Clinical trial NCT01790698: Systems Medicine to Study Necrotizing Soft Tissue Infections (NSTIs).
Official title: Improving Outcome of Necrotizing Fasciitis: Elucidation of Complex Host and Pathogen Signatures That Dictate Severity of Tissue Infection
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Soft Tissue Infections
Necrotizing Fasciitis
Necrotizing Soft Tissue Infections
Keywords: Necrotizing fasciitis
Streptococcus pyogenes
Staphylococcus aureus
Immunopathogenesis
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
Collaborators: name: Rigshospitalet, Denmark
name: Karolinska University Hospital
name: Blekinge County Council Hospital
name: Sahlgrenska University Hospital
name: University of Bergen
name: Helmholtz Centre for Infection Research
name: Wageningen University
name: University of Lyon
name: LifeGlimmer GmbH
name: Anagnostics Bioanalysis GmbH
name: Lee Spark NF Foundation
name: Tel Aviv University
First posted: 2013-02-13
Enrollment: 409
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: Hospitalized patients with NSTI

Brief summary: This proposal focuses on highly lethal destructive tissue infections, i.e. necrotizing fasciitis and other necrotizing soft tissue infections (NSTIs), which are associated with high morbidity and mortality. The fulminant course of NSTIs demands immediate diagnosis and adequate interventions in order to salvage lives and limbs. However, diagnosis and management are difficult due to heterogeneity in clinical presentation, in co-morbidities and in microbiological aetiology. Thus, there is an urgent need for novel diagnostics and therapeutics in order to improve outcome of NSTIs. A comprehensive knowledge of diagnostic features, causative microbial agent, treatment strategies, and pathogenic mechanisms (host and bacterial disease traits and their underlying interaction network) is required for an improved diagnosis and management of NSTIs. The current proposal is designed to obtain such insights through an integrated systems biology approach in patients and experimental models. The project is based on a prospective NSTI patients cohort including a clinical registry to document clinical data and treatment strategies, combined with an isolate and biobank collection. The samples will be analyzed through advanced bioinformatics and computational modelling work flow to identify and quantify pathogen signatures and underlying networks that contribute to disease outcome. One aim is to translate clinical and systems biology data into development of novel diagnostics.

Detailed description: Patients will be prospectively recruited at 5 clinical centers (Rigshospitalet, Karolinska University Hospital, Blekinge University, Sahlgrenska University and University of Bergen). Clinical definition criteria for NSTI: NSTI is a clinical diagnosis. Initial signs are the occurrence of erythema, pain or tenderness beyond margins of erythema and swelling. Imaging and laboratory tests have little predictive value in the early stage. The gold standard modality for diagnosis of NSTI remains operative exploration. Operative findings that are consistent with NSTI include "dishwater or foul smelling discharge, necrosis or lack of bleeding and loss of the normal resistance of the fascia to finger dissection. A patient admitted for critical care and / or surgery due to severe soft tissue infection of the fascia, muscle or subcutaneous tissues will be enrolled in this NSTI study. The patients will be stratified based on several clinical parameters including among others SAPS score, presence of multiorgan failure, and hypotensive shock. This stratification serves to classify the patients in defined severity classes to be used in analyses and modeling. Detailed demographic and clinical information will be documented in the interactive database including: age, gender, medical history, clinical presentation (shock, multiorgan failure etc), treatment and outcome. Disease progress: The clinical database is to contain information on the spread of the infection at the different times of inspection/surgical intervention. Severity of the infections will be documented by use of the updated CREST classification scheme, SAPS III score, and the LRINEC score. Detailed information regarding antimicrobial therapy, surgical intervention, innovative therapy (IVIG and HBO) will be documented.

Samples will be collected from all enrolled patients. Standard operating procedures will be generated and implemented at all sites to ensure a quality assured collection and handling of samples. Samples to be collected include (a) isolates, (b) blood samples to be processed for DNA, RNA and plasma/cells and (c) tissue biopsies in all patients whenever surgical interventions are indicated. The samples will be analyzed using genomics, transcriptomics, metabolomics and proteomics.

Eligibility criteria: Inclusion Criteria:

Necrotizing soft tissue infections

Exclusion Criteria:

Patients under the age of 18 years

Primary outcomes:
measure: Prognostic/diagnostic value (ROC curves: specificity, sensitivity, predictive values) of classification and severity scores in NSTIs
timeFrame: 3 months - further oservation up to 24 month may apply
Secondary outcomes:
measure: Effect of IVIG and HBO-therapy on mortality rates in matched (defined by severity scores and aetiology) NSTI patients
timeFrame: 3 months - further observation up to 24 month may apply
measure: Presence of hypotension, multiorgan failure, or fatal outcome of NSTI in relation to microbiologic aetiology
timeFrame: 3 months - further observation up to 60 month may apply
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Bergen
country: Norway
facility: University of Bergen
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Karlskrona
country: Sweden
facility: Blekinge Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
Study officials:
References:
citation: Palma Medina LM, Rath E, Jahagirdar S, Bruun T, Madsen MB, Stralin K, Unge C, Hansen MB, Arnell P, Nekludov M, Hyldegaard O, Lourda M, Santos VAMD, Saccenti E, Skrede S, Svensson M, Norrby-Teglund A. Discriminatory plasma biomarkers predict specific clinical phenotypes of necrotizing soft-tissue infections. J Clin Invest. 2021 Jul 15;131(14):e149523. doi: 10.1172/JCI149523.
citation: Bergsten H, Madsen MB, Bergey F, Hyldegaard O, Skrede S, Arnell P, Oppegaard O, Itzek A, Perner A, Svensson M, Norrby-Teglund A; INFECT Study Group. Correlation Between Immunoglobulin Dose Administered and Plasma Neutralization of Streptococcal Superantigens in Patients With Necrotizing Soft Tissue Infections. Clin Infect Dis. 2020 Oct 23;71(7):1772-1775. doi: 10.1093/cid/ciaa022.