Background: Pulmonary hypercoagulopathy is intrinsic to inhalation trauma. Nebulized heparin could theoretically be beneficial in patients with inhalation injury, but current data are conflicting. We aimed to investigate the safety, feasibility, and effectiveness of nebulized heparin. Methods: International multicenter, double-blind, placebo-controlled randomized clinical trial in specialized burn care centers. Adult patients with inhalation trauma received nebulizations of unfractionated heparin (25,000 international unit (IU), 5 mL) or placebo (0.9% NaCl, 5 mL) every four hours for 14 days or until extubation. The primary outcome was the number of ventilator-free days at day 28 post-admission. Here, we report on the secondary outcomes related to safety and feasibility. Results: The study was prematurely stopped after inclusion of 13 patients (heparin N = 7, placebo N = 6) due to low recruitment and high costs associated with the trial medication. Therefore, no analyses on effectiveness were performed. In the heparin group, serious respiratory problems occurred due to saturation of the expiratory filter following nebulizations. In total, 129 out of 427 scheduled nebulizations were withheld in the heparin group (in 3 patients) and 45 out of 299 scheduled nebulizations were withheld in the placebo group (in 2 patients). Blood-stained sputum or expected increased bleeding risks were the most frequent reasons to withhold nebulizations. Conclusion: In this prematurely stopped trial, we encountered important safety and feasibility issues related to frequent heparin nebulizations in burn patients with inhalation trauma. This should be taken into account when heparin nebulizations are considered in these patients.

Secondary bacterial pneumonia after influenza infection can cause severe disease with a high mortality. Recently, a new group 2 influenza A antibody (AT10_002) has been developed, which binds to multiple H3 and H7 subtypes. In a mouse model of primary influenza infection, treatment with AT10_002 as a fusion antibody protects against lethal infection, and reduces loss of bodyweight [1]. We hypothesized that treatment with AT10_002 reduces weight loss, lung injury and bacterial outgrowth, in a mouse model of viral infection followed by secondary pneumococcal infection.

The prevalence of viral respiratory tract infections in critically ill patients is uncertain, as well as the optimal diagnostic method to detect these. The aim of this study was to assess the prevalence of viral respiratory tract infections in mechanically ventilated patients, in both the upper and lower respiratory tract.

The prevalence of viral respiratory infections in critically ill patients on the ICU and the diagnostic potential of tracheal aspirate sampling are unknown. For this study, the prevalence of respiratory viruses was investigated in intubated patients by simultaneous sampling of nasopharynx and tracheal aspirate.

. Enhanced intrapulmonary fibrin deposition as a result of abnormal broncho-alveolar fibrin turnover is a hallmark of acute respiratory distress syndrome (ARDS), pneumonia and ventilator-induced lung injury (VILI), and is important to the pathogenesis of these conditions. The mechanisms that contribute to alveolar coagulopathy are localized tissue factor-mediated thrombin generation, impaired activity of natural coagulation inhibitors and depression of bronchoalveolar urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. There is an intense and bidirectional interaction between coagulation and inflammatory pathways in the bronchoalveolar compartment. Systemic or local administration of anticoagulant agents (including activated protein C, antithrombin and heparin) and profibrinolytic agents (such as plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti-inflammatory effects of these therapies in ARDS and pneumonia.

Background: Asthma exacerbations are frequently triggered by rhinovirus infections. Asthma itself is associated with activated coagulation and increased risk of venous thromboembolism1 and also respiratory viruses may activate hemostasis. Vice versa, a prothrombotic state in the lung can also induce or aggravate pulmonary inflammation. Aim: To determine whether rhinovirus infection and asthmatic airway inflammation act on the local and systemic hemostatic balance in patients in vivo. Methods: In a two-groups parallel study design 28 volunteers (14 patients with mild asthma (seven females, 19-26 years) and 14 healthy controls (13 females, 19-31 years)) were experimentalliy infected with low-dose rhinovirus serotype 16 (RV16). Patients with mild asthma were stable after discontinuation of their asthma medication 2 weeks prior to RV16 inoculation. Venous plasma and bronchoalveolar lavage fluid (BAL fluid) were obtained 1 day before and 6 days after rhinovirus challange to evaluate several key markers of coagulation activation in plasma and BAL fluid, as well as the coagulant features of microparticles in BAL fluid. Thrombin-antithrombin complexes (TATc), von Willebrand factor (vWF), Plasmin-antiplasmin complexes (PAP), Plasminogen activator inhibitor type-1 (PAI-1), and eosinophil cationic protein (ECP) in plasma and BAL fluid were measured by immunoassay. Endogenous thrombin potential (ETP) was analysed using the Calibrated Automated Thrombogram® and tissue factor bearing microparticles, measured by fibrin generation test (FGT). Eosinophils were counted on cytospin preparations. Comparisons and correlations were performed by non-parametric testing. Results: In plasma, RV16 challange resulted in increased PAI-1 levels in patients with asthma after viral infection (26.5 ng/mL in patients with astma vs. 10.0 ng/mL in healthy controls, P = 0.01) and decreased PAP levels (318 vs. 534 ng/mL resp., P = 0.04). Changes in PAI-1 levels were significantly elevated in asthma than in control subjects (3.0 vs. -3.5 ng/L respectively, P = 0.024), while changes in TATc, D-dimer, vWF and ETP did not differ between both groups. In BAL fluid, the FGT shortened after viral infection in asthma (t = -1 day: 689s vs. t = 6 days: 516 s; P = 0.011), but not in healthy controls (t = -1 day: 695s vs. t = 6 days: 672 s; P = 0.79). The changes in TATc and PAP did not differ between both groups and vWF, D-dimer and PAI-1 were below the detection limit. Both FGT and TATc in BAL fluid correlated (Spearman) with eosinophil counts and ECP (r = -0.583 and -0.682 resp. for FGT and r = 0.535 and 0.619 resp. for TATc, all P <0.01) Conclusion: Experimental rhinovirus infection induces procoagulant changes in patients with asthma systemically through PAI-1 and in the airways by TF-bearing microparticles. This did not lead to changes in global assays of hemostasis, probably due to the relatively mild infection in patients with mild to intermittent asthma. In the airways, microparticle-associated procoagulant changes are associated with eosinophilic inflammation, suggesting that virus infection and eosinophilic inflammation both act on the hemostatic (dis)balance during asthma exacerbations.

Influenza-related mortality is often caused by secondary bacterial pneumonia. We have previously shown that the tryptophan-catabolizing enzyme indoleamine-2,3-dioxygenase (IDO) critically impairs host defense against secondary bacterial pneumonia [1]. Since inhibition of IDO resulted in increased neutrophil numbers during primary viral infection, we hypothesized that tryptophan degradation and/or the generation of downstream metabolites induces neutrophil apoptosis. In the present study we aimed to investigate the impact of IDO-mediated tryptophan metabolism on neutrophil apoptosis in vitro and in vivo.