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Background: Treatment of hypereosinophilic syndrome (HES) often requires the use of immunomodulators with substantial side effect profiles. The emergence of biologics offers an alternative treatment modality., Objective: To examine real-world practice data to describe the safety and consequences of various biologics suspected to directly or indirectly affect eosinophilic inflammation for the treatment of HES., Methods: Retrospective data from 13 centers were collected via an online Research Electronic Data Capture repository. Inclusion criteria included (1) peripheral eosinophil count of 1,500/mm 3 or greater without a secondary cause; (2) clinical manifestations attributable to the eosinophilia; and (3) having received mepolizumab (anti-IL-5), benralizumab (afucosylated anti-IL-5 receptor α), omalizumab (anti-IgE), alemtuzumab (anti-CD52), dupilumab (anti-IL-4 receptor α), or reslizumab (anti-IL-5) outside a placebo-controlled clinical trial., Results: Of the 151 courses of biologics prescribed for 121 patients with HES, 59% resulted in improved HES symptoms and 77% enabled tapering of other HES medications. Overall, 105 patients were receiving daily systemic glucocorticoids at the time of a biologic initiation and were able to reduce the glucocorticoid dose by a median reduction of 10 mg of daily prednisone equivalents. Biologics were generally safe and well-tolerated other than infusion reactions with alemtuzumab. Thirteen of 24 patients had clinical improvement after switching biologics and nine patients responded to increasing the dose of mepolizumab after a lack of response to a lower dose., Conclusions: Biologics may offer a safer treatment alternative to existing therapies for HES, although the optimal dosing and choice for each subtype of HES remain to be determined. Limitations of this study include its retrospective nature and intersite differences in data collection and availability of each biologic., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Mast cells (MCs) leave evidence of their presence and activation. Aside from increased numbers of MCs in tissues, this evidence includes detecting elevated serum levels of tryptase and discovering increased excretion of urinary metabolites of prostaglandin (PG) D 2 , leukotriene (LT) C 4 , and/or histamine. The importance of measuring these nontryptase mediator metabolites has largely gone unnoticed. We reviewed the utility of quantitating urinary levels of MC mediator metabolites in systemic mastocytosis (SM) and MC activation disorders and summarized the relative production of these mediators by MCs and other cell types. Quantitation of urinary n-methyl histamine, 2,3-dinor-11βPGF 2α , and LTE 4 offers a simple, noninvasive avenue to monitor their constitutive release as well as contemporaneous discharge during MC activation as well as supporting a diagnosis of SM. These increases can occur independently of or in addition to raised levels of tryptase. Quantitation of these mediator metabolites potentially offers targets for therapeutic intervention. Synthesis of PGD 2 , a product nearly exclusively of MCs, can be controlled with aspirin, histamine increase by H1 and H2 receptor blockade, and LTC 4 by a 5-LO inhibitor or LT receptor antagonist. Although other sources are reported, the increase in MC numbers in SM supports this cell as the predominant origin of all 3 mediators., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Patients with clonal mast cell activation syndromes (MCAS) including cutaneous and systemic mastocytosis (SM) may present with symptoms of mast cell activation, but in addition can have organ damage from the local effects of tissue infiltration by clonal mast cells. Patients with nonclonal MCAS may have chronic or episodic mast cell activation symptoms with an increase in serum tryptase and/or urinary metabolites of histamine, prostaglandin D2, and leukotrienes. Symptoms of MCAS and SM can be managed by blockade of mediator receptors (H1 and H2 antihistamines, leukotriene receptor blockade), inhibition of mediator synthesis (aspirin, zileuton), mediator release (sodium cromolyn), anti-IgE therapy, or a combination of these approaches. Acute episodes of mast cell activation require epinephrine, and prolonged episodes may be addressed with corticosteroids. Patients with clonal mast cell syndromes may need a reduction in the number of mast cells to prevent severe symptoms including anaphylaxis and/or progression to aggressive diseases., (Copyright © 2019. Published by Elsevier Inc.)

Background: Urinary leukotriene E4 (LTE4) is a well-validated marker of the cysteinyl leukotriene pathway, and LTE4 elevation has been described in conditions such as asthma, aspirin sensitivity, and chronic rhinosinusitis (CRS). There have been a number of reports investigating the role of spot urine LTE4 to predict aspirin sensitivity; however, variability in urinary LTE4 may affect the accuracy of this approach., Objective: Here, we explored the utility of 24-hour urinary LTE4 in 5 clinical diagnoses of allergic rhinitis, asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), CRS without nasal polyps, and aspirin sensitivity., Methods: This was a retrospective review of patients who had 24-hour quantification of urinary LTE4 by a clinically validated liquid chromatography tandem mass spectrometry method and their assigned diagnoses after assessment and clinical care., Results: Twenty-four-hour urinary LTE4 elevations were seen in those with asthma and those with CRSwNP but influenced by underlying aspirin sensitivity. Elevation in LTE4 was significant in those with CRSwNP after adjusting for aspirin sensitivity. Allergic rhinitis was not associated with elevated LTE4 excretion. Receiver operator characteristic analysis of 24-hour urinary LTE4 showed that a cutoff value of 166 pg/mg Cr suggested the presence of history of aspirin sensitivity with 89% specificity, whereas a cutoff value of 241 pg/mg Cr discriminated "challenge-confirmed" aspirin-sensitive subjects with 92% specificity., Conclusions: Elevated 24-hour excretion of urinary LTE4 is a reliable and simple test to identify aspirin sensitivity in patients with respiratory diagnoses., Competing Interests: The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Mast cell activation syndrome (MCAS) describes patients with episodes of mast cell mediator release, with negative bone marrow biopsy results, and the failure to meet the criteria for systemic mastocytosis., Objective: Identify elevation of mast cell mediators of patients with MCAS., Methods: We performed a retrospective study of 25 patients with MCAS who were evaluated at Mayo Clinic from 2006 to 2012. Patients were reviewed for MCAS symptoms and mast cell mediators, including serum tryptase and 24-hour urine N-methyl histamine (N-MH) and 11β-prostaglandin-F₂α (11β-PGF₂α). The study was approved by the institutional review board., Results: Urinary 11β-PGF₂α was the most frequently elevated product in MCAS of our 25-patient cohort. Flushing and pruritus had the greatest correlation with elevation of 24-hour urine 11β-PGF₂α value at baseline. The serum tryptase level was elevated in 10 patients, whereas the N-MH level was elevated with 2 patients. Eight of 9 patients with MCAS and with elevated 24-hour urine 11β-PGF₂α who underwent aspirin therapy and follow-up urinary studies had normalization of this mediator (1 patient did not have a follow-up urine study). Six of these 9 patients with MCAS who underwent aspirin therapy had symptomatic improvement., Conclusion: We recommend measurement of 24-hour urine 11β-PGF₂α and serum tryptase levels of patients with symptoms suggestive of MCAS. Measurement of 24-hour urine 11β-PGF₂α and serum tryptase levels can help avoid misdiagnosis and overinterpretation of MCAS symptoms in clinical practice. Given that an elevation of 24-hour urine N-MH level was found only in 2 patients, measurement of this mediator may be less helpful in diagnosing MCAS. We recommend aspirin therapy for patients with MCAS and with elevated 24-hour urine 11β-PGF₂α levels., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)