Predictive Value of Nu.Q™ Biomarkers to Help Guiding the Management of Osteoarticular Infections

Predictive Value of Nu.Q™ Biomarkers to Help Guiding the Management of Osteoarticular Infections - a Monocentric Prospective Observational Cohort Study

Diabetic foot ulcers are frequent with average lifetime risk of 15%, and can lead to bone and joint infections. Current protocols for their management include evaluation of ischemia, assessment of underlying bone infection, sharp debridement, off-loading and use of dressings that promote moist wound healing. Extensive debridement is optimal for wound healing and decreases the risk of recurrence. However, extension of surgical debridement is left at the clinician judgement and thus lacks standardised protocols. Plus, there is currently no known risk factors or specific biomarkers that can help guide the clinician for the extent of debridement or that can predict a recurrence in case of non-extensive debridement. The main objectives of the study are to either unravel a new biomarker, and/or identify risk factors associated with poor prognosis following surgical debridement in diabetic foot ulcers. Histones, more specifically H3.1 subtype, have been associated with sepsis.

The main hypothesis is that higher blood levels of H3.1 will be present in participants showing poor prognosis (i.e., having additional surgeries, amputation, death) and that a rise in H3.1 blood levels compared to baseline (before the 1st surgical intervention) would provide an early warning of relapse or treatment failure.

Study Overview

• Status: Completed
• Conditions: Diabetic Foot; Septic Arthritis; Chronic Osteomyelitis
• Intervention / Treatment: Diagnostic test: Histones H3.1 blood levels

• Study Type: Observational
• Enrollment (Actual): 30

Contacts and Locations

Study Locations

• Switzerland
  • Geneva, Switzerland, 1211
    • University Hospitals Geneva

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

All diabetic patients fulfilling the inclusion criteria with no exclusion criteria.

Description

Inclusion Criteria:

• Adults (age ≥ 18 years old) suffering from diabetes mellitus (type 1 or 2)
• Diabetic foot ulcer with severe infection (grade 3 and 4 according to IWGDF 2019 classification)
• Scheduled surgical debridement

Exclusion Criteria:

• Spondylodiscitis
• Pregnant or lactating women
• Previous enrolment in a clinical trial
• Consent declined by participant or tutor in case of incapacitation
• Tutor cannot be reached for consent in case of incapacitation

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	Intervention / Treatment
Diabetic foot ulcer with osteoarticular infections; Diabetic patients suffering from ulcer that led to an osteoarticular infection (e.g. chronic osteomyelitis, septic arthritis)	Diagnostic test: Histones H3.1 blood levels; Measure of blood concentrations of histone subtype H3.1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical failure	Presence of infection (IWGDF 2019 criteria) and No change in H3.1 blood levels from baseline (day -1) or secondary increase after an initial decline ≥ 75%	day 30 and day 60

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Death during the study period from day-1 (day of the 1st intervention)	day 30 and day 60
Amputation rate	Frequency of the event 'amputation' as incidence rate from day-1 (day of the 1st intervention)	day 1 to day 60
Additional surgical interventions rate	Frequency of the event 'additional surgical intervention' (i.e., debridement, amputation) as incidence rate from day-1 (day of the 1st intervention)	day 1 to day 60
Time-to-amputation	Measured in days from day-1 (day of the 1st intervention)	day 1 to day 60
Time-to-additional-intervention	Measured in days from day-1 (day of the 1st intervention)	day 1 to day 60

Collaborators and Investigators

• Sponsor: University Hospital, Geneva

Publications and helpful links

General Publications

• Monteiro-Soares M, Russell D, Boyko EJ, Jeffcoate W, Mills JL, Morbach S, Game F; International Working Group on the Diabetic Foot (IWGDF). Guidelines on the classification of diabetic foot ulcers (IWGDF 2019). Diabetes Metab Res Rev. 2020 Mar;36 Suppl 1:e3273. doi: 10.1002/dmrr.3273.
• Lebrun E, Tomic-Canic M, Kirsner RS. The role of surgical debridement in healing of diabetic foot ulcers. Wound Repair Regen. 2010 Sep-Oct;18(5):433-8. doi: 10.1111/j.1524-475X.2010.00619.x.
• Thiam HR, Wong SL, Qiu R, Kittisopikul M, Vahabikashi A, Goldman AE, Goldman RD, Wagner DD, Waterman CM. NETosis proceeds by cytoskeleton and endomembrane disassembly and PAD4-mediated chromatin decondensation and nuclear envelope rupture. Proc Natl Acad Sci U S A. 2020 Mar 31;117(13):7326-7337. doi: 10.1073/pnas.1909546117. Epub 2020 Mar 13.
• Wong SL, Demers M, Martinod K, Gallant M, Wang Y, Goldfine AB, Kahn CR, Wagner DD. Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat Med. 2015 Jul;21(7):815-9. doi: 10.1038/nm.3887. Epub 2015 Jun 15.
• Li Y, Liu B, Fukudome EY, Lu J, Chong W, Jin G, Liu Z, Velmahos GC, Demoya M, King DR, Alam HB. Identification of citrullinated histone H3 as a potential serum protein biomarker in a lethal model of lipopolysaccharide-induced shock. Surgery. 2011 Sep;150(3):442-51. doi: 10.1016/j.surg.2011.07.003.
• Eichhorn T, Linsberger I, Laukova L, Tripisciano C, Fendl B, Weiss R, Konig F, Valicek G, Miestinger G, Hormann C, Weber V. Analysis of Inflammatory Mediator Profiles in Sepsis Patients Reveals That Extracellular Histones Are Strongly Elevated in Nonsurvivors. Mediators Inflamm. 2021 Mar 17;2021:8395048. doi: 10.1155/2021/8395048. eCollection 2021.
• Morimont L, Dechamps M, David C, Bouvy C, Gillot C, Haguet H, Favresse J, Ronvaux L, Candiracci J, Herzog M, Laterre PF, De Poortere J, Horman S, Beauloye C, Douxfils J. NETosis and Nucleosome Biomarkers in Septic Shock and Critical COVID-19 Patients: An Observational Study. Biomolecules. 2022 Jul 27;12(8):1038. doi: 10.3390/biom12081038.

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2022
• Primary Completion (Actual): August 18, 2023
• Study Completion (Actual): October 31, 2023

Study Registration Dates

• First Submitted: October 17, 2022
• First Submitted That Met QC Criteria: October 22, 2022
• First Posted (Actual): October 25, 2022

Study Record Updates

• Last Update Posted (Actual): May 8, 2024
• Last Update Submitted That Met QC Criteria: May 7, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: diabetic foot; osteoarticular infections
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Endocrine System Diseases; Diabetic Angiopathies; Leg Ulcer; Skin Ulcer; Diabetes Complications; Diabetes Mellitus; Diabetic Neuropathies; Joint Diseases; Musculoskeletal Diseases; Arthritis; Bone Diseases; Bone Diseases, Infectious; Foot Ulcer; Diabetic Foot; Infections; Arthritis, Infectious; Osteomyelitis
• Other Study ID Numbers: 2022-00140

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