Epistaxis limits the performed activities of daily living in proportion to its severity: a cross-sectional survey among patients with hereditary haemorrhagic telangiectasia*

Background: We examined the severity of epistaxis in patients with hereditary haemorrhagic telangiectasia (HHT) and its relationship with the performed activities of daily living. Methodology: This cross-sectional survey included 36 patients with HHT in Japan. An anonymous questionnaire survey was conducted regarding the severity of epistaxis, the measures adopted to prevent epistaxis, and the limitations in the performed activities of daily living. The latter was assessed using a visual analogue scale (VAS). The correlation between epistaxis severity and the VAS score was analysed using Spearman’s rank correlation coefficient. Results: Of the 36 participants surveyed, 94.4% had >1 episode of epistaxis/week. The mean epistaxis severity score (ESS) was 4.3 (range, 0.9–8.4). Limitations in daily life, going out (within a day), meeting with others, eating with others, and going on overnight trips were positively correlated with the ESS. To prevent nosebleeds, 44.4% and 41.7% of the participants used medications and avoided drying their nasal cavities, respectively. Conclusions: Epistaxis impacted the daily life of patients with HHT in proportion to its severity. Nonetheless, less than half of the patients used medications or took precautions. Hence, further educational activities should be considered for medical professionals and patients.


Introduction
Hereditary haemorrhagic telangiectasia (HHT), as named by Hanes in 1909 (also known as Osler-Weber-Rendu or Osler's disease (1)(2)(3)(4) ), is a systemic disease characterised by telangiectasis and arteriovenous malformations in various organs. In the field of otorhinolaryngology, it is well known as the cause of intractable epistaxis (5) . It is diagnosed based on the Curaçao clinical diagnostic criteria (6) . HHT is an autosomal-dominant genetic disorder caused by mutations in the ENG and ACVRL1 genes, referred to as HHT1 and HHT2, respectively (5) . Although ENG and ACVRL1 mutations account for the majority of HHT cases, muta-tions in the SMAD4 gene are also related to HHT development (7) .
In Japan, the prevalence of HHT is estimated to be one in 5,000-8,000 individuals (8) . Interestingly, approximately 99% of Japanese patients may experience recurrent epistaxis, which is the most common symptom (9) . As epistaxis is one of the major factors impairing the quality of life (QoL) of patients with HHT (10)(11)(12)(13) , it is useful for physicians and patients themselves to ascertain the severity of epistaxis and the epistaxis severity score (ESS), as proposed by Hoag et al. (14) . According to previous work, patients with severe epistaxis based on the ESS are more likely to have affected Physical Component Summary and present significantly worse Mental Component Summary scores than those with mild epistaxis (13) . Arai and Akiyama reported that patients with HHT in Japan expected constant updates concerning HHT therapy, convenient access to HHT-specific epistaxis treatment, longer consultation time, acquisition of expert skills by the otolaryngologist, and sufficient knowledge to stop the recurrent nasal bleeding (15) . These expectations suggested that these issues had not been satisfied. Recurrent epistaxis may interfere with the patients' daily life. However, the extent to which epistaxis restricts their daily life and the type of treatment that patients with HHT receive have not been investigated. This information would aid medical professionals in gaining better insights into the patients' condition and would help treatment guidance.
We hypothesised that HHT-related epistaxis limited the performed activities of daily living of these patients. It was also considered necessary to investigate the measures taken by patients with HHT to prevent epistaxis, as it would be beneficial for them to be informed if prevention was inadequate. Although the activities of daily living are an indicator of the patients' QoL, we aimed to investigate the restriction of the activity range more directly by conducting a questionnaire survey using the visual analogue scale (VAS). Therefore, with the cooperation of the Japan Osler's Disease Patient Association, we examined the severity of epistaxis and the correlation between epistaxis and daily behavioural restrictions to obtain knowledge on the severity of epistaxis among patients with HHT in Japan and highlight the importance of epistaxis prevention and treatment.

Questionnaire
We conducted an anonymous questionnaire survey of patients with HHT who attended the 2017 annual meeting of the Japan Osler's Disease Patient Association. The questionnaire (Figure 1) was distributed at the meeting, and the patients were asked to complete it. We used the REDcapTM system as a questionnaire method for online responses. Patients who were unfamiliar with the use of the Internet were asked to fill out a paper questionnaire. A printed QR code form was distributed to those who wanted to complete the questionnaire online, and a questionnaire form was distributed to those who preferred a paperbased response. Both online and paper responses were received within 2 months. The survey items included age, sex, HHT diagnosis, the severity of epistaxis, and the degree of limitation in the activities of daily living.
Regarding the severity of epistaxis, the questions were focused on the following: epistaxis frequency, duration, intensity, and history of epistaxis-related medical consultation, anaemia, and blood transfusion. The normalised ESS was calculated from the answers (14) . The impact on the activities of daily living was

Ethics
This study was approved by the Ethics Committee of Osaka University Hospital (#17092). All participants provided written informed consent.     In the survey on measures taken to prevent epistaxis by themselves, most respondents (77.8%) answered that they did not touch their noses ( of the respondents answered that they had received a type of medication, while 13.9% answered that they did not take any special preventive measures.

Discussion
In the present study, we investigated the severity of epistaxis and the correlation between epistaxis and daily behavioural restrictions among patients with HHT in Japan. Most respondents reported >1 episode of epistaxis per week. All activities of daily living were significantly correlated with the ESS. Moreover, patients with severe epistaxis showed significantly greater limitations in the activities of daily living than those with mild and moderate epistaxis. Furthermore, almost one-fifth of the patients answered that they did not take any special preventive measures.
The prevalence of epistaxis in HHT was reported to be 95-99% (9,14,15) . In our study, the prevalence was 94.4%, which was consistent with the results of having >1 episode of epistaxis per week. Gonzalez et al. reported that the severity of epistaxis was mild in children, even in confirmed HHT cases (16) . Nonetheless, 50% of patients reported the presence of epistaxis by the age of 20 years, which was consistent with our finding that 47.2% of patients had recurrent epistaxis by the age of 19 years. These findings suggested that most patients with HHT have recurrent epistaxis as a part of their lives.
In this study, we found that the ESS was correlated with the limitations in the activities of daily living in patients with HHT. Merlo et al. reported that the ESS is a major determinant of impaired health-related QoL (HR-QoL) in these patients (13) . Geisthoff et al.
stated that the duration of epistaxis, as well as liver involvement, gastrointestinal bleeding, and the number of visible telangiectases, presented a major influence on the HR-QoL of patients with HHT (10) . The management of recurrent epistaxis may be effective for improving the QoL of these patients and for preventing anaemia.
Drug therapy for epistaxis has been tested. In a phase IIIB, randomised, double-blind, placebo-controlled, cross-over study, treatment with tranexamic acid resulted in a decreased ESS by 54% (17) . Gaillard et al. also demonstrated a 17% reduction in the mean duration of epistaxis per month in a controlled randomised, double-blind study (18) . Topical administration of antivascular endothelial growth factor antibodies, bevacizumab, and 5-fluorouracil has been attempted, but these therapies have not been well established (19)(20)(21) . The French Society of Otorhinolaryngology recommends the administration of tranexamic acid if there are no cardiovascular contraindications (22) . However, in our survey, only 41.7% of the patients received medication, suggesting the necessity of educational activities for medical professionals. These results may indicate why patients with HHT expect expertise from otolaryngologists (15) .
Regarding epistaxis prevention, avoiding nasal dryness and crusting may prevent the triggering of bleeding (23) . In a British study, in which a questionnaire survey was conducted in patients with HHT, room humidification, nasal lubrication, and saline treatment were reported to be beneficial (24) . Therefore, at

Conclusions
Epistaxis impacted the daily life of patients with HHT in proportion to its severity. In this study, the cohort mainly consisted of cases with mild and moderate epistaxis. Nevertheless, we found that the group with moderate epistaxis, in particular, experienced significant limitations in daily life. In addition, less than half of the patients took medications or adopted precautionary measures. Hence, further educational activities should be considered for medical professionals and patients.

List of abbreviations
ESS, epistaxis severity score; HHT, haemorrhagic telangiectasia; HR-QoL, health-related quality of life; QoL, quality of life; VAS, visual analogue scale.

Authorship contribution
HI and MH supervised the project. YM, TT, HA, and MH analysed the data and wrote the manuscript. YM, TT, HA, AN, SO, YM, and KT provided advice on project planning and data interpretation.
All authors participated in the discussion of the results and critically polished and approved the final draft.