Hartwig Schütte

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 ≥65u2005years 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 ≥65u2005years (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 CURB-65 score of 0 (confusion of new onset, urea >7 mmol·L−1, 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.

Allergic lung inflammation induces pulmonary vascular hyperresponsiveness

Pulmonary arterial vasoconstriction is an important early component of pulmonary hypertension. Inflammatory mechanisms play a prominent role in the pathogenesis of pulmonary hypertension. The present authors investigated the potential role of acute allergic lung inflammation for alterations in pulmonary haemodynamics. BALB/c mice were intraperitoneally sensitised to ovalbumin and challenged by ovalbumin inhalation. Subsequently, lungs were ventilated and perfused ex vivo, and pulmonary arterial pressure (Ppa) was continuously monitored. Isolated perfused lungs of allergen-sensitised and -challenged mice showed five-fold enhanced Ppa responses to serotonin, which is reported to be a significant contributor to pulmonary hypertension in humans. This increase in Ppa was abolished by the serotonin receptor-2A antagonist ketanserin, but not the serotonin receptor-1B antagonist GR127935. Intracellular signalling to serotonin involved phosphatidylcholine-specific phospholipase C and protein kinase C, as well as Rho-kinase, as assessed by employing the specific inhibitors D609, bisindolylmaleimide and Y27632, respectively. In addition to serotonin, impressively enhanced Ppa increases in allergic lungs were also evoked by the thromboxane receptor agonist U46619, angiotensin II and endothelin-1. In conclusion, allergic lung inflammation was accompanied by impressive pulmonary vascular hyperresponsiveness. These results suggest a possible role for allergic inflammation in the development of pulmonary arterial hypertension.

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

BackgroundSeveral 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.Methods984 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.Results64 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.ConclusionCortisol 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.

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

BACKGROUNDnImmunologic 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.nnnOBJECTIVEnWe sought to investigate the role of SphK1 in allergen-induced lung inflammation.nnnMETHODSnSphK1-deficient mice and C57Bl/6 littermates (wild-type [WT] animals) were subjected to acute or chronic allergen exposure.nnnRESULTSnAfter 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.nnnCONCLUSIONn: 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.

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

ObjectivesWe aimed to explore the association between vitamin D levels and the severity, mortality and microbiological etiology of community-acquired pneumonia.MethodsVitamin 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.ResultsThere 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 (pu2009=u20090.011). 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.ConclusionFor 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.

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 72u2005h and 7u2005days 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 7u2005days, 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.

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.

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

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.

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.