Prenatal exposure to RSV season influences first-year risk of RSV lower respiratory illness and RSV-specific immune responses assessed at birth.

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.

Treating asthma in the time of COVID.

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.

The Precision Interventions for Severe and/or Exacerbation-Prone (PrecISE) Asthma Network: An overview of Network organization, procedures, and interventions.

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.

Immunotherapy for Asthma.

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.

PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment.

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.

Treatment approaches for the patient with T2 low asthma.

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.

Exacerbation-prone asthma in the context of race and ancestry in Asthma Clinical Research Network trials.

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 FEV1 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.

Non-atopic rhinitis at age 6 is associated with subsequent development of asthma.

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.

Transfer of peanut allergy from donor to recipient after liver transplant.

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.

Use of biomarkers to identify phenotypes and endotypes of severeasthma.

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.

A Distinct Low Lung Function Trajectory from Childhood to the Fourth Decade of Life.

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.

Association of aeroallergen sensitization and atopic disease in the Sonoran Desert.

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.

Efficacy of Tezepelumab in Patients with Severe, Uncontrolled Asthma Across Multiple Clinically Relevant Subgroups in the NAVIGATOR Study.

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).

Environmental and structural factors associated with bacterial diversity in household dust across the Arizona-Sonora border.

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.

Chapter 2: Skin testing in allergy.

Skin tests are used in addition to a directed history and physical exam to exclude or confirm IgE-mediated diseases such as allergic rhinitis, asthma, and anaphylaxis to aeroallergens, foods, insect venoms, and certain drugs. There are two types of skin testing used in clinical practice. These include percutaneous testing (prick or puncture) and intracutaneous testing (intradermal). Prick testing involves introducing a needle into the upper layers of the skin through a drop of allergen extract and gently lifting the epidermis up. Other devices are available for prick testing. Intracutaneous (intradermal) testing involves injecting a small amount of allergen (0.01-0.02 mL) into the dermis. The release of preformed histamine from mast cells causes increased vascular permeability via smooth muscle contraction and development of a wheal; inflammatory mediators initiate a neural reflex causing vasodilatation, leading to erythema (the flare). Prick testing methods are the initial technique for detecting the presence of IgE. They may correlate better with clinical sensitivity and are more specific but less sensitive than intradermal testing. Sites of skin testing include the back and the volar aspect of the arm. Although the back is more reactive, the difference is minimal. By skin testing on the arm, the patient can witness the emergence and often sense the pruritus of the skin test reaction. Because more patients are sensitized (have IgE antibodies and positive skin test reactions) than have current symptoms, the diagnosis of allergy can be made only by correlating skin testing results with the presence of clinical symptoms.