Survival in severe alpha-1-antitrypsin deficiency (PiZZ)

Severe alpha-1-antitrypsin deficiency (AATD) is a hereditary condition characterised by low levels of AAT in serum and the lungs, a high risk of developing panacinar emphysema, and an increased risk of liver disease, primarily in early childhood and late adulthood [1–6]. Cigarette smoking is strongly associated with early development of emphysema in PiZZ individuals [2].

Previous studies of the natural history of severe AATD have indicated that it is a severe disorder leading to a considerably reduced life expectancy, and that emphysema is the most common cause of death [2]. However, our recently published study showed that PiZZ individuals, who have never smoked and have been identified by screening, do not have an increased mortality risk compared with the general Swedish population [7]. We also found that emphysema and liver diseases were the most common causes of death. Smokers were not included in the analysis.

The aims of this study were to analyse the mortality of PiZZ individuals, with respect to smoking habits and the mode of identification, to analyse the predictors of mortality, and further, to analyse the most common causes of death.

Fifty six patients received a lung transplant and two patients received a liver transplant; their mortality data are censored at the date of transplant. During the follow-up time 315 (24%) patients died. The median survival time for the whole study population since inclusion was 14 years, which was estimated by the Kaplan-Meier method. When the Kaplan-Meier analysis was stratified by mode of identification, there was a significant difference in survival time between R cases, NR cases and S cases, with estimated median survival times of 12 years, 14 years and 16 years, respectively, (p < 0.001), Figure 1. The Kaplan-Meier analysis was also stratified by smoking habits, Figure 2. The estimated median survival time for the smokers was significantly lower than the never-smokers, 13 and 14 years, respectively, (p < 0.01).

The SMR for the whole study population was 3.80 (95% CI 1.80-2.30). Gender-specific SMRs were 3.80 (95%CI 3.20-4.40) for men and 3.90 (95% CI 3.30-4.60) for women.

The smokers had a higher mortality risk than never-smokers, with a SMR of 4.80 (95%CI 4.20-5.50) for the smokers and 2.80 (95%CI 2.30-3.40) for the never-smokers. The Rate Ratio (RR) was 1.70 (95% CI 1.35-2.20). Stratifying the SMR by the mode of identification, showed that the SMR was 4.70 (95% CI 4.10-5.40) for the R cases and 3.0 (95%CI 2.35-3.70) for the NR cases. It should be noted that the SMR for the S cases was also significantly over 1, with 23 deaths and 9.9 expected (SMR 2.30 (95% CI 1.46-3.46)).

In this study, the survival is presented for a large number of adult PiZZ individuals who have been followed up prospectively. The results confirm that PiZZ smokers, irrespective of mode of identification, have a significantly higher mortality risk than the general Swedish population. Our results show the importance of early detection of AAT deficiency. All individuals with severe AAT deficiency should be identified before they reach the age of their smoking debut.

When the individuals were stratified by mode of identification, and the survival of smokers and never-smokers was analysed, we found that even among the screened cases, smokers had a reduced survival time compared with never-smokers. However, also among the R cases smokers had a significantly higher mortality risk than never-smokers, with a SMR of 5.70 and 3.10, respectively. Our results suggest also that increased mortality was independently associated with higher age, lower FEV₁ and the presence of respiratory symptoms at inclusion, Table 4.

The current study extends previous studies regarding mortality in PiZZ individuals by comparing the survival of a large number of PiZZ individuals [2, 13–17]. The three groups R cases, NR cases and S cases differed with respect to smoking habits, age at inclusion and lung function (Table 1). The NR cases and the S cases seem to have normal lung function, but at the time of inclusion 38% of the NR cases and 30% of the S cases had respiratory symptoms, because in many cases the diagnosis was made a long time before their inclusion in the registry.

Previous studies on the natural history of AATD have been strongly influenced by ascertainment bias due to the fact that AAT analysis is most often performed in subjects with respiratory symptoms [13]. Therefore, many asymptomatic PiZZ individuals escape detection. The earliest study on the natural history of AATD, published by Larsson, indicated that it is a serious disorder associated with a poor prognosis [2]. He determined the cumulative probability of survival in 248 PiZZ subjects and found it to be significantly reduced compared with the normal Swedish population. In his study the median survival time was only about 40 years for smokers, and 65 years for never-smokers. However, the study population was highly selected. Ninety percent of the patients were identified because of symptoms and the majority were smokers. Another study of 124 AAT-deficient patients published by Brantly showed the cumulative probability of survival to age 50 of 52% and only a 16% chance of surviving to 60 years of age [14]. The majority of the individuals in this study were men, ex-smokers who had become dyspnoeic between 25 and 40 years of age. Because of the selection bias in both of these studies, the estimated life expectancy was probably too pessimistic. Recently, some studies have reported long-term survival and causes of death [15–17]. Seersholm analysed the life expectancy of 255 non-index patients who did not have pulmonary symptoms [15]. As in the current study, the survival of smokers in non-index cases was less than that of never-smokers and never-smokers did not have an excess mortality compared with the normal Danish population. However, this study did not show any difference in survival between smokers and never-smokers in index cases. The study included only a limited number of never-smokers and used a different approach for the survival calculation. In another study, Seersholm reported that FEV₁ was a major risk factor for mortality in patients with severe AAT deficiency, stating that the median survival time for patients with FEV₁ below 25% of predicted was only 6.3 years [16]. A mortality study recently published by Stoller et al. showed that severe airflow obstruction was a major determinant of mortality. Increasing age, lower FEV₁ and lower education level were also associated with higher mortality [17]. The most common underlying causes of death were emphysema (72%) and liver cirrhosis (10%). This study compared the clinical features between decedents and survivors in the U.S. registry, but no comparisons between smokers and never-smokers were made. Neither respiratory nor other symptoms were reported, nor was the mode of identification. The SMR was stratified by quintiles of initial postbronchodilator FEV₁, not by smoking habits or mode of identification, In contrast to our study, primary liver carcinoma was not found as a cause of death in the study by Stoller et al.

The natural history of AATD is incompletely known, although more than 40 years have elapsed since the deficiency was discovered. The selection in the Swedish national AAT registry is less skewed than in other registries in which most of the patients are identified because of respiratory symptoms. In the Swedish AAT registry, the majority of subjects is identified by reasons other than respiratory symptoms, and includes a large number of never-smokers. However, only 25% of the individuals were identified by family/population screening, and the remainder was identified by a disease or symptoms. Furthermore, although the detection rate of AATD is relatively high (20%) in Sweden, the majority of adult PiZZ individuals remains unidentified, and their health status is unknown, which is one limitation of our study. Another limitation is that we reported lung function as pre-bronchodilator FEV₁, because a reversibility test was not performed in all cases. The third limitation is that we compared the SMR for the study population with the SMR for the general Swedish population, because no data are available on mortality in the subgroups based on smoking habits in the general Swedish population.

We conclude that PiZZ smokers, irrespective of mode of identification, have a significantly higher mortality risk than the general Swedish population. Early detection of AAT deficiency is important in order to make it possible to implement protective measures such as inhibiting smoking.