Quantification of circulating alpha-1-antitrypsin polymers associated with different SERPINA1 genotypes.

OBJECTIVES: Alpha-1-antitrypsin deficiency is a genetic disorder caused by mutations in the SERPINA1 gene encoding alpha-1-antitrypsin (AAT), the major serine protease inhibitor in plasma. Reduced AAT levels are associated with elevated risk of developing emphysema mainly due to uncontrolled activity of neutrophil elastase in the lungs. The prevalent Z-AAT mutant and many rare pathogenic AAT variants also predispose to liver disease due to their accumulation as polymeric chains in hepatocytes. Part of these polymers are secreted into the bloodstream and could represent biomarkers of intra-hepatic accumulation. Moreover, being inactive, they further lower lung protection against proteases. Aim of our study is to accurately quantify the percentage of circulating polymers (CP) in a cohort of subjects with different SERPINA1 genotypes. METHODS: CP concentration was measured in plasma or Dried Blood Spot (DBS) by a sensitive sandwich ELISA based on capture by the polymer-specific 2C1 monoclonal antibody. RESULTS: CP were significantly elevated in patients with the prevalent PI*SZ and PI*ZZ genotypes, with considerable intra-genotype variability. Notably, higher percentage of polymers was observed in association with elevated C-reactive protein. CP levels were also increased in carriers of the Mmalton variant, and of Mprocida, I, Plowell and Mherleen in heterozygosity with Z-AAT. CONCLUSIONS: These findings highlight the importance of implementing CP quantification in a clinical laboratory. Indeed, the variable amount of CP in patients with the same genotype may correlate with the variable severity of the associated lung and liver diseases. Moreover, CP can reveal the polymerogenic potential of newly discovered ultrarare AAT variants.

Breath-holding physiology, radiological severity and adverse outcomes in COVID-19 patients: A prospective validation study.

BACKGROUND AND OBJECTIVE: COVID-19 remains a major cause of respiratory failure, and means to identify future deterioration is needed. We recently developed a prediction score based on breath-holding manoeuvres (desaturation and maximal duration) to predict incident adverse COVID-19 outcomes. Here we prospectively validated our breath-holding prediction score in COVID-19 patients, and assessed associations with radiological scores of pulmonary involvement. METHODS: Hospitalized COVID-19 patients (N = 110, three recruitment centres) performed breath-holds at admission to provide a prediction score (Messineo et al.) based on mean desaturation (20-s breath-holds) and maximal breath-hold duration, plus baseline saturation, body mass index and cardiovascular disease. Odds ratios for incident adverse outcomes (composite of bi-level ventilatory support, ICU admission and death) were described for patients with versus without elevated scores (>0). Regression examined associations with chest x-ray (Brixia score) and computed tomography (CT; 3D-software quantification). Additional comparisons were made with the previously-validated '4C-score'. RESULTS: Elevated prediction score was associated with adverse COVID-19 outcomes (N = 12/110), OR[95%CI] = 4.54[1.17-17.83], p = 0.030 (positive predictive value = 9/48, negative predictive value = 59/62). Results were diminished with removal of mean desaturation from the prediction score (OR = 3.30[0.93-11.72]). The prediction score rose linearly with Brixia score (ß[95%CI] = 0.13[0.02-0.23], p = 0.026, N = 103) and CT-based quantification (ß = 1.02[0.39-1.65], p = 0.002, N = 45). Mean desaturation was also associated with both radiological assessment. Elevated 4C-scores (≥high-risk category) had a weaker association with adverse outcomes (OR = 2.44[0.62-9.56]). CONCLUSION: An elevated breath-holding prediction score is associated with almost five-fold increased adverse COVID-19 outcome risk, and with pulmonary deficits observed in chest imaging. Breath-holding may identify COVID-19 patients at risk of future respiratory failure.

Breath-holding as a novel approach to risk stratification in COVID-19.

BACKGROUND: Despite considerable progress, it remains unclear why some patients admitted for COVID-19 develop adverse outcomes while others recover spontaneously. Clues may lie with the predisposition to hypoxemia or unexpected absence of dyspnea ('silent hypoxemia') in some patients who later develop respiratory failure. Using a recently-validated breath-holding technique, we sought to test the hypothesis that gas exchange and ventilatory control deficits observed at admission are associated with subsequent adverse COVID-19 outcomes (composite primary outcome: non-invasive ventilatory support, intensive care admission, or death). METHODS: Patients with COVID-19 (N = 50) performed breath-holds to obtain measurements reflecting the predisposition to oxygen desaturation (mean desaturation after 20-s) and reduced chemosensitivity to hypoxic-hypercapnia (including maximal breath-hold duration). Associations with the primary composite outcome were modeled adjusting for baseline oxygen saturation, obesity, sex, age, and prior cardiovascular disease. Healthy controls (N = 23) provided a normative comparison. RESULTS: The adverse composite outcome (observed in N = 11/50) was associated with breath-holding measures at admission (likelihood ratio test, p = 0.020); specifically, greater mean desaturation (12-fold greater odds of adverse composite outcome with 4% compared with 2% desaturation, p = 0.002) and greater maximal breath-holding duration (2.7-fold greater odds per 10-s increase, p = 0.036). COVID-19 patients who did not develop the adverse composite outcome had similar mean desaturation to healthy controls. CONCLUSIONS: Breath-holding offers a novel method to identify patients with high risk of respiratory failure in COVID-19. Greater breath-hold induced desaturation (gas exchange deficit) and greater breath-holding tolerance (ventilatory control deficit) may be independent harbingers of progression to severe disease.

Z-alpha1-antitrypsin polymers and small airways disease: a new paradigm in alfa-1 anti-trypsin deficiency-related COPD development?

The presence of Alpha1-Antitrypsin (AAT) polymers, known to promote a sustained pro-inflammatory activity, has been previously demonstrated in bronchial biopsies of subjects with Z-AAT deficiency (AATD) suggesting a possible role in the development of COPD through a small airway disease impairment. The study aimed to assess the presence of small airways dysfunction and the potential correlation with the presence of Z-AAT polymers obtained by Exhaled Breath Condensate (EBC) collection in PiZZ subjects, as compared with matched healthy PiMM subjects. We enrolled 19 asymptomatic, never smoker subjects: 9 PiZZ and 10 PiMM as controls, without obstructive ventilatory defect (i.e., normal FEV1/VC% ratio). All subjects underwent complete pulmonary function tests (PFT). EBC was collected in all subjects. ELISA test was applied to search for Z-AAT polymers. The PiZZ subjects showed normal lung volumes and DLCO values. However, in comparison with PiMM subjects, the single breath test N2 wash-out revealed significant differences regarding the phase III slope (1.45±0.35 N2/L vs. 0.96±0.40 N2/L) (p<0.02) in the PiZZ subjects, while the closing volume/vital capacity ratio (14.3±4.5 % vs. 11.3±6.3 %) was not significantly increased. The ELISA test detected the presence of Z-AAT polymers in 44% of PiZZ patients. Asymptomatic, never smoker PiZZ subjects with normal spirometry and lung diffusion capacity showed airways impairment when compared to PiMM subjects. Although Z-AAT polymers were found only in 44% of PiZZ subjects, these findings suggest the possibility that chronic bronchiolitis can develop as a result of the long-term pro-inflammatory activity of Z-AAT polymers in subjects with Z-related AATD.

Phenotyping-based treatment improves obstructive sleep apnea symptoms and severity: a pilot study.

BACKGROUND: Obstructive sleep apnea is a common disorder characterized by multiple pathogenetic roots. Continuous positive airway pressure (CPAP) is almost always prescribed as the first-line treatment to all patients regardless of the heterogeneous pathophysiology, because it mechanically splints the airways open and reduces the collapsibility of the upper airway. Despite its high efficacy, CPAP is burdened by poor adherence and compliance rates. In this pilot study, we treated OSA patients with composite approaches different than CPAP, tailoring the therapeutic choice on OSA phenotypic traits. METHODS: We used the CPAP dial down technique to assess phenotypic traits in eight OSA patients with BMI<35. According to these traits, patients received personalized therapies for 2-week period, after which we ran a second polygraphy to compare apnea-hypopnea index (AHI) before and after therapy. RESULTS: Two weeks of combined behavioral and pharmacological therapy induced a significant reduction in mean AHI, which dropped from 26 ± 15 at baseline to 9 ± 7 post-treatment (p = 0.01). Furthermore, there was a significant reduction in mean ODI (p = 0.03) and subjective sleepiness (p = 0.01) documented by Epworth Sleepiness Scale (ESS) from baseline to post-treatment recordings. CONCLUSIONS: Treating OSA patients with a personalized combination of pharmacological and behavioral therapies according to phenotypic traits leads to a significant improvement in AHI, ODI, and subjective sleepiness.

Cardiac Sympathetic Hyperactivity in Patients with Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) coexist in 0.5-1% of the general population. Both OSA and COPD are associated with increased sympathetic nervous activity, and patients affected by both disorders have higher risk for increased morbidity and mortality as compared with patients with COPD or OSA alone. We tested the hypothesis that patients with COPD and OSA (Overlap syndrome) have higher sympathetic and lower parasympathetic modulation of heart rate variability (HRV) in comparison with patients suffering from COPD or OSA alone. HRV indices in the frequency domain were evaluated from daytime electrocardiographic recordings in 14 patients with both severe OSA (apnea-hypopnea index ≥ 30) and mild-to-moderate COPD and compared with those with OSA (n = 24) or COPD (n = 16) alone. We found that, in the Overlap syndrome group, high-frequency (HF, 0.4-0.15 Hz) power was significantly lower (0.18 nu vs 0.34 nu in OSA and 0.44 nu in COPD patients, p < 0.01) and low-frequency (LF, 0.15-0.05 Hz) power was significantly greater (0.82 nu vs 0.66 nu in OSA and 0.57 nu in COPD patients, p < 0.01) compared with COPD and OSA groups. Patients with both OSA and COPD had higher LF/HF ratio as compared with patients in OSA and COPD groups (4.5 [5.9] vs 1.9 [2.6] and 1.3 [1.3], respectively, p < 0.01). For the Overlap syndrome group, there was a significant direct relationship between LF/HF ratio and residual volume (r2 = 0.62, p = 0.007). These findings show that patients with both OSA and COPD have higher sympathetic modulation of heart rate compared with those with OSA or COPD alone. Furthermore, the findings provide a potential mechanism for the increased morbidity and mortality reported in patients suffering from both disorders, suggesting new therapeutic perspectives in Overlap syndrome.

Echocardiographic evaluation in subjects with α1-Antitrypsin deficiency.

BACKGROUND: α1-Antitrypsin (AAT) deficiency (AATD) is a genetic condition associated with early-onset panacinar emphysema and, less often, vascular disease. Recently, abnormal elastic properties of ascending aortic wall were described in ZZ genotype AATD subjects who incidentally showed an increased left ventricular mass. MATERIALS AND METHODS: To evaluate biventricular dimensions, valvular apparatus, systolic and diastolic function, 33 AATD subjects with ZZ genotype and 33 healthy subjects matched for age and sex underwent a complete echocardiographic assessment. RESULTS: Compared to controls, AATD subjects showed increased left ventricular mass (160 ± 59 g vs. 121 ± 70 g, P < 0.001), a higher incidence of left and right ventricular diastolic dysfunction (30% vs. 16%, P < 0.001 and 45% vs. 20%, P < 0.001, respectively) and mitral valve prolapse (35% vs. 6%, P < 0.001). In contrast, there was no difference between the two groups in diameters and systolic function of both ventricles and in the ejection fraction of left ventricle. The functions of aortic and tricuspidal valves were also similar. CONCLUSIONS: In the presence of greater left ventricular mass, a significantly higher incidence of left and right ventricular diastolic dysfunction and mitral valve prolapse occurs in AATD subjects (ZZ genotype). These findings strongly suggest an abnormal remodelling process in cardiac tissue in AATD.

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.

The role of bronchial epithelial cells in the pathogenesis of COPD in Z-alpha-1 antitrypsin deficiency.

BACKGROUND: Alpha-1 antitrypsin is the main inhibitor of neutrophil elastase in the lung. Although it is principally synthesized by hepatocytes, alpha-1 antitrypsin is also secreted by bronchial epithelial cells. Gene mutations can lead to alpha-1 antitrypsin deficiency, with the Z variant being the most clinically relevant due to its propensity to polymerize. The ability of bronchial epithelial cells to produce Z-variant protein and its polymers is unknown. METHODS: Experiments using a conformation-specific antibody were carried out on M- and Z-variant-transfected 16HBE cells and on bronchial biopsies and ex vivo bronchial epithelial cells from Z and M homozygous patients. In addition, the effect of an inflammatory stimulus on Z-variant polymer formation, elicited by Oncostatin M, was investigated. Comparisons of groups were performed using t-test or ANOVA. Non-normally distributed data were assessed by Mann-Whitney U test or the Kruskal-Wallis test, where appropriate. A P value of < 0.05 was considered to be significant. RESULTS: Alpha-1 antitrypsin polymers were found at a higher concentration in the culture medium of ex vivo bronchial epithelial cells from Z-variant homozygotes, compared with M-variant homozygotes (P < 0.01), and detected in the bronchial epithelial cells and submucosa of patient biopsies. Oncostatin M significantly increased the expression of alpha-1 antitrypsin mRNA and protein (P < 0.05), and the presence of Z-variant polymers in ex vivo cells (P < 0.01). CONCLUSIONS: Polymers of Z-alpha-1 antitrypsin form in bronchial epithelial cells, suggesting that these cells may be involved in the pathogenesis of lung emphysema and in bronchial epithelial cell dysfunction.

Oronasal masks require higher levels of positive airway pressure than nasal masks to treat obstructive sleep apnea.

PURPOSE: The purpose of this study was to compare the therapeutic pressure determined by an automated CPAP device (AutoCPAP) during the titration period, between nasal and oronasal mask and the residual apnea-hypopnea index (AHI) on a subsequent poligraphy performed with the established therapeutic CPAP. METHODS: As a retrospective study, 109 subjects with moderate and severe obstructive sleep apnea-hypopnea (apnea-hypopnea index≥15 events/h) were studied. CPAP titration was performed using an auto-titrating device. RESULTS: There was significant difference in the mean pressure delivered with autoCPAP between the group of patients using the nasal mask (mean 10.0 cmH2O±2.0 SD) and the group which used the oronasal mask (mean 11.2 cmH2O±2.1) (p<0.05). Residual apneas were lower when using a nasal mask: average AHI of 2.6±2.5 compared to 4.5±4.0 using an oronasal mask (p<0.05). On multivariate analysis, the only independent predictor of the level of therapeutic pressure of CPAP was the type of mask used (r=0.245, p 0.008). CONCLUSIONS: Therapeutic CPAP level for OSAH is higher when administered via oronasal mask, leaving more residual events. These findings suggest that nasal mask should be the first choice for OSAH treatment.

Tidal expiratory flow limitation at rest as a functional marker of pulmonary emphysema in moderate-to-severe COPD.

BACKGROUND: Tidal expiratory flow limitation (EFL) is a step of paramount importance in the functional decline in COPD. Among mechanisms contributing to EFL, loss of airway-parenchymal interdependence could mostly be involved. AIM: To assess if EFL is a functional marker more frequently linked to prevalent pulmonary emphysema rather than to prevalent chronic bronchiolitis in COPD patients with moderate-to-severe airflow obstruction. METHODS: Forty consecutive stable COPD patients with FEV1 between 59 and 30% of predicted were functionally evaluated by measuring spirometry, maximal flow-volume curve and lung diffusion capacity (DLCO) and coefficient of diffusion (KCO). EFL was assessed by the negative expiratory pressure (NEP) method both in sitting and supine position. Chronic dyspnea was also scored by modified Medical Research Council (mMRC) scale. RESULTS: In sitting position 13 patients (33%) were flow limited (FL) and 27 were non-flow limited (NFL). Only FEV1/FVC, FEV1 and MEF25-75% were different between FL and NFL patients (p < 0.01). In supine position, however, among NFL patients in sitting position those who developed EFL, had significantly lower values of DLCO and KCO (p < 0.05) and higher mMRC score (p < 0.01), but similar values of FEV1 as compared to those who did not have EFL. CONCLUSIONS: In COPD EFL in sitting position is highly dependent by the severity of airflow obstruction. In contrast, the occurrence of EFL in supine position is associated with worse DLCO and KCO and greater chronic dyspnea, reflecting a prevalent emphysematous phenotype in moderate-to-severe COPD patients.

Sleep-disordered breathing and pregnancy outcomes: The impact of maternal oxygen saturation.

OBJECTIVE: To investigate pathological associations between sleep-disordered breathing (SDB) and pregnancy outcomes. METHODS: From May 2016 to September 2019, obese women during their uncomplicated singleton pregnancies underwent screening sleep questionnaires, oxygen saturation monitoring, and, in proper cases, complete overnight polysomnography. Their medical records were also recorded. RESULTS: In all, 112 pregnant women were included in the study cohort; 44 showed an oxygen desaturation index ≥10, and their newborns had a significantly higher rate of congenital abnormalities and respiratory distress syndrome compared with the women with normal pulse oximetry. Stepwise multivariate regression analysis showed that basal oxygen saturation was independently associated with the occurrence of fetal growth restriction. CONCLUSION: Among obese pregnant women, the rate of congenital abnormalities is higher in the ones with altered pulse oximetry. Maternal basal oxygen saturation in the first trimester of pregnancy predicts fetal growth restriction independently of maternal age, ethnicity, body mass index, gravidity, and hypertensive disorders of pregnancy.

Comparison among populations with severe and intermediate alpha1-antitrypsin deficiency and chronic obstructive pulmonary disease.

BACKGROUND: Severe alpha1-antitrypsin (AAT) deficiency (AATD) is associated with a high risk of airflow obstruction and emphysema. The risk of lung disease in those with intermediate AAT deficiency is unclear. Our aims were to compare pulmonary function, time of onset of symptoms, and indicators of quality of life among patients with severe AATD (PI*ZZ), patients with intermediate AATD (PI*MZ) from the Italian Registry of AATD with a chronic obstructive pulmonary disease (COPD) cohort of patients without AATD (PI*MM). METHODS: We considered a total of 613 patients: 330 with the PI*ZZ genotype, 183 with the PI*MZ genotype and 100 with the PI*MM genotype. Radiological exams, pulmonary function test, and measurement of quality of life have been performed on all cohorts of patients. RESULTS: The three populations differ significantly in terms of age at COPD/AATD diagnosis (P=0.00001), respiratory function (FEV1, FVC, DLCO P<0.001), quality of life (P=0.0001) and smoking history (P<0.0001). PI*ZZ genotype had 24.9 times a higher likelihood of developing airflow obstruction. The MZ genotype is not associated with a significant early risk of airflow obstruction. CONCLUSIONS: The comparison of populations with PI*ZZ, MZ and MM genotypes allows to delineate the role of alpha1-antitrypsin deficiency on respiratory function and on the impact on quality of life, in relation to other risk factors. These results highlight the crucial role of primary and secondary prevention on smoking habits in PI*MZ subjects and the importance of an early diagnosis.

Influence of upper airway size on volume exhaled under negative pressure during evaluation of upper airway collapsibility.

STUDY OBJECTIVES: It has been shown that volume exhaled in the first 0.5 s after application at the mouth of 5 cmH(2)O negative pressure (V,NEP(0.5)) during wakefulness strongly reflects critical pressure (Pcrit) during sleep but only in males with neck circumference (NC) >37 cm. The aim of this study was to establish the relationship between upper airway (UA) size and V,NEP(0.5), to obtain V,NEP(0.5) values as percent predicted and then correlate them with Pcrit obtained in the same subjects. PATIENTS AND MEASUREMENTS: In 20 (8 women) normal subjects (age, 39 ± 16 years; BMI, 22.5 ± 3.0 kg/m(2); AHI, 0.8 ± 1.0), NC, mean pharyngeal cross-sectional area (APmean) by acoustic pharyngometry and V,NEP(0.5) in the supine position were measured. Correlations between APmean, NC and V,NEP(0.5) were performed. A strong relationship was found between APmean and NC, and the predicted V,NEP(0.5) values were obtained using the equation derived from the relationship between V,NEP0.5 and NC. Subsequently, nine normal subjects (age, 26.3 ± 2.5 yrs, BMI 23.9 ± 3.2 kg/m(2), AHI 2.3 ± 0.5), ten snorers (age, 68 ± 11 years; BMI, 26.6 ± 4.6 kg/m(2); AHI, 3.5 ± 0.8) and ten OSAH patients (age, 64 ± 9 years; BMI, 32 ± 4.9 kg/m(2); AHI, 43.8 ± 24.4) underwent measurement of V,NEP(0.5) in the supine position while awake and Pcrit during sleep. Correlations between Pcrit and both V,NEP(0.5) and V,NEP(0.5) expressed as percent predicted were performed in all subjects. RESULTS: Controls had V,NEP(0.5) of 387 ± 103 mL (100.1 ± 13% predicted) and Pcrit of -3.7 ± 2.0 cmH(2)O, snorers had V,NEP(0.5) of 320 ± 33 mL (62 ± 12% predicted) and Pcrit of -0.6 ± 0.3 cmH(2)O while OSAH patients had V,NEP(0.5) of 295 ± 67 mL (48 ± 12% predicted) and Pcrit of 1.0 ± 1.0 cmH(2)O. The linear regression analysis showed a close and highly significant correlation between V,NEP(0.5) percent predicted and Pcrit (r (2) = 0.79, p < 0.001). CONCLUSIONS: V,NEP(0.5) expressed as percent predicted according to NC strongly reflects Pcrit in a wide range of values and can be used as a surrogate of Pcrit to assess UA collapsibility independently from UA size and sex.

An Italian expert consensus on the management of alpha1-antitrypsin deficiency: a comprehensive set of algorithms.

BACKGROUND: Alpha1-antitrypsin deficiency (AATD) is a genetic-based risk condition, mainly affecting the lungs and liver. Despite its wide distribution, it is largely underdiagnosed, thus being considered a rare disease, and is consequently managed in ad-hoc reference centers. Unfortunately, an easy-to-use algorithm for managing such a complex disease is still lacking. METHODS: An expert consensus meeting was conducted among experts in the management of AATD to build a comprehensive algorithm, including diagnosis, monitoring, AAT therapy, rehabilitation and lung transplantation, and liver disease, that could serve as a guide for physicians and treating centers. A panel of AATD specialists evaluated the results of their work. RESULTS: Diagnosis is the most delicate phase, and awareness about this condition should be raised among GPs. A set of recommendations has been written about the most suitable follow-up visits. Augmentation therapy with AAT may be useful to reduce the progression of emphysema and lung function decline in selected patients. Exercise capacity may be improved by pulmonary rehabilitation and, in selected cases, by lung volume reduction or lung transplantation. Support therapies are needed for those who develop liver disease, and, in selected cases, liver transplantation may be considered. Patients should be carefully educated about their lifestyle, including smoking cessation, body weight control, and reduced alcohol intake. CONCLUSIONS: The proposed algorithm obtained the endorsement of the Italian Society of Pneumology (SIP). However, further studies and additional clinical data are required to confirm the validity of these recommendations.

Tidal airway closure during bronchoconstriction in asthma: usefulness of lung volume measurements.

BACKGROUND: The presence and extent of tidal airway closure is not routinely assessed in asthma. The objective of this study was to provide a simple functional tool able to detect tidal airway closure during bronchoconstriction in asthma. METHODS: In 20 subjects with mild persistent asthma, we sequentially performed the measurement of functional residual capacity (FRC) by body plethysmography (pleth) and multibreath helium dilutional technique (He) and then computed residual volume (RV) and total lung capacity (TLC) at baseline, at the end of methacholine (MCh) challenge and after bronchodilator (albuterol). MEASUREMENTS AND MAIN RESULTS: Despite substantial bronchoconstriction (fall in FEV(1) = 35 ± 7%), TLC,pleth did not change following MCh challenge, but FRC,pleth because of dynamic pulmonary hyperinflation (+0.68 ± 0.54 L) and RV,pleth because of air trapping (+0.65 ± 0.37 L), invariably increased (on average by 22% and 46%, respectively). In contrast, FRC,He (and RV,He and TLC,He) could either increase, as seen in 13 subjects (Group I), or decrease, as seen in 7 subjects (Group II). Hence, the difference between FRC,pleth and FRC,He (Diff. FRC,pleth - FRC,He) was much greater in Group II (1.03 ± 0.41 L) than in Group I (0.22 ± 0.20 L) (p < .01). No functional differences were found between the two groups, including baseline PD(20)FEV(1) and absolute and percent change in forced vital capacity (FVC) at the end of the MCh challenge. CONCLUSIONS: Comparison between FRC,pleth and FRC,He is useful to identify asthmatics prone to tidal airway closure during MCh-induced bronchoconstriction and Diff. FRC,pleth - FRC,He can be used to measure the overall unventilated lung volume upstream of the airways closed at end-expiratory lung volume (EELV).

Population genetic screening for alpha1-antitrypsin deficiency in a high-prevalence area.

BACKGROUND: Current guidelines for α1-antitrypsin deficiency (AATD) state that adult population screening should only be done in high-risk areas. Up-to-date genetic methods are always recommended. OBJECTIVES: To determine the prevalence of AATD in a suspected high-risk area by population screening, applying new genetic analyses and comparing the prevalence of liver and lung abnormalities in subjects with or without AATD. METHODS: Adult residents of Pezzaze, a village in an Italian alpine valley, voluntarily participated in the screening, and were examined for: nephelometric α1-antitrypsin (AAT) serum level, DNA analysis (mutagenic polymerase chain reaction and restriction fragment length polymorphism tests for Z and S AATD causative mutations, and denaturing high-performance liquid chromatography and/or direct gene sequencing if needed), serum aspartate and alanine transaminases, a respiratory questionnaire and the Medical Research Council dyspnea index scale. The prevalence of AATD was compared with that expected in Italy (Hardy-Weinberg equilibrium), and transaminases and the prevalence of respiratory symptoms were compared between study groups. RESULTS: Of 1,353 residents, 817 (60.4%) participated; 67 (8.2%) had low AAT serum levels (<90 mg/dl); 118 were carriers of AATD-associated alleles, 4 (0.5%) homozygotes or compound heterozygotes (1 Z, 1 S, 2 ZP(brescia)), 114 (14%) heterozygotes (46 Z, 52 S, 9 P(brescia), 4 M(wurzburg), 2 I, 1 P(lowell)). The prevalence and frequency of all AATD-related alleles was higher than expected for Italy (p < 0.001). There were no differences in symptoms of respiratory disease and transaminases between individuals with normal and low serum AAT. CONCLUSION: The screening design is one of the main strengths of this study. The large number of mostly asymptomatic individuals with AATD identified suggests that in high-risk areas adult population screening programs employing the latest genetic methods are feasible. Early recognition of individuals at risk means primary or secondary prevention measures can be taken.

Effects on small airway obstruction of long-term treatments with beclomethasone/formoterol hydrofluoroalkane (metered-dose inhaler) versus fluticasone/salmeterol (dry-powder inhaler) in asthma: a preliminary study.

New formulations of extrafine particles of long-acting beta-2 agonists plus inhaled corticosteroids (LABA + ICS) have been shown to reach peripheral regions of the lung. The aim of the study was to assess the effect on small airway obstruction of long-term treatments with two different LABA + ICS formulations in asthma. Ten subjects with moderate persistent asthma were enrolled. After a 4-week washout period they were treated in a randomized crossover design for 24 weeks with formoterol, 12 micrograms, and beclomethasone, 200 micrograms, hydrofluoroalkane (HFA; by metered-dose inhaler) b.i.d. (FB) or salmeterol, 50 micrograms, and fluticasone, 250 micrograms (by dry-powder inhaler), b.i.d. (SF). At baseline and at the end of each period subjects underwent an Asthma Control Test (ACT) and Pulmonary Function Testing. The N(2) phase III slope and closing volume (CV) during single-breath washout test and difference between the maximal expiratory flow rates with air and heliox at isovolume corresponding to 50% [Delta(heliox-air)MEF(50%)] were measured to assess changes on peripheral airways function. Two subjects dropped out and eight completed the study. After SF and FB, forced expiratory volume at 1 second (FEV(1); p < 0.01) and FEV(1)/forced vital capacity (FVC; p < 0.01 for SF and p < 0.05 for FB) increased when compared with baseline. Although both FB and SF treatments slightly increased delta(heliox-air)MEF(50% isovolume) versus baseline, only after FB the N(2) phase III slope and CV decreased from 1.61 ± 0.61%/L to 1.35 ± 0.49 N(2)%/L (p = 0.054) and from 0.98 ± 0.56 L to 0.88 ± 0.58 L (p < 0.05), respectively. ACT score raised from 19 ± 5 (baseline) to 23 ± 1 after FB (p < 0.02) and 23 ± 2 after SF (p < 0.05). When compared with baseline and in contrast to SF (50/250 micrograms b.i.d.), FB HFA (12/200 micrograms b.i.d.) significantly improved functional parameters reflecting small airway obstruction in asthmatic patients. Registered in the public trial registry at www.ClinicalTrials.gov identifier: NCT01255579.

Lung air trapping lowers respiratory arousal threshold and contributes to sleep apnea pathogenesis in COPD patients with overlap syndrome.

STUDY OBJECTIVES: Overlap syndrome occurs when obstructive sleep apnea (OSA) and chronic obstructive pulmonary disorder (COPD) coexist in the same patient. Although several studies highlighted the importance of clinical phenotyping in OSA, the trait contribution to OSA pathogenesis in overlap syndrome has not been investigated. With this pilot study, we aimed to measure OSA determinants and their relationship with functional respiratory parameters in a sample of patients with overlap syndrome. In particular, we hypothesize that patients with COPD have in the low arousal threshold a major contributor for the development of OSA. METHODS: Ten consecutive non-hypercapnic COPD patients (body mass index<35 kg/m2) suffering from overlap syndrome with no other relevant comorbidities underwent a phenotyping polysomnography. Traits were measured with CPAP dial-downs. RESULTS: Arousal threshold was found to be inversely associated to functional measures of lung air trapping and static hyperinflation. Particularly, correlations with residual volume (r2 = 0.49, p =  0.024) and residual volume to total lung capacity ratio (r2 = 0.48, p =  0.026) were evident. Only 20% of patients showed a high upper airway passive collapsibility as single pathological trait. In contrast, among those patients with multiple altered traits (6 out of 10), all had an elevated loop gain and 4 (∼65%) a low arousal threshold. CONCLUSIONS: High loop gain and particularly low arousal threshold seem important contributors to OSA pathogenesis and severity in patients with COPD. Recognizing in COPD patients these features as key traits may open avenues for personalized medicine in the field of overlap syndrome.