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Mechanisms of benefit of IL4Ra inhibition in Aspirin-Exacerbated Respiratory Disease (AERD); MARINER Study (NIH funded)

The aim of this study is to determine the mechanisms by which the biologic medication dupilumab (anti-IL-4α) decreases nasal polyp burden and improves sense of smell in patients with nasal polyps and AERD. Using a prospective, open-label observational clinical study, approximately 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 will be followed to better understand how 8 weeks of dupilumab treatment affects clinical measures of disease severity in AERD, including nasal polyp burden, sense of smell, nasal congestion, respiratory-related quality of life, lung function, and asthma control. Clinical data and samples from both local (nasal fluid and nasal polyp biopsy) and systemic (blood and urine) sites will be collected at baseline, after 2 weeks, and after 8 weeks of treatment with dupilumab and will be analyzed for a set of mechanistic assays to determine which cellular changes correlate with clinical benefit.

Global immunologic effects of IL-4Rα inhibition and dupilumab-associated arthralgia; GLIDER Study (NIH funded)

This study aims to understand whether inhibition of IL-4Rα through therapeutic use of dupilumab (A) establishes a local immunologic environment that is more inclined towards the develop of tolerogenic T cells and/or (B) induces a systemic immune pathway shift away from Th2 but towards Th1- or Th17-mediated inflammation. Blood and nasal fluid samples are collected from patients with AERD before and after initiation of dupilumab, including from any patients who have developed dupilumab-associated arthralgia, and from healthy controls. Plasma and nasal fluid samples are analyzed with proteomics platforms to detect differences in relevant cytokine levels, and PBMCs are analyzed for T cell subsets and lymphocyte activation.

Impact of reported NSAID allergies on post-operative opioid prescribing and sustained opioid use (NIH-funded)

The goal of this project is to leverage the power of large electronic health record-based datasets 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 development of opioid use disorder. Specific populations of interest include patients undergoing orthopaedic and other elective surgeries, and obstetric patients around and after childbirth.

Collection and analysis of clinical characteristics of patients with NSAID hypersensitivity (NIH-funded)

This is a clinical 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. Through study of these participants, we demonstrated the safety of performing two-step oral NSAID challenges in the outpatient setting, and this testing protocol has been featured in the national American Academy of Allergy, Asthma and Immunology (AAAAI) newsletter and referenced in the 2022 AAAAI Drug Allergy Practice Parameter update. As of December 2022, there are a total of >480 participants in the registry and prospective recruitment is ongoing.

Immune Tolerance in Allergy & Asthma, Immune Tolerance Network (ITN) (NIH funded)

The Immune Tolerance Network is a collaborative network for clinical research funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH. The ITN designs, runs, and oversees clinical trials in several disease areas including allergy and asthma, autoimmunity, type 1 diabetes, and organ transplantation.  The allergy and asthma portfolio seeks to modify validated allergen desensitization protocols to induce durable tolerance, with an emphasis on protocols that combine immunotherapy with an adjuvant (“allergen plus”).  There is also an emphasis on mechanistic research in association with the clinical trials to advance our knowledge of how to induce tolerance.  Members of the Laidlaw Lab oversee the allergy and asthma portfolio of the ITN.

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.

AERD Registry

The purpose of this research study is to collect clinical information from patients with aspirin-exacerbated respiratory disease (AERD) which is stored in our secure database for analysis. We use this information to learn more about symptoms of AERD, patients’ experience with the disease, generate new research ideas, and to hopefully come up with better treatment options in the future. As of 2023, we currently have over 2,600 patients with AERD enrolled in our registry! Some recent data from our registry showed that on a scale of 0-5, 22.8% of our patients ranked their decreased sense of taste/smell as a 4 (severe problem) and 45.5% of patients ranked it as a 5 (problem as bad as it can be). This taught us that as researchers and healthcare providers, we need to pay more attention to the effects of anosmia, or loss of smell, and it inspired us to launch a new study about the potential impacts of smell loss.

Association of reported aspirin and NSAID allergies on cardiovascular outcomes (NIH-funded)

This study will use cohorts of patients who have experienced acute coronary events to determine whether presence of reported aspirin and NSAID allergies may increase risk for poor cardiovascular outcomes over 12 months of follow-up. Because reported aspirin and NSAID allergies often do not reflect an absolute inability to tolerate these medications, determination of the risks conferred by drug allergy labeling may help identify and target the highest-risk populations for allergist evaluation in order to improve patient safety and quality of care.

Role of IL-5 on nasal polyp plasma cells and epithelial cells; RECAP-5 Study (Industry funded)

The aim of this study is to determine the role of IL5Rα expression and IL-5 signaling on cell types in the airway other than eosinophils, including epithelial cells and plasma cells, particularly for cells in the nasal polyps of AERD patients. We suspect that the therapeutic benefits of the anti-IL-5 biologic mepolizumab, which has shown to reduce nasal polyp size and improve sense of smell and congestion for some patients, may be due to IL-5 signaling blockade on cells other than airway eosinophils. Therefore, in a study of sinus tissues from patients with AERD, nasal polyps, chronic sinusitis, and healthy control patients, we will measure the expression of IL5Rα in nasal polyp epithelial and plasma cells, and will determine the consequences of IL-5 stimulation on those cell types in vitro. Our early results so far have shown that IL5Rα is expressed at around 3-4 weeks in maturing nasal epithelial cells. Further analysis will characterize the transcriptional and functional cellular changes that occur during IL-5 stimulation. This will ultimately allow us to understand the significance of IL5Rα expression on these cells.

Human Sample Biorepository and Allocation Core

In collaboration with our ENT/Otolaryngology colleagues in Boston, we have developed a biorepository that provides both stored and fresh samples to collaborators for the advancement of biomedical research. Samples are obtained from participants undergoing elective sinus surgery and include sinus tissue, nasal polyp tissue, nasal fluid, nasal scrapings, nasal brushings, plasma/serum, peripheral blood mononuclear cells, and urine. Participants with the following medical diagnoses are included in the repository: aspirin-exacerbated respiratory disease (AERD), chronic rhinosinusitis with nasal polyposis (CRSwNP), chronic rhinosinusitis without nasal polyposis (CRSsNP), other sinus diseases, and healthy volunteers. All samples are linked to a clinical database as well. 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. Notable protocols have been published in peer-reviewed journals. These samples are stored within the Laidlaw Lab and are available to collaborators so that ongoing and future multidisciplinary research can be carried out. Carolyn Baloh, MD, serves as the director for the biorepository.

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