Real-Time Diagnosis of Life-Threatening Necrotizing Soft Tissue Infections (NSTI) Using Indocyanine Green (ICG) Kinetic Modeling

Necrotizing soft-tissue infections (NSTIs, a.k.a. "necrotizing fasciitis" or "flesh-eating bacteria") are aggressive infections that can progress rapidly from mild symptoms to sepsis, multi-organ failure, and death. NSTI cases present with non-specific clinical, imaging, and laboratory findings, and standard-of-care techniques for NSTI diagnosis lack sensitivity and specificity, resulting in frequent misdiagnosis and delayed care, which is the single most important predictor of survival. Consequently, the cumulative mortality rate for patients with NSTIs is 20- 30%; a dire need exists for more accurate and rapid detection of NSTIs. Fluorescence-guided surgery is a nascent technology seeking to improve the recognition of anatomical structures and disease processes using fluorescent probes (fluorophores). Indocyanine green (ICG) is an FDA-approved, near-infrared fluorophore with a >60-year safety record for vascular perfusion assessment. A distinguishing histological feature of NSTIs is prominent blood vessel thrombosis in affected tissues. Leveraging these pro-thrombotic effects, our study group has demonstrated in a first-in-human study (NCT04839302) that intravenous administration of ICG and immediate fluorescence imaging reveals prominent signal deficits in NSTI-positive tissues that differentiate significantly with increased signal seen with more common-and less virulent-infections such as cellulitis. We seek now to evaluate this imaging technique on a broader scale and determine if our findings are consistent for patients affected by NSTI-causing pathogens that are not endemic to our region. This prospective, observational, multicenter clinical study will involve video-rate ICG fluorescence imaging of patients suspected of having NSTIs who present to eight tertiary, Level 1 medical centers across the United States (Aim 1). Using dynamic contrast-enhanced fluorescence imaging (DCE-FI), time profiles of ICG fluorescence intensity from different tissue pixels/regions will be extracted and parameterized to extract first-pass kinetic features. These DCE-FI features, which characterize tissue perfusion, will be evaluated alone and in combination with anonymized electronic medical record data to create a DCE-FI-based clinical decision tool and a machine- learning-based fusion (DCE FI+lab/imaging data) tool; these will be compared to identify the most accurate means of diagnosing NSTIs (Aim 2). The best-performing tool will then be evaluated-compared to current diagnostic tests-in a prospective observational clinical study of patients presenting to tertiary emergency departments with findings concerning for NSTIs (Aim 3). Based on our human study, fluorescence imaging will not delay current standard of care. To ensure data fidelity, all sites will use similar: 1) commercial fluorescence imaging systems and accessories; and 2) validated commercial fluorescence reference phantoms. Based on our early results, we have strong confidence that following rigorous testing, ICG DCE-FI will lead to an entirely new methodology for rapid identification of patients with NSTIs, which will ultimately reduce patient morbidity and improve survival.

Study Overview

• Status: Recruiting
• Conditions: Necrotizing Fascitis
• Intervention / Treatment: Diagnostic test: Administration of indocyanine green (ICG) and fluorescence imaging

• Study Type: Observational
• Enrollment (Estimated): 420

Contacts and Locations

• Study Contact: Name: Eric R Henderson, MD; Phone Number: 603-650-5133; Email: Eric.R.Henderson@hitchcock.org
• Study Contact Backup: Name: Morgan T Mazanec, MPH; Phone Number: 603-308-9233; Email: Morgan.T.Mazanec@Hitchcock.ORG

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Not yet recruiting
      • University of California, Los Angeles
      • Principal Investigator: Christopher Lee, MD
      • Contact: Christopher Lee, MD; Phone Number: 310-319-1234; Email: ChristopherLee@mednet.ucla.edu
      • Sub-Investigator: Nicholas Bernthal, MD
    • Stanford, California, United States, 94305
      • Recruiting
      • Stanford University
      • Principal Investigator: Joseph Forrester, MD
      • Contact: Joseph Forrester, MD; Email: jdf1@stanford.edu
      • Sub-Investigator: Ariel Knight, MD
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory University/Grady Memorial Hospital
      • Contact: Morgan Fuller; Phone Number: (404) 251-8953; Email: jaimo.ahn@emory.edu
      • Principal Investigator: Jaimo Ahn, MD, PhD
  • Michigan
    • Ann Arbor, Michigan, United States, 48104
      • Recruiting
      • University of Michigan
      • Contact: Molly Hunter, MD; Email: huntmary@med.umich.edu
      • Principal Investigator: Molly Hunter, MD
      • Principal Investigator: Raymond Jean, MD
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Recruiting
      • Dartmouth-Hitchcock Medical Center
      • Contact: Eric R Henderson, MD; Phone Number: 603-650-5133; Email: Eric.R.Henderson@hitchcock.org
      • Sub-Investigator: Jonathan Elliot, PhD
      • Sub-Investigator: Samuel S Streeter, PhD
      • Sub-Investigator: Macgregor Montano, PharmD
      • Sub-Investigator: Scott Rodi, MD
      • Principal Investigator: Eric R Henderson, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania
      • Contact: Niels Martin, MD, PhD; Email: Niels.Martin@pennmedicine.upenn.edu
      • Principal Investigator: Niels Martin, MD, PhD
      • Sub-Investigator: Sunil Singhal, MD, PhD
      • Sub-Investigator: Jane Keating, MD
    • Pittsburgh, Pennsylvania, United States, 15213
      • Not yet recruiting
      • University of Pittsburgh Medical Center
      • Contact: Kurt Weiss, MD; Phone Number: (412) 802-4137; Email: weiskr@UPMC.EDU
      • Principal Investigator: Kurt Weiss, MD
  • Tennessee
    • Nashville, Tennessee, United States, 37235
      • Recruiting
      • Vanderbilt University
      • Contact: Jonathan Schoenecker, MD, PhD; Phone Number: (615) 936-3391; Email: jon.schoenecker@vumc.org
      • Principal Investigator: Jonathan Schoenecker, MD, PhD
      • Sub-Investigator: William Obremskey, MD
      • Sub-Investigator: Eben Rosenthal, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients presenting to the ED or clinic who are considered at intermediate- or high-risk for NSTI.

Description

Inclusion Criteria:

• Age ≥18 years.
• Clinical suspicion of NSTI based on the local standard of care warranting:
• Hospital admission for observation due to suspected NSTI; and/or
• Soft tissue biopsy to rule in/out suspected NSTI; and/or
• Surgical debridement for suspected NSTI; and/or
• Specific institutional threshold criteria for triggering NSTI work-up; and
• Ability to give written informed consent.

Exclusion Criteria:

• History of allergy to ICG and/or iodine.
• Pregnant women or nursing mothers.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine if tissue perfusion, determined by first-pass ICG fluorescence kinetics, is reliably reduced in the setting of a necrotizing infection compared to a non-necrotizing infection.	We will evaluate first-pass fluorescence signal intensity changes from indocyanine green (ICG), a vascular perfusion fluorophore, in the setting of severe soft-tissue infections to determine if ICG fluorescence may be an accurate and reliable diagnostic test for differentiating life-threatening necrotizing infections from non-life-threatening non-necrotizing infections.	From enrollment to the end of fluorescence imaging (about 1 day)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine if first-pass ICG fluorescence kinetics in patients with necrotizing infections vary based on the causative bacterial species.	In patients who had a documented necrotizing soft-tissue infection, we will compare first-pass fluorescence signal intensity changes from ICG based on the predominant causative bacterial species isolated from a patient's infection to determine if ICG signal changes vary by species.	From enrollment to the end of imaging and lab results (about 30 days)

Collaborators and Investigators

• Sponsor: Eric R. Henderson
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2025
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): July 1, 2030

Study Registration Dates

• First Submitted: March 10, 2025
• First Submitted That Met QC Criteria: March 10, 2025
• First Posted (Actual): March 14, 2025

Study Record Updates

• Last Update Posted (Actual): March 19, 2026
• Last Update Submitted That Met QC Criteria: March 17, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Fasciitis; Fasciitis, Necrotizing; Investigative Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Imaging; Optical Imaging
• Other Study ID Numbers: 02002719; 1R01AI184513-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data will only be shared in aggregate.

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No