Current/Ongoing Research Studies
To see if you are eligible for any of our studies or for more information about the studies, please contact one of our Patient Coordinators, at firstname.lastname@example.org. Click HERE for more information on AERD-related research in the Laidlaw Lab at Brigham and Women’s Hospital.
Past Research Studies
Trial of thromboxane receptor inhibition with ifetroban: TP receptors regulate eicosanoid homeostasis in aspirin-exacerbated respiratory disease
This clinical trial compared one month of treatment with ifetroban (a medication that blocks the thromboxane A2 receptor) to placebo in patients with AERD, to see if the ifetroban treatment decreased the severity of aspirin-induced reactions. Unfortunately, there was a small signal that actually the treatment with ifetroban actually worsened patients’ reactions to aspirin. This was unexpected, and to further understand why, additional studies were done, that showed that ifetroban inhibited the production of prostaglandin E2 and increased the levels of cysteinyl leukotrienes, which likely explains why our patients had a negative response to it.
In a collaboration with Knopp Biosciences, Dr. Tanya M. Laidlaw and colleagues designed a study to examine the efficacy dexpramipexole in AERD. Dexpramipexole is an eosinophil-lowering medication that was originally developed for the treatment of ALS. Sixteen patients with nasal polyps (several of whom also had AERD) were enrolled in the study and stayed on the drug for 6 months. Dexpramipexole profoundly lowered eosinophil counts in peripheral blood and nasal polyp tissue; however, patients did not report improvement of symptoms of underlying disease. Though the trial was unsuccessful in finding a new treatment for nasal polyps and AERD, it does force us to rethink the role that eosinophils do or do not play in the disease. Indeed, we now need to consider looking for medications that do more than simply reduce eosinophil counts.
A trial of type 12 purinergic (P2Y12) receptor inhibition with prasugrel identifies a potentially distinct endotype of patients with aspirin-exacerbated respiratory disease.
This study was conducted by Dr. Laidlaw and colleagues of the AERD Center at Brigham and Women’s Hospital. In this double-blind cross-over study, patients were given a platelet-inhibiting medication, prasugrel, or placebo, to determine if prasugrel would minimize reactions to aspirin during an aspirin challenge. After 4 weeks of taking prasugrel or placebo, patients were challenged to aspirin and their symptoms were recorded. There were no significant differences between the aspirin-induced reactions on prasugrel vs placebo for the majority of study measurements. However, a small subset of patients with greater platelet activation and mild upper-respiratory symptoms, experienced no reaction at all during their aspirin challenge after taking prasugrel. This suggests that P2Y12 receptor signaling may be important in a subset of AERD patients. While it did not identify a new medical intervention, the study did teach us more about the disease, particularly about variability among AERD patients. This study helped us to better understand the role of platelets in AERD and helps guide further research looking into potential therapies.
Dietary Fatty Acid Modification for the Treatment of Aspirin-Exacerbated Respiratory Disease: A Prospective Pilot Trial
This study, done by Dr. Laidlaw and the research team at the Brigham and Women’s Hospital AERD Center, was published in 2018 in The Journal of Allergy and Clinical Immunology, In Practice. Based on observations provided by patients with AERD, who reported that certain dietary modifications seemed to improve their health, the investigators aimed to determine if a two-week diet high in omega-3 fatty acids and low in omega-6 fatty acids would be efficacious for the treatment of AERD. It is known that cysteinyl leukotrienes, which are inflammatory lipids present in very high levels in patients with AERD, are derived from the metabolism of omega-6 fatty acids. Therefore it was hypothesized that reducing the omega-6 precursors to the leukotrienes would reduce leukotriene production and decrease inflammation. 10 patients with AERD completed the dietary intervention. Both urinary leukotriene E4 and urinary prostaglandin D2 metabolites decreased after two weeks on the diet. Furthermore, both sinus symptoms and asthma control improved significantly while on the diet. The authors concluded that a high omega-3/low omega-6 diet may be an appropriate adjunct treatment option for patients with AERD, and they now routinely offer dietary changes as a treatment option for their patients with AERD.
Alcohol-induced Respiratory Symptoms Are Common in Patients With Aspirin Exacerbated Respiratory Disease.
With this survey study, done in collaboration with Dr. White at the Scripps Clinic, we found that the prevalence of alcohol-induced upper (runny nose and/or nasal congestion) respiratory reactions in patients with AERD was 75% and the prevalence of alcohol-induced lower (wheezing and/or shortness of breath) respiratory reactions in AERD was 51%. These reactions were generally not specific to one type of alcohol and often occurred after ingestion of only a few sips of alcohol. Therefore we concluded that alcohol ingestion causes respiratory reactions in the majority of patients with AERD, and clinicians should be aware that these alcohol-induced reactions are significantly more common in AERD than in controls who are aspirin tolerant. The results of the study have been published in the Journal of Allergy & Clinical Immunology: In Practice.
Leukotriene E4 (LTE4) is present at very high levels in the respiratory tissues and urine of patients with AERD. For reasons that are unknown, patients with AERD are much more sensitive to wheezing and inflammation caused by LTE4 than asthmatic patients who do not have AERD. This study, done by Dr. Parachuri and colleagues in the laboratory of Dr. Boyce, was published in 2009 in The Journal of Experimental Medicine, showed that LTE4, in contrast to the other leukotrienes, does not work through the receptors for leukotrienes that are blocked by montelukast or other available asthma drugs. Instead, LTE4 acts through platelets and P2Y12 receptors (the targets of certain antiplatelet drugs that are used to prevent heart attacks and strokes) to promote inflammation and airway damage in mice. Thus, the P2Y12 receptor could be a therapeutic target for asthma. This may be especially true in AERD, since that disease is associated with both high levels of LTE4 in the urine and hyperresponsiveness to LTE4
Cysteinyl leukotriene overproduction in aspirin exacerbated respiratory disease is driven by platelet-adherent leukocytes
This study, done by Dr. Laidlaw and colleagues in the laboratory of Dr. Boyce, was published in 2012 by the journal Blood, investigated the role of platelet-adherent white blood cells (leukocytes) in cysteinyl leukotriene overproduction in patients with AERD. Increased percentages of neutrophils, eosinophils, and monocytes with adherent platelets were found in the blood of patients with AERD when compared with those seen in aspirin-tolerant control subjects. The adherent platelets resulted in higher levels of cysteinyl leukotriene production by activated granulocytes. The levels of LTE4 in the urine (which is one of the predictors of how severe a reaction to aspirin may be in a patient with AERD) were strongly correlated with the frequency of circulating platelet-adherent granulocytes in the blood. This study suggests that platelets, which were not previously considered to play a role in AERD, may be a critical part of the process by which leukotrienes are over-produced in AERD. Because leukotrienes are thought to cause many of the signs and symptoms of AERD, the authors speculated that antiplatelet therapies might be useful as treatment for AERD. Such therapies are part of the focus of our clinical trials.