A US-Based Multicenter Retrospective Report of Perioperative Anaphylaxis, 2010-2021.

BACKGROUND: US-based perioperative anaphylaxis (POA) studies are limited to single-center experiences. A recent report found that a serum acute tryptase (sAT) >9.8 ng/mL or mast cell activation (MCA) can predict POA causal agent identification. Urinary mast cell mediator metabolites (uMC) have not been studied in POA. OBJECTIVE: To analyze the epidemiologic data of POA, to determine if sAT or MCA can predict suspected causal agent identification, and to evaluate uMC utility in POA. METHODS: This study is a retrospective multicenter review of POA cases that were subcategorized by suspected causal agent identification status. sAT, MCA (defined as sAT >2 + 1.2 × serum baseline tryptase), and uMC (N-methylhistamine [N-MH], 11ß-prostaglandin-F2α [11ß-PGF2α], leukotriene E4 [LTE4]) were recorded. RESULTS: Of 100 patients (mean age 52 [standard deviation 17] years, 94% adult, 50% female, 90% White, and 2% Hispanic) with POA, 73% had an sAT available, 41% had MCA, 16% had uMC available, and 50% had an identifiable suspected cause. POA cases with an identifiable suspected cause had a positive MCA status (100% vs 78%; P = .01) compared with POA with an unidentifiable cause. An elevated median sAT did not predict causal agent identification. Positive uMC were not associated with suspected causal agent identification during POA. Patients with positive uMC had a higher median sAT (30 vs 6.45 ng/mL; P = .001) and MCA status (96% vs 12%; P = .001) compared with negative uMC patients. Patients with POA had an elevated acute/baseline uMC ratios: 11ß-PGF2α ratio > 1.6, N-MH ratio >1.7, and LTE4 ratio >1.8. CONCLUSIONS: The presence of MCA in POA is associated with suspected causal agent identification. Positive uMC possibly correlate with a higher sAT level and MCA status but require further study. The authors suggest applying an acute/baseline uMC ratio (11ß-PGF2α ratio >1.6, N-MH ratio >1.7, and LTE4 ratio >1.87) in patients with POA for MCA when a tryptase level is inconclusive during POA evaluations.

Mast Cells in Aspirin-Exacerbated Respiratory Disease.

PURPOSE OF REVIEW: Aspirin-exacerbated respiratory disease (AERD) is a syndrome of high type 2 inflammation and is known to critically involve mast cell activation. The mast cell is an important cell in the baseline inflammatory processes in the upper and lower airway by maintaining and amplifying type 2 inflammation. But it also is prominent in the hypersensitivity reaction to COX-1 inhibition which defines this condition. RECENT FINDINGS: Recent work highlights the mast cell as a focal point in AERD pathogenesis. Using AERD as a specific model of both high type 2 asthma and chronic sinusitis, the role of mast cell activity can be better understood in other aspects of airway inflammation. Further dissecting out the mechanism of COX-1-mediated mast cell activation in AERD will be an important next phase in our understanding of NSAID-induced hypersensitivity as well as AERD pathophysiology.

Urine Mast Cell Mediators in the Evaluation and Diagnosis of Mast Cell Activation Syndrome.

PURPOSE OF REVIEW: Mast cell activation syndrome is defined by severe, episodic, and recurrent symptoms induced by mast cell mediators with objective measurement of increase in biomarkers of mast cell activation and treatment response with mast cell therapies. Increase in serum tryptase from baseline during a mast cell activation episode is currently the most accepted biomarker measurement of mast cell release. However, during symptomatic episodes, serum tryptase can be difficult to obtain as it is a venipuncture procedure. Other objective measures of mast cell activation are needed to complement serum tryptase. RECENT FINDINGS: Urine mast cell mediators can be collected at home and are non-invasive tests. There is emerging evidence for the utility of urine mast cell mediators including histamine, cysteinyl leukotrienes, and prostaglandins in the diagnosis of mast cell activation syndrome. In this review, clinically available urine mast cell mediators will be discussed including N-methylhistamine, leukotriene E4, and 2,3-dinor-11beta-prostaglandin F2 alpha. We discuss the rationale for the use of these urine mast cell mediators and examine the studies analyzing their performance for identifying mast cell activation.

Metformin: A potential adjunct for treatment of systemic mastocytosis.

Background: Systemic mastocytosis (SM) is a clonal disorder of mast cells in which the KIT Asp816Val mutation can be detected not only in mature mast cells but also in the hematopoietic stem cell and in non-mast cell lineages. Current treatment with tyrosine kinase inhibitors provides improved clinical responses in patients with advanced mastocytosis but no cures. Targeting of cancer stem cells (CSCs) resistant to chemotherapy and radiation therapy potentially could improve clinical outcomes in mastocytosis. In recent years, nonchemotherapeutic medications such as metformin have been repurposed for this role because of their ability to destroy CSCs from both solid tumors and leukemias and also because of their ability to act as chemosensitizers. Objective: We sought to determine whether those patients with both type 2 diabetes mellitus (DM2) and SM who were receiving metformin, which has been reported to inhibit CSCs, experienced clinical or laboratory benefit to their SM from this agent. Methods: Mayo Clinic databases were searched for patients with diagnoses of DM plus SM. The clinical courses of mastocytosis for patients with DM2 were compared among patients treated with metformin or by other means. Effects of metformin on human mast cell (HMC) leukemia line (HMC-1.1 and HMC-1.2) cell proliferation were tested in vitro. Results: No patient treated with metformin before SM was diagnosed developed advanced forms of disease. A lower percentage of these patients had splenomegaly compared with other groups not treated with metformin, and none of these patients developed Janus kinase 2, tet methylcytosine dioxygenase 2, or serine and arginine-rich splicing factor 2 mutations. In vitro results showed that metformin inhibited the proliferation of both cell lines; HMC-1.1 cells were more sensitive to metformin. Conclusions: These preliminary findings suggest that early use of metformin to target CSCs has the possibility to complement current treatments available for SM.

Omalizumab ameliorates extrarespiratory symptoms in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Omalizumab, an anti-IgE antibody, has clinical efficacy against respiratory symptoms of aspirin-exacerbated respiratory disease (AERD). However, some patients with AERD also present with extrarespiratory (chest, gastrointestinal, and/or cutaneous) symptoms, which are resistant to conventional treatment but can be alleviated by systemic corticosteroids. OBJECTIVE: We evaluated the efficacy of omalizumab on extrarespiratory symptoms related to AERD. METHODS: In study 1, a total of 27 consecutive patients with AERD initially prescribed omalizumab at Sagamihara National Hospital between July 2009 and March 2019 were retrospectively studied. Frequency of exacerbations of AERD-related extrarespiratory symptoms was compared before and after omalizumab treatment. In study 2, we reported 3 AERD cases with aspirin challenge-induced extrarespiratory symptoms among patients studied in our previous randomized trial (registration UMIN000018777), which evaluated the effects of omalizumab on hypersensitivity reactions during aspirin challenge to AERD patients. Extrarespiratory symptoms induced during the aspirin challenge were compared between placebo and omalizumab phases. RESULTS: In study 1, omalizumab treatment was associated with decrease in frequency of exacerbation of chest pain (no. [%] of patients with exacerbation frequency ≥1 time per year, 6 [22.2%] vs 0; P < .001), gastrointestinal symptoms (9 [33.3%] vs 2 [7.4%]; P = .016), and cutaneous symptoms (16 [59.3%] vs 2 [7.4%]; P < .001), even under conditions of treatment-related reduction in systemic corticosteroid dose. Omalizumab also attenuated all the extrarespiratory symptoms during aspirin challenge in study 2. CONCLUSION: Omalizumab ameliorated extrarespiratory symptoms at baseline (without aspirin exposure) and during aspirin challenge.

Updates on immune mechanisms in aspirin-exacerbated respiratory disease.

Aspirin-exacerbated respiratory disease has fascinated and frustrated specialists in allergy/immunology, pulmonology, and otorhinolaryngology for decades. It generally develops in previously healthy young adults and is unremitting and challenging to treat. The classical triad of asthma, nasal polyposis, and pathognomonic respiratory reactions to aspirin and other cyclooxygenase-1 inhibitors is accompanied by high levels of mast cell activation, cysteinyl leukotriene production, platelet activation, and severe type 2 respiratory inflammation. The "unbraking" of mast cell activation and further cysteinyl leukotriene generation induced by cyclooxygenase-1 inhibition reflect an idiosyncratic dependency on cyclooxygenase-1-derived products, likely prostaglandin E2, to maintain a tenuous homeostasis. Although cysteinyl leukotrienes are clear disease effectors, little else was known about their cellular sources and targets, and the contributions from other mediators and type 2 respiratory inflammation effector cells to disease pathophysiology were unknown until recently. The applications of targeted biological therapies, single-cell genomics, and transgenic animal approaches have substantially advanced our understanding of aspirin-exacerbated respiratory disease pathogenesis and treatment and have also revealed disease heterogeneity. This review covers novel insights into the immunopathogenesis of aspirin-exacerbated respiratory disease from each of these lines of research, including the roles of lipid mediators, effector cell populations, and inflammatory cytokines, discusses unanswered questions regarding cause and pathogenesis, and considers potential future therapeutic options.

Rapid and sustained effect of dupilumab on clinical and mechanistic outcomes in aspirin-exacerbated respiratory disease.

BACKGROUND: Dupilumab, a mAb targeting IL-4Rα, improves upper and lower airway symptoms in patients with aspirin-exacerbated respiratory disease (AERD), but the mechanisms leading to clinical improvement are not fully elucidated. OBJECTIVE: Our aim was to identify the mechanistic basis of clinical improvement in patients with AERD treated with dupilumab. METHODS: A total of 22 patients with AERD were treated with dupilumab for 3 months for severe asthma and/or chronic rhinosinusitis with nasal polyps. Clinical outcomes were assessed at baseline and at 1 and 3 months after initiation of dupilumab. Nasal fluid, urine, blood, and inferior turbinate scrapings were collected at the 3 time points for determination of mediator levels, cellular assays, and RNA sequencing. RESULTS: Participants had rapid improvement in clinical measures, including sense of smell, sinonasal symptoms, and lung function after 1 month of treatment with dupilumab; the improvements were sustained after 3 months of dupilumab. Baseline severity of smell loss was correlated with lower nasal prostaglandin E2 levels. Dupilumab increased nasal prostaglandin E2 level and decreased levels of nasal albumin, nasal and urinary leukotriene E4, and serum and nasal IgE. Transcripts related to epithelial dysfunction and leukocyte activation and migration were downregulated in inferior turbinate tissue after treatment with dupilumab. There were no dupilumab-induced changes in nasal eosinophilia. CONCLUSION: Inhibition of IL-4Rα in AERD led to rapid improvement in respiratory symptoms and smell, with a concomitant improvement in epithelial barrier function, a decrease in inflammatory eicosanoid levels, and an increase in the anti-inflammatory eicosanoid prostaglandin E2 level. The therapeutic effects of dupilumab are likely due to decreased IL-4Rα signaling on respiratory tissue granulocytes, epithelial cells, and B cells.

Nontryptase Urinary and Hematologic Biomarkers of Mast Cell Expansion and Mast Cell Activation: Status 2022.

Quantitation of urinary metabolites of histamine, prostaglandin D2, and leukotriene E4 can fill the gap in our current efforts to improve diagnosis and management of symptomatic patients with systemic mastocytosis, and/or mast cell activation syndrome, In addition, patients symptomatic due to mast cell activation but who do not meet all the criteria for mast cell activation syndrome can have elevated baseline mediator metabolites. Serum tryptase levels have been the workhorse in diagnosing these disorders, but it has several drawbacks including the need to obtain acute and baseline samples, which require 2 visits to health care facilities and 2 venipunctures. Recently, increased baseline tryptase level has been reported in hereditary alpha tryptasemia, complicating diagnostic possibilities of an increased baseline tryptase level. Furthermore, no treatment can specifically be targeted at tryptase itself. In contrast, the finding of 1 or more elevated urinary levels of histamine, prostaglandin D2, and/or leukotriene E4 metabolites (1) greatly narrows diagnostic possibilities for causes of symptoms; (2) informs the practitioner what specific metabolic pathways are involved; and (3) targets the treatment in a specific, direct fashion. As a bonus, baseline spot/random urine samples can be obtained by the patients themselves and repeated at exactly the correct time when symptoms occur.

Urine Leukotriene E4: Implications as a Biomarker in Chronic Rhinosinusitis.

OBJECTIVE: To provide a comprehensive state-of-the-art review of the emerging role of urine leukotriene E4 (uLTE4) as a biomarker in the diagnosis of chronic rhinosinusitis (CRS), aspirin-exacerbated respiratory disease (AERD), and asthma. DATA SOURCES: Ovid MEDLINE(R), Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. REVIEW METHODS: A state-of-the-art review was performed investigating the role of uLTE4 as a diagnostic biomarker, predictor of disease severity, and potential marker of selected therapeutic efficacy. CONCLUSIONS: uLTE4 has been shown to be a reliable and clinically relevant biomarker for CRS, AERD, and asthma. uLTE4 is helpful in ongoing efforts to better endotype patients with CRS and to predict disease severity. IMPLICATIONS FOR PRACTICE: Aside from being a diagnostic biomarker, uLTE4 is also able to differentiate aspirin-tolerant patients from patients with AERD and has been associated with objective disease severity in patients with CRS with nasal polyposis. uLTE4 levels have also been shown to predict response to medical therapy, particularly leukotriene-modifying agents.

Exercise-induced anaphylaxis unrelated to food ingestion and with hyperleukotrieneuria during challenge testing.

BACKGROUND: Exercise-induced anaphylaxis (EIA) is a rare and potentially life-threatening disorder that can develop independently without food ingestion. Cold drinks can also trigger symptoms in some patients with cold-induced anaphylaxis. We present a case of a patient with EIA that was diagnosed on the basis of positive exercise loading test with hyperleukotrieneuria. CASE PRESENTATION: A 12-year-old girl presented with acute flushing, cyanosis, swollen eyelids, and dyspnea after an endurance run in winter or swimming in a cold-water pool. She also developed dyspnea after having a cold drink. She had no history of food allergies, atopy, or asthma. No association was noted between anaphylaxis and food intake in her history. On the first day, she ingested 200 mL of 5 °C cold water in 30 s, which did not trigger symptomatic responses, but her urinary leukotriene E4 (LTE4) level increased (pre-challenge test: 295 pg/mg-creatinine (cr), post-challenge test: 400 pg/mg-cr). On the second day, she underwent the exercise loading test according to the Bruce protocol by using an ergometer to increase the power of exercise every 2 min. She had been fasting for > 15 h and did not have breakfast. Just after the exercise loading test, the plasma adrenaline and noradrenaline increased. At 15 min after the exercise loading test, her plasma adrenaline and histamine (pre-challenge test: 0.7 ng/mL, 15 min post-challenge test: 81 ng/mL) rose sharply with anaphylaxis symptoms accompanied by increasing urinary LTE4 (pre-challenge test: 579 pg/mg-cr, post-challenge test: 846 pg/mg-cr). After she was discharged, she was restricted from strenuous exercise especially in cold environments and prescribed an adrenaline autoinjector. CONCLUSION: Cold stimulation can become a co-effector of EIA. Measurements of urinary LTE4 levels during challenge testing are useful for diagnosing EIA and capture the pre-anaphylaxis stage.

Divergent PGD2 and leukotriene C4 metabolite excretion following aspirin therapy: Ten patients with systemic mastocytosis.

Aspirin-exacerbated respiratory disease and some cases of chronic idiopathic urticaria are disorders in which increased baseline urinary excretion of leukotriene(LT)E4 further increases following aspirin administration. Increased urinary excretion of the metabolites of prostaglandin D2, 11ß-prostaglandin(PG)F2α and (2,3-dinor)-11ß-PGF2α, have been documented in systemic mastocytosis (SM) and in mast cell activation syndrome (MCAS). Symptoms due to increased baseline and/or episodic release of PGD2 can be prevented with aspirin, an inhibitor of cyclooxygenase (COX)1 and COX2. Here by retrospective chart review we discovered 8 of 10 patients with SM in whom normalization of an elevated urinary (2,3-dinor)-11ß-PGF2α occurred with aspirin therapy also had a parallel increased excretion of LTE4 by an average of nearly 13-fold. How widespread this phenomenon occurs in SM is unknown; however, this occurrence needs to be considered when interpreting changes in these urinary mast cell mediator metabolites during aspirin therapy.

Mast Cell Activation Disorders.

Background and Objectives: Mast cell disorders comprise a wide spectrum of syndromes caused by mast cells' degranulation with acute or chronic clinical manifestations. Materials and Methods: In this review article we reviewed the latest findings in scientific papers about mast cell disorders with a particular focus on mast cell activation syndrome and mastocytosis in pediatric age. Results: Patients with mast cell activation syndrome have a normal number of mast cells that are hyperreactive upon stimulation of various triggers. We tried to emphasize the diagnostic criteria, differential diagnosis, and therapeutic strategies. Another primary mast cell disorder is mastocytosis, a condition with a long-known disease, in which patients have an increased number of mast cells that accumulate in different regions of the body with different clinical evolution in pediatric age. Conclusions: Mast cell activation syndrome overlaps with different clinical entities. No consensus was found on biomarkers and no clearly resolutive treatment is available. Therefore, a more detailed knowledge of this syndrome is of fundamental importance for a correct diagnosis and effective therapy.

Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.

PURPOSE: Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes. METHODS: The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization. RESULTS: More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects. CONCLUSIONS: NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03849625.

Machine learning of biomarkers and clinical observation to predict eosinophilic chronic rhinosinusitis: a pilot study.

BACKGROUND: Subtyping chronic rhinosinusitis (CRS) by tissue eosinophilia has prognostic and therapeutic implications, and is difficult to predict using peripheral eosinophil counts or polyp status alone. The objective of this study was to test machine learning for prediction of eosinophilic CRS (eCRS). METHODS: Input variables were defined as peripheral eosinophil count, urinary leukotriene E4 (uLTE4) level, and polyp status. The output was diagnosis of eCRS, defined as tissue eosinophil count >10 per high-power field. Patients undergoing surgery for CRS were retrospectively reviewed for complete datasets. Univariate analysis was performed for each input as a predictor of eCRS. Logistic regression and artificial neural network (ANN) machine learning models were developed using random and surgeon-specific training/test datasets. RESULTS: A total of 80 patients met inclusion criteria. In univariate analysis, area under the receiver operator characteristic curve (AUC) for peripheral eosinophil count and uLTE4 were 0.738 (95% confidence interval [CI], 0.616 to 0.840) and 0.728 (95% CI, 0.605 to 0.822), respectively. Presence of polyps was 94.1% sensitive, but 51.7% specific. Logistic regression models using random and surgeon specific datasets resulted in AUC of 0.882 (95% CI, 0.665 to 0.970) and 0.945 (95% CI, 0.755 to 0.995), respectively. ANN models resulted in AUC of 0.918 (95% CI, 0.756 to 0.975) and 0.956 (95% CI, 0.828 to 0.999) using random and surgeon-specific datasets, respectively. Model comparison of logistic regression and ANN was not statistically different. All machine learning models had AUC greater than univariate analyses (all p < 0.003). CONCLUSION: Machine learning of 3 clinical inputs has the potential to predict eCRS with high sensitivity and specificity in this patient population. Prospective investigation using larger and more diverse populations is warranted.

Elevated Urine Leukotriene E4 Is Associated With Worse Objective Markers in Nasal Polyposis Patients.

OBJECTIVES: Urine leukotriene E4 (uLTE4) is a biomarker of leukotriene synthesis and is elevated in patients with aspirin-exacerbated respiratory disease (AERD). It can also be useful to help delineate aspirin-tolerant chronic rhinosinusitis with nasal polyposis (CRSwNP) patients from AERD patients. The purpose of this study is to determine if uLTE4 biomarker levels are associated with objective and subjective markers of disease severity in patients with CRSwNP. METHODS: A retrospective analysis of CRSwNP patients who underwent uLTE4 testing was completed to determine the association of uLTE4 levels to markers of disease severity. uLTE4 levels, as well as presenting subjective (Sinonasal Outcome Test 22 [SNOT22] scores, asthma control test [ACT] scores) and objective data (Lund-Mackay CT score, spirometry and lab values) were collected. RESULTS: Among the 157 CRSwNP patients who met inclusion criteria, uLTE4 levels were associated with history of asthma (P < .001), aspirin sensitivity (P < .001), worse Lund-Mackay CT scores (P = .002) and other objective markers of disease severity including serum IgE (P = .05), presenting blood eosinophil level (P < .001), and the highest recorded eosinophil level (P < .001). In subgroup analysis, associations of uLTE4 to disease markers had stronger correlations in the aspirin sensitive CRSwNP group (R range 0.31-0.52) than the aspirin tolerant CRSwNP group (R range -0.30-0.24). uLTE4 levels were not associated with subjective symptom scores (SNOT22 and ACT scores). CONCLUSION: Elevated uLTE4 biomarker levels are associated with worsened objective markers of disease severity in CRSwNP patients but not patient-reported symptom measures. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:961-966, 2021.

Development of a highly sensitive liquid chromatography-mass spectrometry method to quantify plasma leukotriene E4 and demonstrate pharmacological suppression of endogenous 5-LO pathway activity in man.

Low basal endogenous concentrations (<20 pg/mL) of the 5-lipoxygenase (5-LO) pathway biomarker leukotriene E4 (LTE4) in human plasma present a significant analytical challenge. Analytical methods including liquid chromatography-mass spectrometry and enzyme linked immunosorbent assays have been used to quantify plasma LTE4 in the past but have not provided consistent data in the lower pg/mL-range. With our new method, a detection limit (<1 pg/mL plasma) significantly below basal levels of LTE4 was achieved by combining large volume sample purification and enrichment by anion-exchange mixed mode solid phase extraction (SPE) with large volume injection followed by chromatographic separation by ultra performance liquid chromatography (UPLC) and quantification by highly sensitive negative-ion electrospray tandem mass spectrometry (MS/MS). The method was reproducible, accurate and linear between 1 and 120 pg/mL plasma LTE4. The method was used to perform an analysis of plasma samples collected from healthy volunteers in a Phase 1 study with the FLAP (5-lipoxygenase activating protein) inhibitor AZD5718. Basal endogenous LTE4 levels of 5.1 ± 2.7 pg/mL were observed in healthy volunteers (n = 34). In subjects that had been administered a single oral dose of AZD5718, significant suppression (>80%) of plasma LTE4 level was observed, providing pharmacological evidence that endogenous 5-LO pathway activity could be assessed.

Omalizumab for Aspirin Hypersensitivity and Leukotriene Overproduction in Aspirin-exacerbated Respiratory Disease. A Randomized Controlled Trial.

Rationale: Aspirin-exacerbated respiratory disease is characterized by severe asthma, nonsteroidal antiinflammatory drug hypersensitivity, nasal polyposis, and leukotriene overproduction. Systemic corticosteroid therapy does not completely suppress lifelong aspirin hypersensitivity. Omalizumab efficacy against aspirin-exacerbated respiratory disease has not been investigated in a randomized manner.Objectives: To evaluate omalizumab efficacy against aspirin hypersensitivity, leukotriene E4 overproduction, and symptoms during an oral aspirin challenge in patients with aspirin-exacerbated respiratory disease using a randomized design.Methods: We performed a double-blind, randomized, crossover, placebo-controlled, single-center study at Sagamihara National Hospital between August 2015 and December 2016. Atopic patients (20-79 yr old) with aspirin-exacerbated respiratory disease diagnosed by systemic aspirin challenge were randomized (1:1) to a 3-month treatment with omalizumab or placebo, followed by a >18-week washout period (crossover design). The primary endpoint was the difference in area under logarithm level of urinary leukotriene E4 concentration versus time curve in the intent-to-treat population during an oral aspirin challenge.Measurements and Main Results: Sixteen patients completed the study and were included in the analysis. The area under the logarithm level of urinary leukotriene E4 concentration versus time curve during an oral aspirin challenge was significantly lower in the omalizumab phase (median [interquartile range], 51.1 [44.5-59.8]) than in the placebo phase (80.8 [interquartile range, 65.4-87.8]) (P < 0.001). Ten of 16 patients (62.5%) developed oral aspirin tolerance up to cumulative doses of 930 mg in the omalizumab phase (P < 0.001).Conclusions: Omalizumab treatment inhibited urinary leukotriene E4 overproduction and upper/lower respiratory tract symptoms during an oral aspirin challenge, resulting in aspirin tolerance in 62.5% of the patients with aspirin-exacerbated respiratory disease.

The Utility of Measuring Urinary Metabolites of Mast Cell Mediators in Systemic Mastocytosis and Mast Cell Activation Syndrome.

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) D2, leukotriene (LT) C4, 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-11ßPGF2α, and LTE4 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 PGD2, a product nearly exclusively of MCs, can be controlled with aspirin, histamine increase by H1 and H2 receptor blockade, and LTC4 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.

Mast Cell Activation Syndrome: Tools for Diagnosis and Differential Diagnosis.

The current consensus diagnostic criteria for mast cell activation syndrome(s) (MCAS[s]) were first established in 2012 and updated in 2019. This diagnosis has been attached to multiple medical conditions not intended as part of the diagnosis. In this article, the diagnostic criteria are reviewed and other diseases in the differential diagnosis outlined. The goal of this review is to provide a tool for evaluation of patients with conditions that can mimic MCAS. Furthermore, the potential role for hereditary alpha-tryptasemia in this group of disorders is discussed.