Impact of SARS-CoV-2 infection in patients with hereditary hemorrhagic telangiectasia: epidemiological and clinical data from the comprehensive Italian retrospective multicenter study.

Rare Disease patients manifested high concern regarding the possible increased risk of severe outcomes and worsening of disease-specific clinical manifestation due to the impact of COVID-19. Our aim was to assess the prevalence, outcomes, and impact of COVID-19 in patients with a rare disease such as Hereditary Hemorrhagic Telangiectasia (HHT) in Italian population. A nationwide, multicentric, cross-sectional observational study was conducted on patients with HHT from five Italian HHT centers by online survey. The association between COVID-19-related signs and symptoms and nosebleeds worsening, the impact of personal protective equipment on nosebleeds pattern, and the relationship between the presence of visceral AVMs and severe outcomes were analyzed. Out of 605 total survey responses and eligible for analysis, 107 cases of COVID-19 were reported. A mild-course COVID-19 disease, not requiring hospitalization, was observed in 90.7% of patients, while the remaining eight cases needed hospitalization, two of them requiring intensive-care access. No fatal outcome was recorded and 79.3% of patients reported a complete recovery. No difference in infection risk and outcome between HHT patients and general population was evidenced. No significative interference of COVID-19 on HHT-related bleeding was found. The majority of patients received COVID-19 vaccination, with relevant impact on symptoms and need for hospitalization in case of infection. COVID-19 in HHT patients had an infection profile similar to the general population. COVID-19 course and outcome were independent from any specific HHT-related clinical features. Moreover, COVID-19 and anti-SARS-CoV-2 measures did not seem to affect significantly HHT-related bleeding profile.

A case report on uneventful anticoagulation and persistence of Type 1 Respiratory Failure post severe COVID-19 infection in a patient of Osler-Weber-Rendu syndrome.

The SARS-CoV-2 pandemic has led researchers worldwide to study the patterns of association of SARS-CoV-2 with different diseases, which have been a prime focus of medical literature. Osler-Weber-Rendu syndrome, also known as hereditary hemorrhagic telangiectasia (HHT), is a rare genetic disorder in which patients present with recurrent epistaxis, nostril manipulations, and multiple arteriovenous malformations (AVMs) along with telangiectasias involving internal organs and mucocutaneous areas. In addition, these AVMs are prone to bleeding or act as a nidus for thrombus formation, apart from other serious complications, such as chronic hypoxemia, anemia, pulmonary artery hypertension, heart failure, and cerebrovascular accidents. Here, we present a case report of a patient who presented with acute onset respiratory complaints, had multiple episodes of epistaxis in the past, and was later diagnosed with HHT as per Curaçao criteria in our hospital. Doppler ultrasound over the left calf region showed an AVM. Contrast-enhanced computed tomography (CECT) angiography of the chest and abdomen revealed multiple pulmonary and hepatic AVMs along with splenic and uterine telangiectasias and malformations, who on acquiring severe COVID-19 infection developed complications such as anemia, pulmonary artery hypertension, sepsis, acute kidney injury, and post-COVID-19 persistence of Type 1 respiratory failure. Furthermore, the risk-benefit ratio of anticoagulation therapy in such patients with COVID-19 infection is tricky and challenging. However, our patient was prophylactically anti-coagulated with enoxaparin for 12 days with an uneventful outcome.

Pulmonary arteriovenous malformation and inherent complications with solitary lung nodule biopsy-literature overview and case report.

Pulmonary arteriovenous malformation, also known as an arteriovenous fistula, is typically a congenital disease caused by structural deficiencies, particularly the lack of capillary wall development, leading to the abnormal dilation of the pulmonary capillaries. The majority of pulmonary arteriovenous malformation cases are associated with Rendu-Osler-Weber syndrome, also known as hereditary hemorrhagic telangiectasia. Pulmonary arteriovenous malformation rarely occurs due to chest trauma. Pulmonary arteriovenous malformations are long-lasting and often first diagnosed in adults. More than two-thirds of pulmonary arteriovenous malformation lesions are found in the lower lung lobe and the subpleural area, and the vast majority of cases present with the monofocal form. The initial diagnosis is often based on the identification of a solitary pulmonary nodule. However, a solitary nodule detected on chest computed tomography that is not correctly diagnosed as pulmonary arteriovenous malformation, even after intravenous contrast injection, can lead to the performance of a transthoracic biopsy. Biopsy of pulmonary arteriovenous malformations can lead to stroke occurrence, during which the patient often presents with severe pleural bleeding, which can have lifelong consequences if not immediately treated. We report a case of pulmonary arteriovenous malformation that was discovered incidentally in an adult patient who underwent non-contrast computed tomography. Misdiagnosis occurred, and transthoracic lung biopsy was performed. Complications were discovered late, and the patient underwent surgical pulmonary arteriovenous malformation removal and was treated for hemothorax.

Understanding and Targeting Pulmonary Arteriovenous Malformations Using Repurposed Drugs

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by multiple arteriovenous malformations(AVMs) which are direct connections between arteries and veins, bypassing the capillary bed. Severe epistaxis (nosebleeds) is the most common symptom, yet visceral AVMs in the brain (1-10%), lung (15-45%), liver and gastrointestinal tract cause significant morbidity and mortality due to embolic stroke, cerebral abscess, migraines, hemorrhagic stroke, seizures and life-threatening bleeding complications. In order to reduce the morbidity and mortality associated with HHT, we need a better understanding of HHT development and novel treatment approaches. Our aims are: Aim 1: To understand the cellular and molecular mechanisms of PAVM development in mice and to identify the cell behaviors and populations that give rise to PAVMs. Aim 2: To identify and target pathological downstream signaling in endothelial cells derived from iPSCs (iPSC-ECs)from HHT patients with visceral AVMs. Aim 3: To target pathological downstream signaling with repurposed drugs to prevent and reverse PAVMs in the mouse model. The short-term impact will be a better understanding of how AVMs form in the lung and potentially in other organs. The long-term impact will be the identification of potential novel treatments for AVMs.

Characterization of epidemiological distribution and outcome of COVID-19 in patients with hereditary hemorrhagic telangiectasia: a nationwide retrospective multi-centre study during first wave in Italy.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) continues to have a devastating impact across the world. A number of pre-existing common clinical conditions were reported to represent risk factors for more severe COVID-19 outcomes. Hereditary Hemorrhagic Telangiectasia (HHT) is a rare vascular heritable disorders, characterized by complications secondary to visceral Arterio-Venous Malformations. The impact of HHT, as well as for many Rare Diseases (RDs) on infection susceptibility profile and clinical adverse outcome risk is an unresolved issue. OBJECTIVES: The main objectives were: to assess the clinical features and outcomes of HHT patients infected with COVID-19; to compare the relative infection risk in these patients with the Italian general population throughout the first pandemic wave; to investigate the factors potentially associated with severe COVID-19 outcome in HHT patients, and the possible impact of COVID-19 infection on HHT-related symptoms/complications. Finally, we aimed to estimate how the lockdown-associated wearing of personal protective equipment/individual protection devices could affect HHT-related telangiectasia bleeding frequency. METHODS: The study is a nation-wide questionnaire-based survey, with a multi-Center retrospective cross-sectional design, addressed to the whole Italian HHT population. COVID-19 cases, occurring throughout the first pandemic wave, were collected by a questionnaire-based semi-structured interview. Only the cases ascertained by laboratory confirmation (molecular/serological) were included for epidemiological estimates. Information concerning eventual SarS-Cov-2 infection, as well as regarding HHT-related manifestations and HHT-unrelated co-morbidities were collected by the questionnaire. Prevalence data were compared to Italian general population in the same period. RESULTS: The survey disclosed 9/296 (3.04%) COVID-19 cases, 8/9 of them being resident in Lombardy, the main epidemic epicenter. Pneumonia was reported by 4/9 patients, which prompted hospital admission and intensive care management in 2 cases. No fatal outcome was recorded. After careful refinement of epidemiological analysis, the survey evidenced overlapping infection risk in HHT compared to general population. CONCLUSIONS: COVID-19 infection profile parallels geographical distribution of epidemic foci. COVID-19 in HHT patients can lead to highly variable clinical profile, likely overlapping with that of general population. The HHT disease does not seem to involve a different approach in terms of hospital admission and access to intensive care with respect to general population.

SARS-CoV-2 Infection in Hereditary Hemorrhagic Telangiectasia Patients Suggests Less Clinical Impact Than in the General Population.

At the moment of writing this communication, the health crisis derived from the COVID-19 pandemic has affected more than 120 million cases, with 40 million corresponding to Europe. In total, the number of deaths is almost 3 million, but continuously rising. Although COVID-19 is primarily a respiratory disease, SARS-CoV-2 infects also endothelial cells in the pulmonary capillaries. This affects the integrity of the endothelium and increases vascular permeability. In addition, there are serious indirect consequences, like disruption of endothelial cells' junctions leading to micro-bleeds and uncontrolled blood clotting. The impact of COVID-19 in people with rare chronic cardiovascular diseases is unknown so far, and interesting to assess, because the virus may cause additional complications in these patients. The aim of the present work was to study the COVID-19 infection among the patients with Hereditary Hemorrhagic Telangiectasia (HHT). A retrospective study was carried out in a 138 HHT patients' sample attending an Ear Nose and Throat (ENT) reference consult. The evaluation of the COVID-19 infection in them reveals milder symptoms; among the 25 HHT patients who were infected, only 3 cases were hospitalized, and none of them required ICU or ventilation assistance. The results are discussed in the light of macrophage immune response.

Beneficial Effects of Remote Medical Care for Patients with Hereditary Hemorrhagic Telangiectasia during the COVID-19 Pandemic.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) needs high-quality care and multidisciplinary management. During the COVID-19 pandemic, most non-urgent clinical activities for HHT outpatients were suspended. We conducted an analytical observational cohort study to evaluate whether medical and psychological support, provided through remote consultation during the COVID-19 pandemic, could reduce the complications of HHT. METHODS: A structured regimen of remote consultations, conducted by either video-calls, telephone calls, or e-mails, was provided by a multidisciplinary group of physicians to a set of patients of our HHT center. The outcomes considered were: number of emergency room visits/hospitalizations, need of blood transfusions, need of iron supplementation, worsening of epistaxis, and psychological status. RESULTS: The study included 45 patients who received remote assistance for a total of eight months. During this period, 9 patients required emergency room visits, 6 needed blood transfusions, and 24 needed iron supplementation. This was not different from what was registered among the same 45 patients in the same period of the previous year. Remote care also resulted in better management of epistaxis and improved quality of life, with the mean epistaxis severity score and the Euro-Quality of Life-Visual Analogue Scale that were significantly better at the end than at the beginning of the study. DISCUSSION: Remote medical care might be a valid support for HHT subjects during periods of suspended outpatient surveillance, like the COVID-19 pandemic.

Angiogenesis, hereditary hemorrhagic telangiectasia and COVID-19.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal-dominant disease characterized by pathologic angiogenesis that provokes vascular overgrowth. The evidence about the influence of Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in patients with rare diseases is scarce. We aimed to know the prevalence of coronavirus disease 2019 (COVID-19) in HHT patients. The HHT pathogenic angiogenesis and endothelial injury in COVID-19 are discussed using data from RiHHTa (Computerized Registry of Hereditary Hemorrhagic Telangiectasia) registry. RiHHTa is an open, multicenter, prospective, observational registry including adult patients with HHT. A 27-item survey that captured clinical data of admitted HHT patients for COVID-19 was distributed to all RiHHTa investigators from June 8th to June 24th 2020. Only one out of 1177 HHT patients was admitted for COVID-19 pneumonia. She is a 74 years-old woman with a pathogenic variant in ACVRL1 gene. Her clinical course did not involve mechanical ventilation or worsening epistaxis, and she was successfully discharged after two weeks. The endothelial damage and the consequent angiogenic process in COVID-19 patients deserve further investigation.