Cytokine patterns of fatal hyperinflammatory conditions, caused by secondary hemophagocytic lymphohistiocytosis, bacterial sepsis and COVID-19

Abstract

Introduction. In severe cases of coronavirus disease 2019 (COVID-19) pulmonary infiltration is accompanied by cytokine storm syndrome (CSS) development. Besides COVID-19, CSS can be triggered by the range of pathologies, which include hemophagocytic lymphohistiocytosis (sHLH) and septic shock (SS).

The aim of this study was to compare immunological profiles in fatal cases of COVID-19, sHLH and SS.

Material and methods. Serum levels of IL-1β, IL-2, IL-6, IL-8, IL-10, IL-17A, IL-18, IFN-γ, TNF-α, procalcitonin, neopterin, ferritin with percent of glycosylated fraction (% GF) were measured in 37 COVID-19 fatal cases, collected during 2020 year prospectively; and in 39 sHLH and 47 SS fatal cases, collected within 2018–2019 years retrospectively. Comparison groups also included 194 non-fatal COVID-19 cases and 20 healthy donors, collected during 2020 year. Cytokine concentrations, procalcitonin and neopterin were measured by enzyme-linked immunosorbent assay; the ferritin level was determined by the turbidimetry method. The percent of glycosylated ferritin fraction (% GF) was calculated by the modified method of M. Worwood et al.

Results. Deceased patients with COVID-19 had higher IL-6, IL-8, IL-10, IL-18, procalcitonin median levels compared to the survived. Meanwhile IL-8, IL-18, IFN-γ, TNFα and ferritin concentrations were significantly lower in deceased COVID-19 patients compared to sHLH and SS. The levels of IL-6 and procalcitonin in fatal COVID-19 were comparable to SS, but significantly higher than in sHLH. Leucocytes were higher in COVID-19 compared to both SS and sHLH.

Conclusion. Each fatal condition was accompanied by specific features of the cytokine profile: high IL-6 combined with low IFN-γ, TNFα in COVID-19; high IL-8, IL-6 with low IL-17A, IL-2 in SS; high IL-18, ferritin, IFN-γ with low IL-6, procalcitonin, % GF in sHLH.

Keywords:COVID-19; hyperinflammation; «cytokine storm syndrome»; secondary hemophagocytic lymphohistiocytosis; septic shock

For citation: Pervakova M.Yu., Potapenko V.G., Tkachenko O.Yu., Volchkova E.V., Titova O.N., Lapin S.V., Surkova E.A., Blinova T.V., Kholopova I.V., Kuznetsova D.A., Moshnikova A.N., Mazing A.V., Kulikov A.N., Polushin Yu.S., Afanasyev A.A., Shlyk I.V., Gavrilova E.G., Klimovich A.V., Medvedeva N.V., Emanuel V.L. Cytokine patterns of fatal hyperinflammatory conditions, caused by secondary hemophagocytic lymphohistiocytosis, bacterial sepsis and COVID-19. Immunologiya. 2022; 43 (2): 174–87. DOI: https://doi.org/10.33029/0206-4952-2022- 43-2-174-187

Funding. The study had no sponsor support.

Conflict of interests. The authors declare no conflict of interests.

Authors contribution. Study conception and design – Pervakova M.Yu., Potapenko V.G., Tkachenko O.Yu., Lapin S.V.; material collection and processing – Kulikov A.N., Afanasyev A.A., Shlyk I.V., Gavrilova E.G., Volchkova E.V., Titova O.N., Klimovich A.V., Medvedeva N.V.; laboratory research – Surkova E.A., Blinova T.V., Kholopova I.V., Kuznetsova D.A., Moshnikova A.N., statistical processing – Pervakova M.Yu.; manuscript preparation – Pervakova M.Yu.; editing – Potapenko V.G., Lapin S.V., Mazing A.V.; project supervising – Polushin Yu.S., Emanuel V.L.

References

1.Tisoncik J.R., Korth M.J., Simmons C.P., Farrar J., Martin T.R., Katze M.G. Into the Eye of the Cytokine Storm. Microbiol Mol Biol Rev. 2012; 76 (1): 16–32. DOI: https://www.doi.org/10.1128/MMBR.05015-11

2.Cron R.Q., Behrens E.M. eds. Cytokine Storm Syndrome. Cham: Springer International Publishing; 2019. DOI: https://www.doi.org/10.1007/978-3-030-22094-5

3.Nazinitsky A., Rosenthal K.S. Cytokine storms: Systemic disasters of infectious diseases. Infect Dis Clin Pract. 2010; 18 (3): 188–92. DOI: https://www.doi.org/10.1097/IPC.0b013e3181d2ee41

4.Canedo-Marroquín G., Saavedra F., Andrade C.A., Berrios R. V., Rodríguez-Guilarte L., Opazo M.C., et al. SARS-CoV-2: Immune Response Elicited by Infection and Development of Vaccines and Treatments. Front Immunol. 2020; 11:3259. DOI: https://www.doi.org/10.3389/fimmu.2020.569760

5.Gudima G.O., Khaitov R.M., Kudlay D.A., Khaitov M.R. Molecular immunological aspects of diagnostics, prevention and treatment of coronavirus infection. Immunologiya. 2021; 42 (3): 198–210. DOI: https://doi.org/10.33029/0206-4952-2021-42-3-198-210 (in Russian)

6.Mehta P., McAuley D.F., Brown M., Sanchez E., Tattersall R.S., Manson J.J. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395 (10229): 1033–4. DOI: https://www.doi.org/10.1016/S0140-6736(20)30628-0

7.Wu D., Yang X.O. TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib. J Microbiol Immunol Infect. 2020; 53 (3): 368–70. DOI: https://www.doi.org/10.1016/j.jmii.2020.03.005

8.Machowicz R., Janka G., Wiktor-Jedrzejczak W. Similar but not the same: Differential diagnosis of HLH and sepsis. Crit Rev Oncol Hematol. 2017; 114: 1–12. DOI: https://www.doi.org/10.1016/j.critrevonc.2017.03.023

9.Beltrán-García J., Osca-Verdegal R., Pallardó F.V., Ferreres J., Rodríguez M., Mulet S., et al. Sepsis and Coronavirus Disease 2019: Common Features and Anti-Inflammatory Therapeutic Approaches. Crit Care Med. 2020; 48 (12): 1841–4. DOI: https://www.doi.org/10.1097/CCM.0000000000004625

10.Shoenfeld Y. Corona (COVID-19) time musings: Our involvement in COVID-19 pathogenesis, diagnosis, treatment and vaccine planning. Autoimmun Rev. 2020; 19 (6): 102538. DOI: https://www.doi.org/10.1016/j.autrev.2020.102538

11.Potapenko V.G., Pervakova M.Y., Lapin S.V., Titov A.K., Surkova E.A., Petrova N.N., et al. The role of fraction analysis of ferritin in diagnostic of secondary hemophagocyte syndrome. Klin Lab Diagn.2018; 63 (1): 21–7. DOI: https://www.doi.org/10.18821/0869-2084-2018-63-1-21-27 (in Russian)

12.Henter J-I., Horne A., Aricó M., Egeler R.M., Filipovich A.H., Imashuku S. et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007; 48 (2): 124–31. DOI: https://www.doi.org/10.1002/pbc.21039

13.Fardet L., Galicier L., Lambotte O., Marzac C., Aumont C., Chahwan D., et al. Development and Validation of the HScore, a Score for the Diagnosis of Reactive Hemophagocytic Syndrome. Arthritis Rheumatol. 2014; 66 (9): 2613–20. DOI: https://www.doi.org/10.1002/art.38690

14.Bone R.C., Balk R.A., Cerra F.B., Dellinger R.P., Fein A.M., Knaus W.A., et al. Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis. Chest. 1992; 101 (6): 1644–55. DOI: https://www.doi.org/10.1378/chest.101.6.1644

15.Worwood M., Cragg S.J., Wagstaff M., Jacobs A. Binding of human serum ferritin to concanavalin A. Clin Sci (Lond). 1979; 56 (1): 83–7. DOI: https://www.doi.org/10.1042/cs0560083

16.Singer M., Deutschman C.S., Seymour C.W., Shankar-Hari M., Annane D., Bauer M., et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315 (8): 801. DOI: https://www.doi.org/10.1001/jama.2016.0287

17. Liang J., Alfano D.N., Squires J.E., Riley M.M., Parks W.T., Kofler J., et al. Novel NLRC4 Mutation Causes a Syndrome of Perinatal Autoinflammation With Hemophagocytic Lymphohistiocytosis, Hepatosplenomegaly, Fetal Thrombotic Vasculopathy, and Congenital Anemia and Ascites. Pediatr Dev Pathol. 2017; 20 (6): 498–505. DOI: https://www.doi.org/10.1177/1093526616686890

18.Chen Z., John Wherry E. T cell responses in patients with COVID-19. Nat Rev Immunol. 2020; 20 (9): 529–36. DOI: https://www.doi.org/10.1038/s41577-020-0402-6

19.Zakurskaya V.Ya., Sizyakina L.P., Kharitonova M.V., Shlyk S.V. Dynamics of specific humoral response in COVID-19 patients. Immunologiya. 2022; 43 (1): 71–7. DOI: https://www.doi.org/10.33029/0206-4952-2022-43-1-71-77 (in Russian)

20.Yang L, Xie X, Tu Z, Fu J, Xu D, Zhou Y. Yang L., Xie X., Tu Z., Fu J., Xu D., Zhou Y. The signal pathways and treatment of cytokine storm in COVID-19. Signal Transduct Target Ther. 2021; 6 (1): 255. DOI: https://www.doi.org/10.1038/s41392-021-00679-0

21. Andreev I.V., Nechay K.O., Andreev A.I., Zubaryova A.P., Esaulova D.R., Alenova A.M., Nikolaeva I.A., Chernyavskaya O.P., Lomonosov K.S., Shulzhenko A.E., Kurbacheva O.M., Latysheva E.A., Shartanova N.V., Nazarova E.V., Romanova L.V., Cherchenko N.G., Smirnov V.V., Averkov O.V., Martynov A.I., Vechorko V.I., Gudima G.O., Kudlay D.A., Khaitov M.R., Khaitov R.M. Post-vaccination and post-infection humoral immune response to the SARS-CoV-2 infection. Immunologiya. 2022; 43 (1): 18–32. DOI: https://www.doi.org/10.33029/0206-4952-2022-43-1-18-32 (in Russian)

22.Vanderheiden A., Ralfs P., Chirkova T., Upadhyay A.A., Zimmerman M.G., Bedoya S., et al. Type I and Type III Interferons Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures. Williams BRG, ed. J Virol. 2020; 94 (19). DOI: https://www.doi.org/10.1128/JVI.00985-20

23. Lotfinejad P., Asadzadeh Z., Najjary S., Somi M.H., Hajiasgharzadeh K., Mokhtarzadeh A. et al. COVID-19 Infection: Concise Review Based on the Immunological Perspective. Immunol Invest. 2022; 51 (2): 246–65. DOI: https://www.doi.org/10.1080/08820139.2020.1825480

24.Le Bert N., Clapham H.E., Tan A.T., Chia W.N., Tham C.Y.L., Lim J.M., et al. Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection. J Exp Med. 2021; 218 (5): e20202617. DOI: https://www.doi.org/10.1084/jem.20202617

25.Chen G., Wu D., Guo W., Cao Y., Huang D., Wang H., et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020; 130 (5): 2620–9. DOI: https://www.doi.org/10.1172/JCI137244

26.Liu J., Li S., Liu J., Liang B., Wang X., Wang H., et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine. 2020; 55: 102763. DOI: https://www.doi.org/10.1016/j.ebiom.2020.102763

27.Garai P., Berry L., Moussouni M., Bleves S., Blanc-Potard A-B. Killing from the inside: Intracellular role of T3SS in the fate of Pseudomonas aeruginosa within macrophages revealed by mgtC and oprF mutants. Mecsas J, editor. PLOS Pathog. 2019; 15 (6): e1007812. DOI: https://www.doi.org/10.1371/journal.ppat.1007812.

28.Jiang L., Greene M.K., Insua J.L., Pessoa J.S., Small D.M., Smyth P., et al. Clearance of intracellular Klebsiella pneumoniae infection using gentamicin-loaded nanoparticles. J Control Release. 2018; 279: 316–25. DOI: https://www.doi.org/10.1016/j.jconrel.2018.04.040

29.Slaats J., ten Oever J., van de Veerdonk F.L., Netea M.G. IL-1β/IL-6/CRP and IL-18/ferritin: Distinct Inflammatory Programs in Infections. Bliska JB, ed. PLOS Pathog. 2016; 12 (12): e1005973. DOI: https://www.doi.org/10.1371/journal.ppat.1005973

30.Biancofiore G., Bindi L., Miccoli M., Metelli M.R., Panicucci E., Baggiani A., et al. Balance of pro- and anti-inflammatory cytokines in cirrhotic patients undergoing liver transplantation. Transpl Immunol. 2013; 28 (4): 193–7. DOI: https://www.doi.org/10.1016/j.trim.2013.04.001

31.Karlsson T. Secondary haemophagocytic lymphohistiocytosis: Experience from the Uppsala University Hospital. Ups J Med Sci. 2015; 120 (4): 257–62. DOI: https://www.doi.org/10.3109/03009734.2015.1064500

32.Gujar S., Pol J.G., Kim Y., Lee P.W., Kroemer G. Antitumor Benefits of Antiviral Immunity: An Underappreciated Aspect of Oncolytic Virotherapies. Trends Immunol. 2018; 39 (3): 209–21. DOI: https://www.doi.org/10.1016/j.it.2017.11.006

33.Yasuda K., Nakanishi K., Tsutsui H. Interleukin-18 in Health and Disease. Int J Mol Sci. 2019; 20 (3): 649. DOI: https://www.doi.org/10.3390/ijms20030649

34.Pourakbari B., Mamishi S., Zafari J., Khairkhah H., Ashtiani M.H., Abedini M., et al. Evaluation of procalcitonin and neopterin level in serum of patients with acute bacterial infection. Braz J Infect Dis. 14 (3): 252–5. DOI: https://www.doi.org/10.1016/S1413-8670(10)70052-0

35.Eisenhut M. Neopterin in Diagnosis and Monitoring of Infectious Diseases. J Biomarkers. 2013; 2013: 1–10. DOI: https://www.doi.org/10.1155/2013/196432

36.Pingle S., Tumane R., Jawade A. Neopterin: Biomarker of cell-mediated immunity and potent usage as biomarker in silicosis and other occupational diseases. Indian J Occup Environ Med. 2008; 12 (3): 107. DOI: https://www.doi.org/10.4103/0019-5278.44690

37.Ríos-Toro J-J., Márquez-Coello M., García-Álvarez J-M., Martín-Aspas A., Rivera-Fernández R., Sáez de Benito A., et al. Soluble membrane receptors, interleukin 6, procalcitonin and C reactive protein as prognostic markers in patients with severe sepsis and septic shock. Lazzeri C., editor. PLoS One. 2017; 12 (4): e0175254. DOI: https://www.doi.org/10.1371/journal.pone.0175254

38.Miossec P., Korn T., Kuchroo V.K. Interleukin-17 and Type 17 Helper T Cells. N Engl J Med. 2009; 361 (9): 888–98. DOI: https://www.doi.org/10.1056/NEJMra0707449

39.Hou W., Kang H.S., Kim B.S. Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection. J Exp Med. 2009; 206 (2): 313–28. DOI: https://www.doi.org/10.1084/jem.20082030

40.Ma W-T., Yao X-T., Peng Q., Chen D-K. The protective and pathogenic roles of IL-17 in viral infections: friend or foe? Open Biol. 2019; 9 (7): 190109. DOI: https://www.doi.org/10.1098/rsob. 190109

41.Hot A., Lenief V., Cazalis M-A., Miossec P. Pathogenic role of IL-17 in endothelial dysfunction, a link between rheumatoid arthritis and atherosclerosis. Ann Rheum Dis. 2010; 69 (Suppl 2): A44–5. DOI: https://www.doi.org/10.1136/ard.2010.129635d

42.Eckmann L., Kagnoff M.F., Fierer J. Epithelial cells secrete the chemokine interleukin-8 in response to bacterial entry. Infect Immun. 1993; 61 (11): 4569–74. DOI: https://www.doi.org/10.1128/iai.61.11.4569-4574.1993

43.Aldonyte R., Eriksson S., Piitulainen E., Wallmark A., Janciauskiene S. Analysis of systemic biomarkers in COPD patients. COPD J Chronic Obstr Pulm Dis. 2004; 1 (2): 155–64. DOI: https://www.doi.org/10.1081/COPD-120030828

44.Han H., Ma Q., Li C., Liu R., Zhao L., Wang W., et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect. 2020; 9 (1): 1123–30. DOI: https://www.doi.org/10.1080/22221751.2020.1770129

45.Lu L., Zhang H., Dauphars D.J., He Y.-W. A Potential Role of Interleukin 10 in COVID-19 Pathogenesis. Trends Immunol. 2021; 42 (1): 3–5. DOI: https://www.doi.org/10.1016/j.it.2020.10.012

46.Zhou Y., Kong F., Wang S., Yu M., Xu Y., Kang J., et al. Increased levels of serum interleukin-10 are associated with poor outcome in adult hemophagocytic lymphohistiocytosis patients. 2021; 16 (1): 347. DOI: https://www.doi.org/10.1186/s13023-021-01973-4

47.Peñaloza H.F., Schultz B.M., Nieto P.A., Salazar G.A., Suazo I., Gonzalez P.A., et al. Opposing roles of IL-10 in acute bacterial infection. Cytokine Growth Factor Rev. 2016; 32: 17–30. DOI: https://www.doi.org/10.1016/j.cytogfr.2016.07.003

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)


JOURNALS of «GEOTAR-Media»