Regulation of IFN-γ by IL-13 dictates susceptibility to secondary postinfluenza MRSA pneumonia.

Superinfection in mice at day 7 postinfluenza infection exacerbates bacterial pneumonia at least in part via downstream effects of increased IFN-γ signaling. Here we show that up to 3 days postinfluenza infection, mice have reduced susceptibility to superinfection with methicillin-resistant Staphylococcus aureus (MRSA), but that superinfection during that time exacerbated influenza disease. This was due to IL-13 signaling that was advantageous for resolving MRSA infection via inhibition of IFN-γ, but was detrimental to the clearance of influenza virus. However, if superinfection did not occur until the near resolution of influenza infection (day 7), IL-13 signaling was inhibited, at least in part by upregulation of IL-13 decoy receptor (IL-13Rα2), which in turn caused increases in IFN-γ signaling and exacerbation of bacterial infection. Understanding these cytokine sequelae is critical to development of immunotherapies for influenza-MRSA coinfection since perturbations of these sequelae at the wrong time could increase susceptibility to MRSA and/or influenza.

Thrombelastography-Based Dosing of Enoxaparin for Thromboprophylaxis in Trauma and Surgical Patients: A Randomized Clinical Trial.

Importance: Prophylactic enoxaparin is used to prevent venous thromboembolism (VTE) in surgical and trauma patients. However, VTE remains an important source of morbidity and mortality, potentially exacerbated by antithrombin III or anti-Factor Xa deficiencies and missed enoxaparin doses. Recent data suggest that a difference in reaction time (time to initial fibrin formation) greater than 1 minute between heparinase and standard thrombelastogram (TEG) is associated with a decreased risk of VTE. Objective: To evaluate the effectiveness of TEG-adjusted prophylactic enoxaparin dosing among trauma and surgical patients. Design, Setting, and Participants: This randomized clinical trial, conducted from October 2012 to May 2015, compared standard dosing (30 mg twice daily) with TEG-adjusted enoxaparin dosing (35 mg twice daily) for 185 surgical and trauma patients screened for VTE at 3 level I trauma centers in the United States. Main Outcomes and Measures: The incidence of VTE, bleeding complications, anti-Factor Xa deficiency, and antithrombin III deficiency. Results: Of the 185 trial participants, 89 were randomized to the control group (median age, 44.0 years; 55.1% male) and 96 to the intervention group (median age, 48.5 years; 74.0% male). Patients in the intervention group received a higher median enoxaparin dose than control patients (35 mg vs 30 mg twice daily; P < .001). Anti-Factor Xa levels in intervention patients were not higher than levels in control patients until day 6 (0.4 U/mL vs 0.21 U/mL; P < .001). Only 22 patients (11.9%) achieved a difference in reaction time greater than 1 minute, which was similar between the control and intervention groups (10.4% vs 13.5%; P = .68). The time to enoxaparin initiation was similar between the control and intervention groups (median [range] days, 1.0 [0.0-2.0] vs 1.0 [1.0-2.0]; P = .39), and the number of patients who missed at least 1 dose was also similar (43 [48.3%] vs 54 [56.3%]; P = .30). Rates of VTE (6 [6.7%] vs 6 [6.3%]; P > .99) were similar, but the difference in bleeding complications (5 [5.6%] vs 13 [13.5%]; P = .08) was not statistically significant. Antithrombin III and anti-Factor Xa deficiencies and hypercoagulable TEG parameters, including elevated coagulation index (>3), maximum amplitude (>74 mm), and G value (>12.4 dynes/cm2), were prevalent in both groups. Identified risk factors for VTE included older age (61.0 years vs 46.0 years; P = .04), higher body mass index (calculated as weight in kilograms divided by height in meters squared; 30.6 vs 27.1; P = .03), increased Acute Physiology and Chronic Health Evaluation II score (8.5 vs 7.0; P = .03), and increased percentage of missed doses per patient (14.8% vs 2.5%; P = .05). Conclusions and Relevance: The incidence of VTE was low and similar between groups; however, few patients achieved a difference in reaction time greater than 1 minute. Antithrombin III deficiencies and hypercoagulable TEG parameters were prevalent among patients with VTE. Low VTE incidence may be due to an early time to enoxaparin initiation and an overall healthier and less severely injured study population than previously reported. Trial Registration: clinicaltrials.gov Identifier: NCT00990236.