Inhaled Reliever Therapies for Asthma: A Systematic Review and Meta-Analysis.

Importance: The optimal inhaled reliever therapy for asthma remains unclear. Objective: To compare short-acting ß agonists (SABA) alone with SABA combined with inhaled corticosteroids (ICS) and with the fast-onset, long-acting ß agonist formoterol combined with ICS for asthma. Data Sources: The MEDLINE, Embase, and CENTRAL databases were searched from January 1, 2020, to September 27, 2024, without language restrictions. Study Selection: Pairs of reviewers independently selected randomized clinical trials evaluating (1) SABA alone, (2) ICS with formoterol, and (3) ICS with SABA (combined or separate inhalers). Data Extraction and Synthesis: Two reviewers independently extracted data and assessed risk of bias. Random-effects meta-analyses synthesized outcomes. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was used to evaluate the certainty of evidence. Main Outcomes and Measures: Asthma symptom control (5-item Asthma Control Questionnaire; range, 0-6, lower scores indicate better asthma control; minimum important difference [MID], 0.5 points), asthma-related quality of life (Asthma Quality of Life Questionnaire; range, 1-7, higher scores indicate better quality of life; MID, 0.5 points), risk of severe exacerbations, and risk of serious adverse events. Results: A total of 27 randomized clinical trials (N = 50 496 adult and pediatric patients; mean age, 41.0 years; 20 288 male [40%]) were included. Compared with SABA alone, both ICS-containing relievers were associated with fewer severe exacerbations (ICS-formoterol risk ratio [RR], 0.65 [95% CI, 0.60-0.72]; risk difference [RD], -10.3% [95% CI, -11.8% to -8.3%]; ICS-SABA RR, 0.84 [95% CI, 0.73-0.95]; RD, -4.7% [95% CI, -8.0% to -1.5%]) with high certainty. Compared with SABA alone, both ICS-containing relievers were associated with improved asthma control (ICS-formoterol RR improvement [MID] in total score, 1.07 [95% CI, 1.04-1.10]; RD, 4.1% [95% CI, 2.3%-5.9%]; ICS-SABA RR, 1.09 [95% CI, 1.03-1.15]; RD, 5.4% [95% CI, 1.8%-8.5%]) with high certainty. In an indirect comparison with ICS-SABA, ICS-formoterol was associated with fewer severe exacerbations (RR, 0.78 [95% CI, 0.66-0.92]; RD, -5.5% [95% CI, -8.4% to -2.0%]) with moderate certainty. Compared with SABA alone, ICS-formoterol (RD, -0.6% [95% CI, -1.3% to 0%]) was not associated with increased risk of serious adverse events (high certainty) and ICS-SABA (RD, 0% [95% CI, -1.1% to 1.2%]) was not associated with increased risk of serious adverse events (moderate certainty). Conclusions and Relevance: In this network meta-analysis of patients with asthma, ICS combined with formoterol and ICS combined with SABA were each associated with reduced asthma exacerbations and improved asthma control compared with SABA alone.

Tissue-specific inducible IL-33 expression elicits features of eosinophilic esophagitis.

BACKGROUND: IL-33 is a type 2 inflammatory cytokine that is elevated in the esophageal epithelium of eosinophilic esophagitis (EoE) subjects. We previously developed a mouse model of EoE dependent on constitutive overexpression of IL-33 from the esophageal epithelium (EoE33). OBJECTIVE: Our objective was to develop an inducible, IL-33-dependent model of EoE and examine induction of EoE-associated pathology. METHODS: We utilized a tetracycline-inducible system to express IL-33 in the esophagus by generating 2 transgenic mice. The first (iSophagus) expresses a reverse tetracycline transactivator from the esophageal epithelium. The second (TRE33) features a tetracycline response element driving expression of IL-33. When crossed, these mice generate an inducible model of EoE (iEoE33). Mice were administered doxycycline-infused chow for up to 2 weeks. Cytokines were assessed by ELISA or bead-based multiplex analysis. T cells were assessed by flow cytometry. Pathology was assessed by histology and immunohistochemistry for IL-33, eosinophil peroxidase, CD4, and Ki-67. iEoE33 was treated with steroids and crossed with IL-13-/- mice. RESULTS: Doxycycline-treated iEoE33 mice demonstrated expression of IL-33 in the esophageal epithelium, and esophageal pathology including eosinophilia, CD4+ cell infiltrate, basal zone hyperplasia, and dilated intercellular spaces. These findings became pronounced on day 7 of induction, were accompanied by weight loss and esophageal thickening, and were steroid responsive and IL-13 dependent. CONCLUSION: Inducible IL-33 expression in the esophageal epithelium elicited features pathognomonic of EoE. iEoE33 enables investigation of EoE disease mechanisms as well as initiation, progression, and resolution.

The Immediate and Delayed Maximal Nonirritating Skin Testing Concentrations of ß-Lactam Antibiotics.

BACKGROUND: Maximal skin testing (ST) nonirritant concentrations (NICs) are consistent for penicillin and aminopenicillin among guidelines. However, there is variability among guidelines for maximal ST NICs of cephalosporins. OBJECTIVE: To determine maximal immediate and delayed ST NICs of 15 ß-lactams in ß-lactam-tolerant and ß-lactam-naïve participants. METHODS: We performed a single-center, nonrandomized prospective study between September 2019 and January 2022 in adult participants. Participants received skin prick testing (SPT) and intradermal test (IDT) injections at 6 increasing concentrations of 1 or more ß-lactams. A concentration was considered irritant when more than 5% of participants had a positive test. A positive test was defined as a wheal ≥3 mm compared with negative control accompanied by a ≥5 mm flare for SPT/IDT and induration ≥5 mm with associated erythema at 48 hours for delayed readings (dIDT). Sensitivity analyses using 3 alternative IDT positive criteria were conducted. RESULTS: A total of 747 participants with a median age of 64 (interquartile range: 54-72) years (52% male, 85% White, and 92% non-Hispanic) underwent 20,858 skin tests. All undiluted SPT concentrations were nonirritant. We found the following maximal IDT/dIDT NICs (mg/mL): ampicillin (41.6/125), ampicillin-sulbactam (93.8/187.5), aztreonam (6.3/25), cefazolin (55/165), cefepime (35/140), cefoxitin (45/90), ceftaroline (7.5/15), ceftriaxone (58.3/175), cefuroxime (55/110), ertapenem (16.6/50), imipenem-cilastin (6.3/25), meropenem (8.3/25), nafcillin (31.3/62.5), oxacillin (20.9/83.5), and piperacillin-tazobactam (112.5/225). dIDTs were almost all completely nonirritant close to or at undiluted concentrations. There were no differences when we applied 3 IDT positivity criteria to our raw data. CONCLUSIONS: Our results suggest that SPTs with undiluted stock ß-lactam antibiotic concentrations are nonirritant. Compared with previously published nonirritant concentrations, we propose a 2- to 50-fold increase to the maximal IDT and dIDT NICs of 15 ß-lactam antibiotics. When performing dIDTs, a higher concentration should be used rather than the same IDT concentration.

Incidence of and risk factors for paediatric perioperative anaphylaxis in the USA.

BACKGROUND: Perioperative anaphylaxis is a serious and often life-threatening immediate hypersensitivity reaction. There are few published data on paediatric perioperative anaphylaxis (pPOA). We evaluated the incidence of and risk factors involved in the occurrence of pPOA within a large US national database. METHODS: Deidentified data from the US Nationwide Inpatient Sample from 2005 to 2014 were used to identify pPOA cases and to conduct a retrospective multivariate analysis of preselected independent variables. RESULTS: Among 3,601,180 surgeries and procedures in children aged 0-18 yr, 297 pPOA cases were identified for an incidence of one in 12,125 surgeries and procedures. Compared with controls, pPOA cases had an increased median length of stay (6 vs 2 days; P<0.001) and median hospital cost ($54 719 vs $5109; P<0.0001). The age groups between 6 and 12 yr (odds ratio [OR] 7.1; 95% confidence interval [CI] 3.9-12.9; P<0.001) and 13 and 17 yr (OR 8.5; 95% CI 4.7-15.2; P<0.001) were associated with increased odds of pPOA. Transplant (OR 46.3; 95% CI 20.8-102.9; P<0.001), cardiac (OR 16.4; 95% CI 7.5-35.9; P<0.001), and vascular (OR 15.2; 95% CI 7.5-30.7; P<0.001) procedures posed the highest risk for pPOA. Chronic pulmonary disease, coagulopathy, and fluid and electrolyte disorders were also associated with pPOA (OR 2.2; 95% CI 1.5-3.3; P<0.001). CONCLUSIONS: The incidence of pPOA was one in 12,125 cases. Risk factors included age, procedure type, and comorbidities.

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.

Epithelial overexpression of IL-33 induces eosinophilic esophagitis dependent on IL-13.

BACKGROUND: Eosinophilic esophagitis (EoE) is an increasingly common inflammatory condition of the esophagus; however, the underlying immunologic mechanisms remain poorly understood. The epithelium-derived cytokine IL-33 is associated with type 2 immune responses and elevated in esophageal biopsy specimens from patients with EoE. OBJECTIVE: We hypothesized that overexpression of IL-33 by the esophageal epithelium would promote the immunopathology of EoE. METHODS: We evaluated the functional consequences of esophageal epithelial overexpression of a secreted and active form of IL-33 in a novel transgenic mouse, EoE33. EoE33 mice were analyzed for clinical and immunologic phenotypes. Esophageal contractility was assessed. Epithelial cytokine responses were analyzed in three-dimensional organoids. EoE33 phenotypes were further characterized in ST2-/-, eosinophil-deficient, and IL-13-/- mice. Finally, EoE33 mice were treated with dexamethasone. RESULTS: EoE33 mice displayed ST2-dependent, EoE-like pathology and failed to thrive. Esophageal tissue remodeling and inflammation included basal zone hyperplasia, eosinophilia, mast cells, and TH2 cells. Marked increases in levels of type 2 cytokines, including IL-13, and molecules associated with immune responses and tissue remodeling were observed. Esophageal organoids suggested reactive epithelial changes. Genetic deletion of IL-13 in EoE33 mice abrogated pathologic changes in vivo. EoE33 mice were responsive to steroids. CONCLUSIONS: IL-33 overexpression by the esophageal epithelium generated immunopathology and clinical phenotypes resembling human EoE. IL-33 may play a pivotal role in the etiology of EoE by activating the IL-13 pathway. EoE33 mice are a robust experimental platform for mechanistic investigation and translational discovery.

Predicting Penicillin Allergy: A United States Multicenter Retrospective Study.

BACKGROUND: Using the reaction history in logistic regression and machine learning (ML) models to predict penicillin allergy has been reported based on non-US data. OBJECTIVE: We developed ML positive penicillin allergy testing prediction models from multisite US data. METHODS: Retrospective data from 4 US-based hospitals were grouped into 4 datasets: enriched training (1:3 case-control matched cohort), enriched testing, nonenriched internal testing, and nonenriched external testing. ML algorithms were used for model development. We determined area under the curve (AUC) and applied the Shapley Additive exPlanations (SHAP) framework to interpret risk drivers. RESULTS: Of 4777 patients (mean age 60 [standard deviation: 17] years; 68% women, 91% White, and 86% non-Hispanic) evaluated for penicillin allergy labels, 513 (11%) had positive penicillin allergy testing. Model input variables were frequently missing: immediate or delayed onset (71%), signs or symptoms (13%), and treatment (31%). The gradient-boosted model was the strongest model with an AUC of 0.67 (95% confidence interval [CI]: 0.57-0.77), which improved to 0.87 (95% CI: 0.73-1) when only cases with complete data were used. Top SHAP drivers for positive testing were reactions within the last year and reactions requiring medical attention; female sex and reaction of hives/urticaria were also positive drivers. CONCLUSIONS: An ML prediction model for positive penicillin allergy skin testing using US-based retrospective data did not achieve performance strong enough for acceptance and adoption. The optimal ML prediction model for positive penicillin allergy testing was driven by time since reaction, seek medical attention, female sex, and hives/urticaria.

Eosinophil Peroxidase: A Biomarker for Eosinophilic Chronic Rhinosinusitis Agnostic of Polyp Status.

OBJECTIVE: To evaluate eosinophil peroxidase (EPX) as a biomarker for tissue levels of eosinophilia, cytokines, and chemokines within chronic rhinosinusitis (CRS). METHODS: Twenty-eight subjects undergoing sinonasal surgery were prospectively enrolled. Ethmoid tissue was analyzed with an in-house EPX immunoassay and a 48-plex cytokine-chemokine array. Clinical severity was assessed using SNOT-22 and Lund-Mackay scores. Subjects were grouped as follows: controls, polyp status (CRS with [CRSwNP] and without nasal polyps [CRSsNP]), tissue eosinophilia (eosinophilic CRS [eCRS], non-eosinophilic CRS [neCRS]), or combinations thereof (eCRSwNP, eCRSsNP, neCRSsNP). eCRS was defined as >10 eosinophils per high power field (HPF). Subjects without CRS or asthma were enrolled as controls. RESULTS: EPX was elevated in CRSwNP compared to control (p = 0.007), in eCRS compared to neCRS (p = 0.002), and in eCRSwNP along with eCRSsNP compared to neCRSsNP (p = 0.023, p = 0.015, respectively). eCRS displayed elevated IL-5 compared to neCRS (p = 0.005). No significant differences in EPX or IL-5 were observed between eCRSwNP and eCRSsNP. IL-5 was elevated in eCRSwNP (p = 0.019) compared neCRSsNP. Area under the receiver operator characteristic curve was 0.938 (95% CI, 0.835-1.00) for EPX and tissue eosinophilia, with an optimal cut-point of 470 ng/mL being 100% specific and 81.25% sensitive for tissue eosinophilia. Linear regression revealed a strong correlation between EPX and IL-5 (R2 = 0.64, p < 0.001). Comparing EPX and IL-5, only EPX displayed significant correlation with SNOT-22 (p = 0.04) and Lund-Mackay score (p = 0.004). CONCLUSION: EPX is associated with tissue eosinophilia in CRS patients regardless of polyp status. EPX correlates with IL-5 and could be potentially considered a biomarker for anti-IL-5 therapies. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:69-78, 2024.

Anaphylaxis: A 2023 practice parameter update.

This practice parameter update focuses on 7 areas in which there are new evidence and new recommendations. Diagnostic criteria for anaphylaxis have been revised, and patterns of anaphylaxis are defined. Measurement of serum tryptase is important for diagnosis of anaphylaxis and to identify underlying mast cell disorders. In infants and toddlers, age-specific symptoms may differ from older children and adults, patient age is not correlated with reaction severity, and anaphylaxis is unlikely to be the initial reaction to an allergen on first exposure. Different community settings for anaphylaxis require specific measures for prevention and treatment of anaphylaxis. Optimal prescribing and use of epinephrine autoinjector devices require specific counseling and training of patients and caregivers, including when and how to administer the epinephrine autoinjector and whether and when to call 911. If epinephrine is used promptly, immediate activation of emergency medical services may not be required if the patient experiences a prompt, complete, and durable response. For most medical indications, the risk of stopping or changing beta-blocker or angiotensin-converting enzyme inhibitor medication may exceed the risk of more severe anaphylaxis if the medication is continued, especially in patients with insect sting anaphylaxis. Evaluation for mastocytosis, including a bone marrow biopsy, should be considered for adult patients with severe insect sting anaphylaxis or recurrent idiopathic anaphylaxis. After perioperative anaphylaxis, repeat anesthesia may proceed in the context of shared decision-making and based on the history and results of diagnostic evaluation with skin tests or in vitro tests when available, and supervised challenge when necessary.

Atopic dermatitis (eczema) guidelines: 2023 American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters GRADE- and Institute of Medicine-based recommendations.

BACKGROUND: Guidance addressing atopic dermatitis (AD) management, last issued in 2012 by the American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force, requires updating as a result of new treatments and improved guideline and evidence synthesis methodology. OBJECTIVE: To produce evidence-based guidelines that support patients, clinicians, and other decision-makers in the optimal treatment of AD. METHODS: A multidisciplinary guideline panel consisting of patients and caregivers, AD experts (dermatology and allergy/immunology), primary care practitioners (family medicine, pediatrics, internal medicine), and allied health professionals (psychology, pharmacy, nursing) convened, prioritized equity, diversity, and inclusiveness, and implemented management strategies to minimize influence of conflicts of interest. The Evidence in Allergy Group supported guideline development by performing systematic evidence reviews, facilitating guideline processes, and holding focus groups with patient and family partners. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach informed rating the certainty of evidence and strength of recommendations. Evidence-to-decision frameworks, subjected to public comment, translated evidence to recommendations using trustworthy guideline principles. RESULTS: The panel agreed on 25 recommendations to gain and maintain control of AD for patients with mild, moderate, and severe AD. The eAppendix provides practical information and implementation considerations in 1-2 page patient-friendly handouts. CONCLUSION: These evidence-based recommendations address optimal use of (1) topical treatments (barrier moisturization devices, corticosteroids, calcineurin inhibitors, PDE4 inhibitors [crisaborole], topical JAK inhibitors, occlusive [wet wrap] therapy, adjunctive antimicrobials, application frequency, maintenance therapy), (2) dilute bleach baths, (3) dietary avoidance/elimination, (4) allergen immunotherapy, and (5) systemic treatments (biologics/monoclonal antibodies, small molecule immunosuppressants [cyclosporine, methotrexate, azathioprine, mycophenolate, JAK inhibitors], and systemic corticosteroids) and UV phototherapy (light therapy).

Recent guidelines addressing chronic rhinosinusitis with nasal polyps: practical aspects.

Chronic rhinosinusitis (CRS) is common in adults. It is diagnosed based on a high index of suspicion alongside objective means of assessing sinus inflammation. Determining the impact of CRS on patient quality of life is an important starting point for discussions regarding treatment, and is critical for longitudinal assessment of response to specific treatments. CRS can be further categorized by the presence or absence of nasal polyps. Recent Joint Task Force on Practice Parameters Grading of Recommendations Assessment, Development, and Evaluation guidelines for the management of CRS with nasal polyps (CRSwNP) focused on 3 treatment options: intranasal corticosteroids with multiple delivery methods, biologics (monoclonal antibodies targeting type 2 inflammation), and aspirin therapy after desensitization, which only applies to the subset of patients with CRSwNP who experience acute respiratory reactions following nonsteroidal anti­inflammatory drug ingestion. The authors of the guidelines made conditional recommendations in favor of each of these 3 treatment options, highlighting the importance of shared decision­making when choosing appropriate therapy for individuals with CRSwNP.

One- versus 2-day aspirin desensitization in aspirin exacerbated respiratory disease: A quality improvement project.

Background: Current aspirin desensitization protocols for aspirin-exacerbated respiratory disease (AERD) require from 1 to 3 days to complete. Objective: Our aim was to assess the implementation of a 1-day versus 2-day aspirin desensitization protocol in patients with aspirin-exacerbated respiratory disease. Methods: We used a preintervention-postintervention quality improvement design to compare the completion rates, reaction rates, and estimated costs of a 2-day versus 1-day aspirin desensitization. The cost for each desensitization was estimated on the basis of 2017-2020 US Medicare standards. We included the predesensitization variables for FEV1 value, urinary leukotriene E4 level, absolute eosinophil count (AEC), and total IgE level for each group. Results: A total of 15 patients underwent a 2-day aspirin desensitization in the 4-year (2017-2020) preintervention period and were compared with 8 patients who underwent a 1-day aspirin desensitization in the 1-year (2021) postintervention period. The desensitization completion rate (93% vs 100% [P = 1]) and the mean number of reactions requiring intervention during the desensitization protocols (0.26 vs 0.8 [P = .14]) were similar between groups. The average time frame between last polypectomy and desensitization was longer in the 2-day group (1946 vs 39.2 days [P = .03]). The mean values for FEV1 level, urinary leukotriene E4 level, absolute eosinophil count, and total IgE level were 76% vs 83% (P = .6), 1084 vs 385 pg/mg (P = .2), 686 vs 306 cells/µL (P = .74), and 735 vs 278 kU/L (P = .5), respectively. The estimated direct cost reduction was $762 per aspirin desensitization for using 1-day vs 2-day aspirin desensitization. Conclusion: Compared with a 2-day protocol, the implementation of a 1-day aspirin desensitization was characterized by similar completion and reaction rates as well as lower costs.

The chronic rhinosinusitis practice parameter.

The Allergy-Immunology Joint Task Force on Practice Parameters has published the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines for the medical management of chronic rhinosinusitis with nasal polyposis (CRSwNP). The practice parameter provides evidence-based guidelines on the use of intranasal corticosteroids (INCS) and biologics for CRSwNP, and aspirin therapy after desensitization (ATAD) for the management of aspirin-exacerbated respiratory disease (AERD). Evidence on surgery was not assessed. Overall, the guidelines suggest INCS rather than no INCS (conditional recommendation, low certainty of evidence), biologics rather than no biologics (conditional recommendation, moderate certainty of evidence), and ATAD rather than no ATAD (conditional recommendation, moderate certainty of evidence). Patient-important outcomes are compared across the various INCS delivery modalities and across the different biologics and ATAD. Specific consideration points for shared decision making with patients are detailed in the guideline. These include delivery method and small treatment effect sizes for INCS, disease burden at presentation, variability in efficacy among biologics, cost issues for biologics, and adverse effects of aspirin and risks related to desensitization for ATAD. The guidelines also identify a need for randomized control trials directly comparing treatment modalities and further investigation into which outcomes are important for patients.

Meteorological and environmental factors that impact pollen counts, allergenicity, and thresholds: A scoping review.

Background: Pollen is a key source of aeroallergens responsible for allergic rhinitis, conjunctivitis, and asthma. Objective: The goal of this scoping review was to summarize current available literature on the factors that affect pollen counts, allergenicity, and thresholds that induce symptoms in individuals who were sensitized. Methods: Several databases showed no published articles with a similar scope as of January 2022. A search of these data bases yielded 373 articles for assessment. These were then reviewed for relevance, and articles were selected to demonstrate the breadth of available data on pollen counts, allergenicity, and thresholds that induce symptoms in individuals who were sensitized. Additional articles were identified through examination of bibliographies of search-identified articles. Results: Several environmental factors have shown a correlation with pollen counts and allergen load, including the distance from the source, wind characteristics, pollen size, terrain, urban environments, air composition (particulate matter, CO2 levels, ozone, NO2), and weather conditions (humidity, thunderstorms, precipitation). Pollen thresholds at which symptoms were induced varied by study, pollen type, symptom, disease, and location. In addition, there was heterogeneity in study designs, threshold definition, and outcome measures. Conclusion: This scoping review demonstrates the plethora of variables that influence the relationship between pollen and the symptoms of allergic diseases. Analysis of the available data sheds light on the complex interaction between environmental and biologic factors that affect pollen's role in allergic diseases and provides guidance on multiple areas for further investigation.

Allergies Come Clean: The Role of Detergents in Epithelial Barrier Dysfunction.

PURPOSE OF REVIEW: The prevalence and incidence of allergic disease have been rising in Westernized countries since the twentieth century. Increasingly, evidence suggests that damage to the epithelium initiates and shapes innate and adaptive immune responses to external antigens. The objective of this review is to examine the role of detergents as a potential risk factor for developing allergic disease. RECENT FINDINGS: Herein, we identify key sources of human detergent exposure. We summarize the evidence suggesting a possible role for detergents and related chemicals in initiating epithelial barrier dysfunction and allergic inflammation. We primarily focus on experimental models of atopic dermatitis, asthma, and eosinophilic esophagitis, which show compelling associations between allergic disease and detergent exposure. Mechanistic studies suggest that detergents disrupt epithelial barrier integrity through their effects on tight junction or adhesion molecules and promote inflammation through epithelial alarmin release. Environmental exposures that disrupt or damage the epithelium may account for the increasing rates of allergic disease in genetically susceptible individuals. Detergents and related chemical compounds represent possible modifiable risk factors for the development or exacerbation of atopy.

Eosinophils promote effector functions of lung group 2 innate lymphoid cells in allergic airway inflammation in mice.

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are critical mediators of type 2 respiratory inflammation, releasing IL-5 and IL-13 and promoting the pulmonary eosinophilia associated with allergen provocation. Although ILC2s have been shown to promote eosinophil activities, the role of eosinophils in group 2 innate lymphoid cell (ILC2) responses is less well defined. OBJECTIVE: We sought to investigate the role of eosinophils in activation of ILC2s in models of allergic asthma and in vitro. METHODS: Inducible eosinophil-deficient mice were exposed to allergic respiratory inflammation models of asthma, such as ovalbumin or house dust mite challenge, or to innate models of type 2 airway inflammation, such as inhalation of IL-33. Eosinophil-specific IL-4/13-deficient mice were used to address the specific roles for eosinophil-derived cytokines. Direct cell interactions between ILC2s and eosinophils were assessed by in vitro culture experiments. RESULTS: Targeted depletion of eosinophils resulted in significant reductions of total and IL-5+ and IL-13+ lung ILC2s in all models of respiratory inflammation. This correlated with reductions in IL-13 levels and mucus in the airway. Eosinophil-derived IL-4/13 was necessary for both eosinophil and ILC2 accumulation in lung in allergen models. In vitro, eosinophils released soluble mediators that induced ILC2 proliferation and G protein-coupled receptor-dependent chemotaxis of ILC2s. Coculture of ILC2s and IL-33-activated eosinophils resulted in transcriptome changes in both ILC2s and eosinophils, suggesting potential novel reciprocal interactions. CONCLUSION: These studies demonstrate that eosinophils play a reciprocal role in ILC2 effector functions as part of both adaptive and innate type 2 pulmonary inflammatory events.

Factors Associated With Asthma Biologic Prescribing and Primary Adherence Among Adults in a Large Health System.

BACKGROUND: The availability of asthma biologics may not benefit all patients equally. OBJECTIVE: We sought to identify patient characteristics associated with asthma biologic prescribing, primary adherence, and effectiveness. METHODS: A retrospective, observational cohort study of 9,147 adults with asthma who established care with a Penn Medicine asthma subspecialist was conducted using Electronic Health Record data from January 1, 2016, to October 18, 2021. Multivariable regression models were used to identify factors associated with (1) receipt of a new biologic prescription; (2) primary adherence, defined as receiving a dose in the year after receiving the prescription, and (3) oral corticosteroid (OCS) bursts in the year after the prescription. RESULTS: Factors associated with a new prescription, which was received by 335 patients, included being a woman (odds ratio [OR] 0.66; P = .002), smoking currently (OR 0.50; P = .04), having an asthma hospitalization in the prior year (OR 2.91; P < .001), and having 4+ OCS bursts in the prior year (OR 3.01; P < .001). Reduced primary adherence was associated with Black race (incidence rate ratio 0.85; P < .001) and Medicaid insurance (incidence rate ratio 0.86; P < .001), although most in these groups, 77.6% and 74.3%, respectively, still received a dose. Nonadherence was associated with patient-level barriers in 72.2% of cases and health insurance denial in 22.2%. Having more OCS bursts after receiving a biologic prescription was associated with Medicaid insurance (OR 2.69; P = .047) and biologic days covered (OR 0.32 for 300-364 d vs 14-56 d; P = .03). CONCLUSIONS: In a large health system, primary adherence to asthma biologics varied by race and insurance type, whereas nonadherence was primarily explained by patient-level barriers.

A prediction model for asthma exacerbations after stopping asthma biologics.

BACKGROUND: Little is known regarding the prediction of the risks of asthma exacerbation after stopping asthma biologics. OBJECTIVE: To develop and validate a predictive model for the risk of asthma exacerbations after stopping asthma biologics using machine learning models. METHODS: We identified 3057 people with asthma who stopped asthma biologics in the OptumLabs Database Warehouse and considered a wide range of demographic and clinical risk factors to predict subsequent outcomes. The primary outcome used to assess success after stopping was having no exacerbations in the 6 months after stopping the biologic. Elastic-net logistic regression (GLMnet), random forest, and gradient boosting machine models were used with 10-fold cross-validation within a development (80%) cohort and validation cohort (20%). RESULTS: The mean age of the total cohort was 47.1 (SD, 17.1) years, 1859 (60.8%) were women, 2261 (74.0%) were White, and 1475 (48.3%) were in the Southern region of the United States. The elastic-net logistic regression model yielded an area under the curve (AUC) of 0.75 (95% confidence interval [CI], 0.71-0.78) in the development and an AUC of 0.72 in the validation cohort. The random forest model yielded an AUC of 0.75 (95% CI, 0.68-0.79) in the development cohort and an AUC of 0.72 in the validation cohort. The gradient boosting machine model yielded an AUC of 0.76 (95% CI, 0.72-0.80) in the development cohort and an AUC of 0.74 in the validation cohort. CONCLUSION: Outcomes after stopping asthma biologics can be predicted with moderate accuracy using machine learning methods.