Quantitative Imaging of Regional Aerosol Deposition, Lung Ventilation and Morphology by Synchrotron Radiation CT.

To understand the determinants of inhaled aerosol particle distribution and targeting in the lung, knowledge of regional deposition, lung morphology and regional ventilation, is crucial. No single imaging modality allows the acquisition of all such data together. Here we assessed the feasibility of dual-energy synchrotron radiation imaging to this end in anesthetized rabbits; both in normal lung (n = 6) and following methacholine (MCH)-induced bronchoconstriction (n = 6), a model of asthma. We used K-edge subtraction CT (KES) imaging to quantitatively map the regional deposition of iodine-containing aerosol particles. Morphological and regional ventilation images were obtained, followed by quantitative regional iodine deposition maps, after 5 and 10 minutes of aerosol administration. Iodine deposition was markedly inhomogeneous both in normal lung and after induced bronchoconstrition. Deposition was significantly reduced in the MCH group at both time points, with a strong dependency on inspiratory flow in both conditions (R2 = 0.71; p < 0.0001). We demonstrate for the first time, the feasibility of KES CT for quantitative imaging of lung deposition of aerosol particles, regional ventilation and morphology. Since these are among the main factors determining lung aerosol deposition, we expect this imaging approach to bring new contributions to the understanding of lung aerosol delivery, targeting, and ultimately biological efficacy.

Reference values of spirometry for Finnish adults.

BACKGROUND: Diagnostic assessment of lung function necessitates up-to-date reference values. The aim of this study was to estimate reference values for spirometry for the Finnish population between 18 and 80 years and to compare them with the existing Finnish, European and the recently published global GLI2012 reference values. METHODS: Spirometry was performed for 1380 adults in the population-based FinEsS studies and for 662 healthy non-smoking volunteer adults. Detailed predefined questionnaire screening of diseases and symptoms, and quality control of spirometry yielded a sample of 1000 native Finns (387 men) healthy non-smokers aged 18-83 years. Sex-specific reference values, which are estimated using the GAMLSS method and adjusted for age and height, are provided. RESULTS: The predicted values for lung volumes are larger than those obtained by GLI2012 prediction for the Caucasian subgroup for forced vital capacity (FVC) by an average 6·2% and 5·1% and forced expiratory volume in 1 s (FEV1) by an average 4·2% and 3·0% in men and women, respectively. GLI2012 slightly overestimated the ratio FEV1/FVC with an age-dependent trend. Most reference equations from other European countries, with the exception of the Swiss SAPALDIA study, showed an underestimation of FVC and FEV1 to varying degrees, and a slight overestimation of FEV1/FVC. CONCLUSION: This study offers up-to-date reference values of spirometry for native Finns with a wide age range. The GLI2012 predictions seem not to be suitable for clinical use for native Finns due to underestimation of lung volumes.

Radiation dose and image quality in K-edge subtraction computed tomography of lung in vivo.

K-edge subtraction computed tomography (KES-CT) allows simultaneous imaging of both structural features and regional distribution of contrast elements inside an organ. Using this technique, regional lung ventilation and blood volume distributions can be measured experimentally in vivo. In order for this imaging technology to be applicable in humans, it is crucial to minimize exposure to ionizing radiation with little compromise in image quality. The goal of this study was to assess the changes in signal-to-noise ratio (SNR) of KES-CT lung images as a function of radiation dose. The experiments were performed in anesthetized and ventilated rabbits using inhaled xenon gas in O2 at two concentrations: 20% and 70%. Radiation dose, defined as air kerma (Ka), was measured free-in-air and in a 16 cm polymethyl methacrylate phantom with a cylindrical ionization chamber. The dose free-in-air was varied from 2.7 mGy to 8.0 Gy. SNR in the images of xenon in air spaces was above the Rose criterion (SNR > 5) when Ka was over 400 mGy with 20% xenon, and over 40 mGy with 70% xenon. Although in human thorax attenuation is higher, based on these findings it is estimated that, by optimizing the imaging sequence and reconstruction algorithms, the radiation dose could be further reduced to clinically acceptable levels.

Simultaneous in vivo synchrotron radiation computed tomography of regional ventilation and blood volume in rabbit lung using combined K-edge and temporal subtraction.

In K-edge subtraction (KES) imaging with synchrotron radiation computed tomography (SRCT), two images are taken simultaneously using energies above and below the K-absorption edge of a contrast agent. A logarithmic difference image reveals the contrast agent concentration with good accuracy. Similarly, in temporal subtraction imaging (TSI) the reference image is taken before the introduction of the contrast agent. Quantitative comparisons of in vivo images of rabbit lung indicated that similar results for concentrations of iodine in blood vessels and xenon in airways are obtained by KES and TSI, but the level of noise and artifacts was higher in the latter. A linear fit showed that in the lung parenchyma rho(TSI) = (0.97 +/- 0.03)rho(KES) + (0.00 +/- 0.05) for xenon and rho(TSI) = (1.21 +/- 0.15)rho(KES) + (0.0 +/- 0.1) for iodine. For xenon the calculation of time constant of ventilation gave compatible values for both of the methods. The two methods are combined for the simultaneous determination of the xenon concentration (by KES) and the iodine concentration (by TSI) in lung imaging, which will allow simultaneous in vivo determination of ventilation and perfusion.

Chronic bronchitis and chronic obstructive pulmonary disease. The Finnish Action Programme, interim report.

The Finnish National Prevention and Treatment Programme for Chronic Bronchitis and COPD, launched in 1998, has, to date, been running for 6 years (2003). The goals of this action programme were to reduce the incidence of COPD and the number of moderate and severe cases of the disease, and to reduce both the number of days of hospitalisation and treatment costs. A prevalent implementation of over 250 information and training events started. Health centres and pharmacies appointed a person in charge of COPD patients. In order to improve the cooperation between primary and specialised care, two thirds of hospital districts created local COPD treatment chains. The early diagnosis of COPD by spirometric examination was activated during the programme. Number of health centres with available spirometric services increased to 95%. Before the start of the programme, approximately 5-9% of the adult population had COPD. During the whole programme, the proportion of male and female smokers decreased from 30% to 26% and from 20% to 19%, respectively. The total number of hospitalisation periods and days due to COPD decreased by 15% and 18%, respectively. Both the number of pensioners and daily sickness days due to COPD also decreased by 18%. Registered COPD induced deaths remained at their previous levels during the monitoring period, i.e. around 1000 deaths out of 5.2 millions annually. The measures recommended by the programme have been widely introduced but they need to be still more effective.

Degree and clinical relevance of sensitization to common allergens among adults: a population study in Helsinki, Finland.

BACKGROUND: We aimed to assess the prevalence of allergic sensitization and multiple sensitization, risk factors, and the clinical impact of being sensitized in the adult population of Helsinki, Finland. METHODS: As a part of the FinEsS study, a population-based random sample of 498 adults aged 26-60 years were tested for 15 common aeroallergens with skin prick tests (SPTs) and interviewed on respiratory symptoms and diseases, including respiratory irritants and childhood environment. RESULTS: The prevalence of at least one positive prick test was 46.9%. A large difference by age was found: 56.8% were sensitized among those aged 26-39 years, 49.2% in the age group 40-49 years, and 35.6% in the age group 50-60 years (P<0.001). Sensitization to multiple allergens was common among young subjects with 42% of the sensitized responding to at least four allergens, while this proportion was only 16% of the sensitized among those aged 50-60 years. The prevalence of physician-diagnosed asthma, allergic rhinitis (AR) or conjunctivitis, and wheeze increased significantly with increasing number of positive responses to SPTs. Having a family history of AR or conjunctivitis was a significant risk factor for allergic sensitization and for sensitization to any of the pollens. Further, urban living in childhood yielded an increased risk for pollen sensitization. CONCLUSIONS: The prevalence of allergic sensitization was high in the urban adult population of Helsinki. More than half of those aged 26-39 years was sensitized and 24% was sensitized to at least four allergens. Sensitization to multiple allergens was associated with a high prevalence of asthma, AR or conjunctivitis, and wheeze.

Exhaled nitric oxide and exercise-induced bronchoconstriction in young male conscripts: association only in atopics.

This study was conducted to evaluate how bronchial responsiveness to direct and indirect stimuli relate to nitric oxide producing airway inflammation, and whether the relationship differs between atopic and nonatopic patients with various degrees of bronchial hyperresponsiveness and airway inflammation in a group of otherwise homogenous young men. We studied 181 consecutive non-smoking steroid-naive young male conscripts referred to military hospital because of respiratory symptoms suggesting asthma. Skin prick tests, spirometry, measurement of exhaled nitric oxide (FENO), and standardized airway challenges with histamine and exercise were performed. 128 patients were atopic. FENO was significantly higher in the atopic group, median 21.2 ppb, compared to 10.2 ppb in the nonatopic group. Still, 36% of all nonatopic patients had elevated FENO. Bronchial responsiveness to histamine (HIB) was similar in the two groups, but exercise-induced bronchoconstriction (EIB) was stronger in atopics (P < 0.01). FENO associated significantly with atopy (P < 0.001), severity of EIB (P < 0.001) and HIB (P = 0.006) in multiple linear regression model. In separate regression models for atopic and nonatopic patients FENO associated with severity of EIB and HIB in atopic patients only. The results were similar when patients with confirmed diagnosis of asthma were analyzed separately. Our results indicate that FENO significantly associates with EIB and HIB in atopic, but not in nonatopic steroid-naïve patients with asthmatic symptoms. The finding suggests that in such atopic patients degree of airway hyperresponsiveness may reflect severity of airway inflammation. However, in nonatopic patients with similar symptoms other mechanisms of airway hyperresponsiveness may be more important.

Effect of tidal volume on distribution of ventilation assessed by synchrotron radiation CT in rabbit.

A respiration-gated synchrotron radiation computed tomography (SRCT) technique, which allows visualization and direct quantification of inhaled stable xenon gas, was used to study the effect of tidal volume (Vt) on regional lung ventilation. High-resolution maps (pixel size 0.35 x 0.35 mm) of local washin time constants (tau) and regional specific ventilation were obtained in five anesthetized, paralyzed, and mechanically ventilated rabbits in upright body position at the fourth, sixth, and eighth dorsal vertebral levels with a Vt from 4.9 +/- 0.3 to 7.9 +/- 0.4 ml/kg (means +/- SE). Increasing Vt without an increase in minute ventilation resulted in a proportional increase of mean specific ventilation up to 65% in all studied lung levels and reduced the scattering of washin tau values. The tau values had log-normal distributions. The results indicate that an increase in Vt decreases nonuniformity of intraregional ventilatory gas exchange. The findings suggest that (SRCT) provides a new quantitative tool with high spatial discrimination ability for assessment of changes in peripheral pulmonary gas distribution during mechanical ventilation.

Sustained reduction in bronchial hyperresponsiveness with inhaled fluticasone propionate within three days in mild asthma: time course after onset and cessation of treatment.

BACKGROUND: Bronchial hyperresponsiveness (BHR) is characteristic of asthmatic airways, is induced by airway inflammation, and is reduced by inhaled corticosteroids (ICS). The time course for the onset and cessation of the effect of ICS on BHR is unclear. The effect of inhaled fluticasone propionate (FP) on BHR in patients with mild persistent asthma was assessed using time intervals of hours, days and weeks. METHODS: Twenty six asthmatic patients aged 21-59 years were selected for this randomised, double blind, parallel group study. The effect of 250 micro g inhaled FP (MDI) administered twice daily was compared with that of placebo on BHR assessed using a dosimetric histamine challenge method. The dose of histamine inducing a decrease in forced expiratory volume in 1 second (FEV(1)) by 15% (PD(15)FEV(1)) was measured before and 6, 12, 24 and 72 hours, and 2, 4 and 6 weeks after starting treatment, and 48 hours, 1 week and 2 weeks after cessation of treatment. Doubling doses of changes in PD(15)FEV(1) were calculated and area under the curve (AUC) statistics were used to summarise the information from individual response curves. RESULTS: The increase in PD(15)FEV(1) from baseline was greater in the FP group than in the placebo group; the difference achieved significance within 72 hours and remained significant until the end of treatment. In the FP group PD(15)FEV(1) was 1.85-2.07 doubling doses above baseline between 72 hours and 6 weeks after starting treatment. BHR increased significantly within 2 weeks after cessation of FP treatment. CONCLUSIONS: A sustained reduction in BHR to histamine in patients with mild asthma was achieved within 3 days of starting treatment with FP at a daily dose of 500 micro g. The effect tapered within 2 weeks of cessation of treatment.

Short-term variability of exhaled nitric oxide in young male patients with mild asthma and in healthy subjects.

BACKGROUND: Exhaled nitric oxide (NOexp) is an indicator of eosinophilic airways inflammation. This study evaluated short-term variability of NOexp in 13 healthy subjects (19-41 years, eight males) and in 31 patients with asthmatic respiratory symptoms (19-21 years, all male) to obtain data for assessment of short-term changes of NOexp in clinical situations. METHODS: Mild asthma was confirmed in 10 patients (Group = asthma). Twenty-one patients with asthmatic respiratory symptoms did not fulfill the functional criteria of asthma (Group = respiratory symptoms). The procedure to determine NOexp followed the European Respiratory Society (ERS) guidelines; the mean expiratory flow used during sampling was 0.09-0.12 l/s. NOexp for each subject was determined as the mean of at least three successive measurements at the baseline, followed by determinations at 10 min, 6 h and 24 h after the baseline. RESULTS: At the baseline, the mean (SD) value of NOexp was 6.6 (2.3) parts per billion (ppb) in the healthy controls, and significantly higher both in patients with respiratory symptoms (14.6 (11) ppb, P = 0.0076) and in those with asthma (34.2 (43) ppb, P < 0.001). Intraclass correlation coefficient of NOexp measured at baseline and after an interval of 10 min was 0.959 in healthy subjects, 0.986 in patients with respiratory symptoms and 0.936 in asthma patients, respectively. Short-term variability in terms of coefficient of variation (CoV) of repeated measurements of NOexp at 10 min, 6 hand 24 h was 5.1, 10.8 and 11.7% in healthy subjects, 71, 16.4 and 22.2% in patients with respiratory symptoms and 13.5, 19.4 and 26.4% in asthma patients, respectively. CONCLUSIONS: Reproducibility of NOexp using standardized methods was good both in healthy subjects and in asthmatic patients. However, in asthmatics the short-term variation of NOexp was over two times as high as in healthy subjects. The level of NOexp was elevated, except in asthma, also in patients with asthmatic respiratory symptoms who did not fulfill the functional criteria of asthma.