Identification of biomarkers for COVID-19 associated secondary hemophagocytic lymphohistiocytosis

• Published in: bioRxiv
• Main Authors: Canny, Susan P, Stanaway, Ian B, Holton, Sarah E, Mitchem, Mallorie, O'Rourke, Allison R, Pribitzer, Stephan, Baxter, Sarah K, Wurfel, Mark M, Malhotra, Uma, Buckner, Jane H, Bhatraju, Pavan K, Morrell, Eric D, Speake, Cate, Mikacenic, Carmen, Hamerman, Jessica A
• Format: Journal Article
• Language: English
• Published: United States 15.08.2024
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2024.08.13.607855

We aimed to define and validate novel biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system. In two cohorts of adult patients presenting with COVID-19 in 2020 and 2021, clinical lab values and serum proteomics were assessed. Subjects identified as having sHLH were compared to those with COVID-19 without sHLH. Eight deceased patients defined as COVID-sHLH underwent genomic sequencing in order to identify variants in immune-related genes. Two tertiary care hospitals in Seattle, Washington (Virginia Mason Medical Center and Harborview Medical Center). 186 patients with COVID-19. None. Nine percent of enrolled COVID-19 subjects met our defined criteria for sHLH. Using broad serum proteomic approaches (O-link and SomaScan), we identified three biomarkers for COVID-19 associated sHLH (soluble PD-L1, TNF-R1, and IL-18BP), supporting a role for proteins previously associated with other forms of sHLH (IL-18BP and sTNF-R1). We also identified novel biomarkers and pathways of COVID-sHLH, including sPD-L1 and the syntaxin pathway. We detected variants in several genes involved in immune responses in individuals with COVID-sHLH, including in and in , suggesting that genetic alterations in immune-related genes may contribute to hyperinflammation and fatal outcomes in COVID-19. Biomarkers of COVID-19 associated sHLH, such as soluble PD-L1, and pathways, such as the syntaxin pathway, and variants in immune genes in these individuals, suggest critical roles for the immune response in driving sHLH in the context of COVID-19. To define biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system. In two independent cohorts using two different platforms, we identified sPD-L1, IL-18BP, and sTNF-R1 as COVID-sHLH biomarkers. We identified the syntaxin pathway as important in COVID-sHLH and variants in immune-related genes in a subset of deceased COVID-sHLH subjects. Immune related proteins and pathways are dysregulated in COVID-sHLH.