Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma.

BACKGROUND: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients. METHODS: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry. RESULTS: When quintupling the dose of fluticasone (to 250 µg twice a day) was compared with adding salmeterol (50 µg twice a day) and doubling the fluticasone (to 100 µg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age. CONCLUSIONS: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).

Exercise-induced laryngeal obstruction (EILO) in athletes: a narrative review by a subgroup of the IOC Consensus on 'acute respiratory illness in the athlete'.

Exercise-induced laryngeal obstruction (EILO) is caused by paradoxical inspiratory adduction of laryngeal structures during exercise. EILO is an important cause of upper airway dysfunction in young individuals and athletes, can impair exercise performance and mimic lower airway dysfunction, such as asthma and/or exercise-induced bronchoconstriction. Over the past two decades, there has been considerable progress in the recognition and assessment of EILO in sports medicine. EILO is a highly prevalent cause of unexplained dyspnoea and wheeze in athletes. The preferred diagnostic approach is continuous visualisation of the larynx (via laryngoscopy) during high-intensity exercise. Recent data suggest that EILO consists of different subtypes, possibly caused via different mechanisms. Several therapeutic interventions for EILO are now in widespread use, but to date, no randomised clinical trials have been performed to assess their efficacy or inform robust management strategies. The aim of this review is to provide a state-of-the-art overview of EILO and guidance for clinicians evaluating and treating suspected cases of EILO in athletes. Specifically, this review examines the pathophysiology of EILO, outlines a diagnostic approach and presents current therapeutic algorithms. The key unmet needs and future priorities for research in this area are also covered.

Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations.

BACKGROUND: Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited. METHODS: We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 µg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 µg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. RESULTS: The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06). CONCLUSIONS: In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).

Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma.

BACKGROUND: Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking. METHODS: In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial. RESULTS: Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events. CONCLUSIONS: Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319.).

Individualized therapy for persistent asthma in young children.

BACKGROUND: Phenotypic presentations in young children with asthma are varied and might contribute to differential responses to asthma controller medications. METHODS: The Individualized Therapy for Asthma in Toddlers study was a multicenter, randomized, double-blind, double-dummy clinical trial in children aged 12 to 59 months (n = 300) with asthma necessitating treatment with daily controller (Step 2) therapy. Participants completed a 2- to 8-week run-in period followed by 3 crossover periods with daily inhaled corticosteroids (ICSs), daily leukotriene receptor antagonists, and as-needed ICS treatment coadministered with albuterol. The primary outcome was differential response to asthma medication based on a composite measure of asthma control. The primary analysis involved 2 stages: determination of differential response and assessment of whether 3 prespecified features (aeroallergen sensitization, previous exacerbations, and sex) predicted a differential response. RESULTS: Seventy-four percent (170/230) of children with analyzable data had a differential response to the 3 treatment strategies. Within differential responders, the probability of best response was highest for a daily ICS and was predicted by aeroallergen sensitization but not exacerbation history or sex. The probability of best response to daily ICS was further increased in children with both aeroallergen sensitization and blood eosinophil counts of 300/µL or greater. In these children daily ICS use was associated with more asthma control days and fewer exacerbations compared with the other treatments. CONCLUSIONS: In young children with asthma necessitating Step 2 treatment, phenotyping with aeroallergen sensitization and blood eosinophil counts is useful for guiding treatment selection and identifies children with a high exacerbation probability for whom treatment with a daily ICS is beneficial despite possible risks of growth suppression.

Continuous laryngoscopy quantitates laryngeal behaviour in exercise and recovery.

Exercise-induced laryngeal obstruction (E-ILO) causes exertional dyspnoea. There is no standardised methodology which characterises laryngeal obstruction in relation to exercise or links laryngeal obstruction and dyspnoea severity. Continuous laryngoscopy during exercise (CLE) may improve diagnostic sensitivity by enabling laryngeal visualisation at peak work capacity in patients with rapidly resolving obstruction. The time course of laryngeal obstruction across exercise and recovery has not been quantitated until this report.Adolescents and young adults referred for CLE were laryngoscopically monitored across rest, maximal cycle ergometry exercise, and recovery. Three reviewers, blinded to time sequencing, rated inspiratory glottic and supraglottic obstruction during 10 windows of 15-s corresponding to rest, 25%, 50%, 75%, 90% and 100% of individual symptom-limited peak work capacity (expressed in Watts), and four consecutive recovery windows.85 patients were screened and 71 included. Over 96% of time windows were interpretable. Laryngeal obstruction severity reached observed maximal levels at peak work capacity, and rapidly resolved. A spectrum of observed maximal obstruction was measured.CLE provides interpretable data demonstrating laryngeal obstruction in patients with suspected E-ILO that is more severe at peak work capacity than during rest, submaximal exercise, or recovery. Observed maximal obstruction was infrequently severe and rapidly resolved.

A simple method to clamp end-tidal carbon dioxide during rest and exercise.

Carbon dioxide regulates ventilation and cerebral blood flow during exercise. There are significant limitations in breathing systems designed to control end-tidal gas concentrations when used during high-intensity exercise. We designed a simple, inexpensive breathing system which controls end-tidal carbon dioxide (PET CO2) during exercise from rest to peak work capacity (W(max)). The system is operated by an investigator who, in response to breath-by-breath PET CO2, titrates flow of a 10 % CO(2), 21 % O(2) mixture into an open-ended 5-L inspiratory reservoir. To demonstrate system efficacy, nine fit male subjects performed two maximal, incremental exercise tests (25 W min(-1) ramp) on a cycle ergometer: a poikilocapnic control trial in which PET CO2 varied with work intensity, and an experimental trial, in which we planned to clamp PET CO2 at 50 mmHg. With our breathing system, we maintained PET CO2 at 51 ± 2 mmHg throughout exercise (rest, 50 ± 2; W(max), 52 ± 5 mmHg; mean ± SD) despite large changes in ventilation (range 27-65 at rest, 134-185 L min(-1) BTPS at W (max)) and carbon dioxide production (range 0.3-0.7 at rest, 4.5-5.5 L min(-1) at W (max)). This simple, inexpensive system achieves PET CO2 control at rest and throughout exercise.

Asthma and Comorbid Conditions-Pulmonary Comorbidity.

Pulmonary comorbidities can increase disease severity and health care costs associated with asthma management. Vocal cord dysfunction/inducible laryngeal obstruction is a common comorbidity that results from intermittent laryngeal obstruction. Patients describe distinct episodes of dyspnea that do not respond to bronchodilators. Inspiratory stridor is common. The gold standard diagnostic testing strategy is continuous laryngoscopy performed during exercise or irritant challenges. Dysfunctional breathing (DB) is an overarching term that describes conditions with a chronic change in the pattern of breathing that results in pulmonary and extrapulmonary symptoms. The prevalence of DB in asthma is up to 30%, and breathing retraining can improve symptoms and quality of life in people with DB and asthma. Asthma-chronic obstructive pulmonary disease overlap (ACO) refers to both asthmatics who develop fixed airflow obstruction after a history of exposure to smoke or biomass and patients with chronic obstructive pulmonary disease who have "asthmatic features" such as a large bronchodilator response, elevated levels of serum IgE, or peripheral eosinophil counts ≥300 per µL. Triple inhaler therapy with inhaled corticosteroid/long-acting beta-agonist/long-acting muscarinic should be considered in people with ACO and severe symptoms or frequent exacerbations. The clinical expression of bronchiectasis involves persistent mucus hypersecretion, recurrent exacerbations of infective bronchitis, incompletely reversible airflow obstruction, and lung fibrosis and can occur in up to 30% of adults with longstanding asthma. The treatable traits strategy is a useful model of care to manage the complexity and heterogeneity of asthma with pulmonary comorbidity.

Resumption of Sport at the United States Olympic and Paralympic Training Facilities During the COVID-19 Pandemic.

In this brief report, we describe the safety of reopening US Olympic and Paralympic Training facilities (USOPTFs) during the coronavirus disease 2019 (COVID-19) pandemic from July 2020 through October 2020. We evaluated the prevalence of COVID-19 infection at the time of reentry and cardiopulmonary sequelae of COVID-19 in elite athletes. All athletes returning to a USOPTF were required to go through a reentry protocol consisting of an electronic health history, a 6-day quarantine including twice-daily symptom surveys, COVID-19 polymerase chain reaction and antibody testing, physical examination, 12-lead electrocardiogram, high-sensitivity cardiac troponin I, and pulmonary function testing. Athletes with current or prior COVID-19 infection also underwent an echocardiogram, cardiology consultation, and additional testing as indicated. All athletes followed rigorous infection prevention measures and minimized contact with the outside community following reentry. At the time of this report, 301 athletes completed the reentry protocol among which 14 (4.7%) tested positive for active (positive polymerase chain reaction test, n = 3) or prior (positive antibody test, n = 11) COVID-19 infection. During the study period, this cohort accrued 14,916 days living and training at USOPTFs. Only one (0.3%) athlete was subsequently diagnosed with a new COVID-19 infection. No cardiopulmonary pathology attributable to COVID-19 was detected. Our findings suggest that residential elite athlete training facilities can successfully resume activity during the COVID-19 pandemic when strict reentry and infection prevention measures are followed. Dissemination of our reentry quarantine and screening protocols with COVID-19 mitigation measures may assist the global sports and medical community develop best practices for reopening of similar training centers.

Exercise-Induced Laryngeal Obstruction: When Pediatric Exertional Dyspnea Does not Respond to Bronchodilators.

Exertional dyspnea is a common complaint in general pediatric practice. While a high proportion of the general pediatric population has asthma, other diagnoses, including exercise-induced laryngeal obstruction should be considered, especially when asthma therapy is not sufficient to control symptoms. This review describes some of the key clinical features of exercised-induced laryngeal obstruction as well as preferred diagnostic and therapeutic approaches. Importantly, current diagnostic technology has considerably improved in the last decade at specialty centers. At the same time, infrastructure for clinical trials is emerging and there is not strong evidence to support specific therapies at the current time.

Exercise-Induced Laryngeal Obstruction and Performance Psychology: Using the Mind as a Diagnostic and Therapeutic Target.

Exercise-induced laryngeal obstruction causes severe shortness of breath during exercise. Episodes are associated with severe distress. These patients and those with inducible laryngeal obstruction triggered by other factors have been noted to demonstrate mental health disorders, personality features that may be associated with symptoms, and dysfunctional stress responses. This literature review calls attention to the observation that patients with isolated exercise-induced laryngeal obstruction are generally mentally healthy. We review available metrics to assess traits and stress responses in performance psychology. We also discuss a therapeutic performance psychology framework.

The Future of Exertional Respiratory Problems: What Do We Know About the Total Airway Approach and What Do We Need to Know?

Exercise is increasingly viewed as a preventative and therapeutic modality for medical and behavioral health disorders. Therefore, it is imperative that the medical and scientific communities minimize barriers that discourage exercise. This issue of Immunology and Allergy Clinics of North America details a "total airway approach" to the evaluation of exertional respiratory problems. Reviews guide clinicians through evaluation and therapy. Moving forward, there is much room for growth with respect to research in each of these areas as well as for common inflammatory pathways and neurophysiologic coupling across all airway segments.

The Fortuitous Discovery of the Olin EILOBI Breathing Techniques: A Case Study.

Exercise-induced laryngeal obstruction (EILO) is the term for the condition previously named vocal cord dysfunction and paradoxical vocal fold motion. It is defined by glottic or supraglottic obstruction during periods of intense exercise. Not all patients respond to conventional therapy with speech-language pathology, behavioral health interventions, and treatment of contributing conditions. In this edition of Journal of Voice, the authors describe a novel series of respiratory retraining techniques, now called Olin EILOBI (EILO biphasic inspiratory) breathing techniques, specifically designed for athletes with EILO. This case presentation describes the discovery of one of these techniques during a session of therapeutic laryngoscopy during exercise. The patient was an adolescent with EILO who demonstrated a positive response to therapy with a variant of these techniques over a few days, having previously struggled with symptoms despite multiple sessions of conventional respiratory retraining over the course of months.