Morgan, Wayne J.

Abstract Rationale Deficits in infant lung function—including the ratio of the time to reach peak tidal expiratory flow to the total expiratory time (tptef/te) and maximal expiratory flow at FRC (V̇maxFRC)—have been linked to increased risk for childhood asthma. Objectives To examine the individual and combined effects of tptef/te and V̇maxFRC in infancy on risk for asthma and abnormalities of airway structure into mid-adult life. Methods One hundred eighty participants in the Tucson Children’s Respiratory Study birth cohort had lung function measured by the chest-compression technique in infancy (mean age ± SD: 2.0 ± 1.2 mo). Active asthma was assessed in up to 12 questionnaires between ages 6 and 36 years. Spirometry and chest high-resolution computed tomographic (HRCT) imaging were completed in a subset of participants at age 26. The relations of infant tptef/te and V̇maxFRC to active asthma and airway structural abnormalities into adult life were tested in multivariable mixed models. Measurements and Main Results After adjustment for covariates, a 1-SD decrease in infant tptef/te and V̇maxFRC was associated with a 70% (P = 0.001) and 55% (P = 0.005) increased risk of active asthma, respectively. These effects were partly independent, and two out of three infants who were in the lowest tertile for both tptef/te and V̇maxFRC developed active asthma by mid-adult life. Infant V̇maxFRC predicted reduced airflow and infant tptef/te reduced HRCT airway caliber at age 26. Conclusions These findings underscore the long-lasting effects of the fetal origins of asthma, support independent contributions by infant tptef/te and V̇maxFRC to development of asthma, and link deficits at birth in tptef/te with HRCT-assessed structural airway abnormalities in adult life.

Background: Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems of the body and is characterized by mutation in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Previous work has shown that a single dose of aβ-agonist increases cardiac output (Q) and stroke volume (SV) and decreases systemic vascular resistance (SVR) in healthy subjects. This effect is attenuated in patients with CF; however, the mechanism is unknown. Potential explanations for this decreased cardiovascular response to a β-agonist in CF include inherent cardiovascular deficits secondary to the CFTR mutation, receptor desensitization from prolonged β-agonist use as part of clinical care, or inhibited drug delivery to the bloodstream due to mucus buildup in the lungs. This study sought to determine the effects of endogenous epinephrine (EPI) and norepinephrine (NE) on cardiovascular function in CF and to evaluate the relationship between cardiovascular function and CFTR F508del mutation. Methods: A total of 19 patients with CF and 31 healthy control subjects completed an assessment of Q (C 2 H 2 rebreathing), SV (calculated from Q and heart rate [HR]), Q and SV indexed to body surface area (BSA, QI, and SVI, respectively), SVR (through assessment of Q and mean arterial blood pressure [MAP]), and HR (from 12-lead electrocardiogram [ECG]) at rest along with plasma measures of EPI and NE. We compared subjects by variables of cardiovascular function relative to EPI and NE, and also based on genetic variants of the F508del mutation (homozygous deletion for F508del, heterozygous deletion for F508del, or no deletion of F508del). Results: Cystic fibrosis patients demonstrated significantly lower BSA (CF = 1.71 ± 0.05 m 2 vs healthy = 1.84 ± 0.04 m 2 , P = .03) and SVI (CF = 30.6 ± 2.5 mL/beat/m 2 vs healthy = 39.9 ± 2.5 mL/beat/m 2 , P = .02) when compared with healthy subjects. Cystic fibrosis patients also demonstrated lower Q (CF = 4.58 ± 0.36 L/min vs healthy = 5.71 ± 0.32 L/min, P = .03) and SV (CF = 54 ± 5.5 mL/beat vs healthy = 73.3 ± 4.5 mL/beat, P = .01), and a higher HR (CF = 93.2 ± 3.9 bpm vs healthy = 80.5 ± 2.7 bpm, P < .01) and SVR (CF = 2082 ± 156 dynes*s/cm −5 vs healthy = 1616 ± 74 dynes*s/cm −5 , P = .01) compared with healthy subjects. Furthermore, CF patients demonstrated a lower SV ( P < .01) corrected for NE when compared with healthy subjects. No significant differences were seen in HR or Q relative to NE, or SVR relative to EPI. Differences were seen in SV (F (2,14) = 7.982, P < .01) and SV index (F (2,14) = 2.913, P = .08) when patients with CF were stratified according to F508del mutation (number of deletions). Conclusions: Individuals with CF have lower cardiac and peripheral hemodynamic function parameters at rest. Furthermore, these results suggest that impairment in cardiovascular function is likely the result of F508del CFTR genotype, rather than receptor desensitization or inhibited drug delivery.

Cardiac hemodynamic assessment during cardiopulmonary exercise testing (CPET) is proposed to play an important role in the clinical evaluation of individuals with cystic fibrosis (CF). Cardiac catheterization is not practical for routine clinical CPET. Use of oxygen pulse (O 2 pulse) as a noninvasive estimate of stroke volume (SV) has not been validated in CF. This study tested the hypothesis that peak exercise O 2 pulse is a valid estimate of SV in CF. Measurements of SV via the acetylene rebreathe technique were acquired at baseline and peak exercise in 17 mild-to-moderate severity adult CF and 25 age-matched healthy adults. We calculated [Formula: see text]. Baseline relationships between SV and O 2 pulse were significant in CF ( r = .80) and controls ( r = .40), persisting to peak exercise in CF ( r = .63) and controls ( r = .73). The standard error of estimate for O 2 pulse-predicted SV with respect to measured SV was similar at baseline (14.1 vs 20.1 mL) and peak exercise (18.2 vs 13.9 mL) for CF and controls, respectively. These data suggest that peak exercise O 2 pulse is a valid estimate of SV in CF. The ability to noninvasively estimate SV via O 2 pulse during routine clinical CPET can be used to improve test interpretation and advance our understanding of the impact cardiac dysfunction has on exercise intolerance in CF.

Background: The Vibralung Acoustical Percussor is a new airway clearance therapy (ACT) utilizing intrapulmonary sound waves in addition to positive expiratory pressure (PEP). We evaluated the safety of the Vibralung and collected preliminary data on its ability to mediate sputum expectoration in individuals with cystic fibrosis (CF). Methods: Over two separate studies, 10 and 11 mild to moderate CF patients were recruited for study I and II, respectively. Study I: Vibralung was used for 20 min with either no sound (NS: PEP only) or sound (S: PEP and sound) on randomized visits. Pulmonary function, diffusion capacity of the lungs for carbon monoxide and nitric oxide (DLCO/DLNO), symptoms, and peripheral oxygen saturation (SpO2) were measured at baseline and at 1 and 4 h post treatment. Expectorated sputum was collected over 4 h post treatment. Study II: over 5 days of in-hospital therapy, the Vibralung or vibratory vest therapy (Vest) were used for two therapy sessions per day, with sputum collected for 20 min following each therapy and pulmonary function accessed pre and post each 5-day period (days 1–5 or 7–11) in a randomized crossover design. Results: Vibralung usage resulted in no change from baseline to 4 h post in pulmonary function, SpO2 or symptoms ( p > 0.05). At 4 h post therapy, the DLCO- and DLNO-derived measure of alveolar–capillary unit function (DM/ VC) showed improvement (DM/ VC = 12.5 ± 5.5 versus 7.3 ± 18.8% change, S versus NS) with no difference between S and NS ( p = 0.74). Sputum expectoration was similar between S and NS conditions (wet sputum = 10.5 ± 4.6 versus 9.9 ± 3.2 g, S versus NS, p = 0.25). There were no differences in the improvement in pulmonary function between Vibralung and Vest during either 5-day period during the hospital stay. Conclusions: Vibralung was well tolerated and caused no detrimental changes in pulmonary function metrics. The Vibralung appears to be a safe ACT in individuals with CF.