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Abstract

Background

Studies evaluating health-related quality of life (HRQOL) in patients with hereditary hemorrhagic telangiectasia (HHT) have expanded rapidly in the past decade. These studies have evaluated QOL aspects ranging from the general QOL for patients living with HHT to intervention-specific outcomes. However, few tools have been fully validated across the spectrum of disease manifestations and interventions in HHT.

Objective

In this scoping review, we aim to map the literature on HHT-QOL metrics, identify gaps, inform future QOL research, and facilitate future metric development.

Methods

We analyzed articles in English that assessed at least 1 measure of general HRQOL, including physical health, mental health, social health, or intervention-specific QOL in patients with HHT. Searches across 2 bibliographic databases (PubMed and Scopus) yielded 186 articles after duplicates were removed. Sixty-three studies met eligibility criteria: 22 prospective studies (34.9%), 20 retrospective studies (31.7%), 12 cross-sectional studies (17.5%), 6 randomized controlled trials or secondary analyses of a randomized controlled trials (9.5%), 2 qualitative studies (3.2%), and 1 case-control study (1.6%). Two additional studies—1 prospective and 1 cross-sectional study—were identified at the October 2022 14th International HHT Conference and included, making a total of 65 studies.

Results

The 65 eligible studies used 30 QOL instruments. Twenty studies characterized baseline HRQOL, and 45 studies evaluated QOL before and after treatment. Of those 45 studies, 37 evaluated HRQOL before and after therapies targeting epistaxis and nasal symptoms, 4 targeted therapies for liver arteriovenous malformations and high-output heart failure, 3 evaluated therapies for both epistaxis and gastrointestinal bleeding, and 1 evaluated treatment targeting gastrointestinal bleeding alone.

Conclusions

Comparison of results across studies remains challenging given the heterogeneity in outcomes measures. Further development of HHT-specific patient-reported outcomes instruments that capture the global illness experience of HHT is needed.

Keywords

hereditary hemorrhagic telangiectasia quality of life patient-reported outcome measures epistaxis quality of life metrics symptom burden vascular malformations fatigue disease impact self-perceived health

Introduction

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder with an autosomal dominant inheritance pattern that has a prevalence of 1 in 5000 to 8000 individuals.¹ It is characterized by arteriovenous malformations (AVMs) and telangiectasias with associated bleeding-related complications throughout the body, including but not limited to the nose, skin, lungs, liver, gastrointestinal tract, and central nervous system.^2–4 HHT affects persons of all races, ethnicities, genders, and ages indiscriminately.⁵ Individuals with severe forms of HHT have a limited selection of therapeutic choices, and even with treatment, on average their life-expectancy is 3 years shorter than that of the general population.⁶ The manifestations of HHT lead to significant morbidities, such as chronic blood loss (from chronic epistaxis or gastrointestinal bleeding), intracranial abscesses, and acute hemorrhage from the nose or gastrointestinal tract.⁷ Patients with HHT also frequently experience heightened psychological, social, and occupational stress as a consequence of their disease.⁸ The complex and heterogenous presentation of HHT makes the evaluation of the disease's impact on patients’ quality of life (QOL) challenging.

Patient-reported outcome measures (PROMs) and QOL instruments are needed to evaluate the illness experience of HHT and the effectiveness of HHT treatments. These tools enable clinicians to comprehend HHT's physical, psychological, and social impacts on their patient's QOL from the patient perspective. Healthcare professionals can increase treatment efficacy, identify areas for improvement, and adapt interventions to individual patients by integrating PROMs and QOL instruments into clinical trials and everyday care. The tools enable patients to actively participate in their care by expressing their concerns and priorities to healthcare personnel. PROMs and QOL tools are thus essential for HHT research and patient care.

In recent years, as medical research has increasingly emphasized health-related QOL (HRQOL), researchers have worked to better understand the experience of those living with HHT.^8–12 However, the literature describing the effect of HHT on individuals’ physical health, mental health, and social functioning, the effect of specific symptoms on QOL, and intervention-specific QOL is still incomplete. Furthermore, the inconsistent use of different outcome measures makes comparisons between studies difficult. Comprehensive and accurate QOL tools for evaluating current treatment methods for patients with HHT are needed, and these tools may motivate improvements in care pathways for individuals with HHT. Without assimilated evidence, it remains unclear where further research is needed. Therefore, the purposes of this scoping review were to (1) summarize the HRQOL literature related to HHT, (2) identify gaps in the literature, and (3) recommend steps for future research.

Methods

Literature Review Process

We conducted our scoping review using the Arksey and O’Malley methodological framework.¹³ PubMed and Scopus, 2 bibliographic databases, were queried for studies using keywords relevant to QOL, patient-reported outcomes, and HHT (see Supplemental Material). The timeframe of the final list of publications was 2004 to 2022. Two independent reviewers screened abstracts and full texts. A total of 186 unique articles were identified in the initial search, and 69 studies were selected for full-text review. After full-text screening, we selected 63 articles that described QOL metrics in individuals with HHT. At the 14th HHT International Scientific Conference in October 2022, we identified 2 additional articles, which made a total of 65 articles (Figure 1).

Figure 1.

Flowchart demonstrating literature search and study selection.

Data Abstraction

Data abstraction was performed between August 2021 and October 2022. Data collected from each of the eligible articles included first author, year, study country, sample size, study design, aims of study, study type, outcomes measured, and instruments used to assess each outcome (Tables 1 and 2). Instruments included any validated tools, custom-made instruments/questionnaires, and numerical scales that were reported in the 65 articles.

Table 1.

65 Studies Describing Use of Quality of Life Metrics in Patients with HHT, 2004-2022.

First author	Year	Nation	Sample size of patients with HHT (other) patients	Study design	Study aim	Study type
Al Kadah¹⁴	2014	Germany	11	Retrospective	To describe the use of individua nasal olive for the treatment of nosebleeds in patients with HHT	Treatment (epistaxis)
Albiñana¹⁵	2019	Spain	12	Prospective	To explore whether dobesilate could be used to treat abnormal angiogenesis and subsequent epistaxis associated with HHT	Treatment (epistaxis)
Andersen¹⁶	2020	Denmark	10	Retrospective	To evaluate the results of nasal closure among Danish patients with HHT	Treatment (epistaxis/nasal symptoms)
Baysal¹⁷	2019	Turkey	6	Retrospective	To evaluate the effectiveness of thalidomide for the treatment of nosebleeds in patients with HHT	Treatment (gastrointestinal bleeding and epistaxis)
Bertlich¹⁸	2021	Germany	151	Retrospective	To evaluate the use of blue light laser treatment for the treatment of endonasal manifestations of HHT	Treatment (epistaxis)
Blivet¹⁹	2014	France	56	Prospective	To measure the effect of pulmonary arteriovenous malformations and of their embolization on respiratory-related QOL	Baseline (pulmonary AVMs)
Chaturved²⁰	2017	The United States	222	Cross-sectional	To determine the prevalence of depression and post-traumatic stress disorder related to HHT	Baseline (psych)
Clark²¹	2018	The United States	17	Qualitative	To develop a patient-reported outcome measure for daily administration via electronic diary (eDiary) to assess the severity of nosebleeds in patients with HHT	Baseline (new patient-reported outcome development)
De Gussem²²	2009	The Netherlands	43	Prospective	To investigate if patients with HHT experience a reduction of epistaxis when treated with the O₂-scavenger N-acetylcysteine	Treatment (epistaxis)
de Jel²³	2020	The Netherlands	6	Prospective	To evaluate the effectiveness of fluorouracil for the treatment of nosebleeds in patients with HHT	Treatment (epistaxis)
Dheyauldeen²⁴	2011	Norway	98	Cross-sectional	To describe the natural history of epistaxis in the Norwegian population	Baseline (natural history)
Dheyauldeen²⁵	2012	Germany	8	Prospective	To evaluate the effectiveness of a standardized intranasal bevacizumab injection in treating HHT-associated epistaxis	Treatment (epistaxis)
Droege²⁶	2019	Germany	915	Cross-sectional	To assess the practices of patients with HHT when self-administering nasal packings and the resulting effect on patients’ lives	Treatment (epistaxis)
Dupuis-Girod²⁷	2010	France	13	Retrospective	To determine long-term liver-related morbidity and survival after orthoptic liver transplantation in patients with HHT and hepatic involvement; secondary objectives to evaluate cardiac status, epistaxis, and QOL in these patients	Treatment (liver AVMs)
Dupuis-Girod²⁸	2012	France	25	Prospective	To test the efficacy of bevacizumab in reducing high cardiac output in severe hepatic forms of HHT and to assess improvement in epistaxis duration and QOL	Treatment (high-output heart failure)
Dupuis-Girod²⁹	2020	France	50	RCT	To evaluate the efficacy of tacrolimus nasal ointment for the treatment of nosebleeds in patients with HHT	Treatment (epistaxis)
Esteban-Casado³⁰	2019	Spain	38	Cross-sectional	To analyze whether polidocanol sclerotherapy combined with application of a topical nasal propranolol as maintenance treatment to keep abnormal angiogenesis active could be effective and safe for severe and recurrent epistaxis in a population with high epistaxis score and damaged mucosa after many years of HHT disease	Treatment (epistaxis)
Faughnan³¹	2019	Canada and the United States	7	Prospective	To demonstrate efficacy of pazopanib on HHT-related bleeding, and to measure safety in this population	Treatment (gastrointestinal bleeding and epistaxis)
Fiorella³²	2012	Italy	24	Retrospective	To evaluate the effectiveness and safety of diathermocoagulation of telangiectasia on the nasal mucosa with a diode laser in the treatment of epistaxis in patients with HHT	Treatment (epistaxis)
Gaillard³³	2014	France	118	RCT	To demonstrate the efficacy of tranexamic acid in epistaxis in patients with HHT and to explore its safety of use	Treatment (epistaxis)
Geirdal³⁴	2012	Norway	66	Cross-sectional	To evaluate QOL (general health-related and disease specific) in a Norwegian population	Baseline (natural history)
Geirdal⁸	2013	Norway	66	Cross-sectional	To examine the relationship between coping strategies measured by COPE and psychological distress measured by HADS and BHS in individuals living with HHT, and to examine if coping strategies might have a mediating role between experienced illness and psychological distress	Baseline (psych)
Geisthoff³⁵	2014	Germany	22	RCT	To evaluate the effectiveness of using oral tranexamic acid for treating nose bleeds in patients with HHT	Treatment (epistaxis)
Guldmann³⁶	2012	France	6	Prospective	To evaluate the efficacy and safety of bevacizumab administered at a concentration of 50 mg as an intranasal spray in the treatment of epistaxis in patients suffering from Rendu-Osler disease	Treatment (epistaxis)
Haubner³⁷	2021	Germany	28	Retrospective	To classify nasal lesions of HHT	Baseline (epistaxis)
Hitchings³⁸	2005	The United Kingdom	32	Prospective	To investigate the effect of nasal closure, argon laser, and a combination of septodermoplasty and argon laser treatments on QOL scores and disease severity ratings in patients with HHT	Treatment (epistaxis)
Hoag³⁹	2010	North America	915	Cross-sectional	To develop and create the epistaxis severity score	Baseline (new patient-reported outcome development)
Hochet⁴⁰	2019	France	44	Retrospective	To evaluate the use of submucosal radiofrequency procedure for the treatment of nasal bleeding	Treatment (epistaxis)
Ingrand⁴¹	2011	France	108	Prospective	To develop and validate an epistaxis-specific QOL questionnaire to evaluate the impact on QOL of epistaxis, during hereditary hemorrhagic telangiectasia	Baseline (new patient-reported outcome development)
Invernizzi⁴²	2015	Italy	31	Prospective	To evaluate the efficacy of thalidomide for the treatment of nosebleeds in patients with HHT	Treatment (epistaxis)
Iyer⁴³	2018	The United States	34	Retrospective	To present a multiyear clinical experience with intravenous bevacizumab for the management of severe gastrointestinal bleeding and/or epistaxis in patients with HHT	Treatment (gastrointestinal bleeding and epistaxis)
Karapantzos⁴⁴	2005	Greece	27	Prospective	To describe the results of Nd:YAG laser application to patients with HHT	Treatment (epistaxis)
Kasthuri⁴⁵	2022	The United States	290	Cross-sectional	To develop an HHT-specific HRQoL (HHT-QoL) instrument and evaluate its performance in a cross-sectional survey of individuals with HHT	Baseline (patient-related outcome development epistaxis)
Khoueir⁴⁶	2019	France	31	Retrospective	To report for the first time on the results of submucosal injections of bevacizumab used in conjunction with cyanoacrylate glue sclerotherapy in patients with HHT	Treatment (epistaxis)
Kroon⁴⁷	2019	The Netherlands	11	Prospective	To assess the efficacy of octreotide long-acting release to decrease transfusion requirements and endoscopy frequency in patients with gastrointestinal bleeding and HHT	Treatment (gastrointestinal bleeding)
Kroon⁴⁸	2020	The Netherlands	21	Prospective	To investigate therapeutic potential of itraconazole in HHT	Treatment (epistaxis)
Kuan⁴⁹	2017	The United States	20	Retrospective	To (1) characterize baseline sinonasal symptoms for patients with HHT using the SNOT-22 questionnaire and to (2) analyze changes in sinonasal symptoms and outcomes before and after laser treatment for HHT	Treatment (epistaxis)
Le⁵⁰	2022	France	415	Prospective	To develop and validate a QOL measurement tool specific to HHT disease: the QOL questionnaire in HHT (QoL-HHT)	Baseline (patient-related outcome development epistaxis)
Lee⁵¹	2019	Canada	6	Prospective	To evaluate the efficacy of Floseal® for managing acute anterior epistaxis in patients with HHT	Treatment (epistaxis)
Lerut⁵²	2006	Multiple countries, Europe	40	Prospective	To evaluate HRQOL before and after liver transplantation	Treatment (liver AVMs)
Lesnik⁵³	2007	The United States	7	Retrospective	To review the indications, procedures, and outcomes of patients with severe transfusion-dependent HHT and septal perforation who underwent the combined procedure of septectomy/septal dermoplasty	Treatment (epistaxis)
Levine⁵⁴	2008	The United States	106	Retrospective	To evaluate the complications of septal dermoplasty in the management of transfusion-dependent epistaxis	Treatment (epistaxis)
Liu⁵⁵	2016	China	11	Prospective	To evaluate the effectiveness of double banding/ligation of hepatic arteries in treating patients with HHT	Treatment (liver AVMs)
Loaëc⁵⁶	2011	France	115	Retrospective	To evaluate psychosocial QOL in patients with HHT	Baseline (psych)
Lund⁵⁷	2017	Malayasia	515	Retrospective	To evaluate the efficacy of nasal closure for nosebleeds in patients with HHT	Treatment (epistaxis)
Martinent⁵⁸	2020	France	13	Qualitative	To describe health-related QOL of patients with HHT	Baseline (natural history)
Merlo³⁹	2014	The United States	604	Cross-sectional	To determine whether epistaxis severity is a major factor predicting health-related QOL in patients with HHT	Baseline (epistaxis)
Pagella⁵⁹	2013	Italy	26	Retrospective	The aim of this study was to test the efficacy of APC treatment as a first-line procedure in patients with HHT affected by severe epistaxis	Treatment (epistaxis)
Pasculli⁶⁰	2004	Italy	50 (2031 controls)	Cross-sectional	To evaluate QOL in patients with HHT	Baseline
Peterson⁶¹	2020	The United States	401	Prospective	To create a new, comprehensive epistaxis QOL metric	Baseline (patient-related outcome development epistaxis)
Peterson⁶²	2020	The United States	27	RCT	To determine the efficacy and safety of an intranasal timolol thermosensitive gel versus placebo thermosensitive gel in treating HHT-associated epistaxis	Treatment (epistaxis)
Pfister⁶³	2009	Germany	24	Prospective	To ascertain the influence of HHT genotype and mutation type on the German SF-36 in patients with HHT	Baseline (genotype)
Rohrmeier⁶⁴	2012	Germany	8	Retrospective	To evaluate the effectiveness of bevacizumab as an additive treatment in comparison to laser treatment alone	Treatment (epistaxis)
Simonds⁶⁵	2009	The United States	19 (10 in the bevacizumab/KTP group, 9 in KTP alone)	Retrospective	To determine the effectiveness of treating epistaxis in HHT with potassium titanyl phosphate laser cautery combined with submucosal injection of 100 mg of bevacizumab	Treatment (epistaxis)
Sindhar⁶⁶	2019	The United States	18	Cross-sectional	To determine the presence and characterize the location of retinal vascular lesions in patients with HHT	Baseline (retinal)
Steineger⁶⁷	2020	Norway	33	Prospective	To evaluate the effect of repeated intranasal submucosal bevacizumab injections	Treatment (epistaxis)
Thompson⁶⁸	2014	The United States	6	Prospective	To evaluate the effectiveness of bevacizumab infusion for the treatment of nosebleeds in patients with HHT	Treatment (epistaxis)
Thomson⁶⁹	2018	The United States	32	Case-control	To examine the effects of nasal closure on specific QOL parameters, including sleep, in patients with HHT	Treatment (epistaxis/nasal symptoms)
Timmins⁷⁰	2016	The United States	8	Retrospective	To describe the traditional 3-flap modified Young's procedure in an initial experience with the first 8 patients and the 3-flap traditional Young's procedure	Treatment (epistaxis)
Whitehead⁷¹	2016	The United States	121	RCT	To evaluate the efficacy of topical medical therapy with either bevacizumab, estriol, or tranexamic for the treatment of epistaxis in patients with HHT compared to saline placebo	Treatment (epistaxis)
Wu⁷²	2021	Canada	16	Retrospective	To evaluate the efficacy and safety of in-office potassium titanyl phosphate laser treatment for the management of epistaxis in patients with HHT	Treatment (epistaxis)
Wu⁷³	2021	Canada	7	Secondary analysis of an RCT	To describe the effect of doxycycline or placebo treatment on PRO-WED and ESS scores in patients with HHT	Treatment (epistaxis)
Yaniv⁷⁴	2011	Israel	46	Prospective	To examine the efficacy of an anti-estrogenic agent, tamoxifen, in the treatment of HHT-associated epistaxis	Treatment (epistaxis)
Yin⁷⁵	2016	The United States	604	Cross-sectional	To calculate the minimal important difference of the ESS in HHT using both the anchor-based and distributional methods	Baseline (epistaxis)
Zarrabeitia¹²	2017	Spain	187	Cross-sectional	To assess the QOL in a population of Spanish patients with HHT and compare it with the general population	Baseline (natural history)

Abbreviations: APC, argon plasma coagulation; AVMs, arteriovenous malformations; BHS, Beck's hopelessness scale; COPE, coping orientation to problems experienced scale; ESS, epistaxis severity score; FGF, fibroblast growth factor; HADS, hospital anxiety depression score; HHT, hereditary haemorrhagic telangiectasia; HRQOL, health-related quality of life; QOL, quality of life; PRO-WED, patient-reported outcome-weekly epistaxis duration; RCT, randomized controlled trial; SD/ST, septectomy/septal dermoplasty.

Table 2.

Health-Related Quality of Life Patient-Reported Outcome Measures in the Hereditary Hemorrhagic Telangiectasia Literature.

Name of instrument	Description	Number of items	Time to complete (minutes)	Outcome domains assessed with instrument	Specific for HHT population?	Number of times used (number of studies)
BDI-II⁷⁶	Evaluates the presence of and severity of clinical depression; high scores indicate more severe depression	21	5-6	Mental health	No	1
BHS⁷⁷	Measures participant attitudes toward the future; higher scores indicate a higher pessimism and hopelessness	20	5	Mental health	No	1
BSS⁷⁸	Measures frequency and quantity of nosebleeds	2	<1	Physical health	No	1
Cantril's Self-Anchoring Ladder⁷⁹	Self-perceived QOL measured on a 0-10 vertical ladder scale, with higher scores indicating better self-perceived health	2 (1 measuring self-perceived QOL in the present and the other measuring 5 years in the future)	<1	General health	No	6
CGI⁸⁰	Evaluates observer-perceived global illness severity, change, and response to therapy	3	1	Pretreatment and post-treatment	No	2
COPE⁸¹	Evaluates a participant's coping responses; no summary score system	60	15	Mental health	No	1
EQ-5D-3L⁸²	Self-reported questionnaire used to characterize current health states	15	3–4	General, physical, mental, and social health	No	1
EQ-5D-3L-VAS⁸³	EQ-5D questionnaire, plus a VAS that allows respondents to score a characteristic or attitude across a continuum of values	15 (plus VAS)	3–4	General, physical, mental, and social health	No	1
EQQoL⁴¹	Evaluates psychosocial aspects of health as related to nosebleeds in patients with HHT	13	3–4	Physical, mental, and social health	Yes	1
ESS^a³⁹	Assesses the frequency, duration, and severity of epistaxis as well as anemia, blood transfusions, and the need for medical attention; higher scores indicate more severe nosebleeds	6	2	Physical health	Yes	28
GBI⁸⁴	Evaluates benefit of operation	18	4–5	General, physical, mental, and social health	No	4
HADS⁸⁵	Measures impact on overall health, daily life, and perceived wellbeing; higher scores indicate greater disability	14	3–4	Mental health	No	2
HHT-QOL	Evaluates the impact of epistaxis on social health	4	<1	Social health	Yes	1
IFT^67,69	Measures intensity, frequency, and transfusions required for epistaxis; higher scores indicate more severe epistaxis	3	1	Physical health	No	1
JSS⁸⁶	Evaluates sleep health	4	1	Physical health	No	1
MFI⁸⁷	Evaluates 5 dimensions of fatigue: general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue; higher total scores correlate with higher levels of acute fatigue	20	5	Physical health	No	2
NEI VFQ-25⁸⁸	Evaluates dimensions of self-reported vision-targeted health status that are most important for persons who have chronic eye diseases	25	6-7	Physical, mental, and social health	No	1
NOSE	Evaluates disease-specific health status instrument for use in patients with nasal obstruction	12	3-4	General, physical, mental health	No	1
NOSE-HHT^b⁶¹	Evaluates the psychosocial impact of epistaxis in patients with HHT	28	9-10	Physical, mental health, social health	Yes	2
Nosebleed eDiary²¹	eDiary to be filled out every time participant has a nosebleed; used to assess nosebleed duration, intensity, need for medical care, and overall severity	4	1	Physical health	Yes	1
Pain adjective rating scale	10-point, adjective rating scale; higher scores indicating greater pain	1	<1	Physical health	No	1
PCL-5⁸⁹	Screens, makes preliminary diagnosis, and monitors symptom change during and after treatment	20	5	Mental health	No	1
PRO-WED⁷³	Sum of epistaxis duration derived from daily epistaxis diary over a 1-week period	N/A	N/A	Physical health	Yes	1
PSQI⁹⁰	Evaluates sleep health	24 (19 scored self-rated items, 5 unscored bed partner-rated items)	12	Physical health	No	1
QOL-HHT	Evaluates impact of HHT on physical limitations, social relationships, concern about bleeding, relationship with medical profession, experience of symptoms, concern about the evolution of the disease	24	6-7	Physical and social health	Yes	1
RSDI⁹¹	Evaluates physical, functional, and emotional domains as related to rhinosinusitis diagnoses	30	7-8	Physical, mental, and social health	No	1
SF-36^92,93	Assesses physical functioning, role limitations due to physical health, role limitations due to emotional problems, energy/fatigue, emotional wellbeing, social functioning, pain, and general health	36	8-10	General physical, mental, and social health	No	22
SGRQ⁹⁴	Evaluates impact of obstructive airway disease on general health and daily life	50	12-13	General, physical, mental, and social health	No	1
Slotosch disease-specific QOL questionnaire⁹⁵	Evaluates disease-specific impact on QOL; higher score indicates greater impact	1	<1	General HRQOL	No	1
SNOT-22⁹⁶	Evaluates physical problems, functional limitations, and emotional consequences related to chronic rhinosinusitis	22	5-6	Physical, mental, and social health	No	2

For ESS, the minimal clinically important difference in patients with HHT was .71.⁷⁵

For NOSE-HHT, the minimal clinically important difference in patients with HHT was .46.⁶¹

Abbreviations: BDI-II, Beck depression inventory; BHS, Beck's hopelessness scale; BSS, Bergler-Sadick scale; CGI, clinical global impression; COPE, coping orientation to problems experienced scale; EQ-5D-3L, EuroQol-3 Level; EQ-5D-3L-VAS, EuroQol-3 Level (visual analog scale); EQQoL, epistaxis questionnaire quality of life; ESS, epistaxis severity score; GBI, Glasgow Benefit Inventory; HADS, hospital anxiety depression score; HHT-QOL, hereditary haemorrhagic telangiectasia-specific quality of life instrument; IFT, intensity, frequency, transfusions; JSS, Jenkins Sleep Scale; MFI, Multidimensional Fatigue Inventory; NEI VFQ-25, national eye institute visual function questionnaire-25; NOSE-HHT, nasal outcome score for epistaxis-hereditary hemorrhagic telangiectasia; PCL-5, post-traumatic stress disorder checklist for DSM-5; PRO-WED, patient-reported outcome-weekly epistaxis duration; PSQI, Pittsburg Sleep Quality Index; QOL-HHT, QOL questionnaire in HHT; RSDI: rhinosinusitis disability index; SF-36, Short Form-36; SGRQ, Saint George's respiratory questionnaire; SNOT-22, Sino-Nasal outcome test.

We defined 5 outcome domains that were assessed in QOL studies. Three of them—physical health, mental health, and social health—were in line with the PROMIS adult self-reported health domains.⁹⁷ Social health was defined as social functioning (i.e., the ability to participate and satisfaction with social roles), including but not limited to work and social relationships.⁹⁸ Two additional domains, general HRQOL and intervention-specific QOL, were also added. We defined intervention-specific QOL as QOL directly related to an intervention experience and/or its outcomes. Each instrument reported in the collected studies was assigned to 1 or more of the 5 outcome domains (Table 3). Some instruments satisfied criteria for multiple domains.

Table 3.

QOL and Patient-Reported Outcome Measures by Domain.

Domains	General HRQOL	Physical health	Mental health	Social health	Intervention-specific QOL
Outcomes measured	General HRQOL	Epistaxis characteristics (intensity, frequency, transfusions, duration, quality, quantity), rhinosinusitis disorder physical symptoms, sleep quality, pain, fatigue, vision quality, obstructive airway disease symptoms	Rhinosinusitis-specific emotional consequences, psychosocial illness impacts, Rhinosinusitis Disability Index, epistaxis emotional consequences, anxiety, depression, feelings of hopelessness, coping responses, symptoms of post-traumatic stress disorder, emotional limitations associated with vision	Nasal-specific social consequences, social life, family support, rhinosinusitis impact on social and work function, epistaxis impact on social and work function, role function limitations due to vision	General, social, and mental health after a procedure, pain with procedure, social and work functioning, impact of treatment on epistaxis intensity and severity, social and work functioning limitations related to obstructive airway disease
Instruments used in measurement	Cantril's Self-Anchoring Ladder EQ-5D-3L(VAS) SF-36 Slotosch disease-specific QOL questionnaire Custom questionnaire	BSS EQ-5D-3L EQQoL ESS GBI IFT JSS MFI NEI VFQ-25 NOSE NOSE-HHT Nosebleed eDiary Pain adjective rating scale PSQI PRO-WED QOL-HHT RSDI SF-36 SGRQ SNOT-22 Custom questionnaire	BDI-II BHS COPE EQ-5D-3L EQQoL GBI HADS NEI VFQ-25 NOSE NOSE-HHT PCL-5 RSDI SF-36 SGRQ SNOT-22 Custom questionnaire	EQ-5D-3L EQQoL GBI HHT-QOL NEI VFQ-25 NOSE NOSE-HHT QOL-HHT RSDI SF-36 SGRQ SNOT-22 Custom questionnaire	CGI GBI Custom questionnaire

Abbreviations: BDI-II, Beck depression inventory; BHS, Beck's hopelessness scale; BSS, Bergler-Sadick scale; CGI, clinical global impression; COPE, coping orientation to problems experienced scale; EQ-5D-3L, EuroQol-3 level; EQ-5D-3L-VAS, EuroQol-3 Level (VAS); EQQoL, epistaxis questionnaire quality of life; ESS, epistaxis severity score; GBI, Glasgow benefit inventory; HADS, hospital anxiety depression score; HHT-QOL, hereditary hemorrhagic telangiectasia-specific quality of life instrument; IFT, intensity, frequency, transfusions; JSS, Jenkins Sleep Scale; MFI, multimodal fatigue index; NEI VFQ-25, national eye institute visual function questionnaire-25; NOSE, nasal outcome score for epistaxis; NOSE-HHT, nasal outcome score for epistaxis-hereditary hemorrhagic telangiectasia; PCL-5, post-traumatic stress disorder checklist for DSM-5; PRO-WED, patient-reported outcome-weekly epistaxis duration; PSQI, Pittsburg Sleep Quality Index; QOL-HHT, QOL questionnaire in HHT; RSDI, rhinosinusitis disability index; SF-36, Short Form-36; SGRQ, Saint George's respiratory questionnaire; SNOT-22, Sino-Nasal outcome test.

Results

Study Designs of Eligible Studies

Among the 65 eligible articles, there were 23 prospective studies (35.3%), 20 retrospective studies (30.7%), 13 cross-sectional studies or their secondary analyses (20.0%), 6 randomized controlled trials (RCTs) or their secondary analyses (9.2%), 2 qualitative studies (3.1%), and 1 case-control study (1.5%).

Outcomes Assessed by Study Objective

Twenty-nine pre-existing QOL instruments were used in the studies (Table 2). In addition, custom instruments were developed and used in 18 studies. Thirty-four studies used more than 1 instrument. Twenty studies characterized baseline HRQOL in patients who did not receive treatment, and 45 studies evaluated both pretreatment and post-treatment QOL in patients who underwent treatment. Of these 45 studies, 37 evaluated HRQOL before and after therapies targeting epistaxis and nasal symptoms, 4 evaluated therapies targeting liver AVMs and high-output heart failure, 3 evaluated therapies targeting both epistaxis and gastrointestinal bleeding, and 1 evaluated treatment targeting gastrointestinal bleeding alone.

Outcomes Assessed by Domain

Among the 63 quantitative studies, 56 (88.9%) assessed physical health, 34 (53.9%) assessed mental health, and 36 (57.1%) assessed social health. Thirty-two studies (50.8%) assessed general QOL and 13 (20.6%) assessed intervention-specific QOL. Most studies (45 of 63; 71.4%) measured outcomes in more than 1 domain, and 59.0% (36 of 63) measured outcomes in more than 2 domains. Table 2 shows each instrument, the domains each instrument assessed, whether the instrument was developed and validated specifically for an HHT population, and the number of times the instrument was used across all studies. Table 3 shows the outcome measures and instruments used for each domain. Table 4 reports the validation of each instrument validated in an HHT population for the measurement properties identified in the U.S. Food and Drug Administration's Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims.⁹⁹

Table 4.

Measurement Properties of Instruments Validated for HHT.

Instrument	Content validity	Construct validity	Reliability	Ability to detect change
BHS	No	Yes ⁸	Yes⁸	No
COPE	No	Yes⁸	Yes ⁸	No
EQQoL	Yes ⁴¹	Yes ⁴¹	Yes ⁴¹	Yes ⁴¹
ESS	Yes ³⁹	Yes ¹⁰⁰	No	Yes ⁷⁵
HADS	No	Yes ⁸	Yes ⁸	No
HHT-QOL	Yes ⁴⁵	Yes ⁴⁵	No	No
NOSE-HHT	Yes ⁶¹	Yes ⁶¹	Yes ⁶¹	Yes ⁶¹
Nosebleed eDiary	Yes ²¹	No	No	No
QOL-HHT	Yes ⁵⁰	Yes ⁵⁰	Yes ⁵⁰

Abbreviations: BHS, Beck's hopelessness scale; COPE, coping orientation to problems experienced scale; EQQoL, epistaxis questionnaire quality of life; ESS, epistaxis severity score; HADS, hospital anxiety depression score; HHT-QOL, hereditary hemorrhagic telangiectasia-specific quality of life instrument; NOSE-HHT, nasal outcome score for epistaxis-hereditary hemorrhagic telangiectasia; QOL-HHT, QOL questionnaire in HHT.

General Health-Related Quality of Life

General HRQOL was assessed in 31 studies (50.8%).^{17–19,23,25,27–32,34,37,38,41,43,44,46–48,55,60–64,67,68,74,75,100} Among them, 4 pre-existing instruments were used (Table 3). None of the 4 were fully validated in an HHT population. The Short Form-36 (SF-36) (22 of 31; 67.7%) was the most used instrument, followed by Cantril's Self-Anchoring Ladder (6 of 31; 19.4%), the EuroQol-3 Level (VAS) (1 of 31; 3.2%), and the Slotosch disease-specific QOL questionnaires (1 of 31; 3.2%). Four studies used custom instruments, which included questions regarding general health-related QOL such as “How would you rate your quality of life?”^32,43,64,74

Physical Health

Physical health was assessed in 56 studies (88.9%).^{12,14–17,19,22–32,34–44,46–51,53–55,57,59–75,100} Twenty pre-existing instruments were used, and 15 studies used custom instruments.^{22,24,32,34,35,38,39,42,50,53,54,57,59,65,71} The Epistaxis Severity Score (ESS) was the most used instrument (28; 50.9%), followed by SF-36 (22; 39.2%) and the Glasgow Benefit Inventory (GBI) (4; 7.3%). The GBI is an intervention-specific instrument that measures changes before and after an intervention. The remainder of the instruments were used in fewer than 4 studies each (Tables 2 and 3). Of the instruments used for evaluating physical health, 7 were validated in patients with HHT: the ESS, the Nasal Outcome Score for Epistaxis-HHT (NOSE-HHT), the QOL questionnaire in HHT (QOL-HHT), the HHT-specific QOL (HHT-QOL) instrument, the Epistaxis Questionnaire QOL (EQQoL) scale, the Nosebleed eDiary, and the Patient-Reported Outcome-Weekly Epistaxis Duration (PRO-WED).

Mental Health

Mental health was assessed in 34 studies (54.1%).^{8,12,16,17,20,23,25,27–29,31,34,38,41,44,47–49,55–57,60–63,66–70,74,75,100} The studies used 15 pre-existing instruments and 1 custom instrument. The SF-36 was the most used instrument (22; 62.9%), followed by the Hospital Anxiety Depression Score (HADS) (2; 5.7%), the NOSE-HHT (2; 5.7%), and the Sino-Nasal Outcome Test-22 (SNOT-22) (2; 5.7%). All other instruments were used only once and are shown in Table 2. Most of these instruments were validated for a general population or a population with specific symptoms, and 1 was validated in individuals with HHT.

Social Health

Social health was assessed in 39 studies (61.9%).^{12,16,17,19,22,23,25,27–29,31,34,38,41,44,45,47–50,52,53,55–57,60–63,66–68,70,74,75,100} Among them, 12 pre-existing instruments were used, and 7 studies used custom instruments. The SF-36 (22; 57.9%) was the most used tool, followed by the GBI (4; 6.4%), the NOSE-HHT (2; 5.1%), and the SNOT-22 (2; 5.1%). The remaining instruments (see Tables 2 and 3) were each used once. Two of the custom instruments—the QOL-HHT questionnaire and the HHT-QOL instrument—have been validated in individuals with HHT.^45,50

Intervention-Specific QOL

Intervention-specific QOL was assessed in 13 studies (21.3%).^{14,16,26,33,46,51,53,54,57,61,62,64,70} The GBI (4; 30.8%) was the most used, followed by the Clinical Global Impression (CGI) scale (2; 15.4%). Seven studies used custom instruments. None of the instruments used in 13 studies were validated in individuals with HHT.

Discussion

This scoping review summarizes the multidimensional outcome measures currently used for evaluating HRQOL in individuals with HHT. Patient-centered care relies on patients’ perspective on their disease as a whole and the changes in manifestations and experience of the disease following treatment and interventions.^101–103 Use of pre-existing QOL metrics and patient-reported outcomes is critical to collecting this data in a systematic and reproducible fashion.^104–106 Currently, there are many custom outcomes used as measures of QOL in people with HHT. This heterogeneity in QOL outcomes makes selecting appropriate outcome measures and comparing across studies challenging.^107,108

In this scoping review, the data were organized into the PROMIS domains of physical health, mental health, and social health.^97,109 We found that critical aspects of QOL in individuals with HHT are not captured within these PROMIS domains; therefore, we decided to also include both a general QOL domain and an intervention-specific QOL domain. Physical health was the most frequently assessed domain, with epistaxis being the most often assessed symptom. The evaluation of the physical health domain was likely more common because physical complaints are more readily reported by patients and more easily elicited by physicians in a clinical encounter compared to complaints about mental health and social functioning.^110–113 Additionally, patients with HHT may predominantly report physical concerns.¹¹⁴ Mental health and social health were the next most frequently evaluated QOL domains. HHT is a chronic illness, which can lead to significant stress over time and contribute to mental distress; however, accurate and reproducible assessment of mental health can be difficult.^{12,20,115,116} In our literature search, we found that anxiety and depression were assessed often. Social health investigations included social support and role limitations. In this review, although most studies evaluated pretreatment and post-treatment QOL, only 5 studies were RCTs. RCTs are widely regarded as the gold standard of study design, and more such studies are needed to improve our understanding of changes in pretreatment and post-treatment QOL.¹¹⁷

Although studies used a wide variety of outcome measures, most used generic measures or disease-specific questionnaires not specifically designed for or validated in patients with HHT. Several studies developed custom, nonvalidated measures that were then used for analysis. Ideally, validated instruments specific to the domain(s) under investigation, rather than one-off, nonvalidated instruments, should be used. For instruments that assess many domains, a clear categorization of scores by domain would enable the examination of multiple domains independently. Five of the validated outcome measures currently available for assessing patients with HHT focus on assessing the impact of epistaxis on HRQOL (Table 2), which is logical given that epistaxis may be the only presenting symptom of HHT and it has a prevalence of >90% among patients with HHT. However, these epistaxis-specific measures fall short of capturing the full breadth of disease-related symptoms that individuals with HHT frequently experience. More investigation is needed to expand the scope of HRQOL outcome measures for individuals with HHT. To achieve this, there is a need for content elicitation and validation to identify the full range of symptoms affecting patients with HHT. We believe that this scoping review is a crucial step toward expanding validated outcome measures for individuals with HHT.

A 2022 study examined more than 400 patients with HHT at 20 specialist centers in France. The investigation led to the creation of a 24-item questionnaire with high-quality content validity and psychometric analysis, including tests of construct validity and reliability.⁵⁰ This is the first holistic HHT-QOL measure that focuses on the illness experience beyond epistaxis and includes the following evidence-based domains: physical limitations, social relationships, concern about bleeding, relationship with the medical professional, experience of symptoms, evolution of the disease. To date, the questionnaire has only been tested in French, and neither a minimal clinically significant difference nor clinical relevance has been identified. Further psychometric validation in a diversity of populations is needed.

Our study has some limitations. By keeping our search terms broad and using 2 large bibliographic databases, we attempted to capture all studies that evaluated HRQOL or patient-reported outcomes in patients with HHT; however, it is possible that studies were omitted inadvertently. Further, only studies published in the English language were included on analysis, thus biasing our results to those studies published outside English-speaking countries.

This review highlights the current heterogeneity in QOL metrics and patient-reported outcomes used to measure HRQOL in patients with HHT. We identified 31 unique instruments and cataloged them under 5 domains. Only 7 of these instruments (ESS, EQQOL, Nosebleed eDiary, PRO-WED, NOSE-HHT, HHT-QOL, and QOL-HHT), 6 of which focus on the impact of epistaxis on QOL, were validated in patients with HHT. Although epistaxis is seen in most individuals with HHT, the disease has many other manifestations because of its impact on multiple organ systems. The clinical features and symptoms include but are not limited to gastrointestinal bleeding, symptoms due to visceral AVMs, and neurological dysfunction secondary to brain AVMs. This review can serve as a reference for clinicians and researchers seeking guidance in choosing outcome HRQOL instruments for patients with HHT. Importantly, we want to emphasize the need for validation of pre-existing instruments in the HHT population around the world and for development of tailored, disease-specific instruments in multiple languages that target symptoms beyond epistaxis. Overall, the heterogeneity of outcome measures used in the HRQOL literature makes it challenging to compare results across studies and select appropriate metrics for individuals with HHT. Development and validation of a core set of outcome measures tailored to the complex clinical reality of HHT is urgently needed to advance research aimed at improving patient-centered outcomes and QOL for patients living with HHT.

Supplemental Material

sj-docx-1-ajr-10.1177_19458924231207123 - Supplemental material for Health-Related Quality of Life Outcome Measures in Individuals With Hereditary Hemorrhagic Telangiectasia: A Scoping Review

Supplemental material, sj-docx-1-ajr-10.1177_19458924231207123 for Health-Related Quality of Life Outcome Measures in Individuals With Hereditary Hemorrhagic Telangiectasia: A Scoping Review by Anna J. Gong, Tushar Garg, Adham Khalil, Prateek C. Gowda, Stephen C. Mathai, Nicholas R. Rowan, Christian A. Merlo and Clifford R. Weiss in American Journal of Rhinology & Allergy

Footnotes

Acknowledgements

For their editorial assistance, including submission on the authors’ behalf, we thank Sandy Crump, MPH, Denise Di Salvo, MS, and Rachel Box, MS, in the Editorial Services group of The Johns Hopkins Department of Orthopaedic Surgery.

Declaration of Conflicting Interests

The authors would like to declare the following conflict of interest with respect to the research, authorship, and/or publication of this article: Unrelated funding from Cure HHT.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article

ORCID iDs

Nicholas R. Rowan

Clifford R. Weiss

Supplemental Material

Supplemental material for this article is available online.

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