Capturing the Cytokine Storm: Using Biomarkers in COVID-19 Trials
By Sumit Kar, Lead Scientist – Biomarkers, Celerion
Cytokine biomarkers are released in the body after SARS-CoV-2 viral particles are presented by antigen presenting cells initiating a cytokine storm.1 Cytokine storm, known clinically as haemophagocytic lymphohistiocytosis or cytokine release syndrome, is mostly seen after viral infections, and leads to constant fever, increased ferritin, and multi-organ failure including acute respiratory distress syndrome (ARDS). For this reason, anti-inflammatory drugs, such as some targeting IL-6, are being tested as therapies for COVID-19 to prevent ARDS, the most common reason for fatality in patients suffering from COVID-19.
SARS-CoV-2 studies show alterations in serum IL-2, IL-6, IL-7, granulocyte-colony stimulating factor, IP-10, MCP-1, MIP1-α, and TNF-α, which are positively correlated with COVID-19 disease severity.1 The exact cytokine profile varies between studies. In previous viral challenge trials with neutralizing antibody therapies (e.g. for influenza), only IP-10 and IFN-g were reduced after drug dosing.2 The specific cytokines needed for SARS-COV-2 trials are yet to be well-characterized. Therefore, larger multiplex panels measuring several markers together are recommended for speed – especially those that are well characterized for reliability (e.g. Meso Scale Discovery® (MSD) V-Plex Assays).
Use Cases of Cytokines for COVID-19 Clinical Trials
These cytokine biomarkers can be monitored in SARS-COV-2 trials for vaccines, antivirals, and antibody therapies. Cytokines can be measured for patient enrollment, mechanism of action, and treatment effect contexts of use. For example, drugs trying to prevent ARDS should measure cytokines as a secondary endpoint and to show their mechanism of action. At Celerion, we validate all biomarkers fit-for-purpose based on their context of use in the study following the latest regulatory guidelines.
Celerion’s Cytokine Assays
At Celerion, we have validated MSD Cytokine Panels with up to 10 cytokines and chemokines for quantification via automated electrochemiluminescence (ECL). The panels can be custom designed according to need while maintaining the performance of the assay.
| Celerion MSD Validated Cytokine Panels (human serum) |
| Panel 1: IFN-g, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-a |
| Panel 2: Eotaxin, Eotaxin-3, IL-8, IP-10, MCP-1, MCP-4, MDC, MIP-1a, MIP-1b, TARC |
| Panel 3: GM-CSF, IL-12/IL-23p40, IL-15, IL-16, IL-17A, IL-1α, IL-5, IL-7, TNF-β, VEGF-A |
Exploring Cytokine Profiles in other Matrices
Respiratory specific matrices (i.e., bronchoalveolar lavage fluid (BALF), sputum and saliva) can be a reservoir of cytokine upregulation upon viral exposure via inhalation.3 Celerion has extensive experience measuring biomarkers in these respiratory matrices using the latest technology, which quantitates cytokines at ultra-low concentrations via Quanterix® Simoa and MSD S-Plex platforms.
References
1. Mehta P, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet. 396(10229), 2020
2. McBride JM, Lim JJ, Burgess T, Deng R, Derby MA, Maia M, Horn P, Siddiqui O, Sheinson D, Chen-Harris H, Newton EM, Fillos D, Nazzal D, Rosenberger CM, Ohlson MB, Lambkin-Williams R, Fathi H, Harris JM, Tavel JA. Phase 2 randomized trial of the safety and efficacy of MHAA4549A, a broadly neutralizing monoclonal antibody, in a human influenza a virus challenge model. Antimicrob Agents Chemother 61:e01154-17, 2017
3. Horiuchi T, et al. Biomarker profiles of BALF in ALI/ARDS due to pandemic (H1N1) 2009 influenza. European Respiratory Journal. 38 (Suppl 55), 2017
Acknowledgements
Special thank you to Celerion scientists Curtis Sheldon, Amanda Daugherty, and Aernout van Haarst for their editorial assistance.