Masami Taniguchi, Chihiro Mitsui, Hiroaki Hayashi, Emiko Ono, Keiichi Kajiwara, Haruhisa Mita, Kentaro Watai, Yosuke Kamide, Yuma Fukutomi, Kiyoshi Sekiya, Noritaka Higashi
Aspirin-exacerbated respiratory disease (AERD): Current understanding of AERD.
Allergol Int. 2019 Jul;68(3):289-295. doi: 10.1016/j.alit.2019.05.001. Epub 2019 Jun 21.
Abstract/Text
The characteristics in AERD are severe adult-onset asthma, eosinophilic rhinosinusitis with nasal polyposis, and CysLT overproduction. The cause of AERD have remained unclear, however the decrease in the production of PGE2 caused by the reduction in COX-2 activity is considered to main pathological mechanism of AERD. The mast cell activation and the interaction between platelets and granulocytes are lead to the CysLT overproduction and severe eosinophilic inflammation. The ongoing activation of mast cells is important key pathogenesis in not only stable AERD but exacerbated AERD by aspirin and NSAIDs. In recent years, type 2 inflammation caused by ILC2 activation in patients with AERD have been attracting attention. Omalizumab is effective option for AERD via suppression of mast cell activation and CysLT overproduction. Dupilumab improves sinus symptoms especially in patients with AERD. In near future, anti-platelet drug, CRTH2 antagonist, and anti-TSLP antibody may be useful candidates of therapeutic options in patients with AERD.
Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.
谷口正実、アスピリン喘息（NSAIDs過敏喘息）、日内会誌 102(6)：1426-32,2013.
B Dahlén, A Szczeklik, J J Murray, Celecoxib in Aspirin-Intolerant Asthma Study Group
Celecoxib in patients with asthma and aspirin intolerance. The Celecoxib in Aspirin-Intolerant Asthma Study Group.
N Engl J Med. 2001 Jan 11;344(2):142. doi: 10.1056/NEJM200101113440215.
Abstract/Text
Andrew Szczeklik, Donald D Stevenson
Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management.
J Allergy Clin Immunol. 2003 May;111(5):913-21; quiz 922. doi: 10.1067/mai.2003.1487.
Abstract/Text
In some asthmatic individuals, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygen-ase 1 (COX-1) exacerbate the condition. This distinct clinical syndrome, called aspirin-induced asthma (AIA), is characterized by an eosinophilic rhinosinusitis, nasal polyposis, aspirin sensitivity, and asthma. There is no in vitro test for the disorder, and diagnosis can be established only by provocation challenges with aspirin or NSAIDs. Recent major advances in the molecular biology of eicosanoids, exemplified by the cloning of 2 cysteinyl leukotriene receptors and the discovery of a whole family of cyclooxygenase enzymes, offer new insights into mechanisms operating in AIA. The disease runs a protracted course even if COX-1 inhibitors are avoided, and the course is often severe, many patients requiring systemic corticosteroids to control their sinusitis and asthma. Aspirin and NSAIDs should be avoided, but highly specific COX-2 inhibitors, known as coxibs, are well tolerated and can be safely used. Aspirin desensitization, followed by daily aspirin treatment, is a valuable therapeutic option in most patients with AIA, particularly those with recurrent nasal polyposis or overdependence on systemic corticosteroids.
Marek L Kowalski, Ioana Agache, Sevim Bavbek, Arzu Bakirtas, Miguel Blanca, Grażyna Bochenek, Matteo Bonini, Enrico Heffler, Ludger Klimek, Tanya M Laidlaw, Joaquim Mullol, Ewa Niżankowska-Mogilnicka, Hae-Sim Park, Marek Sanak, Mario Sanchez-Borges, Silvia Sanchez-Garcia, Glenis Scadding, Masami Taniguchi, Maria J Torres, Andrew A White, Aleksandra Wardzyńska
Diagnosis and management of NSAID-Exacerbated Respiratory Disease (N-ERD)-a EAACI position paper.
Allergy. 2019 Jan;74(1):28-39. doi: 10.1111/all.13599. Epub 2018 Oct 2.
Abstract/Text
NSAID-exacerbated respiratory disease (N-ERD) is a chronic eosinophilic, inflammatory disorder of the respiratory tract occurring in patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP), symptoms of which are exacerbated by NSAIDs, including aspirin. Despite some progress in understanding of the pathophysiology of the syndrome, which affects 1/10 of patients with asthma and rhinosinusitis, it remains a diagnostic and therapeutic challenge. In order to provide evidence-based recommendations for the diagnosis and management of N-ERD, a panel of international experts was called by the EAACI Asthma Section. The document summarizes current knowledge on the pathophysiology and clinical presentation of N-ERD pointing at significant heterogeneity of this syndrome. Critically evaluating the usefulness of diagnostic tools available, the paper offers practical algorithm for the diagnosis of N-ERD. Recommendations for the most effective management of a patient with N-ERD stressing the potential high morbidity and severity of the underlying asthma and rhinosinusitis are discussed and proposed. Newly described sub-phenotypes and emerging sub-endotypes of N-ERD are potentially relevant for new and more specific (eg, biological) treatment modalities. Finally, the document defines major gaps in our knowledge on N-ERD and unmet needs, which should be addressed in the future.
© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.
A Szczeklik, E Nizankowska, M Duplaga
Natural history of aspirin-induced asthma. AIANE Investigators. European Network on Aspirin-Induced Asthma.
Eur Respir J. 2000 Sep;16(3):432-6.
Abstract/Text
There is a subset of patients with bronchial asthma who are susceptible to disease exacerbation upon receiving aspirin and other nonsteroidal anti-inflammatory drugs. This is a clinical syndrome, called aspirin-induced asthma (AIA), associated with alterations in arachidonate metabolism and cysteinyl-leukotriene overproduction. The natural history and clinical characteristics of this type of asthma were studied. Sixteen clinical centres in 10 European countries provided standardized information to the specially developed patient-oriented database regarding: medical history, physical examination, diagnosis, and treatment. Diagnosis of AIA was based on a typical history, confirmed by positive aspirin provocation tests, carried out in 91% of the patients. A total of 500 patients were enrolled in the study. AIA developed according to a pattern, characterized by a sequence of symptoms. First, persistent rhinitis, appearing at a mean age of 29.7+/-12.5 yrs, then asthma, aspirin intolerance and nasal polyposis appear. The clinical presentation in different European countries was remarkably similar. In females, who outnumbered males by 2.3:1, the onset of symptoms occurred significantly earlier and the disease was more progressive and severe than in males. Atopy, present in approximately a third of patients, led to earlier manifestation of rhinitis and asthma, but not of aspirin intolerance or nasal polyposis. A family history of aspirin intolerance, recorded in 6% of patients, had a less evident effect on the course of the disease than sex or atopy. Fifty one per cent of patients, in addition to inhaled steroids, required chronic systemic corticosteroid therapy at a mean dose of 8 mg prednisone x day(-1). Surprisingly, 15% of patients were unaware of intolerance to aspirin and learnt about it only after having provocation tests performed. All over Europe, aspirin-induced asthma develops in a similar characteristic way. Its course is influenced by sex and the presence of atopy. In half of the patients, asthma is severe, and steroid-dependent. The uniform natural history of aspirin-induced asthma might suggest a common underlying principle.
Neelam H Shah, Thomas R Schneider, Doreen DeFaria Yeh, Katherine N Cahill, Tanya M Laidlaw
Eosinophilia-Associated Coronary Artery Vasospasm in Patients with Aspirin-Exacerbated Respiratory Disease.
J Allergy Clin Immunol Pract. 2016 Nov - Dec;4(6):1215-1219. doi: 10.1016/j.jaip.2016.04.028. Epub 2016 Jul 7.
Abstract/Text
BACKGROUND: Some patients with aspirin-exacerbated respiratory disease (AERD) and eosinophilia report angina-type chest pain that occurs at rest and responds to corticosteroid therapy. The frequency of eosinophilia-associated coronary artery vasospasm in patients with AERD, a disease characterized by blood and respiratory tissue eosinophilia, however, is unknown.
OBJECTIVE: The objective of this study was to understand the cause of the chest pain described above and determine the most appropriate treatment for it.
METHODS: A chart review of 153 patients with AERD who are followed at Brigham and Women's Hospital was performed. Patients who reported any type of chest pain were assessed for the presence of cardiac risk factors, eosinophilia, and response of chest pain to a variety of treatments. Two patients with AERD and eosinophilia who had recurrent chest pain due to suspected vasospasm are described in detail, and 8 other cases are also summarized.
RESULTS: Of the 153 patients reviewed, 10 had a history of chest pain concerning for ischemia. Of the 10 patients with chest pain, 8 had undergone aspirin desensitization and initiated high-dose aspirin therapy; of these, 6 reported an increase in the frequency or severity of chest pain while on high-dose aspirin with improvement after aspirin discontinuation or dose reduction. Many patients had traditional cardiac risk factors, but none had any evidence of coronary atherosclerosis; almost all had significant eosinophilia. Their chest pain did not improve with typical antianginal treatments but did respond to corticosteroid therapy.
CONCLUSIONS: Although uncommon, patients with AERD can develop eosinophilia-associated coronary artery vasospasm, which is occasionally worsened by high-dose aspirin. Patients with AERD who present with symptoms of ischemic chest pain should be screened for eosinophilia, as early treatment with corticosteroids can be life-saving.
Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Katherine N Cahill, Jillian C Bensko, Joshua A Boyce, Tanya M Laidlaw
Prostaglandin D₂: a dominant mediator of aspirin-exacerbated respiratory disease.
J Allergy Clin Immunol. 2015 Jan;135(1):245-52. doi: 10.1016/j.jaci.2014.07.031. Epub 2014 Sep 11.
Abstract/Text
BACKGROUND: Aspirin desensitization followed by high-dose aspirin therapy is routinely performed for patients with aspirin-exacerbated respiratory disease (AERD). Little is known about the contributions of mediators other than cysteinyl leukotrienes to aspirin reactions and to the therapeutic benefit of high-dose aspirin therapy.
OBJECTIVE: We investigated differences in urinary eicosanoid metabolite levels and blood eosinophil counts in patients with AERD who tolerate and those who fail aspirin desensitization and also in patients with AERD who were successfully treated with high-dose aspirin therapy.
METHODS: Twenty-nine patients with AERD were stratified into those who tolerated aspirin desensitization (group I) and those who did not (group II). Urine was analyzed for eicosanoid metabolites at baseline, during aspirin reactions, and during high-dose aspirin therapy. Blood was analyzed for cell differentials at baseline and during aspirin therapy.
RESULTS: Basal prostaglandin D2 metabolite (PGD-M; 13.6 ± 2.7 vs 7.0 ± 0.8 pmol/mg creatinine [Cr], P < .05) and thromboxane metabolite (TX-M; 1.4 ± 0.3 vs 0.9 ± 0.1 pmol/mg Cr, P < .01) levels were higher in group II than in group I. During aspirin reactions, PGD-M levels remained unchanged, whereas TX-M levels (0.7 ± 0.1 pmol/mg Cr, P = .07) tended to decrease in group I. In contrast, PGD-M levels increased dramatically in group II (61.3 ± 19.9 pmol/mg Cr, P < .05), whereas TX-M levels did not change. The decrease in FEV1 inversely correlated with basal urinary levels of both leukotriene E4 and PGD-M. Blood eosinophil and basophil levels increased and urinary PGD-M levels (2.2 ± 0.8 pmol/mg Cr, P < .001) decreased on 2 months of high-dose aspirin therapy in group I.
CONCLUSION: Failure to tolerate aspirin desensitization in a subset of patients with AERD is associated with prostaglandin D2 overproduction. The increase in blood eosinophil and basophil counts during high-dose aspirin therapy might reflect the functional consequences of decreased prostaglandin D2 release and the therapeutic benefit of aspirin.
Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Tanya M Laidlaw, Joshua A Boyce
Aspirin-Exacerbated Respiratory Disease--New Prime Suspects.
N Engl J Med. 2016 Feb 4;374(5):484-8. doi: 10.1056/NEJMcibr1514013.
Abstract/Text
Joshua A Boyce
Aspirin sensitivity: Lessons in the regulation (and dysregulation) of mast cell function.
J Allergy Clin Immunol. 2019 Oct;144(4):875-881. doi: 10.1016/j.jaci.2019.08.022.
Abstract/Text
The idiosyncratic activation of mast cells (MCs) in response to administration of nonselective COX inhibitors is a cardinal feature of aspirin-exacerbated respiratory disease (AERD). Older studies using MC-stabilizing drugs support a critical role for MCs and their products in driving the severe eosinophilic inflammation and respiratory dysfunction that is typical of AERD. Because patients with AERD react to all nonselective COX inhibitors regardless of their chemical structure, the mechanism of MC activation is not caused by classical, antigen-induced cross-linking of IgE receptors. Recent studies in both human subjects and animal models have revealed a complex and multifactorial process culminating in dysregulation of MC function and an aberrant dependency on COX-1-derived prostaglandin E2 to maintain a tenuous homeostasis. This article reviews the factors most likely to contribute to MC dysregulation in patients with AERD and the potential diagnostic and therapeutic implications.
Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Chihiro Mitsui, Keiichi Kajiwara, Hiroaki Hayashi, Jun Ito, Haruhisa Mita, Emiko Ono, Noritaka Higashi, Yuma Fukutomi, Kiyoshi Sekiya, Takahiro Tsuburai, Kazuo Akiyama, Kazuhiko Yamamoto, Masami Taniguchi
Platelet activation markers overexpressed specifically in patients with aspirin-exacerbated respiratory disease.
J Allergy Clin Immunol. 2016 Feb;137(2):400-11. doi: 10.1016/j.jaci.2015.05.041. Epub 2015 Jul 17.
Abstract/Text
BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by respiratory reactions on ingestion of COX-1 inhibitors and cysteinyl leukotriene overproduction. The hypersensitivity reaction is induced by low doses of aspirin that inhibit COX-1 in platelets.
OBJECTIVE: We sought to explore the role of platelets in the pathogenesis of AERD in patients under stable conditions and during an aspirin challenge test.
METHODS: Stable patients with AERD (n = 30), aspirin-tolerant asthma (ATA; n = 21), or idiopathic chronic eosinophilic pneumonia (n = 10) were enrolled. Platelet activation was estimated based on expression levels of P-selectin (CD62P), CD63, CD69, and GPIIb/IIIa (PAC-1) in peripheral platelets; percentages of circulating platelet-adherent leukocytes; and plasma levels of soluble P-selectin (sP-selectin) and soluble CD40 ligand (sCD40L).
RESULTS: In the stable condition, expression of all surface markers on platelets, the percentage of platelet-adherent eosinophils, and the plasma levels of sP-selectin and sCD40L were significantly higher in patients with AERD compared with those in patients with ATA. P-selectin and CD63 expression on platelets and plasma sP-selectin and sCD40L levels were positively correlated with the percentage of platelet-adherent eosinophils. Among these markers, P-selectin expression and plasma sP-selectin levels positively correlated with urinary concentrations of leukotriene E4. Additionally, plasma sP-selectin and sCD40L levels were negatively correlated with lung function. In contrast, platelet activation markers in patients with AERD did not change during the aspirin challenge test.
CONCLUSION: Peripheral platelets were activated more in patients with stable AERD compared with those in patients with stable ATA, patients with idiopathic chronic eosinophilic pneumonia, and control subjects. Platelet activation was involved in cysteinyl leukotriene overproduction and persistent airflow limitations in patients with AERD.
Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Tanya M Laidlaw, Molly S Kidder, Neil Bhattacharyya, Wei Xing, Shiliang Shen, Ginger L Milne, Mariana C Castells, Heng Chhay, Joshua A Boyce
Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes.
Blood. 2012 Apr 19;119(16):3790-8. doi: 10.1182/blood-2011-10-384826. Epub 2012 Jan 18.
Abstract/Text
Cysteinyl leukotriene (cysLT) overproduction is a hallmark of aspirin-exacerbated respiratory disease (AERD), but its mechanism is poorly understood. Because adherent platelets can convert the leukocyte-derived precursor leukotriene (LT)A(4) to LTC(4), the parent cysLT, through the terminal enzyme LTC(4) synthase, we investigated the contribution of platelet-dependent transcellular cysLT production in AERD. Nasal polyps from subjects with AERD contained many extravascular platelets that colocalized with leukocytes, and the percentages of circulating neutrophils, eosinophils, and monocytes with adherent platelets were markedly higher in the blood of subjects with AERD than in aspirin-tolerant controls. Platelet-adherent subsets of leukocytes had higher expression of several adhesion markers than did platelet nonadherent subsets. Adherent platelets contributed more than half of the total LTC(4) synthase activity of peripheral blood granulocytes, and they accounted for the higher level of LTC(4) generation by activated granulocytes from subjects with AERD compared with aspirin-tolerant controls. Urinary LTE(4) levels, a measure of systemic cysLT production, correlated strongly with percentages of circulating platelet-adherent granulocytes. Because platelet adherence to leukocytes allows for both firm adhesion to endothelial cells and augmented transcellular conversion of leukotrienes, a disturbance in platelet-leukocyte interactions may be partly responsible for the respiratory tissue inflammation and the overproduction of cysLTs that characterize AERD.
Kellen J Cavagnero, Taylor A Doherty
Lipid-mediated innate lymphoid cell recruitment and activation in aspirin-exacerbated respiratory disease.
Ann Allergy Asthma Immunol. 2021 Feb;126(2):135-142. doi: 10.1016/j.anai.2020.09.011. Epub 2020 Sep 17.
Abstract/Text
OBJECTIVE: To synthesize investigations into the role of lipid-mediated recruitment and activation of group 2 innate lymphoid cells (ILC2s) in aspirin-exacerbated respiratory disease (AERD).
DATA SOURCES: A comprehensive literature review of reports pertaining to cellular mechanisms, cytokine, and lipid mediators in AERD, as well as ILC2 activation and recruitment, was performed using PubMed and Google Scholar.
STUDY SELECTIONS: Selections of studies were based on reports of lipid mediators in AERD, cytokine mediators in AERD, type 2 effector cells in AERD, platelets in AERD, AERD treatment, ILC2s in allergic airway disease, and ILC2 activation, inhibition, and trafficking.
RESULTS: The precise mechanisms of AERD pathogenesis are not well understood. Greater levels of proinflammatory lipid mediators and type 2 cytokines are found in tissues derived from patients with AERD relative to controls. After pathognomonic cyclooxygenase-1 inhibitor reactions, proinflammatory mediator concentrations (prostaglandin D2 and cysteinyl leukotrienes) are rapidly increased, as are ILC2 levels in the nasal mucosa. The ILC2s, which potently generate type 2 cytokines in response to lipid mediator stimulation, may play a key role in AERD pathogenesis.
CONCLUSION: Although the literature suggests that lipid-mediated ILC2 activation may occur in AERD, there is a dearth of definitive evidence. Future investigations leveraging novel next-generation single-cell sequencing approaches along with recently developed AERD murine models will better define lipid mediator-induced ILC2 trafficking in patients with AERD.
Copyright © 2020 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
César Picado, Joaquim Mullol, Jordi Roca-Ferrer
Mechanisms by which dupilumab normalizes eicosanoid metabolism and restores aspirin-tolerance in AERD: A hypothesis.
J Allergy Clin Immunol. 2022 Sep 17;. doi: 10.1016/j.jaci.2022.09.012. Epub 2022 Sep 17.
Abstract/Text
Aspirin-exacerbated respiratory disease (AERD) is associated with overproduction of proinflammatory cysteinyl leukotrienes (CysLTs), defective generation of anti-inflammatory prostaglandin E2 (PGE2), and reduced expression of the EP2 receptor for PGE2. Reduced PGE2 synthesis results from the downregulation of inducible COX-2. Because PGE2 signaling via EP2 inhibits the 5-lipoxygenase/leukotriene C4 synthase-dependent pathway, the deficient levels of both PGE2 and EP2 likely contribute to the excessive baseline production of cysteinyl leukotrienes in patients with AERD compared with in patients with aspirin-tolerant asthma. The COX-2 pathway is regulated by an autocrine metabolic loop involving IL-1β, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE2 prostaglandin E2 synthase-1, and PGE2. Previous studies reported that this metabolic loop is dysregulated in patients with AERD. When the downexpressed EP2 receptor is normalized, the entire loop returns to its normal function. Cotreatment of airway cells from healthy subjects with IL-4 and IFN-γ induces alterations in the metabolic loop similar to those seen in patients with AERD. In these patients, IL-4, which is produced in excess in airways of patients with AERD, likely contributes to the alteration of normal functioning of the autocrine metabolic loop involving IL-1β, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE2 prostaglandin E2 synthase-1, and PGE2. We hypothesized that by blocking IL-4 action, dupilumab normalizes EP2 expression and restores the normal functioning of the COX-2 pathway autocrine metabolic loop, thereby normalizing the synthesis of PGE2 and restoring aspirin tolerance.
Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
谷口正実：気道過敏性検査とアスピリン負荷試験の実際. アレルギー 58：87-96, 2009.
谷口正実、渡井健太郎：NSAIDs過敏症. Medical Practice 39(8), 2022.
谷口正実、上気道・下気道アレルギーの連関―ONEAIRWAY ONE DISEASEの新しい考え方―、日内会誌 111(8)：1609-19,2022.
Kentaro Watai, Yuma Fukutomi, Hiroaki Hayashi, Yosuke Kamide, Kiyoshi Sekiya, Masami Taniguchi
Epidemiological association between multiple chemical sensitivity and birth by caesarean section: a nationwide case-control study.
Environ Health. 2018 Dec 14;17(1):89. doi: 10.1186/s12940-018-0438-2. Epub 2018 Dec 14.
Abstract/Text
INTRODUCTION: Multiple chemical sensitivity (MCS) is characterized by recurrent nonspecific symptoms that are attributed to exposure to trace levels of environmental agents. Although the clinical symptoms of MCS have been described in several studies, the risk factors for this condition remain unclear. Our aim was to clarify the risk factors for MCS and the association between MCS and birth by caesarean section.
METHODS: We conducted a nationwide case-control study of Japanese individuals (aged 20-65 years) with physician-diagnosed MCS (183 cases) and without MCS (345 controls). The study participants were selected from among 150,000 people in a web-based research panel with approximately 1,000,000 registrants. They completed an online survey including questions on their sociodemographic characteristics, birth history (i.e., birth by caesarean section), and other potential risk factors for MCS. Multivariate logistic regression analysis was employed to determine the association between sociodemographic characteristics and the risk of MCS.
RESULTS: The proportions of case and control subjects who were born by caesarean section were 39.9 and 7.0%, respectively. The association between birth by caesarean section and MCS was significant even after adjusting for potential confounders (adjusted odds ratio: 6.15; 95% confidence interval: 3.13-12.1). A history of agricultural work, mouth breathing, ≥11 vaccinations in the past 10 years, and residing in a new home (< 1 year-old) ≥3 times were also significantly associated with MCS.
CONCLUSION: Our data indicate an epidemiological link between MCS and birth by caesarean section. Moreover, we show that factors other than chemical exposure may be associated with the development of MCS.
K Watai, Y Fukutomi, H Hayashi, Y Nakamura, Y Hamada, Y Tomita, C Mitsui, Y Kamide, K Sekiya, K Asano, M Taniguchi
De novo sensitization to Aspergillus fumigatus in adult asthma over a 10-year observation period.
Allergy. 2018 Dec;73(12):2385-2388. doi: 10.1111/all.13566. Epub 2018 Aug 16.
Abstract/Text
Anna G Staudacher, Anju T Peters, Roderick G Carter, Kevin C Welch, Whitney W Stevens
Decreased nasal polyp eosinophils but increased mast cells in a patient with aspirin-exacerbated respiratory disease treated with reslizumab.
Ann Allergy Asthma Immunol. 2020 Oct;125(4):490-493.e2. doi: 10.1016/j.anai.2020.06.043. Epub 2020 Jul 4.
Abstract/Text
Masami Taniguchi, Enrico Heffler, Heidi Olze, Andrew White, Joana Côrte-Real, Petter Olsson, Slawomir Lazarewicz
The Role of Omalizumab in NSAID-Exacerbated Respiratory Disease: A Narrative Review.
J Allergy Clin Immunol Pract. 2022 Oct;10(10):2570-2578. doi: 10.1016/j.jaip.2022.06.016. Epub 2022 Jun 25.
Abstract/Text
Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is a condition characterized by the triad of chronic rhinosinusitis with nasal polyps, bronchial asthma, and hypersensitivity to nonsteroidal anti-inflammatory drugs. This article explores the current knowledge on the various pathological mechanism(s) of N-ERD-such as arachidonic acid metabolism, cysteinyl leukotrienes, prostaglandins, platelets, IgE, mast cells, eosinophils, basophils, and innate immune system-and the role of omalizumab in its management. The authors dive deep into the role of IgE in N-ERD and its potential as a therapeutic target. IgE plays a significant role in mediating allergic reactions, is intricately linked with mast cells, interacts with multiple immunopathological pathways involved in N-ERD, and tends to be elevated in patients with N-ERD. Multiple real-world studies, observational studies, and case series, as well as 2 phase III trials, have demonstrated the effectiveness of omalizumab in the management of N-ERD. For a disease with such a well-documented history, the pathophysiology of N-ERD and the most effective ways to manage it remain a mystery. With this background, the authors ask-is IgE a missing piece of the N-ERD puzzle, thus explaining the efficacy of omalizumab in the treatment of the disease?
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Hiroaki Hayashi, Yuma Fukutomi, Chihiro Mitsui, Keiichi Kajiwara, Kentaro Watai, Yosuke Kamide, Yuto Nakamura, Yuto Hamada, Yasuhiro Tomita, Kiyoshi Sekiya, Takahiro Tsuburai, Kenji Izuhara, Keiko Wakahara, Naozumi Hashimoto, Yoshinori Hasegawa, Masami Taniguchi
Omalizumab for Aspirin Hypersensitivity and Leukotriene Overproduction in Aspirin-exacerbated Respiratory Disease. A Randomized Controlled Trial.
Am J Respir Crit Care Med. 2020 Jun 15;201(12):1488-1498. doi: 10.1164/rccm.201906-1215OC.
Abstract/Text
Rationale: Aspirin-exacerbated respiratory disease is characterized by severe asthma, nonsteroidal antiinflammatory drug hypersensitivity, nasal polyposis, and leukotriene overproduction. Systemic corticosteroid therapy does not completely suppress lifelong aspirin hypersensitivity. Omalizumab efficacy against aspirin-exacerbated respiratory disease has not been investigated in a randomized manner.Objectives: To evaluate omalizumab efficacy against aspirin hypersensitivity, leukotriene E4 overproduction, and symptoms during an oral aspirin challenge in patients with aspirin-exacerbated respiratory disease using a randomized design.Methods: We performed a double-blind, randomized, crossover, placebo-controlled, single-center study at Sagamihara National Hospital between August 2015 and December 2016. Atopic patients (20-79 yr old) with aspirin-exacerbated respiratory disease diagnosed by systemic aspirin challenge were randomized (1:1) to a 3-month treatment with omalizumab or placebo, followed by a >18-week washout period (crossover design). The primary endpoint was the difference in area under logarithm level of urinary leukotriene E4 concentration versus time curve in the intent-to-treat population during an oral aspirin challenge.Measurements and Main Results: Sixteen patients completed the study and were included in the analysis. The area under the logarithm level of urinary leukotriene E4 concentration versus time curve during an oral aspirin challenge was significantly lower in the omalizumab phase (median [interquartile range], 51.1 [44.5-59.8]) than in the placebo phase (80.8 [interquartile range, 65.4-87.8]) (P < 0.001). Ten of 16 patients (62.5%) developed oral aspirin tolerance up to cumulative doses of 930 mg in the omalizumab phase (P < 0.001).Conclusions: Omalizumab treatment inhibited urinary leukotriene E4 overproduction and upper/lower respiratory tract symptoms during an oral aspirin challenge, resulting in aspirin tolerance in 62.5% of the patients with aspirin-exacerbated respiratory disease.
Hiroaki Hayashi, Chihiro Mitsui, Eiji Nakatani, Yuma Fukutomi, Keiichi Kajiwara, Kentaro Watai, Kiyoshi Sekiya, Takahiro Tsuburai, Kazuo Akiyama, Yoshinori Hasegawa, Masami Taniguchi
Omalizumab reduces cysteinyl leukotriene and 9α,11β-prostaglandin F2 overproduction in aspirin-exacerbated respiratory disease.
J Allergy Clin Immunol. 2016 May;137(5):1585-1587.e4. doi: 10.1016/j.jaci.2015.09.034. Epub 2015 Nov 11.
Abstract/Text
Monika Świerczyńska-Krępa, Marek Sanak, Grażyna Bochenek, Paweł Stręk, Adam Ćmiel, Anna Gielicz, Hanna Plutecka, Andrzej Szczeklik, Ewa Niżankowska-Mogilnicka
Aspirin desensitization in patients with aspirin-induced and aspirin-tolerant asthma: a double-blind study.
J Allergy Clin Immunol. 2014 Oct;134(4):883-90. doi: 10.1016/j.jaci.2014.02.041. Epub 2014 Apr 24.
Abstract/Text
BACKGROUND: Numerous open trials have demonstrated the beneficial clinical effects of aspirin desensitization (AD) in patients with aspirin-induced asthma (AIA). These beneficial effects might be attributable to aspirin's potent anti-inflammatory properties, but that supposition requires further corroboration.
OBJECTIVE: We sought to compare the clinical and biochemical responses to chronic oral AD in 20 patients with AIA and 14 patients with aspirin-tolerant asthma (ATA). All of the patients had chronic rhinosinusitis and nasal polyposis, and these responses were investigated in a pilot, double-blind, placebo-controlled study.
METHODS: Twelve patients with AIA and 6 patients with ATA were randomly assigned to receive 624 mg of aspirin, and 8 patients with AIA and 8 patients with ATA received placebo. Both aspirin and placebo were administered once daily for 6 months. Nasal symptoms, Sino-Nasal Outcome Test (SNOT20) scores, peak nasal inspiratory flows, Asthma Control Questionnaire scores, spirometric parameters, peak expiratory flows, blood eosinophilia, and corticosteroid doses were assessed on a monthly basis. Levels of urinary leukotriene E4 and the stable plasma prostaglandin (PG) D2 metabolite 9α,11β-PGF2 were evaluated at baseline and after 1, 3, 5, and 6 months.
RESULTS: Only the patients with AIA subjected to AD reported improvements in smell and reductions in sneezing and nasal blockade. The SNOT20 and Asthma Control Questionnaire scores of these patients decreased, and their peak nasal inspiratory flows increased. The dosages of inhaled corticosteroids were reduced. There were no changes in leukotriene E(4) or 9α,11β-PGF(2) levels after AD.
CONCLUSION: The clinically beneficial effects of AD on nasal and bronchial symptoms occurred only in the patients with AIA.
Copyright © 2014. Published by Elsevier Inc.
Jeremy Waldram, Kristen Walters, Ronald Simon, Katherine Woessner, Jill Waalen, Andrew White
Safety and outcomes of aspirin desensitization for aspirin-exacerbated respiratory disease: A single-center study.
J Allergy Clin Immunol. 2017 May 25;. doi: 10.1016/j.jaci.2017.05.006. Epub 2017 May 25.
Abstract/Text
BACKGROUND: Aspirin desensitization is an effective treatment option for aspirin-exacerbated respiratory disease. Aspirin desensitization protocol modifications have improved the safety and efficiency of this procedure, yet some providers remain reluctant to perform it.
OBJECTIVE: The primary objective of this study was to evaluate the safety and outcomes of outpatient aspirin desensitization procedures. A secondary objective was to assess clinical characteristics that might predict reaction severity during aspirin desensitization.
METHODS: Two hundred seventy-five patients underwent aspirin desensitization at Scripps Clinic between January 2009 and August 2015. Baseline patient characteristics and reaction results were analyzed in the 167 patients who reacted during desensitization.
RESULTS: All of the 167 reactors, including 23 who were classified as severe reactors, were successfully desensitized in the outpatient setting. The average desensitization duration among reactors was 1.67 days, and the average duration for gastrointestinal reactors was 2.29 days. The mean baseline Sino-Nasal Outcome Test score was higher in severe reactors compared with nonsevere reactors (P = .05). Overall, patients receiving omalizumab had a similar reaction profile to those not receiving omalizumab.
CONCLUSIONS: Most patients undergoing aspirin desensitization will have symptoms. It remains difficult to predict the severity of these symptoms. However, desensitization can be done safely and efficiently in an appropriately equipped outpatient setting. This treatment option should be made available to all patients with aspirin-exacerbated respiratory disease. The Sino-Nasal Outcome Test score might be able to predict more severe reactions and merits further study. Eight of the 9 patients receiving omalizumab reacted during desensitization, suggesting that it does not block reactions during aspirin desensitization.
Published by Elsevier Inc.
S Imokawa, A Sato, M Taniguchi, M Toyoshima, K Nakazawa, H Hayakawa, K Chida
[Sodium cromoglycate nebulized solution has an acute bronchodilative effect in patients with aspirin-intolerant asthma (AIA)].
Arerugi. 1992 Oct;41(10):1515-20.
Abstract/Text
Sodium cromoglycate (SCG) (Intal) is a well-known anti-allergic agent which protects against allergen- and exercise-induced bronchospasms. The effect has been recognized non-acute, unlike that of bronchodilators. However, we have found that some patients with aspirin-intolerant asthma (AIA) show significant improvement soon after a single inhalation of SCG nebulized solution. In this study, we investigated the acute bronchodilator effect of SCG given by nebulizer in adult asthmatics, especially compairing AIA with non-AIA (aspirin-tolerant asthma) patients. Twenty patients with AIA and 11 with non-AIA participated in the study. After performing spirometry on remission, they inhaled either SCG via a nebulizer or 4 ml of placebo in a randomized double-blind fashion. After inhalation, spirometry was performed every ten minutes for one hour. The placebo used was a saline solution of the same osmolarity as that of the SCG nebulized solution. Placebo inhalation provoked asthmatic attacks in five of the patients with AIA and one with non-AIA, but SCG did not. In the AIA group, twelve out of the twenty patients also had improved nasal symptoms soon after inhalation of SCG. Forced expiratory volume in one second (FEV1) was significantly improved 10 minutes after inhalation of SCG. Fifty minutes after SCG inhalation, the percent degree of FEV1 improvement was approximately 17%. However, FEV1 was significantly decreased by approximately 14% after inhalation of placebo. In the non-AIA group, FEV1 was not increased after inhalation of SCG. V25 was not changed after inhalation of SCG in AIA and non-AIA groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Nicole Bavaro, Deborah Gakpo, Anisha Mittal, Jillian C Bensko, Tanya M Laidlaw, Kathleen M Buchheit
Efficacy of dupilumab in patients with aspirin-exacerbated respiratory disease and previous inadequate response to anti-IL-5 or anti-IL-5Rα in a real-world setting.
J Allergy Clin Immunol Pract. 2021 Jul;9(7):2910-2912.e1. doi: 10.1016/j.jaip.2021.02.020. Epub 2021 Feb 22.
Abstract/Text
Kathleen M Buchheit, Aaqib Sohail, Jonathan Hacker, Rie Maurer, Deborah Gakpo, Jillian C Bensko, Faith Taliaferro, Jose Ordovas-Montanes, Tanya M Laidlaw
Rapid and sustained effect of dupilumab on clinical and mechanistic outcomes in aspirin-exacerbated respiratory disease.
J Allergy Clin Immunol. 2022 Aug;150(2):415-424. doi: 10.1016/j.jaci.2022.04.007. Epub 2022 Apr 20.
Abstract/Text
BACKGROUND: Dupilumab, a mAb targeting IL-4Rα, improves upper and lower airway symptoms in patients with aspirin-exacerbated respiratory disease (AERD), but the mechanisms leading to clinical improvement are not fully elucidated.
OBJECTIVE: Our aim was to identify the mechanistic basis of clinical improvement in patients with AERD treated with dupilumab.
METHODS: A total of 22 patients with AERD were treated with dupilumab for 3 months for severe asthma and/or chronic rhinosinusitis with nasal polyps. Clinical outcomes were assessed at baseline and at 1 and 3 months after initiation of dupilumab. Nasal fluid, urine, blood, and inferior turbinate scrapings were collected at the 3 time points for determination of mediator levels, cellular assays, and RNA sequencing.
RESULTS: Participants had rapid improvement in clinical measures, including sense of smell, sinonasal symptoms, and lung function after 1 month of treatment with dupilumab; the improvements were sustained after 3 months of dupilumab. Baseline severity of smell loss was correlated with lower nasal prostaglandin E2 levels. Dupilumab increased nasal prostaglandin E2 level 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 nasal eosinophilia.
CONCLUSION: Inhibition of IL-4Rα 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 level. The therapeutic effects of dupilumab are likely due to decreased IL-4Rα signaling on respiratory tissue granulocytes, epithelial cells, and B cells.
Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
S Shahzad Mustafa, Karthik Vadamalai
Dupilumab increases aspirin tolerance in aspirin-exacerbated respiratory disease.
Ann Allergy Asthma Immunol. 2021 Jun;126(6):738-739. doi: 10.1016/j.anai.2021.03.010. Epub 2021 Mar 19.
Abstract/Text
重篤副作用疾患別対応マニュアル:非ステロイド性抗炎症薬による喘息発作（アスピリン喘息、解熱鎮痛薬喘息、アスピリン不耐喘息、NSAIDs 過敏喘息）平成18年11月(令和4年2月改定）厚生労働省: https://www.pmda.go.jp/files/000245262.pdf.
