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Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

Our take —

Among a group of COVID-19 patients with a spectrum of disease severity, severe-to-critical disease was associated with an exacerbated inflammatory response (specifically, elevated IL-6 and TNF-alpha), high blood viral load, and a disturbance of the antiviral IFN expression and activation pathway. While additional longitudinal evidence is needed to establish a causal association, these findings provide evidence that a perturbation in the IFN activation pathway and an exaggerated inflammatory response in circulating blood may contribute to disease severity, supporting previous evidence that severe disease is characterized by decreased IFN activation in macrophages. Additional studies in relevant tissue-specific regions (i.e., the lungs) as well as longitudinal assessments are warranted to inform the development of potential targets for therapeutic intervention.

Study design

Cross-Sectional

Study population and setting

This study was conducted using biological samples collected from patients presenting to a single hospital in Paris, France for routine care between March 19 and April 3, 2020. It included 50 patients with laboratory-confirmed SARS-CoV-2 infection and a clinical diagnosis per WHO guidelines (15 mild-moderate severity; 17 severe; and 18 critical) and 18 controls (negative SARS-CoV-2 test and matched by age +/- 5 years). Patients with uncontrolled chronic disease or bacterial co-infection were excluded. Data were extracted from electronic medical records using standardized forms, and a comprehensive immune analysis was conducted.

Summary of Main Findings

The median age of the patients and healthy controls was 55 and 51 years (78% and 72% male), respectively. Data from a median of 10 days following symptom onset were assessed. The following symptoms were documented among the patients: 98% had fever, 98% dyspnea, 96% fatigue, 92% cough, 62% myalgia, and 34% diarrhea. A controlled comorbidity (mainly hypertension or type 2 diabetes) was reported in 44% of patients. The immune phenotype more likely to be associated with severe or critical disease included decreased density of NK cells and CD3+ T cells, increased cell activation and markers of cell exhaustion, high blood viral load, and an up-regulation of genes related to cytokine and chemokine expression (mainly IL-6 and TNF-alpha) and cell apoptosis. Mild-to-moderate disease was more likely to be associated with an up-regulation of genes involving type 1 interferon (IFN) activation, a critical part of the innate antiviral immune response. In contrast, IFN activity was significantly lower in those with severe-critical disease.

Study Strengths

This study provides a fairly comprehensive analysis of various immune factors associated with clinical severity of disease among laboratory-confirmed COVID patients with controlled co-morbidities, including profiling of T cell subsets, quantifying the levels of cytokines and chemokines in plasma, and gene expression analysis, compared to age-matched healthy adults from the same institution.

Limitations

The study was cross-sectional in nature; given the lack of data regarding pre-infection levels of immune response, it is not possible to definitively attribute more severe disease as resulting from increased levels of inflammation or low levels of IFN. Data on immune responses were obtained from blood circulating levels in plasma, and may not accurately characterize pulmonary immune responses. Further, the study consists of a fairly small number of patients from a single hospital, and the immune data obtained are limited to a median of 10 days after symptom onset, which may not characterize immune responses at different time points during disease progression.

Value added

This study presents fairly comprehensive laboratory assessments of immune phenotypes from patients with a wide spectrum of clinical COVID disease severity compared to healthy adults of a similar age.

This review was posted on: 3 August 2020