James R. Gossage

International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia

Background HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. Objective The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. Methods The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. Results The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: Gene–phenotype correlations†‡

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disease with a wide spectrum of vascular malformations (VMs) involving multiple organs. Nine to 16% of patients with HHT harbor brain arteriovenous malformations (AVMs), which can cause intracranial hemorrhage (ICH). Our objective was to study clinical manifestations of brain AVMs in patients with HHT and correlate these with the specific gene mutated. We reviewed records of 171 patients with HHT and brain AVMs. A history of ICH was found in 27% (41/152) patients, with a mean age of 26 ± 18 range, (0–68) years. All of patients with ICH were neurologically asymptomatic prior to ICH. Multiple brain AVMs were found in 23% (170/39) of patients on initial examination. Genetic test results were available in 109 (64%) patients. Mutations in ENG, ACVRL1, and SMAD4 were present in 75 (69%), 18 (17%), and 2 (2%), respectively. A history of ICH was reported in 24% of patients with an ENG mutation and 27% of patients with an ACVRL1 mutation, with a mean age of 26 ± 16 (range, 2–50) and 18 ± 21 (0–48) years, respectively. No statistically significant differences in age at first brain AVM diagnosis, prevalence of ICH history, age at ICH, or other manifestations of brain AVMs were observed among gene groups. In conclusion, no evidence for differences in brain AVM characteristics was observed among HHT gene groups, although we cannot exclude clinically important differences. Larger studies are needed to further guide brain AVM screening decisions in patients with HHT.

Clinical implications of pulmonary shunting on saline contrast echocardiography.

Pulmonary right-to-left shunting can be encountered using transthoracic contrast echocardiography (TTCE) with agitated saline. Diseases associated with pulmonary shunting on saline TTCE include hereditary hemorrhagic telangiectasia (HHT), hepatopulmonary syndrome, and some congenital heart defects after partial or complete cavopulmonary anastomosis. Furthermore, small pulmonary shunts on saline TTCE are also documented in a proportion of healthy individuals. Pulmonary shunting carries the risk for severe neurologic complications due to paradoxical embolization. In HHT, additional chest computed tomography is recommended in case of any pulmonary shunt detected on saline TTCE, to evaluate the feasibility for transcatheter embolotherapy of pulmonary arteriovenous malformations. Furthermore, antibiotic prophylaxis is advised in case of any pulmonary shunt on saline TTCE to prevent brain abscesses after procedures with risk for bacteremia. The present review provides an overview of important aspects of pulmonary shunting and its detection using saline TTCE. Furthermore, advances in understanding the clinical implications of different pulmonary shunt grades on saline TTCE are described. It appears that small pulmonary shunts on saline TTCE (grade 1) lack any clinical implication, as these shunts cannot be used as a diagnostic criterion for HHT, are not associated with an increased risk for neurologic complications, and represent pulmonary arteriovenous malformations too small for subsequent endovascular treatment. This implies that additional chest computed tomography could be safely withheld in all persons with only small pulmonary shunts on saline TTCE and sets the stage for further discussion about the need for antibiotic prophylaxis in these subjects. Besides further optimization of the current screening algorithm for the detection of pulmonary arteriovenous malformations in HHT, these observations can be of additional clinical importance in other diseases associated with pulmonary shunting and in those healthy individuals with documented small pulmonary shunts on saline TTCE.

Age-Dependent Lethality in Novel Transgenic Mouse Models of Central Nervous System Arteriovenous Malformations

Background and Purpose— The lack of an appropriate animal model has been a limitation in studying hemorrhage from arteriovenous malformations (AVMs) in the central nervous system. Methods— Novel mouse central nervous system AVM models were generated by conditionally deleting the activin receptor-like kinase (Alk1; Acvrl1) gene with the SM22-Cre transgene. All mice developed AVMs in their brain and/or spinal cord, and >80% of them showed a paralysis or lethality phenotype due to internal hemorrhages during the first 10 to 15 weeks of life. The mice that survived this early lethal period, however, showed significantly reduced lethality rates even though they carried multiple AVMs. Results— The age-dependent change in hemorrhage rates allowed us to identify molecular factors uniquely upregulated in the rupture-prone AVM lesions. Conclusions— Upregulation of angiopoietin 2 and a few inflammatory genes were identified in the hemorrhage-prone lesions, which may be comparable with human pathology. These models will be an exceptional tool to study pathophysiology of AVM hemorrhage.

Effect of Topical Intranasal Therapy on Epistaxis Frequency in Patients With Hereditary Hemorrhagic Telangiectasia: A Randomized Clinical Trial

IMPORTANCE Epistaxis is a major factor negatively affecting quality of life in patients with hereditary hemorrhagic telangiectasia (HHT; also known as Osler-Weber-Rendu disease). Optimal treatment for HHT-related epistaxis is uncertain. OBJECTIVE To determine whether topical therapy with any of 3 drugs with differing mechanisms of action is effective in reducing HHT-related epistaxis. DESIGN, SETTING, AND PARTICIPANTS The North American Study of Epistaxis in HHT was a double-blind, placebo-controlled randomized clinical trial performed at 6 HHT centers of excellence. From August 2011 through March 2014, there were 121 adult patients who met the clinical criteria for HHT and had experienced HHT-related epistaxis with an Epistaxis Severity Score of at least 3.0. Follow-up was completed in September 2014. INTERVENTIONS Patients received twice-daily nose sprays for 12 weeks with either bevacizumab 1% (4 mg/d), estriol 0.1% (0.4 mg/d), tranexamic acid 10% (40 mg/d), or placebo (0.9% saline). MAIN OUTCOMES AND MEASURES The primary outcome was median weekly epistaxis frequency during weeks 5 through 12. Secondary outcomes included median duration of epistaxis during weeks 5 through 12, Epistaxis Severity Score, level of hemoglobin, level of ferritin, need for transfusion, emergency department visits, and treatment failure. RESULTS Among the 121 patients who were randomized (mean age, 52.8 years [SD, 12.9 years]; 44% women with a median of 7.0 weekly episodes of epistaxis [interquartile range {IQR}, 3.0-14.0]), 106 patients completed the study duration for the primary outcome measure (43 were women [41%]). Drug therapy did not significantly reduce epistaxis frequency (P = .97). After 12 weeks of treatment, the median weekly number of bleeding episodes was 7.0 (IQR, 4.5-10.5) for patients in the bevacizumab group, 8.0 (IQR, 4.0-12.0) for the estriol group, 7.5 (IQR, 3.0-11.0) for the tranexamic acid group, and 8.0 (IQR, 3.0-14.0) for the placebo group. No drug treatment was significantly different from placebo for epistaxis duration. All groups had a significant improvement in Epistaxis Severity Score at weeks 12 and 24. There were no significant differences between groups for hemoglobin level, ferritin level, treatment failure, need for transfusion, or emergency department visits. CONCLUSIONS AND RELEVANCE Among patients with HHT, there were no significant between-group differences in the use of topical intranasal treatment with bevacizumab vs estriol vs tranexamic acid vs placebo and epistaxis frequency. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01408030.

Hemorrhage Rates From Brain Arteriovenous Malformation in Patients With Hereditary Hemorrhagic Telangiectasia

Background and Purpose— Hereditary hemorrhagic telangiectasia (HHT) is a systemic disease characterized by mucocutaneous telangiectasias, epistaxis, and arteriovenous malformations (AVMs). Intracranial hemorrhage (ICH) rates in this population are not well described. We report ICH rates and characteristics in HHT patients with brain AVMs (HHT-BAVMs). Methods— We studied the first 153 HHT-BAVM patients with follow-up data enrolled in the Brain Vascular Malformation Consortium HHT Project. We estimated ICH rates after BAVM diagnosis. Results— The majority of patients were women (58%) and white (98%). The mean age at BAVM diagnosis was 31±19 years (range, 0–70), with 61% of cases diagnosed on asymptomatic screening. Overall, 14% presented with ICH; among symptomatic cases, 37% presented ruptured. During 493 patient-years of follow-up, 5 ICH events occurred yielding a rate of 1.02% per year (95% confidence interval, 0.42–2.44%). ICH-free survival differed significantly by ICH presentation (P=0.003); ruptured cases had a higher ICH rate (10.07%; 95% confidence interval, 3.25–31.21%) than unruptured cases (0.43%; 95% confidence interval, 0.11–1.73%). Conclusions— Patients with HHT-BAVM who present with hemorrhage are at a higher risk for rehemorrhage compared with patients with BAVM detected presymptomatically.

Cerebral vascular malformations in hereditary hemorrhagic telangiectasia: Clinical article

OBJECT Hereditary hemorrhagic telangiectasia (HHT) is a hereditary disorder characterized by mucocutaneous telangiectasias, frequent nosebleeds, and visceral arteriovenous malformations (AVMs). Few reports have outlined the prevalence of the various cerebral vascular malformations found in patients with HHT. The authors set out to define the prevalence of cerebral vascular malformations in a population of HHT patients who underwent imaging with 3-T imaging (MRI/MR angiography [MRA]) of the brain. METHODS A retrospective review of prospectively collected data was carried out using a database of 372 HHT patients who were seen and examined at the Georgia Regents University HHT Center and screened with 3-T MRI/MRA. Data were tabulated for numbers and types of vascular malformations in this population. RESULTS Arteriovenous malformations were identified in 7.7%, developmental venous anomalies in 4.3%, and cerebral aneurysms in 2.4% of HHT patients. The HHT AVMs tended to be supratentorial, small, and cortical in this series, findings consistent with other recent studies in the literature. An arteriovenous fistula, cavernous malformation, and capillary telangiectasia were identified in 0.5%, 1%, and 1.9% of HHT patients, respectively. CONCLUSIONS Few studies have investigated the prevalence of the various vascular malformations found in HHT patients screened with 3-T MRI/MRA of the brain. Hereditary hemorrhagic telangiectasia AVMs are more likely to be multiple and have a tendency toward small size and cortical location. As such, they are often treated using a single-modality therapy.

Early intervention in massive pulmonary embolism: A guide to diagnosis and triage for the critical first hour

PREVIEW In about 50% of patients with pulmonary embolism, the embolism is massive, that is, accompanied by at least one of several potentially compromising conditions. Unfortunately, about three fourths of patients who die of pulmonary embolism do so within 1 hour of symptom onset. Thus, expeditious assessment of patients with suspected massive pulmonary embolism is crucial. In this article, Dr Gossage discusses prompt recognition of this condition and presents several management strategies.

Optimal management of septic shock. Rapid recognition and institution of therapy are crucial.

PREVIEW Septic shock is the most common cause of death in intensive care units in the United States, and its incidence is rising. This growth is most likely due to the increased use of invasive devices and immunosuppressive therapies, higher numbers of immunocompromised patients, and increasing antibiotic resistance. In this article, Drs Fitch and Gossage discuss the natural history and diagnosis of septic shock and optimal management, including optimization of organ perfusion, fluid therapy, and use of vasoactive agents.

Role of contrast echocardiography in screening for pulmonary arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia.

www.chestpubs.org instances, antibiotics could be avoided. Similarly, if viruses are copathogens, then therapy could potentially mitigate the severity of illness or even prevent the development of a bacterial superinfection. However, if the viruses are simply colonizers, as suggested by the 7.1% recovery in the control population when NAAT methods were used, then it is unclear if antiviral therapy would have a benefi t when these colonized patients develop CAP. The data from the study by Lieberman and colleagues 10 are provocative because they have demonstrated that when NAAT methods are used, there is a high frequency of viral detection in patients with lower respiratory tract infection. With the availability of new diagnostic tools, such as NAAT, we will now be able to ask questions about the clinical relevance and impact of respiratory viruses. We might be able to combine a positive test for a respiratory virus with the measurement of a serum biomarker, such as procalcitonin, in patients with radiographic CAP to defi ne individuals who can be managed without antibiotics. New diagnostic tools for viral respiratory tract infections might also encourage the development of new antiviral therapies that could be effective in improving patient outcome. Thus, the currently available data have shown that viruses are commonly present in patients with CAP and that they can cause harm, yet in clinical practice we rarely try to diagnose their presence. This may change once these new diagnostic tools become more widely available, especially if they help us defi ne an etiologic role of these pathogens and if they encourage the development of new and effective antiviral therapies.