Firefighter's Longitudinal Airway and Respiratory Exposome/Multiome Study (FLARES)

Study Description:

This observational natural history study (FLARES) will define the acute and longterm airway, respiratory and immune consequences of anthropogenic smoke exposures that arise from urban and wildland urban interface (WUI) fires. Given their disproportionate exposure, firefighters will be used as a model. The protocol integrates (1) standardized clinical phenotyping, (2) detailed exposure assessment, and (3) multi-omic profiling to enable evidence-based management of smoke- and pollutant-related respiratory impairment.

FLARES will enroll firefighter recruits and active-duty firefighters. Firefighters will be followed longitudinally with twice annual visits to the NIH Clinical Center (NIH CC) and will undergo event-driven evaluations including paired pre- and postexposure assessments around planned fire exposures (eg, live fire simulations) and assessments following unplanned exposures. Systematic evaluation of the upper and lower airways will be coupled with an exposure-informed biorepository of biospecimens - blood, nasal lining fluid, particulates exhaled from deep airways and urine- for multi-omic and exposome analyses to elucidate molecular pathways of smoke- and chemical -related injury. Assessments will include sinus and chest imaging (baseline and 3-year CT with interval magnetic resonance imaging [MRI]), pulmonary function testing (PFT), and detailed exposure questionnaires. Pre/post exposure comparisons and longitudinal trajectories of firefighters will be used to identify early biomarkers, multi-omic trajectories, and clinical indices of perturbed respiratory immunity and sinopulmonary disease in relation to exposure characteristics (eg, frequency, duration, intensity, and fire type), including the growing burden of anthropogenic smoke exposures in the context of climate change.

Objectives:

Primary Objective: Assess changes in multi-omic signatures within airway epithelium/fluids, peripheral blood, and/or urine following anthropogenic smoke exposure.

Secondary Objective: Determine development or progression of upper and/or lower airway disease following anthropogenic smoke exposure at a 3-year interval.

Tertiary Objective: Assess multi-site exposome shifts following anthropogenic smoke exposure.

Exploratory Objectives:

• Perform power calculations for untargeted metabolomic signatures using data from pilot of metabolomic pathway assessment of sigmaOH-fluorenes and sigmaOHphenanthrenes pre and post live fire simulator.
• Assess multi-omic shifts following anthropogenic smoke exposure with standard fire department exposure collection data (eg, nature of biofuel, ambient conditions, personal protective equipment use and condition, decontamination practices).
• Assess organ-specific blood biomarkers on basis of omics level analysis (eg, assess markers of end-neurologic damage in the event of metabolomics pathways suggestive of neurotoxic exposures such as lead or mercury).

Endpoints:

Primary Endpoints:

Fold differences in methylation, transcription, proteomic and/or metabolic pathways:

• Initial pilot of metabolomic data will include pathway assessment of sigmaOHfluorenes and sigmaOH-phenanthrenes pre and post live fire simulator.
• Comparing baseline to acute and subacute phases of anthropogenic smoke exposures (eg, firefighter specific monitoring of either planned or unplanned smoke exposure) relative to preceding baseline.
• Comparing longitudinal changes within individual firefighters relative to time in service.

Primary endpoints may be assessed in context of acute exposures: 0-14 days after defined smoke exposure episode, subacute (15-90 days) post exposure, and chronic (repeated and/or > 90 days post exposure).

Secondary Endpoints: 3-year incidence of participant-reported symptoms corroborated by objective physiologic or inflammatory changes.

1 or more domains identified as meeting at least 1 subjective measure AND at least

1 corresponding objective measure (eg, Chronic Airway Assessment

Test [CAAT] >= 8 AND fractional exhaled nitric oxide [FeNO] > 50 ppb).

Tertiary Endpoint: Direct or estimated smoke chemical levels on wearable, under uniform monitors relative to neutral-location controls (eg, fire station or home) and post-exposure urine versus pre-exposure urine.

Exploratory Endpoints:

• Power calculation for untargeted metabolomics experiments using pilot of metabolomic pathway assessment of sigmaOH-fluorenes and sigmaOHphenanthrenes pre and post live fire simulator.
• Fold differences in methylation, transcription, proteomic and/or metabolic pathways in linear mixed-effects models adjusted for individual aspects of standard International Public Safety Data Institute (IPSDI) Exposure Tracker firefighter reporting systems.
• Direct or estimated smoke chemical levels on wearable, under uniform monitors relative to neutral-location controls (eg, fire station or home) and post-exposure urine vs. pre-exposure in linear mixed-effects models adjusted for individual aspects of standard IPSDI Exposure Tracker firefighter reporting systems.
• Comparing relative baselines of fire na(SqrRoot) ve recruits to recruits with prior exposure during standard firefighter academy training.
• Serum levels of markers indicating end organ damage downstream of identified toxins with established organ-specific effect (eg, neurofilament light chain levels in the event of high lead and mercury levels).