Real-life Ecological Momentary Assessment of Lived Burden in Hereditary AngioEdema

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent attacks of non-pruritic edema, localized at the subcutaneous, submucosal, and visceral levels. These attacks, caused by a temporary and localized increase in vascular permeability mediated by bradykinin, can affect the skin, gastrointestinal tract, face, genitals, and upper airways, resulting in a risk of asphyxiation. The most common forms of HAE are Type 1 (85-90%), caused by a quantitative deficiency of C1-inhibitor (HAE-C1INH-Type1), and Type 2 (10-15%), due to a qualitative dysfunction of the same (HAE-C1INH-Type2). In Italy, the overall prevalence is estimated at approximately 1:65,000.

HAE attacks occur unpredictably, with an average frequency that is highly heterogeneous between subjects, ranging on average from 1 to 26 episodes per year; some severe cases can reach 100 attacks per year. These manifestations have an average duration of about 2-5 days and are often debilitating, significantly compromising quality of life (QoL) and the subject's functional abilities. The impact of the disease is not limited to the presence, duration, or frequency of attacks but persists during intercritical periods, often accompanied by anticipatory anxiety and a constant sense of vulnerability, which can lead to a state of hypervigilance.

Numerous studies describe the Burden of Disease (BoD) as multidimensional. The impact on QoL concerns physical, psychological, social, and professional dimensions. From a psychological and emotional perspective, many HAE patients report high levels of stress, anxiety, and depressive symptoms, often linked to the unpredictability of attacks and the perception of poor control over their condition. Furthermore, despite therapeutic progress, the potential risk of fatal laryngeal edema remains a significant source of concern for many patients, contributing to a persistent emotional burden.

At the professional level, a reduction in productivity is observed due to both absenteeism and presenteeism, with European studies documenting an average of up to 20 days lost per year between school and work. Finally, on a social level, some patients report experiences of stigmatization or discrimination, with a negative impact on relational well-being and social integration.

Until now, BoD in HAE has been assessed primarily through retrospective questionnaires and standardized measures administered at single time points, such as the Angioedema Quality of Life (AE-QoL), the Angioedema Activity Score (AAS), or the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH). While validated and widely used, these instruments present several methodological limitations. In particular, they rely on subjective estimates reported within more or less broad time windows (e.g., the last two weeks or the previous month) and are therefore susceptible to recall bias, the mnemonic distortion in the reconstruction of past experiences. Moreover, these tools are developed to provide a static snapshot of subjective BoD, which may fail to capture the dynamic trends and the intra- and inter-individual fluctuations typical of the HAE experience, especially concerning emotional, social, or symptomatic events occurring in daily life.