The results of our study demonstrate a decreased risk of emphysema and other lung diseases, as well as better lung function and quality of life in PI*SS individuals compared to PI*ZZ subjects in the matched population. However, to our knowledge, no direct comparisons of the risk of lung disease between PI*SS and PI*SZ have been published. Our results indicate that although there were significant differences in serum AAT levels between the PI*SS and PI*SZ genotypes, there were no significant differences in clinical manifestations, i.e. the prevalence of emphysema, COPD, asthma, bronchiectasis, or differences in lung function or quality of life, after careful matching for confounders.

The S allele (Glu264Val) is one of the most frequent variants related to AATD, causing a 40% decrease in circulating AAT protein, with mean serum levels in homozygous PI*SS subjects of 0.82 g/L (95% CI 0.73 to 1.00 g/L) [5]. In addition, the plasma neutrophil elastase inhibitory capacity of PI*SS subjects is approximately half that observed in normal PI*MM individuals, and exposure of the purified S protein to increasing oxidant burdens, as in smokers, resulted in a dose-dependent reduction in the ability of the molecule to inhibit neutrophil elastase [20]. Taken together, these findings suggest that carriers of the PI*SS genotype may be at increased risk of lung disease, particularly if they smoke. On the other hand, AAT serum levels in PI*SS subjects are usually above the considered protective threshold of 0.5 g/L, and the S protein polymerizes very slowly, resulting in negligible hepatic accumulation and circulating polymer concentrations, leading PI*S to be considered as a non-polymerizing variant [4, 9, 21], thereby suggesting a very low (or non-existent) risk of lung disease in the majority of PI*SS individuals. Clarification of the risk of lung disease associated with the PI*SS genotype would require large epidemiological studies, but there is very limited information regarding the clinical characteristics of PI*SS individuals and their risk of lung disease, particularly compared to the most frequent severe deficient genotypes PI*ZZ and PI*SZ.

For the present study we used data from the EARCO international registry, an initiative of the European Respiratory Society, aimed at collecting prospective information about patients with AATD of different deficient genotypes [12]. The EARCO registry provides a unique opportunity to investigate the characteristics of PI*SS individuals and their associated risk for lung disease. The S allele is very common in the Iberian Peninsula, with a prevalence of between 10 and 18% and is particularly frequent in Madeira Island (Portugal), with a prevalence of 18%. It is also frequent in Angola (18.8%) and Namibia (14.7%), probably related to populations of Iberian heritage [2, 4, 10].

Despite the estimated worldwide prevalence of 4,017,900 individuals with the PI*SS genotype, with the greatest prevalence in Central and Western Europe (460,725 individuals) [10], the risk of developing pulmonary disease associated with this genotype is still unclear, as most studies have focused on carriers of the PI*SZ genotype and some individuals with the PI*SS have only occasionally been described [11]. As an example, a meta-analysis on the risk of COPD due to the PI*S allele, found that the OR for COPD in PI*SZ individuals increased by 3.26 compared to normal PI*MM individuals, mainly in active and former smokers. However, there were not enough cases to summarize the risk of COPD in PI*SS homozygotes, nor was the average lung function in this genotype described due to lack of data [7]. Almost 20 years later, publications including PI*SS individuals remain very scarce.

As previously mentioned, our study found no significant differences in clinical manifestations between PI*SS and PI*SZ genotypes. Interestingly, the main lung function parameters analysed (FEV1(%) and KCO(%)) were not significantly different between PI*SS and PI*SZ individuals after matching, but in both cases they were better preserved compared to PI*ZZ subjects. Similarly, the risk of having an impaired FEV1(%) and/or KCO(%) did not significantly differ between PI*SS and PI*SZ genotypes, either before or after accounting for previous episodes of pneumonia and exacerbations. These results suggest that the antielastase protection provided by the two S alleles may be equivalent to the SZ combination; nevertheless, larger prospective studies are needed to confirm this observation.

Our findings raise important questions about the management of PI*SS individuals. Since the PI*SZ genotype increases the risk of emphysema in smokers compared to the “normal” PI*MM population [7, 8], if PI*SS individuals seem to have the same risk, counselling to quit smoking should be similarly intense for both genotypes. Furthermore, the clinical and functional monitoring of PI*SS patients who smoke should be equivalent to that carried out in PI*SZ patients.

Therapeutic considerations can also be raised, since, in selected cases, carriers of the PI*SZ genotype may be candidates for replacement therapy, as expressed in the Summary of Product Characteristics of the different approved ATs and in some guidelines [22,23,24]. In fact, recent data from the Spanish registry showed that 8.2% of registered PI*SZ individuals were receiving AT [25]. Again, if the risk for lung disease associated with PI*SS is not significantly different from that of PI*SZ, it may also be considered that some selected individuals with the PI*SS genotype could benefit from AT [22, 23]. However, similar to PI*SZ, there is no evidence about the efficacy of AT in this population and the great majority (if not all) of subjects with the PI*SS genotype have serum levels above those considered to be protective [5, 6]. In any case, if our results showing a similar risk of lung disease for PI*SS and PI*SZ are confirmed in larger series, this could justify the inclusion of PI*SS subjects in clinical trials of other future preventive treatments under development, such as oral or inhaled elastase inhibitors. It should also encourage debate as to whether there is a universal protective AAT level, and if so where it lies.

The S allele has also been associated with a higher prevalence and increased severity of asthma. Data from the Spanish registry, one of the largest reported samples of PI*SZ individuals, showed that the prevalence of asthma was significantly higher for PI*SZ compared to PI*ZZ subjects [25]. Recent studies have also observed that carriers of the S allele may have more frequent and severe asthma exacerbations [26, 27]. However, our study did not find any significant difference in the prevalence of asthma among the three groups. In fact, the prevalence of neither asthma nor bronchiectasis showed significant differences among the PI*SS, PI*SZ and PI*ZZ genotypes after matching. In any case, our data cannot rule out a possible influence of the S allele on the clinical manifestations, severity or exacerbations of asthma.

Our study has some limitations: firstly, despite careful matching for risk factors we cannot rule out the possibility of other confounders that were not considered. Secondly, there may be some selection bias derived from the potential tendency to register in EARCO the most affected PI*SS individuals, who are the those most frequently diagnosed, but this bias may also apply for the PI*SZ and PI*ZZ individuals. Thirdly, we could not compare PI*SS with a matched cohort of normal PI*MM individuals and, therefore, we can only speculate about an increased risk of lung disease in the PI*SS versus the normal population based on an indirect comparison through the similar risk observed with the PI*SZ genotype. Fourthly, it should be noted that patients in the group characterized by the PI*SS genotype represent only 5.6% of the entire deficient population analysed. Finally, we do not yet have prospective follow-up data that could provide insights into the risk of exacerbations and lung function decline associated with the PI*SS genotype. Future larger studies and/or the future analysis of prospective EARCO data may provide more information about the evolution of these subjects. Conversely, this is the largest study characterizing individuals with the PI*SS genotype and the comparison of these subjects not only with PI*ZZ, but perhaps more importantly, with participants with the PI*SZ genotype, a known risk factor for lung disease in smokers [7, 8] and using propensity score matching and a multivariate analysis of risk factors.