Cytokine Storm Syndrome in COVID-19

Cytokine Storm Syndrome in COVID-19

Introduction

• COVID-19 research focuses on combating cytokine storm syndrome in addition to antiviral treatments.
• A subgroup of patients exhibits cytokine storm signs, including elevated cytokine profiles and respiratory failure from acute respiratory distress syndrome (ARDS).

Immune Response in COVID-19

• Early studies suggest a two-faced immune response:
  • Moderate cases: Immune cells eliminate the virus, producing inflammatory cytokines. Stimulating the immune response may be beneficial.
  • Severe cases: Patients exhibit hyper-inflammation with very high cytokine levels. Lungs may be damaged, leading to ARDS, a leading cause of mortality.

Viral Load and Systemic Inflammation

• High viral load can persist in the lungs of patients with severe respiratory symptoms.
• Extreme inflammation can release cytokines into circulation, affecting secondary organs even as viral load decreases.
• The heart may be affected by systemic inflammation, leading to myocarditis even without the virus present in the heart.

Origin and Causes of Cytokine Storm

• The origin of cytokines in SARS-CoV-2 related cytokine storm syndrome is not fully determined.
• Severe SARS-CoV-2 infection is associated with lymphopenia (severe loss of lymphocytes in the blood), suggesting that cytokines are released by non-T-cell leukocytes like inflammatory macrophages.
• Levels of cytokines such as IL-6, IL-10, and tumor necrosis factor-alpha are inversely correlated with T-cell counts.
• High levels of IL-6 can suppress T-cell activation, contributing to low T-cell counts.
• Cytokine storm theory involves rapid viral replication leading to wide-scale cell pyroptosis (inflammatory apoptosis).
• Pyroptosis recruits macrophages to the lungs, amplifying the inflammatory response.

Specific Cytokines Involved

• Studies comparing cytokine levels in uninfected individuals, patients with moderate symptoms, and patients with severe symptoms found that increased levels of IL-6, IL-10, tumor necrosis factor-alpha, and soluble IL-2 receptor are correlated with disease severity.
• A study examining patients with pneumonia found that IL-2, IL-7, G-CSF, IP-10, MCP-1, and MIP-1 alpha were elevated in ICU patients.
• Decreased production of interferon-alpha (a key antiviral cytokine) by T cells may indicate that the cytokine storm dampens the T-cell adaptive immune response.

Cytokine Profiling and Therapies

• Cytokine storm syndrome is disease and cell type-specific, making cytokine profiling essential.
• Quantifying inflammatory cytokines in serum or bronchoalveolar lavage fluid can help understand involved pathways.
• Multiplexing multiple cytokines in a single assay is critical for screening with small sample volumes and short turnaround times.
• LegendPlex kits can measure up to 13 targets simultaneously using a flow cytometer.
• Treatment may not be as simple as using a broad anti-inflammatory drug, as it may impair the patient's ability to eliminate the viral pathogen in the early stages of the disease.

Targeted Treatments

• Understanding the exact cytokines involved is important for developing treatments.
  • For example, since we know that IL-6 is elevated in patients with severe lung disease, using a specific IL-6 inhibitor may help to fight off the cytokine storm without widespread effects on the immune system.
• Understanding SARS-CoV-2 associated cytokine storm syndrome is a major hurdle in treating the disease, because cytokine storm varies between diseases.
• We must first characterize the cytokines involved and at what stage of the disease blocking them may be effective.

Conclusion

• A subset of COVID-19 patients experiences cytokine storm syndrome with elevated inflammatory cytokine levels in the lungs, leading to tissue damage.
• Multiplex assays like LegendPlex can quantitate the factors made in response to SARS-CoV-2 infection.
• Elevated levels of IL-6, IL-10, tumor necrosis factor-alpha, and soluble IL-2 receptor are present in patients with severe symptoms.