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Published on: October 19, 2014
Proteomic Analyses in COVID-19-Associated Secondary Hemophagocytic Lymphohistiocytosis
Susan P Canny1,2, Ian B Stanaway3, Sarah E Holton4,5
1Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA.
Insights
COVID-19 patients can develop secondary hemophagocytic lymphohistiocytosis (sHLH). Specific proteins like soluble PD-L1 and immune pathway alterations are linked to severe COVID-19 and fatal outcomes in sHLH.
Area of Science:
- Immunology
- Virology
- Genetics
Background:
- COVID-19 can trigger a cytokine storm, resembling secondary hemophagocytic lymphohistiocytosis (sHLH).
- Understanding the molecular mechanisms of COVID-19-associated sHLH is crucial for patient outcomes.
Purpose of the Study:
- To investigate proteins associated with sHLH in COVID-19 patients.
- To identify immune-related pathway defects in fatal COVID-19 cases with sHLH.
Main Methods:
- Observational study of adult COVID-19 patients (n=264) with and without sHLH.
- Plasma proteomics (O-link, SomaScan) and genomic sequencing of deceased patients.
Main Results:
- 24 patients (9%) met sHLH criteria.
- Elevated levels of soluble PD-L1, tumor necrosis factor-R1, and IL-18BP identified in COVID-19-associated sHLH.
- Pathogenic variants in DOCK8 and TMPRSS15 found in fatal cases.
Conclusions:
- Increased sPD-L1 and syntaxin pathway involvement suggest a key immune response role in COVID-19-associated sHLH.
- Immune-related genetic alterations may contribute to hyperinflammation and mortality in severe COVID-19.
Context:
COVID-19 has been associated with features of a cytokine storm syndrome with some patients sharing features with the hyperinflammatory disorder, secondary hemophagocytic lymphohistiocytosis (sHLH).
Hypothesis:
We hypothesized that proteins associated with sHLH from other causes will be associated with COVID-sHLH and that subjects with fatal COVID-sHLH would have defects in immune-related pathways.
Methods And Models:
We identified two cohorts of adult patients presenting with COVID-19 at two tertiary care hospitals in Seattle, Washington in 2020 and 2021. In this observational study, we assessed clinical laboratory values and plasma proteomics. Subjects identified as having sHLH (ferritin > 1000 plus cytopenias in two or more lineages [WBC < 5000 odds ratio [OR] ANC (absolute neutrophil count) < 1000, hemoglobin < 9 or hematocrit < 27, platelets < 100,000], and elevated transaminases [either AST (aspartate aminotransferase) or ALT (alanine aminotransferase) > 30] OR subjects with a ferritin > 3000) were compared with those with COVID-19 without sHLH. We identified 264 patients with COVID-19 of whom 24 met our sHLH definition. Eight patients who died of COVID-sHLH underwent genomic sequencing to identify variants in immune-related genes.
Results:
Nine percent of enrolled COVID-19 subjects met our defined criteria for sHLH (n = 24/264). Using broad serum proteomic approaches (O-link and SomaScan), we identified three proteins increased in subjects with COVID-19-associated sHLH (soluble PD-L1 [sPD-L1], tumor necrosis factor-R1, and interleukin [IL]-18BP, p < 0.05 for O-link and false discovery rate < 0.05 for SomaScan), supporting a role for proteins previously associated with other forms of sHLH (IL-18BP and soluble tumor necrosis factor receptor 1). We also identified candidate proteins and pathways associated with COVID-sHLH, including sPD-L1 and the syntaxin pathway. We detected pathogenic variants in DOCK8 and TMPRSS15 in deceased individuals with COVID-sHLH, further suggesting that alterations in immune-related processes may contribute to hyperinflammation and fatal outcomes in COVID-19.
Interpretations And Conclusions:
Proteins increased in COVID-19-associated sHLH, such as sPD-L1, and pathways, such as the syntaxin pathway, suggest important roles for the immune response in driving sHLH in the context of COVID-19.
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