Faculty Bibliography

RATIONALE/BACKGROUND:People with obesity often have severe, difficult to control asthma. There is a need to develop better treatments in this population. One potential treatment is roflumilast, a phosphodiesterase 4 inhibitor, as it is reported to have efficacy for treatment of asthma and can promote weight loss. OBJECTIVE:to investigate the potential efficacy of roflumilast for the treatment of poorly controlled asthma in people with obesity. METHODS:A randomized, double-masked, placebo-controlled trial of 24 weeks of roflumilast versus placebo for the treatment of poorly controlled asthma in people with obesity (body mass index ≥ 30 kg/m2). The primary outcome was change in asthma control test score (ACT). RESULTS:Twenty-two people were randomized to roflumilast, 16 to placebo. Roflumilast had no effect on change in ACT (increased by 2.6 [IQR 0.5 to 4.4] in those on roflumilast versus 2.0 [IQR 0.7 to 3.3] in those on placebo). Participants assigned to roflumilast had a 3.5 fold (Relative risk [RR] 95% confidence interval [CI] 1.3 to 9.4) increased risk of an episode of poor asthma control and an 8.1-fold (RR 95% CI 1.01 to 65.0) increased risk of an urgent care visit for asthma. Ten participants (56%) assigned to roflumilast required a course of oral corticosteroids for asthma exacerbations and none in the placebo group. Participants losing ≥ 5% of their body weight experienced a clinically and statistically significant improvement in asthma control (ACT increased by 4.4 [IQR 2.5, 6.3] versus 1.5 [IQR 0.0, 3.0] in those who lost < 5%). CONCLUSIONS:Roflumilast had no effect on asthma control. Of concern, roflumilast was associated with an increased risk of exacerbation in in obese individuals with poorly controlled asthma. These results highlight the importance of studying interventions in different sub-populations of people with asthma, particularly people with obesity and asthma who may respond differently to medications than lean people with asthma. Weight loss of at least 5% was associated with improved asthma control indicating that interventions- other than roflumilast -promoting weight loss may have efficacy for treatment of poorly controlled asthma in people with obesity.

BACKGROUND:Many persons with a history of smoking tobacco have clinically significant respiratory symptoms despite an absence of airflow obstruction as assessed by spirometry. They are often treated with medications for chronic obstructive pulmonary disease (COPD), but supporting evidence for this treatment is lacking. METHODS:] to forced vital capacity [FVC] ≥0.70 and FVC ≥70% of the predicted value after bronchodilator use) to receive either indacaterol (27.5 μg) plus glycopyrrolate (15.6 μg) or placebo twice daily for 12 weeks. The primary outcome was at least a 4-point decrease (i.e., improvement) in the St. George's Respiratory Questionnaire (SGRQ) score (scores range from 0 to 100, with higher scores indicating worse health status) after 12 weeks without treatment failure (defined as an increase in lower respiratory symptoms treated with a long-acting inhaled bronchodilator, glucocorticoid, or antibiotic agent). RESULTS:was 2.48 percentage points (95% CI, 1.49 to 3.47) in the treatment group and -0.09 percentage points (95% CI, -1.06 to 0.89) in the placebo group, and the mean change in the inspiratory capacity was 0.12 liters (95% CI, 0.07 to 0.18) in the treatment group and 0.02 liters (95% CI, -0.03 to 0.08) in the placebo group. Four serious adverse events occurred in the treatment group, and 11 occurred in the placebo group; none were deemed potentially related to the treatment or placebo. CONCLUSIONS:Inhaled dual bronchodilator therapy did not decrease respiratory symptoms in symptomatic, tobacco-exposed persons with preserved lung function as assessed by spirometry. (Funded by the National Heart, Lung, and Blood Institute and others; RETHINC ClinicalTrials.gov number, NCT02867761.).

BACKGROUND:Asthma is one of the most common chronic health conditions, and to leverage the wealth of data in the electronic medical record (EMR), it is important to be able to accurately identify asthma diagnosis. OBJECTIVE:We aimed to determine the rule-based algorithm with the most balanced performance for sensitivity and positive predictive value of asthma diagnosis. METHODS:We performed a diagnostic accuracy study of multiple rule-based algorithms intended to identify asthma diagnosis in the EMR. Algorithm performance was validated by manual chart review of 795 charts of patients seen in a multisite, tertiary-level, pulmonary specialty clinic using explicit diagnostic criteria to distinguish asthma cases from controls. RESULTS:An asthma diagnosis anywhere in the medical record had a 97% sensitivity and a 77% specificity for asthma (F-score 80) when tested on a validation set of asthma cases and nonasthma respiratory disease from a pulmonary specialty clinic. The most balanced performance was seen with asthma diagnosis restricted to an encounter, hospital problem, or problem list diagnosis with a sensitivity of 94% and specificity of 85% (F-score 84). High sensitivity was achieved with the modified Health Plan Employer Data and Information Set criteria and high specificity was achieved with the NUgene algorithm, an algorithm developed for identifying asthma cases by EMR for genome-wide association studies. CONCLUSION/CONCLUSIONS:Asthma diagnosis can be accurately identified for research purposes by restricting to encounter, hospital problem, or problem list diagnosis in a pulmonary specialty clinic. Additional rules lead to steep drop-offs in algorithm sensitivity in our population.

BACKGROUND:Corticosteroids are a potential therapeutic agent for patients with COVID-19 pneumonia. The RECOVERY (Randomised Trials in COVID-19 Therapy) trial provided data on the mortality benefits of corticosteroids. The study aimed to determine the association between corticosteroid use on mortality and infection rates and to define subgroups who may benefit from corticosteroids in a real-world setting. METHODS:Clinical data were extracted that included demographic, laboratory data and details of the therapy, including the administration of corticosteroids, azithromycin, hydroxychloroquine, tocilizumab and anticoagulation. The primary outcome was in-hospital mortality. Secondary outcomes included intensive care unit (ICU) admission and invasive mechanical ventilation. Outcomes were compared in patients who did and did not receive corticosteroids using the multivariate Cox regression model. RESULTS:4313 patients were hospitalised with COVID-19 during the study period, of whom 1270 died (29.4%). When administered within the first 7 days after admission, corticosteroids were associated with reduced mortality (OR 0.73, 95% CI 0.55 to 0.97, p=0.03) and decreased transfers to the ICU (OR 0.72, 95% CI 0.47 to 1.11, p=0.02). This mortality benefit was particularly impressive in younger patients (<65 years of age), females and those with elevated inflammatory markers, defined as C reactive protein ≥150 mg/L (p≤0.05), interleukin-6 ≥20 pg/mL (p≤0.05) or D-dimer ≥2.0 µg/L (p≤0.05). Therapy was safe with similar rates of bacteraemia and fungaemia in corticosteroid-treated and non-corticosteroid-treated patients. CONCLUSION:In patients hospitalised with COVID-19 pneumonia, corticosteroid use within the first 7 days of admission decreased mortality and ICU admissions with no associated increase in bacteraemia or fungaemia.

OBJECTIVE:To evaluate diaphragmatic excursion as a quantitative metric for change in lung volume between inspiratory and expiratory chest computed tomography (CT) images. METHODS:A 12-month retrospective review identified 226 chest CT exams with inspiratory and expiratory phase imaging, 63 in individuals referred with diagnosis of asthma by ICD9/10 code. Exams acquired in the supine position at 1.25 mm slice thickness in each phase were included (n = 30, mean age = 62, M = 15, F = 15). Diaphragmatic excursion was calculated as the difference between axial slices through the lungs on inspiration and expiration, using the lung apex as the cranial bound, and the hemidiaphragm caudally. Inspiratory and expiratory lung and tracheal volumes were calculated through volumetric segmentation. Tracheal morphology was assessed at 1 cm above the level of the aortic arch, and 1 cm above the carina. RESULTS:Inspiratory and expiratory lung volumes were higher in men (mean I = 5 + 1.6 L, E = 3.1 + 1.2 L) than women (mean I = 3.6 + 0.8 L, E = 2.4 + 0.7 L), p = .005 and p = .047, respectively. Average inspiratory and expiratory tracheal volumes were higher in men (I = 61 + 17 mL, E = 43 + 14) than women (I = 44 + 14, E = 30 + 8), p = .006 and p = .005. Average change in lung and tracheal volume between inspiratory and expiratory scans did not significantly differ between men and women. Average diaphragmatic excursion was 2.5 cm between inspiratory and expiratory scans (2.7 cm in men, 2.3 cm in women; p = .5). There was a strong positive correlation between diaphragmatic excursion and change in lung (r = .84) and tracheal volume (r = .79). A moderate correlation was also found between change in tracheal volume and change in lung volume (r = 0.67). Change in tracheal morphology between inspiratory and expiratory imaging was associated with change in tracheal volume at both 1 cm above the aortic arch (p = .04) and 1 cm above the carina (p = .008); there was no association with diaphragmatic excursion or lung volume. CONCLUSIONS:Diaphragmatic excursion is a quantitative measure of expiratory effort as validated by both lung and tracheal volumes in asthma patients, and may be more accurate than qualitative assessment based on tracheal morphology.

BACKGROUND:Biomarkers that can predict loss of asthma control among patients being considered for step-down therapy in well-controlled disease are lacking. OBJECTIVE:To evaluate whether baseline biomarkers of type 2 airway inflammation and/or serial measurement of fractional exhaled nitric oxide (Feno) predict loss of asthma control as therapy is stepped down. METHODS:In subanalyses of a multicenter randomized, double-blind, parallel 3-arm trial comparing strategies for step-down therapy in well-controlled asthma (Long-Acting Beta-Agonist Step-Down Study), we assessed whether baseline atopy as determined by serum aeroallergen allergy screening test (Phadiatop), baseline serum eosinophil peroxidase, or baseline or serial Feno measurements during follow-up predicted the time to loss of asthma control among participants. Loss of asthma control was defined in the study protocol. We analyzed these associations in adjusted models including all participants, after testing for interactions with assignment to each of the 3 treatment groups (continuation of stable dose of combination inhaled corticosteroid-long-acting beta-agonist, step-down of inhaled corticosteroid, or discontinuation of long-acting bronchodilator). RESULTS:Four hundred forty-seven of the 553 Long-Acting Beta-Agonist Step-Down Study participants who were randomized to 1 of 3 treatment arms and had at least 1 biomarker measurement were included in this analysis. At baseline, higher levels of Feno were significantly associated with greater levels of multiallergen IgE levels (P < .001), but not with serum eosinophil peroxidase (P = .742). Among all participants as a group, elevations in baseline biomarkers were not predictive of a higher risk of treatment failure. In addition, Feno levels measured serially at 6-week intervals demonstrated that compared with participants with low levels (<25 parts per billion), those with intermediate (25-50 parts per billion) and high (>50 parts per billion) levels did not have significantly increased likelihood of subsequent treatment failure (hazard ratios, 1.03 [95% CI, 0.59-1.78] and 1.29 [95% CI, 0.65-2.54], respectively). There were no significant interactions of treatment group and baseline biomarkers. CONCLUSIONS:In patients with well-controlled asthma, neither baseline levels of type 2 airway inflammatory biomarkers nor serial measures of Feno are strong predictors of treatment failure.

BACKGROUND:Because respiratory tract infections (RTIs) precede most exacerbations, a better understanding of the risk factors of RTIs and RTI-associated exacerbations in patients with asthma is a pressing public health need. Obesity in patients with asthma is associated with worse asthma control and higher asthma-associated health care utilization, but its effect on RTI risk is unknown. OBJECTIVE:We aimed to study the association of body mass index (BMI) classification on the risk of self-reported RTIs and related asthma morbidity among adults and children with asthma. METHODS:This post hoc analysis of 5 large asthma trials involving 747 children and 1287 adults compared BMI classification, defined as lean, overweight, and obese based on age-appropriate BMI and BMI-percentile conventions. The primary outcome was rate of visits with RTIs. Secondary asthma outcomes included upper respiratory infection (URI) severity, systemic steroid use, and health care contact. RESULTS:Children had 1.4 times the rate of RTI compared with adults (95% confidence interval 1.27-1.56). In all participants, BMI classification did not affect the rate of visits with RTI. In children, BMI classification did not affect URI severity, all-cause asthma events, or RTI-associated asthma events. However, in adults, higher BMI classification was associated with an increase in moderate/severe URI (P = .02). Adults with higher BMI classification also had increased rates of all-cause and RTI-associated asthma exacerbations requiring systemic steroids and health care contact. CONCLUSIONS:BMI classification was not associated with an increased risk of RTIs in children or adults. In adults only, obesity was associated with increased URI severity and all-cause and RTI-associated asthma morbidity.

RATIONALE/BACKGROUND:Although national and international guidelines recommend reduction of asthma controller therapy or 'step-down" therapy in patients with well controlled asthma, it is expected that some individuals may experience worsening of asthma symptoms or asthma exacerbations during step-down. Characteristics associated with subsequent exacerbations during step-down therapy have not been well defined. The effect of environmental tobacco smoke (ETS) exposure on risk of treatment failure during asthma step down therapy has not been reported. OBJECTIVES/OBJECTIVE:To identify baseline characteristics associated with treatment failure and asthma exacerbation during maintenance and guideline-based step-down therapy. METHODS:The present analysis uses data collected from a completed randomized controlled trial of optimal step-down therapy in patients with well controlled asthma taking moderate dose combination inhaled corticosteroids/long acting beta agonists. Participants were 12 years or older with physician diagnosed asthma and were enrolled between December 2011 and May 2014. RESULTS:An Emergency Room visit in the previous year was predictive of a subsequent treatment failure (HR 1.53 (1.06, 2.21 CI). For every 10% increase in baseline forced expiratory volume in one second percent predicted, the hazard for treatment failure was reduced by 14% (95% CI: 0.74-0.99). There was no difference in risk of treatment failure between adults and children, nor did duration of asthma increase risk of treatment failure. Age of asthma onset was not associated with increased risk of treatment failure. Unexpected emergency room visit in the previous year was the only risk factor significantly associated with subsequent asthma exacerbations requiring systemic corticosteroids. Time to treatment failure or exacerbation did not differ in participants with and without self-report of ETS exposure. CONCLUSIONS:The present findings can help clinicians identify patients more likely to develop treatment failures and exacerbations and who may therefore require closer monitoring during asthma step-down treatment. Individuals with reduced pulmonary function, a history of exacerbations, and early onset disease, even if otherwise well controlled, may require closer observation to prevent treatment failures and asthma exacerbations. Clinical trial registered with ClinicalTrials.gov (NCT01437995).

BACKGROUND: Stepping down therapy when asthma is well controlled on combination inhaled corticosteroids (ICSs) and long-acting beta-agonists (LABAs) is recommended, but it is not known whether lowering the ICS dose or stopping LABA is superior. OBJECTIVE: To evaluate whether step-down therapy with LABA is superior to one without; and, secondarily, to evaluate whether reducing the ICS dose while maintaining LABA is noninferior to remaining on stable-ICS/LABA. METHODS: The study was a randomized, double-masked 3-arm parallel group trial in participants aged 12 years or older. Following an 8-week run-in, 459 participants were randomly assigned to continue medium-dose ICS/LABA, reduced-dose ICS/LABA, or ICS alone (LABA-step-off) and followed for 48 weeks. The primary outcome was time to treatment failure, a composite of health care utilization, systemic corticosteroid use, increase in rescue therapy, decline in lung function, or participant or physician decision. RESULTS: Time to treatment failure did not differ significantly between reduced- ICS/LABA and LABA-step-off (hazard ratio, 1.07; 95.3% CI, 0.69-1.65, P = .76). Nor was there a difference between stable-ICS/LABA and reduced-ICS/LABA (hazard ratio, 1.11; 95% CI, 0.70-1.76; P = .67), but the 10% noninferiority margin was exceeded. Lung function declines and hospitalization rates were significantly greater in the LABA-step-off group. CONCLUSIONS: The 2 step-down regimens did not differ in terms of treatment failure, although stopping LABA was associated with a decline in lung function and more hospitalizations. There was no evidence to support the noninferiority of reduced-ICS/LABA as compared with stable-ICS/LABA.

Patient-generated health data (PGHD), collected from mobile apps and devices, represents an opportunity for remote patient monitoring and timely interventions to prevent acute exacerbations of chronic illness-if data are seen and shared by care teams. This case report describes the technical aspects of integrating data from a popular smartphone platform to a commonly used EHR vendor and explores the challenges and potential of this approach for disease management. Consented subjects using the Asthma Health app (built on Apple's ResearchKit platform) were able to share data on inhaler usage and peak expiratory flow rate (PEFR) with a local pulmonologist who ordered this data on Epic's EHR. For users who had installed and activated Epic's patient portal (MyChart) on their iPhone and enabled sharing of health data between apps via HealthKit, the pulmonologist could review PGHD and, if necessary, make recommendations. Four patients agreed to share data with their pulmonologist, though only two patients submitted more than one data point across the 4.5-month trial period. One of these patients submitted 101 PEFR readings across 65 days; another submitted 24 PEFR and inhaler usage readings across 66 days. PEFR for both patients fell within predefined physiologic parameters, except once where a low threshold notification was sent to the pulmonologist, who responded with a telephone discussion and new e-prescription to address symptoms. This research describes the technical considerations and implementation challenges of using commonly available frameworks for sharing PGHD, for the purpose of remote monitoring to support timely care interventions.