Essentials
Debated is the role of residual pulmonary obstruction (RPO) in predicting venous thromboembolism.
Whether right ventricular dysfunction (RVD) predicts recurrent venous thromboembolism is ...unknown.
15 studies on RPO and 4 on RVD and venous thromboembolism were included in this meta‐analysis.
RPO is a predictor of recurrent venous thromboembolism when assessed by perfusion lung scan.
RVD after acute pulmonary embolism is not associated with recurrent venous thromboembolism.
Background
There is conflicting evidence regarding the role of residual pulmonary obstruction (RPO) or persistent right ventricular dysfunction (RVD) after pulmonary embolism (PE) as a predictor of recurrent venous thromboembolism (VTE). The aim of this study was to assess whether RPO or persistent RVD after PE is associated with recurrent VTE.
Methods
MEDLINE and EMBASE were searched through December 2018. Studies reporting on (a) RPO either on computed tomography (CT) angiography or perfusion lung scan, or RVD on echocardiography or CT angiography, after therapeutic anticoagulation for the acute PE, and (b) recurrent VTE, were included in this meta‐analysis.
Results
RPO was associated with an increased risk of recurrent VTE (16 studies; 3472 patients; odds ratio OR 2.22; 95% confidence interval CI 1.61‐3.05; I2 = 26%); the association was statistically significant for lung scan–detected RPO (11 studies; 2916 patients; OR 2.21; 95% CI 1.63‐3.01) but not for CT angiography–detected RPO (five studies; 556 patients; OR 2.56; 95% CI 0.82‐7.94). No significant association was found between persistent RVD and recurrent VTE (four studies; 852 patients; OR 1.62; 95% CI 0.63‐4.17).
Conclusions
RPO is a predictor of recurrent VTE after a first acute PE, mainly when assessed by perfusion lung scan.
OBJECTIVE—ALK1 (activin-receptor like kinase 1) is an endothelial cell-restricted receptor with high affinity for BMP (bone morphogenetic protein) 9 TGF-β (transforming growth factor-β) family ...member. Loss-of-function mutations in ALK1 cause a subtype of hereditary hemorrhagic telangiectasia—a rare disease characterized by vasculature malformations. Therapeutic strategies are aimed at reducing potential complications because of vascular malformations, but currently, there is no curative treatment for hereditary hemorrhagic telangiectasia.
APPROACH AND RESULTS—In this work, we report that a reduction in ALK1 gene dosage (heterozygous ALK1 mice) results in enhanced retinal endothelial cell proliferation and vascular hyperplasia at the sprouting front. We found that BMP9/ALK1 represses VEGF (vascular endothelial growth factor)-mediated PI3K (phosphatidylinositol 3-kinase) by promoting the activity of the PTEN (phosphatase and tensin homolog). Consequently, loss of ALK1 function in endothelial cells results in increased activity of the PI3K pathway. These results were confirmed in cutaneous telangiectasia biopsies of patients with hereditary hemorrhagic telangiectasia 2, in which we also detected an increase in endothelial cell proliferation linked to an increase on the PI3K pathway. In mice, genetic and pharmacological inhibition of PI3K is sufficient to abolish the vascular hyperplasia of ALK1 retinas and in turn normalize the vasculature.
CONCLUSIONS—Overall, our results indicate that the BMP9/ALK1 hub critically mediates vascular quiescence by limiting PI3K signaling and suggest that PI3K inhibitors could be used as novel therapeutic agents to treat hereditary hemorrhagic telangiectasia.
Lysosomal Storage Diseases (LSDs) are a group of Rare Diseases (RDs) caused by lysosomal enzyme deficiencies. Patients with LSDs suffer from a wide range of symptoms with a strong impact in their ...daily routines. In this study we aimed to explore the impact of the disease on the lives of patients with four LSDs, as well as how they experience Patient Journey from diagnosis to follow up. Unmet Needs (UNs) perceived by patients and clinicians were assessed to have a better understanding of which initiatives could improve LSDs management and especially those that could result in an improvement of patients' quality of life.
Qualitative research was the research methodology selected for the study. It provides plentiful and holistic insights into people's views and actions. The study was conducted through in-depth face-to-face semi-structured interviews.
In total, 20 patients and 25 Health Care Professionals (HCPs) from different Spanish regions were interviewed. Patients perceived that the highest impact of the LSDs was on their daily routines, specifically on their emotional side, their work/school environment, their family and their social life. Regarding the Patient Journey experience, the worst perceived stage was the pre-diagnosis, where patients only reported negative perceptions, being the delay in diagnosis and misdiagnosis the most commented issues. On the contrary, the follow-up stage was the one with less negative perceptions. Overall, patients and HCPs agreed on the priority UNs, such as accelerating diagnosis, reducing bureaucracy for the treatment access and a more coordinated attention for the patients, not only among different physicians but also with other professionals such as genetic counselors or social workers.
Our data shows that there are still UNs to be addressed from the perspective of patients and HCPs. The main UN is accelerating diagnosis, which could be achieved by medical awareness and education, according to clinicians. A more comprehensive disease management was another main point to be worked on to improve LSD-patient experience and quality of life.
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.
Background
It is important to predict which patients infected by SARS-CoV-2 are at higher risk of life-threatening COVID-19. Several studies suggest that neutralizing auto-antibodies (auto-Abs) ...against type I interferons (IFNs) are predictive of critical COVID-19 pneumonia.
Objectives
We aimed to test for auto-Abs to type I IFN and describe the main characteristics of COVID-19 patients admitted to intensive care depending on whether or not these auto-Abs are present.
Methods
Retrospective analysis of all COVID-19 patients admitted to an intensive care unit (ICU) in whom samples were available, from March 2020 to March 2021, in Barcelona, Spain.
Results
A total of 275 (70.5%) out of 390 patients admitted to ICU were tested for type I IFNs auto-antibodies (α2 and/or ω) by ELISA, being positive in 49 (17.8%) of them. Blocking activity of plasma diluted 1/10 for high concentrations (10 ng/mL) of IFNs was proven in 26 (9.5%) patients. Almost all the patients with neutralizing auto-Abs were men (92.3%). ICU patients with positive results for neutralizing IFNs auto-Abs did not show relevant differences in demographic, comorbidities, clinical features, and mortality, when compared with those with negative results. Nevertheless, some laboratory tests (leukocytosis, neutrophilia, thrombocytosis) related with COVID-19 severity, as well as acute kidney injury (17 65.4% vs. 100 40.2%;
p
= 0.013) were significantly higher in patients with auto-Abs.
Conclusion
Auto-Abs neutralizing high concentrations of type I IFNs were found in 9.5% of patients admitted to the ICU for COVID-19 pneumonia in a hospital in Barcelona. These auto-Abs should be tested early upon diagnosis of SARS-CoV-2 infection, as they account for a significant proportion of life-threatening cases.
Hemorrhagic hereditary telangiectasia (HHT) type 2 patients have increased activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway in telangiectasia. The main objective is to ...evaluate the activation of the PI3K pathway in cutaneous telangiectasia of HHT1 patients. A cutaneous biopsy of a digital hand telangiectasia was performed in seven HHT1 and eight HHT2 patients and compared with six controls. The study was approved by the Clinical Research Ethics Committee of our center. A histopathological pattern with more dilated and superficial vessels that pushed up the epidermis was identified in HHT patients regardless of the type of mutation and was associated with older age, as opposed to the common telangiectasia pattern. The mean proliferation index (Ki-67) was statistically higher in endothelial cells (EC) from HHT1 than in controls. The percentage of positive EC for pNDRG1, pAKT, and pS6 in HHT1 patients versus controls resulted in higher values, statistically significant for pNDRG1 and pS6. In conclusion, we detected an increase in EC proliferation linked to overactivation of the PI3K pathway in cutaneous telangiectasia biopsies from HHT1 patients. Our results suggest that PI3K inhibitors could be used as novel therapeutic agents for HHT.
Introduction
Loss-of-function
TLR7
variants have been recently reported in a small number of males to underlie strong predisposition to severe COVID-19. We aimed to determine the presence of these ...rare variants in young men with severe COVID-19.
Methods
We prospectively studied males between 18 and 50 years-old without predisposing comorbidities that required at least high-flow nasal oxygen to treat COVID-19. The coding region of
TLR7
was sequenced to assess the presence of potentially deleterious variants.
Results
TLR7
missense variants were identified in two out of 14 patients (14.3%). Overall, the median age was 38 (IQR 30-45) years. Both variants were not previously reported in population control databases and were predicted to be damaging by
in silico
predictors. In a 30-year-old patient a maternally inherited variant c.644A>G; p.(Asn215Ser) was identified, co-segregating in his 27-year-old brother who also contracted severe COVID-19. A second variant c.2797T>C; p.(Trp933Arg) was found in a 28-year-old patient, co-segregating in his 24-year-old brother who developed mild COVID-19. Functional testing of this variant revealed decreased type I and II interferon responses in peripheral mononuclear blood cells upon stimulation with the TLR7 agonist imiquimod, confirming a loss-of-function effect.
Conclusions
This study supports a rationale for the genetic screening for
TLR7
variants in young men with severe COVID-19 in the absence of other relevant risk factors. A diagnosis of TLR7 deficiency could not only inform on treatment options for the patient, but also enables pre-symptomatic testing of at-risk male relatives with the possibility of instituting early preventive and therapeutic interventions.
Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease with autosomal dominant inheritance. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) ...genes are detected in more than 90% of cases submitted to molecular diagnosis. We used data from the RiHHTa (Computerized Registry of Hereditary Hemorrhagic Telangiectasia) registry to describe genetic variants and to assess their genotype-phenotype correlation among HHT patients in Spain. By May 2019, 215 patients were included in the RiHHTa registry with a mean age of 52.5 + or - 16.5 years and 136 (63.3%) were women. Definitive HHT diagnosis defined by the Curaçao criteria were met by 172 (80%) patients. Among 113 patients with genetic test, 77 (68.1%) showed a genetic variant in ACVRL1 and 36 (31.8%) in ENG gene. The identified genetic variants in ACVRL1 and ENG genes and their clinical significance are provided. ACVRL1 mutations were more frequently nonsense (50%) while ENG mutations were more frequently, frameshift (39.1%). ENG patients were significantly younger at diagnosis (36.9 vs 45.7 years) and had pulmonary arteriovenous malformations (AVMs) (71.4% vs 24.4%) and cerebral AVMs (17.6% vs 2%) more often than patients with ACVRL1 variants. Patients with ACVRL1 variants had a higher cardiac index (2.62 vs 3.46), higher levels of hepatic functional blood tests, and anemia (28.5% vs 56.7%) more often than ENG patients. ACVRL1 variants are more frequent than ENG in Spain. ACVRL1 patients developed symptomatic liver disease and anemia more often than ENG patients. Compared to ACVRL1, those with ENG variants are younger at diagnosis and show pulmonary and cerebral AVMs more frequently.
Hereditary hemorrhagic telangiectasia (HHT) is characterized by telangiectasia and larger arteriovenous malformations (AVM) in different organs. Mucocutaneous telangiectasia can bleed and cause ...stigmatization, but the best treatment approach has not been defined yet. The aim of the study was to evaluate the efficacy and safety of dual pulsed dye laser and neodymium: yttrium–aluminum–garnet (PDL‐Nd:YAG) laser treatment for mucocutaneous telangiectasia in HHT patients. It is a retrospective case series, where clinical files of all HHT patients treated with PDL‐Nd:YAG laser at our Department between December 2010 and July 2019 were reviewed. Demographic, clinical, and treatment characteristics were recorded. The severity and degree of improvement were evaluated by three blinded examiners scoring pretreatment and posttreatment pictures on a 5‐point scale. Patient satisfaction and procedure pain were assessed using an ordinal scale (0–10). Forty‐three treatment areas from 26 patients were analyzed. Lesions were predominantly located on the lower lip and cheeks. The median number of laser sessions per patient was 3 (interquartile range IQR 2–4). The median global severity score at baseline was 2 and became 0 at endpoint (p < 0.0001), with a median improvement rate of 4 (IQR 3–4). All patients reported a high degree of satisfaction (median 9) and tolerable pain (median 5). In conclusion, dual PDL‐Nd: YAG laser is a convenient, safe, and effective treatment option for mucocutaneous telangiectasia in HHT patients.
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