Evaluation of airway hyperresponsiveness in chronic rhinosinusitis: values of sinus computed tomography.

BACKGROUND: Chronic rhinosinusitis (CRS) is tightly linked to airway hyperresponsiveness (AHR) and asthma. However, the practical surrogate parameters for evaluating AHR in patients with CRS remain unclear. OBJECTIVE: To evaluate the diagnostic values of sinus computed tomography for AHR in patients with CRS. METHODS: We performed a prospective, single-blinded study of 125 consecutive patients with CRS. These patients were subdivided into AHR and non-AHR (NAHR) groups based on histamine provocation test results. The following parameters were compared between 2 groups of CRS patients: Lund-Mackay scores, olfactory cleft (OC) scores, and serum eosinophil counts. RESULTS: Fifty-seven patients (45.4%) presented with AHR. The OC scores, the ratio of OC scores to total scores, and the eosinophil counts in the AHR group were significantly higher than those in the NAHR group (P < .001). Multivariate logistic regression revealed that OC scores and eosinophil counts were independent risk factors for asymptomatic AHR (OC scores P < .001 and eosinophil counts P = .010). The OC score had a higher predictive value for AHR (area under curve, 0.800) than eosinophil counts (area under the curve, 0.637). When the OC score was 3 or higher, the sensitivity was 75.0%, specificity was 77.9%, and positive predictive value was 68.8%. CONCLUSION: The findings validate a prospective assessment of sinus computed tomography as a screening tool for AHR in patients with CRS.

Ultra-high-resolution computed tomography shows changes in the lungs related with airway hyperresponsiveness in a murine asthma model.

In vivo presentation of airway hyper-responsiveness (AHR) at the different time points of the allergic reaction is not clearly understood. The purpose of this study was to investigate how AHR manifests in the airway and the lung parenchyma in vivo following exposure to different stimuli and in the early and late phases of asthma after allergen exposure. Ovalbumin (OVA)-induced allergic asthma model was established using 6-week female BALB/c mice. Enhanced pause was measured with a non-invasive method to assess AHR. The dynamic changes of the airway and lung parenchyma were evaluated with ultra-high-resolution computed tomography (128 multi-detector, 1024 × 1024 matrix) for 10 h. While the methacholine challenge showed no grossly visible changes in the proximal airway and lung parenchyma despite provoking AHR, the OVA challenge induced significant immediate changes manifesting as peribronchial ground glass opacities, consolidations, air-trapping, and paradoxical proximal airway dilatations. After resolution of immediate response, multiple episodes of AHRs occurred with paradoxical proximal airway dilatation and peripheral air-trapping in late phase over a prolonged time period in vivo. Understanding of airflow limitation based on the structural changes of asthmatic airway would be helpful to make an appropriate drug delivery strategy for the treatment of asthma.

Heterogeneity of bronchoconstriction does not distinguish mild asthmatic subjects from healthy controls when supine.

Heterogeneity is a fundamental property of airway constriction; however, whether it is a distinguishing feature of mild asthma is not clear. We used computerized tomography and the forced oscillation technique to compare lung heterogeneity between 18 mildly asthmatic and 19 healthy control subjects at similar levels of bronchoconstriction while subjects were supine. We also assessed the effects of deep inhalation and albuterol on supine lung mechanics. Measures of heterogeneity included lung attenuation, from which we derived a novel index of air-space size, and the frequency dependence of respiratory system resistance between 1 and 20 Hz. We found that asthmatic subjects had airways hyperresponsiveness to methacholine in the sitting position compared with controls, but both groups had similar falls in forced expiratory volume in 1 s after inhaling methacholine while supine. There were no baseline differences between the groups in the frequency dependence of resistance, or lung attenuation, before methacholine, and both groups responded similarly with an increase in air-space size (+9.2% vs. +3.4%), air-space size heterogeneity (+9.8% vs. +4.2%), and frequency dependence of resistance (+76% vs. +86%) after methacholine. Deep inhalation did not affect resistance in either group, but albuterol significantly reduced resistance in both groups. We conclude that both computerized tomography and the forced oscillation technique demonstrate increased heterogeneity of airway narrowing during induced bronchoconstriction while supine and that this heterogeneity is equivalent between subjects with mild asthma and healthy controls when bronchoconstricted to the same degree. Thus heterogeneity appears to be a fundamental feature of bronchoconstriction and is not unique to mild asthma.

Influence of lung parenchymal destruction on the different indexes of the methacholine dose-response curve in COPD patients.

STUDY OBJECTIVES: The interpretation of nonspecific bronchial provocation dose-response curves in COPD is still a matter of debate. Bronchial hyperresponsiveness (BHR) in patients with COPD could be influenced by the destruction of the parenchyma and the augmented mechanical behavior of the lung. Therefore, we studied the interrelationships between indexes of BHR, on the one hand, and markers of lung parenchymal destruction, on the other. PATIENTS AND METHODS: COPD patients were selected by clinical symptoms, evidence of chronic, nonreversible airways obstruction, and BHR, which was defined as a provocative dose of a substance (histamine) causing a 20% fall in FEV(1) (PC(20)) of

Airway edema potentiates airway reactivity.

Thickening of the airway wall has been hypothesized to be one of the mechanisms contributing to airway hyperresponsiveness in asthma. If such thickening of the wall is internal to the airway smooth muscle or otherwise causes a decrease in baseline airway caliber, it should also cause exaggerated airway responsiveness. In the present study, we used high-resolution computed tomography to directly measure the changes in the caliber and wall thickness of conducting airways after aerosol histamine challenge before and after normal saline volume loading. On separate days, five anesthetized dogs received either a baseline aerosol challenge of 3 mg/ml of histamine for five breaths or the same aerosol challenge immediately after a 100 ml/kg bolus of normal saline infused over a 10-min period. Baseline aerosol histamine challenge decreased airway area to 71 +/- 2% (SE) of the control value (P < 0.05). Intravenous administration of 100 ml/kg of normal saline increased wall area by decreasing airway luminal area to 78 +/- 3% of the control value (P < 0.01), with no change in outer airway area. Aerosol histamine challenge superimposed on this engorgement with normal saline challenge further decreased airway luminal area to 54 +/- 3% of the control value (P < 0.01). Quantitative modeling indicated that the edema in the airway wall was mostly outside the smooth muscle and that the smooth muscle shortening with histamine was similar with and without edema. We conclude that a moderate degree of acute airway wall thickening can lead to a potentiated constrictor response to histamine.

Bronchial reactivity in hyperresponsive patients and healthy individuals: demonstration with high resolution computed tomography.

OBJECTIVE: High resolution computed tomography (HRCT) was used to assess the extent of bronchial reactivity after inhalative bronchoprovocation and dilation in hyperresponsive patients and healthy subjects. PATIENTS AND METHODS: Patients with mild intermittent asthma, 15 with a >20% decrease in FEV1 and a >10 mmHg (PC20+) in PaO2, 12 with a <20% decrease in FEV1 and a >10 mmHg (PC20-) in PaO2 after provocation, and eight healthy humans were included in the study. Changes in cross-sectional area in a total of 1256 bronchi and in bronchial wall area (792 bronchi) were evaluated after histamine-triggered bronchoprovocation and salbutamol-induced bronchodilation at high lung volumes (FVC 80%). Data were compared with the results of pulmonary function tests (FEV1, PaO2, PaCO2). RESULTS: In all groups, a significant decrease in bronchial cross-sectional area (P<0.001) and a significant increase in bronchial wall area (P<0.001) were observed subsequent to bronchoprovocation. After bronchodilation, the increase in cross-sectional area (P<0.001) and the further increase in airway wall area (P<0.01) were significant in all groups. In PC20+ and PC20- asthmatics, significant differences (P<0.05) in PaO2, >10 mmHg between baseline and provocation were observed. In healthy persons, the PaO2 decrease was <10 mmHg (P>0.05). After histamine provocation, the decrease in FEV1 was measured in the PC20+ group, whereas a <20% FEV1 decrease was found in the PC20- and the control groups, respectively. No significant correlations were observed between radiological data and the results of pulmonary function tests. CONCLUSIONS: HRCT demonstrated bronchial reactivity in hyperresponsive patients and, unexpectedly, in healthy subjects. The applied pulmonary function tests failed to characterize bronchial reactions in the healthy subjects. Based on these results, HRCT is a useful tool by which to achieve a comprehensive understanding of the pathophysiological processes in asthmatic patients.

High-resolution computed tomography in patients with bronchial asthma: correlation with clinical features, pulmonary functions and bronchial hyperresponsiveness.

The high-resolution computed tomography (HRCT) studies for bronchial asthma (BA) have revealed abnormal radiologic findings such as bronchial wall thickening, bronchiectasis, emphysema and mosaic pattern of lung attenuation. But the clinical significance of these findings are not yet clarified. In this study, we quantified the bronchial wall thickness and evaluated HRCT features in 57 BA subjects (338 bronchi) who had precipitating factors of irreversible airway remodeling, 19 COPD subjects (70 bronchi) and 10 healthy subjects (23 bronchi). Then we correlated HRCT findings with the clinical features, pulmonary functions and methacholine PC20 (PC20M) and studied their clinical significance. The bronchial wall for BA was about 1.48 mm thicker than that for COPD and about 2.34 mm thicker than for healthy controls (p < 0.0001, respectively). But the individual mean ratio of bronchial wall thickness to luminal diameter (BWT/LD) in asthmatics did not correlate with the clinical features, lung functions and PC20M. Abnormal HRCT findings, such as bronchiectasis (17.5%), emphysema (5.3%) and mosaic pattern of lung attenuation (17.5%) were found in BA. These findings were more common in BA with moderate to severe airflow limitation (FEV1 < 80%, p < 0.05) and patients with these changes had a more prolonged history of asthma (p < 0.05). PC20M was higher in BA with these abnormal changes (p < 0.001) but these patients' FEV1 (p < 0.05), FEF25-75 (p < 0.05) and specific airway conductance (p < 0.05) were lower than those having BA without such findings. In this study we showed that the bronchial wall was more significantly thickened in BA but that it did not correlate well with the clinical features, lung functions and PC20M. Additionally, patients having BA with abnormal airway and air space HRCT findings had a prolonged history of asthmatic symptoms, loss of lung functions and decreased bronchial hyperresponsiveness. These results suggested the possibility that HRCT can be used for the differentiation of BA from COPD or healthy controls. Furthermore, patients having BA with abnormal HRCT changes demonstrate poor lung function and less hyperreactive bronchi than those without. We concluded that HRCT may be useful for the prognosis and treatment of bronchial asthma cases who have the precipitating factors of irreversible airway remodelling.

High-resolution computed tomography--physiologic correlation.

High-resolution computed tomography (HRCT) as a tool for investigation of bronchovascular and pulmonary responses to various physiologic and pharmacologic stimuli is a new field of application. The potential of this method has only recently been investigated in animal experiments. To date, research has focused on the determination of airway responses in the context of agonist challenge such as aerosolized or i.v. histamine, isotonic saline, halothane anesthesia, and hypoxia. Likewise, physiologic HRCT has been used in the elucidation of the pulmonary circulatory response to acute hypervolemia and hypoxia. Early results indicate that significant observations can be derived from HRCT as it is the only existing method that not only detects physiologic responses but, unlike existing methods, can characterize their site and locoregional differences. In this article, the rationale for and present status of physiologic HRCT is presented.

Airway closure on imaging relates to airway hyperresponsiveness and peripheral airway disease in asthma.

The regional pattern and extent of airway closure measured by three-dimensional ventilation imaging may relate to airway hyperresponsiveness (AHR) and peripheral airways disease in asthmatic subjects. We hypothesized that asthmatic airways are predisposed to closure during bronchoconstriction in the presence of ventilation heterogeneity and AHR. Fourteen asthmatic subjects (6 women) underwent combined ventilation single photon emission computed tomography/computed tomography scans before and after methacholine challenge. Regional airway closure was determined by complete loss of ventilation following methacholine challenge. Peripheral airway disease was measured by multiple-breath nitrogen washout from which S(cond) (index of peripheral conductive airway abnormality) was derived. Relationships between airway closure and lung function were examined by multiple-linear regression. Forced expiratory volume in 1 s was 87.5 ± 15.8% predicted, and seven subjects had AHR. Methacholine challenge decreased forced expiratory volume in 1 s by 23 ± 5% and increased nonventilated volume from 16 ± 4 to 29 ± 13% of computed tomography lung volume. The increase in airway closure measured by nonventilated volume correlated independently with both S(cond) (partial R(2) = 0.22) and with AHR (partial R(2) = 0.38). The extent of airway closure induced by methacholine inhalation in asthmatic subjects is greater with increasing peripheral airways disease, as measured by ventilation heterogeneity, and with worse AHR.

Airway hyperresponsiveness in allergically inflamed mice: the role of airway closure.

RATIONALE: Allergically inflamed mice exhibit airway hyperresponsiveness to inhaled methacholine, which computer simulations of lung impedance suggest is due to enhanced lung derecruitment and which we sought to verify in the present study. METHODS: BALB/c mice were sensitized and challenged with ovalbumin to induce allergic inflammation; the control mice were sensitized but received no challenge. The mice were then challenged with inhaled methacholine and respiratory system impedance tracked for the following 10 minutes. Respiratory elastance (H) was estimated from each impedance measurement. One group of mice was ventilated with 100% O(2) during this procedure and another group was ventilated with air. After the procedure, the mice were killed and ventilated with pure N(2), after which the trachea was tied off and the lungs were imaged with micro-computed tomography (micro-CT). RESULTS: H was significantly higher in allergic mice than in control animals after methacholine challenge. The ratio of H at the end of the measurement period between allergic and nonallergic mice ventilated with O(2) was 1.36, indicating substantial derecruitment in the allergic animals. The ratio between lung volumes determined by micro-CT in the control and the allergic mice was also 1.36, indicative of a corresponding volume loss due to absorption atelectasis. Micro-CT images and histograms of Hounsfield units from the lungs also showed increased volume loss in the allergic mice compared with control animals after methacholine challenge. CONCLUSIONS: These results support the conclusion that airway closure is a major component of hyperresponsiveness in allergically inflamed mice.

Differences in radiological/HRCT findings in eosinophilic bronchitis and asthma: implication for bronchial responsiveness.

BACKGROUND: Airway hyperresponsiveness in asthmatics is considered to be one of the major consequences of airway inflammation and remodelling. Airway responsiveness is normal in patients with eosinophilic bronchitis (EB), despite eosinophilic inflammation of the airways comparable to that which occurs in asthmatics. Comparisons between asthma and EB should clarify the changes in airway morphology that are related specifically to AHR in asthmatics. METHODS: Eighteen asthmatic patients, 15 patients with EB, and 11 healthy subjects were recruited. Airway wall area percentage (WA%), centrilobular prominence, and air trapping were compared using thin slice section computed tomography. RESULTS: WA% was significantly greater in asthmatics than in patients with EB (72 (3.1)% v 54 (2.1)%, p = 0.032) and was similar in EB patients and controls (54 (2.1)% v 57 (1.8)%, p>0.05). Centrilobular prominence and air trapping were similar in EB patients and asthmatics and were significantly greater than in controls. CONCLUSION: WA% rather than air trapping or centrilobular prominence may be associated with the airway hyperresponsiveness that occurs in asthmatics but not in patients with EB.

Development and testing of image-processing methods for the quantitative assessment of airway hyperresponsiveness from high-resolution CT images.

PURPOSE: Our goal was to develop a protocol and image-processing methods to quantitate both bronchial and lung attenuation changes in patients imaged with helical high-resolution CT (HRCT). METHOD: Human subjects underwent helical HRCT at two suspended breath-hold conditions, functional residual capacity and residual volume, at baseline and following methacholine-induced bronchoprovocation. A semiautomated contouring program was used to define anatomically like bronchi and axial lung sections from the different physiologic sequences, from which automated measurements of area, shape, and attenuation were made. Because the gray level threshold for contouring directly affects the measured area of an anatomic structure, two types of evaluation studies were performed. These included in vivo measurements using baseline parameters of human subjects as the standard of reference and in vitro measurements of a CT phantom designed to simulate the air-soft tissue interfaces of bronchi. RESULTS: Phantom tests showed that the minimum difference between actual and measured areas of holes occurred at a threshold of -500 HU. The smallest diameter holes were most sensitive to changes in threshold value. However, although absolute area measurements of both simulated and human bronchi varied with threshold level, the percent changes in airway areas between baseline and bronchoprovocation sequences were relatively stable at any given threshold. CONCLUSION: These image-processing tools provide reproducible measurements of area as well as attenuation characteristics of pulmonary structures and may offer insights into the practical use of functional imaging in evaluating conditions of airflow obstruction.

Airway hyperreactivity: assessment with helical thin-section CT.

PURPOSE: To determine the accuracy of helical computed tomography (CT) for assessing reversible changes in bronchial size and air trapping due to airway hyperreactivity. MATERIALS AND METHODS: Spirometry and helical CT were performed in 15 patients with mild asthma and six healthy control subjects before and after bronchial provocation with methacholine chloride and after reversal of provocation with albuterol. CT was performed at suspended functional residual capacity and at residual volume in two lung regions (above and below the carina). Bronchial area and lung attenuation measurements were compared. RESULTS: At baseline, lung attenuation frequency distribution curves were similar between the control and asthma groups. After methacholine, control subjects showed a decrease of less than 10% in the forced expiratory volume at 1 second (FEV1) and no significant differences in lung attenuation curves. Patients with asthma showed a 20%-36% decrease in FEV1, with significant decreases in the median and lowest 10th percentile regions of the attenuation curves and in the cross-sectional area of small (< 5-mm2) airways (P < .001 for all comparisons). After albuterol, control subjects showed no change in spirometric measurements, lung attenuation, or bronchial size, whereas all such parameters returned to baseline levels in patients with asthma. CONCLUSION: Functional helical CT can accurately demonstrate reversible airflow obstruction resulting from airway hyperreactivity.

Imaging allergen-invoked airway inflammation in atopic asthma with [18F]-fluorodeoxyglucose and positron emission tomography.

BACKGROUND: Airway inflammation is a feature of asthma and can be quantified invasively with bronchial lavage and endobronchial histology. Inflammatory foci can be imaged non-invasively with positron emission tomography (PET) and [18F]-fluorodeoxyglucose (18FDG) to quantify glucose uptake in activated granulocytes. We used this technique to study airway inflammation in asthma. METHODS: Nine men with mild atopic asthma were studied. In five, we studied the effect of bronchoscopic segmental allergen challenge on 18FDG uptake. Allergen was instilled into the posterior segment of the right upper lobe; a similar volume (20 mL) of isotonic saline was instilled into the posterior segment of the left upper lobe. At 1-32 h after instillation, PET with 18FDG was done. In the other four patients, we administered aerosolised allergen. FINDINGS: 18FDG uptake was increased four-fold in the right compared with the left upper lobe (geometric mean of ratios 4.30, 95% Cl 2.39-7.72, p=0.002). Aerosolised administration of allergen did not significantly increase 18FDG uptake. INTERPRETATION: These data show that local allergen-invoked airway inflammation can be visualised with 18FDG and PET in asthma. The cellular localisation of the 18FDG signal remains to be determined.