Exertional breathlessness related to medical conditions in middle-aged people: the population-based SCAPIS study of more than 25,000 men and women.

BACKGROUND: Breathlessness is common in the population and can be related to a range of medical conditions. We aimed to evaluate the burden of breathlessness related to different medical conditions in a middle-aged population. METHODS: Cross-sectional analysis of the population-based Swedish CArdioPulmonary bioImage Study of adults aged 50-64 years. Breathlessness (modified Medical Research Council [mMRC] ≥ 2) was evaluated in relation to self-reported symptoms, stress, depression; physician-diagnosed conditions; measured body mass index (BMI), spirometry, venous haemoglobin concentration, coronary artery calcification and stenosis [computer tomography (CT) angiography], and pulmonary emphysema (high-resolution CT). For each condition, the prevalence and breathlessness population attributable fraction (PAF) were calculated, overall and by sex, smoking history, and presence/absence of self-reported cardiorespiratory disease. RESULTS: We included 25,948 people aged 57.5 ± [SD] 4.4; 51% women; 37% former and 12% current smokers; 43% overweight (BMI 25.0-29.9), 21% obese (BMI ≥ 30); 25% with respiratory disease, 14% depression, 9% cardiac disease, and 3% anemia. Breathlessness was present in 3.7%. Medical conditions most strongly related to the breathlessness prevalence were (PAF 95%CI): overweight and obesity (59.6-66.0%), stress (31.6-76.8%), respiratory disease (20.1-37.1%), depression (17.1-26.6%), cardiac disease (6.3-12.7%), anemia (0.8-3.3%), and peripheral arterial disease (0.3-0.8%). Stress was the main factor in women and current smokers. CONCLUSION: Breathlessness mainly relates to overweight/obesity and stress and to a lesser extent to comorbidities like respiratory, depressive, and cardiac disorders among middle-aged people in a high-income setting-supporting the importance of lifestyle interventions to reduce the burden of breathlessness in the population.

High prevalence of interstitial lung abnormalities in middle-aged never-smokers.

Background: Interstitial lung abnormalities (ILA) are incidental findings on chest computed tomography (CT). These patterns can present at an early stage of fibrotic lung disease. Our aim was to estimate the prevalence of ILA in the Swedish population, in particular in never-smokers, and find out its association with demographics, comorbidities and symptoms. Methods: Participants were recruited to the Swedish CArdioPulmonary BioImage Study (SCAPIS), a population-based survey including men and women aged 50-64 years performed at six university hospitals in Sweden. CT scan, spirometry and questionnaires were performed. ILA were defined as cysts, ground-glass opacities, reticular abnormality, bronchiectasis and honeycombing. Findings: Out of 29 521 participants, 14 487 were never-smokers and 14 380 were men. In the whole population, 2870 (9.7%) had ILA of which 134 (0.5%) were fibrotic. In never-smokers, the prevalence was 7.9% of which 0.3% were fibrotic. In the whole population, age, smoking history, chronic bronchitis, cancer, coronary artery calcium score and high-sensitive C-reactive protein were associated with ILA. Both ILA and fibrotic ILA were associated with restrictive spirometric pattern and impaired diffusing capacity of the lung for carbon monoxide. However, individuals with ILA did not report more symptoms compared with individuals without ILA. Interpretation: ILA are common in a middle-aged Swedish population including never-smokers. ILA may be at risk of being underdiagnosed among never-smokers since they are not a target for screening.

Consequences of Using Post- or Prebronchodilator Reference Values in Interpreting Spirometry.

Rationale: Postbronchodilator spirometry is used for the diagnosis of chronic obstructive pulmonary disease. However, prebronchodilator reference values are used for spirometry interpretation. Objectives: To compare the resulting prevalence rates of abnormal spirometry and study the consequences of using pre- or postbronchodilator reference values generated within SCAPIS (Swedish CArdioPulmonary bioImage Study) when interpreting postbronchodilator spirometry in a general population. Methods: SCAPIS reference values for postbronchodilator and prebronchodilator spirometry were based on 10,156 and 1,498 never-smoking, healthy participants, respectively. We studied the associations of abnormal spirometry, defined by using pre- or postbronchodilator reference values, with respiratory burden in the SCAPIS general population (28,851 individuals). Measurements and Main Results: Bronchodilation resulted in higher predicted medians and lower limits of normal (LLNs) for FEV1/FVC ratios. The prevalence of postbronchodilator FEV1/FVC ratio lower than the prebronchodilator LLN was 4.8%, and that of postbronchodilator FEV1/FVC lower than the postbronchodilator LLN was 9.9%, for the general population. An additional 5.1% were identified as having an abnormal postbronchodilator FEV1/FVC ratio, and this group had more respiratory symptoms, emphysema (13.5% vs. 4.1%; P < 0.001), and self-reported physician-diagnosed chronic obstructive pulmonary disease (2.8% vs. 0.5%, P < 0.001) than subjects with a postbronchodilator FEV1/FVC ratio greater than the LLN for both pre- and postbronchodilation. Conclusions: Pre- and postbronchodilator spirometry reference values differ with regard to FEV1/FVC ratio. Use of postbronchodilator reference values doubled the population prevalence of airflow obstruction; this was related to a higher respiratory burden. Using postbronchodilator reference values when interpreting postbronchodilator spirometry might enable the identification of individuals with mild disease and be clinically relevant.

Clinical and functional characteristics of individuals with alpha-1 antitrypsin deficiency: EARCO international registry.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a rare disease that is associated with an increased risk of pulmonary emphysema. The European AATD Research Collaboration (EARCO) international registry was founded with the objective of characterising the individuals with AATD and investigating their natural history. METHODS: The EARCO registry is an international, observational and prospective study of individuals with AATD, defined as AAT serum levels < 11 µM and/or proteinase inhibitor genotypes PI*ZZ, PI*SZ and compound heterozygotes or homozygotes of other rare deficient variants. We describe the characteristics of the individuals included from February 2020 to May 2022. RESULTS: A total of 1044 individuals from 15 countries were analysed. The most frequent genotype was PI*ZZ (60.2%), followed by PI*SZ (29.2%). Among PI*ZZ patients, emphysema was the most frequent lung disease (57.2%) followed by COPD (57.2%) and bronchiectasis (22%). Up to 76.4% had concordant values of FEV1(%) and KCO(%). Those with impairment in FEV1(%) alone had more frequently bronchiectasis and asthma and those with impairment in KCO(%) alone had more frequent emphysema and liver disease. Multivariate analysis showed that advanced age, male sex, exacerbations, increased blood platelets and neutrophils, augmentation and lower AAT serum levels were associated with worse FEV1(%). CONCLUSIONS: EARCO has recruited > 1000 individuals with AATD from 15 countries in its first 2 years. Baseline cross sectional data provide relevant information about the clinical phenotypes of the disease, the patterns of functional impairment and factors associated with poor lung function. Trial registration www. CLINICALTRIALS: gov (ID: NCT04180319).

Low Prevalence of Mild Alpha-1-Antitrypsin Deficiency in Hospitalized COVID-19-Patients.

Introduction: Alpha-1-antitrypsin (AAT) has been shown to inhibit SARS-CoV-2 cell entry and suggested as a therapeutic agent for COVID-19. Furthermore, epidemiological association of high prevalence of Alpha-1-antitrypsin deficiency (AATD) and regional severity of COVID-19-impact has been hypothesized. In our study setting, the estimated prevalence rates of mild (PI*MZ, PI*SS or PI*MS) and moderate-to-severe AATD (PI*ZZ or PI*SZ) are high, 9% and 0.2%, respectively. Our primary aim was to examine the prevalence rate of AATD among hospitalized COVID-19-patients. Methods: In this prospective observational study, enrollment occurred from December 2020 to January 2021 in two COVID-19-units at Skåne University Hospital, Lund, Sweden. Case definition was a patient hospitalized due to COVID-19. Patients were screened for AATD with PI-typing and if results were inconclusive, PCR for the S- and Z-genes were performed. Patients were categorized as severe or moderate COVID-19 and 30-day-mortality data were collected. The primary outcome was prevalence rate of AATD. The secondary outcome investigated association between presence of mild AATD and severe COVID-19. Results: We enrolled 61 patients with COVID-19. Two patients out of 61 (3%) had mild AATD (PI*MZ) and none had moderate-to-severe AATD. 30/61 (49%) had severe COVID-19. Both patients with mild AATD developed severe COVID-19. Yet, presence of AATD was not significantly associated with severe COVID-19 (p=0.24). Conclusion: Mild AATD (PI*MS or PI*MZ) was rare in a small cohort of hospitalized patients with COVID-19 in a study setting with a high background prevalence of AATD.

Triglyceride-Glucose Index is a Risk Marker of Incident COPD Events in Women.

Purpose: The triglyceride-glucose index (TyG index) is a marker of insulin resistance and metabolic dysfunction and has the advantage of being universally available. Although recent evidence suggests the TyG index has relevance to respiratory health, there have been no prospective studies assessing its value as a biomarker for chronic lung diseases. We aim to assess the TyG index as a potential risk marker for future incident COPD events in the general population. Patients and Methods: Baseline TyG index was assessed in 28,282 middle-aged men and women without previous history of chronic obstructive pulmonary disease (COPD) from the Malmö Preventive Project (men between 1974 and 1982 and women between 1982 and 1992). All subjects were followed up prospectively, and Cox proportional hazards regression was used to assess incident COPD events according to quartiles of TyG index. Results: After an average of 31 years of follow-up, TyG index was a strong predictor of future COPD events even after adjusting for potential confounders (Q4 (highest TyG index) HR (95% CI): 1.21 (1.09-1.35) vs Q1 (reference), p-trend <0.001). After stratifying by sex, the results remained statistically significant in women only (Q4 vs Q1 HR 1.72 (1.41-2.09)). Additionally, the risk remained significant in a cohort of life-long never smokers (Q4 vs Q1 HR 1.47 (1.08-2.01)). Conclusion: A raised TyG index is a novel risk marker of future incident COPD events in women. Insulin resistance as reflected by the TyG index can precede the development of obstructive lung disease and as such may be an easily measurable and useful predictor of COPD in women.

Cancer risk in severe alpha-1-antitrypsin deficiency.

BACKGROUND: Severe alpha-1-antitrypsin deficiency (AATD), phenotype PiZZ, is a risk factor for pulmonary emphysema and liver disease, but its effect on cancer risk is unknown. Our aim was to evaluate the risk and the risk factors for incident cancer in PiZZ individuals compared with the general population with known smoking habits. METHODS: A longitudinal study of PiZZ individuals (n=1595) from the Swedish National AATD Register, and controls (n=5999) from Swedish population-based cohorts. Data on cancer and mortality were obtained by cross-linkage with national registers. Individuals who had undergone lung transplantation (n=10) and those with a cancer diagnosis within 5 years prior to inclusion (n=63) were excluded. The risk factors for developing cancer were analysed using proportional hazards and Fine-Gray regression models, adjusting for age, sex, smoking habits and the presence of liver disease. RESULTS: The median follow-up time was 17 years (interquartile range 11 years) for the whole study population. The incidence rates of hepatic and non-hepatic cancer per 1000 person-years were 1.6 (95% CI 1.1-2.3) and 8.5 (95% CI 7.2-10.0), respectively, for the PiZZ individuals, and 0.1 (95% CI 0.04-0.2) and 6.6 (95% CI 6.0-7.1), respectively, for the controls. The adjusted hazard ratios for hepatic and for non-hepatic cancer were 23.4 (95% CI 9.9-55.4) and 1.3 (95% CI 1.1-1.5), respectively, in the PiZZ individuals compared with the controls. CONCLUSION: These results suggest that individuals with severe AATD may have an increased risk of developing both hepatic and non-hepatic cancer, compared with the general population.

The Clinical Course of Severe Alpha-1-Antitrypsin Deficiency in Patients Identified by Screening.

BACKGROUND: Severe alpha-1-antitrypsin deficiency (AATD) is a genetic condition predisposing to chronic obstructive pulmonary disease (COPD) and liver disease. Its natural course is not well known. Our aim was to study the natural course of AATD by analyzing the clinical course in individuals with severe AATD identified by screening. MATERIALS AND METHODS: Of the 1585 individuals included in the Swedish AATD register, 377 (24%) were identified by screening and included in this retrospective study. The follow-up time was from the date of inclusion in the register to the first lung transplantation, death or the termination of the study on June 1st, 2016. The risk factors for having a diagnosis of COPD were investigated through a proportional hazards model, adjusted for sex, diagnosis before the age of 14 years, smoking habits, occupational exposure to airway irritants and respiratory symptoms or diseases. RESULTS: At inclusion, 71% of the individuals were asymptomatic, ie, without any respiratory symptoms. Compared to the 156 (41%) ever-smokers, the 221 (59%) never-smokers had better lung function (mean FEV1 98 (SD 18) vs 85 (SD 28) % predicted; p < 0.001), and fewer of them were symptomatic, ie, with respiratory symptoms, at inclusion (20% vs 42%; p < 0.001). They also had a lower annual decline in FEV1 (mean 42 (95% CI 36-47) vs 53 (95% CI 47-60) mL·yr-1; p = 0.011) and better survival than the ever-smokers. The risk factors for having a diagnosis of COPD were the identification of severe AATD at an age of ≥14 years and the presence of respiratory symptoms or diseases. CONCLUSION: Never-smoking individuals with severe AATD identified by screening have better lung function, fewer symptoms, and better survival compared with the ever-smokers. Screening for AATD at an early age may improve the prognosis of AATD.

Advanced Dental Cleaning is Associated with Reduced Risk of COPD Exacerbations - A Randomized Controlled Trial.

PURPOSE: Infections from the oral microbiome may lead to exacerbations of chronic obstructive pulmonary disease (COPD). We investigated whether advanced dental cleaning could reduce exacerbation frequency. Secondary outcomes were disease-specific health status, lung function, and whether the bacterial load and composition of plaque microbiome at baseline were associated with a difference in outcomes. PATIENTS AND METHODS: One-hundred-one primary and secondary care patients with COPD were randomized to intervention with advanced dental cleaning or to dental examination only, repeated after six months. At baseline and at 12 months, data of exacerbations, lung function, COPD Assessment Test (CAT) score, and periodontal status were collected from questionnaires, record review, and periodontal examination. Student's t-test and Mann-Whitney-U (MWU) test compared changes in outcomes. The primary outcome variable was also assessed using multivariable linear regression with adjustment for potential confounders. Microbiome analyses of plaque samples taken at baseline were performed using Wilcoxon signed ranks tests for calculation of alpha diversity, per mutational multivariate analysis of variance for beta diversity, and receiver operating characteristic curves for prediction of outcomes based on machine learning models. RESULTS: In the MWU test, the annual exacerbation frequency was significantly reduced in patients previously experiencing frequent exacerbations (p = 0.020) and in those with repeated advanced dental cleaning (p = 0.039) compared with the non-treated control group, but not in the total population including both patients with a single and repeated visits (p = 0.207). The result was confirmed in multivariable linear regression, where the risk of new exacerbations was significantly lower in patients both in the intention to treat analysis (regression coefficient 0.36 (95% CI 0.25-0.52), p < 0.0001) and in the population with repeated dental cleaning (0.16 (0.10-0.27), p < 0.0001). The composition of microbiome at baseline was moderately predictive of an increased risk of worsened health status at 12 months (AUC = 0.723). CONCLUSION: Advanced dental cleaning is associated with a reduced frequency of COPD exacerbations. Regular periodontal examination and dental cleaning may be of clinical importance to prevent COPD exacerbations.

Severe alpha-1-antitrypsin deficiency increases the risk of venous thromboembolism.

BACKGROUND: Severe alpha-1-antitrypsin deficiency (AATD), phenotype PiZZ, is associated with increased risk of liver disease and chronic obstructive pulmonary disease (COPD), but the risk of venous thromboembolism (VTE) is unknown. Our aim was to evaluate the risk of VTE in individuals with severe AATD compared with control subjects from the general population. METHODS: Individuals with severe AATD (n = 1577) were recruited from the Swedish national AATD register. Control subjects (n = 5969) were selected from the OLIN (Obstructive Lung Disease in Northern Sweden) studies, that include a random general population sample. Longitudinal data on VTE and diagnoses were obtained from the Swedish National Patient Registry. Associations were analyzed using multivariable Cox regression. RESULTS: At inclusion, 46% of the AATD individuals and 53% of the controls were never-smokers. COPD was present in 46% of the AATD individuals compared with 4% of the controls. During a median follow-up of 18 years, 116 (7%) of the AATD individuals and 89 (1%) of the control subjects developed VTE, unadjusted hazard ratio 6.5 (95% confidence interval 4.9-8.6). Risk factors for incident VTE were male gender, age, COPD, cancer, and liver disease. Adjusting for these factors, the AATD individuals had a significantly higher risk of incident VTE, adjusted hazard ratio 4.2 (95% confidence interval 2.9-6.2) as compared with the controls. CONCLUSION: Subjects with severe AATD have considerably increased risk of developing VTE compared with the general population, even after accounting for risk factors. This calls for optimized risk factor management and clinical follow-up of this patient group.

Indications and patterns of use of benzodiazepines and opioids in severe interstitial lung disease: a population-based longitudinal study.

BACKGROUND: Despite evidence that opioids might relieve chronic breathlessness, physicians may still be reluctant to prescribe them due to safety concerns. By contrast, benzodiazepine (BDZ) prescribing often seeks to reduce chronic breathlessness despite no evidence of net benefit. Prescribing patterns and indications for these medications in severe interstitial lung disease (ILD) are unknown. Here, our objective was to evaluate the indications, medications and temporal patterns of BDZ and opioid prescriptions in people with oxygen-dependent ILD. METHODS: This was an observational, population-based, longitudinal study of adults starting long-term oxygen therapy (LTOT) for ILD between 2005 and 2014 in the Swedish National Registry for Respiratory Failure (Swedevox). People dispensed BDZs (n=2000) and opioids (n=2000) from 6 months before start of LTOT throughout follow-up (first of death or study end) were analysed. RESULTS: Of 1635 included patients, 651 (39.8%) received BDZs and 710 (43.4%) received opioids during the study period; 373 (22.8%) patients received both. The most frequently prescribed BDZs and opioids were oxazepam (85.6%) and oxycodone (28.7%), respectively. Indications for breathlessness were uncommon for BDZs (1.4%) and opioids (6.4%). During the last year of life, opioid indications for breathlessness increased from 2.5% (12-10 months before death) to 10.2% in the last 3 months of life (p=0.048). CONCLUSIONS: In oxygen-dependent ILD, opioids are rarely prescribed for breathlessness even in the last months of life, when chronic breathlessness often increases in prevalence and intensity.

Lung Function and Health Status in Individuals with Severe Alpha-1-Antitrypsin Deficiency at the Age of 42.

BACKGROUND: 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.

The ratio FEV1 /FVC and its association to respiratory symptoms-A Swedish general population study.

Chronic airflow limitation (CAL) can be defined as fixed ratio of forced expiratory volume in 1 s (FEV1 )/forced vital capacity (FVC) < 0.70 after bronchodilation. It is unclear which is the most optimal ratio in relation to respiratory morbidity. The aim was to investigate to what extent different ratios of FEV1 /FVC were associated with any respiratory symptom. In a cross-sectional general population study, 15,128 adults (50-64 years of age), 7,120 never-smokers and 8,008 ever-smokers completed a respiratory questionnaire and performed FEV1 and FVC after bronchodilation. We calculated different ratios of FEV1 /FVC from 0.40 to 1.0 using 0.70 as reference category. We analysed odds ratios (OR) between different ratios and any respiratory symptom using adjusted multivariable logistic regression. Among all subjects, regardless of smoking habits, the lowest odds for any respiratory symptom was at FEV1 /FVC = 0.82, OR 0.48 (95% CI 0.41-0.56). Among never-smokers, the lowest odds for any respiratory symptom was at FEV1 /FVC = 0.81, OR 0.53 (95% CI 0.41-0.70). Among ever-smokers, the odds for any respiratory symptom was lowest at FEV1 /FVC = 0.81, OR 0.43 (95% CI 0.16-1.19), although the rate of inclining in odds was small in the upper part, that is FEV1 /FVC = 0.85 showed similar odds, OR 0.45 (95% CI 0.38-0.55). We concluded that the odds for any respiratory symptoms continuously decreased with higher FEV1 /FVC ratios and reached a minimum around 0.80-0.85, with similar results among never-smokers. These results indicate that the optimal threshold associated with respiratory symptoms may be higher than 0.70 and this should be further investigated in prospective longitudinal studies.

Chronic airflow limitation and its relation to respiratory symptoms among ever-smokers and never-smokers: a cross-sectional study.

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 (FEV1:FVC) after bronchodilation, and FEV1:FVC less than the fifth percentile is often used as a cut-off for CAL. The aim was to investigate if increasing percentiles of FEV1: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 FEV1 and FVC after bronchodilation. We calculated their z-scores for FEV1:FVC and defined the fifth percentile using the Global Lung Function Initiative (GLI) reference value, GLI5 and increasing percentiles up to GLI25. 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 GLI15-20 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 GLI5-10 (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 FEV1:FVC and respiratory symptoms differed depending on smoking history. Our results support a higher percentile cut-off for FEV1:FVC for never-smokers and, in particular, for ever-smokers.

Decreased Risk of Ischemic Heart Disease in Individuals with Severe Alpha 1-Antitrypsin Deficiency (PiZZ) in Comparison with the General Population.

Background: Severe alpha-1-antitrypsin deficiency (AATD) is an established risk factor for chronic obstructive pulmonary disease (COPD) and liver disease, but the effect on the incidence of ischemic heart disease (IHD) is not well known. The aim was to evaluate the risk of incident IHD in patients with severe AATD compared with a random sample of the general population, with known smoking habits. Methods: AAT-deficient individuals, phenotype PiZZ (n=1545), were included in the Swedish National AATD Register. Controls (n=5883) were selected from population-based cohorts in Northern Sweden. Data on IHD and comorbidities were obtained by nationwide cross-linkage with the Swedish National Patient Register. Risk factors for incident IHD were analyzed using Cox regression, adjusted for age, gender, smoking status and the presence of COPD, hypertension, hyperlipidemia and diabetes. Results: At inclusion, 46% of the PiZZ individuals and 53% of the controls were never-smokers. During follow-up (median 16 years; range 0.2-23), 8% (n=123) of PiZZ individuals and 12% (n=690) of controls developed IHD. The controls had a significantly higher risk for incident IHD than the PiZZ individuals, with adjusted hazard ratio (HR) of 1.8 (95% CI 1.4-2.3). The risk was higher for controls in both ever-smokers (HR 2.1; 95% CI 1.5-2.9) and never-smokers (HR 1.5; 95% CI 1.1-2.2). Conclusion: PiZZ individuals have a lower risk of developing incident ischemic heart disease than the control subjects with known smoking habits, who had been randomly selected from population-based cohorts.