Pulmonary and Nonpulmonary Sepsis Differentially Modulate Lung Immunity toward Secondary Bacterial Pneumonia: A Critical Role for Alveolar Macrophages.

Clinical observations suggest that the source of primary infection accounts for a major determinant of further nosocomial pneumonia in critically ill patients with sepsis. Here we addressed the impact of primary nonpulmonary or pulmonary septic insults on lung immunity using relevant double-hit animal models. C57BL/6J mice were first subjected to polymicrobial peritonitis induced by cecal ligation and puncture (CLP) or bacterial pneumonia induced by intratracheal challenge with Escherichia coli. Seven days later, postseptic mice received ab intratracheal challenge with Pseudomonas aeruginosa. Compared with controls, post-CLP mice became highly susceptible to P. aeruginosa pneumonia, as demonstrated by defective lung bacterial clearance and increased mortality rate. In contrast, all postpneumonia mice survived the P. aeruginosa challenge and even exhibited improved bacterial clearance. Nonpulmonary and pulmonary sepsis differentially modulated the amounts and some important immune functions of alveolar macrophages. Additionally, we observed a Toll-like receptor 2 (TLR2)-dependent increase in regulatory T cells (Tregs) in lungs from post-CLP mice. Antibody-mediated Treg depletion restored the numbers and functions of alveolar macrophages in post-CLP mice. Furthermore, post-CLP TLR2-deficient mice were found resistant to secondary P. aeruginosa pneumonia. In conclusion, polymicrobial peritonitis and bacterial pneumonia conferred susceptibility or resistance to secondary gram-negative pulmonary infection, respectively. Immune patterns in post-CLP lungs argue for a TLR2-dependent cross-talk between Tregs and alveolar macrophages as an important regulatory mechanism in postseptic lung defense.

Effects of Prone Positioning on Respiratory Mechanics and Oxygenation in Critically Ill Patients With COVID-19 Requiring Venovenous Extracorporeal Membrane Oxygenation.

BACKGROUND: The effect of prone positioning (PP) on respiratory mechanics remains uncertain in patients with severe acute respiratory distress syndrome (ARDS) requiring venovenous extracorporeal membrane oxygenation (VV-ECMO). METHODS: We prospectively analyzed the effects of PP on respiratory mechanics from continuous data with over a thousand time points during 16-h PP sessions in patients with COVID-19 and ARDS under VV-ECMO conditions. The evolution of respiratory mechanical and oxygenation parameters during the PP sessions was evaluated by dividing each PP session into four time quartiles: first quartile: 0-4 h, second quartile: 4-8 h, third quartile: 8-12 h, and fourth quartile: 12-16 h. RESULTS: Overall, 38 PP sessions were performed in 10 patients, with 3 [2-5] PP sessions per patient. Seven (70%) patients were responders to at least one PP session. PP significantly increased the PaO2/FiO2 ratio by 14 ± 21% and compliance by 8 ± 15%, and significantly decreased the oxygenation index by 13 ± 18% and driving pressure by 8 ± 12%. The effects of PP on respiratory mechanics but not on oxygenation persisted after supine repositioning. PP-induced changes in different respiratory mechanical parameters and oxygenation started as early as the first-time quartile, without any difference in PP-induced changes among the different time quartiles. PP-induced changes in driving pressure (-14 ± 14 vs. -6 ± 10%, p = 0.04) and mechanical power (-11 ± 13 vs. -0.1 ± 12%, p = 0.02) were significantly higher in responders (increase in PaO2/FiO2 ratio > 20%) than in non-responder patients. CONCLUSIONS: In patients with COVID-19 and severe ARDS, PP under VV-ECMO conditions improved the respiratory mechanical and oxygenation parameters, and the effects of PP on respiratory mechanics persisted after supine repositioning.