Specific Features of Allergic Reactions in Patients With Comorbidities: Bradykinin-Mediated Reactions

Allergic disorders constitute a significant problem that substantially impairs quality of life, engages practitioners across multiple medical specialties, and imposes a considerable economic burden on healthcare systems. Unsatisfactory therapeutic outcomes in comorbid conditions are frequently attributable to pharmacological hypersensitivity. The widespread and increasing use of angiotensin-converting enzyme (ACE) inhibitors has been associated with a marked rise in the incidence of angioedema. Accurate differentiation among the various forms of angioedema therefore remains a critical element of the diagnostic process. The aim of the work was to analyse the features of hypersensitivity reactions in patients with diabetes mellitus, to examine the characteristics of angioedema cases, and to improve the diagnosis, prognosis, and prevention of this pathology. The attention of practitioners in therapeutic and surgical specialties should be directed towards the specific features of angioedema in patients receiving angiotensin-converting enzyme inhibitor therapy. Materials and methods. Outpatient medical records and case histories of 188 patients with diabetes mellitus who had documented episodes of reactions classified as allergic (main group) and of 122 patients with similar reactions but without diabetes mellitus over a 10-year period (2015–2024) were analysed. Within the main group, a subgroup of 48 patients with hypersensitivity reactions manifesting as angioedema and/or acute urticaria was identified. Data from questionnaires completed by patients who consulted the Department of Clinical Immunology, Allergology and Endocrinology during the specified period were also analysed. General clinical, biochemical, immunoenzymatic, instrumental, statistical, and analytical methods were employed. The study was conducted in accordance with the fundamental principles of bioethics as set out in the World Medical Association Declaration of Helsinki. Clinical data were analysed retrospectively on the basis of medical documentation and questionnaires. Informed consent for the use of the obtained data in scientific research was provided by patients who completed questionnaires and underwent consultative examination. All personal data were anonymised and used exclusively for scientific purposes. No additional invasive interventions were performed, and no risk to patient health was incurred. Statistical processing was performed using descriptive and comparative statistical methods. Data are presented as absolute and relative values (%). Comparisons between groups were conducted with account taken of clinical and anamnestic characteristics. Correlation analysis was applied to assess the relationship between the duration of diabetes mellitus and the frequency of hypersensitivity reactions. Results were considered statistically significant at p < 0.05. The study was performed as part of a pilot project. Further research is planned to expand the sample size and verify the obtained results. Results and discussion. The duration of diabetes mellitus in the patients included in the study ranged from 1 to 30 years. Insulin-dependent diabetes mellitus was diagnosed in 82% of the patients. A positive history of hypersensitivity reactions to medications and food products was elicited nearly three times more frequently in patients with insulin-dependent diabetes mellitus than in the control group, and this frequency correlated directly with the duration of the disease. In recent years (2017–2024), changes were also observed in the overall structure of hyperergic reactions compared with the previously analysed period (2014–2016). A shift towards an increased proportion of cases associated with hypersensitivity reactions to medications was identified. Allergic reactions in patients with diabetes mellitus were more frequently associated with insulin preparations, antibiotics, local anaesthetics, radiocontrast agents, and cardiac medications. Among the medications to which hypersensitivity was documented or reported in the medical history, the frequency distribution was as follows: insulin preparations – 22.7%; medications affecting the digestive system and metabolic processes – 23.17%; antibiotics – 20.5%; nonsteroidal anti-inflammatory medications – 9.7%; cardiac medications – 9.1%; vitamins – 3.6%; phytoforms – up to 2%. In-depth examination of patients with episodes of angioedema included analysis of cases associated with lisinopril use in a 55-year-old woman and a 70-year-old woman who presented with abdominal pain (in the latter case accompanied by vomiting and diarrhoea). Computed tomography demonstrated oedema of the small-intestine wall. After discontinuation of the medication, no further episodes of oedema occurred during the following year. Asymmetric facial angioedema was documented in two men aged 62 and 68 years during ramipril therapy (with an uncomplicated allergic history), as well as in men aged 59 and 75 years with pronounced generalised skin itching without rashes but with isolated asymmetric oedema of the extremities during enalapril therapy. Complete discontinuation of ACE inhibitors resulted in regression of symptoms within 1 week to 2 months. In 4 of the 6 described cases, additional photosensitivity and skin hyperaesthesia were observed. Differential diagnosis primarily excluded IgE-mediated anaphylaxis but also considered hormonal disorders in women (symmetrical facial and extremity swelling), heart failure (pastiness), superior vena cava syndrome (chronic facial oedema), acute allergic contact dermatitis, erysipelas or subcutaneous inflammatory processes of the face, lymphoedema, shingles, Crohn's disease, systemic connective-tissue diseases, and acute abdomen. Conclusions. 1. Patients with insulin-dependent diabetes mellitus exhibit a 2.9-fold higher incidence of hypersensitivity reactions compared with other therapeutic patients, with frequency directly correlating with disease duration and severity. 2. Differentiation between histamine-mediated and bradykinin-mediated angioedema constitutes a critical aspect of clinical practice. A markedly increased risk of angioedema during ACE inhibitor therapy has been demonstrated in patients with a positive allergic history. Failure of angioedema to respond to antihistamines and corticosteroids should raise suspicion of a bradykinin-mediated aetiology. 3. Immediate discontinuation of ACE inhibitor therapy is required, with subsequent replacement by an antihypertensive agent from a different pharmacological class. 4. Knowledge of rare causes of acute abdominal pain expands the differential diagnostic spectrum for surgeons, thereby enabling avoidance of unnecessary interventions. C1-esterase inhibitor deficiency should be excluded in cases presenting with isolated angioedema of the small intestine. 5. Anaesthesiologists must be informed of potential adverse intraoperative reactions in patients on long-term treatment with certain antihypertensive medications. 6. Mandatory professional nutritional education, prevention of polypharmacy, and meticulous recording of documented hypersensitivity reactions in patient records at all levels of care are recommended as integral components of the preventive measures programme.