SummaryIn a UK series, 37 of 445 (8.3%) patients with pulmonary arteriovenous malformations (PAVMs) experienced a cerebral abscess, often pre-PAVM diagnosis as first presentation. Odontogenic organisms, dental interventions, lower oxygen saturation, iron loading, and intravenous iron use were associated with abscess risk.

The abnormal vascular structures of hereditary hemorrhagic telangiectasia (HHT) often cause severe anemia due to recurrent hemorrhage, but HHT-causal genes do not predict the severity of hematological complications. We tested for chance inheritance and clinical associations of rare deleterious variants where loss-of-function causes bleeding or hemolytic disorders in the general population. In double-blinded analyses, all 104 HHT patients from a single reference centre recruited to the 100,000 Genomes Project were categorised on new MALO (more/as-expected/less/opposite) sub-phenotype severity scales, and whole genome sequencing data tested for high impact variants in 75 HHT-independent genes encoding coagulation factors, platelet, hemoglobin, erythrocyte enzyme and erythrocyte membrane constituents. Rare variants (all GnomAD allele frequencies <0.003) were identified in 56 (75%) of these 75 HHT-unrelated genes, and in 38/104 (36.5%) of the HHT patients. Likely deleteriousness assignments by Combined Annotation Dependent Depletion (CADD) scores >15 were supported by gene-level mutation significance cutoff (MSC) scores. CADD>15 variants were found for 1 in 10 patients within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to HHT vessels had more CADD-deleterious variants in platelet (Spearman ρ=0.25, p=0.008) and coagulation (Spearman ρ=0.21, p=0.024) genes. However, the HHT cohort had 60% fewer deleterious variants in platelet and coagulation genes than expected (Mann Whitney p=0.021). In conclusion, HHT patients commonly have rare variants in genes of relevance to their phenotype, offering new therapeutic targets and opportunities for informed, personalised medicine strategies.

Possession of a clinical or molecular disease label alters the context in which life-course events operate, but rarely explains the phenotypic variability observed by clinicians. Whole genome sequencing of unselected endothelial vasculopathy patients demonstrated more than a third had rare, likely deleterious variants in clinically-relevant genes unrelated to their vasculopathy (1 in 10 within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes). High erythrocyte membrane variant rates paralleled genomic damage and prevalence indices in the general population. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to their vasculopathy had more deleterious variants in platelet (Spearman ρ=0.25, p=0.008) and coagulation (Spearman ρ=0.21, p=0.024) genes. We conclude that rare diseases can provide insights for medicine beyond their primary pathophysiology, and propose a framework based on rare variants to inform interpretative approaches to accelerate clinical impact from whole genome sequencing.

IntroductionPatients with pulmonary arteriovenous malformations (PAVMs) usually have underlying hereditary haemorrhagic telangiectasia (HHT), when iron deficiency often develops due to recurrent nasal and gastrointestinal haemorrhage. Iron deficient PAVM/HHT patients have more ischaemic strokes and venous thromboemboli. However, recent UK data indicate that cerebral abscesse are more common in PAVM patients using intravenous iron and/or with high normal transferrin saturation index.1 Furthermore,~1 in 20 HHT patients report that iron treatments exacerbate their nosebleeds.2 The goal of this study was to evaluate clinical patterns of iron treatments in patients with PAVMs and HHT.MethodsIron, red cell and microbiology indices were evaluated as part of routine clinic assessments of patients with PAVMs and/or HHT. With ethical approval, all available patient datasets between 04/2015 and 07/2017 were recorded, categorised according to patient status, and analysed using STATA IC v13 (Statacorp, Texas).ResultsAt first assessment, 72 patients were using oral iron alone, and 21 were using intravenous iron +/-iron tablets. As noted in figure 1, intravenous iron users had lower haemoglobin concentrations than oral iron users, despite higher serum ferritin. None of the 16 selected PAVM patients evaluated had positive blood cultures in the clinic, or developed positive cultures following ex vivo iron treatments. Three of seven selected patients had low serum haptoglobin (0.32–0.36 g/L, reference range 0.5–2.4 g/L) potentially indicative of shortened intravascular red cell survival. 31 patients were commenced on oral or intravenous iron, or recommended a dose increase, but 56 were advised dose reduction. Post assessment, daily iron dosages tended to be lower (elemental iron content 14–130, median 35 mg/day) than at first assessment (elemental iron content 14–260, median 65 mg/day, p=0.08). In two patients, external clinicians advised that iron dose reduction led to at least temporary cessation of blood transfusion requirements. Reported nosebleed improvements were common, though may have also been due to intervening treatment of PAVMs.2 ConclusionsFurther study on the clinical efficacy and sequelae of iron treatments, and a more personalised approach to therapy, appears warranted in this patient group.ReferencesBoother, et al. Clin Infect Dis2017. doi:10.1093/cid/cix373Shovlin, et al. ERJ Open Res2016;2(2).00035–2016.

Introduction and objectivesIndividuals with pulmonary arteriovenous malformations (PAVMs), who often concurrently have hereditary haemorrhagic telangiectasia (HHT), are at increased risk of cerebral abscess, frequently resulting in life-changing deficits. Current aetiological consensus supports paradoxical emboli of periodontal origin, with preventative dental recommendations published in 2008.1 Limited knowledge is available to identify specifically at-risk individuals. This study aimed to characterise a cohort from 2005–2016; recognise potential precipitants; and compare results to an earlier published series.MethodsWith ethical approval, notes of patients newly presenting at a single institution between 2005–2016 were reviewed to collect cohort characteristics. GraphPad Prism was used to calculate descriptive statistics, and to perform Mann-Whitney and Chi-squared statistical tests for comparison between the two cohorts.ResultsOf 488 new patients with PAVMs, 33 (6.8%) had cerebral abscesses. 21 were female (63.6%), 12 male. The rate corrected for ascertainment bias was 3.8%. The median age at abscess was 46 years (range 13–69). The median oxygen saturation (SaO2) was 90.75% (range 70–97.5%), with 9 individuals having respiratory symptoms. There were 29 confirmed HHT diagnoses (87.9%). The median largest feeding artery diameter was 5mm, and for 5 individuals, all feeding arteries had diameter ≤3 mm. In total, 19 (57.6%) had residual PAVMs too small for embolization.Organisms identified (Table 1) suggest periodontal origin; 16 individuals (48.5%) had poor dental hygiene and 9 (27.3%) had dental events as abscess precipitants. Interestingly, 4 individuals had abscesses whilst on holiday abroad. 5 individuals reported worsening migraines and 2 individuals had increased seizure frequency ≤ 3 months pre-abscess.Within the non-overlapping 1999–2005 cohort, there were 28/219 abscesses (12.8%, 9.05% adjusting for ascertainment bias). Compared to the later series, similar proportions of abscesses occurred prior to PAVM diagnosis (18/28 (64.3%) vs. 24/33 (72.3%)). Proportionally more males were affected (57.1%). No other significant differences were found for age, SaO2, feeding artery diameter, presence of respiratory symptoms, or HHT (all p values >0.12).ConclusionThe PAVM cohort remains at high risk of cerebral abscess. Scrupulous dental hygiene appears to remain paramount to reduce risk. The worsening migraines and abscess occurrence whilst abroad are unexpected findings recommended for further investigation.Abstract P35 Table 1A list of the bacterial organisms that were cultured from cerebral abscesses in the 2005–2016 cohortReferenceShovlin C, et al. Post-NICE 2008: Antibiotic prophylaxis prior to dental procedures for patients with pulmonary arteriovenous malformations (PAVMs) and hereditary haemorrhagic telangiectasia. Br Dent J 2008;205(10):531–3.