020.0994
4. Henry BM, de Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clinical Chemistry and Laboratory Medicine 2020; 58 (7): 1021-1028. doi:10.1515/cclm-2020-0369
5. Chen G, Wu D, Guo W, Cao Y, Huang D et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. Journal of Clinical Investigation 2020; 130 (5): 2620-2629. doi:10.1172/JCI137244
6. Li G, Fan Y, Lai Y, Han T, Li Z et al. Coronavirus infections and immune responses. Journal of Medical Virology 2020; 92 (4): 424-432. doi:10.1002/jmv.25685
7. Fu Y, Cheng Y, Wu Y. Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools. Virologica Sinica 2020; 35 (3): 266-271. doi:10.1007/s12250-020-00207-4
8. Jin Y, Yang H, Ji W, Wu W, Chen S et al. Virology, Epidemiology, Pathogenesis, and Control of COVID-19. Viruses 2020; 12 (4): 372. doi:10.3390/v12040372
9. Rodrigues L, Bonorino C. Role of IL-15 and IL-21 in viral immunity: applications for vaccines and therapies. Expert Review of Vaccines 2009; 8 (2): 167-177. doi:10.1586/14760584.8.2.167
10. Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J et al. A critical role for IL-21 in regulating immunoglobulin production. Science 2002; 298 (5598): 1630-1634. doi:10.1126/science.1077002 11. Antalis E, Spathis A, Kottaridi C, Kossyvakis A, Pastellas K et
al. Th17 serum cytokines in relation to laboratory-confirmed respiratory viral infection: A pilot study. Journal of Medical Virology 2019; 91 (6): 963-971. doi:10.1002/jmv.25406
12. Ma SW, Huang X, Li YY, Tang LB, Sun XF et al. High serum IL-21 levels after 12 weeks of antiviral therapy predict HBeAg seroconversion in chronic hepatitis B. Journal of Hepatology 2012; 56 (4): 775-781. doi:10.1016/j.jhep.2011.10.020
13. Chen HM, Liu HL, Yang YC, Cheng XL, Wang YF et al. Serum IL-21 levels associated with chronic hepatitis B and hepatitis B-related liver failure. Experimental and Therapeutic Medicine 2014; 7 (4): 1013-1019. doi:10.3892/etm.2014.1533
14. Chen H, Liu H, Wang Y, Yang Y, Zhao Y. Elevated serum IL21 levels in hantavirus-infected patients correlate with the severity of the disease. Inflammation 2014; 37 (4): 1078-1083. doi:10.1007/s10753-014-9831-3
15. Ministery of Health COVID-19 Treatment Guideline for Adult Patients. https://covid19.saglik.gov.tr/Eklenti/38355/0/ covid19rehberieriskinhastatedavisipdf.pdf
16. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clinical Infectious Diseases 2007; 44 Suppl 2: S27-S72. doi:10.1086/511159
17. Ai T, Yang Z, Hou H, Zhan C, Chen C et al. Correlation of Chest CT and RT-PCR Testing for Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology 2020; 296 (2): E32-E40. doi:10.1148/radiol.2020200642
18. Fang Y, Zhang H, Xie J, Lin M, Ying L, Pang P, Ji W. Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR. Radiology 2020; 296 (2): E115-E117. doi:10.1148/radiol.2020200432
19. Simpson S, Kay FU, Abbara S, Bhalla S, Chung JH et al. Radiological Society of North America Expert Consensus Statement on Reporting Chest CT Findings Related to COVID-19. Endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA - Secondary Publication. Journal of Thoracic Imaging 2020; 35 (4): 219-227. doi:10.1097/RTI.0000000000000524
20. Byrne D, O’Neill SB, Müller NL, Müller CIS, Walsh JP et al. RSNA Expert Consensus Statement on Reporting Chest CT Findings Related to COVID-19: Interobserver Agreement Between Chest Radiologists. Canadian Association of Radiologists Journal 2020; 846537120938328. doi:10.1177/0846537120938328
21. Xu Z, Shi L, Wang Y, Zhang J, Huang L et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respiratory Medicine 2020; 8 (4): 420-422.
22. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19. Journal of Infection 2020; 80 (6): 607-613. doi:10.1016/j.jinf.2020.03.037
23. Maddur MS, Vani J, Hegde P, Lacroix-Desmazes S, Kaveri SV, Bayry J. Inhibition of differentiation, amplification, and function of human TH17 cells by intravenous immunoglobulin. The Journal of Allergy and Clinical Immunology 2011; 127 (3): 823-30.e1-7. doi: 10.1016/j.jaci.2010.12.1102
24. Avery DT, Deenick EK, Ma CS, Suryani S, Simpson N, et al. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. Journal of Experimental Medicine 2010; 207 (1): 155- 71. doi: 10.1084/jem.20091706
25. Bryant VL, Ma CS, Avery DT, Li Y, Good KL, et al. Cytokinemediated regulation of human B cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5+ T follicular helper cells. Journal of Immunology 2007; 179 (12): 8180-90. doi: 10.4049/jimmunol.179.12.8180
26. Xie A, Buras ED, Xia J, Chen W. The Emerging Role of Interleukin-21 in Transplantation. Journal of Clinical and Cellular Immunology 2012; Suppl 9 (2): 1-7. doi: 10.4172/2155- 9899.S9-002
27. Burgmeijer EH, Duijkers R, Lutter R, Bonten MJM, Schweitzer VA, Boersma WG. Plasma cytokine profile on admission related to aetiology in community-acquired pneumonia. Clinical Respiratory Journal 2019; 13 (10): 605-613. doi:10.1111/ crj.13062
28. Lieberman D, Livnat S, Schlaeffer F, Porath A, Horowitz S, Levy R. IL-1beta and IL-6 in community-acquired pneumonia: bacteremic pneumococcal pneumonia versus Mycoplasma pneumoniae pneumonia. Infection 1997; 25 (2): 90-94. doi:10.1007/BF02113582
29. Endeman H, Meijvis SC, Rijkers GT, van Velzen-Blad H, van Moorsel CH et al. Systemic cytokine response in patients with community-acquired pneumonia. European Respiratory Journal 2011; 37 (6): 1431-1438. doi:10.1183/09031936.00074410
30. Azkur AK, Akdis M, Azkur D, Sokolowska M, van de Veen W et al. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy 2020; 75 (7): 1564-1581. doi:10.1111/all.14364
31. Coomes EA, Haghbayan H. Interleukin-6 in Covid-19: A systematic review and meta-analysis. Reviews in Medical Virology 2020; 30 (6): 1-9. doi: 10.1002/rmv.2141
32. Ferreira-Gomes M, Kruglov A, Durek P, Heinrich F, Tizian C, et al. SARS-CoV-2 in severe COVID-19 induces a TGFβ-dominated chronic immune response that does not target itself. Nature Communications 2021; 12 (1): 1961. doi: 10.1038/ s41467-021-22210-3
33. Kandikattu HK, Venkateshaiah SU, Kumar S, Mishra A. IL-15 immunotherapy is a viable strategy for COVID-19. Cytokine & Growth Factor Reviews 2020; 54: 24-31. doi: 10.1016/j. cytogfr.2020.06.008
34. Wilz SW. A clinical trial of IL-15 and IL-21 combination therapy for COVID-19 is warranted. Cytokine & Growth Factor Reviews 2021; 58: 49-50. doi: 10.1016/j.cytogfr.2020.10.005
35. Almansa R, Anton A, Ramirez P, Martin-Loeches I, Banner D et al. Direct association between pharyngeal viral secretion and host cytokine response in severe pandemic influenza. BMC Infectious Diseases 2011; 11: 232. doi:10.1186/1471-2334-11- 232
36. Lee N, Wong CK, Chan PK, Chan MC, Wong RY et al. Cytokine response patterns in severe pandemic 2009 H1N1 and seasonal influenza among hospitalized adults. PLoS One. 2011; 6 (10) :e26050. doi:10.1371/journal.pone.0026050
37. Arevalo-Rodriguez I, Buitrago-Garcia D, Simancas-Racines D, Zambrano-Achig P, Del Campo R, et al. False-negative results of initial RT-PCR assays for COVID-19: A systematic review. PLoS One. 2020; 15 (12): e0242958. doi: 10.1371/journal. pone.0242958
38. Kucirka LM, Lauer SA, Laeyendecker O, Boon D, Lessler J. Variation in False-Negative Rate of Reverse Transcriptase Polymerase Chain Reaction-Based SARS-CoV-2 Tests by Time Since Exposure. Annals of Internal Medicine 2020; 173 (4): 262-267. doi: 10.7326/M20-1495
39. Wikramaratna PS, Paton RS, Ghafari M, Lourenço J. Estimating the false-negative test probability of SARS-CoV-2 by RT-PCR. Eurosurveillance 2020; 25 (50): 2000568. doi: 10.2807/1560- 7917.ES.2020.25.50.2000568