Association of In‐Office Sclerotherapy With Epistaxis Severity and Quality‐of‐Life in Hereditary Hemorrhagic Telangiectasia

Epistaxis affects more than 90% of hereditary hemorrhagic telangiectasia (HHT) patients, but there is no standard-of-care treatment [1]. Sclerotherapy involves injecting a sclerosing agent to obliterate vascular lesions. It has been associated with improved epistaxis severity and general health-related quality of life (QoL) [2, 3]. Doxycycline has also been associated with reduced epistaxis severity and is often used empirically due to its favorable safety profile [4]. Epistaxis affects more than 90% of hereditary hemorrhagic telangiectasia (HHT) patients, but there is no standard-of-care treatment [1]. Sclerotherapy involves injecting a sclerosing agent to obliterate vascular lesions. It has been associated with improved epistaxis severity and general health-related quality of life (QoL) [2, 3]. Doxycycline has also been associated with reduced epistaxis severity and is often used empirically due to its favorable safety profile [4]. This prospective case series investigates the association of sclerotherapy with HHT-related epistaxis severity and QoL across multiple validated outcome measures, assesses how concurrent initiation of doxycycline may modulate these effects, and depicts nasal mucosal changes post-sclerotherapy. Consecutive HHT patients with an average Nasal Outcome Score for Epistaxis in HHT (NOSE HHT) [5] greater than one who presented between 2022 and 2024 for sclerotherapy with or without initiation of doxycycline were prospectively enrolled. Doxycycline was offered to all patients who had not previously tried it and was primarily initiated based on patient's desire for further epistaxis control. Patients receiving additional treatments during the study period were withdrawn from the study but could be re-consented and re-enrolled. Patients already taking medications, including doxycycline, and patients who stopped taking doxycycline before enrollment were placed in the sclerotherapy-only group, as sclerotherapy was the only change to their regimen. The primary outcome measure was change in NOSE HHT 2 weeks and 3 months post-sclerotherapy, which ranges from 0 (less severe impact on QoL) to 4 (more severe impact) and has a minimal clinically important difference (MCID) of 0.46 [5]. The NOSE HHT was chosen since it focuses on the physical problems, functional limitations, and emotional consequences of HHT-related epistaxis specifically. Secondary outcome measures included change in Epistaxis Severity Score (ESS) [6], 3 months post-sclerotherapy, and Clinical Global Impression-Severity (CGI-S) score and Clinical Global Impression–Improvement (CGI-I) score, 2-weeks and 3- months post-sclerotherapy. Acute and self-reported complications were recorded. Repeat endoscopic imaging was offered to patients who lived nearby. Descriptive statistics were calculated. Median difference between baseline, 2-week, and 3-month scores and 95% CI were estimated. Mann–Whitney U and chi-square tests were used to explore differences between the doxycycline and no doxycycline groups. Analysis was conducted using IBM-SPSS version 29.0.2.0. A total of 43 patients were enrolled. Nine (21%) were enrolled multiple times. Only data from the most recent enrollment were analyzed, regardless of response from prior procedures. Of the 43 patients, 22 (51%) were female and 41 (95%) were white. Median NOSE HHT scores were 1.8 at baseline, 1.0 at 2 weeks, and 1.1 at 3 months (Table 1). Median change from baseline to 2 weeks was −0.59 (95% CI −0.76, −0.45; p < 0.001; n = 39) and −0.53 (95% CI −0.69, −0.38; p < 0.001; n = 40) from baseline to 3 months, suggesting a clinically meaningful change. A total of 56% (22/39) of patients experienced a clinically meaningful improvement 2 weeks post-sclerotherapy versus 58% (23/40) 3 months post-sclerotherapy (percent difference = 1.1%; 95% CI −20.7%, 22.9%; p = 0.922). Change from baseline, median (95% CI) Median ESS was 5.7 at baseline and 3.2 at 3 months (median change: −1.9 [95% CI −2.7, −1.0; p = 0.001]). The 95% CI exceeds the MCID of 0.71 [7], indicating a clinically meaningful reduction in epistaxis severity. A total of 77% (20/32) of participants experienced a clinically meaningful improvement in epistaxis severity. Based on CGI-S, more patients reported their nosebleeds were no problem or mild at 2 weeks (percent difference = 57.8%; 95% CI 40.3%, 75.4%; p < 0.001) and 3 months (percent difference = 31.0%; 95% CI 12.5%, 49.6%; p = 0.002) than at baseline (Table 1). The CGI-I scores demonstrated that 61% (24/39) and 43% (17/40) of patients reported their nosebleeds were much improved at 2 weeks and 3 months, respectively. There was no between-groups difference in median change in NOSE HHT score for the doxycycline and no doxycycline groups 2 weeks (p = 0.788) or 3 months (p = 0.656) post-sclerotherapy or in the proportion of patients with a clinically meaningful change in NOSE HHT score 2 weeks (percent difference = 4.8%; 95% CI −30.5%, 40.2%; p = 0.791) or 3 months (percent difference = 11.8%; 95% CI −23.6%, 47.3%; p = 0.572) post-sclerotherapy. Doxycycline patients had a greater reduction in ESS (−2.7; 95% CI −4.7, −0.82) than the no doxycycline group (−1.4; 95% CI −2.6, −0.36), although this was not statistically significant (p = 0.216). No adverse events were reported. The four participants who underwent repeat nasal endoscopy had reduced mucosal erythema and no scarring post-sclerotherapy (Figure 1). Patient 1's Type 3 AVM got smaller. Patient 4 had fewer AVMs. This study suggests that sclerotherapy is safe, is not associated with scarring, and is associated with a statistically and clinically meaningful improvement in epistaxis severity and epistaxis-related QoL. While several treatments exist for HHT-related epistaxis, procedures like cauterization can prompt vascular regrowth [8]. The nasal mucosa remained healthy without scarring in the four participants who underwent repeat nasal endoscopy. These novel findings regarding improvement in epistaxis-related QoL and lack of mucosal scarring post-sclerotherapy give further evidence to support sclerotherapy for HHT-related epistaxis. Approximately 70% of HHT patients have a septal perforation, and repeated sclerotherapy procedures may be less likely to cause perforation compared to cautery [9]. The impact of doxycycline in combination with sclerotherapy remains unclear, as the doxycycline cohort was small, resulting in imprecise effect sizes. Additionally, including patients who were on doxycycline before the study in the sclerotherapy group could have decreased the between-groups difference. Its safety profile permits it to remain a reasonable empiric option. Including patients who recently underwent sclerotherapy by allowing for re-enrollment also improves generalizability, but limits the ability to draw conclusions for these patients. The largest limitation is the lack of a control group and run-in period to assess baseline epistaxis variability, as HHT-related epistaxis studies are prone to the placebo effect and regression to the mean [10]. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR002344 (Jenny Ji) and the DeNardo Education and Research Foundation Grant (Amy E. Ensing) for the MD5 Yearlong Research Program. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or of the DeNardo Education and Research Foundation. Dr. Piccirillo receives royalties from Washington University in St Louis for licensing income of the Sino-Nasal Outcome Test, Nasal Outcome Score for Epistaxis in Hereditary Hemorrhagic Telangiectasia instrument, and Symptoms of Nocturnal Obstruction and Related Events instrument; receives payment from the AMA for his work as Editor-in-Chief of JAMA Otolaryngology-Head & Neck Surgery. Dr. Peterson reported payments from Washington University in St Louis for the licensing of the Nasal Outcome Score for Epistaxis in Hereditary Hemorrhagic Telangiectasia (NOSE HHT) instrument. Dr. Kallogjeri reported payments from Washington University in St Louis for the licensing of the Nasal Outcome Score for Epistaxis in Hereditary Hemorrhagic Telangiectasia (NOSE HHT) instrument, and from AMA for serving as statistics editor for JAMA Otolaryngology-Head & Neck Surgery. The authors declare no conflicts of interest.