Fast Assay for Pathogen Identification and Characterization (FAPIC)

Fast Assay for Pathogen Identification and Characterization - Prospective Observational Study

Sepsis is a life-threatening disease caused by a dysregulated host response to infection. This can lead to organ-dysfunction and septic shock, which is a subset of sepsis where underlying abnormalities increase mortality remarkably. Blood cultures are the gold standard for identifying pathogens in the bloodstream (bacteremia). It is based on cultivation techniques which, theoretically, can detect a single pathogenic cell from a patient sample. However, blood cultures have serious limitations, such as long time to result (3-7 days). This leads to the fact that only a small fraction of the patients obtain a correct diagnosis and in further consequence get the optimal antimicrobial treatment. Patients with sepsis should get antimicrobial treatment within the hour. Thus, physicians start treatment empirically, with broad-spectrum antibiotics. This puts a selective pressure on pathogens and has led to an increased amount of antibiotic resistance. Faster diagnostics are necessary to ensure an immediate and targeted treatment. In the EU-funded FAPIC project, two diagnostic systems that can be used with direct sample material from patients will be developed, avoiding the time-consuming cultivation of pathogens.

In this study, the evaluation of the rapid diagnostics will be performed in patients with sepsis, suspected of bacteremia. To this aim, the performance of the diagnostic systems will be evaluated using blood samples that are collected in parallel with blood cultures. In addition, clinical data of the patients will be collected. In routine care, two blood culture sets (2x2 bottles) per patient are collected. One extra blood samples (EDTA, 9 ml) will be sampled with each blood culture set, totaling 2 samples per patient. In this study, patients presenting at the Emergency Department (ED), and the department of infectious diseases/nephrology will be included. The results will be used to estimate the performance, sensitivity, and specificity of the diagnostic systems compared to blood culture. Furthermore, in order to determine the severity of sepsis and to describe the patient population, clinically relevant parameters and laboratory parameters (ferritin, HLA-DR, serum lactate, SOFA score) will be assessed to determine its association with severity of disease and patient mortality. Evaluation will be done exclusively in the lab, and will not be used directly for the diagnosis or management of patients. Standard care will still be provided.

Study Overview

• Status: Completed
• Conditions: Sepsis; Septic Shock; Bacteremia

Detailed Description

This study is a follow-up study of the first prospective study performed in 2017 in the same hospital. The ClinicalTrials.gov ID number of the previous study was NCT03025802.

• Study Type: Observational
• Enrollment (Actual): 1957

Contacts and Locations

Study Locations

• Belgium
  • Limburg
    • Hasselt, Limburg, Belgium, 3500
      • Jessa hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients with suspected sepsis, for whom blood cultures are drawn.

Description

Inclusion Criteria:

• Patients for whom blood cultures are drawn
• Age ≥ 18

Exclusion Criteria:

• Age < 18
• Patients who are not hospitalized and sent home after ED admission
• Patients from the haematology department
• Duplicate blood cultures from the same bacteraemia episode (blood cultures drawn <7 days after first blood culture)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Patients with suspected sepsis; Patients for whom blood cultures are drawn at the Emergency Department or the department of Infectious Diseases/Nephrology

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed bacteremia based on positive blood cultures (SOFA score)	Differences in SOFA score between patients with positive blood cultures and patients with negative blood cultures. SOFA: Sequential Organ Failure Assessment; Range 0-4 (better to worse).	7 days
Confirmed bacteremia based on positive blood cultures (Serum Lactate)	Differences in Serum Lactate levels between patients with positive blood cultures and patients with negative blood cultures	7 days
Confirmed bacteremia based on positive blood cultures (Ferritin)	Differences in Ferritin levels between patients with positive blood cultures and patients with negative blood cultures	7 days
Test performance	Performance characteristics (Clinical sensitivity, specificity and accuracy) of a new rapid diagnostic systems	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of Stay (SOFA score)	Differences in length of stay between patients with high and with low SOFA score SOFA: Sequential Organ Failure Assessment; Range 0-4 (better to worse).	1 year
Length of Stay (Serum Lactate)	Differences in length of stay between patients with high and with low Serum Lactate levels	1 year
Length of Stay (Ferritin)	Differences in length of stay between patients with high and with low Ferritin levels	1 year
30-day Mortality (Sofa score)	Differences in 30-day mortality between patients with high and with low SOFA score SOFA: Sequential Organ Failure Assessment; Range 0-4 (better to worse).	30 days
30-day Mortality (Serum Lactate)	Differences 30-day mortality between patients with high and with low Serum Lactate levels	30 days
30-day Mortality (Ferritin)	Differences 30-day mortality between patients with high and with low Ferritin levels	30 days

Collaborators and Investigators

• Sponsor: Hasselt University
• Collaborators: Jessa Hospital; University of Warwick; University of Zagreb; Claude Bernard University; AIT Austrian Institute of Technology GmbH; Molzym; BEE Robotics; Axo Science
• Investigators: Principal Investigator: Inge C Gyssens, MD, PhD, Radboud University Medical Center

Publications and helpful links

General Publications

• Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, Cron RQ, Opal SM. Interleukin-1 Receptor Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial. Crit Care Med. 2016 Feb;44(2):275-81. doi: 10.1097/CCM.0000000000001402.
• 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.
• Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, Angus DC, Rubenfeld GD, Singer M; Sepsis Definitions Task Force. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):775-87. doi: 10.1001/jama.2016.0289.
• Faix JD. Biomarkers of sepsis. Crit Rev Clin Lab Sci. 2013 Jan-Feb;50(1):23-36. doi: 10.3109/10408363.2013.764490.
• Gogos CA, Drosou E, Bassaris HP, Skoutelis A. Pro- versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options. J Infect Dis. 2000 Jan;181(1):176-80. doi: 10.1086/315214.
• Lvovschi V, Arnaud L, Parizot C, Freund Y, Juillien G, Ghillani-Dalbin P, Bouberima M, Larsen M, Riou B, Gorochov G, Hausfater P. Cytokine profiles in sepsis have limited relevance for stratifying patients in the emergency department: a prospective observational study. PLoS One. 2011;6(12):e28870. doi: 10.1371/journal.pone.0028870. Epub 2011 Dec 29. Erratum In: PLoS One. 2012;7(1). doi: 10.1371/annotation/bc7e1a29-020d-4320-8f07-4dda4147fe11.
• Kibe S, Adams K, Barlow G. Diagnostic and prognostic biomarkers of sepsis in critical care. J Antimicrob Chemother. 2011 Apr;66 Suppl 2:ii33-40. doi: 10.1093/jac/dkq523.
• Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit Care Med. 2009 Jan;37(1):291-304. doi: 10.1097/CCM.0b013e31819267fb.
• Rosario C, Zandman-Goddard G, Meyron-Holtz EG, D'Cruz DP, Shoenfeld Y. The hyperferritinemic syndrome: macrophage activation syndrome, Still's disease, septic shock and catastrophic antiphospholipid syndrome. BMC Med. 2013 Aug 22;11:185. doi: 10.1186/1741-7015-11-185.
• Schulert GS, Grom AA. Pathogenesis of macrophage activation syndrome and potential for cytokine- directed therapies. Annu Rev Med. 2015;66:145-59. doi: 10.1146/annurev-med-061813-012806. Epub 2014 Nov 5.
• Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014 Apr;6(4):748-73. doi: 10.1039/c3mt00347g.
• Carcillo JA, Simon DW, Podd BS. How We Manage Hyperferritinemic Sepsis-Related Multiple Organ Dysfunction Syndrome/Macrophage Activation Syndrome/Secondary Hemophagocytic Lymphohistiocytosis Histiocytosis. Pediatr Crit Care Med. 2015 Jul;16(6):598-600. doi: 10.1097/PCC.0000000000000460. No abstract available.
• Bennett TD, Hayward KN, Farris RW, Ringold S, Wallace CA, Brogan TV. Very high serum ferritin levels are associated with increased mortality and critical care in pediatric patients. Pediatr Crit Care Med. 2011 Nov;12(6):e233-6. doi: 10.1097/PCC.0b013e31820abca8.
• Kyriazopoulou E, Leventogiannis K, Norrby-Teglund A, Dimopoulos G, Pantazi A, Orfanos SE, Rovina N, Tsangaris I, Gkavogianni T, Botsa E, Chassiou E, Kotanidou A, Kontouli C, Chaloulis P, Velissaris D, Savva A, Cullberg JS, Akinosoglou K, Gogos C, Armaganidis A, Giamarellos-Bourboulis EJ; Hellenic Sepsis Study Group. Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis. BMC Med. 2017 Sep 18;15(1):172. doi: 10.1186/s12916-017-0930-5.
• Antonakos N, Tsaganos T, Oberle V, Tsangaris I, Lada M, Pistiki A, Machairas N, Souli M, Bauer M, Giamarellos-Bourboulis EJ. Decreased cytokine production by mononuclear cells after severe gram-negative infections: early clinical signs and association with final outcome. Crit Care. 2017 Mar 9;21(1):48. doi: 10.1186/s13054-017-1625-1.
• Gainaru G, Papadopoulos A, Tsangaris I, Lada M, Giamarellos-Bourboulis EJ, Pistiki A. Increases in inflammatory and CD14dim/CD16pos/CD45pos patrolling monocytes in sepsis: correlation with final outcome. Crit Care. 2018 Mar 3;22(1):56. doi: 10.1186/s13054-018-1977-1.
• Drewry AM, Ablordeppey EA, Murray ET, Beiter ER, Walton AH, Hall MW, Hotchkiss RS. Comparison of monocyte human leukocyte antigen-DR expression and stimulated tumor necrosis factor alpha production as outcome predictors in severe sepsis: a prospective observational study. Crit Care. 2016 Oct 20;20(1):334. doi: 10.1186/s13054-016-1505-0.
• Cazalis MA, Friggeri A, Cave L, Demaret J, Barbalat V, Cerrato E, Lepape A, Pachot A, Monneret G, Venet F. Decreased HLA-DR antigen-associated invariant chain (CD74) mRNA expression predicts mortality after septic shock. Crit Care. 2013 Dec 10;17(6):R287. doi: 10.1186/cc13150.
• Wang AY, Ma HP, Kao WF, Tsai SH, Chang CK. Red blood cell distribution width is associated with mortality in elderly patients with sepsis. Am J Emerg Med. 2018 Jun;36(6):949-953. doi: 10.1016/j.ajem.2017.10.056. Epub 2017 Nov 10.
• Kim CH, Park JT, Kim EJ, Han JH, Han JS, Choi JY, Han SH, Yoo TH, Kim YS, Kang SW, Oh HJ. An increase in red blood cell distribution width from baseline predicts mortality in patients with severe sepsis or septic shock. Crit Care. 2013 Dec 9;17(6):R282. doi: 10.1186/cc13145.
• D'Onofrio V, Heylen D, Pusparum M, Grondman I, Vanwalleghem J, Meersman A, Cartuyvels R, Messiaen P, Joosten LAB, Netea MG, Valkenborg D, Ertaylan G, Gyssens IC. A prospective observational cohort study to identify inflammatory biomarkers for the diagnosis and prognosis of patients with sepsis. J Intensive Care. 2022 Mar 9;10(1):13. doi: 10.1186/s40560-022-00602-x.
• D'Onofrio V, Van Steenkiste E, Meersman A, Waumans L, Cartuyvels R, Van Halem K, Messiaen P, Gyssens IC. Differentiating influenza from COVID-19 in patients presenting with suspected sepsis. Eur J Clin Microbiol Infect Dis. 2021 May;40(5):987-995. doi: 10.1007/s10096-020-04109-x. Epub 2020 Dec 3.

Helpful Links

• FAPIC project website

Study record dates

Study Major Dates

• Study Start (Actual): February 12, 2019
• Primary Completion (Actual): April 17, 2020
• Study Completion (Actual): April 17, 2020

Study Registration Dates

• First Submitted: February 6, 2019
• First Submitted That Met QC Criteria: February 12, 2019
• First Posted (Actual): February 15, 2019

Study Record Updates

• Last Update Posted (Actual): April 29, 2020
• Last Update Submitted That Met QC Criteria: April 28, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Blood Cultures
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections; Bacterial Infections and Mycoses; Sepsis; Bacteremia
• Other Study ID Numbers: 18.106/infect18.03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No