D2.80 - Development of Standardized Case Report Forms to Support Biomarker-Based Differential Diagnosis of Bradykinin-Mediated Angioedema

Bradykinin accumulation is considered the principal pathogenic mechanism of angiotensin-converting enzyme inhibitor–induced angioedema (ACEi-AE), an adverse drug reaction occurring in approximately 0.1–0.7% of patients. ACEi-AE typically affects the face, persists for more than 24 hours, is not associated with pruritus or urticaria, may follow a life-threatening course, and—unlike histaminergic angioedema (HE-AE)—does not respond to antihistamines or systemic glucocorticoids. Hereditary angioedema (HAE), also bradykinin-mediated, is distinguished by confirmed C1-esterase inhibitor deficiency. However, differentiating ACEi-AE from HE-AE remains challenging due to the absence of validated biomarkers. The first stage of our study, conducted within the framework of grant №25RG-3B035 funded by the Higher Education and Science Committee of the Republic of Armenia, aimed to develop and implement standardized case report forms for patients with different types of angioedema.

In accordance with the main principles, two case report forms with appropriate questions were developed. The case report form for collecting general data from recruited patients consists of eight parts: demographic data, medical history, angioedema history, use of ACE inhibitors (if available), treatment, family history, and other drug use history. The form summarizes the preliminary diagnosis, which is necessary to assign patients to study groups. The emergency case report form for collecting clinical data includes questions about symptoms and the assessment of angioedema severity at the moment of hospitalization. The feasibility of the case report forms was assessed in a pilot phase using clinical data from seven patients enrolled with written informed consent. 

Seven patients with a mean age of 62 years were included (4 males, 57.1%): 5 with ACEi-AE, 1 with HE-AE, and 1 with HAE. The CRFs were completed for all seven enrolled patients without interruption of the routine clinical workflow. More than 70% of predefined clinical variables required for biomarker analysis were successfully captured. Pilot testing identified ambiguities in attack-duration reporting and medication-history documentation, prompting refinement of the corresponding sections. Average completion time was approximately 12–15 minutes and was considered acceptable by treating physicians. Overall, the pilot phase confirmed the feasibility and practical applicability of the developed CRFs for prospective biomarker-oriented studies.

This pilot study provides methodological validation of the newly developed standardized case report forms to support the upcoming large-scale study aimed at identifying specific biomarkers for the differential diagnosis of bradykinin-mediated angioedema.