Shift in bacterial etiology from the CAPNETZ cohort in patients with community-acquired pneumonia: data over more than a decade.

To determine the most relevant pathogens for CAP in Germany, patients with radiologically confirmed pulmonary infiltrates and at least one clinical sign of lung infection were prospectively recruited within the CAPNETZ cohort from 2004 until 2016. In 990 out of 4.672 patients (21%) receiving complete diagnostics the most prominent change of pathogens was a decrease of S. pneumoniae (58% in 2004 to 37.5% in 2016; p ≤ 0.001, ρ = - 0.148) and an increase of H. influenzae (12.2% to 20.8%; p = 0.001, ρ = 0.104).

[Acute Respiratory Failure after Silicone Injection]. / Akutes respiratorisches Versagen durch Silikon-Injektion.

A 35-year-old male patient presented to the emergency department with complains of fever, dyspnea and petechiae. The chest X-ray revealed signs of bipulmonary infiltration. 5 days ago, an illicit silicone injection was performed into the penis for cosmetic reasons. Due to progressive respiratory failure the patient required mechanical ventilation. Bronchoalveolar lavage revealed diffuse alveolar hemorrhage. Silicone pneumonitis with a severe acute respiratory failure based on silicone embolization syndrome was diagnosed. Prone positioning, lung-protective ventilation and corticosteroid therapy were initiated. The patient was discharged from ICU after 19 days. In an outpatient follow up, lung function was fully recovered. CONCLUSION: Silicone pneumonitis should be considered in case of fever, respiratory distress and alveolar hemorrhage linked to cosmetic procedures. High dose corticosteroid therapy and lung-protective ventilation strategies may help for complete recovery of lung function.

Spleen tyrosine kinase inhibition blocks airway constriction and protects from Th2-induced airway inflammation and remodeling.

BACKGROUND: Spleen tyrosine kinase (Syk) is an intracellular nonreceptor tyrosine kinase, which has been implicated as central immune modulator promoting allergic airway inflammation. Syk inhibition has been proposed as a new therapeutic approach in asthma. However, the direct effects of Syk inhibition on airway constriction independent of allergen sensitization remain elusive. METHODS: Spectral confocal microscopy of human and murine lung tissue was performed to localize Syk expression. The effects of prophylactic or therapeutic Syk inhibition on allergic airway inflammation, hyperresponsiveness, and airway remodeling were analyzed in allergen-sensitized and airway-challenged mice. The effects of Syk inhibitors BAY 61-3606 or BI 1002494 on airway function were investigated in isolated lungs of wild-type, PKCα-deficient, mast cell-deficient, or eNOS-deficient mice. RESULTS: Spleen tyrosine kinase expression was found in human and murine airway smooth muscle cells. Syk inhibition reduced allergic airway inflammation, airway hyperresponsiveness, and pulmonary collagen deposition. In naïve mice, Syk inhibition diminished airway responsiveness independently of mast cells, or PKCα or eNOS expression and rapidly reversed established bronchoconstriction independently of NO. Simultaneous inhibition of Syk and PKC revealed additive dilatory effects, whereas combined inhibition of Syk and rho kinase or Syk and p38 MAPK did not cause additive bronchodilation. CONCLUSIONS: Spleen tyrosine kinase inhibition directly attenuates airway smooth muscle cell contraction independent of its protective immunomodulatory effects on allergic airway inflammation, hyperresponsiveness, and airway remodeling. Syk mediates bronchoconstriction in a NO-independent manner, presumably via rho kinase and p38 MAPK, and Syk inhibition might present a promising therapeutic approach in chronic asthma as well as acute asthma attacks.

[New Pathogenetic Concepts and Pharmacological Studies on Adjuvant Therapy in Severe Pneumonia]. / Neue pathogenetische Konzepte und pharmakologische Studien zur adjuvanten Therapie bei schwerer Pneumonie.

Acute lung injury secondary to pneumonia results from inadequate activation of the innate immune system with hyperinflammation and alveolar-capillary barrier dysfunction. To date, effective strategies for prevention or treatment of acute lung injury in pneumonia besides antibiotics are lacking. In preclinical studies, promising therapeutic targets have been identified and novel strategies demonstrated to protect against lung failure in pneumonia. This review highlights some adjuvant therapeutic strategies for modulation of inflammation and stabilization of lung barrier function in pneumonia.

Assessment of oxygenation and comorbidities improves outcome prediction in patients with community-acquired pneumonia with a low CRB-65 score.

BACKGROUND: Addition of assessment of comorbid diseases ('D') and oxygen saturation ('S') to the CRB-65 score has been recommended to improve its accuracy for risk stratification in community-acquired pneumonia (CAP). The aim of this study was to validate the resulting DS-CRB-65 score in a large cohort of patients with CAP. METHODS: A total of 4432 patients prospectively enrolled in the CAPNETZ cohort were included in this study. Predefined end points were 28-day mortality, requirement for mechanical ventilation or vasopressors (MV/VS) and requirement for MV/VS or intensive care unit admission (MV/VS/ICU). Receiver operating characteristic curve analysis was used to determine the accuracy of the CRB-65 score and the addition of D (extra-pulmonary comorbidities) and S (oxygen saturation <90% or partial pressure of oxygen <8 kPa). Binary logistic regression and the method of Hanley and McNeil were used to compare the criteria. RESULTS: The mortality rate was 4.0%, and 4.2% of patients required MV/VS and 6.6% required MV/VS/ICU. After multivariate analysis, D and S independently were added to the CRB-65 criteria for mortality prediction, but only S improved prediction of MV/VS and MV/VS/ICU (P < 0.001 for all). The area under the curve of the CRB-65 score was significantly improved by adding D and S for all end points (P < 0.02). Amongst patients who died or required MV/VS despite a CRB-65 score of 0, 64-80% would have been identified by the DS-CRB-65 score. CONCLUSIONS: The addition of assessment of oxygenation and comorbidities significantly improved the prognostic accuracy of the CRB-65 score. Consequently, the DS-CRB-65 score may have a useful role in risk stratification algorithms for CAP.

Moxifloxacin is not anti-inflammatory in experimental pneumococcal pneumonia.

OBJECTIVES: Anti-inflammatory functions of antibiotics may counteract deleterious hyperinflammation in pneumonia. Moxifloxacin reportedly exhibits immunomodulatory properties, but experimental evidence in pneumonia is lacking. Therefore, we investigated moxifloxacin in comparison with ampicillin regarding pneumonia-associated pulmonary and systemic inflammation and lung injury. METHODS: Ex vivo infected human lung tissue and mice with pneumococcal pneumonia were examined regarding local inflammatory response and bacterial growth. In vivo, clinical course of the disease, leucocyte dynamics, pulmonary vascular permeability, lung pathology and systemic inflammation were investigated. In addition, transcellular electrical resistance of thrombin-stimulated endothelial cell monolayers was quantified. RESULTS: Moxifloxacin reduced cytokine production in TNF-α-stimulated, but not in pneumococci-infected, human lung tissue. In vivo, moxifloxacin treatment resulted in reduced bacterial load as compared with ampicillin, whereas inflammatory parameters and lung pathology were not different. Moxifloxacin-treated mice developed less pulmonary vascular permeability during pneumonia, but neither combination therapy with moxifloxacin and ampicillin in vivo nor examination of endothelial monolayer integrity in vitro supported direct barrier-stabilizing effects of moxifloxacin. CONCLUSIONS: The current experimental data do not support the hypothesis that moxifloxacin exhibits potent anti-inflammatory properties in pneumococcal pneumonia.

The revised dengue fever classification in German travelers: clinical manifestations and indicators for severe disease.

BACKGROUND: The number of dengue cases imported to Germany has increased significantly in recent years. Among returning travelers, dengue is now a frequent cause of hospitalization. The aim of this study was to determine the proportion of patients with severe disease hospitalized in a European, non-endemic country applying the revised 2009 WHO classification system and to determine predictors of severe disease. METHODS: A retrospective single-center analysis of clinical data from 56 patients, 31 (55 %) women and 25 (45 %) men, between 14 and 70 years of age treated in a tertiary care hospital between 1996 and 2010 was conducted. RESULTS: Thirty-nine patients (69.6 %) presented with dengue fever without warning signs, 11 (19.6 %) with warning signs and 6 (10.7 %) with signs for severe dengue fever. Two patients (4 %) developed dengue shock syndrome. Non-European descent (p = 0.001), plasma protein level <6.5 mg/dl (p = 0.001), platelets <30/nl (p = 0.017) and activated partial thromboplastin time (aPTT) >44 s (p = 0.003) were associated with severe disease. CONCLUSIONS: A significant proportion of patients hospitalized with symptomatic imported dengue fever in Germany have evidence of severe disease. Simple routine laboratory parameters such as complete blood count, plasma protein level and aPTT are helpful tools for identifying adult patients at risk for severe disease.

Clindamycin-primaquine for pneumocystis jiroveci pneumonia in renal transplant patients.

BACKGROUND: Trimethoprim/sulfamethoxazole (TMP/SMX) is considered first-line therapy for pneumocystis jiroveci pneumonia (PCP) in renal transplant patients. Alternatives have not been formally studied. Clindamycin-primaquine (C-P) is effective in HIV-associated PCP, but data in renal transplant patients are lacking. PATIENTS AND METHODS: Retrospective cohort study of 57 consecutive renal transplant patients who developed PCP and were treated with C-P (n = 23) or TMP/SMX (n = 34). RESULTS: A non-significantly higher failure rate was observed in patients on C-P due to lack of efficacy (30.4 versus 20.6%, p = 0.545). The difference was more pronounced in severe PCP (60 versus 37.5%, p = 0.611) and a significantly lower efficacy of C-P was seen when used as salvage therapy. The two patients who had received C-P after not responding to TMP/SMX failed this regimen, but all seven patients who had failed initial treatment with C-P and had been switched to TMP/SMX were cured (p = 0.028). No treatment-limiting adverse reactions were reported for patients on C-P while six patients (17.6%) on TMP/SMX developed possibly related treatment-limiting toxicity (p = 0.071). However, in only two patients adverse events were definitely related to TMP/SMX (5.9%). CONCLUSIONS: Clindamycin-primaquine appears to be safe and well tolerated for treating PCP in renal transplant patients but is probably less effective than TMP/SMX, the standard regimen. However, our data indicates that C-P represents an acceptable alternative for patients with contraindications or treatment emergent toxicities during TMP/SMX use. Notably, TMP/SMX was also acceptably tolerated in most patients. TMP/SMX remains an effective salvage regimen in case of C-P failure.

[Ventilator-associated pneumonia]. / Ventilatorassoziierte Pneumonie.

Ventilator-associated pneumonia (VAP) is a severe, not entirely preventable complication of invasive ventilation. Timely and adequate antibiotic treatment is important; therefore, intensivists often initiate broad spectrum antibiotic regimens upon clinical suspicion of VAP. Criteria for the diagnosis of VAP are not perfect and a clear distinction of VAP from ventilator-associated tracheobronchitis is not always possible due to the limitations of chest x-rays in ventilated patients. The attributable mortality of VAP is likely overestimated. All these aspects increase the need to reevaluate the diagnosis of VAP on a daily basis. Microbiology data are helpful in the decision to de-escalate or stop antibiotics. The prudent use of antibiotics and implementation of a number of preventive measures are key for management of VAP in ICUs. These steps will help to minimize the development of multidrug-resistant pathogens and, in turn, may help guarantee more antibiotic options for future patients.

The burden of pneumococcal pneumonia - experience of the German competence network CAPNETZ.

BACKGROUND: Pneumococcal pneumonia is still an important cause of mortality. The objective of this study was to compare frequency, clinical presentation, outcome and vaccination status of patients with pneumococcal community-acquired pneumonia (CAP) to CAP due to other or no detected pathogen based on data of the German Network for community-acquired pneumonia (CAPNETZ). METHODS: Demographic, clinical and diagnostic data were recorded using standardized web-based data acquisition. Standardized microbiological sampling and work-up were conducted in each patient. RESULTS: 7400 patients with CAP from twelve clinical centers throughout Germany were included. In 2259 patients (32 %) a pathogen was identified, Streptococcus pneumonia being the most frequent (n = 676, 30 % of all patients with identified pathogens). Compared to those with non-pneumococcal pneumonia, patients with pneumococcal pneumonia were more frequently admitted to hospital (80 % vs. 66 %, p < 0.001), had higher CURB score values on admission, had more frequently pleural effusion (19 % vs. 14 %, p = 0.001) and needed more frequently oxygen insufflation (58 % vs. 44 %, p < 0.001). There was no relevant difference in overall mortality. CONCLUSIONS: Pneumococcal pneumonia was associated with a more severe clinical course demanding more medical resources as compared to non-pneumococcal pneumonia.

Influenza vaccination is associated with reduced severity of community-acquired pneumonia.

Pneumonia is an important cause of influenza-associated morbidity and mortality. Influenza vaccination has been shown to reduce morbidity and mortality during influenza seasons. Protection from severe pneumonia may contribute to the beneficial effect of influenza vaccination. Therefore, we investigated the impact of prior influenza vaccination on disease severity and mortality in patients with community-acquired pneumonia (CAP). Analysis from an observational, multicentre cohort study initiated by the German competence network for CAP was performed. Patients were analysed separately as an influenza season and off-season cohort. Associations between vaccination status and outcome parameters were evaluated by multivariate analyses. In the season cohort (2,368 patients) CAP in vaccinated patients was significantly less severe according to most analysed parameters (CURB index ≥ 1: OR 0.76, 95% CI 0.60-0.98; procalcitonin ≥ 2.0 ng·mL(-1): OR 0.53, 95% CI 0.35-0.81; procalcitonin ≥ 0.5 ng·mL(-1): OR 0.71, 95% CI 0.51-0.99) and these patients showed a significantly better overall survival within the 6-month follow-up period (HR 0.63, 95% CI 0.45-0.89). Within the off-season cohort (2,632 patients) there was no significant influence of vaccination status on CAP severity or disease outcome. In conclusion, prior influenza vaccination was associated with less severe clinical course and improved overall long-term survival in patients with CAP during influenza seasons.

How deadly is seasonal influenza-associated pneumonia? The German Competence Network for Community-Acquired Pneumonia.

The emergence of new influenza virus subtypes has rekindled the interest in the clinical course and outcome of patients with influenza-associated pneumonia. Based on prospective data from 5,032 patients with community-acquired pneumonia (CAP) included in the German Competence Network for Community-Acquired Pneumonia (CAPNETZ), we studied the incidence, clinical characteristics and outcome of patients with influenza-associated CAP and compared these findings with patients without influenza. Diagnosis relied on a positive PCR for influenza in throat washings. 160 patients with influenza-associated CAP were identified (3.2% of total population, 12% of those with defined aetiology). 34 (21%) patients with seasonal influenza had a concomitant pathogen (mostly Streptococcus pneumoniae). Patients with influenza-associated CAP were significantly older, had been vaccinated less often and had preceding antibacterial treatment less often. 30-day mortality was low (4.4%) and not different to that of patients with pneumonia caused by bacterial (6.2%) or viral (other than influenza) pathogens (4%). Patients with influenza plus a bacterial pathogen (mixed influenza-associated pneumonia) had a higher mortality than those with pure influenza-associated pneumonia (9% versus 3.2%). Mortality was higher in patients with mixed compared with pure influenza-associated pneumonia. However, we could not observe any excess mortality in patients with influenza-associated pneumonia.

Legionella pneumophila-induced IκBζ-dependent expression of interleukin-6 in lung epithelium.

Severe community- and hospital-acquired pneumonia is caused by Legionella pneumophila. Lung airway and alveolar epithelial cells comprise an important sentinel system in airborne infections. Although interleukin (IL)-6 is known as a central regulator of the immune response in pneumonia, its regulation in the lung is widely unknown. Herein, we demonstrate that different L. pneumophila strains induce delayed expression of IL-6 in comparison with IL-8 by human lung epithelial cells. IL-6 expression depended, at early time points, on flagellin recognition by Toll-like receptor (TLR)5, activity of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)1 and p38 mitogen-activated protein (MAP) kinase, and, at later time points, on the type-IV secretion system. In the same manner, but more rapidly, the recently described transcription factor IκBζ was induced by Legionella infection and, binding to the nuclear factor (NF)-κB subunit p50 - recruited to the il6 promoter together with CCAAT-enhancer-binding protein ß and phosphorylated activator protein-1 subunit cJun. Similarly, histone modifications and NF-κB subunit p65/RelA appeared at the iκbζ and subsequently at the il6 gene promoter, thereby initiating gene expression. Gene silencing of IκBζ reduced Legionella-related IL-6 expression by 41%. Overall, these data indicate a sequence of flagellin/TLR5- and type IV-dependent IκBζ expression, recruitment of IκBζ/p50 to the il6 promoter, chromatin remodelling and subsequent IL-6 transcription in L. pneumophila-infected lung epithelial cells.

Pore-forming bacterial toxins potently induce release of nitric oxide in porcine endothelial cells.

Nitric oxide (NO) is believed to play an important role in sepsis-related hypotension. We examined the effects of two pore-forming bacterial exotoxins, Escherichia coli hemolysin and Staphylococcus aureus alpha-toxin, on NO formation in cultured porcine pulmonary artery endothelial cells. NO was quantified using a difference-spectrophotometric method based on the rapid and stoichiometric reaction of NO with oxyhemoglobin. Endothelial cyclic guanosine monophosphate levels were also monitored. Both exotoxins increased NO synthesis in endothelial cells in a time- and dose-dependent manner to an extent exceeding that observed with the ionophore A23187 or thrombin. The capacity of exotoxins to induce NO formation may be relevant in patients with severe local or systemic bacterial infections.

Community-acquired pneumonia through Enterobacteriaceae and Pseudomonas aeruginosa: Diagnosis, incidence and predictors.

The aim of the present study was to determine the relevance of the presence of Enterobacteriaceae (EB) and Pseudomonas aeruginosa (PA) in patients with community-acquired pneumonia (CAP) and how the true incidence of these pathogens can be assessed. Based on prospective data from 5,130 patients with CAP included in the German Competence Network for Community-Acquired Pneumonia (CAPNETZ), the incidence, clinical characteristics, outcome and predictors of patients with CAP due to EB and PA were studied applying strict case definitions. The incidence of EB was 67 (1.3%) out of 5,130, including 27 patients with bacteraemia. PA was found in 22 (0.4%) out of 5,130 patients. These microorganisms were judged to be indeterminate pathogens in an additional 172 and 27 isolates, respectively. Patients with indeterminate pathogens differed considerably from those with definite isolates in terms of clinical presentation, comorbidity, pneumonia severity and outcome. Independent risk factors for EB included cardiac and cerebrovascular disease, and for PA chronic respiratory disease and enteral tube feeding. The 30-day mortality was significantly higher in patients with definite pathogens. In the present large population, the incidence of CAP due to EB/ PA was low. The risk of the presence of these pathogens can be assessed using several predictors, which may identify those patients in need of an extended diagnostic work-up and initial antimicrobial treatment.

[Management of a new influenza A/H1N1 virus pandemic within the hospital. Statement of the German Society of Pneumology]. / Management der Influenza A/H1N1 - Pandemie im Krankenhaus: Update Januar 2010. Eine Stellungnahme der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin.

This update summarized the hospital experience from the first wave of the new influenza A/H1/N1 pandemic.

Suppression of pulmonary innate host defence in smokers.

BACKGROUND: Smoking increases the susceptibility to pulmonary infection and is a risk factor for the development of chronic obstructive pulmonary disease (COPD). It is postulated that cigarette smoke suppresses the activation of the innate immune system in response to bacterial infection. METHODS: Using sensitive ex vivo analysis, the level of the endogenous antibiotic peptide human beta-defensin-2 (hBD-2) was measured in pharyngeal washing fluid and sputum from patients with community acquired pneumonia. The regulation of antibacterial host defence molecules was studied in vitro. The effect of cigarette smoke on the antibacterial activity of differentiated airway epithelium and the expression of host defence molecules was studied in an in vitro infection model. RESULTS: Current or former smoking was associated with significantly reduced hBD-2 levels in pharyngeal washing fluid and sputum from patients with acute pneumonia. Exposure of airway epithelium to smoke in vitro inhibited the induction of hBD-2 by bacteria. This correlated with decreased antimicrobial activity. This effect was mimicked by hydrogen peroxide, and catalase blunted the smoke-induced inhibition of epithelial host defence. CONCLUSIONS: Smoke exposure suppresses the induction of epithelial antibacterial host defences. These findings link smoking with increased susceptibility to infection. This mechanism may be important in the pathogenesis of pneumonia and COPD.

PKC(alpha) and PKC(epsilon) differentially regulate Legionella pneumophila-induced GM-CSF.

Legionella pneumophila is an important causative agent of severe pneumonia in humans. The human alveolar epithelium is an effective barrier for inhaled microorganisms and actively participates in the initiation of innate host defense. Although secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) is essential for the elimination of invading Legionella spp., mechanisms of Legionella pneumophila-induced release of this cytokine are widely unknown. In this study, we have demonstrated a toll-like receptor (TLR)2- and TLR5-dependent release of GM-CSF in L. pneumophila-infected human alveolar epithelial cells. GM-CSF secretion was not dependent on the bacteria type II or type IV secretion system. Furthermore, an increase in protein kinase C (PKC) activity, particularly PKC(alpha) and PKC(epsilon), was noted. Blocking of PKC(alpha) and PKC(epsilon) activity or expression, but not of PKC(beta), PKC(delta), PKC(eta), PKC(theta), and PKC(zeta), significantly reduced the synthesis of GM-CSF in infected cells. While PKC(alpha) was critical for the initiation of a nuclear factor-kappaB-mediated GM-CSF expression, PKC(epsilon) regulated GM-CSF production via activator protein 1. Thus, differential regulation of GM-CSF, production by PKC isoforms, contributes to the host response in Legionnaires' disease.

Impact of intravenous {beta}-lactam/macrolide versus {beta}-lactam monotherapy on mortality in hospitalized patients with community-acquired pneumonia.

OBJECTIVES: Guidelines recommend dual-therapy consisting of a beta-lactam/macrolide (BLM) for hospitalized patients with community-acquired pneumonia. Nevertheless, the superiority over beta-lactam-monotherapy (BL) remains unproven. METHODS: Analyses from an observational study initiated by the German competence network CAPNETZ were performed. RESULTS: One thousand eight hundred and fifty-four patients were treated with either BL (49.0%) or BLM (51.0%). BLM therapy was associated with lower adjusted 14 day mortality [odds ratio (OR) 0.53; 95% confidence interval (CI): 0.30-0.94]. CRB65, neoplastic disease, age and nursing home residency were confirmed as independent predictors of death. Adjusted 14 day mortality risk was clearly reduced in patients with CRB65 = 2 (n = 411; OR 0.35; CI: 0.12-0.99) and CRB65 > or = 2 (n = 519; OR 0.42; CI: 0.18-0.997). However, this could not be shown for adjusted 30 day mortality. Patients with CRB65 < or = 1 showed low mortality (2.1%) without the influence of BLM. BLM therapy was associated with lower adjusted risk of treatment failure at 14 days (n = 1854; OR 0.65; CI: 0.47-0.89) and 30 days (OR 0.69; CI: 0.51-0.94) as well as in the subgroup of patients with CRB65 = 2 and CRB65 > or = 2. CONCLUSIONS: This study suggests the superiority of BLM therapy in patients with CRB65 risk classes of 2 or higher on 14 day mortality. BLM therapy was also associated with lower risk of treatment failure.