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Introduction: Many patients with severe asthma continue to experience symptoms and exacerbations despite treatment with standard-of-care therapy. In the phase 3 NAVIGATOR study, tezepelumab significantly reduced exacerbations over 52 weeks compared with placebo in patients with severe, uncontrolled asthma. This analysis assessed the efficacy of tezepelumab in reducing asthma exacerbations in various clinically relevant subgroups of patients in NAVIGATOR., Methods: NAVIGATOR was a phase 3, multicentre, randomized, double-blind, placebo-controlled study. Participants (12-80 years old) with severe, uncontrolled asthma were randomized 1:1 to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Pre-specified and post hoc analyses were performed to evaluate the annualized asthma exacerbation rate (AAER) over 52 weeks in clinically relevant subgroups of patients defined by baseline patient characteristics, medical history, exacerbation triggers, medication eligibility and medication use before and during the study., Results: Tezepelumab reduced the AAER over 52 weeks compared with placebo across a wide range of patient subgroups assessed. Reductions in exacerbations were similar across subgroups defined by baseline patient characteristics, ranging from 48% (95% confidence interval [CI]: 21, 65) to 60% (95% CI: 44, 71) in subgroups analysed by sex, smoking history and body mass index. Among the asthma-related comorbidity subgroups investigated, patients with aspirin or NSAID sensitivity had the greatest reductions in AAER with tezepelumab compared with placebo (83%; 95% CI: 66, 91). In patients eligible to receive dupilumab, tezepelumab reduced exacerbations compared with placebo by 64% (95% CI: 54, 71). Reductions in the AAER with tezepelumab compared with placebo were also observed irrespective of exacerbation trigger category and the number of asthma controller medications patients were receiving at baseline., Conclusion: These findings further support the benefits of tezepelumab in patients with severe, uncontrolled asthma and can help to inform healthcare providers' treatment decisions., Clinical Trial Registration: NAVIGATOR (NCT03347279)., (© 2024. The Author(s).)

We previously reported that asthma prevalence was higher in the United States (US) compared to Mexico (MX) (25.8% vs. 8.4%). This investigation assessed differences in microbial dust composition in relation to demographic and housing characteristics on both sides of the US-MX Border. Forty homes were recruited in the US and MX. Home visits collected floor dust and documented occupants' demographics, asthma prevalence, housing structure, and use characteristics. US households were more likely to have inhabitants who reported asthma when compared with MX households (30% vs. 5%) and had significantly different flooring types. The percentage of households on paved roads, with flushing toilets, with piped water and with air conditioning was higher in the US, while dust load was higher in MX. Significant differences exist between countries in the microbial composition of the floor dust. Dust from Mexican homes was enriched with Alishewanella, Paracoccus, Rheinheimera genera and Intrasporangiaceae family. A predictive metagenomics analysis identified 68 significantly differentially abundant functional pathways between US and MX. This study documented multiple structural, environmental, and demographic differences between homes in the US and MX that may contribute to significantly different microbial composition of dust observed in these two countries., (© 2024. The Author(s).)

Maternal-to-fetal transmission of respiratory syncytial virus (RSV) has been shown to occur but whether late prenatal exposure to RSV season influences offspring postnatal RSV-lower respiratory illness (LRI) risk in early life or RSV immune status at birth is unclear. In this study, the duration of third trimester RSV season exposure was determined for 1,094 newborns of the Tucson Children's Respiratory Study (TCRS) and found to show an inverse relation to risk for first RSV-LRI in the first year. Cord blood anti-RSV antibody is related to third trimester RSV season exposure but not to first year RSV-LRI risk. In a separate birth cohort (the Infant Immune Study), supernatants from cord blood mononuclear cells stimulated with the recall antigen, UV-inactivated RSV, were assayed for IFN-γ and IL-4. The frequency of detectable IFN-γ (but not IL-4) was increased for those with at least 2 mo of third trimester RSV season exposure, suggestive of a fetal immune response to RSV. IMPORTANCE Our study found that duration of third trimester exposure to RSV season related inversely to subsequent risk of postnatal RSV-LRI in the first year, thus implicating this exposure as an important factor in reducing risk of postnatal RSV-LRIs, a risk reduction that appears to be independent of maternally transferred anti-RSV antibody level. The increase in frequency of detectable IFN-γ and not IL-4 in response to UV-inactivated RSV in cord blood immune cells for infants with greater third trimester exposure to RSV season is suggestive of a Type-1 immune response to RSV occurring in utero ., Competing Interests: F.D. Martinez reports grants from the National Institutes of Health (NIH)/National Heart, Lung and Blood Institute (HL139054, HL132523, HL130045, HL147016), NIH/National Institute of Allergy and Infectious Diseases (AI135108, AI146131, AI148104), NIH/Office of Director (OD023282) and OM Pharma (UANLID46205). M. Halonen reports grants from the NIH during the conduct of the study. A.L. Wright reports grants from the NIH during the conduct of the study. T.F. Carr reports grants from the NIH, consulting fees from AstraZeneca and Novartis, honoraria from GSK and Regeneron, and editorial fees from Wolters Kluwer Health during the conduct of this study, unrelated to this work. D.A. Stern and A. Spangenberg report salaries paid by NIH grants noted earlier during the conduct of the study. Raffaella Nenna reports no conflict of interest.

The Precision Interventions for Severe and/or Exacerbation-Prone Asthma clinical trials network is actively assessing novel treatments for severe asthma during the coronavirus disease (COVID-19) pandemic and has needed to adapt to various clinical dilemmas posed by the COVID-19 pandemic. Pharmacologic interactions between established asthma therapies and novel drug interventions for COVID-19 infection, including antivirals, biologics, and vaccines, have emerged as a critical and unanticipated issue in the clinical care of asthma. In particular, impaired metabolism of some long-acting beta-2 agonists by the cytochrome P4503A4 enzyme in the setting of antiviral treatment using ritonavir-boosted nirmatrelvir (NVM/r, brand name Paxlovid) may increase risk for adverse cardiovascular events. Although available data have documented the potential for such interactions, these issues are largely unappreciated by clinicians who treat asthma, or those dispensing COVID-19 interventions in patients who happen to have asthma. Because these drug-drug interactions have not previously been relevant to patient care, clinicians have had no guidance on management strategies to reduce potentially serious interactions between treatments for asthma and COVID-19. The Precision Interventions for Severe and/or Exacerbation-Prone Asthma network considered the available literature and product information, and herein share our considerations and plans for treating asthma within the context of these novel COVID-19-related therapies., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Asthma represents one of the biggest global health concerns with increasing prevalence and influence on global health. Several distinct asthma phenotypes have been identified with one of the most common, earliest recognized, and described being the allergic asthma phenotype, in which allergens trigger asthma through mechanisms involving allergen-specific immunoglobulin E (IgE). Allergen-specific immunotherapy (AIT), in the forms of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), has been used for many decades as a tool for reducing IgE-mediated sensitization and controlling symptoms of allergic disease, most commonly for allergic rhinitis, and it remains the only currently available disease modifying therapy in atopic patients. AIT has been studied for use in mild to moderate allergic asthma. While the data are often inconsistent, and utilize a multitude of different methods, antigens, and outcome measures, in general, AIT may have several beneficial effects on asthma disease control, quality of life, and requirement for medication. These benefits are notable when immunotherapy is used as an adjunct to pharmacologic treatment in carefully selected and monitored patients with mild to moderate persistent asthma. Patients with severe asthma are excluded from these trials. Importantly, patients with asthma, and in particular severe asthma, may have a higher rate of systemic adverse reactions to SCIT, including anaphylaxis; however, these events are overall rare. Future research in the area is needed to definitively assess the benefit of SCIT and SLIT for patients with asthma, comparing outcomes with different methods, addressing the role of AIT in severe asthma, significance of multiallergen AIT in allergic asthma, and safety concerns in asthma., Competing Interests: None declared., (Thieme. All rights reserved.)

Asthma is a complex, heterogeneous disease in which the underlying mechanisms are not fully understood. Patients are often grouped into phenotypes (based on clinical, biologic, and physiologic characteristics) and endotypes (based on distinct genetic or molecular mechanisms). Recently, patients with asthma have been broadly split into 2 phenotypes based on their levels of type 2 inflammation: type 2 and non-type 2 asthma. However, this approach is likely oversimplified, and our understanding of the non-type 2 mechanisms in asthma remains extremely limited. A better understanding of asthma phenotypes and endotypes may assist in development of drugs for new therapeutic targets in asthma. One approach is to identify "treatable traits," which are specific patient characteristics related to phenotypes and endotypes that can be targeted by therapies. This review will focus on emerging treatable traits in asthma and aim to describe novel patient subgroups and endotypes that may represent the next step in the search for new therapeutic approaches., (© 2022 The Authors.)

Background: Asthma and obesity are major, interconnected public health challenges that usually have their origins in childhood, and for which the relationship is strengthened among those with insulin resistance., Objective: To determine whether high insulin in early life confers increased longitudinal risk for asthma independent of body mass index., Methods: The study used data from the Tucson Children's Respiratory Study (TCRS) and the Avon Longitudinal Study of Parents and Children (ALSPAC). Nonfasting insulin was measured in TCRS participants at age 6 years and fasting insulin in ALSPAC participants at age 8 years. Physician-diagnosed active asthma was determined at baseline and at subsequent assessments up to age 36 years in TCRS and 17 years in ALSPAC., Results: In TCRS, high insulin (upper quartile) at age 6 years was associated with increased odds of having active asthma from ages 8 to 36 years compared with low insulin (odds ratio,1.98; 95% CI, 1.28-3.05; P = .002). Similarly, in ALSPAC, high insulin was associated with a significantly higher risk of active asthma from ages 11 to 17 years compared with low insulin (odds ratio, 1.59; 95% CI, 1.12-2.27; P = .009). These findings were independent of baseline body mass index in both cohorts, and were not related to other demographic and asthma risk factors nor other tested markers of systemic inflammation and metabolic syndrome., Conclusions: In 2 separate birth cohorts, higher blood insulin level in early childhood was associated with increased risk of active asthma through adolescence and adulthood, independent of body mass index. High insulin indicates a novel mechanism for asthma development, which may be a target for intervention., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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. A current 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., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Immunoglobulin E (IgE) is a well-known key factor in allergic airway disease; however, its central role in non-allergic airway inflammation is often underestimated. In some airway diseases, IgE is produced as a result of allergic sensitization. However, in others, IgE production occurs despite the lack of a specific allergen. Although multiple pathways contribute to the production of IgE in airway disease, it is its activity in mediating the inflammatory response that is associated with disease. Therefore, an understanding of IgE as the unifying component of upper and lower airway diseases has important implications for both diagnosis and treatment. Understanding the role of IgE in each upper and lower airway disease highlights its potential utility as a diagnostic marker and therapeutic target. Further classification of these diseases by whether they are IgE mediated or non-IgE mediated, rather than by the existence of an underlying allergic component, accounts for both systemic and localized IgE activity. Improvements in diagnostic methodologies and standardization of clinical practices with this classification in mind can help identify patients with IgE-mediated diseases. In doing so, this group of patients can receive optimal care through targeted anti-IgE therapeutics, which have already demonstrated efficacy across numerous IgE-mediated upper and lower airway diseases., (© 2021. The Author(s).)

Objective: To identify treatment approaches that can be used in the management of patients with asthma who lack significant type 2 inflammation, also called T2 low asthma., Data Sources: Recent expert guideline updates on the management of asthma, recent journal articles and review articles, and foundational journal articles are referenced., Study Selections: This review cites clinical cohort studies of highly characterized patients with asthma, clinical interventional trials of high impact, mechanistic studies relevant to T2 low asthma, and emerging work in this area., Results: T2 low asthma accounts for approximately one-third to one-half of individuals with asthma. Characteristics of participants with T2 low asthma include higher body mass index, cigarette smoking/smoke exposure, relative lack of responsiveness to steroids, less bronchodilator reversibility, and often the presence of neutrophilic inflammation. Multiple available interventions target these characteristics, including standard inhalers, azithromycin, and lifestyle interventions of weight loss and smoking cessation., Conclusion: Treatment of T2 low asthma should involve currently available approaches and will benefit from improved definition and understanding of disease pathobiology., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.

Background: The randomized, controlled PALISADE trial demonstrated the benefit of daily oral immunotherapy with Peanut (Arachis Hypogaea) allergen powder-dnfp (PTAH, formerly AR101) in peanut-allergic children and adolescents., Objective: ARC004, the open-label follow-on study to PALISADE, used 5 dosing cohorts to explore PTAH treatment beyond 1 year and alternative dosing regimens in peanut-allergic individuals., Methods: Active arm (PTAH-continuing) PALISADE participants who tolerated 300-mg peanut protein at the exit double-blind placebo-controlled food challenge and placebo arm (PTAH-naive) participants could enter ARC004. PTAH-continuing participants were assigned to receive daily (cohorts 1 and 3A) or non-daily (cohorts 2, 3B, and 3C) dosing regimens; PTAH-naive participants were built up to 300 mg/d PTAH, followed by maintenance dosing. At study completion, participants underwent an exit double-blind placebo-controlled food challenge with doses up to 2000 mg peanut protein. Data were assessed using descriptive statistics., Results: Overall, 358 (87.5%) eligible participants (4-17 years) entered ARC004 (PTAH-continuing, n = 256; PTAH-naive, n = 102). Among PTAH-continuing participants, exposure-adjusted adverse event rates were 12.94 to 17.54/participant-year and 25.95 to 42.49/participant-year in daily and non-daily dosing cohorts, respectively; most participants (83%) experienced mild or moderate adverse events. Daily dosing cohorts appeared to have higher desensitization rates than non-daily dosing cohorts. Of all PTAH-continuing cohorts, cohort 3A had the longest daily dosing duration and the highest desensitization rates. Changes in immune markers with PTAH continuation demonstrated ongoing immunomodulation. Outcomes in PTAH-naive participants mirrored those of the PALISADE active arm., Conclusions: Continued daily PTAH treatment beyond 1 year showed sustained safety and efficacy. Ongoing immunomodulation was observed during the second year of treatment., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

In the United States, food allergen labeling is regulated by the U.S. Food and Drug Administration with the implementation of the Food Allergen Labeling and Consumer Protection Act in 2006 that requires packaged foods to clearly indicate the presence of any milk, egg, peanut, tree nuts, wheat, soybeans, fish, and crustacean shellfish. Educating patients and their families how to read food labels includes reading the ingredients list as well as the declaration statement that begins with "Contains." In addition, there is widespread use of precautionary advisory labeling, and patients should be counseled that these precautionary statements are not mandatory and not regulated and, therefore, do not necessarily identify foods with allergen contamination. An allergic reaction to undeclared food allergens as well as complacency with label reading, including precautionary advisory statements, remains a relevant risk for patients with food allergy., Competing Interests: The authors have no conflicts of interest to declare pertaining to this article, (Copyright © 2020, The Author(s). Published by OceanSide Publications, Inc., U.S.A.)

Background: Minority groups of African descent experience disproportionately greater asthma morbidity compared with other racial groups, suggesting that genetic variation from a common ancestry could influence exacerbation risk., Objective: We evaluated clinical trial measures in the context of self-reported race and genetic ancestry to identify risk factors for asthma exacerbations., Methods: One thousand eight hundred forty multiethnic subjects from 12 Asthma Clinical Research Network and AsthmaNet trials were analyzed for incident asthma exacerbations with Poisson regression models that included clinical measures, self-reported race (black, non-Hispanic white, and other), and estimates of global genetic African ancestry in a subgroup (n = 760)., Results: Twenty-four percent of 1840 subjects self-identified as black. Black and white subjects had common risk factors for exacerbations, including a history of 2 or more exacerbations in the previous year and FEV 1 percent predicted values, whereas chronic sinusitis, allergic rhinitis, and gastroesophageal reflux disease were only associated with increased exacerbation risk in black subjects. In the combined multiethnic cohort, neither race (P = .30) nor percentage of genetic African ancestry as a continuous variable associated with exacerbation risk (adjusted rate ratio [RR], 1.26 [95% CI, 0.94-1.70; P = .13]; RR per 1-SD change [32% ancestry], 0.97 [95% CI, 0.78-1.19; P = .74]). However, in 161 black subjects with genetic data, those with African ancestry greater than the median (≥82%) had a significantly greater risk of exacerbation (RR, 3.06 [95% CI, 1.09-8.6; P = .03])., Conclusion: Black subjects have unique risk factors for asthma exacerbations, of which global African genetic ancestry had the strongest effect., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

31 years old female with a history of contact dermatitis, eczema, allergic rhinitis, pernicious anemia, alopecia areata and latent tuberculosis was treated concurrently with methotrexate along with isoniazid and pyridoxine. Five months into the therapy she developed acute onset jaundice progressing into fulminant liver failure with altered mentation and worsening liver function tests. Extensive workup including serological and histopathological evaluation revealed drug-induced liver injury as the etiology of her liver failure and she underwent a successful orthotropic liver transplant. On post-transplant follow-up at four months, she was noted to have an allergic reaction consisting of a perioral rash and swelling (without anaphylaxis) after receiving a kiss from her significant other who had just eaten a peanut butter chocolate. She denied any history of allergic reaction to peanuts prior to the transplant. Percutaneous skin testing revealed immediate hypersensitivity to peanut, hazelnut, and pecan believed to be acquired newly post-transplant. Further investigation revealed that the organ donor had a documented history of systemic anaphylaxis from the peanut allergy and a positive peanut-specific IgE level. Also, another parallel solid organ recipient (lung transplant) from the same organ donor experienced a serious anaphylactic reaction after peanut exposure. This is a case of food (peanut) allergy transfer from the donor to the recipient after the liver transplant. This case highlights the importance of incorporating known donor allergies as a part of pre-transplant screening, given the potentially serious consequences from the transfer of allergies to a previously anergic recipient., (Copyright © 2019 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

The lung and gut microbiome are factors in asthma risk or protection. Relevant elements of the microbiome within both niches include the importance of the early life window for microbiome establishment, the diversity of bacteria, richness of bacteria, and effect of those bacteria on the local epithelium and immune system. Mechanisms of protection include direct anti-inflammatory action or induction of non-type 2 inflammation by certain bacterial colonies. The gut microbiome further impacts asthma risk through the contribution of metabolic products. This article reviews the mechanisms that connect the lung and gut microbiota to asthma development and severity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: It has been postulated that the association between allergic rhinitis and asthma is attributable to the progressive clinical expression of respiratory inflammation during childhood. The role of non-allergic rhinitis in early life in relation to subsequent asthma has not been extensively explored., Objective: We sought to determine whether rhinitis in early life was associated with risk of asthma development into adulthood, and whether this relationship is independent of allergic sensitization., Methods: Participants were identified from the Tucson Children's Respiratory Study, a non-selected birth cohort. Allergy skin prick testing was performed at age 6 years using house dust mix, Bermuda, mesquite, olive, mulberry, careless weed, and Alternaria aeroallergens. Atopy was defined as ≥1 positive tests. Physician-diagnosed active asthma from age 6 to 32 and physician-diagnosed rhinitis at age 6 were determined by questionnaire. Participants with asthma or active wheezing at age 6 were excluded from analyses. Risk estimates were obtained with Cox regression., Results: There were 521 participants who met inclusion criteria. The hazard ratio for subsequently acquiring a diagnosis of asthma between the ages of 8 and 32 for those with non-atopic rhinitis was 2.1 (95% CI: 1.2, 3.4, P = 0.005), compared with the non-atopic no rhinitis group, after adjusting for sex, ethnicity, maternal asthma, maternal education and smoking, and history of 4+ colds per year at age 6. Among the atopic participants, both the active and no rhinitis groups were more likely to develop and have asthma through age 32. The relation between non-atopic rhinitis and asthma was independent of total serum IgE levels at age 6., Conclusion and Clinical Relevance: Childhood rhinitis, even in the absence of atopy, confers significant risk for asthma development through adulthood. These findings underscore the importance of non-allergic mechanisms in the development of asthma., (© 2018 John Wiley & Sons Ltd.)

Background: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions., Methods: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms., Results: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older., Conclusions: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).

Objective: Severe asthma can be classified into phenotypes and endotypes, which may inform clinicians about inflammatory pathways leading to disease and ultimately guide optimal therapeutic strategy. Biomarkers, objectively measurable characteristics of the disease, are of increasing interest to clinicians and researchers as powerful tools to distinguish among the severe asthma phenotypes and endotypes. The objective of this review is to highlight current knowledge of biomarker applications to identify phenotypes and endotypes of severe asthma., Data Sources: Sources used include observational cohorts, clinical trials, translational studies, comprehensive reviews, and expert/taskforce statements., Study Selections: Included studies were selected for their relevance to the topic and for strength of data or study design., Results: In severe asthma, biomarkers can be used for diagnosis of phenotype or endotype, can also be predictive of clinical outcomes or response to therapy, and may be dynamic with time or therapy. Fully determining phenotype or endotype of severe asthma will require interpretation of combinations of commercially available biomarkers., Conclusion: Biomarkers have multiple potential clinical applications in severe asthma. Novel biomarkers may add accuracy to this field., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Numerous aeroallergens have been associated with the development of asthma, including Alternaria, house-dust mite, and pet dander. Tucson, Arizona, is located in the Sonoran Desert, which has the highest diversity of vegetation of any desert in the world. Given the unique pollen profile in this region, we sought to identify the most common aeroallergens associated with rhinitis and asthma diagnosis in the local adult population., Objective: To identify the prevalence of aeroallergen sensitivity in the Tucson adult population and to identify which aeroallergens are associated with a diagnosis of asthma., Methods: We conducted a retrospective electronic chart review of 226 consecutive adult patients who underwent aeroallergen skin-prick testing for rhinitis at The University of Arizona Adult Allergy and Immunology Clinic over the course of 1 year. All the subjects were tested to a standard panel of tree, grass, weed, mold, house-dust mite, animal dander, cockroach, and feather extracts. Asthma was diagnosed by using the Expert Panel Report 3 guidelines., Results: Skin testing results were most commonly positive to mesquite (54%), Bermuda (48%), palo verde (47%), olive tree (43%), and chenopodium (43%). Compared with the subjects without asthma, those subjects with asthma were more often sensitized to molds (odds ratio [OR] 2.25 [95% confidence interval {CI}, 1.22-4.14]; p = 0.005), including Alternaria alternata (OR 2.58 [95% CI, 1.23-5.39]; p = 0.011), and cat hair and/or pelt (OR 2.13 [95% CI, 1.24-3.69]; p = 0.006)., Conclusion: Regional pollens contributed significantly to allergic disease in this unique climate. Sensitization to Alternaria and other nonregional aeroallergens were related to asthma, which supported the current practice of testing and treating patients for allergy to both locally significant and ubiquitous aeroallergens.

Severe asthma is associated with significant morbidity and can be challenging to assess and control, due to heterogeneity of disease, complexity of diagnosis, and impact of comorbidities. A structured approach to the assessment and management of severe asthma may be helpful to the practicing clinician. First, it is important to confirm a diagnosis of asthma. In patients who are either not responding to treatment, or who require high doses of medication to control symptoms, it is highly possible that disease mimickers or comorbidities are present and can inhibit therapeutic responsiveness. The assessment and management of common comorbidities of asthma may dramatically impact disease control and thus medication requirement. Determining medication adherence and optimizing drug dose and delivery may separate out truly severe asthmatics from those not using medications regularly or properly. Next, although true personalized medicine for severe asthma is not yet realized, for those individuals with severe asthma, phenotypic characteristics of each patient may guide which therapeutic options may be most effective for that patient. Finally, evaluation and management of severe asthma at a referral center can add additional phenotyping, therapeutic, and diagnostic strategies., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The small airways of the lungs are commonly affected in pediatric and adult asthma. Small airways disease has been related to asthma control, severity, and risk of exacerbation. Diagnosis of small airways disease can be best made through evaluation of surgical lung specimens. Noninvasive techniques including spirometry, plethysmography, nitrogen washout, impulse oscillometry, and cross-sectional imaging have been utilized to assess and infer the extent of small airways disease in asthma and can be used longitudinally to assess response to treatment. Patients with small airways disease seem to benefit from inhaled asthma medications that have improved capacity to reach the distal lung compartment. This is especially important for patients with severe asthma, who rely upon high doses of inhaled corticosteroid and bronchodilators for asthma control. This review will describe the techniques which may be utilized to assess small airways disease, discuss the prevalence and characteristics of small airways disease in severe asthma, and highlight how small airway disease may complicate severe asthma treatment.

Background: Mexican-born children living in the United States have a lower prevalence of asthma than other US children. Although children of Mexican descent near the Arizona (AZ)-Sonora border are genetically similar, differences in environmental exposures might result in differences in asthma prevalence across this region., Objective: The objective of this study was to determine if the prevalence of asthma and wheeze in these children varies across the AZ-Sonora border., Methods: The International Study of Asthma and Allergy in Children written and video questionnaires were administered to 1753 adolescents from 5 middle schools: Tucson (school A), Nogales, AZ (schools B, C), and Nogales, Sonora, Mexico (schools D, E). The prevalence of asthma and symptoms was compared, with analyses in the AZ schools limited to self-identified Mexican American students., Results: Compared with the Sonoran reference school E, the adjusted odds ratio (OR) for asthma was significantly higher in US schools A (OR 4.89, 95% confidence interval [CI] 2.72-8.80), B (OR 3.47, 95% CI 1.88-6.42), and C (OR 4.12, 95% CI 1.78-9.60). The adjusted OR for wheeze in the past year was significantly higher in schools A (OR 2.19, 95% CI 1.20-4.01) and B (OR 2.67, 95% CI 1.42-5.01) on the written questionnaire and significantly higher in A (OR 2.13, 95% CI 1.22-3.75), B (OR 1.95, 95% CI 1.07-3.53), and Sonoran school D (OR 2.34, 95% CI 1.28-4.30) on the video questionnaire compared with school E., Conclusions: Asthma and wheeze prevalence differed significantly between schools and was higher in the United States. Environmental factors that may account for these differences could provide insight into mechanisms of protection from asthma., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this paper was to review the classification of adverse drug reactions, highlight the known pathophysiology of immediate hypersensitivity reactions, and discuss the utility of diagnostic testing for immunologically mediated immediate reactions to gadolinium-based contrast agents (GBCAs)., Methods: Current literature on immediate reactions to GBCA was reviewed and summarized., Results: Adverse drug reactions to GBCA are rare, and can be attributed to physiologic, immunologic, and nonimmunologic processes. When immunologic reaction is suspected, particularly in the case of severe reactions, skin testing may be useful to confirm allergy and identify alternative agents for subsequent studies., Conclusion: As GBCAs are widely used for the diagnosis and monitoring of disease, the incidence of adverse drug reactions to GBCA warrants ongoing development of approaches to diagnosis and avoidance of these adverse events.

Asthma is a common, chronic inflammatory airways disease characterized by a clinical syndrome of bronchial hyperresponsiveness, inflammation, and reversible airflow obstruction. Individuals with asthma can vary widely in clinical presentation, severity, and pathobiology. The incident factors, pathogenesis, prognosis, and treatment of asthma remain incompletely understood. Utilizing measurable characteristics of asthmatic patients, including demographic, physiologic, and biologic markers, can however identify meaningful phenotypic categories in asthma. Identification of these phenotypes may help improve precision therapeutics targeted toward an individual's' disease, and may identify strategies for preventing progression of disease severity.

Rationale: Low maximally attained lung function increases the risk of chronic obstructive pulmonary disease irrespective of the subsequent rate of lung function decline., Objectives: We aimed to determine if there were individuals with a distinct, persistently low lung function trajectory in the CRS (Tucson Children's Respiratory Study)., Methods: The CRS, an ongoing birth cohort study, enrolled 1,246 participants between 1980 and 1984. Latent class linear mixed effects modeling of the ratio of FEV1 to FVC was used to identify distinct lung function trajectories among participants with two or more spirometry measurements between ages 11 and 32 years., Measurements and Main Results: Among 599 participants with 2,142 observations, a model with two distinct trajectories (a low trajectory [n = 56; 9.3%] and a normal trajectory) fit the data significantly better than a model with only one trajectory (P = 0.0007). As compared with those with a normal trajectory, participants with a persistently low trajectory were more likely to have a history of maternal asthma (20.0% vs. 9.9%; P = 0.02); early life lower respiratory illness caused by respiratory syncytial virus (41.2% vs. 21.4%; P = 0.001); and physician-diagnosed active asthma at age 32 years (43.9% vs. 16.2%; P < 0.001). Individuals with a persistently low trajectory also demonstrated lower lung function as measured by average maximal expiratory flow at functional residual capacity during infancy and at age 6 years., Conclusions: A distinct group of individuals in a nonselected population demonstrates a persistently low lung function trajectory that may be partly established at birth and predisposes them to chronic obstructive pulmonary disease later in life.

Chronic bacterial infection is implicated in both the development and severity of asthma. The atypical bacteria Mycoplasma pneumoniae and Chlamydophila pneumoniae have been identified in the airways of asthmatics and correlated with clinical features such as adult onset, exacerbation risks, steroid sensitivity, and symptom control. Asthmatic patients with evidence of bacterial infection may benefit from antibiotic treatment directed towards these atypical organisms. Examination of the airway microbiome may identify microbial communities that confer risk for or protection from severe asthma., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Sinusitis is a common disorder associated with significant patient symptomatology that adversely affects quality of life. Sinusitis can cause further morbidity and mortality through its impact on comorbid disorders, progression of inflammation, and extension of infection., Objective: This review highlights common complications of acute bacterial rhinosinusitis (ABRS) and chronic rhinosinusitis (CRS)., Results: ABRS is complicated by orbital infections, such as pre- or postseptal cellulitis, and by intracranial infections, including abscesses of the epidural and subdural spaces. CRS can contribute to asthma, sleep disordered breathing, and smell disorders. CRS can be complicated by development of allergic fungal rhinosinusitis or deformity of surrounding bony structures. Fungal complications contribute to morbidity and mortality., Conclusion: Complications of ABRS, although relatively rare, can cause significant morbidity and mortality, and must be promptly recognized. CRS commonly complicates or drives comorbid diseases, which adversely impacts quality of life. Treatment of these complications often requires coordinated multidisciplinary care.

Asthma is clearly related to airway or blood eosinophilia, and asthmatics with significant eosinophilia are at higher risk for more severe disease. Eosinophils actively contribute to innate and adaptive immune responses and inflammatory cascades through the production and release of diverse chemokines, cytokines, lipid mediators and other growth factors. Eosinophils may persist in the blood and airways despite guidelines-based treatment. This review details eosinophil effector mechanisms, surface markers, and clinical outcomes associated with eosinophilia and asthma severity. There is interest in the potential of eosinophils or their products to predict treatment response with biotherapeutics and their usefulness as biomarkers. This is important as monoclonal antibodies are targeting cytokines and eosinophils in different lung environments for treating severe asthma. Identifying disease state-specific eosinophil biomarkers would help to refine these strategies and choose likely responders to biotherapeutics.

Background: Recently, there has been tremendous interest in the sinus microbiome and how it relates to disease. However, a lack of a standardized sample collection and DNA extraction methods makes comparison of results across studies nearly impossible. Furthermore, current techniques fail to identify which components of the microbiome are actually alive within the host at the time of sampling., Objective: To develop and optimize a method to differentiate which bacterial species in the human sinus microbiome are live versus dead., Methods: Duplicate samples from the middle meatus of patients with healthy sinus tissue and those patients with chronic rhinosinusitis were collected by using brushes (n = 12), swabs (n = 27), and tissue biopsy (n = 8) methods. One sample from each pair was either deoxyribonuclease I- or control-treated before DNA extraction. The relative bacterial versus human composition of each sample was determined. A 16S ribosomal RNA gene analysis was performed on a six-paired sample from patients with healthy sinus tissue., Results: We found that swabs and brushes collected a higher percentage of bacterial DNA than did tissue biopsy. We also determined that as much as 50% of the bacteria collected in these samples was already dead at the time of collection. The 16S ribosomal RNA gene analysis found significant changes in the relative abundance of taxa identified in the live versus dead bacterial communities of healthy human sinuses., Conclusions: Our findings indicated that swabs provided the best quality microbiome samples and that a large portion of the bacteria identified in the sinus were deoxyribonuclease I sensitive. These results highlighted the need for improved techniques such as those presented here, which can differentiate between living and dead bacteria in a sample, a potentially critical distinction when examining changes in sinus innate immune function because both components play important, but distinct, functions. Further studies will determine how these living and dead bacterial populations shift in different disease states and after clinical intervention.

Importance: Topical mupirocin therapy is used to treat symptomatic chronic sinusitis (CRS). However, the potential adverse impact of this therapy on the sinus microbiota has not been well quantified., Objective: To determine changes in microbiologic culture results before and after topical mupirocin therapy in patients with CRS with medically and surgically refractory disease., Design, Setting, and Participants: We performed a retrospective medical chart review for 22 consecutive adults evaluated and treated between January 1, 2012, and January 1, 2014, at an otolaryngology-rhinology clinic at a regional academic medical center. The patients were 14 men and 8 women, who had undergone functional endoscopic sinus surgery for CRS, and in whom sinus aspirate cultures were performed before and after topical mupirocin therapy for symptomatic disease. Analyses were performed in April 2014., Exposures: Patients underwent treatment with saline sinus rinse, with the addition of mupirocin, for at least 1 week., Main Outcomes and Measures: Bacterial isolates from sinus aspirate culture., Results: The patients included 14 men and 8 women, 18 to 75 years old, who underwent a mean of 1.9 functional endoscopic sinus surgical procedures. The mean (range) duration of mupirocin therapy was 6 (2-12) weeks. Before mupirocin therapy, cultures from symptomatic patients (14 men and 8 women, ages 18-75 years) revealed common bacteria implicated in CRS, which are characteristically gram-positive. After mupirocin therapy, cultures from symptomatic patients shifted significantly: 19 were gram-positive vs 3 gram-negative before treatment; 9 were gram-positive vs 13 gram-negative after treatment (P = .004), with increased growth of pathogenic gram-negative bacteria and Corynebacterium., Conclusions and Relevance: These data present evidence supporting the distinct abrogation of culturable sinus bacteria after mupirocin rinses, identifying a shift toward increased pathogenic bacteria. Consideration of healthy host microbiome and immune dysfunction should guide future treatment considerations.

Background: Albuterol overuse, 3 or more canisters per year, is associated with poor asthma control and frequent exacerbations., Objective: To describe albuterol use on symptom and symptom-free days and identify predictors of albuterol overuse and controller medication underuse., Methods: Secondary analyses of data from adults with mild asthma from the Trial of Asthma Patient Education were carried out. Based on albuterol use of 80% or more on symptom days and less than 20% on symptom-free days, participants were characterized as expected users, overusers, or underusers of albuterol. Good controller medication adherence was defined as 80% or more of prescribed doses. Data included demographic characteristics, diary data, spirometry, and scores from standardized questionnaires. Bivariate associations were examined between categorization of medication use and measured characteristics., Results: Of the 416 participants, 212 (51%) were expected users, 114 (27%) were overusers, and 90 (22%) were underusers of albuterol. No differences were observed among the user groups by demographic characteristics or lung function. Expected users demonstrated the highest asthma-related knowledge, attitudes, and efficacy. Overusers reported the greatest symptom burden, worst asthma control, and highest frequency of symptom days. Overusers also had the highest burden of depression symptoms. More frequent symptom days accounted for 15% of overuse, greater use on symptom days accounted for 31%, and greater use on symptom free days accounted for 54% of overuse. Mean controller adherence was high across all groups, and there were no differences between the groups., Conclusions: Although overusers experienced more frequent symptom days and used more albuterol on those days, most overuse was attributable to unexpected use on symptom-free days. High levels of comorbid depression were observed, particularly among overusers and among those nonadherent to controller medication., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Specific antibody deficiency (SAD) involves a deficient response to a polysaccharide vaccine in the setting of normal immunoglobulin G (IgG) levels and chronic infections. Patients with chronic rhinosinusitis (CRS) are often evaluated for SAD. There are limited data that describe patients with CRS and SAD., Objective: The objective of this study was to better characterize the role of SAD in CRS., Methods: We reviewed electronic records of adults with CRS who were evaluated for immunodeficiency with quantitative Ig levels and pre- and postantibody titers to a pneumococcal polysaccharide vaccine (PPV)., Results: Fourteen pneumococcal serotypes were determined in 239 subjects from 2002 to 2009. Of these subjects, 64 had adequate protective titers of 1.3 μg/mL or higher in 7 or more serotypes of the 14 serotypes checked; 56 (23%) had less than 7 protective titers post-PPV and were diagnosed with SAD; and 119 had an adequate response to the vaccine with 7 or more serotypes being higher than 1.3 μg/mL (>50% response) and were characterized as "responders." Subjects with SAD received more antibiotic courses relative to responders in the 2 years after immunization (3.19 ± 2.64 vs 2.19 ± 2.24, P < .05). Of 56 subjects with SAD, 10 (17.9%) received Ig replacement therapy. Subjects who received Ig had fewer numbers of protective pneumococcal titers post-PPV and had more pneumonia (40.0%) versus subjects with SAD who did not receive Ig (10.9%)., Conclusions: Of the 239 patients with CRS with normal IgG levels evaluated for immunodeficiency, 56 (23.4%) had SAD. A majority of patients with SAD may not need Ig replacement; however, a subset of patients with SAD benefit from Ig replacement., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)