Gaps in Care Among Uncontrolled Severe Asthma Patients in the United States.

BACKGROUND: Understanding the implementation of key guideline recommendations is critical for managing severe asthma (SA) in the treatment of uncontrolled disease. OBJECTIVE: To assess specialist visits and medication escalation in US patients with SA after events indicating uncontrolled disease (EUD) and associations with health outcomes and social disparity indicators. METHODS: Patients with SA appearing in administrative claims data spanning 2015 to 2020 were indexed hierarchically on asthma-related EUD, including hospitalizations, emergency department visits with systemic corticosteroid treatment, or outpatient visits with systemic corticosteroid treatment. Patients with SA without EUD served as controls. Eligibility included age 12 or greater, 12 months enrollment before and after index, no biologic use, and no other major respiratory disease during the pre-period. Escalation of care in the form of specialist visits and medication escalation, health care resource use, costs, and disease exacerbations were assessed during follow-up. RESULTS: We identified 180,736 patients with SA (90,368 uncontrolled and 90,368 controls). Between 35% and 51% of patients with SA with an EUD had no specialist visit or medication escalation. Follow-up exacerbations ranged from 51% to 4% across EUD cohorts, compared with 13% in controls. Among uncontrolled patients with SA who were Black or Hispanic/Latino, 41% and 38%, respectively, had no specialist visit or medication escalation after EUD, compared with 33% of non-Hispanic White patients. CONCLUSIONS: A substantial proportion of uncontrolled patients with SA had no evidence of specialist visits or medication escalation after uncontrolled disease, and there was a clear relationship between uncontrolled disease and subsequent health care resource use and exacerbations. Findings highlight the need for improved guideline-based care delivery to patients with SA, particularly for those facing social disparities.

Tezepelumab reduces exacerbations across all seasons in patients with severe, uncontrolled asthma (NAVIGATOR).

BACKGROUND: Asthma exacerbation frequencies vary throughout the year owing to seasonal triggers. Tezepelumab is a human monoclonal antibody that targets thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab significantly reduced the annualized asthma exacerbation rate (AAER) vs placebo in patients with severe, uncontrolled asthma. OBJECTIVE: To evaluate the effect of tezepelumab on asthma exacerbations across all seasons in NAVIGATOR patients (post hoc). METHODS: NAVIGATOR was a multicenter, randomized, double-blind, placebo-controlled study. Patients (12-80 years old) were randomized 1:1 to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. AAER over 52 weeks was assessed by season. Data from patients in the Southern Hemisphere were transformed to align with Northern Hemisphere seasons. RESULTS: Tezepelumab reduced the AAER vs placebo by 63% (95% confidence interval [CI], 52-72) in winter, 46% (95% CI, 26-61) in spring, 62% (95% CI, 48-73) in summer, and 54% (95% CI, 41-64) in fall. In matched climates, during the spring allergy season (March 1 to June 15) and ragweed allergy season (September), tezepelumab reduced the AAER vs placebo in patients with seasonal allergy by 59% (95% CI, 29-77) and 70% (95% CI, 33-87), respectively. In patients with perennial allergy and in those with seasonal allergy, tezepelumab reduced the AAER vs placebo across all seasons. CONCLUSION: Tezepelumab reduced exacerbations across all seasons vs placebo in patients with severe, uncontrolled asthma, including patients with seasonal and perennial allergies. These data further support the efficacy of tezepelumab in a broad population of patients with severe, uncontrolled asthma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03347279 (https://clinicaltrials.gov/ct2/show/NCT03347279).

Effect of Biologic Therapies on Airway Hyperresponsiveness and Allergic Response: A Systematic Literature Review.

Background: Airway hyperresponsiveness (AHR) is a key feature of asthma. Biologic therapies used to treat asthma target specific components of the inflammatory pathway, and their effects on AHR can provide valuable information about the underlying disease pathophysiology. This review summarizes the available evidence regarding the effects of biologics on allergen-specific and non-allergen-specific airway responses in patients with asthma. Methods: We conducted a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, including risk-of-bias assessment. PubMed and Ovid were searched for studies published between January 1997 and December 2021. Eligible studies were randomized, placebo-controlled trials that assessed the effects of biologics on AHR, early allergic response (EAR) and/or late allergic response (LAR) in patients with asthma. Results: Thirty studies were identified for inclusion. Bronchoprovocation testing was allergen-specific in 18 studies and non-allergen-specific in 12 studies. Omalizumab reduced AHR to methacholine, acetylcholine or adenosine monophosphate (3/9 studies), and reduced EAR (4/5 studies) and LAR (2/3 studies). Mepolizumab had no effect on AHR (3/3 studies), EAR or LAR (1/1 study). Tezepelumab reduced AHR to methacholine or mannitol (3/3 studies), and reduced EAR and LAR (1/1 study). Pitrakinra reduced LAR, with no effect on AHR (1/1 study). Etanercept reduced AHR to methacholine (1/2 studies). No effects were observed for lebrikizumab, tocilizumab, efalizumab, IMA-638 and anti-OX40 ligand on AHR, EAR or LAR; benralizumab on LAR; tralokinumab on AHR; and Ro-24-7472 on AHR or LAR (all 1/1 study each). No dupilumab or reslizumab studies were identified. Conclusion: Omalizumab and tezepelumab reduced EAR and LAR to allergens. Tezepelumab consistently reduced AHR to methacholine or mannitol. These findings provide insights into AHR mechanisms and the precise effects of asthma biologics. Furthermore, findings suggest that tezepelumab broadly targets allergen-specific and non-allergic forms of AHR, and the underlying cells and mediators involved in asthma.

Wheeze is an unreliable endpoint for bronchial methacholine challenges in preschool children.

BACKGROUND: Onset of wheeze is the endpoint often used in the determination of a positive bronchial challenge test (BCT) in young children who cannot perform spirometry. We sought to assess several clinical endpoints at the time of a positive BCT in young children with recurrent wheeze compared to findings in school-aged children with asthma. METHODS: Positive BCT was defined in: (1) preschool children (n = 22) as either persistent cough, wheeze, fall in oxygen saturation (SpO2 ) of ≥5%, or ≥50% increase in respiratory rate (RR) from baseline; and (2) school-aged children (n = 22) as the concentration of methacholine (MCh) required to elicit a 20% decline in FEV1 (PC20 ). RESULTS: All preschool children (mean age 3.4 years) had a positive BCT (median provocative MCh concentration 1.25 mg/ml [IQR, 0.62, 1.25]). Twenty (91%) school-aged children (mean age 11.3 years) had a positive BCT (median PC20 1.25 mg/ml [IQR, 0.55, 2.5]). At the time of the positive BCT, the mean fall in SpO2 (6.9% vs. 3.8%; p = .001) and the mean % increase in RR (61% vs. 22%; p < .001) were greater among preschool-aged than among school-aged children. A minority of children developed wheeze at time of positive BCT (23% preschool- vs. 15% school-aged children; p = .5). CONCLUSIONS: The use of wheeze as an endpoint for BCT in preschool children is unreliable, as it rarely occurs. The use of clinical endpoints, such as ≥25% increase in RR or fall in SpO2 of ≥3%, captured all of our positive BCT in preschool children, while minimizing undue respiratory distress.

Disease burden and treatment adherence among children and adolescent patients with asthma.

OBJECTIVE: To assess asthma burden and medication adherence in a US de-identified patient level claims database. METHODS: This retrospective observational study used the IQVIA PHARMETRICS PLUS database to identify patients aged 5-17 years, diagnosed with asthma between 01/01/2012-09/30/2017 (asthma cohort), and those initiating treatment with twice-daily inhaled corticosteroids (ICS) or twice-daily ICS/long-acting beta2 agonists (LABA) (treatment cohorts; index date = first dispensing). Patient characteristics, asthma medication, and healthcare resource utilization were assessed over a 12-month baseline period. Treatment cohort endpoints were assessed in a 12-month follow-up period, including: adherence using proportion of days covered (PDC); persistence (no gap >45 days between dispensings). RESULTS: The asthma cohort included 186,868 patients (112,689 children, mean age 7.9 years; 74,179 adolescents, mean age 14.3 years). During baseline, 34.5% used ICS or ICS/LABA, 24% used oral corticosteroids, 11.1% had ≥1 asthma-related emergency department visit, 2.2% had ≥1 asthma-related hospitalization. Among treatment cohorts, 47,276 and 10,247 patients initiated twice-daily ICS and ICS/LABA, respectively (mean ages: 9.9; 12.5 years). Mean PDC adherence to twice-daily ICS and ICS/LABA was 30% and 34% at 6 months (PDC ≥0.8: 4.3%; 6.1%); 21% and 24% at 12 months (PDC ≥0.8: 1.8%; 2.8%). Persistence with twice-daily ICS and ICS/LABA was 10.1% and 14.2% at 6 months; 5.6% and 8.0% at 12 months. CONCLUSIONS: A large disease burden and unmet need exist among US children/adolescent asthma patients, evidenced by low use of, and poor adherence to, ICS-containing medication, the notable proportion of oral corticosteroid users, and higher-than-expected asthma-related emergency department and hospitalization rates.

Fractional exhaled nitric oxide response to oral corticosteroids in children with mild-to-moderate asthma: Influence of race.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is a noninvasive biomarker of type 2 asthma that can predict response to inhaled corticosteroid therapy. Little is known regarding the magnitude of FeNO reduction after an oral corticosteroid (OCS) course, and less is known whether there are differential responses based on race in children with mild-to-moderate asthma. OBJECTIVE: To assess the effect of a short course of OCS on FeNO in children with asthma and to determine whether the effect is influenced by race. METHODS: Children presenting with an acute asthma exacerbation, who had a FeNO measurement within the past 6 months when clinically stable, were enrolled. Spirometry and FeNO were obtained at the time of exacerbation and after a short course of prednisone. RESULTS: A total of 92 children were identified (aged 11 ± 3.3 years; white, n = 46 [50%], Hispanics, n = 30 [33%], African Americans [AAs], n = 16 [7%]). At baseline, AAs were more atopic and had higher mean FeNO values than both white (48.9 vs 25.6 ppb; P < .05) and Hispanic children (22.5 ppb; P < .05), despite being prescribed similar inhaled corticosteroid doses. During the exacerbation, AAs had the highest FeNO values, whereas there was no difference in lung function between AAs and non-AAs. After prednisone therapy, there was a 56.6% reduction in FeNO, and although AAs maintained the highest FeNO levels, the relative reduction was similar between AAs and non-AAs (53.9% vs 57.8%, respectively). CONCLUSION: FeNO levels reduced by more than 50% after an OCS course. African American children had a greater degree of type 2-driven airway inflammation at baseline, during an exacerbation and after a short course of OCS, compared with non-AAs, although the relative reduction in FeNO was similar between the groups.

Lung mechanical properties distinguish children with asthma with normal and diminished lung function.

BACKGROUND: Children with asthma, even those with severe persistent disease, can have forced expiratory volume in 1 second (FEV1 ) values ≥100% of predicted, while others have diminished FEV1 . OBJECTIVE: We sought to characterize the lung mechanical properties underlying these two asthma phenotypes and the mechanisms explaining the paradox of severe asthmatic children, whom when clinically stable can have an FEV1 >100% of predicted, but during an acute bronchospastic episode can experience a life-threatening asthma event. METHODS: Lung mechanics were evaluated in three groups of children: asthmatics with FEV1 ≥100% (HFEV1 ; n = 13), asthmatics with FEV1 ≤80% (LFEV1 ; n = 14) and non-asthmatic controls (n = 10). A linear mixed model was used to examine the relationship between volume and static transpulmonary pressures obtained at total lung capacity (TLC); actual TLC %of predicted and flow; and static transpulmonary pressure and flow. RESULTS: HFEV1 asthmatics had larger airways (FEV1 z-scores 1.12 vs -2.37; P < .05), greater lung volumes (mean % of predicted TLC 134.8% vs 109.6%; P < .05) and lower airway resistance (mean %of predicted Raw 101.9% vs 199.9%; P < .05) compared to the LFEV1 group. Moreover, HFEV1 asthmatics had significantly reduced elastic recoil pressure (pressure-volume curve shifted upward and to the left) and higher lung compliance (0.21 vs 00.9 L/cm H2 O; P < .05) compared to the LFEV1 group. The pressure-flow curves revealed the LFEV1 group to have significantly increased resistance to flow in the upstream segment of the airways at all lung volumes studied compared to HFEV1 . CONCLUSION AND CLINICAL RELEVANCE: HFEV1 asthmatic children display distinct lung mechanical proprieties compared to their LFEV1 asthmatic peers. With loss of elastic recoil pressure, the HFEV1 group could generate normal FEV1 due to proportionally enlarged airways and reduced airway resistance, while airflow limitation in the LFEV1 is due to increased airway resistance. Loss of elastic recoil and interdependence during acute bronchoconstriction episodes may predispose the HFEV1 group to catastrophic reductions in airflow.

Anaphylaxis in adolescents.

PURPOSE OF REVIEW: The frequency of hospitalization for anaphylaxis has increased over the last 20 years across Europe, Australia, and North America, particularly, for food and medication triggers. Adolescents show the highest risk for morbidity and fatality from food-induced anaphylaxis, yet there is little high-quality evidence addressing the reasons for this disproportionate vulnerability. RECENT FINDINGS: Recent data seem to suggest a possible increasing burden of food-induced anaphylaxis among adolescents. Trends in anaphylaxis mortality are stable in North America and the United Kingdom, but not in Australia where the incidence of fatal anaphylaxis has recently doubled. The age distribution of fatal anaphylaxis varies according to the nature of the culprit trigger, with data suggesting an age-related predisposition to fatal food anaphylaxis in adolescents and young adults. Adolescence represents a critical phase of transition when rapid and substantial physical, emotional, and social changes occur. Therefore, adolescents show challenges in self-management that are different from other age groups, contributing to a higher risk of poor anaphylaxis outcomes. SUMMARY: The purpose of this review is to summarize recent data on epidemiology and elicitors of anaphylaxis in adolescents and to address currently known barriers and potential facilitators to self-management of anaphylaxis in this vulnerable age group.

Proportion of Severe Asthma Patients Eligible for Mepolizumab Therapy by Age and Age of Onset of Asthma.

BACKGROUND: Mepolizumab is an anti-IL-5 antibody approved for the treatment of severe eosinophilic asthma. However, the prevalence of patients with severe asthma eligible for mepolizumab remains unknown, especially among children. OBJECTIVE: To determine, in a population of patients with severe asthma from a tertiary referral center, the proportion of patients with an eosinophilic phenotype who would be eligible for mepolizumab, when stratified for the age of onset of asthma, and the prevalence of phenotypic features that favor mepolizumab therapy. METHODS: An extensive database of 245 adults and children referred for severe asthma was used. The prevalence of severe asthma was estimated by using the European Respiratory Society/American Thoracic Society criteria. Patients with an eosinophilic uncontrolled phenotype qualified for mepolizumab. RESULTS: In our cohort, 216 (88%) had severe asthma. Based on blood eosinophils of either greater than or equal to 150 cells/µL or greater than or equal to 300 cells/µL, 61%/41% had an eosinophilic phenotype, while 49%/34% were eligible for mepolizumab therapy. A greater percentage of adults (60%/47% of adults with asthma onset in adulthood [AoA] and 48%/26% adults with childhood-onset asthma [<18 years, CoA]) were eligible compared with children (33%/24%), for eosinophil counts of ≥150 and ≥300 cells/µL, respectively; P < .05. Compared with adults, children had a similar number of exacerbations while having better lung function (P < .05). Among adults, those with AoA were older, were more likely to have nasal polyps (28% vs 5%; P < .05), and had higher blood eosinophil counts (272 vs 150 cells/µL; P < .05) compared with those with CoA, with no difference in lung function noted between the 2 groups. Subjects showing greater than or equal to 500 eosinophils/µL, a strong indicator for mepolizumab therapy, had more nasal polyps, higher inhaled steroid dose, lower lung function, and AoA predominance than did those with less than 500 eosinophils/µL (P < .05). CONCLUSIONS: A smaller percentage of children with severe asthma were eligible for mepolizumab compared with their adult peers. Severe AoA has distinct phenotypic features that favor treatment with mepolizumab, including greater eosinophilia and nasal polyposis, in contrast to CoA, which appears to have fewer features of type 2 mucosal inflammation.

The Effect of Viral Infection on Exhaled Nitric Oxide in Children with Acute Asthma Exacerbations.

BACKGROUND: Fraction of exhaled nitric oxide (Feno) level is used as an aid in the diagnosis and management of chronic asthma. Its role in acute asthma remains to be studied. OBJECTIVE: To determine whether Feno levels are elevated in children with asthma exacerbations compared with baseline, and whether there is a difference in Feno levels based on PCR positive (+) (respiratory virus isolated by PCR analysis) versus PCR negative (-) (respiratory virus not isolated by PCR analysis) status. METHODS: Children with a previous Feno level measurement while stable and who presented to an urgent care facility with an asthma exacerbation were enrolled. Feno levels, spirometry, and nasal swabs for viral PCR were obtained at the time of the exacerbation and following a course of prednisone. Data were available on 66 children. Linear mixed models were used to regress the outcomes of interest (FEV1, FEV1/forced vital capacity, forced expiratory flow at 25% to 75% of forced vital capacity, and natural log Feno) on detected virus (yes/no), visit (baseline, exacerbation, follow-up), and the interaction between the detected virus and visit. RESULTS: Compared with baseline, higher Feno values and lower lung function were found at the time of an exacerbation. A respiratory virus was detected in 59% of the exacerbations. The interaction between PCR (+) and PCR (-) groups and visit on log Feno was marginally significant (P = .07). There was no difference in log Feno between the PCR (+) and PCR (-) groups at baseline, while higher log Feno was found in the PCR (-) group at the time of exacerbation and following prednisone (P = .05 and .001, respectively). CONCLUSIONS: Higher Feno concentration in PCR (-) exacerbations suggests an eosinophilic predominance in nonviral compared with viral exacerbations.

The chitinase-like protein YKL-40 is not a useful biomarker for severe persistent asthma in children.

BACKGROUND: The chitinase-like protein YKL-40 is thought to play a role in inflammation and tissue remodeling. In adults with severe asthma, YKL-40 is expressed in the airway and YKL-40 levels are elevated in the serum. OBJECTIVE: To compare YKL-40 levels in children with severe persistent asthma with those in adults with severe persistent asthma and to determine whether YKL-40 levels correlate with increasing asthma severity in childhood asthma. METHODS: In this prospective, cross-sectional study, 23 adults and 19 children with severe persistent asthma, 23 children with moderate persistent asthma, and 19 children with mild persistent asthma were enrolled. The following data were collected on each patient: spirometry, exhaled nitric oxide, percutaneous skin testing results to aeroallergens, peripheral eosinophils, serum IgE levels, and serum YKL-40 levels. RESULTS: Compared with adults, children with severe persistent asthma had significantly lower YKL-40 levels, higher values for forced vital capacity and forced expiration volume in 1 second, higher serum IgE levels, and higher exhaled nitric oxide levels. YKL-40 levels did not correlate with increasing asthma severity in the pediatric cohort. CONCLUSION: Severe persistent asthma in childhood is not associated with elevated YKL-40 levels, unlike in adults with severe persistent asthma. YKL-40 is not a useful biomarker for asthma severity in childhood asthma.

The changing face of severe childhood asthma: a comparison of two cohorts of children evaluated at National Jewish Health over the past 20 years.

Novel asthma pharmacotherapy has changed the management of severe childhood asthma. This study determined whether the introduction and use of second-generation inhaled glucocorticoids (GCs), long-acting beta-agonists (LABAs), and combination inhaled GC/LABA (iGC/LABA) products and leukotriene receptor antagonists (LTRAs) have impacted children with severe asthma. A retrospective review of children (aged 6-18 years) referred to National Jewish Health for severe asthma between 2003 and 2007 (current cohort) was performed (n = 65); the results were compared with a published cohort from 1993 to 1997 (historic cohort; n = 164). When comparing the current cohort to the historic cohort, the percentage requiring chronic oral GC therapy (28% versus 51%; p = 0.001), average dose (3.7 ± 2.4 mg/dose versus 16.7 ± 1.4 mg/dose; p < 0.0001), and duration of oral GC use (17.8 ± 8.6 months versus 33.7 ± 3.5 months; p = 0.09) were less. Ninety-seven percent of the current cohort was on a second-generation iGC either alone or in combination with an LABA, 76% were on an LTRA, and 66% were on combination iGC/LABA product, while none of the historic cohort received these medications. In addition, the current cohort had a higher forced expiratory volume in 1 second (84 ± 2.5% versus 76 ± 2% of predicted; p = 0.008), required less albuterol (33 ± 9 inhalations/week versus 71 ± 7 inhalations/week; p = 0.0007), had fewer intubations in the past (13% versus 21%; p = 0.13) and had fewer GC-induced adverse effects compared with the historic cohort. The current cohort required less chronic oral GCs, had better asthma control, and had fewer GC-induced adverse effects compared with the historic cohort studied 10 years ago. This is most likely because of the use of more effective medications for childhood asthma.

Inflammometry in pediatric asthma: a review of fractional exhaled nitric oxide in clinical practice.

The burden of pediatric asthma remains high with one-third of patients being under- or overtreated because of the unique challenges in the assessment and management of childhood asthma. Until recently, there has been no point of care tool for assessing the underlying airway inflammation (i.e., inflammometry) in asthma. Recently, fractional exhaled nitric oxide (FeNO) has emerged as an important biomarker for the assessment and management of asthma. Recent evidence indicates that FeNO identifies T-helper cell type 2 (Th2)­mediated airway inflammation with a high positive and negative predictive value for identifying corticosteroid responsive airway inflammation. This article examines the evidence for FeNO as a predictor of Th2-mediated inhaled corticosteroid (ICS) responsive airway inflammation and reviews recent studies evaluating the role of FeNO, whether helpful or not, in the assessment and management of pediatric asthma. FeNO is a reliable adjunct to traditional tests in the assessment of suspected asthma. Importantly, it is useful for identifying and for excluding ICS-responsive airway inflammation. Although individual study results have varied, collectively, asthma managed using FeNO is associated with lower exacerbation rates compared with clinical algorithms alone. Finally, FeNO may be useful in identifying patients at risk for future impairment or loss of asthma control during reduction/cessation of ICS treatment. FeNO testing has an important role in the assessment of pediatric patients with suspected asthma and in the management of pediatric patients with established asthma. Additional studies will continue to define the exact role of FeNO testing in pediatric asthma.