Representative population-based data on the epidemiology of bronchiectasis in Europe are limited. The aim of the present study was to investigate the current burden and the trends of bronchiectasis-associated hospitalizations and associated conditions in Germany in order to inform focused patient care and to facilitate the allocation of healthcare resources.
The nationwide diagnosis-related groups hospital statistics for the years 2005–2011 were used in order to identify hospitalizations with bronchiectasis as any hospital discharge diagnosis according to the International Classification of Diseases, 10th revision, code J47, (acquired) bronchiectasis. Poisson log-linear regression analysis was used to assess the significance of trends. In addition, the overall length of hospital stay (LOS) and the in-hospital mortality in comparison to the nationwide overall mortality due to bronchiectasis as the primary diagnosis was assessed.
Overall, 61,838 records with bronchiectasis were extracted from more than 125 million hospitalizations. The average annual age-adjusted rate for bronchiectasis as any diagnosis was 9.4 hospitalizations per 100,000 population. Hospitalization rates increased significantly during the study period, with the highest rate of 39.4 hospitalizations per 100,000 population among men aged 75–84 years and the most pronounced average annual increases among females. Besides numerous bronchiectasis-associated conditions, chronic obstructive pulmonary disease (COPD) was most frequently found in up to 39.2% of hospitalizations with bronchiectasis as the primary diagnosis. The mean LOS was comparable to that for COPD. Overall, only 40% of bronchiectasis-associated deaths occurred inside the hospital.
The present study provides evidence of a changing epidemiology and a steadily increasing prevalence of bronchiectasis-associated hospitalizations. Moreover, it confirms the diversity of bronchiectasis-associated conditions and the possible association between bronchiectasis and COPD. As the major burden of disease may be managed out-of-hospital, prospective patient registries are needed to establish the exact prevalence of bronchiectasis according to the specific underlying condition.
FMS-like tyrosine kinase-3 ligand (Flt3L) is a dendritic cell (DC) growth and differentiation factor with potential in antitumor therapies and antibacterial immunization strategies. However, the effect of systemic Flt3L treatment on lung-protective immunity against bacterial infection is incompletely defined. Here, we examined the impact of deficient (in Flt3L knockout [KO] mice), normal (in wild-type [WT] mice), or increased Flt3L availability (in WT mice pretreated with Flt3L for 3, 5, or 7 days) on lung DC subset profiles and lung-protective immunity against the major lung-tropic pathogen, Streptococcus pneumoniae. Although in Flt3L-deficient mice the numbers of DCs positive for CD11b (CD11bpos DCs) and for CD103 (CD103pos DCs) were diminished, lung permeability, a marker of injury, was unaltered in response to S. pneumoniae. In contrast, WT mice pretreated with Flt3L particularly responded with increased numbers of CD11bpos DCs and with less pronounced numbers of CD103pos DCs and impaired bacterial clearance and with increased lung permeability following S. pneumoniae challenge. Notably, infection of Flt3L-pretreated mice with S. pneumoniae lacking the pore-forming toxin, pneumolysin (PLY), resulted in substantially less lung CD11bpos DCs activation and reduced lung permeability. Collectively, this study establishes that Flt3L treatment enhances the accumulation of proinflammatory activated lung CD11bpos DCs which contribute to acute lung injury in response to PLY released by S. pneumoniae.
Representative population-based data on the epidemiology of pulmonary non-tuberculous mycobacterial (PNTM) infections in Europe are limited. However, these data are needed in order to optimise patient care and to facilitate the allocation of healthcare resources. The aim of the present study was to investigate the current burden and the trends of PNTM infection-associated hospitalisations in Germany.
International Classification of Diseases, 10th revision (ICD-10) discharge diagnosis codes were extracted from the official nationwide diagnosis-related groups (DRG) hospital statistics in order to identify PNTM infection-associated hospitalisations (ICD-10 code A31.0) between 2005 and 2011. Poisson log-linear regression analysis was used to assess the significance of trends.
Overall, 5,959 records with PNTM infection as any hospital discharge diagnosis were extracted from more than 125 million hospitalisations. The average annual age-adjusted rate was 0.91 hospitalisations per 100,000 population. Hospitalisation rates increased during the study period for both males and females, with the highest rate of 3.0 hospitalisations per 100,000 population among elderly men, but the most pronounced average increase of 6.4%/year among females, particularly those of young and middle age, and hospitalisations associated with cystic fibrosis. Overall, chronic obstructive pulmonary disease (COPD) was the most frequent PNTM infection-associated condition in 28.9% of hospitalisations and also showed a significant average annual increase of 4.8%.
The prevalence of PNTM infection-associated hospitalisations is steadily increasing in Germany. COPD is currently the most important associated condition. Our population-based study provides evidence of a changing epidemiology of PNTM infections and highlights emerging clinical implications.
Atypical mycobacterial infection; Bronchiectasis; Clinical epidemiology; COPD epidemiology; Cystic fibrosis; Health services research; International classification of diseases; Mycobacterium avium complex; Non-tuberculous mycobacteria; Tuberculosis
Neutrophil-derived TRAIL induces apoptosis of alveolar macrophages, limiting the spread of S. pneumoniae infection.
Apoptotic death of alveolar macrophages observed during lung infection with Streptococcus pneumoniae is thought to limit overwhelming lung inflammation in response to bacterial challenge. However, the underlying apoptotic death mechanism has not been defined. Here, we examined the role of the TNF superfamily member TNF-related apoptosis-inducing ligand (TRAIL) in S. pneumoniae–induced macrophage apoptosis, and investigated the potential benefit of TRAIL-based therapy during pneumococcal pneumonia in mice. Compared with WT mice, Trail−/− mice demonstrated significantly decreased lung bacterial clearance and survival in response to S. pneumoniae, which was accompanied by significantly reduced apoptosis and caspase 3 cleavage but rather increased necrosis in alveolar macrophages. In WT mice, neutrophils were identified as a major source of intraalveolar released TRAIL, and their depletion led to a shift from apoptosis toward necrosis as the dominant mechanism of alveolar macrophage cell death in pneumococcal pneumonia. Therapeutic application of TRAIL or agonistic anti-DR5 mAb (MD5-1) dramatically improved survival of S. pneumoniae–infected WT mice. Most importantly, neutropenic mice lacking neutrophil-derived TRAIL were protected from lethal pneumonia by MD5-1 therapy. We have identified a previously unrecognized mechanism by which neutrophil-derived TRAIL induces apoptosis of DR5-expressing macrophages, thus promoting early bacterial killing in pneumococcal pneumonia. TRAIL-based therapy in neutropenic hosts may represent a novel antibacterial treatment option.
The growth factor granulocyte/macrophage-colony stimulating factor (GM-CSF) has an important role in pulmonary surfactant metabolism and the regulation of antibacterial activities of lung sentinel cells. However, the potential of intra-alveolar GM-CSF to augment lung protective immunity against inhaled bacterial pathogens has not been defined in preclinical infection models. We hypothesized that transient overexpression of GM-CSF in the lungs of mice by adenoviral gene transfer (Ad-GM-CSF) would protect mice from subsequent lethal pneumococcal pneumonia. Our data show that intra-alveolar delivery of Ad-GM-CSF led to sustained increased pSTAT5 expression and PU.1 protein expression in alveolar macrophages during a 28 day observation period. Pulmonary Ad-GM-CSF delivery two or four weeks prior to infection of mice with S. pneumoniae significantly reduced mortality rates relative to control vector treated mice. This increased survival was accompanied by increased iNOS expression, antibacterial activity and a significant reduction in caspase 3 dependent apoptosis and secondary necrosis of lung sentinel cells. Importantly, therapeutic treatment of mice with recombinant GM-CSF improved lung protective immunity and accelerated bacterial clearance after pneumococcal challenge. We conclude that prophylactic delivery of GM-CSF triggers long-lasting immunostimulatory effects in the lung in vivo and rescues mice from lethal pneumococcal pneumonia by improving antibacterial immunity. These data support use of novel antibiotic-independent immunostimulatory therapies to protect patients against bacterial pneumonias.
GM-CSF; S. pneumoniae; PU.1; pneumonia; therapy; infection
Dendritic cells (DCs) are essential for innate and adaptive immunity, but are purported to exhibit variable radiosensitivity in response to irradiation in various bone marrow transplantation (BMT) protocols. To address this controversy, we analyzed the magnitude of depletion and repopulation of both lung CD11bpos DC and CD103pos DC subsets in response to irradiation and BMT in a murine model. In our study, CD45.2pos donor bone marrow cells were transplanted into irradiated CD45.1pos recipient mice to examine the depletion of recipient DC subsets and the repopulation of donor DC subsets. We observed an apoptosis-mediated and necrosis-mediated depletion (> 90%) of the recipient CD103pos DC subset, and only a 50–60% depletion of recipient CD11bpos DCs from lung parenchymal tissue on Days 3 and 5, whereas recipient alveolar and lung macrophages were much less radiosensitive, showing an approximately 50% depletion by Days 14–21 after treatment. A repopulation of lung tissue with donor DC subsets had occurred by Days 10 and 28 for CD11bpos DCs and CD103pos DCs, whereas alveolar and lung macrophages were repopulated by 6 and 10 weeks after treatment. Furthermore, the infection of mice with Streptococcus pneumoniae further accelerated the turnover of lung DCs and lung macrophage subsets. Our data illustrate the vulnerability of lung CD103pos DCs and CD11bpos DCs to irradiation, and indicate that an accelerated turnover of lung DC subsets occurs, relative to pulmonary and lung macrophages. Our findings may have important implications in the development of adjuvant immune-stimulatory protocols that could reduce the risk of opportunistic infections in patients undergoing BMT.
dendritic cell; macrophage; pneumonia; Streptococcus pneumoniae; CD103
Neutrophil serine proteases cathepsin G (CG), neutrophil elastase (NE), and proteinase 3 (PR3) have recently been shown to contribute to killing of Streptococcus pneumoniae in vitro. However, their relevance in lung-protective immunity against different serotypes of S. pneumoniae in vivo has not been determined so far. Here, we examined the effect of CG and CG/NE deficiency on the lung host defense against S. pneumoniae in mice. Despite similar neutrophil recruitment, both CG knockout (KO) mice and CG/NE double-KO mice infected with focal pneumonia-inducing serotype 19 S. pneumoniae demonstrated a severely impaired bacterial clearance, which was accompanied by lack of CG and NE but not PR3 proteolytic activity in recruited neutrophils, as determined using fluorescence resonance energy transfer (FRET) substrates. Moreover, both CG and CG/NE KO mice but not wild-type mice responded with increased lung permeability to infection with S. pneumoniae, resulting in severe respiratory distress and progressive mortality. Both neutrophil depletion and ablation of hematopoietic CG/NE in bone marrow chimeras abolished intra-alveolar CG and NE immunoreactivity and led to bacterial outgrowth in the lungs of mice, thereby identifying recruited neutrophils as the primary cellular source of intra-alveolar CG and NE. This is the first study showing a contribution of neutrophil-derived neutral serine proteases CG and NE to lung-protective immunity against focal pneumonia-inducing serotype 19 S. pneumoniae in mice. These data may be important for the development of novel intervention strategies to improve lung-protective immune mechanisms in critically ill patients suffering from severe pneumococcal pneumonia.
Chronic obstructive pulmonary disease (COPD) is influenced by environmental and genetic factors. An important fraction of COPD cases harbor a major genetic determinant, inherited ZZ (Glu342Lys) α1-antitrypsin deficiency (AATD). A study was undertaken to investigate gene expression patterns in end-stage COPD lungs from patients with and without AATD.
Explanted lungs of end-stage ZZ AATD-related (treated and non-treated with AAT augmentation therapy) and “normal” MM COPD, and liver biopsies from patients suffering from liver cirrhosis with and without ZZ AATD were used for gene expression analysis by Affymetrix microarrays or RT-PCR.
A total of 162 genes were found to be differentially expressed (p-value ≤ 0.05 and |FC| ≥ 2) between MM and ZZ COPD patients. Of those, 134 gene sets were up-regulated and 28 were down-regulated in ZZ relative to MM lung tissue. A subgroup of genes, zinc finger protein 165, snail homolog 1 (Drosophila) (SNAI1), and Krüppel-like transcription factors (KLFs) 4 (gut), 9 and 10, perfectly segregated ZZ and MM COPD patients. The higher expression of KLF 9 and KLF10 has been verified in the replication cohort with AATD-related end-stage lung emphysema and liver cirrhosis. Furthermore, higher expression of KLF9, SNAI1 and DEFA1 was found in ZZ COPD lungs without augmentation therapy relative to MM COPD or ZZ COPD with augmentation therapy.
These results reveal the involvement of transcriptional regulators of the zinc-finger family in COPD pathogenesis and provide deeper insight into the pathophysiological mechanisms of COPD with and without AATD.
Alpha 1-antitrypsin; COPD; Gene expression, Krüppel-like zinc finger proteins, Affymetrix gene chips
This individual patient data meta-analysis of clinical trials investigating procalcitonin algorithms for antibiotic decision making found no increased risk of death or setting-specific treatment failure but did find significantly lower antibiotic exposure across different acute respiratory infections and clinical settings.
Background. Procalcitonin algorithms may reduce antibiotic use for acute respiratory tract infections (ARIs). We undertook an individual patient data meta-analysis to assess safety of this approach in different ARI diagnoses and different clinical settings.
Methods. We identified clinical trials in which patients with ARI were assigned to receive antibiotics based on a procalcitonin algorithm or usual care by searching the Cochrane Register, MEDLINE, and EMBASE. Individual patient data from 4221 adults with ARIs in 14 trials were verified and reanalyzed to assess risk of mortality and treatment failure—overall and within different clinical settings and types of ARIs.
Results. Overall, there were 118 deaths in 2085 patients (5.7%) assigned to procalcitonin groups compared with 134 deaths in 2126 control patients (6.3%; adjusted odds ratio, 0.94; 95% confidence interval CI, .71–1.23)]. Treatment failure occurred in 398 procalcitonin group patients (19.1%) and in 466 control patients (21.9%; adjusted odds ratio, 0.82; 95% CI, .71–.97). Procalcitonin guidance was not associated with increased mortality or treatment failure in any clinical setting or ARI diagnosis. Total antibiotic exposure per patient was significantly reduced overall (median [interquartile range], from 8 [5–12] to 4 [0–8] days; adjusted difference in days, −3.47 [95% CI, −3.78 to −3.17]) and across all clinical settings and ARI diagnoses.
Conclusions. Use of procalcitonin to guide initiation and duration of antibiotic treatment in patients with ARIs was effective in reducing antibiotic exposure across settings without an increase in the risk of mortality or treatment failure. Further high-quality trials are needed in critical-care patients.
A few international pneumococcal clones dominate the population of antibiotic-resistant pneumococci. Despite the scientific paradigm that a loss in fitness is the price for acquisition of resistance, these clones spread successfully. One hundred fifty-four isolates from adult patients with community-acquired pneumonia (CAP) were analyzed. Thirty percent showed a close relationship to international clones and had fitness equal to or exceeding that of other strains (P = 0.015); these factors may result in the endurance of these strains despite a reduction of antibiotic usage.
The aim of our study was to investigate the predictive value of the biomarkers interleukin 6 (IL-6), interleukin 10 (IL-10) and lipopolysaccharide-binding protein (LBP) compared with clinical CRB and CRB-65 severity scores in patients with community-acquired pneumonia (CAP).
Samples and data were obtained from patients enrolled into the German CAPNETZ study group. Samples (blood, sputum and urine) were collected within 24 h of first presentation and inclusion in the CAPNETZ study, and CRB and CRB-65 scores were determined for all patients at the time of enrollment. The combined end point representative of a severe course of CAP was defined as mechanical ventilation, intensive care unit treatment and/or death within 30 days. Overall, a total of 1,000 patients were enrolled in the study. A severe course of CAP was observed in 105 (10.5%) patients.
The highest IL-6, IL-10 and LBP concentrations were found in patients with CRB-65 scores of 3-4 or CRB scores of 2-3. IL-6 and LBP levels on enrollment in the study were significantly higher for patients with a severe course of CAP than for those who did not have severe CAP. In receiver operating characteristic analyses, the area under the curve values for of IL-6 (0.689), IL-10 (0.665) and LPB (0.624) in a severe course of CAP were lower than that of CRB-65 (0.764) and similar to that of CRB (0.69). The accuracy of both CRB and CRB-65 was increased significantly by including IL-6 measurements. In addition, higher cytokine concentrations were found in patients with typical bacterial infections compared with patients with atypical or viral infections and those with infection of unknown etiology. LBP showed the highest discriminatory power with respect to the etiology of infection.
IL-6, IL-10 and LBP concentrations were increased in patients with a CRB-65 score of 3-4 and a severe course of CAP. The concentrations of IL-6 and IL-10 reflected the severity of disease in patients with CAP. The predictive power of IL-6, IL-10 and LBP for a severe course of pneumonia was lower than that of CRB-65. Typical bacterial pathogens induced the highest LBP, IL-6 and IL-10 concentrations.
Interleukin-6; Interleukin-10; LBP; CAP; Pneumonia; Biomarker; Cytokine
A rapid recruitment of neutrophils to sites of injury or infection is a hallmark of the inflammatory response and is required for effective host defense against pathogenic stimuli. However, neutrophil-mediated inflammation can also lead to chronic tissue destruction; therefore, a better understanding of the mechanisms underlying neutrophil influx and activation is of critical importance. We have previously shown that the acute phase protein α1-antitrypsin (AAT) inhibits neutrophil chemotaxis. In this study, we examine mechanisms related to the effect of AAT on neutrophil responses. We report a previously unknown function of AAT to inactivate calpain I (μ-calpain) and to induce a rapid cell polarization and random migration. These effects of AAT coincided with a transient rise in intracellular calcium, increase in intracellular lipids, activation of the Rho GTPases, Rac1 and Cdc42, and extra-cellular signal-regulated kinase (ERK1/2). Furthermore, AAT caused a significant inhibition of nonstimulated as well as formyl-met-leu-phe (fMLP)-stimulated neutrophil adhesion to fibronectin, strongly inhibited lipopolysaccharide-induced IL-8 release and slightly delayed neutrophil apoptosis. The results presented here broaden our understanding of the regulation of calpain-related neutrophil functional activities, and provide the impetus for new studies to define the role of AAT and other acute phase proteins in health and disease.
The aim of this study was to evaluate epidemiological relationship between chronic obstructive pulmonary disease and sleep apnea syndrome in a sample of Persian population.
As a part of a population-based cross-sectional study, 3900 randomly selected individuals aged 15 years or older were invited to take part in the survey; 3770 individuals (96.6%) agreed to fill out the respiratory and sleep questionnaire. Those subjects suspected to have either chronic obstructive pulmonary disease and/or obstructive sleep apnea underwent spirometry and polysomnography test if indicated. Spirometric measurements were performed on 420 invited responders. Polysomnography measurements were performed on 25 of the responders.
Prevalence rates for sleep apnea, chronic obstructive pulmonary disease and current asthma were 4.98%, 5.7% and 3.1%, respectively. Logistic regression showed independent associations between sleep apnea and chronic obstructive pulmonary disease. There was no significant independent association between sleep apnea symptoms and current asthma and wheeze ever.
These observations indicated relationship between chronic obstructive pulmonary disease and obstructive sleep apnea. These observations indicated the necessity of further studies to explain the possible common pathogenic mechanisms involved in two disease entities.
Chronic Obstructive Pulmonary Disease; Sleep Apnea Syndrome; Iran
Growth-differentiation factor-15 (GDF-15) is a stress-responsive, transforming growth factor-β-related cytokine, which has recently been reported to be elevated in serum of patients with idiopathic pulmonary arterial hypertension (IPAH). The aim of the study was to examine the expression and biological roles of GDF-15 in the lung of patients with pulmonary arterial hypertension (PAH).
GDF-15 expression in normal lungs and lung specimens of PAH patients were studied by real-time RT-PCR and immunohistochemistry. Using laser-assisted micro-dissection, GDF-15 expression was further analyzed within vascular compartments of PAH lungs. To elucidate the role of GDF-15 on endothelial cells, human pulmonary microvascular endothelial cells (HPMEC) were exposed to hypoxia and laminar shear stress. The effects of GDF-15 on the proliferation and cell death of HPMEC were studied using recombinant GDF-15 protein.
GDF-15 expression was found to be increased in lung specimens from PAH patients, com-pared to normal lungs. GDF-15 was abundantly expressed in pulmonary vascular endothelial cells with a strong signal in the core of plexiform lesions. HPMEC responded with marked upregulation of GDF-15 to hypoxia and laminar shear stress. Apoptotic cell death of HPMEC was diminished, whereas HPMEC proliferation was either increased or decreased depending of the concentration of recombinant GDF-15 protein.
GDF-15 expression is increased in PAH lungs and appears predominantly located in vascular endothelial cells. The expression pattern as well as the observed effects on proliferation and apoptosis of pulmonary endothelial cells suggest a role of GDF-15 in the homeostasis of endothelial cells in PAH patients.
Never smokers comprise a substantial proportion of patients with COPD. Their characteristics and possible risk factors in this population are not yet well defined.
We analyzed data from 14 countries that participated in the international, population-based Burden of Obstructive Lung Disease (BOLD) study. Participants were aged ≥ 40 years and completed postbronchodilator spirometry testing plus questionnaires about respiratory symptoms, health status, and exposure to COPD risk factors. A diagnosis of COPD was based on the postbronchodilator FEV1/FVC ratio, according to current GOLD (Global Initiative for Obstructive Lung Disease) guidelines. In addition to this, the lower limit of normal (LLN) was evaluated as an alternative threshold for the FEV1/FVC ratio.
Among 4,291 never smokers, 6.6% met criteria for mild (GOLD stage I) COPD, and 5.6% met criteria for moderate to very severe (GOLD stage II+) COPD. Although never smokers were less likely to have COPD and had less severe COPD than ever smokers, never smokers nonetheless comprised 23.3% (240/1,031) of those classified with GOLD stage II+ COPD. This proportion was similar, 20.5% (171/832), even when the LLN was used as a threshold for the FEV1/FVC ratio. Predictors of COPD in never smokers include age, education, occupational exposure, childhood respiratory diseases, and BMI alterations.
This multicenter international study confirms previous evidence that never smokers comprise a substantial proportion of individuals with COPD. Our data suggest that, in addition to increased age, a prior diagnosis of asthma and, among women, lower education levels are associated with an increased risk for COPD among never smokers.
Virus-associated hemophagocytic syndrome (VAHS) is a severe complication of various viral infections often resulting in multiorgan failure and death. The purpose of this study was to describe baseline characteristics, development of VAHS, related treatments and associated mortality rate of consecutive critically ill patients with confirmed 2009 influenza A (H1N1) infection and respiratory failure.
We conducted a prospective observational study of 25 critically ill patients with 2009 influenza A (H1N1) infection at a single-center intensive care unit in Germany between 5 October 2009 and 4 January 2010. Demographic data, comorbidities, diagnosis of VAHS, illness progression, treatments and survival data were collected. The primary outcome measure was the development of VAHS and related mortality. Secondary outcome variables included duration of mechanical ventilation, support of extracorporeal membrane oxygenation and duration of viral shedding.
VAHS developed in 9 (36%) of 25 critically ill patients with confirmed 2009 influenza A (H1N1) infection, and 8 (89%) of them died. In contrast, the mortality rate in the remaining 16 patients without VAHS was 25% (P = 0.004 for the survival difference in patients with or without VAHS by log-rank analysis). The patients were relatively young (median age, 45 years; interquartile range (IQR), 35 to 56 years of age); however, 18 patients (72%) presented with one or more risk factors for a severe course of illness. All 25 patients received mechanical ventilation for severe acute respiratory distress syndrome and refractory hypoxemia, with a median duration of mechanical ventilation of 19 days (IQR, 13 to 26 days). An additional 17 patients (68%) required extracorporeal membrane oxygenation for a median of 10 days (IQR, 6 to 19 days).
The findings of this study raise the possibility that VAHS may be a frequent complication of severe 2009 influenza A (H1N1) infection and represents an important contributor to multiorgan failure and death.
Bioluminescence imaging is an innovative, noninvasive tool to analyze infectious disease progression under real-life conditions in small laboratory animals. However, the relevance of bioluminescence imaging to monitor invasive compared to noninvasive bacterial infections of the lung has not been examined so far. In the current study, we systematically evaluated the importance of bioluminescence imaging to monitor pneumococcal disease progression by correlating biophotonic signals with lung bacterial loads in two mouse strains (BALB/c, C57BL/6) infected with either self-glowing, bioluminescent serotype 19 Streptococcus pneumoniae causing focal pneumonia or serotype 2 S. pneumoniae causing invasive pneumococcal disease. The best correlations between bioluminescence signals and lung CFU counts were observed in BALB/c mice compared to C57BL/6 mice just on day 3 after infection with invasive serotype 2 S. pneumoniae, while excellent correlations between photon counts and bacterial loads were observed in isolated lungs of BALB/c and C57BL/6 mice, irrespective of the employed pneumococcal serotype. Moreover, good correlations between biophotonic signals and CFU counts were also observed in mice upon infection with serotype 19 S. pneumoniae causing focal pneumonia in mice, again with best correlation values obtained for BALB/c mice at day 3 postinfection. Collectively, we show that the relevance of biophotonic imaging to monitor S. pneumoniae-induced lung infections in mice is largely influenced by the disease model under investigation. The provided data may be important for studies of infectious diseases.
Micro-computed tomography (micro-CT) is a novel tool for monitoring acute and chronic disease states in small laboratory animals. Its value for assessing progressive lung fibrosis in mice has not been reported so far. Here we examined the importance of in vivo micro-CT as non-invasive tool to assess progression of pulmonary fibrosis in mice over time.
Pulmonary fibrosis was induced in mice by intratracheal delivery of an adenoviral gene vector encoding biologically active TGF-ß1 (AdTGF-ß1). Respiratory gated and ungated micro-CT scans were performed at 1, 2, 3, and 4 weeks post pulmonary adenoviral gene or control vector delivery, and were then correlated with respective histopathology-based Ashcroft scoring of pulmonary fibrosis in mice. Visual assessment of image quality and consolidation was performed by 3 observers and a semi-automated quantification algorithm was applied to quantify aerated pulmonary volume as an inverse surrogate marker for pulmonary fibrosis.
We found a significant correlation between classical Ashcroft scoring and micro-CT assessment using both visual assessment and the semi-automated quantification algorithm. Pulmonary fibrosis could be clearly detected in micro-CT, image quality values were higher for respiratory gated exams, although differences were not significant. For assessment of fibrosis no significant difference between respiratory gated and ungated exams was observed.
Together, we show that micro-CT is a powerful tool to assess pulmonary fibrosis in mice, using both visual assessment and semi-automated quantification algorithms. These data may be important in view of pre-clinical pharmacologic interventions for the treatment of lung fibrosis in small laboratory animals.
Sustained neutrophilic infiltration is known to contribute to organ damage, such as acute lung injury. CXC chemokine receptor 2 (CXCR2) is the major receptor regulating inflammatory neutrophil recruitment in acute and chronic inflamed tissues. Whether or not the abundant neutrophil recruitment observed in severe pneumonia is essential for protective immunity against Streptococcus pneumoniae infections is incompletely defined. Here we show that CXCR2 deficiency severely perturbs the recruitment of both neutrophils and exudate macrophages associated with a massive bacterial outgrowth in distal airspaces after infection with S. pneumoniae, resulting in 100% mortality in knockout (KO) mice within 3 days. Moreover, irradiated wild-type mice reconstituted with increasing amounts of CXCR2 KO bone marrow (10, 25, 50, and 75% KO) have correspondingly decreased numbers of both neutrophils and exudate macrophages, which is associated with a stepwise increase in bacterial burden and a reciprocal stepwise decrease in survival in S. pneumoniae-induced pulmonary infection. Finally, application of the CXCR2 antagonist SB-225002 resulted in decreased alveolar neutrophil and exudate macrophage recruitment in mice along with increased lung bacterial loads after infection with S. pneumoniae. Together, these data show that CXC chemokine receptor 2 serves a previously unrecognized nonredundant role in the regulation of both neutrophil and exudate macrophage recruitment to the lung in response to S. pneumoniae infection. In addition, we demonstrate that a threshold level of 10 to 25% of reduced neutrophil recruitment is sufficient to cause increased mortality in mice infected with S. pneumoniae.
The incidence of nosocomial pneumonia involving methicillin-resistant Staphylococcus aureus strains (MRSA) is on the rise worldwide. For years, vancomycin has been used as the drug of choice in the treatment of MRSA infections and was recommended as such by clinical guidelines. There is growing evidence that vancomycin, despite low resistance rates is a suboptimal therapeutic option in critically ill patients, particularly in patients with pneumonia. Disadvantages of vancomycin are i) slow bactericide action, ii) poor penetration into pulmonary tissue, iii) the globally slowly increasing vancomycin MICs ("creep") that result in increased clinical failure despite being susceptible according to defined break points and iv) nephrotoxicity. In contrast to other novel antibiotics with MRSA activity, Linezolid is currently approved for the treatment of nosocomial pneumonia in the USA and Europe. Several studies have compared vancomycin with linezolid for nosocomial pneumonia with conflicting results. This review compares both substances regarding pharmacodynamics, resistance, safety and clinical efficacy and discusses preliminary data of the ZEPHyR study. This study compared linezolid versus vancomycin in patients with proven MRSA pneumonia and was the largest trial ever conducted in this population.
Daptomycin is a novel lipopeptide antibiotic with excellent activity against Gram-positive bacterial pathogens, but its therapeutic value for the treatment of invasive pneumococcal disease compared to that for the treatment of pneumococcal pneumonia is incompletely defined. We investigated the efficacy of daptomycin in two models of Streptococcus pneumoniae-induced lung infection, i.e., pneumococcal pneumonia and septic pneumococcal disease. Mice were infected with a bioluminescent, invasive serotype 2 S. pneumoniae strain or a less virulent serotype 19 S. pneumoniae strain and were then given semitherapeutic or therapeutic daptomycin or ceftriaxone. Readouts included survival; bacterial loads; and septic disease progression, as determined by biophotonic imaging. Semitherapeutic daptomycin treatment fully protected the mice against the progression of septic disease induced by serotype 2 S. pneumoniae, while therapeutic treatment of the mice with daptomycin or ceftriaxone led to ∼70% or ∼60% survival, respectively. In contrast, mice infected with serotype 19 S. pneumoniae developed severe pneumonia and lung leakage even in the presence of increased intra-alveolar daptomycin levels, resulting in only 40% survival, whereas the ceftriaxone-treated mice had 100% survival. Together, although daptomycin demonstrates little efficacy in the treatment of pneumococcal pneumonia, daptomycin is highly effective in preventing S. pneumoniae-induced septic death, thus possibly offering a therapeutic option for patients with life-threatening septic pneumococcal disease.
Despite the availability of powerful antibiotics, community-acquired pneumonia (CAP) remains one of the leading reasons for morbidity and mortality worldwide, and despite the availability of powerful antibiotics, there has been only little improvement in case fatality rates for many years. Consequently, it cannot be expected that novel antibiotics will substantially improve outcomes in CAP. Therefore, this review focuses on novel approaches that may reduce CAP-related mortality: the impact of immunomodulation by macrolides and fluoroquinolones and the prevention of CAP by pneumococcal vaccines.
Passive exposure to environmental tobacco smoke (ETS) is estimated to exert a major burden of disease. Currently, numerous countries have taken legal actions to protect the population against ETS. Numerous studies have been conducted in this field. Therefore, scientometric methods should be used to analyze the accumulated data since there is no such approach available so far.
Methods and Results
A combination of scientometric methods and novel visualizing procedures were used, including density-equalizing mapping and radar charting techniques. 6,580 ETS-related studies published between 1900 and 2008 were identified in the ISI database. Using different scientometric approaches, a continuous increase of both quantitative and qualitative parameters was found. The combination with density-equalizing calculations demonstrated a leading position of the United States (2,959 items published) in terms of quantitative research activities. Charting techniques demonstrated that there are numerous bi- and multilateral networks between different countries and institutions in this field. Again, a leading position of American institutions was found.
This is the first comprehensive scientometric analysis of data on global scientific activities in the field of environmental tobacco smoke research. The present findings can be used as a benchmark for funding allocation processes.
Diseases associated with smoking are a foremost cause of premature death in the world, both in developed and developing countries. Eliminating smoking can do more to improve health and prolong life than any other measure in the field of preventive medicine. Today's medical students will play a prominent role in future efforts to prevent and control tobacco use.
A cross-sectional, self-administered, anonymous survey of fifth-year medical students in Berlin, Germany was conducted in November 2007. The study explored the prevalence of smoking among medical students. We assessed their current knowledge regarding tobacco dependence and the effectiveness of smoking cessation methods. Students' perceived competence to counsel smokers and promote smoking cessation treatments was also explored. Analyses were based on responses from 258 students (86.6% response rate).
One quarter of the medical students surveyed were current smokers. The smoking rate was 22.1% among women, 32.4% among men. Students underestimated smoking-related mortality and the negative effect of smoking on longevity. A considerable number of subjects erroneously assumed that nicotine causes coronary artery disease. Students' overall knowledge of the effectiveness of smoking cessation methods was inadequate. Only one third of the students indicated that they felt qualified to counsel patients about tobacco dependence.
This study reveals serious deficiencies in knowledge and counseling skills among medical students in our sample. The curriculum of every medical school should include a tobacco module. Thus, by providing comprehensive training in nicotine dependence interventions to medical students, smokers will have access to the professional expertise they need to quit smoking.