Title: Addressing Potential Biases in the BEEP Trial’s Cow’s Milk Allergy Overdiagnosis StudyChia-Tsu Kao MD MBA123, I-Han Cheng MD4, Su-Boon Yong567 Chin-Yuan Yii8 Yu-Tsun Su 9,101Department of Rehabilitation, Kaohsiung Municipal United Hospital2Department of Rehabilitation, E-Da Dachang Hospital3Jiahua Health Co., Ltd.4Chung Shan Medical University5 Department of Allergy and Immunology, China Medical University Children’s Hospital, Taichung, Taiwan6Department of Medicine, College of Medicine, China Medical University, Taichung, Taiwan7 Center for Allergy, Immunology, and Microbiome (A.I.M.), China Medical University Hospital, Taichung, Taiwan8 Division of Gastroenterology and Hepatology, Department of Internal Medicine, LandseedInternational Hospital, Taoyuan, Taiwan9 Department of Pediatrics, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan10 School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan

Differential modulation of allergic rhinitis nasal transcriptome by dupilumab and allergy immunotherapy: correspondenceChun-Ting Lin1, Chi-Wei Lin2, Su-Boon Yong3,4,5 Chin-Yuan Yii61. Department of pharmacy, Chung Shan Medical University Hospital, Taiwan.2. College of Nursing, Asia University, Taichung, Taiwan.3. Department of Allergy and Immunology, China Medical University Children’s Hospital, Taichung, Taiwan.4. Department of Medicine, College of Medicine, China Medical University, Taichung, Taiwan5. Center for Allergy, Immunology, and Microbiome (A.I.M.), China Medical University Hospital, Taichung, Taiwan.6. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Landseed International Hospital, Taoyuan, Taiwan.Corresponding author:1.Chin-Yuan Yii, MDDivision of Gastroenterology and Hepatology, Department of Internal Medicine, LandseedInternational Hospital, Taoyuan, TaiwanEmail: [email protected] Yong, MD, PhDDepartment of Allergy and Immunology, China Medical University Children’s Hospital, Taichung, Taiwan, Republic of ChinaE-mail: [email protected] word count of the manuscript: 541Dear Editor,We have carefully examined the study conducted by Dr. Matthew F. Wipperman and colleagues, titled ”Differential Modulation of Allergic Rhinitis Nasal Transcriptome by Dupilumab and Allergy Immunotherapy1.” The research offers significant insights into how treatment with dupilumab alone, or in combination with subcutaneous immunotherapy, affects gene expression in allergic rhinitis. The team’s diligent efforts in this domain are highly commendable. However, it is also crucial to acknowledge certain limitations within the scope of this investigation.Firstly, the reliance on Timothy grass (Phleum pratense) as the principal allergen in this research prompts consideration of its geographic and demographic relevance. While Timothy grass serves as a prevalent allergen in Europe and North America, its distribution and incidence differ across other regions2. This study lacks specific information about the geographic or demographic profiles of the participants, which is crucial given the predominance of Timothy grass in temperate zones. Consequently, the generalizability of the results may be constrained, particularly in tropical or subtropical regions where Timothy grass is uncommon, potentially limiting the applicability of the findings.Second, this study incorporated data from two independent trials, with sample sizes of 15 and 103 participants, respectively. Considering the global prevalence of allergic rhinitis, estimated at 19.1%3, the small sample sizes may undermine the statistical power and the wider applicability of the study’s outcomes. To bolster the statistical robustness and reliability of subsequent investigations, an increase in sample size is recommended. Expanding the cohort would enhance the accuracy in reflecting population variability and ensure more dependable results. Moreover, the initial participant pool was limited to specific geographic areas. Future studies should strive for a more heterogeneous sample by including individuals from diverse geographic and ethnic backgrounds. Such inclusivity would broaden the applicability of the results, ensuring they reflect a more comprehensive demographic spectrum. This methodological refinement is crucial for a deeper understanding of the therapeutic efficacy across varied patient groups.Third, exclusion criteria of this investigation barred participants who had used antihistamines shortly before the screening and nasal allergen challenge visits. Yet, it remains uncertain if the researchers monitored ongoing antihistamine use post-screening through the follow-up period. Notably, research by Erwin W. Gelfand and colleagues4has shown that fexofenadine-a widely used H1 antihistamine in Europe and the United States-can modulate IL-4 and IL-5 levels, which could significantly affect study outcomes. Consequently, this oversight raises concerns regarding the potential influence of antihistamines on the results, emphasizing the necessity for vigilant monitoring of antihistamine use during follow-up assessments. To mitigate these risks and ensure the integrity of the findings, future research should rigorously track all concurrent medication use, including antihistamines, both during and subsequent to the screening phase. Such meticulous oversight will safeguard the study’s conclusions from confounding variables, thus providing a more accurate evaluation of treatment effects.In summary, the research conducted by Dr. Matthew F. Wipperman et al. significantly advances our knowledge of how dupilumab can normalize nasal tissue gene expression. Prior studies highlight that the United States spends roughly $3.4 billion annually on treating allergic rhinitis, a large part of which goes towards medications5. Further research yielding deeper insights and robust data could lessen the impact of allergic rhinitis on patients globally and might also diminish the considerable economic strain it places on healthcare systems.

Letter to the editor:

Comment on “The risk assessment of uveitis after COVID-19 diagnosis”Patrick Wu,1 Chin-Yuan Yii,2 Su-Boon Yong3,4,5College of Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USADivision of Gastroenterology and Hepatology, Department of Internal Medicine, Landseed International Hospital, Taoyuan, TaiwanDepartment of Allergy and Immunology, China Medical University Children’s Hospital, Taichung, TaiwanDepartment of Medicine, College of Medicine, China Medical University, Taichung, TaiwanCenter for Allergy, Immunology, and Microbiome (A.I.M.), China Medical University Hospital, Taichung, Taiwan.Corresponding authors:Chin-Yuan Yii, MDDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Landseed International Hospital, Taoyuan, TaiwanAddress: No.77, Guangtai Rd., Pingzhen Dist., Taoyuan City 32449, Taiwan Telephone: +886 3 494 1234Email: [email protected]. Su-Boon Yong, MD PhDDepartment of Medicine, College of Medicine, China Medical University, Taichung, TaiwanAddress: No. 2, Yuh-Der Road, Taichung City 404, TaiwanTelephone: 00886-4-22052121Email: [email protected] author:Patrick Wu, BSCollege of Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USAAddress: 5000 Lakewood Ranch Blvd, Bradenton, FL 34211, USATelephone: +1(301)3375805Email: [email protected] availability statement: Not applicable. This letter to the editor does not require data collection.Funding statement: Not applicable. Authorship for letter to the editor did not receive any funding.Conflict of interest disclosure: The authors do not have any conflict of interests to declare.Ethics approval statement: Not applicable.Patient consent statement: Not applicable.Permission to reproduce material from other sources: Not applicable.Clinical trial registration: Not applicable.AbstractSeveral suggestions were made for the study by Hsia et al1 regarding uveitis risk following COVID-19 diagnosis. We recommend the authors align the racial composition of study groups more closely with that of U.S. demographics. In addition, we recommend the study to include possibility of false negatives from PCR testing. Lastly, we suggest the authors to consider cases of self-limiting uveitis and relapses independent of COVID-19.Keywords: uveitis risk, COVID-19, racial composition, PCR testing, self-limiting uveitis, relapsesTo the Editor,We read with great interest the study by Hsia et al1regarding the risk assessment of uveitis after COVID-diagnosis. We appreciate the authors’ attention to detail by eliminating possible confounding variables that may contribute to uveitis development. Furthermore, we were impressed by the robust study design incorporating propensity score matching, long follow-ups, and immense study size of more than 4 million patients using the TriNetX analytics platform.Nevertheless, to enhance this study, we recommend the following considerations.First, this study utilized the US research network, covering about 92 million patients to form a COVID-19 cohort and a non-COVID-19 control group, each with 2 million patients, of which 62.5% and 62.4% were white, respectively. This underrepresents the white population by 13% compared to the 75.5% white representation in the 2022 US census. Future studies should align the racial composition of study groups more closely with national demographics.Second, the authors identified COVID-19 cases based on positive PCR tests or antibody immunoassays. Yet, Binny et al’s study in New Zealand illustrates how PCR test sensitivity fluctuates across the COVID-19 infection timeline, influenced by viral load and patient age.2 The sensitivity of PCR tests peaks at 92.7% between 4 to 5 days post-infection, then drops to 88% from 5 to 14 days, while specificity remains near 100%.2 This indicates a higher likelihood of false negatives and very low false positives in PCR testing. Highlighting this significant limitation in the discussion section would be beneficial.Third, this study excluded those diagnosed with uveitis within 6 months before COVID-19 infection, potentially overlooking undiagnosed, self-limiting cases that may resurface post-infection. 10% of intermediate uveitis cases resolve on their own, and anterior uveitis, while often self-limiting, can cause severe complications.3,4 Moreover, uveitis relapses, as reported in Grunwald et al’s study, could occur independently of COVID-19, leading to misattribution of these cases to COVID-19.5 These aspects represent potential limitations of the study that warrant discussion.In conclusion, the study by Hsia et al1 is a major milestone towards incorporating uveitis assessment among COVID-19 patients in healthcare guidelines. This study has tremendous potential to save numerous patients from glaucoma, cataracts, and permanent vision loss. To improve this study, we recommend authors to adjust study groups so that white patients are adequately represented, discuss the possibility of false negatives from PCR testing, and consider cases of self-limiting uveitis and relapses independent of COVID-19.Acknowledgements: noneReferencesHsia NY, Hsu AY, Wang YH, Li JX, Chen HS, Wei JC, Lin CJ, Tsai YY. The risk assessment of uveitis after COVID-19 diagnosis: A multicenter population-based study. J Med Virol. 2023 Oct;95(10):e29188. doi: 10.1002/jmv.29188. PMID: 37881132.Binny RN, Priest P, French NP, Parry M, Lustig A, Hendy SC, Maclaren OJ, Ridings KM, Steyn N, Vattiato G, Plank MJ. Sensitivity of Reverse Transcription Polymerase Chain Reaction Tests for Severe Acute Respiratory Syndrome Coronavirus 2 Through Time. J Infect Dis. 2022 Dec 28;227(1):9-17. doi: 10.1093/infdis/jiac317. PMID: 35876500; PMCID: PMC9384503.Maggon R. INTERMEDIATE UVEITIS PARS PLANITIS. Med J Armed Forces India. 2001 Jan;57(1):84-5. doi: 10.1016/S0377-1237(01)80106-4. Epub 2011 Jul 21. PMID: 27365593; PMCID: PMC4925061.Islam N, Pavesio C. Uveitis (acute anterior). BMJ Clin Evid. 2010 Apr 8;2010:0705. PMID: 21736765; PMCID: PMC2907596.Grunwald L, Newcomb CW, Daniel E, Kaçmaz RO, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Suhler EB, Thorne JE, Foster CS, Kempen JH; Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Risk of relapse in primary acute anterior uveitis. Ophthalmology. 2011 Oct;118(10):1911-5. doi: 10.1016/j.ophtha.2011.02.044. Epub 2011 Jun 16. PMID: 21680024; PMCID: PMC3179829.

Correspondence to “Association between Chronic Rhinosinusitis and New Onset Asthma Implications for Prevention”To the Editor,We have attentively reviewed the article by Schwartz et al. titled ’Sinus inflammation and chronic rhinosinusitis are associated with a diagnosis of new onset asthma in the following year’1. This study significantly advances our understanding of the relationship between chronic rhinosinusitis (CRS) and the onset of new asthma diagnoses. However, we would like to offer some suggestions.First and foremost, it is important to consider potential confounders that might influence the observed association between CRS and the development of asthma. Factors such as environmental exposures or socio-economic status could potentially impact this relationship.2,3Secondly, this study focuses on the CRS-asthma association but doesn’t probe how CRS treatments affect asthma outcomes. Phillips et al4showed timely CRS treatments, such as functional endoscopic sinus surgery (FESS) might lower asthma risks. Addressing eosinophilic inflammation and related conditions, e.g. depression, could also influence asthma results5,6. Understanding CRS treatment impacts on asthma is crucial for patient care, necessitating more research to inform clinical guidance.Furthermore, it’s important to consider that this study might have overestimated the connection between chronic rhinosinusitis (CRS) and asthma due to certain methodological limitations. The study did not take into account the 12-week duration requirement for CRS, potentially leading to an overrepresentation of cases and an overestimation of the associations . Additionally, the reliance on electronic health records (EHR) for identifying disease outcomes introduces the possibility of measurement errors or biases, which could further contribute to the overestimation of the observed associations . Therefore, it is crucial for future research endeavors to refine their methods and address these limitations in order to obtain a more accurate understanding of the strength of the CRS-asthma association.In conclusion, this study by Schwartz et al.’s research highlights a link between CRS and new asthma cases, but further exploration is needed on potential confounders, the effect of CRS treatments, and potential overestimations.1. Schwartz BS, Pollak JS, Bandeen-Roche K, et al. Sinus inflammation and chronic rhinosinusitis are associated with a diagnosis of new onset asthma in the following year. Allergy . Oct 2023;78(10):2659-2668. doi:10.1111/all.157712. Celebi Sozener Z, Cevhertas L, Nadeau K, Akdis M, Akdis CA. Environmental factors in epithelial barrier dysfunction. J Allergy Clin Immunol . Jun 2020;145(6):1517-1528. doi:10.1016/j.jaci.2020.04.0243. Velasquez N, Gardiner L, Cheng TZ, et al. Relationship between socioeconomic status, exposure to airborne pollutants, and chronic rhinosinusitis disease severity. Int Forum Allergy Rhinol . Feb 2022;12(2):172-180. doi:10.1002/alr.228844. Phillips KM, Bergmark RW, Hoehle LP, Caradonna DS, Gray ST, Sedaghat AR. Chronic rhinosinusitis exacerbations are differentially associated with lost productivity based on asthma status. Rhinology . Dec 1 2018;56(4):323-329. doi:10.4193/Rhin18.0335. Shah SA, Kobayashi M. Pathogenesis of chronic rhinosinusitis with nasal polyp and a prominent T2 endotype. Heliyon . Sep 2023;9(9):e19249. doi:10.1016/j.heliyon.2023.e192496. Brunner WM, Schreiner PJ, Sood A, Jacobs DR, Jr. Depression and risk of incident asthma in adults. The CARDIA study. Am J Respir Crit Care Med . May 1 2014;189(9):1044-51. doi:10.1164/rccm.201307-1349OCAuthorIressa Cheng 1, Chin-Yuan Yii MD2,3. Su-Boon Yong4,5,Liang-Chun Shih MD, PhD 4,61 School of Medicine, Chung Shan Medical University, Taichung, Taiwan.2 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Landseed International Hospital, Taoyuan, Taiwan;3 Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan.4 Department of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.5 Department of Allergy and Immunology, China Medical University Children’s Hospital, Taichung, Taiwan.6 Department of Otorhinolaryngology-Head and Neck SurgeryAuthor Contributions:Iressa Cheng: Conceptualization, Writing - Original Draft PreparationChin-Yuan Yii: Conceptualization, Writing - Review & EditingLiang-Chun Shih: Writing - Review & EditingJiu Yao Wang: Conceptualization, Writing - Review & Editing, SupervisionSu-Boon Yong: Conceptualization, Writing - Review & Editing, Supervision, Project Administrationconflict of interests :The authors declare no conflict of interest.Corresponding author:1.Su-Boon Yong MD, PhD.Department of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.Department of Allergy and Immunology, China Medical University Children’s Hospital, Taichung, [email protected]. Jiu Yao Wang MD, PhDCenter for Allergy, Immunology, and Microbiome (A.I.M.), China Medical University Hospital, Taichung, Taiwan, China.Department of Allergy, Immunology, and Rheumatology (AIR), China Medical University Children’s Hospital, Taichung, Taiwan, [email protected]