Italian registry of patients with alpha-1 antitrypsin deficiency: general data and quality of life evaluation.

Alpha1-antitrypsin Deficiency (AATD) is a rare hereditary disorder with an estimated prevalence of about 1/5000 individuals in Italy. Deficient patients are at a higher risk of developing lung emphysema and chronic liver disease. The low estimated prevalence of AATD prompted the establishment of a registry with the aim of learning more about the natural history and the quality of care of these patients. The Italian registry for AATD was established in 1996. In this study, genetic and clinical findings of Italian AATD patients are presented. Moreover, we also evaluated the changes in health-related quality of life (HRQoL) in patients with COPD and AAT deficiency over a three-year period, in relation to augmentation therapy. In a period spanning 18 years (1996-2014) a total of 422 adult subjects with severe AATD were enrolled, namely 258 PI*ZZ, 74 PI*SZ, 4 PI*SS and 86 patients with at least one rare deficient allele. The 21.3% frequency for AATD patients with at least one deficient rare variant is the highest so far recorded in national registries of AATD. The registry data allow a detailed characterization of the natural course of the disease and the level of patient care, as well as confirm the usefulness of early AATD detection.

Exhaled matrix metalloproteinase-9 (MMP-9) in different biological phenotypes of asthma.

BACKGROUND AND OBJECTIVES: Airway remodeling is a main feature of asthma. Different biological phenotypes of severe asthma have been recently recognized by the ENFUMOSA study group and among these one is characterized by neutrophilic airway inflammation. Concentrations of MMP-9 in airways have been suggested as a marker to monitor airway remodeling in asthma. OBJECTIVE: The aim of the present study was to explore airway remodeling in different biological phenotypes of asthma by measuring MMP-9 in EBC and correlating these with other variables. METHODS: Sixty consecutive subjects with asthma and 20 healthy controls were enrolled in the study. Exhaled MMP-9, pH and NO levels and inflammatory cells in sputum were measured in all subjects enrolled. RESULTS: We observed an increase of exhaled MMP-9 in asthmatic subjects compared to controls. Higher exhaled MMP-9 concentrations were described in severe asthmatics compared to mild to moderate especially in those with neutrophilic airway inflammation. We further found a correlation between exhaled MMP-9 and percentage of neutrophils in sputum, FEV1, exhaled NO and pH. CONCLUSION: Our results seem to substantiate the feasibility of measuring exhaled MMP-9 in the breath of asthmatic patients. MMP-9 may be considered a proxy of the amount of the ongoing airway remodeling in asthma. MMP-9 has been shown to be differentially released in different phenotypes of asthma. The measure of exhaled MMP-9 could help to monitor the ongoing airway remodeling, recognize severe stages of asthma, and possibly help determine the appropriate choice of therapy.

Airway cell patterns in patients suffering from COPD and OSAS (Overlap Syndrome).

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD) are two diseases that often coexist within an individual. This coexistence is known as Overlap Syndrome (OS). Both diseases are characterized by local and systemic inflammations, but no studies to date have investigated local airway inflammation in patients suffering from Overlap Syndrome. METHODS: We performed a Berlin Questionnaire to evaluate the presence of the principal OSAS symptoms, a pulmonary function test, and then a nocturnal oximetry and polysomnography in 72 patients that were divided into five groups: OS (n = 18), COPD (n = 15), OSAS (n = 16), 12 obese without OSAS or COPD, and one control group of 11 normal subjects. All patients underwent sputum induction and the analysis of cell patterns were evaluated in all groups. The relationship with the degree of obesity, airway obstruction and OSAS severity was also evaluated. RESULTS: The percentage of neutrophils in induced sputum was higher in OS (74.33% ± 14.8), COPD (63.33% ± 13.22) and OSAS (60.69% ± 17.6) subjects compared with control groups of obese (43.5% ± 17.49) and normal weight (32.04% ± 12.26). No difference was found among Overlap, COPD, and OSAS patients (p = 0.56). A negative correlation was found between PaO(2) and percentage of airway neutrophils (r = -0.29, p < 0.05); similarly, no correlations arose between BMI, FEV(1) or ODI. CONCLUSION: Patients suffering from Overlap Syndrome present a high percentage of neutrophils in induced sputum like patients affected by COPD or OSAS alone. Our result suggests that airway inflammations is always involved in all of these diseases, even though probably sustained by different mechanisms.

Effect of PEEP on induced constriction is enhanced in decorin-deficient mice.

Decorin (Dcn), a small leucine-rich proteoglycan, is present in the extracellular matrix of the airways and lung tissues, contributes to lung mechanical properties, and its deposition is altered in asthma. The effect of Dcn deficiency on airway parenchymal interdependence was examined during induced bronchoconstriction. Studies were performed in C57Bl/6 mice in which the Dcn gene was disrupted by targeted deletion (Dcn(-/-)) and in wild-type controls (Dcn(+/+)). Mice were mechanically ventilated, and respiratory system impedance was measured during in vivo ventilation at positive end-expiratory pressure (PEEP) = 2 and 10 cmH(2)0, before and after aerosol delivery of methacholine (MCh). Length vs. tension curves in isolated tracheal rings were measured in vitro. Dcn distribution in +/+ mice airways was characterized by immunofluorescence; differences in collagen structure in Dcn(+/+) and Dcn(-/-) mouse lungs was examined by electron microscopy. MCh caused similar increases in airway resistance (Raw) and tissue elastance (H) in Dcn(+/+) and Dcn(-/-) mice. During MCh-induced constriction, increasing PEEP caused a decrease in Raw that was greater in Dcn(-/-) mice and a decrease in H in Dcn(-/-) mice only. Tracheal ring compliance was greater in Dcn (-/-) mice. Imaging studies showed that Dcn was deposited primarily in the airway adventitial layer in Dcn(+/+) mice; in Dcn(-/-) mice, collagen had an irregular appearance, especially in the lung periphery. These results show that lack of Dcn alters the normal interaction between airways and lung parenchyma; in asthma, changes in Dcn could potentially contribute to abnormal airway physiology.

The i.v. infusion of mannitol decreases airway responsiveness to methacholine in asthma.

Bronchial asthma and chronic obstructive pulmonary disease (COPD) are characterized by airway inflammation and oedema. The oedema of the airway wall may contribute to airway narrowing and hyperresponsiveness by increasing airway wall thickness, by altering airway compliance, or by impairing the transmission of the lung elastic recoil to the airway smooth muscle (ASM). We hypothesized that the i.v. infusion of mannitol, an osmotic diuretic, would reduce the water content of the airway wall in asthma and COPD, thus decreasing airway responsiveness to methacholine (MCh). In eight asthmatic and in six COPD patients, airway responsiveness to MCh, lung volumes and lung mechanics were measured before and after infusion of mannitol. In the asthmatics, mannitol decreased airway responsiveness to MCh and lung elastic recoil. In the COPD patients, no differences were recorded after mannitol infusion. These data suggest that the airway wall oedema, in asthma, has an impact on airway responsiveness to MCh. The differential effect of mannitol in asthma versus COPD, may relate to the specific pathologic features of the diseases.

Changes in sputum composition during 15 min of sputum induction in healthy subjects and patients with asthma and chronic obstructive pulmonary disease.

INTRODUCTION: The use of sputum induction by inhalation of hypertonic saline to study the cellular and biochemical composition of the airways allows noninvasive sampling of the airways content and identification of markers of airways inflammation. OBJECTIVE: The present study aimed to identify possible changes in the cellular composition of induced sputum between samples obtained sequentially (three periods of 5 min each) during one sputum induction. Moreover, difference between these samples and the mixed one (mixture of samples obtained after 5, 10 and 15 min of induction) was investigated. METHODS: Forty-six subjects (10 healthy volunteers, 12 patients with chronic obstructive pulmonary disease (COPD) and 24 patients with asthma) (mean age 53.0+/-14.0 yr, forced expiratory volume in one second (FEV(1)) 71.8+/-19.0% pred) produced sputum after three consecutive 5 min periods of hypertonic (4.5%) saline inhalation. Stained cytospins from the three periods separately and from the mixed sample were produced and analyzed. RESULTS: The mean percentage of neutrophils, eosinophils, lymphocytes and epithelial cells did not change significantly in samples obtained consecutively after 5, 10 and 15 min of the induction procedure. There was no significant difference in the cellular composition of samples obtained after 5, 10 and 15 min of induction and the cellular composition of the mixed sample (P=0.06). CONCLUSION: The separate analysis of induced sputum from three consecutive sampling and the mixed sample did not demonstrate significant changes in their cellular composition. Fifteen minutes induction procedure with the fixed concentration of hypertonic saline and processing of the mixed sample can be recommended for clinical settings and clinical trials.

Attenuation of induced bronchoconstriction in healthy subjects: effects of breathing depth.

The effects of breathing depth in attenuating induced bronchoconstriction were studied in 12 healthy subjects. On four separate, randomized occasions, the depth of a series of five breaths taken soon (approximately 1 min) after methacholine (MCh) inhalation was varied from spontaneous tidal volume to lung volumes terminating at approximately 80, approximately 90, and 100% of total lung capacity (TLC). Partial forced expiratory flow at 40% of control forced vital capacity (V(part)) and residual volume (RV) were measured at control and again at 2, 7, and 11 min after MCh. The decrease in V(part) and the increase in RV were significantly less when the depth of the five-breath series was progressively increased (P < 0.001), with a linear relationship. The attenuating effects of deep breaths of any amplitude were significantly greater on RV than V(part) (P < 0.01) and lasted as long as 11 min, despite a slight decrease with time when the end-inspiratory lung volume was 100% of TLC. In conclusion, in healthy subjects exposed to MCh, a series of breaths of different depth up to TLC caused a progressive and sustained attenuation of bronchoconstriction. The effects of the depth of the five-breath series were more evident on the RV than on V(part), likely due to the different mechanisms that regulate airway closure and expiratory flow limitation.