Updates in AERD: What is needed further?

To the Editor: Recently, the aspirin-exacerbated respiratory disease (AERD) was summarized in 2 important updates published in the Journal of Allergy and Clinical Immunology. The American Academy of Allergy, Asthma & Immunology presented the diagnosis and management of AERD in its practice parameter.1Khan D.A. Banerji A. Blumenthal K.G. Phillips E.J. Solensky R. White A.A. et al.Drug allergy: a 2022 practice parameter update.J Allergy Clin Immunol. 2022; 150: 1333-1393Google Scholar The clinical aspects of the disease such as the methodology of aspirin challenge tests and therapy after aspirin desensitization, including the use of biologics, were addressed. In 2023, Stevens and Cahill2Stevens W.W. Cahill K.N. Mechanistic and clinical updates in AERD: 2021-2022.J Allergy Clin Immunol. 2023; 151: 1448-1456Google Scholar reviewed the available clinical and translational studies to summarize advances in our understanding of AERD, progress on inflammatory endotypes characteristics, and clinical heterogeneity of the disease. However, some facets of AERD would require further work to systematize the clinical management of the disease. The term aspirin-exacerbated respiratory disease (AERD) is used in the United States and equals the European nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD).1Khan D.A. Banerji A. Blumenthal K.G. Phillips E.J. Solensky R. White A.A. et al.Drug allergy: a 2022 practice parameter update.J Allergy Clin Immunol. 2022; 150: 1333-1393Google Scholar,2Stevens W.W. Cahill K.N. Mechanistic and clinical updates in AERD: 2021-2022.J Allergy Clin Immunol. 2023; 151: 1448-1456Google Scholar To avoid ambiguity with nonerosive reflux disease (NERD of the esophagus), a hyphen is included in the European acronym. The name of the disease referencing to aspirin is remarkable and commonly used by patients and clinicians; however, it does not reflect crossover reactions to other analgesics. The term NERD has other colloquial connotations. Both names reflect a hallmark of the disease, that is, exacerbations triggered by nonselective inhibitors of cyclooxygenase (COX-1). Because nonsteroidal anti-inflammatory drugs comprise selective COX-2 inhibitors (ie, coxibs) also, usually well tolerated by patients with AERD, both names of the disease are imperfect. Perhaps, there is a need for unification of the name of the disease, which ought to be agreed globally. AERD is widely considered as eosinophilic asthma. We suggest, in line with Stevens and Cahill,2Stevens W.W. Cahill K.N. Mechanistic and clinical updates in AERD: 2021-2022.J Allergy Clin Immunol. 2023; 151: 1448-1456Google Scholar that AERD is a chronic respiratory disease characterized by asthma and rhinosinusitis with recurrent nasal polyps and intolerance to nonspecific COX inhibitors, regardless of the cellular inflammatory endotype of asthma (Table I).3Mastalerz L. Celejewska-Wójcik N. Ćmiel A. Wójcik K. Szaleniec J. Hydzik-Sobocińska K. et al.Non-eosinophilic asthma in nonsteroidal anti-inflammatory drug exacerbated respiratory disease.Clin Transl Allergy. 2023; 13e12235Google Scholar Chronic rhinosinusitis with nasal polyps in AERD is difficult to treat, has low inflammatory burden, and can be associated either with type-2 (T2) or with type-1 and type-3 cytokines.4Scott W.C. Cahill K.N. Milne G.L. Li P. Sheng Q. Huang L.C. et al.Inflammatory heterogeneity in aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2021; 147: 1318-1328.e5Google ScholarTable IInduced sputum cellular inflammatory pattern in AERD (n = 133)Cellular endotypeCriterian (%)Eosinophilic≥3% eosinophils and <64% neutrophils67 (50.4)Paucigranulocytic<3% eosinophils and <64% neutrophils50 (37.6)Neutrophilic<3% eosinophils and ≥64% neutrophils16 (12.0)Mixed∗The mixed cellular inflammatory pattern is considered as transient between eosinophilic and neutrophilic. Adapted from Mastalerz et al.3≥3% eosinophils and ≥60% neutrophilsNot observedPaucigranulocytic (37.6%) and neutrophilic (12%) endotypes comprise a noneosinophilic asthma.∗ The mixed cellular inflammatory pattern is considered as transient between eosinophilic and neutrophilic. Adapted from Mastalerz et al.3Mastalerz L. Celejewska-Wójcik N. Ćmiel A. Wójcik K. Szaleniec J. Hydzik-Sobocińska K. et al.Non-eosinophilic asthma in nonsteroidal anti-inflammatory drug exacerbated respiratory disease.Clin Transl Allergy. 2023; 13e12235Google Scholar Open table in a new tab Paucigranulocytic (37.6%) and neutrophilic (12%) endotypes comprise a noneosinophilic asthma. As underlined in the recent updates,1Khan D.A. Banerji A. Blumenthal K.G. Phillips E.J. Solensky R. White A.A. et al.Drug allergy: a 2022 practice parameter update.J Allergy Clin Immunol. 2022; 150: 1333-1393Google Scholar,2Stevens W.W. Cahill K.N. Mechanistic and clinical updates in AERD: 2021-2022.J Allergy Clin Immunol. 2023; 151: 1448-1456Google Scholar AERD is a heterogeneous condition and has a variable inflammatory cell profile in the upper and lower airways. In clinical practice, the most important step of management of an asthmatic patient is to classify the severity of the disease. As recommended in the Global Initiative for Asthma guidelines,5Global Initiative for AsthmaGlobal Strategy for Asthma Management and Prevention.https://ginasthma.org/gina-reports/Date: 2022Date accessed: June 22, 2023Google Scholar endotypes of inflammation based on sputum cell counts are useful for prediction of response to therapeutics. Particularly, the 4 validated inflammatory endotypes in asthma have different recommendations for therapeutic decision making. Therefore, it remains to be confirmed whether inflammatory endotypes in AERD could be discriminated by surrogate markers including peripheral blood eosinophilia, inflammatory mediators assessment, sinonasal mucus cytology, or bronchial brushing2Stevens W.W. Cahill K.N. Mechanistic and clinical updates in AERD: 2021-2022.J Allergy Clin Immunol. 2023; 151: 1448-1456Google Scholar as correlating with induced sputum findings.3Mastalerz L. Celejewska-Wójcik N. Ćmiel A. Wójcik K. Szaleniec J. Hydzik-Sobocińska K. et al.Non-eosinophilic asthma in nonsteroidal anti-inflammatory drug exacerbated respiratory disease.Clin Transl Allergy. 2023; 13e12235Google Scholar Current findings suggest the presence of nonclassical T2 inflammation in about half the patients with AERD. In its classical form, T2 inflammation characterizes patients with severe asthma treated with high-dose inhaled corticosteroids whose peripheral blood eosinophilia exceeds 150/ μL and/or sputum eosinophils are 2% or more.5Global Initiative for AsthmaGlobal Strategy for Asthma Management and Prevention.https://ginasthma.org/gina-reports/Date: 2022Date accessed: June 22, 2023Google Scholar These two Global Initiative for Asthma–defined T2 biomarkers of severe asthma could be predictors of biological therapy benefits in AERD. But the pathomechanism of AERD involves much more diverse immune response, including mast cells and basophils, lymphocytes, leukocyte-adhering platelets, macrophages, and possibly endothelial or plasma cells.2Stevens W.W. Cahill K.N. Mechanistic and clinical updates in AERD: 2021-2022.J Allergy Clin Immunol. 2023; 151: 1448-1456Google Scholar Patients with AERD with paucigranulocytic inflammatory endotype3Mastalerz L. Celejewska-Wójcik N. Ćmiel A. Wójcik K. Szaleniec J. Hydzik-Sobocińska K. et al.Non-eosinophilic asthma in nonsteroidal anti-inflammatory drug exacerbated respiratory disease.Clin Transl Allergy. 2023; 13e12235Google Scholar have the highest sputum macrophages counts. Some plasticity of macrophage phenotype results from epigenetic reprogramming and was suggested in AERD. Therefore, the cellular pattern of inflammation and cytokine profile of mediators among patients with AERD do not comply with TH2-high/low dichotomy.3Mastalerz L. Celejewska-Wójcik N. Ćmiel A. Wójcik K. Szaleniec J. Hydzik-Sobocińska K. et al.Non-eosinophilic asthma in nonsteroidal anti-inflammatory drug exacerbated respiratory disease.Clin Transl Allergy. 2023; 13e12235Google Scholar,4Scott W.C. Cahill K.N. Milne G.L. Li P. Sheng Q. Huang L.C. et al.Inflammatory heterogeneity in aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2021; 147: 1318-1328.e5Google Scholar Khan et al1Khan D.A. Banerji A. Blumenthal K.G. Phillips E.J. Solensky R. White A.A. et al.Drug allergy: a 2022 practice parameter update.J Allergy Clin Immunol. 2022; 150: 1333-1393Google Scholar summarized the aspirin challenge tests and aspirin desensitization in AERD. In the United States, several oral aspirin challenge protocols are endorsed by the American Academy of Allergy, Asthma & Immunology. Differences are in time intervals of increasing doses of aspirin administered (from 60 to 180 minutes) and the first aspirin dose (from 20 to 40.5 mg). Water-soluble lysyl acetylsalicylic acid is not available in the United States and in most European countries. Therefore, bronchial and nasal aspirin challenge tests are not performed commonly. This has to be corrected in the future European Academy of Allergy & Clinical Immunology position paper, which in 2019 recommended 3 types of aspirin challenge tests comprising oral, bronchial, and nasal ones. The European Academy of Allergy & Clinical Immunology recommended a 2-day oral aspirin challenge, and during the first day the placebo test ensured stability of asthma. The recommended first oral dose of aspirin was 10 mg, which in our experience could be omitted because patients with AERD react to a 27-mg dose or higher (44, 117, 312, and 500 mg) administered every 90 minutes. There is a general agreement on indications for aspirin desensitization in patients with AERD who have ischemic heart disease or require a long-term pain reliever due to various comorbidities. Another indication is chronic rhinosinusitis with nasal polyps, smell loss, and recurrent ENT procedures. However, benefits of corticoid-sparing effect in patients with asthma experiencing adverse effects of the systemic glucocorticosteroid need to be compared with those of biologics. Moreover, many patients with AERD during the desensitization regimen have gastrointestinal problems caused by aspirin. Desensitization protocols in the United States1Khan D.A. Banerji A. Blumenthal K.G. Phillips E.J. Solensky R. White A.A. et al.Drug allergy: a 2022 practice parameter update.J Allergy Clin Immunol. 2022; 150: 1333-1393Google Scholar recommend no change in the treatment with inhaled drugs and allow initial administration of a leukotriene modifier (montelukast) to reduce a risk of bronchospasm. There are various medicines with aspirin content ranging from 300 mg to 325 or 500 mg. In the United States, aspirin tolerance is achieved by escalating the dose of aspirin followed by a long-term maintenance dose of 325 to 650 mg twice a day. In Europe, the maintenance dose ranges from 300 to 600 mg twice a day. In our experience, desensitization is safe if it follows oral aspirin challenge test to determine the provocative dose of aspirin. The same day as the challenge test, in a clinically stable patient whose provoked symptoms resolved spontaneously or were reversed with a betamimetic, the patient receives again the threshold dose of aspirin. If no reaction occurs, increasing doses of aspirin are administered every 90 minutes. A target cumulative dose of aspirin is between 600 and 1200 mg. Any intolerance symptoms between the stepped-up doses are managed by a repeated administration of the last dose. On the next day, the maintenance regimen is started. In conclusion, patients with AERD are stratified according to the severity of asthma but have quite variable cellular inflammatory endotypes. Eosinophilic versus noneosinophilic inflammation of airways in AERD can guide some therapeutic approaches, especially treatment with biologics. The aspirin challenge test is laborious, but it can be done along with aspirin desensitization. Aspirin desensitization is inexpensive management of choice in certain patients with AERD. Stratification of clinical trials on biological therapy in AERD by cellular inflammatory endotypes is required to learn whether biological therapy can replace or should follow aspirin desensitization. Editor’s note: The authors of the American Academy of Allergy, Asthma & Immunology practice parameter1Khan D.A. Banerji A. Blumenthal K.G. Phillips E.J. Solensky R. White A.A. et al.Drug allergy: a 2022 practice parameter update.J Allergy Clin Immunol. 2022; 150: 1333-1393Google Scholar declined to reply to this correspondence. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. Mechanistic and clinical updates in AERD: 2021-2022Journal of Allergy and Clinical ImmunologyVol. 151Issue 6PreviewAspirin-exacerbated respiratory disease (AERD) is a unique and often clinically severe disease affecting a subgroup of adults with asthma and chronic rhinosinusitis with nasal polyposis. Works published in 2021-2022 confirmed the critical role of lipid mediator dysregulation and mast cell activation and expanded our understanding of basophils, macrophages, fibrin dysregulation, and the 15-lipoxygenase pathway in disease pathogenesis. Translational studies established inflammatory heterogeneity in the upper and lower airway at baseline and during aspirin-induced respiratory reactions. Full-Text PDF Drug allergy: A 2022 practice parameter updateJournal of Allergy and Clinical ImmunologyVol. 150Issue 6PreviewThe Joint Task Force on Practice Parameters (JTFPP) is committed to ensuring that all guidelines are based on the best scientific evidence at the time of publication, and that such evidence is free of commercial bias to the greatest extent possible. Before confirming the selection of the workgroup chairpersons and members, the JTFPP discusses and resolves all relevant potential conflicts of interest (COI) of each potential workgroup member. The JTFPP recognizes that experts in a field are likely to have interests that could come into conflict with the development of a completely unbiased and objective guideline. Full-Text PDF ReplyJournal of Allergy and Clinical ImmunologyPreviewIn their correspondence, Mastalerz and Sanak1 highlight key areas within the field of aspirin-exacerbated respiratory disease (AERD) that require additional focus: nomenclature, inflammatory endotypes, and discordance in aspirin challenge practices and aspirin therapy dosing between the United States and Europe. We agree that the established nomenclature to date fails to fully capture the clinical and mechanistic processes associated with the clinical disease but finding a truly accurate name consistent across numerous languages remains a challenge. Full-Text PDF