ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
This article is part of the Research TopicHereditary angioedema - C1INH deficiency and beyondView all 6 articles
Behavioural withdrawal during an acute stress test as a marker of psychobiological vulnerability in Hereditary Angioedema
Provisionally accepted
Luca Ranucci1
Francesca Perego2*
Aida Zulueta3
Clara Gino4
Azzurra Cesoni Marcelli2Lorenza Chiara Zingale2
Laura Adelaide Dalla Vecchia5
Beatrice De Maria4
Alessandra Gorini6,7- 1Istituti Clinici Scientifici Maugeri IRCCS, PsyCaRe Lab – Psychology Laboratory for an Integrated Approach to Cardiopulmonary Pathologies and Rare Diseases in the Cardiovascular Field,, Milan, Italy
- 2Istituti Clinici Scientifici Maugeri IRCCS, Department of Internal Medicine and Rehabilitation., Milan, Italy
- 3Istituti Clinici Scientifici Maugeri IRCCS, LaBioN, Milan, Italy
- 4Istituti Clinici Scientifici Maugeri IRCCS, Bioengineering Laboratory, Milan, Italy
- 5Istituti Clinici Scientifici Maugeri IRCCS, Department of Cardiology, Milan, Italy
- 6Dipartimento di Eccellenza 2023-2027, Universita degli Studi di Milano Dipartimento di Scienze Cliniche e di Comunita, Milan, Italy
- 7Istituti Clinici Scientifici Maugeri IRCCS, PsyCaRe Lab –Psychology Laboratory for an Integrated Approach to Cardiopulmonary Pathologies and Rare Diseases in the Cardiovascular Field,, Milan, Italy
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ABSTRACT Introduction: Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) features clinical heterogeneity and stress-triggered attacks. Behavioral tolerance to acute stress may reveal vulnerability profiles beyond standard clinical descriptors. This study aimed to characterize stress response patterns and compare groups based on behavioral tolerance. Methods: HAE-C1INH patients underwent the Socially Evaluated Cold Pressor Test (SECPT) and were stratified as Completers or Non-completers (early withdrawal). Stress appraisal, cardiovascular parameters (heart rate, HR; systolic/diastolic arterial pressure, SAP/DAP), and plasma cytokines (IL-1β, TNF-α, IL-6) were assessed. Disease control and quality of life were measured via Angioedema Control Test (AECT) and Angioedema Quality of life (AE-QoL) questionnaires. Results: Twenty patients were enrolled (15 Completers and 5 Non-completers). Non-completers showed poorer disease control (10.6 ± 5.5 vs 14.5 ± 2.2; p≤0.05) and worse AE-QoL, particularly in the Functioning (8.6 ± 4.3 vs 4.7 ± 1.7; p≤0.05) and Fatigue/Mood (13.6 ± 7.1 vs 10.5 ± 3.5; p≤0.05) domains. They reported higher stress (91 ±8.9 vs 50.5 ± 33.7; p≤0.05), pain (87.8 ± 12.8 vs 50.1 ±31.3; p≤0.05) and unpleasantness (83 ±19.9 vs 49.5 ±30.5; p≤0.05) during the SECPT. Non-completers displayed an attenuated SAP response relative to Completers (128.3 ± 18.0 vs 148.9 ±18.3 mmHg; p≤0.05). Inflammatory profiles also diverged: Non-completers showed higher IL-6 levels at 40 minutes after SECPT (3.5 ±1.1 vs 2.2 ± 0.7 pg/ml; p≤0.05) and opposite TNF-α trajectories compared with Completers (0.9 ± 1.0 vs -0.5 ± 0.9 pg/ml; p≤0.05). Conclusion: Early withdrawal during SECPT identifies a vulnerable HAE-C1INH subgroup with distinct psychological, cardiovascular, and inflammatory patterns.
Keywords: hereditary angioedema, Inflammation, phenotype, Preventive strategies, psychological assessment, rare disease, socially evaluated cold pressor test (SeCPT), stress reactivity
Received: 09 Jan 2026; Accepted: 16 Feb 2026.
Copyright: © 2026 Ranucci, Perego, Zulueta, Gino, Cesoni Marcelli, Zingale, Dalla Vecchia, De Maria and Gorini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Francesca Perego
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