Inefficient Toll-Like Receptor-4 Stimulation Enables Bordetella parapertussis to Avoid Host Immunity

The recognition of bacterial lipopolysaccharide (LPS) by host Toll-like receptor (TLR)4 is a crucial step in developing protective immunity against several gram negative bacterial pathogens. Bordetella bronchiseptica and B. pertussis stimulate robust TLR4 responses that are required to control the infection, but a close relative, B. parapertussis, poorly stimulates this receptor, and TLR4 deficiency does not affect its course of infection. This led us to hypothesize that inefficient TLR4 stimulation enables B. parapertussis to evade host immunity. In a mouse model of infection, B. parapertussis grew rapidly in the lungs, but no measurable increase in TLR4-mediated cytokine, chemokine, or leukocyte responses were observed over the first few days of infection. Delivery of a TLR4 stimulant in the inoculum resulted in a robust inflammatory response and a 10- to 100-fold reduction of B. parapertussis numbers. As we have previously shown, B. parapertussis grows efficiently during the first week of infection even in animals passively immunized with antibodies. We show that this evasion of antibody-mediated clearance is dependent on the lack of TLR4 stimulation by B. parapertussis as co-inoculation with a TLR4 agonist resulted in 10,000-fold lower B. parapertussis numbers on day 3 in antibody-treated wild type, but not TLR4-deficient, mice. Together, these results indicate that inefficient TLR4 stimulation by B. parapertussis enables it to avoid host immunity and grow to high numbers in the respiratory tract of naïve and immunized hosts

Endoscopic iatrogenic esophageal perforation and management: a retrospective outcome analysis in the modern era

Abstract Introduction Iatrogenic esophageal perforation (IEP) is a severe adverse event (AE) of upper endoscopy procedures (UEPs) associated with morbidity. Management has shifted from surgery to endotherapy with clip closure (CC), self-expanding metal stent (SEMS), and vacuum therapy (VT). Limited analyses measure outcomes during contemporary interventional endoscopy periods. Methods IEPs associated with EGD, upper EUS, small bowel enteroscopy (SBE), and ERCP at a 3-hospital academic center from January 2011 to December 2023 were identified retrospectively from a centralized AE database. Additional information was obtained from medical records. Statistical analysis was performed using Microsoft Excel and STATA. Results Thirty-two IEPs from 26 EGDs, 4 EUS, 1 SBE, and 1 ERCP were identified. IEPs occurred mostly after dilation (bougie N = 7; balloon, N = 5) or foreign body removal (N = 6). Most IEPs occurred in the lower esophagus (N = 10) or gastroesophageal junction (N = 8). Diagnosis was made at a median 2 h after the injury by endoscopy (N = 14), CT scan (N = 12), esophagram (N = 5), or x-ray (N = 1). Initial treatment included conservative therapy alone (N = 7), CC (N = 3), SEMS (N = 14), SEMS plus CC (N = 3), or surgery (N = 3). Eleven patients required additional treatment including repeat SEMS or adjustment (N = 4) or VT (N = 1). No surgical interventions were required after 2013. The median hospital stay was 3 days. Disposition included discharge to home (N = 25), long-term care facility (N = 2), 4 deaths (12.5% of IEPs), and 1 unknown. Conclusions IEPs are rare and occur throughout the esophagus after any UEP. The majority are recognized immediately and managed with endotherapy, or rarely, surgery today. These characteristics likely explain the low mortality in this study