Search

Background Signifying the 2-compartments/1-disease paradigm, allergic rhinoconjunctivitis (ARC) and asthma (AA) are prevalent, comorbid conditions triggered by environmental factors (eg, house dust mites [HDMs]). However, despite the ubiquity of triggers, progression to severe ARC/AA is infrequent, suggesting either resilience or adaptation. Objective We sought to determine whether ARC/AA severity relates to maladaptive responses to disease triggers. Methods Adults with HDM-associated ARC were challenged repetitively with HDMs in an aeroallergen challenge chamber. Mechanistic traits associated with disease severity were identified. Results HDM challenges evoked maladaptive (persistently higher ARC symptoms), adaptive (progressive symptom reduction), and resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Nasal airway traits, defined by low inflammation-effectual epithelial integrity, moderate inflammation-effectual epithelial integrity, and higher inflammation-ineffectual epithelial integrity, were hallmarks of the resilient, adaptive, and maladaptive evoked phenotypes, respectively. Highlighting a crosstalk mechanism, peripheral blood inflammatory tone calibrated these traits: ineffectual epithelial integrity associated with CD8+ T cells, whereas airway inflammation associated with both CD8+ T cells and eosinophils. Hallmark peripheral blood maladaptive traits were increased natural killer and CD8+ T cells, lower CD4+ mucosal-associated invariant T cells, and deficiencies along the TLR-IRF-IFN antiviral pathway. Maladaptive traits tracking HDM-associated ARC also contributed to AA risk and severity models. Conclusions Repetitive challenges with HDMs revealed that maladaptation to disease triggers may underpin ARC/AA disease severity. A combinatorial therapeutic approach may involve reversal of loss-of-beneficial-function traits (ineffectual epithelial integrity, TLR-IRF-IFN deficiencies), mitigation of gain-of-adverse-function traits (inflammation), and blocking of a detrimental crosstalk between the peripheral blood and airway compartments.

Pneumonia causes a significant burden of disease worldwide. Although all populations are at risk of pneumonia, those at extremes of age and those with immunosuppressive disorders, underlying respiratory disease, and critical illness are particularly vulnerable. Although clinical practice guidelines addressing the management and treatment of pneumonia exist, few of the supporting studies focus on the crucial contributions of the host in pneumonia pathogenesis and recovery. Such essential considerations include the host risk factors that lead to susceptibility to lung infections; biomarkers reflecting the host response and the means to pursue host-directed pneumonia therapy; systemic effects of pneumonia on the host; and long-term health outcomes after pneumonia. To address these gaps, the Pneumonia Working Group of the Assembly on Pulmonary Infection and Tuberculosis led a workshop held at the American Thoracic Society meeting in May 2018 with overarching objectives to foster attention, stimulate research, and promote funding for short-term and long-term investigations into the host contributions to pneumonia. The workshop involved participants from various disciplines with expertise in lung infection, pneumonia, sepsis, immunocompromised patients, translational biology, data science, genomics, systems biology, and clinical trials. This workshop report summarizes the presentations and discussions and important recommendations for future clinical pneumonia studies. These recommendations include establishing consensus disease and outcome definitions, improved phenotyping, development of clinical study networks, standardized data and biospecimen collection and protocols, and development of innovative trial designs.

PurposeSevere community-acquired pneumonia (CAP) requiring intensive care unit admission is associated with significant acute and long-term morbidity and mortality. We hypothesized that downregulation of systemic and pulmonary inflammation with prolonged low-dose methylprednisolone treatment would accelerate pneumonia resolution and improve clinical outcomes.MethodsThis double-blind, randomized, placebo-controlled clinical trial recruited adult patients within 72-96h of hospital presentation. Patients were randomized in 1:1 ratio; an intravenous 40mg loading bolus was followed by 40mg/day through day 7 and progressive tapering during the 20-day treatment course. Randomization was stratified by site and need for mechanical ventilation (MV) at the time of randomization. Outcomes included a primary endpoint of 60-day all-cause mortality and secondary endpoints of morbidity and mortality up to 1year of follow-up.ResultsBetween January 2012 and April 2016, 586 patients from 42 Veterans Affairs Medical Centers were randomized, short of the 1420 target sample size because of low recruitment. 584 patients were included in the analysis. There was no significant difference in 60-day mortality between the methylprednisolone and placebo arms (16% vs. 18%; adjusted odds ratio 0.90, 95% CI 0.57-1.40). There were no significant differences in secondary outcomes or complications.ConclusionsIn patients with severe CAP, prolonged low-dose methylprednisolone treatment did not significantly reduce 60-day mortality. Treatment was not associated with increased complications.

IntroductionProcalcitonin expression is thought to be stimulated by bacteria and suppressed by viruses via interferon signalling. Consequently, during respiratory viral illness, clinicians often interpret elevated procalcitonin as evidence of bacterial coinfection, prompting antibiotic administration. We sought to evaluate the validity of this practice and the underlying assumption that viral infection inhibits procalcitonin synthesis.MethodsWe conducted a retrospective cohort study of patients hospitalised with pure viral infection (n=2075) versus bacterial coinfection (n=179). The ability of procalcitonin to distinguish these groups was assessed. In addition, procalcitonin and interferon gene expression were evaluated in murine and cellular models of influenza infection.ResultsPatients with bacterial coinfection had higher procalcitonin than those with pure viral infection, but also more severe disease and higher mortality (pDiscussionThese studies reveal that procalcitonin rises during pure viral infection in proportion to disease severity and is not suppressed by interferon signalling, in contrast to prior models of procalcitonin regulation. Applied clinically, our data suggest that procalcitonin represents a better indicator of disease severity than bacterial coinfection during viral respiratory infection.

In recent decades, there has been a growing interest about the role of gram negative bacteria in community-acquired pneumonia (CAP), especially Pseudomonas aeruginosa, Enterobacteriaceae, and Acinetobacter baumannii. The prevalence of these pathogens differs largely according to the local ecology and the geographical location. Identifying gram negative bacteria, and in particular resistant gram negative bacteria, is of paramount importance in patients with CAP because these pathogens are associated with higher clinical severity and unfavorable outcomes. The use of individualized risk factors to predict each pathogen is a helpful strategy that needs to be locally validated. However, it should be taken into account that most of the risk factors identified in the literature are heterogeneously defined or lack consistency. New diagnostic techniques, such as molecular testing, are promising methods for early detection of these gram negative pathogens. The increasing mechanisms of resistance to antibiotics of these pathogens have limited our therapeutic approach. This narrative review focuses on the epidemiology, risk factors, diagnosis, and therapeutic options for the most relevant gram negative bacteria that cause CAP.

Clinical practice guidelines (CPGs) are intended to support clinical decisions and should be based on high-quality evidence. The objective of the study was to evaluate the quality of evidence supporting the recommendations issued in CPGs for therapy, diagnosis, and prevention of hospital-acquired and ventilator-associated pneumonia (HAP/VAP). CPGs released by international scientific societies after year 2000, using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology, were analyzed. Number and strength of recommendations and quality of evidence (high, moderate, low, and very low) were extracted and indexed in the aforementioned sections. High-quality evidence was based on randomized control trials (RCT) without important limitations and exceptionally on rigorous observational studies. Eighty recommendations were assessed, with 7 (8.7%), 24 (30.0%), 29 (36.3%), and 20 (25.0%) being supported by high, moderate, low, and very low-quality evidence, respectively. Highest evidence degree was reported for 26 prevention recommendations, with 7 (26.9%) supported by high-quality evidence and no recommendation based on very low-quality evidence. In contrast, among 9 recommendations for diagnosis and 45 for therapy, none was supported by high-quality evidence, in spite of being recommended as strong in 33.3% and 46.7%, respectively. Among HAP/VAP diagnosis recommendations, the majority of evidence was rated as low or very low-quality (55.6% and 22.2%, respectively) whereas among HAP/VAP therapy recommendations, 4/5 were rated as low and very low-quality (40% each). In conclusion, among HAP/VAP international guidelines, most recommendations, particularly in therapy, remain supported by observational studies, case reports, and expert opinion. Well-designed RCTs are urgently needed. Electronic supplementary material The online version of this article (10.1007/s10096-019-03748-z) contains supplementary material, which is available to authorized users.

Background: This document provides evidence-based clinical practice guidelines on the management of adult patients with community-acquired pneumonia. Methods: A multidisciplinary panel conducted pragmatic systematic reviews of the relevant research and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations. Results: The panel addressed 16 specific areas for recommendations spanning questions of diagnostic testing, determination of site of care, selection of initial empiric antibiotic therapy, and subsequent management decisions. Although some recommendations remain unchanged from the 2007 guideline, the availability of results from new therapeutic trials and epidemiological investigations led to revised recommendations for empiric treatment strategies and additional management decisions. Conclusions: The panel formulated and provided the rationale for recommendations on selected diagnostic and treatment strategies for adult patients with community-acquired pneumonia.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and bronchiectasis can overlap and share pathologic features, such as small airway disease (SAD). Whether the presence of SAD and emphysema in smokers with CT-derived bronchiectasis is associated with exacerbations is unknown. PURPOSE: To assess whether SAD and emphysema in smokers with CT-derived bronchiectasis are associated with future exacerbations. MATERIALS AND METHODS: SAD and emphysema were quantified using the parametric response map method in former and current heavy smokers with and without bronchiectasis at CT from the COPDGene Study (from July 2009 to July 2018). Exacerbations were prospectively assessed through biannual follow-up. An exacerbation was defined as an increase in or new onset of respiratory symptoms treated with antibiotics and/or corticosteroids. Severe exacerbations were defined as those that required hospitalization. The association of a high burden of SAD (≥15.6%) and high burden of emphysema (≥5%) at CT with exacerbations was assessed with generalized linear mixed models. RESULTS: Of 737 participants, 387 (median age, 64 years [interquartile range, 58–71 years]; 223 women) had CT-derived bronchiectasis. During a 9-year follow-up, after adjustment for age, sex, race, body mass index, current smoking status, pack-years, exacerbations before study entry, forced expiratory volume in 1 second, or FEV(1), and bronchiectasis severity CT score, high burden of SAD and high burden of emphysema were associated with a higher number of exacerbations per year (relative risk [RR], 1.89 [95% CI: 1.54, 2.33] and 1.37 [95% CI: 1.13, 1.66], respectively; P ≤ .001 for both). Results were comparable among participants with bronchiectasis meeting criteria for COPD (n = 197) (RR, 1.67 [95% CI: 1.23, 2.27] for high burden of SAD and 1.51 [95% CI: 1.20, 1.91] for high burden of emphysema; P ≤ .001 for both). CONCLUSION: In smokers with CT-derived bronchiectasis and chronic obstructive pulmonary disease, structural damage to lung parenchyma and small airways was associated with a higher number of exacerbations per year. Clinical trial registration no. NCT00608764 © RSNA, 2021

BACKGROUND Allergic asthma (AA) and allergic rhinoconjunctivitis (ARC) are common comorbid environmentally triggered diseases. We hypothesized that severe AA/ARC reflects a maladaptive or unrestrained response to ubiquitous aeroallergens. METHODS We performed provocation studies wherein six separate cohorts of persons (total n = 217) with ARC, with or without AA, were challenged once or more with fixed concentrations of seasonal or perennial aeroallergens in an aeroallergen challenge chamber (ACC). RESULTS Aeroallergen challenges elicited fully or partially restrained vs. unrestrained evoked symptom responsiveness, corresponding to the resilient and adaptive vs. maladaptive AA/ARC phenotypes, respectively. The maladaptive phenotype was evoked more commonly during challenge with a non-endemic versus endemic seasonal aeroallergen. In an AA cohort, symptom responses evoked after house dust mite (HDM) challenges vs. recorded in the natural environment were more accurate and precise predictors of asthma severity and control, lung function (FEV1), and mechanistic correlates of maladaptation. Correlates included elevated levels of peripheral blood CD4+ and CD8+ T-cells, eosinophils, and T-cell activation, as well as gene expression proxies for ineffectual epithelial injury/repair responses. Evoked symptom severity after HDM challenge appeared to be more closely related to levels of CD4+ and CD8+ T-cells than eosinophils, neutrophils, or HDM-specific IgE. CONCLUSIONS Provocation studies support the concept that resilience, adaptation, and maladaptation to environmental disease triggers calibrate AA/ARC severity. Despite the ubiquity of aeroallergens, in response to these disease triggers in controlled settings (ie, ACC), most atopic persons manifest the resilient or adaptive phenotype. Thus, ARC/AA disease progression may reflect the failure to preserve the resilient or adaptive phenotype. The triangulation of CD8+ T-cell activation, airway epithelial injury/repair processes and maladaptation in mediating AA disease severity needs more investigation.

Background: This document provides evidence-based clinical practice guidelines on the diagnostic utility of nucleic acid-based testing of respiratory samples for viral pathogens other than influenza in adults with suspected community-acquired pneumonia (CAP).Methods: A multidisciplinary panel developed a Population-Intervention-Comparison-Outcome question, conducted a pragmatic systematic review, and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations.Results: The panel evaluated the literature to develop recommendations regarding whether routine diagnostics should include nucleic acid-based testing of respiratory samples for viral pathogens other than influenza in suspected CAP. The evidence addressing this topic was generally adjudicated to be of very low quality because of risk of bias and imprecision. Furthermore, there was little direct evidence supporting a role for routine nucleic acid-based testing of respiratory samples in improving critical outcomes such as overall survival or antibiotic use patterns. However, on the basis of direct and indirect evidence, recommendations were made for both outpatient and hospitalized patients with suspected CAP. Testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was not addressed in the literature at the time of the evidence review.Conclusions: The panel formulated and provided their rationale for recommendations on nucleic acid-based diagnostics for viral pathogens other than influenza for patients with suspected CAP.

The clinical evolution of COVID-19 pneumonia is poorly understood. Identifying the metabolic pathways that are altered early with viral infection and their association with disease severity is crucial to understand COVID-19 pathophysiology, and guide clinical decisions. This study aimed at assessing the critical metabolic pathways altered with disease severity in hospitalized COVID-19 patients. Forty-nine hospitalized patients with COVID-19 pneumonia were enrolled in a prospective, observational, single-center study in Barcelona, Spain. Demographic, clinical, and analytical data at admission were registered. Plasma samples were collected within the first 48 h following hospitalization. Patients were stratified based on the severity of their evolution as moderate (N = 13), severe (N = 10), or critical (N = 26). A panel of 221 biomarkers was measured by targeted metabolomics in order to evaluate metabolic changes associated with subsequent disease severity. Our results show that obesity, respiratory rate, blood pressure, and oxygen saturation, as well as some analytical parameters and radiological findings, were all associated with disease severity. Additionally, ceramide metabolism, tryptophan degradation, and reductions in several metabolic reactions involving nicotinamide adenine nucleotide (NAD) at inclusion were significantly associated with respiratory severity and correlated with inflammation. In summary, assessment of the metabolomic profile of COVID-19 patients could assist in disease severity stratification and even in guiding clinical decisions.

Background: Aspiration community-acquired pneumonia (ACAP) and community-acquired pneumonia (CAP) in patients with aspiration risk factors (AspRFs) are infections associated with anaerobes, but limited evidence suggests their pathogenic role. Research Question: What are the aspiration risk factors, microbiology patterns, and empiric anti-anaerobic use in patients hospitalized with CAP? Study Design and Methods: This is a secondary analysis of GLIMP, an international, multicenter, point-prevalence study of adults hospitalized with CAP. Patients were stratified into three groups: (1) ACAP, (2) CAP/AspRF+ (CAP with AspRF), and (3) CAP/AspRF- (CAP without AspRF). Data on demographics, comorbidities, microbiological results, and anti-anaerobic antibiotics were analyzed in all groups. Patients were further stratified in severe and nonsevere CAP groups. Results: We enrolled 2,606 patients with CAP, of which 193 (7.4%) had ACAP. Risk factors independently associated with ACAP were male, bedridden, underweight, a nursing home resident, and having a history of stroke, dementia, mental illness, and enteral tube feeding. Among non-ACAP patients, 1,709 (70.8%) had CAP/AspRF+ and 704 (29.2%) had CAP/AspRF-. Microbiology patterns including anaerobes were similar between CAP/AspRF-, CAP/AspRF+ and ACAP (0.0% vs 1.03% vs 1.64%). Patients with severe ACAP had higher rates of total gram-negative bacteria (64.3% vs 44.3% vs 33.3%, P =.021) and lower rates of total gram-positive bacteria (7.1% vs 38.1% vs 50.0%, P 50% in all groups) independent of AspRFs or ACAP received specific or broad-spectrum anti-anaerobic coverage antibiotics. Interpretation: Hospitalized patients with ACAP or CAP/AspRF+ had similar anaerobic flora compared with patients without aspiration risk factors. Gram-negative bacteria were more prevalent in patients with severe ACAP. Despite having similar microbiological flora between groups, a large proportion of CAP patients received anti-anaerobic antibiotic coverage.

Stool samples from 122 children from urban slum (n = 72) and rural (n = 50) areas were analyzed using multi-parallel real-time qPCR to determine the prevalence of intestinal parasites from two communities in Colombia. Findings indicated a prevalence of 86.1% Blastocystis spp., 62.5% Giardia intestinalis, 19.4% Cryptosporidium spp., 19.4% Ascaris lumbricoides, and 5.6% Trichuris trichiura in an urban slum; and 76% Blastocystis spp., 68% Giardia intestinalis, 20% Entamoeba histolytica, 50% Ascaris lumbricoides, 46% Trichuris trichiura and 2% Strongyloides stercoralis in rural areas. Polyparasitism was higher in rural (58%) compared to urban (25%) areas (p = 0.001). Trichuris trichiura burden was higher in the rural area (p = 0.002). Over 40% of helminth infections in rural areas had a heavy parasite burden by WHO classification. Over half of urban and rural children were infected with Giardia intestinalis and Blastocystis spp. Our data provides accurate epidemiologic surveillance for public health interventions.

Background The 2019 American Thoracic Society/Infectious Diseases Society of America guidelines for community-acquired pneumonia (CAP) revised recommendations for culturing and empiric broad-spectrum antibiotics. We simulated guideline adoption in Veterans Affairs (VA) inpatients. Methods For all VA acute hospitalizations for CAP from 2006–2016 nationwide, we compared observed with guideline-expected proportions of hospitalizations with initial blood and respiratory cultures obtained, empiric antibiotic therapy with activity against methicillin-resistant Staphylococcus aureus (anti-MRSA) or Pseudomonas aeruginosa (antipseudomonal), empiric “overcoverage” (receipt of anti-MRSA/antipseudomonal therapy without eventual detection of MRSA/P. aeruginosa on culture), and empiric “undercoverage” (lack of anti-MRSA/antipseudomonal therapy with eventual detection on culture). Results Of 115 036 CAP hospitalizations over 11 years, 17 877 (16%) were admitted to an intensive care unit (ICU). Guideline adoption would slightly increase respiratory culture (30% to 36%) and decrease blood culture proportions (93% to 36%) in hospital wards and increase both respiratory (40% to 100%) and blood (95% to 100%) cultures in ICUs. Adoption would decrease empiric selection of anti-MRSA (ward: 27% to 1%; ICU: 61% to 8%) and antipseudomonal (ward: 25% to 1%; ICU: 54% to 9%) therapies. This would correspond to greatly decreased MRSA overcoverage (ward: 27% to 1%; ICU: 56% to 8%), slightly increased MRSA undercoverage (ward: 0.6% to 1.3%; ICU: 0.5% to 3.3%), with similar findings for P. aeruginosa. For all comparisons, P Conclusions Adoption of the 2019 CAP guidelines in this population would substantially change culturing and empiric antibiotic selection practices, with a decrease in overcoverage and slight increase in undercoverage for MRSA and P. aeruginosa.

Intensive care units (ICUs) are an appropriate focus of antibiotic stewardship program efforts because a large proportion of any hospital's use of parenteral antibiotics, especially broad-spectrum, occurs in the ICU. Given the importance of antibiotic stewardship for critically ill patients and the importance of critical care practitioners as the front line for antibiotic stewardship, a workshop was convened to specifically address barriers to antibiotic stewardship in the ICU and discuss tactics to overcome these. The working definition of antibiotic stewardship is "the right drug at the right time and the right dose for the right bug for the right duration." A major emphasis was that antibiotic stewardship should be a core competency of critical care clinicians. Fear of pathogens that are not covered by empirical antibiotics is a major driver of excessively broad-spectrum therapy in critically ill patients. Better diagnostics and outcome data can address this fear and expand efforts to narrow or shorten therapy. Greater awareness of the substantial adverse effects of antibiotics should be emphasized and is an important counterargument to broad-spectrum therapy in individual low-risk patients. Optimal antibiotic stewardship should not focus solely on reducing antibiotic use or ensuring compliance with guidelines. Instead, it should enhance care both for individual patients (by improving and individualizing their choice of antibiotic) and for the ICU population as a whole. Opportunities for antibiotic stewardship in common ICU infections, including community- and hospital-acquired pneumonia and sepsis, are discussed. Intensivists can partner with antibiotic stewardship programs to address barriers and improve patient care.

Introduction Serum procalcitonin (PCT) concentration could be increased in patients with renal dysfunction in the absence of bacterial infection. Objective To determine the interactions among serum renal biomarkers of acute kidney injury (AKI) and serum PCT concentration, in patients admitted to the intensive care unit (ICU) due to lung influenza infection. Design Secondary analysis of a prospective multicentre observational study. Setting 148 Spanish ICUs. Patients ICU patients admitted with influenza infection without bacterial co-infection. Clinical, laboratory and hemodynamic variables were recorded. AKI was classified as AKI I or II based on creatinine (Cr) concentrations (≥1.60–2.50 mg/dL and Cr ≥ 2.51–3.99 mg/dL, respectively). Patients with chronic renal disease, receiving renal replacement treatment or with Cr > 4 mg/dL were excluded. Spearman's correlation, simple and multiple linear regression analysis were performed. Interventions None. Results Out of 663 patients included in the study, 52 (8.2%) and 10 (1.6%) developed AKI I and II, respectively. Patients with AKI were significantly older, had more comorbid conditions and were more severally ill. PCT concentrations were higher in patients with AKI (2.62 [0.60–10.0] ng/mL vs. 0.40 [0.13–1.20] ng/mL, p = 0.002). Weak correlations between Cr/PCT (rho = 0.18) and Urea (U)/PCT (rho = 0.19) were identified. Simple linear regression showed poor interaction between Cr/U and PCT concentrations (Cr R2 = 0.03 and U R2 = 0.018). Similar results were observed during multiple linear regression analysis (Cr R2 = 0.046 and U R2 = 0.013). Conclusions Although PCT concentrations were slightly higher in patients with AKI, high PCT concentrations are not explained by AKI and could be warning sign of a potential bacterial infection.

Background Severe community-acquired pneumococcal pneumonia is commonly associated with bacteraemia. Although it is assumed that the bacteraemia solely derives from pneumococci entering the blood from the lungs it is unknown if other organs are important in the pathogenesis of bacteraemia. Using three models, we tested the relevance of the spleen in pneumonia-associated bacteraemia. Methods We used human spleens perfused ex vivo to explore permissiveness to bacterial replication, a non-human primate model to check for splenic involvement during pneumonia and a mouse pneumonia-bacteraemia model to demonstrate that splenic involvement correlates with invasive disease. Findings Here we present evidence that the spleen is the reservoir of bacteraemia during pneumonia. We found that in the human spleen infected with pneumococci, clusters with increasing number of bacteria were detectable within macrophages. These clusters also were detected in non-human primates. When intranasally infected mice were treated with a non-therapeutic dose of azithromycin, which had no effect on pneumonia but concentrated inside splenic macrophages, bacteria were absent from the spleen and blood and importantly mice had no signs of disease. Interpretation We conclude that the bacterial load in the spleen, and not lung, correlates with the occurrence of bacteraemia. This supports the hypothesis that the spleen, and not the lungs, is the major source of bacteria during systemic infection associated with pneumococcal pneumonia; a finding that provides a mechanistic basis for using combination therapies including macrolides in the treatment of severe community-acquired pneumococcal pneumonia. Funding Oxford University, Wolfson Foundation, MRC, NIH, NIHR, and MRC and BBSRC studentships supported the work.

Background: The delivery profile of Aztreonam lysine (AZLI) during mechanical ventilation (MV) is unknown. We evaluated the amount of AZLI drug delivered using an in vitro model of adult MV. Methods: An adult lung model designed to mimic current clinical practice was used. Both nebulizers were placed before a Y-piece and 4 settings were tested: A) Aeroneb solo® [AS] with a t-piece; B) AS with the spacer; C) M-Neb® [MN] with a t-piece and D) MN with the spacer. Performance was evaluated in terms of: 1) Mass median aerodynamic diameter (MMAD); 2) Geometric standard deviation (GSD), 3) Fine particle dose (FPD), 4) Fine particle fraction (FPF), 5) Inhalable mass (IM), and 6) Recovery rate (RR). Results: Both devices showed an adequate delivery of AZLI during MV, with MMAD between 2.4–2.5 µm and 87% of FPF. The FPD (38.8 and 31.7), IM (44.8 and 36.1) and RR (30 and 24) were similar for AS and MN respectively. Nebulizer aerosol delivery increased (50 and 70% respectively) for both nebulizers when using the spacer. Conclusion: Both AS and MN showed a good aerosol delivery profile for AZLI during in vitro mechanical ventilation. Better aerosol delivery performance was obtained using the spacer.

Acid-suppressive therapy for prophylaxis of stress ulcer bleeding is commonly prescribed for hospitalized patients. Although its use in select, at-risk patients may reduce clinically significant gastrointestinal bleeding, the alteration in gastric pH and composition may place these patients at a higher risk of infection. Although any pharmacologic alteration of the gastric pH and composition is associated with an increased risk of infection, the risk appears to be highest with proton pump inhibitors, perhaps owing to the potency of this class of drugs in increasing the gastric pH. With the increased risk of infection, universal provision of pharmacologic acid suppression to all hospitalized patients, even all critically ill patients, is inappropriate and should be confined to patients meeting specific criteria. Nurses providing care in critical care areas may be instrumental in screening for appropriate use of acid-suppressive therapy and ensuring the drugs are discontinued upon transfer out of intensive care or when risk factors are no longer present.

We report that pore-forming toxins (PFTs) induce respiratory epithelial cell necroptosis independently of death receptor signaling during bacterial pneumonia. Instead, necroptosis was activated as a result of ion dysregulation arising from membrane permeabilization. PFT-induced necroptosis required RIP1, RIP3 and MLKL, and could be induced in the absence or inhibition of TNFR1, TNFR2 and TLR4 signaling. We detected activated MLKL in the lungs from mice and nonhuman primates experiencing Serratia marcescens and Streptococcus pneumoniae pneumonia, respectively. We subsequently identified calcium influx and potassium efflux as the key initiating signals responsible for necroptosis; also that mitochondrial damage was not required for necroptosis activation but was exacerbated by MLKL activation. PFT-induced necroptosis in respiratory epithelial cells did not involve CamKII or reactive oxygen species. KO mice deficient in MLKL or RIP3 had increased survival and reduced pulmonary injury during S. marcescens pneumonia. Our results establish necroptosis as a major cell death pathway active during bacterial pneumonia and that necroptosis can occur without death receptor signaling.

Community-acquired pneumonia is not usually considered a high-priority problem by the public, although it is responsible for substantial mortality, with a third of patients dying within 1 year after being discharged from hospital for pneumoniae. Although up to 18% of patients with community-acquired pneumonia who were hospitalised (admitted to hospital and treated there) have at least one risk factor for immunosuppression worldwide, strong evidence on community-acquired pneumonia management in this population is scarce. Several features of clinical management for community-acquired pneumonia should be addressed to reduce mortality, morbidity, and complications related to community-acquired pneumonia in patients who are immunocompetent and patients who are immunocompromised. These features include rapid diagnosis, microbiological investigation, prevention and management of complications (eg, respiratory failure, sepsis, and multiorgan failure), empirical antibiotic therapy in accordance with patient's risk factors and local microbiological epidemiology, individualised antibiotic therapy according to microbiological data, appropriate outcomes for therapeutic switch from parenteral to oral antibiotics, discharge planning, and long-term follow-up. This Seminar offers an updated view on community-acquired pneumonia in adults, with suggestions for clinical and translational research.

Introduction: Aspiration pneumonia is a subclass of community-acquired pneumonia that is expected to have an increasing contribution in mortality and morbidity, particularly in the elderly population over the next coming decades. While studies have revealed significant progress in identifying risk factors for aspiration pneumonia, the clinical presentation and diagnosis remain challenging to healthcare providers. Areas covered: We conducted a broad literature review using the MeSH heading in PubMed/MEDLINE of 'aspiration pneumonia' from January 1970 to July 2019. The understanding of the microbiology of aspiration pneumonia has evolved from a possible shift in the causative organisms away from anaerobes to traditional community-acquired pneumonia organisms. The importance of this shift is not yet known, but it has questioned the pathogenic role of anaerobes, appropriate anaerobic testing and the role of these pathogens in the pulmonary microbiome in patients with pneumonia. The identification of risk factors led to strategies to prevent or minimize the risk of aspiration pneumonia with moderate success. Expert opinion: Our expert opinion is that further research is needed to determine the role of the microbiome with aspiration pneumonia and patient risk factors. There is also a great need to develop clinical tools to help providers diagnose, treat, and prevent aspiration pneumonia.

Community-acquired pneumonia (CAP) is one of the most common causes of mortality world-wide. The mortality rate of patients with CAP is influenced by the severity of the disease, treatment failure and the requirement for hospitalization and/or intensive care unit (ICU) management, all of which may be predicted by biomarkers and clinical scoring systems. Areas covered: We review the recent literature examining the efficacy of established and newly-developed clinical scores, biological and inflammatory markers such as C-Reactive protein (CRP), procalcitonin (PCT) and Interleukin-6 (IL-6), whether used alone or in conjunction with clinical severity scores to assess the severity of CAP, predict treatment failure, guide acute in-hospital or ICU admission and predict mortality. Expert commentary: The early prediction of treatment failure using clinical scores and biomarkers plays a developing role in improving survival of patients with CAP by identifying high-risk patients requiring hospitalization or ICU admission; and may enable more efficient allocation of resources. However, it is likely that combinations of scoring systems and biomarkers will be of greater use than individual markers. Further larger studies are needed to corroborate the additive value of these markers to clinical prediction scores to provide a safer and more effective assessment tool for clinicians.

Purpose The purpose of the study is to evaluate the frequency and barriers to use of ultrasound guidance for central venous catheter (CVC) insertion by physicians specializing in critical care and hospital medicine. Materials and methods A national cross-sectional electronic survey of intensivists and hospitalists was administered from November 2014 to January 2015. Results The survey response rate was 5.9% (1013/17 233). Moderate to very frequent use of ultrasound guidance varied by site: internal jugular vein (80%), subclavian vein (31%), and femoral vein (45%). Nearly all physicians (99%) who insert internal jugular CVCs daily use ultrasound guidance, whereas only 46% of physicians who insert subclavian CVCs daily use ultrasound guidance. Use of real-time ultrasound guidance varied by insertion site: internal jugular vein (73%), subclavian vein (28%), and femoral vein (42%). Most physicians (59%) reported not being comfortable with real-time needle tracking at the subclavian site. The most frequently reported barriers to use of ultrasound guidance were (1) limited availability of ultrasound equipment (28%), (2) perception of increased total procedure time (22%), and (3) concern for loss of landmark skills (13%). Conclusions Most intensivists routinely use ultrasound guidance to insert internal jugular CVCs but not subclavian CVCs. The most commonly reported barrier to ultrasound use was limited access to an ultrasound machine.

BACKGROUND Prognostication of patients hospitalized with acute decompensated heart failure (ADHF) is important to patients, providers, and healthcare systems. Few bedside tools exist to prognosticate patients hospitalized with ADHF. OBJECTIVE The objective of this study was to assess the relationship between inferior vena cava (IVC) diameter and postdischarge mortality in patients hospitalized with ADHF. DESIGN Prospective observational study. SETTING A 247-bed urban teaching hospital in Spain PATIENTS Ninety-seven patients hospitalized with ADHF. INTERVENTION None. MEASUREMENTS The IVC diameter and collapsibility were measured by a hospitalist at the time of admission and discharge. Primary outcome was 90-day all-cause mortality. Secondary outcomes were readmission rates at 90 and 180 days, and 180-day all-cause mortality. Patients were followed for 180 days. RESULTS Data from 80 patients were analyzed. From admission to discharge, a significant improvement in IVC maximum (IVCmax) diameter (2.12 vs 1.87 cm; P < 0.001) and IVC collapsibility (25.7% vs 33.1%; P < 0.001) was seen in the total study cohort. During the 90-day follow-up period, 11 patients (13.7%) died. An admission IVCmax diameter ≥1.9 cm was associated with a higher mortality rate at 90 days (25.4% vs 3.4%; P = 0.009) and 180 days (29.3% vs 3.4%; P = .003). In a multivariate Cox proportional hazards regression analysis, admission IVCmax diameter was an independent predictor of 90-day mortality (hazard ratio [HR]: 5.88; 95% confidence interval [CI]: 1.21-28.10; P = 0.025) and 90-day readmission (HR: 3.20; 95% CI: 1.24-8.21; P = 0.016). CONCLUSION In patients hospitalized with acute decompensated heart failure, a dilated IVC by bedside ultrasound at the time of admission is associated with a higher 90-day mortality after hospitalization. Journal of Hospital Medicine 2016. © 2016 Society of Hospital Medicine

An update and literature review assessing the implications for use of macrolide therapy for patients with pneumonia is very relevant. Multiple studies have focused on assessing the efficacy, clinical effectiveness and clinical risks associated with the use of macrolides.The scope of this review is on recently published literature regarding the use of macrolides in patients with pneumonia. Recent evidence suggests that macrolides may benefit several populations of patients with pneumonia that includes ambulatory care, hospitalized patients with nonsevere pneumonia and severe pneumonia patients requiring ICU admission. In addition, there is benefit among patients with pneumococcal pneumonia, particularly those patients hospitalized with severe disease. The contradictory results that emerged from recent randomized controlled trials testing the efficacy of macrolide are discussed. Important remarks are made to the risks of cardiovascular events related to the use of macrolides and the clinical implications for care.A careful decision on the use of macrolides in patients with pneumonia will need to balance the possible beneficial effects and the risks linked to their use.

Fibroblast growth factor 21 (FGF21) predicts severity of illness, clinical stability and mortality in community-acquired pneumonia. Validation is needed to confirm the application of FGF21 in clinical practice.http://ow.ly/SYI730nuRc1

Pore-forming toxins are the most common virulence factor in pathogenic bacteria. They lead to membrane permeabilization and cell death. Herein, we show that respiratory epithelial cells (REC) undergoing bacterial pore-forming toxin (PFT)-induced necroptosis simultaneously experienced caspase activation independently of RIPK3. MLKL deficient REC treated with a pan-caspase inhibitor were protected in an additive manner against PFT-induced death. Subsequently, cleaved versions of caspases-2, -4 and -10 were detected within REC undergoing necroptosis by immunoblots and monoclonal antibody staining. Caspase activation was observed in lung samples from mice and non-human primates experiencing Gram-negative and Gram-positive bacterial pneumonia, respectively. During apoptosis, caspase activation normally leads to cell shrinkage, nuclear condensation, and immunoquiescent death. In contrast, caspase activity during PFT-induced necroptosis increased the release of alarmins to the extracellular milieu. Caspase-mediated alarmin release was found sufficient to activate resting macrophages, leading to Interleukin-6 production. In a mouse model of Gram-negative pneumonia, deletion of caspases -2 and -11, the mouse orthologue of caspase-4, reduced pulmonary inflammation, immune cell infiltration and lung damage. Thus, our study describes a previously unrecognized role for caspase activation in parallel to necroptosis, and indicates that their activity plays a critical pro-inflammatory role during bacterial pneumonia.

Rationale: Testing for underlying etiology is a key part of bronchiectasis management, but it is unclear whether the same extent of testing is required across the spectrum of disease severity. Objectives: The aim of the present study was to identify the etiology of bronchiectasis across European cohorts and according to different levels of disease severity. Methods: We conducted an analysis of seven databases of adult outpatients with bronchiectasis prospectively enrolled at the bronchiectasis clinics of university teaching hospitals in Monza, Italy; Dundee and Newcastle, United Kingdom; Leuven, Belgium; Barcelona, Spain; Athens, Greece; and Galway, Ireland. All the patients at every site underwent the same comprehensive diagnostic workup as suggested by the British Thoracic Society. Measurements and Main Results: Among the 1,258 patients enrolled, an etiology of bronchiectasis was determined in 60%, including postinfective (20%), chronic obstructive pulmonary disease related (15%), connective tissue disease related (10%), immunodeficiency related (5.8%), and asthma related (3.3%). An etiology leading to a change in patient's management was identified in 13% of the cases. No significant differences in the etiology of bronchiectasis were present across different levels of disease severity, with the exception of a higher prevalence of chronic obstructive pulmonary disease-related bronchiectasis (P < 0.001) and a lower prevalence of idiopathic bronchiectasis (P = 0.029) in patients with severe disease. Conclusions: Physicians should not be guided by disease severity in suspecting specific etiologies in patients with bronchiectasis, although idiopathic bronchiectasis appears to be less common in patients with the most severe disease.

Limited data are available regarding the etiologic impact of health care-associated pneumonia (HCAP) in lung transplant recipients. Therefore, our aim was to evaluate the microbiologic differences between HCAP and hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) in lung transplant recipients with a radiographically confirmed diagnosis of pneumonia.We performed a retrospective cohort study of lung transplant recipients with pneumonia at one transplant center over a 7-year period. Eligible patients included lung transplant recipients who developed a first episode of radiographically confirmed pneumonia ≥ 48 h following transplantation. HCAP, HAP, and VAP were classified according to the American Thoracic Society/Infectious Diseases Society of America 2005 guidelines. χ² and Student t tests were used to compare categorical and continuous variables, respectively.Sixty-eight lung transplant recipients developed at least one episode of pneumonia. HCAP (n = 42; 62%) was most common, followed by HAP/VAP (n = 26; 38%) stratified in HAP (n = 20; 77%) and VAP (n = 6; 23%). Pseudomonas aeruginosa was the predominantly isolated organism (n = 22; 32%), whereas invasive aspergillosis was uncommon (10%). Multiple-drug resistant (MDR) pathogens were less frequently isolated in patients with HCAP compared with HAP/VAP (5% vs 27%; P = .009). Opportunistic pathogens were less frequently identified in lung transplant recipients with HCAP than in those with HAP/VAP (7% vs 27%; P = .02). Lung transplant recipients with HCAP had a similar mortality at 90 days (n = 9 [21%] vs n = 4 [15%]; P = .3) compared with patients with HAP/VAP.HCAP was the most frequent infection in lung transplant recipients. MDR pathogens and opportunistic pathogens were more frequently isolated in HAP/VAP. There were no differences in 30- and 90-day mortality between lung transplant recipients with HCAP and those with HAP/VAP.

Background Methicillin-resistant Staphylococcus aureus (MRSA) has been shown to survive on ambient surfaces for extended periods of time. Leftover MRSA environmental contamination in a hospital room places future patients at risk. Manual disinfection supplemented by pulsed xenon ultraviolet (PX-UV) light disinfection has been shown to greatly decrease the MRSA bioburden in hospital rooms. However, the effect of PX-UV in the absence of manual disinfection has not been evaluated. Methods Rooms that were previously occupied by a MRSA-positive patient (current colonization or infection) were selected for the study immediately postdischarge. Five high-touch surfaces were sampled, before and after PX-UV disinfection, in each hospital room. The effectiveness of the PX-UV device on the concentration of MRSA was assessed employing a Wilcoxon signed-rank test for all 70 samples with MRSA in 14 rooms, as well as by surface location. Results The final analysis included 14 rooms. Before PX-UV disinfection there were a total of 393 MRSA colonies isolated from the 5 high-touch surfaces. There were 100 MRSA colonies after disinfection by the PX-UV device and the overall reduction was statistically significant ( P Conclusions Our study results suggest that PX-UV light effectively reduces MRSA colony counts in the absence of manual disinfection. These findings are important for hospital and environmental services supervisors who plan to adapt new technologies as an adjunct to routine manual disinfection.

Administration of medications via aerosolization is potentially an ideal strategy to treat airway diseases. This delivery method ensures high concentrations of the medication in the targeted tissues, the airways, with generally lower systemic absorption and systemic adverse effects. Aerosolized antibiotics have been tested as treatment for bacterial infections in patients with cystic fibrosis (CF), non-CF bronchiectasis (NCFB), and ventilator-associated pneumonia (VAP). The most successful application of this to date is treatment of infections in patients with CF. It has been hypothesized that similar success would be seen in NCFB and in difficult-to-treat hospital-acquired infections such as VAP. This review summarizes the available evidence supporting the use of aerosolized antibiotics and addresses the specific considerations that clinicians should recognize when prescribing an aerosolized antibiotic for patients with CF, NCFB, and VAP.

Background Inadequate environmental disinfection represents a serious risk for health care–associated infections. Technologic advancements in disinfection practices, including no-touch devices, offer significant promise to improve infection control. We evaluated one such device, portable pulsed xenon ultraviolet (PX-UV) units, on microbial burden during an implementation trial across 4 Veterans Affairs hospitals. Methods Environmental samples were collected before and after terminal room cleaning: 2 facilities incorporated PX-UV disinfection into their cleaning protocols and 2 practiced manual disinfection only. Specimens from 5 high-touch surfaces were collected from rooms harboring methicillin-resistant Staphylococcus aureus (MRSA) or aerobic bacteria colonies (ABC). Unadjusted pre-post count reductions and negative binomial regression modeled PX-UV versus manual cleaning alone. Results Seventy samples were collected. Overall, PX-UV reduced MRSA and ABC counts by 75.3% and 84.1%, respectively, versus only 25%-30% at control sites. Adjusting for baseline counts, manually cleaned rooms had significantly higher residual levels than PX-UV sites. Combined analyses revealed an incident rate ratio of 5.32 (P = .0024), with bedrails, tray tables, and toilet handrails also showing statistically superior PX-UV disinfection. Conclusions This multicenter study demonstrates significantly reduced disinfection across several common pathogens in facilities using PX-UV devices. Clinical impact of laboratory reductions on infection rates was not assessed, representing a critical future research question. However, such approaches to routine cleaning suggest a practical strategy when integrated into daily hospital operations.

Community-acquired pneumonia (CAP) is an important cause of death around the globe. Up to 30% of patients admitted to hospital for CAP develop cardiovascular complications (i.e. new/worsening heart failure, new/worsening arrhythmias, myocardial infarctions and/or strokes), acutely and up to 10 years thereafter. Cardiac complications result from complex interactions between preexisting conditions, relative ischaemia, upregulation of the sympathetic system, systemic inflammation and direct pathogen-mediated damage to the cardiovascular system. The exact mechanisms underlying the direct host-pathogen interactions are of great interest to identify potential therapeutic and preventative targets for CAP. In this review, we summarize the epidemiological data, risk factors and the pathogen-driven cardiovascular damage affecting patients with CAP.

Background Limited data are available regarding fit and healthy patients with pneumonia at different ages. We evaluated the association of age with clinical presentation, serotype and outcomes among healthy and well-functioning patients hospitalized for bacteremic pneumococcal community–acquired pneumonia. Methods We performed a prospective cohort study of consecutive healthy and well-functioning patients hospitalized for this type of pneumonia. Patients were stratified into younger (18 to 64 years) and older (≥65 years) groups. Results During the study period, 399 consecutive patients were hospitalized with bacteremic pneumococcal pneumonia. We included 203 (50.8%) patients who were healthy and well-functioning patients, of whom 71 (35%) were classified as older. No differences were found in antibiotic treatment, treatment failure rate, antibiotic resistance, or serotype, except for serotype 7F that was less common in older patients. In the adjusted multivariate analysis, the older patients had higher 30-day mortality (OR 6.83; 95% CI 1.22–38.22; P = 0.028), but were less likely to be admitted to the ICU (OR 0.14; 95% CI 0.05–0.39; P

Community acquired pneumonia (CAP) is associated with high rates of morbidity and mortality, especially among the elderly. Antibiotic treatment for CAP in the elderly is particularly challenging for many reasons, including compliance issues, immunosuppression, polypharmacy and antimicrobial resistance. There are few available antibiotics that are able to address these concerns. Areas covered: After a systematic review of the current literature, we describe seven novel antibiotics that are currently in advanced stages of development (phase 3 and beyond) and show promise for the treatment of CAP in those over the age of 65. These antibiotics are: Solithromycin, Pristinamycin, Nemonaxacin, Lefamulin, Omadacycline, Ceftobiprole and Delafloxacin. Using a novel conceptual framework designed by the present authors, known as the 'San Antonio NIPS model', we evaluate their strengths and weaknesses based on their ability to address the unique challenges that face the elderly. Expert opinion: All seven antibiotics have potential value for effective utilization in the elderly, but to varying degrees based on their NIPS model score. The goal of this model is to reorganize a clinician's focus on antibiotic choices in the elderly and bring attention to a seldom discussed topic that may potentially become a health-care crisis in the next decade.

To estimate 1-year mortality risk associated with preoperative serious mental illness (SMI) as defined by the Veterans Health Administration (schizophrenia, bipolar disorder, posttraumatic stress disorder [PTSD], major depression) following nonambulatory cardiac or vascular surgical procedures compared to patients without SMI. Cardiac/vascular operations were selected because patients with SMI are known to be at elevated risk of cardiovascular disease.Retrospective analysis of system-wide data from electronic medical records of patients undergoing nonambulatory surgery (inpatient or day-of-surgery admission) October 2005-September 2009 with 1-year follow-up (N=55,864; 99% male;30 days of postoperative hospitalization). Death was hypothesized to be more common among patients with preoperative SMI.One in nine patients had SMI, mostly PTSD (6%). One-year mortality varied by procedure type and SMI status. Patients had vascular operations (64%; 23% died), coronary artery bypass graft (26%; 10% died) or other cardiac operations (11%; 15%-18% died). Fourteen percent of patients with PTSD died, 20% without SMI and 24% with schizophrenia, with other groups intermediate. In multivariable stratified models, SMI was associated with increased mortality only for patients with bipolar disorder following cardiac operations. Bipolar disorder and PTSD were negatively associated with death following vascular operations.SMI is not consistently associated with postoperative mortality in covariate-adjusted analyses.

A comparison is made of epidemiological variables (demographic and clinical characteristics) and outcomes in patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) caused by methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA) in the Latin American VAP (LATINVAP) vs. the European Union VAP (EUVAP) cohorts of patients admitted to intensive care units (ICUs).The EUVAP project was a prospective, multicenter observational study reporting 827 patients with HAP/VAP in 27 ICUs from 9 European countries. The LATINVAP project was a multicenter prospective observational study, with an identical design, performed in 17 ICUs from 4 Latin American countries involving 99 patients who developed HAP/VAP. Episodes of VAP/HAP caused by S. aureus, MSSA, and MRSA were compared in both cohorts.Forty-five patients had S. aureus HAP/VAP in the EUVAP cohort vs. 11 patients in the LATINVAP cohort. More patients had MRSA in the LATINVAP study than in the EUVAP (45% vs. 33%). ICU mortality among patients with MSSA HAP/VAP in EUVAP was 10% vs. 50% for LATINVAP (OR=9.75, p=0.01). Fifteen patients in the EUVAP cohort developed MRSA HAP/VAP as opposed to 5 in LATINVAP. In the EUVAP study there was an ICU mortality rate of 33.3%. In the LATINVAP cohort, the ICU mortality rate was 60% (OR for death=3.0; 95%CI 0.24-44.7).MRSA pneumonia was associated with poorer outcomes in comparison with MSSA. Our study suggests significant variability among European and Latin American ICU practices that may influence clinical outcomes. Furthermore, patients with pneumonia in Latin America have different outcomes.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia. The panel's recommendations for the diagnosis and treatment of HAP and VAP are based upon evidence derived from topic-specific systematic literature reviews.

Objectives To characterize physical and mental diseases and use of healthcare services and identify factors associated with mortality in the oldest individuals using the Veterans Health Administration (VHA). Design Retrospective study with 5-year survival follow-up. Setting VHA, system-wide. Participants Veterans using the VHA aged 80 and older as of October 2008 (N = 721,588: n = 665,249 aged 80–89, n = 56,118 aged 90–99, n = 221 aged 100–115). Measurements Demographic characteristics, physical and mental diseases, healthcare services, and 5-year survival were measured. Results Accelerated failure time models identified protective and risk factors associated with mortality according to age group. During 5 years of follow-up, 44% of participants died (survival rate: 59% aged 80–89, 32% aged 90–99, 15% aged ≥100). In the multivariable model, protective effects for veterans aged 80–99 were female sex, minority race or ethnicity, being married, having certain physical and mental diagnoses (hypertension, cataract, dyslipidemia, posttraumatic stress disorder, bipolar disorder), having urgent care visits, having invasive surgery, and having few (1–3) prescriptions. Risk factors were lower VHA priority status, physical and mental conditions (diabetes mellitus, anemia, congestive heart failure, dementia, anxiety, depression, smoking, substance abuse disorder), hospital admission, and nursing home care. For those aged 100 and older, being married, smoking, hospital admission, nursing home care, invasive surgery, and prescription use were significant risk factors; only emergency department (ED) use was protective. Conclusion Although the data are limited to VHA care (thus missing Medicare services), this study shows that many veterans served by the VHA live to advanced old age despite multiple chronic conditions. Further study is needed to determine whether a comprehensive, coordinated care system like VHA is associated with greater longevity for very old persons.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia. The panel's recommendations for the diagnosis and treatment of HAP and VAP are based upon evidence derived from topic-specific systematic literature reviews.

Streptococcus pneumoniae (the pneumococcus) is capable of invading the heart. Herein we observed that pneumococcal invasion of the myocardium occurred soon after development of bacteremia and was continuous thereafter. Using immunofluorescence microscopy (IFM), we observed that S. pneumoniae replication within the heart preceded visual signs of tissue damage in cardiac tissue sections stained with hematoxylin and eosin. Different S. pneumoniae strains caused distinct cardiac pathologies: strain TIGR4, a serotype 4 isolate, caused discrete pneumococcus-filled microscopic lesions (microlesions), whereas strain D39, a serotype 2 isolate, was, in most instances, detectable only using IFM and was associated with foci of cardiomyocyte hydropic degeneration and immune cell infiltration. Both strains efficiently invaded the myocardium, but cardiac damage was entirely dependent on the pore-forming toxin pneumolysin only for D39. Early microlesions caused by TIGR4 and microlesions formed by a TIGR4 pneumolysin-deficient mutant were infiltrated with CD11b + and Ly6G-positive neutrophils and CD11b + and F4/80-positive (F4/80 + ) macrophages. We subsequently demonstrated that macrophages in TIGR4-infected hearts died as a result of pneumolysin-induced necroptosis. The effector of necroptosis, phosphorylated mixed-lineage kinase domain-like protein (MLKL), was detected in CD11b + and F4/80 + cells associated with microlesions. Likewise, treatment of infected mice and THP-1 macrophages in vitro with the receptor-interacting protein 1 kinase (RIP1) inhibitor necrostatin-5 promoted the formation of purulent microlesions and blocked cell death, respectively. We conclude that pneumococci that have invaded the myocardium are an important cause of cardiac damage, pneumolysin contributes to cardiac damage in a bacterial strain-specific manner, and pneumolysin kills infiltrated macrophages via necroptosis, which alters the immune response.

Objective: The purpose of our study was to examine in patients hospitalized with communityacquired pneumonia (CAP) the association between abnormal Pa CO 2 and ICU admission and 30-day mortality. Methods: A retrospective cohort study was conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of CAP. Arterial blood gas analyses were obtained with measurement of Pa CO 2 on admission. Multivariate analyses were performed using 30-day mortality and ICU admission as the dependent measures. Results: Data were abstracted on 453 subjects with a documented arterial blood gas analysis. One hundred eighty-nine patients (41%) had normal Pa CO 2 (35-45 mm Hg), 194 patients (42%) had a Pa CO 2 , 35 mm Hg (hypocapnic), and 70 patients (15%) had a Pa CO 2 . 45 mm Hg (hypercapnic). In the multivariate analysis, after adjusting for severity of illness, hypocapnic patients had greater 30-day mortality (OR 5 2.84; 95% CI, 1.28-6.30) and a higher need for ICU admission (OR 5 2.88; 95% CI, 1.68-4.95) compared with patients with normal Pa CO 2 . In addition, hypercapnic patients had a greater 30-day mortality (OR 5 3.38; 95% CI, 1.38-8.30) and a higher need for ICU admission (OR 5 5.35; 95% CI, 2.80-10.23). When patients with COPD were excluded from the analysis, the differences persisted between groups. Conclusion: In hospitalized patients with CAP, both hypocapnia and hypercapnia were associated with an increased need for ICU admission and higher 30-day mortality. These fi ndings persisted after excluding patients with CAP and with COPD. Therefore, Pa CO 2 should be considered for inclusion in future severity stratifi cation criteria to appropriate identifi ed patients who will require a higher level of care and are at risk for increased mortality. CHEST 2012; 142(5):1193–1199 Abbreviations: CAP 5 community-acquired pneumonia; HR 5 hazard ratio; LOS 5 length of stay; PSI 5 pneumonia severity index