Rhinovirus (RV) infections trigger asthma exacerbations. Genome-wide expression analysis of RV1A-infected primary bronchial epithelial cells from normal and asthmatic donors was performed to determine whether asthma is associated with a unique pattern of RV-induced gene expression. Virus replication rates were similar in cells from normal and asthmatic donors. Overall, RV downregulated 975 and upregulated 69 genes. Comparisons of transcriptional profiles generated from microarrays and confirmed by quantitative reverse transcription PCR and cluster analysis showed some up-and downregulated genes in asthma cells involved in immune responses (IL1B, IL1F9, IL24, IFI44) and airway remodeling (LOXL2, MMP10, FN1). Notably, most of the asthma-related differences in RV-infected cells were also present in the cells before infection. These findings suggest that differences in RV-induced gene expression profiles of cells from normal and mild asthmatic subjects could affect the acute inflammatory response to RV and subsequent airway repair and remodeling.

Airflow obstruction can have a circadian pattern with nocturnal worsening. Airway inflammation is a cardinal feature of asthma, and it has been shown to increase at night in association with the decline in pulmonary function. Although the mechanisms regulating enhanced airway inflammation in asthma at night have yet to be ascertained, we hypothesized that circadian variation in cytokine expression or production is an important factor in the development of nocturnal airflow limitation. To investigate this possibility, spirometry and bronchoscopy were performed; the bronchoalveolar lavage (BAL) fluid obtained at 4:00 A.M. and at 4:00 P.M. were measured for IL-1 beta in asthmatics with (n = 5) and without (n = 9) nocturnal asthma. In addition, the activity of IL-3, IL-5, and GM-CSF was measured using a biologic assay (eosinophil survival-enhancing activity). BAL fluid concentrations of IL-1 beta were significantly greater at 4:00 A.M. than at 4:00 P.M. (1.14 +/- 0.6 versus 0.7 +/- 0.6 pg/ml; p = 0.05) in asthmatics with nocturnal airflow obstruction. Moreover, IL-1 beta levels at 4:00 A.M. tended to be higher in subjects with nocturnal asthma than in those without nighttime airflow reduction (1.14 +/- 0.6 versus 0.3 +/- 0.4 pg/ml; p = 0.1). On the other hand, eosinophil survival-enhancing activity in BAL fluid, which is usually associated with IL-3, IL-5, or GM-CSF, was not detected in relationship to nocturnal asthma. Because IL-1 beta can activate air-space cells, particularly alveolar macrophages, we propose that an increased release of this cytokine is a significant contributor to nocturnal airway inflammation and obstruction in asthma.

Airway obstruction (AO) in exercise-induced asthma (EIA) is considered a postexercise phenomenon. However, many with EIA complain of respiratory distress during exercise. We evaluated AO in six asthmatic subjects during a short (SX = 6 min) and a long (LX = 20 min) exercise session. We measured peak expiratory flow (PEF) rate, forced expiratory volume in one second (FEV1), and forced expiratory flow at 50% of vital capacity (Vmax50) and calculated expiratory and inspiratory pulmonary resistance (RLe and RLi). Rated perceived exertion (RPE) was evaluated as a measure of dyspnea. All three indices of airflow significantly decreased following SX and LX, but RLi and RLe increased. During SX, PEF, FEV1, and Vmax50 did not decrease, but RLi decreased. During LX, PEF, FEV1, and Vmax50 decreased (20.0, 26.0, and 17.7%, respectively), whereas RLi and RLe significantly increased (74.0 and 53.0%). Rated perceived exertion correlated highly with RLi during exercise (r = 0.95). In summary, there was little or no AO during SX but a frank AO during LX in asthmatic subjects. We conclude that AO occurs during LX and that the manifestation of dyspnea is associated with AO during exercise, as well as in recovery.

Disclosure of potential conflict of interest: J. C. Celed on has received research materials from GSK and Merck (inhaled steroids) and Pharmavite (vitamin D and placebo capsules) to provide medications free of cost to participants in NIH-funded studies unrelated to the current work. The rest of the authors declare that they have no relevant conflicts of interest.

BACKGROUND: Relative enlargement of the pulmonary artery (PA) on chest CT imaging is associated with respiratory exacerbations in patients with COPD or cystic fibrosis. We sought to determine whether similar findings were present in patients with asthma and whether these findings were explained by differences in ventricular size. METHODS:We measured the PA and aorta diameters in 233 individuals from the Severe Asthma Research Program III cohort. We also estimated right, left, and total epicardial cardiac ventricular volume indices (eERVVI, eELVVI, and eETVVI, respectively). Associations between the cardiac and PA measures (PA-to-aorta [PA/A] ratio, eERVVI-to-eELVVI [eRV/eLV] ratio, eERVVI, eELVVI, eETVVI) and clinical measures of asthma severity were assessed by Pearson correlation, and associations with asthma severity and exacerbation rate were evaluated by multivariable linear and zero-inflated negative binomial regression.RESULTS: Asthma severity was associated with smaller ventricular volumes. For example, those with severe asthma had 36.1 mL/m 2 smaller eETVVI than healthy control subjects (P ¼ .003) and 14.1 mL/m 2 smaller eETVVI than those with mild/moderate disease (P ¼ .011). Smaller ventricular volumes were also associated with a higher rate of asthma exacerbations, both retrospectively and prospectively. For example, those with an eETVVI less than the median had a 57% higher rate of exacerbations during follow-up than those with eETVVI greater than the median (P ¼ .020). Neither PA/A nor eRV/eLV was associated with asthma severity or exacerbations. CONCLUSIONS:In patients with asthma, smaller cardiac ventricular size may be associated with more severe disease and a higher rate of asthma exacerbations.