Publications

Rose C Corcoran, Laura B Bailey, Alyson N Brown, Kathleen M Buchheit, Jillian C Bensko, Tanya M Laidlaw 

Aspirin-lowering and ibuprofen-bridging protocols are safe and effective for patients with aspirin-exacerbated respiratory disease to decrease aspirin dosing prior to elective surgical procedures, but were only utilized in half of surveyed participants, suggesting need for increased awareness. Click here to see our BWH aspirin-lowering protocol.

Alyson N. Brown, Tanya M. Laidlaw, Kathleen M. Buchheit, Jillian C. Bensko, Rose C. Corcoran, Laura B. Bailey

This study found that 32% of AERD patients on dupilumab for asthma or nasal polyposis had attempted a dosing interval other than every 2 weeks. Of those, 68% chose to continue with less frequent injections, most commonly every 3 weeks, without reduction in their perceived clinical benefit. Our data highlight the potential for patients with AERD to reduce their dupilumab dosing frequency in the future and the need for provider education about this option.

Laura B. Bailey, Alyson N. Brown, Rose C. Corcoran, Jillian C. Bensko, Kathleen M. Buchheit, Tanya M. Laidlaw

This study demonstrates that celecoxib offers effective pain management for patients with AERD, and that non-selective NSAIDs (like ibuprofen and Naprosyn) are effective and safe for most AERD patients to take after aspirin desensitization.
We found that there is a high rate of narcotic overprescribing for patients with AERD, suggesting that reported NSAID allergies predispose our patients to the use of stronger and potentially less safe pain medications. Interestingly, despite multiple studies pointing to celecoxib as an appropriate option for many patients with AERD, narcotics were more often prescribed for pain in place of a non-selective NSAID than was celecoxib. Additional education of our pain-management colleagues regarding the safety and efficacy of celecoxib in patients with AERD may help avoid unnecessary opioid over prescribing.

Andrew D Supron, Victor Omilabu, Laura Bailey, Kathleen M Buchheit, Tanya M Laidlaw

This study describes the distribution and extent of blood eosinophilia in patients with AERD and assesses for correlations between absolute eosinophil count and various metrics of disease severity. In 225 patients with AERD, the absolute eosinophil count ranged from 10-4400 cells/µL, with a median 490 cells/µL, and with 78% of patients having a baseline eosinophil count >250 cells/µL, and 46% >500 cells/µL. Absolute eosinophil count was inversely correlated with lung function (FEV1 % predicted), and AERD patients with an eosinophil count >500 cells/µL had significantly lower FEV1 readings than those with eosinophil counts ≤500 cells/µL. In summary, patients with AERD have a marked eosinophilia that is even more pronounced than that of their aspirin-tolerant counterparts, and that this eosinophilia is predictive of a patient’s respiratory function via its inverse correlation with FEV1.

Marie Lundberg, Rie Maurer, Raffi Tchekmedyian, Jyotsna Mullur, Jillian C. Bensko, Kathleen M. Buchheit, Tanya M. Laidlaw

This study examined the validation of the questionnaires used for a prior study from our group that examined how loss of smell impacted the mental health and quality of life of patients with AERD. We determined that this new Consequences of Smell Loss (COSL) questionnaire can be used as a brief, valid, reliable tool that can effectively screen for a high burden of smell loss in patients with AERD and other patient populations where smell and olfaction are affected.

Aaqib Sohail , Jonathan Hacker, Tessa Ryan, Alanna McGill , Regan Bergmark, Neil Bhattacharyya , Stella E Lee, Alice Maxfield, Rachel Roditi , Amélie M Julé, Alec Griffith,  James Lederer, Tanya M Laidlaw, Kathleen M Buchheit 

Nasal polyp tissue was collected from patients with AERD and sinus disease, to explore differences in the transcriptomic profile, activation markers, and IL-5Rα expression and function of the nasal tissue plasma cells and antibody-secreting cells. It was found that  nasal polyp tissue antibody secreting cells from patients with AERD express higher levels of functional IL-5Rα and increased markers associated with cell cycling and proliferation compared to those from aspirin-tolerant nasal polyp patients. This may be clinically relevant in terms of disease severity and recurrence of nasal polyposis.

Aaqib Sohail, Carolyn H. Baloh, Jonathan Hacker,  Laura Cho, Tessa Ryan, Regan W. Bergmark , Stella E. Lee, Alice Maxfield , Rachel Roditi, Daniel F. Dwyer, Kathleen M. Buchheit,  Tanya M. Laidlaw

Nasal polyp tissue can be cryopreserved as whole tissue chunks or as digested cell suspensions, and this study investigated which technique would be best for preserving nasal polyp tissue for future analyses. We determined that both methods work quite well. However, mast cell numbers were reduced in samples cryopreserved as whole tissue chunks and thawed epithelial cells had reduced proliferation rates when preserved as dissociated cell suspensions. Therefore, the right cryopreservation method to choose may depend on the goals and cell-type focus of the project and on the planned future uses.

Kathleen M. Buchheit, Jonathan Hacker, Rie Maurer, Alanna McGill, Tessa Ryan, Jillian C. Bensko, Tanya M. Laidlaw

In this study, we evaluated 22 patients with AERD who were treated with dupilumab for 3 months, and 8 of those patients had also undergone aspirin desensitization prior to the start of dupilumab and continued on their high-dose daily aspirin throughout the study. We found that treatment with dupilumab in patients who were also on daily aspirin therapy led to a reduction in sinonasal eosinophilic inflammation. We did not see a reduction in sinonasal eosinophilic inflammation in the patients who were only on dupilumab without the additional daily aspirin therapy. Conversely, we saw that patients who were only on the dupilumab did develop a significant increase in the eosinophil levels in their blood, but for the patients who were on daily aspirin therapy and then started dupilumab treatment, there was no significant change in their blood eosinophil levels after starting dupilumab. Both daily aspirin therapy after aspirin desensitization, and dupilumab therapy, have been important treatments for patients with AERD, and further studies may be needed to fully understand how these two treatment options work together

Tanya M. Laidlaw, MD,a,b Kathleen M. Buchheit, MD,a,b Katherine N. Cahill, MD,c ,Jonathan Hacker, BA,b Laura Cho, BA,b, Jing Cui, PhD,a,d Chunli Feng, MD,b Chongjia C. Chen, MD,a,b Meghan Le, MS,e Elliot Israel, MD,a,b,e and Joshua A. Boyce, MDa,b  Boston, Mass, and Nashville, Tenn

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.

Baloh CH, Huffaker MF, Laidlaw T. Biomarkers and mechanisms of tolerance induction in food allergic patients drive new therapeutic approaches. Front Immunol. 2022 Oct 3;13:972103. doi: 10.3389/fimmu.2022.972103. PMID: 36263023; PMCID: PMC9574092.

Immunotherapy for food-allergic patients has been effective in inducing desensitization in some populations, but long-term tolerance has remained an elusive target. A challenge facing our field is how to differentiate immune markers that are impacted by immunotherapy from those that are critical biomarkers of tolerance. Data from recent clinical trials have identified several biomarkers and mechanisms for achieving tolerance. These biomarkers include younger age, lower food-specific IgE, lower food component-specific IgE, specific linear epitope profiles, and subsets of food-specific CD4+ T cells. Additional biomarkers under investigation for their relevance in tolerance induction include TCR repertoires, gastrointestinal and skin microbiome, and local tissue immunity. This review highlights recent advances in understanding biomarkers and mechanisms of tolerance induction in food immunotherapy and how these are influencing clinical trial development.

Morris J, Olonisakin TF, Moore JA, Phan B, Parker DM, Uribe BA, Barel SJ, Bowers EMR, Buchheit KM, Laidlaw TM, Lee SE. Inhibiting the type 2 inflammatory pathway with dupilumab is associated with an increase in interleukin-4 and interleukin-18 production. Int Forum Allergy Rhinol. 2022 Oct;12(10):1313-1316. doi: 10.1002/alr.23003. Epub 2022 Apr 29. PMID: 35394682.

Given the widespread expression of IL-4Rα across effector cells in the respiratory tract, and the potential immune consequences that global inhibition of IL-4Rα may have, our goal with this study, led by Dr. Stella Lee, was to understand how the local inflammatory milieu of patients with CRSwNP changes after treatment with dupilumab. We observed a dupilumab-induced increased level of the cytokines IL-4 and IL-18 into the nasal secretions, as well as a trend toward increased CXCL8/IL-8. These may suggest a shift toward Th17/type 3 immune response, which may be indicative of a type 1/type 3 “escape” with inhibition of IL-4Rα. It has not yet been fully investigated how the local inflammatory environment changes in CRSwNP patients treated with dupilumab. Although exploratory—and thus limited in the power of our statistical analysis—these preliminary data reinforce the need for further exploration of the consequences of inhibiting the type 2 inflammatory pathway.

Laidlaw TM, Boyce JA. Updates on immune mechanisms in aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2023 Feb;151(2):301-309. doi: 10.1016/j.jaci.2022.08.021. Epub 2022 Sep 30. PMID: 36184313; PMCID: PMC9905222.

This review covers novel insights into the immunopathogenesis of AERD from each of these lines of research, including the roles of lipid mediators, effector cell populations, and inflammatory cytokines, discusses unanswered questions regarding cause and pathogenesis, and considers potential future therapeutic options.

Mullur J, Steger CM, Gakpo D, Bensko JC, Maurer R, Laidlaw TM, Buchheit KM Ann Allergy Asthma Immunol. 2022 May;128(5):575-582. doi: 10.1016/j.anai.2022.01.043. PMID: 35131410; PMCID: PMC9058196.

In this study we surveyed 98 patients with AERD in the Brigham and Women’s Hospital AERD registry. Patients completed an online questionnaire describing their medication history and treatment experience. A total of 52 (53.0%) patients reported a history of use of one or more respiratory biologics (omalizumab, mepolizumab, reslizumab, benralizumab, or dupilumab), and 84 (85.7%) reported undergoing aspirin desensitization. There were 24 patients (24.4%) who reported concurrent use of a biologic and daily aspirin therapy. Compared with those on daily aspirin therapy alone, patients taking a biologic and aspirin therapy concurrently were less likely to report that aspirin was effective for their AERD symptoms. Whereas patients reported varying efficacy with biologics, dupilumab had the highest odds of patients reporting it worked “very well”. We conclude that biologics are emerging as a treatment option for AERD and are generally well tolerated. Biologic efficacy in AERD is variable by agent, though most patients taking dupilumab found it to be effective. Patients on a biologic in conjunction with daily aspirin therapy may represent a more severe subset of AERD for which daily aspirin therapy alone is insufficient.

Buchheit KM, Sohail A, Hacker J, Maurer R, Gakpo D, Bensko JC, Taliaferro F, Ordovas-Montanes J, Laidlaw TM. J Allergy Clin Immunol. 2022 Aug;150(2):415-424. doi: 10.1016/j.jaci.2022.04.007.  PMID: 35460728; PMCID: PMC9378638.

This study  followed 22 patients with AERD who were treated with dupilumab for 3 months. Participants had rapid improvement in their symptoms, including sense of smell, sinonasal symptoms, and lung function after just 1 month of dupilumab, which were sustained after 3 months of dupilumab. Baseline severity of smell loss correlated with lower nasal prostaglandin E2 levels. Dupilumab increased nasal prostaglandin E2 and decreased levels of nasal albumin, nasal and urinary leukotriene E4, and serum and nasal IgE. Transcripts related to epithelial dysfunction and leukocyte activation and migration were downregulated in inferior turbinate tissue after treatment with dupilumab. There were no dupilumab-induced changes in markers of nasal eosinophilia. We conclude that inhibition of IL-4Ra in AERD led to rapid improvement in respiratory symptoms and smell, with a concomitant improvement in epithelial barrier function, a decrease in inflammatory eicosanoid levels, and an increase in the anti-inflammatory eicosanoid prostaglandin E2. The therapeutic effects of dupilumab are likely due to decreased IL-4Ra signaling on respiratory tissue granulocytes, epithelial cells, and B cells.

Raffi Tchekmedyian, Marie Lundberg, Kathleen M Buchheit, Rie Maurer, Deborah Gakpo, Jyotsna Mullur, Jillian C Bensko, Tanya M Laidlaw. Clin Exp Allergy. 2022 May 3.1414-1421 doi: 10.1111/cea.14157 PMID: 35506180. PMCID: PMC9630163

A common problem for AERD patients is loss of sense of smell, or anosmia, but its impact on patients’ quality of life, mental health, and physical wellbeing has been poorly studied. We developed a new questionnaire about the consequences of anosmia, which, along with several other quality-of-life questionnaires was sent to all our Registry patients. Eighty-five percent of the 853 patients who answered the questionnaires (Thank you!) reported diminished sense of smell and/or taste, and we learned that their loss of smell severely impacts their physical, emotional, and mental health. Many patients with diminished smell responded that they could not identify spoiled food (86%), did not enjoy food (71%), felt unsafe (63%), and had encountered dangerous situations (51%) because of their poor smell.
We think that the importance of sense of smell and the relevance of anosmia to patients’ lives should be acknowledged and evaluated by clinicians caring for these patients.

Buchheit KM, Hacker JJ, Gakpo DH, Mullur J, Sohail A, Laidlaw TM.  Clin Exp Allergy. 2021 Jul;51(7):968-971. doi: 10.1111/cea.13898.  PMID: 33987897; PMCID: PMC8239915.

In this study, we studied samples of plasma, nasal fluid, and nasal cells from patients with and without AERD or asthma, to determine if 8 weeks of treatment with 650mg aspirin twice daily changed nasal epithelial transcript expression of either ACE2 or TMPRSS2 or altered levels of angiotensin-derived peptides that may be relevant to survival of acute respiratory distress syndrome. We found that the high-dose aspirin treatment did not have any significant effect on any of these biomarkers. Furthermore, consistent with studies showing asthma is generally not a risk factor for severe COVID-19, our data show that asthmatic subjects did not have any difference in angiotensin-derived peptide levels compared to controls. Although we are not able to extrapolate these results out for patients who are on aspirin for more than eight weeks, our data suggest that there is no immunologic indication that daily aspirin therapy would lead to an increased susceptibility to more severe COVID-19.

Patel P, Bensko JC, Bhattacharyya N, Laidlaw TM, Buchheit KM. Ann Allergy Asthma Immunol. 2022 Mar;128(3):326-328. doi: 10.1016/j.anai.2021.11.020. PMID: 34863953; PMCID: PMC8882131.

We report a series of eight patients with AERD who had experienced a rapid recurrence of nasal polyps after a prior endoscopic sinus surgery, and who subsequently went on to have a revision endoscopic sinus surgery with perioperative initiation of dupilumab, a monoclonal antibody targeting interleukin 4Ra. We found that dupilumab led to no or slower nasal polyp recurrence after surgery compared to the prior sinus surgery, and perioperative initiation of dupilumab therapy also improved upper airway symptoms. This study provides evidence for the use of dupilumab as an adjunct to surgery to prevent polyp regrowth for patients with AERD and insufficient response to standard-of-care therapies.

Miss Ozuna L, Ryan T, Bensko JC, Laidlaw TM, Buchheit KM. Ann Allergy Asthma Immunol. 2022 Apr;128(4):469-472. doi: 10.1016/j.anai.2022.01.036. PMID: 35124224; PMCID: PMC8977235.

We report a series of eight patients with AERD who developed arthralgias after initiating dupilumab. We found that 8 patients out of the 160 (5%) with AERD who have been prescribed dupilumab at our center developed possible dupilumab-associated arthralgias. Of the patients who underwent extensive rheumatologic work-up, no etiology of the joint symptoms was identified. All 8 patients experienced significant improvement in upper and lower respiratory tract symptoms and ultimately decided to continue dupilumab even with the possible dupilumab-associated arthralgias. Out of the eight subjects, the arthralgias spontaneously resolved in five of the patients. The cause of the dupilumab-associated arthralgias is unknown, but one possible explanation is a Type 1 or Type 3 “escape” with inhibition of IL-4Ra.

Buchheit KM, Lewis E, Gakpo D, Hacker J, Sohail A, Taliaferro F, Berreondo Giron E, Asare C, Vukovic M, Bensko JC, Dwyer DF, Shalek AK, Ordovas-Montanes J, Laidlaw TM.  J Allergy Clin Immunol. 2021 Aug;148(2):574-584. doi: 10.1016/j.jaci.2021.05.043.  PMID: 34144111; PMCID: PMC9096876.

To identify the mechanisms by which anti-IL-5 treatment improves respiratory inflammation in AERD, we studied 18 patients with AERD on mepolizumab for severe eosinophilic asthma compared to 18 matched control patients with AERD not on mepolizumab. Subjects with AERD treated with mepolizumab, had decreased production of inflammatory eicosanoids, and upregulation of nasal epithelial cell transcripts involved in tight junction pathways and cilium organization, compared to AERD patients not treated with mepolizumab. These effects of mepolizumab are likely due to decreased signaling of IL-5 on local respiratory tissue eosinophils, basophils, mast cells, and epithelial cells – all of which have functional IL-5Rα. We determined that the mechanism by which IL-5 inhibition provides therapeutic benefit in respiratory inflammation is not due exclusively to anti-eosinophil effects.

Bavaro N, Gakpo D, Mittal A, Bensko JC, Laidlaw TM, Buchheit KM. J Allergy Clin Immunol Pract. 2021 Feb 22:S2213-2198(21)00200-2. doi: 10.1016/j.jaip.2021.02.020. PMID: 33631410; PMCID: PMC8277677

In recent years, biologics have become a more common treatment option for patients with aspirin-exacerbated respiratory disease (AERD).  Respiratory biologic medications targeting interleukin (IL)-4Ra, IL-5, IL-5Ra, and IgE are approved for severe asthma and have recently been approved or being studied for CRSwNP. Treatment with biologic medications targeting type 2 cytokines and cytokine receptors is an attractive option for treating AERD, but data guiding selection of the appropriate agent are limited. In this study, we examined 41 patients who were treated with mepolizumab, reslizumab, or benralizumab. 27 of the 41 patients transitioned to dupilumab for inadequately controlled symptoms while 14 remained on mepolizumab.

For the 27 who switched to dupilumab, their SNOT-22 and ACT scores, and the FEV1% predicted did not improve while they were on the anti-IL-5/IL-5Ra biologic. However, there was significant improvement in symptoms scores and lung function, and reduction in asthma exacerbations while on dupilumab. For the 14 patients that remained on mepolizumab, they saw a significant improvement in total SNOT-22 and ACT scores but not in lung function. Of note, the only difference between the two groups was the baseline IgE level, which may serve as a useful biomarker for biologic selection in AERD patients. Although the study is limited by the retrospective nature of the data, it highlights the need for head-to-head, prospective studies aimed at understanding identifying responder endotypes to guide selection of appropriate biologic therapy.

Bergmark RW, Palumbo M, Rahman S, Maurer R, Dominas C, Roditi R, Bhattacharyya N, Maxfield A, Buchheit KM, Laidlaw TM. J Allergy Clin Immunol Pract. 2020 Dec 8:S2213-2198(20)31278-2. doi: 10.1016/j.jaip.2020.11.051.PMID: 33307278.

This study looked to establish and understand the connection between pulmonary and sinonasal symptoms in aspirin-exacerbated respiratory disease (AERD). To better understand the connection, the investigators reviewed the Sino-Nasal Outcomes Test (SNOT) 22-item and Asthma Control Test (ACT) scores, and percent predicted FEV1 (FEV1% predicted) from 1065 AERD Registry participants. The SNOT-22 was used as the predictor variable while ACT score and FEV1% predicted served as primary outcomes.  Any ten-point increase in SNOT-22 was associated with a 0.87-point decrease in ACT and a 0.75% decrease in FEV1%. Any one-point increase in ACT was associated with a 1.0% increase in FEV1% This study also demonstrates an association between subjective and objective measures of asthma severity.

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Li L, Chang Y, Song S, Losina E, Costenbader KH, Laidlaw TM.  J Allergy Clin Immunol. 2020 Sep 9:S0091-6749(20)31236-7. doi: 10.1016/j.jaci.2020.08.025.  PMID: 32916184; PMCID: PMC7995999.

Li et al. investigated the clinical impact of reported nonsteroidal anti-inflammatory drug (NSAID) allergy on opioid use disorder (OUD) in patients with chronic back pain. NSAIDs are commonly prescribed for treatment of acute and chronic pain, but their therapeutic use is limited by reported allergies. Allergy overreporting and lack of further investigation can lead to unnecessary avoidance of NSAIDs and increased utilization of alternative analgesics, including opioids, to manage pain. The investigators looked at over 47,000 patients with chronic back pain of whom over 3,600 (7.7%) had an NSAID allergy listed in their health record. They found that patients with chronic back pain and self-reported NSAID allergies are at increased risk of being prescribed opioids and developing OUD. Patients with chronic back pain and NSAID allergies should be referred to allergy specialists for potential allergy delabeling in order to minimize unnecessary opioid prescribing and to reduce the risk of OUD.

Buchheit KM, Dwyer DF, Ordovas-Montanes J, Katz HR, Lewis E, Vukovic M, Lai J, Bankova LG, Bhattacharyya N, Shalek AK, Barrett NA, Boyce JA, Laidlaw TM. J Allergy Clin Immunol. 2020 June;145(6):1574-1584. doi: 10.1016/j.jaci.2020.02.035. PMID: 32199912;PMCID: PMC7282948.

This study showed that sinus tissue IgE and IgG4 levels were elevated in patients with AERD compared to controls and that subjects with AERD whose nasal polyps recurred rapidly had higher IgE levels than did subjects with AERD, with slower polyp regrowth. Single-cell RNA sequencing revealed increased IL5RA, IGHG4, and IGHE in antibody-expressing cells from patients with AERD compared to those from NSAID-tolerant patients with CRSwNP, and there were more IL-5Rα⁺plasma cells in the polyp tissue from AERD than in polyp tissue from CRSwNP. IL-5 stimulation of plasma cells in vitro induced changes in a distinct set of transcripts. These findings suggest a role for IL-5Rα⁺ antibody-expressing cells in facilitating local antibody production and severe nasal polyps in AERD.