Deposition of inhaled nanoparticles is reduced in subjects with COPD and correlates with the extent of emphysema: proof of concept for a novel diagnostic technique.

BACKGROUND: The diagnosis of chronic obstructive pulmonary disease (COPD) is often based on spirometry, which is not sensitive to early emphysema. We have recently described a method for assessing distal airspace dimensions by measuring recovery of nanoparticles in exhaled air after a single-breath inhalation followed by breath-hold. Recovery refers to the non-deposited particle fraction. The aim of this study was to explore differences in the recovery of exhaled nanoparticles in subjects with COPD and never-smoking controls. A secondary aim was to determine whether recovery correlates with the extent of emphysema. METHOD: A total of 19 patients with COPD and 19 controls underwent three repeats of single-breath nanoparticle inhalation followed by breath-hold. Particle concentrations in the inhaled aerosol, and in an alveolar sample exhaled after breath-hold, were measured to obtain recovery. FINDINGS: The patients with COPD had a significantly higher mean recovery than controls, 0·128 ± 0·063 versus 0·074 ± 0·058; P = 0·010. Also, recovery correlated significantly with computed tomography (CT) densitometry variables (P<0·01) and diffusing capacity for carbon monoxide (DL,CO ; P = 0·002). INTERPRETATION: Higher recovery for emphysema patients, relative to controls, is explained by larger diffusion distances in enlarged distal airspaces. The nanoparticle inhalation method shows potential to be developed towards a tool to diagnose emphysema.

The forced oscillation technique is a sensitive method for detecting obstructive airway disease in patients with primary Sjögren's syndrome.

OBJECTIVES: To study signs of obstructive airway disease (OAD) in patients with primary Sjögren's syndrome (pSS) using the forced oscillation technique (FOT). METHOD: Thirty-seven female pSS patients (median age 64, range 38-77 years) without previous physician-diagnosed OAD, participating in a longitudinal follow-up study of pulmonary function, and 74 female population-based controls (median age 64, range 47-77 years), also without physician-diagnosed OAD, and matched with regard to age, height, weight, and tobacco consumption, were included in the study. The pSS patients and controls were studied by the FOT, evaluating resistance and reactance of the respiratory system. RESULTS: pSS patients had significantly increased resistances at 5-25 Hz, decreased reactance at 10-35 Hz, and an increased resonant frequency (Fres) in comparison with controls. Resistance was correlated negatively and reactance positively to the vital capacity (VC), the forced expiratory volume in 1 s (FEV1), and the diffusing capacity for carbon monoxide (DLCO). Compared with controls, pSS patients with (n = 14) and without OAD (n = 21), as determined by spirometry, had significantly increased resistances at 5-25 Hz and decreased reactances at 10-35 Hz. In never-smoking subjects, identical FOT signs were found. CONCLUSIONS: pSS patients showed FOT signs of obstruction affecting both peripheral and central airways. pSS patients without spirometric signs of OAD and never-smoking pSS patients also showed clear FOT signs of obstruction. FOT therefore seems to be a sensitive method for detecting obstruction in pSS patients.

The liver in 30-year-old individuals with alpha(1)-antitrypsin deficiency.

OBJECTIVE. Severe (PiZZ) alpha(1)-antitrypsin (AAT) deficiency is a risk factor for liver disease, i.e. juvenile cirrhosis in infancy, and cirrhosis and hepatoma in adulthood. Little is known about the risk of liver disease in individuals with moderate (PiSZ) AAT deficiency. To investigate the natural course of AAT deficiency, a cohort of PiZZ and PiSZ individuals identified by the Swedish National neonatal screening programme in 1972-74 is followed regularly. The aim of this study was to compare liver function in this cohort with healthy control subjects aged 30 years. MATERIAL AND METHODS. Blood samples were obtained from 89 PiZZ, 40 PiSZ, and 84 control subjects (PiMM), and plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl (GT) transpeptidase were analysed. RESULTS. The mean values of all liver enzymes were within the normal range in all Pi subgroups. However, the mean AST was higher in the PiZZ and PiSZ subgroups than in the PiMM subgroup (p < 0.001), and the mean ALT was higher in the PiZZ individuals than in the controls (p < 0.05), while GT did not differ significantly among the Pi subgroups. The PiZZ women taking oral contraceptives had higher mean AST and ALT (p < 0.01) and GT (p < 0.05) than the control women taking oral contraceptives. CONCLUSIONS. At the age of 30 years, PiZZ and PiSZ individuals have normal plasma levels of the transaminases AST and ALT, although they are significantly higher than those in healthy control subjects. Use of oral contraceptives seems to influence liver enzymes in PiZZ women.

Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency.

Assessment of emphysema-modifying therapy is difficult, but newer outcome measures offer advantages over traditional methods. The EXAcerbations and Computed Tomography scan as Lung End-points (EXACTLE) trial explored the use of computed tomography (CT) densitometry and exacerbations for the assessment of the therapeutic effect of augmentation therapy in subjects with alpha(1)-antitrypsin (alpha(1)-AT) deficiency. In total, 77 subjects (protease inhibitor type Z) were randomised to weekly infusions of 60 mg x kg(-1) human alpha(1)-AT (Prolastin) or placebo for 2-2.5 yrs. The primary end-point was change in CT lung density, and an exploratory approach was adopted to identify optimal methodology, including two methods of adjustment for lung volume variability and two statistical approaches. Other end-points were exacerbations, health status and physiological indices. CT was more sensitive than other measures of emphysema progression, and the changes in CT and forced expiratory volume in 1 s were correlated. All methods of densitometric analysis concordantly showed a trend suggestive of treatment benefit (p-values for Prolastin versus placebo ranged 0.049-0.084). Exacerbation frequency was unaltered by treatment, but a reduction in exacerbation severity was observed. In patients with alpha(1)-AT deficiency, CT is a more sensitive outcome measure of emphysema-modifying therapy than physiology and health status, and demonstrates a trend of treatment benefit from alpha(1)-AT augmentation.

Clinical course and prognosis of never-smokers with severe alpha-1-antitrypsin deficiency (PiZZ).

BACKGROUND: Previous studies of non-smoking individuals with severe alpha(1)-antitrypsin deficiency (PiZZ) have been sparse and included only a limited number of individuals, mostly identified by respiratory symptoms. The aim of this study was to estimate the prognosis of non-smoking PiZZ individuals and to analyse the most common causes of death by including a large number of individuals who had been identified by other means than respiratory symptoms. METHODS: The study included 568 non-smoking PiZZ subjects who were selected from the Swedish National AAT Deficiency Registry and followed up from 1991 to September 2007. Of these, 156 (27%) were identified by respiratory symptoms (respiratory cases) and 412 were identified by extrapulmonary symptoms or screening (non-respiratory cases). RESULTS: 93 subjects (16%) died during the follow-up period. The specific standardised mortality rate (SMR) for the whole study population was 2.32 (95% CI 1.87 to 2.83) with no significant difference between men and women. The SMR was 2.55 (95% CI 1.91 to 2.83) for the respiratory cases and 2.07 (95% CI 1.49 to 2.81) for the non-respiratory cases. Further calculation of SMR for subgroups in the non-respiratory cases showed that the SMR was 0.70 (95% CI 0.14 to 2.04) for individuals identified by family/population screening. Emphysema and liver cirrhosis were the most common causes of death (45% and 28%, respectively). Malignant transformation was found in 38% of the cases with cirrhosis. CONCLUSION: Non-smoking PiZZ individuals identified by screening do not have an increased mortality risk compared with the Swedish general population.

Ongoing research in Europe: Alpha One International Registry (AIR) objectives and development.

In 1997, the World Health Organization recommended establishing an international registry of alpha1-antitrypsin deficiency. The objective of the present article is to describe the organisation of an international network of registries, the Alpha One International Registry (AIR), and the processes of enrolling and entering data. By the end of 2005, the registry included individuals from 21 countries (from four continents). The inclusion criterion was either phenotypes PiZZ, PiSZ or other severely deficient variants. Demographic and clinical information have been collected by a standardised questionnaire, translated for each country. Data are transferred to the AIR database at the Dept of Respiratory Medicine, University Hospital, Malmö, Sweden, either by e-mail or via two web-enabled questionnaires in HTML. All data are merged and checked for consistency and missing values. Collection of data started in 1999 and, by September 2005, data on 2,150 individual patients (1,180 male) had been submitted. Of these, 1,855 (84%) have phenotype PiZ, 181 (8%) PiSZ and 114 (5%) other rare Pi phenotypes. The mean age at inclusion was 49.8 yrs (SD = 13.3) and the majority were index cases (64.1%). The Alpha One International Registry is the largest specific alpha1-antitrypsin deficiency registry, fulfilling a major World Health Organization recommendation. The success related to the convergence of national registries into a common database creating a unique registry beyond geographic boundaries and encompassing alpha1-antitrypsin deficiency from various ethnic groups.

Experience with a new percutaneous port system, Percuseal, for intravenous injection in patients with haemophilia, von Willebrand disease and severe alpha1-antitrypsin deficiency.

We have implanted a new port system (Percuseal) in altogether 13 patients with haemophilia A, B, von Willebrand disease and alpha1-antitrypsin deficiency in order to facilitate venous access. The Percuseal system differs from subcutaneous ports, such as Port-a-Cath, in that the upper part of the device protrudes above the skin. In this way, the patient can easily puncture the port membrane under the guidance of his eyes without penetrating the skin. In the present study cohort, a number of complications occurred. These were mainly caused by repeated local infections (in five patients), which made it necessary to replace the ports in three of the patients and to permanently remove the ports as the first option in two of the patients. In one patient, the port was removed because of inconvenience when doing physical exercise. In one additional patient, a severe systemic infection occurred, causing spondylitis. Despite the high infection rate, most patients considered the device very convenient to use. Because of the side-effects seen in our study, the Percuseal port in its present form is not to be recommended for regular use. A reconstruction of the port, making it smaller and giving it an antibacteriostatic cap, may possibly make this kind of port system a feasible alternative to use in order to improve pharmacoeconomics in the prophylactic treatment of haemophilia and patients with alpha1-antitrypsin deficiency.

Respiratory symptoms and lung function in young adults with severe alpha(1)-antitrypsin deficiency (PiZZ).

BACKGROUND: Neonatal screening for alpha(1)-antitrypsin (AAT) deficiency was undertaken in Sweden between 1972 and 1974 when 129 infants with severe AAT deficiency (phenotype PiZ) were identified. The cohort has been followed up prospectively. METHODS: 124 PiZ subjects, still alive and still living in Sweden, were invited to a follow up examination at about 22 years of age. The check up included a clinical examination, spirometric tests, and a questionnaire on smoking habits and respiratory symptoms. RESULTS: Ninety eight subjects (97 PiZZ and 1 PiZ-) subjects attended the follow up. The mean age of the subjects was 22.5 years (range 19.8-24.8). The mean (SD) forced expiratory volume in 1 second (FEV(1)) was 98 (14)% predicted, vital capacity (VC) was 103 (14)% predicted, and the mean FEV(1)/VC ratio was 83 (7)%. Eighty six subjects had previously undergone spirometric tests. The median follow up time was 4.3 years (range 0.9-7.3). The mean annual change in FEV(1) (% predicted) was -1.2% (95% CI -2.1 to -0.3), in VC (% predicted) was -1.5% (95% CI -2.0 to -0.9), and in the FEV(1)/VC ratio (%) was -0.3% (95% CI -0.7 to 0.2). Twenty eight individuals (29%) reported recurrent wheezing. Fifteen subjects (15%) had been diagnosed by a physician as having asthma. Eighteen subjects reported that they had smoked at some time; 10 were current smokers. The mean number of pack years among the ever smokers was 3.4 (range 0.6-10.5). Ten of 18 ever-smokers and 18 of 80 non-smokers reported recurrent wheezing (p<0.01), while exertional dyspnoea was reported by six ever smokers and 11 non-smokers (p<0.05). Lung function test results did not differ significantly between ever smokers and non-smokers. CONCLUSIONS: Young PiZ adults have essentially normal lung function, but have a high prevalence of asthma symptoms. Smoking in these individuals is associated with an increased frequency of respiratory symptoms.

Decline in FEV1 related to smoking status in individuals with severe alpha1-antitrypsin deficiency (PiZZ).

Severe alpha1-antitrypsin (AAT) deficiency predisposes to emphysema development. Highly variable rates of decline in lung function are reported in PiZZ individuals. The annual decline in forced expiratory volume in one second (FEV1; delta FEV1) was analysed in relation to smoking status in a cohort of 608 adult PiZZ individuals included in the Swedish national AAT deficiency register. Delta FEV1 was analysed in 211 never-smokers, in 351 exsmokers, and in 46 current smokers after performing at least two spirometries during a follow-up time of 1 yr or longer (median 5.5 yrs, range 1-31). The adjusted mean delta FEV1 in never-smokers was 47 mL x yr(-1) (95% confidence interval (CI) 41-53 mL x yr(-1)), 41 mL x yr(-1) (95% CI 36-48 mL x yr(-1)) in exsmokers, and 70 mL x yr(-1) (95% CI 58-82 mL x yr(-1)) in current smokers. A dose-response relationship was found between cigarette consumption and delta FEV1 in current smokers and exsmokers. In never-smokers, a greater delta FEV1 was found after 50 yrs of age than before. No sex differences were found in delta FEV1. In conclusion, among PiZZ individuals, the change in forced expiratory volume in one second is essentially the same in never-smokers and exsmokers. Smoking is associated with a dose-dependent increase in the change in forced expiratory volume in one second.

Adolescents with alpha1-antitrypsin deficiency have high alpha2-macroglobulin and low neutrophil lipocalin and elastase levels in plasma.

Eighteen-year-old adolescents with alpha1-antitrypsin (alpha1AT) deficiency have mostly normal lung function tests. We hypothesized that compensatory increases in other protease inhibitors and/or a decreased leukocyte activity might favorably affect the protease/protease-inhibitor balance in alpha1AT-deficient adolescents. At the age of 18 y 46 PiZZ (severe deficiency), 22 PiSZ (moderate deficiency), and 41 control subjects were studied. The plasma protease inhibitors alpha2-macroglobulin (alpha2M), alpha1-antichymotrypsin (Achy), and secretory leukocyte protease inhibitor (SLPI) were studied, and the protease elastase complexed with alpha1AT (HEAT) and neutrophil gelatinase-associated lipocalin (NGAL) as indicators of neutrophil leukocyte activity. Significantly higher concentrations of alpha2M were found in PiZ (p < 0.0001) and PiSZ (p < 0.0001) individuals compared with control subjects. The PiZZ and SZ adolescents had low levels of NGAL (p < 0.0001). Low levels of HEAT were found in PiZZ subjects (p < 0.0005). Higher concentrations of Achy were found in PiZZ (p < 0.04) and PiSZ (p < 0.05) individuals. Increased concentrations of alpha2M and Achy combined with decreased levels of HEAT and NGAL, indicating decreased leukocyte activity may, to some extent, compensate for the protease/protease inhibitor imbalance in the alpha1AT-deficiency state.

Effect of environmental and clinical factors on lung function and respiratory symptoms in adolescents with alpha1-antitrypsin deficiency.

Individuals identified in the Swedish neonatal alpha1-antitrypsin (AAT) screening study were followed prospectively from their first to their eighteenth year of life. The aim of this study was to analyse the effect of environmental factors, i.e. active and passive smoking, and of clinical factors on lung function and the occurrence of respiratory symptoms in AAT-deficient adolescents. The study group consisted of 88 protease inhibitor (Pi)ZZ and 40 PiSZ adolescents. Medical history including respiratory symptoms, and active and passive smoking were recorded at each follow-up up to the age of 18 y. Lung function tests were performed at the present check-up. At the age of 18 y, both forced expiratory volume in one second (FEV ) and FEV1/vital capacity (VC) were significantly lower in the smoking than in the non-smoking subgroup, and significantly more smokers than non-smokers reported the presence of phlegm. The mean FEV1/VC ratio was lower for those presently exposed to parental smoking. Multiple linear regression analysis indicated that clinical liver disease in early life, active smoking and parental smoking were independent determinants of FEV1/VC. The results suggest that marginal deviations in lung function and the symptom of phlegm among AAT-deficient adolescents occur characteristically early in the subgroup of smokers. Parental smoking may contribute to decreased lung function.

Environmental correlates of impaired lung function in non-smokers with severe alpha 1-antitrypsin deficiency (PiZZ).

BACKGROUND: Active smoking is the most important risk factor for pulmonary emphysema in subjects with severe alpha 1-antitrypsin (AAT) deficiency. The aim of this study was to analyse the effects of environmental risk factors other than active smoking on lung function and on respiratory symptoms in non-smoking PiZZ individuals. METHODS: Lifetime exposure to passive smoking, domiciliary use of a kerosene (paraffin) heater or gas cooker, and all occupations since leaving school were reported by 205 non-smoking PiZZ individuals (95 men and 110 women) included in the Swedish AAT deficiency register. Lung function test results and histories of respiratory symptoms (chronic bronchitis, recurrent wheezing, and exertional dyspnoea) were elicited from the AAT register records. RESULTS: After adjustment for age, agricultural employment and domiciliary kerosene heater usage, but not gas cooker usage or passive smoking, were both associated with significantly decreased lung function. Multiple linear regression analysis showed age, sex, kerosene heater usage, and agricultural employment to be independent determinants of lung function impairment. Age and passive smoking for 10 years or more, both at home and at the work place, were associated with the presence of chronic bronchitis. Age and agricultural employment for > or = 10 years were associated with recurrent wheezing and exertional dyspnoea. CONCLUSIONS: Domiciliary kerosene heater usage and an agricultural occupation therefore appear to be environmental factors associated with decreased lung function in non-smoking PiZZ individuals, and passive smoking is associated with an increased frequency of chronic bronchitis, but not with impaired lung function.

Changes in aortic wall stiffness in men with alpha 1-antitrypsin deficiency.

OBJECTIVES: To examine the diameter and distensibility of the abdominal aorta in patients with severe alpha 1-antitrypsin deficiency, and to compare the results with those of normal subjects. MATERIAL AND METHODS: Abdominal aortic diameter and stiffness (beta) was measured using echo-tracking sonography in 19 men (mean age 50, range 25-79) and 17 women (mean age 46, range 26-62) with severe alpha 2-antitrypsin deficiency. The results were compared with those of healthy individuals of corresponding age and gender. RESULTS: There was no significant difference in the abdominal aortic diameter between controls and patients with alpha 1-antitrypsin deficiency when corrected for age, sex and body surface area (men p = 0.20, women p = 0.10). Men with alpha 1-antitrypsin deficiency showed significantly lower stiffness in the abdominal aorta compared to controls (p = 0.025), whereas women did not (p = 0.17). CONCLUSIONS: No significant difference in abdominal aortic diameter could be detected in patients with alpha 1-antitrypsin deficiency compared with controls. However, aortic distensibility in men with alpha 1-antitrypsin deficiency is altered. This may reflect early vessel wall abnormality.

Effect of age and occupational exposure to airway irritants on lung function in non-smoking individuals with alpha 1-antitrypsin deficiency (PiZZ).

BACKGROUND: Severe alpha 1-antitrypsin (AAT) deficiency (PiZZ) is associated with an increased risk of lung emphysema, especially in smokers. The aim of this study was to identify risk factors other than smoking for declining lung function. METHODS: Lung function was studied in 225 self-reported never-smoking PiZZ individuals included in the Swedish AAT deficiency register. RESULTS: Lung function was poorer in men than in women (mean (SD) forced expiratory volume in one second (FEV1) 80 (30) versus 88 (17)% predicted) despite the fact that the men were younger (mean (SD) age 45 (18) versus 51 (17) years), and poorer in those aged 50 or older than in those aged under 50 (mean (SD) FEV1 70 (30) versus 98 (16)% predicted). Self-reported occupational exposure to gas, fumes, or dust occurred more frequently in men than in women. In those aged 50 or older lung function was lower in individuals exposed to airway irritants than those who were not exposed (mean (SD) FEV1 63 (29) versus 76 (31)% predicted). Male sex, increasing age, and previous symptoms of wheezing were independent risk factors for lung function impairment, and male sex, wheeziness, and occupational exposure to airway irritants were independent risk factors in the subjects aged 50 years or more. CONCLUSIONS: In non-smoking PiZZ individuals lung function declines with increasing age, especially after 50. Men are at greater risk of lung function deterioration than women. Asthmatic symptoms and occupational exposure to airway irritants appear to constitute additional risk factors.

Lung function in adolescents with alpha 1-antitrypsin deficiency.

Children with alpha 1-antitrypsin deficiency, screened at birth, were followed prospectively. At 16 years of age, 150 adolescents (103 PiZ, 1 PiZ-, 1 PiS-, 45 PiSZ) were interviewed using a standardized questionnaire and asked to participate in an extensive lung function study including part or all of the following tests: FVC, FEV1 before and 15 min after four inhaled doses of salbutamol, TLC, RV and FRC. Fifty age-, sex- and height-matched adolescents participated as controls. No significant differences in age, height or weight were found between the PiZ, PiSZ and control groups. No significant differences were found in respiratory symptoms, parental smoking history or the smoking habits of PiZ, PiSZ and control subjects. Asthma occurred in 10.7% of PiZ, 6.5% of PiSZ and 4% of control adolescents (p = 0.33). Only 3 of 100 PiZ and 1 of 45 PiSZ adolescents were smokers. No significant contribution of alpha 1-antitrypsin Pi-type was found to explain the variation in lung function variables studied. We conclude that children with alpha 1-antitrypsin deficiency have a favourable prognosis and normal lung development up to 16 years of age. Anti-smoking advice was found to be reasonably successful; only 3% of those answering the questionnaire had started to smoke.

Efficacy and tolerance of a 12-week treatment with inhaled formoterol in patients with reversible obstructive lung disease.

Formoterol, a new beta 2-agonist, and salbutamol were given as aerosols twice and four times daily, respectively, to patients with reversible obstructive lung disease. The study was controlled and double blind, and continued for 12 weeks. Ninety-nine patients from five study centers were included and 89 patients could be properly evaluated. The formoterol-treated patients used significantly less rescue medicine (salbutamol aerosol) and had higher morning PEF values. For the other efficacy variables (daytime FEV1.0, evening PEF, patient and investigator global evaluations, night sleeping time) and tolerance (side effects noted by patients, blood and urine laboratory values, ECG, patient and investigator global evaluation), there were no significant differences between the formoterol- and the salbutamol-treated groups.

Airway inflammation in smokers with nonobstructive and obstructive chronic bronchitis.

To assess the manifestation and location of airway inflammation in smokers with chronic bronchitis (CB) or chronic obstructive pulmonary disease (COPD), we lavaged the airways of 12 smokers with CB and 11 smokers with COPD and coexisting CB (OCB). For comparison, the airways of 5 asymptomatic smokers (AS) and 10 healthy nonsmokers (HNS) were lavaged. In all cases, the first lavage aliquot, labeled "bronchial lavage" (BL), was processed separately from the four subsequent aliquots, which were combined and labeled "bronchoalveolar lavage" (BAL). The composition of BL and BAL fluids indicate an ongoing inflammatory process in the airways of all three groups of smokers. CB patients with obstruction had significantly lower concentrations of inflammatory cells in the BL and BAL fluids compared with subjects with nonobstructed CB. Furthermore, airway obstruction, indicated by a reduced FEV1, was significantly correlated with the concentrations of glutathione (p < 0.001), myeloperoxidase (MPO; p < 0.01), and eosinophil cationic protein (ECP; p < 0.01) in BAL fluids. Taken together, these findings suggest that the manifestations of inflammation present in the airways of smokers with CB are different in those who have developed obstruction compared with those who have not.