Whole-Blood Gene Expression Profiles Associated with Mortality in Community-Acquired Pneumonia.

(1) Background: Information regarding gene expression profiles and the prognosis of community-acquired pneumonia (CAP) is scarce. We aimed to examine the differences in the gene expression profiles in peripheral blood at hospital admission between patients with CAP who died during hospitalization and those who survived. (2) Methods: This is a multicenter study of nonimmunosuppressed adult patients who required hospitalization for CAP. Whole blood samples were obtained within 24 h of admission for genome-expression-profile analysis. Gene expression profiling identified both differentially expressed genes and enriched gene sets. (3) Results: A total of 198 samples from adult patients who required hospitalization for CAP were processed, of which 13 were from patients who died. Comparison of gene expression between patients who died and those who survived yielded 49 differentially expressed genes, 36 of which were upregulated and 13 downregulated. Gene set enrichment analysis (GSEA) identified four positively enriched gene sets in survivors, mainly associated with the interferon-alpha response, apoptosis, and sex hormone pathways. Similarly, GSEA identified seven positively enriched gene sets, associated with the oxidative stress, endoplasmic reticulum stress, oxidative phosphorylation, and angiogenesis pathways, in the patients who died. Protein-protein-interaction-network analysis identified FOS, CDC42, SLC26A10, EIF4G2, CCND3, ASXL1, UBE2S, and AURKA as the main gene hubs. (4) Conclusions: We found differences in gene expression profiles at hospital admission between CAP patients who died and those who survived. Our findings may help to identify novel candidate pathways and targets for potential intervention and biomarkers for risk stratification.

Characteristics and Outcomes by Ceiling of Care of Subjects Hospitalized with COVID-19 During Four Waves of the Pandemic in a Metropolitan Area: A Multicenter Cohort Study.

INTRODUCTION: The profiles of patients with COVID-19 have been widely studied, but little is known about differences in baseline characteristics and in outcomes between subjects with a ceiling of care assigned at hospital admission and subjects without a ceiling of care. The aim of this study is to compare, by ceiling of care, clinical features and outcomes of hospitalized subjects during four waves of COVID-19 in a metropolitan area in Catalonia. METHODS: Observational study conducted during the first (March-April 2020), second (October-November 2020), third (January-February 2021), and fourth wave (July-August 2021) of COVID-19 in five centers of Catalonia. All subjects were adults (> 18 years old) hospitalized with a proven SARS-CoV-2 infection and with therapeutic ceiling of care assessed by the attending physician at hospital admission. RESULTS: A total of 5813 subjects were analyzed. Subjects with a ceiling of care were mainly older (difference in median age of 20 years), with more comorbidities (Charlson index 3 points higher) and with fewer clinical signs at baseline than patients without a ceiling of care. Some features of their clinical profiles changed among waves. There were differences in treatments received during hospital admission across waves, but not between subjects with and without a ceiling of care. Subjects with a ceiling of care had a death incidence more than four times the death incidence of subjects a without a ceiling of care (risk ratio (RR) ranging from 3.5 in the first wave to almost 6 in the third and fourth). Incidence of severe pneumonia and complications for subjects with a ceiling of care was around 1.5 times the incidence in subjects without a ceiling of care. DISCUSSION: Analysis of hospitalized subjects with SARS-CoV-2 infection should be stratified according to therapeutic ceiling of care to avoid bias and outcome misestimation.

Effects of age and comorbidities on serum levels of inflammatory markers in community-acquired pneumonia.

INTRODUCTION: Studies have suggested that an inappropriate inflammatory response is a major cause of treatment failure and mortality in patients with community-acquired pneumonia (CAP). We aimed to determine the effect of age and comorbidities on serum inflammatory markers in CAP. METHODS: We performed a prospective cohort study of adults hospitalized with CAP. For the purposes of this study, we compared patients according to comorbidities and age. Inflammatory markers were measured at hospital admission, focusing on acute phase proteins, cytokines and monocyte human leucocyte antigen DR (mHLA-DR) expression. RESULTS: In patients with chronic pulmonary disease (COPD), serum cytokines had significantly decreased levels of tumour necrosis factor (TNF)-α, interleukin (IL)-6 and mHLA-DR expression, as well as the C-reactive protein (CRP), compared with patients who had no comorbidities. Similarly, patients with chronic heart disease had a significantly reduced CRP levels and mHLA-DR expression, whereas patients with chronic kidney disease had significantly higher serum levels of procalcitonin and TNF-α. Lower procalcitonin, IL-6 and IL-10 levels, as well as mHLA-DR expression, were documented in older patients, but with no significant differences compared to younger patients. Multimorbidity in older patients was associated with significant lower levels of CRP and mHLA-DR expression. CONCLUSIONS: The circulating inflammatory markers to CAP have profiles that differ with age and underlying comorbidities. Multimorbidity in the elderly is also associated with lower serum levels of some inflammatory markers. Our findings suggest that inflammatory markers in CAP should be interpreted after considering age and comorbid conditions.

Changing trends in the aetiology, treatment and outcomes of bloodstream infection occurring in the first year after solid organ transplantation: a single-centre prospective cohort study.

To analyse trends in the aetiology, treatment and outcomes of bloodstream infection (BSI) within the first year post-transplant over the last 10-year period, we prospectively recorded all episodes of BSI occurring in solid organ transplant (SOT) recipients during the first year post-transplant from 2007 to 2016. Trends of factors were analysed by 2-year periods. Of 475 consecutive episodes of BSI, 218 occurred within a year of SOT in 178 SOT recipients. Gram-positive BSI decreased over time (40.5-2.2%). In contrast, there was a steady increase in Gram-negative bacilli (GNB) BSI (54.1-93.3%; P < 0.001), mainly due to Pseudomonas aeruginosa (2.4-20.4%) and Klebsiella pneumoniae (7.1-26.5%). Multidrug-resistant (MDR) GNB (4.8-38.8%; P < 0.001) rose dramatically, especially due to extended-spectrum ß-lactamase (ESBL) production (7.1-34.7%). There was a sharp rise in the use of carbapenems, both as empirical (11.9-55.3%; P < 0.001) and as targeted antibiotic treatment (11.9-46.9%; P < 0.001). In conclusion, today, GNB are the leading causative agents of BSI in SOT recipients within the first year after SOT. In addition, MDR GNB have emerged mainly due to ESBL-producing strains. In spite of these changes, length of hospital stay, days of treatment and mortality have remained stable over time.

Solithromycin for the treatment of community-acquired bacterial pneumonia.

INTRODUCTION: Community-acquired pneumonia is a major public health problem worldwide. In recent years, there has been an increase in the frequency of resistance to the antimicrobials such as ß-lactams or macrolides which have habitually been used against the causative pathogens. Solithromycin, a next-generation macrolide, is the first fluoroketolide with activity against most of the frequently isolated bacteria in community-acquired pneumonia, including typical and atypical bacteria as well as macrolide-resistant Streptococcus pneumoniae. Areas covered: A detailed assessment of the literature relating to the antimicrobial activity, pharmacokinetic/pharmacodynamic properties, efficacy, tolerability and safety of solithromycin for the treatment of community-acquired bacterial pneumonia Expert commentary: Recent randomized controlled phase II/III trials have demonstrated the equivalent efficacy of oral and intravenous solithromycin compared with fluoroquinolones in patients with lower mild-to-moderate respiratory infections, and have shown that systemic adverse events are comparable between solithromycin and alternative treatments. However, studies of larger populations which are able to identify infrequent adverse events are now needed to confirm these findings. On balance, current data supports solithromycin as a promising therapy for empirical treatment in adults with community-acquired bacterial pneumonia.

Impact of antibiotic de-escalation on clinical outcomes in community-acquired pneumococcal pneumonia.

BACKGROUND: Although antibiotic de-escalation is regarded as a measure that reduces selection pressure, adverse drug effects and costs, evidence supporting this practice in community-acquired pneumococcal pneumonia (CAPP) is lacking. METHODS: We carried out a retrospective analysis of prospectively collected data of a cohort of hospitalized adults with CAPP. Pneumococcal aetiology was established in patients with one or more positive cultures for Streptococcus pneumoniae obtained from blood, sterile fluids or sputum, and/or a positive urinary antigen test. De-escalation therapy was considered when the initial antibiotic therapy was narrowed to penicillin, amoxicillin or amoxicillin/clavulanate within the first 72 h after admission. The primary outcomes were 30 day mortality and length of hospital stay (LOS). Adjustment for confounders was performed with multivariate and propensity score analyses. RESULTS: Of 1410 episodes of CAPP, antibiotic de-escalation within the first 72 h after admission was performed in 166 cases. After adjustment, antibiotic de-escalation was not associated with a higher risk of mortality (OR = 0.83, 95% CI = 0.24-2.81), but it was found to be a protective factor for prolonged LOS (above the median) (OR = 0.46, 95% CI = 0.30-0.70). Similar results were found in patients classified into high-risk pneumonia severity index classes (IV-V), those with clinical instability and those with bacteraemia. No significant differences were documented in adverse drug reactions or readmission (<30 days). CONCLUSIONS: Antibiotic de-escalation seems to be safe and effective in reducing the duration of LOS, and did not adversely affect outcomes of patients with CAPP, even those with bacteraemia and severe disease, and those who were clinically unstable.

Biomarkers for predicting short-term mortality in community-acquired pneumonia: A systematic review and meta-analysis.

OBJECTIVES: The pneumonia severity index and CURB-65 are risk assessment tools widely used in community-acquired pneumonia (CAP). However, limitations in these prognostic scores have led to increasing interest in finding biomarkers that might provide additional information. To date, the role of these biomarkers has not been fully elucidated. METHODS: We systematically searched the Medline, Web of Knowledge, Science Direct, and LILACS databases. We included studies that assessed the accuracy of biomarkers for the prediction of in-hospital or ≤30-day mortality, in hospitalized adults with CAP. Two independent investigators extracted patient and study characteristics, which were thereafter pooled using a random effects model. Relationships between sensitivity and specificity of biomarkers and prognostic scores were plotter using the area under the receiver operator characteristic curve (AUC). RESULTS: We included 24 articles and 2 databases from 1069 reviewed abstracts, which provided 10,319 patients for analysis. Reported mortality rates varied from 2.4% to 34.6%. The highest AUC values for predicting mortality were associated with pro-adrenomedullin (0.80) and prohormone forms of atrial natriuretic peptide (0.79), followed by cortisol (0.78), procalcitonin (0.75), copeptin (0.71), and C-reactive protein (0.62). There were no statistically significant differences between the AUCs of the studied biomarkers, other than for copeptin and C-reactive protein, which performed comparatively poorly. When compared with the CAP-specific scores, the AUCs were not significantly different from those of most biomarkers. CONCLUSIONS: The identified biomarkers are able to predict mortality with moderate to good accuracy in CAP. However, biomarkers have no clear advantage over CAP-specific scores for predicting mortality.

The effect of simvastatin on inflammatory cytokines in community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial.

OBJECTIVES: It has been suggested that statins have an effect on the modulation of the cytokine cascade and on the outcome of patients with community-acquired pneumonia (CAP). The aim of this prospective, randomised, double-blind, placebo-controlled trial was to determine whether statin therapy given to hospitalised patients with CAP improves clinical outcomes and reduces the concentration of inflammatory cytokines. SETTING: A tertiary teaching hospital in Barcelona, Spain. PARTICIPANTS: Thirty-four patients were randomly assigned and included in an intention-to-treat analysis (19 to the simvastatin group and 15 to the placebo group). INTERVENTION: Patients were randomly assigned to receive 20 mg of simvastatin or placebo administered in the first 24 h of hospital admission and once daily thereafter for 4 days. OUTCOME: Primary end point was the time from hospital admission to clinical stability. The secondary end points were serum concentrations of inflammatory cytokines and partial pressure of arterial oxygen/fractional inspired oxygen (PaO2/FiO2) at 48 h after treatment administration. RESULTS: The trial was stopped because enrolment was much slower than originally anticipated. The baseline characteristics of the patients and cytokine concentrations at the time of enrolment were similar in the two groups. No significant differences in the time from hospital admission to clinical stability were found between study groups (median 3 days, IQR 2-5 vs 3 days, IQR 2-5; p=0.47). No significant differences in PaO2/FiO2 (p=0.37), C reactive protein (p=0.23), tumour necrosis factor-α (p=0.58), interleukin 6 (IL-6; p=0.64), and IL-10 (p=0.61) levels at 48 h of hospitalisation were found between simvastatin and placebo groups. Similarly, transaminase and total creatine kinase levels were similar between study groups at 48 h of hospitalisation (p=0.19, 0.08 and 0.53, respectively). CONCLUSIONS: Our results suggest that the use of simvastatin, 20 mg once daily for 4 days, since hospital admission did not reduce the time to clinical stability and the levels of inflammatory cytokines in hospitalised patients with CAP. TRIAL REGISTRATION NUMBER: ISRCTN91327214.

Management of community-acquired pneumonia in older adults.

Community-acquired pneumonia (CAP) is an increasing problem among the elderly. Multiple factors related to ageing, such as comorbidities, nutritional status and swallowing dysfunction have been implicated in the increased incidence of CAP in the older population. Moreover, mortality in patients with CAP rises dramatically with increasing age. Streptococcus pneumoniae is still the most common pathogen among the elderly, although CAP may also be caused by drug-resistant microorganisms and aspiration pneumonia. Furthermore, in the elderly CAP has a different clinical presentation, often lacking the typical acute symptoms observed in younger adults, due to the lower local and systemic inflammatory response. Several independent prognostic factors for mortality in the elderly have been identified, including factors related to pneumonia severity, inadequate response to infection, and low functional status. CAP scores and biomarkers have lower prognostic value in the elderly, and so there is a need to find new scales or to set new cut-off points for current scores in this population. Adherence to the current guidelines for CAP has a significant beneficial impact on clinical outcomes in elderly patients. Particular attention should also be paid to nutritional status, fluid administration, functional status, and comorbidity stabilizing therapy in this group of frail patients. This article presents an up-to-date review of the main aspects of CAP in elderly patients, including epidemiology, causative organisms, clinical features, and prognosis, and assesses key points for best practices for the management of the disease.

Neonatal Candida albicans septic thrombosis of the portal vein followed by cavernous transformation of the vessel.

We report two premature neonates with Candida albicans septic thrombosis of the portal vein who developed, in very early childhood, the sonographic appearance of cavernous transformation of the vessel and/or clinical signs of extrahepatic portal hypertension.