Tables
- 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 3.3There 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
74.6Smoking 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
Asthma83.1
44.6
42.3
20Tobacco 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
COPD26
63.1
11
19
78.4PiZZ patients had more severe respiratory disease than those with PiSZ, despite lower smoking levels. AATD PiSZ (n=124) Chronic bronchitis
Emphysema
Asthma
Bronchiectasis
COPD22.6
33.9
17.7
12.9
43.5AATD Spain (n=416) Chronic bronchitis
Emphysema
Asthma
Bronchiectasis
COPD36.1
66.6
15.9
27.2
76.2AATD Italy (n=329) Chronic bronchitis
Emphysema
Asthma
Bronchiectasis
COPD9.4
45.9
5.5
4
67.8Hepatic 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 52Strnad, 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 52.2Stage 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 21.7Fromme, 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 15.5AATD PiZZ (n=35): cohort 2 Stage 1 34.3
Stage 2 37.1
Stage 3 2.9AATD PiMZ (n=84): cohort 2 Liver fibrosis Stage 1 13.1
Stage 2 28.6
Stage 3 28.6
Stage 4 16.7AATD PiZZ (n=35): cohort 2 Stage 1 5.7
Stage 2 20.0
Stage 3 42.9
Stage 4 28.6AATD 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
Others76.9
67.3
70.6
87.5
87.5
88.8
89.3Rates 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
Others23.0
22.0
20.0
10.0
5.6
3.2
10.7Other 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 3.7–7.4Subjects 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 1.1–2.2PiZZ 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 1.3–2.2PiZZ 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
Anxiety3.0
0
18.2
15.2The 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.] 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+1.87Tanash, 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=19Tanash, 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 casesStoller, 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%), respectivelyCatterall, 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 populationDawkins, 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 analysesEllis, 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-smokersTanash, 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 5999Total 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.
- 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 Bernhard, 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 Piitulainen, 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 Luisetti, 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 Gauvain, 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 Bradi, 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 Stolk, 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) Annunziata, 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 Schramm, 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 Sandhaus, 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 Crossley, 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.
- 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 - 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±7.3Patients 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 238NR 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 002NR 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 0.6Patients 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 daysThere 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 613Hospitalisation
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 daysHigher 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 171AATD 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 daysFor 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 AATDAnnual 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 079Mean hospital stay
Age 20–39 years: 5.0 days
Age >80 years: 8.2 daysThere 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 907Hospitalisation 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 daysThere 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 7145Hospital admissions
5.14 per patient over 6 yearsAATD 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 604Physician 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 673NR 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 000NR 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 3Adjusted 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.
Supplementary Materials
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Supplementary material ERR-0262-2021.SUPPLEMENT
Vol 31 Issue 163
Table of Contents
Disease burden associated with alpha-1 antitrypsin deficiency: systematic and structured literature reviews
