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. 2026 Mar 3:17:1784326.
doi: 10.3389/fimmu.2026.1784326. eCollection 2026.

Behavioural withdrawal during an acute stress test as a marker of psychobiological vulnerability in hereditary angioedema

Luca Ranucci #  1 , Francesca Perego #  2 , Aida Zulueta  3 , Clara Gino  4 , Azzurra Cesoni Marcelli  2 , Lorenza Chiara Zingale  2 , Laura Adelaide Dalla Vecchia  5 , Beatrice De Maria #  4 , Alessandra Gorini #  1   6
Affiliations

Behavioural withdrawal during an acute stress test as a marker of psychobiological vulnerability in hereditary angioedema

Luca Ranucci et al. Front Immunol. .

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.

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Conflict of interest statement

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author BDM declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Schematic representation of the experimental protocol. The figure was created in Biorender.com.
Figure 2
Figure 2
Group comparison of stress ratings (VAS stress) prior and immediately after the SECPT. Stress Pre, VAS stress before SECPT; Stress Post, VAS stress after SECPT.
Figure 3
Figure 3
Group comparison of unpleasantness and pain ratings (VAS unpleasantness and VAS pain) immediately after SECPT. Unpleasantness, perceived unpleasantness during SECPT; Pain, perceived pain during SECPT.
See this image and copyright information in PMC

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