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.

False-Negative Testing for FIP1L1::PDGFRA by Fluorescence in situ Hybridization Is a Frequent Cause of Diagnostic Delay.

The imatinib-sensitive fusion gene FIP1L1::PDGFRA is the most frequent molecular abnormality identified in patients with eosinophilic myeloid neoplasms. Rapid recognition of this mutation is essential given the poor prognosis of PDGFRA-associated myeloid neoplasms prior to the availability of imatinib therapy. We report a case of a patient in whom delayed diagnosis resulted in cardiac transplantation for eosinophilic endomyocardial fibrosis. The delay in diagnosis was due, in part, to a false-negative result in fluorescence in situ hybridization (FISH) testing for FIP1L1::PDGFRA. To explore this further, we examined our cohort of patients presenting with confirmed or suspected eosinophilic myeloid neoplasms and found 8 additional patients with negative FISH results despite a positive reverse-transcriptase polymerase chain reaction test for FIP1L1::PDGFRA. More importantly, false-negative FISH results delayed the median time to imatinib treatment by 257 days. These data emphasize the importance of empiric imatinib therapy in patients with clinical features suggestive of PDGFRA-associated disease.

Clinical and histopathological features of hypereosinophilic syndrome with cutaneous involvement: The Mayo Clinic Experience.

BACKGROUND: Hypereosinophilic syndrome (HES) encompasses a group of diseases with blood hypereosinophilia and eosinophil-mediated organ dysfunction. HES-associated skin abnormalities, termed cutaneous HES (cHES) here, may influence diagnosis of HES. We sought to better define clinical and histopathological features of cHES. METHODS: We retrospectively reviewed clinical records and cutaneous histopathology of adult patients with HES evaluated at our institution from 2007 to 2018. RESULTS: Forty-one percent (61/150) patients with HES had cHES. The most common clinical morphologies were urticarial (30%) and eczematous (26%). Skin specimens most often showed a spongiotic pattern (31%) with abundant inflammation (50%) including eosinophils (85%). Two specimens (8%) showed interstitial granulomatous dermatitis, and two specimens showed eosinophilic fasciitis (8%). Vasculitis was not identified in any specimen. Eighty-four percent of patients with cHES had ≥1 other organ system involved: pulmonary 41%, ENT 26%, and nervous 23%. Sixty percent (53/89) of non-cHES patients had at least two organ systems involved. Cardiac or gastrointestinal involvement was more common in non-cHES than cHES (p < 0.05). CONCLUSION: Our review confirms that there are no specific clinical or histopathological cHES patterns, but HES should be considered in patients who have eczematous or urticarial reactions of unknown etiology and persistent peripheral hypereosinophilia.

Risks and safety of biologics: A practical guide for allergists.

Biologic agents are a rapidly expanding class of medications, and several options are now available for the management of allergic and immunologic disorders. The risks of biologic therapy need to be understood in order to adequately counsel patients and appropriately monitor for potential adverse events. We sought to provide a comprehensive review of the risks and adverse effects reported for the current FDA-approved biologics used in management of allergic and immunologic disorders, including omalizumab, benralizumab, dupilumab, mepolizumab, reslizumab, tezepelumab and tralokinumab. Our review focuses on the risk of hypersensitivity reactions, pregnancy-specific considerations, risk of infection and risk of malignancy. We also highlight drug-specific adverse events and unique safety issues identified in case reports.

Automated Identification of Aspirin-Exacerbated Respiratory Disease Using Natural Language Processing and Machine Learning: Algorithm Development and Evaluation Study.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is an acquired inflammatory condition characterized by the presence of asthma, chronic rhinosinusitis with nasal polyposis, and respiratory hypersensitivity reactions on ingestion of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Despite AERD having a classic constellation of symptoms, the diagnosis is often overlooked, with an average of greater than 10 years between the onset of symptoms and diagnosis of AERD. Without a diagnosis, individuals will lack opportunities to receive effective treatments, such as aspirin desensitization or biologic medications. OBJECTIVE: Our aim was to develop a combined algorithm that integrates both natural language processing (NLP) and machine learning (ML) techniques to identify patients with AERD from an electronic health record (EHR). METHODS: A rule-based decision tree algorithm incorporating NLP-based features was developed using clinical documents from the EHR at Mayo Clinic. From clinical notes, using NLP techniques, 7 features were extracted that included the following: AERD, asthma, NSAID allergy, nasal polyps, chronic sinusitis, elevated urine leukotriene E4 level, and documented no-NSAID allergy. MedTagger was used to extract these 7 features from the unstructured clinical text given a set of keywords and patterns based on the chart review of 2 allergy and immunology experts for AERD. The status of each extracted feature was quantified by assigning the frequency of its occurrence in clinical documents per subject. We optimized the decision tree classifier's hyperparameters cutoff threshold on the training set to determine the representative feature combination to discriminate AERD. We then evaluated the resulting model on the test set. RESULTS: The AERD algorithm, which combines NLP and ML techniques, achieved an area under the receiver operating characteristic curve score, sensitivity, and specificity of 0.86 (95% CI 0.78-0.94), 80.00 (95% CI 70.82-87.33), and 88.00 (95% CI 79.98-93.64) for the test set, respectively. CONCLUSIONS: We developed a promising AERD algorithm that needs further refinement to improve AERD diagnosis. Continued development of NLP and ML technologies has the potential to reduce diagnostic delays for AERD and improve the health of our patients.

Avapritinib versus Placebo in Indolent Systemic Mastocytosis.

BACKGROUND: Indolent systemic mastocytosis (ISM) is a clonal mast-cell disease driven by the KIT D816V mutation. We assessed the efficacy and safety of avapritinib versus placebo, both with best supportive care, in patients with ISM. METHODS: We randomized patients with moderate to severe ISM (total symptom score [TSS] of ≥28; scores range from 0 to 110, with higher numbers indicating more severe symptoms) two to one to avapritinib 25 mg once daily (n=141) or placebo (n=71). The primary end point was mean change in TSS based on the 14-day average of patient-reported severity of 11 symptoms. Secondary end points included reductions in serum tryptase and blood KIT D816V variant allele fraction (≥50%), reductions in TSS (≥50% and ≥30%), reduction in bone marrow mast cells (≥50%), and quality of life measures. RESULTS: From baseline to week 24, avapritinib-treated patients had a decrease of 15.6 points (95% CI, −18.6 to −12.6) in TSS compared to a decrease of 9.2 points (−13.1 to −5.2) in the placebo group; P<0.003. From baseline to Week 24, 76/141 patients (54%; 45% to 62%) in the avapritinib group compared to 0/71 patients in the placebo group achieved a ≥50% reduction in serum tryptase level; P<0.001. Edema and increases in alkaline phosphatase were more common with avapritinib than placebo; there were few treatment discontinuations because of adverse events. CONCLUSIONS: In this trial, avapritinib was superior to placebo in reducing uncontrolled symptoms and mast-cell burden in patients with ISM. The long-term safety and efficacy of this approach for patients with ISM remain the focus of the ongoing trial. (Funded by Blueprint Medicines Corporation; ClinicalTrials.gov number, NCT03731260.)

Rethinking blood eosinophil counts: Epidemiology, associated chronic diseases, and increased risks of cardiovascular disease.

Background: The distribution and determinants of blood eosinophil counts in the general population are unclear. Furthermore, whether elevated blood eosinophil counts increase risk for cardiovascular disease (CVD) and other chronic diseases, other than atopic conditions, remains uncertain. Objective: We sought to describe the distribution of eosinophil counts in the general population and determine the association of eosinophil count with prevalent chronic disease and incident CVD. Methods: A population-based adult cohort was followed from January 1, 2006, to December 31, 2020. Electronic health record data regarding demographic characteristics, prevalent clinical characteristics, and incident CVD were extracted. Associations between blood eosinophil counts and demographic characteristics, chronic diseases, laboratory values, and risks of incident CVD were assessed using chi-square test, ANOVA, and Cox proportional hazards regression. Results: Blood eosinophil counts increased with age, body mass index, and reported smoking and tobacco use. The prevalence of chronic obstructive pulmonary disease, hypertension, cardiac arrhythmias, hyperlipidemia, diabetes mellitus, chronic kidney disease, and cancer increased as eosinophil counts increased. Eosinophil counts were significantly associated with coronary heart disease (hazard ratio [HR], 1.44; 95% CI, 1.12-1.84) and heart failure (HR, 1.62; 95% CI, 1.30-2.01) in fully adjusted models and with stroke/transient ischemic attack (HR, 1.37; 95% CI, 1.16-1.61) and CVD death (HR, 1.49; 95% CI, 1.10-2.00) in a model adjusting for age, sex, race, and ethnicity. Conclusions: Blood eosinophil counts differ by demographic and clinical characteristics as well as by prevalent chronic disease. Moreover, elevated eosinophil counts are associated with risk of CVD. Further prospective investigations are needed to determine the utility of eosinophil counts as a biomarker for CVD risk.

Combining Biologics Targeting Eosinophils (IL-5/IL-5R), IgE, and IL-4/IL-13 in Allergic and Inflammatory Diseases.

The indications for biologic therapy are expanding. Patients may benefit from different biologics for separate conditions or one condition with multiple pathogenic mechanisms targeted by different biologics. We sought to determine the frequency and safety of combining biologics targeting IgE, IL-5, IL-5R, and IL-4/IL-13 in patients referred to a large academic health system through retrospective chart review. Between January 1, 2015 and July 31, 2021, 25 patients receiving multiple biologics simultaneously were identified. Combinations included omalizumab + mepolizumab (n = 11), omalizumab + dupilumab (n = 6), omalizumab + benralizumab (n = 4), mepolizumab + dupilumab (n = 3), and omalizumab + dupilumab + mepolizumab (n = 1). Sixteen patients were receiving multiple biologics for the same condition, most commonly asthma (n = 10). Nine patients were treated for separate conditions, with chronic spontaneous urticaria and atopic dermatitis being the most common combination (n = 3). The median duration of combination biologic use was 17.5 months. There were no reports of anaphylaxis, other allergic reaction, immune dysfunction, pneumonia, or development of malignancy. The use of multiple biologics appears to be well tolerated in this case series. Prospective study is needed to better determine the efficacy, safety, and cost-effectiveness of this approach.

Current and emerging biologic therapies targeting eosinophilic disorders.

Eosinophilic disorders include a wide array of conditions in which eosinophils play a primary pathophysiologic role. While historically treated with corticosteroids and immunosuppressants, knowledge of eosinophil biology has led to the development of several biologics targeting eosinophils. In this review, we discuss the current US Food and Drug Administration (FDA) approved eosinophil-specific biologics targeting IL-5 (mepolizumab and reslizumab) and IL-5R (benralizumab) along with biologics under investigation targeting siglec-8 (lirentelimab). We discuss efficacy and safety data from trials of these medications in conditions including eosinophilic asthma, hypereosinophilic syndrome (HES), eosinophilic granulomatosis with polyangiitis (EGPA), chronic rhinosinusitis with nasal polyposis (CRSwNP), eosinophilic esophagitis (EoE), and eosinophilic gastrointestinal disease (EGID). Additionally, we discuss case reports utilizing these medications in conditions including drug reaction with eosinophilia and systemic symptoms (DRESS), allergic bronchopulmonary aspergillosis (ABPA), and eosinophilic pneumonia, among others. While eosinophilic targeting biologic therapy has been successful in eosinophilic asthma, HES, EGPA, and CRSwNP leading to FDA approval for these conditions, trials treating EoE and EGID have been disappointing to date. Given the increasing number of trials utilizing these biologics, it will be imperative for the allergist-immunologist to stay up to date on the latest treatment options to provide the most optimal care for eosinophilic disorders.

An International, Retrospective Study of Off-Label Biologic Use in the Treatment of Hypereosinophilic Syndromes.

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/mm3 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.

AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management.

Our current recommendations for diagnosing and treating primary mast cell (MC) activation syndrome make use of the latest studies and consensus guidelines for clinically recognizing systemic anaphylaxis in real time, regardless of whether allergen-triggered or other pathways are involved; our current understanding of the biomarkers secreted by activated MCs that best discriminate this disorder from other conditions; and the therapeutic drugs that might selectively affect those mediators or MCs themselves. Finding familial or somatic mutations of genes that cause MCs to be hyperactivatable would extend our diagnostic tools and potentially indicate new therapeutic interventions, targeting either the mutated gene product or the associated molecular pathway. In conclusion, we trust that the clinical, laboratory, and therapeutic criteria for primary MC activation syndromes described herein will provide clinicians with practical criteria of sufficient sensitivity and specificity to diagnose most cases without overdiagnosing the disorder in patients who likely have other conditions.

Mast Cell Mediators of Significance in Clinical Practice in Mastocytosis.

Mast cells leave evidence, a "fingerprint," of their participation in acute and chronic clinical events. That fingerprint is an elevation, either chronic or acute, in levels of their secreted mediators or their metabolites. Of these, only serum tryptase is currently one of the diagnostic criteria for systemic mastocytosis or mast cell activation. Combinations of easily obtained and quantified urinary mast cell mediator metabolite levels correlate well with bone marrow findings of systemic mastocytosis. By inhibiting synthesis of or blockading receptors to the elevated mast cell mediator, relief of clinical symptoms can often be achieved.

Exercise-induced bronchoconstriction.

OBJECTIVE: To review the literature regarding the pathophysiology of exercise-induced bronchoconstriction (EIB). DATA SOURCES: The databases of PubMed, Ovid MEDLINE, and Scopus were searched for articles using the subject headings and/or keywords asthma, exercise-induced/etiology, exercise, mechanism, pathogenesis, and bronchoconstriction. STUDY SELECTIONS: Articles were selected based on their relevance to the focus of this review, with emphasis on the specific pathophysiologic mechanisms of EIB. RESULTS: EIB occurs in response to the loss of water from the lower airways that results from heating and humidifying large volumes of air in a short period. The resulting hyperosmolar environment activates various cellular mechanisms to release mediators from mast cells, eosinophils, epithelial cells, and sensory nerves. These mediators, in turn, lead to airway smooth muscle contraction and bronchoconstriction. Airway hyperresponsiveness in elite athletes may develop from a process of airway injury and changes in the contractile properties of airway smooth muscle. CONCLUSION: EIB commonly affects individuals with and without clinically recognized asthma, especially those who participate in competitive athletics. Through years of research, the pathophysiology of EIB is now better understood and involves a complex interaction between several different cell types and mediators. Continued research to improve the knowledge regarding the mechanisms of EIB should aid the identification, diagnosis, and treatment of this common condition.