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Disease burden associated with alpha-1 antitrypsin deficiency: systematic and structured literature reviews

Marc Miravitlles, Mike Herepath, Asim Priyendu, Sheetal Sharma, Tatiana Vilchez, Oliver Vit, Michaela Haensel, Virginie Lepage, Helena Gens, Timm Greulich
European Respiratory Review 2022 31: 210262; DOI: 10.1183/16000617.0262-2021
Marc Miravitlles
1Pneumology Dept, Hospital Universitari Vall d'Hebron/Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
2CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain
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  • For correspondence: marcm@separ.es
Mike Herepath
3Optimal Access Life Science Consulting, Swansea, UK
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Asim Priyendu
4Access Consulting, HEOR, Parexel International, Mohali, India
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Sheetal Sharma
4Access Consulting, HEOR, Parexel International, Mohali, India
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Tatiana Vilchez
5CSL Behring, Barcelona, Spain
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Oliver Vit
6CSL Behring, Bern, Switzerland
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Michaela Haensel
7CSL Behring, Marburg, Germany
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Virginie Lepage
8CSL Behring, Paris, France
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Helena Gens
9CSL Behring, Hattersheim, Germany
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Timm Greulich
10Dept of Medicine, Pulmonary and Critical Care Medicine, University Medical Centre Giessen and Marburg, Philipps-University, Centre for Lung Research (DZL), Marburg, Germany
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  • TABLE 1

    Clinical burden review: morbidity associated with alpha-1 antitrypsin deficiency (AATD)

    First author, year [ref.]Patient populationType of complicationPatients affected %Risk factors for morbidity (value estimate)Main outcomes
    Pulmonary morbidity
     Herrera, 2021 [43]Severe AATD (n=711)COPD75.8Not evaluatedPatients with severe AATD-related PM requiring hospitalisation are substantially burdened by more frequent events and a more severe clinical course.
    Nonsevere AATD (n=1963)COPD56.9
    Severe AATD (n=711)Emphysema33.8
    Nonsevere AATD (n=1963)Emphysema23.8
     Tanash, 2019 [25]Severe AATD (n=1595)COPD53The proportion of subjects with COPD was higher among individuals with than those without liver disease.
     Hiller, 2019 [26]Severe AATD (n=1132)COPD52Smoking#
    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)75.6Not evaluatedPiSZ 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)Bronchiectasis3.8Not evaluatedPatients 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)Emphysema21.2
     Cortese, 2016 [45]AATD (n=475)Bronchiectasis12Patients with bronchiectasis had more comorbidities (p=0.008) and were more frequently affected by pneumonia (p=0.024) than those without bronchiectasisThe 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)Bronchiectasis24PiZZ#PiZZ individuals were significantly more likely to have severe bronchiectasis versus those with other alleles.
    AATD with bronchiectasis (n=26)Emphysema53.8
     Kawkgi, 2013 [47]AATD (PiSZ) with smoking history (n=29)Emphysema36Smoking#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)Bronchiectasis54
     Ferrarotti,  2012 [48]Severe AATD (n=312)Overall (not specified)79Smoking 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)COPD73Smoking#
    Dust exposure#
    AATD led to significant morbidity in affected subjects.
     Subramanian,  2010 [40]AATD PiMZ (n=497)Lung nodule26.8hs-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 cancerPiMM 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)
    EmphysemaPatients 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
    SmokingPatients 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)
    COPDNot statedNot statedPiSZ 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)Bronchiectasis27 (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)88Not evaluatedThis 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)10Not evaluatedThis 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)29AST (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 fibrosis3Not evaluatedPatients 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 fibrosis23
    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 fibrosis18Not evaluatedPiMZ 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 fibrosis21Not evaluatedAATD 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 steatosis37
    AATD (n=19)Cirrhosis11
     Hamesch,  2019 [38]AATD with homozygous PiZZ (n=403)Liver fibrosis (LSM)23.6Age >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)Cirrhosis7Male 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 carcinoma2
     Stone, 2014 [37]AATD (n=651)Cirrhosis4Not evaluated
     Clark, 2018 [27]AATD (n=94)Liver fibrosis35.1Sex (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 diseaseStage 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 1Liver fibrosis/cirrhosisLiver 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 1Liver primary cancerPiSZ 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 2Liver fibrosis/cirrhosis24
    AATD PiSZ (n=239): cohort 213
    Controls (noncarriers n= 279): cohort 25
    AATD PiMZ (n=419): cohort 1Liver fibrosis10
     Schneider,  2020 [55]AATD PiZZ (n=309): cohort 1LSM >7.1 kPa25Obesity and diabetes were the most important factors associated with LSM ≥7.1 kPa in subjects with the PiMZ genotype.
    Control (noncarriers n=284): cohort 14
    AATD PiMZ (n=84): cohort 2Liver steatosisStage 1 40.5
    Stage 2 28.5
    Stage 3 15.5
    AATD PiZZ (n=35): cohort 2Stage 1 34.3
    Stage 2 37.1
    Stage 3 2.9
    AATD PiMZ (n=84): cohort 2Liver fibrosisStage 1 13.1
    Stage 2 28.6
    Stage 3 28.6
    Stage 4 16.7
    AATD PiZZ (n=35): cohort 2Stage 1 5.7
    Stage 2 20.0
    Stage 3 42.9
    Stage 4 28.6
    AATD PiMZ (n=84): cohort 3Perisinusoidal fibrosis69.1
    AATD PiZZ (n=35): cohort 397.1
     Hakim, 2021 [56]SERPINA 1 Z allele (n=299 939)Cirrhosis0.5The 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<1Four out of 1595 patients with a PiZZ genotypeNo patients with panniculitis developed liver disease.
     Stone, 2014 [37]AATD (n=651)Panniculitis0.9The 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 polyangiitis0.8
    Inflammatory bowel disease (UC and Crohn disease)1.5
    Hypothyroidism4
     Choate, 2019 [44]AATD PiZZ (n=3031)High blood pressure38.4A statistically significant greater proportion of PiSZ in our cohort were diagnosed with the six most prevalent comorbidities.
    Reflux33.9
    Sinus disease15.4
    Heart rhythm problems12.0
    Tumour/cancer11.2
    Diabetes7.3
    Skin problems (including panniculitis)8.6
    Pulmonary hypertension6.3
    PVD6.3
    CTD6.0
    AATD (PiSZ=504)High blood pressure52.0
    Reflux40.4
    Sinus disease20.4
    Heart rhythm problems18.6
    Tumour/cancer16.2
    Diabetes17.0
    Skin problems (including panniculitis)7.0
    Pulmonary hypertension8.1
    PVD7.0
    CTD7.4
     Basil, 2021 [30]Severe AATDVTE7Unadjusted 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.
    Controls1
     Tanash, 2020 [41]AATD (PiZZ) (n=1545)Ischaemic heart disease8HR 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)Cancer12Adjusted 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)Periodontitis88Periodontitis 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.

    • TABLE 2

      Mortality associated with alpha-1 antitrypsin deficiency (AATD)

      First author, year [ref.]CountryYearsSubjects nMain mortality outcomes
      Attaway, 2019 [60]USA2004–20148039#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]Sweden1991–20141561#,¶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]Sweden1991–2007568Total 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]USA1989–19921129#,+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]USA1979–1991Overall 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]UK1999–202019522 (35.4%) PiZZ patients died within the audit period
      Mortality was higher for PiZZ patients compared with the overall COPD population
      Dawkins, 2009 [66]UK1996–2005488Total 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]UK1996–2001256Total 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/USA1535Estimated 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]Denmark1978–1992397Total 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]Sweden1991–20081339Total 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]Sweden1991–2015PiZZ 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]Portugal2006–2016143Total 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.

      • 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/ treatmentSubjects nTime pointSGRQ scores Main SGRQ outcomes
        TotalSymptomsActivityImpact
        Bernhard,  2017 [79]AATD (PiZZ): never-smokers22336.9±21.844.5±23.845.3±26.828.7±21.5In 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-smokers3322.5±21.635.0±23.925.2±29.616.7±19.3
        AATD (PiZZ): moderate (ex-) smokers (0<pack-years<30)49146.9±19.855.7±22.758.3±22.637.3±21.0
        AATD (PiSZ): moderate (ex-) smokers (0<pack-years<30)4438.9±25.643.3±28.248.8±30.429.0±24.3
        AATD (PiZZ): intensive (ex-) smokers (≥30 pack-years)12653.2±16.562.8±19.767.5±18.141.9±18.7
        AATD (PiSZ): intensive (ex-) smokers (≥30 pack-years)3359.8±19.062.1±20.771.6±20.149.2±22.3
        Piitulainen,  2017 [80]AATD (PiZZ): never-smokers1523.7 (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 smokers405.0 (0–34.4)7.5 (0–52.2)8.8 (0–41.1)0 (0–24.2)
        AATD (PiZZ): current smokers1914.2 (2.9–20.1)18.4 (5.9–36.3)24.6 (6.0–47.7)#2.8 (0–8.7)
        AATD (PiSZ): never-smokers1526.2 (61.8)11.8 (0–58.9)12.2 (0–66.9)0 (0–59.9)
        AATD (PiSZ): former smokers404.7 (2.0–7.3)5.5 (0–18.4)12.2 (6.0–18.5)0 (0–0)
        AATD (PiSZ): current smokers1913.937.818.514.2
        Luisetti, 2015 [81]AATD52Baseline29.8±26.3Patients who received AAT therapy had poorer baseline QoL versus patients who did not receive AAT therapy (p=0.001).
        AATD index cases35Baseline41.2±24.4
        AATD non-index cases17Baseline6.3±8.3
        AATD + AAT therapy18Baseline52.7±20.6
        AATD without AAT therapy19Baseline28.0±21.8
        Gauvain, 2015 [76]AATD273Baseline49.0±20.052.5±22.063.6±22.339.4±22.2The 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: females101Baseline52.7±20.7
        AATD: males172Baseline46.8±18.2
        Bradi, 2015 [82]AATD + AAT therapy241 year50±14AAT therapy status was significantly correlated with SGRQ scores when controlling for baseline FEV1 (p=0.014).
        AATD without AAT therapy34±22
        Stolk, 2003 [14]AATD22Baseline32.4±20.1Changes 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).
        AATD2230 monthsCFB: 6.5 (–2.9–17.5)
        Annunziata,  2021 [73]AATD16Baseline18.0±3.0All 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).
        AATD163 months22.6±3.3
        Schramm, 2020 [83]AATD (PiZZ)8412.014.018.87.3There 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 control723.84.57.81.0
        Sandhaus,  2020 [84]AATD (PiZZ or worse) + AAT therapy655Annual 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 therapy655
        Crossley, 2020 [85]AATD18745.2 (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 emphysema20Baseline55.2±16.0After 6 months, SGRQ had decreased substantially compared with baseline in patients fitted with an endobronchial valve.
        206 monthsCFB: –14.3±12.9
        2012 monthsCFB: –8.2±12.9
         Durkan, 2019 [87]AATD + COPD30NR36.5±18.542.4±41.624.9±17.3For the same level of COPD impairment, PiZZ patients presented with lower SGRQ scores than PiMM patients.
         Stockley, 2018 [88]AATD (without obstruction)84Baseline14.0 (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 + COPD370Baseline48.2 (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 decline35Baseline16.2 (4.8–35.5)35 (11.7–57.1)23.3 (0–41.6)11.2 (0–21.4)
        AATD with FEV1 decline22Baseline11.5 (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 decline72Baseline51.8 (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 decline189Baseline45.2 (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)84Annual decline0.2 (–0.8–1.1)0.00 (−2.5–2.0)0.00 (−0.8–1.4)0.14 (−0.5–0.9)
        AATD + COPD370Annual decline0.7 (–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 decline35Annual decline0.04 (–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 decline22Annual decline0.5 (–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 decline72Annual decline0.5 (–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 decline189Annual decline1.07 (–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 + COPD131NR44.8±17.2No 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 therapy106NR46.6±16.4
        AATD + COPD without AAT therapy25NR37.5±20.2
         Chapman, 2015 [12]AATD + emphysema + A1P1 therapy93Baseline44.3±17.146.5±22.762.1±18.633.6±18.4Improvements were reported in only the SGRQ symptom domain after 24 months of treatment.
        AATD + emphysema + placebo87Baseline42.4±18.044.1±24.860.1±21.431.4±17.6
        AATD + emphysema + AAT therapy9324 monthsCFB: 1.4±11.1CFB: –1.4±16.7CFB: 1.7±12.4CFB: 2.1±14.8
        AATD + emphysema + placebo8724 monthsCFB: 2.2±11.7CFB: 2.0±20.1CFB: 2.6±13.5CFB: 1.8±12.5
         Ponce, 2014 [89]AATD + COPD573Baseline46.0±17.8Poorer SGRQ scores were observed in obese versus non-obese AATD patients diagnosed with COPD.
        AATD + COPD5735 years51.0±17.7
         Holm, 2013 [90]AATD + COPD57848.5±19.4AATD 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: overweight2411 year47.2±16.0SGRQ 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: obese1041 year48.7±17.1
        AATD + COPD + AAT therapy: morbidly obese611 year55.5±17.1
        AATD + COPD + AAT therapy: normal BMI2041 year43.4±16.6
         Campos, 2009 [74]AATD + COPD + AAT therapy922Baseline48.1±18.4Subjects 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 exacerbations83Baseline37.3±17.333.1±43.557.5±23.427.0±16.5
        AATD + COPD + AAT therapy; 1–2 exacerbations per year391Baseline44.5±16.643.0±22.164.1±21.233.6±16.5
        AATD + COPD + AAT therapy; ≥3 exacerbations per year448Baseline52.4±16.554.0±21.471.0±20.541.2±17.6
         Dawkins, 2009 [92]AATD + COPD with fast FEV1 decline3349.6±20.1SGRQ total scores in fast decliners as measured by FEV1 were not significantly different from middle or slow decliners.
        AATD + COPD with middle FEV1 decline3456.2±18.5
        AATD + COPD with slow FEV1 decline3451.6±24.7
        AATD with other comorbidity
         Stone, 2016 [93]AATD + lung transplant32Baseline64.2±2.575.4±2.593 (73–95)50.1±2.9Pre-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 transplant48Baseline55.3±2.067.4±2.279 (59–91)40.3±2.4
        AATD + pre-transplant14Baseline67.5 (51.0–77.8)76.5 (64.5–88.5)93.0 (4.8–98.3)50.0 (31.3–65.5)
        AATD + post-transplant141 year7.5 (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 expectoration5064.4 (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 expectoration6742.0 (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.

        • TABLE 4

          Caregiver burden review: summary of included studies

          First author, year [ref.]Study designCountryAffected domain
          Bruscino, 2019 [98]SurveyUSAAnxiety, despair
          Wienke, 2014 [99]Registry-based studyUSADelayed diagnosis, genetic discrimination, travel time
          Williams, 2013 [100]SurveyUSAGenetic discrimination, decisional burden to test
          Mahadeva, 2013 [102]SurveyEnglandFinance, routine, delayed diagnosis
          Sveger, 1999 [101]Prospective studySwedenMental anxiety
        • TABLE 5

          Economic burden review: cost and resource use associated with alpha-1 antitrypsin deficiency (AATD)

          First author, year [ref.]CountrySubjects nCost-yearHealthcare costHealthcare resource useMain economic burden outcomes
          Herrera, 2021 [43]USA51092017Median (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]USANRNRImpact 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
          NRThe 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]USA91172017Annual direct costs for AAT therapy users:
          Total: USD 127 537
          Physician visits: USD 15 064
          AAT therapy: USD 82 002
          NRThere 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]USA3535NRNRAnnual 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]USA8039NRNRHospitalisation
          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]USA14932015Hospitalisation
          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]Germany1312012Annual 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]Germany590NRNRConsultations 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]USA279NRTotal 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]USA6842009Mean 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]Spain127NRHospitalisation 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]Australia5582007–2008Direct 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]
          USA6881998Direct 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 yearSelf-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.
          1997–1999Total 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
          NRAnnual healthcare costs for patients with ZZ AATD were high versus non-ZZ, whether they were receiving augmentation therapy or not.
          Piitulainen, 2003 [104]Sweden52002Annual direct cost associated with AAT therapy
          Tailored dose: SEK 1 560 400
          Standard dose: SEK 2 600 000
          NRTailored pharmacokinetic dosing of human AAT reduces the total annual dose and cost of i.v. AAT therapy.
          Stoller, 2000 [116]USA7121997–1999NRResource 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]USA12582011–2017After 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-diagnosisHealthcare 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]USA88812000–2017Adjusted 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, respectivelyAATD 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, respectively12 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]USA68322010–2015The introduction of a DMP was estimated to decrease costs of the management of patients with AATD by USD 13.5 million over 5 yearsThe savings attributed to the programme were due to 2555 exacerbations, 5180 ER visits, 9342 specialist visits and 105 358 GP visits avoidedA 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]France3652014–2017Mean 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]USA2002–2014In 2014, hospitalisation costs adjusted to 2020 dollars for AATD was USD 108 million relative to all annual NIS dischargesAATD 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]USA1872 AATD-related cirrhosis, 7488 non-AATD-related cirrhosis2011–2017Hospitalisation 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.

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          Disease burden associated with alpha-1 antitrypsin deficiency: systematic and structured literature reviews
          Marc Miravitlles, Mike Herepath, Asim Priyendu, Sheetal Sharma, Tatiana Vilchez, Oliver Vit, Michaela Haensel, Virginie Lepage, Helena Gens, Timm Greulich
          European Respiratory Review Mar 2022, 31 (163) 210262; DOI: 10.1183/16000617.0262-2021

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          Disease burden associated with alpha-1 antitrypsin deficiency: systematic and structured literature reviews
          Marc Miravitlles, Mike Herepath, Asim Priyendu, Sheetal Sharma, Tatiana Vilchez, Oliver Vit, Michaela Haensel, Virginie Lepage, Helena Gens, Timm Greulich
          European Respiratory Review Mar 2022, 31 (163) 210262; DOI: 10.1183/16000617.0262-2021
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