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Epinephrine is a lifesaving medication to treat systemic allergic reactions including anaphylaxis. Epinephrine autoinjectors (EAIs) are expensive, not available everywhere in the world, and shortages can limit their access. Epinephrine prefilled syringes and epinephrine kits are lower-cost alternatives to EAIs. Advantages, disadvantages, and costs of available products are discussed and the socioeconomic factors impacting access to EAIs described. EAIs designed for infants also are discussed.

Delayed administration of epinephrine (adrenaline), the first-line and only effective treatment of a systemic allergic reaction (SAR) and anaphylaxis, is associated with increased mortality. However, epinephrine is underused because of a lack of consensus as to when it should be administered and an inappropriate fear of using epinephrine and potential adverse effects from the medication. The authors emphasize that SARs and anaphylaxis should be considered as a spectrum, and that affected individuals be educated on its safety and repeatedly given instructions as to when and how epinephrine should be used at the first symptoms or signs of SAR and anaphylaxis.

Osteoporosis is a silent disorder with dire consequences, and glucocorticoid use remains the most common iatrogenic cause illustrated by the fact that 30% to 50% of subjects on such long-term therapy experience fractures (Oimomi M, Nakamichi T, Ohara T, Sakai M, Igaki N, Hata F, et al. Fructose-related glycation. Diabetes Res Clin Pract 1989;7:137-9; Reid IR. Glucocorticoid osteoporosis--mechanisms and management. Eur J Endocrinol 1997;137:209-17). By directly affecting bone quality while actively used, glucocorticoids increase the risk of fracture that is independent of a subject's bone density status at the time (Weinstein RS. True strength. J Bone Miner Res 2000;15:621-5). A large number of subjects seen in an allergy and immunology clinic have asthma, chronic rhinosinusitis, or other chronic inflammatory diseases, necessitating the use of these medications and placing them at higher risk for this disease. Data on the effects of both oral and inhaled glucocorticoids on fracture risk are presented. This review concretizes the importance of osteoporosis, its pathophysiology, and provides practical guidelines to prevent and treat it. Management recommendations are tailored to 2 different age groups. The first group consists of children, adolescents, and adults 40 years or younger with a focus on attaining peak bone mass. The second group consists of adults 40 years or older where the use of imaging modalities and Fracture Risk Assessment Tool scores helps triage subjects into fracture risk categories. Those at moderate to high risk require bone-sparing medications. Universal preventive measures for both groups are reviewed. Complicated and severe cases may need additional expertise by an endocrinologist or rheumatologist.

Chronic rhinosinusitis, historically, has been considered to be caused by upper airway anatomical abnormalities. However, today that concept has changed, for it is now recognized as an inflammatory disorder of the nasal and sinus mucosa. Acute rhinosinusitis is usually caused by a viral infection, whereas chronic rhinosinusitis is a persistent and heterogeneous inflammatory disorder with increased expression of type 1, 2, or 17 cytokines in the nasal and sinus mucosa, similar to that which occurs in asthma. Exacerbations are caused by aeroallergens in the allergic individual and irritants, pollutants, and viral/bacterial infections in all subjects. It may be categorized by phenotypes, examples of which include chronic rhinosinusitis with nasal polyps or chronic rhinosinusitis without nasal polyps. Defined endotypes are based on underlying pathophysiological mechanisms. Knowledge of chronic rhinosinusitis endotypes will optimize management by employing targeted medical therapies. Understanding that rhinosinusitis is a heterogeneous inflammatory disease has led to the identification of a variety of different predisposing conditions, new medical treatment options, and the concept that rhinosinusitis is primarily a medical problem.

Harmful algal blooms occur when toxin-producing algae grow rapidly. These occur worldwide and have significant impacts on aquatic ecosystems and on human health. Specifically, the toxic blooms of Karenia brevis in Florida may affect humans via inhalation or ingestion. On retrospective reviews, health care costs appear to rise during these outbreaks because of respiratory and gastrointestinal manifestations. Treatment for exposure is supportive care, though traditional inhalers may help with respiratory complications.

Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast-feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.

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.

Hormones significantly influence the pathogenesis of asthma, rhinitis, and eczema. This review aims to summarize relevant clinical considerations for practicing allergists and immunologists. The first section reviews the effects of sex hormones: estrogen, progesterone, and testosterone. The second concerns insulin production in the context of type 1 and type 2 diabetes. The third concludes with a discussion of thyroid and adrenal pathology in relationship to asthma, rhinitis, and eczema.

Flexible rhinolaryngoscopy is an underused procedure that can provide allergists-immunologists and other physicians with several benefits over existing imaging techniques. In this article, we highlight the many benefits of flexible rhinolaryngoscopy and expand on its safety, cost-effectiveness, and convenience. This article also covers current procedure techniques and assesses the most common indications and relevant clinical findings for which flexible rhinolaryngoscopy can be used to evaluate the nasopharyngeal tract. Videos for the clinician showing some of the most common findings are included.

Asthma is a chronic heterogeneous airway disease. Common comorbid conditions are often disproportionately present in severe asthma. Optimal care of patients with asthma requires the recognition and treatment of these comorbid conditions. This review outlines the pathophysiological mechanisms between nonrespiratory comorbid conditions and asthma and their effect on asthma outcomes. They include: type 2 diabetes mellitus, hypertension, atherosclerotic cardiovascular disease, adrenal and thyroid gland diseases, pregnancy, osteoporosis, adverse effects from medications, and mental health disorders. Studies indicate how poor glycemic control of type 2 diabetes mellitus is associated with not only greater health care utilization but poorer asthma outcomes. Also, a large health care claims database indicates that a substantial proportion of pregnant women have uncontrolled asthma and are prescribed suboptimal controller therapy. Additional data about these nonrespiratory comorbidities and medications known to benefit both nonrespiratory comorbidities and asthma are necessary.

Background: It is hypothesized that parents of children with allergic conditions believe dairy products are potentially harmful to their child. Objectives: This study compares the calcium and vitamin D intake of allergic versus non-allergic children and parental beliefs about milk and dairy products. Methods: A survey and food-frequency-questionnaire were administered to parents of children between 3 and 13 years, 110 with allergic disease (allergic rhinitis, asthma, food allergy, and/or atopic dermatitis) versus 110 without allergic disease. Calcium and vitamin D intake was calculated from the food-frequency-questionnaire and compared to National Institutes of Health recommendations. Associations between atopy, calcium and vitamin D intake, and beliefs were investigated using Chi-square test (α = 0.05). Distribution across subjects was investigated using Mann-Whitney-U test (α = 0.05). Results: Fewer allergic (51.8%) versus non-allergic children (77.3%) met the recommended calcium intake (p

Early sensitization is ~50% higher in children with atopic dermatitis compared to children from a high-risk allergy cohort with comparable rates of parental atopy. AD may increase sensitization risk over heredity alone.

Allergists/immunologists see a variety of skin disorders, some of which have a known immunologic basis whereas others do not. We review the prevalence, etiology, clinical presentation, and effective and low-cost care of common dermatologic conditions seen in outpatient practices. Conditions discussed include pityriasis alba, seborrheic dermatitis, rosacea, acne, tinea infections, intertrigo, lichen planus, tinea versicolor, lichen simplex chronicus, scabies, pityriasis rosea, keratosis pilaris, and seborrheic keratosis. An understanding of frequently encountered cutaneous diseases and their therapies will help provide immediate access to treatment and improve the experience for both the affected patient and the clinician.

OBJECTIVE: We previously reported that children exposed to secondhand smoke (SHS) that carried variants in the NAT1 gene had over two-fold higher hair cotinine levels. Our objective was to determine if NAT1 polymorphisms confer increased risk for developing asthma in children exposed to SHS. METHODS: White participants in the Cincinnati Childhood Allergy and Air Pollution Study (n= 359) were genotyped for 10 NAT1 variants. Smoke exposure was defined by hair cotinine and parental report. Asthma was objectively assessed by spirometry and methacholine challenge. Findings were replicated in the Genomic Control Cohort (n=638). RESULTS: Significant associations between 5 NAT1 variants and asthma were observed in the CCAAPS exposed group compared to none in the unexposed group. There was a significant interaction between NAT1 rs13253389 and rs4921581 with smoke exposure (p=0.02, p=0.01) and hair cotinine level (p=0.048, p=0.042). Children wildtype for rs4921581 had increasing asthma risk with increasing hair cotinine level, whereas those carrying the NAT1 minor allele had an increased risk of asthma regardless of cotinine level. In the GCC, 13 NAT1 variants were associated with asthma in the smoke-exposed group, compared to 0 in the unexposed group, demonstrating gene-level replication. CONCLUSIONS: Variation in the NAT1 gene modifies asthma risk in children exposed to secondhand-smoke. To our knowledge, this is the first report of a gene-environment interaction between NAT1 variants, smoke exposure, cotinine levels, and pediatric asthma. NAT1 genotype may have clinical utility as a biomarker of increased asthma risk in children exposed to smoke.

Background The "atopic march" has been considered a linear progression starting with eczema and culminating with development of asthma. Not all asthma cases, however, are preceded by eczema, and not all children with eczema go on to develop asthma. Objective The aim of this study was to explore the impact of allergic sensitization patterns on the association between early eczema and later childhood asthma. Given the numerous reported associations of the ciliary gene KIF3A with the atopic march, we also examined the impact of KIF3A risk allele rs12186803 on our analyses. Methods We studied 505 participants in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS), a prospective birth cohort, with longitudinal eczema and asthma outcomes as well as prospective data regarding timing of sensitization to foods and aeroallergens. KIF3A genotypes were available on all children. Results Two high-risk groups were identified: one with and one without early eczema. The high-risk group with early eczema was more likely to be sensitized to food allergens, while the group without early eczema was more likely to be polysensitized to aeroallergens. The KIF3A rs12186803 risk allele interacted with food sensitization to increase asthma risk in children with eczema (P = 0.02). In children without eczema, asthma was associated with the interaction between rs12186803 and aeroallergen sensitization (P = 0.007). Conclusions & clinical relevance KIF3A interacted differentially with sensitization pattern to increase the risk of asthma in two high-risk groups of children with and without early eczema. Given the reported role of KIF3A in epithelial cell functioning, the results add evidence to the hypothesis that an impaired epithelial barrier is a key aspect in the development of allergic disease.

Pollen and fungal spores are associated with seasonal and perennial allergies. However, most scientific literature thus far suggests that pollen allergy is more clinically relevant than fungal allergy. Several environmental and biological factors and the difficulty in producing reliable fungal extracts account for this. Biodiversity, taxonomy, and meteorology are responsible for the types and levels of pollen and fungal spores, their fragments, and the presence of free airborne allergens. Therefore, it is difficult to accurately measure both pollen and fungal allergen exposure. In addition, understanding the enzymatic nature of fungal and some pollen allergens, the presence of allergenic and nonallergenic substances that may modulate the allergic immune response, and allergen cross-reactivity are all necessary to appropriately evaluate both sensitivity and exposure. The raw materials and manufacturing processes used to prepare pollen versus fungal extracts differ, further increasing the complexity to properly determine allergic sensitivity and degrees of exposure. The pollen extracts used for diagnosis and treatment are relatively consistent, and some have been standardized. However, obtaining clinically relevant fungal extracts is more difficult. Doing so will allow for the proper selection of such extracts to more appropriately diagnose and treat both pollen- and fungal-induced allergic diseases.

Identifying the culprit medication in cases of perioperative anaphylaxis can be extremely challenging. A detailed and accurate history, coupled with the appropriate testing, plays a key role in discovering the etiology of perioperative anaphylaxis. We present the case of a 48-year-old woman with a cranial meningioma who was scheduled for surgery. Chlorhexidine, midazolam, lidocaine, propofol, fentanyl, rocuronium, and furosemide were administered during the perioperative period. She developed hypotension, urticaria, bronchospasm, and other symptoms of anaphylaxis soon after general anesthesia. The serum tryptase level obtained during anaphylaxis was 119 ng/mL (normal

BackgroundChimeric antigen receptor modified (CAR) T cells have revolutionized the treatment of blood cancers, though some patients still show a poor response in either CAR expansion, effector response, or persistence.1 In this study, we determined the features of pre-infusion CAR-transduced T cells that generated optimally functional responses after infusion.MethodsUsing both the pre-infusion product and PBMCs isolated at weeks 1–4, 8, and 3-months post-infusion from 15 patients undergoing experimental anti-CD19 CAR T cell treatment for refractory or relapsed B-ALL, we generated a comprehensive single cell gene expression and T cell receptor (TCR) sequencing dataset on over 180,000 CAR T cells (figure 1).ResultsAs expected, pre-infusion CAR T cells tend to highly express genes associated with proliferation, while post-infusion CARs show signs of either cytotoxic effector differentiation or dysfunctional terminal differentiation. Sequencing of the endogenous TCR, at the single cell level, allows us to track the trajectories of clonally and transcriptionally related cells (figure 2). Post-infusion cells with significant cytotoxic effector function share TCRs with a statistically defined subset of CARs in the pre-infusion sample (figure 3). Using a machine learning approach, we found that potent effector precursor CAR T cells have a specific transcriptional profile distinct from the other pre-infusion CAR T cells, including markers of early effector function such as increased EOMES, GNLY, GZMH, GZMK, KLRD1, and IFNγ. Formalizing this signature, we have developed a robust classifier that can predict with 82.8% accuracy whether a CAR T is likely to become a favorable effector based on its pre-infusion profile (figure 4). This prediction model can be used to evaluate the extent to which a patient‘s generated CAR product will be able to mount a robust response after encountering its target. Additionally, there are a number of genes, as a part of this signature, that are expressed on the cell surface and can be utilized as a method to differentiate the effector precursor pre-infusion CAR T cells from other pre-infusion CARs, including CD52, CD74, CD86, and LAG3, among others.Abstract 152 Figure 1Clustering of 184, 791 CAR-transduced T cells based on gene expressionAbstract 152 Figure 2Alluvial plot depicting CAR T cell lineage tracing using the endogenous T cell receptorAbstract 152 Figure 3Visualization of CAR T cell clusters with arrows indicating the shared TCRs between pre-infusion and post-infusion cellsAbstract 152 Figure 4Machine learning classifier of pre-infusion, early effector CAR T cell phenotypeConclusionsOur findings suggest a therapeutic approach that enriches these cells prior to infusion resulting in superior per cell CAR effector activity.ReferenceXu X, Huang S, Xiao X, Sun Q, Liang X, Chen S, et al. Challenges and Clinical Strategies of CAR T-cell Therapy for Acute Lymphoblastic Leukemia: Overview and Developments. Front Immunol 2020;11:569117.Ethics ApprovalThis study was approved by St. Jude Children’s Research Hospital’s Institutional Review Board (IRB); IRB number Pro00007661. All patients consented to the use of materials for the research study.

Current chimeric antigen receptor-modified (CAR) T cell therapy products are evaluated in bulk, without assessment of the possible heterogeneity in effector potential between cells. Conceivably, only a subset of the pre-infusion product differentiates into optimal effectors. We generated a comprehensive single-cell gene expression and T cell receptor (TCR) sequencing dataset using both pre- and post-infusion CD19-CAR T cells from peripheral blood and bone marrow of pediatric patients with B cell acute lymphoblastic leukemia (B-ALL). We identified potent effector post-infusion cells with identical TCRs to a subset of pre-infusion CAR T cells. Effector precursor CAR T cells exhibited a unique transcriptional profile compared to other pre-infusion cells, and the number of effector precursor cells infused correlated with peak CAR T cell expansion. Additionally, we identified an unexpected cell surface phenotype (TIGIT+, CD62Llo, CD27−), conventionally associated with inhibiting effective T cell responses, that we used to successfully enrich for subsequent effector potential. Collectively, these results demonstrate that highly diverse effector potentials are present among cells in pre-infusion cell products, which can be exploited for diagnostic and therapeutic applications. Furthermore, we provide an integrative experimental and analytical framework for elucidating the biological mechanisms underlying effector development in other CAR T cell therapy products. This work was supported by the National Institutes of Health (NIH)/National Cancer Institute grant P30CA021765, NIH grants U01AI150747 and R01AI136514 (PGT), the American Society of Transplantation and Cellular Therapy (AT), the American Society of Hematology (AT), the Key for a Cure Foundation (PGT), the Mark Foundation ASPIRE Award (PGT), and the American Lebanese Syrian Associated Charities (SG, PGT). Part of the laboratory studies were performed by the Center for Translational Immunology and Immunotherapy (CeTI2), which is supported by SJCRH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Epinephrine is a life-saving medication used to treat systemic allergic reactions including anaphylaxis. Epinephrine autoinjectors (EAIs) are expensive and worldwide availability is limited. Epinephrine prefilled syringes and epinephrine kits are potentially lower-cost alternatives to EAIs. Advantages, disadvantages, and costs of available products are discussed. The socioeconomic factors impacting access to EAIs are described.

Background Large sample sizes are needed for sublingual immunotherapy (SLIT) trials because of inherent data variability secondary to inconsistent allergen exposure. Obtaining large sample sizes for pediatric SLIT trials is challenging, but a Bayesian approach using prior adult data can reduce the necessary sample size. Objective We sought to describe how a Bayesian framework using prior information from adult trials can be used to improve pediatric SLIT clinical development. Methods Data were compiled by using a frequentist approach (conventional clinical trial approach independent of prior data) from trials conducted during the clinical development of timothy grass SLIT-tablets. Results The treatment effect of timothy grass SLIT-tablets was considered similar between pediatric (n = 795) and adult (n = 2299) data pools, with relative total combined symptom plus medication score improvement versus placebo of 21% (95% CI, 11.0% to 30.4%) and 20% (95% CI, 14.6% to 24.4%), respectively. Phleum pratense –specific IgG 4 and IgE-blocking factor increased from baseline in both children and adults treated with timothy grass SLIT-tablets. Given the reasonable assumption in similarity of treatment response between adults and children, a Bayesian approach is described to demonstrate rigorous efficacy criteria for pediatric trials incorporating information from prior adult trials and thereby reduce the sample size. Conclusions Data support the similarity of efficacy and immunologic changes between children and adults treated with SLIT for allergic rhinoconjunctivitis. Therefore it is appropriate to use data from adult trials to design feasible trials in children, which might reduce unsafe off-label use by promoting more quickly proper labeling of approved products.

Background: CD19-CAR T-cell therapy has emerged as a curative approach for patients with relapsed/refractory B-cell malignancies, including lymphoma and acute lymphoblastic leukemia (ALL). However, many patients develop recurrent disease after initial responses. Therapeutic failure is most likely due to T cell extrinsic and intrinsic mechanisms. While CD19-negative relapse has emerged as a major extrinsic mechanism, T cell intrinsic mechanisms remain elusive. T-cell exhaustion is driven by epigenetic programs, however epigenetic changes in CAR T cells pre and post infusion have not been determined longitudinally. Thus, the goal of this study was to determine the epigenetic landscape of CD19-CAR T cells pre and post infusion as an initial step to elucidate intrinsic mechanisms that limit CAR T-cell effector functions in humans. Methods/Results: A longitudinal analysis of CD8+ CD19-CAR T cell epigenetic changes was performed by whole-genome DNA methylation profiling of CAR T cells during manufacturing and from peripheral blood mononuclear cells (PBMCs) of infused patients. DNA methylation profiling was performed on samples from 15 patients enrolled on our institutional, autologous CD19-CAR T cell therapy study (NCT03573700). CAR T cell expansion and persistence was determined by measuring vector copy numbers in the PBMCs of treated patients. B cell aplasia was tracked by monitoring B cell reconstitution as an additional measure of CD19-CAR T cell function. We had previously established novel exhaustion DNA methylation datasets that delineate between progenitor and fully exhausted T cells. These datasets served as a guide for stratifying our post-infusion CAR T cells along the exhaustion developmental trajectory. Lastly, publicly available single-cell transcriptional profiles of CD19-CAR T cells from patients were mined to validate expression of the transitory exhaustion signature. Our data show that CD19-CAR T cells lose repressive DNA methylation at effector loci (e.g. PRF1, TBET) while gaining methylation at genes (e.g. LEF1, TCF7) associated with memory potential. We confirmed that these epigenetic changes are coupled to endogenous human T cell effector and memory differentiation by cross-referencing our epigenetic data with publicly available transcriptional profiles for antigen-specific effector and long-lived memory CD8 T cells from individuals vaccinated for yellow fever. Furthermore, we show that CAR T cells were unable to mount an in vivo recall response after recovery of antigen-positive B cells or disease relapse. This observation, coupled to the fact that these patients' CAR T cells developed exhaustion-associated DNA methylation programs, further supports the broader conclusion that CAR T cells acquire stable epigenetic exhaustion programs that limit their protective capacity. Conclusion: Our data demonstrate for the first time that CAR T cell expansion during a clinical response is coupled to progressive restriction of gene regulatory programs that control T cell fate potential. Furthermore, we show that CD19-CAR T cells undergo exhaustion epigenetic programs that are coupled to an inability to mount a recall response in the presence of antigen-positive normal and malignant B cells. This work lays the foundation for future efforts aimed at improving the efficacy of cellular therapy by reversing epigenetic programs that are coupled to CAR T-cell exhaustion. Disclosures Triplett: Miltenyi: Other: Travel, meeting registration. Gottschalk: Other: Other: patents and patent applications in the field of cancer cell and gene therapy ; Catamaran Bio: Consultancy; Novartis: Consultancy; Tidal: Consultancy; Immatics: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Consultancy. Youngblood: ElevateBio: Consultancy; ElevateBio: Honoraria; AstraZeneca: Honoraria; Cell Signaling: Honoraria; Merck: Research Funding; other: Other: patents and patent applications in the field of cancer cell and gene therapy .

Background Asthma is associated with adverse pregnancy outcomes. At the same time there is a worldwide increase in asthma and hay fever. Objective This study addresses whether asthma and/or hay fever adversely influence pregnancy outcomes. Methods Data from the 1995 National Survey of Family Growth that include a history of diagnosed asthma, hay fever, and adverse pregnancy outcomes in 10,847 women representative of the US population aged 15 to 44 years were analyzed. Results Women with the allergic phenotypes asthma and hay fever and hay fever only had no significant increase in adverse pregnancy outcomes (spontaneous pregnancy loss, preterm birth, infant low birth weight), whereas women with the nonatopic phenotype asthma only (without hay fever) did. The study did not evaluate endotypes. Conclusions This study provides new data that the allergic phenotypes, asthma and hay fever and hay fever only, are compatible with healthy pregnancy, whereas the nonatopic asthma phenotype, asthma only, adversely impacts pregnancy.

Medication-induced angioedema is a bradykinin-mediated process that results from increased production or decreased degradation of bradykinin. These reactions are documented for several cardiac medications including blockers of the renin-angiotensin-aldosterone system (RAAS). Other cardiovascular and diabetes medications further increase the risk of medication-induced angioedema, particularly with concomitant use of RAAS inhibitors. Dipeptidyl peptidase IV inhibitors are a class of oral diabetic agents that affect bradykinin and substance P degradation and therefore can lead to angioedema. Neprilysin inhibitors are a separate class of cardiac medications, which includes sacubitril, and can lead to drug-induced angioedema especially when used in combination with RAAS inhibitors. This article discusses the proposed mechanisms by which these medications cause angioedema and how medication-induced angioedema differs from mast cell-mediated angioedema. It also details how to recognize medication-induced angioedema and the treatment options available.

The classification of asthma into phenotypes and endotoypes allows for the use of targeted therapies, including three biologics which target interleukin 5 (IL-5) signaling in eosinophilic asthma. Areas covered: As of December 2016, two monoclonal antibodies, mepolizumab and reslizumab, are approved by U.S. Food and Drug Administration and one, benralizumab, is in clinical development. Two phase 3 trials for benralizumab, SIROCCO and CALIMA, were published in September 2016. Although there are no direct comparisons among these three anti-IL-5 therapies, the goal of this review is to summarize the current data and discuss their potential similarities and differences, with a focus on benralizumab. Expert commentary: Compared to mepolizumab and reslizumab, the possible advantages of benralizumab are less frequent dosing and a potential to reduce exacerbations irrespective of the blood eosinophil count. Some improvements in asthma symptom scores and quality of life occur with all three biologics, but the clinical meaningfulness of these improvements is less clear. A more defined reference range for eosinophil levels is necessary to determine which subjects will best benefit from these medications. Until quality randomized controlled trials directly compare the three, choosing among them for the treatment of eosinophilic asthma remains difficult.

Rhinitis is an umbrella term of a group of upper airway diseases with nasal symptoms and signs with different etiologies and various clinical features or traits. It can be classified into different "phenotypes," based on these observable traits. A proper differential diagnosis is necessary to adequately manage the disease. The objective of this review is to clarify the concept of rhinitis phenotypes while analyzing the clinical features and/or traits of each in order to determine a proper differential diagnosis and appropriate treatment.

BACKGROUND: Asthma phenotypes are currently not amenable to primary prevention or early intervention because their natural history cannot be reliably predicted. Clinicians remain reliant on poorly predictive asthma outcome tools because of a lack of better alternatives.OBJECTIVE: We sought to develop a quantitative personalized tool to predict asthma development in young children.METHODS: Data from the Cincinnati Childhood Allergy and Air Pollution Study (n = 762) birth cohort were used to identify factors that predicted asthma development. The Pediatric Asthma Risk Score (PARS) was constructed by integrating demographic and clinical data. The sensitivity and specificity of PARS were compared with those of the Asthma Predictive Index (API) and replicated in the Isle of Wight birth cohort.RESULTS: PARS reliably predicted asthma development in the Cincinnati Childhood Allergy and Air Pollution Study (sensitivity = 0.68, specificity = 0.77). Although both the PARS and API predicted asthma in high-risk children, the PARS had improved ability to predict asthma in children with mild-to-moderate asthma risk. In addition to parental asthma, eczema, and wheezing apart from colds, variables that predicted asthma in the PARS included early wheezing (odds ratio [OR], 2.88; 95% CI, 1.52-5.37), sensitization to 2 or more food allergens and/or aeroallergens (OR, 2.44; 95% CI, 1.49-4.05), and African American race (OR, 2.04; 95% CI, 1.19-3.47). The PARS was replicated in the Isle of Wight birth cohort (sensitivity = 0.67, specificity = 0.79), demonstrating that it is a robust, valid, and generalizable asthma predictive tool.CONCLUSIONS: The PARS performed better than the API in children with mild-to-moderate asthma. This is significant because these children are the most common and most difficult to predict and might be the most amenable to prevention strategies.

Aspirin (ASA)-exacerbated respiratory disease (AERD) is characterized by upper airway congestion due to eosinophilic inflammation of the nasal and sinus membranes and nasal polyposis, associated with increased leukotriene production that is further accentuated by ASA or other nonsteroidal anti-inflammatory drug (NSAID) ingestion. It occurs in 5% to 10% of subjects with chronic rhinosinusitis (CRS) and in 15% to 40% of those with nasal polyposis. Although AERD with CRS is usually associated with asthma, this is not always the case. The eosinophilic airway inflammation and symptoms precede clinical reactions to ASA or other NSAIDs, but ultimately affected subjects experience worsening of symptoms with ingestion of ASA/NSAIDs. The endotypic mechanism for this worsening is related to a chronic increase in leukotriene and a decrease in prostaglandin production, particularly prostaglandin E2, that is further aggravated by the inhibition of cycloxgenase I. IgE does not likely play a role in the pathogenesis of the disease although nasal and sinus staphylococcal infection increases local IgE level and may increase total IgE and specific IgE levels. Genetic studies suggest that multiple genes may be involved, but the genetic abnormalities may differ in affected subjects from different ethnicities and candidate genes have not been confirmed in multiple studies. Genome-wide association studies have not been revealing. The phenotype is recognized by the mucosal inflammation and worsening of symptoms acutely with ASA/NSAID. There is clinical improvement with ASA desensitization followed by regular ingestion of ASA or other NSAIDs. Further understanding of this unique phenotype and endotype of CRS will likely improve the understanding of other eosinophilic airway diseases.