ABSTRACT
This review summarizes the current information on the relationship between severe alpha-1 antitrypsin deficiency (AATD), asthma and COPD. AATD is a genetic predisposition to the development of early COPD in susceptible individuals and reduction in known factors that enhance lung function loss is the paramount aim of management. Asthma is one controllable condition that leads to the accelerated decline in lung function. Current literature indicates that asthma signs and symptoms are common in those AATD with or without COPD and that bronchodilator response is a risk factor for FEV1 decline. Furthermore AATD itself predisposes to airway hyper responsiveness, an essential ingredient for reversible airflow obstruction. In the absence of well-characterized markers to distinguish COPD from asthma, clinical diagnosis leads to a delay in the recognition that asthma symptoms such as wheezing can be an early manifestation of COPD in AATD. In addition failure to appreciate asthma overlap in AATD may lead to inadequate suppression of airway inflammation leading to the development of airflow obstruction. The implications of this are discussed as are potential approaches and recommendations for treatment.
INTRODUCTION
Severe alpha-1 antitrypsin deficiency (AATD) is genetic disorder that predisposes, especially in smokers, to the early development of a severe panacinar form of emphysema. The deficiency results from a conformational change in the molecule which leads to the retention of alpha-1 antitrypsin polymers in the liver (1, 2). The resulting serum deficiency leads to a functional elastase anti-elastase imbalance in the pulmonary parenchyma and airways. Uninhibited elastolysis leads to early emphysema. The commonest phenotype for the severe deficiency is PiZ (protease inhibitor) accounting for over 95% of cases. Mildly reduced levels occur with carrier variants PiMZ, PiMS. The condition is inherited as an autosomal recessive. It has a prevalence from 1 in 3500 to 1 in 1500 and the severe deficiency is estimated to be present in approximately 1 in 200 patients with COPD (1, 2).
In 1961 Dutch researchers suggested that airway diseases such as asthma and emphysema had a common genetic origin and that the development of severe disease is dependent on both intrinsic (host) and extrinsic (environment) influences (3). The development of airways hyper-responsiveness (AHR) was considered to be the mechanism by which these influences determine the ultimate phenotype of disease. AATD described 2 years later (4) provides a unique genetic model to study how the substrates of environment, and genetic predisposition through AHR influence the development of COPD.
The purpose of this review is to summarize information about the relationship between asthma and severe AATD. This review explores the evidence that subjects with severe AATD are especially predisposed to airway hyper responsiveness (AHR) that is associated with bronchodilator responsiveness, asthma and allergy. This review summarizes the evidence indicating that the development of asthma related AHR with reversible bronchospasm in AATD is a risk factor for the development of COPD. Genetic influences to asthma development such as atopy enhance this predisposition.
The various phenotypes of asthma result from an interaction between complex polygenic inheritance and the environment. In this review the various definitions of asthma, based on those used in the referenced papers, include a reported diagnosis of asthma by the subject or physician with or without associated bronchodilator response and wheezing attacks, allergy and with or without an elevated IgE. Bronchodilator response itself is reported variably ranging from the ATS criteria of an FEV1 increase of 200 cc and 12% of baseline to lesser or poorly defined changes in lung function after bronchodilator. Atopic asthma is associated with allergic manifestations, skin test response, eczema and rhinitis and has triggers for attacks of wheezing and shortness of breath.
Work by Fabbri (5) and others indicates that for the same degree of airflow obstruction those with a history of asthma represent a distinct clinical entity compared to those with a history of COPD. The former show more eosinophilic inflammation, higher exhaled nitric oxide and a greater bronchodilator response. Most clinicians use symptoms such as wheezing and reversible airflow obstruction (bronchodilator response) for the diagnosis of asthma. In contrast COPD is defined as progressive airflow obstruction associated inflammation and with a history of exposure to noxious fumes. Bronchodilator response, if present, does not reverse the obstruction completely. In clinical practice the lack of well-established markers makes the distinction between asthma and COPD very difficult, especially as individuals with established airflow obstruction may show features of both. As this review highlights, these operational definitions lead to diagnosis bias in the AATD population where COPD develops much earlier. The diagnosis of asthma in an unrecognized case of AATD may delay the diagnosis of COPD. Conversely, as this review examines, a delay in the diagnosis of asthma in AATD potentially predisposes individuals to FEV1 loss, and a more rapid development of COPD.
EVIDENCE FOR THE ASSOCIATION BETWEEN AATD AND ASTHMA
Prevalence of asthma in selected cohorts with AATD
Earlier case series and reports (6–9) indicate a potential association between asthma and AATD. Problems with such studies is that of phenotype overlap and recall bias. Symptoms are similar once airway obstruction is established and patients are likely to be diagnosed with both asthma and COPD at some point in their history of respiratory illness (10).
shows a summary of important papers reporting the prevalence rates of asthma in selected cohorts with AATD. Once COPD develops the self-reported and MD-diagnosed asthma rates are as high as 50%, which is likely to represent over-diagnosis and is based on the assumption that wheezing attacks to dust, fumes and strong odors is asthma (11). In the Alpha-1 Foundation Research Registry (12) for example, the diagnosis of asthma was commonly associated with emphysema and or chronic bronchitis. This diagnostic overlap increases the likelihood of asthma over diagnosis in subjects with COPD. Asthma prevalence in those with AATD but without COPD range from 12.5–17% (11, 12) and non-index cases have even lower asthma prevalence (13).
Table 1. Prevalence of asthma in selected populations with AATD
An alternative “Dutch” explanation for the high prevalence of reported asthma in those with COPD is that these subjects represent a selected subset of susceptible individuals who have suffered the consequences of AHR and asthma. In these individuals a precipitous FEV1 loss leads to the rapid development of airflow obstruction.
Wheezing, whether associated with asthma or COPD can be an early manifestation of severe AATD. In the Alpha-1 Foundation Registry self reported asthma was first diagnosed at age 39 ± 16 years for homozygotes and 28 ± 18 years for heterozygotes (12). The first wheezing attack occurred at 32 years in severe AATD.
Analysis of non-index cases removes ascertainment bias to some extent. Indeed the AAT Genetic Modifier study indicates that asthma is significantly associated with the COPD phenotype in non-index cases (13).
also summarizes an important longitudinal cohort study from Pittulainin et al who reported on a birth cohort of 98 screened individuals, representing 79% of the 1972–1974 births with AATD (14). At 22 years, asthma was diagnosed in 15% with 29% reported recurrent wheezing. In non-smokers recurrent wheezing was present in over 22%, while 56% of smokers reported this symptom. This study suggests that severe AATD predisposes to early wheezing and asthma, especially in smokers, but does not necessarily indicate a predisposition to COPD as pulmonary function decline was not compared to controls. Interpretation should be cautious as over diagnosis bias may occur in children with AATD in whom any respiratory illness would be scrutinized. However the development of asthma in childhood in those with AATD can represent a specific and significant risk factor in some for the later development of COPD later.
Evidence that phenotypic variants that lead to a reduced AAT predispose to asthma
summarizes important selected studies (15–21). Although there is methodological bias in all studies, the prevalence of AAT variants in Hispanic and Spanish populations is higher whether asthmatic or not. Colp's initial report suggesting an association between AAT variation and asthma (15) has not been confirmed in other studies (20, 21). The results from asthma cohorts indicate a prevalence of AAT variants ranging from 9–20% (16–21), which does not indicate that the prevalence of AATD variation is greater than in control populations. Neither is there evidence that mild reductions in AAT lead to more severe asthma. Van Veen's study (18) in 122 severe asthmatics with persistent airflow limitation (FEV1 < 75%) demonstrated that there was no increase in the prevalence of AATD or variants compared to controls. However, Von Ehrenstein reported a trend to a lower FEV1% and greater AHR in those with asthma and persistent airflow obstruction and the PiMZ phenotype (19).
Table 2. Prevalence of AATD in asthma populations
In those participating in an AAT Registry, about a third of heterozygous subjects with reductions in AAT report wheezing symptoms after dust, fumes, strong smells, allergy contact and nearly a half during a viral infection (12). Yet in the National Birth cohort study conducted in 2 different populations (22), carriers for AATD showed no association with day or night wheezing at age 53. Therefore there is no uniform evidence that AAT variations predispose to asthma although the relationship of phenotype MS to asthma is worth exploring with further studies in Hispanic or Latino populations (15, 16).
Prevalence of AATD in selected populations with occupational lung disease
AATD may enhance AHR development and asthma in subjects with atopy exposed to environmental sensitizers. In a Danish study the prevalence of sensitization to environmental antigen and AHR was increased in farmers with AAT variants compared with controls (23). The same was found in cotton workers who developed byssinosis (24). These two studies suggest a complex interaction between low serum AAT, atopy, environmental exposure to sensitizing antigen and the development of AHR or lung disease.
In summary AAT phenotypes that can lead to reductions in AAT appear more common in sub populations of asthmatics under certain environmental conditions compared to the asthma populations in general. Lower levels of AAT interacting with environmental and or other genetic factors may predispose to asthma. The effect of AAT variation on asthma phenotype is uncertain and worth further study.
Inherent difficulties associated with the diagnosis of asthma in AATD
Although prompt recognition of severe AATD in those with symptoms is essential, Stoller et al. reported that the diagnosis of severe AATD from initial symptoms was delayed by 5.6 years on average. Younger patients tend to be diagnosed more quickly (25). Non-reversible airflow obstruction may prompt testing for AATD in younger subjects, but delay from the first symptom to diagnosis was longer. Younger subjects may not seek medical help as quickly thereby adding to diagnostic delay.
Asthma is the most common respiratory diagnosis in patients with AATD prior to the diagnosis of AATD (26) but may be based on a mistaken clinical evaluation. False positive and negative associations occur with an asthma diagnosis. Wheezing attacks can be related to airway narrowing through loss of elastic recoil in COPD and may be misdiagnosed as asthma. Furthermore spirometry may show a bronchodilator response in COPD. The increase in % FEV1 after bronchodilator increases as baseline FEV1 declines (23). In the IPPB trial (27) up to 30% of subjects with COPD responded to bronchodilator at any given follow-up exam, and 68% showed at least one such response during the 3 years.
In many patients, however, bronchodilator response was not significant by current ATS criteria. As asthma is common in the young and COPD is not, a diagnosis of asthma would be biased to a younger patient and COPD to an older patient who smokes (10). Gender bias leads to males being diagnosed with COPD, while females are more readily diagnosed with asthma (10). As reported for AATD (12), current smokers or ex-smokers with a physician diagnosis of asthma are more likely to be also diagnosed with emphysema and/or chronic bronchitis than nonsmokers (41% vs.18%, respectively). A physician diagnosis of asthma occurred in 13% of those never reporting a wheezing attack. Also 15–23% report ever wheezing without reporting any physician diagnosis.
The clinical overlap of COPD with asthma will confound the association of asthma in the development of airflow obstruction in studies of those referred or presenting with established lung disease. Therefore without more specific and clinically easily applicable markers for asthma, the diagnosis of asthma in AATD in subjects with established airway obstruction is a subjective clinical diagnosis.
ROLE OF AATD IN THE PATHOGENESIS OF ASTHMA THROUGH THE DEVELOPMENT OF AHR
If AATD contributes to the pathogenesis of asthma then the lack of airway anti-neutrophil elastase would set up conditions of inflammation leading to AHR. Under conditions of neutrophil airway inflammation in asthma and chronic bronchitis both total and active pro-inflammatory elastase are increased in airways. There is a compensatory increase in airway AAT (28) but the excess of elastase indicates protease anti-protease imbalance.
Evidence from animal models
In animal models, allergic sensitization that increases AHR reduces airway AAT (29) in bronchoalveolar lavage fluid. The effect was inversely related to tissue kallikrein. In this model, aerosolized recombinant alpha-1 proteinase inhibitor blocked AHR to neutrophil elastase, kinninogen and antigen in sensitized sheep (30). Animal experiments have also indicated that inflammatory mediators such as LTB4 enhance CD8 T cell accumulation, airway inflammation and AHR (31). Animal models provide a basis for suggesting that AATD predisposes to AHR and restoration of elastase anti-elastase balance ameliorates AHR.
Evidence from human studies
Airway inflammatory mediators such as neutrophil elastase are in higher concentrations in the sputum (32). Inflammatory mediators of the thromboxane family such as LTB4 are released more readily from alveolar macrophages of those patients with severe AAT deficiency at baseline and during exacerbations (31–34). The development of asthma may further reduce functional anti-elastase activity in normal subjects (35).
Although the experimental basis for the development of AHR in AATD is compelling it has not been supported directly. Malerba et al. (36) measured AHR by methacholine challenge in 24 subjects with severe AATD participating in an Italian Registry. The prevalence of COPD was only 7% and asthma 5%. Mean FEV1 was 90% in the severely deficient group and only 12% were smokers. AHR was not significantly different in the deficient group (12.5%) compared with subjects with mildly reduced and normal serum AAT. All with AHR had a diagnosis of asthma and of interest the degree of methacholine responsiveness correlated positively with the severity of AATD.
This study does not address the possibility that lack of airway AAT interacts with risk factors for AHR such as atopy and smoking, to enhance the development of asthma. As cigarette smoking pre-disposes to AHR (37) and is also a risk factor for FEV1 decline in asthmatics (38) (and in AATD), an asthma interaction with cigarette smoking may be the mechanism for the development of COPD in susceptible individuals.
ROLE OF ATOPY IN THE DEVELOPMENT OF ASTHMA IN AATD
Atopy confers a genetic predisposition to asthma (39) and is an independent risk factor for FEV1 decline in non-asthmatic men (40). Eden et al. (41) first showed that positive skin reactions to common aeroallergens occurred in 48% in a group with severe AATD and COPD compared with 28% in COPD controls. Using criteria for asthma of attacks of wheezing, bronchodilator response, atopy and an IgE > 100 IU/ml, asthma prevalence was 22% in the group with AATD compared to 5% in controls with COPD.
In the NHLBI cohort study (11), allergen-induced wheezing was reported in about a third and was independent of AATD phenotype. Only 5% with airflow obstruction and self reported asthma had an elevated IgE (>100 IU/ml). As expected an elevated IgE was associated with a history of allergy, asthma and wheezing but not bronchodilator response.
In the Alpha 1 Foundation Research Registry (12), physician diagnosed asthma with allergies was reported in nearly 50% of those with severe AATD. Wheezing after allergen exposure was reported in 33% and in over 50% from inhaled irritant exposure. In participants with a physician diagnosis of asthma, self-reported allergies were almost universally present whereas physician diagnosed allergy and asthma occurred from 49–64%.
Many patients with severe AATD report symptoms of allergy but this history may not be a reliable indicator for allergen triggered exacerbations and symptoms. Self-reported seasonal rhinitis or itching and wheezing to allergen exposure may more reliably point to an allergic diathesis. Symptomatic subjects with AATD who report asthma symptoms should be evaluated for aeroallergen sensitivity.
Evidence for the overrepresentation of asthma susceptibility genes in AATD
Genetic predispositions to asthma and airflow obstruction partly explain the varying lung function phenotypes in severely deficient patients. In one study (12), 56% of PiZ participants and 76% of PiMZ carriers reported a family history of asthma. In the Genetic Modifier study Demeo et al. studied 378 participants from 167 families with homozygous PiZ to search for common single nucleotide polymorphisms (SNP) associations at loci of 10 candidate genes with the phenotype of airflow obstruction (42). Of this cohort 37% reported a physician diagnosis of asthma. One previously reported modifier gene for asthma codes for the anti-inflammatory cytokine IL10 (42). Five SNPs found on the IL10 locus were significantly and consistently associated with the quantitative and qualitative COPD phenotypes. When those with physician diagnosed asthma were excluded, the association of these IL10 SNPs remained robust. Excluding a physician diagnosis of asthma did not reduce the significant association suggesting that the genetic modifier IL10, although associated with COPD, is not associated with COPD through asthma.
As an extension to the genetic modifier program, SNPs in candidate genes (IL10, TNF and NOS3) previously associated with an airflow obstruction phenotype and asthma did not improve the predictive power of models, which accounted for 50% of the FEV1 variance (43). Therefore, no asthma candidate genes have yet been identified to predict the ultimate development of severe COPD in AATD.
Evidence that AHR in severe AATD predisposes to an enhanced decline in FEV1 and the development of COPD
In some studies AHR in COPD is associated with more rapid FEV1 decline and higher mortality (37, 44) while others find no relationship (45). Asthma is also a risk factor for an accelerated decline in FEV1 (37, 45, 47–50). For example in the Copenhagen Heart Study new asthma in non-smokers led to an excessive FEV1 loss (48). In a 20-year follow-up study from Tucson, physician-diagnosed asthma was a risk factor for COPD with the length of time to asthma diagnosis an additional independent risk factor (49). Long-term randomized studies indicate that asthma exacerbations are associated with an increased rate of FEV1 decline. In the START study, asthmatics with at least 1 severe exacerbation lost significantly greater lung function compared to those that did not (50). Those taking an inhaled corticosteroid suffered from fewer exacerbations and less decline. These observations raise the notion that those with AATD, asthma, especially if uncontrolled, act together to increase the decline in lung function.
Anthonisen (46) and others argue that the role of AHR developing with cigarette smoking in those with early COPD is not an important risk factor for loss of FEV1. In patients with early COPD participating in the Lung Health Study, baseline bronchodilator response did not predict subsequent decline in FEV1 over an 11-year period. The number of subjects in this study was large but the bronchodilator response of 4.3% was not significant by ATS criteria.
shows selected studies reporting FEV1 decline and asthma in populations with AATD. Depending on the study population all suggest that bronchodilator response and or asthma are useful predictors for FEV1 decline, reduced FEV1 or the development of severe COPD.
Table 3. Role of AHR in the decline in lung function in selected cohorts with AATD
Using ATS criteria for bronchodilator response, the NHLBI Registry results indicate that a bronchodilator response significantly increased FEV1 decline from about 41 cc to 68 cc/year. (11). Factors that did not contribute were wheezing attacks, a physician diagnosis of asthma and elevated IgE level (>100IU/ml).
In the U.K. ADAPT program analysis was performed on the tertiles showing fast, moderate and slow FEV1 declines over 3 years (51). FEV1 decline was fastest in the group with moderate airflow obstruction (50–80% predicted). In the group showing greatest FEV1 decline 73% showed a bronchodilator response compared with 41% in the other groups. ATS defined bronchodilator response was a risk factor (OR 4.3 p 0.017) for rapid decline as was the magnitude of percent bronchodilator reversibility. These predictors remained robust after adjustment for baseline FEV1. Over 50% of subjects reported symptoms of chronic bronchitis suggesting this population may be more susceptible to airway disease (and AHR) in comparison to a USA AATD population where chronic bronchitis is reported less often (30%) (12).
The AAT genetic modifier study (42) controlled for ascertainment bias (index v non-index cases). In a multivariable analysis, asthma was a predictor for severe COPD in index and non-index cases. In index cases, the diagnosis of childhood asthma before age 16 and a physician diagnosis of asthma in men (not women) was a significant predictor of severe COPD (OR 4.2). A physician diagnosis of asthma was a risk factor for COPD in non-index cases.
A history of asthma was not a predictor of lung function in non-index cases. Overall however asthma before 16 was reported in only 5% of the group whereas MD diagnosed asthma was up to 37%. Gender differences in propensity to COPD are highlighted by this study as men with a diagnosis of asthma before 16 years and a physician diagnosis of asthma developed the greatest airflow obstruction.
More recently Castaldi et al. (43) using genetic, clinical and demographic variables constructed several models for predicting FEV1 and severe COPD using the same AATD cohort enrolled through the Genetic Modifier Study. The authors reported that bronchodilator response was a significant predictor for FEV1% as well as severe COPD. Asthma before age 30 was also a significant predictor for FEV1% only if bronchodilator response was not included in the model. This result supports the NHLBI Registry findings (11).
In a cohort of patients older than 60 with COPD and severe AATD asthma was reported less commonly than younger subjects (52). Allergic diseases were diagnosed in 64% of the cohort. In general the older group smoked less and had fewer exacerbations. Although the results may be explained by diagnostic bias to asthma in younger subjects, those with a more benign course suffer less from asthma and by extension have less severe AHR.
In summary, bronchodilator responsiveness, physician diagnosed asthma and asthma at an early age are risk factors for COPD and FEV1, loss depending on the population studied and method of ascertainment. Bronchodilator responsiveness rather than asthma diagnosis appears a more important determinant of FEV1 decline when COPD is established (11, 43). Overall these studies support the Dutch hypothesis.
Potential for therapeutic effectiveness of Augmentation therapy on AHR and asthma
A physician diagnosis of asthma and asthma symptoms are reported significantly more often in PiZZ participants receiving augmentation therapy in whom COPD tended to be more severe. The Lung Health Study indicated that degrees of AHR were associated with accelerated FEV1 decline in smokers with early airflow obstruction (37). Reduction in AHR by augmentation could then be a mechanism by which augmentation exerts its therapeutic effect (53–57) and may be more effective in a subset of patients with asthma. The airway concentrations of AAT achieved during recommended doses of augmentation reduce free elastase and leukotriene B4 in sputum (34). However results from the NHLBI Registry indicated that FEV1 decline in subjects with asthma features, adjusted for other risk factors, is not reduced by augmentation therapy (11). Therefore, the potential therapeutic effect of augmentation in asthma was not demonstrated but the currently recommended weekly dose of 60 mg/kg may be too small to substantially reduce AHR.
Nevertheless, despite the lack of objective evidence, many patients receiving augmentation report improved asthma symptoms (12). Anecdotal patient surveys suggest that those on augmentation experience less severe pulmonary exacerbations (55–58) although exacerbations are still frequent (57). In the Dirksen randomized study placebo controlled trial (58), exacerbation rate was not different between treatment and placebo groups yet severe exacerbations defined as those requiring hospitalization was lower in the treatment group. A study from Stockley's group indicates exacerbation frequency predicts FEV1 decline only in those with a post-bronchodilator FEV1 of greater than 35% (44). Without direct measurement or a well-designed prospective trial, the effect of augmentation on AHR in AATD is unknown.
SUMMARY AND CONCLUSIONS
The evidence provided by this review lends some support to the concept that the development of lung disease in AATD is determined by the development of AHR. Current evidence shows that asthma is diagnosed frequently in those with AATD before they develop signs of airflow obstruction. Once airflow obstruction develops the prevalence of asthma diagnosis increases and reversible airflow obstruction and asthma features, such as triggered wheezing attacks, remain commonly reported even in advanced disease. However diagnostic bias and the overlap of COPD with asthma confound estimates of asthma prevalence.
The literature also supports the notion that asthma may be diagnosed as the first manifestation of AATD. The diagnosis of asthma is biased by age, family history and ascertainment where the development of emphysema in relative youth is not considered seriously as a diagnosis. Several reports also indicate that screening of asthmatics yields the incidence of alpha-1 variants ranging from 9–16%. It is not clear whether mild AATD impacts asthma severity. The phenotype MS is more common in Hispanic populations and may be independently associated with asthma severity. AAT variants are found more commonly in some populations sensitized to specific environmental antigens.
Asthma diagnosis is a risk factor for FEV1 decline. However its contribution to FEV1 loss in AATD has not been conclusively demonstrated independently of bronchodilator response. There is however sufficient evidence to indicate that bronchodilator response is a risk factor for loss of lung function and the development of COPD in AATD. Gender may be an important modifying factor. In so far as bronchodilator response is associated with AHR the latter is a likely important risk factor for FEV1 decline in AATD and supports the notion of the Dutch hypothesis. Only a large prospective study would settle the question.
There is anecdotal evidence that replacement therapy, perhaps by reducing the indices of airway inflammation ameliorates asthma symptoms. Objective evidence for effectiveness in those with reversible airflow obstruction is lacking, although existing studies may be underpowered to show such benefit. Evidence suggests augmentation reduces the severity of exacerbations and may as a consequence reduce AHR.
Several well-performed and convincing cohort studies indicate that in a subset of those with AATD, asthma presenting at a young age increases the likelihood of severe COPD in adulthood. The interaction with teen smoking, atopy and increased IgE can be inferred but has not been proven. The notion of therapy with inhaled steroids to prevent COPD and asthma exacerbations is also suggested and, in the absence of more definitive evidence, should be recommended for those with severe AATD, asthmatic features and symptoms and signs of atopy or allergic sensitization. An allergy evaluation should be strongly considered in such patients.
The long-term treatment of asthma with inhaled corticosteroids reduces lung function decline (59) and may be of particular value in those patients with an elevated IgE (60). Although not all studies have shown an effect (61), it seems prudent to maximize anti-inflammatory therapy in those with AATD and asthma and to treat aggressively during asthma exacerbations. Following asthma treatment guidelines, inhaled steroid therapy at higher doses should be provided to those with AATD, who show clinical features of uncontrolled asthma. A more definitive study would require enrollment of subjects with AATD and defined asthma features to use higher or lower doses of inhaled steroids. Endpoints would be lung function decline measured by FEV1, CT scanning and or inflammatory biomarkers.
In conclusion, AATD provides a unique genetic model for the study of intrinsic and extrinsic factors that influence the development of lung disease. This review provides evidence that intrinsic; atopy and modifier genes and extrinsic factors; environment and cigarette smoke acting through the development of AHR and asthma accelerate lung function decline in AATD.
Declaration of interest
The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.
ACKNOWLEDGMENTS
The author thanks Prof. Gerard M. Turino and Prof. Edwin K Silverman for their comments and suggestions.
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