Trikafta Rescues CFTR and Lowers Monocyte P2X7R-induced Inflammasome Activation in Cystic Fibrosis.

Rationale: Cystic fibrosis (CF) is caused by mutations in the CFTR (CF transmembrane conductance regulator) gene and is characterized by sustained inflammation. ATP triggers IL-1ß secretion via P2X7R (P2X7 receptor) and activation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome. Objectives: To explore the effect of the CFTR modulator elexacaftor/tezacaftor/ivacaftor (Trikafta) on CFTR expression and the ATP/P2X7R signaling axis in monocytes and on circulating proinflammatory markers. Methods: Inflammatory mediators were detected in blood from 42 patients with CF before and after 3 months of Trikafta therapy. Markers of inflammasome activation and IL-1ß secretion were measured in monocytes before and after stimulation with ATP and LPS, in the presence or absence of the P2X7R inhibitor A438079. Measurements and Main Results: P2X7R is overexpressed in CF monocytes, and receptor inhibition decreased NLRP3 expression, caspase-1 activation, and IL-1ß secretion. In vitro and in vivo, P2X7R expression is regulated by CFTR function and intracellular chloride (Cl-) levels. Trikafta therapy restored CFTR expression yet decreased P2X7R in CF monocytes, resulting in normalized Cl- and potassium efflux, and reduced intracellular calcium levels. CFTR modulator therapy decreased circulating levels of ATP and LPS and reduced inflammasome activation and IL-1ß secretion. Conclusions: P2X7R expression is regulated by intracellular Cl- levels and in CF monocytes promotes inflammasome activation. Trikafta therapy significantly increased CFTR protein expression and reduced ATP/P2X7R-induced inflammasome activation. P2X7R may therefore be a promising target for reducing inflammation in patients with CF who are noneligible for Trikafta or other CFTR modulator therapy.

Human cercarial dermatitis (HCD) in the UK: an overlooked and under-reported nuisance?

BACKGROUND: Human cercarial dermatitis (HCD) is a clinical disease typically caused by skin-penetrative larvae of avian schistosomes. Its geographical epidemiology is firmly tied with that of infected freshwater intermediate snail hosts. To better understand the current distribution of HCD and its level of nuisance in the UK, we undertook a systematic literature review. METHODS: Following PRIMSA guidelines, PubMed and Scopus databases were searched with keywords "human cercarial dermatitis" OR "swimmer's itch" AND "United Kingdom". Articles about imported cases of HCD, or HCD outside the UK, were not formally included. RESULTS: A total of 30 articles were initially identified. A further two were gained by inspection of all citations. After screening, eight publications were analysed where the location, number of cases and putative avian schistosome species incriminated were tabulated. HCD is mainly found in the south of England, though gaps in evidence and reporting remain across the UK. CONCLUSIONS: Despite its noted recent rise in open water swimmers, published literature on HCD across the UK is sparse; this condition is both overlooked and under-reported. We therefore recommend establishing a national database that raises awareness and encourages self-reporting of this nuisance disease.