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.

Qualitative Evaluation of RADx-UP Projects Addressing COVID-19 Testing Disparities Among Underserved Populations.

In this article, we present findings from a May 2022 to March 2023 qualitative evaluation of Rapid Acceleration of Diagnostics-Underserved Populations (RADx-UP) projects addressing COVID-19 testing disparities among underserved populations. Interviews with academic and community partners from 13 RADx-UP projects revealed that despite the pandemic, projects were able to build trust and relationships with underserved populations. By prioritizing community voices during a public health emergency, RADx-UP projects improved health equity and pandemic preparedness in these communities, successfully conducted community-engaged research, and built long-lasting community partnerships. (Am J Public Health. 2024;114(S5):S410-S415. https://doi.org/10.2105/AJPH.2024.307632).

Patient and Clinician Preferences for Biologic Treatments for Severe Uncontrolled Asthma: A Discrete Choice Experiment (DCE).

OBJECTIVES: To estimate the preferences of patients with asthma and asthma-treating clinicians for attributes of biologic treatments, to compare patients' and clinicians' preferences, and to better understand the reasons for their preferences. METHODS: Adults with moderate-to-severe asthma and clinicians who treat asthma in the US completed a cross-sectional, online survey including a discrete choice experiment (DCE) that consisted of seven attributes spanning treatment efficacy, risk and convenience. Marginal utilities were estimated using a mixed logit model, and relative attribute importance scores calculated. Clinicians were also asked about the value of biomarker agnostic biologic treatments. The survey was followed by qualitative interviews targeting a sub-sample of survey participants, in which the rationale behind their survey responses was discussed. RESULTS: In the DCE, both patients and clinicians placed the most importance on exacerbation and hospitalization rate reduction, and risk of injection site reaction. Patients valued location of administration more than clinicians. Rationale for individual-level preferences varied, with patients and clinicians reporting their preference depended on event frequency and anticipated quality of life impacts. Clinicians mentioned compliance and financial impacts, while patients mentioned personal experience, particularly around site reactions. Most patients and clinicians would value a biomarker agnostic asthma treatment. CONCLUSIONS: Asthma treatment preferences are largely driven by treatment efficacy and minimizing the risk of site reactions, although preferences differ between patients and clinicians across other attributes, highlighting the need for shared decision-making and individualized care.

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.

Confirmatory factor analysis of the infant feeding styles questionnaire in infant and toddler child care teachers.

Early childhood is a critical time of development. Caregiver feeding style, including of child care providers, has been implicated in influencing children's food preferences and obesity. A better understanding of the determinants of child care providers' feeding styles is important as children increasingly receive daily care and nutrition in child care centers. Valid instruments to measure provider feeding styles specifically for infants are needed. This study's objective was to validate, for use with child care providers, the Infant Feeding Styles Questionnaire (IFSQ), an instrument originally designed for parents of infants and toddlers. Study data came from the Baby Nutrition and Physical Activity Self-Assessment for Child Care (Baby NAP SACC) study, a cluster randomized trial, designed to evaluate the efficacy of a six-month-long obesity prevention intervention in child care centers. The IFSQ was administered at baseline and follow-up to infant and toddler teacher participants (n = 244). Scores for baseline IFSQ teacher responses (n = 219) were calculated for the 13 sub-constructs across the five feeding styles. We tested reliability with Cronbach's alpha coefficients and performed confirmatory factor analysis to examine factor loadings and goodness of fit characteristics, modifying constructs to achieve best fit. Reliability coefficients ranged from 0.42 to 0.82 for all sub-constructs. Goodness of fit indices for the final model ranged from: root mean square error of approximation (RMSEA) 0.000-0.082; comparative fit index (CFI) 0.943-1.000; Tucker-Lewis index (TLI) 0.906-1.000; and standardized root mean squared error (SRMR) 0.006-0.130. In a sample of racially diverse infant and toddler child care teachers, final models of the laissez-faire, pressuring, and responsive constructs and the restrictive-diet quality sub-construct performed well. Overall model fit was poor for the indulgence construct, but good for solely its corresponding belief items.

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.