Alpha-1-Antitrypsin Deficiency: Disease Management and Learning from Studies

ABSTRACT

Alpha-1-antitrypsin deficiency (AATD) is one of the most frequent genetic causes of liver and lung diseases. Despite its known association with chronic obstructive pulmonary disease (COPD), AATD is largely unrecognised and underdiagnosed. Cases of AATD exist within every COPD or spirometry population but must be actively investigated. AATD is a laboratory diagnosis that must be confirmed by a blood test. A number of clinical ‘clues’ can raise suspicion of AATD, potentially facilitating earlier diagnosis and initiation of appropriate treatment. Alpha-1-antitrypsin augmentation therapy has a clear role in patients with severe AATD and a FEV₁ ≤65% predicted. Emerging evidence suggests that attenuating the decline in lung density may prolong the time to respiratory failure.

KEYWORDS:

• Alpha-1-antitrypsin deficiency
• augmentation therapy
• case finding
• lung density

Identifying AATD cases

Alpha-1-antitrypsin deficiency (AATD) is an autosomal genetic disorder and one of the most frequent genetic causes of liver and lung diseases (1). Inherited low concentrations of alpha-1-antitrypsin lead to unopposed proteolysis in the lungs, predisposing individuals to early-onset emphysema, which predominantly affects the lower zones of the lungs. Despite its known association with chronic obstructive pulmonary disease (COPD), and the substantial health and economic burden it carries, AATD is largely unrecognised and underdiagnosed (2).

In the COPD population, certain patients may show clinical characteristics or ‘clues’ suggestive of AATD, as illustrated by the example in Table 1.

Table 1. Case study of AATD

History	49-year-old male
	Smoking history: very little, ‘only at parties …’
	Recorded diagnoses:
	• Granulomatosis with polyangiitis (GPA)
	• Chronic obstructive pulmonary disease (COPD)
Medical therapy	Methotrexate 15 mg/week
	Budesonide + formoterol/Tiotropium bromide
Presentation	Dyspnoea worsening in last months
	• Only mild exercise possible
	• Occasional productive cough
Differential diagnosis	Pulmonary manifestation of GPA?
	Methotrexate-related toxicity?
Investigations	Lung function: hyperinflation, FEV1 36% predicted
	CT scan: basal-predominant emphysema
	Genotyping: PiZZ, alpha-1-antitrypsin test 0.3 g/L
Diagnosis	AATD

The main diagnostic clues in this patient are absence of a significant smoking history, extent of lung damage for age, emphysema-predominant disease and the presence of antineutrophil cytoplasmic antibodies (ANCA)-positive vasculitis, which is known to be associated with AATD (3). However, rather than having to rely on clinical clues (which may or may not be present), the American Thoracic Society/European Respiratory Society have issued clear recommendations to screen every COPD patient for AATD once in his/her lifetime (4). AATD is a laboratory diagnosis that must be confirmed by a blood test. A proactive approach is therefore essential to identify cases and differentiate them from COPD. Case finding or targeted detection in at-risk groups is considered to be the most efficient method of identifying individuals most likely to benefit from management and treatment strategies for AATD.

AATD testing is recommended in the following populations (4):

•	Symptomatic adults with persistent obstruction with emphysema, COPD and asthma;
•	Asymptomatic individuals with persistent obstruction with risk factors (smoking and exposure);
•	Individuals with unexplained liver disease;
•	Adults with necrotising panniculitis;
•	Family screening.

AATD prevalence

The true prevalence of AATD is difficult to determine due to the absence of population-based newborn screening studies in most world countries. The best approach to estimating prevalence identified to date has been to limit analysis to studies with adequate methodologies that examined control group cohorts (e.g. blood donors, workers, healthy unrelated persons). Using this approach, it must be accepted that true prevalence will be underestimated as individuals with disease are generally excluded from control group populations. Blanco and colleagues identified 68 cohorts comprising 75,390 individuals from 21 countries in Europe; about 125,000 individuals were estimated to carry the PiZZ genotype (5). Investigating for AATD in COPD populations would be expected to yield higher estimates and, indeed, applying the estimated 0.63% prevalence of severe AAT deficiency in patients with fixed airflow obstruction (GOLD II–IV) reported by US investigators (6) to the overall European population indicated a potential PiZZ genotype population of about 400,000 individuals. The actual prevalence of AATD probably lies somewhere between these estimates. Among COPD populations, there are almost certainly to be cases of AATD, but these cases must be actively investigated to reduce the diagnostic delay from the current 5–8 years (2).

AATD knowledge relates to testing frequency

The^{Table 1} failure to identify all patients with AATD relates in large part to a knowledge gap, which translates into a testing gap. German and Italian physicians from the specialties of pulmonology, internal medicine and general practice were surveyed about their knowledge of AATD and testing frequency (7). Pulmonologists ranked highest for knowledge and testing frequency, whereas comparatively poor results for physicians from internal medicine and general practice (Figure 1) highlighted the need to increase knowledge and awareness of AATD among other specialties likely to encounter patients with respiratory diseases.

Figure 1. Self-reported level of knowledge about alpha-1-antitrypsin deficiency (AATD) and AATD testing frequency among pulmonologists (Pu), internal medicine specialists (In) and general practitioners (GP) from Germany (n = 180) and Italy (n = 181). Constructed from (7).

Underdiagnosis of AATD is a global issue. A study from Spain reported that, despite nearly 7,000 new cases of COPD diagnosed in the Catalan region each year from 2007 to 2012, less than 400 AAT tests per year in COPD patients were performed (8,9). In Germany and Italy, only 18–25% of surveyed physicians (pulmonologists, internal medicine specialists and general practitioners) reported performing AATD testing in their COPD populations (7). On the other hand, and in line with current recommendations, testing frequency was considerably greater in at-risk populations such as those diagnosed with COPD at <45 years of age (83 and 77%, respectively) and in family members of patients with AATD (69 and 72%, respectively) (7).

Differentiating AATD and COPD

In addition to registry populations, several other sources can be used to estimate AATD prevalence in the general population. Our group in Marburg, Germany, interrogated a national insurance database for the International Classification of Diseases (ICD) code E88.0, which classifies cases of AATD (and bisalbuminaemia) (10). Approximately 20,000 individuals with AATD were identified, inclusive of homozygous and heterozygous genotypes. To verify the internal validity of these estimates, we then investigated the prevalence of conditions known to be associated with AATD (vasculitis, chronic hepatitis, liver cirrhosis and panniculitis) among patients with AATD (ICD code E88.0) or COPD (11). Chronic hepatitis and cirrhosis were significantly more prevalent in patients with AATD than in those with COPD. There was a trend towards more vasculitis in AATD patients, whereas panniculitis was associated solely with COPD (Figure 2).

Figure 2. Prevalence of associated comorbidities in patients with alpha-1-antitrypsin deficiency (AATD) and chronic obstructive pulmonary disease (COPD) identified from a national insurance database in Germany. Reproduced from (11) with permission.

Compared with an age- and gender-matched reference population, AATD patients were found to have significantly more comorbidities, including arterial hypertension, congestive heart failure, ischaemic heart disease, chronic kidney disease, depression, diabetes, osteoporosis, gastroesophageal reflux disease and lung cancer (all p < 0.001), although the analysis incorporated a degree of selection bias as AATD testing was performed in patients already with disease (11). Patients with AATD typically have a more severe clinical course compared to those with other obstructive lung diseases, as evidenced by the significantly higher frequency of annual outpatient consultations and hospitalisations (Figure 3) observed in AATD patients compared to those with COPD, emphysema and asthma (11).

Figure 3. Percentage of hospitalisations in Germany according to disease type: alpha-1-antitrypsin deficiency (AATD), chronic obstructive pulmonary disease (COPD), emphysema or asthma. Reproduced from (11) with permission.

Treatment of AATD

In terms of treating patients with AATD, smoking cessation (as required) is a very clear recommendation supported by good quality evidence. With regard to other treatments such as pulmonary rehabilitation, vaccination (influenza and pneumococcal), inhaled therapy and endoscopic lung volume reduction, scant data are available but AATD may be subsumed under the umbrella term COPD.

AAT augmentation therapy

The benefits of treating AATD patients with alpha-1-antitrypsin (AAT) augmentation therapy were first documented in analyses of patient registries. A comparison of the annual change in FEV₁ between a German group who received weekly infusions of AAT 60 mg/kg and an untreated Danish group showed a significant treatment effect in the treated subgroup with a baseline FEV₁ 31–65% predicted (12). Similar trends were observed in the National Heart, Lung, and Blood Institute Registry study (13).

The role of computed tomography (CT) densitometry in assessing the effects of augmentation therapy in AATD patients was explored in the EXAcerbations and Computed Tomography scan as Lung Endpoints (EXACTLE) trial (14). AATD patients (n = 77) were randomised to receive weekly infusions of AAT 60 mg/kg or placebo for up to 2.5 years. The mean decline in lung density was significantly attenuated in the group receiving AAT replacement therapy versus the placebo-treated group, although the differences did not relate to clinical outcomes. A subsequent analysis pooled EXACTLE data with those from a comparably designed Danish Dutch study (n = 54) (15) to increase the statistical power (16). Based on densitometric data from 119 patients, the mean decline in lung density from baseline to last CT scan was significantly less with AAT augmentation therapy than with placebo (−4.08 vs −6.38; p = 0.006).

To substantiate the benefits of AAT augmentation therapy as suggested by the pooled analysis, a large international study was conducted. In the double-blind, multicentre, phase III/IV RAPID Lung Density study, 180 adult patients with AATD-related emphysema and FEV₁ 35–70% predicted were randomised to receive AAT 60 mg/kg weekly or placebo for 24 months, followed by a 24-month extension phase in which all patients received open-label AAT treatment (17). At the end of double-blind treatment, the annual rate of lung density loss (at total lung capacity) was significantly lower in the AAT group (−1.45 vs −2.19 g/L with placebo). During the extension phase of the study, the magnitude of lung density decline decreased in placebo-treated patients switched to open-label treatment, such that it aligned with that of patients treated with AAT from the beginning of the study and was in the range of that reported in the ECLIPSE study (18). Nevertheless, analysis of secondary endpoints of the RAPID Lung Density study showed no discernible effects for AAT augmentation therapy on FEV₁ or quality of life (17).

Whether attenuating lung function decline is a clinically meaningful outcome was addressed by an observational study of the AATD registry in the United Kingdom (19). For analysis purposes, augmentation-naïve PiZZ patients with two successive quantitative CT scans (n = 110) were divided into two groups: those with a decline in CT density and those with stable CT density. Even after adjusting for baseline lung density, a decline in lower zone lung density was associated with significantly decreased survival (p = 0.048), with the difference being driven mainly by patients with FEV₁ >30% predicted (Figure 4).

Figure 4. Survival curves in augmentation-naïve alpha-1-antitrypsin deficiency patients with a decline in CT density (▪) or stable CT density (•), based on two successive quantitative CT scans. Adapted from (19) with permission.

Collectively, the studies suggest that it is reasonable to treat AATD patients with augmentation therapy with the aim of stabilising lung density decline. However, patient selection is important. The role of augmentation therapy is clear in patients with severe AATD (AAT levels <11 μM) and a FEV₁ ≤65% predicted. In patients with AATD-related lung disease and FEV₁ >65% predicted, there is less evidence at present to support augmentation therapy (20). Other factors such as biology, competing risk factors, CT appearance and disease activity must be considered. Individuals with a less significant smoking history, more severe emphysema, those who are rapid decliners (FEV₁ and KCO) or have severe disease in relation to age are likely to benefit most from augmentation therapy. Individual patient discussions and shared decision making are essential.

Conclusions

Cases of AATD exist within every COPD or spirometry population but must be actively investigated. All patients with COPD, and particularly those who require more medical attention, should be examined closely to identify a specific AATD endotype. In appropriate patients, use of intravenous AAT augmentation therapy appears to prolong the time to respiratory failure.

Declaration of Interest

TG has received speaker's fees from AstraZeneca, Boehringer-Ingelheim, Chiesi, CSL-Behring, Grifols, GSK, Mundipharma and Novartis.

Editorial assistance was provided by Content Ed Net (Madrid, Spain) with funding from Grifols SA (Barcelona, Spain).