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1.  The Impact of Age on Outcomes in Chronic Obstructive Pulmonary Disease Differs by Relationship Status 
Journal of behavioral medicine  2013;37(4):654-663.
Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that can lead to early-onset chronic obstructive pulmonary disease (COPD). The objective of this study was to examine the impact of age on psychological and clinical outcomes among individuals with AATD-associated COPD. 468 individuals with AATD-associated COPD (age 32 to 84 at baseline) completed questionnaires at baseline, 1- and 2-year follow-up. Age was examined as a predictor of depression, anxiety, health-related quality of life, and breathlessness at all three time points using linear mixed models. Age was associated with anxiety (b = −0.09, SE = 0.02, p < 0.001) and health-related quality of life (b = −0.29, SE = 0.09, p < 0.001). Age also had a statistically significant interaction with relationship status when predicting depression, health-related quality of life, and breathlessness. Among individuals who were single, younger age was associated with more symptoms of depression (b = −0.08, SE = 0.03, p < 0.01), worse health-related quality of life (b = −0.61, SE = 0.16, p < 0.001), and more breathlessness (b = −0.023, SE = 0.009, p < 0.01) throughout the two-year study. Age was not associated with these three outcomes among individuals who were married/part of an unmarried couple. Results suggest that individuals who develop a chronic illness at a young age, particularly those who are single, may be more likely to have worse psychological and clinical outcomes.
PMCID: PMC3772963  PMID: 23645147
Age; Relationship Status; Chronic Obstructive Pulmonary Disease; Depression; Anxiety; Clinical Outcomes
2.  Prospective Impact of Illness Uncertainty on Outcomes in Chronic Lung Disease 
To determine which aspect of illness uncertainty (i.e., ambiguity or complexity) has a stronger association with psychological and clinical outcomes over a two year period among individuals with a genetic subtype of chronic obstructive pulmonary disease (COPD). Ambiguity reflects uncertainty about physical cues and symptoms, and complexity reflects uncertainty about treatment and the medical system.
407 individuals with alpha-1 antitrypsin deficiency-associated COPD completed questionnaires at baseline, 1- and 2-year follow-up. Uncertainty was measured using the Mishel Uncertainty in Illness Scale. Outcomes were measured using the Hospital Anxiety and Depression Scale, St. George's Respiratory Questionnaire, and MMRC Dyspnea Scale. Ambiguity and complexity were examined as predictors of depressive symptoms, anxiety, quality of life, and breathlessness using linear mixed models adjusting for demographic and health characteristics.
Ambiguity was associated with more depressive symptoms (b = 0.09, SE = 0.02, p < 0.001) and anxiety (b = 0.13, SE = 0.02, p < 0.001), worse quality of life (b = 0.57, SE = 0.10, p < 0.001), and more breathlessness (b = 0.02, SE = 0.006, p < 0.001). Complexity did not have an independent effect on any outcome. Interactions between ambiguity and time since diagnosis were not statistically significant.
Ambiguity was prospectively associated with worse mood, quality of life, and breathlessness. Thus, ambiguity should be targeted in psychosocial interventions. Time since diagnosis did not affect the association between ambiguity and outcomes, suggesting that the impact of ambiguity is equally strong throughout the course of COPD.
PMCID: PMC3966193  PMID: 23772888
Uncertainty; Mishel Uncertainty in Illness Scale (MUIS); Chronic Obstructive Pulmonary Disease (COPD); Alpha One Antitrypsin Deficiency (AATD)
3.  The Prospective Association of Perceived Criticism with Dyspnea in Chronic Lung Disease 
Journal of psychosomatic research  2013;74(5):450-453.
Perceived criticism from family members influences mental health. The link between perceived criticism and physical health has not been thoroughly investigated. The objective of this study was to examine the association of perceived criticism with dyspnea in chronic obstructive pulmonary disease (COPD).
401 individuals with alpha-1 antitrypsin deficiency-associated COPD completed questionnaires at baseline, 1- and 2-year follow-up. Perceived criticism at baseline was examined as a predictor of dyspnea at all three time points using a linear mixed model that adjusted for demographic and health characteristics.
There was an interaction between perceived criticism and psychological distress (p = 0.038). Perceived criticism was associated with dyspnea only among individuals with elevated psychological distress (b = 0.32, SE = 0.13, p = 0.018).
Further research is needed to replicate these findings and determine the extent to which they apply to other common subjective physical symptoms such as pain.
PMCID: PMC3631318  PMID: 23597335
Alpha-1 antitrypsin deficiency (AATD); Chronic obstructive pulmonary disease (COPD); Dyspnea; Perceived criticism; Psychological distress
4.  Differences in Adjustment between Individuals with Alpha-1 Antitrypsin Deficiency (AATD) Associated COPD and Non-AATD COPD 
COPD  2013;10(2):226-234.
Smokers who have severe alpha-1 antitrypsin deficiency (AATD) are at risk for developing COPD earlier in life than smokers without AATD, and are likely to experience challenges adjusting to their illness because they are in a highly productive life stage when they are diagnosed with COPD. This study examined whether individuals with AATD-associated COPD differ from individuals with non-AATD COPD with regard to depression, anxiety, dyspnea, and health-related quality of life (HRQL). Cross-sectional data were collected via self-report questionnaires completed by 480 individuals with non-AATD COPD and 578 individuals with AATD-associated COPD under protocols with IRB approval. Multiple linear regression models were used to test whether individuals with non-AATD COPD differed from individuals with AATD-associated COPD with regard to depression, anxiety, dyspnea, and HRQL. All models adjusted for demographic and health characteristics. Individuals with AATD-associated COPD did not report more symptoms of depression or anxiety; however, they did report more dyspnea (B = 0.31, 95% CI = 0.16 to 0.47, p < 0.001) and impairment in HRQL (B = 4.75, 95% CI = 2.10 to 7.41, p < 0.001) than other individuals with COPD. Individuals with AATD-associated COPD were more likely to be a member of a couple (rather than single) and had a higher level of education when compared to individuals with non-AATD COPD. Resources available to persons with AATD-associated COPD, such as being in a serious relationship and having higher education, may offset the effect of age when considering symptoms of depression and anxiety in patients with COPD.
PMCID: PMC3616400  PMID: 23547634
Alpha-1 Antitrypsin Deficiency; Anxiety; Depression; Dyspnea; Health Status; Psychological Adjustment
5.  Human Treg responses allow sustained recombinant adeno-associated virus–mediated transgene expression 
The Journal of Clinical Investigation  2013;123(12):5310-5318.
Recombinant adeno-associated virus (rAAV) vectors have shown promise for the treatment of several diseases; however, immune-mediated elimination of transduced cells has been suggested to limit and account for a loss of efficacy. To determine whether rAAV vector expression can persist long term, we administered rAAV vectors expressing normal, M-type α-1 antitrypsin (M-AAT) to AAT-deficient subjects at various doses by multiple i.m. injections. M-specific AAT expression was observed in all subjects in a dose-dependent manner and was sustained for more than 1 year in the absence of immune suppression. Muscle biopsies at 1 year had sustained AAT expression and a reduction of inflammatory cells compared with 3 month biopsies. Deep sequencing of the TCR Vβ region from muscle biopsies demonstrated a limited number of T cell clones that emerged at 3 months after vector administration and persisted for 1 year. In situ immunophenotyping revealed a substantial Treg population in muscle biopsy samples containing AAT-expressing myofibers. Approximately 10% of all T cells in muscle were natural Tregs, which were activated in response to AAV capsid. These results suggest that i.m. delivery of rAAV type 1–AAT (rAAV1-AAT) induces a T regulatory response that allows ongoing transgene expression and indicates that immunomodulatory treatments may not be necessary for rAAV-mediated gene therapy.
PMCID: PMC3859421  PMID: 24231351
6.  Alcohol Use Predicts ER Visits in Individuals with Alpha-1 Antitrypsin Deficiency (AATD) Associated COPD 
COPD  2012;9(4):417-425.
Excessive alcohol use in COPD has been associated with increased mortality; however, little is known about alcohol use in AATD-associated COPD. 538 individuals with AATD-associated COPD completed questionnaires at baseline and 330 also completed 2 years of follow-up questionnaires. Demographic and health information was collected, including information about alcohol use, ER visits for COPD, and hospitalizations for COPD. Problem alcohol use was characterized using the CAGE screening questionnaire and recent alcohol consumption. Demographic and clinical characteristics associated with problem drinking were identified using logistic regression. Problem drinking at baseline was examined as a predictor of ER visits and hospital admissions for COPD in the subsequent two years using logistic regression adjusting for demographic variables and baseline health status. 14% of the sample reported a history of problem drinking per the CAGE and 8% reported problem drinking in the past week. Problem drinking was associated with higher education and greater lifetime tobacco exposure. Recent alcohol consumption was a significant predictor of having an ER visit for COPD in the subsequent two years. Compared to individuals who reported problem drinking in the past week, individuals with no consumption (OR= 0.32, 95% CI= 0.10 to 0.97, p= .043) and individuals with low to moderate consumption (OR= 0.25, 95% CI= 0.08 to 0.77, p= .016) had significantly lower odds of an ER visit. Neither measure of problem drinking predicted hospital admission. Screening for recent excessive alcohol use in this population may identify individuals at risk for use of costly emergency health services.
PMCID: PMC3603142  PMID: 22651849
Alpha One Antitrypsin Deficiency (AATD); Alcohol Use; Emergency Room Use; Emergency Room Visits
7.  Association of cigarette smoking and CRP levels with DNA methylation in α-1 antitrypsin deficiency 
Epigenetics  2012;7(7):720-728.
Alpha-1 antitrypsin (AAT) deficiency and tobacco smoking are confirmed risk factors for Chronic Obstructive Pulmonary Disease. We hypothesized that variable DNA methylation would be associated with smoking and inflammation, as reflected by the level of C-Reactive Protein (CRP) in AAT-deficient subjects. Methylation levels of 1,411 autosomal CpG sites from the Illumina GoldenGate Methylation Cancer Panel I were analyzed in 316 subjects. Associations of five smoking behaviors and CRP levels with individual CpG sites and average methylation levels were assessed using non-parametric testing, linear regression and linear mixed effect models, with and without adjustment for age and gender. Univariate linear regression analysis revealed that methylation levels of 16 CpG sites significantly associated with ever-smoking status. A CpG site in the TGFBI gene was the only site associated with ever-smoking after adjustment for age and gender. No highly significant associations existed between age at smoking initiation, pack-years smoked, duration of smoking, and time since quitting smoking as predictors of individual CpG site methylation levels. However, ever-smoking and younger age at smoking initiation associated with lower methylation level averaged across all sites. DNA methylation at CpG sites in the RUNX3, JAK3 and KRT1 genes associated with CRP levels. The most significantly associated CpG sites with gender and age mapped to the CASP6 and FZD9 genes, respectively. In summary, this study identified multiple potential candidate CpG sites associated with ever-smoking and CRP level in AAT-deficient subjects. Phenotypic variability in Mendelian diseases may be due to epigenetic factors.
PMCID: PMC3414392  PMID: 22617718
68kDa (TGFBI); C-Reactive Protein (CRP); Chronic Obstructive Pulmonary Disease (COPD); Illumina GoldenGate Methylation Cancer Panel I; alpha-1 antitrypsin (AAT) deficiency; beta-induced; methylation; smoking behaviors; transforming growth factor
8.  Phase 2 Clinical Trial of a Recombinant Adeno-Associated Viral Vector Expressing α1-Antitrypsin: Interim Results 
Human Gene Therapy  2011;22(10):1239-1247.
Recombinant adeno-associated virus (rAAV) vectors offer promise for the gene therapy of α1-antitrypsin (AAT) deficiency. In our prior trial, an rAAV vector expressing human AAT (rAAV1-CB-hAAT) provided sustained, vector-derived AAT expression for >1 year. In the current phase 2 clinical trial, this same vector, produced by a herpes simplex virus complementation method, was administered to nine AAT-deficient individuals by intramuscular injection at doses of 6.0×1011, 1.9×1012, and 6.0×1012 vector genomes/kg (n=3 subjects/dose). Vector-derived expression of normal (M-type) AAT in serum was dose dependent, peaked on day 30, and persisted for at least 90 days. Vector administration was well tolerated, with only mild injection site reactions and no serious adverse events. Serum creatine kinase was transiently elevated on day 30 in five of six subjects in the two higher dose groups and normalized by day 45. As expected, all subjects developed anti-AAV antibodies and interferon-γ enzyme-linked immunospot responses to AAV peptides, and no subjects developed antibodies to AAT. One subject in the mid-dose group developed T cell responses to a single AAT peptide unassociated with any clinical effects. Muscle biopsies obtained on day 90 showed strong immunostaining for AAT and moderate to marked inflammatory cell infiltrates composed primarily of CD3-reactive T lymphocytes that were primarily of the CD8+ subtype. These results support the feasibility and safety of AAV gene therapy for AAT deficiency, and indicate that serum levels of vector-derived normal human AAT >20 μg/ml can be achieved. However, further improvements in the design or delivery of rAAV-AAT vectors will be required to achieve therapeutic target serum AAT concentrations.
Flotte and colleagues report on a phase 2 trial in which the same α1-antitrypsin (AAT) AAV vector as in phase 1 is administered intramuscularly to nine AAT-deficient individuals at one of three doses. Vector-derived expression of normal (M-type) AAT in serum is shown to be dose dependent, peaks on day 30, and persists for at least 90 days, although AAT levels were sub-therapeutic.
PMCID: PMC3205788  PMID: 21609134
9.  Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency 
Respiratory Research  2012;13(1):16.
The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).
We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency.
The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD.
Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed.
IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.
PMCID: PMC3306733  PMID: 22356581
CHRNA3; Chronic obstructive pulmonary disease; Genetic association analysis; Genetic modifiers; IREB2
10.  Pharmacokinetic comparability of Prolastin®-C to Prolastin® in alpha1-antitrypsin deficiency: a randomized study 
Alpha1-antitrypsin (AAT) deficiency is characterized by low blood levels of alpha1-proteinase inhibitor (alpha1-PI) and may lead to emphysema. Alpha1-PI protects pulmonary tissue from damage caused by the action of proteolytic enzymes. Augmentation therapy with Prolastin® (Alpha1-Proteinase Inhibitor [Human]) to increase the levels of alpha1-PI has been used to treat individuals with AAT deficiency for over 20 years. Modifications to the Prolastin manufacturing process, incorporating additional purification and pathogen-reduction steps, have led to the development of an alpha1-PI product, designated Prolastin®-C (Alpha1-Proteinase inhibitor [Human]). The pharmacokinetic comparability of Prolastin-C to Prolastin was assessed in subjects with AAT deficiency.
In total, 24 subjects were randomized to receive 60 mg/kg of functionally active Prolastin-C or Prolastin by weekly intravenous infusion for 8 weeks before crossover to the alternate treatment for another 8 weeks. Pharmacokinetic plasma samples were drawn over 7 days following last dose in the first treatment period and over 10 days following the last dose in the second period. The primary end point for pharmacokinetic comparability was area under the plasma concentration versus time curve over 7 days post dose (AUC0-7 days) of alpha1-PI determined by potency (functional activity) assay. The crossover phase was followed by an 8-week open-label treatment phase with Prolastin-C only.
Mean AUC0-7 days was 155.9 versus 152.4 mg*h/mL for Prolastin-C and Prolastin, respectively. The geometric least squares mean ratio of AUC0-7 days for Prolastin-C versus Prolastin had a point estimate of 1.03 and a 90% confidence interval of 0.97-1.09, demonstrating pharmacokinetic equivalence between the 2 products. Adverse events were similar for both treatments and occurred at a rate of 0.117 and 0.078 per infusion for Prolastin-C (double-blind treatment phase only) and Prolastin, respectively (p = 0.744). There were no treatment-emergent viral infections in any subject for human immunodeficiency virus, hepatitis B or C, or parvovirus B19 during the course of the study.
Prolastin-C demonstrated pharmacokinetic equivalence and a comparable safety profile to Prolastin.
Trial Registration Identifier: NCT00295061
PMCID: PMC2958874  PMID: 20920295
11.  Quantitative airway assessment on computed tomography in patients with α1-antitrypsin deficiency 
COPD  2009;6(6):468-477.
The relationship between quantitative airway measurements on computed tomography (CT) and airflow limitation in individuals with severe α1-antitrypsin deficiency (AATD) is undefined.
To clarify the relationship between CT-based airway indices and airflow limitation in AATD.
52 patients with AATD underwent chest CT and pre-bronchodilator spirometry at three institutions. In the right upper (RUL) and lower (RLL) lobes, wall area percent (WA%) and luminal area (Ai) were measured in the third, fourth, and fifth generations of the bronchi. The severity of emphysema was also calculated in each lobe and expressed as low attenuation area percent (LAA%). Correlations between obtained measurements and FEV1% predicted (FEV1%P) were evaluated by the Spearman rank correlation test.
In RUL, WA% of all generations was significantly correlated with FEV1%P (3rd,R=−0.33, p=0.02; 4th,R=−0.39, p=0.004; 5th,R=−0.57, p<0.001; respectively). Ai also showed significant correlations (3rd,R=0.32, p=0.02; 4th,R=0.34, p=0.01; 5th,R=0.56, p<0.001; respectively). Measured correlation coefficients improved when the airway progressed distally from the third to fifth generations. LAA% also correlated with FEV1%P (R=−0.51, p<0.001). In RLL, WA% showed weak correlations with FEV1%P in all generations (3rd,R=−0.34, p=0.01; 4th,R=−0.30, p=0.03; 5th,R=−0.31, p=0.03; respectively). Only Ai from the fifth generation significantly correlated with FEV1%P in this lobe (R=0.34, p=0.01). LAA% strongly correlated with FEV1%P (R=−0.71, p<0.001).
Quantitative airway measurements are significantly correlated with airflow limitation in AATD, particularly in the distal airways of RUL. Emphysema of the lower lung is the predominant component; however, airway disease also has a significant impact on airflow limitation in AATD.
PMCID: PMC2945281  PMID: 19938971
12.  Determinants of airflow obstruction in severe alpha‐1‐antitrypsin deficiency 
Thorax  2007;62(9):806-813.
Severe α1‐antitrypsin (AAT) deficiency is an autosomal recessive genetic condition associated with an increased but variable risk for chronic obstructive pulmonary disease (COPD). A study was undertaken to assess the impact of chronic bronchitis, pneumonia, asthma and sex on the development of COPD in individuals with severe AAT deficiency.
The AAT Genetic Modifier Study is a multicentre family‐based cohort study designed to study the genetic and epidemiological determinants of COPD in AAT deficiency. 378 individuals (age range 33–80 years), confirmed to be homozygous for the SERPINA1 Z mutation, were included in the analyses. The primary outcomes of interest were a quantitative outcome, forced expiratory volume in 1 s (FEV1) percentage predicted, and a qualitative outcome, severe airflow obstruction (FEV1 <50% predicted).
In multivariate analysis of the overall cohort, cigarette smoking, sex, asthma, chronic bronchitis and pneumonia were risk factors for reduced FEV1 percentage predicted and severe airflow obstruction (p<0.01). Index cases had lower FEV1 values, higher smoking histories and more reports of adult asthma, pneumonia and asthma before age 16 than non‐index cases (p<0.01). Men had lower pre‐ and post‐bronchodilator FEV1 percentage predicted than women (p<0.0001); the lowest FEV1 values were observed in men reporting a history of childhood asthma (26.9%). This trend for more severe obstruction in men remained when index and non‐index groups were examined separately, with men representing the majority of non‐index individuals with airflow obstruction (71%). Chronic bronchitis (OR 3.8, CI 1.8 to 12.0) and a physician's report of asthma (OR 4.2, CI 1.4 to 13.1) were predictors of severe airflow obstruction in multivariate analysis of non‐index men but not women.
In individuals with severe AAT deficiency, sex, asthma, chronic bronchitis and pneumonia are risk factors for severe COPD, in addition to cigarette smoking. These results suggest that, in subjects severely deficient in AAT, men, individuals with symptoms of chronic bronchitis and/or a past diagnosis of asthma or pneumonia may benefit from closer monitoring and potentially earlier treatment.
PMCID: PMC2117297  PMID: 17389752
13.  IL10 Polymorphisms Are Associated with Airflow Obstruction in Severe α1-Antitrypsin Deficiency 
Severe α1-antitrypsin (AAT) deficiency is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD), especially in individuals who smoke. There is marked variability in the development of lung disease in individuals homozygous (PI ZZ) for this autosomal recessive condition, suggesting that modifier genes could be important. We hypothesized that genetic determinants of obstructive lung disease may be modifiers of airflow obstruction in individuals with severe AAT deficiency. To identify modifier genes, we performed family-based association analyses for 10 genes previously associated with asthma and/or COPD, including IL10, TNF, GSTP1, NOS1, NOS3, SERPINA3, SERPINE2, SFTPB, TGFB1, and EPHX1. All analyses were performed in a cohort of 378 PI ZZ individuals from 167 families. Quantitative spirometric phenotypes included forced expiratory volume in one second (FEV1) and the ratio of FEV1/forced vital capacity (FVC). A qualitative phenotype of moderate-to-severe COPD was defined for individuals with FEV1 ⩽ 50 percent predicted. Six of 11 single-nucleotide polymorphisms (SNPs) in IL10 (P = 0.0005–0.05) and 3 of 5 SNPs in TNF (P = 0.01–0.05) were associated with FEV1 and/or FEV1/FVC. IL10 SNPs also demonstrated association with the qualitative COPD phenotype. When phenotypes of individuals with a physician's diagnosis of asthma were excluded, IL10 SNPs remained significantly associated, suggesting that the association with airflow obstruction was independent of an association with asthma. Haplotype analysis of IL10 SNPs suggested the strongest association with IL10 promoter SNPs. IL10 is likely an important modifier gene for the development of COPD in individuals with severe AAT deficiency.
PMCID: PMC2176135  PMID: 17690329
chronic obstructive pulmonary disease; genetic modifiers; interleukin 10; family-based association analysis
14.  Risk factors for symptom onset in PI*Z alpha-1 antitrypsin deficiency 
In an early study of highly symptomatic patients with PI*Z alpha-1 antitrypsin deficiency (AAT), tobacco smoking was identified as a risk factor by comparing the age of symptom onset in smokers and nonsmokers. Age of symptom onset has not been well studied in relationship to other environmental exposures.
Environmental exposures were assessed in 313 PI*Z adults through retrospective self-administered questionnaire. Age of onset of symptoms with and without these exposures were analyzed through survival analysis.
Personal smoking was the most important risk factor, associated with earlier onset of cough and wheeze, and showed a dose-dependent relationship with the onset of dyspnea. Childhood environmental tobacco smoke (ETS) exposure was independently associated with younger age of onset of cough. Earlier onset of wheeze was also associated with childhood respiratory infections and family history of emphysema. The report of childhood respiratory infections was associated with childhood ETS exposure, but no statistically significant interactions were noted.
We conclude that both personal and secondhand exposure to tobacco smoke in childhood are likely to accelerate the onset of symptoms in AAT deficient patients. Respiratory infections in childhood may also contribute to this risk.
PMCID: PMC2707814  PMID: 18044105
alpha-1 antitrypsin deficiency; tobacco smoke pollution; respiratory symptoms; lower respiratory illness
15.  Environmental, occupational, and genetic risk factors for alpha-1 antitrypsin deficiency. 
Environmental Health Perspectives  2003;111(14):1749-1752.
Alpha-1 antitrypsin (AAT) deficiency is an inherited genetic disorder currently diagnosed in approximately 5,000 people in the United States. Although some individuals with AAT deficiency are asymptomatic, the condition often leads to deterioration of lung function in adults and is associated with emphysema, asthma, chronic obstructive pulmonary disease, and other respiratory diseases. In children, AAT deficiency can result in severe liver disease, including fatal cirrhosis in newborn infants. Although much is known about the clinical pathology of AAT deficiency, researchers are just beginning to characterize environmental, occupational, and genetic modifiers affecting the onset and progression of diseases related to AAT deficiency. On 19 August 2002, a group of basic scientists, clinicians, environmental health researchers, and public interest groups gathered at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, to discuss ongoing research on these topics. The goals of this workshop were to a) assess the present state of knowledge regarding environmental and occupational risk factors contributing to AAT deficiency morbidity and mortality, b) define future research needs in this area, and c) explore collaborative opportunities to advance understanding of risk factors affecting the progression of AAT deficiency-related disease. Participants agreed that new research initiatives in these areas represent an opportunity to benefit both basic science, through enhanced understanding of gene-environment interaction, and the AAT deficiency patient community, through innovative new approaches to disease management and treatment.
PMCID: PMC1241718  PMID: 14594626

Results 1-15 (15)