Accurate phenotyping of cross-reactive hypersensitivity is essential to shed light on the underlying mechanisms in NSAID-induced urticaria/angioedema

The article "Distinct transcriptomic and metabolomic profiles characterize NSAID-induced urticaria/angioedema patients undergoing aspirin desensitization" by Tay et al1Tay SH, Santosa A, Goh ECH, Xu CX, Wu LH, Bigliardi-Qi M, et al. Distinct transcriptomic and metabolomic profiles characterize NSAID-induced urticaria/angioedema patients undergoing aspirin desensitization [e-pub ahead of print]. J Allergy Clin Immunol https://doi.org/10.1016/j.jaci.2022.07.025. Accessed August 31, 2022.Google Scholar in The Journal of Allergy and Clinical Immunology tries to characterize transcriptomic and metabolomic profiles in patients with nonsteroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema (NIUA) who are undergoing aspirin desensitization. Patients were included exclusively on the basis of clinical history, without an aspirin drug provocation test (DPT). We would like to comment on both patient selection and transcriptomic analysis. Concerning the patients, 7 of 10 reported only 1 reaction (4 to aspirin and 3 to other NSAIDs). As only 1 reaction occurred, it would not be possible to declare that the patients developed cross-reactive hypersensitivity reactions (CRHRs). To consider a potential CRHR, patients must experience at least 2 reactions to 2 or more unrelated strong COX-1 inhibitors.2Kowalski M.L. Asero R. Bavbek S. Blanca M. Blanca-Lopez N. Bochenek G. et al.Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs.Allergy. 2013; 68: 1219-1232Crossref PubMed Scopus (375) Google Scholar,3Dona I. Blanca-Lopez N. Cornejo-Garcia J.A. Torres M.J. Laguna J.J. Fernandez J. et al.Characteristics of subjects experiencing hypersensitivity to non-steroidal anti-inflammatory drugs: patterns of response.Clin Exp Allergy. 2011; 41: 86-95Crossref PubMed Scopus (191) Google Scholar Nevertheless, this condition was not met in the study by Tay et al.1Tay SH, Santosa A, Goh ECH, Xu CX, Wu LH, Bigliardi-Qi M, et al. Distinct transcriptomic and metabolomic profiles characterize NSAID-induced urticaria/angioedema patients undergoing aspirin desensitization [e-pub ahead of print]. J Allergy Clin Immunol https://doi.org/10.1016/j.jaci.2022.07.025. Accessed August 31, 2022.Google Scholar The remaining patients (apparently 3) reported 2 to 4 reactions (1 to aspirin and 3 to other NSAIDs); however, neither the exact number nor the specific culprit were specified. If only clinical history is taken into account, diagnosis may be ruled out in around 24% of patients in whom NIUA is suspected.4Blanca-Lopez N. J Torres M. Dona I. Campo P. Rondon C. Seoane Reula M.E. et al.Value of the clinical history in the diagnosis of urticaria/angioedema induced by NSAIDs with cross-intolerance.Clin Exp Allergy. 2013; 43: 85-91Crossref PubMed Scopus (74) Google Scholar Indeed, confirmation is achieved in only 63% of patients reporting 2 reactions. Tay et al1Tay SH, Santosa A, Goh ECH, Xu CX, Wu LH, Bigliardi-Qi M, et al. Distinct transcriptomic and metabolomic profiles characterize NSAID-induced urticaria/angioedema patients undergoing aspirin desensitization [e-pub ahead of print]. J Allergy Clin Immunol https://doi.org/10.1016/j.jaci.2022.07.025. Accessed August 31, 2022.Google Scholar stated that NSAID DPTs need to be interpreted carefully. We do not agree with this statement. Oral aspirin DPT is the criterion standard to confirm CRHRs, particularly in cases involving nonsevere reactions such as NIUA, and the potential confounding factors mentioned (viral infection, physical activity) are easily controllable. Tay et al1Tay SH, Santosa A, Goh ECH, Xu CX, Wu LH, Bigliardi-Qi M, et al. Distinct transcriptomic and metabolomic profiles characterize NSAID-induced urticaria/angioedema patients undergoing aspirin desensitization [e-pub ahead of print]. J Allergy Clin Immunol https://doi.org/10.1016/j.jaci.2022.07.025. Accessed August 31, 2022.Google Scholar explained that their patients did not undergo a high-dose aspirin DPT on account of the cardiovascular risk. However, as NIUA involves only skin and no other organs, DPTs are safe even at high doses. Thus, the risk-benefit balance may not be a contraindication for a DPT. Additionally, in these patients, NIUA lasted a median of 9 years. We have demonstrated that 60% of patients with NIUA develop NSAID tolerance over time (median time 5 years).5Dona I. Barrionuevo E. Salas M. Cornejo-Garcia J.A. Perkins J.R. Bogas G. et al.Natural evolution in patients with nonsteroidal anti-inflammatory drug-induced urticaria/angioedema.Allergy. 2017; 72: 1346-1355Crossref PubMed Scopus (38) Google Scholar Therefore, aspirin DPT is required for diagnosis of NIUA, as many patients may no longer be hypersensitive. Finally, the aspirin doses commonly used as antiplatelets (100 mg) are usually tolerated by patients with NIUA, and if a reaction occurs, it induces only mild cutaneous symptoms. Consequently, whether desensitization is really needed should be evaluated. Regarding transcriptomics, doubts arise about the lack of explanation for the use of 2 different annotations to generate gene-level counts and a radial 2-dimensional plot instead of volcano or radial 3-dimensional plots (including P values), as well as about the absence of tables with full differential expression analysis and functional enrichment. Furthermore, a principal component analysis plot displays 3 overlapping confidence ellipses, showing no separation between the 3 groups considered. In addition to issues related to patient selection, this might also suggest a bias affecting some unaddressed variables (age, sex, and ethnicity, among others). Consequently, the differential expression results found may arise not really from NIUA but rather from undeclared variables. Finally, the primary objective of the study by Tay et al1Tay SH, Santosa A, Goh ECH, Xu CX, Wu LH, Bigliardi-Qi M, et al. Distinct transcriptomic and metabolomic profiles characterize NSAID-induced urticaria/angioedema patients undergoing aspirin desensitization [e-pub ahead of print]. J Allergy Clin Immunol https://doi.org/10.1016/j.jaci.2022.07.025. Accessed August 31, 2022.Google Scholar was to characterize patients with NIUA who are undergoing aspirin desensitization profiles; however, no differences before and after this procedure seem to have been found. Taken together, our comments about the study by Tay et al1Tay SH, Santosa A, Goh ECH, Xu CX, Wu LH, Bigliardi-Qi M, et al. Distinct transcriptomic and metabolomic profiles characterize NSAID-induced urticaria/angioedema patients undergoing aspirin desensitization [e-pub ahead of print]. J Allergy Clin Immunol https://doi.org/10.1016/j.jaci.2022.07.025. Accessed August 31, 2022.Google Scholar aim to raise various concerns not only about patient selection and transcriptomic analysis but also about the potential findings. Distinct transcriptomic and metabolomic profiles characterize NSAID-induced urticaria/angioedema patients undergoing aspirin desensitizationJournal of Allergy and Clinical ImmunologyVol. 150Issue 6PreviewThere is limited data on the mechanisms of aspirin desensitization in patients with nonsteroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema (NIUA). Full-Text PDF Open AccessReplyJournal of Allergy and Clinical ImmunologyVol. 151Issue 3PreviewWe thank Cornejo-García et al1 for their interest in our article "Distinct transcriptomic and metabolomic profiles characterize NSAID-induced urticaria/angioedema patients undergoing aspirin desensitization."2 We agree that patient selection is important in biomarker discovery and had acknowledged the limitations in the article. As explained in the discussion, we had adopted a pragmatic approach in patient recruitment, as the patients with nonsteroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema (NIUA) had active coronary artery disease requiring aspirin before urgent percutaneous coronary intervention. Full-Text PDF