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Chronic rhinitis encompassing both allergic and nonallergic rhinitis affects a significant portion of the population worldwide, having a great impact on patient quality of life, and associated comorbid conditions, with an important societal economic burden. Allergists are often the first to evaluate and treat allergic and nonallergic rhinitis, addressing the individual triggers of the disease as well as the patient-specific responses to these triggers. This review focuses on the advances that have been made in the diagnosis, management, and treatment of nonallergic and allergic rhinitis over the past 10 years, including specific allergen immunotherapy, care pathways, and digital health.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is associated with a significant disease burden. The optimal use of and administration route for intranasal corticosteroids (INCS) when managing CRSwNP are unclear.We systematically synthesized the evidence addressing INCS for CRSwNP.We searched studies archived in Medline, Embase, and Central from database inception until September 1, 2021, for randomized controlled trials comparing INCS using any delivery method to placebo or other INCS administration types. Paired reviewers screened records, abstracted data, and rated risk of bias (CLARITY revision of Cochrane Risk of Bias version 1 tool) independently and in duplicate. We synthesized the evidence for each outcome using random effects network meta-analyses. We critically appraised the evidence following the GRADE (Grades of Recommendation Assessment, Development, and Evaluation) approach.We analyzed 61 randomized controlled trials (7176 participants, 8 interventions). Sinusitis-related quality of life might improve with INCS rinse (mean difference [MD] -6.83, 95% confidence interval [CI] -11.94 to -1.71) and exhalation delivery system (EDS) (MD -7.86, 95% CI -14.64 to -1.08) compared to placebo (both low certainty evidence). Nasal obstruction symptoms are likely improved when receiving INCS via stent/dressing (MD -0.31, 95% CI -0.54 to -0.08), spray (MD -0.51, 95% CI -0.61 to -0.41), and EDS (MD -0.35, 95% CI -0.51 to -0.18) (all moderate to high certainty) compared to placebo. We found no important differences in adverse effects among interventions (moderate certainty for INCS spray, very low to low certainty for others).Multiple delivery forms of INCS are viable therapeutic options for CRSwNP, resulting in improvement of patient-important outcomes. INCS via stent, spray, and EDS appear to be beneficial across the widest range of considered outcomes.

Systematic reviews (SR) are a category of literature review that presents a comprehensive synthesis and analysis of all available literature evidence addressing a specific clinical question. Meta-analysis (MA) is a quantitative technique that is applied to data collected through SR that provides an estimate of an effect across a larger population. By synthesizing data from a large number of sources SR and MA often provide insights that cannot be obtained from single studies and can aid in clinical decision-making. However, these techniques are subject to important limitations. Both the validity and the usefulness of the results of an SR/MA depend on the methodological rigor used in preparing the review and the quality of included studies. In applying SR/MA to clinical decision-making the reader should be able to assess these features. Here we present an overview of important concepts in understanding SR and MA. We provide a general approach to interpretation and evaluation of an SR/MA, model the use of a critical appraisal tool for SR, and discuss the applications of SR and MA to clinical practice.

Background Little is known on the persistence of asthma biologic use in clinical practice. Objective To evaluate the persistence of asthma biologic use and time to clinical response in clinical practice. Methods A cohort of people with asthma who used at least 1 asthma biologic was constructed using data from 2003 to 2019 in the OptumLabs Data Warehouse. Treatment persistence was defined by the length of time that a person continuously used an asthma biologic, allowing for a lapse in use up to 4 months before confirming that a person stopped. Clinical response to treatment (defined as a decline in asthma exacerbations of at least 50% compared with the 6 months before starting an asthma biologic) was described over time and in relation to biologic persistence. Results There were 9575 people who had at least 1 episode of asthma biologic use. There were 5319 people (64%, 95% confidence interval, 63%-65%) who completed 6 months or more on an asthma biologic and 3284 (45%, 95% confidence interval, 44%-46%) who completed 12 months or more. Of people with 1 or more asthma exacerbation 6 months before index biologic use, 63%, 76%, 80%, and 81% realized a 50% or more reduction in postindex asthma exacerbations in the first 6 months, 6 to 12 months, 12 to 18 months, and 18 to 24 months, respectively. Conclusion Between 48% and 64% of people remained on an asthma biologic for 6 months or more after first use. Most people who achieved a reduction in asthma exacerbations did so in the first 6 months of treatment.

Background The incidence of fatal and near-fatal outcomes after perioperative anaphylaxis is unknown in the USA. Previously identified risk factors of neuromuscular-blocker-induced fatal perioperative anaphylaxis include male sex, obesity, and use of beta blockers. We examined the incidence of fatal and near-fatal outcomes after perioperative anaphylaxis in the USA and the underlying risk factors using a large national database. Methods Using the Nationwide Inpatient Sample from 2005 to 2014, we identified cases of fatal and near-fatal perioperative anaphylaxis, defined as perioperative anaphylaxis cases complicated by respiratory or cardiac arrest, using the International Classification of Diseases, Ninth Revision, Clinical Modification codes. Results Amongst 5223 perioperative anaphylaxis cases, the proportion of near-fatal or fatal cases attributable to perioperative anaphylaxis was 7.0% (95% confidence interval [CI]: 6.2–7.7), with near-fatal perioperative anaphylaxis cases accounting for 5.0% (95% CI: 4.4–5.6%) and fatal cases accounting for 2.0% (95% CI: 1.5–2.5%) of cases overall. Thus, the incidence of fatal or near-fatal perioperative anaphylaxis is 1.26 in 100 000 procedures. Risk factors for fatal or near-fatal perioperative anaphylaxis include age (≥65 yr); undergoing a cardiac procedure; and comorbid conditions of weight loss, non-metastatic solid tumours, metastatic cancer, paralysis, coagulopathy, renal failure, congestive heart failure, fluid and electrolyte disorder, and neurological disorders. Individuals with near-fatal or fatal perioperative anaphylaxis reactions had increased lengths of stay and hospital costs compared with controls. Conclusions The incidence of fatal or near-fatal perioperative anaphylaxis in the USA was 1.26 in 100 000 procedures. Risk factors for fatal or near-fatal outcomes include older age, cardiac procedures, and specific comorbidities.

The Allergy-Immunology Joint Task Force on Practice Parameters has published 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, as well as 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, and 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.

These evidence-based guidelines support patients, clinicians, and other stakeholders in decisions about the use of intranasal corticosteroids (INCS), biologics, and aspirin therapy after desensitization (ATAD) for the management of chronic rhinosinusitis with nasal polyposis (CRSwNP). It is important to note that the current evidence on surgery for CRSwNP was not assessed for this guideline, nor were management options other than INCS, biologics, and ATAD. The Allergy-Immunology Joint Task Force on Practice Parameters formed a multidisciplinary guideline panel balanced to include the views of multiple stakeholders and to minimize potential biases. Systematic reviews for each management option informed the guideline. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to inform and develop recommendations. The guideline panel reached consensus on the following statements: (1) In people with CRSwNP, the guideline panel suggests INCS rather than no INCS (conditional recommendation, low certainty of evidence) (2) In people with CRSwNP, the guideline panel suggests biologics rather than no biologics (conditional recommendation, moderate certainty of evidence) (3) In people with aspirin (nonsteroidal anti-inflammatory drug) exacerbated respiratory disease, the guideline panel suggests ATAD rather than no ATAD (conditional recommendation, moderate certainty of evidence). The conditions for each recommendation are discussed in the guideline.

Little is known regarding the prediction of the risks of asthma exacerbation after stopping asthma biologics.To develop and validate a predictive model for the risk of asthma exacerbations after stopping asthma biologics using machine learning models.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%).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.Outcomes after stopping asthma biologics can be predicted with moderate accuracy using machine learning methods.

Background Little is known about adherence to asthma biologics. Research Question Is adherence to inhaled corticosteroid (ICS) associated with subsequent asthma biologic adherence? Study Design and Methods We analyzed individuals with asthma who started asthma biologics in the OptumLab Data Warehouse and used that data until October 2019. We calculated proportion days covered (PDC) for ICS ± long-acting β-agonists in the 6 months before and after asthma biologics were started and asthma biologic PDC for the first 6 months of use. We performed a multivariable analysis to identify factors associated with asthma biologic PDC ≥0.75, ICS PDC ≥0.75 during the 6-month period after asthma biologic were started, and achievement of a ≥50% reduction in asthma exacerbations during the first 6 months of asthma biologic use. Results We identified 5,319 people who started asthma biologics. The mean PDC for asthma biologics was 0.76 (95% CI, 0.75-0.77) in the first 6 months after starting, higher than the mean PDCs for ICS in the 6 months before (0.44 [95% CI, 0.43-0.45]) and after (0.40 [95% CI, 0.39-0.40]) starting the asthma biologic. PDC ≥0.75 for ICS 6 months before index biologic use is associated with PDC for asthma biologics ≥0.75 (OR, 1.25; 95% CI, 1.10-1.43) and for ICS during the first 6 months of biologic use (OR, 9.93; 95% CI, 8.55-11.53). Neither ICS PDC ≥0.75 (OR, 0.92; 95% CI, 0.74-1.14) nor asthma biologic PDC ≥0.75 (OR, 1.15; 95% CI, 0.97-1.36) is associated with a statistically significant reduction in asthma exacerbations during the first 6 months of asthma biologic use among people with any exacerbation in the 6 months before first use. Interpretation Adherence to asthma biologic is higher than to ICS and is associated with different factors.

Background Asthma and some chronic rhinosinusitis (CRS) subtypes are mediated by similar pathophysiologic mechanisms. The purpose of this study was to evaluate the effects of biologic therapy for asthma on co-existent CRS in the "real-world" setting. Methods A review of electronic health records (2016-2019) at Mayo Clinic was conducted to identify asthma patients treated with biologics who had co-existent CRS. Matched-pair analyses compared pretherapy and posttherapy Lund-Mackay computed tomography (CT) scores and 22-item Sino-Nasal Outcome Test (SNOT-22) scores. Performance of endoscopic sinus surgery (ESS) after initiating biologics was studied. Results We identified 247 patients who received anti-asthma biologic therapy and had co-existent CRS. Of these, 181 patients (73.3%) had CRS with nasal polyposis (CRSwNP) and 66 (26.7%) had CRS without nasal polyposis (CRSsNP). The biologics utilized were omalizumab (51.0%), mepolizumab (46.6%), benralizumab (10.5%), reslizumab (1.6%), and dupilumab (2.4%). Anti-interleukin-5 (anti-IL-5) intervention was associated with significant improvement in CT scores (CRS overall, CRSwNP subgroup, CRSsNP subgroup) and SNOT-22 scores (CRS overall, CRSwNP subgroup). Patients on omalizumab had a decrease in CT scores, but not SNOT-22 scores. ESS was performed in 206 patients (84.1%); 55 (22.3%) underwent surgery post-biologic intervention (anti-IL-5: 16.5%; omalizumab 27.8% of patients). Conclusion Anti-IL-5 agents were associated with improved CT and SNOT-22 scores in the overall CRS group and in CRSwNP subgroup; CRSsNP patients showed improved CT scores only. Omalizumab improved CT but not SNOT-22 scores. ESS was performed in 22% of patients after initiating biologics. These real-world results may influence future trial designs and clinical applications of biologics for CRS. ©2021 ARSAAOA, LLC.

This comprehensive practice parameter for allergic rhinitis (AR) and nonallergic rhinitis (NAR) provides updated guidance on diagnosis, assessment, selection of monotherapy and combination pharmacologic options, and allergen immunotherapy for AR. Newer information about local AR is reviewed. Cough is emphasized as a common symptom in both AR and NAR. Food allergy testing is not recommended in the routine evaluation of rhinitis. Intranasal corticosteroids (INCS) remain the preferred monotherapy for persistent AR, but additional studies support the additive benefit of combination treatment with INCS and intranasal antihistamines in both AR and NAR. Either intranasal antihistamines or INCS may be offered as first-line monotherapy for NAR. Montelukast should only be used for AR if there has been an inadequate response or intolerance to alternative therapies. Depot parenteral corticosteroids are not recommended for treatment of AR due to potential risks. While intranasal decongestants generally should be limited to short-term use to prevent rebound congestion, in limited circumstances, patients receiving regimens that include an INCS may be offered, in addition, an intranasal decongestant for up to 4 weeks. Neither acupuncture nor herbal products have adequate studies to support their use for AR. Oral decongestants should be avoided during the first trimester of pregnancy. Recommendations for use of subcutaneous and sublingual tablet allergen immunotherapy in AR are provided. Algorithms based on a combination of evidence and expert opinion are provided to guide in the selection of pharmacologic options for intermittent and persistent AR and NAR.

BACKGROUND: Diagnosis of eosinophilic esophagitis (EoE) requires manual quantification of tissue eosinophils. Eosinophil peroxidase (EPX) is an eosinophil-specific, cytoplasmic granule protein released during degranulation. AIMS: The objective of this study was to evaluate image analysis of EPX immunohistochemistry as an automated method for histologic diagnosis of EoE. METHODS: We performed a secondary analysis of prospectively collected esophageal biopsies obtained from adult subjects with EoE and controls. Tissue sections were stained with hematoxylin and eosin (H&E) and evaluated for peak eosinophils per high power field (eos/hpf). The same slides were de-stained and re-stained to detect EPX for direct comparison. Slides were digitized and EPX staining area/mm(2) was quantified using image analysis. Paired samples were compared for changes in EPX staining in treatment responders and non-responders. RESULTS: Thirty-eight EoE cases and 49 controls were analyzed. Among EoE subjects, matched post-treatment biopsies were available for 21 responders and 10 non-responders. Baseline EPX/mm(2) was significantly increased in EoE subjects and decreased in treatment responders. EPX quantification correlated strongly with eos/hpf (r = 0.84, p < 0.0001) and identified EoE subjects with high diagnostic accuracy (AUC 0.95, p < 0.0001). The optimal diagnostic EPX-positive pixel/area threshold was 17,379 EPX/mm(2). Several controls (5/49) with < 15 eos/hpf on H&E staining exceeded this cutoff. CONCLUSIONS: EPX/mm(2) correlates strongly with eos/hpf, accurately identifies subjects with EoE, and decreases in treatment responders. Automated quantification of intact eosinophils and their degranulation products may enhance pathologic assessment. Future studies are needed to correlate EPX/mm(2) with symptoms, endoscopic findings, and esophageal distensibility.

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. Acurrent challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Objective: The objective of this study was to evaluate the impact of an electronic alert on the prescription rate of inhaled corticosteroids (ICS) by ED providers for poorly controlled persistent a...

Background There is limited information about outcomes associated with stopping asthma biologics. Objective To compare outcomes in people who stopped or continued asthma biologics. Methods We identified a cohort of people with asthma who stopped or continued asthma biologics in the Optum Labs Database Warehouse, using a propensity matching method for case and control groups with the variables of age, sex, race, region, insurance, income, specialist access, Charlson comorbidity, specific medical conditions, pre-index exacerbation count, pre-index rescue inhaler pharmacy fills, and pre-index inhaled corticosteroid with or without long-acting β-agonist pharmacy fills. Primary outcome used to assess failure of stopping was an increase of 50% or more in the asthma exacerbation rate in the 6 months after discontinuing the biologic compared with the 6-month period before biologic initiation. Results Among a cohort of 4960 asthma biologic users, 1249 were observed to stop use after 6 to 12 months of use. We identified a matched cohort of 1247 stoppers and 1247 people who continued biologic use for at least 18 months. In the first 6 months after stopping or sham stopping, 10.2% of stoppers and 9.5% of continuers had an increase of 50% or more in asthma exacerbations. We found a similar adjusted odds of failing among stoppers and continuers (odds ratio = 1.085; 95% confidence interval, 0.833-1.413). Conclusions An increase in asthma exacerbations is infrequently observed in people who stopped asthma biologics and was observed at similar rates as in matched controls who continued asthma biologics.

Concerns for anaphylaxis may hamper severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization efforts. We convened a multidisciplinary group of international experts in anaphylaxis composed of allergy, infectious disease, emergency medicine, and front-line clinicians to systematically develop recommendations regarding SARS-CoV-2 vaccine immediate allergic reactions. Medline, EMBASE, Web of Science, the World Health Organizstion (WHO) global coronavirus database, and the gray literature (inception, March 19, 2021) were systematically searched. Paired reviewers independently selected studies addressing anaphylaxis after SARS-CoV-2 vaccination, polyethylene glycol (PEG) and polysorbate allergy, and accuracy of allergy testing for SARS-CoV-2 vaccine allergy. Random effects models synthesized the data to inform recommendations based on the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach, agreed upon using a modified Delphi panel. The incidence of SARS-CoV-2 vaccine anaphylaxis is 7.91 cases per million (n = 41,000,000 vaccinations; 95% confidence interval [95% CI] 4.02-15.59; 26 studies, moderate certainty), the incidence of 0.15 cases per million patient-years (95% CI 0.11-0.2), and the sensitivity for PEG skin testing is poor, although specificity is high (15 studies, very low certainty). We recommend vaccination over either no vaccination or performing SARS-CoV-2 vaccine/excipient screening allergy testing for individuals without history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient, and a shared decision-making paradigm in consultation with an allergy specialist for individuals with a history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient. We recommend further research to clarify SARS-CoV-2 vaccine/vaccine excipient testing utility in individuals potentially allergic to SARS-CoV2 vaccines or their excipients.

Community transmission of severe acute respiratory illness Coronavirus-2 (SARS-CoV-2) in Arizona was noted in March 2020. It was our hypothesis that the associated implementation of physical distancing and masking led to a decline in circulation and detection of common respiratory viruses. Nasopharyngeal swabs processed with the Biofire, Film Array respiratory panel at Mayo Clinic Arizona were reviewed from January 1, 2017, to July 31, 2020. A total of 13,324 nasopharyngeal swabs were analyzed. Between April and July 2017- 2019 (Period A) a mean of 262 tests were performed monthly, falling to 128 for the corresponding months of 2020 (Period B). A reduction in the monthly mean number of positive tests (Period A 71.5; Period B 2.8) and mean positivity rate (Period A 25.04%; Period B 2.07%) was observed. Rhinovirus/enterovirus was the most prevalent virus, with a monthly mean of 21.6 cases (30.2% of positives) for Period A and 2 cases (72.7% of positives) for Period B. Positivity for a second virus occurred in a mean of 2.1 positive tests (3.3%) in Period A but was absent in Period B. Implementation of distancing and masking coincides with a marked reduction in respiratory virus detection and likely circulation. Data from the fall/winter of 2020 will help clarify the potential role for distancing and masking as a mitigation strategy, not only for SARS-CoV-2 but also in the seasonal battle against common respiratory viruses.

Given the burden of disease and the consequences of a diagnosis of peanut allergy, it is important that peanut allergy be accurately diagnosed so that an appropriate treatment plan can be developed. However, a test that indicates there is peanut sensitization present (eg, a "positive" test) is not always associated with clinical reactivity. This practice parameter addresses the diagnosis of IgE-mediated peanut allergy, both in children and adults, as pertaining to 3 fundamental questions, and based on the systematic reviews and meta-analyses, makes recommendations for the clinician who is evaluating a patient for peanut allergy. These questions relate to when diagnostic tests should be completed, which diagnostic tests to utilize, and the utility (or lack thereof) of diagnostic testing to predict the severity of a future allergic reaction to peanut.

To review GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methods and discuss the clinical application of conditional recommendations in clinical guidelines, specifically in the context of anaphylaxis.Articles that described GRADE, evidence synthesis, evidence to recommendation frameworks, and shared decision making were used to discuss conditional recommendations of the 2020 Anaphylaxis GRADE guideline.A narrative review detailing concepts of GRADE and approaches to translate conditional recommendations to individualized and contextualized patient care.GRADE methods encourage a nuanced relationship between certainty of evidence and strength of recommendations. Strength of recommendation must incorporate key factors, including the balance between benefits and harms, patient values and preferences, and resource allocation (costs), with equity, feasibility, and acceptability also often included as considerations. GRADE guidelines provide recommendations that are characterized by directionality (for or against) and strength (strong or conditional). A conditional recommendation is tailored to context and primarily applied through a lens of patient preferences related to the likelihood of outcomes of importance and a shared decision-making approach. Although the 2020 Anaphylaxis GRADE guideline better informs the practice of anaphylaxis prevention through (1) identification and mitigation of risk factors for biphasic anaphylaxis and (2) evaluation of the use of glucocorticoid and/or antihistamine pretreatment, all GRADE recommendations, although directional, are conditional and as such should not be universally applied to every circumstance.Clinical guidelines provide an important opportunity to critically appraise evidence and translate evidence to practice. Patients, practitioners, and policy makers should appreciate the strength of recommendation and certainty of evidence and understand how this affects guideline applicability and implementation.

Background Eosinophilic esophagitis (EoE) is a chronic, inflammatory disease of the esophagus that currently requires repeated endoscopic biopsies for diagnosis and monitoring because no reliable noninvasive markers have been identified. Objective To identify promising minimally invasive EoE biomarkers and remaining gaps in biomarker validation. Methods We performed a systematic review of EMBASE, Ovid MEDLINE, PubMed, and Web of Science from inception to June 6, 2017. Studies were included if patients met the 2007 consensus criteria for EoE diagnosis, a minimally invasive biomarker was assessed, and the study included at least 1 control for comparison. Results The search identified 2094 studies, with 234 reviewed at full-text level, and 49 included in the analysis (20 adult, 19 pediatric, 7 pediatric and adult, and 3 not stated). Most (26 of 49) were published after 2014. Thirty-five studies included healthy controls, 9 analyzed atopic controls, and 29 compared samples from patients with active and inactive EoE. Minimally invasive biomarkers were obtained from peripheral blood (n = 41 studies), sponge or string samples (n = 3), oral or throat swab secretions (n = 2), breath condensate (n = 2), stool (n = 2), and urine (n = 2). The most commonly reported biomarkers were peripheral blood eosinophils (n = 16), blood and string eosinophil granule proteins (n = 14), and eosinophil surface or intracellular markers (n = 12). EoE biomarkers distinguished active EoE from healthy controls in 23 studies, atopic controls in 2 studies, and inactive EoE controls in 20 studies. Conclusion Several promising minimally invasive biomarkers for EoE have emerged; however, few are able to differentiate EoE from other atopic diseases.

To describe the variation in asthma quality and costs among children with different Medicaid insurance plans.We used 2013 data from the Center for Health Information and Research, which houses a database that includes individuals who have Medicaid insurance in Arizona. We analyzed children ages 2-17 years-old who lived in Maricopa County, Arizona. Asthma medication ratio (AMR, a measure of appropriate asthma medication use), outpatient follow-up within 2 weeks after asthma-related hospitalization (a measure of continuity of care), asthma-related hospitalizations, and all emergency department (ED) visits were the primary quality metrics. Direct costs were reported in 2013 $US dollars. We used one-way analysis of variance to compare the health plans for AMR and per member cost (total, ER, and hospital), and the chi-squared test for the outpatient follow-up measure. We used coefficient of variation to identify variation of each measure across all individuals in the study.In 2013, 90,652 children in Maricopa County were identified as having asthma. The average patient-weighted AMR for children with persistent asthma was 0.35, well short of the goal of ≥0.70, and only 36% of hospitalized asthma patients had outpatient follow-up within 2 weeks of hospitalization. AMR, total costs, and ED costs varied significantly (p.0001) when comparing health plans while hospital costs and outpatient follow-up showed no significant variation.Targeting appropriate medication use for asthma may help reduce variation, improve outcomes, and increase healthcare value for children with asthma and Medicaid insurance in the US.

Background & Aims Gastrointestinal side effects are common during oral immunotherapy (OIT) and eosinophilic esophagitis (EoE) is a potential complication. We aimed to characterize eosinophilic gastrointestinal responses to peanut OIT, in which peanut protein is given orally, with incremental increases in dose over time. Methods Twenty adults with IgE-mediated peanut allergy were randomly assigned to groups given peanut OIT (n = 15) or placebo (n = 5); 1 additional subject withdrew before randomization. Serial gastrointestinal biopsies were collected at baseline (n = 21, 0 weeks), following dose escalation (n = 10, 52 weeks), and during the maintenance phase (n = 11, 104 weeks). Endoscopic findings were characterized using the EoE endoscopic reference score. Biopsies were assessed for eosinophils per high-power field (eos/hpf) and other pathology features using EoE histologic scoring system scores. We performed immunohistochemical analyses of eosinophil peroxidase deposition, quantified using automated image analysis. Results At baseline, no subjects reported current gastrointestinal symptoms. However, 3 of the 21 subjects (14%) had esophageal peak eosinophil counts ≥15 eos/hpf and all subjects had dilated intercellular spaces (DIS). OIT induced or exacerbated esophageal eosinophilia (EE) at 52 weeks in most subjects (peak eosinophil counts >5 eos/hpf in 6 of 7 patients [86%]; peak eosinophil counts ≥15 eos/hpf in 4 of 7 patients [57%]). One subject met clinicopathologic criteria for EoE and withdrew; no significant changes in esophageal peak eosinophil counts were observed in the placebo group. EE in the OIT group corresponded with significant increases in EoE histologic scoring system scores and deposition of eosinophil peroxidase. In 4 of 6 participants (67%), OIT-induced EE and gastrointestinal eosinophilia resolved by the end of the maintenance phase. Gastrointestinal symptoms were not clearly associated with EE or gastrointestinal eosinophilia. Conclusions In this pilot study, we found that peanut OIT-induced EE and gastrointestinal eosinophilia are usually transient and are not always associated with gastrointestinal symptoms. Clinicaltrials.gov no: NCT02103270

The purpose of this special article is to describe a new, 4-year Science of Health Care Delivery curriculum at Mayo Clinic School of Medicine, including curricular content and structure, methods for instruction, partnership with Arizona State University, and implementation challenges. This curriculum is intended to ensure that graduating medical students enter residency prepared to train and eventually practice within person-centered, community- and population-oriented, science-driven, collaborative care teams delivering high-value care. A Science of Health Care Delivery curriculum in undergraduate medical education is necessary to successfully prepare physicians so as to ensure the best clinical outcomes and patient experience of care, at the lowest cost.

Background Previous studies have found increased rates of musculoskeletal problems in adults with allergic disease, but whether this association holds true for children is unknown. Objective To investigate the association of bone, joint, and muscle problems in children with a history of allergic disease. Methods Data were obtained from the 2007 Child and Adolescent Health Measurement Initiative. Univariable and multivariable logistic regression models accounting for the sampling design were used to evaluate associations of bone, joint, and muscle problems with allergic diseases, such as asthma, hay fever, food allergies, and eczema. Associations were summarized with odds ratios (ORs) and 95% confidence intervals (CIs). Results The survey included 91,642 individuals aged 0 to 17 years. Multivariable modeling found statistically significant associations between the number of allergic diseases and bone, joint, and muscle problems (1 allergic disease: adjusted OR, 1.28; 95% CI, 1.04–1.56; P = .02; 2 allergic diseases: adjusted OR, 2.55; 95% CI, 1.92–3.39; P P P P P = .002). Conclusion Self-reported allergic diseases in children were associated with bone, joint, and muscle problems, and associations strengthened with allergic disease severity and number of allergic diseases. Severe eczema may be associated with bone problems in children. Bone, joint, and muscle problems must be considered in children with severe allergic disease, and prospective studies are necessary to define this association.

Background The role of microbiota in sinonasal inflammation can be further understood by targeted sampling of healthy and diseased subjects. We compared the microbiota of the middle meatus (MM) and inferior meatus (IM) in healthy, allergic rhinitis (AR), and chronic rhinosinusitis (CRS) subjects to characterize intrasubject, intersubject, and intergroup differences. Methods Subjects were recruited in the office, and characterized into healthy, AR, and CRS groups. Endoscopically-guided swab samples were obtained from the MM and IM bilaterally. Bacterial microbiota were characterized by sequencing the V3-V4 region of the 16S ribosomal RNA (rRNA) gene. Results Intersubject microbiome analyses were conducted in 65 subjects: 8 healthy, 11 AR, and 46 CRS (25 CRS with nasal polyps [CRSwNP]; 21 CRS without nasal polyps [CRSsNP]). Intrasubject analyses were conducted for 48 individuals (4 controls, 11 AR, 8 CRSwNP, and 15 CRSwNP). There was considerable intersubject microbiota variability, but intrasubject profiles were similar (p = 0.001, nonparametric t test). Intrasubject bacterial diversity was significantly reduced in MM of CRSsNP subjects compared to IM samples (p = 0.022, nonparametric t test). CRSsNP MM samples were enriched in Streptococcus, Haemophilus, and Fusobacterium spp. but exhibited loss of diversity compared to healthy, CRSwNP, and AR subject-samples (p < 0.05; nonparametric t test). CRSwNP patients were enriched in Staphylococcus, Alloiococcus, and Corynebacterium spp. Conclusion This study presents the sinonasal microbiome profile in one of the larger populations of non-CRS and CRS subjects, and is the first office-based cohort in the literature. In contrast to healthy, AR, and CRSwNP subjects, CRSsNP MM samples exhibited decreased microbiome diversity and anaerobic enrichment. CRSsNP MM samples had reduced diversity compared to same-subject IM samples, a novel finding.

Background Few data exist regarding the use of venom immunotherapy (VIT) in specific high-risk chronic medical conditions and pregnancy, and in young children. Methods A Web-based survey was sent to American Academy of Asthma Allergy & Immunology members to explore their VIT experience in potential high-risk medical conditions and pregnancy, and in young children. Major problems were defined as "activation of underlying disease and/or VIT not well tolerated (systemic adverse events) and/or VIT discontinued for medical reasons." Results were expressed descriptively. Results A total of 697 of 5123 surveys (14%) were completed: 87% of the respondents were based in the United States, and 28% worked in an academic setting. Most respondents (71%) believed that pregnancy was a contraindication for starting VIT. Most were comfortable continuing VIT (51%) if the woman became pregnant after starting therapy. Of the allergists who treated children, many would give VIT down to age 5 years (42%) or younger, ages 1-4 years (35%). The following list is of the specific medical condition, the number of allergists who used VIT in patients with this condition, and the percentage who reported major problems: severe asthma, 212 (4.2%); hypertension, 287 (1.1%); coronary artery disease, 222 (3.6%); arrhythmias, 136 (3.4%); cerebrovascular disease, 104 (5.1%); cancer in remission, 166 (0%); cancer stable but still under treatment, 44 (7.2%); a history of bone marrow transplantation, 15 (4.9%); a history of solid organ transplantation, 29 (3.6%); human immunodeficiency virus, 53 (1.4%); acquired immunodeficiency syndrome, 24 (6.2%); stable autoimmune disease, 164 (2.8%); mastocytosis, 66 (18.4%); elevated serum tryptase, 101 (10.8%); immunodeficiency 59 (2.5%). Conclusion Many allergists were comfortable using VIT in young children and continuing but not starting pregnant women on VIT. VIT was commonly used in patients with hypertension, coronary artery disease, arrhythmias, cancer in remission, and stable autoimmune disease. Major problems were most frequently reported in use with mastocytosis, elevated tryptase, and cancer still under treatment.

Background Endotyping chronic rhinosinusitis (CRS) through simplified cytokine assays may help direct individualized therapy such as corticosteroids, antibiotics, or biologics. We performed an unsupervised network analysis to endotype CRS and control subjects using a commercially available cytokine-chemokine immunoassay. Methods A 41-plex cytokine-chemokine array along with major basic protein (MBP) assay was performed on sinonasal surgical tissue of 32 adults. Subjects were defined as non-CRS controls (n = 6), CRS with nasal polyps (CRSwNP; n = 13), and CRS without nasal polyps (CRSsNP; n = 13). Unsupervised network modeling was performed to reveal association cytokine-chemokine (“analyte”) clusters and “subject” groups. Results Network mapping and unsupervised clustering revealed 3 analyte clusters and 3 subject groups. Analyte cluster-1 was composed of T helper 1 (Th1)/Th17 type markers, analyte cluster-2 Th2 markers, and analyte cluster-3 chemokines (CC) and growth factors (GF). Subject group-1 was devoid of CRSwNP, had fewer asthmatics, and was associated most strongly with analyte cluster-3 (CC/GF) (p < 0.001). Subject group-2 was characterized with the most asthmatics (86%) and CRSwNP (100%) patients, and was associated with analyte cluster-2 (Th2; p < 0.001). Subject group-3 was associated with both analyte cluster-1 (Th1/Th17) and analyte cluster-3 (CC/GF) (p < 0.001), and had the highest proportion of CRSsNP patients (62.5%). Tissue levels of MBP, eosinophilia, and computed tomography (CT) scores were significantly higher in subject group-2 vs other groups (p ≤ 0.05). Conclusion An unbiased network-mapping approach using a commercially available immunoassay kit reveals 3 distinct tissue cytokine-chemokine signatures that endotype CRS patients and controls. These signatures are prominent even in a limited number of patients, and may help formulate individualized therapy and optimize outcomes.

Anaphylaxis is an acute, potential life-threatening systemic allergic reaction that may have a wide range of clinical manifestations. Severe anaphylaxis and/or the need for repeated doses of epinephrine to treat anaphylaxis are risk factors for biphasic anaphylaxis. Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis, although evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy. Evidence is lacking to support the role of antihistamines and/or glucocorticoid routine premedication in patients receiving low- or iso-osmolar contrast material to prevent recurrent radiocontrast media anaphylaxis. Epinephrine is the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis. After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully resolved. All patients with anaphylaxis should receive education on anaphylaxis and risk of recurrence, trigger avoidance, self-injectable epinephrine education, referral to an allergist, and be educated about thresholds for further care.

Background From 2003 to 2015, only 1 biologic was approved for the treatment of moderate to severe asthma in the United States. Since 2015, 4 new asthma biologics were approved by the US Food and Drug Administration. Objective To describe trends and disparities of asthma biologic use in the United States from 2003 to 2018. Methods We conducted a retrospective analysis using a cohort developed from the OptumLabs Data Warehouse. Prevalent and incident asthma biologic users were identified, and characteristics of users and nonusers were analyzed using regression analysis. Clinician prescribing behavior was described. Results Use of biologic medications remains uncommon among individuals with asthma, with prevalence peaking in 2006 at 3 in 1000 individuals with asthma. Several factors are associated with a higher likelihood of asthma biologic use: middle age, higher income, commercial insurance, and access to a specialist. Most clinicians (65%) in the cohort prescribed only 1 biologic. Conclusions We report low overall use of asthma biologics and evidence of disparities in access to asthma biologics.

The inflammatory responses in chronic airway diseases leading to emphysema are not fully defined. We hypothesised that lung eosinophilia contributes to airspace enlargement in a mouse model and to emphysema in patients with chronic obstructive pulmonary disease (COPD).A transgenic mouse model of chronic type 2 pulmonary inflammation (I5/hE2) was used to examine eosinophil-dependent mechanisms leading to airspace enlargement. Human sputum samples were collected for translational studies examining eosinophilia and matrix metalloprotease (MMP)-12 levels in patients with chronic airways disease.Airspace enlargement was identified in I5/hE2 mice and was dependent on eosinophils. Examination of I5/hE2 bronchoalveolar lavage identified elevated MMP-12, a mediator of emphysema. We showed,in vitro, that eosinophil-derived interleukin (IL)-13 promoted alveolar macrophage MMP-12 production. Airspace enlargement in I5/hE2 mice was dependent on MMP-12 and eosinophil-derived IL-4/13. Consistent with this, MMP-12 was elevated in patients with sputum eosinophilia and computed tomography evidence of emphysema, and also negatively correlated with forced expiratory volume in 1 s.A mouse model of chronic type 2 pulmonary inflammation exhibited airspace enlargement dependent on MMP-12 and eosinophil-derived IL-4/13. In chronic airways disease patients, lung eosinophilia was associated with elevated MMP-12 levels, which was a predictor of emphysema. These findings suggest an underappreciated mechanism by which eosinophils contribute to the pathologies associated with asthma and COPD.