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.