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Abstract

α1 Antitrypsin deficiency (AATD) increases the risk of chronic obstructive pulmonary disease (COPD), liver disease and other conditions. Although it is not a rare disease, it is a condition rarely diagnosed because of unawareness by most healthcare providers who manage subjects at risk. Testing recommendations have been published and strongly suggest testing all subjects with confirmed COPD, cryptogenic liver cirrhosis, subjects with incompletely reversible airflow obstruction and siblings of affected individuals. Testing strategies usually imply a combination of measures of α1 antitrypsin (AAT) levels, phenotyping and genotyping, techniques that have been facilitated for in-office use by development of testing kits using dried blood spots. Early detection of subjects is crucial to apply effective preventive measures and early institution of therapy.

The only specific Food and Drug Administration - approved therapy for this condition is lifelong weekly intravenous AAT replacement (augmentation therapy). Observational studies strongly suggest a beneficial effect of augmentation therapy in slowing lung function decline and randomized trials suggest a beneficial effect in slowing the progression of emphysema over time as measured by computed tomography. In addition, augmentation therapy has been shown to modulate systemic inflammatory responses and affect markers of elastin degradation. As new markers of disease progression are discovered, new doses of AAT replacement are tested and sub-phenotypes of disease are described, treatment recommendations are likely to change towards a more individualized therapeutic approach.

Keywords

Alpha-1 antitrypsin Alpha-1 antitrypsin deficiency augmentation therapy COPD genetic testing

Introduction

α1 Antitrypsin deficiency (AATD) is the most well characterized genetic risk factor for developing chronic obstructive pulmonary disease (COPD). Since Laurell and Eriksson made the first description of this condition more than 50 years ago [Laurell and Eriksson, 1963], much has been learned about the functions of the α1 antitrypsin (AAT) protein and the pathophysiology, clinical presentations, genetics and epidemiology of the disease. Altogether, these discoveries have led to important therapeutic steps towards finding a cure of the condition.

Currently it is estimated that, worldwide, more than 3.4 million individuals are severely AAT deficient and approximately 116 million carry at least one abnormal AAT allele [De Serres, 2002]. In the USA and Europe it is estimated that approximately 1 of 4700 individuals in the general population are homozygous for the Z mutation, the most common mutation associated with severe deficiency [De Serres et al. 2003a, 2003b; American Thoracic Society/European Respiratory Society, 2003]. The prevalence increases as testing is targeted towards more specific high-risk groups. Unfortunately, the condition is widely underdiagnosed. In the early 1980s it was calculated that less than 5% of expected cases were identified [Tobin et al. 1983; Silverman et al. 1989], an estimation that did not change much in later reports [Luisetti and Seersholm, 2004]. Nowadays as a result of more recent disease awareness efforts and the publication of testing recommendations [American Thoracic Society/European Respiratory Society, 2003], case detection appears to be improving, with more than 1000 cases detected per year in the USA [Campos et al. 2012]. This review summarizes the current state of testing and treatment of AATD.

Testing for AATD

To better understand the rationale for testing recommendations and the tools available for the diagnosis of AATD, the clinician should be familiar with the genetics and pathophysiology of the disease and its various clinical manifestations.

Overview of genetics and pathophysiology of AATD

AATD is caused by mutations in the SERPINA1 gene located in chromosome 14q32 (previously named the Pi locus). Over 100 mutations have been described and have been named by a letter based on the migration speed of the resulting protein on isoelectric focusing, with the normal AAT protein called M and the most common mutations being Z (Glu342Lys) and S (Glu264Val) [Lomas, 2004]. It has been estimated that combinations of M, S and Z alleles encompass over 98% of the world population and therefore are the initial focus of AAT testing in the laboratory [American Thoracic Society/European Respiratory Society, 2003, Rodriguez-Frias et al. 2012].

The hepatocyte is the most important cell that produces the AAT present in serum, although local AAT production by intestinal cells, respiratory epithelia, corneal cells, macrophages and neutrophils occurs as well. The Z mutation consists of a single amino acid substitution that results in the production of a misfolded protein that not only affects its reactive loop (active site) but also configures it in a way that predisposes the AAT molecules to polymerize while still in the endoplasmic reticulum (ER), impeding any secretion of AAT into the circulation [Lomas and Parfrey, 2004]. This triggers cellular responses to clear the accumulated misfolded proteins with disposal either through the proteasome (ER-associated degradation) or autophagy. Z-AAT accumulation can also induce cellular ER stress, with activation of discrete signaling pathways that can lead to a proinflammatory state and cell death through apoptosis (including the processes known as the unfolded protein response and ER overload response) [Greene and McElvaney, 2010]. This ‘gain-of-toxic function’ may result in clinical liver disease.

One of the most important functions of AAT as a member of the serine protease inhibitor (‘serpin’) family is to inhibit neutrophil elastase. Circulating AAT released by the liver normally gets to the lung parenchyma where it buffers any excess in neutrophil elastase activity. Deficiency of AAT leads to protease/antiprotease imbalance, particularly during moments of increased elastase activity such as during acute disease exacerbations or exposure to inhaled irritants (i.e. tobacco smoke) [Lomas, 2004]. The result of this ‘loss of function’ is an accelerated progression of emphysema and other manifestations of COPD.

Clinical features of AATD

The prevalence of liver disease in AATD is less common than the prevalence of lung disease and has a bimodal presentation. Experience from newborn screening programs has shown that approximately 70% of PiZZ subjects develop elevation of liver enzymes with only 10–15% becoming symptomatic with cholestasis, neonatal hepatitis or different degrees of histologic evidence of fibrosis [Sveger, 1976, 1988, Sveger and Eriksson, 1995]. The second peak in clinical liver disease is seen in late adulthood, although with a more obscure natural history due to the underdiagnosis of AATD. It is estimated that cirrhosis develops in 10–12% of affected individuals and hepatocellular carcinoma in 3% [Silverman and Sandhaus, 2009; Nelson et al. 2012]. Risk factors of developing clinical liver disease include age over 50 years, sex, alcohol consumption and obesity [Bowlus et al. 2005; Nelson et al. 2012].

Pulmonary manifestations of AATD include emphysema and chronic bronchitis (COPD) that may present earlier than what is expected compared with regular tobacco-induced disease in non-AATD subjects. The average age at diagnosis is around 45 years and the average interval between onset of symptoms and diagnosis is 7–8 years [Campos et al. 2005]. Subjects diagnosed in more recent years are older and have longer diagnostic delays, probably as a result of increased disease awareness that prompted testing of individuals who should have been diagnosed years before [Campos et al. 2005; Stoller et al. 2005].

Deficiency of AAT alone does not appear be enough to induce lung disease. The presence of additional factors, such as exposure to inhaled environmental noxious substances, in particular tobacco smoke, is usually required for accelerated lung function decline and clinical lung disease to develop [Piitulainen and Eriksson, 1999; Demeo et al. 2007]. In fact, it is not uncommon to observe preservation of lung function and lower mortality rates among nonsmoking individuals with AATD [Silverman et al. 1989; Seersholm et al. 1994].

Bronchiectasis is another pulmonary manifestation linked to AATD. In a computed tomography (CT) scan study, it was noted that bronchiectasis was present in 70 of 74 subjects, being clinically significant in 27% of cases [Parr et al. 2007]. Bronchiectasis can occur without coexistence with emphysema.

AATD is associated with some uncommon inflammatory conditions. One of them is necrotizing panniculitis, a condition characterized by the presence of proinflammatory AAT polymers in the subcutaneous fat tissue and red, hot and tender nodules that may ulcerate, usually on the thighs or buttocks [American Thoracic Society/European Respiratory Society, 2003; Gross et al. 2009]. Necrotizing panniculitis is rare and thought to occur in 1 of 1000 cases. AAT is a natural inhibitor of proteinase 3 (PR3) and AATD appears to be more prevalent in conditions associated with anti-PR3 autoantibodies, such as granulomatosis with poliangiitis (formerly known as Wegener’s granulomatosis) [American Thoracic Society/European Respiratory Society, 2003]. In fact, in the Wegener’s Granulomatosis Genetic Repository the odds ratio of finding the abnormal PiSS, PiZZ and PiSZ allele combinations was 14.5 times more frequent than in the control group [Mahr et al. 2010].

Laboratory diagnosis of AATD

Measurement of AAT levels is usually performed by rocket immunoelectropheresis, radial immunodiffusion or nephelometry and is a test widely available in most clinical laboratories. Although measurement of serum or plasma AAT levels for the diagnosis of AATD may detect individuals who are severely deficient, the underlying type (PiZZ, PiSZ and combinations with null mutations) cannot be discerned and a finding of a low level warrants further genetic testing. Another caveat of using AAT levels for diagnosis is that heterozygous carriers may be missed as their AAT levels may overlap with those of nondeficient individuals [Brantly, 1991]. However, a recent study in the SEPALDIA cohort (n = 6057) showed that if inflammation is accounted for, the overlap in AAT levels between PiMZ and PiMM subjects is not observed, although with a very close limit between the groups (66–100 mg/dl for PiMZ and 105–164 mg/dl for PiMM) [Ferrarotti et al. 2012].

Phenotyping with or without immunoblotting uses isoelectric focusing to differentiate the different AAT variants present in serum. This is a relatively inexpensive test that requires significant expertise in interpretation. It is mostly available in specialized laboratories and is the gold standard to detect rare variants (except null variants) after it is determined that AAT levels are below normal [Greene et al. 2013].

Advances in molecular diagnostics have made genetic testing more readily available. Genotyping usually implies the detection of specific AAT mutations by polymerase chain reaction (PCR) using a relatively small sample containing the subject’s DNA. Use of dried blood samples (DBS) for AAT genotyping has become now widely available and has facilitated testing [Costa et al. 2000]. AAT levels can be measured from DBS with good correlation with serum AAT levels measured by standard laboratory assays. Most laboratories and screening programs test for the most common S and Z mutations either concomitantly or only after the DBS AAT level is proven to be below a certain threshold [Miravitlles et al. 2010]. Discrepancies between DBS AAT levels and PCR results are usually followed by phenotyping or more expensive tests such as gene sequencing.

Testing recommendations

Current standards of care endorsed by major respiratory societies have been published with different recommendation strengths for who should be tested for AATD [American Thoracic Society/European Respiratory Society, 2003]. Recommendations balance the likelihood of detecting a subject with the potential benefits of treatment, institution of preventive measures and benefits of counseling.

As can be seen in Table 1, there is a strong recommendation to test all subjects with COPD. Although the risk is particularly higher in subjects with early disease onset, rapid decline in lung function or family history of AATD, the recommendation applies to all subjects with COPD, regardless of age, smoking history, emphysema distribution or race. Up to one-third of subjects with AATD are diagnosed after age 50 and over 85% have a history of smoking [Campos et al. 2005]. In fact, smoking appears to be the most important factor that influences the risk of developing COPD, including the age of onset of symptoms and age at diagnosis [Mayer et al. 2006; Campos et al. 2009a]. AATD has been classically associated with lower lobe panacinar emphysema, but it has been noted that up to one-third of subjects have predominantly upper lobe emphysema distribution, likely because of the tobacco smoke exposure [Parr et al. 2004]. AATD has been described in practically every race/ethnic group, however the prevalence appears to be higher in groups with some degree of white admixture. In other words, it is impossible to distinguish AATD as the cause of COPD based on demographic, clinical or radiologic features. Therefore, AATD testing should be viewed as a laboratory diagnosis and not a clinical one, similar to glucose testing to diagnose diabetes.

Table 1.

Summary of AATD testing recommendations.

Clinical	Population		Risk of AATD	Strategy	Guidelines recommendations*
Symptomatic	Any subject with COPD and:	Early onset emphysema	Very high	Diagnostic detection	A
		Rapid decline of lung function
		Family history of AATD
	Any subject withliver disease and:	Unexplained etiology (children or adult)		“Very High” under RISK OF AATD, “Diagnostic Detection”	A
	Any subject withliver disease and:	Hepatoma without cirrhosis		“Very High” under RISK OF AATD, “Diagnostic Detection”	A
	Any subject with:	COPD or emphysema	High	Diagnostic Detection	A
		Cirrhosis
		Necrotizing panniculitis
		Asthma, smoking history or occupational risk with persistent airflow obstruction
	Any subject with:	Bronchiectasis	Moderate	Diagnostic Detection	B
		COPD if in low prevalence regions or from ethnic groups with low prevalence (i.e. Pacific islanders)
		Adolescents with persistent airflow obstruction
		Persistent airflow obstruction and no risk factors
		Multisystemic vasculitis (anti-proteinase-3 positive)
Asymptomatic with family history	Individuals (adults and adolescents) with a family member with AAT homozygosity	Siblings	High	Predispositional testing	A
		Offspring	Moderate		B
		Parents	Moderate		B
		Distant relative	Moderate		B
	Individuals (adults and adolescents) with a family member with AAT heterozygosity	Siblings	Moderate	Predispositionaltesting	B
		Offspring	Moderate	Predispositionaltesting	B
		Parents	Moderate		B
		Distant relative	Moderate		B
	Individuals with a family history of persistent obstructive lung disease or liver disease		Moderate –low	Predispositionaltesting	B
	Partners of individuals who are either homozygous or heterozygous for AATD		Low	Predispositionaltesting	B
Asymptomatic with no family history	Neonates, adolescents > 11 years, any adult		Low	Screening	D
Asymptomatic with no family history	Asymptomatic smokers		Low	Screening	C

Strength of recommendation for AATD testing as in American Thoracic Society/European Respiratory Society [2003]. A: testing is recommended; B: testing should be discussed, acknowledging that it could be reasonably accepted or declined; C: testing should not be recommended; D: it is recommended that testing should not be performed.

AAT, α1 antitrypsin; AATD, α1 antitrypsin deficiency; COPD, chronic obstructive pulmonary disease.

Other high-grade recommendations for testing include subjects with cryptogenic liver disease, although this may be extended to all subjects with chronic liver disease as the presence of an abnormal AAT allele likely worsens the condition. Subjects with the rare manifestations of necrotizing panniculitis as well as subjects with persistent airflow obstruction with or without a history of asthma should be tested as well, in particular those with a history of exposure to inhaled irritants. Testing is encouraged for subjects with bronchiectasis or anti-PR3-positive vasculitis.

Siblings of affected individuals should be tested as the chances of having AATD range from 25% to 50% if both parents are carriers or one has AATD, respectively. Other degrees of relativity have lower chances of being affected and testing should be discussed, acknowledging that it could reasonably be accepted or declined.

Testing individuals with chronic lung disease

It is widely quoted that the prevalence of AATD among individuals with COPD is approximately 1–2% [American Thoracic Society/European Respiratory Society, 2003]. However, the yield of detection reported by targeted testing programs or case detection efforts in subjects with COPD vary depending on the geographical location or the definition of disease used. In the USA, there is strong testing encouragement by pharmaceutical companies interested in the detection of subjects with lung disease and the yield of these efforts is around 1.1% [Campos et al. 2012]. This relatively low yield of detection can discourage many clinicians to continue testing. A report from Germany and Italy found that less than 25% of clinicians tested all their patients with COPD [Greulich et al. 2013]. Given the relatively low cost of testing and the potential impact on individuals and their families, efforts to continue to enforce guidelines are ongoing. AATD testing should be viewed as a ‘rule-out’ and not a ‘rule-in’ process.

Probably one of the most important factors that influences the underdiagnosis of AATD is the poor diagnosis of COPD. Most population surveys from different countries show that over 80% of cases have not been properly diagnosed, evaluated and treated [Soriano et al. 2009]. Efforts should concentrate on increasing disease awareness among nonspecialist healthcare providers who usually encounter these patients first. In addition, up to two-thirds of patients diagnosed with COPD have their condition primarily managed by a nonspecialist provider [Barr et al. 2005]. New efforts to increase AATD testing include placing testing reminders in pulmonary function test reporting airflow obstruction [Rahaghi et al. 2009], adding decision-making tools to an electronic medical record [Jain et al. 2011], or educating respiratory therapists [Stoller et al. 2013]. A more recently reported strategy using an electronic record in primary care used a COPD screening questionnaire, followed by automatic spirometry ordering for high-risk patients and AATD screening for patients found to have COPD. This strategy resulted in many new diagnoses of COPD and increased AATD testing rates from 0% to 73% [Campos et al. 2011]. With the increased availability of electronic medical records, it is likely that similar strategies will more readily enforce testing guidelines and increase AATD detection.

Treatment of AATD

The care of subjects with AATD requires close monitoring and prompt treatment of pulmonary and liver complications. Recommendations for usual care have been outlined in several reviews [American Thoracic Society/European Respiratory Society, 2003; Silverman and Sandhaus, 2009; Nelson et al. 2012]. These include yearly monitoring of liver function laboratory parameters, frequent liver ultrasounds, and usual COPD care, including vaccination, bronchodilator therapy and pulmonary rehabilitation. Although promising new therapies for AATD-related liver disease are in the pipeline [Teckman, 2013], the only specific US Food and Drug Administration (FDA) approved treatment available for AATD is to prevent the progression of lung disease with augmentation therapy.

Historical perspective

Treating protein deficiency conditions was not new three decades ago when the first attempt to administer purified AAT was performed in five subjects with AATD [Gadek et al. 1981]. The impressive part is that this occurred only 17 years after the initial association between lung disease and AATD was originally reported [Eriksson, 1964]. The next step was to determine a target AAT serum level above which the lung will be protected from the deleterious effects of neutrophil elastase (‘threshold level’). It was evident at the time that subjects with different genotypes will have different AAT levels and variable predisposition to developing emphysema. This threshold level was decided to be a midpoint between the levels observed in patients with genotype PiSS who are not at risk of emphysema and patients with a genotype SZ who are at moderate risk [American Thoracic Society/European Respiratory Society, 2003].

The first clinical trial to assess the safety and optimal dosing and frequency was conducted in three phases, concluding that weekly administration of 60 mg/kg was safe and effective to maintain not only serum levels but also bronchoalveolar lavage levels above the predicted thresholds [Wewers et al. 1987]. Based on these results, the FDA approved augmentation therapy supported by the Orphan Drug Act with the requirement to establish a patient registry program to follow and monitor 1000 subjects for long-term safety and compare them with nontreated individuals.

Clinical evidence of efficacy

Proving the efficacy of any treatment for patients with COPD has always being difficult. The lack of an efficient marker of progression of the disease as well as its slow natural history makes it extremely challenging. The case of AATD is not different. A summary of published clinical trials has been summarized in Table 2. The initial studies focused on forced expiratory volume in 1 s (FEV₁) decline or mortality in patients receiving augmentation therapy compared with those who were not in observational cohorts. In 1997, a study comparing 198 patients receiving augmentation with 97 patients on no treatment showed a significantly greater FEV₁ decline in the group who were not on augmentation therapy [Seersholm et al. 1997]. A year later the results from the National Institutes of Health registry (N = 1129) showed decreased mortality in subjects receiving augmentation therapy but failed to show a decrease in FEV₁ decline in the treatment group [The Alpha-1-Antitrypsin Deficiency Registry Study Group, 1998]. More recently, a meta-analysis including clinical trials comparing augmentation therapy with a control regimen reported a significantly slower decline in FEV₁ in the augmentation therapy group compared with nontreated controls, in particular among subjects with FEV₁ between 30% and 65% of predicted [Chapman et al. 2009].

Table 2.

Summary of studies addressing the effect of augmentation therapy on lung function decline or emphysema progression.

Observational studies on lung function decline
	N	FEV₁ decline with augmentation therapy (ml/year)	N	FEV₁ decline without augmentation therapy (ml/year)	p value	Subgroup analysis (%FEV₁)	FEV₁ decline with augmentation therapy (ml/year)	FEV₁ decline without augmentation therapy	p value
A: Seersholm et al. [1997]	198	−53	97	−75	0.02	31–65	−62	−83	0.04
B: NHLBI [The Alpha-1-Antitrypsin Deficiency Registry Study Group, 1998]	581	−51	317	−56	NS	35–49	−66	−93	0.03
C: Wencker et al. [2001]	96	−34	96	−49	0.019	30–65>65	−38−49	−49−122	NS 0.001
D: Chapman et al. [2005]	21	−26	143	−59	0.019	30–65	−23	−79	<0.05
Meta-analysis of A–D [Chapman et al. 2009]	924	−48	681	−59	0.012	30–65	−51	−68	<0.05

Randomized trials with CT densitometry
	N	CT lung density change with augmentation therapy (g/liter)	N	CT lung density change without augmentation therapy (g/liter)	p value

A: Dirksen et al. [1999]	28	−1.5	28	−2.6	0.07
B: Dirksen et al. [2009]	35	−2.9	32	−4.2	0.049
C: RAPID study [Chapman et al. 2013]	84	−1.45	69	−2.19	0.017
Meta-analysis of A and B [Stockley et al. 2010]	60	−4.08	59	−6.37	0.006
Cochrane Review of A and B [Gotzsche and Johansen, 2010]	63	NR	60	NR	<0.05

CT, computed tomography; FEV₁, forced expiratory volume in 1 s; NR, not reported; NS, nonsignificant.

In an effort to further assess the efficacy of augmentation therapy in patients with AATD, new markers of disease progression have been evaluated. Changes in chest CT densitometry as a marker of emphysema progression have gained particular attention, not only because changes can be measured in a relatively short period of time, but also because of their reported association with FEV₁ decline, health status, exercise capacity and even mortality in subjects with AATD [Dowson et al. 2001; Dawkins et al. 2003]. The first double-blind, randomized placebo-controlled trial compared the effect of 250 mg/kg of AAT against 625 mg/kg of albumin administered at 4-week intervals for at least 3 years in 56 patients with AATD [Dirksen et al. 1999]. Although powered to assess differences in lung function and not differences on CT, the study showed a trend towards a reduction in the loss of lung tissue in the group who received augmentation therapy compared with the placebo group. The Exacerbations and CT scan as Lung Endpoints (EXACTLE) trial explored CT densitometry as a primary outcome in 77 subjects for up to 30 months. They were able to show a significant reduction in the loss of lung tissues in subjects receiving augmentation therapy (60 mg/kg intravenously every week) versus those receiving placebo [Dirksen et al. 2009]. Two published meta-analyses of these trials concluded that augmentation therapy is an effective treatment to slow emphysema progression assessed by CT densitometry [Gotzsche and Johansen, 2010; Stockley et al. 2010]. The more recent RAPID trial has been concluded [ClinicalTrial.gov identifier: NCT00261833] and presented as an abstract. This study randomized 180 subjects to receive either augmentation therapy or placebo for 2 years, with CT scan lung density measured at baseline, 3 months, 1 and 2 years. They reported that the annual rate of lung density loss was significantly less in subjects receiving replacement therapy when CT measures are done at total lung capacity (p = 0.017) [Chapman, 2013]. Nowadays, the FDA and European Medicines Agency accept CT densitometry as a primary outcome parameter, a very important step forward in assessing the efficacy of several treatment options for emphysema [Stoel et al. 2008].

Biochemical and molecular evidence of efficacy

Biomarkers that correlate with emphysema progression include markers of elastin degradation. Two of these markers, desmosine and isodesmosine, can be measured in urine, serum or bronchoalveolar lavage and have been found to be more elevated in subjects with AATD [Ma et al. 2007; Fregonese et al. 2011]. When patients receiving augmentation were compared with those not receiving therapy, and patients were compared before and after receiving augmentation therapy, it was found that AAT replacement decreases these biomarker levels, supporting the beneficial effect of augmentation therapy in protecting against elastin degradation [Ma et al. 2013].

In recent years it has been observed that AAT has physiological effects other than protease inhibition, including cellular protection against apoptosis and modulation of inflammation [Petrache et al. 2006; Jonigk et al. 2013]. AAT has an inhibitory effect over neutrophil chemotaxis and modulates tumor necrosis factor α production and synthesis from neutrophils. These effects are lost in subjects with AATD, with a subsequent increase in the production of inflammatory markers, an effect that can be mitigated with the administration of augmentation therapy [Bergin et al. 2010, 2014]. The role inflammation plays in disease progression in COPD is well recognized. In subjects with AATD with even mild reductions in lung function, significant increases in neutrophil counts and inflammatory markers such as interleukin (IL)-8, IL-6 and IL-1β can be observed in bronchoalveolar lavage compared with subjects without AATD [Rouhani et al. 2000]. Therefore, these novel effects of AAT further support the use of augmentation therapy as a treatment for AATD.

Treatment recommendations

Current guidelines recommend augmentation therapy for individuals with abnormal AAT genotypes who have AAT levels below the protective threshold of 11 µM and documented evidence of airflow obstruction in pulmonary function testing [American Thoracic Society/European Respiratory Society, 2003]. Since weekly infusions of AAT at 60 mg/kg have been proved to restore plasma AAT concentrations to protective levels as well as restoring the epithelial lung fluid’s antielastase properties, regulatory agencies have recommended this dose and schedule for the treatment of affected individuals. Adverse reactions are rare (<0.03 event per patient month), are usually transitory and may include headache, nausea and dizziness [Stoller et al. 2003]. It is feasible to expand the interval dosing to 14 or even 21 days while keeping acceptable trough total AAT concentrations, options that are well described [Soy et al. 2006]. The cons of augmentation therapy are that it is a lifelong treatment and highly expensive, with costs ranging between $60,000 and $150,000 per year, depending on body weight, pricing and the costs of nursing care [Silverman and Sandhaus, 2009].

The high cost of treatment has prompted clinicians to pay more attention to when therapy should be prescribed. As for regular COPD, different disease phenotypes can be observed in this condition, with some subjects having no lung function impairment, different rates of lung function decline, different severity of bronchiectasis, and so on. Affected individuals have been classified as ‘rapid’ or ‘slow’ lung function decliners, with the rapid decliners experiencing the most dramatic improvement when receiving augmentation therapy [Wencker et al. 2001]. For this reason, it has been proposed that individualized therapy decisions should be based on age and degrees of impairment and yearly change of FEV₁ or diffusing capacity of carbon monoxide [Stockley et al. 2013]. Ideally these should be performed in specialized centers with expertise so that there is a systematic approach for monitoring and management.

Finally, it is important to highlight that several considerations about augmentation therapy continue to be controversial. So far, evidence suggests a beneficial effect on FEV₁ decline and emphysema progression, but no high-degree evidence exists supporting a beneficial effect on acute disease exacerbations, healthcare utilization or mortality. The persistence of significant FEV₁ decline and number of exacerbations observed in subjects on treatment [Wencker et al. 2001; Campos et al. 2009b] has raised the question of inadequate dosing. The recommendation to keep AAT levels above 11 µM [American Thoracic Society/European Respiratory Society, 2003] is below the levels found in normal individuals (20–28 µM). It is also possible that therapy should be individualized based on inflammatory parameters. For this reason, it is not infrequent for many AATD experts to prescribe higher doses when patients are doing poorly, even if the evidence from clinical trials is lacking. A recently published trial showed that doubling the weekly dose is safe, well tolerated and elevates AAT trough levels to the normal range [Campos et al. 2013]. A large ongoing trial testing this higher dose formulation is under way [ClinicalTrial.gov identifier: NCT01983241].

Conclusion and recommendations

Several advantages exist to the prompt diagnosis of subjects with AATD, including the early institution of preventive measures and therapy aimed at preventing further disease progression. Disseminating information to increase disease awareness among healthcare providers is crucial to enforce testing guidelines and enhance early detection. Screening all subjects with COPD and other high-risk groups should enable detection of large numbers of individuals.

Different pieces of evidence point towards the beneficial effects of replacement therapy for subjects with AATD with evidence of lung disease. Current treatment guidelines are broad, with only a single regimen recommended. As new markers of disease progression are discovered, new doses of AAT replacement are tested and subphenotypes of disease are described, these recommendations are likely to change. Augmentation therapy will remain the only disease-specific therapy for AATD in the immediate future until other therapeutic approaches, such as inhaled AAT or gene therapy, are further developed.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

M. Campos has received grants for PI-initiated trials from Grifols, CSL Behring and the Alpha-1 Foundation and has participated in advisory boards for Grifols and CSL Behring. J. Lascano: none declared.

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α1 Antitrypsin deficiency: current best practice in testing and augmentation therapy

Abstract

Keywords

Introduction

Testing for AATD

Overview of genetics and pathophysiology of AATD

Clinical features of AATD

Laboratory diagnosis of AATD

Testing recommendations

Testing individuals with chronic lung disease

Treatment of AATD

Historical perspective

Clinical evidence of efficacy

Biochemical and molecular evidence of efficacy

Treatment recommendations

Conclusion and recommendations

Footnotes

Funding

Conflict of interest statement

References