Rationale: Neutrophils are key effectors in the host's immune response to sepsis. Excessive stimulation or dysregulated neutrophil functions are believed to be responsible for sepsis pathogenesis. However, the mechanisms regulating functional plasticity of neutrophils during sepsis have not been fully determined. Objectives: We investigated the role of autophagy in neutrophil functions during sepsis in patients with community-acquired pneumonia. Methods: Neutrophils were isolated from patients with sepsis and stimulated with phorbol 12-myristate 13-acetate (PMA). The levels of reactive oxygen species generation, neutrophil extracellular trap (NET) formation, and granule release, and the autophagic status were evaluated. The effect of neutrophil autophagy augmentation was further evaluated in a mouse model of sepsis. Measurements and Main Results: Neutrophils isolated from patients who survived sepsis showed an increase in autophagy induction, and were primed for NET formation in response to subsequent PMA stimulation. In contrast, neutrophils isolated from patients who did not survive sepsis showed dysregulated autophagy and a decreased response to PMA stimulation. The induction of autophagy primed healthy neutrophils for NET formation and vice versa. In a mouse model of sepsis, the augmentation of autophagy improved survival via a NET-dependent mechanism. Conclusions: These results indicate that neutrophil autophagy primes neutrophils for increased NET formation, which is important for proper neutrophil effector functions during sepsis. Our study provides important insights into the role of autophagy in neutrophils during sepsis.

Mortality rates associated with sepsis have increased progressively in Korea, but domestic epidemiologic data remain limited. The objective of this study was to investigate the characteristics, management and clinical outcomes of sepsis patients in Korea. This study is a multicenter retrospective cohort study. A total of 64,021 adult patients who visited an emergency department (ED) within one of the 19 participating hospitals during a 1-month period were screened for eligibility. Among these, patients diagnosed with sepsis based on the third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) were included in the study. Using the Sepsis-3 criteria, 977 sepsis patients were identified, among which 36.5% presented with septic shock. The respiratory system (61.8%) was the most common site of infection. The pathogen involved was identified in 444 patients (45.5%) and multi-drug resistance (MDR) pathogens were isolated in 171 patients. Empiric antibiotic therapy was appropriate in 68.6% of patients, but the appropriateness was significantly reduced in infections associated with MDR pathogens as compared with non-MDR pathogens (58.8% vs. 76.0%, P<0.001). Hospital mortality was 43.2% and 18.5% in sepsis patients with and without shock, respectively. Of the 703 patients who survived to discharge, 61.5% were discharged to home and 38.6% were transferred to other hospitals or facilities. This study found the prevalence of sepsis in adult patients visiting an ED in Korea was 1.5% (15.2/1,000 patients). Patients with sepsis, especially septic shock, had a high mortality and were often referred to step-down centers after acute and critical care.

Asthma is a common disease that is expensive and burdensome for patients. Inhaled corticosteroids (ICS) are the most important drugs for asthma treatment and are often prescribed long-term. However, the use of ICS has been reported to increase pneumonia, though this remains controversial. We evaluated whether the use of ICS increases the risk of pneumonia in asthmatic patients using the Health Insurance Review and Assessment Service (HIRA) database in Korea. The Asthma Management Adequacy Assessment was performed by the HIRA in Korea. Patients with claimed insurance benefits for asthma disease codes and who were prescribed asthma medications more than 2 times were enrolled. Patient demographics, asthma medications, healthcare use, and complications were analyzed. The total number of asthma patients was 831,613. Patients using ICS were older and had more comorbidities than those not using ICS; they also visited outpatient clinics and emergency departments, and were more often hospitalized. Pneumonia and other complications occurred more often in patients using ICS, and they used more respiratory medications, except for theophylline. Multiple logistic regression analysis showed that ICS prescription was associated with pneumonia (odds ratio, 1.38; 95% confidence interval, 1.36-1.41). Age, sex, medical care, use of secondary and tertiary hospitals, and hospitalization due to asthma in the previous year were also associated with pneumonia. ICS use was associated with increasing pneumonia in asthmatic patients in Korea. Therefore, it is critical to acknowledge that the use of ICS may increase the risk of pneumonia and should be meticulously monitored in asthmatics.

Lung injury is characterized by diffuse lung inflammation, alveolar-capillary destruction, and alveolar flooding, resulting in respiratory failure. Polydexyribonucleotide (PDRN) has an anti-inflammatory effect, decreasing inflammatory cytokines, and suppressing apoptosis. Thus, we investigated its efficacy in the treatment of lung injury, which was induced in rats using lipopolysaccharide (LPS). Rats were randomly divided into three groups according to sacrifice time, and each group split into control, lung injury-induced, and lung injury-induced + PDRN-treated groups. Rats were sacrificed 24 h and 72 h after PDRN administration, according to each group. Lung injury was induced by intratracheal instillation of LPS (5 mg/kg) in 0.2 mL saline. Rats in PDRN-treated groups received a single intraperitoneal injection of 0.3 mL distilled water including PDRN (8 mg/kg), 1 h after lung injury induction. Percentages of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive, cleaved caspase-3-, -8-, and -9-positive cells, the ratio of Bcl-2-associated X protein (Bax) to B-cell lymphoma 2 (Bcl-2), and expressions of inflammatory cytokines (tumor necrosis factor-α, interleukin-6) were decreased by PDRN treatment in the LPS-induced lung injury rats. Therefore, treatment with PDRN reduced lung injury score. This anti-apoptotic effect of PDRN can be ascribed to the enhancing effect of PDRN on adenosine A_2A receptor expression. Based on these results, PDRN might be considered as a new therapeutic agent for the treatment of lung injury.

Platelets play an important role in hemostasis, inflammation, and immunity. Mean platelet volume (MPV), considered a marker of platelet function and activation, is associated with increased morbidity and mortality in sepsis, coronary artery disease, and chronic inflammatory disease. However, the clinical characteristics and prognostic significance of MPV changes for patients with pneumonia in the intensive care unit (ICU) have not been investigated. This retrospective study was conducted using data from an operational database of patients admitted to a medical ICU between October 2010 and October 2017. Of 235 adult patients with pneumonia admitted to the ICU, clinical characteristics and in-hospital mortality values were compared according to MPV, ΔMPV_day1–2, ΔMPV_day1–3, ΔMPV_day1–4, and ΔMPV_{day1–Discharge} between those who survived and those who did not. The MPV increased during the first four days for both non-survivors and survivors (P < 0.001). However, repeated measures analysis of variance revealed a significantly higher MPV rate over the first four days in non-survivors than in survivors. Additionally, the ΔMPV_day1–2, ΔMPV_day1–3, ΔMPV_day1–4, and ΔMPV_{day1–Discharge} values were significantly greater in non-survivors than in survivors. For in-hospital mortality, the optimal ΔMPV values were >0.9 fL, P = 0.020; >0.9 fL, P < 0.001; >0.8 fL, P < 0.001; and >1.3 fL, P < 0.001 on day 2, day 3, day 4, and at discharge, respectively. In conclusion, our findings demonstrate that ΔMPV during ICU admission may be used as a prognostic marker of mortality in ICU patients with pneumonia. Repeated MPV measurements throughout hospitalization may improve risk stratification for these patients, which could aid in improving patient outcomes.

Lee SM, et al. J Korean Med Assoc. 2018 Aug;61(8):509-521. https://doi.org/10.5124/jkma.2018.61.8.509