Systems Medicine to Study Necrotizing Soft Tissue Infections (NSTIs). (INFECT)

Improving Outcome of Necrotizing Fasciitis: Elucidation of Complex Host and Pathogen Signatures That Dictate Severity of Tissue Infection

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.

Study Overview

• Status: Completed
• Conditions: Soft Tissue Infections; Necrotizing Fasciitis; Necrotizing Soft Tissue Infections

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.

• Study Type: Observational
• Enrollment (Actual): 409

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet
• Norway
  • Bergen, Norway, 5021
    • University of Bergen
• Sweden
  • Gothenburg, Sweden, SE-416 50
    • Sahlgrenska University Hospital
  • Karlskrona, Sweden, SE-371 85
    • Blekinge Hospital
  • Stockholm, Sweden, SE-171 76
    • Karolinska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Hospitalized patients with NSTI

Description

Inclusion Criteria:

Necrotizing soft tissue infections

Exclusion Criteria:

Patients under the age of 18 years

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Prognostic/diagnostic value (ROC curves: specificity, sensitivity, predictive values) of classification and severity scores in NSTIs	3 months - further oservation up to 24 month may apply

Secondary Outcome Measures

Outcome Measure	Time Frame
Effect of IVIG and HBO-therapy on mortality rates in matched (defined by severity scores and aetiology) NSTI patients	3 months - further observation up to 24 month may apply
Presence of hypotension, multiorgan failure, or fatal outcome of NSTI in relation to microbiologic aetiology	3 months - further observation up to 60 month may apply

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Collaborators: Karolinska University Hospital; Rigshospitalet, Denmark; University of Bergen; Tel Aviv University; Sahlgrenska University Hospital, Sweden; Wageningen University; University of Lyon; Blekinge County Council Hospital; Helmholtz Centre for Infection Research; LifeGlimmer GmbH; Anagnostics Bioanalysis GmbH; Lee Spark NF Foundation

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• website of INFECT

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (ACTUAL): June 1, 2017
• Study Completion (ACTUAL): January 1, 2018

Study Registration Dates

• First Submitted: February 4, 2013
• First Submitted That Met QC Criteria: February 11, 2013
• First Posted (ESTIMATE): February 13, 2013

Study Record Updates

• Last Update Posted (ACTUAL): April 23, 2018
• Last Update Submitted That Met QC Criteria: April 20, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Staphylococcus aureus; Streptococcus pyogenes; Immunopathogenesis; Necrotizing fasciitis
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Musculoskeletal Diseases; Infections; Communicable Diseases; Soft Tissue Infections; Fasciitis; Fasciitis, Necrotizing
• Other Study ID Numbers: INFECT-FP7305340