PROGRESS - prospective observational study on hospitalized community acquired pneumonia.

BACKGROUND: Community acquired pneumonia (CAP) is a high incidence disease resulting in about 260,000 hospital admissions per year in Germany, more than myocardial infarction or stroke. Worldwide, CAP is the most frequent infectious disease with high lethality ranging from 1.2 % in those 20-29 years old to over 10 % in patients older than 70 years, even in industrial nations. CAP poses numerous medical challenges, which the PROGRESS (Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis) network aims to tackle: Operationalization of disease severity throughout the course of disease, outcome prediction for hospitalized patients and prediction of transitions from uncomplicated CAP to severe CAP, and finally, to CAP with sepsis and organ failure as a life-threatening condition. It is a major aim of PROGRESS to understand and predict patient heterogeneity regarding outcome in the hospital and to develop novel treatment concepts. METHODS: PROGRESS was designed as a clinical, observational, multi-center study of patients with CAP requiring hospitalization. More than 1600 patients selected for low burden of co-morbidities have been enrolled, aiming at a total of 3000. Course of disease, along with therapy, was closely monitored by daily assessments and long-term follow-up. Daily blood samples allow in depth molecular-genetic characterization of patients. We established a well-organized workflow for sample logistics and a comprehensive data management system to collect and manage data from more than 50 study centers in Germany and Austria. Samples are stored in a central biobank and clinical data are stored in a central data base which also integrates all data from molecular assessments. DISCUSSION: With the PROGRESS study, we established a comprehensive data base of high quality clinical and molecular data allowing investigation of pressing research questions regarding CAP. In-depth molecular characterization will contribute to the discovery of disease mechanisms and establishment of diagnostic and predictive biomarkers. A strength of PROGRESS is the focus on younger patients with low burden of co-morbidities, allowing a more direct look at host biology with less confounding. As a resulting limitation, insights from PROGRESS will require validation in representative patient cohorts to assess clinical utility. TRIAL REGISTRATION: The PROGRESS study was retrospectively registered on May 24(th), 2016 with ClinicalTrials.gov: NCT02782013.

[CAPNETZ. The competence network for community-acquired pneumonia (CAP)]. / CAPNETZ. Das Kompetenzzentrum für ambulant erworbene Pneumonie.

CAPNETZ is a medical competence network for community-acquired pneumonia (CAP), which was funded by the German Ministry for Education and Research. It has accomplished seminal work on pneumonia over the last 15 years. A unique infrastructure was established which has so far allowed us to recruit and analyze more than 11,000 patients. The CAPNETZ cohort is the largest cohort worldwide and the results obtained relate to all relevant aspects of CAP management (epidemiology, risk stratification via biomarkers or clinical scores, pathogen spectrum, pathogen resistance, antibiotic management, prevention and health care research). Results were published in more than 150 journals and informed the preparation and update of the national S3-guideline. CAPNETZ was also the foundation for further networks like the Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis) (PROGRESS), the Systems Medicine of Community Acquired Pneumonia Network (CAPSyS) and SFB-TR84 (Sonderforschungsbereich - Transregio 84). The main recipients (Charité Berlin, University Clinic Ulm and the Hannover Medical School) founded the CAPNETZ foundation and transferred all data and materials rights to this foundation. Moreover, the ministry granted the CAPNETZ foundation the status of being eligible to apply for research proposals and receive research funds. Since 2013 the CAPNETZ foundation has been an associated member of the German Center for Lung Research (DZL). Thus, a solid foundation has been set up for CAPNETZ to continue its success story.

Community-acquired pneumonia as medical emergency: predictors of early deterioration.

BACKGROUND: Early organ dysfunction determines the prognosis of community-acquired pneumonia (CAP), and recognition of CAP as a medical emergency has been advocated. OBJECTIVE: To characterise patients with 'emergency CAP' and evaluate predictors for very early organ failure or death. METHODS: 3427 prospectively enrolled patients of the CAPNETZ cohort were included. Emergency CAP was defined as requirement for mechanical ventilation or vasopressor support (MV/VS) or death within 72 h and 7 days after hospital admission, respectively. To determine independent predictors, multivariate Cox regression was employed. The ATS/IDSA 2007 minor criteria were evaluated for prediction of emergency CAP in patients without immediate need of MV/VS. RESULTS: 140 (4%) and 173 (5%) patients presented with emergency CAP within 3 and 7 days, respectively. Hospital mortality of patients presenting without immediate need of MV/VS was highest. Independent predictors of emergency CAP were the presence of focal chest signs, home oxygen therapy, multilobar infiltrates, altered mental status and altered vital signs (hypotension, raised respiratory or heart rate, hypothermia). The ATS/IDSA 2007 minor criteria showed a high sensitivity and negative predictive value, whereas the positive predictive value was low. Reduction to 6 minor criteria did not alter accuracy. CONCLUSIONS: Emergency CAP is a rare but prognostic relevant condition, mortality is highest in patients presenting without immediate need of MV/VS. Vital sign abnormalities and parameters indicating acute organ dysfunction are independent predictors, and the ATS/IDSA 2007 minor criteria show a high negative predictive value.

Vitamin D deficiency in community-acquired pneumonia: low levels of 1,25(OH)2 D are associated with disease severity.

OBJECTIVES: We aimed to explore the association between vitamin D levels and the severity, mortality and microbiological etiology of community-acquired pneumonia. METHODS: Vitamin D levels (both, the reservoir form 25-OH and the activated form 1,25-OH2) of 300 randomly selected patients with community-acquired pneumonia due to pre-specified pathogens included in the German competence network (CAPNETZ) study were measured. Prior to statistical analysis, values of 25-OH and 1,25-OH2 were power-transformed to achieve parametric distribution. All further analyses were performed with seasonally and age adjusted values. RESULTS: There was only a modest (Spearman Coefficient 0.38) positive correlation between 25-OH and 1,25-OH2. For 1,25-OH2 but not 25-OH, the general linear model revealed a significant inverse correlation between serum concentration and CURB score (p = 0.011). Liver and respiratory co-morbidity were associated with significantly lower 25-OH values and renal co-morbidity with significantly lower 1,25-OH2 values. No significant differences of 1,25-OH2 or 25-OH between different pathogens (influenza virus, Legionella spp., Streptococcus pneumoniae) were detected. CONCLUSION: For 1,25-OH2, we found a significant and independent (controlled for age, season and pathogen) negative correlation to pneumonia severity. Therefore, supplementation of non-activated vitamin D to protect from pneumonia may be non-sufficient in patients that have a decreased capacity to hydroxylate 25-OH to 1,25-OH2.

Nursing-home-acquired pneumonia in Germany: an 8-year prospective multicentre study.

OBJECTIVE: To determine differences in aetiologies, initial antimicrobial treatment choices and outcomes in patients with nursing-home-acquired pneumonia (NHAP) compared with patients with community-acquired pneumonia (CAP), which is a controversial issue. METHODS: Data from the prospective multicentre Competence Network for Community-acquired pneumonia (CAPNETZ) database were analysed for hospitalised patients aged ≥65 years with CAP or NHAP. Potential differences in baseline characteristics, comorbidities, physical examination findings, severity at presentation, initial laboratory investigations, blood gases, microbial investigations, aetiologies, antimicrobial treatment and outcomes were determined between the two groups. RESULTS: Patients with NHAP presented with more severe pneumonia as assessed by CRB-65 (confusion, respiratory rate, blood pressure, 65 years and older) score than patients with CAP but received the same frequency of mechanical ventilation and less antimicrobial combination treatment. There were no clinically relevant differences in aetiology, with Streptococcus pneumoniae the most important pathogen in both groups, and potential multidrug-resistant pathogens were very rare (<5%). Only Staphylococcus aureus was more frequent in the NHAP group (n=12, 2.3% of the total population, 3.1% of those with microbial sampling compared with 0.7% and 0.8% in the CAP group, respectively). Short-term and long-term mortality in the NHAP group was higher than in the CAP group for patients aged ≥65 years (26.6% vs 7.2% and 43.8% vs 14.6%, respectively). However, there was no association between excess mortality and potential multidrug-resistant pathogens. CONCLUSIONS: Excess mortality in patients with NHAP cannot be attributed to a different microbial pattern but appears to result from increased comorbidities, and consequently, pneumonia is frequently considered and managed as a terminal event.

Community-acquired pneumonia in younger patients is an entity on its own.

Community-acquired pneumonia (CAP) is now most frequent in elderly patients. CAP in the younger patient has attracted much less attention. Therefore, we compared patients with CAP aged 18 to <65 yrs with those aged ≥ 65 yrs. Data from the prospective multicentre Competence Network for Community Acquired Pneumonia Study Group (CAPNETZ) database were analysed for potential differences in baseline characteristics, comorbidities, clinical presentation, microbial investigations, aetiologies, antimicrobial treatment and outcomes. Overall, 7,803 patients were studied. The proportion of younger patients (aged <65 yrs) was 52.3% (18 to <30 yrs 6.4%; <40 yrs 17.1%; <50 yrs 29.4%). Comorbidity was present in only half of the younger patients (46.6% versus 88.2%). Fever and chest pain were more common. Most younger patients presented with mild CAP (74.0% had a CRB-65 [corrected] score of 0 (confusion of new onset, [corrected] respiratory rate of ≥ 30 breaths · min(-1), blood pressure <90 mmHg or diastolic blood pressure ≤ 60 mmHg, age ≥ 65 yrs)). Overall, Streptococcus pneumoniae and Mycoplasma pneumoniae were the most frequent pathogens in the younger patients. Short-term mortality was very low (1.7% versus 8.2%) and even lower in patients without comorbidity (0.3% versus 2.4%). Long-term mortality was 3.2% versus 15.9%, also lower in patients without comorbidity (0.8% versus 6.1%). Most of the differences found clearly arise after the fifth or within the middle of the sixth decade. CAP in the younger patient is a clinically distinct entity.

Serum cortisol predicts death and critical disease independently of CRB-65 score in community-acquired pneumonia: a prospective observational cohort study.

BACKGROUND: Several biomarkers and prognostic scores have been evaluated to predict prognosis in community-acquired pneumonia (CAP). Optimal risk stratification remains to be evaluated. The aim of this study was to evaluate serum cortisol as biomarker for the prediction of adverse outcomes independently of the CRB-65 score und inflammatory biomarkers in a large cohort of hospitalised patients with CAP. METHODS: 984 hospitalised CAP-patients were included. Serum cortisol was measured and its prognostic accuracy compared to the CRB-65 score, leucocyte count and C-reactive protein. Predefined endpoints were 30-day mortality and the combined endpoint critical pneumonia, defined as presence of death occurring during antibiotic treatment, mechanical ventilation, catecholamine treatment or ICU admission. RESULTS: 64 patients died (6.5%) and 85 developed critical pneumonia (8.6%). Cortisol levels were significantly elevated in both adverse outcomes (p < 0.001) and predicted mortality (AUC 0.70, cut-off 795 nmol/L) and critical pneumonia (AUC 0.71) independently of all other measured variables after logistic regression analysis (p = 0.005 and 0.001, respectively). Prognostic accuracy of CRB-65 was significantly improved by adding cortisol levels (combined AUC 0.81 for both endpoints). In Kaplan-Meier analysis, cortisol predicted survival within different CRB-65 strata (p = 0.003). In subgroup analyses, cortisol independently predicted critical pneumonia when compared to procalcitonin, the CURB65 score and minor criteria for severe pneumonia according to the 2007 ATS/IDSA-guideline. CONCLUSION: Cortisol predicts mortality and critical disease in hospitalised CAP-patients independently of clinical scores and inflammatory biomarkers. It should be incorporated into trials assessing optimal combinations of clinical criteria and biomarkers to improve initial high risk prediction in CAP.

Surgical Repair of a Traumatic Gastrobronchial Fistula.

BACKGROUND Gastrobronchial fistulas mostly occur as a result of postoperative complications, including those of bariatric, esophageal, and spleno-pancreatic surgery. Other causes are pneumonia, neoplasm, gastric ulcer, and subphrenic abscess. Traumatic fistulous communications between the stomach and the lung tissue are rare, with only 8 cases reported in the English-language literature (PubMed search) until now. CASE REPORT We report a 49-year-old female patient with a gastrobronchial fistula secondary to diaphragm rupture 7 years prior, with intrathoracic herniation of the gastric fundus. She underwent thoracotomy for surgical repair. She presented in our Emergency Department with recurrent hemoptysis and painful cough. The diagnosis of the gastrobronchial fistula was confirmed by computed tomography and simultaneous bronchoscopy and esophagogastroscopy, with injection of toluidine blue. As a multidisciplinary team, we opted for surgical repair owing to the fistula extent and severity and the need of repair of the diaphragm hernia. The patient underwent left-sided thoracoscopy. However, owing to dense adhesions and chronic inflammation, we converted to an open procedure. The herniated gastric fundus was repaired by wedge resection. The affected lung tissue was debrided and reconstructed by suture repair. The diaphragmatic defect was closed by sutures with mesh augmentation. The patient's postoperative course was uncomplicated, and she was discharged in good clinical condition on postoperative day 7. CONCLUSIONS Owing to the scarcity of the disease, the management of a gastrobronchial fistula is not standardized. The establishment of the diagnosis of the disease is often challenging. Therapeutic options include conservative measures, endoscopic options, and surgical repair. Our case showed that a multidisciplinary workup is essential for successful treatment.

Role of sphingosine kinase 1 in allergen-induced pulmonary vascular remodeling and hyperresponsiveness.

BACKGROUND: Immunologic processes might contribute to the pathogenesis of pulmonary arterial hypertension (PAH), a fatal condition characterized by progressive pulmonary arterial remodeling, increased pulmonary vascular resistance, and right ventricular failure. Experimental allergen-driven lung inflammation evoked morphologic and functional vascular changes that resembled those observed in patients with PAH. Sphingosine kinase 1 (SphK1) is the main pulmonary contributor to sphingosine-1-phosphate (S1P) synthesis, a modulator of immune and vascular functions. OBJECTIVE: We sought to investigate the role of SphK1 in allergen-induced lung inflammation. METHODS: SphK1-deficient mice and C57Bl/6 littermates (wild-type [WT] animals) were subjected to acute or chronic allergen exposure. RESULTS: After 4 weeks of systemic ovalbumin sensitization and local airway challenge, airway responsiveness increased less in SphK1(-/-) compared with WT mice, whereas pulmonary vascular responsiveness was greatly increased and did not differ between strains. Acute lung inflammation led to an increase in eosinophils and mRNA expression for S1P phosphatase 2 and S1P lyase in lungs of WT but not SphK1(-/-) mice. After repetitive allergen exposure for 8 weeks, airway responsiveness was not augmented in SphK1(-/-) or WT mice, but pulmonary vascular responsiveness was increased in both strains, with significantly higher vascular responsiveness in SphK1(-/-) mice compared with that seen in WT mice. Increased vascular responsiveness was accompanied by remodeling of the small and intra-acinar arteries. CONCLUSION: : The data support a role for SphK1 and S1P in allergen-induced airway inflammation. However, SphK1 deficiency increased pulmonary vascular hyperresponsiveness, which is a component of PAH pathobiology. Moreover, we show for the first time the dissociation between inflammation-induced remodeling of the airways and pulmonary vasculature.

Immunostimulation with macrophage-activating lipopeptide-2 increased survival in murine pneumonia.

Community-acquired pneumonia (CAP) is associated with high morbidity and mortality, and Streptococcus pneumoniae is the most prevalent causal pathogen identified in CAP. Impaired pulmonary host defense increases susceptibility to pneumococcal pneumonia. S. pneumoniae may up-regulate Toll-like receptor (TLR)-2 expression and activate TLR-2, contributing to pneumococcus-induced immune responses. In the current study, the course of severe murine pneumococcal pneumonia after pulmonary TLR-2-mediated immunostimulation with synthetic macrophage-activating lipopeptide-2 (MALP-2) was examined. Intratracheal MALP-2 application evoked enhanced proinflammatory cytokine and chemokine release, resulting in recruitment of polymorphonuclear neutrophils (PMN), macrophages, and lymphocytes into the alveolar space in WT, but not in TLR-2-deficient mice. In murine lungs as well as in human alveolar epithelial cells (A549), MALP-2 increased TLR-2 expression at both mRNA and protein level. Blood leukocyte numbers and populations remained unchanged. MALP-2 application 24 hours before intranasal pneumococcal infection resulted in increased levels of CCL5 associated with augmented leukocyte recruitment, and decreased levels of anti-inflammatory IL-10 in bronchoalveolar lavage fluid. Clinically, MALP-2-treated as compared with untreated mice showed increased survival, reduced hypothermia, and increased body weight. MALP-2 also reduced bacteremia and improved bacterial clearance in lung parenchyma, as examined by immunohistochemistry. In conclusion, pulmonary immunostimulation with MALP-2 before infection with S. pneumoniae improved local host defense and increased survival in murine pneumococcal pneumonia.

Systemic use of the endolysin Cpl-1 rescues mice with fatal pneumococcal pneumonia.

OBJECTIVES: Community-acquired pneumonia is a very common infectious disease associated with significant morbidity and mortality. Streptococcus pneumoniae is the predominant pathogen in this disease, and pneumococcal resistance to multiple antibiotics is increasing. The recently purified bacteriophage endolysin Cpl-1 rapidly and specifically kills pneumococci on contact. The aim of this study was to determine the therapeutic potential of Cpl-1 in a mouse model of severe pneumococcal pneumonia. DESIGN: Controlled, in vivo laboratory study. SUBJECTS: Female C57/Bl6 mice, 8-12 weeks old. INTERVENTIONS: Mice were transnasally infected with pneumococci and therapeutically treated with Cpl-1 or amoxicillin by intraperitoneal injections starting 24 or 48 hours after infection. MEASUREMENTS AND MAIN RESULTS: Judged from clinical appearance, decreased body weight, reduced dynamic lung compliance and Pao2/Fio2 ratio, and morphologic changes in the lungs, mice suffered from severe pneumonia at the onset of therapy. When treatment was commenced 24 hours after infection, 100% Cpl-1-treated and 86% amoxicillin-treated mice survived otherwise fatal pneumonia and showed rapid recovery. When treatment was started 48 hours after infection, mice had developed bacteremia, and three of seven (42%) Cpl-1-treated and five of seven (71%) amoxicillin-treated animals survived. Cpl-1 dramatically reduced pulmonary bacterial counts, and prevented bacteremia, systemic hypotension, and lactate increase when treatment commenced at 24 hours. In vivo, treatment with Cpl-1 or amoxicillin effectively reduced counts of penicillin-susceptible pneumococci. The inflammatory response in Cpl-1-and amoxicillin-treated mice was lower than in untreated mice, as determined by multiplex cytokine assay of lung and blood samples. In human epithelial cell cultures, lysed bacteria evoked less proinflammatory cytokine release and cell death, as compared with viable bacteria. CONCLUSIONS: Cpl-1 may provide a new therapeutic option in the treatment of pneumococcal pneumonia.

Phosphodiesterase 2 inhibition diminished acute lung injury in murine pneumococcal pneumonia.

OBJECTIVE: Severe pneumococcal pneumonia frequently causes respiratory failure. Both pathogen factors and an uncontrolled host response may contribute to acute lung injury by impairing microvascular barrier function. Phosphodiesterase 2 (PDE2) was examined as a potential target in pneumonia-induced lung microvascular hyperpermeability. DESIGN: Controlled, in vitro, ex vivo, and in vivo laboratory study. SUBJECTS: Female Balb/C and C57Bl/6 mice, 8-12 weeks old. INTERVENTIONS: Human umbilical vein endothelial cells and isolated mouse lungs were challenged with the pneumococcal exotoxin pneumolysin in the presence or absence of the selective PDE2 inhibitors 9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6one (PDP) or hydroxy-PDP. Transcellular electrical resistance or human serum albumin leakage in bronchoalveolar lavage fluid was determined, respectively. In addition, we induced pneumococcal pneumonia in mice and treated with hydroxy-PDP via continuous subcutaneous application by osmotic pumps. Human serum albumin leakage in bronchoalveolar lavage fluid was measured 48 hours after transnasal infection, and lung specimens were analyzed by TaqMan real-time polymerase chain reaction and Western blot for PDE2 gene and protein expression. MEASUREMENTS AND MAIN RESULTS: In isolated perfused mouse lungs and in human umbilical vein endothelial cell monolayers, selective inhibition of PDE2 markedly decreased pneumolysin-induced hyperpermeability. Furthermore, in murine pneumococcal pneumonia, pulmonary PDE2-mRNA and -protein expression was significantly increased, and pneumonia-induced vascular permeability was distinctively reduced by PDE2 inhibition. CONCLUSIONS: PDE2 inhibition diminished microvascular leakage in pneumococcal pneumonia, and pulmonary PDE2 upregulation may play a crucial role in this respect. Selective PDE2 inhibitors thus may offer a promising therapeutic approach in severe pneumococcal pneumonia.

Rho-kinase and contractile apparatus proteins in murine airway hyperresponsiveness.

Airway hyperresponsiveness (AHR) is a hallmark of bronchial asthma. Increased expression of smooth muscle contractile proteins or increased responsiveness of the contractile apparatus due to RhoA/Rho-kinase activation may contribute to AHR. BALB/c mice developed AHR following systemic sensitization by intraperitoneal injections of 20 microg ovalbumin (OVA) in presence of 2mg Al(OH)(3) on days 1 and 14, and airway challenge by 1% OVA-inhalation for 20 min each on days 28, 29 and 30. As assessed by Western blot, protein expression of RhoA, MLC (myosin light chain) and smMLCK (smooth muscle myosin light chain kinase) was increased in lungs of OVA/OVA-animals with AHR, as well as in lungs of OVA-sensitized and sham-challenged animals (OVA/PBS) without AHR, compared with lungs of PBS/PBS-animals. Pretreatment with the specific Rho-kinase inhibitor Y-27632 reduced MLC-phosphorylation and AHR. Contribution of Rho-kinase to bronchoconstriction was increased in lungs of OVA/OVA-animals compared with OVA/PBS- and PBS/PBS-animals, respectively. Furthermore, bronchoconstriction following MCh stimulation was significantly reduced after Y-27632 application. In conclusion, systemic allergen-sensitization increased pulmonary expression of proteins involved in smooth muscle contraction, which may contribute to development of AHR. However, this observation was independent from local allergen challenge, suggesting that additional cofactors may be required for the activation of Rho-kinase and thereby the induction of AHR. Rho-kinase may play an important role in murine AHR, and the bronchodilating action of Rho-kinase inhibition may offer a new therapeutic perspective in obstructive airway disease.

Adrenomedullin reduces endothelial hyperpermeability.

Endothelial hyperpermeability induced by inflammatory mediators is a hallmark of sepsis and adult respiratory distress syndrome. Increased levels of the regulatory peptide adrenomedullin (ADM) have been found in patients with systemic inflammatory response. We analyzed the effect of ADM on the permeability of cultured human umbilical vein endothelial cell (HUVEC) and porcine pulmonary artery endothelial cell monolayers. ADM dose-dependently reduced endothelial hyperpermeability induced by hydrogen peroxide (H2O2), thrombin, and Escherichia coli hemolysin. Moreover, ADM pretreatment blocked H2O2-related edema formation in isolated perfused rabbit lungs and increased cAMP levels in lung perfusate. ADM bound specifically to HUVECs and porcine pulmonary artery endothelial cells and increased cellular cAMP levels. Simultaneous inhibition of cAMP-degrading phosphodiesterase isoenzymes 3 and 4 potentiated ADM-dependent cAMP accumulation and synergistically enhanced ADM-dependent reduction of thrombin-induced hyperpermeability. However, ADM showed no effect on endothelial cGMP content, basal intracellular Ca2+ levels, or the H2O2-stimulated, thrombin-stimulated, or Escherichia coli hemolysin-stimulated Ca2+ increase. ADM diminished thrombin- and H2O2-related myosin light chain phosphorylation as well as stimulus-dependent stress fiber formation and gap formation in HUVECs, suggesting that ADM may stabilize the barrier function by cAMP-dependent relaxation of the microfilament system. These findings identify a new function of ADM and point to ADM as a potential interventional agent for the reduction of vascular leakage in sepsis and adult respiratory distress syndrome.

Detection of reactive oxygen species in isolated, perfused lungs by electron spin resonance spectroscopy.

BACKGROUND: The sources and measurement of reactive oxygen species (ROS) in intact organs are largely unresolved. This may be related to methodological problems associated with the techniques currently employed for ROS detection. Electron spin resonance (ESR) with spin trapping is a specific method for ROS detection, and may address some these technical problems. METHODS: We have established a protocol for the measurement of intravascular ROS release from isolated buffer-perfused and ventilated rabbit and mouse lungs, combining lung perfusion with the spin probe 1-hydroxy-3-carboxy-2,2,5,5-tetramethylpyrrolidine (CPH) and ESR spectroscopy. We then employed this technique to characterize hypoxia-dependent ROS release, with specific attention paid to NADPH oxidase-dependent superoxide formation as a possible vasoconstrictor pathway. RESULTS: While perfusing lungs with CPH over a range of inspired oxygen concentrations (1-21 %), the rate of CP* formation exhibited an oxygen-dependence, with a minimum at 2.5 % O2. Addition of superoxide dismutase (SOD) to the buffer fluid illustrated that a minor proportion of this intravascular ROS leak was attributable to superoxide. Stimulation of the lungs by injection of phorbol-12-myristate-13-acetate (PMA) into the pulmonary artery caused a rapid increase in CP* formation, concomitant with pulmonary vasoconstriction. Both the PMA-induced CPH oxidation and the vasoconstrictor response were largely suppressed by SOD. When the PMA challenge was performed at different oxygen concentrations, maximum superoxide liberation and pulmonary vasoconstriction occurred at 5% O2. Using a NADPH oxidase inhibitor and NADPH-oxidase deficient mice, we illustrated that the PMA-induced superoxide release was attributable to the stimulation of NADPH oxidases. CONCLUSION: The perfusion of isolated lungs with CPH is suitable for detection of intravascular ROS release by ESR spectroscopy. We employed this technique to demonstrate that 1) PMA-induced vasoconstriction is caused "directly" by superoxide generated from NADPH oxidases and 2) this pathway is pronounced in hypoxia. NADPH oxidases thus may contribute to the hypoxia-dependent regulation of pulmonary vascular tone.

Increased Severity and Mortality of CAP in COPD: Results from the German Competence Network, CAPNETZ.

Background:Mortality of community acquired pneumonia (CAP) remains high despite significant research efforts. Knowledge about comorbidities including chronic obstructive pulmonary disease (COPD) might help to improve management and ultimately, survival. The impact of COPD on CAP severity and mortality remains a point of discussion. Objectives:Assess the prevalence and clinical characteristics of COPD in the observational German Competence Network for CAP, CAPNETZ, and to study the impact of COPD on CAP severity and mortality. Methods:1307 consecutive patients with CAP (57.0% males, age 59.0±18.5), classified as CAP-only (n=1043; 78.0%) and CAP-COPD (n=264; 20.2%) were followed up for 180 days. Associations between CAP, COPD and mortality were evaluated by univariate/multivariate and Kaplan-Meier survival analyses. Results:CAP-COPD patients were older, more often males, current/former smokers, with higher confusion-urea-respiratory rate-blood pressure, (CURB) scores. Length of hospital stay, urea, glucose and leucocytes plasma levels, and arterial carbon dioxide tension (PaCO2) were significantly increased in CAP-COPD. Thirty, 90- and 180-day mortality rates were significantly increased in CAP-COPD (p=0.046, odds ratio [OR]=2.48, 95% confidence interval [CI] 1.015-6.037; p=0.003, OR=2.80, 95%CI 1.430-5.468; p=0.001, OR=2.57, 95%CI 1.462-4.498; respectively). Intensive care unit (ICU)-admission and age, but not COPD, were identified as independent predictors of short- and long-term mortality. Conclusion:Severity as well as mortality was significantly higher in COPD patients with CAP. To improve CAP management with the aim to decrease its still-too-high mortality, underlying comorbidities, particularly COPD, need to be assessed.

Increase in alveolar antioxidant levels in hyperoxic and anoxic ventilated rabbit lungs during ischemia.

Increases in free radicals are believed to play a central role in the development of pulmonary ischemia/reperfusion (I-R) injury, leading to microvascular leakage and deterioration of pulmonary surfactant. Continued ventilation during ischemia offers significant protection against I-R injury, but the impact of alveolar oxygen supply both on lung injury and on radical generation is still unclear. We investigated the influence of hyperoxic (95% O2) and anoxic (0% O2) ventilation during ischemia on alveolar antioxidant status and surfactant properties in isolated rabbit lungs. Normoxic and hyperoxic ventilated, buffer-perfused lungs (n = 5 or 6) and native lungs (n = 6) served as controls. As compared with controls, biophysical and biochemical surfactant properties were not altered in anoxic as well as hyperoxic ventilated ischemic (2, 3, and 4 h) lungs. Assessment of several antioxidants (reduced glutathione (GSH), alpha-tocopherol (vitamin E), retinol (vitamin A), ascorbic acid (vitamin C), uric acid, and plasmalogens (1-O-alkenyl-2-acyl-phospholipids)) in bronchoalveolar lavage fluid (BALF) revealed a significant increase in antioxidant compounds under anoxic and hyperoxic ventilation, with maximum levels occuring after 3 h of ischemia. For example, GSH increased to 5.1 +/- 0.8 microM (mean +/- SE, p <.001) after 3 h of anoxic ventilated ischemia and to 2.7 +/- 0.2 microM (p <.01) after hyperoxic ventilated ischemia compared with native controls (1.3 +/- 0.2 microM), but did not significantly change under anoxic and hyperoxic ventilation alone. In parallel, under ischemic conditions, oxidized glutathione (GSSG) increased during hyperoxic (3 h: 0.81 +/- 0.04 microM, p <.001), but remained unchanged during anoxic (3 h: 0.31 +/- 0.04 microM) ventilation compared with native controls (0.22 +/- 0.02 microM), whereas F2-isoprostanes were elevated under both hyperoxic (3 h: 63 +/- 15 pM, p <.01) and anoxic (3 h: 50 +/- 9 pM, p <.01) ventilation compared with native controls (16 +/- 4 pM). We conclude that oxidative stress is increased in the lung alveolar lining layer during ischemia, during both anoxic and hyperoxic ventilation. This is paralleled by an increase rather than a decrease in alveolar antioxidant levels, suggested to reflect an adaptive response to oxidative stress during ischemia.

Subthreshold doses of nebulized prostacyclin and rolipram synergistaically protect against lung ischemia-reperfusion.

BACKGROUND: Pulmonary edema caused by increased microvascular permeability is an important feature of lung ischemia-reperfusion (I/R) injury. METHODS: We investigated the impact of co-aerosolized prostaglandin (PG)I(2) and the 3',5-cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase inhibitor rolipram on microvascular leakage following I/R injury. Buffer-perfused rabbit lungs were exposed to 270 minutes of warm ischemia while anoxic ventilation and a positive intravascular pressure were maintained. RESULTS: On reperfusion, a massive increase of the capillary filtration coefficient and severe edema formation were noted, whereas microvascular pressures displayed only minor changes. Short-time aerosolization of subthreshold doses of either rolipram (33 microg) or PGI(2) (2.6 microg) at the beginning of ischemia did not attenuate the leakage response, whereas the co-aerosolization of both agents largely blocked any permeability increase and edema formation, independent of hemodynamic effects. The same was true when the co-aerosolization was undertaken before onset of ischemia. Similarly, the intravascular administration of rolipram and PGI(2) showed a synergistic reduction of I/R-induced vascular leak but demanded 10-fold higher doses. Intravascular release of cAMP was markedly enhanced on combined PGI(2)-rolipram administration but depended on the mode of delivery of these agents. CONCLUSIONS: Low doses of aerosolized prostacyclin and rolipram synergistically protect against severe lung I/R injury and can be used independently of lung perfusion. This strategy may be suitable for an improvement of organ preservation in lung transplantation including early management of non-heart-beating donors.

Adult patients with nosocomial pneumonia: epidemiology, diagnosis, and treatment.

BACKGROUND: Nosocomial pneumonia is among the most common types of infection in hospitalized patients. The increasing prevalence of multi-drug resistant organisms (MDROs) in recent years points to the need for an up-to-date clinical guideline. METHODS: An interdisciplinary S3 guideline was created on the basis of a systematic literature review in the PubMed and Cochrane Library databases, with assessment and grading of the evidence according to the GRADE system. RESULTS: 9097 abstracts and 808 articles were screened in full text, and 22 recommendations were issued. It is recommended that any antimicrobial treatment should be preceded by a microbiological diagnostic evaluation with cultures of blood and respiratory samples. The diagnosis of nosocomial pneumonia should be suspected in any patient with a new or worsened pulmonary infiltrate who meets any two of the following three criteria: leucocyte count above 10,000 or below 4000/µL, temperature above 38.3°C, and/or the presence of purulent respiratory secretions. The initially calculated antimicrobial treatment should be begun without delay; it should be oriented to the locally prevailing resistance pattern, and its intensity should be a function of the risk of infection with MDROs. The initial treatment should be combination therapy if there is a high risk of MDRO infection and/or if the patient is in septic shock. In the new guideline, emphasis is laid on a strict de-escalation concept. In particular, antimicrobial treatment usually should not be continued for longer than eight days. CONCLUSION: The new guideline's recommendations are intended to encourage rational use of antibiotics, so that antimicrobial treatment will be highly effective while the unnecessary selection of multi-drug-resistant organisms will be avoided.

Presentation, etiology and outcome of pneumonia in younger nursing home residents.

OBJECTIVE: Nursing home-acquired pneumonia characteristically affects elderly patients with multiple comorbidities; it is associated with multidrug-resistant (MDR) pathogens and a high mortality. We studied the specific impact of age on the presentation, etiology and outcome of patients with NHAP. METHODS: Data from the prospective multicenter CAPNETZ database were used for a comparison of the hospitalized younger nursing home residents with pneumonia to those aged ≥ 65 years as regards clinical presentation, comorbidity, severity at presentation, etiology, and outcome. RESULTS: Amongst 618 patients with NHAP, 16% of patients (n = 100) were aged; 65 years. Comorbidity was present in most patients with NHAP but the pattern of comorbidity differed significantly. The rate of potential MDR pathogens was low among both age groups (together around 5%). According to the CRB-65 score, NHAP presentation was less severe in the younger patients. Short- and long-term mortality was twice as low in the younger patients with rates of 12.9% vs 26.6%, and 24.3% vs 43.8%, p = 0.014 and 0.002), respectively. In contrast, the usage of mechanical ventilation was more than two-fold higher (12% vs 5%) (p = 0.008) in younger patients. Antimicrobial treatment strategies did not account for different outcomes. CONCLUSIONS: A considerable proportion of patients with NHAP are: 65 years of age. They differ from older patients in terms of clinical presentation, frequency and type of comorbidity, as well as outcome. NHAP is a heterogeneous entity, with age and comorbidity as the main determinant of NHAP characteristics.