# Functional physiological, psychological, and biochemical reactivity to socially evaluated cold pressor test in hereditary angioedema patients (FRoSEn).

- **DOI:** [10.3389/fimmu.2025.1736589](https://doi.org/10.3389/fimmu.2025.1736589)
- **Rating:** Sound (3.0 out of 5)
- **Verdict:** A controlled rare-disease stress study yields useful psychophysiological observations, but unadjusted BMI and prophylaxis confounding limits the inflammatory interpretation.
- **Framework version:** v5.9
- **Pipeline version:** v0.4
- **Evaluation date:** 2026-09-18
- **Evaluation page:** https://www.nabu.science/paper/10.3389%2Ffimmu.2025.1736589

## Key claims

1. patients reported higher perceived stress in response to SECPT and were characterized by higher pain magnification compared to HC
   - Support: Supported
   - Type: Primary finding
   - Basis: direct group differences support the claim, though the small sample and unequal SECPT completion temper certainty
   - Location: Discussion, Psychological Response to SECPT
2. patients showed higher resting values of inflammatory biomarkers than HC
   - Support: Tentative
   - Type: Secondary
   - Basis: unadjusted BMI and prophylaxis differences prevent secure attribution of the cytokine elevation to HAE-C1INH
   - Location: Discussion, Main Findings; Reaction of the Inflammatory Cytokines
3. the cardiovascular response to SECPT is similar between HAE-C1INH patients and HC
   - Support: Supported
   - Type: Secondary
   - Basis: the prospectively measured and power-aligned cardiovascular responses were similar, with incomplete immersion limiting the strongest inference
   - Location: Conclusion; Discussion, Cardiovascular Control Response to SECPT
4. none of the patients experienced attacks within 72 hours following the test
   - Support: Supported
   - Type: Secondary
   - Basis: direct follow-up supports the observation, but sample size and near-universal prophylaxis limit implications for triggering
   - Location: Discussion, Attacks After SECPT in HAE-C1INH Patients

## Strengths

- **Controlled evidence for a narrative-only question** 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.
  - Dimension: contribution
  - Location: Introduction; Methods, Experimental Protocol
- **Prospective multidimensional stress-response 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.
  - Dimension: methodological rigour
  - Location: Methods, Experimental Procedure; Cytokines Quantification; Statistical Analysis
- **Contrasting evidence receives substantive discussion** 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.
  - Dimension: positioning
  - Location: Discussion, Reaction of the Inflammatory Cytokines

## Limitations

- **Inflammatory comparisons retain major confounding** 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.
  - Dimension: methodological rigour
  - Location: Results, Population; Discussion, Reaction of the Inflammatory Cytokines; Limitations
- **Incomplete exposure receives no sensitivity analysis** 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.
  - Dimension: methodological rigour
  - Location: Results, Population; Results, Inflammatory Cytokines Quantification
- **Acute interplay framing exceeds results** 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.
  - Dimension: reporting
  - Location: Abstract, Discussion; Conclusion

## Reliability checks

Caveats (4 of 4 checks).

- **Internal coherence:** Noted. 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.
- **Research conduct:** Clean. 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.
- **Reference integrity:** Clean. 48 of 48 checkable references verified
  - 48 references in manuscript
  - References not verified automatically are resolved manually within 24 hours.

## Post-publication record

- **Status:** Clean
- **Summary:** No retraction or expression of concern found in Crossref (includes Retraction Watch).
- **Last checked:** 2026-10-17