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Georg Rüdiger Schramm,1 Behrouz Mostafavi,1 Eeva Piitulainen,1 Per Wollmer,2 Hanan A Tanash1 1Department of Respiratory Medicine and Allergology, Skåne University Hospital, Lund University, Malmö, Sweden; 2Department of Medical Imaging and Physiology, Skåne University Hospital, Lund University, Malmö, SwedenCorrespondence: Georg Rüdiger SchrammDepartment of Respiratory Medicine and Allergology, Skåne University Hospital, Jan Waldenströms Gata 24, Malmö, S – 205 02, SwedenTel +46 40 33 25 85Fax +46 40 33 74 90Email Georg.Schramm@med.lu.seBackground: Severe hereditary alpha-1-antitrypsin deficiency (AATD) is a known risk factor for the early development of pulmonary emphysema and COPD, especially in smokers. By the Swedish national screening programme carried out from 1972 to 1974, a cohort of individuals with severe (PiZZ) AATD was identified and has been followed up regularly. The aim of this study was to investigate health status, quality of life and lung function in this cohort at the age of 42 years compared with an age-matched control group randomly selected from the population registry.Methods: All study participants answered a questionnaire on smoking habits, symptoms, occupation, exposure to airway irritants and quality of life using Saint George’s Respiratory Questionnaire (SGRQ). They underwent complete pulmonary function tests (PFT) and forced oscillation technique (FOT) for the measurement of airway resistance and reactance. Blood samples were taken for allergies and IgG-subclasses as an indicator of increased risk of airway infections.Results: The residual volume (RV), total lung capacity (TLC) and RV/TLC ratio were significantly higher in the PiZZ ever-smokers compared to the PiMM ever-smokers and PiZZ never-smokers (p < 0.05). The resistance in the upper, small and total airways was significantly lower in PiZZ subjects compared to PiMM subjects (p < 0.05). A greater proportion of PiZZ never-smokers had an FEV1/VC ratio < 0.7 than PiMM never-smokers (p = 0.043). PiZZ subjects with occupational exposure to airway irritants showed a significantly lower FEV1, VC and higher RV/TLC ratio than PiMM individuals with exposure (p < 0.05).Conclusion: At the age of 42, ever-smoking PiZZ individuals have signs of COPD, and also PiZZ never-smokers have early, physiological signs of emphysema.Keywords: alpha-1-antitrypsin deficiency, COPD, lung function, quality of life

Behrouz Mostafavi, Eeva Piitulainen, Hanan A Tanash Department of Respiratory Medicine and Allergology, Skåne University Hospital, Lund University, Malmö, Sweden Background: Alpha-1-antitrypsin deficiency (AATD) is a hereditary disorder. AATD is a known risk factor for the development of emphysema and liver disease. A cohort of severe (PiZZ) and moderate (PiSZ) AAT-deficient newborn infants was identified by the Swedish national neonatal AAT screening in 1972–1974 and has been followed up since birth. Our aim was to study survival in this cohort up to 43–45 years of age in comparison with the general Swedish population.Methods: Data from 127 PiZZ, 2 PiZnull, 54 PiSZ, and 1 PiSnull subjects, who were identified by the neonatal screening in 1972–1974, were included in the study. To compare death rates in the PiZZ and PiSZ individuals with the general Swedish population, a standardized mortality ratio (SMR) was calculated as the ratio of observed to expected deaths.Results: Seven PiZZ subjects died during the follow-up, to be compared with an expected 3.66 deaths for the general population, giving an SMR of 1.91 (95% CI 0.77–3.94). Four PiSZ subjects died compared to an expected 1.53 deaths, giving an SMR of 2.61 (95% CI 0.71–6.71). The cumulative probability of survival up to the age of 45 years was 94% (95% CI 90%–98%) for the study population. Six deaths occurred before the age of 8 years.Conclusion: Up to 43–45 years of age, there was no difference in survival between PiZZ and PiSZ individuals in comparison with the Swedish general population. The majority of deaths occurred during childhood. Keywords: alpha-1-antitrypsin deficiency, causes of death, screening, survival

Behrouz Mostafavi,1 Sandra Diaz,2 Eeva Piitulainen,1 Berend C Stoel,3 Per Wollmer,4 Hanan A Tanash1 1Department of Respiratory Medicine and Allergology Malmö, Skåne University Hospital, Lund University, Malmö, Sweden; 2Department of Clinical Physiology Malmö, Skåne University Hospital, Lund University, Malmö, Sweden; 3Division of Image Processing, Department of Radiology, Leiden University Medical, Leiden, the Netherlands; 4Department of Translational Medicine, Lund University, Malmö, Sweden Background: Alpha-1-antitrypsin (AAT) deficiency is a hereditary disorder that predisposes to emphysema. A cohort of severe (PiZZ) and moderate (PiSZ) AAT-deficient newborn infants was identified by the Swedish national neonatal AAT screening program in 1972–1974 and has been followed-up since birth. Our aim was to study whether the cohort has signs of emphysema in pulmonary function tests (PFTs) and computed tomography (CT) densitometry at 38 years of age in comparison with an age-matched control group, randomly selected from the population registry. Methods: Forty-one PiZZ, 18 PiSZ, and 61 control subjects (PiMM) underwent complete PFTs, measurement of resistance and reactance in the respiratory system by impulse oscillometry (IOS)/forced oscillation technique (FOT), and CT densitometry. The results were related to self-reported smoking habits. Results: The total lung capacity (TLC) % of the predicted value was significantly higher in the PiZZ ever-smokers than in the PiZZ never-smokers (P

Magnus Ekström,1 Gerdt C Riise,2 Hanan A Tanash3 1Department of Clinical Sciences, Division of Respiratory Medicine & Allergology, Lund University, Lund, Sweden; 2Department of Respiratory Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden; 3Department of Respiratory Medicine, Skåne University Hospital, Lund University, Malmö, Sweden Background: The risk of cancer is increased and affects survival after lung transplantation (LTx), but has not been well characterized in COPD. We aimed to evaluate the incidence and prognosis of cancer following LTx for COPD.Methods: A prospective, population-based study of patients undergoing LTx for end-stage COPD at the two transplantation centers in Sweden between 1990-2013, with follow-up for incident cancer and death, using national registers. The excess risk of cancer was calculated as standardized incidence ratios compared with the general population matched for age, sex, and calendar year. Risk factors for cancer were analyzed using Fine-Gray regression, and survival after cancer diagnosis with Kaplan–Meier.Results: In total, 331 patients (mean age 55.4 years; 64% women; 97% former smokers) were included. At a median follow-up of 2.8 years, 35% of patients had developed cancer and the risk was increased more than 10-fold ([95% CI] 8.1-11.8). The highest excess risks were for non-Hodgkin lymphoma (20.8-66.7), skin cancer (20.3-35.2), lung (11.7-31.2), liver (3.6-51.6), and colorectal cancer (6.1-19.5). Median survival was longer for skin cancer (8 years; 95% CI, 3-15) compared with non-skin cancer (4 years; 95% CI, 2.8-4.8; p

Eeva Piitulainen, Behrouz Mostafavi, Hanan A Tanash Department of Respiratory Medicine and Allergology, Skåne University Hospital, Lund University, Malmö, Sweden Background: Severe alpha 1-antitrypsin (AAT) deficiency (genotype PiZZ) is a well-known risk factor for COPD. A cohort of PiZZ and PiSZ individuals was identified by the Swedish national neonatal AAT screening program in 1972–1974 and followed up regularly since birth. Our aim was to study the lung function, respiratory symptoms and health status at the age of 38 years in comparison with a random sample of control subjects selected from the population registry.Methods: The study group included 120 PiZZ, 46 PiSZ and 164 control subjects (PiMM), who answered a questionnaire on smoking habits and symptoms and the Saint George Respiratory Questionnaire (SGRQ) on quality of life. A total of 89 PiZZ, 33 PiSZ and 92 PiMM subjects underwent spirometry.Results: Four percent of the PiZZ, 2% of the PiSZ and 12% of the control subjects were current smokers (P=0.008), and 17% of the PiZZ, 9% of the PiSZ and 21% of the control subjects had stopped smoking. The PiZZ current smokers had a significantly higher (ie, poorer) median activity score according to the SGRQ than the PiZZ never-smokers (P=0.032). The PiMM current smokers had significantly higher activity score (P

Hanan A Tanash,1 Thomas Ringbaek,2 Fredrik Huss,3,4 Magnus Ekström1 1Department of Respiratory Medicine, Skåne University Hospital, Lund University, Lund, Sweden; 2Respiratory Department, Hvidovre Hospital, Copenhagen, Denmark; 3Department of Surgical Sciences, Plastic Surgery, 4Department of Plastic and Maxillofacial Surgery, Burn Center, Uppsala University Hospital, Uppsala, Sweden Background: Long-term oxygen therapy (LTOT) increases life expectancy in patients with COPD and severe hypoxemia. Smoking is the main cause of burn injury during LTOT. Policy regarding smoking while on LTOT varies between countries. In this study, we compare the incidence of burn injury that required contact with a health care specialist, between Sweden (a country with a strict policy regarding smoking while on LTOT) and Denmark (a country with less strict smoking policy). Methods: This was a population-based, cohort study of patients initiating LTOT due to any cause in Sweden and Denmark. Data on diagnoses, external causes, and procedures were obtained from the Swedish and Danish National Patient Registers for inpatient and outpatient care. Patients were followed from January 1, 2000, until the first of the following: LTOT withdrawal, death, or study end (December 31, 2009). The primary end point was burn injury during LTOT. Results: A total of 23,741 patients received LTOT in Denmark and 7,754 patients in Sweden. Most patients started LTOT due to COPD, both in Sweden (74%) and in Denmark (62%). The rate of burn injury while on LTOT was higher in Denmark than in Sweden; 170 (95% confidence interval [CI], 126–225) vs 85 (95% CI, 44–148) per 100,000 person-years; rate ratio 2.0 (95% CI, 1.0–4.1). The risk remained higher after adjustment for gender, age, and diagnosis in multivariate Cox regression, hazard ratio 1.8 (95% CI, 1.0-3.5). Thirty-day mortality after burn injury was 8% in both countries. Conclusion: Compared to Sweden, the rate of burn injury was twice as high in Denmark where smoking is not a contraindication for prescribing LTOT. Keywords: burn injury, COPD, long-term oxygen therapy, smoking

Hanan A Tanash,1 Magnus Ekström,2 Philippe Wagner,3 Eeva Piitulainen1 1Department of Respiratory Medicine, Skåne University Hospital, 2Department of Respiratory Medicine, Blekinge Hospital Karlskrona, Lund University, Lund, 3Centre for Clinical Research, Västmanland, Uppsala University, Uppsala, Sweden Background: Severe alpha 1-antitrypsin deficiency (PiZZ) predisposes to morbidity and mortality due to early-onset emphysema and liver disease. The risk of death from other causes, including cardiovascular disease and cancer, has not been well investigated. We aimed to analyze cause-specific mortality in PiZZ individuals compared with the general Swedish population. Methods: Data on 1,561 PiZZ individuals from the Swedish National AAT Deficiency Register, prospectively followed from 1991 to 2014, were analyzed. Causes of death according to the Swedish National Causes of Death Register for the study group were compared with those for the general Swedish population matched for age, sex, and calendar year, with the excess mortality expressed as standardized mortality ratios (SMRs) with 95% confidence intervals (CIs). Results: There were 524 deaths during the follow-up period. PiZZ individuals had excess all-cause mortality compared with the Swedish general population (SMR 3.6, 95% CI 3.3–3.9). SMR for ischemic heart disease (IHD) was 0.5 (95% CI 0.3–0.8) and was similar for never and ever-smokers, and in males and females. SMR for lung cancer was 0.9 (95% CI 0.4–1.7). PiZZ individuals had increased mortality compared with the general population for the following diseases: respiratory disease, SMR 48.4 (95% CI 43.0–54.5); primary liver carcinoma, SMR 90.0 (95% CI 59.3–130.9); complicated colon diverticulitis, SMR 20.8 (95% CI 6.7–48.6); and pulmonary embolism, SMR 6.9 (95% CI 3.3–12.7). Conclusion: PiZZ individuals had a reduced mortality risk of IHD. Mortality due to respiratory, hepatic disease, diverticulitis, and pulmonary embolism was markedly increased compared with the age- and sex-matched Swedish population. Keywords: alpha 1-antitrypsin deficiency, cause-specific mortality, ischemic heart disease, pulmonary embolism, standardized mortality ratio

Hanan A Tanash,1 Fredrik Huss,2,3 Magnus Ekström41Department of Respiratory Medicine and Allergology, Skåne University Hospital, Lund University, Lund, 2Department of Surgical Sciences, Plastic Surgery, Uppsala University, 3Burn Center, Department of Plastic and Maxillofacial Surgery, University Hospital of Uppsala, Uppsala, 4Department of Clinical Sciences, Division of Respiratory Medicine & Allergology, Lund University, Lund, SwedenBackground: Long-term oxygen therapy (LTOT) improves the survival time in hypoxemic chronic obstructive pulmonary disease. Despite warnings about potential dangers, a considerable number of patients continue to smoke while on LTOT. The incidence of burn injuries related to LTOT is unknown. The aim of this study was to estimate the rate of burn injury requiring health care contact during LTOT.Methods: Prospective, population-based, consecutive cohort study of people starting LTOT from any cause between January 1, 1992 and December 31, 2009 in the Swedish National Register of Respiratory Failure (Swedevox).Results: In total, 12,497 patients (53% women) were included. The mean (standard deviation) age was 72±9 years. The main reasons for starting LTOT were chronic obstructive pulmonary disease (75%) and pulmonary fibrosis (15%). Only 269 (2%) were active smokers when LTOT was initiated. The median follow-up time to event was 1.5 years (interquartile range, 0.55–3.1). In total, 17 patients had a diagnosed burn injury during 27,890 person-years of LTOT. The rate of burn injury was 61 (95% confidence interval, 36–98) per 100,000 person-years. There was no statistically significant difference in the rate of burn injury between ever-smokers and never-smokers, or between men and women.Conclusion: The rate of burn injuries in patients on LTOT seems to be low in Sweden. The strict requirements in Sweden for smoking cessation before LTOT initiation may contribute to this finding.Keywords: respiratory failure, oxygen, fire, burn, mortality, smoking

Abstract Background Previous studies of the natural history of alpha-1-antitrypsin (AAT) deficiency are mostly based on highly selected patients. The aim of this study was to analyse the mortality of PiZZ individuals. Methods Data from 1339 adult PiZZ individuals from the Swedish National AAT Deficiency Registry, followed from 1991 to 2008, were analysed. Forty-three percent of these individuals were identified by respiratory symptoms (respiratory cases), 32% by liver diseases and other diseases (non-respiratory cases) and 25% by screening (screened cases). Smoking status was divided into two groups: smokers 737 (55%) and 602 (45%) never-smokers. Results During the follow-up 315 individuals (24%) died. The standardised mortality rate (SMR) for respiratory cases was 4.70 (95% Confidence Interval (CI) 4.10-5.40), 3.0 (95%CI 2.35-3.70) for the non-respiratory cases and 2.30 (95% CI 1.46-3.46) for the screened cases. The smokers had a higher mortality risk than never-smokers, with a SMR of 4.80 (95%CI 4.20-5.50) for the smokers and 2.80(95%CI 2.30-3.40) for the never-smokers. The Rate Ratio (RR) was 1.70 (95% CI 1.35-2.20). Also among the screened cases, the mortality risk for the smokers was significantly higher than in the general Swedish population (SMR 3.40 (95% CI 1.98-5.40). Conclusion Smokers with severe AAT deficiency, irrespective of mode of identification, have a significantly higher mortality risk than the general Swedish population.

Background: Previous studies of the natural history of alpha-1-antitrypsin (AAT) deficiency are mostly based on highly selected patients. The aim of this study was to analyse the mortality of PiZZ individuals.Methods: Data from 1339 adult PiZZ individuals from the Swedish National AAT Deficiency Registry, followed from 1991 to 2008, were analysed. Forty-three percent of these individuals were identified by respiratory symptoms (respiratory cases), 32% by liver diseases and other diseases (non-respiratory cases) and 25% by screening (screened cases). Smoking status was divided into two groups: smokers 737 (55%) and 602 (45%) never-smokers.Results: During the follow-up 315 individuals (24%) died. The standardised mortality rate (SMR) for respiratory cases was 4.70 (95% Confidence Interval (CI) 4.10-5.40), 3.0 (95%CI 2.35-3.70) for the non-respiratory cases and 2.30 (95% CI 1.46-3.46) for the screened cases. The smokers had a higher mortality risk than never-smokers, with a SMR of 4.80 (95%CI 4.20-5.50) for the smokers and 2.80(95%CI 2.30-3.40) for the never-smokers. The Rate Ratio (RR) was 1.70 (95% CI 1.35-2.20). Also among the screened cases, the mortality risk for the smokers was significantly higher than in the general Swedish population (SMR 3.40 (95% CI 1.98-5.40).Conclusion: Smokers with severe AAT deficiency, irrespective of mode of identification, have a significantly higher mortality risk than the general Swedish population. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of chronic obstructive pulmonary disease is based on the presence of persistent respiratory symptoms and chronic airflow limitation (CAL). CAL is based on the ratio of forced expiratory volume in 1 s to forced vital capacity (FEV 1 :FVC) after bronchodilation, and FEV 1 :FVC less than the fifth percentile is often used as a cut-off for CAL. The aim was to investigate if increasing percentiles of FEV 1 :FVC were associated with any respiratory symptom (cough with phlegm, dyspnoea or wheezing) in a general population sample of never-smokers and ever-smokers., Methods: In a cross-sectional study comprising 15 128 adults (50-64 years), 7120 never-smokers and 8008 ever-smokers completed a respiratory questionnaire and performed FEV 1 and FVC after bronchodilation. We calculated their z -scores for FEV 1 :FVC and defined the fifth percentile using the Global Lung Function Initiative (GLI) reference value, GLI 5 and increasing percentiles up to GLI 25 . We analysed the associations between different strata of percentiles and prevalence of any respiratory symptom using multivariable logistic regression for estimation of OR., Results: Among all subjects, regardless of smoking habits, the odds of any respiratory symptom were elevated up to the GLI 15-20 strata. Among never-smokers, the odds of any respiratory symptom were elevated at GLI <5 (OR 3.57, 95% CI 2.43 to 5.23) and at GLI 5-10 (OR 2.57, 95% CI 1.69 to 3.91), but not at higher percentiles. Among ever-smokers, the odds of any respiratory symptom were elevated from GLI <5 (OR 4.64, 95% CI 3.79 to 5.68) up to GLI ≥25 (OR 1.33, 95% CI 1.00 to 1.75)., Conclusions: The association between percentages of FEV 1 :FVC and respiratory symptoms differed depending on smoking history. Our results support a higher percentile cut-off for FEV 1 :FVC for never-smokers and, in particular, for ever-smokers., Competing Interests: Competing interests: AA reports personal fees from Novartis and AstraZeneca, outside this work. AL reports personal fees from Boehringer Ingelheim, AstraZeneca, Novartis and Active Care, outside the submitted work. JV reports personal fees from Boehringer Ingelheim, outside the submitted work. PW reports personal fees from AstraZeneca and Chiesi Pharmaceuticals, outside the submitted work. CMS reports personal fees from Boehringer Ingelheim, GlaxoSmithKline, Novartis, AstraZeneca, Roche and Genzyme, outside the submitted work. PW has a patent device and method for pulmonary capacity measurements issued. MS reports personal fees from AstraZeneca, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Breathlessness is common in the population, especially in women and associated with adverse health outcomes. Obesity (body mass index (BMI) >30 kg/m 2 ) is rapidly increasing globally and its impact on breathlessness is unclear., Methods: This population-based study aimed primarily to evaluate the association of current BMI and self-reported change in BMI since age 20 with breathlessness (modified Research Council score ≥1) in the middle-aged population. Secondary aims were to evaluate factors that contribute to breathlessness in obesity, including the interaction with spirometric lung volume and sex., Results: We included 13 437 individuals; mean age 57.5 years; 52.5% women; mean BMI 26.8 (SD 4.3); mean BMI increase since age 20 was 5.0 kg/m 2 ; and 1283 (9.6%) reported breathlessness. Obesity was strongly associated with increased breathlessness, OR 3.54 (95% CI, 3.03 to 4.13) independent of age, sex, smoking, airflow obstruction, exercise level and the presence of comorbidities. The association between BMI and breathlessness was modified by lung volume; the increase in breathlessness prevalence with higher BMI was steeper for individuals with lower forced vital capacity (FVC). The higher breathlessness prevalence in obese women than men (27.4% vs 12.5%; p<0.001) was related to their lower FVC. Irrespective of current BMI and confounders, individuals who had increased in BMI since age 20 had more breathlessness., Conclusion: Breathlessness is independently associated with obesity and with weight gain in adult life, and the association is stronger for individuals with lower lung volumes., Competing Interests: Competing interests: SS reports being an advisory board member and receiving speakers honoraria from Actelion, Bayer, MSD, outside the submitted work. Dr Olin reports having a patent WO2009045163 (Collection and measurement of exhaled particles) and being a chairholder and board member of PExA AB, outside the submitted work. JS reports advisory board work for Itrim, outside the submitted work., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The proportion of adults with liver disease due to severe alpha-1-antitrypsin deficiency (AATD), with PiZZ phenotype, is not clear. The markers of the AATD liver disease, how it progresses, and measures for its prevention have not been established. The aim of this study was to analyze the risk of liver disease in individuals with severe AAT deficiency (PiZZ)., Methods: Longitudinal clinical and laboratory data were obtained from the Swedish National registers, by cross-linkage between the Swedish national AATD register, the Swedish National Patient Register, the National Cancer Register and the National Causes of Death Register., Results: A total of 1595 PiZZ individuals were included in the analyses. The mean follow-up time was 12 years (range 0.3-24). The mean number of follow-ups was 5 (range 2-15). Two or more liver function tests (LFTs) were available in 1123 individuals, and 26% of them (n = 290) had repeated elevated LFTs during the follow-up. The prevalence of any liver disease was 10% (n = 155). Liver cirrhosis was found in 7% of the individuals (n = 116) and hepatocellular carcinoma in 2% (n = 29). The mean age at the onset of liver disease was 61 (SD 15) years. In multivariate analyses, the male gender, age over 50 years, repeated elevated LFTs, hepatitis virus infection, and a diagnosis of diabetes were associated with increased risk of developing liver disease in adulthood (p < 0.01)., Conclusion: The prevalence of liver disease in adult PiZZ individuals is 10%. Age over 50 years, the male gender, repeated elevated liver enzymes, hepatitis, and the presence of diabetes mellitus are risk factors for developing liver disease.

Background: Acoustic radiation force impulse (ARFI) elastography has been used to assess liver stiffness non-invasively. However, its usefulness in alpha-1 antitripsin-deficient (AATD) individuals is unknown., Purpose: To assess if liver fibrosis is present in a cohort of AATD individuals using ARFI elastography., Material and Methods: Eighty-three participants aged 38-39 years, except for two who were aged 40 years, underwent ultrasound elastography of the liver with ARFI technique. Twenty-nine were homozygote ZZ genotype, PiZZ (14 men, 15 women); 12 were SZ genotype, Pi SZ (8 men, 4 women), and 42 were healthy volunteers, PiMM (16 men, 26 women). Three specific liver anatomical regions were examined: segments 2/3 (left lobe) in the subcostal plane, and 5/6 and 7/8 (right lobe) in the intercostal space. In each region, three measurements were registered., Results: There was no statistically significant difference between ARFI-median in the AATD group and the control group ( P value = 0.877) and neither between AATD groups (PiZZ and PiSZ) with a P value = 0.259. The ARFI-median was lower in the right liver lobe than in the left lobe in all groups and the difference between both lobes was statistically significant ( P  = 0.001). No statistically significant difference was found in ARFI-median of the right liver lobe between the AATD group and the control group ( P  = 0.759), nor between the AATD group ( P  = 0.384). No gender difference was found in ARFI-median., Conclusions: ARFI values in AATD individuals aged 38-39 years showed no difference compare to healthy participants.

Knowledge about the natural history of severe alpha 1-antitrypsin (AAT) deficiency (PiZZ) is limited. Our aim was to compare the survival of PiZZ individuals with randomly selected controls from the Swedish general population.The PiZZ subjects (n=1585) were selected from the Swedish National AATD Register. The controls (n=5999) were randomly selected from the Swedish population register. Smoking habits were known for all subjects.Median follow-up times for the PiZZ subjects (731 never-smokers) and controls (3179 never-smokers) were 12 and 17 years, respectively (p<0.001). During follow-up, 473 PiZZ subjects (30%), and 747 controls (12%) died. The PiZZ subjects had a significantly shorter survival time than the controls, p<0.001. After adjustment for gender, age, smoking habits and presence of respiratory symptoms, the risk of death was still significantly higher for the PiZZ individuals than for the controls, hazard ratio (HR) 3.2 (95% CI 2.8-3.6; p<0.001). By contrast, the risk of death was not increased in never-smoking PiZZ individuals identified by screening, compared to never-smoking controls, HR 1.2 (95% CI 0.6-2.2).The never-smoking PiZZ individuals identified by screening had a similar life expectancy to the never-smokers in the Swedish general population. Early diagnosis of AAT deficiency is of utmost importance., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Severe alpha-1-antitrypsin (AAT) deficiency (PiZZ) is a risk factor for liver disease, but the prevalence of liver cirrhosis and hepatocellular cancer in PiZZ adults is unknown. The risk of liver disease in adults with moderate AAT deficiency (PiSZ) is also unknown. A cohort of 127 PiZZ, 2 PiZnull, 54 PiSZ, and 1 PiSnull individuals were identified by the Swedish national neonatal AAT screening program between 1972 and 1974, when all 200,000 newborn infants in Sweden were screened for AAT deficiency. The cohort has been followed up since birth. Our aim was to study liver function and signs of liver disease in this cohort at 37 to 40 years of age in comparison with a matched, random sample of control subjects identified from the population registry.Eighty seven PiZZ, 32 PiSZ, and 92 control subjects (PiMM) answered a questionnaire on medication and alcohol consumption and provided blood samples. Liver stiffness was assessed by Acoustic Radiation Force Impulse (ARFI) elastography in 32 PiZZ, 15 PiSZ, and 51 PiMM subjects.The median of liver function tests and procollagen-III-peptide were within the normal range in all Pi subgroups. However, the PiZZ men had significantly higher plasma bilirubin than the PiMM men (P = 0.018). Plasma [Latin Small Letter Gamma]-glutamyl transferase (GGT) was significantly higher in the PiZZ men (P = 0.009) and the PiSZ men (P = 0.021) compared with the PiMM men. The median of liver stiffness was significantly higher in the PiZZ men (P = 0.037) and the PiSZ men (P = 0.032) compared with the PiMM men. The PiZZ women taking medication influencing liver enzymes had significantly higher GGT than the PiMM women on the corresponding treatment (P = 0.023).These AAT-deficient individuals identified by neonatal screening have normal plasma levels of liver function tests, and no clinical signs indicating liver disease at the age of 37 to 40 years. However, bilirubin, GGT, and liver stiffness are significantly higher in PiZZ men than PiMM men.

Rationale: All Swedish newborn infants were screened for α1-antitrypsin (AAT) deficiency between 1972 and 1974. The cohort of 127 individuals with severe AAT deficiency (PiZZ) and 54 with moderate AAT deficiency (PiSZ) has been followed up regularly., Objectives: To compare smoking habits, quality of life, respiratory symptoms, and lung and liver function at the age of 34 years in this cohort and among 300 age-matched control subjects randomly selected from the Swedish population registry., Methods: The study participants answered a questionnaire on smoking habits and symptoms; underwent spirometry, including FEV1 and FVC; and provided blood samples. Health-related quality of life was assessed by using the St. George's Respiratory Questionnaire (SGRQ)., Measurements and Main Results: One hundred sixteen PiZZ, 48 PiSZ, and 229 control subjects (normal AAT level [PiMM]) answered the questionnaire. Eighty-eight PiZZ (76%), 36 PiSZ (75%), and 144 PiMM (63%) subjects had never smoked (P = 0.02). No significant differences were found in lung function parameters between the protease inhibitor (Pi) subgroups, nor were any discovered between the smoking subgroups. In all Pi subgroups, the symptom score on the SGRQ was significantly lower in ever-smokers than in never-smokers (P = 0.01 for PiZZ, P = 0.009 for PiSZ, and P = 0.01 for PiMM). The mean plasma levels of liver enzymes and albumin were within normal range in all Pi subgroups. However, the mean γ-glutamyl transpeptidase and albumin levels were significantly higher in the PiZZ than in the PiMM subjects (P < 0.05)., Conclusions: In this population-based study, no differences in lung function or symptoms were found between subjects with AAT deficiency and control subjects, but smoking frequency was significantly lower among the subjects with AAT deficiency than in the controls at age 34 years.

The Swedish national register of severe alpha1-antitrypsin (AAT) deficiency was established in 1991. The main aims are to prospectively study the natural history of severe AAT deficiency, and to improve the knowledge of AAT deficiency. The inclusion criteria in the register are age ≥ 18 years, and the PiZ phenotype diagnosed by isoelectric focusing. The register is kept updated by means of repeated questionnaires providing data to allow analysis of the mode of identification, lung and liver function, smoking-habits, respiratory symptoms and diagnoses as reported by physicians. Until February 2014, a total of 1553 PiZZ individuals had been included in the register. The 1102 subjects still alive constituted about 20% of the adult PiZZ individuals in Sweden. Forty-three percent of the subjects had been identified during investigation of respiratory symptoms, 7% by an investigation of liver disease, 26% in an investigation of other pathological conditions, and 24% in a population or family screening. Forty five percent of the subjects had never smoked, 47% were ex-smokers, and 8% current smokers. Twenty-eight percent of the never-smokers, 72% of the ex-smokers, and 61% of the current smokers fulfilled the criteria for COPD with a FEV1/FVC ratio of <0.70. Among the 451 deceased, the most common cause of death was respiratory diseases (55%), followed by liver diseases (13%). We conclude that the detection rate of severe AAT deficiency is relatively high in Sweden. Large numbers of subjects are identified for other reasons than respiratory symptoms, and the majority of these have never smoked.

Alpha-1-antitrypsin (AAT) deficiency is a genetic risk factor for pulmonary emphysema. In 1972-74 all 200,000 Swedish new-born infants were screened for AAT deficiency. The aim of the present study was to investigate whether the PiZZ and PiSZ individuals identified by this screening have signs of emphysema and the role of smoking in this, compared with a random sample of control subjects at 35 years of age. The study participants underwent complete pulmonary function tests (PFT) and CT densitometry. The fifteenth percentile density (PD15) and the relative area below -910 HU (RA-910) were analyzed. Fifty-four PiZZ, 21 PiSZ and 66 PiMM control subjects participated in the study. No significant differences were found in lung function between the never-smoking AAT-deficient and control subjects. The 16 PiZZ ever-smokers had significantly lower carbon monoxide transfer coefficient (KCO) than the 20 PiSZ never-smokers (p = 0.014) and the 44 PiMM never-smokers (p = 0.005). After correction for the CT derived lung volume, the PiZZ ever-smokers had significantly lower PD15 (p = 0.046) than the ever-smoking controls. We conclude that 35-year-old PiZZ and PiSZ never-smokers have normal lung function when compared with never-smoking control subjects. The differences in KCO and CT densitometric parameters between the PiZZ ever-smokers and the control subjects may indicate early signs of emphysema.

Background: Lung transplantation (LTx) is a therapeutic option for patients with life-threatening chronic obstructive pulmonary disease (COPD) that is refractory to conventional therapies. The survival benefit of LTx for COPD is difficult to assess. The aim of this study was to evaluate the Swedish series of LTx performed to treat COPD and to identify differences in outcome between COPD related to severe alpha-1-antitrypsin deficiency (AATD) and COPD with normal alpha-1-antitrypsin (AAT) levels., Methods: We retrospectively reviewed the data of 342 patients (128 AATD and 214 non-AATD) receiving lung transplants for end stage COPD from 1990 through 2012., Results: The majority (71%) of patients received a single lung transplant. The median survival time after LTx for all COPD patients was 9 years (95% confidence interval [CI]: 8 to 10). Non-AATD recipients had a shorter survival time than AATD recipients, 6 years (95% CI: 5.0 to 8.8) versus 12 years (95% CI: 9.6 to 13.5, p = 0.000). Mortality was higher among non-AATD recipients after adjusting for age, pack-years of smoking, body mass index, oxygen therapy use, exercise capacity, donor age, cytomegalovirus mismatch, and transplant type (hazard ratio 1.70, 95% CI: 1.02 to 2.82). The 5-year and 10-year survival rates for the AATD recipients were 75% and 59%, respectively, compared with 60% and 31% for the non-AATD recipients. Early deaths were mainly due to cardio/cerebrovascular accidents and sepsis, and late deaths to bronchiolitis obliterans syndrome and pulmonary infections., Conclusions: Survival after LTx is significantly better for patients with severe AATD and end stage COPD than for the patients with COPD related to cigarette smoking., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The objective of lung transplantation (LTx) is to prolong life, but the survival benefit for patients with severe α(1)-anti-trypsin deficiency (PiZZ) and emphysema is still unclear. The aim of this study was to assess whether PiZZ patients who have undergone lung transplantation (the lung transplant group, TxG) do better than patients who have continued on the usual medical therapy (the non-transplant group, NTxG)., Methods: Between 1990, when the first patient received a lung transplant in Sweden, until June 2010, a total of 83 PiZZ patients with severe emphysema underwent transplantation. Seventy appropriate controls were identified from the Swedish National AAT Deficiency Registry. Each control was matched with a patient who had received a lung transplant, for age, gender, smoking history (number of pack-years) and lung function at the time of transplantation., Results: Both controls and lung transplant patients had low spirometric values with a mean FEV(1) of 23 ± 6% and 22 ± 9% of predicted value, respectively (not a statistically significant difference). Of the 83 transplant patients, 62 (75%) underwent single-lung transplantation (SLTx). During follow-up, 37 (45%) deaths occurred in the TxG and 45 (64%) in the NTxG. In the TxG, the estimated median survival time was 11 years (95% confidence interval [CI] 9 to 14 years), compared with 5 years (95% CI 4 to 6 years) for the NTxG (p = 0.006). The most common cause of death was pulmonary infection among the transplant patients (38%) and respiratory failure (60%) among the controls., Conclusion: Lung transplantation significantly improves long-term survival of patients with severe α(1)-anti-trypsin deficiency (PiZZ) and emphysema., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

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.