Clinical trial NCT02180906: Biomarkers in Patients With Flesh-eating Bacterial Infections
Official title: Biomarkers in Necrotizing Soft Tissue Infections - Aspects of the Innate Immune Response
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Necrotizing Soft Tissue Infection
Necrotizing Fasciitis
Gas Gangrene
Fournier Gangrene
Keywords: Fasciitis
Gangrene
Fasciitis, Necrotizing
Soft Tissue Infections
Fournier's Gangrene
Streptococcal septic shock syndrome
Flesh eating bacteria
Meleneys ulcer
Wounds and Injuries
Streptococcus pyogenes
Staphylococcus aureus
Immunopathogenesis
Soft Tissue Infections/blood
Necrosis/blood
Necrosis/diagnosis
Necrosis/mortality
Necrosis/surgery
Prognosis
Risk Factors
Bacterial Infections
Infection
Skin Diseases, Bacterial
Observational study
Biological markers
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Seventh Framework Programme
First posted: 2014-07-03
Enrollment: 169
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: All NSTI patients treated at the University Hospital of Copenhagen, Rigshospitalet

Brief summary: The purpose of this study is to investigate the immune response in patients with necrotizing soft tissue infections (NSTI). The investigation will focus on inflammatory and vasoactive biomarkers as prognostic markers of severity and mortality at admission to Rigshospitalet and the following 3 days

Detailed description: Necrotizing soft tissue infection (NSTI) is a complex, multi-factorial disease with diverse microbiological etiology and varying co-morbidities. The rapidly spreading infection may cause extensive soft tissue damage, limb loss, and multiple organ failure. The incidence of NSTIs has increased over the past years and the fatality rates are still high despite increased focus on these patients (20-30%). The extensive inflammatory response is thought to be a main course of death. However, it is unknown which biomarkers that are responsible for the deleterious effects and how these molecular mediators are modulated during the infection and treatment regimes. Thus, there is a need for novel insight into the immune system disturbances in order to improve outcome of NSTIs.

Location: Copenhagen University Hospital, Rigshospitalet, Denmark.

Design: Observational cohort study.

Cohort: NSTI patients in Denmark.

Controls: 50-100 Patients undergoing elective, orthopedic surgery at Rigshospitalet.

Biomarkers: The investigators will focus on three major groups of biomarkers: Acute-phase proteins, cytokines and vasoactive biomarkers.

Sample size calculations:

1. Acute-phase proteins: The investigators expect a mean PTX3-concentration at admission at 120 nmol/L in patients without septic shock and a mean PTX3-concentration at 210 nmol/L in patients with septic shock. With an estimated standard deviation at 100 nmol/L, the inclusion of 52 patients will be able to detect a significant difference with a statistical power of 90% at a 5% significance level. Since the groups are unequal the investigators will need to include 82 patients (N'=52(1+4)\^2/4\*4).
2. Cytokines: In a pilot study with seven NSTI patients, the investigators found a minimal clinically relevant difference in IL-6 concentration in NSTI patients with LRINEC \< 6 and ≥ 6 to be 1050 pg/ml. With an estimated standard deviation at 2000 pg/ml, the inclusion of 114 patients will be able to detect a significant difference with a statistical power of 80% at a 5% significance level.
3. Vasoactive proteins: The investigators expect a mean NOx-concentration at admission at 90 μmol/L in patients without septic shock and a mean NOx-concentration at 145 μmol/Lin patients with septic shock. With an estimated standard deviation at 70 μmol/L, the inclusion of 70 patients will be able to detect a significant difference with a statistical power of 90% at a 5% significance level. Since the groups are unequal the investigators will need to include 110 patients (N'=70(1+4)\^2/4\*4).

Data: Data will be handled according to the National Data Protection Agency. All original records (incl. consent forms and questionnaires) will be archived at trial site for 15 years. The National Data Protection Agency has approved the biobank (2007-58-0015, J. nr. 30-1282).

Ethics: The trial will adhere to the Helsinki Declaration and Danish law. The National Ethics Committee and the Regional Ethics Committee have approved the inclusion of the NSTI patients (CVK-1211709) and the control patients, including biomarker analyses (H-2-2014-071).

Biomarker analyses, data extraction and interpretation will be performed once the recruiting of participants has ended.

Eligibility criteria: Inclusion Criteria for patients with NSTI:

* Necrotizing soft tissue infection based on surgical findings
* Age \>18 years
* Admitted to/planned to be admitted to the ICU at Rigshospitalet and/or operated for NSTI at Rigshospitalet

Exclusion Criteria for patients with NSTI:

* Patients who at the operating theatre were categorized as non-NSTI patients

Inclusion Criteria for control patients:

* Patients undergoing elective orthopedic surgery (non-pathologic fractures, joint replacement surgery, back surgery) at Rigshospitalet
* Age \>18 years

Exclusion Criteria for control patients:

* Patients with ongoing infections

Primary outcomes:
measure: PTX3, NOx and IL-6 as early markers of disease severity in NSTI patients with and without septic shock
timeFrame: Admission, first 24 hours
Secondary outcomes:
measure: Mortality
timeFrame: 28, 90, 180 days
measure: Amputation rate
timeFrame: During ICU admission (expected average of 8 days)
measure: ICU-scoring systems
timeFrame: During ICU admission (expected average of 8 days)
measure: Multiple organ failure
timeFrame: During ICU admission (expected average of 8 days)
measure: Number of debridements
timeFrame: During ICU admission (expected average of 8 days)
measure: Microbial etiology
timeFrame: During ICU admission (expected average of 8 days)
measure: Time from admission to primary hospital until first surgery/debridement
timeFrame: 2 days
measure: Ventilator treatment, renal replacement therapy, vasopressor treatment during stay at ICU
timeFrame: During ICU admission (expected average of 8 days)
measure: Steroid treatment (injection/oral intake) up to development of NSTI
timeFrame: Up to 7 days before surgical diagnose at primary hospital
measure: Inflammatory biomarkers
timeFrame: Admission and the following 3 days
measure: Vasoactive biomarkers
timeFrame: Admission and the following 3 days
measure: The effects of immunoglobulin on inflammatory biomarkers
timeFrame: Admission and the following 3 days
measure: Biomarkers and Severity of disease
timeFrame: Admission and the following 3 days
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Copenhagen University Hospital, Rigshospitalet
Study officials:
affiliation: Rigshospitalet, Denmark
name: Marco Bo Hansen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rigshospitalet, Denmark
name: Ole Hyldegaard, MD, PhD
role: STUDY_DIRECTOR
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citation: Kristensen MK, Hansen MB, Madsen MB, Hansen CB, Pilely K, Hyldegaard O, Garred P. Complement Activation Is Associated With Mortality in Patients With Necrotizing Soft-Tissue Infections-A Prospective Observational Study. Front Immunol. 2020 Jan 31;11:17. doi: 10.3389/fimmu.2020.00017. eCollection 2020.
citation: Hansen MB, Rasmussen LS, Garred P, Bidstrup D, Madsen MB, Hyldegaard O. Pentraxin-3 as a marker of disease severity and risk of death in patients with necrotizing soft tissue infections: a nationwide, prospective, observational study. Crit Care. 2016 Feb 15;20:40. doi: 10.1186/s13054-016-1210-z.
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