Research

It has been shown that inhibiting IL-5 signaling can provide therapeutic benefits for patients with CRSwNP and AERD, whose IL-5Rα are overexpressed. While the efficacy of anti-IL-5 biologics for CRSwNP had been initially attributed to their actions on eosinophils, there is also IL-5Rα expression on nasal plasma cells and epithelial cells in the nasal polyps. By using plasma cells isolated from nasal polyp biopsies and by growing nasal epithelial cells through air-liquid interfaces (ALI), we hope to unravel the underlying mechanisms of IL-5 inhibition on these cell types. The objective is to gain insights into the off-target effects of anti-IL5 treatment in patients with CRSwNP and AERD – these laboratory studies will help us more fully understand the relevance of IL-5 in respiratory inflammation.

The results from our work in this area thus far have recently been published. Those papers are: “Human nasal epithelial cells express IL-5Rα but not the co-receptor CSF2RB and do not signal to IL-5” published in 2024 and “Nasal polyp antibody secreting cells display proliferation signature in aspirin-exacerbated respiratory disease” published in 2024.

This study is focused on identification of biomarkers associated with nasal polyp recurrence following endoscopic sinus surgery (ESS) in patients with aspirin-exacerbated respiratory disease (AERD) and chronic rhinosinusitis with nasal polyps (CRSwNP). Many patients with CRSwNP and AERD have recurrence of disease following ESS, even with adjuvant treatments such as aspirin therapy after desensitization or intranasal corticosteroids, which can prevent nasal polyp recurrence after ESS in some patients. We are utilizing samples collected from patients pre-operatively to identify biomarkers in the nasal fluid and tissue that are associated with poor post-operative outcomes. These studies will advance our understanding of the pathogenesis of AERD and CRS and will lead to the identification of novel diagnostic tests and therapeutic targets for these diseases.

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.

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.

The first results from our work in this area have been published as “The IL-4Rα signaling promotes barrier-altering oncostatin M and IL-6 production in AERD” in 2024.

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.

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.

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. https://www.immunetolerance.org/researchers/clinical-trials/allergy-asthma

Asthma is a heterogeneous disease encompassing several different clinical phenotypes, but the current approach to asthma endotyping relies primarily on FeNO and a limited set of blood-based biomarkers: serum IgE and blood eosinophils. While these markers can identify “Type 2 high” asthma, they miss other endotypes, and even within Type 2 high asthma, many patients don’t respond to therapies targeting eosinophils or IgE, suggesting additional, unidentified inflammatory pathways. Hunts for additional differentiating biomarkers in the blood have failed. Nasal mucosal fluid can be collected non-invasively and we suspect it will be a useful source for biomarkers of respiratory disease. This study aims to identify novel asthma biomarkers by analyzing the inflammatory milieu of upper respiratory tract nasal fluid. We will define the proteomic landscape of nasal fluid in different cohorts of asthmatic patients and non-asthmatic controls, and will compare the proteomic profiles of nasal fluid and paired plasma samples in different disease endotypes.

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.

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.