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Background:: Consolidative radiotherapy (RT) has been shown to improve overall survival in oligometastatic non-small cell lung cancer (NSCLC), as demonstrated by a growing number of prospective trials. Objective:: We quantified the costs of delivery of consolidative RT for common clinical pathways associated with treating oligometastatic NSCLC, by applying time-driven activity-based costing (TDABC) methodology. Methods:: Full cycle costs were evaluated for 4 consolidative treatment regimens: (Regimen #1) 10-fraction 3D conformal radiation therapy (3D-CRT) as palliation of a distant site; (#2) 15-fraction intensity-modulated RT (IMRT) to the primary thoracic disease; (#3) 15-fraction IMRT to the primary plus 4-fraction stereotactic ablative radiotherapy (SABR) to a single oligometastatic site; and (#4) 15-fraction IMRT to the primary plus two courses of 4-fraction SABR for two oligometastatic sites. Results:: For each of the four treatment regimens, personnel represented a greater proportion of total cost when compared with equipment, totaling 61.0%, 65.9%, 66.2%, and 66.4% of the total cost of each care cycle, respectively. In total, a 10-fraction regimen of 3D-CRT to a distant site represented just 37.2% of the total cost of the most expensive course. Compared to total costs for 15-fraction IMRT alone, each additional sequential course of 4-fraction SABR imparted a cost increase of 43%. Conclusion:: This analysis uses TDABC to estimate the relative internal costs of various RT strategies associated with treating oligometastatic NSCLC. This methodology will become increasingly relevant to each organization in context of the anticipated mandate of alternative/bundled payment models for radiation oncology by the Centers for Medicare and Medicaid Services.

Background: Despite the lung involvement in patients with chronic heart failure (CHF), the significance of lung function abnormalities to functional status in these patients is still controversial. We postulated that in patients with CHF, resting lung function assessment may provide information of clinical relevance on exercise capacity, expressed as peak oxygen uptake (VO2) and ventilatory response to CO2 production (VE/VCO2) during a maximal exercise., Methods: We studied 49 clinically stable patients with CHF (38 men, age range: 25-78 years) (New York Heart Association class range: I-IV) with left ventricular ejection fraction <40%. Patients with chronic obstructive pulmonary disease were excluded. Patients performed pulmonary function tests and maximal incremental exercise test., Results: Resting spirometry was related to the exercise capacity (P < 0.05), expressed as peak VO2. By means of receiver operating characteristic curve analysis, the forced expiratory volume at first second (FEV1) cutoff point, which better identified patients with a peak VO2 < or =14 mL/kg/min, was <79% of predicted value (0.79 sensitivity and 0.73 specificity). Resting lung diffusion capacity for carbon monoxide and end-tidal pressure of CO2 (PETCO2) were inversely correlated to VE/VCO2 (P < 0.01). The lung diffusion capacity for carbon monoxide and PETCO2 cutoff points, which better identified patients with VE/VCO2 value >34, were <58% of predicted (0.92 sensitivity and 0.42 specificity) and <33 mm Hg (0.67 sensitivity and 0.92 specificity), respectively., Conclusions: In patients with CHF, resting lung function, including spirometry, lung diffusion capacity, and PETCO2, can provide clinically useful information on exercise capacity, by predicting peak VO2 and VE/VCO2 slope. The results of this study highlight the role of resting lung function in the assessment of the functional status of cardiac patients.

Background: Exhaled NO (FE(NO)) is a useful biomarker for the monitoring of asthma control and response to therapy. However, there is a lack of data on FE(NO) levels and their interpretation in Primary Care asthma population depending on their treatment and smoking habit. Besides, the majority of current FE(NO) tests have been done by stationary chemiluminescence analysers whose use is limited to research laboratories., Methods: FE(NO) measurements by the novel hand-held NO monitoring device (NIOX MINO) were made in 96 asthma patients (32 males, mean age 53+/-12) at five local General Practices during their scheduled 15-20 min visits for lung function assessment., Results: Success rate was 78% and the intra-subject coefficient of variation was 8.7%. Inhaled corticosteroid treatment had an overall reducing effect on the FE(NO) value (30.5 [19.8-49.8]) vs. patients not on the ICS (26.5 [19-94]) (p<0.044). FE(NO) levels in the ICS treated current or ex-smokers group of patients were still significantly above the normal values (p<0.0001). FE(NO) levels were similar in patients receiving ICS whether there were current, ex-smokers or non-smokers. The highest FE(NO) levels (94 [15.8-151]) were found in asthmatic current smokers and not receiving treatment with ICS. The most "normalised" FE(NO) levels (35.3 [13.5-35.3]) were seen in ex-smokers., Conclusions: FE(NO) measurements performed with a new hand-held monitoring device are reproducible and feasible in General Practice in the majority of patients of different ages and asthma severities. A high percentage of patients with different severities of asthma and regardless of their treatment with ICS and current smoking habit (current and/or ex-smokers) had highly elevated FE(NO) values, suggesting that their current therapy was possibly insufficient to control the underlying degree of airway inflammation and asthma symptoms.

Background: Obstructive sleep apnea syndrome (OSAS) is associated with cardiovascular diseases, in particular systemic arterial hypertension. We postulated that intermittent nocturnal hypoxia in OSAS may be associated to decreased fractional exhaled nitric oxide (FENO) levels from distal airspaces., Methods: Multiple flow rate measurements have been used to fractionate nitric oxide (NO) from alveolar and bronchial sources in 34 patients with OSAS, in 29 healthy control subjects, and in 8 hypertensive non-OSAS patients. The effect of 2 days of treatment with nasal continuous positive airway pressure (nCPAP) on FENO was examined in 18 patients with severe OSAS., Results: We found that the mean [+/- SE] concentrations of exhaled NO at a rate of 50 mL/s was 21.8 +/- 1.9 parts per billion (ppb) in patients with OSAS, 25.1 +/- 3.3 ppb in healthy control subjects, and 15.4 +/- 1.7 ppb in hypertensive control patients. The mean fractional alveolar NO concentration (CANO) in OSAS patients was significantly lower than that in control subjects (2.96 +/- 0.48 vs 5.35 +/- 0.83 ppb, respectively; p < 0.05). In addition, CANO values were significantly lower in OSAS patients with systemic hypertension compared to those in normotensive OSAS patients and hypertensive patients without OSAS. The mean values of CANO significantly improved after nCPAP therapy (2.67 +/- 0.41 to 4.69 +/- 0.74 nL/L, respectively; p = 0.01)., Conclusions: These findings suggest that alveolar FENO, and not bronchial FENO, is impaired in patients with OSAS and that this impairment is associated with an increased risk of hypertension. NO production within the alveolar space is modified by treatment with nCPAP.

In 102 healthy Caucasians, 20-50 years old, we investigated the effect of anthropometrics on the 6-min walk test (6MWT), in order to provide reference values for walk distance (6MWD), oxygen saturation (SpO2), pulse rate (PR), respiratory rate (RR), breathlessness perception (VAS) and for the walking distance and body weight product (DW). The mean 6MWD and DW values were 593 +/- 57 and 638+/-44 m (P < 0.01) and 35,030 +/- 5306 and 48,882 +/- 6555 kg m (P < 0.01), respectively for women and for men. While walking, SpO2 remained unaltered and subjects reached 67 +/- 10% of their maximal predicted heart rate and a RR mean value of 19 +/- 4 bpm. VAS ratings were significantly higher in females as compared to males (24 +/- 15 vs. 18 +/- 5 mm, P < 0.05), however, when corrected for PR change while walking, they were not different. The equation by stepwise multiple regression analysis included height, age and gender for the 6MWD and accounted for 42% of the total variance. This study confirms the relevant effect of anthropometrics on walking capacity and suggests that when rating dyspnea, the change in heart rate during walking should be considered.

Background: Increased oxidative stress is important in the pathogenesis of chronic obstructive pulmonary disease (COPD). We postulated that treatment with the antioxidant N-acetylcysteine would reduce the rate of lung-function decline, reduce yearly exacerbation rate, and improve outcomes., Methods: In a randomised placebo-controlled study in 50 centres, 523 patients with COPD were randomly assigned to 600 mg daily N-acetylcysteine or placebo. Patients were followed for 3 years. Primary outcomes were yearly reduction in forced expiratory volume in 1 s (FEV1) and the number of exacerbations per year. Analysis was by intention to treat., Findings: The yearly rate of decline in FEV1 did not differ between patients assigned N-acetylcysteine and those assigned placebo (54 mL [SE 6] vs 47 mL [6]; difference in slope between groups 8 mL [9]; 95% CI -25 to 10). The number of exacerbations per year did not differ between groups (1.25 [SD 1.35] vs 1.29 [SD 1.46]; hazard ratio 0.99 [95% CI 0.89-1.10, p=0.85]). Subgroup analysis suggested that the exacerbation rate might be reduced with N acetylcysteine in patients not treated with inhaled corticosteroids and secondary analysis was suggestive of an effect on hyperinflation., Interpretation: N-acetylcysteine is ineffective at prevention of deterioration in lung function and prevention of exacerbations in patients with COPD.

Background: Inhaled corticosteroids (ICSs) are an effective treatment of asthma even when administered at a low dose. Once asthma is controlled, current guidelines recommend that the dose of ICS be reduced to the lowest possible and effective dose. Although the most appropriate strategy for the stepping down has not yet been defined, quantification of sputum eosinophils and bronchial hyperresponsiveness (BHR) are indeed measures of asthma control., Objective: To compare the efficacy of step-down and fixed-dose strategies in the control of BHR to methacholine and eosinophilic inflammation patients with mild-to-moderate asthma., Methods: We performed a double-blind, randomized study to compare inhaled fluticasone propionate (FP), 1,000 microg/d, then reduced to 200 microg/d (group 1; n = 18) to a fixed dose of FP, 200 microg/d (group 2; n = 17) administered for 6 weeks and then 8 weeks in reducing the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) and sputum eosinophils in 35 patients. The duration of the efficacy was also followed subsequently after 8 weeks of placebo treatment., Results: PD20 remarkably increased with both treatment strategies, but differences between groups were not significant. Sputum eosinophils (median values, percentage) at baseline and after each treatment period were not different (group 1, 16.4 to 1.0 to 2.7%; group 2, 16.7 to 2.8 to 2.8%, respectively). The percentages of patients in whom sputum eosinophilia was normalized (< or = 3%) were as follows: group 1, 69% and 60%; group 2, 50% and 57%. After placebo treatment, sputum eosinophils were still "normalized" in approximately one third of patients., Conclusion: Step-down and fixed-dose strategies with FP improved PD20 and sputum eosinophilia to a similar degree. The effect on sputum eosinophils persisted longer than that on methacholine.

Background and Aim: Hypersensitivity pneumonitis (HP) is an immunologically induced inflammation of the lung parenchyma, though bronchial airways may be also involved. The aim of this study was to compare the cellular profiles of induced sputum (IS) in patients with newly diagnosed HP to that of healthy subjects, and to examine the relationship between inflammatory cells from IS and BAL., Methods: Nine HP patients and 9 healthy volunteers were studied. IS was obtained by inhalation of hypertonic saline solution in all subjects. Bronchoscopy was performed on a different occasion in all patients and in five controls., Results: IS was well tolerated and preferred to BAL by all subjects. Both IS and BAL from HP patients showed a significant increase in total cells (P < 0.02 and P < 0.001) and in lymphocytes (P < 0.02 and P < 0.001) and a significant decrease in macrophages (P < 0.05 and P < 0.001), when compared with normal subjects. In HP patients, total cells number in IS was higher than that in BAL (P < 0.02). Moreover, the percentage of lymphocytes was significantly lower in IS than in BAL (P < 0.001). No significant relationship was found between total cells or inflammatory cells from IS and the corresponding ones from BAL and wide limits of agreement were found between lymphocytes from IS and BAL., Conclusions: This study demonstrated that both BAL and IS from newly diagnosed HP patients contained significantly more total cells and lymphocytes, when compared to healthy subjects. Moreover, differential cell counts in HP patients showed that IS and BAL reflected different compartments of inflammation. Thus, IS could represent a complementary, but not alternative tool to bronchoscopy both in research and in the clinical monitoring of HP patients.

To ascertain whether fatigue perception is linked to exertion dyspnea and/or to an impaired cardiorespiratory response during walk, 11 patients (8 females, age range 21-46 years) with multiple sclerosis (MS) and mild disability underwent the 6-min walk test. Ten healthy subjects (7 females, age range 25-49 years) were studied, as a control group. Patients did not differ from controls in spirometry, lung volumes and respiratory muscle strength. There was a significant difference in walk distance between patients and controls (P<0.001), but not in dyspnea perception. In patients, the walk distance significantly related to disability score (P<0.01), but not to fatigue. Compared to controls, patients had a significant decrease in oxygen pulse during walk (P<0.05) and a significant increase in the ventilatory equivalent of CO2 both at baseline and during walk (P<0.05). The relative contribution of both the tidal volume and of the ratio of inspiratory to total breathing cycle duration to the increase in minute ventilation during walk was significantly less in patients, as compared to controls (P<0.05). We conclude that in MS patients with mild disability, fatigue and exertion dyspnea are different sensations without any link and a peripheral limitation during walk can occur.

We compare the efficacy including spirometry, peak expiratory flow (PEFR) and quality of life and safety of an 8-week treatment with inhaled oxitropium, theophylline or their combination in patients with mild-to-severe chronic obstructive pulmonary disease (COPD). We conducted a multicentre, double-blind, double-dummy randomized, parallel-group study at 29 Italian outpatients clinics. A group of 236 patients with mild-to-severe COPD (baseline FEV1 < or = 70% of predicted value) were recruited. Treatments were as follows: Inhaled oxitropium bromide 200 microg (N=75), sustained-release oral theophylline 300 mg (N=81) or their combination (N=80), taken twice daily. Spirometry (FEV1 and FVC) was evaluated every 4 weeks, and morning and evening PEFR (before and 2-4 h after drug intake) was measured daily. Symptoms, cough and dysponea, were recorded daily. Health status was evaluated at baseline and week 8 using the disease specific St George' Respiratory Questionnaire (SGRQ). Any adverse event occurring during the treatment period was recorded on a diary card. FEV1 and FVC improved in all the groups at 4 and 8 weeks, but the difference between treatment groups did not reach statistically significant levels. Differences between groups in pre-dosing morning and evening PEFR were not significant. Post-dosing morning and evening PEFR were increased and the largest increase was seen in patients treated with both drugs. However, differences between groups was significant only for evening values (P=0.008). The proportion of patients who experienced a decrease in symptoms was high in all groups but no differences among groups were observed. SGRQ total scores decreased in all treatment groups after 8 weeks, particularly in the oxitropium and combination groups. Clinically significant change (> or = 4 units) was only observed in patients treated with oxitropium bromide whether with or without theophylline. Adverse events related to treatments were higher in the group treated with theophylline alone (P < 0.02). We conclude that inhaled oxitropium bromide alone was associated with an improvement in FEV1, PEFR and symptoms in patients with COPD that was not statistically different from that of oral theophylline alone or of the combination of both drugs. Oxitropium bromide in combination with theophylline provided a greater improvement in evening post-dosing PEFR. Oxitropium bromide alone or in combination with theophylline improved the quality of life better than theophylline alone.

Cigarette smoking is the dominant risk factor for chronic obstructive pulmonary disease (COPD). However, only 10-15% of smokers develop the disease and early changes within the airways are poorly defined. We aimed to compare cell profiles in induced sputum (IS) from asymptomatic smokers to that from healthy subjects, and to ascertain whether or not inflammatory cells in IS are related to lung function and smoking habit. We recruited 34 heavy, non-allergic asymptomatic smokers with normal lung function and 15 healthy volunteers, who performed lung function tests and IS by hypertonic saline (3%) solution. In smokers, significantcorrelation between pack-years and FEF25-75 (rs = -0.43, P < 0.02) was found. In IS, smokers had higher counts of macrophages (P < 0.01) and eosinophils (P < 0.02), when compared to those of healthy subjects. Additionally, eosinophils were found in IS of 14 out of 34 smokers, with eosinophils had a higher pack-years (31 +/- 25 vs. 13 +/- 10, P = 0.02) and lower FEF 25-75% value (78% +/- 34 vs. 100% +/- 23. P < 0.04). when compared to smokers without eosinophils. Additionally, on the basis of regression equations by stepwise multiple regression analysis, eosinophils were predicted by pack-years (r2 = 0.41). Our results showed that asymptomatic smokers have evidence of inflammatory cells in IS samples. In addition, we found thatthe degree of eosinophilic inflammation is related to early changes of lung function and can be predicted by smoking habit.

The six-minute walking test (6MWT) has been widely utilized to evaluate global exercise capacity in patients with cystic fibrosis. The aim of this study was to assess the exercise capacity by 6MWT, measuring four outcome measures: walk distance, oxygensaturation and pulse rate during the walk, and breathlessness perception after the walk, in a group of cystic fibrosis adults with mild to moderate lung disease, and in healthy volunteers, as the control group. Moreover, the study examined the relationship between 6MWT outcome measures and pulmonary function in patients. Twenty-five adults (15 females, age range 18-39 years) with cystic fibrosis and 22 healthy volunteers (14 females, age range 20-45 years) performed a 6MWT following a standard protocol. Walk distance, oxygen saturation (SpO2) and pulse rate at rest and during walk, and breathlessness perception after walk assessed by visual analogue scale (VAS) were measured. Cystic fibrosis patients did notdiffer from healthy volunteers in walk distance (626 +/- 49 m vs. 652 +/- 46 m) and pulse rate. Patients significantly differed from healthy volunteers in SPO2 during the walk (mean SpO2) (P < 0.0001) and VAS (P < 0.0001). In patients, SPO2 during the walk significantly correlated with forced expiratory volume in 1 sec (FEV1) (P < 0.0001), residual volume (RV) (P < 0.001), resting SPO2 (base SpO2) (P < 0.001), and inspiratory capacity (IC) (P < 0.01). In addition, VAS significantly correlated with resting SPO2 (P < 0.01) and IC (P < 0.01). On the basis of regression equations by stepwise multiple regression analysis, SpO2 during walk was predicted by FEV1 (r2 = 0.60) and VAS by IC (r2 = 0.31), whereas walk distance was not reliably predicted by any assessed variables. This study showed that cystic fibrosis adults with mild to moderate lung disease covered a normal walk distance with unimpaired cardiac adaptation, but experienced a significant fall in oxygen saturation and an increased breathlessness perception during exercise. Resting pulmonary function was related to oxygen saturation and breathlessness perception during walk, but contributed significantly only tothe prediction of oxygen saturation. We suggest that 6MWT could be valuable for identifying patients who might experience oxygen desaturation and dyspnoea during demanding daily activities.

Mucociliary clearance (MCC) is one of the most important nonspecific defense mechanisms of the respiratory tract, and its impairment is a well-documented feature of chronic respiratory diseases, including asthma. In vitro and in vivo data suggest that several inflammatory mediators influence the mucociliary apparatus. Epithelial damage and functional abnormalities have been described in bronchial asthma, along with changes in mucus-secreting cells and the chemical and rheological properties of airway fluid. Although the mechanisms of MCC impairment in asthma are not clearly understood, data in the recent literature suggest that airway inflammation plays a major role. In this article, we review studies on MCC alterations in light of up-to-date findings on pathogenetic mechanisms in asthma.

Background: Sputum production induced by inhalation of hypertonic saline solution has been proposed as a technique to collect secretions and inflammatory cells from the airways of subjects with bronchial asthma or with a history of smoking. The aim of this study was to determine the effect of a sputum induction procedure on spirometric results and arterial oxygen saturation (SaO(2)) in asthmatic patients, smokers, and healthy subjects., Methods: We recruited 14 subjects suffering from asthma (11 men and 3 women; age range, 18 to 49 years), 14 subjects with a history of smoking (5 men and 9 women; age range, 23 to 64 years), and 9 healthy volunteers (7 men and 2 women; age range, 28 to 54 years). To obtain a sample of induced sputum, all subjects inhaled a mist of 3% hypertonic saline solution nebulized for 5 min and repeated the cycle no more than four times. Asthmatic patients were pretreated with 200 microg salbutamol (inhaled). During sputum induction, the transcutaneous SaO(2) was continuously measured and baseline, fall, and the differences between baseline and fall SaO(2) were recorded. Additionally, we measured the duration of mild desaturation (change in SaO(2), < 4%) and of marked desaturation (change in SaO(2), > 5%) in each subject. Finally, baseline FEV(1) and changes in FEV(1) as a percentage of baseline values were recorded in all subjects., Results: We found that baseline and fall SaO(2) values for the three groups were similar. However, in each group a significant mean change in SaO(2) was evident during sputum production (asthmatic patients, 6.0%; smokers, 5.3%; healthy subjects, 6.0%). Moreover, the mean durations of mild desaturation were 7 min, 21 s in asthma patients; 8 min, 24 s in smokers; and 7 min, 16 s in healthy subjects. Similarly, the durations of marked desaturation were 1 min, 25 s in asthmatic patients, 1 min, 19 s in smokers, and 1 min, 21 s in healthy subjects. The mean (+/- SD) fall in FEV(1) was not statistically different among the three groups (asthmatic patients, 1.36 +/- 5.6%; smokers, 7.58 +/- 11.76%; and healthy subjects, 0.05 +/- 9.6%). However, one smoker did experience excessive bronchoconstriction (fall in FEV(1), > 20%)., Conclusions: This study demonstrated a significant and comparable fall in SaO(2) during sputum induction by inhalation of hypertonic saline solution in asthmatic patients, smokers, and healthy subjects. The results suggest that subjects who are hypoxemic before sputum induction require SaO(2) monitoring during the procedure.

Objectives: Sarcoidosis is characterized by a diffuse alveolar inflammatory process, although bronchial airways are often involved. This study compares the cellular profiles of induced sputum (IS), bronchial washing (BW), and BAL in newly diagnosed sarcoidosis patients to those in control subjects, and examines whether inflammatory cell counts from IS are correlated with inflammatory cell counts from BW and BAL in sarcoidosis patients., Patients and Measurements: We recruited 15 untreated patients with stage I and II pulmonary sarcoidosis and 12 healthy volunteers. Sputum was induced with hypertonic saline solution in all individuals. Bronchoscopy was performed on a different occasion in all patients and in five control subjects., Results: Mean lymphocyte counts in IS, BW, and BAL fluid from sarcoidosis patients were significantly higher than in control subjects (9.4% vs 3.8%, p < 0.05; 12.6% vs 3.9%, p < 0.05; 24.1% vs 2.6%, p < 0.05, respectively). Moreover, total cell count and percentage of epithelial cells in IS were significantly higher in sarcoidosis patients than in control subjects (p < 0.01 and p < 0.05, respectively). In sarcoidosis patients, comparison between different samples showed significantly higher percentages of macrophages in BW and BAL than in IS (p < 0.05 and p < 0.01, respectively), whereas the percentage of neutrophils was higher in IS compared with BW and BAL (p < 0.01 and p < 0.001, respectively). Finally, the percentage of lymphocytes in IS was significantly lower than that in BAL (p < 0.05) but not that in BW., Conclusions: We demonstrated that, compared with IS in healthy control subjects, IS in untreated pulmonary sarcoidosis patients contains more total cells, lymphocytes, and epithelial cells. Although the relative proportion of inflammatory cells in the three samples differed, lymphocyte counts in IS were high. This finding suggests that IS could be used as a valuable alternative to more conventional invasive techniques in clinical assessment of pulmonary sarcoidosis patients.

In recent years, the emerging concept of bronchial inflammation as a prominent histopathologic characteristic of asthma has profoundly modified the view of the role of the mast cell, which was traditionally thought to be linked to the release of soluble chemical mediators substantially involved in the genesis of acute, immediate bronchospasm. The finding that the production of proinflammatory cytokines by mast cells in asthmatic airways is comparable, in some circumstances, to that of T-cell origin, has led to the hypothesis that mast cells, along with T lymphocytes and eosinophils, may also contribute to the genesis of chronic, persistent asthma. This hypothesis is further supported by the finding that mast cells are able to functionally interact with B cells (promoting IgE synthesis) and T lymphocytes (acting as antigen presenting cells), thus taking part in the immune network. Moreover, mast cells produce an exclusive family of proteases (tryptases and chymases) that exert many biological actions relevant to airways inflammation and remodeling. Future studies will better explain the role of mast cells in asthma and, more specifically, the links with bone marrow-where mast cell progenitors originate-and the airways, where mast cells develop, differentiate, and assume the functions of mature cells. This article reviews recent data available on these topics.

Lung epithelial permeability of asthmatic patients has been reported to be similar or lower than that of healthy subjects and to be correlated or not to bronchial hyperresponsiveness. To clarify these discrepancies, we evaluated 99mTc-DTPA pulmonary clearance in a group of carefully selected asthmatic patients with mild, stable asthma (n = 13; seven women; mean age +/- SD = 27.69 +/- 6.63 years), and compared them with a group of healthy, nonsmoking subjects (n = 8; six women; mean age +/- SD = 24.38 +/- 5.15 years). Selection criteria for asthmatics were as follows: baseline FEV1 > or = 80% of predicted values, no bronchial infections, and/or no asthma attacks during 4 weeks prior to study and peak expiratory flow rate variability lower than 20%, over a period of 3 weeks. Patients controlled symptoms with beta 2-adrenergic drugs only, regularly or on demand. Mean baseline FEV1 (+/-SD) as percent of predicted was 102.38 +/- 13.97 and 112.88 +/- 18.36, respectively (p < 0.05). In the asthmatic group, bronchial responsiveness to methacholine (PC20 M FEV1) ranged between 0.55 and 28.5 mg/mL. Mean value (+/-SD) of DTPA clearance from lungs to blood (evaluated on the first 10 min out of 30 min of the curves) in the asthmatic group was not different from that of control group (68.31 +/- 21.46 and 69.5 +/- 15.73). In the asthmatic patients, there was no correlation between PC20 M values and DTPA T1/2 min of the whole lung, nor between PC20 M and inner and outer lung clearance zones. Moreover, both in asthmatics and healthy subjects, DTPA clearance of outer (alveolar) zones was significantly faster than that of inner (bronchial) zones (57.69 +/- 19.94 vs 102.08 +/- 38.19, p < 0.001, and 59.75 +/- 12.49 vs 103.5 +/- 31.86, p < 0.003, respectively). Our data show that DTPA clearance in patients with stable asthma is similar to that found in healthy subjects; it is not correlated to degree of bronchial responsiveness and occurs more rapidly in the outer zones than in the inner zones, both in asthmatic patients and in healthy subjects. Thus, to date, DTPA clearance index is not a valid tool for identifying and/or monitoring asthmatic patients.

Purpose: Airways remodeling, evaluated as the subepithelial layer thickness, was compared in asthmatic patients with that of healthy subjects, and was related to clinical grading of disease, presence of atopy, and length of asthmatic history., Subjects and Methods: Thirty-four patients with stable asthma (mean age+/-SD: 26.5+/-9.2 years; 10 female) treated with only inhaled beta2-agonists and eight healthy volunteers (mean age+/-SD: 24.6+/-2.5 years; four female) were recruited for the study. Twenty-seven of 34 asthmatics had atopy. Eleven patients had newly diagnosed conditions (duration of disease < or = 1 year), nine patients had long asthmatic history (> 1 year and < or = 10 years), and 14 had prolonged asthmatic history (> 10 years). Bronchial responsiveness to methacholine (M) was expressed as provocative concentration of M causing a 20% fall in FEV1 (PC20) (mg/mL). Degree of asthma severity was assessed using a 0- to 12-point score based on symptoms, bronchodilator use, and daily peak expiratory flow variability over a 3-week period. Bronchoscopy and bronchial biopsy were performed successfully for all subjects; the subepithelial layer thickness, in biopsy samples, was measured from the base of bronchial epithelium to the outer limit of reticular lamina., Results: In asthmatics, baseline FEV1 values (percent of predicted) ranged from 75.7 to 137.0%, and PC20 M ranged from 0.15 to 14.4 mg/mL. According to the asthma severity score, 14 asthmatics were classified as having mild disease, 14 as having moderate disease, and six as having severe disease. The mean values of subepithelial layer thickness were 12.4+/-3.3 microm (range, 6.8 to 22.1 microm) in asthmatics, and 4.4+/-0.5 microm (range, 3.8 to 5.2 microm) in healthy subjects (p<0.001). Subepithelial layer thickness of those with severe asthma differed significantly from that of patients with moderate and mild asthma (16.7+/-3.1 microm vs 12.1+/-2.7 microm and 10.8+/-2.4 microm, p<0.01 and p<0.003, respectively). Moreover, in asthmatics, degree of thickening was positively correlated to asthma severity score (Spearman rank correlation coefficient [rs]=0.581; p<0.001), and negatively correlated with baseline FEV1 (rs=-0.553; p<0.001) and PC20 M (rs=-0.510; p<0.01). No difference was found between degree of thickening observed in atopic asthmatics, compared with that of nonatopic asthmatics, or between degree of thickening in patients with different lengths of asthmatic history. Lastly, multiple regression analysis revealed that asthma severity score was the significant predictive factor for thickness of subepithelial layer., Conclusions: We confirmed that airways remodeling is a very distinctive and characteristic pathologic finding of asthma. We also demonstrated that it is related to the clinical and functional severity of asthma, but not to atopy or length of asthmatic history.

Chronic bronchitis (CB) is characterized by inflammatory changes in the bronchial tissue and by recurrent bronchitis exacerbations. In addition, defective systemic and local immune mechanisms have been demonstrated and biologic response modifiers (BRMs) have been recently introduced for clinical use in patients with CB. We studied 24 patients with CB by bronchoalveolar lavage (BAL), before and after a 4-week treatment protocol with inhaled Immucytal (Pierre-Fabre Pharma Srl, Milan, Italy), a BRM composed of bacterial ribosomal fractions and membrane proteoglycans. Compared with normal controls (NC), before treatment BAL in patients with CB contained increased proportions of neutrophils (NC, 0.8 +/- 0.2 percent; CB, 3 +/- 1 percent), of eosinophils (NC, 0.1 +/- 0.02 percent; CB, 0.6 +/- 0.2 percent); and of lymphocytes (NC, 6 +/- 1 percent; CB, 13 +/- 2 percent; p < 0.01 each comparison) with higher percentages of CD3+ and CD8+ lymphocytes (p < 0.01 each comparison). In BAL from patients with CB there were also higher levels of albumin and of the ratio IgG/albumin (p < 0.01 and p < 0.05, respectively, compared with NC). After Immucytal treatment, the proportions of lymphocytes in BAL in patients with CB were decreased (13 +/- 2 percent before, 6 +/- 1 percent after; p < 0.01). In addition, the posttreatment BAL samples contained significantly fewer neutrophils per milliliter of BAL (3.7 +/- 0.8 x 10(3) neutrophils per milliliter of BAL before, 1.5 +/- 0.5 x 10(3) neutrophils per milliliter after; p < 0.05). No differences were seen for the proportions of lymphocyte subpopulations and for the protein levels between the BAL obtained before and after Immucytal treatment. These data demonstrate the presence of a lower respiratory tract inflammation in patients with CB and suggest that treatment of patients with CB with a BRM may change the proportions of inflammatory cells present in BAL.

The aim of this study was to evaluate the cellular and biochemical characteristics of the bronchoalveolar lavage (BAL) fluid in patients with farmer's lung disease (FLD). Total cell numbers in BAL fluids from patients with FLD (n = 30) were significantly higher than in normal subjects (n = 7; p < 0.01), and differential cell counts were significantly different. Lymphocytes were the most numerous cell type in BAL fluids from patients with FLD (65.4 +/- 2.5 percent vs 6.8 +/- 0.5 percent), and analysis of lymphocyte subsets revealed increased percentages of CD3+ and CD8+ cells (91.8 +/- 0.9 percent vs 68.8 +/- 3 percent, p < 0.01, and 54.3 +/- 3.1 percent vs 30.1 +/- 3.2 percent, p < 0.01, respectively). A marked increase in mast cell numbers, as revealed by the specific alcian blue/safranin staining, was observed in patients with FLD (4.2 +/- 0.57 percent, n = 12, vs 0.18 +/- 0.04 percent, n = 7, p < 0.001). Histamine levels in BAL supernatants were increased in patients with FLD (mean = SEM, 4.4 +/- 0.8 ng/ml vs 0.9 +/- 0.1 ng/ml; median, 2.4 ng/ml vs 0.9 ng/ml, p < 0.01), and correlated positively with mast cell numbers and percentages (r = +0.63, p < 0.03, and r = +0.69, p < 0.02, respectively); conversely, a negative correlation was found between histamine levels and CD8+ lymphocyte percentages (r = -0.48, p < 0.01). Raised neutrophil percentages (5.1 +/- 0.8 vs 0.5 +/- 0.18, p < 0.05) and albumin concentrations (29.2 +/- 3.9 mg/dl vs 3.4 +/- 1.3 mg/dl, p < 0.01) were also found in patients with FLD. These findings show that increased numbers of mast cells, lymphocytes, and neutrophils can be found in BAL fluids of patients with FLD. The increased histamine levels in the supernatants of BAL fluids indicate that mast cells are activated. These data allow us to postulate a role for mast cell accumulation and histamine release in the inflammatory process of FLD.

Fibrotic lung disorders are chronic inflammatory diseases in which inflammatory processes in the lower respiratory tract injure the lung and modulate the proliferation of mesenchymal cells that form the basis of the fibrotic scar. The pathogenesis of fibrosis in fibrotic lung disorders remains unclear; however, recent attention has focused on the potential role of the mast cell in the genesis of fibrosis. To determine whether mast cells are implicated in the pathogenesis of lung fibrosis, mast cells were compared with the degree of fibrosis in transbronchial lung biopsy specimens from 49 patients with fibrotic lung disorders (16 sarcoidosis, 15 farmer's lung disease, 9 cryptogenic fibrosing alveolitis, 6 bronchiolitis obliterans organizing pneumonia, 3 histiocytosis X). In lung tissue of patients with fibrotic lung disorders, there was an increased number of mast cells in respect to the control group (98.6 +/- 7.7 vs 27.8 +/- 5.1 mast cells per square millimeter, p < 0.01). Mast cell counts in lung biopsy specimens were significantly correlated with the degree of fibrosis (r = 0.87, p < 0.001); 80.8 percent of mast cells were found in the alveolar septa, 9.6 percent within alveoli, 1.9 percent among alveolar lining cells, and 5 percent along blood vessels. No mast cells were located within alveoli in controls. Our data suggest that mast cells participate in chronic inflammation and that their presence is related to interstitial fibrosis in a much broader spectrum of fibrotic lung disorders.

We evaluated tolerance, safety, and effects on lung function and bronchial responsiveness of BAL (4 x 50 ml) combined with BB (three to five specimens) performed without premedication in 13 mild and stable asthmatics and eight healthy volunteers. All subjects tolerated bronchoscopy procedures well and without serious side effects. During procedures, no supplemental oxygen was administered and no ECG abnormalities were noted. The PEFR was measured before and immediately after bronchoscopy and at 5-min intervals up until recovery. The maximal percentage fall in PEFR after bronchoscopy was significantly greater in asthmatics (23.1 +/- 13.9 percent) compared to normal subjects (7.8 +/- 8.2 percent, p less than 0.01). Changes in PEFR returned to baseline values within 120 min in all asthmatics. The tcPO2 was recorded at baseline, during and after bronchoscopy. In both groups, a significant change in tcPO2 was measured during the infusion of BAL aliquots, and persisted throughout the procedure. A significant difference in asthmatics compared to healthy subjects was evident during BB and at the end of the procedure (p less than 0.05). In asthmatics, M challenge was performed on three different days over a three-week period prior to bronchoscopy, and was repeated at intervals of 2, 6, and 24 h following procedure. The PC20 M values measured before bronchoscopy were found to have a very high reproducibility (intraclass correlation coefficient = 0.93). The PC20 values measured during experiment times after bronchoscopy were not significantly different from baseline values. These data demonstrate that in mild and stable asthmatics, BAL combined with BB can be safely performed following administration of only local anesthesia. In carefully selected asthmatic subjects, transient bronchoconstriction and a lowering of oxygen tension can be induced by BAL and BB, whereas changes in bronchial responsiveness are more unlikely to occur.

Recently, an increased number of mast cells have been reported in bronchoalveolar lavage fluid (BAL) of patients with farmer's lung disease. Some authors pointed out the pathogenetic importance of mast cells in farmer's lung on the basis of their correlation with the activity of the disease, with the BAL lymphocyte counts, and with the markers of lung fibrosis. To determine whether BAL reflects the histologic aspects of the lung histologic features in patients with farmer's lung disease, mast cells recovered from lavage fluid were compared with tissue sections from transbronchial lung biopsies in 15 patients. Mast cell counts in BAL and lung biopsy specimens were significantly correlated (r = 0.88; p less than 0.01), while no other correlations between BAL inflammatory cells and tissue mast cells were found. In lung tissue, there were four times the increased number of mast cells in respect to the control group (84.4 +/- 28.8 vs 20.4 +/- 13.4 mast cells per square millimeter); 83.2 percent of mast cells were found in the alveolar septa, 14.9 percent within alveoli, 0.7 percent among alveolar lining cells, and 1 percent along blood vessels. No mast cells were located within alveoli in controls. In BAL, only lymphocyte and mast cell counts (56.4 +/- 18.6 percent, p less than 0.001; 3.9 +/- 1.5 5 percent, p less than 0.001, respectively) were significantly increased. Our data suggest that in farmer's lung disease, BAL correctly samples the alveolitis. Mast cells, such as lymphocytes, seem to be primary inflammatory cells involved at the site of the disease activity.

Bronchoalveolar lavage and BB were performed in 13 asthmatic and six healthy subjects to characterize cellular markers of inflammation in BAL and BB; to compare cellular profile of BAL with cell infiltration in BB; to examine the relationship between bronchial responsiveness and markers of inflammation in BAL and BB. Eosinophils and mast cells were increased in BAL in asthmatic subjects; eosinophils were positively correlated with neutrophils and mast cells. Epithelial shedding was present in nine asthmatic and five control subjects. Intraepithelial cells and cells in submucosa were increased in asthmatic subjects. Eosinophils and intraepithelial mast cells were higher. Thickened basement membrane was associated with more marked cell infiltration in submucosa. Ciliated cells in BAL relate to intraepithelial cells; cells in BAL broadly reflect cell infiltration of submucosa. In the asthmatic group, the degree of bronchial responsiveness correlated with ciliated cells in BAL and with intra-epithelial cells in BB. Marked airway inflammation is associated with stable asthma; inflammatory changes within bronchial epithelium may be linked to the development of bronchial hyperresponsiveness.

This study was carried out to compare bronchial responses to inhaled propranolol (P) and methacholine (M) in a group of asthmatic subjects with mild to moderate bronchial hyperresponsiveness to M; to determine the short term reproducibility of bronchial response to propranolol; and to examine the shape of dose-response curve to P relative to that of M. Doses of M and P were given in mumoles and bronchial responses to both agents were expressed as the provocative dose that induced a 20 percent fall in FEV1 (PD20 FEV1). In 16 asthmatic patients, there was no correlation between the PD20 of the two agents. Mean PD20 M (+/- SD in log scale) was approximately nine times lower than mean PD20 P (0.64 +/- 0.96 and 5.80 +/- 1.65, respectively). This difference was statistically significant (t = 4.58, p less than 0.001). In six asthmatic patients, the reproducibility of PD20 P was similar to that of M (intraclass correlation coefficient 0.969 and 0.957, respectively). The shape of the dose-response curves to P was different from that of M in five of nine asthmatic patients when all experimental points were analyzed by double-reciprocal plot. We noticed that even small doses of inhaled P may cause a severe bronchoconstriction. Therefore, special caution should be taken to increase P doses very gradually, when studying the dose-response curve. We demonstrated that P inhalation induced a measurable bronchoconstriction in subjects with mild to moderate hyperresponsiveness and it was reproducible. However, the bronchial sensitivity to P was lower than to M. Our findings suggest that P and M have different mechanisms of action.