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Introduction The detrimental impact of pulmonary exacerbations on lung function in Alpha-1 Antitrypsin Deficiency (AATD) is well established. However, limited research exists on the relationship between patient-reported outcomes (PROs) and exacerbation frequency. Exploring this link is important, as it integrates patient experience with clinical indicators, supports early intervention, and connects subjective symptom reporting with objective clinical deterioration in this rare chronic disease.Study Aim To examine the association between exacerbation frequency and patient-reported outcomes in individuals with alpha-1 antitrypsin deficiency and assess the strength of these associations in relation to lung function (FEV1%).Method Data for patients with PiZZ AATD was extracted from a cohort/registry held at Queen Elizabeth Hospital Birmingham. Patients were categorized, based on their self-reported exacerbation frequency over the previous 12 months, into frequent exacerbators FE (≥2), infrequent exacerbators IE (<2), and non-exacerbators (0). PROs were measured using the St. George’s Respiratory Questionnaire (SGRQ), the COPD Assessment Test (CAT), and the Modified Medical Research Council (mMRC) Dyspnea Scale. Associations were analyzed using non-parametric tests, Spearman correlation, and multivariable linear regression to control for confounders such as smoking history, COPD diagnosis, and FEV1%.Results A total of 234 PiZZ patients were included in this study. The FE group (n=69) reported significantly poorer PROs when compared to the IE group (n=165), even though FEV1% was not significantly different between the two groups (p = 0.055). When comparing exacerbators (both FE and IE) to non-exacerbators, all PROs and FEV1% were significantly different with poorer results seen in the exacerbators group. Spearman rank correlation supported that lower FEV1% and more exacerbations are significantly correlated with poorer PROs (p ≤ 0.001 in all correlations). Multiple regression analysis confirmed that both exacerbation frequency and FEV1% independently predicted PRO scores, with FEV1% showing stronger correlations with activity and dyspnea severity.Abstract S128 Table 1Demographic characteristics and clinical parameters of all patients with association between exacerbation frequency groups, demographic, and clinical characteristics Variables Total n=234 FE 69 (29.49) IE 165 (70.51) p-value# Age 53 (45–62) 51 (42–60) 55 (46–63) 0.051 a Gender Male 129 (55.13) 32 (43.68) 97 (58.79) 0.082 b Female 105 (44.87) 37 (53.62) 68 (41.21) Pack-year 8 (0–19) 10 (0–19) 8 (0–19.50) 0.380 a Smoking status Current smoker 16 (6.84) 4 (5.80) 12 (7.27) 0.386b Never smoking 78 (33.33) 19 (27.54) 59 (35.76) Former smoking 140 (59.83) 46 (66.67) 94 (56.97) Genotype ZZ 196 (83.76) 57 (82.61) 139 (84.24) 0.757 b Genotype SZ 38 (16.24) 12 (17.39) 26 (15.76) COPD diagnosis Yes 172 (73.50) 52 (75.36) 120 (72.73) 0.747 b No 62 (26.50) 17 (24.64) 45 (27.27) FEV1% 58.50 (39.38–91) 50.47 (31.93–83.00) 60 (43.51–93.85) 0.057 a CAT 20 (2–26) 22 (15.50–29.00) 19 (11.00–25.00) 0.010 a * SGRQ Symptoms 62.25 (45.30–78.50) 70.30 (56.12–88.45) 59.80 (36.50–73.70) <0.001 a * SGRQ Activity 66.19 (41.31–92.51) 84.98 (47.69- 92.51) 60.35 (35.36–91.97) 0.016 a * SGRQ Impact 30.82 (17.39–52.47) 45.04 (21.25–63.19) 25.98 (13.38–47.66) 0.001 a * SGRQ Total 47.38 (29.42–67.26) 59.64 (37.29–74.39) 42.18 (25.13–63.57) <0.001 a * mMRC 0 70 (29.91) 16 (23.19) 54 (32.73) 0.037 b * mMRC 1 57 (24.36) 15 (27.14) 42 (25.45) mMRC 2 50 (21.37) 12 (17.39) 38 (23.03) mMRC 3 39 (16.67) 19 (27.54) 20 (12.12) mMRC 4 18 (7.69) 7 (10.14) 11 (6.67) Parameters are reports as median (IQR) or n (%) ; a: Mann Whitney U test; b: Chi-square or Fisher exact test; *-Significant p value < 0.05; #-comparison reported between FE and IE. IQR: Inter quartile range; FE: Frequent exacerbators; IE: infrequent exacerbators; SGRQ: St George’s Respiratory Questionnaire; COPD: chronic obstructive pulmonary disease; FEV1%: forced expiratory volume in one second; CAT: COPD Assessment Test; mMRC: Modified Medical Research Council Dyspnea ScaleConclusion Exacerbation frequency and impaired lung function are associated with poorer PROs in individuals with AATD. These findings support the clinical relevance of integrating PROs into routine assessment for AATD patients, especially those at risk of frequent exacerbations. Routine PRO monitoring may facilitate early intervention, improve patient-cantered care and quality-of-life outcomes.