Distinct Cytokine Profiles in Severe COVID-19 and Non-Alcoholic Fatty Liver Disease

Neven Papic, Lara Samadan, Nina Vrsaljko, Leona Radmanic, Karlo Jelicic, Petra Simicic, Petra Svoboda, Snjezana Zidovec Lepej, Adriana Vince, Neven Papic, Lara Samadan, Nina Vrsaljko, Leona Radmanic, Karlo Jelicic, Petra Simicic, Petra Svoboda, Snjezana Zidovec Lepej, Adriana Vince

Abstract

Non-alcoholic fatty liver disease (NAFLD) is identified as a risk factor for developing severe COVID-19. While NAFLD is associated with chronic low-grade inflammation, mechanisms leading to immune system hyperactivation remain unclear. The aim of this prospective observational study is to analyze cytokine profiles in patients with severe COVID-19 and NAFLD. A total of 94 patients with severe COVID-19 were included. Upon admission, clinical and laboratory data were collected, a liver ultrasound was performed to determine the presence of steatosis, and subsequently, 51 were diagnosed with NAFLD according to the current guidelines. There were no differences in age, sex, comorbidities, and baseline disease severity between the groups. Serum cytokine concentrations were analyzed using a multiplex bead-based assay by flow cytometry. Upon admission, the NAFLD group had higher C-reactive protein, procalcitonin, alanine aminotransferase, lactate dehydrogenase, and fibrinogen. Interleukins-6, -8, and -10 and CXCL10 were significantly higher, while IFN-γ was lower in NAFLD patients. Patients with NAFLD who progressed to critical illness had higher concentrations of IL-6, -8, -10, and IFN-β, and IL-8 and IL-10 appear to be effective prognostic biomarkers associated with time to recovery. In conclusion, NAFLD is associated with distinct cytokine profiles in COVID-19, possibly associated with disease severity and adverse outcomes.

Keywords: COVID-19; MAFLD; NAFLD; SARS-CoV2; cytokines; inflammation; interferons; interleukin-6; interleukin-8; obesity.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Serum concentrations of selected cytokines in patients with COVID-19, with or without NAFLD. Data are presented as mean with 95% confidence intervals and analyzed by the Mann–Whitney U test.
Figure 2
Figure 2
Serum concentrations of selected cytokines in patients with COVID-19 and NAFLD, with or without obesity. Data are presented as mean with 95% confidence intervals and the significance between the two groups was analyzed by the Mann–Whitney U test.
Figure 3
Figure 3
Panel (A)—Serum concentrations of cytokines with NAFLD and severe and critical illness. Data are presented as mean with 95% confidence intervals and analyzed by Mann–Whitney U test. Panel (B)—ROC curve analysis of IL-6, IL-8, IL-10, CRP, and LDH with corresponding AUC.
Figure 4
Figure 4
Association of time to recovery with IL-8 (panel (A)) and IL-10 (panel (B)). Kaplan–Meier curves on “time to recovery” in patients with NAFLD and COVID-19 are stratified by IL-6 and IL-8. Hazard ratios with 95% confidence intervals and p-values were calculated by the log-rank test.
Figure 5
Figure 5
Spearman’s correlation correlogram. The strength of the correlation between two variables is represented by the color at the intersection of those variables. Colors range from dark blue (strong negative correlation; r = −1.0) to red (strong positive correlation; r = 1.0). Results were not represented if p > 0.05.

References

    1. Mather M.W., Jardine L., Talks B., Gardner L., Haniffa M. Complexity of immune responses in COVID-19. Semin. Immunol. 2021;55:101545. doi: 10.1016/j.smim.2021.101545.
    1. Ragab D., Salah Eldin H., Taeimah M., Khattab R., Salem R. The COVID-19 Cytokine Storm; What We Know So Far. Front. Immunol. 2020;11:1446. doi: 10.3389/fimmu.2020.01446.
    1. Sahin T.T., Akbulut S., Yilmaz S. COVID-19 pandemic: Its impact on liver disease and liver transplantation. World J. Gastroenterol. 2020;26:2987–2999. doi: 10.3748/wjg.v26.i22.2987.
    1. European Association for the Study of the Liver. European Association for the Study of Diabetes. European Association for the Study of Obesity EASL-EASD-EASO Clinical Practice Guidelines for the management of the non-alcoholic fatty liver disease. J. Hepatol. 2016;64:1388–1402. doi: 10.1016/j.jhep.2015.11.004.
    1. Hegyi P.J., Vancsa S., Ocskay K., Dembrovszky F., Kiss S., Farkas N., Eross B., Szakacs Z., Hegyi P., Par G. Metabolic Associated Fatty Liver Disease Is Associated with an Increased Risk of Severe COVID-19: A Systematic Review with Meta-Analysis. Front. Med. 2021;8:626425. doi: 10.3389/fmed.2021.626425.
    1. Chalasani N., Younossi Z., Lavine J.E., Charlton M., Cusi K., Rinella M., Harrison S.A., Brunt E.M., Sanyal A.J. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67:328–357. doi: 10.1002/hep.29367.
    1. Mahamid M., Nseir W., Khoury T., Mahamid B., Nubania A., Sub-Laban K., Schifter J., Mari A., Sbeit W., Goldin E. Nonalcoholic fatty liver disease is associated with COVID-19 severity independently of metabolic syndrome: A retrospective case-control study. Eur. J. Gastroenterol. Hepatol. 2021;33:1578–1581. doi: 10.1097/MEG.0000000000001902.
    1. Pan L., Huang P., Xie X., Xu J., Guo D., Jiang Y. Metabolic associated fatty liver disease increases the severity of COVID-19: A meta-analysis. Dig. Liver Dis. 2021;53:153–157. doi: 10.1016/j.dld.2020.09.007.
    1. Roca-Fernandez A., Dennis A., Nicholls R., McGonigle J., Kelly M., Banerjee R., Banerjee A., Sanyal A.J. Hepatic Steatosis, Rather Than Underlying Obesity, Increases the Risk of Infection and Hospitalization for COVID-19. Front. Med. 2021;8:636637. doi: 10.3389/fmed.2021.636637.
    1. Vrsaljko N., Samadan L., Viskovic K., Mehmedovic A., Budimir J., Vince A., Papic N. Association of Nonalcoholic Fatty Liver Disease With COVID-19 Severity and Pulmonary Thrombosis: CovidFAT, a Prospective, Observational Cohort Study. Open Forum Infect. Dis. 2022;9:ofac073. doi: 10.1093/ofid/ofac073.
    1. Dongiovanni P., Meroni M., Longo M., Fracanzani A.L. MAFLD in COVID-19 patients: An insidious enemy. Expert Rev. Gastroenterol. Hepatol. 2020;14:867–872. doi: 10.1080/17474124.2020.1801417.
    1. Byrne C.D., Targher G. NAFLD: A multisystem disease. J. Hepatol. 2015;62:S47–S64. doi: 10.1016/j.jhep.2014.12.012.
    1. Foroughi M., Maghsoudi Z., Khayyatzadeh S., Ghiasvand R., Askari G., Iraj B. Relationship between non-alcoholic fatty liver disease and inflammation in patients with non-alcoholic fatty liver. Adv. Biomed. Res. 2016;5:28. doi: 10.4103/2277-9175.176368.
    1. Coomes E.A., Haghbayan H. Interleukin-6 in COVID-19: A systematic review and meta-analysis. Rev. Med. Virol. 2020;30:1–9. doi: 10.1002/rmv.2141.
    1. Gao F., Zheng K.I., Yan H.D., Sun Q.F., Pan K.H., Wang T.Y., Chen Y.P., Targher G., Byrne C.D., George J., et al. Association and Interaction between Serum Interleukin-6 Levels and Metabolic Dysfunction-Associated Fatty Liver Disease in Patients with Severe Coronavirus Disease 2019. Front. Endocrinol. 2021;12:604100. doi: 10.3389/fendo.2021.604100.
    1. ECDC Data on SARS-CoV-2 Variants in the EU/EEA. [(accessed on 1 April 2022)]. Available online: .
    1. Twohig K.A., Nyberg T., Zaidi A., Thelwall S., Sinnathamby M.A., Aliabadi S., Seaman S.R., Harris R.J., Hope R., Lopez-Bernal J., et al. Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: A cohort study. Lancet Infect. Dis. 2022;22:35–42. doi: 10.1016/S1473-3099(21)00475-8.
    1. Siegelman E.S., Rosen M.A. Imaging of hepatic steatosis. Semin. Liver Dis. 2001;21:71–80. doi: 10.1055/s-2001-12930.
    1. Halim C., Mirza A.F., Sari M.I. The Association between TNF-alpha, IL-6, and Vitamin D Levels and COVID-19 Severity and Mortality: A Systematic Review and Meta-Analysis. Pathogens. 2022;11:195. doi: 10.3390/pathogens11020195.
    1. Oruc N., Ozutemiz O., Yuce G., Akarca U.S., Ersoz G., Gunsar F., Batur Y. Serum procalcitonin and CRP levels in non-alcoholic fatty liver disease: A case-control study. BMC Gastroenterol. 2009;9:16. doi: 10.1186/1471-230X-9-16.
    1. Han M.S., White A., Perry R.J., Camporez J.P., Hidalgo J., Shulman G.I., Davis R.J. Regulation of adipose tissue inflammation by interleukin 6. Proc. Natl. Acad. Sci. USA. 2020;117:2751–2760. doi: 10.1073/pnas.1920004117.
    1. Nagant C., Ponthieux F., Smet J., Dauby N., Doyen V., Besse-Hammer T., De Bels D., Maillart E., Corazza F. A score combining early detection of cytokines accurately predicts COVID-19 severity and intensive care unit transfer. Int. J. Infect. Dis. 2020;101:342–345. doi: 10.1016/j.ijid.2020.10.003.
    1. Liu Q.P., Zhou D.X., Lin P., Gao X.L., Pan L., Jin F.G. Participation of autophagy in acute lung injury induced by seawater. Exp. Lung Res. 2013;39:441–452. doi: 10.3109/01902148.2013.845626.
    1. Lauszus J.S., Eriksen P.L., Hansen M.M., Eriksen L.L., Shawcross D.L., Vilstrup H., Thomsen K.L., Stoy S. Activation and Functional Priming of Blood Neutrophils in Non-Alcoholic Fatty Liver Disease Increases in Non-Alcoholic Steatohepatitis. Clin. Exp. Gastroenterol. 2021;14:441–449. doi: 10.2147/CEG.S329424.
    1. Peng Y., Li Y., He Y., Wei Q., Xie Q., Zhang L., Xia Y., Zhou X., Zhang L., Feng X., et al. The role of neutrophil to lymphocyte ratio for the assessment of liver fibrosis and cirrhosis: A systematic review. Expert Rev. Gastroenterol. Hepatol. 2018;12:503–513. doi: 10.1080/17474124.2018.1463158.
    1. Li X., Liu C., Mao Z., Xiao M., Wang L., Qi S., Zhou F. Predictive values of neutrophil-to-lymphocyte ratio on disease severity and mortality in COVID-19 patients: A systematic review and meta-analysis. Crit. Care. 2020;24:647. doi: 10.1186/s13054-020-03374-8.
    1. du Plessis J., Korf H., van Pelt J., Windmolders P., Vander Elst I., Verrijken A., Hubens G., Van Gaal L., Cassiman D., Nevens F., et al. Pro-Inflammatory Cytokines but Not Endotoxin-Related Parameters Associate with Disease Severity in Patients with NAFLD. PLoS ONE. 2016;11:e0166048. doi: 10.1371/journal.pone.0166048.
    1. Gao J., Wu L., Wang S., Chen X. Role of Chemokine (C-X-C Motif) Ligand 10 (CXCL10) in Renal Diseases. Mediat. Inflamm. 2020;2020:6194864. doi: 10.1155/2020/6194864.
    1. Van Herck M.A., Weyler J., Kwanten W.J., Dirinck E.L., De Winter B.Y., Francque S.M., Vonghia L. The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity. Front. Immunol. 2019;10:82. doi: 10.3389/fimmu.2019.00082.
    1. Todorovic-Rakovic N., Whitfield J.R. Between immunomodulation and immunotolerance: The role of IFNgamma in SARS-CoV-2 disease. Cytokine. 2021;146:155637. doi: 10.1016/j.cyto.2021.155637.
    1. Hu Z.J., Xu J., Yin J.M., Li L., Hou W., Zhang L.L., Zhou Z., Yu Y.Z., Li H.J., Feng Y.M., et al. Lower Circulating Interferon-Gamma Is a Risk Factor for Lung Fibrosis in COVID-19 Patients. Front. Immunol. 2020;11:585647. doi: 10.3389/fimmu.2020.585647.
    1. Gudowska-Sawczuk M., Mroczko B. What Is Currently Known about the Role of CXCL10 in SARS-CoV-2 Infection? Int. J. Mol. Sci. 2022;23:3673. doi: 10.3390/ijms23073673.
    1. Sakamoto Y., Yoshio S., Doi H., Mori T., Matsuda M., Kawai H., Shimagaki T., Yoshikawa S., Aoki Y., Osawa Y., et al. Increased Frequency of Dysfunctional Siglec-7(-)CD57(+)PD-1(+) Natural Killer Cells in Patients with Non-alcoholic Fatty Liver Disease. Front. Immunol. 2021;12:603133. doi: 10.3389/fimmu.2021.603133.
    1. Wen W., Wu P., Zhang Y., Chen Z., Sun J., Chen H. Comprehensive Analysis of NAFLD and the Therapeutic Target Identified. Front. Cell Dev. Biol. 2021;9:704704. doi: 10.3389/fcell.2021.704704.
    1. Duan X., Lv J., Jiang H., Zheng K., Chen Y. Inflammatory Cytokines, Adipocytokines, and Th17/Treg Balance in Patients with Nonalcoholic Fatty Liver Disease following Administration of Dahuang Zhechong Pills. Genet. Res. 2022;2022:8560831. doi: 10.1155/2022/8560831.
    1. Fontes-Cal T.C.M., Mattos R.T., Medeiros N.I., Pinto B.F., Belchior-Bezerra M., Roque-Souza B., Dutra W.O., Ferrari T.C.A., Vidigal P.V.T., Faria L.C., et al. Crosstalk Between Plasma Cytokines, Inflammation, and Liver Damage as a New Strategy to Monitoring NAFLD Progression. Front. Immunol. 2021;12:708959. doi: 10.3389/fimmu.2021.708959.
    1. Han H., Ma Q., Li C., Liu R., Zhao L., Wang W., Zhang P., Liu X., Gao G., Liu F., et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg. Microbes Infect. 2020;9:1123–1130. doi: 10.1080/22221751.2020.1770129.
    1. Islam H., Chamberlain T.C., Mui A.L., Little J.P. Elevated Interleukin-10 Levels in COVID-19: Potentiation of Pro-Inflammatory Responses or Impaired Anti-Inflammatory Action? Front. Immunol. 2021;12:2485. doi: 10.3389/fimmu.2021.677008.
    1. Lu L., Zhang H., Dauphars D.J., He Y.W. A Potential Role of Interleukin 10 in COVID-19 Pathogenesis. Trends Immunol. 2021;42:3–5. doi: 10.1016/j.it.2020.10.012.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다