BACKGROUND: Hereditary angioedema associated to C1 inhibitor deficiency (C1-INH-HAE) is a pathological condition characterized by episodes of subcutaneous swelling and it is frequently associated with discomfort and social impairment of the patients, due to the anxiety experienced for an unpreventable manifestation of an attack during daily life. In children increased level of stress and alexithymia have been associated to C1-INH-HAE, and the latter correlated also with the severity of the disease. We hypothesized that the involvement of psychological issues may impact on the severity of C1-INH-HAE in adult patients as well, interfering with their ability to engage with the management of the disease.
METHODS: 28 adult patients with C1-INH-HAE were evaluated for clinical (C1-INH-HAE Severity Score) and psychological factors (alexithymia, emotion regulation, stress, patient health engagement, general severity index) by means of validated questionnaires.
RESULTS: Mean age (standard deviation [SD]) was 45 (11) years and time from diagnosis was 20 (12) years. The mean C1-INH-HAE severity score was 6.4. Alexithymia was absent in 22 (78%) patients. Moderate and high stress levels were present in 17 (61%) and 4 (14%) patients, respectively. Moderate-high discomfort was experienced by 9 (36%) patients and a discomfort beyond the clinical attention threshold was shown by 3 (12%) patients. Stress correlated with patient health engagement and with psychological discomfort.
CONCLUSIONS: In C1-INH-HAE, patients health engagement and moderate-high psychological discomfort are linked with stress but not with the severity of the disease or alexithymia. A better patient health engagement may be a target for psychological intervention in clinics to ameliorate the stress perceived by C1-INH-HAE patients.
Stress correlated with patient health engagement and with psychological discomfort.
small concomitant sample and sparse PHE contingency cells limit confidence in the association
severity of C1-INH-HAE was not found to be associated with stress nor with health engagement.
cross-sectional null tests in 28 patients have limited power to exclude clinically relevant relationships
Alexithymia rarely occurred in this group of patients; only three subjects had a high TAS score, and emotion regulation strategies do not differ from the ones of the normative healthy sample’s scores.
direct sample descriptions support the scoped claim, though normative comparison and sample size constrain generalisation
alexithymia and deficits in emotion regulation characterize the experience of children with chronic diseases due to their developmental stage, whereas adults become able to recognize and regulate their own emotions independently from being affected by the disease
a cross-sectional adult sample without a pediatric comparison cannot identify the proposed developmental explanation
Derived from the full evaluation — not a separate score.
Strengths
The study tests psychological patterns in adults with C1-INH-HAE and explicitly contrasts the results with prior pediatric findings, including the absence of the expected severity relationship.
↳ Background, final paragraph; Discussion, alexithymia and pediatric-comparison paragraphs
Clinical and psychological variables were measured with validated Italian translations of the severity score, TAS-20, ERC, PSS, PHE-S, and SCL-90-R.
↳ Patients and Methods, Assessments
Tables 4 and 5 present non-significant severity, engagement, alexithymia, GSI, and psychoticism comparisons rather than limiting reporting to significant findings.
↳ Results, Tables 4 and 5
Limitations
All scales were completed concomitantly, yet the Discussion states that better knowledge causes less stress and proposes engagement as a therapeutic target. The design cannot establish this temporal or causal pathway.
↳ Patients and Methods, Assessments; Discussion, PHE interpretation and conclusion
The PHE–stress chi-square analysis includes zero and small cells without a reported exact alternative or approximation check, limiting confidence in the principal association.
↳ Results, Tables 2 and 5; Statistical Analysis
The 28 participants came from three referral centres, but recruitment flow, participation denominators, and sensitivity analyses are not reported. The resulting generalisability and stability of the estimates are uncertain.
↳ Patients and Methods, Study Design; Discussion, limitations paragraph
The adult rare-disease sample provides a useful exploratory extension of prior pediatric work, particularly through its transparent descriptive and null findings. The largest score constraint is the move from concomitant bivariate associations to directional claims that knowledge or engagement reduces stress. Tables 2 and 5 further weaken the headline PHE–stress result because sparse cells are analysed by chi-square without a reported exact alternative. Relevant prior work and the regression limitation are acknowledged, but recruitment, reverse direction, and small-sample precision are not fully integrated into the interpretation.
Nabu’s assessment, alongside the field’s view.
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Limited2.6
Confidence mediumThe study adds adult C1-INH-HAE data on stress, engagement, alexithymia, emotion regulation, and severity, extending a sparse pediatric-focused literature. Its contribution remains preliminary because only 28 participants were examined cross-sectionally.
“we propose our patient series as a starting point in this field of research”
Validated Italian instruments and transparent null reporting support the exploratory analysis, but measurements were concomitant and the main associations were unadjusted. Directional clinical interpretations, sparse chi-square cells, unexamined selection, and self-report measurement limit the resulting inference.
“The different scales were concomitantly evaluated by the patients during the meeting.”
The article follows a clear rationale–methods–results–discussion sequence and most empirical conclusions are readily locatable. Its precision drops where the Discussion converts concurrent associations into claims that disease knowledge causes less stress and that engagement may improve stress.
“a better knowledge of the disease causes less stress to the patients”
The article contrasts its adult findings with pediatric HAE studies and acknowledges that sample size prevented regression, reducing the relevance of the results. It does not adequately trace concurrent measurement, recruitment, and reverse-direction possibilities through the clinical interpretation.
“performing a regression analysis would result not appropriate”
Caveats4 of 4 checks
The reported counts generally preserve the direction of the findings, but sparse contingency cells and several percentage errors reduce confidence in the precision of the tabular statistical reporting.
Ethics approval and informed consent are explicitly declared. No supplied-text evidence indicates a conduct concern; unreported COI, registration, data, and code statements are not treated as adverse findings.
Flags: 1 declared / 5 total
16 of 16 checkable references verified
20 references in manuscript 4 have no canonical index record — counted, but not index-checkable 4 references confirmed by manual review
References not verified automatically are resolved manually within 24 hours.
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 evidence is at the initial observational stage: all scales were measured during one meeting and no intervention was evaluated. Considerable longitudinal and experimental work is required before the proposed therapeutic target is actionable.
“This was an exploratory, observational study”
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