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In severe respiratory virus infections, including influenza, an exaggerated host immune response has been linked to the severe disease and death. Control of the overwhelming immune response is thus essential. Efforts with broad-spectrum immunosuppressive agents such as steroids are disappointing. A better understanding of host immune response using animal experimental system is required to avoid undesired outcome of experimental manipulation.Following severe influenza virus infection in influenza hemagglutinin antigen-specific transgenic mouse experimental model, step-wise evolving cells from a pool of naïve hemagglutinin-specific CD4Naïve CD4Origin of regulatory from the effector cells of LAG-3-marked Th1 immunity alleviates lung inflammation without impairment of virus eradication.

Background Mechanical power (MP) refers to the energy delivered by a ventilator to the respiratory system per unit of time. MP referenced to predicted body weight (PBW) or respiratory system compliance have better predictive value for mortality than MP alone in acute respiratory distress syndrome (ARDS). Our objective was to assess the potential impact of consecutive changes of MP on hospital mortality among ARDS patients receiving extracorporeal membrane oxygenation (ECMO). Methods We performed a retrospective analysis of patients with severe ARDS receiving ECMO in a tertiary care referral center in Taiwan between May 2006 and October 2015. Serial changes of MP during ECMO were recorded. Results A total of 152 patients with severe ARDS rescued with ECMO were analyzed. Overall hospital mortality was 53.3%. There were no significant differences between survivors and nonsurvivors in terms of baseline values of MP or other ventilator settings. Cox regression models demonstrated that mean MP alone, MP referenced to PBW, and MP referenced to compliance during the first 3 days of ECMO were all independently associated with hospital mortality. Higher MP referenced to compliance (HR 2.289 [95% CI 1.214–4.314], p = 0.010) was associated with a higher risk of death than MP itself (HR 1.060 [95% CI 1.018–1.104], p = 0.005) or MP referenced to PBW (HR 1.004 [95% CI 1.002–1.007], p 14.4 J/min) during the first 3 days of ECMO was significantly higher than that of patients with low MP (≦ 14.4 J/min) (70.7% vs. 46.8%, p = 0.004), and the 90-day hospital mortality of patients with high MP referenced to compliance (> 0.53 J/min/ml/cm H2O) during the first 3 days of ECMO was significantly higher than that of patients with low MP referenced to compliance (≦ 0.53 J/min/ml/cm H2O) (63.6% vs. 29.7%, p Conclusions MP during the first 3 days of ECMO was the only ventilatory variable independently associated with 90-day hospital mortality, and MP referenced to compliance during ECMO was more predictive for mortality than was MP alone.

The high mortality rate of patients with severe acute respiratory distress syndrome (ARDS) warrants aggressive clinical intervention. Extracorporeal membrane oxygenation (ECMO) is a salvage therapy for life-threatening hypoxemia. Randomized controlled trials of ECMO for severe ARDS comprise a number of ethical and methodological issues. Therefore, indications and optimal timing for implementation of ECMO, and predictive risk factors for outcomes have not been adequately investigated. We performed propensity score matching to match ECMO-supported and non-ECMO-supported patients at 48 h after ARDS onset for comparisons based on clinical outcomes and hospital mortality. A total of 280 severe ARDS patients were included, and propensity score matching of 87 matched pairs revealed that the 90-d hospital mortality rate was 56.3% in the ECMO group and 74.7% in the non-ECMO group (p = 0.028). Subgroup analysis revealed that greater severity of ARDS, higher airway pressure, or a higher Sequential Organ Failure Assessment score tended to benefit from ECMO treatment in terms of survival. Multivariate logistic regression revealed that hospital mortality was significantly lower among patients who received ECMO than among those who did not. Our findings suggested that early initiation of ECMO (within 48 h) may increase the likelihood of survival for patients with severe ARDS.

Additional file 1: Table S1. Ventilator settings before and during the first 3 days of ECMO between the earlier years and later years.

Additional file 2: Table S2. Ventilator settings parameters during the first 3 days of ECMO.

Additional file 4: Table S4. Cox proportional hazard regression analysis of factors associated with 90-day hospital mortality.

Additional file 3: Table S3. Cox proportional hazard regression analysis of factors associated with 90-day hospital mortality.

Patients with sepsis frequently require mechanical ventilation (MV) to survive. However, MV has been shown to induce the production of proinflammatory cytokines, causing ventilator-induced lung injury (VILI). It has been demonstrated that hypoxia-inducible factor (HIF)-1&alpha, plays a crucial role in inducing both apoptotic and inflammatory processes. Low-molecular-weight heparin (LMWH) has been shown to have anti-inflammatory activities. However, the effects of HIF-1&alpha, and LMWH on sepsis-related acute lung injury (ALI) have not been fully delineated. We hypothesized that LMWH would reduce lung injury, production of free radicals and epithelial apoptosis through the HIF-1&alpha, pathway. Male C57BL/6 mice were exposed to 6-mL/kg or 30-mL/kg MV for 5 h. Enoxaparin, 4 mg/kg, was administered subcutaneously 30 min before MV. We observed that MV with endotoxemia induced microvascular permeability, interleukin-6, tumor necrosis factor-&alpha, macrophage inflammatory protein-2 and vascular endothelial growth factor protein production, neutrophil infiltration, oxidative loads, HIF-1&alpha, mRNA activation, expression, bronchial epithelial apoptosis, and decreased respiratory function in mice (p &lt, 0.05). Endotoxin-induced augmentation of VILI and epithelial apoptosis were reduced in the HIF-1&alpha, deficient mice and in the wild-type mice following enoxaparin administration (p &lt, 0.05). Our data suggest that enoxaparin reduces endotoxin-augmented MV-induced ALI, partially by inhibiting the HIF-1&alpha, pathway.

Supplemental material, Reviewer_2_v.1 for Reclassifying severity after 48 hours could better predict mortality in acute respiratory distress syndrome by Li-Chung Chiu, Shih-Wei Lin, Pi-Hua Liu, Li-Pang Chuang, Chih-Hao Chang, Chen-Yiu Hung, Shih-Hong Li, Chung-Shu Lee, Huang-Pin Wu, Chung-Chi Huang, Hsin-Hsien Li, Kuo-Chin Kao and Han-Chung Hu in Therapeutic Advances in Respiratory Disease

Supplemental material, Author_Response_2 for Reclassifying severity after 48 hours could better predict mortality in acute respiratory distress syndrome by Li-Chung Chiu, Shih-Wei Lin, Pi-Hua Liu, Li-Pang Chuang, Chih-Hao Chang, Chen-Yiu Hung, Shih-Hong Li, Chung-Shu Lee, Huang-Pin Wu, Chung-Chi Huang, Hsin-Hsien Li, Kuo-Chin Kao and Han-Chung Hu in Therapeutic Advances in Respiratory Disease

Background: Obstetric patients comprise a limited portion of intensive care unit patients, but they often present with unfamiliar conditions and exhibit the potential for catastrophic deterioration. This study evaluated the maternal and neonatal outcomes of respiratory failure during pregnancy. Methods: Information on 71 patients at >25 weeks gestation in the ICU with respiratory failure was recorded between 2009 and 2013. The characteristics and outcomes of mothers and fetuses were determined through a retrospective chart review and evaluated using Student's t test, chi-square test, and Fisher's exact test. Results: The leading causes of respiratory failure were postpartum hemorrhage and severe preeclampsia in the obstetric causes group and pneumonia in the nonobstetric causes group during pregnancy and the peripartum period. The non-obstetric causes group exhibited a higher incidence of acute respiratory distress syndrome and renal replacement therapy as well as requiring more ventilator days. The patients in the obstetric causes group showed significant improvement after delivery in the partial pressure of arterial oxygen to the fraction of inspired oxygen and peak inspiratory pressure decrease. Both groups exhibited high incidences of neonatal respiratory distress syndrome. Neonatal complications resulting from meconium aspiration syndrome (MAS) and sepsis were more common in the non-obstetric causes group; however, neurological development impairment was more common in the obstetric causes group. Conclusion: Obstetric cause was associated with longer ventilator free days and fewer episodes of ARDS after delivery. Neonatal complications resulting from different etiologies of respiratory failure were found to differ. Keywords: Acute respiratory distress syndrome, Neonatal, Obstetric, Outcome, Respiratory failure

Influenza hemagglutinin (HA)-specific T-Cell-Receptor (TCR) transgenic mice sustain the influenza virus infection of an inoculum size which is fatal in wild type mice. There is a prominent IL-17 response of the HA-specific TCR transgenic CD4+ T cells in late phase of infection in the transgenic mice. We have demonstrated that the late phase IL-17 response is a de novo response of naïve T cells under guidance of the Th1 cells with influenza viral neuraminidase-activated TGF-β. There is also a late phase up-regulation of epidermal growth factor receptor (EGFR) on the transgenic CD4+ T cells in the lungs. EGFR inhibition with Gefitinib resulted in impaired sustainability of the infection of the transgenic mice. They suffered from profound body weight loss and severe disease with significant mortality. IL-17-induced EGFR-mediated signaling cascade has been documented in skin stem cells that are involved in wound healing. We will further dissect the role of this cascade in alleviation of lung inflammation and recovery from the disease during the late phase of acute influenza virus infection.

The 6.5 CD4+ T cell receptor (TCR) transgenic mice have a monotonous CD4+ TCR which responds to the hemagglutinin (HA) antigen of PR8 influenza virus. Naive 6.5 CD4+ T cells adoptively transferred into wild type mice were activated by PR8 influenza virus with Th1 response. With PR8 influenza virus infection, all CD4+ T cells in 6.5 mice were activated and they were predominantly Th1 in phenotype at the early phase of infection and Th17 at the late phase. Th1 effector responses made infected mice sick and even succumb to death. The 6.5 mice were sicker at the early phase but recovered with better survival at last. IL-17KO 6.5 mice cannot display Th17 responses and lost the survival benefit as well. IL-17 supplement at the late phase of infection enhanced survival of wild type mice with PR8 influenza virus infection. With consecutive two adoptive transfers of naive 6.5 CD4+ T cells, 6.5 CD4+ T cells of the first transfer evolved into Th1 cells but 6.5 CD4+ T cells of the second transfer demonstrated a de novoTh17 response. Thymectomy or aging in 6.5 mice limited the thymic output of naive 6.5 CD4+ T cells and diminished the Th17 response. Viral neuraminidase activated TGF-β in the Th1 6.5 CD4+ T cells at the early phase. T-bet dominance was altered with excessive ROR-γt activation in the following responding 6.5 CD4+ T cells. They have substantial IL-17 with restrained IFN-γ production. We demonstrated a Th1 guided evolution of protective Th17 response in severe influenza.

Bacterial superinfection aggravates the disease of influenza virus infection. Streptococcus pneumoniae is a frequently encountered bacterial pathogen. Superinfection with neuraminidase (Nan) C deficient wild type pneumococcus, which expresses NanA and NanB only, suppressed antigen-specific anti-influenza immunity, with impaired viral clearance. There was augmented TGF-β activation in the lung-infiltrating influenza hemagglutinin (HA)-specific CD4+ T cells. Mice suffered from exacerbated disease and died with higher virus loads in the lung. We modified this wild type strain with NanC insertion. This modified strain expresses all neuraminidases A, B and C. Superinfection with this NanC inserted pneumococcus reverted the immune-suppressive effect of the wild type pneumococcus with NanA and NanB only. There were augmented inflammatory cytokines IFN-γ and TNF-α production and suppressed TGF-β activation in the lung-infiltrating influenza HA-specific CD4+ T cells. The pro-inflammatory response enhanced viral clearance. Even the virus eradication is enhanced, the mice actually suffered from even more severe disease. Our results demonstrated the important role of NanC-mediated inflammation in the disease of severe influenza with pneumococcal superinfection.

Naïve CD4+ T cells respond in influenza with T-bet expression, a transcription factor up-regulated with Th1 commitment. We report concomitant LAG-3 expression on these Th1 committed cells with evolution into regulatory T cells. LAG-3 expression increases with activation as revealed by CFSE cell division study. Cells with moderate LAG-3 expression produce IFN-γ and contribute to inflammation and disease. They no longer produce IFN-γ with higher LAG-3 expression upon further activation. High LAG-3 cells suppress and decouple effector function from the preserved proliferation of CD8+ T cells. They restrain inflammation with facilitated viral clearance and ameliorate the disease of severe influenza. Foxp-3+CD4+ T cells suppress both effector and proliferative responses with impaired viral clearance and they are less potent in disease amelioration. Principal component analysis of genome-wide expression further confirmed the stepwise evolution from effector to regulatory T cells. Regulatory genes are up-regulated progressively from LAG-3Neg to LAG-3Med and to LAG-3High cells.

Background: Disease severity may change in the first week after acute respiratory distress syndrome (ARDS) onset. The aim of this study was to evaluate whether the reclassification of disease severity after 48 h (i.e. day 3) of ARDS onset could help in predicting mortality and determine factors associated with ARDS persistence and mortality. Methods: We performed a secondary analysis of a 3-year prospective, observational cohort study of ARDS in a tertiary care referral center. Disease severity was reclassified after 48 h of enrollment, and cases that still fulfilled the Berlin criteria were regarded as nonresolving ARDS. Results: A total of 1034 ARDS patients were analyzed. Overall hospital mortality was 57.7% (56.7%, 57.5%, and 58.6% for patients with initial mild, moderate, and severe ARDS, respectively, p = 0.189). On day 3 reclassification, the hospital mortality rates were as follows: resolved (42.1%), mild (47.9%), moderate (62.4%), and severe ARDS (76.1%) ( p 2/FiO2, or higher positive end-expiratory pressure on day 1 were significantly associated with nonresolving ARDS on day 3. A Cox regression model with ARDS severity as a time-dependent covariate and competing risk analysis demonstrated that ARDS severity was independently associated with hospital mortality, and nonresolving ARDS had significantly increased hazard of death than resolved ARDS ( p Conclusions: Reclassification of disease severity after 48 h of ARDS onset could help to divide patients into subgroups with greater separation in terms of mortality. The reviews of this paper are available via the supplemental material section.

Background Extracorporeal membrane oxygenation (ECMO) can be used as a salvage therapy, but the effectiveness is controversial. The aim of this study was to investigate the predictors of mortality and the influence of organ dysfunction scores in severe acute respiratory distress syndrome (ARDS) patients treated with ECMO. Methods The records of adult severe ARDS patients receiving ECMO support from May 2006 to December 2011 at Chang Gung Memorial Hospital were retrospectively analyzed. Results The records of 65 patients with severe ARDS who received venovenous ECMO were analyzed. The hospital survival rate was 47.7%. Survivors were younger than nonsurvivors (41.4 ± 15.4 versus 54.1 ± 16.9 years, respectively; p = 0.002) and had shorter duration of mechanical ventilation before ECMO (52.7 ± 51.1 versus 112.1 ± 101.0 hours, respectively; p = 0.01). Before ECMO, Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, and Multiple Organ Dysfunction scores were significantly lower for survivors than for nonsurvivors. Mortality rate increased with rising predictive score. During 7 days of ECMO use, organ dysfunction scores were significantly lower for survivors than nonsurvivors. Conclusions Severe ARDS patients who are younger, have shorter duration of mechanical ventilation, and lower organ dysfunction scores before ECMO initiation have more favorable survival outcome. Early application of ECMO, especially if predictive score is below 2, may improve survival. Organ dysfunction scores before and during ECMO support are correlated with survival.

Background: Pneumonia is the leading risk factor of acute respiratory distress syndrome (ARDS). It is increasing studies in patients with pneumonia to reveal that coinfection with viral and bacterial infection can lead to poorer outcomes than no coinfection. This study evaluated the role of coinfection identified through bronchoalveolar lavage (BAL) examination on the outcomes of pneumonia-related ARDS. Methods: We performed a prospective observational study at Chang Gung Memorial Hospital from October 2012 to May 2015. Adult patients were included if they met the Berlin definition of ARDS. The indications for BAL were clinically suspected pneumonia-related ARDS and no definite microbial sample identified from tracheal aspirate or sputum. The presence of microbial pathogens and clinical outcomes were analyzed. Results: Of the 19,936 patients screened, 902 (4.5%) fulfilled the Berlin definition of ARDS. Of these patients, 255 (22.7%) had pneumonia-related ARDS and were included for analysis. A total of 142 (55.7%) patients were identified to have a microbial pathogen through BAL and were classified into three groups: a virus-only group (n = 41 [28.9%]), no virus group (n = 60 [42.2%]), and coinfection group (n = 41 [28.9%]). ARDS severity did not differ significantly between the groups (P = 0.43). The hospital mortality rates were 53.7% in virus-only identified group, 63.3% in no virus identified group, and 80.5% in coinfection identified group. The coinfection group had significantly higher mortality than virus-only group (80.5% vs. 53.7%; P = 0.01). Conclusion: In patients with pneumonia-related ARDS, the BAL pathogen-positive patients had a trend of higher mortality rate than pathogen-negative patients. Coinfection with a virus and another pathogen was associated with increased hospital mortality in pneumonia-related ARDS patients.

Background The survival predictors and optimal mechanical ventilator settings in patients with severe acute respiratory distress syndrome (ARDS) undergoing extracorporeal membrane oxygenation (ECMO) are uncertain. This study was designed to investigate the influences of clinical variables and mechanical ventilation settings on the outcomes for severe ARDS patients receiving ECMO. Methods We reviewed severe ARDS patients who received ECMO due to refractory hypoxemia from May 2006 to October 2015. Serial mechanical ventilator settings before and after ECMO and factors associated with survival were analyzed. Results A total of 158 severe ARDS patients received ECMO were finally analyzed. Overall intensive care unit (ICU) mortality was 55.1%. After ECMO initiation, tidal volume, peak inspiratory pressure and dynamic driving pressure were decreased, while positive end-expiratory pressure levels were relative maintained. After ECMO initiation, nonsurvivors had significantly higher dynamic driving pressure until day 7 than survivors. Cox proportional hazards regression model revealed that immunocompromised [hazard ratio 1.957; 95% confidence interval (CI) 1.216–3.147; p = 0.006], Acute Physiology and Chronic Health Evaluation (APACHE) II score (hazard ratio 1.039; 95% CI 1.005–1.073; p = 0.023), ARDS duration before ECMO (hazard ratio 1.002; 95% CI 1.000–1.003; p = 0.029) and mean dynamic driving pressure from day 1 to 3 on ECMO (hazard ratio 1.070; 95% CI 1.026–1.116; p = 0.002) were independently associated with ICU mortality. Conclusions For severe ARDS patients receiving ECMO, immunocompromised status, APACHE II score and the duration of ARDS before ECMO initiation were significantly associated with ICU survival. Higher dynamic driving pressure during first 3 days of ECMO support was also independently associated with increased ICU mortality.

Mechanical ventilation used in patients with acute respiratory distress syndrome (ARDS) can damage pulmonary epithelial cells by producing inflammatory cytokines and depositing excess collagen. Src participates in plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor-β1(TGF-β1) production during the fibroproliferative phase of ARDS, which involves a process of epithelial–mesenchymal transition (EMT). The mechanisms regulating interactions between mechanical ventilation and EMT are unclear. We hypothesized that EMT induced by high-tidal volume (VT) mechanical stretch-augmented lung inflammation occurs through upregulation of the Src pathway. Five days after administering bleomycin to simulate acute lung injury (ALI), male C57BL/6 mice, either wild-type or Src-deficient, aged 3 months, weighing between 25 and 30 g, were exposed to low-VT (6 ml/kg) or high-VT (30 ml/kg) mechanical ventilation with room air for 1–5 h. Nonventilated mice were used as control subjects. We observed that high-VT mechanical ventilation increased microvascular permeability, PAI-1 and TGF-β1 protein levels, Masson’s trichrome staining, extracellular collagen levels, collagen gene expression, fibroblast accumulation, positive staining of α-smooth muscle actin and type I collagen, activation of Src signaling and epithelial apoptotic cell death in wild-type mice (P

Background: Millions of people are infected by the influenza virus worldwide every year. Current selections of anti-influenza agents are limited and their effectiveness and drug resistance are still of concern. Purpose: Investigation on in vitro and in vivo effect of aloin from Aloe vera leaves against influenza virus infection. Methods: In vitro antiviral property of aloin was measured by plaque reduction assay in which MDCK cells were infected with oseltamivir-sensitive A(H1N1)pdm09, oseltamivir-resistant A(H1N1)pdm09, H1N1 or H3N2 influenza A or with influenza B viruses in the presence of aloin. In vivo activity was tested in H1N1 influenza virus infected mice. Aloin-mediated inhibition of influenza neuraminidase activity was tested by MUNANA assay. Aloin treatment-mediated modulation of anti-influenza immunity was tested by the study of hemagglutinin-specific T cells in vivo. Results: Aloin significantly reduced in vitro infection by all the tested strains of influenza viruses, including oseltamivir-resistant A(H1N1)pdm09 influenza viruses, with an average IC50 value 91.83 ± 18.97 μM. In H1N1 influenza virus infected mice, aloin treatment (intraperitoneal, once daily for 5 days) reduced virus load in the lungs and attenuated body weight loss and mortality. Adjuvant aloin treatment also improved the outcome with delayed oseltamivir treatment. Aloin inhibited viral neuraminidase and impeded neuraminidase-mediated TGF-β activation. Viral neuraminidase mediated immune suppression with TGF-β was constrained and influenza hemagglutinin-specific T cell immunity was increased. There was more infiltration of hemagglutinin-specific CD4+ and CD8+ T cells in the lungs and their production of effector cytokines IFN-γ and TNF-α was boosted. Conclusion: Aloin from Aloe vera leaves is a potent anti-influenza compound that inhibits viral neuraminidase activity, even of the oseltamivir-resistant influenza virus. With suppression of this virus machinery, aloin boosts host immunity with augmented hemagglutinin-specific T cell response to the infection. In addition, in the context of compromised benefit with delayed oseltamivir treatment, adjuvant aloin treatment ameliorates the disease and improves survival. Taken together, aloin has the potential to be further evaluated for clinical applications in human influenza.

Induced regulatory T cells (iTreg) is an adaptive response in inflammation with disease processes such as infection, autoimmunity or cancer. A small number of iTreg may exert long-lasting regulation. Here we report the LAG-3+ iTreg transfer regulatory activity to the CD4+ T cells they suppress. This infectious propagation of regulatory activity exemplify a dominant immune regulation in vivo. Naïve hemagglutinin (HA) antigen-specific CD4+ T cells are induced to differentiate into IFN-γ competent effector T cells and then LAG-3+ Tregs in HA transgenic mice inherently expressing the cognate HA antigen. The LAG-3+ iTreg suppresses activation of effector function of cognate naïve CD4+ T cells in HA transgenic mice, with silenced IFN-γ machinery including STAT1 phosphorylation and T-bet induction. The LAG-3 iTreg suppressed, IFN-γ disarmed CD4+ T cells still proliferate and acquire LAG-3 expression on their surface in vivo. They become the next generation LAG-3+ iTregs with the ability of suppression of activation of effector function of cognate naïve CD4+ T cells in HA transgenic mice, with the same mechanism of silenced IFN-γ machinery. LAG-3+ iTreg exercises regulation in vivo by suppression of effector function decoupled from reserved proliferative response. The effector function suppressed CD4+ T cells still proliferate upon activation and acquire LAG-3+ iTreg phenotype, a reminiscence of the infectious tolerance proposed in 1970.

T-bet induced CD4+ T cells are committed to be IFN-γ competent Th1 cells. The Th1 response is essential for virus eradication, but is also a major cause of inflammation and disease aggravation in severe influenza. In our influenza hemagglutinin (HA) Ag-specific mouse experimental system, naïve CD4+ T cells respond to the infection with T-bet expression. However, they suppress cognate CD8+ T cell effector response-mediated inflammation and alleviate the disease. Here we report concomitant LAG-3 expression and IFN-γ competence in Th1 committed CD4+ T cells. LAG-3 expression increases with activation by virus as revealed by CFSE based cell division study. The Th1 committed cells with moderate LAG-3 expression produce IFN-γ and contribute to inflammation and aggravated disease. They can no longer produce IFN-γ with higher LAG-3 expression upon further activation. Th1 committed CD4+ T cells with high LAG-3 expression suppress cognate CD8+ T cells by decoupling their effector function from proliferative response, restrain lung inflammation and facilitate viral clearance. They are better than Foxp-3+HA-specific CD4+ T cells in disease amelioration. The Foxp-3+ cells suppress both effector function and proliferative response of CD8+ T cells. They moderate inflammation but impair viral clearance. Principal component analysis of genome-wide gene expression profiles further confirmed the stepwise evolution. Several regulatory function-associated genes such as Lag3, Pdcd1, Tigit, Ctla2a, Nr4a2, Klrc1, Rgs16, Sytl3, Il21, Il1r2 and Dusp4 are up-regulated graduallly as well from LAG-3Neg to LAG-3Med and LAG-3High cells.

Immunosuppressants have impacts on the development of polyomavirus-associated nephropathy. We previously demonstrated that cyclosporin A (CsA) suppressed polyomavirus BK (BKV) replication. The role of cyclophilin A (CypA) and nuclear factor of activated T cells (NFAT) in CsA-imposed suppression of BKV replication was determined in this study. Results demonstrated that knockdown of CypA but not CypB significantly reduced BKV large T antigen (TAg) expression and BKV titer. Overexpression of CypA reversed CypA siRNA-induced inhibition in BKV TAg expression. In addition, CypA overexpression attenuated the suppressive effect of CsA on TAg expression, suggesting CypA implicated in CsA-mediated anti-BKV effect. Knockdown of NFATc3 abrogated TAg expression, while overexpression of NFATc3 promoted TAg expression and augmented BKV promoter activity. NFATc3 binding to the BKV promoter was verified by chromatin immunoprecipitation assay and electrophoretic mobility shift assay. Renal histology also displayed an increase in NFATc3 expression in tubulointerstitium of BKV-associated nephropathy. Furthermore, overexpression of NFATc3 rescued CsA-mediated inhibition of BKV load and TAg expression. A CsA analog, NIM811, which cannot block NFAT functionality, failed to suppress TAg expression. In conclusion, CypA and NFAT are indispensable in BKV replication. CsA inhibits BKV replication through CypA and NFAT, which may be potential targets of anti-BKV treatment.

Introduction Diffuse alveolar damage (DAD) is the pathological hallmark of acute respiratory distress syndrome (ARDS), however, the presence of DAD in the clinical criteria of ARDS patients by Berlin definition is little known. This study is designed to investigate the role of DAD in ARDS patients who underwent open lung biopsy. Methods We retrospectively reviewed all ARDS patients who met the Berlin definition and underwent open lung biopsy from January 1999 to January 2014 in a referred medical center. DAD is characterized by hyaline membrane formation, lung edema, inflammation, hemorrhage and alveolar epithelial cell injury. Clinical data including baseline characteristics, severity of ARDS, clinical and pathological diagnoses, and survival outcomes were analyzed. Results A total of 1838 patients with ARDS were identified and open lung biopsies were performed on 101 patients (5.5 %) during the study period. Of these 101 patients, the severity of ARDS on diagnosis was mild of 16.8 %, moderate of 56.5 % and severe of 26.7 %. The hospital mortality rate was not significant difference between the three groups (64.7 % vs 61.4 % vs 55.6 %, p = 0.81). Of the 101 clinical ARDS patients with open lung biopsies, 56.4 % (57/101) patients had DAD according to biopsy results. The proportion of DAD were 76.5 % (13/17) in mild, 56.1 % (32/57) in moderate and 44.4 % (12/27) in severe ARDS and there is no significant difference between the three groups (p = 0.113). Pathological findings of DAD patients had a higher hospital mortality rate than non-DAD patients (71.9 % vs 45.5 %, p = 0.007). Pathological findings of DAD (odds ratio: 3.554, 95 % CI, 1.385–9.12; p = 0.008) and Sequential Organ Failure Assessment score on the biopsy day (odds ratio: 1.424, 95 % CI, 1.187–1.707; p Conclusions The correlation of pathological findings of DAD and ARDS diagnosed by Berlin definition is modest. A pathological finding of DAD in ARDS patients is associated with hospital mortality and there are no clinical characteristics that could identify DAD patients before open lung biopsy.

The population of elderly patients entering chronic dialysis programmes is increasing. Elderly patients are susceptible to malnutrition and have multiple complicating disorders in addition to uraemia. Selecting appropriate dialysis modality is particularly critical in elderly patients. Continuous ambulatory peritoneal dialysis (CAPD) has many advantages to elderly patients; however, the clinical outcome varies for elderly CAPD patients. In comparison with Westerners, Southeast Asians have a small body mass index and may be more suited to CAPD therapy. To identify the prognostic predictors in elderly Southeast Asian patients, this historical cohort study analysed 144 patients aged > or = 65 years at initiation of CAPD. A group of haemodialysis (HD) patients aged > or = 65 years was utilised as the control group. Survival curves for patient and technique were derived from Kaplan-Meier analysis and were further analysed by Cox-Mantel log-rank test. To elucidate the impact of individual factors on patient survival, various significant univariables were further subjected to multivariate analysis. No significant increase existed for relative risk of technique failure in elderly patients compared with younger patients. This analytical data indicates that CAPD was as good as HD for elderly uraemic patients regarding to the patient survival. Diabetes, dependent patients, low albumin levels and previous HD history were significant poor prognostic factors for survival of elderly CAPD patients. In conclusion, CAPD is an effective modality of renal replacement therapy for Southeast Asian elderly patients. The technique survival was not affected by patient age.

Background Staphylococcus aureus is one of most common pathogens in humans. Methicillin-resistant S. aureus (MRSA) accounts for 64 % of S. aureus bacteremia isolated in intensive care units (ICUs), and heteroresistant vancomycin-intermediates S. aureus (hVISA) is a phenotype of MRSA. However, studies focusing on the hVISA impact on critically ill patients are scarce. Methods This was a retrospective study conducted in a tertiary medical center from January 2009 to December 2010. All adult patients in ICUs with MRSA bloodstream infection were eligible. A modified population analysis profile and area under the curve method was applied to all isolates to confirm hVISA phenotype. Multilocus sequence typing (MLST), staphylococcal cassette chromosome mec (SCCmec) and the accessory gene regulator (agr) typing were performed individually. Clinical outcomes including in-hospital mortality, length of stay in intensive care unit and hospital after MRSA bacteremia of the patients were also analyzed. Results A total of 48 patients were enrolled and 14 patients were confirmed to have the hVISA phenotype. The prevalence of hVISA was 29.2 %. There was no difference in the age, sex, comorbidity, Charlson’s comorbidity score and previous vancomycin therapy between the hVISA and VSSA groups. The hVISA group had a significantly higher in-hospital mortality than the VSSA group (13/14 versus 22/34; p = 0.046). All of the 14 hVISA patients had an MIC = 2 mg/L by E-test and this represented a significant association between high MIC and the development of hVISA (p

Relapsing polychondritis is a rare autoimmune disease causing inflammation in cartilaginous structures and other tissues throughout the body. Negative-pressure pulmonary edema (NPPE) due to laryngeal swelling from relapsing polychondritis is rare and has not been reported. Here, we report a case of relapsing polychondritis in an 18-y-old female who presented with recurrent NPPE and acute respiratory failure, which was diagnosed initially as ARDS during the influenza season. She underwent an emergent tracheotomy to relieve the upper airway obstruction resulting from severe laryngeal edema. A chest radiograph showed diffuse infiltrations, pneumothorax, and pneumomediastinum. The pulmonary infiltrations resolved rapidly in 2 d, and NPPE was diagnosed. Left ear swelling with erythematous change and saddle nose developed during the course of hospitalization, and an ear biopsy demonstrated severe cartilage necrosis. Relapsing polychondritis was diagnosed based on clinical images and pathological findings.

Background Diffuse alveolar damage (DAD) is a typical pathological finding of open lung biopsies in patients with acute respiratory distress syndrome (ARDS). Patients with ARDS and DAD have been reported to have a poorer prognosis than those without DAD. The aim of this study was to investigate the survival predictors in patients with ARDS and DAD. Methods We retrospectively reviewed all ARDS patients who underwent an open lung biopsy which showed evidence of DAD from January 2006 to June 2015 at Chang Gung Memorial Hospital. Clinical data including baseline characteristics, medication, and survival outcomes were analyzed. Results A total of 64 ARDS patients with DAD were eligible for analysis and divided into known etiology (n = 17, 26.6%) and unknown etiology groups (n = 47, 73.4%). There was no significant difference in hospital mortality rate between the two groups (71.9% vs. 70.6%, p = 0.890). Univariate logistic regression analysis revealed that sequential organ failure assessment (SOFA) score at the time of a diagnosis of ARDS, and SOFA score, PaO2/FiO2 ratio, and positive end expiratory pressure level when the biopsy was performed were associated with hospital mortality. Multivariate analysis showed that the SOFA score on the day of the biopsy was an independent predictor of hospital mortality (odds ratio 1.413, 95% confidence interval 1.127-1.772; p = 0.03). There were no significant differences in the use, dose, duration and timing from ARDS to glucocorticoid therapy between the survivors and nonsurvivors. Conclusion For selected ARDS patients who underwent an open lung biopsy with pathological DAD, SOFA score was an independent predictor of hospital mortality.

The host immune system responds to influenza virus infection for eradication of the virus but the immune response associated inflammation causes tissue injury and damage to the host as well. Severe influenza with morbidity and mortality is commonly believed to be the result of overwhelming immune response. In addition to antiviral agent, adjuvant therapy with immune modulating agent is a reasonable approach for severe influenza and has been reported to be effective in clinical series. As the immunity is also critical for virus eradication and recovery, we investigated to try to define the appropriate window for immune modulation in our murine animal model of influenza virus infection. Rapamycin treatment in a wide dose range did not alter the clinical course of severe influenza. In combination with antiviral agent Oseltamivir, rapamycin failed to offer additional benefit beyond treatment with Oseltamivir alone. Oseltamivir barely rescued the mice from severe influenza if the treatment was delayed until 48 hours after infection. Rapamycin did not provide salvage effect in this scenario. In fact, rapamycin suppressed influenza antigen specific CD4+ T cell response and impaired the virus eradication capacity. The virus burden in the lung increased with intense neutrophil infiltration and hyaline deposition in the alveoli. In conclusion, rapamycin cannot be relied upon as a salvage measure in severe influenza with progressive illness under treatment with Oseltamivir. T cell immunity is suppressed but other arms of immunity are recruited with undesirable effect on the disease outcome.

Critical illnesses in pregnancy account for 0.11 to 0.89% of deliveries resulting in ICU admissions. The high rate of perinatal asphyxia in infants and high mortality rate in gravid patients supported a strategy of early delivery during the third trimester. The mortality rate of acute respiratory distress syndrome (ARDS) is high and varied from 15 to 72% among the studies. The present study reports the outcomes of early delivery within 48 hours after ICU admission in pregnant patients with ARDS.

Transpulmonary thermodilution cardiac output (CO) correlates closely with pulmonary artery (PA) thermodilution CO. Levels of CO may contribute varying amounts of thermal indicator loss and recirculation during thermodilution CO measurement. This study aimed to investigate the effects of CO levels on the agreement between transpulmonary and PA thermodilution CO in acute lung injury (ALI) patients.