Addressing Quality of Life, Clinical Outcomes, and Mechanisms in Uncontrolled Asthma Following the DASH Dietary Pattern

The 15-item Juniper Mini Asthma-Specific Quality of Life Questionnaire (AQLQ) has been shown to have excellent reliability and responsiveness to change in asthma control. It consists of 5 items on symptoms, 4 items on activity limitations, 3 items on emotional function, and 3 items concerning environmental stimuli. Each item is rated on a scale from 1=maximum impairment to 7=no impairment over the last 2 weeks. The overall AQLQ score is an average of the item scores equally weighted. The primary outcome is the percentage of participants achieving the minimal clinically important difference (MCID) of at least a 0.5-point increase in AQLQ scores from baseline to 12 months. The percentages of responders at 3 and 6 months are secondary outcomes.

The overall AQLQ score is the mean of all the items on the Mini AQLQ. Items are equally weighted. A domain score is calculated as the mean of all the items within each of the 4 domains: symptoms, activity limitations, emotional function, and environmental stimuli. Changes in overall and domain scores from baseline to each follow-up time point are secondary outcomes.

The overall ACQ score is an average of the item scores equally weighted and ranges from 0=well controlled to 6=extremely poorly controlled. Change in ACQ scores from baseline to each follow-up time point are secondary outcomes.

The Juniper Asthma Control Questionnaire (ACQ) is a validated composite measure of asthma control recommended for research purposes. It consists of 7 items on daytime and nocturnal symptoms, activity limitations, rescue medication use (excluding prophylactic use for exercise-induced bronchospasm), and FEV1% of predicted norm. Each item is rated on a 7-point scale from 0 (least severe) to 6 (most severe). ACQ has been validated for self-administration (except for the FEV1 item, which is obtained by spirometry) and has high internal reliability (intra-class correlation coefficient=0.90). The overall ACQ score is an average of the item scores equally weighted. The proportion of responders is the percentage of participants achieving the MCID of at least a 0.5-point increase in ACQ scores. Percentages at each follow-up time point are secondary outcomes.

Lung function will be assessed by forced spirometry as per the American Thoracic Society (ATS) standards, both before and after bronchodilator. Post-bronchodilator spirometry will be performed at 15 minutes and 2 hours after bronchodilator administration. Participants will be instructed to refrain from taking inhaled medications for breathing during the 6-24 hours prior to their visit depending on the medication, unless they are having trouble with their breathing. Participants will blow forcefully for at least 6 seconds for 3-8 times until 3 acceptable results show repeatability. Spirometry outcomes for Aim 1 include PRE-bronchodilator measurements of forced expiratory volume in 1 second (FEV1)

Lung function will be assessed by forced spirometry as per the American Thoracic Society (ATS) standards, both before and after bronchodilator. Post-bronchodilator spirometry will be performed at 15 minutes and 2 hours after bronchodilator administration. Participants will be instructed to refrain from taking inhaled medications for breathing during the 6-24 hours prior to their visit depending on the medication, unless they are having trouble with their breathing. Participants will blow forcefully for at least 6 seconds for 3-8 times until 3 acceptable results show repeatability. Spirometry outcomes for Aim 1 include PRE-bronchodilator measurements of forced vial capacity (FVC).

Lung function will be assessed by forced spirometry as per the American Thoracic Society (ATS) standards, both before and after bronchodilator. Post-bronchodilator spirometry will be performed at 15 minutes and 2 hours after bronchodilator administration. Participants will be instructed to refrain from taking inhaled medications for breathing during the 6-24 hours prior to their visit depending on the medication, unless they are having trouble with their breathing. Participants will blow forcefully for at least 6 seconds for 3-8 times until 3 acceptable results show repeatability. Spirometry outcomes for Aim 1 include PRE-bronchodilator measurements of FEV1/FVC.

The Adult Asthma Adherence Questionnaire is a validated and practical questionnaire that reflects nonadherence risk and identifies potential adherence barriers.

Episodes of poorly controlled asthma will be assessed as per a modified ALA-ACRC definition if any of the following apply: (1) addition of oral corticosteroid (prednisone or prednisolone) to treat asthma symptoms or (2) unscheduled contact with a health care provider (ED visit, physician office, hospital) for asthma symptoms.

The 12-item Short-Form Health Survey (SF-12) is a 12-item version of the SF-36 that measures overall health-related quality of life. Physical and mental health composite scores are computed using the scores of 12 questions and range from 0 to 100, with 0 indicating the lowest level of health and 100 indicating the highest level of health. Test-retest correlation is 0.89 for the physical health subscale and 0.76 for the mental health subscale.

The American Heart Association recommendations for BP measurement will be followed. Participants will be told not to engage in vigorous exercise, ingest food or caffeine, or smoke within a half hour of BP measurements. If a half hour has not elapsed, the BP measurements must be delayed until a half hour has passed. BP will be measured in the seated position after at least a 5-minute rest in a quiet room where no other activity is taking place and where temperature fluctuations are minimal. At baseline, both arms will be measured once and 2 more times on the arm with higher systolic reading using standard equipment at participating clinics. This same arm will be measured 3 times at each follow-up assessment. Wait 1 minute between each measurement.

The Depression, Anxiety and Stress Scale-21 items (DASS21) is a set of 3 self-report scales designed to measure the emotional states of depression, anxiety, and stress. Each of the 3 scales contains 7 items. Each item is scaled from 0 (did not apply to me at all) to 3 (applied to me very much or most of the time). The depression scale assesses dysphoria, hopelessness, devaluation of life, self-deprecation, lack of interest/involvement, anhedonia and inertia. The anxiety scale assesses autonomic arousal, skeletal muscle effects, situational anxiety, and subjective experience of anxious affect. The stress scale assesses difficulty relaxing, nervous arousal, and being easily upset/agitated, irritable/over-reactive and impatient. Each scale is scored as the sum of the item scores.

Sleep quality will be assessed on the 8-item PROMIS sleep disturbance (SD) scale. It measures symptoms of insomnia. Each item is scaled from 1 (not at all) to 5 (very much).

The 8-item PROMIS sleep-related impairment (SRI) scale measures symptoms of daytime sleepiness. Each item is scaled from 1 (not at all) to 5 (very much). Correlation between the SD short form and the Pittsburgh Sleep Quality Index (PSQI, hypothesized to measure similar attributes) is 0.83 and correlation between the SRI short form and the Epworth Sleepiness Scale (ESS, hypothesized to measure a related but slightly different construct, the propensity to doze during activities) is 0.46, similar to the correlations between the SD full banks and PSQI (0.85) and between SRI full banks and the ESS (0.45).

Bronchodilator responsiveness will be measured based on percent change in FEV1 from prebronchodilator to 15 minutes and 2 hours postbronchodilator. Forced spirometry will be performed as per the American Thoracic Society (ATS) standards both before and after bronchodilator. Post-bronchodilator spirometry will be performed at 15 minutes and 2 hours after bronchodilator administration. Participants will be instructed to refrain from taking inhaled medications for breathing during the 6-24 hours prior to their visit depending on the medication, unless they are having trouble with their breathing. Participants will blow forcefully for at least 6 seconds for 3-8 times until 3 acceptable results show repeatability.

Circulating short chain fatty acids (SCFA) will be measured with approximately 4 cc serum, aliquoted into 200 µl cryovials and kept frozen at -80°C. These samples will be shipped overnight on dry ice to the University of Michigan metabolomic core for measurement of propionate, butyrate and acetate, as circulating measures of products of gut microbial fermentation.

To measure changes in adaptive and innate immune function pertinent to obese asthma, we will use the Tru-Culture® (myriad RBM tubes, 1 cc blood for each tube): one containing TruCulture® media + 0.1 μg/mL lipopolysaccharide, one containing TruCulture® media + 0.4 μg/mL anti-CD3, and one containing TruCulture® media alone. Samples will be incubated upright in a dry heat block at 37°C for 24 hours. Supernatant and cells will be isolated and frozen at -80°C, then shipped overnight on dry ice to the University of Vermont for cytokine and gene expression studies, respectively. For effects on T cell function pertinent to adaptive immunity we will measure cytokines pertinent to TH1 (interferon gamma), TH2 (IL-5), TH17 (IL-17A) and Tregs (IL-10) in media from cells incubated with anti-CD3 versus media alone. For effects on mononuclear cell responses pertinent to innate immunity, we will measure IL-1β, IL-6, IL-8 and TNFα in response to lipopolysaccharide versus media.

Dietary intake will be determined from 3 unannounced 24-hour dietary recalls (2 non-consecutive weekdays and 1 weekend day with a 2-week period) by interview using the US Department of Agriculture multiple pass method. The Nutrition Data System for Research (NDSR) (Minneapolis, MN) will be used for data collection and nutrient analysis. The DASH score using the National Health and Nutrition Survey (NHANES) method sums an individual's adherence points for 9 nutrients (total fat, saturated fat, protein, cholesterol, fiber, magnesium, calcium, sodium and potassium) based on the DASH diet plan. NDSR outputs will provide the values of these 9 nutrients.

The DII will be applied to dietary intake data collected using the 3 unannounced 24-hour dietary recalls. The DII is a scale developed using data from epidemiologic, animal and in-vitro studies and is a useful marker of diet quality as it quantifies the overall inflammatory potential of diet, which is calculated based on the known inflammatory effects of up to 45 component nutrients and foods.

4mL blood will be collected in an EDTA tube, centrifuged at 4oC, for 10 minutes at 3000g. Plasma will be stored at -80oC until analysis. High-performance liquid chromatography (HPLC) will be used to measure plasma carotenoid concentrations (lycopene, lutein, β-cryptoxanthin, α-carotene and β-carotene), as an objective indicator of fruit and vegetable intake. Carotenoids will be extracted from plasma samples (with canthaxanthin added as an internal standard) with a series of ethyl acetate and hexane washes. Chromatography will be performed on a Hypersil ODS column with a flow rate of 0.3 mL/min, using mobile phase of acetonitrile:dichloromethane:methanol (0.05% ammonium acetate (85:10:5, vol:vol)). Carotenoids will be detected at 470 nm using a photodiode array detector.

Self-efficacy for dietary change will be measured using the Eating Habits Confidence Survey. The Eating Habits Confidence Survey is a reliable and valid measure of dietary self-efficacy. Cronbach's alpha coefficients ranged from 0.85 to 0.93 for the 5 factors (resisting relapse, reducing calories, reducing salt, reducing fat, and behavioral skills). Test-retest reliabilities ranged from 0.43 to 0.64.

Social support for dietary change will be measured using the Social Support and Eating Habits Survey. Cronbach's alpha coefficients ranged from 0.70 to 0.83 for the friend and family social support subscales.

The 13-item Patient Activation Measure (PAM) assesses patient's self-reported knowledge, skill, and confidence for self-managing his or her health condition. It demonstrated acceptable internal consistency (Conbrach's alpha = 0.81). The 13-item PAM score accounts for 92% of the variation in the activity measured by the original 22-item PAM. The score is also significantly correlated with general preventive behaviors and disease-specific self-management behaviors.