INTRODUCTION: Stressful physical or psychological events can trigger acute swelling attacks in patients with Hereditary Angioedema due to C1 Inhibitor deficiency (HAE-C1INH), although the stress-disease relationship remains unclear. The Socially Evaluated Cold Pressor Test (SECPT) reliably induces acute stress under controlled conditions. This study aimed to compare perceived stress, inflammatory markers, and cardiovascular responses to SECPT between HAE-C1INH patients and healthy controls (HC).
METHODS: Twenty HAE-C1INH patients (9 males, 44 ± 14 years) and age and sex matched HC underwent a 3-minute SECPT. Participants completed questionnaires assessing anxiety and depression (HADS), pain catastrophizing (PCS), and subjective stress (0-100 scale) before and after SECPT. Heart rate (HR) and arterial pressure (AP) were recorded. Blood samples for inflammatory cytokines (IL-6, IL-1ß, TNF-α) were collected at baseline, and 10 and 40 minutes after SECPT.
RESULTS: Compared to HC, patients showed higher baseline HADS-A (7.3 ± 4.5 vs 4.7 ± 2.7), overall PCS (19.7 ± 12.6 vs 12.9 ± 8.7), and perceived stress during SECPT (60.6 ± 34.3 vs 34.6 ± 23.8). IL-6 levels were higher at baseline and 10 minutes post-test (2.63 ± 1.21 vs 1.84 ± 0.87; 2.78 ± 1.20 vs 1.91 ± 0.79 pg/ml), as were TNF-α levels across all phases (4.19 ± 1.38 vs 3.26 ± 1.55; 4.09 ± 1.39 vs 3.40 ± 1.48; 4.09 ± 1.28 vs 3.20 ± 1.57) while IL-1 ß remained unchanged. HR and AP variations were similar between groups.
DISCUSSION: HAE-C1INH patients exhibited heightened perceived stress response to SECPT, and elevated baseline inflammation, despite comparable cardiovascular reactivity. These findings highlight a complex psychophysiological-inflammatory interplay in acute stress responses, suggesting the need to integrate psychological and biological frameworks in understanding HAE-C1INH triggers.
CLINICAL TRIALS CODE: NCT06414252.
patients reported higher perceived stress in response to SECPT and were characterized by higher pain magnification compared to HC
direct group differences support the claim, though the small sample and unequal SECPT completion temper certainty
patients showed higher resting values of inflammatory biomarkers than HC
unadjusted BMI and prophylaxis differences prevent secure attribution of the cytokine elevation to HAE-C1INH
the cardiovascular response to SECPT is similar between HAE-C1INH patients and HC
the prospectively measured and power-aligned cardiovascular responses were similar, with incomplete immersion limiting the strongest inference
none of the patients experienced attacks within 72 hours following the test
direct follow-up supports the observation, but sample size and near-universal prophylaxis limit implications for triggering
Derived from the full evaluation — not a separate score.
Strengths
The study applies SECPT under laboratory conditions to a stress–HAE relationship previously described mainly through patient reports, adding cardiovascular, inflammatory, and psychological measurements in the same protocol.
↳ Introduction; Methods, Experimental Protocol
Cardiovascular signals were recorded continuously across four phases, plasma cytokines were measured in duplicate, and psychological responses were assessed before and after the standardized stressor.
↳ Methods, Experimental Procedure; Cytokines Quantification; Statistical Analysis
The Discussion compares its null cytokine response with SECPT studies using salivary measures or a 90-minute sampling point and relates baseline inflammation to prior HAE findings.
↳ Discussion, Reaction of the Inflammatory Cytokines
Limitations
Patients had higher BMI and 18 of 20 received long-term prophylaxis, yet neither factor was adjusted, stratified, or tested in the cytokine analyses. Both could affect attribution of IL-6 and TNF-α differences to HAE-C1INH.
↳ Results, Population; Discussion, Reaction of the Inflammatory Cytokines; Limitations
Five patients and two controls ended SECPT early, while cytokine analyses omitted one patient and two controls. The paper reports these observations but does not evaluate their effect on group comparisons.
↳ Results, Population; Results, Inflammatory Cytokines Quantification
Cytokines did not change across SECPT phases, yet the abstract frames the findings as an acute psychophysiological-inflammatory interplay and the conclusion links inflammation to attack promotion.
↳ Abstract, Discussion; Conclusion
The standardized SECPT protocol and repeated cardiovascular, inflammatory, and psychological measurements provide a coherent controlled description of stress reactivity. The strongest methodological constraint is that higher BMI and near-universal long-term prophylaxis in the patient group were not addressed analytically, limiting the HAE-specific interpretation of IL-6 and TNF-α differences. Unequal SECPT completion and missing cytokine observations add uncertainty but are disclosed in the Results. The Discussion engages relevant contrasting evidence, although the abstract and conclusion imply a dynamic inflammatory interplay that the unchanged post-stressor cytokines do not demonstrate.
Nabu’s assessment, alongside the field’s view.
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Confidence mediumThe study provides a controlled, multidimensional comparison where the stress–HAE relationship had largely rested on patient narratives. Its advance remains exploratory because no attacks occurred and the dynamic cardiovascular and cytokine responses were largely similar between groups.
“this evidence has never been investigated under controlled conditions”
The prospective repeated-measures SECPT protocol, power calculation, continuous cardiovascular recording, and duplicate ELISA measurements fit the descriptive comparison. Unadjusted BMI and prophylaxis differences materially confound the inflammatory comparisons, while differential test completion and cytokine missingness were not examined analytically.
“nearly all patients included were undergoing LTP treatment, whose effects on inflammatory markers and stress reactivity remain unknown”
The paper follows a clear aim-to-protocol-to-results structure and reports the main group differences and null findings plainly. Its acute psychophysiological-inflammatory “interplay” framing is stronger than evidence showing baseline cytokine differences without cytokine reactivity.
“These findings highlight a complex psychophysiological-inflammatory interplay in acute stress responses”
The Discussion engages relevant HAE autonomic and inflammatory studies as well as SECPT studies with different cytokine sampling times. BMI, prophylaxis, and sample-size limitations are discussed, although the conclusion still characterizes the cytokine difference as systemic inflammation despite unresolved attribution.
“This finding underlines a state of low-grade systemic inflammation”
Caveats4 of 4 checks
The main reported results are broadly internally consistent, but one enrolled participant falls outside the stated age criterion and incomplete observations are not analytically reconciled. These issues warrant caution without demonstrating that the reported findings are unreliable.
Ethics approval, written consent, Declaration of Helsinki compliance, and prospective trial registration are declared. The absent conflict-of-interest statement and unverified data-request process are treated as assessability gaps rather than supplied-text conduct concerns.
Flags: 3 declared / 5 total
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No retraction or expression of concern found in Crossref (includes Retraction Watch).
Sources: Crossref (incl. Retraction Watch) ✓
Where this paper’s evidence sits on the path from initial observation to real-world use.
The work characterizes responses to a laboratory stressor but does not test a diagnostic, preventive, behavioural, or pharmacological intervention. No attacks occurred, leaving translation to trigger management dependent on substantial further research.
“None of the patients experienced attacks within 72 hours following the test”
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