Introduction
Hereditary angioedema (HAE) is a rare, life-threatening inherited disease characterized by mucosal and submucosal swelling, which thereby affects health-related quality of life (HRQoL). The most common cause of HAE involves deficiency (type 1) or dysfunction (type 2) of C1 inhibitor (C1INH) [1–3], results from a mutation in the SERPING1 gene which encodes C1INH [4], leading to overproduction of bradykinin and activation of the bradykinin receptor B2. This increases vascular permeability and causes attacks of angioedema [5].
This is manifested by recurrent episodes of nonpruritic subcutaneous or submucosal swelling. Commonly affected areas are the upper respiratory tract, face, extremities, genitals, and digestive system [6]. It is known that HAE is inherited in an autosomal dominant manner, approximately 75% of patients have positive family history; 25% have de novo mutation (no family history) [7].
Due to its dominant inheritance pattern, screening should be conducted for families of diagnosed individuals even if they are asymptomatic. The management of HAE is broadly divided into two main strategies: acute attack (on-demand) treatment and long-term prophylaxis. Short-term prophylaxis represents a specific clinical application within these strategies, primarily used in high-risk situations such as surgical or dental procedures [6].
It is known that the frequency and uncontrolled nature of attacks negatively affect the quality of life in patients diagnosed with HAE despite the available targeted therapeutic options [8]. To the best of our knowledge, previous studies on HAE patients, and quality of life have either assessed quality of life alone or been conducted using a combination of angioedema quality of life and activity scores. No studies have been found regarding the combination of angioedema activity score, angioedema control test, and quality of life.
The combined use of angioedema activity, control, and quality-of-life instruments may provide a more comprehensive assessment of disease burden and its impact on patients’ quality of life [8–12]. We hereby evaluate the impact of attack frequency and disease control on the quality of life of HAE patients in our cohort and additionally provide their demographic, clinical characteristics and treatment, as well as their attack frequencies in relation to HRQoL.
Materials and Methods
In the current study, HAE-C1INH patients from six medical centers in Turkey were enrolled. The diagnosis of HAE was made according to the EAACI guidelines, with C1 inhibitor antigen level and/or decreased C1 inhibitor function measured at least 2 months apart on two occasions [6]. Attacks recorded by patients during hospital admission were queried and noted.
At the moment, the Angioedema Control Test (AECT), Angioedema Activity Score (AAS), and Angioedema Quality of Life questionnaire (AE-QoL) were filled out, and family screenings were conducted only for patients who provided consent. The Institutional Review Board of Marmara University, School of Medicine, approved the study protocol (protocol number 09.2022.1472, dated 04.11.2022). Written informed consent was obtained from all adult participants prior to any study procedure.
For participants under 18 years of age, written informed consent for study participation was obtained from their parent and/or legal guardian. Written informed consent for publication of anonymized medical information was obtained from all adult participants and from the parents/legal guardians of all minors. All study procedures were conducted in accordance with the ethical principles of the Declaration of Helsinki.
AE-QoL, AECT, and AAS
The objective of HAE therapy is the absence of attacks, attainment of complete control, and restoration of normal quality of life. Validated scales, specifically measuring disease control level and quality of life, are utilized during follow-up assessments. There are measurement tools adapted to Turkish enabling patients to evaluate their conditions, including the AAS [13], the AECT [14, 15] measuring angioedema control levels, and the AE-QoL [13] assessing quality of life.
The AAS-28 enables the regular documentation of patients’ attacks. Patients self-assess each day of the past month, indicating whether they experienced an attack, its localization, severity, duration, and its impact on daily life and cosmetic appearance. Each question is scored from 0 to 3, resulting in a daily score ranging from 0 to 15.
The total score is evaluated over a 4-week/monthly period. An increase in the score indicates more active attacks. Although no universally accepted minimal clinically important difference has been defined for AAS-28, higher scores consistently reflect increased disease activity [16, 17].
The AECT consists of four questions, measuring the frequency of symptoms, impact on quality of life, the unpredictability of attacks, and the level of disease control achieved with current treatment. Each question is scored from 0 to 4, with 0 indicating no control and 16 considered complete control. A threshold value of 10 points has been reported for poor and good controls [14, 17].
The AE-Qol is a questionnaire consisting of 17 questions that assess the quality of life in angioedema patients. Patients are asked about the extent to which their daily activities have been affected by angioedema attacks in the past 4 weeks. Patients receive a total score ranging from 0 (good) to 100 (poor).
The AE-QoL consists of 17 questions divided into four different domains. The first domain, functional impairment, includes 4 questions assessing the impact of angioedema on daily activities such as mobility, social relationships, and work performance. The second subdomain, fatigue/mood, includes 5 questions assessing the effects of the disease on sleep and other psychological effects.
The third subdomain, fears/shame, consists of 6 questions focusing on the fear of unexpected angioedema attacks and the associated shame or social stigma. Finally, the fourth subdomain, nutrition, includes 2 questions measuring the impact of angioedema on restrictions in food and drink choices. Each question is rated on a Likert scale where higher scores reflect greater impairment, making the AE-QoL a comprehensive tool for assessing the impact of angioedema on quality of life across multiple domains [13, 18, 19].
Each domain is evaluated with its average score and total score percentage. A higher score is associated with greater impairment in quality of life. For AE-QoL, a minimal clinically important difference of 6 points has been established, indicating that a change of 6 or more points represents a clinically meaningful improvement or deterioration [17–19].
Data Analysis
Statistical analysis was conducted for all participants by using the Jamovi 2.3.26 version (The Jamovi Project, Sydney, Australia). Descriptive statistics are reported according to the distributional characteristics of the data; mean and standard deviation were used for normally distributed variables, while median and interquartile range (IQR) were used for non-normally distributed variables. The normality of the data distribution was assessed using the normality test used, e.g., Shapiro-Wilk test.
Based on this assessment, the Mann-Whitney U test was used for continuous variables that were not normally distributed, while Student’s t test was applied for normally distributed continuous variables. Wilcoxon signed rank test was used for pairwise comparisons of non-normally distributed data.
Since normal distribution was not observed in any of the questionnaires, correlation analyses were evaluated using Spearman’s test. If p > 0.05, it was stated that there was no correlation. If p < 0.05, the rho value was interpreted as follows: a rho value <0.20 indicated a very weak relationship, 0.20–0.39 indicated a weak relationship, 0.40–0.59 indicated a moderate level of relationship, 0.60–0.79 indicated a high level of relationship, and 0.80–1 indicated a very high relationship.
The figure was created by inputting data into Graphad Prism 8XML version (GraphPad Software Inc., San Diego, CA, USA) and Adobe Illustrator 25.2.1 (Adobe Inc., San Jose, CA, USA).
Results
In our study, there were 82 patients diagnosed with HAE, and the demographic characteristics in Table 1, comorbidities of the patients are summarized in Figure 1a. Fifteen patients (18.2%) were diagnosed before their first clinical attack through family screening (asymptomatically) based on a positive family history, while additionally 15 patients received the diagnosis post-attack despite having a family history of the condition, not through screening. Among patients diagnosed through family screening, 8 individuals (9.7%) with HAE type 1 (3 males [37.5%] and 5 females [62.5%]) remained completely attack-free throughout follow-up and were, therefore, excluded from all analyses.
The median current age of these patients was 24.5 years (range: 3–55), and the median age at diagnosis was 13 years (range: 2–46). After exclusion of these attack-free individuals, the final analysis was conducted in a total of 74 patients (Table 1). The distribution of attack regions among patients is summarized in Figure 1b.
In 91% of the patients (n = 61), prodromal symptoms were reported prior to attacks, and in 89.6% (n = 60), triggers were reported for the attacks (Fig. 1c, d). Patients diagnosed with HAE-C1INH Type 1 and Type 2 had C4 levels of mean 0.11 (±0.16) g/L and 0.05 (±0.03) g/L, respectively (normal: 0.10–0.40 g/L).
The levels of C1 inhibitor antigen were 7.83 (±3.25) mg/dL and 31.5 (±6.17) mg/dL, respectively (normal: 15–35 mg/dL). The mean C1 inhibitor functions were 23.9% (±16.1) and 26.6% (±9.56), respectively. According to the reference range of the performing laboratory, normal C1 inhibitor function was defined as >70%.
Sixty (81.1%) patients were utilizing the recommended on-demand treatment during acute attacks, with 33 (44.6%) patients receiving bradykinin receptor antagonists, 6 (8.1%) patients receiving C1 esterase inhibitor, and 21 (28.4%) patients using both. Twenty-nine patients used short-term prophylaxis, with 26 (35.1%) of them receiving C1 esterase inhibitor and 3 (4%) receiving danazol. Thirteen patients (17.6%) were on long-term prophylaxis: seven with danazol, five with C1 esterase inhibitor, and one with tranexamic acid.
In the patient receiving tranexamic acid prophylaxis, the attack frequency before and after LTP was the same, whereas in the other patients receiving long-term prophylaxis, before prophylaxis, the median annual attack frequency was 108 (IQR: 70–224), which decreased to 4 (IQR: 0–27) after prophylaxis (p = 0.004).
Questionnaires for Quality of Life, AECT, and AAS
For patients who experienced attacks completed the questionnaire (n = 64), the median AECT score was 9 (IQR: 6–12), the median AAS-28 score was 30 (IQR: 5.75–54.8), and the highest recorded AAS-28 score was 200 points The AE-QoL scores of the patients were evaluated, revealing a median total score of 44 (IQR: 21.6–59.5). Analysis of the subdomains showed the following median scores: functioning, 43.8 (IQR: 23.4–62.5); fatigue/mood, 35 (IQR: 20–55); fears/shame, 50 (IQR: 25–70.8); and food, 37.5 (IQR: 12.5–62.5) (Fig. 2a).
Additionally, no significant differences were observed in AAS-28, AECT, and AE-QoL scores in relation to sex, age group (adult/child), asymptomatic diagnosis, subphenotype, diagnostic delay greater than 2 years, or long-term prophylaxis use. However, in patients with comorbidities, AECT scores were lower (p = 0.06), and AE-QoL scores were higher (p = 0.054), but only the increase in AAS-28 scores (p = 0.001) was statistically significant. AECT scores were lower in patients with extremity attacks (p < 0.001) and in those with laryngeal/pharyngeal attacks (p = 0.028), whereas AAS-28 scores were significantly higher in patients with extremity attacks (p = 0.008), abdominal attacks (p = 0.018), face and neck attacks (p = 0.004), laryngeal/pharyngeal attacks (p < 0.001), and tongue, uvula, or palate involvement (p < 0.001).
AE-QoL scores indicated poorer quality of life in patients with extremity attacks (p = 0.011), abdominal attacks (p = 0.028), face and neck attacks (p = 0.011), laryngeal/pharyngeal attacks (p < 0.001), and tongue, uvula, or palate involvement (p = 0.009) (Table 2).
Statistically significant differences in AE-QoL extremity attack scores were observed across all subdomains except for the Food subdomain when compared to the ones without extremity attacks. The p values were as follows: functioning (p = 0.014), fatigue/mood (p = 0.020), fears/shame (p = 0.023), and food (p = 0.057) (Fig. 2b).
In patients with abdominal attacks, the impairment in quality of life was attributed to the functioning (p = 0.005) and food (p = 0.037) subdomains (Fig. 2c). For face and neck attacks, quality of life impairment was primarily due to the fatigue/mood (p = 0.002), functioning (p = 0.044), and fears/shame (p = 0.039) subdomains (Fig.
2d). Patients experiencing laryngeal/pharyngeal attacks demonstrated significant deterioration in quality of life across the functioning (p = 0.002), fatigue/mood (p = 0.003), and fears/shame (p = 0.005), food (p = 0.038) subdomains (Fig. 2e).
Patients with involvement of the tongue, uvula, or palate showed significant impairments in the functioning (p = 0.004), fatigue/mood (p = 0.015) subdomains (Fig. 2f).
Spearman’s rank correlation analysis revealed a moderate negative correlation between AECT and AAS-28 (rho = −0.564, p < 0.001), a strong negative correlation between AECT and AE-QoL (rho = −0.647, p < 0.001), and a moderate positive correlation between AE-QoL and AAS-28 (rho = 0.594, p < 0.001) (Fig. 3a–c). As the number of attacks increased, the level of control declined, activity scores rose, and quality of life significantly deteriorated.
Discussion
HAE patients experience a significant physical and psychological burden that negatively impacts HRQoL. The unpredictable nature of attacks presents considerable challenges for patients. The number of attacks experienced over time correlates with worse scores across various domains of health-related quality-of-life assessments, including functioning, fatigue/mood, fears/shame, food [20].
In our cohort, we aimed to evaluate the factors affecting the quality of life in patients diagnosed with HAE. Although the HAE-QoL is specifically designed for HAE, we chose to use the AE-QoL to assess quality of life in bradykinin-mediated angioedema patients. This decision was based on the challenges of the 6-month retrospective assessment required by HAE-QoL, compared to the 4-week recall period of AE-QoL, which is easier for patients to remember, reducing the risk of recall bias.
The AE-QoL is a validated and reliable tool for assessing quality of life in patients with both histamine- and bradykinin-mediated angioedema. It has also been widely utilized in the follow-up of patients diagnosed with HAE, demonstrating its applicability across different angioedema subtypes [13, 19].
In our cohort, no significant differences were observed in AAS-28, AECT, and AE-QoL scores when analyzed based on age, gender, asymptomatic diagnosis, subphenotype, diagnostic delay longer than 2 years, or long-term prophylaxis use. In contrast, findings from a Hungarian cohort assessed annually over 3 years revealed consistently higher AE-QoL scores among women compared to men. These scores also exhibited changes with age, which were attributed to hormonal fluctuations associated with aging.
The higher quality-of-life impairment observed in women, potentially related to increased attack frequency, may be influenced by the physiological or pharmacological elevation of serum estrogen levels, which has been linked to a rise in attack frequency in some female HAE patients [21, 22]. However, in our cohort, no differences in attack frequency were observed between genders, which likely explains the lack of a significant difference in quality-of-life scores. The strongest correlation was identified between the annual attack frequency and AE-QoL scores, while no significant associations were found between AE-QoL and other complementary parameters (including age, sex, diagnostic delay, comorbidities, and long-term prophylaxis use).
Thus, it was concluded that monitoring complementary parameters may not be essential for tracking quality of life, whereas monitoring attack frequency appears to be more meaningful [21, 23]. In our cohort, the correlations observed between AE-QoL and measures indicating attack control and frequency, such as AECT and AAS-28, align with similar findings in other studies. Similar to our findings, previous studies have also demonstrated a negative correlation between attack frequency and quality of life in patients with HAE.
Notably, the recent cross-sectional study by Fijen et al. [24], conducted in the Netherlands, provided further evidence for this association and additionally evaluated the economic burden of HAE, including healthcare utilization, productivity losses, and treatment costs – parameters not assessed in our study. Their findings reinforce the relevance of attack frequency as a critical determinant of both quality of life and societal costs in HAE management.
When evaluating attack localization, similar to other cohorts, extremities, abdomen, and face are the most common sites of attacks in our cohort as well [22, 25–27]. The 41.9% of our patients experiencing laryngeal attacks is consistent with previously published literature, where approximately 50% of patients have been reported to experience laryngeal attacks in various studies [22, 26]. When evaluating the relationship between attack localization and quality of life, it was observed that patients experiencing attacks in the extremities, abdomen, face-neck, laryngeal/pharyngeal areas, and tongue/uvula/palate had more significant impairments in quality of life.
In our cohort, extremity attacks were the most frequent and were associated with deterioration in the functioning subdomain of the AE-QoL. This distribution is consistent with previous national and multicenter cohorts, in which extremity, abdominal, and facial attacks have been reported as the most common localizations. Accordingly, our findings do not suggest a unique attack localization pattern but rather support the existing literature on attack distribution in HAE.
The functional impact of extremity attacks is a known feature, and previous literature has also highlighted the functional impairment associated with such attacks, where the functional consequences are particularly prominent [28]. In the literature, long-term prophylaxis with lanadelumab has been shown to lead to the greatest improvements in the functioning subdomain, particularly with a reduction in attack frequency. As one of the most common attack types, extremity attacks cause functional impairment due to their peripheral localization, which also leads to functional deterioration.
This relationship between extremity attacks and functional impairment has been highlighted in previous studies on long-term prophylaxis and its effects on patients’ quality of life [29].
Laryngeal/pharyngeal attacks and attacks involving the tongue/uvula/palate have been shown to cause significant impairment in several quality-of-life domains, including functioning, fatigue/mood, and fears/shame. The potential for laryngeal attacks to result in asphyxiation and death may explain the broader impact of these attacks across multiple subdomains and their psychological effects. Different attack locations lead to impairments in various psychological and physical subdomains of quality of life.
This association underscores the multi-faceted impact of attack localization on patients’ well-being, as observed in both the physical and psychological dimensions of quality-of-life assessments [30]. Numerous international cohorts evaluating the impact of long-term prophylaxis on quality of life have demonstrated a significant reduction in attack frequency alongside notable improvements in quality-of-life scores with prophylactic treatment [20, 31, 32].
Similar to reports in the literature, intravenous C1 inhibitor was the most frequently used prophylactic treatment in our cohort, followed by danazol [25]. Currently, C1 esterase inhibitor is administered intravenously only in hospital settings within our country’s healthcare services. This highlights a significant need for innovative prophylactic treatments that support long-term management of HAE.
Similar to advancements in other complementopathies [33, 34], the development of targeted therapies is crucial beyond the acute, on-demand treatment during attacks, also for achieving better disease control to prevent acute attacks. Kallikrein targeted cascade-focused therapies, such as lanadelumab, berotralstat, and donidalorsen, represent important steps toward improving patient outcomes [31, 35, 36]. These treatments may offer a more individualized precise and effective approach compared to older modalities like danazol or tranexamic acid.
Prioritizing research and accessibility of such advanced therapies will likely enhance both the management and quality of life for patients with HAE.
In patients with inborns errors of immunity (IEI) including HAE, HRQoL assessments have increased and the need for a multidisciplinary approach to improve quality of life has been emphasized more frequently. Although treatments for IEI have improved patient care, they continue to struggle with frequent hospitalizations as in the case HAE. This significantly impacts their physical and psychological health, reducing their overall quality of life and well-being [37, 38].
However, long-term prophylaxis of HAE targeted therapies has been associated with improved quality of life due to its ease of administration at home, lack of impact on social life and limited potential for side effects.
Our study encompasses a multicenter cohort of 82 HAE patients, highlighting several strengths and limitations. A key strength is its multicenter design, which enhances the generalizability of findings across different healthcare settings and patient populations. Furthermore, the use of validated tools such as AAS-28, AECT, and AE-QoL ensures reliable and standardized assessment of attack frequency, control, and quality of life.
Additionally, the long-term follow-up of patients in our cohort provides a robust dataset for evaluating disease progression and treatment outcomes. However, the retrospective nature of the study introduces potential recall bias, particularly regarding the self-reported history of attacks.
In conclusion, the most important factor affecting quality of life in patients with HAE is the frequency of attacks, which can be assessed by AAS-28 and AECT. In addition to the use and/or development of tools that can detect quality of life impairment in patients with HAE, investment in new targeted therapies aimed at controlling attacks should be prioritized. Widespread global access to targeted therapies, individualized treatment and a multidisciplinary approach are essential for HRQoL improvement.
Statement of Ethics
The study protocol was reviewed and approved by the Ethics Committee of Marmara University, School of Medicine (Approval No. 09.2022.1472, dated 04.11.2022). Written informed consent was obtained from all adult participants prior to study participation.
For participants under 18 years of age, written informed consent was obtained from their parents and/or legal guardians. Written informed consent for publication of anonymized medical information was obtained from all adult participants and from the parents/legal guardians of all minors. All study procedures were conducted in accordance with the ethical principles of the Declaration of Helsinki.
The authors declare that no generative artificial intelligence (AI) or AI-assisted technologies were used in the preparation, writing, or editing of this manuscript.
Conflict of Interest Statement
E.K.-A., E.Y.G., E.K., M.Y.A., S.C., E.T.O., O.A., U.D., Z.M., I.O., R.A., N.O., S.B., I.E.S., A.K., E.O.Y., G.B., M.A., F.M.T., O.O., E.A.Y., E.N.M.G., S.B.-E., S.B., and A.O. have no conflict of interest to disclose.
Funding Sources
No financial support was received for this study.
Author Contributions
E.K.-A. and E.Y.G. conceptualized and supervised the study, performed calculations of questionnaires and statistical analyses; and wrote the paper. E.Y.G., E.K., M.Y.A., S.C., E.T.O., O.A., U.D., Z.M., I.O., R.A., N.O., S.B., I.E.S., A.K., E.O.Y., G.B., M.A., F.M.T., O.O., E.A.Y., E.N.M.G., S.B.-E., S.B., A.O., and E.K.-A. provided patient care, collected clinical data, and conducted the questionnaires. All authors reviewed and approved the final version of the manuscript.