Inhaled endotoxin induces a systemic neutrophil response without affecting cardiovascular measures in a randomized cross-over exposure study.

OBJECTIVE: The gram-negative bacterial cell wall component endotoxin (lipopolysaccharide, LPS) is a key component of particulate matter (PM). PM exposure is associated with cardiovascular morbidity and mortality. However, the contribution of individual components of PM to acute and chronic cardiovascular measures is not clear. This study examines whether systemic inflammation induced by LPS inhalation causes acute changes in cardiovascular physiology measures. MATERIALS AND METHODS: In this double blinded, placebo-controlled crossover study, fifteen adult volunteers underwent inhalation exposure to 20,000 EU Clinical Center Reference Endotoxin (CCRE). Peripheral blood and induced sputum neutrophils were obtained at baseline and six hours post-exposure. Blood pressure, measures of left ventricular function (ejection fraction (LVEF) and global longitudinal strain (LVGLS)), and indices of endothelial function (flow mediated dilation (FMD) and velocity time integral during hyperemia (VTIhyp)) were measured before and after treatment. Wilcoxon sign-rank tests and linear mixed models were used for statistical analysis. RESULTS: In comparison with normal saline, LPS inhalation resulted in significant increases in peripheral blood and sputum neutrophils but was not associated with significant alterations in blood pressure, LVGLS, LVEF, FMD, or VTIhyp. DISCUSSION AND CONCLUSIONS: In healthy adults, systemic inflammation after LPS inhalation was not associated with acute changes in cardiovascular physiology. Larger studies are needed to investigate the effects of other PM components on inflammation induced cardiovascular dysfunction.

Using Cost Conversations to Address Financial Toxicity in Pediatric Asthma Care: Findings From a Survey of Caregivers.

INTRODUCTION: Asthma care teams are well-positioned to help caregivers address financial toxicity in pediatric asthma care, although discussing cost can be challenging. We sought to characterize cost conversations in pediatric asthma specialty care. METHOD: We surveyed 45 caregivers of children aged 4-17 with asthma. Eligible caregivers reported costs concerns and had accompanied their child to a multisite asthma specialty practice in North Carolina. RESULTS: About one-third of caregivers reported a cost conversation (36%). Cost conversations were less common among caregivers whose child had public versus private health insurance (16% vs. 56%), who attended a telehealth versus in-person visit (6% vs. 52%), or who did not versus did want a conversation (19% vs. 77%, all p < .05). Common cost conversation topics were medications and equipment like spacers. DISCUSSION: Our findings suggest cost conversations may be relatively uncommon in pediatric asthma care, particularly for publicly insured patients and telehealth visits.

Race-specific spirometry equations may overestimate asthma control in Black children and adolescents.

BACKGROUND: A growing body of evidence suggests that use of race terms in spirometry reference equations underestimates disease burden in Black populations, which may lead to disparities in pulmonary disease outcomes. Data on asthma-specific health consequences of using race-adjusted spirometry are lacking. METHODS: We performed a secondary analysis of 163 children from two observational asthma studies to determine the frequencies of participants with ppFEV1 < 80% (consistent with uncontrolled asthma) or ppFEV1 ≥ 80% using race-specific (GLI-African American or Caucasian) vs. race-neutral (GLI-Global) spirometry and their alignment with indicators of asthma control (Asthma Control Test™, ACT). Comparisons of mean ppFEV1 values were conducted using Wilcoxon matched-pairs signed-rank tests. Two group comparisons were conducted using Wilcoxon rank-sum tests. RESULTS: Data from 163 children (100 Black, 63 White) were analyzed. Mean ppFEV1 was 95.4% (SD 15.8) using race-specific spirometry and 90.4% (16.3) using race-neutral spirometry (p < 0.0001). Among 54 Black children with uncontrolled asthma (ACT ≤ 19), 20% had ppFEV1 < 80% using race-specific spirometry compared to 40% using race-neutral spirometry. In Black children with controlled asthma (ACT > 19), 87% had ppFEV1 ≥ 80% using race-specific compared to 67% using race-neutral spirometry. Children whose ppFEV1 changed to ≤ 80% with race-neutral spirometry had lower FEV1/FVC compared to those whose ppFEV1 remained ≥ 80% [0.83 (0.07) vs. 0.77 (0.05), respectively; p = 0.04], suggesting greater airway obstruction. Minimal changes in alignment of ppFEV1 with ACT score were observed for White children. CONCLUSIONS: Use of race-specific reference equations in Black children may increase the risk of inappropriately labeling asthma as controlled.

Robust Cough Detection With Out-of-Distribution Detection.

Cough is an important defense mechanism of the respiratory system and is also a symptom of lung diseases, such as asthma. Acoustic cough detection collected by portable recording devices is a convenient way totrack potential condition worsening for patients who have asthma. However, the data used in building current cough detection models are often clean, containing a limited set of sound categories, and thus perform poorly when they are exposed to a variety of real-world sounds which could be picked up by portable recording devices. The sounds that are not learned by the model are referred to as Out-of-Distribution (OOD) data. In this work, we propose two robust cough detection methods combined with an OOD detection module, that removes OOD data without sacrificing the cough detection performance of the original system. These methods include adding a learning confidence parameter and maximizing entropy loss. Our experiments show that 1) the OOD system can produce dependable In-Distribution (ID) and OOD results at a sampling rate above 750 Hz; 2) the OOD sample detection tends to perform better for larger audio window sizes; 3) the model's overall accuracy and precision get better as the proportion of OOD samples increase in the acoustic signals; 4) a higher percentage of OOD data is needed to realize performance gains at lower sampling rates. The incorporation of OOD detection techniques improves cough detection performance by a significant margin and provides a valuable solution to real-world acoustic cough detection problems.

Social determinants of health and asthma.

PURPOSE OF REVIEW: Social determinants of health play a major role in healthcare utilization and outcomes in patients with asthma. Continuing to understand how these complex and interwoven relationships interact to impact patient care will be crucial to creating innovative programmes that address these disparities. RECENT FINDINGS: The current literature continues to support the association of substandard housing, urban and rural neighbourhoods, and race/ethnicity with poor asthma outcomes. Targeted interventions with community health workers (CHWs), telemedicine and local environmental rectifications can help improve outcomes. SUMMARY: The link between social determinants and poor asthma outcomes continues to be supported by recent literature. These factors are both nonmodifiable and consequences of institutionalized racist policies that require innovative ideas, technologic equity and funding for groups most at risk for poorer outcomes.

IL-1 receptor antagonist attenuates proinflammatory responses to rhinovirus in airway epithelium.

BACKGROUND: Rhinoviruses (RVs) are the most common trigger for asthma exacerbations, and there are currently no targeted therapies for viral-induced asthma exacerbations. RV infection causes neutrophilic inflammation, which is often resistant to effects of glucocorticoids. IL-1 receptor antagonist (IL-1RA) treatment reduces neutrophilic inflammation in humans challenged with inhaled endotoxin and thus may have therapeutic potential for RV-induced asthma exacerbations. OBJECTIVE: We sought to test the hypothesis that IL-1RA treatment of airway epithelium reduces RV-mediated proinflammatory cytokine production, which is important for neutrophil recruitment. METHODS: Human bronchial epithelial cells from deceased donors without prior pulmonary disease were cultured at air-liquid interface and treated with IL-13 to approximate an asthmatic inflammatory milieu. Human bronchial epithelial cells were infected with human RV-16 with or without IL-1RA treatment. RESULTS: RV infection promoted the release of IL-1α and the neutrophil-attractant cytokines IL-6, IL-8, and CXCL10. Proinflammatory cytokine secretion was significantly reduced by IL-1RA treatment without significant change in IFN-ß release or RV titer. In addition, IL-1RA reduced MUC5B expression after RV infection without impacting MUC5AC. CONCLUSIONS: These data suggest that IL-1RA treatment significantly reduced proinflammatory cytokines while preserving the antiviral response. These results provide evidence for further investigation of IL-1RA as a novel targeted therapy against neutrophil-attractant cytokine release in RV-induced airway inflammatory responses.

Environmental justice and allergic disease: A Work Group Report of the AAAAI Environmental Exposure and Respiratory Health Committee and the Diversity, Equity and Inclusion Committee.

Environmental justice is the concept that all people have the right to live in a healthy environment, to be protected against environmental hazards, and to participate in decisions affecting their communities. Communities of color and low-income populations live, work, and play in environments with disproportionate exposure to hazards associated with allergic disease. This unequal distribution of hazards has contributed to health disparities and is largely the result of systemic racism that promotes segregation of neighborhoods, disinvestment in predominantly racial/ethnic minority neighborhoods, and discriminatory housing, employment, and lending practices. The AAAAI Environmental Exposure and Respiratory Health Committee and Diversity, Equity and Inclusion Committee jointly developed this report to improve allergy/immunology specialists' awareness of environmental injustice, its roots in systemic racism, and its impact on health disparities in allergic disease. We present evidence supporting the relationship between exposure to environmental hazards, particularly at the neighborhood level, and the disproportionately high incidence and poor outcomes from allergic diseases in marginalized populations. Achieving environmental justice requires investment in at-risk communities to increase access to safe housing, clean air and water, employment opportunities, education, nutrition, and health care. Through policies that promote environmental justice, we can achieve greater health equity in allergic disease.

Effects of combination treatment with tezepelumab and allergen immunotherapy on nasal responses to allergen: A randomized controlled trial.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) has been shown to play a central role in the initiation and persistence of allergic responses. OBJECTIVE: We evaluated whether tezepelumab, a human monoclonal anti-TSLP antibody, improved the efficacy of subcutaneous allergen immunotherapy (SCIT) and promoted the development of tolerance in patients with allergic rhinitis. METHODS: We conducted a double-blind parallel design trial in patients with cat allergy. A total of 121 patients were randomized to receive either intravenous tezepelumab plus subcutaneous cat SCIT, cat SCIT alone, tezepelumab alone, or placebo for 52 weeks, followed by 52 weeks of observation. Nasal allergen challenge (NAC), skin testing, and blood and nasal samples were obtained throughout the study. RESULTS: At week 52, the NAC-induced total nasal symptom scores (TNSS) (calculated as area under the curve [AUC0-1h] and as peak score [Peak0-1h] during the first hour after NAC) were significantly reduced in patients receiving tezepelumab/SCIT compared to SCIT alone. At week 104, one year after stopping treatment, the primary end point TNSS AUC0-1h was not significantly different in the tezepelumab/SCIT group compared to SCIT alone, while TNSS Peak0-1h was significantly lower in those receiving combination treatment versus SCIT. Transcriptomic analysis of nasal epithelial samples demonstrated that treatment with the combination of SCIT/tezepelumab, but neither monotherapy, caused persistent downregulation of a gene network related to type 2 inflammation that was associated with improvement in NAC responses. CONCLUSIONS: Inhibition of TSLP augments the efficacy of SCIT during therapy and may promote tolerance after a 1-year course of treatment. (ClinicalTrials.gov NCT02237196).

Ozone in the Development of Pediatric Asthma and Atopic Disease.

Ozone (O3) is a ubiquitous outdoor air pollutant, which may be derived from various primary pollutants such as nitrates, hydrocarbons, and volatile organ compounds through ultraviolet radiation exposure, and has been shown to negatively impact respiratory health. O3 is the most common noninfectious environmental cause of asthma exacerbations among children and adults. Its effects on pediatric respiratory health could be due to multiple physiologic factors that may contribute to enhanced O3 exposure seen in children compared with adults, including differences in lung surface area per unit of body weight and ventilation rates. O3 can reach the distal regions of human lungs due to its low water solubility, resulting in either injury or activation of airway epithelial cells and macrophages. Multiple epidemiologic studies have highlighted a link between exposure to air pollution and the development of asthma. This review article specifically focuses on examining the impact of early life O3 exposure on lung development, lung function, and the risk of developing atopic diseases including asthma, allergic rhinitis, and atopic dermatitis among children.

Development of a screening protocol to identify persons who are responsive to wood smoke particle-induced airway inflammation with pilot assessment of GSTM1 genotype and asthma status as response modifiers.

BACKGROUND: We are currently screening human volunteers to determine their sputum polymorphonuclear neutrophil (PMN) response 6- and 24-hours following initiation of exposure to wood smoke particles (WSP). Inflammatory responders (≥10% increase in %PMN) are identified for their subsequent participation in mitigation studies against WSP-induced airways inflammation. In this report we compared responder status (<i>N</i> = 52) at both 6 and 24 hr time points to refine/expand its classification, assessed the impact of the GSTM1 genotype, asthma status and sex on responder status, and explored whether sputum soluble phase markers of inflammation correlate with PMN responsiveness to WSP. RESULTS: Six-hour responders tended to be 24-hour responders and vice versa, but 24-hour responders also had significantly increased IL-1beta, IL-6, IL-8 at 24 hours post WSP exposure. The GSTM1 null genotype significantly (<i>p</i> &lt; 0.05) enhanced the %PMN response by 24% in the 24-hour responders and not at all in the 6 hours responders. Asthma status enhanced the 24 hour %PMN response in the 6- and 24-hour responders. In the entire cohort (not stratified by responder status), we found a significant, but very small decrease in FVC and systolic blood pressure immediately following WSP exposure and sputum %PMNs were significantly increased and associated with sputum inflammatory markers (IL-1beta, IL-6, IL-8, and PMN/mg) at 24 but not 6 hours post exposure. Blood endpoints in the entire cohort showed a significant increase in %PMN and PMN/mg at 6 but not 24 hours. Sex had no effect on %PMN response. CONCLUSIONS: The 24-hour time point was more informative than the 6-hour time point in optimally and expansively defining airway inflammatory responsiveness to WSP exposure. GSTM1 and asthma status are significant effect modifiers of this response. These study design and subject parameters should be considered before enrolling volunteers for proof-of-concept WSP mitigation studies.

Caribbean Latinx with moderate-severe asthma bear greater asthma morbidity than other Latinx.

BACKGROUND: Hispanic/Latinx (HL) ethnicity encompasses racially and culturally diverse subgroups. Studies suggest that Puerto Ricans (PR) may bear greater asthma-related morbidity than Mexicans, but these were conducted in children or had limited clinical characterization. OBJECTIVES: This study sought to determine whether disparities in asthma morbidity exist among HL adult subgroups. METHODS: Adults with moderate-severe asthma were recruited from US clinics, including from Puerto Rico, for the Person Empowered Asthma Relief (PREPARE) trial. Considering the shared heritage between PR and other Caribbean HL (Cubans and Dominicans [C&D]), the investigators compared baseline self-reported clinical characteristics between Caribbean HL (CHL) (PR and C&D: n = 457) and other HLs (OHL) (Mexicans, Spaniards, Central/South Americans; n = 141), and between CHL subgroups (C&D [n = 56] and PR [n = 401]). This study compared asthma morbidity measures (self-reported exacerbations requiring systemic corticosteroids, emergency department/urgent care (ED/UC) visits, hospitalizations, health care utilization) through negative binomial regression. RESULTS: CHL compared to OHL were similar in age, body mass index, poverty status, blood eosinophils, and fractional exhaled nitric oxide but were prescribed more asthma controller therapies. Relative to OHL, CHL had significantly increased odds of asthma exacerbations (odds ratio [OR]: 1.84; 95% CI: 1.4-2.4), ED/UC visits (OR: 1.88; 95% CI: 1.4-2.5), hospitalization (OR: 1.98; 95% CI: 1.06-3.7), and health care utilization (OR: 1.91; 95% CI: 1.44-2.53). Of the CHL subgroups, PR had significantly increased odds of asthma exacerbations, ED/UC visits, hospitalizations, and health care utilization compared to OHL, whereas C&D only had increased odds of exacerbations compared to OHL. PR compared to C&D had greater odds of ED/UC and health care utilization. CONCLUSIONS: CHL adults, compared with OHL, adults reported nearly twice the asthma morbidity; these differences are primarily driven by PR. Novel interventions are needed to reduce morbidity in this highly impacted population.

Reliever-Triggered Inhaled Glucocorticoid in Black and Latinx Adults with Asthma.

BACKGROUND: Black and Latinx patients bear a disproportionate burden of asthma. Efforts to reduce the disproportionate morbidity have been mostly unsuccessful, and guideline recommendations have not been based on studies in these populations. METHODS: In this pragmatic, open-label trial, we randomly assigned Black and Latinx adults with moderate-to-severe asthma to use a patient-activated, reliever-triggered inhaled glucocorticoid strategy (beclomethasone dipropionate, 80 µg) plus usual care (intervention) or to continue usual care. Participants had one instructional visit followed by 15 monthly questionnaires. The primary end point was the annualized rate of severe asthma exacerbations. Secondary end points included monthly asthma control as measured with the Asthma Control Test (ACT; range, 5 [poor] to 25 [complete control]), quality of life as measured with the Asthma Symptom Utility Index (ASUI; range, 0 to 1, with lower scores indicating greater impairment), and participant-reported missed days of work, school, or usual activities. Safety was also assessed. RESULTS: Of 1201 adults (603 Black and 598 Latinx), 600 were assigned to the intervention group and 601 to the usual-care group. The annualized rate of severe asthma exacerbations was 0.69 (95% confidence interval [CI], 0.61 to 0.78) in the intervention group and 0.82 (95% CI, 0.73 to 0.92) in the usual-care group (hazard ratio, 0.85; 95% CI, 0.72 to 0.999; P = 0.048). ACT scores increased by 3.4 points (95% CI, 3.1 to 3.6) in the intervention group and by 2.5 points (95% CI, 2.3 to 2.8) in the usual-care group (difference, 0.9; 95% CI, 0.5 to 1.2); ASUI scores increased by 0.12 points (95% CI, 0.11 to 0.13) and 0.08 points (95% CI, 0.07 to 0.09), respectively (difference, 0.04; 95% CI, 0.02 to 0.05). The annualized rate of missed days was 13.4 in the intervention group and 16.8 in the usual-care group (rate ratio, 0.80; 95% CI, 0.67 to 0.95). Serious adverse events occurred in 12.2% of the participants, with an even distribution between the groups. CONCLUSIONS: Among Black and Latinx adults with moderate-to-severe asthma, provision of an inhaled glucocorticoid and one-time instruction on its use, added to usual care, led to a lower rate of severe asthma exacerbations. (Funded by the Patient-Centered Outcomes Research Institute and others; PREPARE ClinicalTrials.gov number, NCT02995733.).

Gamma-tocopherol, a major form of vitamin E in diets: Insights into antioxidant and anti-inflammatory effects, mechanisms, and roles in disease management.

γ-Tocopherol (γT) is a major form of vitamin E in the US diet and the second most abundant vitamin E in the blood and tissues, while α-tocopherol (αT) is the predominant vitamin E in tissues. During the last >25 years, research has revealed that γT has unique antioxidant and anti-inflammatory activities relevant to disease prevention compared to αT. While both compounds are potent lipophilic antioxidants, γT but not αT can trap reactive nitrogen species by forming 5-nitro-γT, and appears to show superior protection of mitochondrial function. γT inhibits ionophore-stimulated leukotrienes by blocking 5-lipoxygenase (5-LOX) translocation in leukocytes, decreases cyclooxygenase-2 (COX-2)-catalyzed prostaglandins in macrophages and blocks the growth of cancer cells but not healthy cells. For these activities, γT is stronger than αT. Moreover, γT is more extensively metabolized than αT via cytochrome P-450 (CYP4F2)-initiated side-chain oxidation, which leads to formation of metabolites including 13'-carboxychromanol (13'-COOH) and carboxyethyl-hydroxychroman (γ-CEHC). 13'-COOH and γ-CEHC are shown to be the predominant metabolites found in feces and urine, respectively. Interestingly, γ-CEHC has natriuretic activity and 13'-COOH inhibits both COX-1/-2 and 5-LOX activity. Consistent with these mechanistic findings of γT and metabolites, studies show that supplementation of γT mitigates inflammation and disease symptoms in animal models with induced inflammation, asthma and cancer. In addition, supplementation of γT decreased inflammation markers in patients with kidney diseases and mild asthma. These observations support that γT may be useful against inflammation-associated diseases.

Airway IL-1ß associates with IL-5 production following dust mite allergen inhalation in humans.

BACKGROUND: Preclinical studies implicate interleukin (IL)-1ß as a key mediator of asthma and have shown the efficacy of IL-1 antagonism for treatment of allergic airway inflammation; human studies in this area are lacking. OBJECTIVES: Our aim was to study the relationship of airway IL-1ß to features of acute allergen-induced asthma exacerbation in humans. METHODS: Dust mite-allergic adults with mild asthma underwent inhalation challenge with Dermatophagoides farinae. Fractional exhaled nitric oxide (FeNO), induced sputum and peripheral blood samples were obtained pre- and 24 h post-challenge. Spirometry was performed before and throughout the challenge at 10-min intervals, and allergen responsiveness was defined by a 20% fall in Forced Expiratory Volume in 1 s (FEV1). Sputum samples were analyzed for inflammatory cells, cytokines and chemokines. Multiple linear regression was employed to test the association between sputum IL-1ß concentration and biomarkers of T helper type 2 (T2)-dominant inflammation. RESULTS: Fourteen volunteers underwent inhaled allergen challenge. Allergen responsive volunteers showed a greater positive change in IL-1ß in sputum following allergen challenge compared to non-responders. Higher pre-challenge sputum IL-1ß was associated with greater increase in sputum IL-5 (p = 0.004), sputum eosinophils (p = 0.001) and blood IL-5 (p = 0.003) following allergen challenge. Allergen-induced sputum IL-1ß production was significantly associated with sputum and blood IL-5 (p < 0.001 and p = 0.007, respectively), sputum IL-4 (p = 0.001), IL-13 (p = 0.026), eosinophils (p = 0.008) and FeNO (p = 0.03). CONCLUSIONS: The positive association between production of IL-1ß and biomarkers of T2 inflammation, particularly IL-5, in humans is consistent with work in animal models that demonstrates a link between IL-1ß and the pathophysiology of allergic asthma. The role of IL-1ß in human asthma warrants further study.

Climate change and global issues in allergy and immunology.

The steady increase in global temperatures, resulting from the combustion of fossil fuels and the accumulation of greenhouse gases (GHGs), continues to destabilize all ecosystems worldwide. Although annual emissions must be halved by 2030 and reach net zero by 2050 to limit some of the most catastrophic impacts associated with a warming planet, the world's efforts to curb GHG emissions fall short of the commitments made in the 2015 Paris Agreement. To this effect, July 2021 was recently declared the hottest month ever recorded in 142 years. The ramifications of these changes for global temperatures are complex and further promote outdoor air pollution, pollen exposure, and extreme weather events. Besides worsening respiratory health, air pollution promotes atopy and susceptibility to infections. The effects of GHGs on pollen affect the frequency and severity of asthma and allergic rhinitis. Changes in temperature, air pollution, and extreme weather events exert adverse multisystemic health effects and disproportionally affect disadvantaged and vulnerable populations. This review article is an update for allergists and immunologists about the health impacts of climate change that are already evident in our daily practices. It is also a call to action and advocacy, including to integrate climate change-related mitigation, education, and adaptation measures to protect our patients and avert further injury to our planet.