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Rationale: The ratio of neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR) and platelet-to-lymphocyte (PLR) are biomarkers that have shown potential for predicting mortality in several diseases. For patients hospitalized with community-acquired pneumonia (CAP), the prognostic capabilities of these biomarkers are unknown., Objective: Investigate whether NLR, MLR or PLR were associated with 90-day mortality in CAP. Further, investigate whether the prediction rule CURB-65 could be improved by adding these biomarkers., Methods: A derivation-validation study using a Danish multicentre retrospective cohort as the derivation cohort (N = 831) and a European multicentre prospective cohort as the validation cohort (N = 2463). Associations between biomarkers and mortality were assessed using Cox proportional hazard models with adjustments for sex, CURB-65 and comorbidities. A cut-off value for biomarkers was determined using Youden's J Statistics. The performance of CURB-65 with added biomarkers was evaluated using receiver-operating characteristics., Results: In both cohorts increasing NLR and PLR were associated with 90-day mortality. In the derivation cohort, the hazard ratios for NLR and PLR were 1.016 (95% confidence interval (CI) 1.001-1.032, P = 0.038) and 1.001 (95% CI 1.000-1.001, P = 0.035), respectively. Adding these biomarkers to CURB-65 did not improve its performance., Conclusions: NLR and PLR were associated with 90-day mortality in CAP, but did not improve CURB-65., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: Serum neurofilament light chain (sNfL) is a biomarker for neuroaxonal damage and has been found to be elevated in several neurological diseases with neuronal destruction. New onset of confusion is a hallmark of severity in infections. The objective of this study was to determine whether sNfL levels are increased in patients with community-acquired pneumonia (CAP) and if increased sNfL levels are associated with disease-associated confusion or disease severity., Methods: In this observational study, sNfL levels were determined with single-molecule array technology in CAP patients of the CAPNETZ cohort with validated CRB (confusion, respiratory rate, and blood pressure)-65 score. We determined associations between log-transformed sNfL concentrations, well-defined clinical characteristics, and unfavorable outcome in multivariable analyses. Receiver operating characteristic (ROC) analysis was performed to assess the prediction accuracy of sNfL levels for confusion in CAP patients., Results: sNfL concentrations were evaluated in 150 CAP patients. Patients with confusion had higher sNfL levels as compared to non-confusion patients of comparable overall disease severity. ROC analysis of sNfL and confusion provided an area under the curve (AUC) of 0.73 (95% CI 0.62-0.82). Log-transformed sNfL levels were not associated with general disease severity. In a logistic regression analysis, log2-sNfL was identified as a strong predictor for an unfavorable outcome., Interpretation: sNfL levels are specifically associated with confusion and not with pneumonia disease severity, thus reflecting a potential objective marker for encephalopathy in these patients. Furthermore, sNfL levels are also associated with unfavorable outcome in these patients and might help clinicians to identify patients at risk., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Despite improvements in medical science and public health, mortality of community-acquired pneumonia (CAP) has barely changed throughout the last 15 years. The current SARS-CoV-2 pandemic has once again highlighted the central importance of acute respiratory infections to human health. The "network of excellence on Community Acquired Pneumonia" (CAPNETZ) hosts the most comprehensive CAP database worldwide including more than 12,000 patients. CAPNETZ connects physicians, microbiologists, virologists, epidemiologists, and computer scientists throughout Europe. Our aim was to summarize the current situation in CAP research and identify the most pressing unmet needs in CAP research., Methods: To identify areas of future CAP research, CAPNETZ followed a multiple-step procedure. First, research members of CAPNETZ were individually asked to identify unmet needs. Second, the top 100 experts in the field of CAP research were asked for their insights about the unmet needs in CAP (Delphi approach). Third, internal and external experts discussed unmet needs in CAP at a scientific retreat., Results: Eleven topics for future CAP research were identified: detection of causative pathogens, next generation sequencing for antimicrobial treatment guidance, imaging diagnostics, biomarkers, risk stratification, antiviral and antibiotic treatment, adjunctive therapy, vaccines and prevention, systemic and local immune response, comorbidities, and long-term cardio-vascular complications., Conclusion: Pneumonia is a complex disease where the interplay between pathogens, immune system and comorbidities not only impose an immediate risk of mortality but also affect the patients' risk of developing comorbidities as well as mortality for up to a decade after pneumonia has resolved. Our review of unmet needs in CAP research has shown that there are still major shortcomings in our knowledge of CAP., (© 2022. The Author(s).)

There are few data on mortality after discharge with community-acquired pneumonia (CAP). Therefore, we evaluated risk factors for 30-day post-discharge mortality after CAP. We included all patients of the prospective multi-national CAPNETZ study between 2002 and 2018 with (1) hospitalized CAP, (2) survival until discharge, and (3) complete follow-up data. The study endpoint was death within 30 days after discharge. We evaluated risk factors including demographics, comorbidities, admission CAP severity, and laboratory values and treatment-related factors in uni- and multivariable analyses. A total of 126 (1.6%) of 7882 included patients died until day 30 after discharge, corresponding to 26% of all 476 deaths. After multivariable analysis, we identified 10 independent risk factors: higher age, lower BMI, presence of diabetes mellitus, chronic renal or chronic neurological disease (other than cerebrovascular diseases), low body temperature or higher thrombocytes on admission, extended length of hospitalization, oxygen therapy during hospitalization, and post-obstructive pneumonia. By addition these factors, we calculated a risk score with an AUC of 0.831 (95%CI 0.822-0.839, p < 0.001) for prediction of post-discharge mortality. Early post-discharge deaths account for ¼ of all CAP-associated deaths and are associated with patient- and CAP-severity-related risk factors. Additional studies are necessary to replicate our findings in independent cohorts. Study registration: NCT02139163., (© 2022. The Author(s).)

Purpose: Thorough knowledge of the nature and frequency of co-infections is essential to optimize treatment strategies and risk assessment in cases of coronavirus disease 2019 (COVID-19). This study aimed to evaluate the multiplex polymerase chain reaction (PCR) screening approach for community-acquired bacterial pathogens (CABPs) at hospital admission, which could facilitate identification of bacterial co-infections in hospitalized COVID-19 patients., Methods: Clinical data and biomaterials from 200 hospitalized COVID-19 patients from the observational cohort of the Competence Network for community-acquired pneumonia (CAPNETZ) prospectively recruited between March 17, 2020, and March 12, 2021 in 12 centers in Germany and Switzerland, were included in this study. Nasopharyngeal swab samples were analyzed on hospital admission using multiplex real-time reverse transcription (RT)-PCR for a broad range of CABPs., Results: In total of 200 patients Staphylococcus aureus (27.0%), Haemophilus influenzae (13.5%), Streptococcus pneumoniae (5.5%), Moraxella catarrhalis (2.5%), and Legionella pneumophila (1.5%) were the most frequently detected bacterial pathogens. PCR detection of bacterial pathogens correlated with purulent sputum, and showed no correlation with ICU admission, mortality, and inflammation markers. Although patients who received antimicrobial treatment were more often admitted to the ICU and had a higher mortality rate, PCR pathogen detection was not significantly related to antimicrobial treatment., Conclusion: General CABP screening using multiplex PCR with nasopharyngeal swabs may not facilitate prediction or identification of bacterial co-infections in the early phase of COVID-19-related hospitalization. Most patients with positive PCR results appear to be colonized rather than infected at that time, questioning the value of routine antibiotic treatment on admission in COVID-19 patients., (© 2021. The Author(s).)

The present guideline provides a new and updated concept of the management of adult patients with community-acquired pneumonia. It replaces the previous guideline dating from 2016.The guideline was worked out and agreed on following the standards of methodology of a S3-guideline. This includes a systematic literature search and grading, a structured discussion of recommendations supported by the literature as well as the declaration and assessment of potential conflicts of interests.The guideline has a focus on specific clinical circumstances, an update on severity assessment, and includes recommendations for an individualized selection of antimicrobial treatment.The recommendations aim at the same time at a structured assessment of risk for adverse outcome as well as an early determination of treatment goals in order to reduce mortality in patients with curative treatment goal and to provide palliation for patients with treatment restrictions., Competing Interests: Eine Übersicht der Interessenkonflikte findet sich im Internet unter http://awmf.org; AWMF-Registriernummer 020-020., (Thieme. All rights reserved.)

Background: To investigate the use of do-not-resuscitate (DNR) orders in patients hospitalized with community-acquired pneumonia (CAP) and the association with mortality., Methods: We assembled a cohort of 1317 adults hospitalized with radiographically confirmed CAP in three Danish hospitals. Patients were grouped into no DNR order, early DNR order (≤48 h after admission), and late DNR order (> 48 h after admission). We tested for associations between a DNR order and mortality using a cox proportional hazard model adjusted for patient and disease related factors., Results: Among 1317 patients 177 (13%) patients received a DNR order: 107 (8%) early and 70 (5%) late, during admission. Patients with a DNR order were older (82 years vs. 70 years, p < 0.001), more frequently nursing home residents (41% vs. 6%, p < 0.001) and had more comorbidities (one or more comorbidities: 73% vs. 59%, p < 0.001). The 30-day mortality was 62% and 4% in patients with and without a DNR order, respectively. DNR orders were associated with increased risk of 30-day mortality after adjustment for age, nursing home residency and comorbidities. The association was modified by the CURB-65 score Hazard ratio (HR) 39.3 (95% CI 13.9-110.6), HR 24.0 (95% CI 11.9-48,3) and HR 9.4 (95% CI: 4.7-18.6) for CURB-65 score 0-1, 2 and 3-5, respectively., Conclusion: In this representative Danish cohort, 13% of patients hospitalized with CAP received a DNR order. DNR orders were associated with higher mortality after adjustment for clinical risk factors. Thus, we encourage researcher to take DNR orders into account as potential confounder when reporting CAP associated mortality.

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled "a randomized embedded multifactorial adaptive platform." The design has five key features: 1 ) randomization, allowing robust causal inference; 2 ) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3 ) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4 ) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5 ) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas.Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

Background: Although blood cultures (BCs) are the "gold standard" for detecting bacteremia, the utility of BCs in patients with community-acquired pneumonia (CAP) is controversial. This study describes the proportion of patients with CAP and afebrile bacteremia and identifies the clinical characteristics predicting the necessity for BCs in patients who are afebrile., Methods: Bacteremia rates were determined in 4,349 patients with CAP enrolled in the multinational cohort study The Competence Network of Community-Acquired Pneumonia (CAPNETZ) and stratified by presence of fever at first patient contact. Independent predictors of bacteremia in patients who were afebrile were determined using logistic regression analysis., Results: Bacteremic pneumonia was present in 190 of 2,116 patients who were febrile (8.9%), 101 of 2,149 patients who were afebrile (4.7%), and one of 23 patients with hypothermia (4.3%). Bacteremia rates increased with the CURB-65 score from 3.5% in patients with CURB-65 score of 0 to 17.1% in patients with CURB-65 score of 4. Patients with afebrile bacteremia exhibited the highest 28-day mortality rate (9.9%). Positive pneumococcal urinary antigen test (adjusted OR [AOR], 4.6; 95% CI, 2.6-8.2), C-reactive protein level > 200 mg/L (AOR, 3.1; 95% CI, 1.9-5.2), and BUN level ≥ 30 mg/dL (AOR, 3.1; 95% CI, 1.9-5.3) were independent positive predictors, and antibiotic pretreatment (AOR, 0.3; 95% CI, 0.1-0.6) was an independent negative predictor of bacteremia in patients who were afebrile., Conclusions: A relevant proportion of patients with bacteremic CAP was afebrile. These patients had an increased mortality rate compared with patients with febrile bacteremia or nonbacteremic pneumonia. Therefore, the relevance of fever as an indicator for BC necessity merits reconsideration., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Rationale: Hyperglycemia is associated with mortality in patients with community-acquired pneumonia (CAP), and hyperglycemia may be a biomarker of severity. However, hyperglycemia has a major disadvantage because the association is diminished in patients with diabetes mellitus (DM). This hampers the use of hyperglycemia as a biomarker. Accounting for habitual glucose levels could overcome this disadvantage. Objectives: We hypothesized that the glycemic gap (the difference between plasma glucose and the estimated average glucose) may be associated with mortality irrespective of DM. Methods: Among 1,933 adults with CAP included in a prospective multicenter cohort, we investigated the association between the glycemic gap and 90-day mortality. Hemoglobin A 1c was used to estimate the average glucose. The association was assessed with Cox proportional hazard models after adjustment for age, sex, CURB-65 (Confusion, urea >7 mmol/L, respiratory rate ≥30 breaths/minute, systolic blood pressure <90 mmHg or diastolic blood pressure ≤60 mmHg and age ≥65 years), and comorbidities. In the prespecified analysis the absolute and relative glycemic gaps were used as a continuous variable. In a post hoc analysis, the absolute and relative glycemic gaps were used as a categorical variable grouped according to quartiles. Results: In the post hoc analysis, patients with the lowest (negative) and highest (positive) absolute glycemic gap quartiles had increased risk of 90-day mortality (hazard ratio, 2.6; 95% confidence interval, 1.02-6.65; and hazard ratio, 2.5; 95% confidence interval, 1.01-6.06, respectively). A similar association was found for the relative glycemic gap. The associations were independent of age, CURB-65 score, sex, or number of comorbidities and not modified by DM. Conclusions: Patients with the highest and lowest glycemic gap may have an increased risk of 90-day mortality, and the association was not modified by DM. These associations were found in an exploratory post hoc analysis and should be validated in other populations before further conclusions can be made.

Human rhinoviruses (RV) belong to the Picornaviridae and are divided into three species: rhinovirus A, B and C. As causative viruses of upper airway infections (common cold), they possess enormous epidemiological and clinical importance. Furthermore, rhinoviruses are significant pathogens of acute exacerbations of chronic airway diseases such as asthma and chronic obstructive pulmonary disease. Their role as a cofactor in the development of pneumonia and their relevance in critically ill patients is still unclear and the focus of current research. Due to the unspecific clinical symptoms, diagnosis is difficult. Laboratory detection is sophisticated and a distinction between clinically relevant infection and contamination not always possible. Specific therapeutic antiviral strategies against rhinovirus infection do not exist as yet and, due to the large variety of subtypes, the development of vaccines remains a considerable challenge.

Pneumonia belongs to the most frequent and most deadly infectious diseases worldwide. It represents an increasing problem for the aging population. The incidence and mortality rises with every decade. The clinical presentation of pneumonia differs between elderly and younger patients. Multiple factors including functional status (self-dependency and immobilization), comorbidities, immunosenescence, nutritional status, swallowing disorders have to be accounted for. Pneumonia in the elderly has to be differentiated from nursing home acquired pneumonia. Diagnosis of pneumonia of the elderly demands special attention as the diagnostic value of common biomarkers and prognostic scores is different., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: nein; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.);Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein.Erklärung zu nichtfinanziellen InteressenVorstandsvorsitzender CAPNETZ-Stiftung, (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: It is still a matter of debate whether the outcome of community acquired pneumonia is more severe in patients with chronic obstructive pulmonary disease. We aimed to determine whether chronic obstructive pulmonary disease was associated with increased mortality and to identify risk-factors for mortality in patients with community acquired pneumonia and chronic obstructive pulmonary disease., Methods: Retrospective cohort study comparing patients with community acquired pneumonia and chronic obstructive pulmonary disease to patients without chronic obstructive pulmonary disease. We included 1309 patients with community acquired pneumonia admitted from 2011 until 2012 (243 patients with chronic obstructive pulmonary disease and 1066 without chronic obstructive pulmonary disease)., Results: At admission patients with community acquired pneumonia and chronic obstructive pulmonary disease presented with more severe pneumonia as measured by CURB-65 score compared to patients without chronic obstructive pulmonary disease. Mortality on day 30 was generally high, and higher among patients with community acquired pneumonia and chronic obstructive pulmonary disease compared to those without chronic obstructive pulmonary disease (16.0% versus 11.3%, p = .04). In an adjusted analysis, however, chronic obstructive pulmonary disease was not independently associated with 30-d mortality (odds ratio 0.94, confidence interval 95% 0.59-1.50). Factors related to mortality in patients with community acquired pneumonia and chronic obstructive pulmonary disease were age, premorbid condition, severity of pneumonia as determined by CURB-65 score, and pleural effusion and multi-lobular infiltrate on chest X-ray., Conclusions: Chronic obstructive pulmonary disease was not independently associated with 30-d mortality in patients with community acquired pneumonia.

To investigate whether hemoglobin, white blood cell count (WBC), urea, sodium, albumin, and C-reactive protein at discharge in patients hospitalized for community-acquired pneumonia (CAP) are associated with 30-day readmission. This study is a retrospective cohort study, which included all adult patients discharged after hospitalization for CAP from three Danish hospitals between January 2011 and July 2012. The outcome was all-cause, unplanned, 30-day readmission. Biomarker concentrations at discharge were transformed into binary variables by using either upper or lower quartiles as cut-off; the upper quartile was used for WBC, urea, and C-reactive protein, and the lower quartile was used for hemoglobin, sodium, and albumin. The study population consisted of 1149 patients. One hundred eighty-four (16.0%) patients were readmitted. Independent risk factors of readmission were WBC ≥ 10.6 cells × 10 9 /L (hazard ratio 1.50; 95% CI, 1.07-2.11) and albumin <32 g/L (hazard ratio 1.78; 95% CI, 1.24-2.54) at discharge and the presence of ≥ 2 co-morbidities (hazard ratio 1.74; 95% CI, 1.15-2.64). When WBC, albumin, and co-morbidities were combined into a risk-stratification tool, there was a step-wise increase in risk of readmission for patients with 1, 2, or 3 risk factors with hazard ratios of 1.76 (95% CI, 1.25-2.49), 2.59 (95% CI, 1.71-3.93), and 6.15 (95% CI 3.33-11.38), respectively. WBC ≥ 10.6 cells × 10 9 /L and albumin < 32 g/L at discharge and the presence of ≥ 2 co-morbidities were independently associated with increased risk of 30-day readmission.

Background: Diabetes mellitus is an important risk factor for community-acquired pneumonia, whereas the prevalence of undiagnosed diabetes mellitus and prediabetes in patients with community-acquired pneumonia is largely unknown. We aimed to determine the prevalence of prediabetes, undiagnosed diabetes mellitus, and risk factors associated with undiagnosed diabetes mellitus in a large European community-acquired pneumonia cohort., Methods: This was a multicenter prospective cohort study of hospitals and private practices in Germany and Austria encompassing 1961 adults with community-acquired pneumonia included in the German Community-Acquired Pneumonia Competence Network (CAPNETZ) study between 2007 and 2014. The prevalence of undiagnosed diabetes mellitus and prediabetes was estimated based on hemoglobin A1c measurements. Logistic regression was used to assess risk factors for undiagnosed diabetes mellitus., Results: Fifteen percent of patients had known diabetes mellitus. Among patients without known diabetes mellitus, 5.0% had undiagnosed diabetes mellitus and 37.5% had prediabetes. Male sex (odds ratio [OR], 2.45 [95% confidence interval {CI}, 1.35-4.45]), body mass index ≥25 kg/m2 (OR, 2.64 [95% CI, 1.48-4.72]), and hyperglycemia at admission (6-11 mM: OR, 2.93 [95% CI, 1.54-5.60] and ≥11 mM: OR, 44.76 [95% CI, 17.58-113.98]) were associated with undiagnosed diabetes mellitus. Patients with undiagnosed diabetes mellitus had a higher 180-day mortality rate compared to patients without diabetes mellitus (12.1% vs 3.8%, respectively; P = .001)., Conclusions: Undiagnosed diabetes mellitus was prevalent among community-acquired pneumonia. Male sex, overweight, and hyperglycemia at admission were associated with undiagnosed diabetes mellitus. The long-term mortality among patients with undiagnosed diabetes mellitus was high compared to patients without diabetes mellitus., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: C-reactive protein (CRP) is a well-known acute phase protein used to monitor the patient's response during treatment in infectious diseases. Mortality from Community-acquired Pneumonia (CAP) remains high, particularly in hospitalized patients. Better risk prediction during hospitalization could improve management and ultimately reduce mortality levels. The aim of this study was to evaluate CRP on the 3rd day (CRP3) of hospitalization as a predictor for 30 days mortality., Methods: A retrospective multicentre cohort study of adult patients admitted with CAP at three Danish hospitals. Predictive associations of CRP3 (absolute levels and relative decline) and 30 days mortality were analysed using receiver operating characteristics and logistic regression., Results: Eight hundred and fourteen patients were included and 90 (11%) died within 30 days. The area under the curve for CRP3 level and decline for predicting 30 days mortality were 0.64 (0.57-0.70) and 0.71 (0.65-0.76). Risk of death was increased in patients with CRP3 level >75 mg/l (OR 2.44; 95%CI 1.36-4.37) and in patients with a CRP3 decline <50% (OR 4.25; 95%CI 2.30-7.83). In the multivariate analysis, the highest mortality risk was seen in patients who failed to decline by 50%, irrespective of the actual level of CRP (OR 7.8; 95%CI 3.2-19.3). Mortality risk increased significantly according to CRP decline for all strata of CURB-65 score., Conclusions: CRP responses day 3 is a valuable predictor of 30 days mortality in hospitalized CAP patients. Failure to decline in CRP was associated with a poor prognosis irrespective of the actual level of CRP or CURB-65.

Severity assessment is a crucial step in the initial management of patients with community-acquired pneumonia (CAP). While approximately half of patients are at low risk of death and can be safely treated as outpatients, around 20% are at increased risk. While CURB-65 (confusion, respiratory rate, blood pressure, urea) and pneumonia severity index (PSI) scores are equally useful as an adjunct to clinical judgment to identify patients at low risk, the so-called minor American Thoracic Society/Infectious Diseases Society of America criteria are predictive of patients in need of intensified treatment (i.e., mechanical ventilation and/or vasopressor treatment). Such patients represent medical emergencies. In elderly patients, CRB-65 (confusion, respiratory rate, blood pressure, age) is no longer predictive of low risk; instead, poor functional status is the best predictor of death. In addition to scores, assessment of oxygenation and unstable comorbidity, as well as lactate and biomarkers remain important to consider. The added value of combined clinical and biomarker risk stratification strategies should be evaluated in large prospective interventional trials.Survivors of hospitalized CAP have a considerable excess long-term mortality. Risk factors include age, male gender, and nursing home residency, as well as increased PSI and CURB-65 scores. Cardiovascular, pulmonary, renal, and neoplastic comorbidities are prominent causes of long-term mortality. Comorbidities are vulnerable to both the acute and chronic subclinical inflammatory challenge delivered by pulmonary infection and are thereby drivers of mortality. Biomarkers are promising in identifying patients at increased risk of long-term mortality. Future studies should develop consistent strategies of risk stratification and intervention to improve long-term outcomes of patients with CAP., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Dipeptidyl-peptidase-4 inhibitors (DPP4Is) are drugs for the treatment of type 2 diabetes mellitus (T2DM). There is increasing evidence that DPP4Is may result in suppression of the immune system and may increase the risk of infections such as pneumonia. Aim of this study was to evaluate the association between the use of DPP4Is and the risk of pneumonia in a population-based study., Methods: We conducted a population-based cohort study using data from the world's largest primary care database, the UK Clinical Practice Research Datalink (CPRD). We selected all users of non-insulin antidiabetic drugs (NIADs), including DPP4Is, between 2007 and 2012. To each NIAD user, we matched randomly selected non-users. The NIAD user's first prescription defined the index date, which was then assigned to the matched non-users. Patients were followed from their first prescription until end of data collection or the first event of pneumonia, whichever came first. Cox regression analysis estimated the association between pneumonia and current use of DPP4Is versus 1) current use of other NIADs and 2) non-users. DPP4I use was then stratified to daily and cumulative dose. Analyses were statistically adjusted for age, sex, lifestyle factors and comorbidities and concomitant use of various other drugs., Results: Risk of pneumonia was not increased with current DPP4I use versus use of other NIADs, adjusted Hazard Ratio (HR) 0.70; 95% Confidence Interval (CI) 0.55-0.91. Also higher cumulative doses or daily doses did not further increase risk of pneumonia., Conclusion: We found no increased risk of pneumonia in T2DM patients using DPP4Is compared to T2DM patients using other NIADs. Our finding is in line with direct and indirect evidence from observational studies and RCTs. There is probably no need to avoid prescribing of DPP4Is to elderly patients who are at risk of pneumonia.

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., (© 2015 The Association for the Publication of the Journal of Internal Medicine.)

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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Dysnatremia is a frequent finding in patients with community acquired pneumonia (CAP) and a predictor of mortality. We studied the relation between dysnatremia, comorbidities and CT-pro-AVP and MR-proANP., Methods: We enrolled 2138 patients (60 ± 18 years, 55% male) with CAP from the CAPNETZ database. Pro-atrial natriuretic peptide (proANP), pro-vasopressin (proAVP), serum sodium and CRB-65 score were determined on admission. Patients were followed up for 28 days. Sodium concentration on admission was examined as a function of mortality at 28 days. Hyponatremia (HypoN) was defined as admission serum sodium <136 mmol/L, hypernatremia (HyperN) as admission serum sodium >145 mmol/L., Results: HypoN was diagnosed in 680 (31.8%) patients, HyperN in 29 (1.4%) patients. Comorbidities were associated with sodium levels, and CT-pro-AVP and MR-proANP were inversely related to sodium levels. Patients with HypoN were older, had a higher CRB-65 score and higher values of CT-proAVP and MR-proANP (all p < 0.05). When examined as a function of sodium values, a U-shaped association was found between sodium levels and 28 day mortality. In multivariate Cox proportional hazards analysis, HypoN and HyperN were independent predictors of 28 day mortality. Sodium levels added to the predictive potential of proAVP and proANP., Conclusion: HypoN is common at admission among CAP patients and is independently associated with mortality. HyperN is rare at admission among CAP patients but is also independently associated with mortality. The combination of sodium and CT-pro-AVP and MR-proANP levels achieved the highest prediction of mortality., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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.

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., (Copyright © 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Objective: To examine whether acute dysglycaemia predicts death in people admitted to hospital with community acquired pneumonia., Design: Multicentre prospective cohort study., Setting: Hospitals and private practices in Germany, Switzerland, and Austria., Participants: 6891 patients with community acquired pneumonia included in the German community acquired pneumonia competence network (CAPNETZ) study between 2003 and 2009., Main Outcome Measures: Univariable and multivariable hazard ratios adjusted for sex, age, current smoking status, severity of community acquired pneumonia using the CRB-65 score (confusion, respiratory rate >30/min, systolic blood pressure ≤ 90 mm Hg or diastolic blood pressure ≤ 60 mm Hg, and age ≥ 65 years), and various comorbidities for death at 28, 90, and 180 days according to serum glucose levels on admission., Results: An increased serum glucose level at admission to hospital in participants with community acquired pneumonia and no pre-existing diabetes was a predictor of death at 28 and 90 days. Compared with participants with normal serum glucose levels on admission, those with mild acute hyperglycaemia (serum glucose concentration 6-10.99 mmol/L) had a significantly increased risk of death at 90 days (1.56, 95% confidence interval 1.22 to 2.01; P<0.001), and this risk increased to 2.37 (1.62 to 3.46; P<0.001) when serum glucose concentrations were ≥ 14 mmol/L. In sensitivity analyses the predictive value of serum glucose levels on admission for death was confirmed at 28 days and 90 days. Patients with pre-existing diabetes had a significantly increased overall mortality compared with those without diabetes (crude hazard ratio 2.47, 95% confidence interval 2.05 to 2.98; P<0.001). This outcome was not significantly affected by serum glucose levels on admission (P = 0.18 for interaction)., Conclusions: Serum glucose levels on admission to hospital can predict death in patients with community acquired pneumonia without pre-existing diabetes. Acute hyperglycaemia may therefore identify patients in need of intensified care to reduce the risk of death from community acquired pneumonia.

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.

Background: Biomarkers have been intensively studied in community-acquired pneumonia (CAP) in recent years. In the context of the CAPNETZ study we had the unique opportunity to evaluate old and new biomarkers in a multicentre study with a high number of patients., Results: In several substudies we found the following results: procalcitonin, CRP and leukocytes show highest values in patients with typical bacterial etiology of CAP, but do not allow individual prediction of etiology. Patients without antibiotic pre-treatment show higher values of biomarkers compared to patients with antibiotic pre-treatment. New cardiovascular biomarkers are good predictors for short- and long-term mortality in CAP, superior to the inflammatory markers procalcitonin, CRP and leukocytes and at least comparable to the clinical CRB-65 score. Pro-Adrenomedullin is among the new biomarkers the one with the best prognostic value., Conclusions: Biomarkers correlate with the severity of CAP but do not allow individual prediction of etiology. New cardiovascular biomarkers are suitable for the evaluation of short- and long-term prognosis in CAP. The combination of several biomarkers reflecting different pathophysiological pathways has the potential to improve management of CAP in the future., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Flexible, fibreoptic bronchoscopy (FFB) and bronchoalveolar lavage (BAL) have been used for diagnostic purposes in critically ill ventilated patients. The additional diagnostic value compared to tracheal aspirations in ventilator-associated pneumonia (VAP) has been questioned. Nevertheless, BAL can provide extra information for the differential diagnosis of respiratory disease and good antibiotic stewardship. These benefits should outweigh potential hazards caused by the invasiveness of this diagnostic technique. The focus of the present study was on the clinical course and complications of patients following BAL procedures up to 24 h.Methods: Hundred sixty-four FFB guided BAL procedures for suspected pneumonia were analysed in an observational study. The clinical course of patients was monitored by respiratory and haemodynamic data before BAL, 1 and 24 h after BAL. Complications were defined and registered. Factors associated with complications were analysed by logistic regression.Results: Clinical Course: a decrease in average pO2/FiO2 ratio 1 h after BAL from 29 kPa (218 mmHg) to 25 kPa (189 mmHg) (p < 0.05) was observed which fully recovered within 24 h. Respiratory complications: the incidence of procedure related hypo-oxygenation (SaO2 ≤ 88 %) and/or bronchospasm was 9 %; a decrease of >25 % PaO2/FiO2 ratio 1 h after BAL was found in 29 % of patients; no bleeding or pneumothorax were registered. Haemodynamic complications: there were no cases of hypertension and cardiac rhythm disturbances; haemodynamic instability within the first 24 h after BAL was recorded in 22 %; this was correlated with a cardiovascular diagnosis at admission (OR 2.9; 95 % CI 1.2 - 6.7) and the presence of cardiovascular co-morbidity (OR 3.5; 95 % CI 1.5 - 8.3). The incidence of bacteraemia was 7 %. There was no case of procedure related death.Discussion: Frequently occurring haemodynamic and respiratory instability but no cases of cardiac rhythm disturbances, bleeding, pneumothorax or procedure related death were attributable to diagnostic FFB and BAL. The procedures should be conducted under careful supervision by experienced physicians. Only a randomized controlled trial that compares diagnostic FFB and BAL with a non-invasive strategy could ultimately establish the safety profile and clinical utility of these procedures in critically ill ventilated patients. [ABSTRACT FROM AUTHOR]

Background and methods: Human metapneumovirus (hMPV) is a recently discovered respiratory virus associated with bronchiolitis, pneumonia, croup and exacerbations of asthma. Since respiratory viruses are frequently detected in patients with acute exacerbations of COPD (AE-COPD) it was our aim to investigate the frequency of hMPV detection in a prospective cohort of hospitalized patients with AE-COPD compared to patients with stable COPD and to smokers without by means of quantitative real-time RT-PCR. Results: We analysed nasal lavage and induced sputum of 130 patients with AE-COPD, 65 patients with stable COPD and 34 smokers without COPD. HMPV was detected in 3/130 (2.3%) AE-COPD patients with a mean of 6.5 x 105 viral copies/ml in nasal lavage and 1.88 x 105 viral copies/ml in induced sputum. It was not found in patients with stable COPD or smokers without COPD. Conclusion: HMPV is only found in a very small number of patients with AE-COPD. However it should be considered as a further possible viral trigger of AE-COPD because asymptomatic carriage is unlikely. [ABSTRACT FROM AUTHOR]