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Secondary HLH is acquired and commonly triggered by malignancies, autoimmune diseases, or infections; Epstein-Barr virus is typical, whereas hepatitis C virus (HCV) is rarely reported. A 61-year-old man with untreated HCV presented with concern for septic shock, underwent extensive negative infectious evaluation, and met five of eight HLH-2004 criteria, improving after HLH-directed therapy. Rare fungal and mycobacterial signals were considered, yet the trigger was ultimately attributed to untreated HCV.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/a-complex-case-of-hemophagocytic-lymphohistiocytosis-secondary-to-untreated-hepatitis-c-diagnostic-challenges/416569/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/a-complex-case-of-hemophagocytic-lymphohistiocytosis-secondary-to-untreated-hepatitis-c-diagnostic-challenges/416569.png","ImageObject",300,407,{"name":92,"@type":93},"Mary Man","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-28",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is hemophagocytic lymphohistiocytosis (HLH) and why is it dangerous?","Question",{"text":112,"@type":113},"HLH is a rare, potentially life-threatening hyperinflammatory condition caused by overactivation of cytotoxic T cells, macrophages, and NK cells. It can lead to cytokine storm and organ damage.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How is HLH diagnosed using the HLH-2004 criteria?",{"text":117,"@type":113},"HLH is established either by a molecular diagnosis consistent with HLH or by meeting five of eight objective criteria. The eight criteria include fever, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low/absent NK activity, ferritin ≥ 500 µg/L, and soluble IL-2 receptor ≥ 2,400 U/L.",{"name":119,"@type":110,"acceptedAnswer":120},"Why was untreated hepatitis C identified as the trigger in this case?",{"text":121,"@type":113},"Despite multiple possible infectious findings during a broad workup, infectious results did not provide definitive pathogenic levels for the suspected rare organisms. HLH-directed therapy led to rapid fever resolution, and the causative trigger was ultimately attributed to the patient’s untreated HCV.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},416569,1790678199,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":24,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144,"preview_page_count":4},7421720224475,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Case Report J Hematol. 2025;14(6):324-328  \nA Complex Case of Hemophagocytic Lymphohistiocytosis Secondary to Untreated Hepatitis C: Diagnostic  \nChallenges  \nZachrieh Alhaja, c, Alexander Konopnickib, Zaid Almubaida, Khushali Royb,  \nThomas Leb, Paul S. Parkb  \nAbstract  \nHemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by uncontrolled activation of cytotoxic T cells and macrophages, leading to cytokine storm and organ failure. Secondary HLH is the acquired form that is commonly triggered by underlying malignancies, autoimmune diseases, or infections. While Epstein-Barr virus (EBV) is a common infectious trigger for HLH, hepatitis C virus (HCV) is rarely reported in the literature. Herein, we present the case of a patient with HLH with multiple possible infectious triggers that was ultimately attributed to HCV. A 61-year-old male with a history of untreated HCV was admitted with concerns for septic shock. Infectious workup was largely negative throughout his hospitalization. Lumbar puncture was concerning for a fungal meningitis, but fungal workup was negative except for a positive Blastomyces dermatitidis antibody. In addition, acid-fast bacilli culture eventually grew Mycobacterium porcinum (M. porcinum) . He was treated with broad-spectrum antibiotics and anti-fungals but continued to fever. He met five of eight criteria per HLH-2004 protocol and was initiated on HLH-directed therapy with immediate resolution of his fevers. A Karius test did not identify pathogenic levels of Blastomyces dermatitidis or M. porcinum in the serum, and the causative trigger was determined to be his untreated HCV. This case highlights the importance of early recognition and treatment of HLH in a patient with fever of unknown origin. It brings attention to HCV as a highly unusual trigger of HLH. It also illustrates the difficulty in addressing the underlying source of secondary HLH when a broad infectious workup yields several rare but possible pathogens.  \nKeywords: HLH-2004; HLH; HCV; Cytokine; Immune-mediated inflammatory disease  \nManuscript submitted June 12, 2025, accepted August 14, 2025  \nPublished online December 30, 2025  \naJohn Sealy School of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA  \nbDepartment of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA  \ncCorresponding Author: ZachriehAlhaj, John Sealy School of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.  \nEmail: [ztalhaj@utmb.edu](ztalhaj@utmb.edu)  \ndoi: [https://doi.org/10.14740/jh2101](https://doi.org/10.14740/jh2101)  \nIntroduction  \nHemophagocytic lymphohistiocytosis (HLH) is a rare, potentially life-threatening hyperinflammatory condition caused by the overactivation of cytotoxic T cells, macrophages, and natural killer (NK) cells, which can lead to a cytokine storm and ultimately organ damage [1] .  \nHLH can be classified into primary or secondary HLH. Primary, or familial, HLH involves genetic mutations such as PRF1, UNC13D, STXBP2, which affect the cytotoxic activation ofT lymphocytes, leading to unregulated activation. Secondary, or acquired, HLH occurs with an underlying trigger such as infection, autoimmune diseases, and malignancies [2, 3]. Among secondary causes, the most common are due to malignancies, accounting for 42% of secondary HLH cases [4, 5] . The next most common cause is autoimmune conditions, which account for 40.9% of cases according to a Chinese cohort, and is often associated with systemic juvenile idiopathic arthritis and adult-onset Still’s disease [6] . Infections can also be a common trigger, with Epstein-Barr virus (EBV) seen in 69% of secondary HLH due to infections, and less commonly cytomegalovirus (CMV) [5] .  \nHLH clinically presents as persistently high fevers, cytopenias, hepatosplenomegaly, and may sometimes include neurologic and hepatologic dysfunction. The Histiocyte Society developed the HLH-2004 criteria ","cbCaifPuqWJop4T9","https://ap.wps.com/l/cbCaifPuqWJop4T9","pdf",633630,"English","# Introduction\n## HLH classification and diagnostic framework (HLH-2004)\n## Secondary HLH triggers and clinical presentation\n## Treatment principles for HLH and secondary HLH\n# Case presentation and diagnostic challenges\n## Infectious workup and evolving microbiologic findings\n## Application of HLH-2004 criteria and HLH-directed therapy\n## Identification of untreated HCV as the trigger","[{\"question\":\"What is hemophagocytic lymphohistiocytosis (HLH) and why is it dangerous?\",\"answer\":\"HLH is a rare, potentially life-threatening hyperinflammatory condition caused by overactivation of cytotoxic T cells, macrophages, and NK cells. It can lead to cytokine storm and organ damage.\"},{\"question\":\"How is HLH diagnosed using the HLH-2004 criteria?\",\"answer\":\"HLH is established either by a molecular diagnosis consistent with HLH or by meeting five of eight objective criteria. The eight criteria include fever, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low/absent NK activity, ferritin ≥ 500 µg/L, and soluble IL-2 receptor ≥ 2,400 U/L.\"},{\"question\":\"Why was untreated hepatitis C identified as the trigger in this case?\",\"answer\":\"Despite multiple possible infectious findings during a broad workup, infectious results did not provide definitive pathogenic levels for the suspected rare organisms. HLH-directed therapy led to rapid fever resolution, and the causative trigger was ultimately attributed to the patient’s untreated HCV.\"}]","A Complex Case of Hemophagocytic Lymphohistiocytosis Secondary to Untreated Hepatitis C - Diagnostic Challenges | PDF",1790605886,13]