Reply to Eker et al. Comment on "Kilian et al. Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT. J. Clin. Med. 2023, 12, 2704".

We are grateful to Eker et al. for their thoughtful analysis and response to our publication titled Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT [...].

Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease characterized by the development of vascular malformations (VMs) in organs such as the brain and lungs, as well as telangiectases on mucosal surfaces. Prophylactic treatment of organ VMs may prevent potential complications, such as hemorrhage. However, brain VM treatment-surgical resection, embolization, and/or radiosurgery-is not recommended for all patients due to the associated risks. Given the scarcity of data regarding HHT-related brain VM presentation and treatment trends in pediatric patients, we aim to describe the clinical presentations and the patterns of treatment of HHT-related brain VMs in a pediatric cohort, and compare pediatric trends to those of adults. Demographic and clinical data were analyzed in 114 pediatric patients with HHT-related brain VMs and compared with a cohort of 253 adult patients enrolled in the multicenter Brain Vascular Malformation Consortium HHT Project. Our data demonstrated that a higher proportion of pediatric patients with HHT-related brain VMs were symptomatic at presentation (p = 0.004). Moreover, a higher proportion of pediatric patients presented with intracranial hemorrhage (p < 0.001) and seizure (p = 0.002) compared to adult patients. Surgical resection was the most common brain VM treatment modality in both children and adults. We conclude that pediatric patients may be more likely to present with symptoms and complications from brain VMs, supporting the case for screening for brain VMs in children with HHT.

Genotype-Phenotype Correlations in Children with HHT.

Hereditary hemorrhagic telangiectasia (HHT), a rare autosomal dominant disease mostly caused by mutations in three known genes (ENG, ACVRL1, and SMAD4), is characterized by the development of vascular malformations (VMs). Patients with HHT may present with mucocutaneous telangiectasia, as well as organ arteriovenous malformations (AVMs) of the central nervous system, lungs, and liver. Genotype-phenotype correlations have been well described in adults with HHT. We aimed to investigate genotype-phenotype correlations among pediatric HHT patients. Demographic, clinical, and genetic data were collected and analyzed in 205 children enrolled in the multicenter Brain Vascular Malformation Consortium HHT Project. A chi-square test was used to determine the association between phenotypic presentations and genotype. Among 205 patients (age range: 0-18 years; mean: 11 years), ENG mutation was associated with the presence of pulmonary AVMs (p < 0.001) and brain VM (p < 0.001). The presence of a combined phenotype-defined as both pulmonary AVMs and brain VMs-was also associated with ENG mutation. Gastrointestinal bleeding was rare (4.4%), but was associated with SMAD4 genotype (p < 0.001). We conclude that genotype-phenotype correlations among pediatric HHT patients are similar to those described among adults. Specifically, pediatric patients with ENG mutation have a greater prevalence of pulmonary AVMs, brain VMs, and a combined phenotype.

Diagnostic Yield of Rescreening Adults for Pulmonary Arteriovenous Malformations.

PURPOSE: To determine the yield of rescreening adult hereditary hemorrhagic telangiectasia (HHT) patients with initial negative screening CT for pulmonary arteriovenous malformations (PAVMs). MATERIALS AND METHODS: Patients with a definite diagnosis of HHT were identified in the University of Toronto, Université de Montréal, and Mayo Clinic HHT databases. Inclusion criteria were: (i) definite diagnosis of HHT; (ii) initial negative PAVM screening based on bubble echocardiography and/or chest CT; and (iii) minimum 2-year imaging follow-up. A positive rescreen was defined as a newly detected PAVM on follow-up CT. Frequency of new PAVMs was calculated at 3 ± 1 years, 5 ± 1 years, 7-9 years, and ≥10 years. The primary endpoint was the rate of new PAVMs at 5 ± 1 years. RESULTS: One hundred seventy-two patients (mean age, 49.6 ± 16.7 years; 59% female) were followed for a median of 7 years. Nine patients (5.2%) had newly detected PAVMs. At the 3-, 5-, 7-, and ≥10-year time points, the cumulative rate of newly detected PAVMs was 1.8% (3/166), 5.0% (7/140), 8.8% (8/91), and 13.8% (9/65), respectively. Median feeding artery diameter was 1.3 mm. One patient had a feeding artery larger than 3 mm discovered after 6 years and was treated with embolization. The overall rate of newly detected PAVMs was 0.7%/patient-year. CONCLUSIONS: There is a definite but low rate of newly detected PAVMs in HHT patients with initial negative screening studies. No new treatable PAVMs were identified at the 5-year mark, although 1 treatable case was identified after 6 years. These findings suggest that a longer screening interval may be warranted.

Variability in Response to Intravenous Immunoglobulin in the Treatment of Kawasaki Disease.

OBJECTIVES: To characterize the pattern of temperature response to intravenous immunoglobulin (IVIG) infusion in patients with Kawasaki disease (KD). STUDY DESIGN: Patients nonresponsive to IVIG (axillary temperature ≥37.5°C >24 hours after end of IVIG) were identified. Each patient with IVIG-nonresponsive KD was matched to a control patient with IVIG-responsive KD of the same age, sex, and duration of fever before IVIG. Hourly temperature profiles were obtained from immediately before the start of IVIG infusion until complete defervescence. RESULTS: A total of 182 patients nonresponsive to IVIG were matched (total n = 364). Nonresponders were further classified as partial nonresponders (68%) (axillary temperature decreased to <37.5°C but fever recurred) and complete nonresponders (32%) (axillary temperature consistently ≥37.5°C throughout IVIG treatment). The temperature profile during IVIG infusion was similar between responders and partial nonresponders (EST: -0.061 [0.007]°C/h, P < .001 for responders vs EST: -0.027 (0.012)°C/h, P = .03 for partial nonresponders [responders vs partial nonresponders, P = .65]), where EST is the parameter estimate from the regression model, representing the change in degrees Celsius for each hour since start of IVIG. In complete nonresponders, IVIG was not associated with significant decreases in temperature (EST: -0.008 [0.010]°C, P = .42). Factors associated with complete (vs partial) nonresponse included laboratory-confirmed infection, greater C-reactive protein, and IVIG brand. Defervescence in partial nonresponders was achieved with a second IVIG dose for 72% of patients compared with 58% of complete nonresponders (P = .001). Complete nonresponders were more likely to develop coronary artery aneurysms vs partial nonresponders (OR: 2.4 [1.1-5.4], P = .03) or responders (OR: 3.2 [1.5-6.9], P = .002). CONCLUSIONS: Nonresponse to initial IVIG can be further characterized by temperature profile, and complete nonresponders may require more aggressive second-line therapy.

Targeting under-diagnosis in hereditary hemorrhagic telangiectasia: a model approach for rare diseases?

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT), a rare autosomal dominant disease, is considered under-diagnosed. Our primary objective was to provide evidence of under-diagnosis of HHT in a North American population. We hypothesized that variation would exist in the diagnosed prevalence (D-prevalence) across regions in the province of Ontario, Canada and across age groups, due to under-diagnosis in certain groups. Our secondary objective was to collect data regarding contact and local access to consult specialists by HHT patients to help guide potential future diagnostic programs. METHODS: Primary objective- 556 adult patients with a definite HHT diagnosis seen at the Toronto HHT Centre were identified and geocoded with postal codes. Prevalence rates were calculated using Canadian census data. Secondary objective- A driving network model was developed in ArcGIS. Service area buffers around ear, nose and throat (ENT) clinics in Ontario were generated to evaluate the proportion of the Ontario population with access to these clinics. A survey was also sent to the email contact list of HHT Foundation International, targeting people with diagnosed HHT, regarding consultation with ENT physicians for epistaxis and timing of HHT diagnosis. RESULTS: Primary objective- D-prevalence rates varied among regions, from no cases to 1.1 cases per 5000 in large Ontario cities. There were no significant differences between urban and rural prevalence rates. Variation in prevalence was seen across age groups, with greater prevalence in older adults (≥50 years-old) compared with adults 20-49 years-old (0.36 versus 0.26 per 5000, p < 0.0005). Secondary objective- Most Ontarians had access to ENT clinics within a 30, 60 and 90 minute modeled drive time (92.7%, 97.8% and 98.6%, respectively). Nearly 40% of surveyed patients consulted an ENT physician for their epistaxis, on average 13.9 ± 12.2 years prior to being diagnosed with HHT. CONCLUSIONS: The prevalence of HHT in Ontario is highly variable across regions and age-groups, suggesting under-diagnosis. Given that patients with HHT frequently consult ENT physicians for epistaxis prior to HHT diagnosis, and that there is almost universal access to ENTs in Ontario, we propose targeting ENT clinics as a province-wide approach to detect undiagnosed HHT patients and families.

The diagnostic yield of rescreening for arteriovenous malformations in children with hereditary hemorrhagic telangiectasia.

The diagnostic yield of rescreening children with hereditary hemorrhagic telangiectasia at regular intervals for arteriovenous malformations is unclear. Here, we show that when children with initially negative screening were reassessed after 5 years, no new arteriovenous malformations were detected suggesting that longer intervals between screenings may be adequate.

Severity score for hereditary hemorrhagic telangiectasia.

BACKGROUND: A disease severity score in hereditary hemorrhagic telangiectasia (HHT) would be a useful tool for assessing burden of disease and for designing clinical trials. Here, we propose the first known HHT severity score, the HHT-score. METHODS: Demographics and disease characteristics were collected for the first 525 HHT patients recruited to the HHT Project of the Brain Vascular Malformation Consortium (BVMC). HHT-score was calculated based on presence of: organ arteriovenous malformations (maximum 3 points); chronic bleeding (maximum 2 points); and severe organ involvement (maximum 2 points). Points were summed and patients categorized as having mild (0-2), moderate (3-4) or severe (5-7) disease. The occurrence of "any adverse outcome" was evaluated for association with HHT-score categories. RESULTS: The frequency of "any adverse outcome" was significantly different across the three groups (49.6% in mild, 65.8% in moderate and 89.5% in severe, p<0.001). Adjusting for age and gender, the risk of "any adverse outcome" was higher in the moderate (OR=1.84, 95% CI: 1.15-2.95, p=0.011) and severe groups (OR=9.16, 95% CI: 1.99-42.09, p=0.004) compared to the mild. CONCLUSIONS: We have taken the first steps toward creating a global measure of disease severity in HHT. While the initial results are promising, further validation of the HHT-score is still required.

Brain arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia: clinical presentation and anatomical distribution.

BACKGROUND: Hereditary hemorrhagic telangiectasia is an autosomal dominant genetic disease with a wide array of vascular malformations involving multiple organs. Brain arteriovenous malformations can lead to intracranial hemorrhage and are often diagnosed only after patients become symptomatic. Early diagnosis and interventional treatment may prevent neurologic sequelae or death. Because of the rarity of defined cases, the spectrum of presentations in children with brain arteriovenous malformations and hereditary hemorrhagic telangiectasia has not been explored in detail. Here, we report our experience in children with hereditary hemorrhagic telangiectasia and brain arteriovenous malformations regarding both disease manifestations at presentation and the spectrum of brain arteriovenous malformation manifestations. METHODS: A retrospective review of demographics, clinical manifestations, and brain magnetic resonance imaging/computed tomography scan findings in 115 patients with confirmed hereditary hemorrhagic telangiectasia (HHT) was conducted using the Hospital for Sick Children's HHT Clinic database for the years 1997-2012. RESULTS: Eleven patients (four girls and seven boys) were diagnosed with hereditary hemorrhagic telangiectasia and brain arteriovenous malformations during this period. Five patients initially presented with epistaxis, four presented with intracranial hemorrhage, and two were asymptomatic with a positive family history of confirmed hereditary hemorrhagic telangiectasia. Although all children had an index case with hereditary hemorrhagic telangiectasia in the family, in three patients, hereditary hemorrhagic telangiectasia was not diagnosed before the child's presentation with intracranial hemorrhage. Multiple brain arteriovenous malformations were found in five patients, with one patient having bithalamic arteriovenous malformations. CONCLUSIONS: This study highlights the importance of both family history and early clinical signs to prompt further diagnostic testing to avoid intracranial hemorrhage from brain arteriovenous malformations in children with hereditary hemorrhagic telangiectasia.

Prevalence of pulmonary arteriovenous malformations in children versus adults with hereditary hemorrhagic telangiectasia.

It is unclear whether pulmonary arteriovenous malformations (PAVMs) in hereditary hemorrhagic telangiectasia develop later in life or are preformed in childhood. We show that the prevalence of PAVMs in children is similar to that in their parents, providing evidence against de novo PAVM formation in hereditary hemorrhagic telangiectasia.

Macrophage activation syndrome in the acute phase of Kawasaki disease.

Rare cases of macrophage activation syndrome (MAS) occurring during the acute phase of Kawasaki disease (KD) have been reported. We sought to characterize, review treatment, and outcomes of KD patients with clinical features of MAS. Medical histories of patients treated for KD and MAS between January 2001 and March 2008 were reviewed. Of 638 KD patients seen, 12 (1.9%) had additional clinical findings usually associated with MAS; 7 of them were males older than 5 years (6.1%; odds ratio: 6.8, P=0.002). Clinically, 9 patients had at least 4 of 5 KD clinical signs, and all patients had prolonged fever beyond initial intravenous immunoglobulin treatment. Hepatosplenomegaly, cytopenia in two or more cell lines, hypertriglyceridemia and/or hypofibrinogenemia, and increased D-dimers were seen in 11 patients. Hyperferritinemia and elevated hepatic enzymes were seen in all patients. Four patients had biopsy-proven evidence of hemophagocytosis. All but 2 patients met at least 5 of 8 criteria necessary for MAS diagnosis. Treatment beyond the standard KD protocol (aspirin + intravenous immunoglobulin) was necessary in all but 1 patient. All patients eventually recovered with no long-term sequelae. A high index of suspicion for clinical features associated with MAS is warranted for KD patients to provide appropriate and timely treatment.