Alpha-1 antitrypsin deficiency is significantly associated with atopy in asthmatic patients.

Background: Although the etiology and disease mechanisms of asthma and alpha-1 antitrypsin deficiency (AATD) are distinct, several reports indicate that asthma is common in AATD patients, however the relationships between asthma and AATD are poorly described in the literature.Objectives: The aim of the study was to investigate in a cohort of outpatients affected by mild to moderate asthma the clinical features that may differentiate asthmatic patients with and without mutation on SERPINA1 gene.Methods: Seven hundred thirty-five asthmatic outpatients underwent quantitative analysis of the serum level of alpha-1antitrypsin. According to the literature only sixty-seven out of seven hundred thirty-five asthmatic patients were submitted to genetic analysis to identify AATD and non-AATD subjects. Fifty-eight patients were studied. Clinical and functional data, including lung function, atopy and bronchial hyperactivity, were recorded.Results: The fifty-eight asthmatic patients were divided in AATD patients (n = 22) and non AATD patients (n = 36), according to genotype. The presence of atopy was significantly higher in patients with AATD than in those without AATD (91% vs. 64%; p = 0.031). AATD patients reported allergic manifestations more than non AATD patients (77% vs. 47%; p = 0.030).Conclusion: Our study shows that the presence of atopy in asthmatic patients with AATD is significantly higher than in asthmatic patients without gene mutation. In addition, a higher percentage of AATD patients self-reported allergic manifestations. No significant differences in respiratory symptoms, physical examination, disease severity or inflammation markers were found between AATD patients and non AATD patients.

The COPD assessment test and the modified Medical Research Council scale are not equivalent when related to the maximal exercise capacity in COPD patients.

INTRODUCTION: The management and treatment of Chronic Obstructive Pulmonary Disease (COPD) are based on a cutoff point either of ≥ 10 on the COPD Assessment Test (CAT) or of ≥ 2 of the Medical Research Council (mMRC). Up to now, no study has assessed the equivalence between CAT and mMRC, as related to exercise tolerance in COPD. The aim of this study was to investigate as primary outcome the relationship between CAT and mMRC and maximal exercise capacity in COPD patients. We also evaluated as secondary outcome the agreement between CAT (≥ 10) and mMRC (≥ 2) to categorize patients according to their exercise tolerance. MATERIAL AND METHODS: 118 consecutive COPD patients (39 females), aged between 47 and 85 years with a wide range of airflow obstruction and lung hyperinflation were studied. Maximal exercise capacity was assessed by cardiopulmonary exercise test. RESULTS: CAT and mMRC scores were significantly related to VO2 peak (p<0.01). CAT (≥ 10) and mMRC (≥ 2) have a high likelihood to be associated to a value of VO2 peak less than 15.7 and 15.6 mL/kg/min, respectively. The interrater agreement between CAT (≥ 10) and mMRC (≥ 2) was found to be fair (κ = 0.20) in all patients but slight when they were subdivided in those with VO2 peak < 15 mL/kg/min and in those with VO2 peak ≥ 15 mL/kg/min (κ = 0.10 and κ = 0.20 respectively). CONCLUSION: This study shows that CAT and mMRC are useful tools to predict exercise tolerance in COPD, but they cannot be considered as supplementary measures.

Mast cells in bronchoalveolar lavage fluid and in transbronchial biopsy specimens of patients with farmer's lung disease.

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.

Mast cells in fibrotic lung disorders.

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.

Lung function and bronchial responsiveness after bronchoalveolar lavage and bronchial biopsy performed without premedication in stable asthmatic subjects.

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.

Inflammatory markers in bronchoalveolar lavage and in bronchial biopsy in asthma during remission.

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.

Airways remodeling is a distinctive feature of asthma and is related to severity of disease.

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.

Mast cell and histamine involvement in farmer's lung disease.

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.

Bronchoalveolar lavage analysis of interstitial lung disease in CREST syndrome.

The bronchoalveolar lavage (BAL) technique was used to characterize inflammatory cells in the lower respiratory tract of seven nonsmoking patients with CREST syndrome and interstitial pulmonary fibrosis. Differential cell counts in the BAL fluid showed a significant increase of neutrophils (p less than 0.05) and eosinophils (p less than 0.01) in comparison to normal subjects. In three patients there was also an increase of lymphocytes. No correlation was found between BAL and duration of scleroderma and/or lung function tests. The BAL findings in these scleroderma patients resemble those of idiopathic interstitial fibrosis suggesting that a similar inflammatory process occurs within the lower respiratory tract.

Eosinophils and the lung.

An increase in the number of eosinophils in blood, tissues or sputum is found in many pulmonary disorders, although the review is mainly concerned with the association of eosinophilia with bronchial asthma and pulmonary eosinophilia. In this review, the morphology and life cycle of eosinophils is discussed. The role played by eosinophil secretions and eosinophil chemoattractants in the pathophysiology of the lung is also reviewed.

Eosinophilic alveolitis in immunologic interstitial lung disorders.

To analyze the role of eosinophils in alveolitis due to immunological interstitial lung disorders, 568 bronchoalveolar lavage (BAL) from 537 patients affected by 13 types of interstitial lung disease involving immunologic mechanisms were considered. An arbitrary cut-off of 4% of eosinophils in BAL was assumed. In five (idiopathic pulmonary fibrosis (IPF), allergic bronchopulmonary aspergillosis (ABPA), amiodarone-induced pneumonitis (AIP), chronic eosinophilic pneumonia (CEP), Churg-Strauss syndrome (CSS)) out of the thirteen groups we took into consideration, the level of eosinophils was greater than 4%. In CEP and CSS in particular, the arbitrary cut-off of 4% was greatly exceeded (28.9% +/- 27.4, p less than 0.01 and 33.6% +/- 14.5, p less than 0.01, respectively). In the same two groups the increase of eosinophils in BAL was isolated with a direct correlation to the number of eosinophils in blood. By contrast, the increase of eosinophils in BAL of IPF, AIP and ABPA was of lesser extent (4.7% +/- 5.7 p less than 0.01, 5.0% +/- 3.0 p less than 0.01 and 6.1% +/- 10.4 p less than 0.01, respectively) and was accompanied by an increase of neutrophils in IPF, of lymphocytes in AIP and both in ABPA. These patterns are generally defined as "mixed alveolitis." On the basis of these data we conclude that the term "eosinophilic alveolitis" should be reserved for CEP and CSS.

Histochemical characteristics and degranulation of mast cells in epithelium and lamina propria of bronchial biopsies from asthmatic and normal subjects.

We examined the staining characteristics and degranulation of mast cells in bronchial biopsy specimens taken by fiberoptic bronchoscopy from 13 stable asthmatic patients and eight normal nonsmoking subjects. Specimens were fixed in periodate-lysine-paraformaldehyde, embedded in glycol methacrylate, and stained with toluidine blue (2%) for 30 min (pH 2.7) and 7 days (pH 0.5). The number of mast cells in the epithelium and in the lamina propria was counted under light microscopy. In addition, the distribution of mast cells with different granule contents, arbitrarily defined as degranulated or partly degranulated and fully granulated, was estimated at the two levels. In asthmatic subjects, the number of mast cells in the epithelium after either staining method was significantly higher compared with that in control subjects. The number of mast cells in the lamina propria, but not in the epithelium, was significantly higher after 7 days compared with 30-min toluidine blue stain both in asthmatic (135.6/mm2 versus 74.8/mm2; p < 0.001) and control subjects (121.5/mm2 versus 71.5/mm2; p < 0.01). There was evidence of a progressive mast cell degranulation when moving toward the airway lumen in both groups. However, degranulation was more evident in asthmatic subjects. In both groups, granulated mast cells were absent in the epithelium, whereas in the lamina propria granulated mast cells were approximately one-third of total in asthmatic and two-thirds of total in normal subjects. These observations suggest that mast cells in human bronchial mucosa are heterogeneous with respect to histochemical characteristics. They provide evidence that degranulation of mast cells occurs in both asthmatic and normal subjects and that degranulation is greater in asthmatics.

Mast cells in the airway lumen and bronchial mucosa of patients with chronic bronchitis.

In order to evaluate the degree of mast cell infiltration and determine their granulation state in the airways of patients with chronic bronchitis, bronchoscopy was performed in 25 chronic bronchitis subjects (10 smokers and 15 ex-smokers) with mucoid sputum production and in seven normal nonsmoking control subjects. Bronchoalveolar lavage and bronchial biopsies were examined using histochemical techniques. Subjects with chronic bronchitis had higher numbers of mast cells both in the epithelium (1.22 +/- 1 versus 0.22 +/- 0.2 mast cells per mm) and in the bronchial glands (137.4 +/- 37.9 versus 38 +/- 5.1 mast cells per mm2) than did control subjects (p < 0.01 and p < 0.001, respectively), whereas the numbers of mast cells in bronchoalveolar lavage (0.21 +/- 0.1 versus 0.18 +/- 0.1 mast cells percentage, nonsignificant [NS]) and in the lamina propria (87.5 +/- 66.4 versus 87.2 +/- 61.8 mast cells per mm2, NS) were similar in the two groups. In the smoking group of bronchitics an increase in mast cell numbers was observed in epithelium (1.6 +/- 1.3 versus 0.95 +/- 0.7 mast cells per mm, NS), in lamina propria (112.2 +/- 86.5 versus 71.7 +/- 45.7 mast cells per mm2), and in BAL (0.26 +/- 0.21 versus 0.16 +/- 0.17 mast cell percentage of total cells, NS) in comparison with the ex-smoker's group of bronchitics.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary involvement in Sjögren's syndrome.

In this study we tried to value the frequency and the characteristics of the physiological abnormalities affecting the lungs in Sjögren's syndrome (SS). We studied 18 female nonsmokers (average age 53 years). The diagnosis has been made on the presence of at least two of the following abnormalities: keratoconjunctivitis sicca (Schirmer's test), xerostomia (scanning of the salivary glands, lip biopsy) and collagen vascular disease. We made the following tests: clinical examination, chest roentgenogram, spirometry, TGV, RAW and SAW valuation, study of the flow-volume curves, diffusion capacity test, bronchoalveolar lavage, bronchial biopsy. The physiological results have demonstrated the presence of a restrictive syndrome affecting above all the small airways (MEF25-32.7%) and a decrease of the diffusion capacity (DLCO-25%). There is, moreover, a constant lymphocytic infiltration of the bronchial mucosa and of the lung's interstitium. In conclusion the pulmonary involvement in SS seems to be constant, unpredictable and of remarkable clinical-physiological importance.

Clinical physiological data on the bronchodilator effect of Duovent versus salbutamol in chronic obstructive lung disease.

We studied the bronchodilator effect of a combination of fenoterol (100 micrograms) and ipratropium bromide (40 micrograms) (Duovent) versus salbutamol and placebo in 16 patients with chronic obstructive lung disease (COLD). FEV1 and the side-effects (palpitations, tremors, excitation) were measured at 0, 30, 60, 120, 240, 360 and 420 min after administration. The drugs were administered in aerosol form following a randomization schedule. The bronchodilator effect of Duovent was greater than that of salbutamol; moreover, Duovent had a lasting efficacy and few side-effects. Duovent is thus a useful drug therapeutically.