**3. Results**

#### *3.1. Patient Selection and Baseline Characteristics*

In total, 1541 individuals had been screened for presence of HHT between 2004 and November 2016. From these individuals, 717 patients could be included in the HHT group and 471 in the non-HHT control group. In the HHT group, 319 patients (45%) suffered from HHT type 1, 325 (45%) from HHT type 2, 29 (4%) from juvenile polyposis/HHT overlap syndrome and in 44 patients no disease-causing mutations could be identified. The mean age at presentation in the HHT group was 40.6 years and 54% was female. In the control group the mean age was 40.9 years with 57% female. The mean birthyear for both groups was the year 1969. The control group consisted of family members of HHT patients in whom HHT was ruled out (*n* = 368), patients with recurrent epistaxis (*n* = 28) without HHT, patients with mucocutaneous telangiectases without HHT (*n* = 17) or patients with the suspicion of visceral AVM (*n* = 58) without HHT. The suspected visceral AVMs (not all were confirmed) were located in the lungs (PAVM: *n* = 43), digestive tract telangiectases (*n* = 5), brain (CAVM: *n* = 4) and four suspected AVMs were located in other organs. In Figure 1 the flowchart of the patient selection is depicted. The demographic characteristics of the included subjects are shown in Table 1.

**Figure 1.** Flowchart of included patients. HHT, Hereditary Hemorrhagic Telangiectasia; SSN, social security number.


**Table 1.** Demographic characteristics of the included patients. *ACVRL1*, activin receptor-like kinase 1 (HHT type 2); *ENG*, endoglin (HHT type 1); HHT, Hereditary Hemorrhagic Telangiectasia; SD, standard deviation; *SMAD4*, SMAD family member 4 (juvenile polyposis/HHT overlap syndrome).

#### *3.2. Visceral AVMs, Comorbidities and Disease Complications*

In Table 2, the number of visceral AVMs, comorbidities and disease complications of the HHT patients and controls are shown. In the HHT group, 255 patients (36%) had PAVMs versus 32 (7%) individuals in the control group. In the HHT group, 60% (432 patients) underwent CVM screening. In 28 out of 432 patients (6%) a CVM was detected. Furthermore, (symptomatic) HVMs and gastrointestinal telangiectases were diagnosed in 75 (11%) and 72 (10%) patients, respectively. The prevalence of anemia was significantly higher in the HHT group compared to the controls (*p* < 0.001). Comorbidities and disease complications were similar between groups with the exception of higher prevalence of pulmonary hypertension (3% vs. <1%, Fisher's exact test: *p* = 0.003) and high-output heart failure (Fisher's exact test: 2% vs. 0%, *p* = 0.001) in the HHT group.

**Table 2.** Visceral AVMs and comorbidities of the included patients. *ACVRL1*, activin receptor-like kinase 1 (HHT type 2); AVM, arteriovenous malformation; COPD, chronic obstructive pulmonary disease; CVM, cerebrovascular malformations; *ENG*, endoglin (HHT type 1); HHT, Hereditary Hemorrhagic Telangiectasia; HVM, hepatic vascular malformation; SD, standard deviation; *SMAD4*, SMAD family member 4 (juvenile polyposis/HHT overlap syndrome). \* For these AVMs, screening is only performed on indication.



**Table 2.** *Cont.*

#### *3.3. Survival of HHT Patients and Controls*

In Table 3, the number of patients, and the age and cause of death are shown. In the HHT group 57 patients (8%) had died versus 24 (5%) in the control group. The most frequent cause of death in the HHT was infectious disease, followed by malignancy. The cause of death in the control group was not recorded. There was no di fference in survival between the HHT and the non-HHT control group (Mantel–Cox test: *p* = 0.29; Figure 2). The survival of patients with HHT type 1 did not di ffer from patients with HHT type 2 (Mantel–Cox test: *p* = 0.28; Figure 3A). Compared to the non-HHT control group, the survival of both patients with HHT type 1 (Mantel-Cox test: *p* = 0.28) and patients with HHT type 2 (Mantel–Cox test: *p* = 0.85) did not di ffer (Figure 3B,C). The mean life expectancy of the HHT population was 75.9 years (95% CI 73.3–78.6 years), comparable to the non-HHT control group (79.3 years, 95% CI 74.8–84.0 years). The mean life expectancy for patients with HHT type 1 was 76.4 years (95% CI 71.6–82.3 years) and 77.9 years (95% CI 74.5–81.3 years) for patients with HHT type 2. The survival of patients with a genetically confirmed HHT diagnosis (HHT type 1, type 2 or juvenile polyposis/HHT overlap syndrome) was comparable to the survival of their relatives in whom HHT was ruled out (e.g., a known family mutation, the individual did not inhere the specific mutation) (Mantel–Cox test: *p* = 0.43; Figure 3D). There was no significant di fference in survival of men and women with HHT (Mantel–Cox test: *p* = 0.10; Figure 4A). HHT patients with visceral AVMs had a worse survival compared to HHT patients without visceral AVMs (Mantel–Cox test: *p* = 0.017). The survival in HHT patients with and without PAVM, CVM or gastrointestinal telangiectases did

not differ, only patients with HVM had significantly worse survival compared to HHT patients without HVM (see Figure 4B–F). HHT patients without anemia showed a tendency to a better survival (see Figure 4G).

**Figure 2.** Left-truncated Kaplan–Meier curve of HHT and controls. The dotted lines represent the 95% confidence intervals. HHT, Hereditary Hemorrhagic Telangiectasia.

**Figure 3.** Left-truncated Kaplan–Meier curves of HHT subtypes and controls (**A**) HHT type 1 and HHT type 2. (**B**) HHT type 1 and controls. (**C**) HHT type 2 and controls. (**D**) Patients with genetically confirmed HHT (HHT type 1, type 2 and juvenile polyposis/HHT overlap syndrome) and their relatives without HHT. The dotted lines represent the 95% confidence intervals. HHT, Hereditary Hemorrhagic Telangiectasia.


**Table 3.** Number of deceased patients, age and cause of death. HHT, Hereditary Hemorrhagic Telangiectasia; SD, standard deviation.

**Figure 4.** Left-truncated Kaplan–Meier curves of HHT patients. (**A**) Survival of females and males with HHT. (**B**) Survival of HHT patients with and without visceral AVM. (**C**) Survival of HHT patients with and without PAVM. (**D**) Survival of HHT patients with and without CVM. (**E**) Survival of HHT patients with and without HVM. (**F**) Survival of HHT patients with and without gastrointestinal telangiectases. (**G**) Survival of HHT patients with and without anemia. The dotted lines represent the 95% confidence intervals. AVM, arteriovenous malformation; CVM, cerebrovascular malformation; HHT, Hereditary Hemorrhagic Telangiectasia; HVM, hepatic vascular malformation.

## **4. Discussion**

We found that the life expectancy of patients with HHT who have been systematically screened for HHT-related organ involvement, treated if needed and followed in a center with HHT expertise did not di ffer from the life expectancy of the non-HHT control group. These results emphasize the importance of systematic screening of HHT patients, treatment and follow-up in an HHT expertise center.

Previous studies have shown conflicting results on life expectancy in patients with HHT. A study with 73 patients with HHT and 218 controls with a 20-year follow-up did not reveal any significant di fferences in survival between both groups [18]. However, two studies assessing survival in parents of a current HHT population showed worse survival in these parents with HHT compared to their non-HHT partners [10,12]. Since the population of the latter studies was comprised of parents with HHT, these studies concerned a largely unscreened and untreated population. In the study by De Gussem et al., patients with HHT type 1 had especially worse survival compared to non-HHT partners. The authors stated that this was probably caused by the higher prevalence of (untreated) PAVMs and CVMs and subsequent complications [10]. Donaldson et al. observed higher risks of stroke, cerebral abscess and bleeding complications and showed poorer survival in a study on a primary care database including almost 700 HHT patients in comparison to age and sex matched controls [9]. However, as emphasized by the authors, many of the HHT-related complications were amenable to intervention, early diagnosis and treatment. Their study also showed a higher mortality rate in the time period closest to the diagnosis of HHT. This might be related to the fact that some patients presented with HHT-related complications at the time of diagnosis. Once patients have been diagnosed with HHT, they are followed and treated for organ involvement to reduce morbidity and mortality.

Our study shows that the life expectancy of patients, who are screened for HHT-related organ involvement and if needed, treated in a center with HHT expertise, is similar to the life expectancy of their relatives without HHT. We did not observe di fference in survival between HHT type 1 and type 2. This is an important finding because a previous study by our group showed worse survival in (largely untreated) HHT type 1 population [10]. In addition, survival of men and women with HHT and HHT patients with and without PAVMs, CVMs or gastrointestinal telangiectases did not di ffer. We observed a significant di fference in HHT patients with and without visceral AVMs and patients with and without HVMs. This is probably caused by the fact that screening for HVMs is only done on indication in our center and thus the majority of these patients probably su ffered from symptomatic HVMs.

This improvement in survival of HHT patients in comparison to previous publications is most likely due to the benefit of screening for the presence of PAVMs and PAVM treatment if indicated. Additionally, screening methods and treatment options for PAVMs, CVMs, epistaxis, gastro-intestinal bleeding and subsequent anemia have improved over the years, which most likely benefits survival as well. In addition to this, several studies have suggested that patients with HHT possibly have a natural protection against certain cancers and myocardial infarction, possibly benefiting survival rates [19,20]. While we did not observe a negative e ffect of HHT on the survival in this study, it is important to realize that the quality of life in these patients will probably still be lower compared to their controls even if optimal screening and treatment was performed. Two studies investigated the quality of life in an HHT population screened and treated in two di fferent HHT centers. The authors observed that the HHT-related symptoms and organ involvement had a major negative e ffect on the quality of life [21,22].

We have not compared the survival of the HHT patients and controls to the Dutch population. However, we think that they are in line with each other. The life expectancy of Dutch people born in 1969 was 73.54 years [23]. We observed a slightly higher life expectancy of our HHT patients and controls, most likely because the patients included in this study already lived to an average age of approximately 40 years. The comorbidities were comparable between the HHT group and the controls with the exception of anemia, higher rates of pulmonary hypertension and high-output heart failure in the HHT group. It would be very informative to compare our HHT group, to HHT patients that did not receive screening; however, this is not ethically possible.

We acknowledge that there is selection bias of the patients who passed away prior to the HHT diagnosis and were thus not included in this study. Additionally, there is a small chance of presence of undiagnosed HHT patients in the non-HHT control group. However, in view of the number of patients and non-HHT controls in this study and in view of the convincing results, it seems unlikely that this would influence the outcomes significantly. Strengths of this study are the use of consecutive data in a large patient population. Although the control group also consists of patients that were referred to our hospital with visceral AVMs, the largest part of the controls included first-degree family members of HHT patients. Therefore, the lifestyle and socio-economic conditions are to some degree comparable which makes the non-HHT controls a better control group than the Dutch population for evaluation the influence of HHT on life expectancy.

In conclusion, the survival of patients with HHT is not negatively a ffected by HHT if the HHT patients have been systematically screened and treated for HHT-related organ involvement in a center with HHT expertise. These findings demonstrate the importance of systematic screening of HHT patients and treatment of PAVMs and other HHT-related organ involvement.

**Author Contributions:** Study concept and design: E.M.d.G., A.E.H., J.C.K., R.J.S., J.J.M. Acquisition of the data: E.M.d.G., S.K., A.E.H., J.C.K., R.J.S., J.J.M. Analysis and Interpretation of data: E.M.d.G., S.K., A.E.H., J.C.K., M.C.P., R.J.S., J.J.M. Critical writing of the manuscript: E.M.d.G., S.K., A.E.H. Revising the intellectual content: A.E.H., J.C.K., M.C.P., R.J.S., J.J.M. Final approval of the version to be published: E.M.d.G., S.K., A.E.H., J.C.K., M.C.P., R.J.S., J.J.M. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.
