Luis F. Reyes

Severe Pneumococcal Pneumonia Causes Acute Cardiac Toxicity and Subsequent Cardiac Remodeling

Rationale: Up to one‐third of patients hospitalized with pneumococcal pneumonia experience major adverse cardiac events (MACE) during or after pneumonia. In mice, Streptococcus pneumoniae can invade the myocardium, induce cardiomyocyte death, and disrupt cardiac function following bacteremia, but it is unknown whether the same occurs in humans with severe pneumonia. Objectives: We sought to determine whether S. pneumoniae can (1) translocate the heart, (2) induce cardiomyocyte death, (3) cause MACE, and (4) induce cardiac scar formation after antibiotic treatment during severe pneumonia using a nonhuman primate (NHP) model. Methods: We examined cardiac tissue from six adult NHPs with severe pneumococcal pneumonia and three uninfected control animals. Three animals were rescued with antibiotics (convalescent animals). Electrocardiographic, echocardiographic, and serum biomarkers of cardiac damage were measured (troponin T, N‐terminal pro‐brain natriuretic peptide, and heart‐type fatty acid binding protein). Histological examination included hematoxylin and eosin staining, immunofluorescence, immunohistochemistry, picrosirius red staining, and transmission electron microscopy. Immunoblots were used to assess the underlying mechanisms. Measurements and Main Results: Nonspecific ischemic alterations were detected by electrocardiography and echocardiography. Serum levels of troponin T and heart‐type fatty acid binding protein were increased (P < 0.05) after pneumococcal infection in both acutely ill and convalescent NHPs. S. pneumoniae was detected in the myocardium of all NHPs with acute severe pneumonia. Necroptosis and apoptosis were detected in the myocardium of both acutely ill and convalescent NHPs. Evidence of cardiac scar formation was observed only in convalescent animals by transmission electron microscopy and picrosirius red staining. Conclusions: S. pneumoniae invades the myocardium and induces cardiac injury with necroptosis and apoptosis, followed by cardiac scarring after antibiotic therapy, in an NHP model of severe pneumonia.

Infiltrated Macrophages Die of Pneumolysin-Mediated Necroptosis following Pneumococcal Myocardial Invasion

ABSTRACT 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.

Global initiative for meticillin-resistant Staphylococcus aureus pneumonia (GLIMP): an international, observational cohort study.

BACKGROUND Antibiotic resistance is a major global health problem and pathogens such as meticillin-resistant Staphylococcus aureus (MRSA) have become of particular concern in the management of lower respiratory tract infections. However, few data are available on the worldwide prevalence and risk factors for MRSA pneumonia. We aimed to determine the point prevalence of MRSA pneumonia and identify specific MRSA risk factors in community-dwelling patients hospitalised with pneumonia. METHODS We did an international, multicentre study of community-dwelling, adult patients admitted to hospital with pneumonia who had microbiological tests taken within 24 h of presentation. We recruited investigators from 222 hospitals in 54 countries to gather point-prevalence data for all patients admitted with these characteristics during 4 days randomly selected during the months of March, April, May, and June in 2015. We assessed prevalence of MRSA pneumonia and associated risk factors through logistic regression analysis. FINDINGS 3702 patients hospitalised with pneumonia were enrolled, with 3193 patients receiving microbiological tests within 24 h of admission, forming the patient population. 1173 (37%) had at least one pathogen isolated (culture-positive population). The overall prevalence of confirmed MRSA pneumonia was 3·0% (n=95), with differing prevalence between continents and countries. Three risk factors were independently associated with MRSA pneumonia: previous MRSA infection or colonisation (odds ratio 6·21, 95% CI 3·25-11·85), recurrent skin infections (2·87, 1·10-7·45), and severe pneumonia disease (2·39, 1·55-3·68). INTERPRETATION This multicountry study shows low prevalence of MRSA pneumonia and specific MRSA risk factors among community-dwelling patients hospitalised with pneumonia. FUNDING None.

Use of ultrasound guidance for central venous catheterization: a national survey of intensivists and hospitalists

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.

A non-human primate model of severe pneumococcal pneumonia

Rationale Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and infectious death in adults worldwide. A non-human primate model is needed to study the molecular mechanisms that underlie the development of severe pneumonia, identify diagnostic tools, explore potential therapeutic targets, and test clinical interventions during pneumococcal pneumonia. Objective To develop a non-human primate model of pneumococcal pneumonia. Methods Seven adult baboons (Papio cynocephalus) were surgically tethered to a continuous monitoring system that recorded heart rate, temperature, and electrocardiography. Animals were inoculated with 109 colony-forming units of S. pneumoniae using bronchoscopy. Three baboons were rescued with intravenous ampicillin therapy. Pneumonia was diagnosed using lung ultrasonography and ex vivo confirmation by histopathology and immunodetection of pneumococcal capsule. Organ failure, using serum biomarkers and quantification of bacteremia, was assessed daily. Results Challenged animals developed signs and symptoms of pneumonia 4 days after infection. Infection was characterized by the presence of cough, tachypnea, dyspnea, tachycardia and fever. All animals developed leukocytosis and bacteremia 24 hours after infection. A severe inflammatory reaction was detected by elevation of serum cytokines, including Interleukin (IL)1Ra, IL-6, and IL-8, after infection. Lung ultrasonography precisely detected the lobes with pneumonia that were later confirmed by pathological analysis. Lung pathology positively correlated with disease severity. Antimicrobial therapy rapidly reversed symptomology and reduced serum cytokines. Conclusions We have developed a novel animal model for severe pneumococcal pneumonia that mimics the clinical presentation, inflammatory response, and infection kinetics seen in humans. This is a novel model to test vaccines and treatments, measure biomarkers to diagnose pneumonia, and predict outcomes.

Admission inferior vena cava measurements are associated with mortality after hospitalization for acute decompensated heart failure.

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;11:778-784.

Pore-forming toxin-mediated ion dysregulation leads to death receptor-independent necroptosis of lung epithelial cells during bacterial pneumonia

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.

Pneumonia as a cardiovascular disease: Pneumonia-related cardiac damage

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.

Endothelial adhesion molecules and multiple organ failure in patients with severe sepsis

OBJECTIVE To determine if serum levels of endothelial adhesion molecules were associated with the development of multiple organ failure (MOF) and in-hospital mortality in adult patients with severe sepsis. DESIGN This study was a secondary data analysis of a prospective cohort study. SETTING Patients were admitted to two tertiary intensive care units in San Antonio, TX, between 2007 and 2012. PATIENTS Patients with severe sepsis at the time of intensive care unit (ICU) admission were enrolled. Inclusion criteria were consistent with previously published criteria for severe sepsis or septic shock in adults. Exclusion criteria included immunosuppressive medications or conditions. INTERVENTIONS None. MEASUREMENTS Baseline serum levels of the following endothelial cell adhesion molecules were measured within the first 72h of ICU admission: Intracellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1), and Vascular Endothelial Growth Factor (VEGF). The primary and secondary outcomes were development of MOF (⩾2 organ dysfunction) and in-hospital mortality, respectively. MAIN RESULTS Forty-eight patients were enrolled in this study, of which 29 (60%) developed MOF. Patients that developed MOF had higher levels of VCAM-1 (p=0.01) and ICAM-1 (p=0.01), but not VEGF (p=0.70) compared with patients without MOF (single organ failure only). The area under the curve (AUC) to predict MOF according to VCAM-1, ICAM-1 and VEGF was 0.71, 0.73, and 0.54, respectively. Only increased VCAM-1 levels were associated with in-hospital mortality (p=0.03). These associations were maintained even after adjusting for APACHE and SOFA scores using logistic regression. CONCLUSIONS High levels of serum ICAM-1 was associated with the development of MOF. High levels of VCAM-1 was associated with both MOF and in-hospital mortality.

Understanding the Concept of Health Care-Associated Pneumonia in Lung Transplant Recipients.

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.