Quality of life and burden of disease in patients with hereditary angioedema and their caregivers

Abstract

Background:

Hereditary angioedema (HAE) substantially impairs patients’ quality of life (QoL), both physically and psychologically, with unpredictable attacks that cause disruptions in education, work, and social life.

Objective:

To identify key themes and existing knowledge gaps around the multifaceted burden of HAE.

Methods:

A literature review was conducted in January 2024 through a search of medical literature data bases. English-language studies considered relevant to patient burden and QoL were selected for analysis.

Results:

A total of 48 studies were included in the analysis; 50% were cross-sectional and 54% were conducted in North America. Twenty-three studies reported outcomes on QoL and pain, 10 studies reported outcomes on psychological distress, 16 studies reported outcomes on experiences with long-term prophylaxis, 36 studies reported outcomes on HAE attacks, and one study detailed caregiver burden. Patients with HAE had worse QoL compared with the general population, and worse QoL was associated with a higher frequency or severity of attacks, anxiety, and depression. The use of long-term prophylaxis improved QoL, and treatment satisfaction was driven by improvements in mental health and fostering a sense of control and independence.

Conclusion:

HAE continues to substantially impact QoL of patients. Although recent work has demonstrated progress in standardizing assessment tools for QoL in HAE, additional research is needed to determine the correlation between individual patient factors and QoL.

Hereditary angioedema (HAE) is a rare, potentially life-threatening autosomal dominant genetic disease characterized by recurrent and unpredictable episodes of angioedema that commonly affect the extremities, upper airway, and gastrointestinal tract.^1,2 Two primary variants of HAE are caused by mutations in the serpin family G member 1 (SERPING1) gene, which results in deficiency of C1 esterase inhibitor (C1INH) protein: type 1, which accounts for 85% of patients and is characterized by low plasma levels of C1INH, and type 2, which represents 15% of patients and involves normal levels of dysfunctional C1INH. Deficiency or dysfunction of C1INH leads to uncontrolled activation of the contact system and overproduction of bradykinin, which results in the characteristic swelling seen in HAE due to increased vascular permeability.¹

Despite HAE affecting ∼1 in 50,000 individuals and typically emerging during childhood or adolescence,^2,3 the path to proper HAE diagnosis and management remains challenging for many patients. Diagnosis is often delayed by 1.4 to 8.5 years from symptom onset to diagnosis. This diagnostic delay carries substantial risks because misdiagnosis can increase morbidity and mortality rates. Currently, with no definitive cure available, management strategies focus on treating acute attacks while implementing both short- and long-term preventive measures.¹

The impact of HAE extends beyond its clinical manifestations, profoundly affecting patients' lives across multiple dimensions. Unpredictable attacks can temporarily disable patients, preventing them from walking, using their hands, performing daily tasks, and leaving the house.^1,4 Furthermore, they can cause disruptions in education, work, and social life, frequently leading to anxiety, depression, and reduced productivity. The psychological burden of HAE typically intensifies with attack severity, creating a cycle of physical and emotional challenges that extends beyond the individual patient, to affect family members and caregivers.⁵

Given the complex nature of HAE management and its far-reaching implications, our literature review sought to examine the multifaceted burden of HAE, with particular focus on quality of life (QoL) and unmet needs in both research and current prophylactic treatments. This analysis is particularly timely given three key developments: (1) the growing recognition of the comprehensive impact of HAE beyond physical symptoms, (2) the recent expansion of prophylactic treatment options, and (3) the limited understanding of caregiver burden in HAE management. A holistic analysis of the literature may help identify patterns in patient experiences, highlight gaps in current understanding, and inform both clinical practice and future research priorities. In addition, because health-care systems increasingly emphasize patient-centered care and value-based treatment decisions, understanding the full burden of HAE is critical for optimal care delivery and improving patient and caregiver QoL.

METHODS

To assess key themes and identify knowledge gaps around the physical and psychological burdens of HAE, a literature review was conducted in January 2024 through review of Medline (National Library of Medicine, Bethesda, MD, USA) and Embase (Elsevier, Amsterdam, the Netherlands) via Ovid (Wolters Kluwer N.V., Alphen aan den Rijn, the Netherlands), and EconLit (American Economic Association, Nashville, TN, USA). The Northern Light (Northern Light Group, LLC, Boston, MA, USA) data base (via Ovid) and individual conference web sites were also searched to identify conference abstracts from nine meetings, including key international congresses and rare disease advocacy summits that focused on angioedema, allergy, and rare disease management. The search strategy was limited to identify articles in English, and conference abstracts were limited to meetings from the previous two years (January 2022 to January 2024) to capture the most recent research. No date range was set for full articles. MeSH (Medical Subject Headings) terms were used to refine the population of interest (angioneurotic edema, HAE, etc.) and outcomes of interest (patient satisfaction, psychological stress, fatigue, QoL, etc.). Studies were selected for inclusion if they described data on outcomes relevant to patient burden and QoL; these included pain, psychological distress, frequency and severity of attacks, burden, and preferences and/or satisfaction associated with long-term prophylaxis (LTP). Studies that described caregiver burden or QoL were also selected. Included studies were further refined to select those from North America and Europe to analyze data from jurisdictions that are expected to have similar management options for HAE.

RESULTS

Overall Description of Included Studies

A total of 1975 abstracts were returned from initial searches (1867 from Medline and Embase, 48 from Northern Light, 60 from individual conferences, none from EconLit), which were refined to 270 studies after a screening of abstracts for relevant themes (Fig. 1). On review of full-text articles and assessment of data on outcomes of interest, 48 studies were included in the analysis.^6–53 Half of the studies were cross-sectional and primarily conducted in the United States (21 studies [44%]) (Fig. 2).^{11–15,17–20,22–25,28–31,34,37,52,54} Key findings are detailed subsequently and summarized in Table 1.

Figure 1.

Identified and included studies. *Abstracts were eligible for full-text analysis if they (1) outlined studies conducted in North America or Europe, (2) included adults with hereditary angioedema (HAE) types 1 and/or 2, and (3) presented data on quality of life and impact on daily life, including pain, psychological distress, frequency and severity of attacks, burden and preferences, and/or satisfaction associated with long-term prophylactic treatments, or caregiver burden and quality of life. **“Other” included commentaries, study protocols, or articles in languages other than English.

Figure 2.

Overall description of included studies. HAE, hereditary angioedema. Adapted from Ref. 56.

Table 1.

Key findings

QoL = Quality of life; LTP = long-term prophylaxis; HAE = hereditary angioedema.

^*A single publication can include multiple topics or studies.

^#Adapted from Refs. 6, 8–16, 20, 23, 25, 27, 31, 32, 35, 44–47.

^§Twenty-three studies were described in 21 publications.

^¶Adapted from Refs. 6, 13–15, 17–21, 25.

^‖Adapted from Refs. 10, 13–16, 20–30, 48.

^**Sixteen studies were described in 17 publications.

^##Adapted from Refs. 6, 8, 10–15, 17, 20–24, 26–29, 31–40, 46, 47, 49–55.

^§§Thirty-six studies were described in 37 publications.

^¶¶Adapted from Ref. 41.

QoL

Twenty-three studies reported outcomes on QoL and pain (Fig. 3).^{6,8–16,20,23,25,27,31,32,35,42–45} Patients with HAE had worse QoL (overall, as well as in specific QoL domains, such as fatigue/mood and fears/shame on the Angioedema Quality of Life Questionnaire [AE-QoL] instrument) compared with the general population,^6,7 with lower QoL among female patients when compared with male patients, although this was not always statistically significant.^6,8–10 A higher attack frequency was associated with worse QoL,^8,9,11–13 and patients experiencing laryngeal attacks had worse QoL compared with those whose attacks involved only the extremities.¹³ The severity of anxiety and depression was associated with worse QoL.¹³ Pain visual analog scale scores increased with attack severity, consistent with greater levels of pain.¹⁴ The use of LTP improved QoL, and improvements were significant when compared with patients who use on-demand treatment only.^11,15,16

Figure 3.

QoL assessment tools. QoL = Quality of life; HAE = hereditary angioedema. ^aIncluded the Angioedema Quality of Life (AE-QoL) and Hereditary Angioedema Quality of Life (HAE-QoL) questionnaires. ^bIncluded the RAND 36-Item Short Form Health Survey (SF-36) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5L) instrument. ^cThe Dermatology Life Quality Index (DLQI) was utilized. Adapted from Ref. 56.

Psychological Distress

Ten studies reported outcomes on psychological distress,^{6,13–15,17–21,25} including studies that provide data on stress (1 study),⁶ anxiety (8 studies),^{6,13,15,17–20,25} and depression (8 studies).^{6,13–15,17–20} Depression and anxiety were prevalent among patients with HAE, with rates that ranged from 5.6 to 76.5% and 15 to 88%, respectively.^{6,11,13,14,17,18} The wide ranges of observed prevalence were the result of different methods being used for mental health assessment across these studies. Older patients (ages ≥ 60 years) with HAE experienced a slightly higher prevalence of both anxiety and depression compared with healthy individuals of similar age.¹⁹ Drivers of anxiety and depression fell into two main categories: societal perceptions (e.g., feeling “embarrassed/self-conscious” about visible swelling, concerns about “going out in public”) and disease burden (e.g., “feeling like a victim” of HAE, unpredictability of attacks, pain during episodes, disability that affects employment).^15,20 In addition, a lack of disease awareness from emergency care teams increased anxiety and stress among patients.²¹ Patients often felt unheard, and their knowledge about HAE and their treatment was dismissed.²¹ Laryngeal attacks were traumatic, and fear of their recurrence drove anxiety.²¹ Factors such as attack severity, HAE treatment, and age impacted patients’ experiences with anxiety and depression. More severe anxiety and depression were reported among those experiencing more severe attacks.¹⁴ LTP was associated with reduced anxiety and depression.¹⁵ As patients aged, their acceptance of HAE increased, although patients still noted anxiety about unknown attack timing, financial burdens, and living with chronic illness.²⁰

Experience With LTP

Sixteen studies reported experiences with LTP,^{10,13–16,20–30,46} which included treatment satisfaction (9 studies),^{11,15,20,22–24} treatment dissatisfaction (11 studies),^{10,14–16,20–22,24–27} and treatment preferences (6 studies).^{15,20,22,28–30} Consistent LTP has been shown to alleviate anxiety and depression, and to improve QoL, compared with only on-demand treatment.¹¹ High satisfaction with prophylactic treatment was driven by improvements in mental health, social life, daily functioning, and fostering a sense of control and independence.^20,22–24 Despite positive impacts, patients described the inconvenience of current prophylactic treatments, including their demanding nature and administration routes.^{15,16,21,22,24,25} In regard to specific treatments for HAE, a higher treatment burden was experienced by patients receiving C1INH subcutaneously or intravenously compared with those receiving lanadelumab.²² For tranexamic acid and androgens, patients discontinued treatment due to adverse effects, ineffectiveness, or the perception that they no longer needed the medication.^15,20,26,27 Patients taking androgens had a higher burden from treatment adverse effects than those taking other treatments.¹⁴ When switching to a new prophylactic therapy or stating their preferences, patients mainly considered discreetness, the ability to administer where and when needed, fewer dosages, fewer attacks, fewer adverse effects, and route of administration as important factors.^{15,20,22,28–30}

Attack Outcomes

Thirty-six studies reported outcomes related to HAE attacks,^{6,8,10–15,17,20–24,26–29,31–40,44,45,47–53} including frequency (33 studies),^{6,8,10–12,14,15,20–24,26–28,31–38,40,44,45,47,48–51,53} location (22 studies),^{8,10,13,14,20,21,29,31–40,45,49–53} severity (15 studies),^{13,14,20,23,31,33,34,37,38,40,44,45,49,50,52} and duration (9 studies).^{14,20,22,26,34,35,40,49,50} Attack frequency varied according to several factors, including age, sex, and treatment type. As patients aged, they reported higher attack frequency, worse attack severity, and longer recovery time from attacks.²⁰ Annual attack frequency was higher among females than males.³¹ Patients receiving LTP with subcutaneous lanadelumab or subcutaneous C1INH had fewer attacks than those treated with nonsubcutaneous LTP (intravenous C1INH/recombinant human C1INH or oral androgens) or on-demand treatment.¹¹ Although the frequency of attacks in different locations varied across studies, abdominal and peripheral locations were consistently common across studies.^13,32–36 Among studies that reported the proportion of attacks as mild, moderate, or severe, the most common severity level was moderate, although definitions of severity levels were often not reported.^{13,14,31,34,37} One study showed the abdominal area to be most prone to severe attacks and the genitourinary area most prone to mild attacks.³⁷ In a study of 728 patients, 70 had a fatal HAE attack due to asphyxiation secondary to a laryngeal attack.³⁸ The five most-reported triggers for acute attacks include stress, emotional distress, physical trauma, menstruation, and surgery.^{24,35,36,39,40}

Caregiver Burden

The burden experienced by caregivers of patients with HAE was described by one qualitative study. Major sources of caregiver burden included severity of HAE symptoms, unpredictability of HAE attacks, and negative experiences in the health-care system, including delays in diagnosis. Receipt of a confirmed diagnosis reduced the emotional impact on caregivers. After the diagnosis, caregivers described relief and integration of HAE management into family routines.⁴¹

Gaps in Current Evidence and Future Research Priorities

Understanding the path to personalized HAE management requires a deeper examination of individual factors that influence QoL. Despite substantial advances in treatment options, several critical knowledge gaps persist in our understanding of how patient characteristics affect disease outcomes and treatment efficacy. Current research is limited on correlations of patient sex, HAE type, and attack duration with QoL. In addition, limited information was available in this analysis on any differences in QoL between HAE type 1 and HAE type 2 as well as any influence of patient age on attack outcomes. This patient-specific data would not only help better characterize this heterogeneous patient population but also could inform the development of more targeted therapeutic approaches.

The advancement of HAE treatment options in recent years has created both opportunities and challenges in optimizing patient care. Characterizing the impact of currently available therapies on QoL would help to differentiate treatment options, and identifying differences in treatment experiences for patients of varying age, sex, and socioeconomic status could allow for a more personalized therapeutic approach. Although options for LTP have expanded, there remains a crucial need for additional information surrounding patient preferences on currently available LTP. Furthermore, additional research is needed to explore potential risk factors associated with anxiety and depression in patients with HAE to facilitate tailored treatment plans and patient-led interventions.

One of the most substantial gaps in current HAE research lies in understanding the broader impact on families and support systems. Caregiver or family burden is a critically unexplored subject area. Only one study was identified on caregiver burden in HAE, and it contained no information on the extent of caregiver impact or the impact of clinical outcomes or disease severity on caregiver burden.⁴¹ Understanding how factors such as HAE type, attack frequency, and attack duration contribute to caregiver burden could allow for development or enhancement of support services. In addition, there was a gap in the literature on the impact of socioeconomic factors, including household income and access to care, and on the QoL and experiences of caregivers as they navigated the health-care system from HAE diagnosis through disease management over the years.

Relatedly, future research should continue to address emerging patient-centric challenges in HAE management that may negatively impact adherence and control of disease, including high rates of anxiety and depression, financial strain from high-cost treatments, and difficulties with medication administration.^11,13,42 These factors can contribute to interruptions in access to treatment, which may be experienced by > 50% of patients on prophylactic therapy.¹¹ In addition, global disparities in access to HAE care should be emphasized, particularly in low-resource settings where highly effective medications, diagnostic facilities, specialist expertise, and support services are often limited. Addressing these real-world complexities may contribute to the development of sustainable, patient-centered care strategies that can enhance HAE management across diverse populations and health-care systems.⁴³

Another challenge in advancing HAE research and treatment lies in the methodological inconsistencies across studies. The ability to compare QoL outcomes among studies has historically been limited by the heterogeneity of assessment tools used. However, we strongly commend and encourage the recent progress in standardizing patient-reported outcomes across ongoing and planned HAE studies. According to a screen of current clinical trials (Karissa Johnston, PhD, Principal, Broadstreet HEOR, written protocol, January 15, 2024), of 120 clinical trials on HAE across multiple clinical trial registries (ClinicalTrials.gov, the International Clinical Trials Registry Platform, and the European Clinical Trials Register), 20 measured QoL, with most (n = 18) using the disease-specific AE-QoL assessment tool rather than generic measures. In contrast, treatment satisfaction was being measured by five trials, with most (n = 4) using the Treatment Satisfaction Questionnaire for Medication assessment tool. This shift toward uniformity in patient-reported outcomes, particularly the increased implementation of disease-specific measures, e.g., AE-QoL, represents a substantial advancement in HAE research. However, because data on treatment satisfaction from trials may still be limited, evidence from real-world studies (particularly from studies that used standardized or disease-specific instruments) may be needed to supplement the insights surrounding QoL and treatment satisfaction from clinical trials.

CONCLUSION

The present work analyzed information from contemporary literature on the patient and caregiver burden of HAE. Whereas LTP contributes to improved QoL, the high treatment burden and presence of attacks continue to negatively impact patients. Future research on the impact of individual factors, such as age, sex, HAE type, and attack duration, can serve to better understand and treat this complex patient population, and standardization of assessment tools would allow for more accurate comparisons of treatment options. Several limitations of this literature review should be considered, including the nonsystematic method of evidence identification and analysis, and restriction to studies of adults with HAE types 1 or 2 in North America and Europe. Data from the included studies also had limitations, including inconsistent reporting of attack severity and frequency, limited longitudinal data, potential selection bias, lack of standardized outcome measures, and variable definitions of treatment success. Therefore, whereas this review provides valuable insights into HAE burden and treatment impacts, the findings may not fully represent the broader HAE population and should be interpreted within the context of these methodological constraints.

Together, the gathered literature identified research gaps and methodological challenges that present clear opportunities for advancing our understanding of the impact of HAE on both patients and caregivers, ultimately working toward the goal of providing more personalized, effective care that improves outcomes for the entire HAE community.