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Prostaglandin D2: A Key Mediator of Aspirin-Exacerbated Respiratory Disease (NIH funded)

The major goal of this project is to define the contribution of prostaglandin D2 to AERD, with the aim to determine the consequences of the release of prostaglandin D2 during aspirin-induced reactions, and of the suppression of prostaglandin D2 by high-dose aspirin treatment. By following 30 patients with AERD as they go through an aspirin desensitization and then begin treatment with high-dose or medium-dose daily aspirin therapy, we hope to understand more about what occurs immunologically during the NSAID-induced reactions, and about how daily aspirin therapy can be therapeutic for these patients.

Therapeutic Control of Aspirin-Exacerbated Respiratory Disease with Ifetroban (NIH funded)

The goal of this project is to determine whether blockade of the thromboxane A2 receptor with ifetroban improves control of symptoms in the disorder and lessens the severity of aspirin-induced reactions. Using a double-blinded, placebo-controlled trial of ifetroban, a potent and selective thromboxane receptor antagonist, we will test the hypothesis that thromboxane receptor signaling promotes eosinophilic respiratory inflammation, drives cysteinyl leukotriene overproduction, and mediates bronchoconstriction in response to thromboxane and prostaglandin D2 released during reactions to aspirin in AERD.

Mechanisms and biomarkers of therapeutic benefit of dupilumab in aspirin-exacerbated respiratory disease (Industry funded and philanthropically funded)

The aim of this study is to determine whether the therapeutic improvement provided by IL-4Rα inhibition with dupilumab in patients with AERD is due to the drug’s anti-mast cell effects, and whether an early dupilumab-induced decrease in local nasal mast cell mediators will correlate with later clinically measurable therapeutic improvement to allow for a biomarker of response. We suspect that overproduction of cysLTs from locally activated respiratory mast cells may conspire with underproduction of PGE2 from defective epithelial cells to induce an inflammatory environment sufficient to cause anosmia and severe nasal congestion. With a prospective, open-label observational clinical study, this study will follow 30 adult patients with nasal polyps and AERD who meet clinical criteria for the FDA-approved use of dupilumab for treatment of their recalcitrant nasal polyps. Clinical data and samples from both local (nasal fluid and nasal epithelial cell curettage) and systemic (blood and urine) sites will be collected at baseline, after 1 month and 3 months of dupilumab treatment.

The Effect of IL-5 and Mepolizumab on Nasal Immunoglobulin Production in Patients with AERD (Industry funded)

The aim of this study is to determine whether IL-5 signaling in the nasal polyps of patients with AERD drive an inflammatory antibody and mast cell response that would be inhibited by the therapeutic use of mepolizumab. We suspect that the therapeutic effect of mepolizumab on the upper respiratory symptoms of patients with AERD, which includes both improvement in sense of smell and improvement in nasal congestion, may be due to an effect of mepolizumab that is not solely explained by a reduction in respiratory tissue eosinophil levels. In this case-control study of 30 adult patients with AERD who are (15 cases) or are not (15 controls) treated with mepolizumab, we will measure the anti-inflammatory effects of mepolizumab on the local nasal tissue levels of antibody production and mast cell activation in patients with AERD. We will also use deep RNA sequencing to characterize the mepolizumab-induced transcriptional changes on the local nasal tissue cells.

Biobanking

In collaboration with our ENT and Otolaryngology colleagues in Boston, we have created a human tissue biorepository that collects blood, cells, urine, and nasal fluid, and samples of sinus/nasal tissue from patients undergoing elective sinus surgery with the goal of improving our understanding of the underlying causes of respiratory inflammation. These samples are stored within the Laidlaw Lab and are available to collaborators so that ongoing and future multidisciplinary research can be carried out. We have established protocols for all stages of cell processing and analysis, including histopathologic techniques as well as freezing, thawing, and culturing of isolated cells. Further, we regularly perform sinus tissue digestion and cell isolation through flow cytometric sorting, as well as single cell RNAseq from cell suspensions. As of 2020, we currently have specimens from over 600 patients within our Human Respiratory Inflammation Biorepository.

2-Year Follow-up of AERD Registry (2-FAR) Study (Industry funded and philanthropically funded)

The aim of this study is to establish the average healthcare utilization and quality-of-life burden of patients with AERD, and to determine the typical disease course and progression over a two-year period for patients with AERD. The study is a prospective, observational two-year study that will gather survey-based information from 100 patients with AERD. Currently, there is a lack of longitudinal data that describes the typical disease progression of AERD. Subsequently, the average healthcare utilization and cost burden of patients with AERD remains unknown. The completion of our study objectives will represent a step forward in the clinical management and long-term treatment of AERD, and will hopefully lay the groundwork for future prospective clinical trials.

Influence of NSAIDs and AERD on the expression and function of ACE2 – implications for SARS-CoV2 severity (NIH funded)

The aim of this study is to determine whether the use of NSAIDs increases the risk of severe complications from COVID-19, and to investigate whether patients with asthma and Type 2 respiratory inflammation are at increased risk of severe complications from COVID-19. Our results will aim to answer two key questions that are currently plaguing the ongoing clinical assessment and treatment of patients with COVID-19: (1) Does use of NSAIDs change expression of ACE2 in nasal epithelial cells or affect levels of SARS-CoV2-relevant angiotensin peptides in serum and nasal fluid? (2) Compared to healthy controls, do patients with aspirin-exacerbated respiratory disease (AERD) have altered expression of nasal ACE2 or altered levels of angiotensin peptides in serum and nasal fluid?

Impact of reported NSAID allergies on opioid use disorder in back pain and on postoperative analgesic use

These studies use retrospective chart review to investigate the impact of having a reported allergy to aspirin or another NSAID on the outcomes of pain medication prescriptions, opioid prescriptions, and the subsequent risk of sustained opioid use or of developing opioid use disorder in populations of patients who have chronic back pain or who undergo elective surgeries.

Collection and analysis of clinical characteristics of patients with NSAID hypersensitivity

This is a prospective registry of patients with a history of possible allergic reaction to aspirin or another NSAID who undergo a formal allergy evaluation and potentially oral NSAID challenge in order to better understand the risk factors for true NSAID hypersensitivities.

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