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Infectious complications are a central problem in the treatment of patients with rheumatic diseases. The increased infection rate is mainly caused by immunosuppressive medication, particularly glucocorticoids. A more aggressive diagnostic approach, often including bronchoscopic procedures, is often necessary to obtain samples for microbiological examinations. In immuno-compromised patients the failure of a calculated empiric antibiotic therapy is associated with a higher risk of fatal outcome. Among possible opportunistic infections Pneumocystis jirovecii pneumonia (PCP), invasive aspergillosis and CMV reactivations are most relevant. Furthermore, particularly with the use of TNF-blocking agents, reactivation of latent tuberculosis (TB) might be observed. There are only a few situations in which anti-infective chemo-prophylaxis is established: In the case of latent TB INH-prophylaxis should be given when anti-TNF-therapy is considered. There is evidence in favour of PCP prophylaxis with trimethoprim/cotrimoxazole in patients receiving intense immunosuppression with high dose glucocorticoids and cyclophosphamide.

Community-acquired pneumonia remains a major cause of mortality in developed countries. There is much discrepancy in the literature regarding factors influencing the outcome in the elderly population. Data were derived from a multicentre prospective study initiated by the German Competence Network for Community-Acquired Pneumonia. Patients with community-acquired pneumonia (n = 2,647; 1,298 aged < 65 yrs and 1,349 aged > or = 65 yrs) were evaluated, of whom 72.3% were hospitalised and 27.7% treated in the community. Clinical history, residence status, course of disease and antimicrobial treatment were prospectively documented. Microbiological investigations included cultures and PCR of respiratory samples and blood cultures. Factors related to mortality were included in multivariate analyses. The overall 30-day mortality was 6.3%. Elderly patients exhibited a significantly higher mortality rate that was independently associated with the following: age; residence status; confusion, urea, respiratory frequency and blood pressure (CURB) score; comorbid conditions; and failure of initial therapy. Increasing age remained predictive of death in the elderly. Nursing home residents showed a four-fold increased mortality rate and an increased rate of gram-negative bacillary infections compared with patients dwelling in the community. The CURB score and cerebrovascular disease were confirmed as independent predictors of death in this subgroup. Age and residence status are independent risk factors for mortality after controlling for comorbid conditions and disease severity. Failure of initial therapy was the only modifiable prognostic factor.

Objectives: In Germany the estimation of a population based annual incidence of community acquired pneumonia (CAP) in adults has been referred to the denominator problem. To estimate a population based annual incidence of CAP in an urban German area we compared the incidence estimated on four different approaches., Methods: We estimated the annual incidence on the basis of the covered population of sentinel practices from Luebeck participating in the German competence network CAPNETZ. We estimated the incidence on the basis of a population based survey, on the basis of the mortality and lethality in Luebeck, and on the basis of data of the regional Association of Statutory Health Insurance Physicians ("Kassenärztliche Vereinigung (KV) Schleswig-Holstein")., Results: The annual incidence of CAP in Luebeck was 3.7/1000 inhabitants (95% confidence interval (CI) 2.4-5.5), 6.0/1000 inhabitants, 8.7/1000 inhabitants (95% CI 8.2-9.1), or 10.1/1000 inhabitants (95% CI 9.6-10.5) depending on the approach of estimation. According to this, in Germany we would expect 400,000-680,000 new CAP cases per year., Conclusions: The true incidence of CAP in Luebeck might range between 3.7 and 10 per 1000 inhabitants. Comparisons with the rates in the literature are difficult due to the differences in the applied methods.

Pneumonias are common, life threatening complications in immunodeficient patients. A rapid, targeted diagnosis and therapy are decisive for the course of the disease. The etiological spectrum is substantially broader than for immunocompetent patients. Important indications are provided by the type and intensity of the immunosuppression, gaps in the prophylactic concept and particular exposures. For diagnostic planning, high resolution computed tomogram of the thorax is necessary. The standard method for isolating the pathogen is flexible bronchoscopy with bronchoalveolar lavage. Indications for invasive bioptic measures depend on the individual situation, the expected spectrum of pathogens as well as risk factors and adverse effects. Non-invasive antigen and PCR tests complement the diagnostic spectrum, especially for difficult to cultivate pathogens such as fungi and Herpes viruses. The selection of the initial, targeted antimicrobial therapy is based on guidelines. The treatment should be followed after obtaining the relevant microbiological data.

Introduction: Since 2002, the German competence network CAPNETZ has been collecting data from inpatients and outpatients with community acquired pneumonia (CAP) at eight local clinical centres. Contrary to the literature reports, the proportion of outpatients in CAPNETZ averages out at 28 %. Therefore, this study determines whether an active reporting system can increase the number of cases reported in medical practices., Method: In ten medical practices in Lübeck, the passive reporting system was changed to an active reporting system consisting of a) a weekly announcement of CAP cases including negative reporting, b) a study nurse who was responsible for the reporting, c) additional payment, d) a telephone call after two weeks by absent announcements and e) incentives like benchmarking or additional information. The number of the reported cases between the active reporting period (2004) and the same period in the year before was recorded., Results: The number of reported cases increased in eight of the ten medical practices. Overall 72 CAP cases were reported, 33 % more than in the period of passive reporting. The number of patients encompassed in CAPNETZ increased from 17 to 34., Conclusion: We did not find a comparable increase of CAP cases either in Lübeck overall (including inpatients) or in all the local clinical centres together. Thus, it is assumed that the increase of reported cases depends on the methodical effect.

Chronic bronchitis is a frequent underlying disease in community-acquired pneumonia (CAP). It is unclear to what extent an impaired or exaggerated innate immune response contributes to disease manifestations and severity. To assess the role of neutrophil activation and recruitment during acute pneumonic episodes, peripheral polymorphonulcear neutrophil (PMN) activation, chemotactic activity, interleukin-8 (CXCL-8) and CXCL-8 receptor (CXCR) expression and apoptosis rate were evaluated in CAP patients with and without chronic bronchitis. In addition, the expression of CXCRs and CXCL-8 was assessed on pulmonary neutrophils in chronic bronchitis patients to compare the activation of the chemokine system in different compartments. CAP severity was assessed by the simplified acute physiology score II and the prognosis of disease was assessed by the pneumonia severity index (PSI). An increased chemotactic activity of PMN from chronic bronchitis patients with CAP was found, which was not related to the expression of CXCRs. In addition, a decreased apoptosis rate of PMN was observed. Chemotactic activity was related to the PSI. Comparison of peripheral and pulmonary PMN revealed enhanced CXCL-8 levels and a decreased CXCR expression in the lung. In conclusion, neutrophil function in patients with chronic bronchitis and community-acquired pneumonia is characterised by an increased chemotactic activity combined with a decreased apoptosis rate. The downregulation of interleukin-8 receptors in the pulmonary compartment deserves further investigation.

In hospital-acquired pneumonia, extracellular matrix destruction is common and may be caused by excessive activity of matrix metalloproteinases (MMPs). Thirty patients with hospital-acquired pneumonia and 16 control subjects were studied. We evaluated the concentrations of MMP-8, MMP-9, and tissue inhibitor of metalloproteinase-1 in mini-bronchoalveolar lavage fluid (mini-BALF) and blood using zymography and specific immunoassays. In patients with hospital-acquired pneumonia concentrations of MMP-8 and MMP-9 in mini-BALF were increased 10-fold, whereas their specific inhibitor tissue inhibitor of metalloproteinase-1 was not concomitantly increased. In 80% of patients with pneumonia, but in none of the control subjects, the active form of MMP-9 was detected by zymography. Zymography furthermore showed the banding pattern of neutrophil-derived MMP-9, indicating that neutrophils were the main source of MMP-9. Comparison of neutrophils from blood and mini-BALF showed higher basal release of MMPs by pulmonary neutrophils. Stimulation analysis indicated that pulmonary neutrophils were already maximally activated. In patients with detection of potentially pathogenic microorganisms, concentrations of MMPs were fivefold increased compared with patients with negative cultures. Furthermore, MMP-levels were related to clinical severity. These are the first data suggesting that neutrophil-derived MMPs are increased in hospital-acquired pneumonia in association to the detection of causative microorganisms and clinical severity.

Background: In the host defence of the lung neutrophils (PMN) play a central role. Apart from antimicrobial properties, recent data indicate that PMN also exert anti-inflammatory effects by stimulation and release of cytokine antagonists such as interleukin-1 receptor antagonist (IL-1ra)., Methods: Cytokine release from lipopolysaccharide stimulated whole blood was studied in 18 patients with community acquired pneumonia (CAP) and severe co-morbidities at admission and after 24 hours. Release of IL-1ra, interleukin-1beta (IL-1beta), tumour necrosis factor alpha (TNFalpha), soluble TNF receptor type I (sTNF-RI), and IL-8 was determined by ELISA., Results: The mean (SD) leucocyte level at admission was 12.5 (4.1)/nl. There was a significant correlation between the release of anti-inflammatory cytokines such as IL-1ra and sTNF-RI and the leucocyte count at admission and after 24 hours. Additional in vitro experiments showed that co-incubation of peripheral blood mononuclear cells with autologous PMN led to a marked dose dependent increase in IL-1ra and sTNF-RI release., Conclusion: These results indicate that PMN may be responsible for the increase in anti-inflammatory cytokines in CAP. Strategies to increase neutrophil counts may exert beneficial effects, not only by augmenting the antimicrobial activity but also by modulating the inflammatory cytokine response.

Background: Pulmonary inflammation in bronchiectasis, pneumonia and idiopathic pulmonary fibrosis (IPF) is dominated by neutrophils. Pathophysiologic differences are seen in the degree of airway and tissue destruction. Neutrophil activation and neutrophil proteolytic activity might differ between bronchiectasis, pneumonia and IPF., Objective: The aim of this study was to determine whether levels of inflammatory and protective markers in bronchoalveolar lavage (BAL) differed among cases of bronchiectasis, pneumonia and IPF., Methods: We studied 11 bronchiectasis patients (group 1), 30 pneumonia patients (group 2), 15 IPF patients (group 3) and 12 healthy volunteers (group 4). In the bronchoalveolar lavage fluid, concentrations of alpha(1)-proteinase inhibitor, myeloperoxidase (MPO) and elastase-alpha(1)PI complex were determined using immunoluminometric assays. Elastase inhibition capacity (EIC) and elastase activity were determined using a colorimetric assay., Results: No EIC, but free elastase activity, was found in 82% of group 1, 20% of group 2, 20% of group 3 and 0% of group 4. Median MPO concentration was highest in group 1: 7,951 ng/ml (16th-84th percentile [16-84%]: 256-36,342) vs. 692 ng/ml (106-2,279; group 2), 332 ng/ml (98-1,657; group 3), and 0.12 ng/ml (0.08-0.26; group 4). Bronchiectasis patients with bronchial Pseudomonas infection showed higher amounts of neutrophils (p < 0.01) and higher elastase activity (p < 0.05) than patients with sterile lavage., Conclusion: Bronchiectasis patients show a severe imbalance between neutrophil activity and protective molecules leading to possible lung destruction. Chronic Pseudomonas infection might trigger neutrophil activation. Future research and treatment strategies should focus on increased bacterial clearance and inhibition of neutrophil toxicity., (Copyright 2000 S. Karger AG, Basel)

Background: In medically immunosuppressed patients with pneumonia, the BAL cell differential and neutrophils secretion products were determined and compared to patients with pneumonia without defined immunodeficiency in order to define a possibly deficient neutrophil function., Patients and Methods: Forty-eight medically immunosuppressed patients were studied: 24 pts. after renal transplantation receiving threefold immunosuppression (cyclosporine, azathioprine, prednisolone), 14 pts. with non-Hodgkin-lymphoma receiving polychemotherapy and 10 pts. with rheumatologic disorders (rheumatoid arthritis n = 3, M. Wegener n = 5 und SLE n = 2) receiving cyclophosphamide or methotrexate. For comparison, 116 patients without defined immunodeficiency and pneumonia and 16 healthy adults were studied. In addition to the cell differential the BALF concentrations of the neutrophil degranulation products myeloperoxidase (MPO) and lactoferrin were determined using immunoluminometric assays. For identification of microorganisms semiquantitative cultures were used., Results: Neutrophilia > 5% in BAL was present in only 36% of the immunosuppressed pts. in contrast to 91.3% of the immunocompetent pts. (p < 0.01). The same pathogen was found in 14 pts. of each group, so that a pathogen matched comparison was possible. The neutrophil percentage and the BALF concentration of lactoferrin was significantly lower in the immunosuppressed group. In blood there was no difference with regard to the neutrophil count between the groups., Conclusions: BAL characteristics of immunosuppressed pts. are different from those of immunocompetent pts. with pneumonia. The pathogen-matched comparison proved that this is not due to different pathogens. Medically immunosuppressed patients with pneumonia exhibit a disturbed neutrophil recruitment. A neutrophil percentage < 5% in BAL of medically immunosuppressed patients does not preclude a bacterial infection.

Objective: In pneumonia the influx of neutrophils to the lungs is thought to be of primary importance with regard to host defence and to complications like the adult respiratory distress syndrome. We wanted to evaluate the neutrophil function in patients in acute respiratory failure who required admission to the intensive care unit., Design: We determined the luminolenhanced chemiluminescence (CL) of neutrophils isolated both from central venous and arterial blood. In addition, the plasma-concentrations of alpha 1-proteinase inhibitor, (alpha 1PI), alpha 2-macroglobulin (alpha 2PI) and elastase-alpha 1PI-complex (elastase) were determined by chemiluminescence immunoassay, and the intracellular elastase content of blood neutrophils was determined using immuno activation assay., Patients: 28 Patients, 18 with acute pneumonia (group 1) and 10 with cardiac pulmonary edema (group 2)., Measurements and Results: In group 1, luminol enhanced CL was significantly higher than in group 2 (mean 87.7 vs 30.4 x 10(6) counts per minute, p < 0.01). The production of reactive oxygen species was significantly higher in central venous than in arterial neutrophils in the patients with pneumonia (p < 0.03). In patients with pulmonary edema there was no such difference. The plasma concentration of elastase in group 1 was significantly higher than in group 2, that of alpha 2PI were significantly lower. The intracellular elastase content of neutrophils was lower in group 1 than in group 2. In group 1, there was a trend for a correlation between lower intracellular elastase content and a higher elastase plasma concentration. There were no central venous-arterial differences with regard to leukocyte count, cell differential or protein concentration in either group., Conclusion: The central venous-arterial differences in neutrophil production of reactive oxygen species support the concept of compartmentalization of activated neutrophils from the systemic to the pulmonary compartment.

The oxidative response of activated phagocytes is a primary host defense mechanism in pneumonia, but is in addition capable of causing tissue damage. We evaluated amount and significance of the local oxidant production in immunocompetent and immunocompromised pneumonia patients; the relative contribution of neutrophils and alveolar macrophages to the total oxidant load was differentiated using chemiluminescence (CL) with different amplifiers. Luminol-enhanced CL correlated to neutrophil percentage and myeloperoxidase levels in the bronchoalveolar lavage and was markedly increased in both pneumonia groups. Lucigenin-enhanced CL was produced by both phagocyte types and not significantly increased. In both pneumonia groups elevated levels of serum proteins indicated severe alveolocapillary leakage. In conclusion the oxidative response in acute pneumonia was mainly due to neutrophil recruitment and activation; this defense mechanism was preserved even in severely immunocompromised patients.

In order to clarify the mode of inactivation of alpha1-proteinase inhibitor (alpha 1-PI) in pneumonia, 21 immunocompetent patients and 19 immunocompromised patients with acute pneumonia (Groups I and II) were studied. Nine patients successfully treated for pneumonia and 10 healthy volunteers served as controls (Groups III and IV, respectively). The concentrations of alpha 1-PI, elastase and myeloperoxidase (MPO) in bronchoalveolar lavage fluid (BALF) were determined using a luminometric assay. Elastase inhibition capacity was determined using a colorimetric assay. Thus, the functional activity of alpha 1-PI was calculated. Both elastase and MPO were significantly higher in group I, when compared with the other groups. The mean concentration of alpha 1-PI was significantly higher in patients with acute pneumonia (Group I 13 mg.l-1, Group II 4.22 mg.l-1) than in Groups III and IV (2.65 and 0.33 mg.l-1, respectively), whereas, the proportion of active alpha 1-PI was significantly lower in Group I than in the other groups. Only a small proportion was present as a complex with elastase (ca. 5.9%) or in oxidised form (ca. 4.8%), 85% of alpha 1-PI was irreversibly proteolyzed. This resulted in free elastase activity in 7 of the 40 patients (18%) with acute pneumonia. We conclude that functional activity of alpha 1-PI is markedly impaired due to irreversible proteolysis in acute pneumonia, despite high immunological concentrations.

In 29 patients with community-acquired pneumonia, 24 patients with hospital-acquired pneumonia and 35 patients with pneumonia in the immunocompromised host the diagnostic value of bronchoalveolar lavage (BAL) with quantitative bacterial and fungal cultures was studied; 32 patients with noninfectious pulmonary diseases and 14 healthy volunteers served as controls. An infectious etiology could be established in 81% of the pneumonia patients without differences between the three groups; significant infection was associated with colony counts of > or = 10(4) cfu/ml. Prior antibiotic therapy lowered the yield of BAL culture only in community-acquired pneumonia (94% vs 55% positive cultures in untreated vs pretreated patients, p < 0.02). Furthermore the culture results were related to the radiographic extension of pulmonary infiltrates (92% positive cultures in multilobar vs 54% in lobar or segmental infiltrates, p < 0.001). Therapeutic consequences of BAL were shown by resistance of the isolated organisms to predefined empiric treatment regimens in 41% community-acquired pneumonia, 43% pneumonia in the immunocompromised host and 67% hospital-acquired pneumonia patients.

Neutrophilic granulocytes in the lower respiratory tract are of decisive importance for the elimination of pathogenic germs in bacterial pneumonia. On the other hand, the liberation of phagocyte products (e.g. elastase) can result in tissue damage in the parenchyma of the lungs. For this reason, we determined in patients suffering from acute pneumonia (n = 21), in patients with acute pneumonia associated with immunosuppression (n = 12), in patients who had overcome their pneumonia (n = 9) and in controls (n = 17) in bronchoalveolar lavage (BALF) and in plasma, the concentration of the locally produced granulocyte products myeloperoxidase (MPO), lactoferrin (LF) and elastase-alpha 1 proteinase complex (ELA) as well as of the alpha 1 proteinase inhibitor (alpha 1 Pi) and alpha 2 proteinase inhibitor (alpha 2 Pi) via chemoluminescence immunoassay, and compared the same with the differential cell count in the BALF. The protein concentrations were referred to the albumin concentration (Alb) for standardisation. This concentration did not differ significantly between the various patients and control groups. The BALF concentration of ELA in the group with pneumonia (median: 86.3 micrograms/l or 8.5 micrograms/mg Alb) was about eight times higher than in the group of patients suffering from pneumonia with immunosuppression (median: 16 micrograms/l or 1.0 micrograms/l Alb, p less than 0.001) or in whom the pneumonia was no longer present (17.6 micrograms/l or 0.5 micrograms/mg), and approximately 40 times higher than in the control group (3 micrograms/l or 0.2 micrograms/mg, respectively). Similar results were obtained for LF (61 micrograms/mg Alb vs. 11.3; 16.8 and 5.9 micrograms/mg; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Micro-organism counts of bronchoalveolar lavage (BAL) and microbrush swabs were obtained from 40 immunocompetent (group A) and 23 immunosuppressed (group B) patients with nosocomial pneumonia, and a control group consisting of 40 patients with noninfectious pulmonary infiltrates. The sensitivity of BAL was high: 77.5% for group A and 85% for group B, while microbrush swabs gave many false-negative results. Microorganism counts were at or above 10(5) cfu/ml in 32 of 44 examinations (bacterial or mycotic pneumonia), but in only one case of the control group. Lower counts were obtained with localized infection and microorganisms difficult to culture (Aspergilla and Legionella). Granulocytosis in the lavage fluid was demonstrated in 38 of 41 patients with bacterial pneumonia and thus proved useful in the differential diagnosis. In 16 of 40 immunocompetent and 13 of 23 immunosuppressed patients with pneumonia the results were therapeutically of importance. Thus, invasive diagnosis is indicated especially in complicated or treatment-resistant nosocomial infections.

In 18 renal transplant patients with pneumonia under ciclosporin therapy the diagnostic value of BAL and of covered micro brush smears were compared. In 10 out of 18 cases partly atypical bacterial pathogens were cultivated and cytomegaly was diagnosed 4 times, mycosis twice, whereas 2 cases could not be clarified. A granulocytosis in the differential cell pattern correlated with a bacterial infection.

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Background:Despite antibiotic treatment, the mortality of severe community-acquired pneumonia (CAP), especially in patients with severe comorbidity, remains high. Innate defense mechanisms including polymorphonuclear neutrophil (PMN) activation and survival, orchestrated by cytokines, are primarily responsible for the elimination of bacterial organisms from the alveolus. Objectives: The aim of this study was to evaluate the effect of granulocyte colony-stimulating factor (G-CSF) on PMN activation, apoptosis and cytokine response in patients with CAP. Methods: Patients received a single dose of G-CSF (1 × 300 or 480 μg s.c.) prior to standard antibiotic treatment (n = 8) or standard treatment only (n = 8). Apoptosis rate and expression of CD11b, CD66b, CD64 and CD114 surface molecules on systemic PMN were assessedusing fluorescence-activated cell sorter analysis. Levels of the interleukin-1 receptor antagonist (IL-1RA), the soluble tumor necrosis factor receptor inhibitor (sTNF-p55) and G-CSF were measured by ELISA. Results: In the treatment group, 12 h after G-CSF application, neutrophil count increased, neutrophil activation marker CD11b was stimulated (CD11b: 48.6 ± 9.7 vs. 71.2 ± 17.7, p < 0.01), neutrophil apoptosis decreased (apoptosis: 1.36 ± 0.27 vs. 0.2 ± 0.12%, p < 0.01) and the concentration of IL-1RA and sTNF-p55 increased (IL-1RA 136.4 ± 72.2 vs. 340.1 ± 194.6 ng/ml, p < 0.01; sTNF-p55 382 ± 4,243 vs. 632 ± 4,714 ng/ml, p < 0.01; control group nonsignificant). These effects were not seen in the control group. Conclusions: The application of a single dose of G-CSF in patients with CAP caused a prolonged survival and increased activation of neutrophils combined with a sustained release of anti-inflammatory cytokines. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]