{"doi":"10.1101/2024.08.13.607855","title":"Identification of biomarkers for COVID-19 associated secondary hemophagocytic lymphohistiocytosis","abstract":"Abstract OBJECTIVES 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. DESIGN 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. SETTING Two tertiary care hospitals in Seattle, Washington (Virginia Mason Medical Center and Harborview Medical Center). PATIENTS 186 patients with COVID-19 INTERVENTIONS None MEASUREMENTS AND MAIN RESULTS 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 DOCK8 and in TMPRSS15 , suggesting that genetic alterations in immune-related genes may contribute to hyperinflammation and fatal outcomes in COVID-19. CONCLUSIONS 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. Key Points QUESTION 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. FINDINGS 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. MEANING Immune related proteins and pathways are dysregulated in COVID-sHLH.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":487265,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.953,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":279183,"name":"Ian B. Stanaway","orcid":"0000-0002-0783-0918","position":1,"is_corresponding":false},{"id":442159,"name":"Sarah E. Holton","orcid":"0000-0002-6373-3768","position":2,"is_corresponding":false},{"id":1054396,"name":"Mallorie Mitchem","orcid":null,"position":3,"is_corresponding":false},{"id":468773,"name":"Allison R. O’Rourke","orcid":null,"position":4,"is_corresponding":false},{"id":499822,"name":"Stephan Pribitzer","orcid":"0000-0003-4124-0484","position":5,"is_corresponding":false},{"id":1028484,"name":"Sarah K. Baxter","orcid":"0000-0002-3097-3212","position":6,"is_corresponding":false},{"id":253256,"name":"Mark M. Wurfel","orcid":null,"position":7,"is_corresponding":false},{"id":432349,"name":"Uma Malhotra","orcid":"0000-0003-0132-0885","position":8,"is_corresponding":false},{"id":226226,"name":"Jane H. Buckner","orcid":"0000-0002-9005-1885","position":9,"is_corresponding":false},{"id":249666,"name":"Pavan K. Bhatraju","orcid":"0000-0002-2606-4366","position":10,"is_corresponding":false},{"id":305235,"name":"Eric D. Morrell","orcid":"0000-0001-9900-3604","position":11,"is_corresponding":false},{"id":271012,"name":"Cate Speake","orcid":"0000-0003-1480-4272","position":12,"is_corresponding":false},{"id":305239,"name":"Carmen Mikacenic","orcid":"0000-0001-8966-5161","position":13,"is_corresponding":false},{"id":108914,"name":"Jessica A. Hamerman","orcid":"0000-0001-5864-5299","position":14,"is_corresponding":false},{"id":655396,"name":"Susan Canny","orcid":"0000-0002-1762-6718","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T02:08:06.013846Z","pmid":"39185173","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}