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.

A retrospective review of outcomes using a fecal management system in acute care patients.

Intrarectal catheters (ie, large bore, soft, silicone catheters with a retention balloon intended to hold the catheter within the rectum and create a seal) may be used for the temporary management of diarrhea and fecal incontinence, to protect perineal skin and wounds, and to prevent cross infection. To evaluate reasons for insertion, duration, and outcomes of use, a retrospective study of patients who used a fecal management system (FMS) in an acute care, non-ICU setting was conducted at a tertiary-referral hospital between August 2005 and November 2012. Reasons for FMS implementation, patient demographics, history, length of FMS use, reason for removal or reinsertion, and results/complications data were abstracted from the medical records. Continuous variables were analyzed for mean, range, and standard deviation, and statistical significance was assessed using unpaired t-tests; categorical variables were expressed as counts and percentages, with significance assessed using chi-squared tests. The records of 50 patients (29 women, 21 men; average age 63 [range 21-90] years) who had a total of 69 study FMS inserted (mean 1.4 FMS) were available and included in the study. The majority (43) had their FMS inserted for <29 days (mean 17.4 days, range 1-74). Indications for use included diarrhea (31; 62%); burn injury (10; 20%); pressure ulcer (7; 14%); and necrotizing fasciitis (2; 4%). Most patients (37, 74%) experienced no complications; 7 (14%) had their retention balloon overinflated but suffered no injury to the rectal mucosa; 4 (8%) experienced temporary anal atony; and 2 (4%) suffered excessive leak of stool around the device. The complication rate for longer duration use (17+ days) was significantly higher than in the shorter duration (<17 days) group (44% and 15%, respectively, P = 0.024). The longer the FMS was in place, the more likely sphincter tone would be compromised. No serious adverse events - eg, fistula or mucosal necrosis - occurred, but overinflation of the balloon was noted in 7 patients. Overall, these results suggest intrarectal catheters such as the FMS are safe and effectively contained fecal material when used judiciously and checked regularly. Further prospective studies of the device in relation to its continuing safety, efficacy, and cost effectiveness, together with educational support requirements and policy/ procedure development, may lead to greater acceptance of its increased use in general hospital wards. Comparison studies involving other intrarectal catheters examining aspects such as safety, ease of insertion, and patient comfort also are warranted.