Advancements in biologic therapy in eosinophilic asthma.

INTRODUCTION: Asthma encompasses a spectrum of phenotypes often categorized into two groups- type 2 high (T2 high) and type 2 low (T2 low). T2 high includes atopic and eosinophilic presentations whereas T2 low is non-atopic, non-eosinophilic, and oft associated with neutrophilic inflammation. Eosinophilic asthma is often driven by IgE, IL-4, IL-5, and IL-13 and TSLP. This can lead to eosinophilic inflammatory response in the airways which in turn can be used as target for treatment. AREAS COVERED: The article will focus on biologic therapy that is currently being used in eosinophilic asthma management in mainly the adult population including clinical trials and co-morbidities that can be treated using the same biologics. A review on asthma biologics for pediatric population has been reviewed elsewhere. EXPERT OPINION: Biological therapy for asthma targeting the IgE, IL-4, IL-5, IL-13, and TSLP pathways are shown to have benefit for the treatment of eosinophilic asthma, as exemplified in real-world studies. When choosing the right biological agent factors such as phenotype, comorbidities, and cost-effectiveness of the biologic agent must be taken into consideration.

Critical Care Management of Severe Asthma Exacerbations.

Severe asthma exacerbations, including near-fatal asthma (NFA), have high morbidity and mortality. Mechanical ventilation of patients with severe asthma is difficult due to the complex pathophysiology resulting from severe bronchospasm and dynamic hyperinflation. Life-threatening complications of traditional ventilation strategies in asthma exacerbations include the development of systemic hypotension from hyperinflation, air trapping, and pneumothoraces. Optimizing pharmacologic techniques and ventilation strategies is crucial to treat the underlying bronchospasm. Despite optimal pharmacologic management and mechanical ventilation, the mortality rate of patients with severe asthma in intensive care units is 8%, suggesting a need for advanced non-pharmacologic therapies, including extracorporeal life support (ECLS). This review focuses on the pathophysiology of acute asthma exacerbations, ventilation management including non-invasive ventilation (NIV) and invasive mechanical ventilation (IMV), the pharmacologic management of acute asthma, and ECLS. This review also explores additional advanced non-pharmacologic techniques and monitoring tools for the safe and effective management of critically ill adult asthmatic patients.

Pharmacoequity in Allergy-Immunology: Disparities in Access to Medications for Allergic Diseases and Proposed Solutions in the United States and Globally.

Pharmacoequity is the principle that individuals should have access to high-quality medications regardless of race and ethnicity, socioeconomic status, or availability of resources. In this review, we summarize access to therapeutics for allergic diseases in the United States and other selected countries. We focus on domains of health care access (health insurance coverage, medication availability, and specialist access) as well as system-level factors and clinician- and patient-level factors such as interpersonal racism and cultural beliefs, and how they can affect timely access to appropriate therapy for allergic diseases. Finally, we propose how pharmacoequity in allergy-immunology can be achieved by highlighting solutions to factors limiting access to medications for allergic diseases, and identify potential future research directions.

Asthma morbidity measures across Black ethnic subgroups.

BACKGROUND: Black adults are disproportionately affected by asthma and are often considered a homogeneous group in research studies despite cultural and ancestral differences. OBJECTIVE: We sought to determine if asthma morbidity differs across adults in Black ethnic subgroups. METHODS: Adults with moderate-severe asthma were recruited across the continental United States and Puerto Rico for the PREPARE (PeRson EmPowered Asthma RElief) trial. Using self-identifications, we categorized multiethnic Black (ME/B) participants (n = 226) as Black Latinx participants (n = 146) or Caribbean, continental African, or other Black participants (n = 80). African American (AA/B) participants (n = 518) were categorized as Black participants who identified their ethnicity as being American. Baseline characteristics and retrospective asthma morbidity measures (self-reported exacerbations requiring systemic corticosteroids [SCs], emergency department/urgent care [ED/UC] visits, hospitalizations) were compared across subgroups using multivariable regression. RESULTS: Compared with AA/B participants, ME/B participants were more likely to be younger, residing in the US Northeast, and Spanish speaking and to have lower body mass index, health literacy, and <1 comorbidity, but higher blood eosinophil counts. In a multivariable analysis, ME/B participants were significantly more likely to have ED/UC visits (incidence rate ratio [IRR] = 1.34, 95% CI = 1.04-1.72) and SC use (IRR = 1.27, 95% CI = 1.00-1.62) for asthma than AA/B participants. Of the ME/B subgroups, Puerto Rican Black Latinx participants (n = 120) were significantly more likely to have ED/UC visits (IRR = 1.64, 95% CI = 1.22-2.21) and SC use for asthma (IRR = 1.43, 95% CI = 1.06-1.92) than AA/B participants. There were no significant differences in hospitalizations for asthma among subgroups. CONCLUSIONS: ME/B adults, specifically Puerto Rican Black Latinx adults, have higher risk of ED/UC visits and SC use for asthma than other Black subgroups.

Association of Sputum Eosinophilia With Easily Measured Type-2 Inflammatory Biomarkers in Untreated Mild Persistent Asthma.

BACKGROUND: A multicenter clinical trial in patients with mild persistent asthma indicated that response to inhaled corticosteroids (ICS) is limited to those with sputum eosinophilia. However, testing for sputum eosinophilia is impractical in most clinical settings. OBJECTIVE: We examined associations between sputum eosinophilia and type 2 inflammatory biomarkers in untreated mild persistent asthma. METHODS: Induced sputum, blood eosinophil count (BEC), fractional exhaled nitric oxide (FeNO), and serum periostin were obtained twice during the 6-week run-in period in a clinical trial that enrolled patients 12 years and older with symptomatic, mild persistent asthma without controller therapy. The optimal threshold for each biomarker was based on achieving 80% or greater sensitivity. Performance of biomarkers (area under the receiver operating characteristics curve [AUC], range 0.0-1.0) in predicting sputum eosinophilia 2% or greater was determined; AUCs of 0.8 to 0.9 and more than 0.9 define excellent and outstanding discrimination, respectively. RESULTS: Of 564 participants, 27% were sputum eosinophilic, 83% were atopic, 70% had BEC of 200/uL or higher or FeNO of 25 ppb or greater; 64% of participants without sputum eosinophilia had elevated BEC or FeNO. The AUCs for BEC, FeNO, and both together in predicting sputum eosinophilia were all below the threshold for excellent discrimination (AUC 0.75, 0.78, and 0.79, respectively). Periostin (in adults) had poor discrimination (AUC 0.59; P = .02). CONCLUSIONS: In untreated mild persistent asthma, there is substantial discordance between sputum eosinophilia, BEC, and FeNO. Until prospective trials test the ability of alternative biomarkers to predict ICS response, BEC or FeNO phenotyping may be an option to consider ICS through a shared decision-making process with consideration of other clinical features.

Preference for and impact of telehealth vs in-person asthma visits among Black and Latinx adults.

BACKGROUND: Black and Latinx adults experience disproportionate asthma-related morbidity and limited specialty care access. The severe acute respiratory syndrome coronavirus 2 pandemic expanded telehealth use. OBJECTIVE: To evaluate visit type (telehealth [TH] vs in-person [IP]) preferences and the impact of visit type on asthma outcomes among Black and Latinx adults with moderate-to-severe asthma. METHODS: For this PREPARE trial ancillary study, visit type preference was surveyed by e-mail or telephone post-trial. Emergency medical record data on visit types and asthma outcomes were available for a subset (March 2020 to April 2021). Characteristics associated with visit type preferences, and relationships between visit type and asthma outcomes (control [Asthma Control Test] and asthma-related quality of life [Asthma Symptom Utility Index]), were tested using multivariable regression. RESULTS: A total of 866 participants consented to be surveyed, with 847 respondents. Among the participants with asthma care experience with both visit types, 42.0% preferred TH for regular checkups, which associated with employment (odds ratio [OR] = 1.61; 95% confidence interval [CI], 1.09-2.39; P = .02), lower asthma medication adherence (OR = 1.06; 95% CI, 1.01-1.11; P = .03), and having more historical emergency department and urgent care asthma visits (OR = 1.10 for each additional visit; 95% CI, 1.02-1.18; P = .02), after adjustment. Emergency medical record data were available for 98 participants (62 TH, 36 IP). Those with TH visits were more likely Latinx, from the Southwest, employed, using inhaled corticosteroid-only controller therapy, with lower body mass index, and lower self-reported asthma medication adherence vs those with IP visits only. Both groups had comparable Asthma Control Test (18.4 vs 18.9, P = .52) and Asthma Symptom Utility Index (0.79 vs 0.84, P = .16) scores after adjustment. CONCLUSION: TH may be similarly efficacious as and often preferred over IP among Black and Latinx adults with moderate-to-severe asthma, especially for regular checkups. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02995733.

What Patients Call Their Inhalers Is Associated with "Asthma Attacks".

BACKGROUND: Clinician-patient miscommunication contributes to worse asthma outcomes. What patients call their asthma inhalers and its relationship with asthma morbidity are unknown. METHODS: Inhaler names were ascertained from Black and Latinx adults with moderate-severe asthma and categorized as "standard" if based on brand/generic name or inhaler type (i.e., controller vs. rescue) or "non-standard" for other terms (i.e., color, device type, e.g., "puffer," or unique names). Clinical characteristics and asthma morbidity measures were evaluated at baseline: self-reported asthma exacerbations one year before enrollment (i.e., systemic corticosteroid bursts, emergency department (ED)/urgent care (UC) visits, or hospitalizations), and asthma control and quality of life. Multivariable regression models tested the relationship between non-standard names and asthma morbidity measures, with adjustments. RESULTS: Forty-four percent (502/1150) of participants used non-standard inhaler names. These participants were more likely to be Black (p=0.006), from the Southeast (p<0.001), and have fewer years with asthma (p=0.012) relative to those who used standard names. Non-standard inhaler names was associated with an incidence rate ratio (IRR) of 1.29 (95% confidence interval [CI], 1.11-1.50, p=0.001; 1.8 vs. 1.5 events) for corticosteroid bursts for asthma, an IRR=1.43 (95% CI, 1.21-1.69, p<0.001; 1.9 vs. 1.4 events) for ED/UC visits for asthma, and an odds ratio=1.57 (95% CI, 1.12-2.18, p=0.008; 0.5 vs. 0.3 events) for asthma hospitalizations after adjustment. CONCLUSIONS: Patients who use non-standard names for asthma inhalers experience increased asthma morbidity. Ascertaining what patients call their inhalers may be a quick method to identify those at higher risk of poor outcomes.

"As-Needed" Inhaled Corticosteroids for Patients With Asthma.

Prevention of severe asthma exacerbations is a primary management goal for asthma across the severity spectrum. Inhaled corticosteroids (ICSs) decrease the risk of asthma exacerbations, but patient adherence to ICS-containing medications as a daily maintenance therapy is poor, and many patients overuse short-acting beta2-agonist relievers; both are associated with increased risk of severe exacerbations and death. Airway inflammation also varies over time, influenced by exposures such as viral infections and allergen. As-needed ICS strategies, in which patients receive ICSs (or additional ICSs, if already taking controller therapy) whenever they take their reliever inhaler, empower patients to adjust their ICS intake in response to symptom fluctuation. These strategies can improve asthma morbidity outcomes, particularly by reducing severe exacerbations and reducing the risk of adverse effects of oral corticosteroids. In this review, the evidence for combination ICS-formoterol in a single inhaler, ICS and short-acting beta2-agonists in separate inhalers, and combination ICS-albuterol in a single inhaler is presented, along with practical considerations, evidence gaps, and implications for clinical practice for each strategy, presented by level of asthma severity and age group. Improving access to such strategies on a global scale is imperative to improve asthma outcomes and achieve equity across populations.

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.

The Impact of Insulin Resistance on Loss of Lung Function and Response to Treatment in Asthma.

Rationale: The role of obesity-associated insulin resistance (IR) in airflow limitation in asthma is uncertain. Objectives: Using data in the Severe Asthma Research Program 3 (SARP-3), we evaluated relationships between homeostatic measure of IR (HOMA-IR), lung function (cross-sectional and longitudinal analyses), and treatment responses to bronchodilators and corticosteroids. Methods: HOMA-IR values were categorized as without (<3.0), moderate (3.0-5.0), or severe (>5.0). Lung function included FEV1 and FVC measured before and after treatment with inhaled albuterol and intramuscular triamcinolone acetonide and yearly for 5 years. Measurements and Main Results: Among 307 participants in SARP-3, 170 (55%) were obese and 140 (46%) had IR. Compared with patients without IR, those with IR had significantly lower values for FEV1 and FVC, and these lower values were not attributable to obesity effects. Compared with patients without IR, those with IR had lower FEV1 responses to ß-adrenergic agonists and systemic corticosteroids. The annualized decline in FEV1 was significantly greater in patients with moderate IR (-41 ml/year) and severe IR (-32 ml/year,) than in patients without IR (-13 ml/year, P < 0.001 for both comparisons). Conclusions: IR is common in asthma and is associated with lower lung function, accelerated loss of lung function, and suboptimal lung function responses to bronchodilator and corticosteroid treatments. Clinical trials in patients with asthma and IR are needed to determine if improving IR might also improve lung function.

Socioeconomic status associates with worse asthma morbidity among Black and Latinx adults.

BACKGROUND: Asthma disproportionately affects African American/Black (AA/B) and Hispanic/Latinx (H/L) patients and individuals with low socioeconomic status (SES), but the relationship between SES and asthma morbidity within these racial/ethnic groups is inadequately understood. OBJECTIVE: To determine the relationship between SES and asthma morbidity among AA/B and H/L adults with moderate to severe asthma using multidomain SES frameworks and mediation analyses. METHODS: We analyzed enrollment data from the PeRson EmPowered Asthma RElief randomized trial, evaluating inhaled corticosteroid supplementation to rescue therapy. We tested for direct and indirect relationships between SES and asthma morbidity using structural equation models. For SES, we used a latent variable defined by poverty, education, and unemployment. For asthma morbidity, we used self-reported asthma exacerbations in the year before enrollment (corticosteroid bursts, emergency room/urgent care visits, or hospitalizations), and Asthma Control Test scores. We tested for mediation via health literacy, perceived stress, and self-reported discrimination. All models adjusted for age, sex, body mass index, ethnicity, and comorbidities. RESULTS: Among 990 AA/B and H/L adults, low SES (latent variable) was directly associated with hospitalizations (ß = 0.24) and worse Asthma Control Test scores (ß = 0.20). Stress partially mediated the relationship between SES and increased emergency room/urgent care visits and worse asthma control (ß = 0.03 and = 0.05, respectively). Individual SES domains were directly associated with asthma morbidity. Stress mediated indirect associations between low educational attainment and unemployment with worse asthma control (ß = 0.05 and = 0.06, respectively). CONCLUSIONS: Lower SES is directly, and indirectly through stress, associated with asthma morbidity among AA/B and H/L adults. Identification of stressors and relevant management strategies may lessen asthma-related morbidity among these populations.

Hormonal Effects on Asthma, Rhinitis, and Eczema.

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.

Clinical and molecular implications of RGS2 promoter genetic variation in severe asthma.

BACKGROUND: Regulator of G protein signaling (RGS) 2 terminates bronchoconstrictive Gαq signaling; murine RGS2 knockout demonstrate airway hyperresponsiveness. While RGS2 promoter variants rs2746071 and rs2746072 associate with a clinical mild asthma phenotype, their impact on human airway smooth muscle (HASM) contractility and asthma severity outcomes is unknown. OBJECTIVE: We sought to determine whether reductions in RGS2 expression seen with these 2 RGS2 promoter variants augment HASM contractility and associate with an asthma severity phenotype. METHODS: We transfected HASM with a range of RGS2-specific small interfering RNA (siRNA) concentrations and determined RGS2 protein expression by Western blot analysis and intracellular calcium flux induced by histamine (a Gαq-coupled H1 receptor bronchoconstrictive agonist). We conducted regression-based genotype association analyses of RGS2 variants from 611 patients from the National Heart, Lung, and Blood Institute Severe Asthma Research Program 3. RESULTS: RGS2-specific siRNA caused dose-dependent increases in histamine-stimulated bronchoconstrictive intracellular calcium signaling (2-way ANOVA, P < .0001) with a concomitant decrease in RGS2 protein expression. RGS2-specific siRNA did not affect Gαq-independent ionomycin-induced intracellular calcium signaling (P = .42). The minor allele frequency of rs2746071 and rs2746072 was 0.46 and 0.28 among African American/non-Hispanic Black patients and was 0.28 and 0.27 among non-Hispanic White patients, among whom these single nucleotide polymorphisms were in stronger linkage disequilibrium (r2 = 0.97). Among non-Hispanic White patients, risk allele homozygotes for rs2746072 and rs2746071 each had nearly 2-fold greater asthma exacerbation rates relative to alternative genotypes with wild-type alleles (Padditive = 2.86 × 10-5/Precessive = 5.22 × 10-6 and Padditive = 3.46 × 10-6/Precessive = 6.74 × 10-7, respectively) at baseline, which was confirmed by prospective longitudinal exacerbation data. CONCLUSION: RGS2 promoter variation associates with a molecular and clinical phenotype characterized by enhanced bronchoconstrictive stimulation in vitro and higher asthma exacerbations rates in non-Hispanic White patients.

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.).

Nebulizer Use by Black and Latinx Adults with Moderate to Severe Asthma.

BACKGROUND: Generally, a short-acting beta-2 agonist (SABA) delivered via metered-dose inhaler (MDI) is recommended for quick relief of asthma symptoms. However, in the PeRson EmPowered Asthma RElief (PREPARE) pragmatic trial, 67% of patients reported having used a nebulizer for SABA administration. OBJECTIVE: To understand preferences, experiences, and decision making regarding the use of nebulizers in Black and Latinx adults with uncontrolled asthma. METHODS: We interviewed 40 of the 1,201 PREPARE patients employing a matrix analysis. Those interviewed were Black (n = 20) and Latinx (n = 20) adults with uncontrolled asthma seeking primary or specialty care in clinics throughout the United States. Data were analyzed used a Rapid Assessment Procedures qualitative methodology, informed by grounded theory. RESULTS: Substudy participants, on average, reported using a nebulizer 3.5 times/wk. Daily use was common, and frequency ranged from less than daily to up to 6 times daily. Nearly all participants reported a longstanding history of nebulizer use. Participants tended to use their nebulizer at home, and some shared it with others in the home. Many reported preferring a nebulizer over an MDI for relief of severe symptoms and to avoid emergency room visits or hospitalizations. The extent to which cost affected nebulizer use varied among participants. CONCLUSIONS: Despite asthma guideline recommendations that MDIs be used rather than nebulizers for SABA administration, nebulizer use was common among PREPARE study participants. Clinicians should explore patients' history and experiences with nebulizer use as part of evaluation of asthma control.

Biomarkers to Predict Response to Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists in Adolescents and Adults with Mild Persistent Asthma.

Rationale: Whether biomarkers can be used to predict response to inhaled corticosteroids (ICS) or long-acting muscarinic antagonists (LAMA) in mild persistent asthma is unclear. Objectives: In a prespecified exploratory analysis of a randomized clinical trial of 295 participants 12 years of age or older with uncontrolled mild persistent asthma, we sought to identify biomarkers of treatment response after 12 weeks of ICS (mometasone, 200 µg or 220 µg twice/d), LAMA (tiotropium, 5 µg/d), or placebo in adults (⩾18 yr) and adolescents (12-17 yr) separately. Methods: The primary outcome was a composite outcome of asthma control (treatment failure, asthma control days, and forced expiratory volume in 1 second [FEV1]). Analyses examined type 2 inflammatory biomarkers and physiologic biomarkers. We assessed the area under the receiver operating characteristic curve (AUC) for response to ICS and LAMA (each versus placebo). An AUC of 0.5 suggests no discrimination, 0.7-0.8 is considered acceptable, more than 0.8-0.9 is considered excellent, and more than 0.9 is considered outstanding. Results: In 237 adults, sputum and blood eosinophil levels and fractional exhaled nitric oxide (FeNO) each predicted ICS response (AUCs: 0.61 [95% confidence interval (CI), 0.53-0.69], 0.64 [95% CI, 0.56-0.72], and 0.62 [95% CI, 0.54-0.70], respectively; all P < 0.01); the AUC for blood eosinophil levels and FeNO together was 0.66 (95% CI, 0.58-0.74; P < 0.001). In 58 adolescents, the number of positive aeroallergens and total serum immunoglobulin E each predicted ICS response (AUCs: 0.69 [95% CI, 0.52-0.85] and 0.73 [95% CI, 0.58-0.87], respectively; both P < 0.03); the AUC for both together was 0.73 (95% CI, 0.58-0.87; P = 0.003). After ipratropium bromide, FEV1 reversibility predicted LAMA response in adults (AUC: 0.61 [95% CI, 0.53-0.69], P = 0.007) but not in adolescents. Conclusions: The AUCs of the type 2 inflammatory biomarkers and physiological biomarkers we examined may not be high enough to confidently identify individuals with asthma who respond to ICS and LAMA. However, our findings indicate that the biomarkers that predict response to ICS or LAMA may differ in adults versus adolescents with uncontrolled mild persistent asthma. Prospective, biomarker-stratified clinical trials are needed to confirm these findings and to identify first-line controllers tailored for each population.

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.

Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma.

BACKGROUND: Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent. METHODS: We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 µg in children, 100 µg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV1. We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 µg twice daily in children and 500 µg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 µg twice daily in children, 250 µg twice daily in adolescents and adults), and 5 × ICS versus 100 µg fluticasone plus a LABA (salmeterol 50 µg twice daily). We used a genome-wide significance threshold of p<1·6 × 10-4, and tested for replication using independent cohorts of individuals of African descent with asthma. FINDINGS: We included 249 unrelated children and 267 unrelated adolescents and adults in the BARD pharmacogenetic analysis. In children, we identified a significant admixture mapping peak for superior responsiveness to 5 × ICS versus 100 µg fluticasone plus salmeterol on chromosome 12 (odds ratio [ORlocal African] 3·95, 95% CI 2·02-7·72, p=6·1 × 10-5) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, ORallele dose 0·17, 95% CI 0·07-0·42, p=8·4 × 10-5). In adolescents and adults, we identified a peak for superior responsiveness to 5 × ICS versus 2·5 × ICS on chromosome 22 (ORlocal African 3·35, 1·98-5·67, p=6·8 × 10-6) containing a locus adjacent to TPST2 (rs5752429, ORallele dose 0·21, 0·09-0·52, p=5·7 × 10-4). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts. INTERPRETATION: BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of individuals of African descent to detect and replicate genome-wide significant loci. Admixture mapping of the composite BARD trial outcome enabled the identification of novel pharmacogenetic variation accounting for differential therapeutic responses in people of African descent with asthma. FUNDING: National Institutes of Health, National Heart, Lung, and Blood Institute.

Strategies for choosing a biologic for your patient with allergy or asthma.

OBJECTIVE: To summarize the therapeutic effects and safety of biologics either approved or in clinical development for asthma, chronic obstructive pulmonary disease, urticaria, nasal polyps, atopic dermatitis, and eosinophilic esophagitis. This review attempts to provide some guidance when choosing among agents. DATA SOURCES: Recently published articles obtained through PubMed database searches including research articles, review articles, and case reports. STUDY SELECTIONS: PubMed database searches were conducted using the following keywords: biologics, asthma, COPD, urticaria, atopic dermatitis, food allergy, nasal polyps, and eosinophilic esophagitis. RESULTS: The approval of omalizumab by the Food and Drug Administration in 2003 for patients with asthma paved the way for the development of multiple biologics for a variety of respiratory and allergic diseases. Agents approved by the Food and Drug Administration include mepolizumab, reslizumab, benralizumab, and dupilumab, and several more are in the late stages of clinical development. Owing to the overlap in the pathogenesis of respiratory and allergic diseases, many of these biologics target multiple respiratory and allergic diseases simultaneously. CONCLUSION: The numerous biologic options have made the selection of the best biologic for each patient a potential conundrum for clinicians. Adequate point of care biomarkers to facilitate personalized medical therapy are generally lacking. Furthermore, although clinically effective and generally safe, none of the biologics discussed in this review have induced long-standing disease remission. Nevertheless, these agents have given us the opportunity to treat the most severe patients and to better understand the biology of respiratory and allergic diseases. As knowledgeable physicians, we should embrace and be educated on these novel therapies and the pathways they target.