Lower Circulating Interferon-Gamma Is a Risk Factor for Lung Fibrosis in COVID-19 Patients.

Zhong-Jie Hu,Li Li,Jia Xu,Ji-Ming Yin,Ying-Mei Feng,Yi-Zhou Yu,Rong-Hua Jin,Wei Hou,Zhen Zhou,Hong-Jun Li,Li-Li Zhang

doi:10.3389/fimmu.2020.585647

Abstract

Cytokine storm resulting from SARS-CoV-2 infection is one of the leading causes of acute respiratory distress syndrome (ARDS) and lung fibrosis. We investigated the effect of inflammatory molecules to identify any marker that is related to lung fibrosis in coronavirus disease 2019 (COVID-19). Seventy-six COVID-19 patients who were admitted to Youan Hospital between January 21 and March 20, 2020 and recovered were recruited for this study. Pulmonary fibrosis, represented as fibrotic volume on chest CT images, was computed by an artificial intelligence (AI)-assisted program. Plasma samples were collected from the participants shortly after admission, to measure the basal inflammatory molecules levels. At discharge, fibrosis was present in 46 (60.5%) patients whose plasma interferon-γ (IFN-γ) levels were twofold lower than those without fibrosis (p > 0.05). The multivariate-adjusted logistic regression analysis demonstrated the inverse association risk of having lung fibrosis and basal circulating IFN-γ levels with an estimate of 0.43 (p = 0.02). Per the 1-SD increase of basal IFN-γ level in circulation, the fibrosis volume decreased by 0.070% (p = 0.04) at the discharge of participants. The basal circulating IFN-γ levels were comparable with c-reactive protein in the discrimination of the occurrence of lung fibrosis among COVID-19 patients at discharge, unlike circulating IL-6 levels. In conclusion, these data indicate that decreased circulating IFN-γ is a risk factor of lung fibrosis in COVID-19.

Highlights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the family Coronaviridae, has induced the coronavirus disease 2019 (COVID-19) pandemic [1]
When the baseline levels of the inflammatory molecules were categorized by COVID-19 severity, circulating IL-5, IL-27, and VEGF-A levels were 1. 7, 1. 5, and 2.0-fold higher, but the MDC levels were 1.5-fold lower, in severe cases compared to non-severe cases (Supplementary Table S1)
The main findings of the study include [1] multivariate-adjusted logistic analysis demonstrated that the odds of having a risk of lung fibrosis at discharge were decreased with higher baseline levels of IFN-γ and MCP-3, measured in the early stage of the disease; [2] per 1-SD increase at baseline, the fibrotic volume decreased by 0.070% for IFN-γ; and [3] the basal levels of IFN-γ and MCP-3 were comparable with the C-reactive protein (CRP) in the discrimination of the occurrence of lung fibrosis in COVID-19 patients, whereas IL6 were not

Summary

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the family Coronaviridae, has induced the coronavirus disease 2019 (COVID-19) pandemic [1]. Clinical data from different countries have shown that approximately one third of the patients have suffered from acute respiratory distress syndrome (ARDS) [2], which is a fundamental cause of mortality and could progress to pulmonary fibrosis in survivors. Through ACE2mediated endocytosis, SARS-CoV-2 endocytosed in epithelial cells are released and undergo rapid replication, leading to pyroptosis, a typical virus-linked programmed cell death [8]. The release of virus RNA and damage-associated molecular patterns from dead epithelial cells further triggers inflammatory cascade in the lung, resulting in ARDS and fibrosis formation [9, 10]

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