Single-Cell Profiling Reveals Immune Aberrations in Progressive Idiopathic Pulmonary Fibrosis.

RATIONALE: Changes in peripheral blood cell populations have been observed but not detailed at single-cell resolution in idiopathic pulmonary fibrosis (IPF). OBJECTIVES: To provide an atlas of the changes in the peripheral immune system in stable and progressive IPF. METHODS: Peripheral blood mononuclear cells (PBMCs) from IPF patients and controls were profiled using 10x Chromium 5' single-cell RNA sequencing (scRNA-seq). Flow cytometry was used for validation. Protein concentrations of Regulatory T-cells (Tregs) and Monocytes chemoattractants were measured in plasma and lung homogenates from patients and controls. MEASUREMENTS AND MAIN RESULTS: Thirty-eight PBMC samples from 25 patients with IPF and 13 matched controls yielded 149,564 cells that segregated into 23 subpopulations. Classical monocytes were increased in progressive and stable IPF compared to controls (32.1%, 25.2%, 17.9%, respectively, p<0.05). Total lymphocytes were decreased in IPF vs controls, and in progressive vs stable IPF (52.6% vs 62.6%, p=0.035). Tregs were increased in progressive vs stable IPF (1.8% vs 1.1% of all PBMC, p=0.007), although not different than controls, and may be associated with decreased survival (P=0.009 in Kaplan-Meier analysis; P=0.069 after adjusting for age, sex, and baseline FVC). Flow cytometry analysis confirmed this finding in an independent cohort of IPF patients. Fraction of Tregs out of all T cells was also increased in two cohorts of lung scRNA-seq. CCL22 and CCL18, ligands for CCR4 and CCR8 Treg chemotaxis receptors, were increased in IPF. CONCLUSIONS: The single-cell atlas of the peripheral immune system in IPF, reveals an outcome-predictive increase in classical monocytes and Tregs, as well as evidence for a lung-blood immune recruitment axis involving CCL7 (for classical monocytes) and CCL18/CCL22 (for Tregs).

Damage sensing through TLR9 Promotes Viral Clearance and Recovery During Influenza Infection.

Host response aimed at eliminating the infecting pathogen, as well as the pathogen itself, can cause tissue injury. Tissue injury leads to the release of a myriad of cellular components including mitochondrial DNA, which the host senses through pattern recognition receptors. How the sensing of tissue injury by the host shapes the anti-pathogen response remains poorly understood. In this study, we utilized mice that are deficient in toll-like receptor-9 (TLR9), which binds to unmethylated CpG DNA sequences such as those present in bacterial and mitochondrial DNA. To avoid direct pathogen sensing by TLR9, we utilized the influenza virus, which lacks ligands for TLR9, to determine how damage sensing by TLR9 contributes to anti-influenza immunity. Our data show that TLR9-mediated sensing of tissue damage promotes an inflammatory response during early infection, driven by the myeloid cells and associated cytokine responses. Along with the diminished inflammatory response, the absence of damage sensing through TLR9 led to impaired viral clearance manifested as a higher and prolonged influenza burden in the lung. The absence of TLR9 led to extensive infection of myeloid cells including monocytes and macrophages rendering them highly inflammatory, despite having a low initial inflammatory response. The persistent inflammation driven by infected myeloid cells led to persistent lung injury and impaired recovery in influenza-infected TLR9-/- mice. Further, we show elevated circulating TLR9 ligands in the plasma samples of patients with influenza, demonstrating its clinical relevance. Overall, over data show an essential role of damage sensing through TLR9 in promoting anti-influenza immunity.

Single-cell profiling reveals immune aberrations in progressive idiopathic pulmonary fibrosis.

Rationale: Changes in peripheral blood cell populations have been observed but not detailed at single-cell resolution in idiopathic pulmonary fibrosis (IPF). Objectives: To provide an atlas of the changes in the peripheral immune system in stable and progressive IPF. Methods: Peripheral blood mononuclear cells (PBMCs) from IPF patients and controls were profiled using 10x Chromium 5' single-cell RNA sequencing (scRNA-seq). Flow cytometry was used for validation. Protein concentrations of Regulatory T-cells (Tregs) and Monocytes chemoattractants were measured in plasma and lung homogenates from patients and controls. Measurements and Main Results: Thirty-eight PBMC samples from 25 patients with IPF and 13 matched controls yielded 149,564 cells that segregated into 23 subpopulations, corresponding to all expected peripheral blood cell populations. Classical monocytes were increased in progressive and stable IPF compared to controls (32.1%, 25.2%, 17.9%, respectively, p<0.05). Total lymphocytes were decreased in IPF vs controls, and in progressive vs stable IPF (52.6% vs 62.6%, p=0.035). Tregs were increased in progressive IPF (1.8% vs 1.1%, p=0.007), and were associated with decreased survival (P=0.009 in Kaplan-Meier analysis). Flow cytometry analysis confirmed this finding in an independent cohort of IPF patients. Tregs were also increased in two cohorts of lung scRNA-seq. CCL22 and CCL18, ligands for CCR4 and CCR8 Treg chemotaxis receptors, were increased in IPF. Conclusions: The single-cell atlas of the peripheral immune system in IPF, reveals an outcome-predictive increase in classical monocytes and Tregs, as well as evidence for a lung-blood immune recruitment axis involving CCL7 (for classical monocytes) and CCL18/CCL22 (for Tregs).

α1 Adrenoreceptor antagonism mitigates extracellular mitochondrial DNA accumulation in lung fibrosis models and in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is increasingly associated with nerve-driven processes and endogenous innate immune ligands such as mitochondrial DNA (mtDNA). Interestingly, a connection between these entities has not been explored. Here, we report that noradrenaline (NA) derived from the lung's adrenergic nerve supply drives α-smooth muscle actin (αSMA)-expressing fibroblast accumulation via mechanisms involving α1 adrenoreceptors and mtDNA. Using the bleomycin model, we compared ablation of the lung's adrenergic nerve supply with surgical adrenal resection and found that NA derived from local but not adrenal sources contributes to experimentally induced lung fibrosis and the emergence of an αSMA+ve fibroblast population expressing adrenoreceptor α-1D (ADRA1D). Therapeutic delivery of the α1 adrenoreceptor antagonist terazosin reversed these changes and suppressed extracellular mtDNA accumulation. Cultured normal human lung fibroblasts displayed α1 adrenoreceptors and in response to costimulation with TGFß1 and NA adopted ACTA2 expression and extracellular mtDNA release. These findings were opposed by terazosin. Evaluation of a previously studied IPF cohort revealed that patients prescribed α1 adrenoreceptor antagonists for nonpulmonary indications demonstrated improved survival and reduced concentrations of plasma mtDNA. Our observations link nerve-derived NA, α1 adrenoreceptors, extracellular mtDNA, and lung fibrogenesis in mouse models, cultured cells, and humans with IPF. Further study of this neuroinnate connection may yield new avenues for investigation in the clinical and basic science realms.

Evolving Perspectives on Innate Immune Mechanisms of IPF.

While epithelial-fibroblast interactions are viewed as the primary drivers of Idiopathic Pulmonary Fibrosis (IPF), evidence gleaned from animal modeling and human studies implicates innate immunity as well. To provide perspective on this topic, this review synthesizes the available data regarding the complex role of innate immunity in IPF. The role of substances present in the fibrotic microenvironment including pathogen associated molecular patterns (PAMPs) derived from invading or commensal microbes, and danger associated molecular patterns (DAMPs) derived from injured cells and tissues will be discussed along with the proposed contribution of innate immune populations such as macrophages, neutrophils, fibrocytes, myeloid suppressor cells, and innate lymphoid cells. Each component will be considered in the context of its relationship to environmental and genetic factors, disease outcomes, and potential therapies. We conclude with discussion of unanswered questions and opportunities for future study in this area.

Elevated IL-15 concentrations in the sarcoidosis lung are independent of granuloma burden and disease phenotypes.

Sarcoidosis is a systemic granulomatous disease predominantly affecting the lungs. The mechanisms promoting disease pathogenesis and progression are unknown, although interleukin-15 (IL-15) has been associated with the immune-mediated inflammation of sarcoidosis. Because the identification of a mechanistically based, clinically relevant biomarker for sarcoidosis remains elusive, we hypothesized this role for IL-15. Pulmonary sarcoidosis granuloma formation was modeled using trehalose 6,6'-dimicolate (TDM), which was administered into wild-type and three lineages of mice: those overexpressing IL-15, deficient in IL-15, and deficient in IL-15 receptor α. The number of granulomas per lung was counted and normalized to the wild type. IL-15 concentrations were measured in the bronchoalveolar lavage (BAL) from healthy controls and subjects with sarcoidosis in our cohort, where associations between IL-15 levels and clinical manifestations were sought. Findings were validated in another independent sarcoidosis cohort. TDM administration resulted in similar granuloma numbers across all lineages of mice. IL-15 concentrations were elevated in the BAL of both human cohorts, irrespective of disease phenotypes. In exploratory analysis, an association with obesity was observed, and various other soluble mediators were identified in the BAL of both cohorts. Although IL-15 is enriched in the sarcoidosis lung, it was independent of disease pathogenesis or clinical manifestations in our mouse model and human cohorts of sarcoidosis. An association with obesity perhaps reflects the ongoing inflammatory processes of these comorbid conditions. Our findings showed that IL-15 is redundant for disease pathogenesis and clinical progression of sarcoidosis.

Macrophage-derived netrin-1 drives adrenergic nerve-associated lung fibrosis.

Fibrosis is a macrophage-driven process of uncontrolled extracellular matrix accumulation. Neuronal guidance proteins such as netrin-1 promote inflammatory scarring. We found that macrophage-derived netrin-1 stimulates fibrosis through its neuronal guidance functions. In mice, fibrosis due to inhaled bleomycin engendered netrin-1-expressing macrophages and fibroblasts, remodeled adrenergic nerves, and augmented noradrenaline. Cell-specific knockout mice showed that collagen accumulation, fibrotic histology, and nerve-associated endpoints required netrin-1 of macrophage but not fibroblast origin. Adrenergic denervation; haploinsufficiency of netrin-1's receptor, deleted in colorectal carcinoma; and therapeutic α1 adrenoreceptor antagonism improved collagen content and histology. An idiopathic pulmonary fibrosis (IPF) lung microarray data set showed increased netrin-1 expression. IPF lung tissues were enriched for netrin-1+ macrophages and noradrenaline. A longitudinal IPF cohort showed improved survival in patients prescribed α1 adrenoreceptor blockade. This work showed that macrophages stimulate lung fibrosis via netrin-1-driven adrenergic processes and introduced α1 blockers as a potentially new fibrotic therapy.

Shared and Tissue-Specific Expression Signatures between Bone Marrow from Primary Myelofibrosis and Essential Thrombocythemia.

Megakaryocytes have been implicated in the micro-environmental abnormalities associated with fibrosis and hematopoietic failure in the bone marrow (BM) of primary myelofibrosis (PMF) patients, the Philadelphia-negative myeloproliferative neoplasm (MPN) associated with the poorest prognosis. To identify possible therapeutic targets for restoring BM functions in PMF, we compared the expression profiling of PMF BM with that of BM from essential thrombocytopenia (ET), a fibrosis-free MPN also associated with BM megakaryocyte hyperplasia. The signature of PMF BM was also compared with published signatures associated with liver and lung fibrosis. Gene set enrichment analysis (GSEA) identified distinctive differences between the expression profiles of PMF and ET. Notch, K-Ras, IL-8, and apoptosis pathways were altered the most in PMF as compared with controls. By contrast, cholesterol homeostasis, unfolded protein response, and hypoxia were the pathways found altered to the greatest degree in ET compared with control specimens. BM from PMF expressed a noncanonical transforming growth factor ß (TGF-ß) signature, which included activation of ID1, JUN, GADD45b, and genes with binding motifs for the JUN transcriptional complex AP1. By contrast, the expression of ID1 and GADD45b was not altered and there was a modest signal for JUN activation in ET. The similarities among PMF, liver fibrosis, and lung fibrosis were modest and included activation of integrin-α9 and tropomyosin-α1 between PMF and liver fibrosis, and of ectoderm-neural cortex protein 1 and FRAS1-related extracellular matrix protein 1 between PMF and lung fibrosis, but not TGF-ß. These data identify TGF-ß as a potential target for micro-environmental therapy in PMF.

Concomitant Interstitial Lung Disease with Psoriasis.

Background: We encounter interstitial lung disease (ILD) patients with psoriasis. The aim of this case series was to examine clinical and radiographic characteristics of patients with concomitant psoriasis and ILD. Methods: This is a retrospective review of our institutional experience of ILD concomitant with psoriasis, from the database in the Advanced Lung/Interstitial Lung Disease Program at the Mount Sinai Hospital. Out of 447 ILD patients, we identified 21 (4.7%) with antecedent or concomitant diagnosis of psoriasis. Clinical, radiographic, pathological, and outcome data were abstracted from our medical records. Results: Median age was 66 years (range, 46-86) and 14 (66.7%) were male. Thirteen (61.9%) had not previously or concomitantly been exposed to immunosuppressive therapy directed against psoriasis. Two (9.5%) ultimately died. Clinical diagnosis of ILD included idiopathic pulmonary fibrosis, 11 (52.4%); nonspecific interstitial pneumonia (NSIP), 2 (9.5%); cryptogenic organizing pneumonia, 2 (9.5%); chronic hypersensitivity pneumonitis, 2 (9.5%); and the others, while radiographic diagnosis included usual interstitial pneumonia pattern, 9 (42.9%); NSIP pattern, 6 (28.6%); organizing pneumonia pattern, 4 (19.0%); hypersensitivity pneumonitis pattern, 2 (9.5%); and the others. Conclusions: We report 21 ILD cases with antecedent or concomitant diagnosis of psoriasis. Further prospective studies are required to determine the association between ILD and psoriasis.

Is It Idiopathic Pulmonary Fibrosis or Not?

Pulmonary fibrosis is not uncommon. Usual interstitial pneumonitis (UIP)/idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic pulmonary fibrotic diseases and has the worst prognosis with a mean life expectancy of 3.8 years. The American Thoracic Society has provided guidelines for the accurate diagnosis of IPF.In 2014, 2 antifibrotic medications were approved in the United States that target the multiple fibrotic pathways of UIP, which increased the need for early and accurate diagnosis of IPF. The early and correct diagnosis is hampered by mimickers that include nonspecific interstitial pneumonitis, chronic hypersensitivity pneumonitis, and fibrotic sarcoidosis. Careful history taking, serologic testing, and Computer Tomography (CT) inspection can frequently make the correct diagnosis without need of invasive procedure. The purpose of this article is to share the most important aspects of the clinical and radiology presentation of IPF and its mimickers to enhance primary care clinician's ability to correctly and noninvasively diagnose UIP/IPF.

Elevated serum D-dimer level is associated with an increased risk of acute exacerbation in interstitial lung disease.

BACKGROUND: Early recognition of patients with interstitial lung disease (ILD) who have an increased risk of developing acute exacerbation (AE) or preclinical AE may be clinically useful, since AE is associated with poor outcome and preventive measures would be of interest to ILD researchers. This study evaluated the relationship between elevated serum D-dimer level (≥0.4 mcg/mL) and subsequent AE or preclinical AE in patients with ILD. METHODS: This single-center, retrospective study was performed from October 2009 through September 2015 in patients with ILD who were ≥18 years old and had idiopathic pulmonary fibrosis, other idiopathic interstitial pneumonias, chronic hypersensitivity pneumonitis, ILD related to collagen tissue disease, or combined pulmonary fibrosis/emphysema. The primary outcome measure was AE development within three months from each D-dimer measurement. The secondary outcome measures were respiratory-related hospitalization, all-cause hospitalization, venous thromboembolism (VTE), and all-cause mortality within three months. RESULTS: A total of 263 patients (mean age, 64.1 years) with 374 D-dimer measurements (median, 0.44 mcg/mL) were included. The risk of developing AE was significantly higher in patients with elevated serum D-dimer level (adjusted odds ratio: 10.46; 95% CI: 1.24-88.11; p = 0.03). Patients with elevated serum D-dimer level had increased risk for respiratory-related hospitalization, all-cause hospitalization, VTE, and all-cause mortality. The other factors predictive for AE were home oxygen therapy, increased serum lactate dehydrogenase, decreased FVC, and decreased FEV1.0. CONCLUSIONS: Elevated serum D-dimer is associated with the risk of developing AE. Serum D-dimer may be used as a prognostic marker to predict AE or recognize preclinical AE.

Evaluation of the rapid immunochromatographic ODK0501 assay for Streptococcus pneumoniae antigen detection with nasopharyngeal swabs: preliminary report.

BACKGROUND: Early identification and control of pathogenic bacteria are important in the treatment of pneumonia. Currently, two rapid antigen detection kits for pneumococcal pneumonia are available: one uses urine samples and the other, named RAPIRUN® S. pneumoniae, uses sputum samples. RAPIRUN® has shown high sensitivity with nasopharyngeal swab samples from pediatric patients. In this study, we investigated the performance of RAPIRUN® with nasopharyngeal swabs from adult patients. METHODS: All adult patients diagnosed with pneumonia from November 2011 to April 2012 in St. Luke's International hospital were included in this cross-sectional study. Single sputum, nasopharyngeal swab, and urine samples obtained from patients were investigated using a rapid antigen detection kit. Sputum and blood cultures were also evaluated. We compared the characteristics of pneumococcal pneumonia patients diagnosed using RAPIRUN with a nasopharyngeal swab to those patients diagnosed using other methods. Sensitivity and specificity were also calculated. RESULTS: Seventeen out of 60 patients with pneumonia were diagnosed with pneumococcal pneumonia. In 4 out  of the 17 cases, a positive test result was obtained using RAPIRUN with a nasopharyngeal swab. The sensitivity and specificity were 23.5 and 100 %, respectively. CONCLUSION: RAPIRUN performed with nasopharyngeal swabs from adult patients exhibited lower sensitivity for the diagnosis of pneumococcal pneumonia than the other compared methods. The causative pathogen of pneumonia should be identified using not only sputum cultures or rapid antigen detection kits but also clinical features or gram staining of sputum.

Analysis of the clinical backgrounds of patients who developed respiratory acidosis under high-flow oxygen therapy during emergency transport.

Aim: High-flow oxygen is often administered to patients during emergency transport and can sometimes cause respiratory acidosis with disturbed consciousness, thereby necessitating mechanical ventilation. Although oxygen titration in chronic obstructive pulmonary disease patients during emergency transport reduces mortality rates, the clinical risk factors for respiratory acidosis in emergency settings are not fully understood. Therefore, we analyzed the clinical backgrounds of patients who developed respiratory acidosis during pre-hospital transport. Methods: This was a retrospective study of patients who arrived at our hospital by emergency transport in 2010 who received high-flow oxygen while in transit. Respiratory acidosis was defined by the following arterial blood gas readings: pH, ≤7.35; PaCO 2, ≥45 mmHg; and HCO 3-, ≥24 mmol/L. The risk factors were identified using multivariable logistic regression analysis. Results: In 765 study patients, 66 patients showed respiratory acidosis. The following risk factors for respiratory acidosis were identified: age, ≥65 years (odds ratio [OR] 1.4; 95% confidence interval [CI], 0.7-2.8); transportation time, ≥10 min (OR 2.0; 95% CI, 1.1-3.7); three digits on the Japan Coma Scale (OR 3.1; 95% CI, 1.7-5.8); percutaneous oxygen saturation, ≤90% (OR 1.6; 95% CI, 0.8-3.0); tuberculosis (OR 4.5; 95% CI, 1.4-15.1); asthma (OR 1.8; 95% CI, 0.6-5.3); pneumonia (OR 1.5; 95% CI, 0.7-3.1); and lung cancer (OR 3.9; 95% CI, 1.5-10.1). These underlying diseases as risk factors included both comorbid diseases and past medical conditions. Conclusions: The factors identified may contribute to the development of respiratory acidosis. Further studies on preventing respiratory acidosis will improve the quality of emergency medical care.

Efficacy of early switch from intravenous to oral antimicrobials in patients with aspiration pneumonia: A prospective observational study.

BACKGROUND: Previous reports have documented the efficacy of an early switch from intravenous to oral antimicrobials in community-acquired pneumonia, but not aspiration pneumonia. Therefore, we assessed the feasibility and efficacy of these newly developed criteria for community-acquired pneumonia in patients with aspiration pneumonia. METHODS: This prospective observational study included consecutive patients admitted with aspiration pneumonia over a 10-month period at St. Luke's International Hospital; we excluded patients that required intensive care. The criteria for an early switch were stability of vital signs (temperature ≤ 38 °C; respiratory rate ≤ 24 breaths/min; pulse rate ≤ 100 beats/min for >24 h) and a successful swallow evaluation (repetitive saliva swallowing test score ≥ 2; modified water swallowing test score ≥ 4). Our primary endpoint was successful completion of antimicrobial treatment 30 days after the switch, without reversion to intravenous antimicrobials. Our anticipated success rate was set as 60-75%, based on a previous study. RESULTS: Of the 70 patients admitted with aspiration pneumonia, 32 (45.7%) were excluded, and 38 (54.3%) met the inclusion criteria. Of these 38 patients, 29 (76.3%) met the switch criteria. The median duration of hospital stay for the included patients was 16 (5-30) days and 30 (12-68) days, respectively (P=0.03). Among patients who met the switch criteria, 26 (89.7%) completed oral treatment successfully while 3 (10.3%) reverted to intravenous antimicrobials. CONCLUSIONS: Approximately 75% of patients met the switch criteria; of these, nearly 90% underwent safe conversion to oral therapy. These results demonstrate the efficacy and feasibility of our switch criteria.

A patient with lung squamous cell carcinoma presenting with severe cardiac dysfunction similar to dilated cardiomyopathy with left bundle branch block induced by myocardial metastasis.

A patient with severe cardiac dysfunction similar to dilated cardiomyopathy expired because of lung squamous cell carcinoma. He was admitted with respiratory failure and was diagnosed with congestive heart failure due to dilated cardiomyopathy based on the chest X-ray, electrocardiography, echocardiography, and coronary angiography. Chest computed tomography showed a mass shadow in the right lower lobe, and the patient was diagnosed with lung squamous cell carcinoma by bronchoscopy. The patient expired, and the autopsy revealed that a myocardial metastasis disrupted the cardiac-conduction system without dilated cardiomyopathy in myocytes. Left bundle branch block caused by myocardial metastasis presumably induced left cardiac dysfunction.

Long-term survival of a patient with extensive small cell carcinoma of unknown primary etiology complicated by nephrotic syndrome.

We experienced a case of nephrotic syndrome (membranous nephropathy) complicated by extensive small cell carcinoma of unknown primary etiology that was diagnosed based on the findings of bilateral cervical and mediastinal lymphadenopathy. A complete cancer response and proteinuria remission following radical chemoradiation therapy were documented. The status of a complete response and nephrosis remission persisted for more than three years. This is the first report to demonstrate the long-term survival of a patient with extensive small cell carcinoma of unknown primary etiology complicated by paraneoplastic nephrotic syndrome.

A case of pulmonary tumor thrombotic microangiopathy diagnosed by transbronchial lung biopsy and treated with chemotherapy and long-term oxygen and anticoagulation therapies.

A 41-year-old woman, who underwent breast resection for cancer of the right breast and adjuvant chemotherapy 2 years ago, was admitted to our hospital due to shortness of breath upon exertion. High-resolution computed tomography of the chest showed small nodular opacities in the peribronchiolar area in both lungs, as well as mediastinal and hilar lymphadenopathy. A transbronchial lung biopsy revealed breast cancer metastasis and pulmonary tumor thrombotic microangiopathy (PTTM). Treatment of PTTM is rarely reported due to the difficulty of antemortem diagnosis; however, the patient was effectively treated with chemotherapy and oxygen and anticoagulation therapies for 3 months.

Impact of blood cultures on the changes of treatment in hospitalized patients with community-acquired pneumonia.

BACKGROUND: Initial blood cultures (BCs) with severe community-acquired pneumonia (CAP) are warranted. However, other than severity, the specific contributing factors that affect the decision to change antimicrobial agents have not been evaluated previously. METHODS: Consecutive adults with CAP hospitalized between January 2008 and December 2010 were assessed retrospectively. We enrolled those who were over 18 years old with typical symptoms of pneumonia and with an infiltrate consistent with pneumonia, from which 2 sets of BCs were obtained. Those who had been immunocompromised, hospitalized, or prescribed antibiotics in the past 30 days were excluded. We retrospectively assessed the factors contributing to the change in antimicrobial agents as well as the frequency of these changes in the enrolled patients based on the initial BC results. RESULTS: In total, 793 patients with initial diagnosis of CAP were admitted; 399 met the inclusion criteria. Among them, 386 were made definitive diagnosis of CAP after admission (the remaining 13 were made alternative diagnosis [non-pneumonia illnesses]). BC results were positive in 17 (4.4%) out of 386 CAP patients, among whom antimicrobial therapy was changed based on the BC results in 8 (2.1%) (Pneumonia Severity Index [PSI] grade IV; 2, PSI grade V; 6). Alternative diagnosis after admission was contributing factors for changing antimicrobial agents based on the positive blood culture results. CONCLUSIONS: The use of BCs should be limited to patients with very severe cases. It would be helpful to find alternative diagnosis and modify treatment.