Pediatric Urine Mast Cell Mediator Levels

Pediatric Urine Mast Cell Mediator Levels | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 27 January 2025 V1 Latest version Share on Pediatric Urine Mast Cell Mediator Levels Authors : Deepti Vellaichamy Manian 0009-0008-8263-3288 [email protected] , Joseph Butterfield 0000-0002-6830-2190 , Jeffrey Meeusen W , Angela Mattke , and Anupama Ravi Authors Info & Affiliations https://doi.org/10.22541/au.173798093.32202133/v1 356 views 162 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: Urine mast cell mediator levels have found significant clinical utility in supporting the diagnosis of various allergic disorders in the adult population. There are few studies on the range of these mediator levels in the children and its clinical utility. Objectives: We determined the range of the urine mast cell mediator levels in children. Methods: Pediatric allergy and community-based pediatric clinics including children with and without an allergic disorder, respectively, served as the source of the study. Baseline urine mast cell mediator levels were obtained for all children. Demographics, atopic disorders, clinical symptoms and response to medication were documented. Results: Urine 2,3-Dinor-11Beta-Prostaglandin F2 Alpha (BPG) values were significantly higher in children with an underlying allergic disorder when compared to those without. Stratification based on age, sex and allergic disorder was performed in patients with an allergic disorder. Urine Leukotriene E 4 (LTE 4 ) and n-Methylhistamine (NMH) were significantly correlated with age (Spearman’s rho -0.4874 and -0.6902 respectively). With every year of age, the level of the urine NMH decreased by 18 units and urine LTE 4 by 3 units approximately. Urine LTE 4 and NMH levels were significantly higher in males when compared to females. Urine BPG levels were not significantly affected by age or sex. Conclusion: Distribution of urine mast cell mediator levels are slightly different from the values derived from studies in the adult population. Urine mast cell mediators may provide clinical utility in the diagnosis and management of allergic disorders. Further large-scale studies are warranted to validate clinical utility. Title: Pediatric Urine Mast Cell Mediator Levels Urine Mast Cell Mediator Levels in the Pediatric Population with and without Allergic Disease Stratified by age and gender: A Novel Diagnostic Insight Deepti Vellaichamy Manian, M.D. 1* , Joseph H Butterfield, M.D. 1 , Jeffrey W Meeusen, Ph.D. 2 , Angela Mattke, M.D. 3 , Anupama Ravi, M.D. 4 1 Division of Allergic Diseases, Mayo Clinic, Rochester, Minnesota, USA. 2 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA. 3 Department of Pediatric and Adolescent Medicine, Mayo Clinic School of Medicine, Rochester, Minnesota, USA. 4 Department of Pediatrics; Division of Allergic Diseases, Mayo Clinic, Rochester, Minnesota, USA. * Author currently works at Stormont Vail Health, Topeka, Kansas, USA. Acknowledgements: The study was supported in part by The Mastocytosis Society research award (2018) for pediatric mastocytosis. Conflict of interest: None Word Count: 1185 Abstract : 250 Tables : 4 Online supplemental information: 3 tables. Background: Urine mast cell mediator levels have found significant clinical utility in supporting the diagnosis of various allergic disorders in the adult population. There are few studies on the range of these mediator levels in the children and its clinical utility. Objectives: We determined the range of the urine mast cell mediator levels in children. Methods: Pediatric allergy and community-based pediatric clinics including children with and without an allergic disorder, respectively, served as the source of the study. Baseline urine mast cell mediator levels were obtained for all children. Demographics, atopic disorders, clinical symptoms and response to medication were documented. Results: Urine 2,3-Dinor-11Beta-Prostaglandin F2 Alpha (BPG) values were significantly higher in children with an underlying allergic disorder when compared to those without. Stratification based on age, sex and allergic disorder was performed in patients with an allergic disorder. Urine Leukotriene E 4 (LTE 4 ) and n-Methylhistamine (NMH) were significantly correlated with age (Spearman’s rho -0.4874 and -0.6902 respectively). With every year of age, the level of the urine NMH decreased by 18 units and urine LTE 4 by 3 units approximately. Urine LTE 4 and NMH levels were significantly higher in males when compared to females. Urine BPG levels were not significantly affected by age or sex. Conclusion: Distribution of urine mast cell mediator levels are slightly different from the values derived from studies in the adult population. Urine mast cell mediators may provide clinical utility in the diagnosis and management of allergic disorders. Further large-scale studies are warranted to validate clinical utility. Keywords 2,3-Dinor-11Beta-Prostaglandin F2 Alpha, Leukotriene E4, n-Methylhistamine, Pediatrics, Urine mast cell mediators. Introduction: Mast cells are derived from the multilineage hematopoietic cells in the bone marrow, that later migrate, mature and reside in the tissues and end organs. They are primary effector cells in allergic reactions. 1 Activation through receptors such as mast cell related G-protein coupled receptors (MRGPRX2) and high affinity receptors for IgE causes secretion of both preformed and newly synthesized mediators. 2 Potent proinflammatory mediators released include tryptase, histamine, prostaglandin D2 (PGD2), leukotriene C4 (LTC4) and cytokines leading to various clinical manifestations. 3 Clinical utility of mast cell mediator levels as a biochemical evidence of systemic mast cell activation has been well established for several disorders. LTE 4 levels in the diagnosis and management has been demonstrated for allergen-induced asthma (4-7) , asthma exacerbation (8) , chronic rhinosinusitis 9 , nasal polyps 10 , aspirin challenge, aspirin exacerbated respiratory disease (AERD) (11-13) and systemic mastocytosis. 14 Clinical utility of PGD2 and its metabolites has been studied in mast cell activation syndrome 20 , atopic asthma and aspirin sensitivity 21 , food allergy 22 and systemic mastocytosis. (22, 23) Histamine can be produced by mast cells and basophils. The normal ranges have been previously studied in the adult population. We sought to study the distribution of these mediator levels in the pediatric population. Methods: Study subjects Patients seen in pediatric allergy clinic and diagnosed with atopic disorders constituted the cohort of subjects with allergic disorder. Patients evaluated for well-child care at community-based pediatric clinic constituted the cohort of non-atopic/healthy children. Patients were screened for the presence of an allergic disorder at the time of recruitment using a screening questionnaire. Patients aged <18 years of age were included in this study. Data was abstracted using an institutional review board approved protocol with signed consent. Medical and laboratory records were abstracted for both cohorts from the Epic electronic medical record system (Epic Systems Corporation). Data abstracted include demographic details, laboratory data including urine mast cell mediator levels: NMH, BPG, and LTE 4 for both cohorts. For the atopic children, if clinically indicated, serum tryptase levels were obtained at baseline and during an episode with symptoms suggestive of an allergic reaction. From the clinical record we compiled information on the presence or absence of a diagnosed allergic condition, symptoms that may be present in a patient with mast cell disorder, and clinical response to medications. Other data specific to the patient that may aid interpretation of the laboratory data was also noted. Statistics: Statistical analysis was computed using the JMP software (SAS Institute, Cary, NC). Descriptive data was presented as median (25 th percentile, 75 th percentile), total range as well as the range excluding the outliers. Distribution between the two cohorts was analyzed using pooled t test and Wilcoxon/Kruskal Wallis test. Further analysis of distribution of the mediator levels by age, sex and presence or absence of various allergic diagnoses was done in patients with a diagnosis of at least one allergic disorder. This was done using regression analysis and non-parametric analysis, and the spearman correlation coefficient estimated for continuous variables. For categorical variables, groups were compared by non-parametric (Wilcoxon/Kruskal Wallis test). The statistical significance was defined as p < 0.05. Results: 75 patients with a diagnosis of at least one allergic disorder were recruited from the pediatric allergy clinic. 35 of the 75 patients completed the urine collection. For clinical purposes, these patients completed multiple collections of urine mast cell mediator. Hence, a total of 197 unique values were available from the cohort of children with an allergic disorder. 54 patients were recruited from well child visits at community-based pediatric clinics to serve as non-atopic/healthy control. 38 of the 54 patients completed the urine collection. Range of the BPG levels in children with and without allergic are as noted in Tables 5 and 6. Urine BPG values were significantly higher in children with an underlying allergic disorder when compared to those without (Median 4343.5 verus 2146.5, p < 0.0001). Difference of urine NMH and LTE 4 levels among the two groups were not statistically significant (Table 1). Stratification based on age, sex and allergy diagnosis was done in patients with a diagnosis of an allergic disorder. Urine LTE 4 and NMH were significantly correlated with age. With every year of age, the level of the urine NMH decreased by 18 mcg/g Cr and urine LTE 4 by 3 pg/mg Cr approximately (Table 2). Urine LTE 4 and NMH levels were significantly higher in males when compared to females (Table 3). Urine NMH levels were significantly higher in patients with eczema, food allergy and MCAS (Table 4). Range of all mediator levels stratified by allergic condition are as noted in table 7. Discussion: We demonstrate the distribution of the urine mast cell mediator levels and their relationship to various demographic and clinical variables. Established adult reference range for the urine mast cell mediator levels for BPG, LTE4, and NMH are <5205 pcg/mg Cr, ≤ 104 pcg/mg Cr, and 30-200 mcg/g creatinine. (24, 25) The median urine mast cell mediators in children obtained in our study is within this range. However, the range of distribution of these urine mast cell mediators is broader for children in our study compared to that reported in adults. Hence, the adult reference range does not best apply to the pediatric population. Children, including those without an allergic disorder, may excrete higher urine mast cell mediators at baseline. Notably higher excretion of urine mast cell mediators in children may not always signify an underlying mast cell disorder. Hence, in addition to the urine mast cell mediator levels, clinical correlation and presence of the other criteria for a mast cell disorder is essential for diagnosis. Based on our data, urine BPG is most likely to be helpful in identifying children with an underlying allergic disorder. However, urine BPG at baseline alone cannot distinguish one allergic diagnosis from another. It is unclear why the levels of urine NMH and LTE 4 are affected by age and sex, while that of urine BPG is not. Based on the data regarding urine NMH, there is some degree of mast cell activation occurring even at baseline in children with an allergic disorder such as eczema, MCAS and food allergy. Further, there can be variations in the baseline values of these mediators in the same patient with time. There are some limitations to the study. The two cohorts were not age and sex matched. This was a single center study. Strengths of the study include recruitment of participants by different physicians from the pediatric allergy and community-based pediatric clinics and hence reduced bias. This is the first study to our knowledge that has sought to establish urine mast cell mediator levels in the pediatric population. Larger studies with age and sex matched cohort will be helpful. The urine mast cell mediator levels may have further utility in identification of anaphylaxis events with comparison of episode to that of baseline as well as identification of allergic disorder. Reference 1. Metcalfe DD. Mast cells and mastocytosis. Blood. 2008;112(4):946-56. 2. McNeil BD, Pundir P, Meeker S, Han L, Undem BJ, Kulka M, et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature. 2015;519(7542):237-41. 3. Galli SJ, Grimbaldeston M, Tsai M. Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol. 2008;8(6):478-86. 4. Bancalari L, Conti I, Giannessi D, Lazzerini G, Dente FL, De Caterina R, et al. Early increase in urinary leukotriene E4 (LTE4) is dependent on allergen dose inhaled during bronchial challenge in asthmatic subjects. Allergy. 1999;54(12):1278-85. 5. Sanak M, Bochenek G, Faber J, Plutecka H, Szczeklik A. 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Increased production of prostaglandin D2 in patients with systemic mastocytosis. N Engl J Med. 1980;303(24):1400-4. 24. NMHR1 - Overview: N-Methylhistamine, Random, Urine [Internet]. Mayocliniclabs.com. [cited 2023 Apr 23]. Available from: https://www.mayocliniclabs.com/test-catalog/overview/605015 25. RLTE4 - Overview: Leukotriene E4, Random, Urine [Internet]. Mayocliniclabs.com. [cited 2023 Apr 23]. Available from: https://www.mayocliniclabs.com/test-catalog/Overview/606354 Supplementary Material File (3 tables.docx) Download 17.17 KB Information & Authors Information Version history V1 Version 1 27 January 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords allergy diagnosis anaphylaxis biomarkers histamine mast cells pediatrics urticaria Authors Affiliations Deepti Vellaichamy Manian 0009-0008-8263-3288 [email protected] Mayo Clinic Division of Allergic Diseases View all articles by this author Joseph Butterfield 0000-0002-6830-2190 Mayo Clinic Division of Allergic Diseases View all articles by this author Jeffrey Meeusen W Mayo Clinic Minnesota Department of Laboratory Medicine and Pathology View all articles by this author Angela Mattke Mayo Clinic Department of Pediatric and Adolescent Medicine View all articles by this author Anupama Ravi Mayo Clinic Division of Allergic Diseases View all articles by this author Metrics & Citations Metrics Article Usage 356 views 162 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Deepti Vellaichamy Manian, Joseph Butterfield, Jeffrey Meeusen W, et al. Pediatric Urine Mast Cell Mediator Levels. Authorea . 27 January 2025. 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