Introduction
Hereditary haemorrhagic telangiectasia (HHT) is a rare autosomal-dominant inherited disorder characterised by widespread mucocutaneous telangiectasias and visceral arterio-venous malformations. It affects approximately 1 in 6000 Europeans.Reference Shovlin, Buscarini, Sabbà, Mager, Kjeldsen and Pagella1
Common genetic mutations include ENG (52 per cent), ACVRL1 (44 per cent) and SMAD4 (2 per cent), each having overlapping phenotypes with the latter additionally predisposing to gastrointestinal malignancies.Reference McDonald and Stevenson2 Downstream signalling results in upregulation of vascular endothelial growth factor (VEGF), causing endothelial proliferation and the characteristic arteriovenous malformations and telangiectasia.Reference Thalgott, Dos-Santos-Luis, Hosman, Martin, Lamandé and Bracquart3
Presence of these malformations in the nasal mucosa cause recurrent and severe epistaxis which typically has a significant impact on the patient's quality of life.Reference AAssar, Friedman and White4 Telangiectasias are thin-walled and lack contractile elements, so bleeding can be challenging to control.Reference McDonald, Bayrak-Toydemir and Pyeritz5
Diagnosis is based on the Curaçao criteria (Figure 1). Certain diagnosis requires three of the following criteria: recurrent spontaneous epistaxis, mucocutaneous telangiectasia, visceral malformations, family history (first-degree relative).Reference McDonald, Bayrak-Toydemir, DeMille, Wooderchak-Donahue and Whitehead6 Genetic testing for the aforementioned mutations is used to confirm the diagnosis and variant.
Curacao criteria for diagnosis of HHT.
Management of recurrent epistaxis in patients with HHT is challenging, requiring a multidisciplinary approach with haematologists, otolaryngologists, geneticists, respiratory physicians, hepatologists, paediatricians and clinical nurse specialists.Reference Shovlin, Buscarini, Sabbà, Mager, Kjeldsen and Pagella1 Conservative, medical and surgical treatments are frequently used in tandem.
Patients are educated in first aid and may be provided with methods to reduce the severity of nosebleeds at home. Medical management with topical moisturising therapy or rotating antibacterial creams can be beneficial.Reference Whitehead, Sautter, McWilliams, Chakinala, Merlo and Johnson7 Two randomised controlled trials have shown oral tranexamic acid significantly reduces the severity of nosebleeds.Reference Geisthoff, Seyfert, Kübler, Bieg, Plinkert and König8,Reference Gaillard, Dupuis-Girod, Boutitie, Rivière, Morinière and Hatron9
Bevacizumab (Avastin®) is increasingly being used for refractory cases. It prevents formation of new vascular malformations in the nasal mucosa by inhibiting vascular endothelial growth factor (VEGF) and therefore acts as an anti-angiogenic agent.
A recent international multi-centre study, the InHIBIT-Bleed study, found reduced epistaxis severity, increased haemoglobin levels and reduced requirement for blood transfusions with systemic use.Reference Al-Samkari, Kasthuri, Parambil, Albitar, Almodallal and Vázquez10 However, the study is limited by its retrospective nature, resulting in heterogeneous delivery of intervention across sites. Additionally, the lack of randomisation increased the risk of confounding factors, which could have affected outcomes. The study identified six severe adverse events amongst participants, possibly, probably or certainly related to the treatment.
Studies have also shown only a short-term benefit from bevacizumab, in addition to no perceivable effect on frequency and duration of epistaxis episodes in a recent systematic review and meta-analysis.Reference Chen, Zhang, Chen, Wang, Chen and Liao11 Furthermore, bevacizumab is contraindicated in patients with arteriopathy (atherosclerotic disease with a history of ischaemic complications), risk factors for or recent thromboembolic events and severe pulmonary hypertension.Reference Dupuis-Girod, Shovlin, Kjeldsen, Mager, Sabba and Droege12,Reference Buscarini, Botella, Geisthoff, Kjeldsen, Mager and Pagella13
Surgical management traditionally includes ablation of vascular malformations either with potassium titanyl phosphate (KTP)/argon/blue laser, radiofrequency, electrosurgery or coblation.Reference Faughnan, Mager, Hetts, Palda, Lang-Robertson and Buscarini14 Repeated ablative procedures can lead to septal perforation; and the laser tends to cause less surrounded thermal damage to tissues than electrocautery or coblation. Should ablative therapies fail, patients are considered for septodermoplasty in which nasal mucosa is covered with split-thickness skin flaps.Reference Rimmer and Lund15
In recent years, nasal closure has been used with increasing frequency for severe refractory epistaxis in HHT, but there is limited research on its efficacy. Austen Young first described nasal closure in 1967 as a treatment for atrophic rhinitis.Reference Young16 Two flaps are raised and sutured together to close the nasal vestibule. A modified three-flap technique, the Lund-modification of Young's procedure, was first pioneered in the late 1990s and is used for patients with severe refractory epistaxis in HHT.Reference Lund and Howard17
Theoretically, nasal closure prevents the drying of nasal mucosa caused by constant airflow, thus reducing the frequency of epistaxis.Reference Gluckman and Portugal18 Lund et al. found dramatic improvements in subjective epistaxis severity and post-operative quality of life in their case series,Reference Lund, Darby, Rimmer, Amin and Husain19 with similar results among other large centres.Reference Thomson, Molin, Whitehead, Ashby, Johnson and Ward20–Reference Ichimura, Kikuchi, Imayoshi, Yamauchi and Ishikawa23
For the past three years, we have been performing nasal closure for HHT patients with severe transfusion-dependent epistaxis which persists despite optimal medical and surgical management. Due to concurrent co-morbidities, a number of these patients were ineligible for bevacizumab therapy. Here, we present a case series evaluating the effectiveness of nasal closure in the management of severe transfusion-dependent epistaxis through a combination of patient reported and objective outcome measures.
Materials and methods
This is a retrospective case series of patients undergoing nasal closure for epistaxis secondary to HHT.
Patient selection
Patients who underwent nasal closure between 2020 and 2022 were identified from our cohort of HHT patients under follow up via their electronic medical records. All patients gave informed consent for participation in the study, and all patient data were anonymised. All identified were eligible for inclusion.
Outcomes
Patients were contacted and asked about the frequency of blood transfusion since they underwent nasal closure; this was compared with clinic documentation of pre-operative blood transfusion. Haemoglobin concentration pre-operatively and 3, 6 and 12 months post-operatively was collected from hospital and primary care records.
Pre-operative and post-operative Epistaxis Severity Score (ESS) scores (Appendix 1) were ascertained from clinic documentation or via telephone call. Finally, patients were asked to complete a Glasgow Benefit Inventory (GBI) to evaluate the change in quality of life post-operatively (Appendix 2).
Statistical analysis
Paired t-tests were performed on the pre- versus post-operative ESS data using a p value less than 0.05 to indicate statistical significance.
Surgical technique
Modified nasal closure is performed by making a circumferential incision at the mucocutaneous junction and raising three retrograde flaps. Meticulous care is taken to avoid provoking epistaxis. The nasal vestibule is then closed by joining these flaps with absorbable suture (Figure 2).
Modified young’s procedure technique; patient’s left nostril has the three mucocutaneous flaps being raised; the patient’s right nostril is closed.
Results and analysis
Five patients underwent nasal closure at our centre between 2020 and 2023.
The cohort consisted of two women and three men aged between 44 and 76 years at the time of interview. Patients were generally co-morbid (Table 1): two patients had severe pulmonary hypertension and three had severe cardiovascular co-morbidity with history of thromboembolic events. These co-morbidities contraindicated the use of bevacizumab in all patients. The follow-up period ranged from 14 to 34 months.
Individual patient descriptions
ESS = Epistaxis Severity Score; GBI = Glasgow Benefit Inventory; Hb = haemoglobin; KTP = potassium titanyl phosphate.
The indication for surgery in all cases was severe transfusion-dependent refractory epistaxis. In addition, one case (patient 5) was performed as a definitive procedure to prevent epistaxis-related anaemia from worsening severe pulmonary hypertension. This procedure was performed at a specialist centre with intensive care support.
Four patients underwent bilateral nasal closure. One patient had re-closure of one nostril performed following a left unilateral Young's reversal procedure two months prior. After re-opening of the nostril, this patient suffered severe epistaxis requiring weekly transfusion and developed transfusion reactions, hence, the re-closure two months later.
Mean haemoglobin concentration pre-operatively was 81 mg/dlReference Thalgott, Dos-Santos-Luis, Hosman, Martin, Lamandé and Bracquart3 (range 68–96); between 6 and 12 months post-operatively, it was 128.2 mg/dlReference Thalgott, Dos-Santos-Luis, Hosman, Martin, Lamandé and Bracquart3 (range 102–151) (Figure 3). All patients demonstrated an increase in their haemoglobin concentration post-operatively, with a mean increment of 47.2 mg/dlReference Thalgott, Dos-Santos-Luis, Hosman, Martin, Lamandé and Bracquart3. The post-operative haemoglobin data were incomplete for one patient due to retrospective collection.
Individual post-operative haemoglobin trends.
The majority of patients required at least once-monthly blood transfusions pre-operatively with a mean of 1.8 transfusions per month. No patients required a blood transfusion for anaemia secondary to epistaxis at any point post-operatively. Two patients required admission and blood transfusion after nasal closure due to bleeding from gastrointestinal arterio-venous malformations.
All patients had a reduction in ESS. The mean ESS prior to surgery was 7.8 (range 6–10); the mean after surgery was 0.4 (range 0–2). The mean reduction in ESS was 7.4. These findings demonstrated a statistically significant reduction in ESS post-operatively (paired t-test; t = -9.89, p = 0.0006). Four of five patients reported an ESS of 0 post-operatively, representing complete cessation of epistaxis for these patients.
The GBI is calculated from 18 questions and represents health-related quality of life. Scores range between -100 (maximum negative) and +100 (maximum positive). The mean GBI was +49.2 (range -6–83) with four of five patients returning positive GBI scores. One patient returned a weakly negative GBI of -6.
Three of nine closed nostrils developed unilateral pinhole defects which required re-closure (Figure 4). Two were re-closed operatively 7 and 9 months after the initial operation. One used petroleum jelly to close the pinhole to good effect. Operations were otherwise uncomplicated.
Pinhole reopening.
Discussion
Our results demonstrate that nasal closure appears to be a safe and effective management option for severe refractory epistaxis in HHT. This is a particularly important consideration in patients for whom bevacizumab is contraindicated. Additionally, the exact efficacy of bevacizumab remains difficult to determine in the long term.
We found that nasal closure was effective in reducing the frequency and severity of epistaxis in patients with HHT, as well as in increasing haemoglobin concentrations and reducing the need for blood transfusions. Patients generally reported an improved health-related quality of life post-operatively. These findings support the use of nasal closure as an effective management option for HHT patients with transfusion-dependent epistaxis refractory to optimal medical and surgical management, whose co-morbidities contraindicate the use of bevacizumab.
In 2022, the European Reference Network for Rare Vascular Diseases (VASCERN) published guidelines on when and how to use bevacizumab for epistaxis in HHT. Contraindications include severe pulmonary hypertension (World Health Organisation [WHO] grade 2 and above) and severe arteriopathyReference Dupuis-Girod, Shovlin, Kjeldsen, Mager, Sabba and Droege12; all our patients therefore had contraindications for bevacizumab use. It is likely that many HHT patients, in whom there is high cardiorespiratory co-morbidity,Reference Droege, Thangavelu, Stuck, Stang, Lang and Geisthoff24 will similarly have contraindications to bevacizumab. Nonetheless, we would advocate for modified nasal closure being considered for all patients with transfusion-dependent epistaxis, particularly those whose co-morbidity contraindicates bevacizumab. Furthermore, given the relatively short-term impact of bevacizumab displayed in the existing literature, we would support the use of a shared decision-making approach, counselling the patient on the pros and cons of both treatments.
Our use of patient reported outcome measures ensured a direct and unbiased measure of the patient's real-world experience after surgery.Reference Nelson, Eftimovska, Lind, Hager, Wasson and Lindblad25 The GBI is a validated patient reported outcome measure which is widely used in research evaluating otorhinolaryngological interventions.Reference Kubba, Swan and Gatehouse26 Four of five of our participants returned significantly positive GBI scores, with an average score of +49.2. These findings imply that, for our patients, nasal closure has a higher level of patient satisfaction (according to mean GBI score) when compared to other common ear/nose/throat (ENT) procedures, such as cochlear implant (+38.4), stapes surgery (+29.9), tonsillectomy (+27.0) or vestibular schwannoma surgery (-4.8).Reference Hendry, Chin, Swan, Akeroyd and Browdoining27
The one patient with limited improvement in GBI score, patient 5, presented a complex case. Although her epistaxis was less profuse, she had severe pulmonary hypertension exacerbated by anaemia secondary to epistaxis. Nasal closure was therefore recommended to address the anaemia. This operation was successfully performed at a tertiary centre with specialist intensive care support, and the patient has since maintained her haemoglobin levels and had no further epistaxis.
The ESS is a validated tool which provides a standardised and objective way to measure the severity of epistaxis.Reference Hoag, Terry, Mitchell, Reh and Merlo28 In our cohort, ESS was reduced in all patients by a statistically significant average of 7.4 out of a possible 10 points. This reduction is also clinically significant, as it exceeds the minimal clinically important difference in ESS, which has been determined to be 0.71.Reference Yin, Reh, Hoag, Mitchell, Mathai and Robinson29
The decision for nasal closure should involve careful consideration by both patient and clinician. Although the procedure has the potential to dramatically improve and potentially stop epistaxis, it results in the inevitable consequence of obligate mouth-breathing and impairment of taste and smell. It is therefore imperative to provide robust pre-operative counselling to patients, with the decision for surgery taking place over multiple clinic contacts. We are fortunate to have three patients who volunteer to speak with prospective surgical candidates, answering questions and addressing misconceptions. This ensures patients are thoroughly well-informed prior to consenting and adequately prepared for the physical consequences post-operatively.
The study is limited by its small size, retrospective design and consequent incomplete data on haemoglobin trends for one patient. We used several outcome measures, both subjective and objective, to offset this limitation and provide a comprehensive evaluation on the impact of nasal closure for our patients.
• Modified nasal closure is an effective option for the management of refractory transfusion-dependent epistaxis in patients with HHT.
• For patients with transfusion-dependent epistaxis secondary to HHT, particularly those whose co-morbidities contraindicate bevacizumab, nasal closure should be considered as a definitive treatment option.
• While recent studies highlight the efficacy of bevacizumab in this subgroup, the exact efficacy of bevacizumab remains difficult to determine in the long term.
• There remains to be a lack of controlled evidence regarding the use of nasal closure for refractory epistaxis in HHT, and larger controlled studies assessing long-term outcomes are required.
There remains to be a lack of controlled evidence regarding the use of nasal closure for refractory epistaxis in HHT, although all cohorts appear to have similar positive findings. This paucity of quality evidence would be addressed with larger controlled studies assessing long-term outcomes.
Conclusions
In conclusion, this study provides evidence that modified nasal closure is an effective option for the management of refractory transfusion-dependent epistaxis in patients with HHT. We found an improvement in quality of life, incremented haemoglobin concentrations and reduced transfusion requirement in patients post-operatively. For all patients with severe transfusion-dependent epistaxis secondary to HHT, particularly those whose co-morbidities contraindicate bevacizumab, nasal closure should be considered as a definitive treatment option. Further research is required to confirm these findings and to evaluate the long-term outcomes of this procedure.
Acknowledgements
We thank all patients included in the study, particularly those who are generous enough with their time to talk with potential surgical candidates.
Conflicting interests
None to declare.
Funding
None to declare.
Ethical statement
This retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Authorship contribution
Robert Bickerton: methodology, data acquisition and analysis, writing - original draft and revisions. Benjamin Kennard: writing – review and editing. Nikita Mehtani: methodology. Elizabeth Bullock: methodology. Talisa Ross: writing – review and editing. Vikas Acharya: conceptualisation, methodology, writing – review and editing. Catherine Rennie: overall supervision, conceptualisation, writing – review and editing, final approval of article prior to submission.
Appendix 1. Epistaxis Severity Score (ESS) and method for calculation
Appendix 2. Glasgow Benefit Inventory (GBI)
