PD-L1 upregulation promotes drug-induced pulmonary fibrosis by inhibiting vimentin degradation.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality and limited therapeutic options. The immune checkpoint PD1/PD-L1 axis is related to the pathogenesis of pulmonary fibrosis, and upregulated expression levels of PD-L1 have been demonstrated in IPF patients. However, the mechanism of PD-L1 in pulmonary fibrosis is not fully understood. Here, we demonstrated upregulated expression of PD-L1 in fibrotic lung tissues and sera of IPF patients. Bleomycin (BLM) treatment induced PD-L1 upregulation, EMT (Epithelial-Mesenchymal Transition) and fibrosis-like morphology changes in human pulmonary alveolar epithelial cells (HPAEpiCs). Silencing PD-L1 attenuated BLM-induced EMT and fibrosis-like morphology changes in HPAEpiCs. In addition, we identified that PD-L1 directly binds to vimentin and inhibits vimentin ubiquitination, thereby increasing vimentin levels in HPAEpiCs. Silencing of vimentin inhibited BLM- and PD-L1-induced fibrosis in HPAEpiCs. The correlation between PD-L1 and EMT or vimentin expression was further confirmed in clinical samples and animal models. Finally, we used BLM- and paraquat-induced pulmonary fibrosis animal models to confirm the anti-pulmonary fibrosis effects of PD-L1 silencing. Taken together, our findings suggest that upregulated PD-L1 stimulates EMT of alveolar epithelial cells by increasing vimentin levels by inhibiting vimentin ubiquitination, thereby contributing to pulmonary fibrosis.

Clinical manifestations and outcome of anti-aminoacyl-transfer RNA synthetase antibody and anti-melanoma differentiation-associated gene 5 antibody positive patients with interstitial lung disease.

OBJECTIVES: To analyse the clinical features and risk factors of acute/subacute interstitial pneumonia (A/SIP) and death in patients with positive anti-aminoacyl-transfer RNA synthetase antibody (anti-ARS Ab) and positive anti-melanoma differentiation-associated gene 5 antibodies (anti-MDA5 Ab). METHODS: Interstitial lung disease (ILD) patients with anti-ARS+ or anti-MDA5+ were recruited. Their demographics, clinical manifestations, laboratory data were collected and they were followed up for 1 year. Risk factors of A/SIP and mortality were analysed. RESULTS: 71 patients with anti-ARS+ ILD and 31 patients with anti-MDA5+ ILD were included. Incidence of ulcerative rash, Gottron's sign, pulmonary infection and A/SIP in the anti-MDA5+ group were significantly higher than those in the anti-ARS+ group, Creatine kinase (CK), leukocyte count, and lymphocyte count were lower, the value of serum ferritin (SF) was higher, and 12-month cumulative survival rate was lower. Advanced age, anti-MDA5+ and low immunoglobulin G (IgG) level were independent predictors of A/SIP. The decreased PaO2 and elevated SF were independent predictors for poor prognosis in A/SIP patients. CONCLUSIONS: Compared to anti-ARS+ group, the anti-MDA5+ group was more prone to ulcerative rash, Gottron's sign and pulmonary infection. Patients with anti-MDA5+, advanced age and decreased values of IgG were more likely to have A/SIP, while patients with A/SIP had lower incidence of myositis and arthritis. Mortality of A/SIP patients increased with higher serum ferritin level.

A randomized, open, multicenter clinical study on the short course of intravenous infusion of 750 mg of levofloxacin and the sequential standard course of intravenous infusion/oral administration of 500 mg of levofloxacin for treatment of community-acquired pneumonia.

BACKGROUND: To compare 5-day regimen of levofloxacin 750 mg IV daily with 7-14-day conventional regimen of levofloxacin 500 mg intravenous to oral (IV/PO) daily for treatment of community-acquired pneumonia (CAP) in Chinese population. METHODS: This was a non-inferiority study to assess the difference of clinical efficacy at the end of treatment (EOT) between two regimens. Adult CAP patients with CURB-65 score 0-2 were enrolled from 17 hospitals in China from November 2012 to July 2014. The subjects were randomized into levofloxacin 750 or 500 mg group and the clinical data were collected. Sputum and blood specimens were sent for bacterial culture. The urinary antigen of Streptococcus pneumoniae (S. pneumoniae) was detected as well. At EOT, the clinical efficacy (primary endpoint), microbiological efficacy and safety were evaluated. RESULTS: A total of 457 patients were enrolled. Intent-to-treat (ITT) for primary endpoint analysis and per-protocol set (PPS) populations were 448 and 427 patients respectively. The therapeutic durations were 4.86 and 10.35 days and the mean drug exposure was 3,641.4 and 5,169.6 mg in 750 and 500 mg groups respectively. The clinical efficacy rate was 91.40% (202/221) in 750 mg group and 94.27% (214/227) in 500 mg group (ITT, P=0.2449). The difference in clinical efficacy rate was -2.87 (95% CI: -7.64, 1.90) between the two groups. The non-inferiority hypothesis of two groups was tenable (Δ=10%). The bacterial eradication rate was 100.00% in both groups. The most common drug-related clinical adverse events were injection site and gastrointestinal reactions. The most common drug-related laboratory abnormalities were WBC decrease and ALT/AST elevation. No statistical difference was found between two groups (P>0.05). CONCLUSIONS: The 5-day regimen of levofloxacin 750 mg daily is non-inferior to 7-14-day conventional regimen of 500 mg daily in clinical efficacy for treatment of mild to moderate Chinese CAP population. The short course regimen allows the reduction of antimicrobial drug exposure and is well tolerated.

Treatment of community-acquired pneumonia with moxifloxacin: a meta-analysis of randomized controlled trials.

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality throughout the world. To investigate whether moxifloxacin monotherapy is associated with better clinical outcomes than other antibiotics recommended for CAP among adults with mild-to-moderate or severe CAP, we performed a meta-analysis. MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched for randomized control trials (RCTs). The efficacy and safety of moxifloxacin were compared with other antimicrobial agents used to treat CAP. Fourteen RCTs, consisting of 6923 total patients, were included in the meta-analysis. No difference was found regarding the incidence of adverse events and mortality between moxifloxacin and the compared regimens. We found that moxifloxacin is as effective and well-tolerated as other recommended antibiotics for the treatment of CAP and possesses a better pathogen eradication rate than beta-lactam-based therapy.

[Adult hospital acquired pneumonia: a multicenter study on microbiology and clinical characteristics of patients from 9 Chinese cities].

OBJECTIVE: To investigate the etiology and clinical characteristics of hospital-acquired pneumonia (HAP) in China and to provide evidence for appropriate therapy. METHODS: We performed a prospective multicenter study in 13 Chinese urban tertiary hospitals. All HAP cases diagnosed at respiratory general ward and respiratory intensive care unit (RICU) from August 2008 to December 2010 were studied. Epidemiological data, etiology and clinical characteristics of enrolled patients were collected. Sputum or tracheal aspirate and blood cultures, Legionella antibodies and Streptococcus pneumoniae urinary antigen tests were performed. Bacteria to antimicrobial susceptibility test was performed. RESULTS: A total of 610 cases of HAP were diagnosed during the study, with an overall incidence of 1.4% among 42 877 hospitalized patients, while the incidence was 0.9% (362/41 261) in respiratory general ward and 15.4% (248/1616) in RICU. 93.9% (573 cases) of patients had at least one underlying disease, and 91.0% (555 cases) had exposure to at least one antimicrobial agent within 90 days prior to HAP diagnosis. Pathogens were identified in 487 patients, with Acinetobacter baumannii [30.0% (183/610)], Pseudomonas aeruginosa [22.0% (134/610)], Staphylococcus aureus [13.4% (82/610)] and Klebsiella pneumonia [9.7% (59/610)] being the most common pathogens. Eighteen patients (3.0%) had infection with fastidious bacteria. A. baumannii and S. aureus were the more frequent pathogens in the ventilator-associated pneumonia (VAP) cases [50.5% (97/192) and 21.4% (41/192)] as compared to non-VAP cases [20.6% (86/418) and 9.8% (41/418), P < 0.01]. A. baumannii and S. aureus were also frequent pathogens in cases with a score of more than 20 by the acute physiology and chronic health evaluation II (APACHEII) scoring [45.7% (69/151) and 20.5% (31/151)], as compared to cases with a score of less than 20 of APACHE II [24.8% (114/459) and 11.1% (51/459), P < 0.01]. A. baumannii showed high resistance rates to carbapenems [more than 70% (109/142)], and the susceptibility to cefoperazone/sulbactam, polymyxin B and tigecycline were 40.8% (58/142), 99.3% (141/142) and 95.8% (136/142) respectively. Resistance rates of P. aeruginosa to meropenem and imipenem were 48.8% (40/82) and 70.7% (58/82) respectively. Methicillin-resistant S. aureus (MRSA) accounted for 87.8% (43/49) in all strains of S. aureus. Mortality rate of VAP cases was 34.5% (61/177), significantly more than that of HAP patients [22.3% (135/605), P < 0.05]. The average hospital stay of patients with HAP was (23.8 ± 20.5) days, significantly more than that of the average for inpatients [(13.2 ± 13.6) days, P < 0.01] during the study period. Mean costs of HAP were (108 950 ± 116 608) yuan, significantly higher than the average hospital costs of respiratory inpatients (17 999 ± 33 364) yuan. CONCLUSIONS: Among Chinese patients hospitalized in urban tertiary medical centers, HAP incidence and mortality rate were high, which increased the patients' hospital stay and the medical costs. Common pathogens were A. baumannii, P. aeruginosa, S. aureus and K. pneumonia. The common bacteria of HAP in China showed high resistance rates to antibiotics.

[Clinical analysis of non-invasive positive pressure ventilation in immunocompromised host with acute respiratory failure].

OBJECTIVE: To evaluate the value of non-invasive positive pressure ventilation (NPPV) in immunocompromised host (ICH) complicated by acute respiratory failure (ARF), and to investigate predictive variables of success with NPPV in ICH with ARF. METHODS: A retrospective study of immunocompromised patients with ARF, who were admitted to respiratory intensive care unit (RICU) from March 2008 to March 2011, was performed. Based on clinical data, univariate Logistic regression was done for prediction for independent factors affecting the success of NPPV treatment. Immunization status was assessed according to clinical outcome. RESULTS: NPPV was instituted in all 33 cases with ARF initially. Among these patients, 9 patients (27.3%) received sequential invasive mechanical ventilation (IMV, failure group) and all of them died finally; among 24 cases (72.7%) who only received NPPV (success group), 7 patients died (29.2%). There was significant difference between the two groups in mortality (P<0.01). The simplified acute physiology scoreII (SAPSII) in the success group was lower than that in the failure group (33±9 vs. 43±5, P<0.01). However, other clinical data showed no statistical significance between two groups. Univariate Logistic regression analysis identified SAPSII was the independent factor associated with the success of NPPV treatment [odds ratio (OR) =0.83, 95% confidence interval (95% CI) 0.709-0.964, P<0.05]. And SAPSII≥38 was a risk factor for the failure of NPPV [area under receiver operating characteristic (ROC) curve 0.73]. In addition, the lung injury scores (LIS) in the survival group was significantly lower than that of the death group (1.95±0.48 vs. 2.57±0.52, P<0.01), the difference was statistically significant. CD3(+) and CD8(+) T counts in the survivors were higher than that of non-survivors (CD3(+):0.73±0.16 vs. 0.41±0.20; CD8(+): 0.51±0.18 vs. 0.21±0.15, both P<0.01), and the difference was statistically significant. CONCLUSION: As an early treatment for ICH with pulmonary infections suffering from ARF, NPPV can be effective for the ICH patients suffering from severe pulmonary infection through improving hypoxemia, ameliorating respiratory distress symptoms, and avoiding complications associated with IMV when SAPSIIis less than 38. CD3(+), CD8(+), and the LIS can be used to evaluate the prognosis of those patients.

Blastomycosis in China: a case report and literature review.

Blastomycosis is a fungal disease that is endemic in parts of North America. It is very rare in China and also commonly misdiagnosed, often as cancer or other infectious diseases. The clinical profile of a case of disseminated blastomycosis with pulmonary changes and skin ulcers was described. He had been misdiagnosed with tuberculosis, after adequate therapy with a lipid formulation of amphotericin B, followed by itraconazole, the lung and skin lesions improved. Then the five cases reported in China and literatures were reviewed. The aim of this report was to improve the knowledge regarding blastomycosis for physicians in China to avoid delaying adequate therapy.

N-acetylcysteine inhibit biofilms produced by Pseudomonas aeruginosa.

BACKGROUND: Pseudomonas aeruginosa is a common pathogen in chronic respiratory tract infections. It typically makes a biofilm, which makes treatment of these infections difficult. In this study, we investigated the inhibitory effects of N-acetylcysteine (NAC) on biofilms produced by P. aeruginosa. RESULTS: We found that minimum inhibitory concentrations (MICs) of NAC for most isolates of P. aeruginosa were 10 to 40 mg/ml, the combination of NAC and ciprofloxacin (CIP) demonstrated either synergy (50%) or no interaction (50%) against the P. aeruginosa strains. NAC at 0.5 mg/ml could detach mature P. aeruginosa biofilms. Disruption was proportional to NAC concentrations, and biofilms were completely disrupted at 10 mg/ml NAC. Analysis using COMSTAT software also showed that PAO1 biofilm biomass decreased and its heterogeneity increased as NAC concentration increased. NAC and ciprofloxacin showed significant killing of P. aeruginosa in biofilms at 2.5 mg/ml and > 2 MIC, respectively (p < 0.01). NAC-ciprofloxacin combinations consistently decreased viable biofilm-associated bacteria relative to the control; this combination was synergistic at NAC of 0.5 mg/ml and CIP at 1/2MIC (p < 0.01). Extracellular polysaccharides (EPS) production by P. aeruginosa also decreased by 27.64% and 44.59% at NAC concentrations of 0.5 mg/ml and 1 mg/ml. CONCLUSIONS: NAC has anti-bacterial properties against P. aeruginosa and may detach P. aeruginosa biofilms. Use of NAC may be a new strategy for the treatment of biofilm-associated chronic respiratory infections due to P. aeruginosa, although it would be appropriate to conduct clinical studies to confirm this.

Causative agent distribution and antibiotic therapy assessment among adult patients with community acquired pneumonia in Chinese urban population.

BACKGROUND: Knowledge of predominant microbial patterns in community-acquired pneumonia (CAP) constitutes the basis for initial decisions about empirical antimicrobial treatment, so a prospective study was performed during 2003-2004 among CAP of adult Chinese urban populations. METHODS: Qualified patients were enrolled and screened for bacterial, atypical, and viral pathogens by sputum and/or blood culturing, and by antibody seroconversion test. Antibiotic treatment and patient outcome were also assessed. RESULTS: Non-viral pathogens were found in 324/610 (53.1%) patients among whom M. pneumoniae was the most prevalent (126/610, 20.7%). Atypical pathogens were identified in 62/195 (31.8%) patients carrying bacterial pathogens. Respiratory viruses were identified in 35 (19%) of 184 randomly selected patients with adenovirus being the most common (16/184, 8.7%). The nonsusceptibility of S. pneumoniae to penicillin and azithromycin was 22.2% (Resistance (R): 3.2%, Intermediate (I): 19.0%) and 79.4% (R: 79.4%, I: 0%), respectively. Of patients (312) from whom causative pathogens were identified and antibiotic treatments were recorded, clinical cure rate with beta-lactam antibiotics alone and with combination of a beta-lactam plus a macrolide or with fluoroquinolones was 63.7% (79/124) and 67%(126/188), respectively. For patients having mixed M. pneumoniae and/or C. pneumoniae infections, a better cure rate was observed with regimens that are active against atypical pathogens (e.g. a beta-lactam plus a macrolide, or a fluoroquinolone) than with beta-lactam alone (75.8% vs. 42.9%, p = 0.045). CONCLUSION: In Chinese adult CAP patients, M. pneumoniae was the most prevalent with mixed infections containing atypical pathogens being frequently observed. With S. pneumoniae, the prevalence of macrolide resistance was high and penicillin resistance low compared with data reported in other regions.

[A multicentre study on the pathogenic agents in 665 adult patients with community-acquired pneumonia in cities of China].

OBJECTIVE: To investigate the pathogenic causes of community-acquired pneumonia (CAP) in adult patients in China, the relation of previous antibiotic use and the Pneumonia Patient Outcome Research Team (PORT) classification to microbial etiology, and the prevalence of drug resistance of common CAP bacteria. METHODS: A prospective study was performed on 665 consecutive adult patients with CAP at 12 centers in 7 Chinese cities during one year. The etiology of pneumonia was considered if one of the following criteria was met: (1) valid sputum sample yielding one or more predominant strains; (2) blood cultures yielding a bacterial pathogen; (3) seroconversion, a > or = 4-fold increase or decrease titers of antibodies to Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila. Minimum inhibitory concentration (MIC) of respiratory tract isolates was determined using the agar dilution method. RESULTS: Pathogens were identified in 324/610 patients (53.1%) with valid serum samples and sputum cultures as follows: Mycoplasma pneumoniae (126, 20.7%), Streptococcus pneumoniae (63, 10.3%), Haemophilus influenzae (56, 9.2%), Chlamydia pneumoniae (40, 6.6%), Klebsiella pneumoniae (37, 6.1%), Legionella pneumophila (31, 5.1%), Staphylococcus aureus (23, 3.8%), Escherichia coli (10, 1.6%), Moraxella catarrhalis (8, 1.3%), Pseudomonas aeruginosa (6, 1.0%). Of 195 patients with a bacterial pathogen, an atypical pathogen was identified in 62 (10.2%) cases. The non-susceptibility rate of Streptococcus pneumoniae to penicillin, azithromycin, and moxifloxacin was 20.3%, 75.4% and 4.3% respectively. CONCLUSIONS: Atypical pathogens have important role in CAP, with Mycoplasma pneumoniae being the most common pathogen, and mixed infection of atypical pathogens with bacteria was found in 10.2% of the cases. Streptococcus pneumoniae and Haemophilus influenzae remain the most important bacteria for CAP. More than 75.0% of Streptococcus pneumoniae was resistant to macrolides and 20.3% was resistant to penicillin.

[The phenotype and genotype patterns of erythromycin-resistant Streptococcus pneumoniae].

OBJECTIVE: To investigate the resistance phenotypes and genotypes in erythromycin-resistant Streptococcus (S.) pneumoniae. METHODS: The minimum inhibitory concentration (MIC) of erythromycin, clindamycin, penicillin and fluoroquinolones against 192 strains of S. pneumoniae was tested with broth microdilution method according to the guidelines of the National Committee for Clinical Laboratory Standards. Of 148 clinical isolates of erythromycin resistant S. pneumoniae, the macrolide resistance phenotypes were observed by the erythromycin-clindamycin-spiramycin triple-disc test and erythromycin resistance genes were detected by polymerase chain reaction. RESULTS: 42.7% S. pneumoniae isolates was resistant (intermediate and resistant) to penicillin while the resistance rates to erythromycin and clindamycin were 77.6% and 66.7% respectively. The ermB gene, being the most prevalent, was detected in 79.1% of the 148 erythromycin-resistant strains. The main phenotype (85.1%) of erythromycin-resistant strains was constitutive macrolide, lincosamide, and streptogramin B resistance phenotype (cMLS). Erythromycin MICs for S. pneumoniae ermB-positive isolates were higher than those for mefA-positive isolates. 74.4% of the ermB-positive isolates demonstrated erythromycin MICs of > 16.0 micro g/ml, and the erythromycin MICs for mefA-positive isolates ranged from 0.5 approximately 4.0 micro g/ml. CONCLUSIONS: The resistance rate of S. pneumoniae to erythromycin is high in China. The main phenotype is cMLS. Ribosomal modification (ermB gene coded) is the main resistance mechanism against erythromycin in S. pneumoniae

[Prevalence of atypical pathogens in adult patients with community-acquired pneumonia in Beijing].

OBJECTIVE: To study the pathogens in community-acquired pneumonia (CAP), especially the prevalence of atypical pathogens. METHODS: A prospective study was performed on 103 consecutive adult patients with CAP between November 2001 and June 2002. Antibodies of the paired serum samples to Mycoplasma pneumoniae, Legionella pneumophilia, and Chlamydia pneumoniae were detected. The P1 adhesion gene of Mycoplasma pneumoniae and the 16S ribosome gene specific for Chlamydia pneumoniae were detected with polymerase chain reaction (PCR). Legionella antigen in urine was detected using enzyme immunoassay (EIA) method. Sputum samples were collected for culture, and bacteria were isolated and identified using conventional methods. RESULTS: The etiology of CAP was identified in 50 (48.5%) patients. The distribution of causal agents was as follows: Mycoplasma pneumoniae in 23 (22.3%) cases, Legionella pneumophilia 3 (2.9%), Chlamydia pneumoniae 2 (1.9%), streptococcus pneumoniae 12 (11.7%), Haemophilus influenzae 9 (8.7%), and Klebsiella pneumoniae 7(6.8%). In 6 patients (5.8%) more than one causal agent were found, among them Mycoplasma pneumoniae was found in 5 cases with mixed infections. CONCLUSIONS: Atypical pathogens especially Mycoplasma pneumoniae have an important role in CAP. Streptococcus pneumoniae and Haemophilus influenzae remain the most common bacteria, and mixed infection should not be ignored.