**Background:** Hereditary angioedema (HAE) is a rare, potentially fatal disorder characterized by recurrent swelling of the skin and submucosa, mediated by bradykinin release via the contact activation system. C1 inhibitor (C1-INH) deficiency (type I, 85% of cases) or dysfunction (type II, 15%) leads to uncontrolled activation of factor XII and kallikrein. HAE with normal C1-INH (nC1-INH) has been linked to mutations in F12, PLG, ANGPT1, KNG1, MYOF, and HS3ST6 genes. Prevalence is estimated at approximately 1:40,000 (range 1:10,000–1:50,000). Onset typically occurs in childhood or adolescence and persists lifelong. Attacks involve skin, gastrointestinal, and respiratory systems, resolve within 3–5 days if untreated, and cause considerable morbidity and mortality. HAE impairs HRQoL to a degree equivalent to severe asthma and Crohn's disease. Diagnosis is delayed in about one-third of cases by more than 10 years. This narrative review compares the effects of acute vs. long-term prophylaxis on HRQoL and assesses the prevalence of anxiety and depression.
**Methods:** A PubMed search using MeSH terms "Quality of Life" and "Hereditary Angioedema" was conducted in December 2021 for English-language articles published between 2011 and 2021. An additional search identified publications reporting QoL with treatments for acute attacks and long-term prophylaxis. Long-term prophylaxis treatments of interest were restricted to berotralstat and lanadelumab. Abstracts, conference posters, and secondary sources were excluded. Fourteen key studies were included and summarized in two tables.
*Productivity:* HAE causes substantial work and school absenteeism. On average, 20 work or school days are lost per year. In Sweden, 44% of patients were absent from work during an attack, and 81% of severe attacks resulted in absenteeism. A European Union report found that 42% of patients experienced delayed educational advancement, 40% were restrained from applying for specific jobs, and 36% had reduced career development. In Brazil, a systematic intervention study reported mild-to-moderate impairment, with 88.1% reporting no absenteeism.
*Anxiety and Depression:* A survey of 242 patients across eight countries found 38% experienced moderate to severe anxiety and 17.4% depression (HADS). A US study reported 39% of adult HAE patients had depression and 15% had anxiety. A noninterventional US survey of 445 adults found anxiety in 35.3% and depression in 20.9%, with 7.6% of anxiety and 3.4% of depression cases being severe (HADS ≥15). Among 186 European patients, depression was reported in 23% (Spain), 8% (Germany), and 10% (Denmark); anxiety in 46%, 39%, and 24%, respectively. Anxiety and depression levels correlate with HAE severity. A German study using both HADS and GAD-7 reported discrepant results: 43.2% via HADS anxiety scale vs. 25% via GAD-7.
*On-Demand Treatment:* Nunes et al. (2021) reported HAE-QoL total score increases of 15.2 (95% CrI: 1.23–29.77) at 8 months and 26 (95% CrI: 14.56–39.02) at 14 months with systematic intervention. Zanichelli et al. (2018) found no statistically significant HAE-QoL changes after 12 months of C1-INH-nf self-infusion (baseline median 86 [IQR: 76–103] to 94 [IQR: 86–113]). Bewtra et al. (2012) reported positive SF-12 impacts with single-dose C1-INH for acute attacks.
*Prophylactic Treatment:* Buttgereit et al. (2021) reported AE-QoL reduction from 45.8 to 13.8 (mean change 32; p < 0.001) with lanadelumab in real-life. The HELP study showed lanadelumab 300 mg every 2 weeks achieved the highest proportion (81%; p = 0.001) achieving MCID, with 7.2 times greater likelihood vs. placebo. Mean AE-QoL total score change for the lanadelumab total group was −19.47 ± 2.02 (p < 0.01). Watt et al. (2021) reported sustained improvements over 132 weeks. Berotralstat (APeX-2) showed AE-QoL total score improvement from week 4 through week 48; after 48 weeks, 67% of patients achieved MCID. Aygören-Pürsün et al. (2018) reported a least-squares mean change of −29.0 for berotralstat 125 mg vs. −4.5 for placebo (difference −24.5; p < 0.001). C1-INH(SC) in the COMPACT open-label extension showed mean total AE-QoL scores between 13.39 and 17.89 and mean HAE-QoL global scores between 115.7 and 122.3 (best possible 135). Lumry et al. (2021) reported EQ-5D health state value improvement of 0.07 (95% CI: 0.01–0.12), HADS anxiety reduction of −1.23 (95% CI: −2.08 to −0.38), and depression reduction of −0.95 (95% CI: −1.57 to −0.34).
**Clinical Implications:** Both on-demand and long-term prophylaxis improve HRQoL in HAE patients. Prophylactic treatments (lanadelumab, berotralstat, C1-INH[SC]) consistently improve functioning, fears/shame, and nutrition domains, with approximately 60% of patients achieving MCID. The high prevalence of anxiety (8–46%) and depression (8–23%) underscores the need for routine mental health screening using appropriate instruments (e.g., GAD-7, PHQ-9) rather than HADS alone. Disease-specific tools (AE-QoL, HAE-QoL) should be used in clinical practice instead of generic instruments. A multidisciplinary approach addressing both medical and psychological aspects is essential. No validated pediatric HAE-specific QoL instruments exist, representing an unmet need.