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

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.

Keywords: COVID-19; IFN-γ; SRAS-CoV-2; artificial intelligence 2; inflammation; pulmonary fibrosis.

FIGURE 1

Flowchart of COVID-19 patients in the analysis.

FIGURE 2

Flowchart of AI-based quantification of pulmonary fibrosis in chest CT images.

FIGURE 3

AI-assisted quantification of pneumonia lesions in COVID-19 patients. Sequential CT images of a patient with non-severe (A) and that of another with severe case of COVID-19 (B). In the patient with severe COVID-19, CT images were obtained on the 4th, 14th, and 43rd days after disease onset (A,i–iii). In patients with critical illness, CT examination was performed on the 1st, 43rd, and 80th days after disease onset (B,i–iii). Fibrosis index was computed by AI system to represent fibrosis. Fibrosis volume and percentage in the entire lung are shown in images (C,D). The blue and red arrows indicate typical SARS-CoV-2 infection-induced ground glass opacity and fibrosis images, respectively.

FIGURE 4

Circulating IFN-γ at baseline in relation to fibrosis at discharge. (A–C) Baseline levels of IFN-γ, IFN-α2, and MCP-3 in healthy controls and COVID-19 patients with the presence or absence of fibrosis at discharge. (D) Receiver operating characteristic (ROC) curves for discrimination of lung fibrosis (fibrotic volume >0 vs. fibrotic volume = 0) at discharge. Blue, red, green, and brown lines identify baseline CRP, MCP-3, IFN-γ, and IL-6, respectively.