Detection of Alpha-1 Antitrypsin Levels in Chronic Obstructive Pulmonary Disease in Respiratory Clinics in Spain: Results of the EPOCONSUL 2021 Audit

Citation: Calle Rubio, M.; Miravitlles, M.; López-Campos, J.L.; Soler-Cataluña, J.J.; Alcazar Navarrete, B.; Fuentes-Ferrer, M.E.; Rodriguez Hermosa, J.L. Detection of Alpha-1 Antitrypsin Levels in Chronic Obstructive Pulmonary Disease in Respiratory Clinics in Spain: Results of the EPOCONSUL 2021 Audit. J. Clin. Med. 2024,13, 955. https:// doi.org/10.3390/jcm13040955 Academic Editor: Silvano Dragonieri Received: 11 January 2024 Revised: 29 January 2024 Accepted: 1 February 2024 Published: 7 February 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Journal of Clinical Medicine Article Detection of Alpha-1 Antitrypsin Levels in Chronic Obstructive Pulmonary Disease in Respiratory Clinics in Spain: Results of the EPOCONSUL 2021 Audit Myriam Calle Rubio 1,2,* , Marc Miravitlles 3,4 , JoséLuis López-Campos 4,5 , Juan J. Soler-Cataluña 6,7 , Bernardino Alcazar Navarrete 8, Manuel E. Fuentes-Ferrer 9and Juan Luis Rodriguez Hermosa 1,2 1Pulmonology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain; [email protected] 2Department of Medicine, School of Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain 3Pulmonary Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; [email protected] 4Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28029 Madrid, Spain; [email protected] 5 Respiratory Disease Medical-Surgical Unit, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/Universidad de Sevilla, 41009 Sevilla, Spain 6Pulmonology Department, Hospital Arnau de Vilanova-Lliria, 46015 Valencia, Spain; [email protected] 7Medicine Department, Valencia University, 46010 Valencia, Spain 8Pulmonary Department, Hospital Universitario Virgen de las Nieves, Instituto Biosanitario de Granada, 18014 Granada, Spain; [email protected] 9 Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; [email protected] *Correspondence: [email protected] Abstract: Background: Alpha-1 antitrypsin deficiency (AATD) is an underdiagnosed condition despite being one of the most common inherited disorders in adults that is associated with an increased risk of developing chronic obstructive pulmonary disease (COPD). The aim was to evaluate the frequency of performing AAT levels and associated factors in COPD patients in an audit conducted in 2021–2022, as well as to compare with a previous audit conducted in 2014–2015. Methods: EPOCONSUL 2021 is a cross-sectional audit that evaluated the outpatient care provided to COPD patients in respiratory clinics in Spain based on available data from medical registries. Results: 4225 patients with a diagnosis of COPD from 45 centers were audited in 2021. A total of 1670 (39.5%) patients underwent AAT determination. Being treated at a specialized COPD outpatient clinic (OR 1.88, p= 0.007), age ≤ 55 years old (OR 1.84, p= 0.007) and a FEV1 < 50% (OR 1.86, p< 0.001) were associated with a higher likelihood of being tested for AAT, while Charlson index ≥ 3 (OR 0.63, p< 0.001) and genotyping of AATD availability (OR 0.42, p< 0.001) showed a statistically significant negative association. The analysis of cases included in respiratory units that participated in both audits showed an increase in the proportion of cases with AAT serum level testing available (adjusted OR 2.81, p< 0.001). The percentage of individuals with serum AAT levels < 60 mg/dL (a severe AATD) was 4%. Conclusions: Our analysis identifies significant improvements in adherence to the recommendation to test AAT levels in COPD patients, performed in 4 out of 10 patients, being more likely at younger ages and with higher COPD severity, and with a detection of severe AATD of 4% among those tested, suggesting that clinicians still perform AAT testing in COPD patients selectively. Therefore, efforts are still needed to optimize AATD screening and establish new early detection strategies to reduce morbidity and mortality in these patients. Keywords: α 1-antitrypsin deficiency; diagnosis; chronic obstructive pulmonary disease; clinical audit; outpatient respiratory clinics J. Clin. Med. 2024,13, 955. https://doi.org/10.3390/jcm13040955 https://www.mdpi.com/journal/jcm J. Clin. Med. 2024,13, 955 2 of 15 1. Introduction Alpha-1 antitrypsin deficiency (AATD) is one of the most common hereditary disorders in adults [ 1 ]. It is characterized by abnormally reduced serum alpha-1 antitrypsin (AAT) levels and associated with increased risk for the development of early-onset pulmonary emphysema and liver disease [ 2 ]. It has been suggested that 1–2% of subjects with chronic obstructive pulmonary disease (COPD) have AATD [ 3 ] and that around 1/800 patients with COPD in Europe have severe AATD [ 4 ]. Despite its considerable prevalence, healthcare providers still fail to search for AATD in subjects with pulmonary diseases, and this condition remains largely underdiagnosed [ 5 – 7 ]. Diagnosis is made by the demonstration of reduced blood levels of AAT. Recommendations of healthcare institutions such as the World Health Organization (WHO) [ 8 ], the Spanish National Guidelines for Chronic Obstructive Pulmonary Disease (GesEPOC) [ 9 ] and the American and European Thoracic/Respiratory Societies (ATS/ERS) [ 10 , 11 ] indicate that all COPD patients should be tested for AATD at least once during their lifetime. However, the real-life implementation of these clinical practice guidelines (CPG) is low [12–15]. Clinical audits have emerged as a tool to assess healthcare and provide healthcare professionals with information they can use to improve clinical care provided to patients and clinical outcomes. In this context, Spain used an auditing process that evaluated outpatient care provided to patients with COPD in respiratory clinics in Spain, called EPOCONSUL [ 15 , 16 ], which resulted in the completion of two clinical audits based on available data from medical records. The first of these audits was performed between 1 May 2014, and 1 May 2015, and the second between 15 April 2021, and 31 January 2022. In the present study, we evaluated the results of two consecutive clinical audits performed in Spain to assess the outpatient care provided to COPD patients. This analysis evaluates the frequency of AAT levels and associated factors in the 2021 − 2022 audit and compares it with data from the 2014 − 2015 audit conducted in the same centers. It also analyzes the frequency and clinical characteristics of COPD patients by AAT level. The aim is to provide health professionals with information that they can use to assess and adjust their performance. 2. Materials and Methods The methodology of the 2021 EPOCONSUL audit is similar to that of the 2015 EPOCONSUL audit, which has been reported in previous publications [ 15 , 16 ]. The COPD audit promoted by the Spanish Society of Pneumology and Thoracic Surgery (SEPAR) was designed to evaluate clinical practice as well as clinical and organizational factors related to managing patients with COPD across Spain. It was designed as an observational noninterventional cross-sectional study. The SEPAR sent an official invitation to participate in the study to all the respiratory units in Spain with outpatient respiratory clinics according to the Registry of the Ministry of Health and to the register of members of the SEPAR. Participating investigators in the 2021 EPOCONSUL are included in Supplementary Table S1. Recruitment was intermittent; every month, each investigator recruited the clinical records of the first 10 patients identified as being diagnosed with COPD that were seen in the outpatient respiratory clinic. Subsequently, the patients identified were reevaluated to determine whether they met the inclusion/exclusion criteria described in Supplementary Table S2. The information collected was historical in nature for the clinical data from the last visit pre-pandemic (performed before March 2020) and previous visits; the information about hospital resources was concurrent and is described in Supplementary Table S3. Based on the serum AAT levels, individuals were classified as follows: no deficiency, AAT ≥ 116 mg/dL; intermediate deficiency, AAT between 60 mg/dL and 116 mg/dL; and severe deficiency, AAT < 60 mg/dL [17]. The protocol was approved by the Ethics Committee of the Hospital Clínico San Carlos (Madrid, Spain; internal code 20/722-E, approval 11/2020). Additionally, according to current research laws in Spain, the ethics committee at each participating hospital evaluated and agreed to the study protocol. The need for informed consent was waived J. Clin. Med. 2024,13, 955 3 of 15 because this was a clinical audit, in addition to the non-interventional nature of the study, the anonymization of data and the blind evaluation of the clinical performance. This circumstance was clearly explained in the protocol, and the ethics committees approved this procedure. To avoid modifications to the usual clinical practice and preserve the blinding of the clinical performance evaluation, the medical staff responsible for the outpatient respiratory clinic were not informed about the audit. Data were entered remotely at each participating location to a centrally controlled server. Statistical Analysis Qualitative variables were summarized by their frequency distribution and quantitative variables by their mean and standard deviation (SD). The association between each independent variable (patient characteristics and hospital resources) and the dependent variable AAT level determination were assessed by calculating the crude odds ratio (OR) via logistic regression with cluster robust standard errors to account for patients being tested within hospitals. A multivariable logistic model was fitted in order to evaluate the independent effect of the selected variables. Candidate predictors with a value of p< 0.10 in the bivariate analysis were accepted for inclusion in the multivariate analysis. To compare the determination of AAT levels between the two audits, a logistic regression with cluster robust standard errors was fitted including only patients from hospitals that participated in both audits. The adjustment variables of the model were those factors that were related to the determination of AAT in both the first and second audit and were collected in a homogeneous way. AAT levels were grouped into three categories (<60 mg/dL, ≥ 60–<116 mg/dL, and ≥ 116 mg/dL). Comparisons between the ≥ 116 group and the other groups were made by logistic regression with cluster robust standard errors. Statistical significance was assumed as p< 0.05. All analyses were performed using Stata software version 16 (StataCorp LLC, CollegeStation, TX, USA). 3. Results A total of 4225 patients with a diagnosis of COPD from 45 centers were audited. Of the analyzed cohort, only 1670 (39.5%) patients underwent AAT determination. 3.1. Characteristics of the Participating Hospitals and Resources of the Respiratory Units and Their Association with AAT Testing Most participating centers were university hospitals (85%) and had a complexity level III (77.4%). There were 64.6% centers with a specialized COPD outpatient clinic, and the availability of AAT genetic testing was 88.8%. The center-level variables were not associated with AAT testing, except the availability of genotyping of AAT (OR 0.58, p= 0.030) and being treated at a specialized COPD outpatient clinic (OR 1.63, p= 0.032). Table 1describes the logistic regression bivariate analysis with the variables related to centers and the association with AAT testing. Table 1. Characteristics of the participating hospitals, resources of the respiratory units and association with levels of AAT available (logistic regression bivariate analysis). All Patients (n= 4.225) AAT Levels Test n= 1670 (39.5%) AAT Levels Not Tested n= 2555 (60.5%) OR (95%CI) p Hospital complexity level, n (%) Level II (reference) 1 Level III 3271 (77.4) 1255 (75.1) 2016 (78.9) 0.80 (0.43–1.49) 0.499 University hospital, n (%) No (reference) 1 Yes 3593 (85) 1412 (84.6) 2181 (85.4) 0.93 (0.47–1.84) 0.853 J. Clin. Med. 2024,13, 955 4 of 15 Table 1. Cont. Minutes at outpatient respiratory visit available, n (%) <15 min (reference) 1 ≥15 min 2258 (53.4) 979 (58.6) 1279 (50.1) 1.41 (0.85–2.32) 0.173 Genotyping of AATD availability, n (%) Not available (reference) 1 Yes 3750 (88.8) 1426 (85.4) 2324 (91) 0.58 80.35–0.94) 0.030 Specialized COPD outpatient clinic available, n (%) Not available (reference) 1 Yes 2729 (64.6) 1076 (64.4) 1653 (64.7) 0.98 (0.58–1.66) 0.965 Outpatient respiratory nursing clinic availability, n (%) Not (reference) 1 Yes 2373 (56.2) 969 (58) 1404 (55) 1.13 (0.67–1.88) 0.632 Written COPD protocol available, n (%) Not available (reference) 1 Yes 1747 (41.3) 761 (45.6) 986 (38.6) 1.33 (0.78–2.25) 0.286 Attended in specialized COPD outpatient clinic, n (%) Not available (reference) 1 Yes 1620 (38.5) 757 (45.5) 863 (33.9) 1.63 (1.04–2.55) 0.032 Data are represented as absolute (relative) frequencies. Odd Ratio (OR), 95% confidence interval and pvalue obtained via logistic regression with cluster robust standard errors. 3.2. Clinical Characteristics of the Audited Cases and Their Association with AAT Testing Table 2describes the characteristics of the evaluated patients in the 2021 audit and the patient-level variables that were associated with AAT level determination in logistic regression bivariate analysis. In the adjusted model, summarized in Table 3, being treated at a specialized COPD outpatient clinic (OR 1.88, p= 0.007), age ≤ 55 years old (OR 1.84, p= 0.007) and a FEV1(% predicted) < 50% (OR 1.86, p< 0.001) were associated with a higher likelihood of being tested for AAT, while Charlson index ≥ 3 (OR 0.63, p< 0.001) and genotyping of AATD availability (OR 0.42, p< 0.001) showed a statistically significant negative association. Table 2. Characteristics of the patient and association with levels of AAT available (logistic regression bivariate analysis). All Patients (n= 4.225) Patients with Levels of AAT n= 1670 (39.5%) Patients without Levels of AAT n= 2555 (60.5%) OR (95%CI) p Sex, n (%) Male (reference) 1 Female 1152 (27.2) 498 (29.8) 654 (25.5) 1.23 (1.04–1.47) 0.016 Age (years), m (SD) 70.0 (9.3) 67.9 (8.9) 71.3 (9.2) 0.96 (0.94–0.97) <0.001 >55, (n, %) (reference) 1 ≤55, (n, %) 268 (6.3) 150 (9) 118 (4.6) 2.03 (1.36–3.04) 0.001 IPA (×10 Pack-years), m (SD) 49.6 (24.0) 48.9 (23.1) 50.1 (24.6) 0.99 (0.99–1.00) 0.368 Active smokers, n (%) No (reference) 1 Yes 1053 (24.9) 439 (26.3) 614 (24) 1.12 (0.91–1.38) 0.225 BMI kg/m2, m (SD) 27.8 (5.6) 27.1 (5.6) 28.3 (5.6) 0.96 (0.95–0.97) 0.001 >21 (n, %) (reference) 1 ≤21 (n, %) 364 (9.1) 172 (10.6) 192 (8.1) 1.33 (1.02–1.74) 0.031 Charlson index, n (%) <3 (reference) 1 ≥3 1185 (28.1) 388 (23.3) 797 (31.2) 0.66 (0.54–0.81) <0.001 Dyspnea (MRC-m), n (%) <2 (reference) 1 ≥2 1787 (56) 746 (54.8) 1041 (56.9) 0.91 (0.70–1.189 0.512 Chronic bronchitis criteria, n (%) Not (reference) 1 Yes 1298 (30.7) 552 (33.1) 746 (29.2) 1.19 (0.89–1.599 0.217 J. Clin. Med. 2024,13, 955 5 of 15 Table 2. Cont. All Patients (n= 4.225) Patients with Levels of AAT n= 1670 (39.5%) Patients without Levels of AAT n= 2555 (60.5%) OR (95%CI) p History of asthma, n (%) Not (reference) Yes 411 (9.7) 211 (12.6) 200 (7.8) 1.70 (1.11–2.60) 0.014 FEV1 (%predicted post-BD), m (SD) ≥80, 53.1 (18.5) 50.7 (18.1) 54.7 (18.6) 0.98 (0.98–0.99). <0.001 n (%) (reference) 346 (8.2) 96 (5.8) 250 (9.8) 1 50–79%, n (%) 1952 (46.3) 727 (43.6) 1225 (48) 1.54 (1.13–2.10) 0.006 <50%, n (%) 1992 (45.5) 846 (50.7) 1076 (42.2) 2.04 (1.48–2.82) <0.001 GesEPOC Phenotype, n (%) Non-exacerbator (reference) 1226 (46.2) 515 (43.3) 711 (48.5) 1 Exacerbator with chronic bronchitis 446 (16.8) 190 (16) 256 (17.5) 1.02 (0.71−1.8) 0.893 Exacerbator with emphysema 570 (21.5) 279 (23.4) 291 (19.8) 1.32 (0.94−1.8) 0.101 Asthma-COPD 414 (15.6) 206 (17.3) 208 (14.2) 1.36 (0.93−1.9) 0.103 Number of hospital admissions in the last year, n (%) <1 (reference) 1 ≥1 692 (16.4) 316 (18.9) 376 (14.7) 1.35 (1.03−1.76) 0.025 Chronic colonization, n (%) Not (reference) 1 Yes 494 (11.7) 227 (13.6) 267 (10.5) 1.34 (0.83−2.17) 0.219 Triple therapy, n (%) Not (reference) 1 Yes 2034 (50.3) 870 (54.3) 1164 (47.7) 1.30 (1.07−1.58) 0.007 Long-term oxygen therapy, n (%) Not (reference) 1 Yes 1059 (25.1) 408 (24.4) 651 (25.5) 0.94 (0.76−1.16) 0.601 Home ventilation, n (%) Not (reference) 1 Yes 362 (8.6) 125 (7.5) 237 (9.3) 0.79 (0.56−1.11) 0.180 Respiratory care follow-up (years), (median, IQR) 5.8 (3.6−9.0) 5.6 (3.5−8.8) 6 (3.7−9.2) 0.98 (0.95−1.00) 0.185 Data are represented as mean (standard deviation), absolute (relative) frequencies or median (IQR: interquartile range); Odds Ratio (OR), 95% confidence interval and pvalue obtained via logistic regression with cluster robust standard errors. Abbreviations: BMI—body mass index; IPA—tobacco pack-years; mMRC—modified Medical Research Council; %predicted post-BD FEV1—percent predicted post-bronchodilator FEV1; GesEPOC—Spanish National Guidelines for COPD; Triple therapy—long-acting beta-2 agonists, long-acting antimuscarinic agents and inhaled corticosteroids. Table 3. Multivariate logistic regression to identify independent factors associated with testing of levels of AAT in COPD patients. Variable OR (95%CI) p Genotyping of AATD availability Not (reference) 1 Yes 0.42 (0.26−0.68) 0.001 Attended in specialized COPD outpatient clinic Not (reference) 1 Yes 1.88 (1.19−2.99) 0.007 %FEV1 postBD ≥80% (reference) 1 50−79% 1.50 (1.08−2.08) 0.013 <50% 1.86 (1.36−2.55) <0.001 BMI kg/m2 >21 (reference) 1 ≤21 1.18 (0.91−1.53) 0.193 Age (years) >55 (reference) 1 ≤55 1.84 (1.18−2.85) 0.007 Gender Male (reference) 1 Female 1.16 (0.97−1.40) 0.101 J. Clin. Med. 2024,13, 955 6 of 15 Table 3. Cont. Variable OR (95%CI) p Number of hospital admissions in the last year <1 (reference) 1 ≥1 1.25 (0.96−1.64) 0.093 Charlson index <3 (reference) 1 ≥3 0.63 (0.52−0.76) <0.001 History of asthma Not (reference) 1 Yes 1.53 (0.96−1.43) 0.069 Odds Ratio (OR), 95% confidence interval and pvalue obtained via logistic regression with cluster robust standard errors. Abbreviations: BMI—body mass index; %predicted post-BD FEV1—percent predicted post-bronchodilator FEV1. 3.3. Variations in Testing AAT between the 2 Audits A total of 25 hospitals participated in both audits. The analysis of cases included in respiratory units that participated in both audits showed an increase in the proportion of cases with AAT serum level testing available (audit 1: 18.9%; audit 2: 38.7%, p< 0.001), presented in Figure 1. In the adjusted model, the analysis showed an increase in the percentage of requests adjusting for factors influencing the request between the two audits, (OR 2.81, p< 0.001), summarized in Table 4, which shows some characteristics of interest in relation to testing AAT of patients and centers that participated in both audits. Figure 1. Distribution of patients according to availability of determination of alpha-1 antitrypsin levels in serum in 2014/2015 and 2021/2022 in the centers that participated in both audits. Table 4. Multilevel logistic regression models of the variations in testing AAT between the 2 audits. Number of Participating Hospitals Total Number of Patients Assessed in the Two Audits % Patients with Levels of Alpha-1 Antitrypsin Serum Testing in Audit 2015 % Patients with Levels of Alpha-1 Antitrypsin Serum Testing in Audit 2021 OR (95 % CI) p Adjusted OR * (95 % CI) p 25 4573 408 (18.9) 934 (38.7) 2.70 (1.70−4.28) <0.001 2.81 (1.63−4.84) <0.001 Center and patient characteristics in the 2015 and 2021 audits of variables of interest for AAT testing in COPD In Audit 2015 (n= 2157) In Audit 2021 (n= 2416) p Genotyping of AATD availability, n(%) 1566 (72.6) 2406 (99.6) <0.001 Number of attendees in specialized COPD outpatient clinic, n(%) 765 (35.5) 1300 (53.9) <0.001 %FEV1 postBD < 50%, n(%) 658 (44.6) 1196 (49.6) 0.011 BMI (kg/m2)≤21, n(%) 156 (7.3) 229 (10) 0.001 Age (years) ≤55, n(%) 184 (8.5) 138 (5.7) <0.001 Female, n(%) 318 (14.7) 685 (28.4) <0.001 J. Clin. Med. 2024,13, 955 7 of 15 Table 4. Cont. Number of Participating Hospitals Total Number of Patients Assessed in the Two Audits % Patients with Levels of Alpha-1 Antitrypsin Serum Testing in Audit 2015 % Patients with Levels of Alpha-1 Antitrypsin Serum Testing in Audit 2021 OR (95 % CI) p Adjusted OR * (95 % CI) p Number of hospital admissions in the last year ≥1, n(%) 538 (24.9) 380 (15.7) <0.001 Charlson index ≥3, n(%) 920 (42.7) 666 (27.6) <0.001 Have history or symptoms of asthma, n(%) 540 (25) 237 (9.8) <0.001 Chronic bronchitis criteria, n(%) 843 (39.1) 661 (27.4) <0.001 Home ventilation, n(%) 177 (8.2) 224 (9.3) 0.111 * The adjustment variables of the model were adjusted by being treated at a specialized COPD outpatient clinic, age ≤ 55 years old, FEV1 < 50%, BMI ≤ 21, female, number of hospital admissions in the last year ≥ 1, medical history of asthma, home ventilation, Charlson index ≥ 3 and genotyping of AATD availability. Odds Ratio (OR), 95% confidence interval and pvalue obtained via logistic regression with cluster robust standard errors. 3.4. Clinical Characteristics of Patients According to AAT Levels and Procedures Conducted for COPD Evaluation In total, 331 (20%) of the 1651 patients tested had serum AAT levels < 116 mg/dL. Of them, 265 (16) patients had serum AAT levels between 60 mg/dL and 116 mg/dL (might be considered an intermediate AATD) with a mean plasma AAT level of 98.9 (SD 14.2) mg/dL, while 66 (4% of those tested) patients had serum AAT levels < 60 mg/dL (a severe AATD) with a mean plasma AAT level of 19.3 (SD 14.6) mg/dL (Figure 2). Patients with severe AATD had more dyspnea (MRC-m) ≥ 2 (OR 2.56, p< 0.001), were more likely to have phenotype of exacerbator chronic bronchitis (OR 3.34, p= 0.023) and were less likely to be active smokers (OR 0.58, p= 0.023) than individuals with normal AAT levels ≥116 mg/dL. During follow-up, the chest CT scan was more frequently carried out in patients with severe AATD (OR 13.6, p= 0.026), as summarized in Table 5. Figure 2. Distribution of patients according to availability of AAT level determination and based on the AAT levels in patients audited in 2021/2022. Severe AATD: serum AAT levels < 60 mg/dL; Intermediate AATD: serum AAT levels between 60 mg/dL and 116 mg/dL; Normal AAT level: serum AAT levels > 116 mg/dL. J. Clin. Med. 2024,13, 955 8 of 15 Table 5. Characteristics of patients and procedures conducted during the follow-up for COPD evaluation according to AAT levels (binary logistic regression). Characteristics of the Patient Tested for AAT n= 1651 Patients with AAT Level < 60 mg/dL n= 66 (4%) Patients with AAT Level ≥ 60 and <116 mg/dL n= 265 (16%) Patients with AAT Level ≥116 mg/dL n= 1320 (80%) OR (95%CI) AAT Level ≥60 and <116 mg/dL vs. ≥ 116 mg/dL (Reference) p OR (95%CI) AAT Level < 60 mg/dL vs. ≥116 mg/dL (Reference) p AAT plasma level (mg/dL), m(SD) 19.3 (14.6) 98.9 (14.2) 160.9 (58.0) Clinical characteristics Age (years), m (SD) 0.98 (0.96−0.99) 0.99 (0.92−1.06) 0.836 >55, (n, %) (reference) 67.6 (11.4) 66.7 (8.5) 68.1 (8.8) 1 0.015 1 ≤55, (n, %) 12 (18.2) 23 (8.7) 114 (8.6) 1.00 (0.61−1.63) 0.985 2.34 (0.89−6.15) 0.082 Sex (female), (reference) 1 1 Male n (%) 49 (74.2) 187 (70.6) 919 (69.6) 1.04 (0.77−1.41) 0.772 1.25 (0.61−2.58) 0.533 Active smokers, n (%) No (reference) 1 Yes 12 (18.2) 58 (21.9) 364 (27.6) 0.73 (0.45−1.18) 0.206 0.58 (0.36−0.92) 0.023 IPA (Pack-years), m (SD) 42.7 (19.9) 47.7 (24) 49.4 (23.1) 0.99 (0.98−1.00) 0.454 0.98 (0.96−1.00) 0.192 BMI kg/m2, m (SD) 26.4 (4.0) 27.5 (5.2) 27.1 (5.8) 0.6 (0.98−1.03) 0.426 0.97 (0.93−1.01) 0.174 >21 n (%) (reference) 1 1 ≤21 n (%) 5 (7.7) 23 (9.1) 144 (11.2) 0.79 (0.48−1.28) 0.347 0.66 (0.18−2.42) 0.536 Dyspnea (MRC-m), n (%) <2 (reference) 1 1 ≥2 46 (75.4) 109 (51.4%) 584 (54.4) 0.88 (0.64−1.21) 0.457 2.56 (1.67−3.94) <0.001 Charlson index, n (%) <3 (reference) 1 ≥3 24 (36.4) 45 (17) 315 (23.9) 0.65 (0.46−0.91) 0.012 1.81 (0.99−3.33) 0.053 Chronic bronchitis criteria, n (%) Not (reference) 1 Yes 27 (40.9) 78 (29.4) 439 (33.3) 0.83 (0.61−1.14) 0.260 1.38 (0.52−3.69) 0.510 History of asthma, n (%) Not (reference) 1 Yes 3 (4.5) 35 (13.6) 167 (12.8) 1.07 (0.67−1.68) 0.768 0.32 (0.06−1.65) 0.176 GesEPOC Phenotype, n (%) Non-exacerbator (reference) 18 (33.3) 89 (48.4) 404 (43) 1 1 Exacerbator chronic bronchitis 21 (38.9) 25 (13.6) 141 (15) 0.80 (0.42−1.52) 0.504 3.34 (1.21−9.20) 0.020 Exacerbator with emphysema 12 (22.2) 36 (19.6) 228 (24.3) 0.71 (0.45−1.11) 0.143 1.18 (0.66−2.09) 0.560 Asthma-COPD 3 (5.6) 34 (18.5) 166 (17.7) 0.92 (0.53−1.62) 0.798 0.40 (0.13−1.18) 0.098 Number of hospital admissions in the last year, n (%) <1 (reference) 1 1 ≥1 25 (37.9) 46 (17.4) 240 (18.2) 0.94 (0.65−1.35) 0.761 2.74 (0.84−8.87) 0.092 FEV1 (%), m (SD) 52.8 (16.8) 51.5 (17.6) 50.4 (18.4) 0.6 (0.99−1.00) 0.335 1.00 (0.99−1.02) 0.411 ≥80, n (%) (reference) 31 (47) 14 (5.3) 78 (5.9) 1 1 50–79%, n (%) 31 (47) 125 (47.2) 562 (42.6) 1.23 (0.63−2.41) 0.914 1.07 (0.24−4.78) 0.924 <50%, n (%) 4 (6.1) 126 (47.5) 679 (51.5) 1.03 (0.56−1.89) 0.528 0.89 (0.33−2.33) 0.813 BODE index, m (DE) 3.8 (2.2) 3.1 (2.2) 4.0 (2.0) 0.83 (0.74−0.93) 0.003 0.95 (0.76−1.19) 0.689 Long-term oxygen therapy, n (%) Not (reference) 1 1 Yes 18 (27.3) 56 (21.1) 329 (24.9) 0.80 (0.60−1.07) 0.149 1.12 (0.53−2.36) 0.747 J. Clin. Med. 2024,13, 955 9 of 15 Table 5. Cont. Characteristics of the Patient Tested for AAT n= 1651 Patients with AAT Level < 60 mg/dL n= 66 (4%) Patients with AAT Level ≥ 60 and <116 mg/dL n= 265 (16%) Patients with AAT Level ≥116 mg/dL n= 1320 (80%) OR (95%CI) AAT Level ≥60 and <116 mg/dL vs. ≥ 116 mg/dL (Reference) p OR (95%CI) AAT Level < 60 mg/dL vs. ≥116 mg/dL (Reference) p Diagnostic procedures conducted during the follow-up for COPD evaluation Diffusion capacity measured on any occasion, n (%) Not (reference) 1 1 Yes 51 (77.3) 265 (80.1) 996 (75.5) 1.36 (0.94−1.97) 0.100 1.10 (0.56−2.16) 0.769 Lung volumes measured on any occasion, n (%) Not (reference) 1 1 Yes 21 (31.8) 790 (58.8) 970 (58.8) 1.00 (0.72−1.39) 0.970 0.31 (0.09−1.00) 0.051 6-min walk test carried out on any occasion, n (%) Not (reference) 1 1 Yes 27 (40.9) 786 (59.5) 962 (58.3) 0.87 (0.62−1.22) 0.431 0.47 (0.09−2.34) 0.358 BODE index calculated on any occasion, n (%) Not (reference) 1 1 Yes 17 (25.8) 565 (42.8) 699 (42.3) 1.05 (0.77−1.44) 0.733 0.46 (0.08−2.63) 0.386 Chest CT carried on any occasion, n (%) Not (reference) 1 1 Yes 65 (98.5) 1091 (82.7) 1381 (83.6) 1.18 (0.85−1.63) 0.320 13.6 (1.36−136.0) 0.026 Data are represented as mean (standard deviation) or absolute (relative) frequencies or median (IQR: interquartile range); Abbreviations: AAT—alpha-1 antitrypsin; IP—tobacco pack-years; BMI—body mass index; mMRC—modified Medical Research Council; %predicted post-BD FEV1—percent predicted post-bronchodilator FEV1; GesEPOC—Spanish National Guidelines for COPD; BODE—body mass index, airflow obstruction, dyspnea and exercise capacity; 6MWT—6-min walk test; CT—computerized tomography; Odds Ratio (OR), 95% confidence interval and pvalue obtained via logistic regression with cluster robust standard errors.