Abstract
Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disorder characterised by reduced levels of circulating alpha-1 antitrypsin and an increased risk of lung and liver disease. Recent reviews of AATD have focused on diagnosis, epidemiology and clinical management; comprehensive reviews examining disease burden are lacking. Therefore, we conducted literature reviews to investigate the AATD disease burden for patients, caregivers and healthcare systems. Embase, PubMed and Cochrane libraries were searched for AATD publications from database inception to June 2021, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Most published AATD studies were small and short in duration, with variations in populations, designs, measures and outcomes, complicating cross-study comparisons. AATD was associated with significant pulmonary and hepatic morbidity. COPD, emphysema and bronchiectasis were common lung morbidities, where smoking was a key risk factor. Fibrosis and steatosis were the most common liver complications reported in patients with a PiZ allele. Health status analyses suggested a poorer quality of life for AATD patients diagnosed with COPD versus those with non-AATD-associated COPD. The burden for caregivers included loss of personal time due to caring responsibilities, stress and anxiety. AATD was also associated with high direct medical costs and healthcare resource utilisation.
Short abstract
AATD is a rare genetic disorder associated with a considerable burden of lung and liver disease and high healthcare resource utilisation. However, available data are scarce and further research is needed to better understand the burden of this disease. https://bit.ly/3IWtQQ1
Introduction
Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disorder characterised by reduced levels of the proteinase inhibitor alpha-1 antitrypsin (AAT) in the circulation [1]. Individuals with AATD typically have a mutation in the SERPINA1 (or protease inhibitor (Pi)) gene, leading to a change in the structure of the AAT protein [1]. Normal alleles are known as PiM, while the most common deficiency alleles are PiS and PiZ, with PiMS, PiMZ, PiSS, PiSZ and PiZZ genotypes accounting for most variants [2]. >90% of patients with AATD express the PiZZ genotype; however, there are hundreds of rare and ultra-rare genotypes that result in circulating AAT concentrations of <11 µM, including the null/null genotype, which produces no AAT [2, 3]. Worldwide, it has been estimated that there are 3.4 million individuals with deficiency allele combinations (PiZZ, PiSZ or PiSS genotypes), and ⩾116 million carriers of deficiency alleles (i.e. heterozygous for the PiZ and PiS genotypes) [4].
AAT is produced mainly in the liver and circulates to the lungs, where it inhibits neutrophil elastase [5, 6]. If AAT is significantly reduced or absent, excess neutrophil elastase can degrade the lung extracellular matrix, as well as alveolar structures and blood vessels [7]. Individuals with AATD are therefore at increased risk of developing pulmonary disease, especially emphysema, which is often found in the basal areas of the lung [6]. AATD affects males and females equally, and the approximate age of diagnosis is 40–45 years [8].
Some individuals with AATD are prone to developing liver disease, which is secondary to accumulation of mutant AAT in hepatocytes [1, 6]. Patients with the Z variant (both heterozygotes and homozygotes) can develop liver disease due to abnormal folding of the Z AAT protein, which enables individual PiZ AAT proteins to polymerise and aggregate within the endoplasmic reticulum with eventual apoptosis of hepatocytes leading to toxicity, liver injury and increased risk of liver disease [9]. Liver complications are not observed in patients who have the null/null phenotype, because of the lack of aggregation of mutant proteins in the endoplasmic reticulum [10].
Infusion of purified human plasma-derived AAT protein (AAT therapy) has been available to treat AATD since it was first authorised by the United States Food and Drug Administration in 1987. Approval of this therapy was based on biochemical efficacy outcomes, i.e. inhibiting neutrophil elastase activity ex vivo, and maintaining AAT concentrations above presumed therapeutic thresholds in both serum and bronchoalveolar lavage fluid samples in patients with AATD [11]. In 2015, the RAPID trial reported a significantly reduced rate of lung density decline as measured by computed tomography (CT) for AAT therapy versus placebo [12, 13].
Although CT densitometry is useful for evaluating patients’ responses to AATD therapies [14], the assessment of disease severity and progression is conventionally based on pulmonary function tests, such as forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO), where declines over time are largely accepted as indicative of disease progression [2]. These measures can correlate with changes in quality of life (QoL), as measured by QoL instruments specifically designed for patients with obstructive airways disease, such as the St George's Respiratory Questionnaire (SGRQ) [14]. As for most pulmonary diseases, exacerbation severity and frequency can accelerate disease progression in AATD. Dyspnoea is a common complaint among patients with AATD and can be assessed using the modified Medical Research Council (mMRC) dyspnoea scale. These measures provide a means to assess disease burden in patients with AATD, comparing it with observations in patients with non-AATD-associated COPD.
Recent reviews of AATD have focused on the epidemiology and distribution of genetic variants, disease screening, diagnosis and care, as well as AAT therapy [2, 3, 15–19]. In contrast, comprehensive reviews that assess the burden of AATD on patients, caregivers and healthcare systems are lacking. An increased understanding of this burden may help improve awareness and diagnosis rates, as well as healthcare resource planning and allocation. Consequently, we conducted systematic and structured literature reviews to assess the clinical, economic and QoL-related disease burden associated with AATD worldwide.
Methods
Systematic reviews of the AATD literature were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [20]. The objective of this analysis was to assess 1) clinical burden and mortality associated with AATD; 2) QoL for patients; 3) caregiver burden; and 4) healthcare costs and resource utilisation.
Data sources
Embase, MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews and the Essential Reference Tool for Economics Literature were collectively searched from database inception to June 2021 to identify English-language studies on AATD using defined search strategies. Congress proceedings from 2017–2021 were also searched. In addition, registry websites (including the Tufts Cost-effectiveness Analysis Registry, the Alpha-1 Antitrypsin Deficiency Spanish Registry (REDAAT) and EUROCAT) and health technology assessment reports were searched for relevant studies. Finally, relevant systematic reviews identified through database searches were used for bibliography searching.
Population characteristics
The patient population of interest was adults (aged ≥18 years) of any race or gender with AATD. There were no restrictions on inclusion of studies based on intervention and comparator, country or publication timeframe. Publications that included patients with other diseases and studies that enrolled a mixed population of children and adults were excluded if subgroup data for adult patients with AATD were not available.
Search strategy, procedures and information extraction
All titles were downloaded into a systematic review database. Citations obtained from the searches were initially screened by two independent reviewers and conflicts resolved by a third independent reviewer/consensus. Citations that did not match the eligibility criteria were excluded, as were any duplicates due to overlap in coverage of the databases. Full-text papers were then screened in a similar fashion, with any discrepancies between the two reviewers resolved by a third independent reviewer. One reviewer then extracted data into a pre-defined extraction grid, which was validated by another independent reviewer. Where more than one publication was identified as describing a single study, the data were compiled into a single entry to avoid double counting of patients and studies. The search strategies used are shown in the supplementary figures.
Critical appraisal
Critical appraisal of included randomised controlled trials was conducted using comprehensive assessment criteria based on recommendations by the National Institute for Health and Care Excellence [21]. Observational studies were critically appraised using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist [22].
Results
Clinical burden review
A total of 38 studies were included in the clinical burden review (supplementary figure S1), 17 of which were conference abstracts. 23 studies were conducted in Europe; nine in North America; and the remainder did not report the study location. Study sample size ranged from 19 patients in a small case–control study [23] to 422 506 patients from a UK population-based cohort [24]. 31 of the included studies reported clinical characteristics of patients with AATD (supplementary table S1). Mean age ranged from 39.9 to 69.6 years across 29 studies, and the proportion of males was ≥50% in 18 studies. Data on smoking status were reported in 17 studies; in 15 of these, most patients were current or former smokers (52–84%) [25–35]. The remaining two studies involved nonsmoking patients, who comprised all patients in one study [36] and 73% of patients in the other study [29]. PiZZ was the most commonly identified genotype, and was the only genotype identified in 10 studies [25, 27, 30, 31, 37–42].
Of the 38 included studies, all reported data regarding specific morbidities in patients with AATD including pulmonary, liver and skin disease; overall, 50 different morbidities were reported (table 1) [23–30, 32–59]. Pulmonary morbidity was commonly reported, and included COPD with a prevalence of 36.3–75.8% [25, 26, 33, 43, 49], emphysema (14.4–53.8%) [29, 43, 46, 47] and bronchiectasis (3.8–73.1%) (table 1) [29, 45–47].
TABLE 1.
Clinical burden review: morbidity associated with alpha-1 antitrypsin deficiency (AATD)
| First author, year [ref.] | Patient population | Type of complication | Patients affected % | Risk factors for morbidity (value estimate) | Main outcomes |
| Pulmonary morbidity | |||||
| Herrera, 2021 [43] | Severe AATD (n=711) | COPD | 75.8 | Not evaluated | Patients with severe AATD-related PM requiring hospitalisation are substantially burdened by more frequent events and a more severe clinical course. |
| Nonsevere AATD (n=1963) | COPD | 56.9 | |||
| Severe AATD (n=711) | Emphysema | 33.8 | |||
| Nonsevere AATD (n=1963) | Emphysema | 23.8 | |||
| Tanash, 2019 [25] | Severe AATD (n=1595) | COPD | 53 | The proportion of subjects with COPD was higher among individuals with than those without liver disease. | |
| Hiller, 2019 [26] | Severe AATD (n=1132) | COPD | 52 | Smoking# Middle age# Frequent exacerbation# Respiratory symptoms# |
Active smoking, age, respiratory symptoms at baseline and repeated severe exacerbations of COPD were associated with accelerated decline of lung function in severe AATD. |
| Choate, 2019 [44] | AATD (PiZZ n=3031) | Exacerbation over the past year (lung condition not specified) | 75.6 | Not evaluated | PiSZ patients reported more frequent exacerbations than PiZZ patients, even after adjusting for age, sex, current smoking status and CCI score. |
| AATD (PiSZ n=504) | 78.3 | ||||
| Costa, 2017 [29] | AATD (PiSS and PiMS n=32; PiMZ n=64; PiSZ n=8) | Bronchiectasis | 3.8 | Not evaluated | Patients with intermediate AATD were often symptomatic and some had mild obstruction and emphysema. Exposure to risk factors seemed to be more important than AATD serum level in determining lung function. |
| AATD (PiSS and PiMS n=32; PiMZ n=64; PiSZ n=8) | Emphysema | 21.2 | |||
| Cortese, 2016 [45] | AATD (n=475) | Bronchiectasis | 12 | Patients with bronchiectasis had more comorbidities (p=0.008) and were more frequently affected by pneumonia (p=0.024) than those without bronchiectasis | The presence or absence of bronchiectasis should be ascertained in patients affected by severe AATD because of its clinical consequences. |
| Araújo, 2015 [46] | AATD (n=110) | Bronchiectasis | 24 | PiZZ # | PiZZ individuals were significantly more likely to have severe bronchiectasis versus those with other alleles. |
| AATD with bronchiectasis (n=26) | Emphysema | 53.8 | |||
| Kawkgi, 2013 [47] | AATD (PiSZ) with smoking history (n=29) | Emphysema | 36 | Smoking# | Individuals with the SZ phenotype were at risk of developing emphysema if they smoked; however, the rate of bronchiectasis in this population was high, regardless of smoking history. |
| AATD (PiSZ) with smoking history (n=29) | Bronchiectasis | 54 | |||
| Ferrarotti, 2012 [48] | Severe AATD (n=312) | Overall (not specified) | 79 | Smoking and possession of rare deficient allele other than S or Z# | This database enabled a detailed characterisation of the natural course of the disease and the status of patient care. |
| Guttmann, 2011 [49] | Severe AATD (n=713) | COPD | 73 | Smoking# Dust exposure# |
AATD led to significant morbidity in affected subjects. |
| Subramanian, 2010 [40] | AATD PiMZ (n=497) | Lung nodule | 26.8 | hs-CRP due to lung nodule (p<0.005) | An association between the presence of lung nodules (accompanied by a significant increase in hs-CRP) and the subsequent development of COPD was suggested. |
| Torres-Durán, 2015 [36] | AATD (n=212) | Lung cancer |
PiMM 70 PiMS 21.1 PiMZ 3.8 PiSZ 1.4 PiSS 3.3 |
There was a significant four-fold increase in lung cancer risk in never-smokers with PiSS compared with PiMM genotypes (OR 4.64; 95% CI 1.08–19.92). | |
| Gupta, 2020 [32] | No deficiency (n=1149) Mild deficiency (n=147) Intermediate deficiency (n=59) Severe deficiency (AATD) (n=4) |
Emphysema | Patients with severe AATD (ZZ, SZ and SDonostiZ) had lower diffusion capacity and greater CT-based emphysema versus patients without AATD. | ||
| Franciosi, 2021 [50] | AATD PiMZ (n=91) AATD PiSZ (n=72) AATD PiZZ/rare (n=130) |
Lung disease, airflow obstruction¶ | 47.3 45.9 74.6 |
Smoking | Patients with AATD and a PiZZ genotype were more likely to have been diagnosed with AATD due to lung disease, demonstrated by worse airflow obstruction. |
| Franciosi, 2020 [33] | AATD PiSZ (n=70) AATD PiMM/MS (controls) (n=46) |
COPD | Not stated | Not stated | PiSZ never-smokers demonstrated no increased risk of COPD, regardless of AAT concentration. |
| Esquinas, 2018 [35] | AATD PiZZ (n=122) | Emphysema Chronic bronchitis Bronchiectasis Asthma |
83.1 44.6 42.3 20 |
Tobacco consumption (p=0.001) Previous pneumonia (p=0.026) Higher baseline FEV1 % (p=0.010) |
Tobacco consumption, previous pneumonia and better lung function at baseline were related to a faster decline in FEV1. |
| Parr, 2007 [51] | AATD PiMZ (n=74) | Bronchiectasis | 27 (clinically significant) | Emphysema was the predominant component of COPD in AATD, but the prevalence and impact of airway disease was expected to be greater than is currently recognised. | |
| Piras, 2013 [34] | AATD PiZZ (n=547) | Chronic bronchitis Emphysema Asthma Bronchiectasis COPD |
26 63.1 11 19 78.4 |
PiZZ patients had more severe respiratory disease than those with PiSZ, despite lower smoking levels. | |
| AATD PiSZ (n=124) | Chronic bronchitis Emphysema Asthma Bronchiectasis COPD |
22.6 33.9 17.7 12.9 43.5 |
|||
| AATD Spain (n=416) | Chronic bronchitis Emphysema Asthma Bronchiectasis COPD |
36.1 66.6 15.9 27.2 76.2 |
|||
| AATD Italy (n=329) | Chronic bronchitis Emphysema Asthma Bronchiectasis COPD |
9.4 45.9 5.5 4 67.8 |
|||
| Hepatic morbidity | |||||
| Teckman, 2019 [52] | AATD with liver disease (n=93) | Liver fibrosis (Ishak score 0–1) | 88 | Not evaluated | This study documented a highly variable range of findings with fibrosis. |
| AATD with liver disease (n=93) | Liver fibrosis (Ishak score 2) | 2 | |||
| AATD with liver disease (n=93) | Liver fibrosis (Ishak score 3) | 2 | |||
| AATD with liver disease (n=93) | Liver fibrosis (Ishak score 4–6) | 8 | |||
| Ferrarotti, 2012 [48] | Severe AATD (n=312) | Overall (not specified) | 10 | Not evaluated | This database enabled a detailed characterisation of the natural course of the disease and the status of patient care. |
| Chakraborty, 2016 [28] | AATD (n=212) | Overall (not specified) | 29 | AST (p=0.001) BMI (p=0.04) Platelet reduction (OR 0.97, 95% CI 0.96–0.98) |
Liver disease in this AATD cohort was high, with obese individuals at greatest risk. |
| Mandorfer, 2017 [53] | Severe AATD with PM (n=31) | Advanced liver fibrosis | 3 | Not evaluated | Patients with severe pulmonary manifestation AATD rarely developed advanced liver fibrosis during adulthood. Autopsy reports, which observed cirrhosis in about one-third of PiZZ patients, may have overestimated the risk of end-stage liver disease. |
| Severe AATD with PM (n=31) | Liver fibrosis | 23 | |||
| Severe AATD with PM (n=31) | Liver steatosis | <Stage 1 65 <Stage 2 52 |
|||
| Strnad, 2017 [39] | AATD with PiMZ without known liver disease (n=115) | Liver fibrosis | 18 | Not evaluated | PiMZ heterozygotes had higher serum ALT, AST and GGT levels than controls. Alcohol misusers carrying the PiZ variant were more prone to develop cirrhosis. |
| Matched controls without AAT mutations (n=100) | 6 | ||||
| Arslanow, 2017 [23] | AATD (n=19) | Advanced liver fibrosis | 21 | Not evaluated | AATD presented with both impaired body composition and liver function tests. A third of the patients displayed abnormal TE measurements, indicating steatosis or advanced fibrosis. |
| AATD (n=19) | Liver steatosis | 37 | |||
| AATD (n=19) | Cirrhosis | 11 | |||
| Hamesch, 2019 [38] | AATD with homozygous PiZZ (n=403) | Liver fibrosis (LSM) | 23.6 | Age >50 years Male sex Elevated ALT/AST/GGT Reduced platelet count Lung function PiZ carrier (OR 19.8, 95% CI 4.6–84.1) |
Male sex, age >50 years, increased levels of ALT/AST/GGT and low numbers of platelets were associated with a higher liver fibrosis burden. No evidence for a relationship between lung function and liver fibrosis was found. |
| AATD without PiZ mutation (n=234) | Liver fibrosis (LSM) | 6.4 | |||
| AATD with homozygous PiZZ (n=403) | Advanced liver fibrosis (LSM) | 13.6 | |||
| AATD without PiZ mutation (n=234) | Advanced liver fibrosis (LSM) | 1.3 | |||
| AATD with homozygous PiZZ (n=403) | Liver fibrosis (APRI) | 19.6 | |||
| AATD without PiZ mutation (n=234) | Liver fibrosis (APRI) | 5.4 | |||
| AATD with homozygous PiZZ (n=403) | Advanced liver fibrosis (APRI) | 4.5 | |||
| AATD without PiZ mutation (n=234) | Advanced liver fibrosis (APRI) | 0.5 | |||
| AATD with homozygous PiZZ (n=403) | Liver fibrosis (HepaScore) | 36.3 | |||
| AATD without PiZ mutation (n=234) | Liver fibrosis (HepaScore) | 13.5 | |||
| AATD with homozygous PiZZ (n=403) | Advanced liver fibrosis (HepaScore) | 25.6 | |||
| AATD without PiZ mutation (n=234) | Advanced liver fibrosis (HepaScore) | 4.1 | |||
| AATD with homozygous PiZZ (n=403) | Liver steatosis (mild) | 61.1 | |||
| AATD without PiZ mutation (n=234) | Liver steatosis (mild) | 48.2 | |||
| AATD with homozygous PiZZ (n=403) | Liver steatosis (severe) | 38.7 | |||
| AATD without PiZ mutation (n=234) | Liver steatosis (severe) | 28.4 | |||
| Tanash, 2019 [25] | PiZZ AATD (n=1595) | Cirrhosis | 7 | Male gender (risk ratio 1.45, 95% CI 1.15–2.14; p=0.03) Age >50 years (risk ratio 2.02, 95% CI 1.30–3.16; p=0.002) Ever-smokers (risk ratio 0.85, 95% CI 0.56–1.30; p=0.46) Repeated elevated LFTs (risk ratio 7.66, 95% CI 5.10–11.73) Hepatitis infection (risk ratio 3.12, 95% CI 1.21–8.08; p=0.02) COPD (risk ratio 2.20, 95% CI 1.32–3.70; p=0.003) Diabetes (risk ratio 3.87, 95% CI 2.18–6.87) Hypertension (risk ratio 0.91, 95% CI 0.50–1.66; p=0.76) |
In this large study, the prevalence of liver disease in PiZZ individuals was 10%. Age >50 years, male gender, repeated elevated liver enzymes, hepatitis and the presence of diabetes mellitus and COPD were risk factors for developing liver disease. |
| PiZZ AATD (n=1595) | Hepatocellular carcinoma | 2 | |||
| Stone, 2014 [37] | AATD (n=651) | Cirrhosis | 4 | Not evaluated | |
| Clark, 2018 [27] | AATD (n=94) | Liver fibrosis | 35.1 | Sex (p=0.04) Diabetes (p=0.002) Impaired fasting glucose (p=0.003) Obesity (p=0.01) Metabolic syndrome (p<0.001) |
Individuals with large amounts of AAT on biopsy may be at risk of liver injury and fibrosis. Metabolic syndrome was associated with a greater degree of liver injury. |
| Black, 2020 [54] | Heterozygous AATD (chronic liver disease + AAT globules) (n=23) | Liver disease | Stage 1 13.0 Stage 2 8.7 Stage 3 26.1 Stage 4 52.2 |
Stage 4 (p=0.017) | Heterozygous AATD may potentiate the progression of concurrent liver diseases. |
| Controls (chronic liver disease, no AAT globules) (n=120) | Stage 1 30.8 Stage 2 23.3 Stage 3 24.2 Stage 4 21.7 |
||||
| Fromme, 2022 [24] | AATD PiMZ (n=17 006): cohort 1 | Liver fibrosis/cirrhosis | Liver fibrosis/cirrhosis was 20 times more common in PiZZ versus noncarriers (adjusted OR 21.7, 95% CI 8.8–53.7; p<0.0001), but also markedly enriched in Pi*SZ subjects (adjusted OR 3.1, 95% CI 1.1–8.2; p=0.027) and moderately in Pi*MZ participants (adjusted OR 1.7, 95% CI 1.2–2.2; p=0.001) | The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. | |
| AATD PiSS (n=1014): cohort 1 | Liver primary cancer | PiSZ and PiZZ increased the risk of primary liver cancer (adjusted OR 6.6, 95% CI 1.6–26.9 and adjusted OR 44.5, 95% CI 10.8–183.6) versus noncarriers | |||
| AATD PiSZ (n=864): cohort 1 | |||||
| AATD PiZZ (n=138): cohort 1 | |||||
| Controls (noncarriers n=422 506): cohort 1 | |||||
| AATD PiZZ (n= 586): cohort 2 | Liver fibrosis/cirrhosis | 24 | |||
| AATD PiSZ (n=239): cohort 2 | 13 | ||||
| Controls (noncarriers n= 279): cohort 2 | 5 | ||||
| AATD PiMZ (n=419): cohort 1 | Liver fibrosis | 10 | |||
| Schneider, 2020 [55] | AATD PiZZ (n=309): cohort 1 | LSM >7.1 kPa | 25 | Obesity and diabetes were the most important factors associated with LSM ≥7.1 kPa in subjects with the PiMZ genotype. | |
| Control (noncarriers n=284): cohort 1 | 4 | ||||
| AATD PiMZ (n=84): cohort 2 | Liver steatosis | Stage 1 40.5 Stage 2 28.5 Stage 3 15.5 |
|||
| AATD PiZZ (n=35): cohort 2 | Stage 1 34.3 Stage 2 37.1 Stage 3 2.9 |
||||
| AATD PiMZ (n=84): cohort 2 | Liver fibrosis | Stage 1 13.1 Stage 2 28.6 Stage 3 28.6 Stage 4 16.7 |
|||
| AATD PiZZ (n=35): cohort 2 | Stage 1 5.7 Stage 2 20.0 Stage 3 42.9 Stage 4 28.6 |
||||
| AATD PiMZ (n=84): cohort 3 | Perisinusoidal fibrosis | 69.1 | |||
| AATD PiZZ (n=35): cohort 3 | 97.1 | ||||
| Hakim, 2021 [56] | SERPINA 1 Z allele (n=299 939) | Cirrhosis | 0.5 | The SERPINA1 Z allele was associated with cirrhosis in an allele dose-dependent manner (OR 1.69; p=2.3×10−07) The SERPINA1 Z allele was associated with higher odds of cirrhosis in both heterozygotes versus noncarriers (OR 1.53; p=1.1×10−04) and homozygotes versus noncarriers (OR 11.8; p=1.8×10−09) |
SERPINA1 Z allele heterozygosity was an important risk factor for liver disease. |
| SERPINA 1 PiMZ (n=12 603) | 0.7 | ||||
| SERPINA 1 PiZZ (n=129) | 4.7 | ||||
| Abu Rmilah, 2021 [57] | AATD PiMM with cirrhosis (n=1094) | Cryptogenic cirrhosis NASH ALD Autoimmune Viral hepatitis PSC/PBC Others |
76.9 67.3 70.6 87.5 87.5 88.8 89.3 |
Rates of pre-operative and post-operative pulmonary complications were found to be higher for PiMZ than PiMM. The MZ phenotype was significantly enriched in NASH, ALD and cryptogenic cirrhosis. | |
| AATD PiMZ with cirrhosis (n=130) | Cryptogenic cirrhosis NASH ALD Autoimmune Viral hepatitis PSC/PBC Others |
23.0 22.0 20.0 10.0 5.6 3.2 10.7 |
|||
| Other morbidity | |||||
| Tanash, 2019 [25] | Severe AATD (n=1595) | Panniculitis | <1 | Four out of 1595 patients with a PiZZ genotype | No patients with panniculitis developed liver disease. |
| Stone, 2014 [37] | AATD (n=651) | Panniculitis | 0.9 | The prevalence of inflammatory bowel disease and hypothyroidism was higher than that predicted in the UK, supporting a potential link between AATD and these conditions. | |
| Granulomatosis with polyangiitis | 0.8 | ||||
| Inflammatory bowel disease (UC and Crohn disease) | 1.5 | ||||
| Hypothyroidism | 4 | ||||
| Choate, 2019 [44] | AATD PiZZ (n=3031) | High blood pressure | 38.4 | A statistically significant greater proportion of PiSZ in our cohort were diagnosed with the six most prevalent comorbidities. | |
| Reflux | 33.9 | ||||
| Sinus disease | 15.4 | ||||
| Heart rhythm problems | 12.0 | ||||
| Tumour/cancer | 11.2 | ||||
| Diabetes | 7.3 | ||||
| Skin problems (including panniculitis) | 8.6 | ||||
| Pulmonary hypertension | 6.3 | ||||
| PVD | 6.3 | ||||
| CTD | 6.0 | ||||
| AATD (PiSZ=504) | High blood pressure | 52.0 | |||
| Reflux | 40.4 | ||||
| Sinus disease | 20.4 | ||||
| Heart rhythm problems | 18.6 | ||||
| Tumour/cancer | 16.2 | ||||
| Diabetes | 17.0 | ||||
| Skin problems (including panniculitis) | 7.0 | ||||
| Pulmonary hypertension | 8.1 | ||||
| PVD | 7.0 | ||||
| CTD | 7.4 | ||||
| Basil, 2021 [30] | Severe AATD | VTE | 7 | Unadjusted HR 6.5, 95% CI 4.9–8.6 Adjusting for risk factors: male, age, COPD, cancer and liver disease HR 5.2, 95% CI 3.7–7.4 |
Subjects with severe AATD had considerably increased risk of developing VTE versus the general population, even after accounting for risk factors. |
| Controls | 1 | ||||
| Tanash, 2020 [41] | AATD (PiZZ) (n=1545) | Ischaemic heart disease | 8 | HR 1.8, 95% CI 1.4–2.3 Ever-smokers HR 2.1, 95% CI 1.5–2.9 Never-smokers HR 1.5, 95% CI 1.1–2.2 |
PiZZ individuals had a lower risk of developing incident ischaemic heart disease than controls with known smoking habits. |
| Controls (n=5883) | 12 | ||||
| Hiller, 2020 [42] | AATD (PiZZ) (n=1585) | Cancer | 12 | Adjusted HR 1.6, 95% CI 1.3–1.9 Ever-smokers HR 1.5, 95% CI 1.2–1.8 Never-smokers HR 1.7, 95% CI 1.3–2.2 |
PiZZ individuals had a lower risk of developing incident cancer than the general population adjusting for age and sex, both in ever- and never-smokers. |
| Controls (n=5999) | 10 | ||||
| Sapey, 2020 [58] | AATD (n=68) | Periodontitis | 88 | Periodontitis severity associated with lung disease severity (AATD, periodontitis versus no periodontitis; FEV1 56% versus 99% predicted; TLCO 59% versus 81% predicted; p<0.0001 for both) | The results supported shared pathophysiology between periodontitis and COPD, especially when associated with AATD. |
| COPD (n=88) | 95 | ||||
| Mandich, 2011 [59] | AATD (n=33) | Bipolar disorder Schizophrenia Depression Anxiety |
3.0 0 18.2 15.2 |
The incidence of psychiatric disorders was higher than the national incidence. | |
PM: pulmonary manifestation; PiMM/MZ/SZ/ZZ: Pi (or SERPINA1 gene) MM, MZ, SZ and ZZ alleles; CCI: Charlson Comorbidity Index; hs-CRP: high-sensitivity C-reactive protein; CT: computed tomography; AAT: alpha-1 antitrypsin; FEV1: forced expiratory volume in 1 s; AST: aspartate aminotransferase; BMI: body mass index; ALT: alanine aminotransferase; GGT: γ-glutamyl transferase; TE: transient elastography; LSM: liver stiffness measurement; APRI: AST-to-platelet ratio index; LFT: liver function test; NASH: nonalcoholic steatohepatitis; ALD: alcoholic liver disease; PSC: primary sclerosing cholangitis; PBC: primary biliary cirrhosis; UC: ulcerative colitis; PVD: peripheral vascular disease; CTD: connective tissue disease; VTE: venous thromboembolism; HR: hazard ratio; TLCO: transfer factor of the lung for carbon monoxide. #: no estimated value was presented, although a qualitative statement establishing a relationship between variable and complication was reported (the majority were conference abstracts); ¶: Global Initiative for Chronic Obstructive Lung Disease classification 1–4 representing airflow obstruction with an FEV1 80–100% pred, 50–79% pred, 30–49% pred and <30% pred, respectively.
One study reported lung nodules in 26.8% of patients [40]. Risk factors for developing lung morbidity in individuals with AATD were reported in 10 studies. Smoking was cited as a risk factor in six studies [26, 35, 47–50], and current smoking, age (40–59 years) and frequent severe exacerbations of COPD were associated with an accelerated decline of FEV1 in individuals with severe AATD [26, 35]. The remaining studies did not examine the influence of smoking on risk.
There are mixed results reported for the influence of genotype on lung disease, with some studies reporting that PiSZ is a risk for exacerbation of lung disease [44, 47], others that PiZZ results in more severe disease [34, 46, 50] and one study reporting no increased risk of COPD due to PiSZ (table 1) [33]. One study reported on the effects of PiSS and PiMM and reported a significant four-fold increase in lung cancer risk in never-smokers with PiSS compared with PiMM genotypes (OR 4.64, 95% CI 1.08–19.92) [36].
Liver fibrosis was the most reported hepatic morbidity, with a wide variation in prevalence (1–88%) in those with AATD [23, 24, 27, 31, 38, 39, 52, 53, 55]. Advanced liver fibrosis was reported in 0.5–25.6% of patients [23, 31, 38, 53]. Cirrhosis was seen in 4–11% of patients [23–25, 37, 56]. A single study reported hepatocellular carcinoma in 2% of patients and hepatitis in 1% [25]. Genotype was an important risk factor for liver morbidity, with PiZZ associated with an increased risk of advanced liver fibrosis [38] and steatosis [53] (table 1). Among individuals with a PiZZ genotype, additional risk factors for liver disease included male sex [25, 38, 39] and the presence of metabolic dysfunction including diabetes [25, 27], metabolic syndrome and obesity [27]. Age >50 years, elevated liver enzyme levels, hepatitis viral infection and COPD were also associated with liver disease [25]. In addition, while PiZZ individuals had more liver stiffness and raised liver enzymes than individuals with an PiMZ or a wild-type PiMM genotype, PiMZ carriers appeared to have an intermediate risk of hepatic morbidity versus those without AATD-associated genotypes [55].
Panniculitis, a neutrophilic inflammation of subcutaneous fat, was reported in <1–8.6% of patients with AATD across three studies [25, 37, 44] (table 1). Other complications associated with AATD included increased psychiatric disorders [59], inflammatory bowel disease [37], venous thromboembolism [30] and cancer [24, 25, 36, 42, 44], and decreased ischaemic heart disease [41].
Mortality
13 publications discussed mortality associated with AATD (table 2) [60–72], four of which were conference abstracts. Four Swedish studies included the same population, although different aspects were analysed [61, 62, 70, 71].
TABLE 2.
Mortality associated with alpha-1 antitrypsin deficiency (AATD)
| First author, year [ref.] | Country | Years | Subjects n | Main mortality outcomes |
| Attaway, 2019 [60] | USA | 2004–2014 | 8039# | In-hospital mortality rate (2004): 3.1% (unchanged over the study period) Higher rates of mortality associated with sepsis: 56/351 (16%) and respiratory failure: 42/741 (5.7%) Univariate analysis for higher mortality, mean+sd: congestive heart failure 2.07+0.70; pulmonary hypertension 2.29+0.83; cirrhosis 2.47+0.69; malnutrition 2.62+1.36; acute renal failure 6.59+1.87 |
| Tanash, 2016 [61] | Sweden | 1991–2014 | 1561#,¶ | Total deaths n=524 SMR (95% CI) PiZZ versus Swedish population 3.6 (3.3–3.9) Main causes of death were COPD + complications (respiratory failure and infections) (n=281, 54%); liver diseases (n=74, 14%); CVD (n=76, 15%); and cancer (n=87, 17%) Cause-specific SMR (95% CI): IHD 0.5 (0.3–0.8); COPD 48.4 (43.0–54.5), n=28; liver failure/complications 47.8 (35.8–64.2), n=44 Cause-specific SMR (95% CI) in ever-smokers: COPD 71.3 (62.1–81.6), n=214; liver failure/complications 47.2 (30.5–69.6), n=25 Cause-specific SMR (95% CI) in never-smokers: COPD 24 (18.5–30.4), n=67; liver failure/complications 48.7 (29.3–76.1), n=19 |
| Tanash, 2008 [62] | Sweden | 1991–2007 | 568 | Total deaths n=93 (16%) SMR (95% CI) for whole study population 2.32 (1.87–2.83); no difference between sexes. SMR (95% CI) for respiratory and nonrespiratory cases was 2.55 (1.91–2.83) and 2.07 (1.49–2.81), respectively. SMR (95% CI) for subgroups in nonrespiratory cases 0.70 (0.14–2.04) for individuals identified by family/population screening. Emphysema and liver cirrhosis were the most common causes of death (45% and 28%, respectively). Malignant transformation was found in 38% of cirrhosis cases |
| Stoller, 2005 [63] | USA | 1989–1992 | 1129#,+ | Total deaths n=204 (18.1%) Attributable mortality SMR 6.3 Male versus female SMR 5.8 versus 7.4 Emphysema and cirrhosis were the most common causes of death: 85/118 (72%) and 12/118 (10%), respectively, and SMR indicated that excess mortality was due to lung and liver disease. |
| Browne, 1996 [64] | USA | 1979–1991 | Overall records 26 866 600# | Number of individuals who died with AATD listed as cause of death n=1930 Rate per 100 000 deaths 7.18 Rate ratio of males to females 1.35 Proportion with COPD or hepatic disease 1206/1930 (62%) and 413/1930 (21%), respectively |
| Catterall, 2020 [65] | UK | 1999–2020 | 195 | 22 (35.4%) PiZZ patients died within the audit period Mortality was higher for PiZZ patients compared with the overall COPD population |
| Dawkins, 2009 [66] | UK | 1996–2005 | 488 | Total deaths n=56 Cause of death: emphysema n=30; lung transplant n=4; liver disease n=6; malignancy n=5; cardiovascular n=3; cardiac n=3; PE n=2; other n=3 Mortality: 2% per year. Cumulative mortality of 18.1% over 9-year period. FEV1 % predicted: severe impairment had increased mortality (p<0.001) versus mild, with a direct relationship between severity and mortality Severe impairment had increased mortality versus mild impairment when categorised for KCO % predicted (p<0.001), RV/TLC ratio (p<0.001) or emphysema score on CT scan (p<0.001 upper zone) |
| Dawkins, 2003 [67] | UK | 1996–2001 | 256 | Total deaths n=22 Respiratory deaths n=10; lung transplant n=3; liver transplant n=1; nonrespiratory deaths n=8 Mortality rate ∼4% per year Baseline FEV1, KCO and CT scores were significantly lower in nonsurvivors than survivors Upper-zone expiratory scan had best association with all-cause (p=0.001) and respiratory mortality (p=0.001) FEV1 (p=0.158 all-cause, p=0.015 respiratory) and KCO (p=0.002 all-cause, p=0.012 respiratory) had poorer associations with mortality Age provided further independent predictive information for all-cause or respiratory mortality when CT scan was entered into survival analyses |
| Ellis, 2019 [68] | UK/USA | 1535 | Estimated mean (95% CI) survival was significantly longer in the treatment group: AAT therapy 20.3 (19.4–21.2) years, control 13.7 (13.1–14.3) years; p<0.001 | |
| Seersholm, 1994 [69] | Denmark | 1978–1992 | 397 | Total deaths n=112 Median survival 54.2 years Survival for index cases versus nonindex cases regardless of smoking history (49.4 years, 95% CI 42.4–53.6 years and 69.3 years, 95% CI 65.9–82.1 years, respectively) Survival of smokers was significantly less than for nonsmokers (p<0.0001) with a median survival time of 51.8 years (95% CI 47.2–56.1 years) for smokers and 66.8 years (95% CI 65.3–75.1 years) for never-smokers |
| Tanash, 2010 [70] | Sweden | 1991–2008 | 1339 | Total deaths n=315 (24%) SMR respiratory deaths 4.70 (95% CI 4.10–5.40) SMR nonrespiratory deaths 3.0 (95% CI 2.35–3.70) SMR smokers 4.80 (95% CI 4.20–5.50) SMR never-smokers 2.80 (95% CI 2.30–3.40) Rate ratio 1.70 (95% CI 1.35–2.20) Cause of death: respiratory 58%; hepatic 12%; other 30% |
| Tanash, 2017 [71] | Sweden | 1991–2015 |
PiZZ 1585 Controls 5999 |
Total deaths PiZZ 473 (30%); controls 747 (12%) PiZZ patients had a significantly shorter survival time than controls (p<0.001) No increase in risk of death in never-smoking PiZZ patients identified by screening, compared with never-smoking controls, HR 1.2 (95% CI 0.6–2.2) After adjustment for gender, age, smoking habits and presence of respiratory symptoms, the risk of death for the PiZZ patients versus controls was HR 3.2 (95% CI 2.8–3.6; p<0.001) Causes of death: PiZZ respiratory disease 52%; CVD 16%; hepatic disease 15%; cancer 11% |
| Da Costa Dias de Souza, 2017 [72] | Portugal | 2006–2016 | 143 | Total deaths n=19 Mean age 60 years; males 63% Cause of death for all: liver disease 44%; respiratory disease 31%; other 25% Main cause of death for PiZZ and PiMZ: respiratory disease 83%; liver disease 57%, respectively Obstructive ventilatory disease was present in 42%; 78% with a FEV1 <50% predicted. 42% were smokers/former smokers. The most frequent radiological finding was emphysema (57%) |
PiZZ: Pi (or SERPINA1 gene) ZZ allele; SMR: standardised mortality ratio; CVD: cardiovascular disease; IHD: ischaemic heart disease; PE: pulmonary embolism; FEV1: forced expiratory volume in 1 s; KCO: transfer coefficient of the lung for carbon monoxide; RV: residual volume; TLC: total lung capacity; CT: computed tomography; AAT: alpha-1 antitrypsin; HR: hazard ratio. #: no treatment reported; ¶: during follow-up, 86 out of 1561 patients underwent lung transplantation; +: receipt of AATD therapy was considered a model parameter in the multivariate analyses.
Sample sizes of the studies ranged from 143 to 8039; however, one study examined death certificate records from the United States National Center for Health Statistics, which comprised >26 000 000 cases [64]. In general, these studies showed that mortality in patients with AATD resulted primarily from respiratory diseases, followed by liver complications. The Attaway et al. [60] study, which examined inpatient hospitalisations among patients with AATD, reported an in-hospital mortality rate of 3.1%. One study from Sweden reported a standardised mortality ratio of 3.6 compared with the general population [61], whereas another reported a standardised mortality ratio of 6.3 among National Heart, Lung, and Blood Institute AATD registry patients [63]. Respiratory disease, hepatic disease, diverticulitis and pulmonary embolism were associated with a higher risk of mortality among patients with AATD in the Swedish study [61]. Another study confirmed that patients who were treated with AAT therapy had prolonged survival or time to lung transplantation compared with those who were AAT therapy-naïve [68]. Although patients with the PiZZ genotype had a higher rate of mortality compared with patients without AATD [61, 65, 71], one study observed no difference in mortality rates between never-smoking PiZZ individuals and never-smoking controls [61, 71].
Quality of life
The QoL review included 30 studies (supplementary figure S2), 23 of which were journal articles. The sample size ranged from 16 patients [73] to 922 patients [74]. Where reported, the mean age ranged from 40.7 years [14] to 60.3 years [75], and there were more males than females in 19 out of 30 studies, with the proportion of males ranging from 50.3% to 83% (supplementary table S2) [12, 76–78]. Most studies assessed QoL using the SGRQ (22 studies; table 3 [12, 14, 73–76, 78–93]). Other disease-specific patient-reported outcomes included the COPD Assessment Test (CAT), the Chronic Respiratory Disease Questionnaire (CRQ) and the Living with COPD (LCOPD) scale. The generic 36-item short-form survey (SF-36) was used in eight studies and the EQ-5D in two [75, 77] (see supplementary table S2 for the QoL instruments used in each study).
TABLE 3.
Quality of life review: St George's Respiratory Questionnaire (SGRQ) scores in patients with alpha-1 antitrypsin deficiency (AATD)
| First author, year [ref.] | Population/ treatment | Subjects n | Time point | SGRQ scores | Main SGRQ outcomes | |||
| Total | Symptoms | Activity | Impact | |||||
| B ernhard, 2017 [79] | AATD (PiZZ): never-smokers | 223 | 36.9±21.8 | 44.5±23.8 | 45.3±26.8 | 28.7±21.5 | In contrast to never- and intensive (ex-) smokers, moderate-smoking PiSZ individuals had a significantly better SGRQ total score (p=0.020) and fewer exacerbations (p=0.037) than individuals with a PiZZ genotype. | |
| AATD (PiSZ): never-smokers | 33 | 22.5±21.6 | 35.0±23.9 | 25.2±29.6 | 16.7±19.3 | |||
| AATD (PiZZ): moderate (ex-) smokers (0<pack-years<30) | 491 | 46.9±19.8 | 55.7±22.7 | 58.3±22.6 | 37.3±21.0 | |||
| AATD (PiSZ): moderate (ex-) smokers (0<pack-years<30) | 44 | 38.9±25.6 | 43.3±28.2 | 48.8±30.4 | 29.0±24.3 | |||
| AATD (PiZZ): intensive (ex-) smokers (≥30 pack-years) | 126 | 53.2±16.5 | 62.8±19.7 | 67.5±18.1 | 41.9±18.7 | |||
| AATD (PiSZ): intensive (ex-) smokers (≥30 pack-years) | 33 | 59.8±19.0 | 62.1±20.7 | 71.6±20.1 | 49.2±22.3 | |||
| P iitulainen, 2017 [80] | AATD (PiZZ): never-smokers | 152 | 3.7 (0–56.3) | 2.5 (0–78.4) | 6.0 (0–59.5) | 0 (0–47.6) | PiZZ current smokers had a significantly higher median SGRQ activity score than the PiZZ never-smokers (p=0.032).# PiMM current smokers had significantly higher SGRQ activity (p<0.001), symptom (p<0.001) and total (p=0.001) scores than PiMM never-smokers. | |
| AATD (PiZZ): former smokers | 40 | 5.0 (0–34.4) | 7.5 (0–52.2) | 8.8 (0–41.1) | 0 (0–24.2) | |||
| AATD (PiZZ): current smokers | 19 | 14.2 (2.9–20.1) | 18.4 (5.9–36.3) | 24.6 (6.0–47.7)# | 2.8 (0–8.7) | |||
| AATD (PiSZ): never-smokers | 152 | 6.2 (61.8) | 11.8 (0–58.9) | 12.2 (0–66.9) | 0 (0–59.9) | |||
| AATD (PiSZ): former smokers | 40 | 4.7 (2.0–7.3) | 5.5 (0–18.4) | 12.2 (6.0–18.5) | 0 (0–0) | |||
| AATD (PiSZ): current smokers | 19 | 13.9 | 37.8 | 18.5 | 14.2 | |||
| L uisetti, 2015 [81] | AATD | 52 | Baseline | 29.8±26.3 | Patients who received AAT therapy had poorer baseline QoL versus patients who did not receive AAT therapy (p=0.001). | |||
| AATD index cases | 35 | Baseline | 41.2±24.4 | |||||
| AATD non-index cases | 17 | Baseline | 6.3±8.3 | |||||
| AATD + AAT therapy | 18 | Baseline | 52.7±20.6 | |||||
| AATD without AAT therapy | 19 | Baseline | 28.0±21.8 | |||||
| G auvain, 2015 [76] | AATD | 273 | Baseline | 49.0±20.0 | 52.5±22.0 | 63.6±22.3 | 39.4±22.2 | The number of exacerbations in the past year was significantly associated with SGRQ score (R=0.36; p<0.0001) and SGRQ scores had the strongest association with dyspnoea (R=0.65; p<0.0001). Multivariate analysis suggested that 57% of the variability seen in SGRQ scores resulted from dyspnoea (p<0.0001), DLCO (% predicted) (p<0.001), chronic bronchitis (p=0.002), age (p=0.0088) and 6-min walk distance (p=0.037). |
| AATD: females | 101 | Baseline | 52.7±20.7 | |||||
| AATD: males | 172 | Baseline | 46.8±18.2 | |||||
| B radi, 2015 [82] | AATD + AAT therapy | 24 | 1 year | 50±14 | AAT therapy status was significantly correlated with SGRQ scores when controlling for baseline FEV1 (p=0.014). | |||
| AATD without AAT therapy | 34±22 | |||||||
| S tolk, 2003 [14] | AATD | 22 | Baseline | 32.4±20.1 | Changes in lung density as measured by CT scan (15th percentile point and relative area <–950 HU) were correlated with SGRQ total scores (R= –0.56, p=0.007 and R=0.6, p=0.003, respectively). | |||
| AATD | 22 | 30 months | CFB: 6.5 (–2.9–17.5) | |||||
| A nnunziata, 2021 [73] | AATD | 16 | Baseline | 18.0±3.0 | All the questionnaires completed at 3 months showed an increase in score compared with the questionnaire completed during the last hospital administration session (p<0.01). | |||
| AATD | 16 | 3 months | 22.6±3.3 | |||||
| S chramm, 2020 [83] | AATD (PiZZ) | 84 | 12.0 | 14.0 | 18.8 | 7.3 | There was no significant difference in SGRQ score between PiZZ ever-smokers and never-smokers, but PiZZ ever-smokers had significantly higher scores in all categories compared with never-smoking controls (symptom p=0.04, activity p=0.01, impact p=0.03, total p<0.01). | |
| Never-smoking control | 72 | 3.8 | 4.5 | 7.8 | 1.0 | |||
| S andhaus, 2020 [84] | AATD (PiZZ or worse) + AAT therapy | 655 | Annual worsening of SGRQ total was on average 1.3 points per year worse in control group patients versus those receiving AAT therapy (95% CI 0.41–2.19, p=0.004). | |||||
| AATD without AAT therapy | 655 | |||||||
| C rossley, 2020 [85] | AATD | 187 | 45.2 (3.3–62.1) | Median SGRQ score was 45.2 (33.3–62.1) and related to the GOLD stage (p<0.001). There were significant correlations between QoL measures and spirometry, as measured by FEV1 (% predicted), FVC (% predicted), FEV1/FVC (%) and with gas transfer coefficient (% predicted) and gas trapping as measured by RV/TLC (%) (p<0.01 all comparisons). Total SGRQ correlated significantly with CT density, although the relationship was weak (r2<0.1). | ||||
| AATD plus COPD or emphysema | ||||||||
| Hogarth, 2019 [86] | AATD + severe emphysema | 20 | Baseline | 55.2±16.0 | After 6 months, SGRQ had decreased substantially compared with baseline in patients fitted with an endobronchial valve. | |||
| 20 | 6 months | CFB: –14.3±12.9 | ||||||
| 20 | 12 months | CFB: –8.2±12.9 | ||||||
| Durkan, 2019 [87] | AATD + COPD | 30 | NR | 36.5±18.5 | 42.4±41.6 | 24.9±17.3 | For the same level of COPD impairment, PiZZ patients presented with lower SGRQ scores than PiMM patients. | |
| Stockley, 2018 [88] | AATD (without obstruction) | 84 | Baseline | 14.0 (4.8–5.5) | 30.9 (11.7–57.1) | 12.2 (0–41.6) | 5.8 (0–21.4) | Baseline SGRQ scores were correlated with baseline FEV1 in patients with AATD with or without COPD (r2=0.34, p<0.0001). Annual SGRQ decline was greater for patients with AATD diagnosed with COPD who had a rapid FEV1 decline. |
| AATD + COPD | 370 | Baseline | 48.2 (33.9–62.4) | 62.5 (46.2–78.6) | 60.4 (47.4–79.7) | 34.9 (21.3–49.9) | ||
| AATD with no FEV1 decline | 35 | Baseline | 16.2 (4.8–35.5) | 35 (11.7–57.1) | 23.3 (0–41.6) | 11.2 (0–21.4) | ||
| AATD with FEV1 decline | 22 | Baseline | 11.5 (33.9–62.4) | 30.5 (46.2–78.6) | 11.7 (47.4–79.7) | 5.3 (21.3–49.9) | ||
| AATD + COPD with no FEV1 decline | 72 | Baseline | 51.8 (35.0–63.3) | 62.4 (51.5–78.1) | 66.6 (47.7–80.9) | 35.6 (22.3–49.5) | ||
| AATD + COPD with FEV1 decline | 189 | Baseline | 45.2 (30.5–61.5) | 60.5 (42.9–74.6) | 59.5 (41.4–79.9) | 34.1 (17.0–47.2) | ||
| AATD (without obstruction) | 84 | Annual decline | 0.2 (–0.8–1.1) | 0.00 (−2.5–2.0) | 0.00 (−0.8–1.4) | 0.14 (−0.5–0.9) | ||
| AATD + COPD | 370 | Annual decline | 0.7 (–0.8–2.4) | 0.21 (−2.3–2.1) | 1.2 (−0.5–3.6) | 0.4 (−1.1–2.2) | ||
| AATD with no FEV1 decline | 35 | Annual decline | 0.04 (–0.7–0.8) | –0.2 (–3.0–1.6) | 0.05 (–1.4–1.3) | 0.03 (–0.6–0.7) | ||
| AATD with FEV1 decline | 22 | Annual decline | 0.5 (–1.0–1.9) | 0.9 (–1.5–2.3) | 0.9 (0.0–3.0) | 0.3 (–1.0–1.3) | ||
| AATD + COPD with no FEV1 decline | 72 | Annual decline | 0.5 (–0.8–1.5) | –0.2 (–1.9–1.3) | 0.7 (–0.4–2.3) | 0.1 (–0.9–1.5) | ||
| AATD + COPD with FEV1 decline | 189 | Annual decline | 1.07 (–1.1–2.9) | 0.5 (–2.6–2.7) | 1.5 (–0.5–4.3) | 0.7 (–1.0–3.0) | ||
| Karl, 2017 [75] | AATD + COPD | 131 | NR | 44.8±17.2 | No significant differences in SGRQ scores were observed between patients with AATD diagnosed with COPD who were recipients and non-recipients of AAT therapy. | |||
| AATD + COPD + AAT therapy | 106 | NR | 46.6±16.4 | |||||
| AATD + COPD without AAT therapy | 25 | NR | 37.5±20.2 | |||||
| Chapman, 2015 [12] | AATD + emphysema + A1P1 therapy | 93 | Baseline | 44.3±17.1 | 46.5±22.7 | 62.1±18.6 | 33.6±18.4 | Improvements were reported in only the SGRQ symptom domain after 24 months of treatment. |
| AATD + emphysema + placebo | 87 | Baseline | 42.4±18.0 | 44.1±24.8 | 60.1±21.4 | 31.4±17.6 | ||
| AATD + emphysema + AAT therapy | 93 | 24 months | CFB: 1.4±11.1 | CFB: –1.4±16.7 | CFB: 1.7±12.4 | CFB: 2.1±14.8 | ||
| AATD + emphysema + placebo | 87 | 24 months | CFB: 2.2±11.7 | CFB: 2.0±20.1 | CFB: 2.6±13.5 | CFB: 1.8±12.5 | ||
| Ponce, 2014 [89] | AATD + COPD | 573 | Baseline | 46.0±17.8 | Poorer SGRQ scores were observed in obese versus non-obese AATD patients diagnosed with COPD. | |||
| AATD + COPD | 573 | 5 years | 51.0±17.7 | |||||
| Holm, 2013 [90] | AATD + COPD | 578 | 48.5±19.4 | AATD patients diagnosed with COPD had an SGRQ total score almost 5 points higher than non-AATD patients diagnosed with COPD when adjusting for demographic and health characteristics. | ||||
| Lascano, 2010 [91] | AATD + COPD + AAT therapy: overweight | 241 | 1 year | 47.2±16.0 | SGRQ scores were higher in obese patients versus patients with a normal BMI; however, the obese patients had similar FEV1 to the normal BMI group, but more comorbidity. Underweight patients had worse QoL and significantly lower FEV1 versus normal BMI individuals. | |||
| AATD + COPD + AAT therapy: obese | 104 | 1 year | 48.7±17.1 | |||||
| AATD + COPD + AAT therapy: morbidly obese | 61 | 1 year | 55.5±17.1 | |||||
| AATD + COPD + AAT therapy: normal BMI | 204 | 1 year | 43.4±16.6 | |||||
| Campos, 2009 [74] | AATD + COPD + AAT therapy | 922 | Baseline | 48.1±18.4 | Subjects with frequent exacerbations had the worst baseline HRQoL scores, as well as more physician visits, emergency room visits and hospitalisations. | |||
| AATD + COPD + AAT therapy; no exacerbations | 83 | Baseline | 37.3±17.3 | 33.1±43.5 | 57.5±23.4 | 27.0±16.5 | ||
| AATD + COPD + AAT therapy; 1–2 exacerbations per year | 391 | Baseline | 44.5±16.6 | 43.0±22.1 | 64.1±21.2 | 33.6±16.5 | ||
| AATD + COPD + AAT therapy; ≥3 exacerbations per year | 448 | Baseline | 52.4±16.5 | 54.0±21.4 | 71.0±20.5 | 41.2±17.6 | ||
| Dawkins, 2009 [92] | AATD + COPD with fast FEV1 decline | 33 | 49.6±20.1 | SGRQ total scores in fast decliners as measured by FEV1 were not significantly different from middle or slow decliners. | ||||
| AATD + COPD with middle FEV1 decline | 34 | 56.2±18.5 | ||||||
| AATD + COPD with slow FEV1 decline | 34 | 51.6±24.7 | ||||||
| AATD with other comorbidity | ||||||||
| Stone, 2016 [93] | AATD + lung transplant | 32 | Baseline | 64.2±2.5 | 75.4±2.5 | 93 (73–95) | 50.1±2.9 | Pre-transplant, although matched for FEV1, the transplant group had worse health status. Post-transplant, physiology and health status improved significantly (p<0.002). |
| AATD + no transplant | 48 | Baseline | 55.3±2.0 | 67.4±2.2 | 79 (59–91) | 40.3±2.4 | ||
| AATD + pre-transplant | 14 | Baseline | 67.5 (51.0–77.8) | 76.5 (64.5–88.5) | 93.0 (4.8–98.3) | 50.0 (31.3–65.5) | ||
| AATD + post-transplant | 14 | 1 year | 7.5 (5.0–13.8) | 14.0 (9.0–30.3) | 11.0 (1.3–20.3) | 4.5 (1.0–9.5) | ||
| Dowson, 2002 [78] | AATD with chronic sputum expectoration | 50 | 64.4 (48.3–74.4) | 75.6 (68.0–83.7) | 82.9 (60.4–100) | 49.9 (33.0–62.7) | Patients with chronic sputum expectoration had worse health status, as assessed by SGRQ (p<0.01 for all domains), than patients who did not. | |
| AATD without chronic sputum expectoration | 67 | 42.0 (23.9–59.5) | 47.6 (28.9–66.7) | 59.5 (32.7–86.3) | 28.9 (11.7–47.6) | |||
Data are presented as mean±sd or median (range), unless otherwise stated. PiSZ/ZZ: Pi (or SERPINA1 gene) SZ and ZZ alleles; AAT: alpha-1 antitrypsin; QoL: quality of life; DLCO: diffusing capacity of the lung for carbon monoxide; FEV1: forced expiratory volume in 1 s; CFB: change from baseline; CT: computed tomography; GOLD: Global Initiative for Chronic Obstructive Lung Disease; FVC: forced vital capacity; RV: residual volume; TLC: total lung capacity; NR: not reported; A1P1: α1 proteinase inhibitor; BMI: body mass index; HRQoL: health-related QoL. #: p=0.032 versus PiZZ never-smokers.
Two of the 30 included studies were randomised controlled trials. One of these studies evaluated AAT therapy which used the SGRQ [12] and another that assessed endobronchial valves in patients with AATD which used the SGRQ, mMRC and CAT [86]. The overall STROBE scores [22] among the remaining 24 studies are shown in supplementary table S3.
SGRQ scores (table 3) tended to be worse in patients with AATD who were diagnosed with COPD at baseline versus those with AATD, but without COPD at baseline [12, 88, 90] and in those with frequent exacerbations versus those without [74].
In addition, SGRQ scores were better in patients who never smoked compared with current or former smokers [79, 80, 83]. Several studies examined correlations between SGRQ score, lung function and other measures of physiological decline in AATD [14, 76, 82, 85, 88, 89, 91, 92], while others evaluated the impact of treatment on SGRQ score (table 3 and supplementary table S2) [12, 75, 81, 82].
Finally, a study reported worse QoL among patients with AATD diagnosed with chronic sputum expectoration versus those without chronic sputum expectoration [78].
Among studies reporting CAT scores, one reported similar scores between AATD patients diagnosed with COPD and a non-AATD COPD cohort, despite the AATD group being significantly younger, and having significantly fewer pack-years of smoking and significantly less comorbidity [77]. Regression analysis to assess the relationship between CAT scores and FEV1 showed that the relationship approached statistical significance in the group of AATD patients diagnosed with COPD [77]. A second study reported no significant differences in CAT scores between patients with COPD who were receiving AAT therapy versus those who were not (supplementary table S4) [75].
Other disease-specific measures were reported in several studies. One study reported no differences in LCOPD scores between AATD patients diagnosed with COPD and patients with general COPD (7.2 versus 7.9, p=0.60) [77]. Linear regression analysis showed a significant correlation between FEV1 (%) and LCOPD in both groups with a stronger relationship in AATD patients diagnosed with COPD (r2=0.252, p=0.002 versus r2=0.092, p=0.017 for general COPD) [77]. In another study, patients with AATD-related COPD were found to have a similar level of QoL impairment to patients with AATD and non-AATD-related COPD, but there was no correlation between CRQ scores and FEV1 over time [94].
Six studies evaluated QoL in patients with AATD diagnosed with COPD using the nonspecific SF-36 instrument [74, 87, 89, 91, 92, 95], and two studies evaluated patients with AATD and emphysema with this tool [78, 96] (supplementary tables S2 and S5) [74, 87, 89, 91, 92, 95]. Higher SF-36 scores, indicating better health status, were reported in patients with AATD diagnosed with COPD and a PiZZ genotype (n=30) compared with patients diagnosed with general COPD (n=9) who had the same COPD severity, as measured by FEV1 and DLCO [87]. Exacerbation frequency was associated with significantly poorer SF-36 scores across all domains in patients with AATD diagnosed with COPD receiving AAT therapy [74]. Better QoL was reported for patients with AATD diagnosed with COPD receiving AAT therapy (pulmonary rehabilitation) compared with patients with non-AATD-related COPD [95]. Two studies in patients with AATD diagnosed with COPD suggested that obesity or increased body mass index (BMI) were associated with poorer QoL compared with patients with normal BMI, where obesity was associated with greater comorbidity (table 3) [89, 91]. The association of poorer QoL in patients with a BMI >30 kg·m−2 versus normal BMI was shown to be independent of FEV1 decline in one of these studies [91]. SF-36 scores improved following implementation of comprehensive pulmonary rehabilitation in patients with AATD diagnosed with emphysema awaiting lung transplant [96].
The majority of the papers identified in this review focused on physical aspects of QoL, although mental component scores were reported for the SF-36 questionnaire; most of these were baseline measurements (supplementary table S5) [74, 92, 95]. One study utilising a patient survey reported that patients with severe deficiency were found to have adverse effects on their relationships [97]. No studies within the scope of this review reported on emotional or psychological burden in patients with AATD.
There is no consensus on the difference in QoL burden in patients with AATD with COPD compared with patients with general COPD. No difference between these patient groups was reported in two studies [77, 94]. Better QoL was reported in patients with AATD with COPD versus general COPD in patients with the PiZZ AATD genotype in two studies [87, 95].
Caregiver burden
Five studies were included in the caregiver burden review (supplementary figure S3). The studies were performed in the USA [98–100], Sweden [101] and England (table 4) [102]. All studies were qualitative, with no specific instruments used to measure this burden.
TABLE 4.
Caregiver burden review: summary of included studies
| First author, year [ref.] | Study design | Country | Affected domain |
| Bruscino, 2019 [98] | Survey | USA | Anxiety, despair |
| Wienke, 2014 [99] | Registry-based study | USA | Delayed diagnosis, genetic discrimination, travel time |
| Williams, 2013 [100] | Survey | USA | Genetic discrimination, decisional burden to test |
| Mahadeva, 2013 [102] | Survey | England | Finance, routine, delayed diagnosis |
| Sveger, 1999 [101] | Prospective study | Sweden | Mental anxiety |
A review of the key issues for caregivers and family members of patients with AATD reported loss of flexibility in their work and social lives as the partner or spouse was forced to change schedules to provide care [103]. Caregivers also reported anxiety, stress and despair as a result of having to see their diagnosed family members struggling with their condition (table 4) [98, 101, 102]. In addition, some felt guilty that their genetic makeup may have been responsible for the disease in the affected family member, with many reporting fears for future generations [99, 100]. A study examining outcomes 20 years after an AATD neonatal screening programme in Sweden reported more anxiety among mothers of children with AATD than those without [101].
Financial pressure for caregivers in England was reported to result from the need to work reduced hours or taking time off work to attend medical appointments or provide care [102]. There was also concern about the lack of public and healthcare provider knowledge on AATD, as well as a lack of access to information for both patients and caregivers in the USA [99].
Economic burden
The cost and resource use review included 21 studies (supplementary figure S4): 10 were from the USA, and nine out of 21 were presented as conference abstracts. The sample size of studies ranged from five [104] to 9117 [105] patients, and the mean age of AATD patients was 48.3–64.6 years across studies. Where smoking status was reported, patients were typically former smokers (72.9–100%) (supplementary table S6). 14 studies reported the years for which costs were estimated, which ranged from 1997 to 2017 (table 5).
TABLE 5.
Economic burden review: cost and resource use associated with alpha-1 antitrypsin deficiency (AATD)
| First author, year [ref.] | Country | Subjects n | Cost-year | Healthcare cost | Healthcare resource use | Main economic burden outcomes |
| Herrera, 2021 [43] | USA | 5109 | 2017 | Median (IQR) annual total healthcare costs USD 9753 (3070–45 266) Median (IQR) total medical costs USD 4927 (1569–16 340) Median (IQR) total pharmacy costs USD 2063 (214–10 000) |
Mean±sd annual number of visits: ER visits: 0.5±2.4 Inpatient visits: 0.6±2.7 Outpatient visits: 6.4±12.1 Other visits: 2.0±7.3 |
Patients with severe AATD-related pulmonary manifestations requiring hospitalisation are substantially burdened by higher healthcare resource use. |
| Rozario, 2019 [113] | USA | NR | NR | Impact of a missed AAT therapy dose on total monthly healthcare costs (not including AAT therapy cost) With dose: USD 1862 Without dose: USD 2100 Difference: +USD 238 |
NR | The increased cost for patients with AATD who missed a dose of AATD therapy was possibly due to the higher downstream systemic healthcare costs that are associated with nonadherence to therapy. |
| Sieluk, 2018 [105] | USA | 9117 | 2017 | Annual direct costs for AAT therapy users: Total: USD 127 537 Physician visits: USD 15 064 AAT therapy: USD 82 002 |
NR | There were higher costs for AAT therapy users for all cost drivers (physician and emergency visits, inpatient stays, AAT therapy and other drugs). A consistent trend of increasing cost was observed between 1993 and 2015, although inpatient and physician visit costs remained steady over the last 10 years of the study. |
| Choate, 2019 [44] | USA | 3535 | NR | NR | Annual visits SZ versus ZZ genotypes of AATD# Primary physician visits: 3.7 versus 3.1 Lung specialist visits: 3.2 versus 2.9 Hospitalisations: 0.8 versus 0.6 |
Patients with a PiSZ genotype reported more primary physician visits (p<0.001), lung specialist visits (p<0.001) and hospitalisations (p=0.012) than patients with a PiZZ genotype. |
| Attaway, 2019 [60] | USA | 8039 | NR | NR | Hospitalisation average length of stay: 5.3 days |
There was a stable low rate of in-hospital mortality throughout the study (2004–2014). |
| Aggarwal, 2018 [109] | USA | 1493 | 2015 | Hospitalisation Overall cost per stay: USD 50 612 0–18 years: USD 120 026 18–45 years: USD 39 192 45–59 years: USD 53 118 >60 years: USD 48 613 |
Hospitalisation Mean length of stay: 5.43 days 0–18 years: 8 days 18–45 years: 4.4 days 45–59 years: 5.6 days >60 years: 5.4 days |
Higher inpatient costs in the USA were reported for adults aged ≥45 years with AATD compared with adults aged <45 years based on national inpatient data. |
| Karl, 2017 [75] | Germany | 131 | 2012 | Annual direct cost for AATD patients diagnosed with COPD (excluding AAT therapy cost¶) Patients receiving AAT therapy: EUR 7117 Patients not receiving AAT therapy: EUR 6099 Annual indirect costs (human capital approach) Patients receiving AAT therapy: EUR 18 813 Patients not receiving AAT therapy: EUR 16 171 |
AATD patients diagnosed with COPD versus those with COPD alone Outpatient visits: two-fold higher with AATD Hospitalisation: 24% versus 39% Inpatient length of stay: 2.3 versus 5.8 days Patients with AATD receiving AAT therapy versus those without Inpatient length of stay: 2.2 versus 2.7 days |
For patients with AATD in Germany, annual direct medical costs in 2012 were higher for those receiving AAT therapy than for those not on AAT therapy. The study excluded the mean annual AAT therapy cost of EUR 72 255. Indirect costs were based on a human capital approach that considered full labour costs for all sick days and premature retirement at age <65 years. |
| Greulich, 2017 [106] | Germany | 590 | NR | NR | Consultations and hospitalisation rates higher in patients with AATD than in matched patients in reference groups (COPD, emphysema or asthma) | When compared with non-AATD patients diagnosed with COPD, AATD patients had significantly more consultations. |
| Zacherle, 2015 [107] | USA | 279 | NR | Total annual healthcare costs AATD versus COPD USD 27 674 greater for AATD |
Annual visits AATD versus COPD Emergency: 58.4% versus 42.5% Inpatient: 58.0% versus 19.5% |
Higher mean annual costs were reported for AATD patients diagnosed with COPD versus those with general COPD (p<0.001); 13% of the AATD cohort were receiving AAT therapy. |
| Blanchette, 2015 [110] | USA | 684 | 2009 | Mean hospitalisation cost Age 20–39 years: USD 13 820 Age >80 years: USD 16 079 |
Mean hospital stay Age 20–39 years: 5.0 days Age >80 years: 8.2 days |
There was an increased cost for AATD inpatients versus general COPD patients (+USD 1487 per stay; p=0.0251). |
| Barros-Tizón, 2012 [111] | Spain | 127 | NR | Hospitalisation cost before AAT therapy use versus after Savings per patient: EUR 417 Savings in patients with exacerbations: EUR 907 |
Hospitalisation with versus without AAT therapy Length of stay with no exacerbations: 3.0 versus 3.9 days Length of stay with exacerbations: 4.6 versus 6.7 days |
There were substantial hospitalisation-derived cost savings in patients who were treated with AAT therapy. |
| Dye, 2011 [112] | Australia | 558 | 2007–2008 | Direct cost Hospitalisation per patient: USD 36 764 Per admission: USD 7145 |
Hospital admissions 5.14 per patient over 6 years |
AATD was reported to be one of the most expensive single-gene and chromosome disorders evaluated in this study. |
|
Mullins, 2003 [114];
Mullins, 2001 [115] |
USA | 688 | 1998 | Direct costs associated with treatment+, physician visits, emergency department visits and hospitalisation Annual: USD 36 471 PiZZ: USD 38 632 Non-PiZZ: USD 30 604 |
Physician visits: 8.5 per year | Self-reported medical costs were higher for patients with a PiZZ genotype versus non-ZZ individuals. AAT therapy was the major driver of self-reported cost. |
| 1997–1999 | Total annual healthcare costs associated with all medical visits, medications, and all other expenditures (e.g. emergency department visits) PiZZ: USD 30 948 Non-PiZZ: USD 20 673 |
NR | Annual healthcare costs for patients with ZZ AATD were high versus non-ZZ, whether they were receiving augmentation therapy or not. | |||
| Piitulainen, 2003 [104] | Sweden | 5 | 2002 | Annual direct cost associated with AAT therapy Tailored dose: SEK 1 560 400 Standard dose: SEK 2 600 000 |
NR | Tailored pharmacokinetic dosing of human AAT reduces the total annual dose and cost of i.v. AAT therapy. |
| Stoller, 2000 [116] | USA | 712 | 1997–1999 | NR | Resource use (number of physician visits) | The mean±sd number of physician visits reported by patients with AATD was 7.8±9.4 per year. |
| Stone, 2020 [117] | USA | 1258 | 2011–2017 | After adjustment, compared with pre-diagnosis (USD 24 782±161 896), median±sd total healthcare costs were USD 9962 greater (USD 34 744±80 792; p<0.05) in year 1 post-diagnosis; USD 3703 less (USD 21 079±51 186; p>0.05) in year 2; and USD 12 567 less (USD 12 215±46 594; p>0.05) in year 3 Adjusted median±sd medical costs in the pre-diagnosis year were USD 10 825±89 936; USD 2304 greater (USD 13 129±52 953); p>0.05) in year 1; USD 791 less (USD 10 034±26 600; p<0.05) in year 2; and USD 5186 less (USD 5639±9838; p<0.05) in year 3 |
Adjusted median±sd number of inpatient events per patient in the pre-diagnosis year were 0.34±0.75; 26% less (0.27±0.58; p<0.05) in year 1; 240% less (0.10±0.42); p<0.05) in year 2; and 340% less (0.00±0.35; p<0.05) in year 3 post-diagnosis | Healthcare costs increased in the first year following diagnosis of AATD; however, they decreased in subsequent years, primarily due to the reduction of inpatient admissions and medical costs. |
| Sieluk, 2020 [108] | USA | 8881 | 2000–2017 | Adjusted total all-healthcare cost ratios for AATD patients diagnosed with COPD versus controls were 2.04 (95% CI 1.60–2.59) and 1.98 (95% CI 1.55–2.52), while the incremental cost difference totalled USD 6861 (95% CI 3025–10 698) and USD 5772 (95% CI 1940–9604) per patient before and after the index date, respectively | AATD patients diagnosed with COPD had higher expenditures and use of office visits and other services, as well as office visits, outpatient, ER and prescription drugs before and after the index date, respectively | 12 months before and after their initial COPD diagnosis, patients with AATD incurred higher healthcare utilisation costs that were double the cost of similar COPD patients without AATD. Increased costs of AATD-associated COPD were not solely attributable to AAT therapy use. |
| Rueda, 2020 [118] | USA | 6832 | 2010–2015 | The introduction of a DMP was estimated to decrease costs of the management of patients with AATD by USD 13.5 million over 5 years | The savings attributed to the programme were due to 2555 exacerbations, 5180 ER visits, 9342 specialist visits and 105 358 GP visits avoided | A comprehensive DMP for a rare condition might provide cost savings to a health plan. BIAs for rare disease may be more informative if they focus on DMPs rather than on individual drugs. |
| Borget, 2020 [119] | France | 365 | 2014–2017 | Mean annual cost per patient was EUR 13 680 (excluding AAT therapy) driven by ambulatory-related costs (45%) and hospital-related costs (35%). Paid sick time represents 20% of the total annual cost. | This was the first study to evaluate the number of patients treated and the economic burden of AATD in France. | |
| Sieloff, 2021 [120] | USA | 2002–2014 | In 2014, hospitalisation costs adjusted to 2020 dollars for AATD was USD 108 million relative to all annual NIS discharges | AATD was associated with the greatest number of hospitalisations of all the genetic liver diseases over the 12-year study period for both NACLD and NALC. | ||
| Lee, 2020 [121] | USA | 1872 AATD-related cirrhosis, 7488 non-AATD-related cirrhosis | 2011–2017 | Hospitalisation costs for AATD-related cirrhosis versus non-AATD-related cirrhosis (USD 72 406 versus USD 59 386; p=0.38) | There was no difference in hospitalisation costs for AATD-related cirrhosis versus non-AATD-related cirrhosis. |
IQR: interquartile range; ER: emergency room; NR: not reported; AAT: alpha-1 antitrypsin; PiSZ/ZZ: Pi (or SERPINA1 gene) SZ and ZZ alleles; i.v.: intravenous; DMP: disease management programme; GP: general practitioner; BIA: budget impact analysis; NIS: National Inpatient Sample; NACLD: nonalcoholic chronic liver disease; NALC: nonalcoholic liver cirrhosis. #: a greater proportion of ZZs than SZs received AAT therapy (93.5% versus 87.1%, p<0.001); ¶: total direct costs do not include AAT therapy costs; +: values given as 1998 USD.
Resource use overall was higher in patients with AATD diagnosed with COPD versus those with general COPD [75, 106–108] and those with more severe disease [43]. AlphaNet's Disease Management and Prevention Program in the USA reported greater resource use (primary care, lung specialist visits and hospitalisation) for patients with PiSZ versus PiZZ genotypes who had lung disease, but the authors noted that this may have been due to the latter having better adherence to management recommendations and maintaining a healthier lifestyle [44].
Across studies, the mean length of hospital stay ranged from 2.3 to 8.2 days [60, 75, 109–112] (table 5 [43, 44, 60, 75, 104–121]). The hospitalisation rate and length of stay increased with age [109, 110].
The annual direct medical cost for patients with AATD in the USA was estimated to be USD 127 537 for users of AAT therapy versus USD 15 874 for nonusers [105]. A second US study reported that the median annual total healthcare costs were USD 9753, and the median total medical costs were USD 4927 and total pharmacy costs were USD 2063, although the proportion of patients receiving AAT therapy was not reported [43] (table 5). In Germany, the mean annual direct medical costs per patient were EUR 6099 for users of AAT therapy versus EUR 7117 for nonusers, excluding costs for AAT therapy [75].
Discussion
This review summarises the available evidence on various facets of disease burden in patients with AATD. Based on the studies reviewed, the evidence suggests that AATD is a significant burden for patients, caregivers and healthcare systems. However, the included studies differed greatly in their sample sizes, populations, observational periods, designs, measures and outcomes, making meta-analysis or cross-study comparisons and generalisations difficult.
Many studies in this review included <100 patients, which is expected given the rarity of AATD, and study follow-up also tended to be relatively short, with many prospective studies assessing patients for ≤1 year. Only the larger registries [25, 26, 122] or retrospective, population-based studies [43, 60, 64, 109] were able to include a robust sample size and consider a longer time frame. Moreover, many studies were published only as conference abstracts, particularly those discussing the clinical burden (20 out of 40 studies) and economic burden (nine out of 21), limiting the details available for analysis. Approximately half of all the papers included in this review were published in 2015 or later, particularly those that discussed clinical burden, of which only six studies of clinical burden were published before 2015. Other publications that discussed QoL and costs were ⩾10 years old, with some published in the 1990s. Therefore, the standards of care that are discussed are likely to be outdated. In addition, standards of care and medical costs vary regionally and between countries, making it particularly difficult to compare studies from the USA and Europe that report resource use and costs.
Patients with AATD typically develop pulmonary and hepatic morbidity, and our review suggests that this represents a considerable clinical burden. Among studies reporting lung morbidity in AATD, COPD and emphysema were common (occurring in up to 76% and 54% of patients, respectively). Unsurprisingly, smoking was identified as a key risk factor for the development of lung morbidity in patients with AATD. However, a single study suggested an increased risk of lung cancer in never-smokers with AATD [36]. Fibrosis was the most common liver complication in the studies reviewed here. Risk factors associated with liver fibrosis included male sex, diabetes and age >50 years. Panniculitis is a rare AATD comorbidity that was reported in <1% of patients in two studies reviewed here, whereas in a third study 8.6% of PiZZ patients had skin conditions including panniculitis [25, 37, 44]. The reason for the relatively high prevalence in the third study appears to be the reporting of panniculitis within a general comorbidity of “skin conditions” [44]. There was little consistency between the reporting of mortality rates between the studies [60, 61, 64] (table 2). Mortality data that are derived from index cases of AATD often indicate higher mortality rates compared with the general population; however, the data are difficult to interpret because severely affected individuals are systematically over-represented in registries. Survival was shown to be prolonged among patients with AATD and lung disease who received AAT therapy [68]; however, among never-smokers, there may not be any difference in survival for individuals with a PiZZ genotype versus the general population [69, 71].
Studies reporting QoL in individuals with AATD were heterogeneous, with a variety of disease-specific and generic instruments used across studies. While most studies used the SGRQ, a QoL questionnaire developed for respiratory diseases, many studies used generic QoL measures, including the SF-36, which do not account for parameters that may be unique to patients with AATD, such as having to receive weekly infusions of AAT therapy. Other disease-specific measures that assess dyspnoea and are predictive of survival in COPD, such as the CAT, CRQ and LCOPD scales, were reported in only a few studies. Among studies that used the SGRQ (table 3) and had baseline results, most reported a total mean score >40, indicating moderate impairment of QoL in patients with AATD. In general, worse QoL outcomes were reported for patients with AATD diagnosed with COPD than for patients diagnosed with general COPD, and for current smokers versus never-smokers or former smokers. No studies within the scope of this review reported on emotional or psychological burden in patients with AATD.
Tools used to measure the impact and progression of AATD, including pulmonary function tests (e.g. FEV1) and QoL instruments (e.g. SGRQ) are not sensitive to the small changes that occur over clinically feasible trial periods of 1–3 years in a disease that typically progresses over decades [2, 88]. Trials aimed at detecting a treatment effect over periods of >3 years are impractical to conduct due to the ethical concerns of prolonged placebo exposure and patient retention. Moreover, standards of care could change during study conduct, confounding data interpretation. Recruiting a large enough number of patients, e.g. >1000, to overcome the insensitivity of the measurements is also unfeasible in AATD, given its rarity [123]. The European Respiratory Society statement on AATD reported that a sample size of 550 per treatment group over 3 years would be needed to examine FEV1 decline as an outcome [2]. In addition, data from the UK AATD registry indicated that in order to detect the minimal clinically important difference in SGRQ (a four-point increase), a sufficiently powered, placebo-controlled trial of up to 8 years’ duration would be needed. In addition, this study determined that >8000 patients per treatment arm would be required to detect a 25% reduction in SGRQ score [88].
Patients with AATD and rapid FEV1 decline had worse QoL than those with slower FEV1 decline in one large study (n=772), but not in a second smaller study (n=101) [88, 92]. Clinical disease burden and QoL are likely to be influenced by the rate at which the disease progresses, the sensitivity of progression measurements and the time at which a diagnosis is finally given. Some patients with AATD have been reported to be “fast decliners”, as measured by CT lung density [13] and FEV1 [124]. However, the minimum clinically important difference for either of these outcomes in patients with AATD has not been established [13, 14, 88, 125–128].
Our review suggests that patients with AATD who have frequent exacerbations (≥3 per year) or chronic sputum expectoration have a poorer QoL than patients without [74], and that SGRQ scores may be significantly correlated with both exacerbations and dyspnoea [76]. Exacerbations are often associated with long-term sequelae including significant, permanent loss of lung function [26, 129, 130]. However, exacerbations are random events that are driven by infections and outcomes can vary substantially. The clinical trials conducted so far with either intravenous or inhaled AAT therapy showed inconclusive results in terms of prevention of exacerbations, which may be due to lack of power (or similar) [126, 131]. However, it is important to note that in these studies the event rate and sample sizes were limited, and no plausible mechanism linking the effect to AAT therapy was confirmed.
Our literature search identified limited evidence describing the impact of AATD on the life of caregivers, with only five published studies [98–102]. All studies were qualitative, and no specific instruments were used to measure the burden. This review suggests that caregivers of family members with AATD experience disruption to previously established routines and experience stress and anxiety.
Estimates of the total direct healthcare cost of AATD reviewed here came mainly from the USA and suggested median annual costs of USD 9753 excluding AAT therapy [43]. In Europe, annual costs were approximately EUR 1000 higher for patients who received AAT therapy versus those who did not [75]. The major direct cost drivers were AAT therapy, physician visits and inpatient stays. Little information was available on costs from other countries, making comparisons difficult. Only one study from Germany [75] attempted to estimate indirect costs, highlighting the need for further studies. Resource-use data suggest more annual visits, consultations and longer stays for patients with AATD compared with patients with general COPD and for patients with more severe AATD.
Disease burden is typically measured by the frequency of specific outcomes in a patient population, whether it is change in lung function, QoL or prevalence of a specific morbidity. Only registries can accurately capture such “big data” for AATD. While registries have existed historically, they were mainly national entities that were not centrally coordinated and as a result were not well harmonised in terms of the measurements used and the data collected [132]. Our review found wide variation in the clinical burden and other outcomes for patients with AATD across studies, highlighting the need for more thorough analyses with more consistent measures.
Implications for future research
This review illustrates the difficulties with drawing consistent and meaningful conclusions based on small, variable population samples and study designs. This has serious clinical consequences, as characterising efficacy and safety profiles of treatments is complex in the absence of a clear understanding of the burden, natural history and prognosis of the disease. Hence, there is an urgent need to include all affected patients in a multinational registry based on a consistent and structured reporting framework, and patients, caregivers, healthcare professionals and researchers are urged to form multinational collaborations in order to achieve this. The European Alpha-1 Research Collaboration (EARCO) [133] is seeking to coordinate clinical sites internationally and harmonise methodologies by carrying out quality control of data collection. This registry aims to provide an understanding of the natural history of the disease, to assess the value of AAT therapy in the real world, to evaluate QoL scores and to examine genotypes. This should enable more effective comparative research into the burden of AATD supporting future clinical development, which is an ongoing challenge for rare diseases. In addition, the authors would urge researchers in the field to publish their findings in peer-reviewed journals to increase the impact and reliability of the published literature.
Conclusion
This review found that AATD is associated with a significant clinical and QoL burden, and high direct medical costs and healthcare resource utilisation when compared with the general population. However, there were inconsistencies in the data, with many studies being small, of short duration and with a variety of different measures used for the same outcomes. As a result, considerable gaps in the true burden of this disease remain.
Supplementary material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material ERR-0262-2021.SUPPLEMENT (1.1MB, pdf)
Acknowledgements
Editorial and writing support was provided by Jo Fetterman (Parexel International, Uxbridge, UK) and was funded by CSL Behring GmbH.
Provenance: Submitted article, peer reviewed.
Author contributions: All authors contributed to the study design and data interpretation, and reviewed and approved all manuscripts drafts, including the final draft.
Conflict of interest: M. Miravitlles has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Menarini, Rovi, Bial, Sandoz, Zambon, CSL Behring, Grifols and Novartis; consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, Palobiofarma SL, Spin Therapeutics, pH Pharma, Novartis, Sanofi and Grifols; and research grants from Grifols.
Conflict of interest: M. Herepath is the owner and director of Optimal Access Life Science Consulting Limited.
Conflict of interest: A. Priyendu is an employee of Parexel.
Conflict of interest: S. Sharma is an employee of Parexel.
Conflict of interest: T. Vilchez is an employee of CSL Behring.
Conflict of interest: O. Vit is an employee of CSL Behring.
Conflict of interest: M. Haensel is an employee of CSL Behring.
Conflict of interest: V. Lepage is an employee of CSL Behring.
Conflict of interest: H. Gens is an employee of CSL Behring.
Conflict of interest: T. Greulich reports personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, CSL Behring, GlaxoSmithKline and Novartis; grants and personal fees from Grifols; and grants from German Centre for Lung Research (DZL), Marburg, Germany (Deutsches Zentrum für Lungenforschung), all outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Support statement: This study was funded by CSL Behring GmbH. Funding information for this article has been deposited with the Crossref Funder Registry.
Published in volume 31, issue 163 of the European Respiratory Review on 23 March 2022; republished 31 March 2022 with minor amendments to the layout of tables 1 and 3.
References
- 1.Torres-Durán M, Lopez-Campos JL, Barrecheguren M, et al. Alpha-1 antitrypsin deficiency: outstanding questions and future directions. Orphanet J Rare Dis 2018; 13: 114. doi: 10.1186/s13023-018-0856-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Miravitlles M, Dirksen A, Ferrarotti I, et al. European Respiratory Society statement: diagnosis and treatment of pulmonary disease in alpha1-antitrypsin deficiency. Eur Respir J 2017; 50: 1700610. doi: 10.1183/13993003.00610-2017 [DOI] [PubMed] [Google Scholar]
- 3.Blanco I, Diego I, Bueno P, et al. Prevalence of α1-antitrypsin PiZZ genotypes in patients with COPD in Europe: a systematic review. Eur Respir Rev 2020; 29: 200014. doi: 10.1183/16000617.0014-2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.de Serres FJ. Worldwide racial and ethnic distribution of alpha1-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys. Chest 2002; 122: 1818–1829. doi: 10.1378/chest.122.5.1818 [DOI] [PubMed] [Google Scholar]
- 5.Ogushi F, Fells GA, Hubbard RC, et al. Z-type alpha 1-antitrypsin is less competent than M1-type alpha 1-antitrypsin as an inhibitor of neutrophil elastase. J Clin Invest 1987; 80: 1366–1374. doi: 10.1172/JCI113214 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Strnad P, McElvaney NG, Lomas DA. Alpha1-antitrypsin deficiency. N Engl J Med 2020; 382: 1443–1455. doi: 10.1056/NEJMra1910234 [DOI] [PubMed] [Google Scholar]
- 7.Kalfopoulos M, Wetmore K, ElMallah MK. Pathophysiology of alpha-1 antitrypsin lung disease. Methods Mol Biol 2017; 1639: 9–19. doi: 10.1007/978-1-4939-7163-3_2 [DOI] [PubMed] [Google Scholar]
- 8.Stoller JK, Sandhaus RA, Turino G, et al. Delay in diagnosis of alpha1-antitrypsin deficiency: a continuing problem. Chest 2005; 128: 1989–1994. doi: 10.1378/chest.128.4.1989 [DOI] [PubMed] [Google Scholar]
- 9.Karatas E, Di-Tommaso S, Dugot-Senant N, et al. Overview of alpha-1 antitrypsin deficiency-mediated liver disease. EMJ Hepatol 2019; 7: 65–79. [Google Scholar]
- 10.Rametta R, Nebbia G, Dongiovanni P, et al. A novel alpha1-antitrypsin null variant (PiQ0Milano). World J Hepatol 2013; 5: 458–461. doi: 10.4254/wjh.v5.i8.458 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Wewers MD, Casolaro MA, Sellers SE, et al. Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema. N Engl J Med 1987; 316: 1055–1062. doi: 10.1056/NEJM198704233161704 [DOI] [PubMed] [Google Scholar]
- 12.Chapman KR, Burdon JG, Piitulainen E, et al. Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 386: 360–368. doi: 10.1016/S0140-6736(15)60860-1 [DOI] [PubMed] [Google Scholar]
- 13.McElvaney NG, Burdon J, Holmes M, et al. Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE). Lancet Respir Med 2017; 5: 51–60. doi: 10.1016/S2213-2600(16)30430-1 [DOI] [PubMed] [Google Scholar]
- 14.Stolk J, Ng WH, Bakker ME, et al. Correlation between annual change in health status and computer tomography derived lung density in subjects with alpha1-antitrypsin deficiency. Thorax 2003; 58: 1027–1030. doi: 10.1136/thorax.58.12.1027 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Quinn M, Ellis P, Pye A, et al. Obstacles to early diagnosis and treatment of alpha-1 antitrypsin deficiency: current perspectives. Ther Clin Risk Manag 2020; 16: 1243–1255. doi: 10.2147/TCRM.S234377 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.McElvaney GN, Sandhaus RA, Miravitlles M, et al. Clinical considerations in individuals with α1-antitrypsin PI*SZ genotype. Eur Respir J 2020; 55: 1902410. doi: 10.1183/13993003.02410-2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Brantly M, Campos M, Davis AM, et al. Detection of alpha-1 antitrypsin deficiency: the past, present and future. Orphanet J Rare Dis 2020; 15: 96. doi: 10.1186/s13023-020-01352-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Chorostowska-Wynimko J, Barrecheguren M, Ferrarotti I, et al. New patient-centric approaches to the management of alpha-1 antitrypsin deficiency. Int J Chron Obstruct Pulmon Dis 2020; 15: 345–355. doi: 10.2147/COPD.S234646 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Parr DG, Lara B. Clinical utility of alpha-1 proteinase inhibitor in the management of adult patients with severe alpha-1 antitrypsin deficiency: a review of the current literature. Drug Des Devel Ther 2017; 11: 2149–2162. doi: 10.2147/DDDT.S105207 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339: b2700. doi: 10.1136/bmj.b2700 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.National Institute for Health and Care Excellence (NICE) . The Guidelines Manual. Process and Methods. London, National Institute for Health and Care Excellence, 2012. [Google Scholar]
- 22.Vandenbroucke JP, von Elm E, Altman DG, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Epidemiology 2007; 18: 805–835. doi: 10.1097/EDE.0b013e3181577511 [DOI] [PubMed] [Google Scholar]
- 23.Arslanow A, Reichert MC, Gatter S. Simultaneous non-invasive assessment of liver injury and body composition in alpha1-antitrypsin deficiency. J Hepatol 2017; 66: S172. doi: 10.1016/S0168-8278(17)30626-8 [DOI] [Google Scholar]
- 24.Fromme M, Schneider CV, Pereira V, et al. Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency. Gut 2022; 71: 415–423. doi: 10.1136/gutjnl-2020-323729 [DOI] [PubMed] [Google Scholar]
- 25.Tanash HA, Piitulainen E. Liver disease in adults with severe alpha-1-antitrypsin deficiency. J Gastroenterol 2019; 54: 541–548. doi: 10.1007/s00535-019-01548-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Hiller AM, Piitulainen E, Jehpsson L, et al. Decline in FEV1 and hospitalized exacerbations in individuals with severe alpha-1 antitrypsin deficiency. Int J Chron Obstruct Pulmon Dis 2019; 14: 1075–1083. doi: 10.2147/COPD.S195847 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Clark VC, Marek G, Liu C, et al. Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort. J Hepatol 2018; 69: 1357–1364. doi: 10.1016/j.jhep.2018.08.005 [DOI] [PubMed] [Google Scholar]
- 28.Chakraborty J, Perbtani YB, Shuster JJ, et al. Predictors of liver disease in adults with alpha 1 antitrypsin deficiency: a single center retrospective analysis. Am J Gastroenterol 2016; 111: S67–S68. [Google Scholar]
- 29.Costa A, Saraiva R, Asseiro M. Pulmonary disease in intermediate alpha1-antitrypsin deficient patients. Eur Respir J 2017; 50: PA706. doi: 10.1183/1393003.congress-2017.PA706 [DOI] [Google Scholar]
- 30.Basil N, Ekström M, Piitulainen E, et al. Severe alpha-1-antitrypsin deficiency increases the risk of venous thromboembolism. J Thromb Haemost 2021; 19: 1519–1525. doi: 10.1111/jth.15302 [DOI] [PubMed] [Google Scholar]
- 31.Pons M, Núñez A, Esquinas C, et al. Utility of transient elastography for the screening of liver disease in patients with alpha1-antitrypsin deficiency. J Clin Med 2021; 10: 1724. doi: 10.3390/jcm10081724 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Gupta N, Gaudreault N, Thériault S, et al. Granularity of SERPINA1 alleles by DNA sequencing in CanCOLD. Eur Respir J 2020; 56: 2000958. doi: 10.1183/13993003.00958-2020 [DOI] [PubMed] [Google Scholar]
- 33.Franciosi AN, Hobbs BD, McElvaney OJ, et al. Clarifying the risk of lung disease in SZ alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2020; 202: 73–82. doi: 10.1164/rccm.202002-0262OC [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Piras B, Ferrarotti I, Lara B, et al. Clinical phenotypes of Italian and Spanish patients with α1-antitrypsin deficiency. Eur Respir J 2013; 42: 54–64. doi: 10.1183/09031936.00104712 [DOI] [PubMed] [Google Scholar]
- 35.Esquinas C, Serreri S, Barrecheguren M, et al. Long-term evolution of lung function in individuals with alpha-1 antitrypsin deficiency from the Spanish registry (REDAAT). Int J Chron Obstruct Pulmon Dis 2018; 13: 1001–1007. doi: 10.2147/COPD.S155226 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Torres-Durán M, Ruano-Ravina A, Parente-Lamelas I, et al. Alpha-1 antitrypsin deficiency and lung cancer risk: a case-control study in never-smokers. J Thorac Oncol 2015; 10: 1279–1284. doi: 10.1097/JTO.0000000000000609 [DOI] [PubMed] [Google Scholar]
- 37.Stone H, Pye A, Stockley RA. Disease associations in alpha-1-antitrypsin deficiency. Respir Med 2014; 108: 338–343. doi: 10.1016/j.rmed.2013.10.006 [DOI] [PubMed] [Google Scholar]
- 38.Hamesch K, Mandorfer M, Pereira VM, et al. Liver fibrosis and metabolic alterations in adults with alpha-1-antitrypsin deficiency caused by the Pi*ZZ mutation. Gastroenterology 2019; 157: 705–719. doi: 10.1053/j.gastro.2019.05.013 [DOI] [PubMed] [Google Scholar]
- 39.Strnad P, Buch S, Hamesch KJ, et al. Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver fibrosis. Hepatology 2017; 66: 428A–429A. [DOI] [PubMed] [Google Scholar]
- 40.Subramanian D, Edgar R, Ward H, et al. Frequency and clinical significance of lung nodules in alpha 1-antitrypsin deficiency (AATD). Am J Respir Crit Care Med 2010; 181: A2884. doi: 10.1164/ajrccm-conference.2010.181.1_MeetingAbstracts.A2884 [DOI] [Google Scholar]
- 41.Tanash H, Ekström M, Basil N, et al. Decreased risk of ischemic heart disease in individuals with severe alpha 1-antitrypsin deficiency (PiZZ) in comparison with the general population. Int J Chron Obstruct Pulmon Dis 2020; 15: 1245–1252. doi: 10.2147/COPD.S247377 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Hiller A-M, Ekström M, Piitulainen E, et al. Risk of cancer in individuals with severe alpha-1-antitrypsin deficiency (PiZZ) compared with the Swedish general population. Eur Respir J 2020; 56: Suppl. 64, 1124. doi: 10.1183/13993003.congress-2020.1124 [DOI] [Google Scholar]
- 43.Herrera EM, Joseph C, Brouwer ES, et al. Alpha-1 antitrypsin deficiency-associated clinical manifestations and healthcare resource use in the United States. COPD 2021; 18: 315–324. doi: 10.1080/15412555.2021.1917532 [DOI] [PubMed] [Google Scholar]
- 44.Choate R, Mannino DM, Holm KE, et al. Comparing patients with ZZ versus SZ alpha-1 antitrypsin deficiency: findings from AlphaNet's disease management program. Chronic Obstr Pulm Dis 2019; 6: 29–39. doi: 10.15326/jcopdf.6.1.2018.0134 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Cortese R, Mennitti MC, Mariani F, et al. Bronchiectasis in patients with alpha1-antitrypsin deficiency: prevalence and characteristics. Eur Respir J 2016; 48: Suppl. 60, PA737. doi: 10.1183/13993003.congress-2016.PA737 [DOI] [Google Scholar]
- 46.Araújo D, Sucena M. Association between alpha 1 antitrypsin and bronchiectasis. Eur Respir J 2015; 46: PA1248. [Google Scholar]
- 47.Kawkgi O, Hamadi Y, O'Connor E, et al. The classification of the SZ phenotype of alpha-1 antitrypsin deficiency in Ireland. Ir J Med Sci 2013; 182: S439. doi: 10.1007/s11845-013-0909-y [DOI] [PubMed] [Google Scholar]
- 48.Ferrarotti I, Ottaviani S, Gorrini M, et al. Database of the Italian Registry for Alpha-1 Antitrypsin Deficiency (AATD): confirmations and controversy surrounding AATD natural history. Am J Respir Crit Care Med 2012; 185: A4358. [Google Scholar]
- 49.Guttmann C, Lepper PM, Bachhuber M, et al. Alpha1-antitrypsin deficiency: an analysis of patient subgroups of the German registry. Eur Respir J 2011; 38: 3596. [Google Scholar]
- 50.Franciosi AN, Alkhunaizi MA, Woodsmith A, et al. Alpha-1 antitrypsin deficiency and tobacco smoking: exploring risk factors and smoking cessation in a registry population. COPD 2021; 18: 76–82. doi: 10.1080/15412555.2020.1864725 [DOI] [PubMed] [Google Scholar]
- 51.Parr DG, Guest PG, Reynolds JH, et al. Prevalence and impact of bronchiectasis in alpha1-antitrypsin deficiency. Am J Respir Crit Care Med 2007; 176: 1215–1221. doi: 10.1164/rccm.200703-489OC [DOI] [PubMed] [Google Scholar]
- 52.Teckman J, Di Bisceglie A, Loomba R, et al. Clustering at the extremes of mild and severe fibrosis is seen on liver biopsy in preliminary analysis of a multi-center, prospective adult cohort of alpha-1-antitrypsin deficiency. Hepatology 2019; 70: 1173–1174. [Google Scholar]
- 53.Mandorfer M, Bucsics T, Hutya V, et al. Advanced liver fibrosis is uncommon among adults with alpha 1-antitrypsin deficiency and severe pulmonary manifestation, while heterozygosity for the z allele predisposes for clinically significant portal hypertension. Hepatology 2017; 66: 440A. [Google Scholar]
- 54.Black M, Whitsett M, Jacobson I, et al. Heterozygous alpha-1 antitrypsin deficiency potentiates liver fibrosis with other chronic liver diseases. Mod Pathol 2020; 33: 1504. [Google Scholar]
- 55.Schneider CV, Hamesch K, Gross A, et al. Liver phenotypes of European adults heterozygous or homozygous for Pi∗Z variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and noncarriers. Gastroenterology 2020; 159: 534–548. doi: 10.1053/j.gastro.2020.04.058 [DOI] [PubMed] [Google Scholar]
- 56.Hakim A, Moll M, Qiao D, et al. Heterozygosity of the alpha 1-antitrypsin Pi*Z allele and risk of liver disease. Hepatol Commun 2021; 5: 1348–1361. doi: 10.1002/hep4.1718 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Abu Rmilah A, Fencl R, Watt K, et al. Association of α 1 antitrypsin phenotype and development of advanced liver disease and pulmonary complications before and after liver transplantation. Transplantation 2021; 105: 1576–1584. doi: 10.1097/TP.0000000000003390 [DOI] [PubMed] [Google Scholar]
- 58.Sapey E, Yonel Z, Edgar R, et al. The clinical and inflammatory relationships between periodontitis and chronic obstructive pulmonary disease. J Clin Periodontol 2020; 47: 1040–1052. doi: 10.1111/jcpe.13334 [DOI] [PubMed] [Google Scholar]
- 59.Mandich N, Sweeney P, Hogarth DK. Psychiatric diagnosis and alpha one antitrypsin deficiency phenotypes. Am J Respir Crit Care Med 2011; 183: A2988. [Google Scholar]
- 60.Attaway A, Hatipoglu U, Majumdar U, et al. In-hospital mortality trends for alpha-1 antitrypsin deficiency in the United States. Am J Respir Crit Care Med 2019; 199: A3997. [Google Scholar]
- 61.Tanash HA, Ekström M, Wagner P, et al. Cause-specific mortality in individuals with severe alpha 1-antitrypsin deficiency in comparison with the general population in Sweden. Int J Chron Obstruct Pulmon Dis 2016; 11: 1663–1669. doi: 10.2147/COPD.S109173 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Tanash HA, Nilsson PM, Nilsson JA, et al. Clinical course and prognosis of never-smokers with severe alpha-1-antitrypsin deficiency (PiZZ). Thorax 2008; 63: 1091–1095. doi: 10.1136/thx.2008.095497 [DOI] [PubMed] [Google Scholar]
- 63.Stoller JK, Tomashefski J Jr, Crystal RG, et al. Mortality in individuals with severe deficiency of alpha1-antitrypsin: findings from the National Heart, Lung, and Blood Institute Registry. Chest 2005; 127: 1196–1204. doi: 10.1378/chest.127.4.1196 [DOI] [PubMed] [Google Scholar]
- 64.Browne RJ, Mannino DM, Khoury MJ. Alpha 1-antitrypsin deficiency deaths in the United States from 1979–1991. An analysis using multiple-cause mortality data. Chest 1996; 110: 78–83. doi: 10.1378/chest.110.1.78 [DOI] [PubMed] [Google Scholar]
- 65.Catterall F, Anderson D. Prevalence of alpha-1 antitrypsin deficiency (AATD) in Greater Glasgow and Clyde (GG&C) and current practises. Eur Respir J 2020; 56: 2431. doi: 10.1183/13993003.congress-2020.2431 [DOI] [Google Scholar]
- 66.Dawkins P, Wood A, Nightingale P, et al. Mortality in alpha-1-antitrypsin deficiency in the United Kingdom. Respir Med 2009; 103: 1540–1547. doi: 10.1016/j.rmed.2009.04.004 [DOI] [PubMed] [Google Scholar]
- 67.Dawkins PA, Dowson LJ, Guest PJ, et al. Predictors of mortality in alpha1-antitrypsin deficiency. Thorax 2003; 58: 1020–1026. doi: 10.1136/thorax.58.12.1020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Ellis P, Holm K, Choate R, et al. Comparison of outcomes in augmentation naïve and augmented patients with alpha-1 antitrypsin deficiency related lung disease. Eur Respir J 2019; 54: PA3383. doi: 10.1183/13993003.congress-2019.PA3383 [DOI] [Google Scholar]
- 69.Seersholm N, Kok-Jensen A, Dirksen A. Survival of patients with severe alpha 1-antitrypsin deficiency with special reference to non-index cases. Thorax 1994; 49: 695–698. doi: 10.1136/thx.49.7.695 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Tanash HA, Nilsson PM, Nilsson JA, et al. Survival in severe alpha-1-antitrypsin deficiency (PiZZ). Respir Res 2010; 11: 44. doi: 10.1186/1465-9921-11-44 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Tanash HA, Ekström M, Rönmark E, et al. Survival in individuals with severe alpha 1-antitrypsin deficiency (PiZZ) in comparison to a general population with known smoking habits. Eur Respir J 2017; 50: 1700198. doi: 10.1183/13993003.00198-2017 [DOI] [PubMed] [Google Scholar]
- 72.da Costa Dias de Sousa C, Meira L, Sucena M. Alpha-1 antitrypsin deficiency – a potentially fatal disease. Eur Respir J 2017; 50: PA4463. doi: 10.1183/1393003.congress-2017.PA4463 [DOI] [Google Scholar]
- 73.Annunziata A, Lanza M, Coppola A, et al. Alpha-1 antitrypsin deficiency: home therapy. Front Pharmacol 2021; 12: 575402. doi: 10.3389/fphar.2021.575402 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74.Campos MA, Alazemi S, Zhang G, et al. Exacerbations in subjects with alpha-1 antitrypsin deficiency receiving augmentation therapy. Respir Med 2009; 103: 1532–1539. doi: 10.1016/j.rmed.2009.04.008 [DOI] [PubMed] [Google Scholar]
- 75.Karl FM, Holle R, Bals R, et al. Costs and health-related quality of life in alpha-1-antitrypsin deficient COPD patients. Respir Res 2017; 18: 60. doi: 10.1186/s12931-017-0543-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Gauvain C, Mornex JF, Pison C, et al. Health-related quality of life in patients with alpha-1 antitrypsin deficiency: the French experience. COPD 2015; 12: Suppl. 1, 46–51. doi: 10.3109/15412555.2015.1022645 [DOI] [PubMed] [Google Scholar]
- 77.Manca S, Rodriguez E, Huerta A, et al. Usefulness of the CAT, LCOPD, EQ-5D and COPDSS scales in understanding the impact of lung disease in patients with alpha-1 antitrypsin deficiency. COPD 2014; 11: 480–488. doi: 10.3109/15412555.2014.898030 [DOI] [PubMed] [Google Scholar]
- 78.Dowson LJ, Guest PJ, Stockley RA. The relationship of chronic sputum expectoration to physiologic, radiologic, and health status characteristics in α1-antitrypsin deficiency (PiZ). Chest 2002; 122: 1247–1255. doi: 10.1378/chest.122.4.1247 [DOI] [PubMed] [Google Scholar]
- 79.Bernhard N, Lepper PM, Vogelmeier C, et al. Intensive smoking diminishes the differences in quality of life and exacerbation frequency between the alpha-1-antitrypsin deficiency genotypes PiZZ and PiSZ. Respir Med 2017; 130: 1–8. doi: 10.1016/j.rmed.2017.07.004 [DOI] [PubMed] [Google Scholar]
- 80.Piitulainen E, Mostafavi B, Tanash HA. Health status and lung function in the Swedish alpha 1-antitrypsin deficient cohort, identified by neonatal screening, at the age of 37-40 years. Int J Chron Obstruct Pulmon Dis 2017; 12: 495–500. doi: 10.2147/COPD.S120241 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81.Luisetti M, Ferrarotti I, Corda L, et al. Italian registry of patients with alpha-1 antitrypsin deficiency: general data and quality of life evaluation. COPD 2015; 12: Suppl. 1, 52–57. doi: 10.3109/15412555.2015.1023393 [DOI] [PubMed] [Google Scholar]
- 82.Bradi AC, Audisho N, Casey DK, et al. Alpha-1 antitrypsin deficiency in Canada: regional disparities in diagnosis and management. COPD 2015; 12: Suppl. 1, 15–21. doi: 10.3109/15412555.2015.1021908 [DOI] [PubMed] [Google Scholar]
- 83.Schramm G, Piitulainen E, Wollmer P, et al. Early signs of COPD in 42 years old individuals with severe alpha-1-antitrypsin deficiency. Eur Respir J 2020; 56: Suppl. 64, 2479. doi: 10.1183/13993003.congress-2020.2479 [DOI] [Google Scholar]
- 84.Sandhaus RA, Ellis P, Holm K, et al. Augmentation therapy for alpha-1 antitrypsin deficiency: improved survival and quality of life compared to matched augmentation naive controls followed for up to 15 years. Am J Respir Crit Care Med 2020; 201: A2486. doi: 10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A2486 [DOI] [Google Scholar]
- 85.Crossley D, Stockley J, Bolton CE, et al. Relationship of CT densitometry to lung physiological parameters and health status in alpha-1 antitrypsin deficiency: initial report of a centralised database of the NIHR rare diseases translational research collaborative. BMJ Open 2020; 10: e036045. doi: 10.1136/bmjopen-2019-036045 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 86.Hogarth D. Endobronchial valve treatment of severe emphysema in patients with alpha-1 antitrypsin deficiency. Chest 2019; 156: A1771. doi: 10.1016/j.chest.2019.08.1540 [DOI] [Google Scholar]
- 87.Durkan E, Carroll T, Moyna N, et al. Exercise capacity may be more strongly associated with health status in alpha-1 antitrypsin COPD patients than in alpha-1 antitrypsin replete COPD patients. Am J Respir Crit Care Med 2019; 199: A2063. doi: 10.1164/ajrccm-conference.2019.199.1_MeetingAbstracts.A2063 [DOI] [Google Scholar]
- 88.Stockley RA, Edgar RG, Starkey S, et al. Health status decline in α-1 antitrypsin deficiency: a feasible outcome for disease modifying therapies? Respir Res 2018; 19: 137. doi: 10.1186/s12931-018-0844-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89.Ponce M, Sandhaus R, Campos M. The relation of body mass index and health related quality of life in subjects with alpha 1-antitrypsin deficiency and COPD. Am J Respir Crit Care Med 2014; 189: A5782. [Google Scholar]
- 90.Holm KE, Borson S, Sandhaus RA, et al. Differences in adjustment between individuals with alpha-1 antitrypsin deficiency (AATD)-associated COPD and non-AATD COPD. COPD 2013; 10: 226–234. doi: 10.3109/15412555.2012.719049 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91.Lascano J, Salathe M, Alazemi S, et al. Relation between body mass index and health-related quality of life in subjects with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2010; 181: A4114. doi: 10.1164/ajrccm-conference.2010.181.1_MeetingAbstracts.A4114 [DOI] [Google Scholar]
- 92.Dawkins PA, Dawkins CL, Wood AM, et al. Rate of progression of lung function impairment in alpha1-antitrypsin deficiency. Eur Respir J 2009; 33: 1338–1344. doi: 10.1183/09031936.00061208 [DOI] [PubMed] [Google Scholar]
- 93.Stone HM, Edgar RG, Thompson RD, et al. Lung transplantation in alpha-1-antitrypsin deficiency. COPD 2016; 13: 146–152. doi: 10.3109/15412555.2015.1048850 [DOI] [PubMed] [Google Scholar]
- 94.Knebel AR, Leidy NK, Sherman S. Health related quality of life and disease severity in patients with alpha-1 antitrypsin deficiency. Qual Life Res 1999; 8: 385–391. doi: 10.1023/A:1008945316646 [DOI] [PubMed] [Google Scholar]
- 95.Jarosch I, Hitzl W, Koczulla AR, et al. Comparison of exercise training responses in COPD patients with and without alpha-1 antitrypsin deficiency. Respir Med 2017; 130: 98–101. doi: 10.1016/j.rmed.2017.07.009 [DOI] [PubMed] [Google Scholar]
- 96.Kenn K, Gloeckl R, Soennichsen A, et al. Predictors of success for pulmonary rehabilitation in patients awaiting lung transplantation. Transplantation 2015; 99: 1072–1077. doi: 10.1097/TP.0000000000000472 [DOI] [PubMed] [Google Scholar]
- 97.Stoller JK, Smith P, Yang P, et al. Physical and social impact of alpha 1-antitrypsin deficiency: results of a survey. Cleve Clin J Med 1994; 61: 461–467. doi: 10.3949/ccjm.61.6.461 [DOI] [PubMed] [Google Scholar]
- 98.Bruscino N. The Coping Strategies of Alpha-1 Deficient Patients and Their Family Caregivers. Walden Dissertations and Doctoral Studies: Walden University, 2019. https://scholarworks.waldenu.edu/dissertations/7275
- 99.Wienke S, Strange C, Walker D, et al. Social impact identified in and by the alpha-1 antitrypsin deficiency community. Rare Dis Orphan Drugs 2014; 1: 75–82. [Google Scholar]
- 100.Williams PH, Shore L, Sineath M, et al. Genetics’ influence on patient experiences with a rare chronic disorder: a photovoice study of living with alpha-1 antitrypsin deficiency. Nurs Clin North Am 2013; 48: 627–636. doi: 10.1016/j.cnur.2013.09.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 101.Sveger T, Thelin T, McNeil TF. Neonatal alpha1-antitrypsin screening: parents’ views and reactions 20 years after the identification of the deficiency state. Acta Paediatr 1999; 88: 315–318. doi: 10.1080/08035259950170097 [DOI] [PubMed] [Google Scholar]
- 102.Mahadeva R. Alpha-1 Alliance. Alpha-1 Antitrypsin Deficiency Policy Report. England. 2013. https://alpha1.org.uk/alpha-1-alliance/ Date last accessed: 15 August 2021.
- 103.Anzueto A. Alpha-1 antitrypsin deficiency-associated chronic obstructive pulmonary disease: a family perspective. COPD 2015; 12: 462–467. doi: 10.3109/15412555.2014.974746 [DOI] [PubMed] [Google Scholar]
- 104.Piitulainen E, Bernspång E, Björkman S, et al. Tailored pharmacokinetic dosing allows self-administration and reduces the cost of IV augmentation therapy with human α1-antitrypsin. Eur J Clin Pharmacol 2003; 59: 151–156. doi: 10.1007/s00228-003-0589-z [DOI] [PubMed] [Google Scholar]
- 105.Sieluk J, Levy J, Sandhaus RA, et al. Costs of medical care among augmentation therapy users and non-users with alpha-1 antitrypsin deficiency in the United States. Chron Obstr Pulm Dis 2018; 6: 6–16. doi: 10.15326/jcopdf.6.1.2017.0187 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 106.Greulich T, Nell C, Hohmann D, et al. The prevalence of diagnosed α1-antitrypsin deficiency and its comorbidities: results from a large population-based database. Eur Respir J 2017; 49: 1600154. doi: 10.1183/13993003.00154-2016 [DOI] [PubMed] [Google Scholar]
- 107.Zacherle E, Noone JM, Runken MC, et al. Health care cost and utilization associated with alpha-1 antitrypsin deficiency among a cohort of medicare beneficiaries with COPD. Value Health 2015; 18: A664. doi: 10.1016/j.jval.2015.09.2419 [DOI] [Google Scholar]
- 108.Sieluk J, Slejko JF, Silverman H, et al. Medical costs of alpha-1 antitrypsin deficiency-associated COPD in the United States. Orphanet J Rare Dis 2020; 15: 260. doi: 10.1186/s13023-020-01523-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109.Aggarwal S, Kumar S, Topaloglu O. Trends in hospitalization length of stay and costs in patients with alpha 1 antitrypsin deficiency disorder: analysis of US national in-patient data for 2015. Value Health 2018; 21: PRS18. [Google Scholar]
- 110.Blanchette C, Noone JM, Roy D, et al. Natural progression of alpha-1 antitrypsin deficiency among hospitalized COPD patients in the US. Chest 2015; 148: 497A. doi: 10.1378/chest.2281578 [DOI] [Google Scholar]
- 111.Barros-Tizón JC, Torres ML, Blanco I, et al. Reduction of severe exacerbations and hospitalization-derived costs in alpha-1-antitrypsin-deficient patients treated with alpha-1-antitrypsin augmentation therapy. Ther Adv Respir Dis 2012; 6: 67–78. doi: 10.1177/1753465812438387 [DOI] [PubMed] [Google Scholar]
- 112.Dye DE, Brameld KJ, Maxwell S, et al. The impact of single gene and chromosomal disorders on hospital admissions in an adult population. J Community Genet 2011; 2: 81–90. doi: 10.1007/s12687-011-0043-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 113.Rozario N, Blanchette C, Howden R, et al. The effect of missing a specialty medication dose on total healthcare cost burden. Value Health 2019; 22: S168. doi: 10.1016/j.jval.2019.04.712 [DOI] [Google Scholar]
- 114.Mullins CD, Wang J, Stoller JK. Major components of the direct medical costs of α1-antitrypsin deficiency. Chest 2003; 124: 826–831. doi: 10.1378/chest.124.3.826 [DOI] [PubMed] [Google Scholar]
- 115.Mullins CD, Huang X, Merchant S, et al. The direct medical costs of α1-antitrypsin deficiency. Chest 2001; 119: 745–752. doi: 10.1378/chest.119.3.745 [DOI] [PubMed] [Google Scholar]
- 116.Stoller JK, Brantly M, Fleming LE, et al. Formation and current results of a patient-organized registry for α1-antitrypsin deficiency. Chest 2000; 118: 843–848. doi: 10.1378/chest.118.3.843 [DOI] [PubMed] [Google Scholar]
- 117.Stone GA, Blanchette CM, Stranton D, et al. Healthcare cost and utilization before and after diagnosis of alpha-1 antitrypsin deficiency in the United States. Am J Respir Crit Care Med 2020; 201: A6275. doi: 10.1164/rccm.202001-0089LE [DOI] [Google Scholar]
- 118.Rueda JD, Sieluk J, Sandhaus RA, et al. Limitations and challenges of conducting budget impact analyses in rare diseases: a case study of alpha-1 antitrypsin deficiency. Value Health Reg Issues 2020; 23: 70–76. doi: 10.1016/j.vhri.2020.04.003 [DOI] [PubMed] [Google Scholar]
- 119.Borget I, Willemin MC, Pison C, et al. Prevalence and burden of alpha-1 antitrypsin deficiency in France: an analysis from the French National Health Database (SNDS). Value Health 2020; 23: S714. doi: 10.1016/j.jval.2020.08.1873 [DOI] [Google Scholar]
- 120.Sieloff EM, Rutledge B, Huffman C, et al. National trends and outcomes of genetically inherited non-alcoholic chronic liver disease in the USA: estimates from the National Inpatient Sample (NIS) database. Gastroenterol Rep 2021; 9: 38–48. doi: 10.1093/gastro/goaa091 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 121.Lee DU, Fan GH, Karagozian RS. S1039: The clinical outcomes of hospitalized patients with alpha-1-antitrypsin deficiency-related cirrhosis. Am J Gastroenterol 2020; 115: S528. [Google Scholar]
- 122.Alpha-1-Antitrypsin Deficiency Registry Study Group . Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. Am J Respir Crit Care Med 1998; 158: 49–59. doi: 10.1164/ajrccm.158.1.9712017 [DOI] [PubMed] [Google Scholar]
- 123.Schluchter MD, Stoller JK, Barker AF, et al. Feasibility of a clinical trial of augmentation therapy for α1-antitrypsin deficiency. The Alpha 1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med 2000; 161: 796–801. doi: 10.1164/ajrccm.161.3.9906011 [DOI] [PubMed] [Google Scholar]
- 124.Wencker M, Fuhrmann B, Konietzko N, et al. Longitudinal follow-up of patients with α1-protease inhibitor deficiency before and during therapy with IV α1-protease inhibitor. Chest 2001; 119: 737–744. doi: 10.1378/chest.119.3.737 [DOI] [PubMed] [Google Scholar]
- 125.Parr DG, Stoel BC, Stolk J, et al. Validation of computed tomographic lung densitometry for monitoring emphysema in alpha1-antitrypsin deficiency. Thorax 2006; 61: 485–490. doi: 10.1136/thx.2005.054890 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 126.Dirksen A, Piitulainen E, Parr DG, et al. Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency. Eur Respir J 2009; 33: 1345–1353. doi: 10.1183/09031936.00159408 [DOI] [PubMed] [Google Scholar]
- 127.Stolk J, Stockley RA, Piitulainen E, et al. Relationship between change in lung density and long-term progression of lung function. Am J Respir Crit Care Med 2015; 192: 114–116. doi: 10.1164/rccm.201502-0370LE [DOI] [PubMed] [Google Scholar]
- 128.Barrecheguren M, O'Hara K, Wilkens M, et al. Research priorities in α1-antitrypsin deficiency: results of a patients’ and healthcare providers’ international survey from the EARCO Clinical Research Collaboration. ERJ Open Res 2020; 6: 00523-02020. doi: 10.1183/23120541.00523-2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 129.Fähndrich S, Bernhard N, Lepper PM, et al. Exacerbations and duration of smoking abstinence are associated with the annual loss of FEV1 in individuals with PiZZ alpha-1-antitrypsin deficiency. Respir Med 2017; 129: 8–15. doi: 10.1016/j.rmed.2017.05.011 [DOI] [PubMed] [Google Scholar]
- 130.Bernhard N, Lepper PM, Vogelmeier C, et al. Deterioration of quality of life is associated with the exacerbation frequency in individuals with alpha-1-antitrypsin deficiency – analysis from the German Registry. Int J Chron Obstruct Pulmon Dis 2017; 12: 1427–1437. doi: 10.2147/COPD.S130925 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 131.Stolk J, Tov N, Chapman KR, et al. Efficacy and safety of inhaled α1-antitrypsin in patients with severe α1-antitrypsin deficiency and frequent exacerbations of COPD. Eur Respir J 2019; 54: 1900673. doi: 10.1183/13993003.00673-2019 [DOI] [PubMed] [Google Scholar]
- 132.Miravitlles M, Chorostowska-Wynimko J, Ferrarotti I, et al. The European Alpha-1 Research Collaboration (EARCO): a new ERS clinical research collaboration to promote research in alpha-1 antitrypsin deficiency. Eur Respir J 2019; 53: 1900138. doi: 10.1183/13993003.00138-2019 [DOI] [PubMed] [Google Scholar]
- 133.Greulich T, Altraja A, Barrecheguren M, et al. Protocol for the EARCO Registry: a pan-European observational study in patients with α1-antitrypsin deficiency. ERJ Open Res 2020; 6: 00181-02019. doi: 10.1183/23120541.00181-2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material ERR-0262-2021.SUPPLEMENT (1.1MB, pdf)