Prevention of serious infections in hereditary hemorrhagic telangiectasia: roles for prophylactic antibiotics, the pulmonary capillaries-but not vaccination

High definition analyses of single cohort, whole genome sequencing data provides a direct route to defining sub-phenotypes and personalising medicine

“…Notably, in this group of patients ‘selected’ purely due to the absence of a known family HHT genotype and attendance at the UK reference centre during recruitment to the 100,000 Genomes Project, 36/104 (35%) were categorised with severe hemorrhage, 29/104 (28%) with disproportionate anemia, and 8 (8%) had venous thromboembolic disease. Deep-seated infections affected 13/104 (13%): 10 were in association with concurrent and presumed causative pulmonary AVMs (cerebral and spinal abscesses, spinal discitis, and septic arthritis, due to polymicrobial flora, particularly anaerobic and aerobic commensals of the gastrointestinal and periodontal spaces, as described [19-21]).…”

“…Similarly, the observed enrichment of deleterious erythrocyte membrane gene variants in patients experiencing severe deep-seated infection warrants further study in the setting of the common (daily) bacteremias that can seed abscesses by currently unknown mechanisms. [19,48] Mechanistic examination of whether erythrocyte membrane changes modify macrophage opsonisation rates[49] may influence clinical risk assessments, resulting in extension or restriction of HHT patient cohorts for whom prophylactic antibiotics are recommended. [19-22] Notably, in both study cohort and GnomAD 3.1 populations, the greatest proportion of variants were for the red cell membrane category, where relevance to evolutionary fitness could be postulated.…”

“…[19,48] Mechanistic examination of whether erythrocyte membrane changes modify macrophage opsonisation rates[49] may influence clinical risk assessments, resulting in extension or restriction of HHT patient cohorts for whom prophylactic antibiotics are recommended. [19-22] Notably, in both study cohort and GnomAD 3.1 populations, the greatest proportion of variants were for the red cell membrane category, where relevance to evolutionary fitness could be postulated.…”

“…[16] Counterintuitively, age-adjusted incidence rates of venous thromboembolism (VTE) are several-fold higher in HHT than in the general population,[17,18] while HHT-affected individuals who have VTE are more likely to have a major deep-seated infection that is a particular risk when venous blood can evade pulmonary capillary processing by passage through right-to-left shunts provided by pulmonary AVMs. [19-22] Socio-environmental exposures can aggravate HHT, as detailed elsewhere,[3,16,17,20,23-30] but only a proportion of patients with these added “risk factors” develop the respective clinical phenotypes. There are hints of familial predispositions [16,17,20,23,24,27] supported by case series where occasional individuals had coincidental non-HHT genetic contributors to their complications.…”

Life-Threatening Intraventricular Rupture of Brain Abscess in a Patient With Undiagnosed Hereditary Hemorrhagic Telangiectasia

“…The propensity for neurological manifestations increases with larger sized feeding arteries (>3 mm) and with increasing number of PAVMs [ 7 ]. Several proposed mechanisms of BA formation secondary to HHT exist; however, the majority implicate the pulmonary capillaries as either a crucial mechanical filter of septic emboli or being a major contributor to the body’s adaptive immune system attributable to the presence of cytokines, macrophages, and other immunoregulators in close proximity to the capillaries [ 8 , 9 ]. It could also be hypothesized that gastrointestinal and hepatic AVMs would allow a greater baseline translocation of gut bacteria into the portal system through the inferior vena cava, ultimately entering the right heart circulation, and contributing to BA formation in the presence of PAVMs.…”