Perspective: Sepsis Biomarker Research Requires a Move to the Emergency Department and More Collaboration
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Feb 27, 2024
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Abstract
Despite years of research and multiple potential candidate biomarkers for sepsis, few have had sufficient sensitivity or specificity to be integrated into routine practice. There have been only 11 observational studies that have collected samples from patients presenting to the emergency department with suspected sepsis. This has resulted in gaps in the ability to accurately diagnose sepsis in patients presenting with infections and give an accurate prognosis for patients or their families. Recent work has shown the importance of immunothrombosis, particularly in the prognosis for patients admitted to the intensive care unit with sepsis. Significantly some of the most impactful markers are actually decreased. In this perspective we summarize the current sepsis biomarker literature, highlight the limitations, particularly in diagnosis, and suggest some strategies for moving this field forward.
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How to Cite
FOX-ROBICHAUD, Alison E.; ARORA, Jaskirat.
Perspective: Sepsis Biomarker Research Requires a Move to the Emergency Department and More Collaboration.
Medical Research Archives, [S.l.], v. 12, n. 2, feb. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5023>. Date accessed: 28 apr. 2024.
doi: https://doi.org/10.18103/mra.v12i2.5023.
Section
Editorial
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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13. Becker KL, Nylen ES, White JC, Muller B, Snider RH, Jr. Clinical review 167: Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab. Apr 2004;89(4):1512-25. doi:10.1210/jc.2002-021444
14. Garcia de Guadiana-Romualdo L, Berger M, Jimenez-Santos E, et al. Pancreatic stone protein and soluble CD25 for infection and sepsis in an emergency department. Eur J Clin Invest. Apr 2017;47(4):297-304. doi:10.1111/eci.12732
15. Garcia de Guadiana Romualdo L, Albaladejo Oton MD, Rebollo Acebes S, et al. Diagnostic accuracy of lipopolysaccharide-binding protein for sepsis in patients with suspected infection in the emergency department. Ann Clin Biochem. Jan 2018;55(1):143-148. doi:10.1177/ 0004563217694378
16. Liu B, Chen YX, Yin Q, Zhao YZ, Li CS. Diagnostic value and prognostic evaluation of Presepsin for sepsis in an emergency department. Crit Care. Oct 20 2013;17(5):R244. doi:10.1186/ cc13070
17. Magrini L, Gagliano G, Travaglino F, et al. Comparison between white blood cell count, procalcitonin and C reactive protein as diagnostic and prognostic biomarkers of infection or sepsis in patients presenting to emergency department. Clin Chem Lab Med. Oct 2014;52(10):1465-72. doi:10.1515/ cclm-2014-0210
18. Hausfater P, Robert Boter N, Morales Indiano C, et al. Monocyte distribution width (MDW) performance as an early sepsis indicator in the emergency department: comparison with CRP and procalcitonin in a multicenter international European prospective study. Crit Care. Jun 30 2021;25(1):227. doi:10.1186/s13054-021-03622-5
19. Crouser ED, Parrillo JE, Seymour CW, et al. Monocyte Distribution Width: A Novel Indicator of Sepsis-2 and Sepsis-3 in High-Risk Emergency Department Patients. Crit Care Med. Aug 2019;47(8):1018-1025. doi:10.1097/ CCM.0000000000003799
20. Song J, Park DW, Moon S, et al. Diagnostic and prognostic value of interleukin-6, pentraxin 3, and procalcitonin levels among sepsis and septic shock patients: a prospective controlled study according to the Sepsis-3 definitions. BMC Infect Dis. Nov 12 2019;19(1):968. doi:10.1186/s12879-019-4618-7
21. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. Feb 23 2016;315(8):801-10. doi:10.1001/ jama.2016.0287
22. Huang YH, Chen CJ, Shao SC, et al. Comparison of the Diagnostic Accuracies of Monocyte Distribution Width, Procalcitonin, and C-Reactive Protein for Sepsis: A Systematic Review and Meta-Analysis. Crit Care Med. May 1 2023;51(5):e106-e114. doi:10.1097/ CCM.0000000000005820
23. Hicks CW, Engineer RS, Benoit JL, Dasarathy S, Christenson RH, Peacock WF. Procalcitonin as a biomarker for early sepsis in the emergency department. Eur J Emerg Med. Apr 2014;21(2):112-7. doi:10.1097/MEJ.0b013e328361fee2
24. Ling H, Chen M, Dai J, Zhong H, Chen R, Shi F. Evaluation of qSOFA combined with inflammatory mediators for diagnosing sepsis and predicting mortality among emergency department. Clin Chim Acta. Apr 1 2023;544:117352. doi:10.1016/j.cca.2023.117352
25. Tan TL, Ahmad NS, Nasuruddin DN, et al. CD64 and Group II Secretory Phospholipase A2 (sPLA2-IIA) as Biomarkers for Distinguishing Adult Sepsis and Bacterial Infections in the Emergency Department. PLoS One. 2016;11(3):e0152065. doi:10.1371/journal.pone.0152065
26. Wang M, Zhang Q, Zhao X, Dong G, Li C. Diagnostic and prognostic value of neutrophil gelatinase-associated lipocalin, matrix metalloproteinase-9, and tissue inhibitor of matrix metalloproteinases-1 for sepsis in the Emergency Department: an observational study. Crit Care. Nov 19 2014;18(6):634. doi:10.1186/s13054-014-0634-6
27. Martinod K, Deppermann C. Immunothrombosis and thromboinflammation in host defense and disease. Platelets. Apr 3 2021;32(3):314-324. doi:10.1080/09537104.2020.1817360
28. Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. Jan 2013;13(1):34-45. doi:10.1038/nri3345
29. Arora J, Klowak JA, Parpia S, et al. Diagnostic Potential of Coagulation-Related Biomarkers for Sepsis in the Emergency Department: Protocol for a Pilot Observational Cohort Study. Crit Care Explor. Apr 2021;3(4):e0414. doi:10.1097/CCE.0000000000000414
30. Farrah K, McIntyre L, Doig CJ, et al. Sepsis-Associated Mortality, Resource Use, and Healthcare Costs: A Propensity-Matched Cohort Study. Crit Care Med. Feb 1 2021;49(2):215-227. doi:10.1097/CCM.0000000000004777
31. Fernando SM, Fox-Robichaud AE, Rochwerg B, et al. Prognostic accuracy of the Hamilton Early Warning Score (HEWS) and the National Early Warning Score 2 (NEWS2) among hospitalized patients assessed by a rapid response team. Crit Care. Feb 21 2019;23(1):60. doi:10.1186/s13054-019-2355-3
32. Angriman F, Rosella LC, Lawler PR, Ko DT, Wunsch H, Scales DC. Sepsis hospitalization and risk of subsequent cardiovascular events in adults: a population-based matched cohort study. Intensive Care Med. Apr 2022;48(4):448-457. doi:10.1007/s00134-022-06634-z
33. Angriman F, Rosella LC, Lawler PR, et al. Risk Factors for Major Cardiovascular Events in Adult Sepsis Survivors: A Population-Based Cohort Study. Crit Care Med. Apr 1 2023;51(4):471-483. doi:10.1097/CCM.0000000000005793
34. Angriman F, Lawler PR, Shah BR, Martin CM, Scales DC, the Sepsis Canada N. Prevalent diabetes and long-term cardiovascular outcomes in adult sepsis survivors: a population-based cohort study. Crit Care. Jul 31 2023;27(1):302. doi:10.1186/s13054-023-04586-4
35. Molano-Franco D, Arevalo-Rodriguez I, Muriel A, et al. Basal procalcitonin, C-reactive protein, interleukin-6, and presepsin for prediction of mortality in critically ill septic patients: a systematic review and meta-analysis. Diagn Progn Res. Aug 3 2023;7(1):15. doi:10.1186/s41512-023-00152-2
36. Zuercher P, Moser A, Garcia de Guadiana-Romualdo L, et al. Discriminative performance of pancreatic stone protein in predicting ICU mortality and infection severity in adult patients with infection: a systematic review and individual patient level meta-analysis. Infection. Dec 2023;51(6):1797-1807. doi:10.1007/ s15010-023-02093-w
37. Hu J, Xie S, Li W, Zhang L. Diagnostic and prognostic value of serum S100B in sepsis-associated encephalopathy: A systematic review and meta-analysis. Front Immunol. 2023;14:1102126. doi:10.3389/fimmu.2023.1102126
38. Dwivedi DJ, Toltl LJ, Swystun LL, et al. Prognostic utility and characterization of cell-free DNA in patients with severe sepsis. Crit Care. Aug 13 2012;16(4):R151. doi:10.1186/cc11466
39. Liaw PC, Fox-Robichaud AE, Liaw KL, et al. Mortality Risk Profiles for Sepsis: A Novel Longitudinal and Multivariable Approach. Crit Care Explor. Aug 2019;1(8):e0032. doi:10.1097/CCE.0000000000000032
40. Sohrabipour S, Muniz VS, Sharma N, Dwivedi DJ, Liaw PC. Mechanistic Studies of DNase I Activity: Impact of Heparin Variants and PAD4. Shock. Dec 1 2021;56(6):975-987. doi:10.1097/SHK.0000000000001804
41. Charoensappakit A, Sae-Khow K, Rattanaliam P, et al. Cell-free DNA as diagnostic and prognostic biomarkers for adult sepsis: a systematic review and meta-analysis. Sci Rep. Nov 10 2023;13(1):19624. doi:10.1038/ s41598-023-46663-2
42. Catenacci V, Sheikh F, Patel K, Fox-Robichaud AE. The prognostic utility of protein C as a biomarker for adult sepsis: a systematic review and meta-analysis. Crit Care. Jan 14 2022;26(1):21. doi:10.1186/s13054-022-03889-2
43. Schupp T, Weidner K, Rusnak J, et al. Diagnostic and prognostic role of platelets in patients with sepsis and septic shock. Platelets. Dec 2023;34(1):2131753. doi:10.1080/09537104.2022.2131753
44. Singh K, Kwong AC, Madarati H, et al. Characterization of ADAMTS13 and von Willebrand factor levels in septic and non-septic ICU patients. PLoS One. 2021;16(2):e0247017. doi:10.1371/journal.pone.0247017
2. Usman OA, Usman AA, Ward MA. Comparison of SIRS, qSOFA, and NEWS for the early identification of sepsis in the Emergency Department. Am J Emerg Med. Aug 2019;37(8):1490-1497. doi:10.1016/j.ajem.2018.10.058
3. Biomarkers Definitions Working G. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. Mar 2001;69(3):89-95. doi:10.1067/ mcp. 2001.113989
4. Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit Care. 2010;14(1):R15. doi:10.1186/cc8872
5. Pierrakos C, Velissaris D, Bisdorff M, Marshall JC, Vincent JL. Biomarkers of sepsis: time for a reappraisal. Crit Care. Jun 5 2020;24(1):287. doi:10.1186/s13054-020-02993-5
6. Bossuyt PM, Reitsma JB, Bruns DE, et al. STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies. BMJ. Oct 28 2015;351:h5527. doi:10.1136/bmj.h5527
7. Collins GS, Reitsma JB, Altman DG, Moons KG. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement. BMJ. Jan 7 2015;350:g7594. doi:10.1136/ bmj.g7594
8. De Backer D, Deutschman CS, Hellman J, et al. Surviving Sepsis Campaign Research Priorities 2023. Crit Care Med. Feb 1 2024;52(2):268-296. doi:10.1097/CCM.0000000000006135
9. Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S. Recognizing Sepsis as a Global Health Priority - A WHO Resolution. N Engl J Med. Aug 3 2017;377(5):414-417. doi:10.1056/NEJMp1707170
10. Rhee C, Wang R, Zhang Z, et al. Epidemiology of Hospital-Onset Versus Community-Onset Sepsis in U.S. Hospitals and Association With Mortality: A Retrospective Analysis Using Electronic Clinical Data. Crit Care Med. Sep 2019;47(9):1169-1176. doi:10.1097/CCM.0000000000003817
11. Liu VX, Fielding-Singh V, Greene JD, et al. The Timing of Early Antibiotics and Hospital Mortality in Sepsis. Am J Respir Crit Care Med. Oct 1 2017;196(7):856-863. doi:10.1164/ rccm.201609-1848OC
12. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. Nov 1 2021;49(11):e1063-e1143. doi:10.1097/CCM.0000000000005337
13. Becker KL, Nylen ES, White JC, Muller B, Snider RH, Jr. Clinical review 167: Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab. Apr 2004;89(4):1512-25. doi:10.1210/jc.2002-021444
14. Garcia de Guadiana-Romualdo L, Berger M, Jimenez-Santos E, et al. Pancreatic stone protein and soluble CD25 for infection and sepsis in an emergency department. Eur J Clin Invest. Apr 2017;47(4):297-304. doi:10.1111/eci.12732
15. Garcia de Guadiana Romualdo L, Albaladejo Oton MD, Rebollo Acebes S, et al. Diagnostic accuracy of lipopolysaccharide-binding protein for sepsis in patients with suspected infection in the emergency department. Ann Clin Biochem. Jan 2018;55(1):143-148. doi:10.1177/ 0004563217694378
16. Liu B, Chen YX, Yin Q, Zhao YZ, Li CS. Diagnostic value and prognostic evaluation of Presepsin for sepsis in an emergency department. Crit Care. Oct 20 2013;17(5):R244. doi:10.1186/ cc13070
17. Magrini L, Gagliano G, Travaglino F, et al. Comparison between white blood cell count, procalcitonin and C reactive protein as diagnostic and prognostic biomarkers of infection or sepsis in patients presenting to emergency department. Clin Chem Lab Med. Oct 2014;52(10):1465-72. doi:10.1515/ cclm-2014-0210
18. Hausfater P, Robert Boter N, Morales Indiano C, et al. Monocyte distribution width (MDW) performance as an early sepsis indicator in the emergency department: comparison with CRP and procalcitonin in a multicenter international European prospective study. Crit Care. Jun 30 2021;25(1):227. doi:10.1186/s13054-021-03622-5
19. Crouser ED, Parrillo JE, Seymour CW, et al. Monocyte Distribution Width: A Novel Indicator of Sepsis-2 and Sepsis-3 in High-Risk Emergency Department Patients. Crit Care Med. Aug 2019;47(8):1018-1025. doi:10.1097/ CCM.0000000000003799
20. Song J, Park DW, Moon S, et al. Diagnostic and prognostic value of interleukin-6, pentraxin 3, and procalcitonin levels among sepsis and septic shock patients: a prospective controlled study according to the Sepsis-3 definitions. BMC Infect Dis. Nov 12 2019;19(1):968. doi:10.1186/s12879-019-4618-7
21. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. Feb 23 2016;315(8):801-10. doi:10.1001/ jama.2016.0287
22. Huang YH, Chen CJ, Shao SC, et al. Comparison of the Diagnostic Accuracies of Monocyte Distribution Width, Procalcitonin, and C-Reactive Protein for Sepsis: A Systematic Review and Meta-Analysis. Crit Care Med. May 1 2023;51(5):e106-e114. doi:10.1097/ CCM.0000000000005820
23. Hicks CW, Engineer RS, Benoit JL, Dasarathy S, Christenson RH, Peacock WF. Procalcitonin as a biomarker for early sepsis in the emergency department. Eur J Emerg Med. Apr 2014;21(2):112-7. doi:10.1097/MEJ.0b013e328361fee2
24. Ling H, Chen M, Dai J, Zhong H, Chen R, Shi F. Evaluation of qSOFA combined with inflammatory mediators for diagnosing sepsis and predicting mortality among emergency department. Clin Chim Acta. Apr 1 2023;544:117352. doi:10.1016/j.cca.2023.117352
25. Tan TL, Ahmad NS, Nasuruddin DN, et al. CD64 and Group II Secretory Phospholipase A2 (sPLA2-IIA) as Biomarkers for Distinguishing Adult Sepsis and Bacterial Infections in the Emergency Department. PLoS One. 2016;11(3):e0152065. doi:10.1371/journal.pone.0152065
26. Wang M, Zhang Q, Zhao X, Dong G, Li C. Diagnostic and prognostic value of neutrophil gelatinase-associated lipocalin, matrix metalloproteinase-9, and tissue inhibitor of matrix metalloproteinases-1 for sepsis in the Emergency Department: an observational study. Crit Care. Nov 19 2014;18(6):634. doi:10.1186/s13054-014-0634-6
27. Martinod K, Deppermann C. Immunothrombosis and thromboinflammation in host defense and disease. Platelets. Apr 3 2021;32(3):314-324. doi:10.1080/09537104.2020.1817360
28. Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. Jan 2013;13(1):34-45. doi:10.1038/nri3345
29. Arora J, Klowak JA, Parpia S, et al. Diagnostic Potential of Coagulation-Related Biomarkers for Sepsis in the Emergency Department: Protocol for a Pilot Observational Cohort Study. Crit Care Explor. Apr 2021;3(4):e0414. doi:10.1097/CCE.0000000000000414
30. Farrah K, McIntyre L, Doig CJ, et al. Sepsis-Associated Mortality, Resource Use, and Healthcare Costs: A Propensity-Matched Cohort Study. Crit Care Med. Feb 1 2021;49(2):215-227. doi:10.1097/CCM.0000000000004777
31. Fernando SM, Fox-Robichaud AE, Rochwerg B, et al. Prognostic accuracy of the Hamilton Early Warning Score (HEWS) and the National Early Warning Score 2 (NEWS2) among hospitalized patients assessed by a rapid response team. Crit Care. Feb 21 2019;23(1):60. doi:10.1186/s13054-019-2355-3
32. Angriman F, Rosella LC, Lawler PR, Ko DT, Wunsch H, Scales DC. Sepsis hospitalization and risk of subsequent cardiovascular events in adults: a population-based matched cohort study. Intensive Care Med. Apr 2022;48(4):448-457. doi:10.1007/s00134-022-06634-z
33. Angriman F, Rosella LC, Lawler PR, et al. Risk Factors for Major Cardiovascular Events in Adult Sepsis Survivors: A Population-Based Cohort Study. Crit Care Med. Apr 1 2023;51(4):471-483. doi:10.1097/CCM.0000000000005793
34. Angriman F, Lawler PR, Shah BR, Martin CM, Scales DC, the Sepsis Canada N. Prevalent diabetes and long-term cardiovascular outcomes in adult sepsis survivors: a population-based cohort study. Crit Care. Jul 31 2023;27(1):302. doi:10.1186/s13054-023-04586-4
35. Molano-Franco D, Arevalo-Rodriguez I, Muriel A, et al. Basal procalcitonin, C-reactive protein, interleukin-6, and presepsin for prediction of mortality in critically ill septic patients: a systematic review and meta-analysis. Diagn Progn Res. Aug 3 2023;7(1):15. doi:10.1186/s41512-023-00152-2
36. Zuercher P, Moser A, Garcia de Guadiana-Romualdo L, et al. Discriminative performance of pancreatic stone protein in predicting ICU mortality and infection severity in adult patients with infection: a systematic review and individual patient level meta-analysis. Infection. Dec 2023;51(6):1797-1807. doi:10.1007/ s15010-023-02093-w
37. Hu J, Xie S, Li W, Zhang L. Diagnostic and prognostic value of serum S100B in sepsis-associated encephalopathy: A systematic review and meta-analysis. Front Immunol. 2023;14:1102126. doi:10.3389/fimmu.2023.1102126
38. Dwivedi DJ, Toltl LJ, Swystun LL, et al. Prognostic utility and characterization of cell-free DNA in patients with severe sepsis. Crit Care. Aug 13 2012;16(4):R151. doi:10.1186/cc11466
39. Liaw PC, Fox-Robichaud AE, Liaw KL, et al. Mortality Risk Profiles for Sepsis: A Novel Longitudinal and Multivariable Approach. Crit Care Explor. Aug 2019;1(8):e0032. doi:10.1097/CCE.0000000000000032
40. Sohrabipour S, Muniz VS, Sharma N, Dwivedi DJ, Liaw PC. Mechanistic Studies of DNase I Activity: Impact of Heparin Variants and PAD4. Shock. Dec 1 2021;56(6):975-987. doi:10.1097/SHK.0000000000001804
41. Charoensappakit A, Sae-Khow K, Rattanaliam P, et al. Cell-free DNA as diagnostic and prognostic biomarkers for adult sepsis: a systematic review and meta-analysis. Sci Rep. Nov 10 2023;13(1):19624. doi:10.1038/ s41598-023-46663-2
42. Catenacci V, Sheikh F, Patel K, Fox-Robichaud AE. The prognostic utility of protein C as a biomarker for adult sepsis: a systematic review and meta-analysis. Crit Care. Jan 14 2022;26(1):21. doi:10.1186/s13054-022-03889-2
43. Schupp T, Weidner K, Rusnak J, et al. Diagnostic and prognostic role of platelets in patients with sepsis and septic shock. Platelets. Dec 2023;34(1):2131753. doi:10.1080/09537104.2022.2131753
44. Singh K, Kwong AC, Madarati H, et al. Characterization of ADAMTS13 and von Willebrand factor levels in septic and non-septic ICU patients. PLoS One. 2021;16(2):e0247017. doi:10.1371/journal.pone.0247017