Cytokine/Chemokine Expression Is Closely Associated Disease Severity of Human Adenovirus Infections in Immunocompetent Adults and Predicts Disease Progression.

Zhixiang Xu,Yingxia Liu,Litao Sun,Yang Yang,Chunmei Jiang,Jie Chen,Yuelong Shu,Jin Li,Minghui Yang,Mianhuan Li,Yanjie Li,Yuchen Gu,Jinli Wei,Fuxiang Wang

doi:10.3389/fimmu.2021.691879

Abstract

Increasing human Adenovirus (HAdV) infections complicated with acute respiratory distress syndrome (ARDS) even fatal outcome were reported in immunocompetent adolescent and adult patients. Here, we characterized the cytokine/chemokine expression profiles of immunocompetent patients complicated with ARDS during HAdV infection and identified biomarkers for disease severity/progression. Forty-eight cytokines/chemokines in the plasma samples from 19 HAdV-infected immunocompetent adolescent and adult patients (ten complicated with ARDS) were measured and analyzed in combination with clinical indices. Immunocompetent patients with ARDS caused by severe acute respiratory disease coronavirus (SARS-CoV)-2, 2009 pandemic H1N1 (panH1N1) or bacteria were included for comparative analyses. Similar indices of disease course/progression were found in immunocompetent patients with ARDS caused by HAdV, SARS-CoV-2 or panH1N infections, whereas the HAdV-infected group showed a higher prevalence of viremia, as well as increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase (CK). Expression levels of 33 cytokines/chemokines were increased significantly in HAdV-infected patients with ARDS compared with that in healthy controls, and many of them were also significantly higher than those in SARS-CoV-2-infected and panH1N1-infected patients. Expression of interferon (IFN)-γ, interleukin (IL)-1β, hepatocyte growth factor (HGF), monokine induced by IFN-γ (MIG), IL-6, macrophage-colony stimulating factor (M-CSF), IL-10, IL-1α and IL-2Ra was significantly higher in HAdV-infected patients with ARDS than that in those without ARDS, and negatively associated with the ratio of the partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2). Analyses of the receiver operating characteristic curve (ROC) showed that expression of IL-10, M-CSF, MIG, HGF, IL-1β, IFN-γ and IL-2Ra could predict the progression of HAdV infection, with the highest area under the curve (AUC) of 0.944 obtained for IL-10. Of note, the AUC value for the combination of IL-10, IFN-γ, and M-CSF reached 1. In conclusion, the “cytokine storm” occurred during HAdV infection in immunocompetent patients, and expression of IL-10, M-CSF, MIG, HGF, IL-1β, IFN-γ and IL-2Ra was closely associated with disease severity and could predict disease progression.

Highlights

Human adenoviruses (HAdVs) are double-stranded, non-enveloped icosahedral viruses that typically cause mild infections involving the upper or lower respiratory tract, gastrointestinal tract, or conjunctiva [1,2,3]
Patients complicated with acute respiratory distress syndrome (ARDS) caused by infection with SARS-CoV-2 (n = 28), pandemic H1N1 (panH1N1) (n = 21), suffering from bacterial pneumonia (n = 10) and healthy controls (HCs) (n = 8) were included for analyses
There was no significant difference in the proportion of patients developing severe ARDS, needing mechanical ventilation or transfer to the intensive unit care unit (ICU), or in-hospital prevalence of death (Table S2)

Summary

Introduction

Human adenoviruses (HAdVs) are double-stranded, non-enveloped icosahedral viruses that typically cause mild infections involving the upper or lower respiratory tract, gastrointestinal tract, or conjunctiva [1,2,3]. HAdV infections in the respiratory tract in immunocompetent adults can occur, typically with mild and selflimiting symptoms in most cases [1, 2]. Increasingly severe HAdV infections complicated by acute respiratory distress syndrome (ARDS) in immunocompetent adolescents and adults have been reported with a mortality prevalence of ≤80% [8,9,10,11,12,13,14,15,16], which poses a serious threat to public health. Due to distinct prognoses and treatments among these respiratory viruses, differentiating HAdV infections accurately and in a timely manner is crucial for clinicians and epidemiologists

Methods

Results

Conclusion