Longitudinal Profiling of Cytokines and Chemokines in COVID-19 Reveals Inhibitory Mediators IL-1Ra and IL-10 Are Associated with Disease Severity While Elevated RANTES Is an Early Predictor of Mild Disease

Authors: Yan Zhao et al. 2020

Link to paper: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3576836

Journal/ Pre-Print: The Lancet (Pre-print)

Tags: Clinical, Diagnostics (disease severity/prognostics)

Research Highlights 

1. IP-10 and MCP-1 are elevated in blood of COVID-19 patients compared to healthy patients, but significantly higher in severe cases compared to mild cases

2. IL-1RA (1 and 2 weeks post-symptom) and IL-10 (2 and 4 weeks post-symptom) in blood are significantly increased in severe COVID-19 cases compared to mild COVID-19 cases, whereas CCL2/RANTES (1, 2, 3 and 4 weeks post-symptom) is significantly decreased in blood of severe cases compared to mild cases.

3. CCL5, IL-1RA and IL-10 clustered K-means analysis can predict disease severity of patients, indicating their use as a prognostic biomarker

Summary 

A longitudinal study measuring cytokine and chemokine levels in peripheral blood every 4-7 days for over 1 month in patients infected with COVID-19. Patients were stratified according to mild (n=53) and severe cases (n=18) and compared to healthy controls (n=18). Levels of IP-10 and MCP-1 were higher in severe cases compared to mild, whereas levels of RANTES(CCL5) was lower in severe cases compared to mild. Other cytokines involved in the cytokine storm (IL-6 and IFNy) were only elevated in the late stage of severe cases. Authors suggest levels of CCL5, IL-1Ra and IL-10 may be used to predict disease severity for patients.

Impact for SARS-CoV2/COVID19 research efforts

Clinical symptoms and pathogenesis of SARS-Cov2/COVID19

Significant increase in cytokines between mild and severe COVID-19 patients indicate a role for IL-10 and IL-1Ra in disease progression and severity (and decrease of CCL5), rather than the previously presumed “cytokine storm”, highlighting them as possible targets

Develop diagnostic tools for SARS-CoV2/COVID19 (prognostic tools)

Study takes healthy patients, mild COVID-19 patients and severe COVID-19 patients and identifies cytokines from a 34 multiplex that are significantly different between mild and severe cases of COVID-19 and might serve as prognostic marker

Study Type

· Clinical Cohort study (e.g. drug trials)

Strengths and limitations of the paper

Novelty: CCL5, IL-10 and IL-RA as prognostic markers of COVID-19 disease progression/symptom severity

Longitudinal study across 4 weeks

Standing in the field: Two clinical cohort studies on cytokines have previously been published (Chaolin Huang et al. 2020, The Lancet) (Fei Zhou et al. 2020, The Lancet)

Appropriate statistics: Yes

Viral model used: COVID-19 patients (RT-PCR confirmed) from Beijing You’an Hospital, Capital Medical University, Beijing (January – March 2020)

Translatability: Authors suggest that early interventions to reduce IL-10 and IL-1Ra levels or increase CCL5 as possible strategies to prevent patients from developing severe disease

Main limitations:

-Poor positive correlation (R=0.26) between lymphocyte count and RANTES levels

-Data for blood cells counts for healthy controls not shown in Figure 1

-Authors state that levels of IL-10 in severe cases were significantly higher than those in mild cases in the first two weeks but from the graphs significance is only in week 2 and 4