D1.257 - Hereditary Angioedema in Bulgaria (1972-2025): A Longitudinal Comparative Study of Trends in Diagnosis, Mortality, and the Impact of Modern Therapies

Hereditary angioedema (HAE) is a rare, potentially life-threatening genetic disorder characterized by recurrent angioedema attacks. Since the first Bulgarian case in 1972, a unique five-decade national experience has accumulated. This study presents the first longitudinal comparison of HAE in Bulgaria, reflecting the transition from limited diagnostic and therapeutic options to modern targeted care.

Two cohorts were analysed: a retrospective cohort (1972–2012) and a prospective cohort (2013–2025) followed under structured care with access to C1-INH concentrates, bradykinin receptor antagonists and long-term prophylaxis. Diagnosis was based on clinical features, quantitative and functional C1-INH, C4, C1q and genetic testing. Outcomes included age at symptom onset and diagnosis, attack frequency and severity, and survival.

The retrospective cohort comprised 202 patients from 41 families and the prospective cohort 150 patients from 44 families. Median age at symptom onset was similar (14.6 vs 15.9 years), while diagnostic delay increased from 10.2 to 13.9 years. Before long-term prophylaxis, disease activity was high, with a mean of 4.9 attacks per month; 67% of patients had ≥3 and 36% ≥5 attacks monthly. Accordingly, most patients had Bygum severity scores ≥5, indicating a predominantly severe phenotype. In the historical cohort, 27% died (median age 36.6 years), mainly from laryngeal edema (60.7%, median age 33.3 years). In contrast, only two HAE related deaths (1.5%) occurred in the modern cohort, confirming a marked reduction in mortality after the introduction of bradykinin-targeted therapies. Children and elderly patients were under-represented compared with the general population (9.2% and 21.4% vs 14.0% and 23.9%), suggesting persistent underdiagnosis and reduced life expectancy in earlier generations. Genetic testing revealed previously unreported SERPING1 variants, allowing reclassification of apparently unrelated families.

Over the past five decades, HAE-related mortality in Bulgaria has markedly declined with the advent of modern targeted therapies; however, diagnostic delay remains substantial. Enhancing disease awareness and establishing earlier diagnostic pathways are essential to maximize the benefits of contemporary treatment.