Assessment of Inflammatory Biomarkers in Sepsis

ORIGINAL ARTICLE
Anila Lika, Iris Mone, Irena Korita, Nevila Heta, Alma Barbullushi, Anyla Bulo-Kasneci

 
For citation: Lika A, Mone I, Korita I, Heta N, Barbullushi A, Bulo-Kasneci A. Assessment of Inflammatory Biomarkers in Sepsis. International Journal of Biomedicine. 2024;14(3):410-416. doi:10.21103/Article14(3)_OA3
 
Originally published September 6, 2024

Abstract: 

Background: Sepsis is a clinical syndrome of life-threatening organ dysfunction due to a dysregulated host response to infection. Many biomarkers have been used clinically to assist in diagnosing sepsis. The aim of this study was to assess the blood levels of procalcitonin (PCT) and four inflammation markers, C-reactive protein (CRP), IL-6, IL-8, and TNF-α, with respect to sepsis diagnosis.
Methods and Results: This case series study enrolled 188 patients (67 females and 121 males) treated in the University Hospital Centre “Mother Teresa” in Tirana with three different diagnoses: sepsis (n=103), systemic inflammatory response syndrome (SIRS) (n=71), and local bacterial infection (LBI) (n=14). Levels of PCT and serum cytokines TNF-α, IL-6, and IL-8 were measured by enzyme-linked immunosorbent assay (ELISA).
Patients with sepsis had higher values ​​of the studied biomarkers than those with SIRS and LBI (PCT: 10.0±18.7 ng/mL, 0.3±0.2 ng/mL, 0.4±0.4 ng/mL, respectively; CRP: 149±100 mg/L, 42.3±45.3 mg/L, and 74.4±75.6 mg/L, respectively; IL-6: 286.8±330.7 pg/mL, 21.0±27.5 pg/mL, and 34.6±75.1 mg/mL, respectively; IL-8: 310.2±292.5 pg/mL, 29.5±32.7 pg/mL, and 111.7±252.3 mg/mL, respectively; TNF-α: 131.2±254.0 pg/mL, 33.6±118.9 pg/mL, and 164.6±355.1 mg/mL, respectively). Multiple comparison tests demonstrated a statistically significant difference between the sepsis and SIRS group in PCT, CRP, IL-6, IL-8, and TNF-α (P<0.01 in all cases).
ROC curves demonstrated high sensitivity and specificity for PCT (97% and 93% for 0.5 ng/mL and 60% and 100%, respectively, for 1.99 ng/mL), but the other biomarkers showed lower sensitivity and specificity values.
Conclusion: Markers of inflammation are very helpful in diagnosing sepsis. CRP, IL-6, and IL-8 are sensitive parameters but do not have high specificity. PCT is the parameter chosen for the diagnosis of sepsis, with higher sensitivity and specificity than all other parameters included in this study.

Keywords: 
CRP • IL6 • IL8 • procalcitonin • SISR • TNF-α • sepsis • Albania
References: 
  1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287. PMID: 26903338; PMCID: PMC4968574.
  2. Barichello T, Generoso JS, Singer M, Dal-Pizzol F. Biomarkers for sepsis: more than just fever and leukocytosis-a narrative review. Crit Care. 2022 Jan 6;26(1):14. doi: 10.1186/s13054-021-03862-5. PMID: 34991675; PMCID: PMC8740483.
  3. Chakraborty RK, Burns B. Systemic Inflammatory Response Syndrome. 2023 May 29. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 31613449.
  4. Fernando SM, Rochwerg B, Seely AJE. Clinical implications of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). CMAJ. 2018 Sep 10;190(36):E1058-E1059. doi: 10.1503/cmaj.170149. PMID: 30201611; PMCID: PMC6131078.
  5. Vincent JL, Martin GS, Levy MM. qSOFA does not replace SIRS in the definition of sepsis. Crit Care. 2016 Jul 17;20(1):210. doi: 10.1186/s13054-016-1389-z. PMID: 27423462; PMCID: PMC4947518.
  6. Yende S, Kellum JA, Talisa VB, Peck Palmer OM, Chang CH, Filbin MR, Shapiro NI, Hou PC, Venkat A, LoVecchio F, Hawkins K, Crouser ED, Newman AB, Angus DC. Long-term Host Immune Response Trajectories Among Hospitalized Patients With Sepsis. JAMA Netw Open. 2019 Aug 2;2(8):e198686. doi: 10.1001/jamanetworkopen.2019.8686. PMID: 31390038; PMCID: PMC6686981.
  7. Barichello T, Generoso JS, Dominguini D, Córneo E, Giridharan VV, Sahrapour TA, Simões LR, Rosa MID, Petronilho F, Ritter C, Sharshar T, Dal-Pizzol F. Postmortem Evidence of Brain Inflammatory Markers and Injury in Septic Patients: A Systematic Review. Crit Care Med. 2022 Mar 1;50(3):e241-e252. doi: 10.1097/CCM.0000000000005307. PMID: 34402457.
  8. van der Poll T, Shankar-Hari M, Wiersinga WJ. The immunology of sepsis. Immunity. 2021 Nov 9;54(11):2450-2464. doi: 10.1016/j.immuni.2021.10.012. PMID: 34758337.
  9. Arina P, Singer M. Pathophysiology of sepsis. Curr Opin Anaesthesiol. 2021 Apr 1;34(2):77-84. doi: 10.1097/ACO.0000000000000963. PMID: 33652454.
  10. Torres LK, Pickkers P, van der Poll T. Sepsis-Induced Immunosuppression. Annu Rev Physiol. 2022 Feb 10;84:157-181. doi: 10.1146/annurev-physiol-061121-040214. Epub 2021 Oct 27. PMID: 34705481.
  11. Kumar S, Ingle H, Prasad DV, Kumar H. Recognition of bacterial infection by innate immune sensors. Crit Rev Microbiol. 2013 Aug;39(3):229-46. doi: 10.3109/1040841X.2012.706249. Epub 2012 Aug 6. PMID: 22866947.
  12. Heckenberg SG, Brouwer MC, van de Beek D. Bacterial meningitis. Handb Clin Neurol. 2014;121:1361-75. doi: 10.1016/B978-0-7020-4088-7.00093-6. PMID: 24365425.
  13. Wiersinga WJ, van der Poll T. Immunopathophysiology of human sepsis. EBioMedicine. 2022 Dec;86:104363. doi: 10.1016/j.ebiom.2022.104363. Epub 2022 Dec 2. PMID: 36470832; PMCID: PMC9783164.
  14. Yuki K, Koutsogiannaki S. Pattern recognition receptors as therapeutic targets for bacterial, viral and fungal sepsis. Int Immunopharmacol. 2021 Sep;98:107909. doi: 10.1016/j.intimp.2021.107909. Epub 2021 Jun 25. PMID: 34182242; PMCID: PMC8380728.
  15. Raymond SL, Holden DC, Mira JC, Stortz JA, Loftus TJ, Mohr AM, Moldawer LL, Moore FA, Larson SD, Efron PA. Microbial recognition and danger signals in sepsis and trauma. Biochim Biophys Acta Mol Basis Dis. 2017 Oct;1863(10 Pt B):2564-2573. doi: 10.1016/j.bbadis.2017.01.013. Epub 2017 Jan 20. PMID: 28115287; PMCID: PMC5519458.
  16. Denning NL, Aziz M, Gurien SD, Wang P. DAMPs and NETs in Sepsis. Front Immunol. 2019 Oct 30;10:2536. doi: 10.3389/fimmu.2019.02536. PMID: 31736963; PMCID: PMC6831555.
  17. Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010 Dec;10(12):826-37. doi: 10.1038/nri2873. Epub 2010 Nov 19. PMID: 21088683; PMCID: PMC3114424.
  18. Wiersinga WJ, Leopold SJ, Cranendonk DR, van der Poll T. Host innate immune responses to sepsis. Virulence. 2014 Jan 1;5(1):36-44. doi: 10.4161/viru.25436. Epub 2013 Jun 17. PMID: 23774844; PMCID: PMC3916381.
  19. Mantovani A, Garlanda C. Humoral Innate Immunity and Acute-Phase Proteins. N Engl J Med. 2023 Feb 2;388(5):439-452. doi: 10.1056/NEJMra2206346. PMID: 36724330; PMCID: PMC9912245.
  20. Bottazzi B, Doni A, Garlanda C, Mantovani A. An integrated view of humoral innate immunity: pentraxins as a paradigm. Annu Rev Immunol. 2010;28:157-83. doi: 10.1146/annurev-immunol-030409-101305. PMID: 19968561.
  21. Garlanda C, Bottazzi B, Bastone A, Mantovani A. Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Annu Rev Immunol. 2005;23:337-66. doi: 10.1146/annurev.immunol.23.021704.115756. PMID: 15771574.
  22. Skinner M, Cohen AS. Amyloid P component. Methods Enzymol. 1988;163:523-36. doi: 10.1016/0076-6879(88)63048-5. PMID: 3237088.
  23. Agrawal A. CRP after 2004. Mol Immunol. 2005 May;42(8):927-30. doi: 10.1016/j.molimm.2004.09.028. Epub 2004 Dec 7. PMID: 15829284; PMCID: PMC3833354.
  24. Volanakis JE. Human C-reactive protein: expression, structure, and function. Mol Immunol. 2001 Aug;38(2-3):189-97. doi: 10.1016/s0161-5890(01)00042-6. PMID: 11532280.
  25. Osmand AP, Friedenson B, Gewurz H, Painter RH, Hofmann T, Shelton E. Characterization of C-reactive protein and the complement subcomponent C1t as homologous proteins displaying cyclic pentameric symmetry (pentraxins). Proc Natl Acad Sci U S A. 1977 Feb;74(2):739-43. doi: 10.1073/pnas.74.2.739. PMID: 265538; PMCID: PMC392369.
  26. Livaditi O, Kotanidou A, Psarra A, Dimopoulou I, Sotiropoulou C, Augustatou K, Papasteriades C, Armaganidis A, Roussos C, Orfanos SE, Douzinas EE. Neutrophil CD64 expression and serum IL-8: sensitive early markers of severity and outcome in sepsis. Cytokine. 2006 Dec;36(5-6):283-90. doi: 10.1016/j.cyto.2007.02.007. Epub 2007 Mar 26. PMID: 17368039.
  27. Bozza FA, Salluh JI, Japiassu AM, Soares M, Assis EF, Gomes RN, Bozza MT, Castro-Faria-Neto HC, Bozza PT. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care. 2007;11(2):R49. doi: 10.1186/cc5783. PMID: 17448250; PMCID: PMC2206478.
  28. Mera S, Tatulescu D, Cismaru C, Bondor C, Slavcovici A, Zanc V, Carstina D, Oltean M. Multiplex cytokine profiling in patients with sepsis. APMIS. 2011 Feb;119(2):155-63. doi: 10.1111/j.1600-0463.2010.02705.x. Epub 2010 Dec 10. PMID: 21208283.
  29. Gregoriano C, Heilmann E, Molitor A, Schuetz P. Role of procalcitonin use in the management of sepsis. J Thorac Dis. 2020 Feb;12(Suppl 1):S5-S15. doi: 10.21037/jtd.2019.11.63. PMID: 32148921; PMCID: PMC7024752.
  30. Wiedermann FJ, Kaneider N, Egger P, Tiefenthaler W, Wiedermann CJ, Lindner KH, Schobersberger W. Migration of human monocytes in response to procalcitonin. Crit Care Med. 2002 May;30(5):1112-7. doi: 10.1097/00003246-200205000-00025. PMID: 12006810.
  31. Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis. 2013 May;13(5):426-35. doi: 10.1016/S1473-3099(12)70323-7. Epub 2013 Feb 1. PMID: 23375419.
  32. Schmidt de Oliveira-Netto AC, Morello LG, Dalla-Costa LM, Petterle RR, Fontana RM, Conte D, Pereira LA, Raboni SM. Procalcitonin, C-Reactive Protein, Albumin, and Blood Cultures as Early Markers of Sepsis Diagnosis or Predictors of Outcome: A Prospective Analysis. Clin Pathol. 2019 Jun 18;12:2632010X19847673. doi: 10.1177/2632010X19847673. PMID: 31245791; PMCID: PMC6582287.
  33. Linscheid P, Seboek D, Schaer DJ, Zulewski H, Keller U, Müller B. Expression and secretion of procalcitonin and calcitonin gene-related peptide by adherent monocytes and by macrophage-activated adipocytes. Crit Care Med. 2004 Aug;32(8):1715-21. doi: 10.1097/01.ccm.0000134404.63292.71. PMID: 15286549.
  34. Müller B, Schuetz P, Trampuz A. Circulating biomarkers as surrogates for bloodstream infections. Int J Antimicrob Agents. 2007 Nov;30 Suppl 1:S16-23. doi: 10.1016/j.ijantimicag.2007.06.032. Epub 2007 Sep 19. PMID: 17884358.
  35. Cuquemelle E, Soulis F, Villers D, Roche-Campo F, Ara Somohano C, Fartoukh M, Kouatchet A, Mourvillier B, Dellamonica J, Picard W, Schmidt M, Boulain T, Brun-Buisson C; A/H1N1 REVA-SRLF Study Group. Can procalcitonin help identify associated bacterial infection in patients with severe influenza pneumonia? A multicentre study. Intensive Care Med. 2011 May;37(5):796-800. doi: 10.1007/s00134-011-2189-1. Epub 2011 Mar 3. PMID: 21369807; PMCID: PMC7080069.
  36. Jensen JU, Hein L, Lundgren B, Bestle MH, Mohr TT, Andersen MH, Thornberg KJ, Løken J, Steensen M, Fox Z, Tousi H, Søe-Jensen P, Lauritsen AØ, Strange D, Petersen PL, Reiter N, Hestad S, Thormar K, Fjeldborg P, Larsen KM, Drenck NE, Ostergaard C, Kjær J, Grarup J, Lundgren JD; Procalcitonin And Survival Study (PASS) Group. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med. 2011 Sep;39(9):2048-58. doi: 10.1097/CCM.0b013e31821e8791. PMID: 21572328.
  37. Karlsson S, Heikkinen M, Pettilä V, Alila S, Väisänen S, Pulkki K, Kolho E, Ruokonen E; Finnsepsis Study Group. Predictive value of procalcitonin decrease in patients with severe sepsis: a prospective observational study. Crit Care. 2010;14(6):R205. doi: 10.1186/cc9327. Epub 2010 Nov 15. PMID: 21078153; PMCID: PMC3219988.
  38. Schuetz P, Amin DN, Greenwald JL. Role of procalcitonin in managing adult patients with respiratory tract infections. Chest. 2012 Apr;141(4):1063-1073. doi: 10.1378/chest.11-2430. PMID: 22474148.
  39. Alan M, Grolimund E, Kutz A, Christ-Crain M, Thomann R, Falconnier C, Hoess C, Henzen C, Zimmerli W, Mueller B, Schuetz P; ProHOSP study group. Clinical risk scores and blood biomarkers as predictors of long-term outcome in patients with community-acquired pneumonia: a 6-year prospective follow-up study. J Intern Med. 2015 Aug;278(2):174-84. doi: 10.1111/joim.12341. Epub 2015 Jan 27. PMID: 25529395.
  40. Schuetz P, Kutz A, Grolimund E, Haubitz S, Demann D, Vögeli A, Hitz F, Christ-Crain M, Thomann R, Falconnier C, Hoess C, Henzen C, Marlowe RJ, Zimmerli W, Mueller B; ProHOSP Study Group. Excluding infection through procalcitonin testing improves outcomes of congestive heart failure patients presenting with acute respiratory symptoms: results from the randomized ProHOSP trial. Int J Cardiol. 2014 Aug 20;175(3):464-72. doi: 10.1016/j.ijcard.2014.06.022. Epub 2014 Jun 27. PMID: 25005339.
  41. Schuetz P, Maurer P, Punjabi V, Desai A, Amin DN, Gluck E. Procalcitonin decrease over 72 hours in US critical care units predicts fatal outcome in sepsis patients. Crit Care. 2013 Jun 20;17(3):R115. doi: 10.1186/cc12787. PMID: 23787145; PMCID: PMC4057444.
  42. Schuetz P, Beishuizen A, Broyles M, Ferrer R, Gavazzi G, Gluck EH, González Del Castillo J, Jensen JU, Kanizsai PL, Kwa ALH, Krueger S, Luyt CE, Oppert M, Plebani M, Shlyapnikov SA, Toccafondi G, Townsend J, Welte T, Saeed K. Procalcitonin (PCT)-guided antibiotic stewardship: an international experts consensus on optimized clinical use. Clin Chem Lab Med. 2019 Aug 27;57(9):1308-1318. doi: 10.1515/cclm-2018-1181. PMID: 30721141.
  43. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644-55. doi: 10.1378/chest.101.6.1644. PMID: 1303622.
  44. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999 Feb 11;340(6):448-54. doi: 10.1056/NEJM199902113400607. Erratum in: N Engl J Med 1999 Apr 29;340(17):1376. PMID: 9971870.
  45. Anush MM, Ashok VK, Sarma RI, Pillai SK. Role of C-reactive Protein as an Indicator for Determining the Outcome of Sepsis. Indian J Crit Care Med. 2019 Jan;23(1):11-14. doi: 10.5005/jp-journals-10071-23105. PMID: 31065202; PMCID: PMC6481256.
  46. Shimetani N, Shimetani K, Mori M. Levels of three inflammation markers, C-reactive protein, serum amyloid A protein and procalcitonin, in the serum and cerebrospinal fluid of patients with meningitis. Scand J Clin Lab Invest. 2001;61(7):567-74. doi: 10.1080/003655101753218337. PMID: 11763415.
  47. Toikka P, Irjala K, Juvén T, Virkki R, Mertsola J, Leinonen M, Ruuskanen O. Serum procalcitonin, C-reactive protein and interleukin-6 for distinguishing bacterial and viral pneumonia in children. Pediatr Infect Dis J. 2000 Jul;19(7):598-602. doi: 10.1097/00006454-200007000-00003. PMID: 10917215.
  48. Lacour AG, Gervaix A, Zamora SA, Vadas L, Lombard PR, Dayer JM, Suter S. Procalcitonin, IL-6, IL-8, IL-1 receptor antagonist and C-reactive protein as identificators of serious bacterial infections in children with fever without localising signs. Eur J Pediatr. 2001 Feb;160(2):95-100. doi: 10.1007/s004310000681. PMID: 11271398.
  49. Kothari N, Bogra J, Abbas H, Kohli M, Malik A, Kothari D, Srivastava S, Singh PK. Tumor necrosis factor gene polymorphism results in high TNF level in sepsis and septic shock. Cytokine. 2013 Feb;61(2):676-81. doi: 10.1016/j.cyto.2012.11.016. Epub 2013 Jan 11. PMID: 23317877.
  50. Surbatovic M, Veljovic M, Jevdjic J, Popovic N, Djordjevic D, Radakovic S. Immunoinflammatory response in critically ill patients: severe sepsis and/or trauma. Mediators Inflamm. 2013;2013:362793. doi: 10.1155/2013/362793. Epub 2013 Nov 24. PMID: 24371374; PMCID: PMC3859159.
  51. Baghel K, Srivastava RN, Chandra A, Goel SK, Agrawal J, Kazmi HR, Raj S. TNF-α, IL-6, and IL-8 cytokines and their association with TNF-α-308 G/A polymorphism and postoperative sepsis. J Gastrointest Surg. 2014 Aug;18(8):1486-94. doi: 10.1007/s11605-014-2574-5. Epub 2014 Jun 19. PMID: 24944154.
  52. Ulloa L, Tracey KJ. The "cytokine profile": a code for sepsis. Trends Mol Med. 2005 Feb;11(2):56-63. doi: 10.1016/j.molmed.2004.12.007. PMID: 15694867.
  53. Zhai GH, Zhang W, Xiang Z, He LZ, Wang WW, Wu J, Shang AQ. Diagnostic Value of sIL-2R, TNF-α and PCT for Sepsis Infection in Patients With Closed Abdominal Injury Complicated With Severe Multiple Abdominal Injuries. Front Immunol. 2021 Oct 22;12:741268. doi: 10.3389/fimmu.2021.741268. PMID: 34745113; PMCID: PMC8569904.
  54. Prat C, Domínguez J, Rodrigo C, Giménez M, Azuara M, Jiménez O, Galí N, Ausina V. Procalcitonin, C-reactive protein and leukocyte count in children with lower respiratory tract infection. Pediatr Infect Dis J. 2003 Nov;22(11):963-8. doi: 10.1097/01.inf.0000095197.72976.4f. PMID: 14614368.

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Received June 6, 2024.
Accepted August 7, 2024.
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