This study aims to evaluate the differences in objective and subjective stress responses between patients with hereditary angioedema and healthy individuals to a stress-induced challenge like socially-evaluated cold pressure test. The study also investigates the role of psychological variables in influencing the stress response.

Stressful encounters, ranging from daily hassles to major life events, are ubiquitous in our everyday lives and are often responsible for significant changes in affective and cognitive processes. In various physical diseases, including hereditary angioedema (HAE) due to C1 inhibitor deficiency, stressful events are also frequently reported by patients to trigger acute attacks. These include physical stress (such as injury, pain, viral infections, medical and dental procedures, and surgery) and mental stress (including stress from life events and school or work, clinical depression, and anxiety), or stress originating from the disease itself, especially if the disease is characterized by an unpredictable nature like HEA that directly impacts patients' choices in everyday life. Available literature related to the link between HAE and stress is limited and mainly focused on the patients' narratives. Self-reported data suggested that the main HAE trigger seems to be stress, followed by physical trauma. These observations suggest analyzing the perceived psychological effects consequent to stress exposure together with biochemical and physiological responses. The effect of stress could be systematically examined in a laboratory environment using a standardized protocol that reliably induces stress and activates major stress responses in experimental contexts. A reliable test to induce stress in HAE patients combining these two aspects may be the Socially Evaluated Cold Pressor Test (SECPT). SECPT is an extension of the classical Cold Pressor Test, in which participants immerse one of their hands in ice water with socio-evaluative elements, and has been proven to be a highly efficient tool for experimental stress induction in humans. Adding social-evaluative elements to the original physical stress boosted the cortisol response, making the SECPT a well-established standard protocol in human stress research that may represent an efficient alternative to other established protocols, such as the Trier Social Stress Test, a 'gold standard' in the field. A recent review confirmed that exposure to the SECPT leads to changes in subjective feeling, and triggers a significant sharp increase in systolic and diastolic blood pressure. The present study aims to evaluate objective and subjective stress responses between HAE patients and healthy controls due to SECPT. Moreover, as secondary aims, the study wants to investigate if the presence of anxiety and depressive symptoms, as well as body appreciation, trust in the body, pain catastrophizing, pain interference, and pain intensity, affect or mediate stress response in patients and healthy subjects similarly or differently.

Inclusion Criteria:

• Documented diagnosis of hereditary angioedema due to C1 inhibitor deficiency aged between 18 and 65 years (for the group of patients)

Exclusion Criteria:

• Any type of chronic disease requiring chronic treatment (i.e. hypertension, previous myocardial infarction, diabetes, chronic heart failure, autoimmune disease, neurodegenerative disease)
• Active acute disease;
• Sars-Cov2 infection in the previous 3 months.
• An acute attack experienced within the previous week and within 72 hours after the registration (a posteriori exclusion).

The group of patients with hereditary angioedema were recruited during an out-patient visit in a tertiary care center. The group of healthy individuals were volunteers recruited from community.