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| Name | Class |
|---|---|
| Seventh Framework Programme | OTHER |
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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
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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patients with NSTI | Definition: An infection that requires acute hospitalization with intensive care treatment and/or surgery as a consequence of severe soft tissue infection in subcutis, muscle and/or fascia and are spreading along tissue structures. |
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| Measure | Description | Time Frame |
|---|---|---|
| PTX3, NOx and IL-6 as early markers of disease severity in NSTI patients with and without septic shock | Primary analysis: Association between PTX3-, NOx-, and IL6-concentration and septic shock (PTX3, NOx) or LRINEC ≥ 6 (IL-6) in NSTI patients at time of admission to Rigshospitalet | Admission, first 24 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Mortality | 28, 90, 180 days | |
| Amputation rate | At any anatomical site | During ICU admission (expected average of 8 days) |
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Inclusion Criteria for patients with NSTI:
Exclusion Criteria for patients with NSTI:
Inclusion Criteria for control patients:
Exclusion Criteria for control patients:
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All NSTI patients treated at the University Hospital of Copenhagen, Rigshospitalet
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| Name | Affiliation | Role |
|---|---|---|
| Marco Bo Hansen, MD | Rigshospitalet, Denmark | Principal Investigator |
| Ole Hyldegaard, MD, PhD | Rigshospitalet, Denmark | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Copenhagen University Hospital, Rigshospitalet | Copenhagen | 2100 | Denmark |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 15817551 | Background | Hasham S, Matteucci P, Stanley PR, Hart NB. Necrotising fasciitis. BMJ. 2005 Apr 9;330(7495):830-3. doi: 10.1136/bmj.330.7495.830. | |
| 22822005 | Background | Sultan HY, Boyle AA, Sheppard N. Necrotising fasciitis. BMJ. 2012 Jul 20;345:e4274. doi: 10.1136/bmj.e4274. No abstract available. |
| Label | URL |
|---|---|
| Research website: INFECT-study. Further description of funding from EU 7th Framework Programme | View source |
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| ID | Term |
|---|---|
| D019115 | Fasciitis, Necrotizing |
| D005738 | Gas Gangrene |
| D018934 | Fournier Gangrene |
| D005208 | Fasciitis |
| D005734 | Gangrene |
| D018461 | Soft Tissue Infections |
| D014947 | Wounds and Injuries |
| D013203 | Staphylococcal Infections |
| D009336 | Necrosis |
| D004194 | Disease |
| D001424 | Bacterial Infections |
| D007239 | Infections |
| D017192 | Skin Diseases, Bacterial |
| ID | Term |
|---|---|
| D009140 | Musculoskeletal Diseases |
| D003015 | Clostridium Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
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Whole blood and plasma/serum
| ICU-scoring systems |
SAPS II (day 1) APACHE II (day 1) SOFA, GCS excluded (day 1-7), Anaya-score |
| During ICU admission (expected average of 8 days) |
| Multiple organ failure | During ICU admission (expected average of 8 days) |
| Number of debridements | During ICU admission (expected average of 8 days) |
| Microbial etiology | Tissue and blood samples | During ICU admission (expected average of 8 days) |
| Time from admission to primary hospital until first surgery/debridement | 2 days |
| Ventilator treatment, renal replacement therapy, vasopressor treatment during stay at ICU | During ICU admission (expected average of 8 days) |
| Steroid treatment (injection/oral intake) up to development of NSTI | Up to 7 days before surgical diagnose at primary hospital |
| Inflammatory biomarkers | Secondary analysis: The association between inflammatory biomarkers such as CRP, procalcitonin, mannose-binding-lectin and ficolin-1,2,3, cytokines and septic shock, LRINEC ≥ 6 and SAPS II at admission and the following 3 days | Admission and the following 3 days |
| Vasoactive biomarkers | Secondary analysis: The association between vasoactive biomarkers such as NOx (nitrite, NO2-, and nitrate, NO3-,), L-arginine, asymmetric dimethylarginine, hydrogen sulfide, reactive oxygen species, ICAM-1, E-selectin and septic shock, LRINEC ≥ 6 and SAPS II at admission and the following 3 days | Admission and the following 3 days |
| The effects of immunoglobulin on inflammatory biomarkers | A subgroup analysis will be performed on patients randomized to immunoglobulin or saline as immunoglobulin might affect the biomarker response (PTX3, NO, IL-6). The randomized double-blinded study was initiated April 2014 and registered at ClinicalTrials.gov (NCT02111161). | Admission and the following 3 days |
| Biomarkers and Severity of disease | Subgroup analysis: Systemic inflammatory response syndrome, sepsis, severe sepsis and septic shock will be diagnosed according to standardized criteria (American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee) and the biomarkers will be investigated to see if there is a correlation between disease severity and mortality in these groups. | Admission and the following 3 days |
| 17440360 | Background | Golger A, Ching S, Goldsmith CH, Pennie RA, Bain JR. Mortality in patients with necrotizing fasciitis. Plast Reconstr Surg. 2007 May;119(6):1803-1807. doi: 10.1097/01.prs.0000259040.71478.27. |
| 11445697 | Background | Muller B, Peri G, Doni A, Torri V, Landmann R, Bottazzi B, Mantovani A. Circulating levels of the long pentraxin PTX3 correlate with severity of infection in critically ill patients. Crit Care Med. 2001 Jul;29(7):1404-7. doi: 10.1097/00003246-200107000-00017. |
| 24039869 | Background | Bastrup-Birk S, Skjoedt MO, Munthe-Fog L, Strom JJ, Ma YJ, Garred P. Pentraxin-3 serum levels are associated with disease severity and mortality in patients with systemic inflammatory response syndrome. PLoS One. 2013 Sep 9;8(9):e73119. doi: 10.1371/journal.pone.0073119. eCollection 2013. |
| 15640628 | Background | Panacek EA, Marshall JC, Albertson TE, Johnson DH, Johnson S, MacArthur RD, Miller M, Barchuk WT, Fischkoff S, Kaul M, Teoh L, Van Meter L, Daum L, Lemeshow S, Hicklin G, Doig C; Monoclonal Anti-TNF: a Randomized Controlled Sepsis Study Investigators. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med. 2004 Nov;32(11):2173-82. doi: 10.1097/01.ccm.0000145229.59014.6c. |
| 18959694 | Background | Su YC, Chen HW, Hong YC, Chen CT, Hsiao CT, Chen IC. Laboratory risk indicator for necrotizing fasciitis score and the outcomes. ANZ J Surg. 2008 Nov;78(11):968-72. doi: 10.1111/j.1445-2197.2008.04713.x. |
| 32082310 | Derived | 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. |
| 26880104 | Derived | 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. |
| 25967993 | Derived | Hansen MB, Simonsen U, Garred P, Hyldegaard O. Biomarkers of necrotising soft tissue infections: aspects of the innate immune response and effects of hyperbaric oxygenation-the protocol of the prospective cohort BIONEC study. BMJ Open. 2015 May 11;5(5):e006995. doi: 10.1136/bmjopen-2014-006995. |
| D005832 | Genital Diseases, Male |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012874 | Skin Diseases, Infectious |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |