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Defining Potential Therapeutic Targets in Coronavirus Disease 2019: A Cross-Sectional Analysis of a Single-Center
Nishkantha Arulkumaran1, Timothy Arthur Chandos Snow1, Adarsh Kulkarni1
1Bloomsbury Institute of Intensive Care Medicine, University College London, London, United Kingdom.
Objectives:
Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. Therapeutic approaches need to be underpinned by sound biological rationale. We evaluated whether serum levels of a range of proposed coronavirus disease 2019 therapeutic targets discriminated between patients with mild or severe disease.
Design:
A search of ClinicalTrials.gov identified coronavirus disease 2019 immunological drug targets. We subsequently conducted a retrospective observational cohort study investigating the association of serum biomarkers within the first 5 days of hospital admission relating to putative therapeutic biomarkers with illness severity and outcome.
Setting:
University College London, a tertiary academic medical center in the United Kingdom.
Patients:
Patients admitted to hospital with a diagnosis of coronavirus disease 2019.
Interventions:
None.
Measurements And Main Results:
Eighty-six patients were recruited, 44 (51%) with mild disease and 42 (49%) with severe disease. We measured levels of 10 cytokines/signaling proteins related to the most common therapeutic targets (granulocyte-macrophage colony-stimulating factor, interferon-α2a, interferon-β, interferon-γ, interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-7, interleukin-8, tumor necrosis factor-α), immunoglobulin G antibodies directed against either coronavirus disease 2019 spike protein or nucleocapsid protein, and neutralization titers of antibodies. Four-hundred seventy-seven randomized trials, including 168 different therapies against 83 different pathways, were identified. Six of the 10 markers (interleukin-6, interleukin-7, interleukin-8, interferon-α2a, interferon-β, interleukin-1 receptor antagonist) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or severe disease had detectable spike protein or nucleocapsid protein immunoglobulin G antibodies with equivalent levels between groups. Neutralization titers were higher among patients with severe disease.
Conclusions:
Some therapeutic and prognostic biomarkers may be useful in identifying coronavirus disease 2019 patients who may benefit from specific immunomodulatory therapies, particularly interleukin-6. However, biomarker absolute values often did not discriminate between patients with mild and severe disease or death, implying that these immunomodulatory treatments may be of limited benefit.
Insights
Biomarkers like interleukin-6 may help identify severe COVID-19 patients for immunomodulatory therapies. However, absolute biomarker levels often failed to distinguish mild from severe disease, suggesting limited treatment benefit.
Area of Science:
- Immunology
- Infectious Diseases
- Biomarker Research
Background:
- Multiple mechanisms are proposed for COVID-19 severity.
- Therapeutic strategies require a strong biological basis.
- Evaluating potential therapeutic targets is crucial for effective COVID-19 treatment.
Purpose of the Study:
- To assess if serum levels of proposed COVID-19 therapeutic targets differentiate between mild and severe disease.
- To investigate the association of early serum biomarkers with COVID-19 illness severity and outcomes.
Main Methods:
- Retrospective observational cohort study of hospitalized COVID-19 patients.
- Measured serum levels of 10 cytokines/signaling proteins and antibodies against SARS-CoV-2 spike and nucleocapsid proteins.
- Analyzed neutralization titers and correlated with clinical severity within the first 5 days of admission.
Main Results:
- Six of ten measured cytokines (IL-6, IL-7, IL-8, IFN-α2a, IFN-β, IL-1RA) distinguished between mild and severe COVID-19.
- Antibody levels against spike and nucleocapsid proteins were similar in mild and severe groups.
- Higher neutralization titers were observed in patients with severe COVID-19.
Conclusions:
- Certain biomarkers, notably IL-6, may identify COVID-19 patients who could benefit from immunomodulatory therapies.
- Absolute biomarker values often did not significantly discriminate between mild and severe disease or mortality.
- The findings suggest that immunomodulatory treatments may have limited efficacy based on these biomarkers.
