Oral itraconazole for epistaxis in hereditary hemorrhagic telangiectasia: a proof of concept study.

The inhibiting effects of itraconazole, an antifungal drug on vascular endothelial growth factor (VEGF) have recently been discovered. By inhibiting VEGF, itraconazole has shown potential in clinical trials as anti-cancer treatment. In hereditary hemorrhagic telangiectasia (HHT) patients, VEGF levels are elevated and inhibition of VEGF can decrease bleeding. Itraconazole could potentially serve as anti-angiogenic therapy for HHT-related bleeding. We report a proof of concept study with HHT patients and severe epistaxis. Patients were treated with daily 200 mg orally administered itraconazole for sixteen weeks. Twenty-one HHT patients, 8 females (38%), 13 males (62%), median age of 59 years (interquartile range (IQR) 55-69) were enrolled. Of these patients, 13 (62%) were diagnosed with HHT type 1, seven (33%) with HHT type 2 and in one patient (5%), no pathognomonic HHT mutation was found. Four patients (19%) prematurely terminated the study (3 due to mild or moderate side-effects) resulting in 17 patients included in the analyses. The median epistaxis severity score significantly decreased during treatment from 6.0 (IQR 5.1-7.2) to 3.8 (IQR 3.1-5.2) (p = 0.006). The monthly epistaxis frequency decreased from 56 to 38 epistaxis episodes (p = 0.004) and the monthly duration from 407 to 278 minutes (p = 0.005). Hemoglobin levels did not significantly change. The quality of life showed a small but significant improvement. In conclusion, oral itraconazole significantly improved epistaxis in HHT patients. The potential benefit of itraconazole in HHT should be further investigated.

Reproducibility of right-to-left shunt quantification using transthoracic contrast echocardiography in hereditary haemorrhagic telangiectasia.

AIM: Transthoracic contrast echocardiography (TTCE) is recommended for screening of pulmonary arteriovenous malformations (PAVMs) in hereditary haemorrhagic telangiectasia. Shunt quantification is used to find treatable PAVMs. So far, there has been no study investigating the reproducibility of this diagnostic test. Therefore, this study aimed to describe inter-observer and inter-injection variability of TTCE. METHODS: We conducted a prospective single centre study. We included all consecutive persons screened for presence of PAVMs in association with hereditary haemorrhagic telangiectasia in 2015. The videos of two contrast injections per patient were divided and reviewed by two cardiologists blinded for patient data. Pulmonary right-to-left shunts were graded using a three-grade scale. Inter-observer and inter-injection agreement was calculated with κ statistics for the presence and grade of pulmonary right-to-left shunts. RESULTS: We included 107 persons (accounting for 214 injections) (49.5% male, mean age 45.0 ± 16.6 years). A pulmonary right-to-left shunt was present in 136 (63.6%) and 131 (61.2%) injections for observer 1 and 2, respectively. Inter-injection agreement for the presence of pulmonary right-to-left shunts was 0.96 (95% confidence interval (CI) 0.9-1.0) and 0.98 (95% CI 0.94-1.00) for observer 1 and 2, respectively. Inter-injection agreement for pulmonary right-to-left shunt grade was 0.96 (95% CI 0.93-0.99) and 0.95 (95% CI 0.92-0.98) respectively. There was disagreement in right-to-left shunt grade between the contrast injections in 11 patients (10.3%). Inter-observer variability for presence and grade of the pulmonary right-to-left shunt was 0.95 (95% CI 0.91-0.99) and 0.97 (95% CI 0.95-0.99) respectively. CONCLUSION: TTCE has an excellent inter-injection and inter-observer agreement for both the presence and grade of pulmonary right-to-left shunts.

Cancer and hereditary haemorrhagic telangiectasia.

OBJECTIVE: To examine associations between cancer incidence and hereditary haemorrhagic telangiectasia (HHT). METHODS: Two studies with contrasting conclusions were compared. The first had used a registry-based, matched-pairs approach, while the second utilised HHT family-based, survey methodology. RESULTS: The first manuscript captured data on cancer incidence in a total of 316,581 matched cancer patients-non-cancer controls, which included 431 HHT cases. No association was found between HHT and pooled cases of lung, breast, prostate, and colorectal cancer (adjusted OR 0.978, 95% CI [0.795, 1.204]). The second, which was powered to examine these four cancers individually, captured data from 2161 HHT cases and 2817 related controls. Fewer HHT-affected individuals had cancer (398/2161, [18.4%]) compared to 668/2817 (23.7%) related controls (p = 0.0012). Of the four most common cancers, prostate and colorectal cancer rates were equivalent, but lung cancers were significantly less frequent in HHT (adjusted OR 0.48 [0.30, 0.70], p = 0.0012), and breast cancer was more frequent (adjusted OR 1.52 [1.07, 2.14] p = 0.018). CONCLUSIONS: The respective studies had different methodological strengths and weaknesses. Potential reasons for the discrepant conclusions include study power, particularly important to dissect specific cancers where differential contributions from HHT genotypes and environmental confounders might be predicted.

Life expextancy of parents with Hereditary Haemorrhagic Telangiectasia.

BACKGROUND: Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant disease associated with epistaxis, arteriovenous malformations and telangiectasias. Disease complications may result in premature death. METHOD: We investigated life-expectancies of parents of HHT patients compared with their non-HHT partners using self- or telephone-administered questionnaires sent to their children. Patients were extracted from the databases of 2 participating HHT Centres: the Toronto HHT Database (Toronto, Canada) and the St. Antonius Hospital HHT Database (Nieuwegein, The Netherlands). RESULTS: Two hundred twenty five/407 (55%) of respondents were included creating HHT- (n = 225) and control groups (n = 225) of equal size. Two hundred thirteen/225 (95%) of the HHT group had not been screened for organ involvement of the disease prior to death. The life expectancy in parents with HHT was slightly lower compared to parents without (median age at death 73.3 years in patients versus 76.6 years in controls, p0.018). Parents with ACVRL 1 mutations had normal life expectancies, whereas parents with Endoglin mutations died 7.1 years earlier than controls (p = 0.024). Women with Endoglin mutations lived a median of 9.3 years shorter than those without (p = 0.04). Seven/123 (5%) of deaths were HHT related with a median age at death of 61.5 years (IQ range 54.4-67.7 years). CONCLUSION: Our study showed that the life expectancy of largely unscreened HHT patients was lower than people without HHT. Female patients with Endoglin mutations were most strikingly at risk of premature death from complications. These results emphasize the importance of referring patients with HHT for screening of organ involvement and timely intervention to prevent complications.

Acute sinusitis and blindness as the first presentation of chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is the most frequent form of leukaemia among adults in the Western world, presenting at a median age of 65 years. The diagnosis is usually made incidentally during routine blood examination while the disease is still in its early phase. We report a case of blindness of 24 hours due to acute sinusitis based on CLL localisation in a patient with undiagnosed CLL. Emergency endoscopic sinus surgery and intra- and extra-ocular orbital decompression were performed. The sinusitis resolved after surgery and intravenous antibiotics. Her vision improved within 24 hours and eventually recovered completely after six months. Her CLL remained in an indolent state, needing no active treatment. This case illustrates that blindness from a lymphoproliferative disorder may be treated with emergency endoscopic sinus surgery instead of conventional chemotherapy in order to salvage the vision first, even if the vision is lost for more than 24 hours.