The guideline writing group consisted of the following: (a) a scientific committee comprising 5 experts and members of the REDAAT committee, which was responsible for the literature review, the selection and synthesis of the evidence, the prioritization of questions and outcomes, and the drafting of the guideline and recommendations; (b) a methodological group comprising 2 methodologists, which conducted the systematic review of the evidence and assessed the results of the systematic review questions; (c) an expert panel comprising the REDAAT committee, consisting of 13 pulmonology specialists, 1 internal medicine and hepatology specialist, 1 pediatrics specialist, 2 nurses specialized in respiratory diseases, 1 clinical biochemistry specialist, 1 biology specialist, and 1 genetics and genomics specialist; and (d) a patient representative group comprising 1 patient and 1 family member of a patient with severe AATD.

These guidelines were developed following the SEPAR development process for clinical practice guidelines, available at https://gestiondocumentalsepar.com/. We used the guidelines of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) group [3] and ADOLOPMENT (Adopt, Adapt, and Develop) [4] to adapt recommendations and avoid unnecessary duplication of existing guidelines [5], supplementing them with an updated literature review.

For the recommendations regarding the diagnostic process, it was decided to use a narrative approach to answer 2 questions: In which populations is assessment for the presence of AATD necessary? What is the most appropriate diagnostic approach for detecting AATD? To this end, the writing/development group used the 2017 European Respiratory Society statement [6] as a source, and a systematic literature search was conducted to identify systematic reviews published up to August 2025. The search used MeSH terms, keywords, and methodological filters, and was conducted through PubMed (see online supplement).

For the recommendations on AAT augmentation therapy, the drafting/development group used the Canadian Thoracic Society guideline updated in 2025 as the reference document [5]. Randomized clinical trials and observational studies published from 2023, the date of the search included in the Canadian guideline, to September 2025 were searched. Case-control studies and case series were excluded. The question addressed was formulated in PICO format (Patient, Intervention, Comparator, Outcome) as follows: adult individuals aged ≥18 years with COPD and AATD; intervention, intravenous AAT augmentation therapy; comparator, placebo or no treatment; and outcomes, improvement or slowing of the rate of decline in lung function, lung density, and clinical outcomes, including mortality and exacerbations. In addition, the working group identified subgroups of special interest for analysis: populations with baseline FEV1<35%, PiSZ genotype, and advanced age (>70 years). Details of the literature search and evidence tables are provided in the supplementary material.

After completion of the literature searches, the scientific committee shared the results of the evidence review with the expert panel and patient representatives to prioritize the outcomes and develop the recommendations. Some of the proposed considerations are not supported by high-quality published evidence but instead represent consensus opinions of the members of the steering committee and expert panel based on the search results, their clinical experience, and the perspective of the patient representative group.

Human AAT is encoded by the SERPINA1 gene, an acronym for serine protease inhibitor A1, which is located in region 14q31-32.3 of the distal end of chromosome 14 [8]. The main function of AAT is to act as a protease inhibitor (Pi). Mutations are usually named according to a letter of the alphabet determined by migration of the protein in an electrophoretic test, isoelectric focusing (IEF) in a pH gradient, which is the procedure used for phenotypic study. In this system, the intermediate position identifies the normal allele (PiM), and the remaining positions correspond to altered alleles. When 2 mutations coincide with the same letter assigned according to their migration on IEF, they are differentiated according to the city of birth of the index case, for example, PiMmalton and Pi*Siiyama. Some mutations do not usually produce protein because they have a genotype with a stop codon that prevents protein transcription. These null mutations are named with the expression Q0 followed by the name of the city of birth of the index case, for example, PiQ0bellingham and PiQ0madrid [8]. Null mutations have no plasma protein expression, which confers a very high risk of respiratory disease, but they do not produce liver involvement.

The normal PiMM genotype is present in approximately 80% to 95% of individuals and expresses 100% of AAT. More than 500 SERPINA1 mutations have been identified, although not all are pathogenic [8]. ThePiZ variant (p.Glu342Lys) is the most frequent severe deficiency variant and is characterized by the production of defective AAT that is retained within the rough endoplasmic reticulum of hepatocytes, forming stable polymers. This leads to a reduction in its plasma concentration, an 80–90% decrease in the activity of the secreted protein [9], and the accumulation of intrahepatic AAT polymers, favoring the development of liver involvement at all ages. In addition, neutrophilic panniculitis and granulomatosis with polyangiitis are other conditions rarely associated with AATD [10]. This accumulation of intrahepatic AAT may occur in other variants, such as PiMmalton, explaining the AAT deficiency associated with them.

The inheritance pattern is mendelian autosomal codominant, so both alleles are expressed. This means that there is no healthy/diseased state, but rather that the different allelic combinations determine different blood concentrations of AAT, such that the lower the concentration, the greater the risk of clinical consequences.

The list of clinical situations that should be routinely assessed to rule out AATD is summarized in Table 1. There is broad consensus on the need to determine AAT levels in all patients with COPD, regardless of age, disease severity, or history of tobacco exposure [11–13,6]. The working group recommends investigating AATD in all patients with COPD (high-quality evidence).

Several studies suggest a possible relationship between AATD and the development of bronchiectasis [14–17], although systematic testing of AAT levels in patients with bronchiectasis in general populations has a low diagnostic yield. However, it may be relevant in selected contexts or in regions with a higher prevalence of AATD because, although most patients with AATD develop emphysema, mutations have been described in patients with bronchiectasis. Therefore, some societies recommend determining AAT concentrations in patients with bronchiectasis as part of the initial etiologic assessment [18,19]. Consequently, the working group recommends investigating AATD in all patients with bronchiectasis of unknown etiology (low-quality evidence).

The relationship between AATD and asthma has been evaluated in several studies. At present, there is no evidence that AATD is a risk factor for the development of asthma [20,21]. The relationship between AATD and worse clinical outcomes in asthma is also controversial; consequently, systematic investigation of AATD in all patients with asthma is not recommended. Instead, testing should be individualized and targeted to patients who develop progressive bronchial obstruction or in whom associated pulmonary emphysema is present (conditional recommendation; low-quality evidence).

We recommend investigating AATD in all individuals with COPD at the time of diagnosis, in individuals with bronchiectasis of unknown etiology, and in individuals with adult-onset asthma who develop persistent airflow obstruction or have associated pulmonary emphysema (Table 2).

Isolated measurement of serum AAT levels may be insufficient to diagnose severe AATD because of intraindividual variability, the effect of acute-phase reactants, and the presence of rare genetic variants that may alter function without substantially modifying AAT concentration. These circumstances support a 2-step diagnostic approach combining serum AAT levels with characterization of the genetic defect (genotype) or the protein abnormality (phenotype).

In individuals with clinical suspicion of AATD (Table 1), the panel recommends initial measurement of AAT levels together with serum C-reactive protein (CRP) as the first diagnostic step (Fig. 1). The main techniques used to quantify blood AAT levels are nephelometry, turbidimetry, and ELISA [22]. Serum AAT concentration may be expressed according to the International System of Units in micromolar units (μM or μmol/L) or in clinical concentration units as mg/dL or g/L. The 2 units are often used interchangeably in the United States and in some countries of continental Europe [13]. Conversion from mg/dL to μM is performed by multiplying the concentration in mg/dL by 0.1923.

Fig. 1.

Diagnostic algorithm. (1) Determination by nephelometry. For other techniques, consult the laboratory regarding the equivalent cutoff value. (2) If CRP is persistently elevated (≥5mg/L), perform genotyping if clinical suspicion is high. AAT, alpha-1 antitrypsin; AATD, alpha-1 antitrypsin deficiency; CRP, C-reactive protein.

AAT is an acute-phase reactant, and its concentration may increase by up to 100% in heterozygotes and compound homozygotes in response to inflammatory stimuli, an increase that may persist for 1 to several weeks after the onset of an acute inflammatory process [23]. Serum concentrations also increase moderately with the use of contraceptives and during pregnancy [24]. However, they do not increase significantly in PiZZ individuals in response to inflammatory or infectious stimuli because most of the synthesized PiZ molecules are retained in hepatocytes and are not secreted into the blood. Therefore, it is advisable to determine AAT and CRP concentrations simultaneously to avoid incorrectly classifying a deficient patient as normal because of values that are transiently increased under these circumstances [6,25].

Population studies have shown considerable variability in serum AAT levels attributable to factors such as inflammatory status and, to a lesser extent, demographic and environmental factors [26]. The normal values established in clinical laboratory testing for the different analytical techniques are largely those established by the manufacturer. However, these values have been obtained without considering the distribution of the different genotypes in the reference population. In addition, in Spain, many laboratories use immunoturbidimetry because it is easier to automate and more cost-effective, despite its lower sensitivity at low AAT values. There is a lack of harmonization among analytical methodologies, making it necessary for each laboratory to review and establish its own reference values. For all these reasons, the optimal cutoff point for AAT concentration to establish a diagnosis of AATD remains a matter of debate [21]. In the absence of further national population-based studies in Spain evaluating normal values in the PiMM population, an AAT concentration<116mg/dL measured by immunonephelometry is proposed to initiate the diagnostic evaluation of AATD with phenotype/genotype characterization. This cutoff is based on a study conducted in Barcelona in 1996, in which normal AAT values measured by serum immunonephelometry in healthy individuals established a reference interval for PiMM individuals ranging from 116mg/dL to 232mg/dL [27]. The adoption of the reference value of 116mg/dL by nephelometry optimizes the detection of individuals carrying Z alleles, who will require family testing to detect possible subjects with severe PiSZ or PiZZ deficiency [28].

Although the recommendations on the diagnostic process for AATD are not based on high-quality evidence, the expert panel placed great importance on definitive characterization of the genetic or protein defect. Knowing the nature of the mutation is relevant for interpreting the alteration in AAT protein levels and function, understanding the risk of disease, and facilitating family screening. Consequently, all subjects with AAT<116mg/dL, first-degree relatives of carriers of mutations associated with AATD, and subjects with persistent elevations of CRP should proceed to the second diagnostic step with phenotype or genotype characterization.

Phenotyping by isoelectric focusing (IEF) detects the AAT protein isoforms present in the patient's serum, differentiating between normal forms and deficient variants according to their migration pattern in the pH gradient. However, correct interpretation of IEF patterns requires a high level of technical expertise and experience; therefore, results may vary between laboratories, particularly in the identification of rare variants or variants similar to Pi*M, which may be confused with the normal phenotype if expert reading is not performed. Likewise, detection of very rare variants and characterization of new variants are complex. In addition, IEF does not detect null variants [28].

Genotyping. Currently, REDAAT recommends using the REDAAT-Progenika diagnostic pathway with the A1AT Genotyping Test, which identifies the 14 most frequent allelic variants using a saliva sample, dried blood spot, or whole blood sample [29,30]. Genotyping for the most common mutations, PiS andPiZ, using specific panels can be performed in some centers with laboratories for genetic testing, such as through real-time polymerase chain reaction techniques based on melting peaks [31,32].

The panel emphasizes the importance of contextualized interpretation of AAT levels along with the genotype and the patient's clinical situation. Given the variability in AAT levels and the evaluation of a limited number of genetic variants that may have been studied, discrepancies between the genotype/phenotype and the AAT level may be found. In these cases, it is recommended to: (1) perform a new AAT determination to rule out possible laboratory errors and (2) perform SERPINA1 gene sequencing if the AAT value is confirmed. Sequencing was considered a complex and costly technique and, therefore, was recommended only in well-selected cases. The increasing introduction of high-throughput next-generation sequencing methods into clinical laboratories will make it possible in the near future to perform rapid, accurate, and affordable sequencing of large amounts of DNA fragments in a single reaction, which will improve diagnostic protocols and reduce process costs [33,34].

In situations in which plasma AAT concentration cannot be determined, genotyping may be performed directly. In these cases, AAT concentration should subsequently be determined as soon as possible to confirm the genotyping result [6].

The working group, with the participation of the patient representative group, considered that patients would place great value on an early and definitive diagnosis of AATD to optimize clinical management, preventive measures, and genetic counseling for patients and family members. Early diagnosis will provide patients and their families with the best opportunity to live a long and healthy life.

After completion of the diagnostic pathway described here (Fig. 1), the subjects evaluated will be categorized into 1 of the following groups:

• •

  AATD ruled out. These are patients whose AAT level is above the threshold for suspicion (116mg/dL) after considering CRP values or who, after characterization, show a PiMM genotype/phenotype.

• •

  Carriers of alleles related to AATD. These are subjects with circulating AAT levels above the normality threshold of their reference laboratory but who carry a mutation in the SERPINA1 gene.

• •

  Confirmed AATD. These are subjects with AAT values below the normal range according to their reference laboratory and who carry a mutation in the SERPINA1 gene.

• •

  Severe AATD. These are subjects with AAT values below the protective threshold (11μM or 57.2mg/dL). Severe AATD is associated in 96% of cases with PiZZ genotypes and occasionally with other genotypes resulting from combinations of Z, S, rare, and null alleles [7,8].

Since 1987, purified AAT derived from donor plasma has been available for intravenous administration. Its biochemical efficacy has been demonstrated because administration maintains its enzymatic activity in plasma and bronchoalveolar lavage, and its activity in the lung correlates directly with its plasma concentration. Since 1981 [35], it has been known that, in severe AATD, intravenous AAT therapy at a dose of 60mg/kg of body weight per week can maintain serum levels above an estimated protective threshold of 11μmol/L (57.2mg/dL), with a half-life of infused AAT of 4–5 days. In addition, the study showed that weekly infusion of purified AAT restored antielastase activity in the pulmonary epithelial lining fluid, suggesting a protective biochemical effect on lung tissue.

The evidence for the efficacy of augmentation therapy with exogenous AAT derived from human plasma is supported by 3 clinical trials including a total of 313 randomized patients, the largest of which included 180 patients. All trials were conducted in adults, the vast majority with a PiZZ genotype, with trial durations ranging from 24 to 36 months, as well as 8 observational studies (Tables S1–S4 in the supplement).

Randomized clinical trials have not been able to directly and statistically significantly demonstrate an effect on mortality because they were not designed with the statistical power required for this purpose [37,38]. However, large registry studies have shown that subjects receiving this therapy have a significantly lower risk of mortality [40,41], with an adjusted hazard ratio, approximately 0.64 compared with those not receiving treatment. This survival benefit is particularly pronounced in the subgroup of patients with baseline FEV1 between 35% and 49% of the predicted value [40]. This improvement in survival appears to be uncoupled from the decline in FEV1, implying that the survival benefit occurs even if it is not reflected by marked changes in forced expiratory volume. Based on extrapolations from loss of lung density measured by CT, augmentation therapy is estimated to provide a gain of approximately 5.6–5.8 years of life before the patient reaches end-stage respiratory failure or requires transplantation [38]. This represents moderate-quality evidence.

Clinical trials have not demonstrated a statistically significant difference in the annual rate of FEV1 decline or changes in diffusing capacity for carbon monoxide (DLCO) or in the transfer coefficient (KCO) between the treatment and placebo groups [36–38]. In contrast to clinical trials, registry studies include much larger cohorts and longer follow-up periods, which have made it possible to identify functional benefits in specific subgroups, with a significant slowing of FEV1 decline in treated patients, especially in those with moderate obstruction [42–45]. In this regard, recent analyses indicate that therapy is more effective in attenuating decline in patients with GOLD stage 2 disease [46]. This represents low-quality evidence.

The efficacy of augmentation therapy on quality of life has been insufficiently explored. In short-duration controlled settings (2–4 years), therapy has not demonstrated a statistically significant improvement in quality of life compared with placebo [37,38,47]. Further studies are needed to explore this relationship in greater depth. This represents low-quality evidence.

Large clinical trials and most observational studies have not demonstrated a statistically significant reduction in the frequency or severity of exacerbations [37,38,48]. In addition, the indication for augmentation therapy is to slow the progression of emphysema in patients with severe AATD and not to reduce the number or severity of exacerbations. This represents moderate-quality evidence.

Augmentation therapy with AAT is well tolerated and considered safe. In randomized studies and registries, the incidence of serious adverse events did not differ significantly between the treated group and the placebo group. The most frequently reported adverse events are mild and transient, including fever, chills, urticaria, nausea, vomiting, and fatigue. Severe reactions, such as anaphylaxis, are extremely rare. No cases of viral transmission, including HIV or hepatitis, have been reported in large registries or long-term observational studies [36–38]. This represents high-quality evidence.

Based on the background described above, the panel considers that the objective of AAT augmentation therapy is to slow the progression of emphysema in patients with severe AATD, with a possible benefit on other clinical outcomes. The criteria for defining emphysema with abnormalities on pulmonary function tests and chest computed tomography to establish the indication for augmentation therapy were widely discussed by the expert panel, with consideration given to the possibility of establishing specific thresholds for FEV1, FEV1 decline, DLCO, or KCO, as well as quantification of the extent of emphysema. However, given that there is currently insufficient evidence to support more specific and homogeneous criteria, consensus was reached to maintain wording that reflects the need for a broad and comprehensive assessment of lung disease associated with AATD. Consequently, individuals with AATD who meet all the specific conditions listed in Table 3 should be offered intravenous AAT augmentation therapy for this purpose.

Augmentation therapy may offer benefits in terms of survival and preservation of lung density also in elderly patients. Consequently, age is not a decisive factor, although clinical conditions, life expectancy, and the implications of long-term intravenous therapy must be taken into consideration.

In the context of lung transplantation, there are 2 controversies: whether to withdraw treatment once the patient is placed on the waiting list and whether to maintain it after transplantation. There is no evidence of the clinical benefit of augmentation therapy after lung transplantation in preventing rejection or improving lung function or posttransplant survival in patients with AATD [62–66]. The treatment decision should be assessed by the transplant team and the AATD reference center, taking into consideration the patient's values and expectations.

Pregnancy produces an increase in serum AAT levels compared with those in nonpregnant women. This increase is observed from the first trimester and progresses during gestation, reaching its highest values in the third trimester [67]. There are no clinical trials or observational studies that have evaluated augmentation therapy in pregnant women, and it is not recommended during pregnancy, although cases have been reported of pregnant women with rare AATD variants who received augmentation therapy without maternal or fetal complications attributable to treatment [68,69].

To date, no clinical trial or observational study has been specifically designed to evaluate the effect of augmentation therapy in patients with AATD and bronchial asthma. In addition, augmentation therapy trials do not specifically include patients with asthma. Therefore, there are currently no recommendations regarding augmentation therapy in patients with AATD and asthma. Given that the objective of augmentation therapy is to prevent the progression of emphysema, its indication is not recommended in patients with asthma (Table 2).

Although some patients with AATD may present with bronchiectasis as the predominant manifestation [14], augmentation therapy has not been studied or recommended in this subgroup. Therefore, no recommendation can be made regarding its use in bronchiectasis without emphysema. Given that the objective of augmentation therapy is to prevent the progression of emphysema, its indication is not recommended in patients with bronchiectasis (Table 2).

AAT augmentation therapy is not indicated and has not demonstrated efficacy in the treatment of liver disease associated with AATD. AAT augmentation therapy has been shown to be safe for the liver, and some studies have associated it with better liver parameters and lower liver stiffness indices in adults with the PiZZ genotype. However, augmentation therapy does not appear to reduce the amount of AAT polymers accumulated within hepatocytes [70].

In the case of panniculitis, intravenous administration of AAT has been shown to induce clinical remission, especially in patients refractory to conventional treatments such as dapsone and corticosteroids. Some case series suggest its use, with rapid and sustained responses after restoration of plasma AAT levels. The dose usually used is the same as that for the pulmonary indication (60mg/kg/week), although remission has been reported with single doses of 120mg/kg [71,72].

Regarding vasculitis associated with AATD, cases of systemic necrotizing vasculitis have been described in this context, but the evidence on the benefit of augmentation therapy is limited to isolated reports, and there are no controlled studies or formal recommendations for its routine use [73,74].

Well-informed patients understand that the studies published to date may not provide solid evidence of the benefits of augmentation therapy; however, it would be logical to think that replacing a missing protein should have a positive clinical effect. In Spain, augmentation therapy is funded for those who have been diagnosed with severe AATD and meet the defined criteria. However, although the therapy is approved and available within the national health system, the decision regarding funding and effective access depends on the policies and resources of each autonomous community, generating variability and lack of equity in access to costly treatments for rare diseases such as AATD. In addition, there are differences in the availability of reference centers and in clinical expertise, which may limit access to therapy in regions with less specialization or lower health care budgets [75,76]. Referral processes, monitoring, and communication between professionals and patients should be improved to reduce inequalities in access to AAT augmentation therapy.

• •

  They do not require specific follow-up.

• •

  Management should focus on genetic counseling, avoidance of risk factors, and monitoring if symptoms appear.

• •

  The initial evaluation should include spirometry with bronchodilator testing to confirm or rule out a diagnosis of COPD, chest radiography, and laboratory testing with liver function tests.

• •

  Individualized follow-up is recommended according to clinical status, including lung function testing (spirometry and DLCO) and liver function tests with abdominal ultrasound or liver elastography in all allelic variants with risk of liver disease [78].

• •

  The initial evaluation should include spirometry with bronchodilator testing to confirm or rule out a diagnosis of COPD, DLCO, liver function tests, and imaging studies (chest CT to characterize emphysema and liver ultrasound or elastography, if available). Inclusion in the international EARCO (European Alpha-1 Research Collaboration) registry (https://www.earco.org/) is advised.

• •

  Follow-up should be individualized according to clinical status and progression of lung disease [79].

• •

  In patients without respiratory disease or with stable lung disease, annual follow-up with spirometry and clinical assessment is recommended. If symptoms or lung function worsen, closer follow-up with monitoring every 6 months should be considered.

• •

  During follow-up, spirometry with bronchodilator testing, DLCO, lung volumes, liver function tests, and liver ultrasound or elastography, if available, are recommended. Routine serial CT scans are not advised during follow-up, except in the presence of relevant clinical changes or complications.

• •

  Monitoring of the response to augmentation therapy is based mainly on clinical and functional evolution. AAT treatment should not be discontinued in patients already receiving therapy if their lung function deteriorates and/or their FEV1 falls below 25%. Determination of trough plasma concentrations is not recommended because their interpretation is complex and subsequent dose adjustments would require individualized pharmacokinetic analysis.