Takuma Isshiki

Recombinant human soluble thrombomodulin treatment for acute exacerbation of idiopathic pulmonary fibrosis: a retrospective study.

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) can be fatal, and abnormalities in the coagulation system of patients with AE-IPF have been reported. Recombinant human soluble thrombomodulin (rhTM) forms a complex with thrombin to inactivate coagulation. It also inhibits high-mobility group box protein 1 (HMGB-1), which results in the suppression of inflammation. Objectives: We aimed to evaluate the effectiveness of rhTM for the treatment of AE-IPF. Methods: We retrospectively reviewed the medical records of 41 patients with AE-IPF who were admitted to our institution during the period 2006-2013. The clinical features and outcomes of 16 patients treated with rhTM (rhTM group) were compared with those of 25 patients treated with conventional therapy (control group). Patients were treated with corticosteroid (CS) pulse therapy for 3 days, followed by maintenance treatment with a tapered dose of CS. Patients in the rhTM group also received rhTM (0.06 mg/kg/day) for 6 days as an initial treatment, in combination with CS. Results: Except for D-dimer level, there were no significant differences in the baseline characteristics of the 2 groups. When compared with the control group, the rhTM group had a significantly higher survival rate at 3 months (40 vs. 69%, p = 0.048). A univariate Cox proportional hazards regression model showed that the predictive factors for survival were lactate dehydrogenase level and rhTM treatment. Regarding adverse events, 1 patient in the rhTM group developed mild bleeding events. Conclusion: rhTM as an add-on to conventional treatment may improve survival in patients with AE-IPF.

ICOS promotes group 2 innate lymphoid cell activation in lungs

Group 2 innate lymphoid cells (ILC2s) are newly identified, potent producers of type 2 cytokines, such as IL-5 and IL-13, and contribute to the development of allergic lung inflammation induced by cysteine proteases. Although it has been shown that inducible costimulator (ICOS), a costimulatory molecule, is expressed on ILC2s, the role of ICOS in ILC2 responses is largely unknown. In the present study, we investigated whether the interaction of ICOS with its ligand B7-related protein-1 (B7RP-1) can promote ILC2 activation. Cytokine production in ILC2s purified from mouse lungs was significantly increased by coculture with B7RP-1-transfected cells, and increased cytokine production was inhibited by monoclonal antibody-mediated blocking of the ICOS/B7RP-1 interaction. ILC2 expansion and eosinophil influx induced by papain, a cysteine protease antigen, in mouse lungs were significantly abrogated by blocking the ICOS/B7RP-1 interaction. Dendritic cells (DCs) in the lungs expressed B7RP-1 and the number of DCs markedly increased with papain administration. B7RP-1 expression on lung DCs was reduced after papain administration. This downregulation of B7RP-1 expression may be an indication of ICOS/B7RP-1 binding. These results indicate that ILC2s might interact with B7RP-1-expressing DCs in allergic inflammatory lung, and ICOS signaling can positively regulate the protease allergen-induced ILC2 activation followed by eosinophil infiltration into the lungs.

Primary Antiphospholipid Syndrome Associated with Diffuse Alveolar Hemorrhage and Pulmonary Thromboembolism

Antiphospholipid syndrome (APS) is clinically characterized by arterial or venous thrombosis; however, non-thromboembolic lung manifestations, such as diffuse alveolar hemorrhage (DAH), have also been previously reported. DAH is relatively common in APS patients with systemic lupus erythematosus, although it is rare in primary APS. We encountered a 78-year-old man who presented with hemoptysis and dyspnea. Chest CT showed diffuse ground-glass opacity with pulmonary thromboembolism. He was successfully treated with corticosteroids and heparin; however, DAH recurred after the corticosteroid treatment was stopped. The treatment was intricate due to the concurrent bleeding and thrombotic manifestations.

Recombinant human soluble thrombomodulin for acute exacerbation of idiopathic pulmonary fibrosis: A historically controlled study

BACKGROUND AND OBJECTIVES Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an often-fatal condition associated with endothelial damage and abnormalities of the coagulation system. Recombinant human soluble thrombomodulin (rhTM) has anti-inflammatory effects and regulates the coagulation pathway. This study evaluated the effectiveness of rhTM for the treatment of AE-IPF. METHODS This historically controlled study included 80 patients with AE-IPF admitted to our center during the period from 2006 through 2016. The clinical features and outcomes of 45 patients treated with rhTM (rhTM group) were compared with those of 35 patients who did not receive rhTM (control group). Patients in both groups were treated with corticosteroid pulse therapy for 3 days, followed by a tapered maintenance dose. Patients in the rhTM group also received rhTM (0.06mg/kg/day) for 6 days as initial treatment. RESULTS There were no significant differences in the baseline characteristics between the groups. The survival rate at 3 months was significantly higher in the rhTM group than in the control group (66.6% vs 37.1%; p = 0.003). Overall survival was also significantly better in the rhTM group than in the control group (p = 0.003). On univariate and multivariate analysis, the partial pressure of arterial oxygen / fractional of inspired concentration of oxygen (PaO2/FiO2) ratio and rhTM treatment were predictive factors for 3-month survival. Regarding adverse events, mild bleeding was observed in 1 patient in the rhTM group. CONCLUSION The addition of rhTM to conventional treatment improved overall survival in patients with AE-IPF.

Cutting Edge: Anti–TIM-3 Treatment Exacerbates Pulmonary Inflammation and Fibrosis in Mice

Promising results of immune checkpoint inhibitors have indicated the use of immunotherapy against malignant tumors. However, they cause serious side effects, including autoimmune diseases and pneumonitis. T cell Ig and mucin domain (TIM)-3 is a new candidate immune checkpoint molecule; however, the potential toxicity associated with anti–TIM-3 treatment is unknown. In this study, we investigated the pathological contribution of anti–TIM-3 mAb in a bleomycin-induced lung inflammation and fibrosis model. Anti–TIM-3–treated mice showed more severe inflammation and peribronchiolar fibrosis compared with control IgG-treated mice. Anti–TIM-3 mAb was associated with increased numbers of myofibroblasts, collagen deposition, and TGF-β1 production in lungs. TIM-3 expression was only detected on alveolar macrophages that protect against fibrosis by apoptotic cell clearance. Treatment with anti–TIM-3 mAb inhibited the phagocytic ability of alveolar macrophages in vivo, resulting in the defective clearance of apoptotic cells in lungs. In summary, anti–TIM-3 mAb treatment might cause pneumonitis and it should be used with caution in clinical settings.

Association of serum high-mobility group box protein 1 level with outcomes of acute exacerbation of idiopathic pulmonary fibrosis and fibrosing nonspecific interstitial pneumonia

Background and objective High-mobility group box 1 (HMGB1) protein is important in acute lung injury. However, the role of HMGB-1 in acute exacerbation of fibrosing interstitial pneumonia (AE-FIP) has not been adequately studied. Methods We prospectively measured serum HMGB1 level from disease onset to day 7 in 36 patients with AE-FIP6 patients had missing data because of early death (within 7 days). We then examined the association of HMGB1 level and outcome, and the associations of rhTM with HMGB1 level and outcome in 19 patients who were treated with rhTM (rhTM group) and 11 patients who were not (control group). Results Data from 36 AE-FIP patients (mean age, 73.5±6.7years) were analyzed. Serum HMGB1 level was significantly higher in patients with AE-FIP than in those with stable idiopathic pulmonary fibrosis (16.4±13.5 vs 5.7±2.6 ng/ml, respectively; p = 0.003). HMGB1 was significantly lower on day 7 than at AE-FIP onset in survivors (6.5±4.8 vs 14.7±12.9 ng/ml, respectively; p = 0.02) but not in nonsurvivors (14.6±10.5 vs 9.2±4.8 ng/ml, respectively; p = 0.08). Although HMGB1 level at day 7 was significantly lower after rhTM treatment than at AE-FIP onset (8.4±6.1 vs 15.2±12.5 ng/ml, respectively; p = 0.02), it did not significantly decrease in patients receiving treatments other than rhTM (11.3±11.3 vs 8.3±5.3 ng/ml, respectively; p = 0.37). Three-month survival was 60.0% in the rhTM group and 36.4% in the control group (p = 0.449). In multivariate analysis, a decrease in HMGB1 was a significant independent predictor of 3-month survival (Odds ratio, 12.4; p = 0.007). Conclusion rhTM lowers serum HMGB1 level and may improve survival after AE-FIP. HMGB1 may be a promising therapeutic target for AE-FIP.

The Activities of Daily Living after an Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Objective An acute exacerbation (AE) of idiopathic pulmonary disease (IPF) represents a life threatening condition. The activities of daily living (ADL) and quality of life of patients who survive an AE of IPF (AE-IPF) are often diminished. However, the association between AE-IPF and the ADL has yet to be evaluated. To evaluate the effect of AE-IPF on the ADL. Methods, Patients Patients treated for AE-IPF from 2010 to 2014 were identified. We retrospectively evaluated their ADL before and after AE-IPF using a modified Barthel index (BI) composed of 6 items. Results Twenty-eight of the 47 AE-IPF patients remained alive at 3 months after the onset of AE-IPF. The BI values of 22 survivors (79%) showed a full score (70 points) before the onset of AE-IPF. The evaluation of the BI scores at four weeks after the onset of AE-IPF revealed that the scores of 12 patients had decreased by >15 points and more than half of the survivors showed scores of <55. Logistic regression analyses showed that persistent hypeoxemia at 28 days after an AE, both at exertion (odds ratio, 24.20; 95% confidence interval, 2.42-242.31; p=0.009) and at rest (odds ratio, 21.00; 95% confidence interval, 2.05-215.18; p=0.010), was associated with a >15-point decrease in the BI score at 4 weeks after AE-IPF. Conclusion AE-IPF survivors with persistent hypoxemia showed diminished ADL after treatment.