Interferon-dependent signaling is critical for viral clearance in airway neutrophils.

Neutrophilic inflammation characterizes several respiratory viral infections, including COVID-19-related acute respiratory distress syndrome, although its contribution to disease pathogenesis remains poorly understood. Blood and airway immune cells from 52 patients with severe COVID-19 were phenotyped by flow cytometry. Samples and clinical data were collected at 2 separate time points to assess changes during ICU stay. Blockade of type I interferon and interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) signaling was performed in vitro to determine their contribution to viral clearance in A2 neutrophils. We identified 2 neutrophil subpopulations (A1 and A2) in the airway compartment, where loss of the A2 subset correlated with increased viral burden and reduced 30-day survival. A2 neutrophils exhibited a discrete antiviral response with an increased interferon signature. Blockade of type I interferon attenuated viral clearance in A2 neutrophils and downregulated IFIT3 and key catabolic genes, demonstrating direct antiviral neutrophil function. Knockdown of IFIT3 in A2 neutrophils led to loss of IRF3 phosphorylation, with consequent reduced viral catabolism, providing the first discrete mechanism to our knowledge of type I interferon signaling in neutrophils. The identification of this neutrophil phenotype and its association with severe COVID-19 outcomes emphasizes its likely importance in other respiratory viral infections and potential for new therapeutic approaches in viral illness.

Type I interferon-dependent IFIT3 signaling is critical for viral clearance in airway neutrophils.

Neutrophilic inflammation characterizes several respiratory viral infections including COVID-19-related ARDS, although its contribution to disease pathogenesis remains poorly understood. Here, we identified two neutrophil subpopulations (A1 and A2) in the airway compartment of 52 severe COVID-19 subjects, where loss of the A2 subset correlated with increased viral burden and reduced 30-days survival. A2 neutrophils showcased a discrete antiviral response with an increased interferon signature. Blockade of type I interferon attenuated viral clearance in A2 neutrophils and downregulated IFIT3 and key catabolic genes, demonstrating direct antiviral neutrophil function. Knockdown of IFIT3 in A2 neutrophils led to loss of IRF3 phosphorylation with consequent reduced viral catabolism, providing the first discrete mechanism of type I interferon signaling in neutrophils. The identification of this novel neutrophil phenotype and its association with severe COVID-19 outcomes emphasizes its likely importance in other respiratory viral infections and potential for new therapeutic approaches in viral illness.

Elevated D-Dimer Levels Are Associated With Increased Risk of Mortality in Coronavirus Disease 2019: A Systematic Review and Meta-Analysis.

The 2019 novel coronavirus, declared a pandemic, has infected 2.6 million people as of April 27, 2020, and has resulted in the death of 181,938 people. D-dimer is an important prognostic tool, is often elevated in patients with severe coronavirus disease-19 (COVID-19) infection and in those who suffered death. In this systematic review, we aimed to investigate the prognostic role of D-dimer in COVID-19-infected patients. We searched PubMed, Medline, Embase, Ovid, and Cochrane for studies reporting admission D-dimer levels in COVID-19 patients and its effect on mortality. Eighteen studies (16 retrospective and 2 prospective) with a total of 3682 patients met the inclusion criteria. The pooled weighted mean difference (WMD) demonstrated significantly elevated D-dimer levels in patients who died versus those who survived (WMD, 6.13 mg/L; 95% confidence interval [CI] 4.16-8.11; P < 0.001). Similarly, the pooled mean D-dimer levels were significantly elevated in patients with severe COVID-19 infection (WMD, 0.54 mg/L; 95% CI 0.28-0.80; P < 0.001). The risk of mortality was fourfold higher in patients with positive D-dimer versus negative D-dimer (risk ratio, 4.11; 95% CI, 2.48-6.84; P < 0.001) and the risk of developing severe disease was twofold higher in patients with positive D-dimer levels versus negative D-dimer (risk ratio, 2.04; 95% CI, 1.34-3.11; P < 0.001). Our meta-analysis demonstrates that patients with COVID-19 infection presenting with elevated D-dimer levels have an increased risk of severe disease and mortality.

The Association of Low Income and High Stress with Acute Care Use in COPD Patients.

INTRODUCTION: Low-income chronic obstructive pulmonary disease (COPD) individuals are known to have higher rates of COPD-related hospitalizations and readmissions. Levels of psychological stress are also higher in low-income populations and may be associated with acute care use. We sought to: (1) determine the association between stress and acute care use in COPD, (2) evaluate the social determinants of health (SDH) in low and high stress individuals, and (3) determine the association between low income and high stress with acute care use. MATERIALS AND METHODS: Using results from a survey-based study of individuals with COPD at the University of Alabama (UAB), we used multivariable regression modeling to evaluate the association of high stress with acute care use (COPD-related emergency department [ED] visits or hospitalizations). We then compared SDH between low and high stress groups and evaluated the association of low income + high stress with acute care use in a secondary model. RESULTS: We included 126 individuals in our study. The high stress group was more likely to be < 65 years old and female. No differences in race, smoking, years of smoking, body mass index, dyspnea, or lung function (forced expiratory volume in 1 second [FEV1]%) by stress group were observed. The high stress group had a 2.5-fold increased adjusted odds of acute care use (adjusted odds ratio [AOR]95% confidence interval [CI], 2.51, 1.06-5.98) compared to the low stress group, while the low-income + high stress group had a 4-fold increased adjusted odds of acute care use (AOR, 95% CI, 4.38, 1.25-15-45) compared to high-income + low-stress group. CONCLUSIONS: Acute care use and stress are associated in COPD. These associations are more pronounced in the low-income + high stress population who disproportionately contribute to health care utilization and frequently lack the resources needed to cope with stress.