Fatal Hemophagocytic Lymphohistiocytosis Triggered by Incompletely Treated Brucellosis: A Case Report and Warning from an Endemic Region

Fatal Hemophagocytic Lymphohistiocytosis Triggered by Incompletely Treated Brucellosis: A Case Report and Warning from an Endemic Region | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Fatal Hemophagocytic Lymphohistiocytosis Triggered by Incompletely Treated Brucellosis: A Case Report and Warning from an Endemic Region Nahal Khoshdel, Shahram Sabeti, Ronak Nalini, Seyed Hamid Hosseini, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8338379/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Background: Brucellosis, a common zoonosis in endemic areas, can rarely precipitate the life-threatening hyperinflammatory syndrome, hemophagocytic lymphohistiocytosis (HLH). This complication carries a high mortality rate, especially when diagnosis and treatment are delayed. Case Presentation: A 75-year-old male farmer from a brucellosis-endemic region in Iran presented with hematochezia, fever, weight loss, and pancytopenia. He had been diagnosed with active brucellosis 40 days prior but discontinued antibiotic therapy after four weeks. During hospitalization, he developed progressive cytopenias, hyperferritinemia (6,022 ng/mL), hypertriglyceridemia, and splenomegaly. A bone marrow biopsy confirmed hemophagocytosis, leading to a diagnosis of secondary HLH. Despite initiating treatment per HLH-2004 protocols with corticosteroids, etoposide, and intravenous immunoglobulin, his condition deteriorated rapidly. He developed altered mental status, required intubation, and succumbed to the illness. Conclusion: This case underscores brucellosis as a potential trigger for HLH. It highlights the critical importance of ensuring complete treatment for brucellosis and maintaining a high index of suspicion for HLH in patients with persistent fever, cytopenias, and hepatosplenomegaly, even in the context of a known infection. Early, aggressive immunomodulatory therapy alongside appropriate antimicrobials is essential, though outcomes can remain poor, particularly in elderly patients. Hemophagocytic Lymphohistiocytosis (HLH) Brucellosis Infection-associated HLH Figures Figure 1 Figure 2 Figure 3 Introduction Brucellosis remains a major zoonotic infection in endemic regions transmitted primarily through unpasteurized dairy products or direct contact with infected animals. The disease exhibits a wide clinical spectrum, ranging from mild episodic fever to severe multisystem involvement ( 1 ). Although hematologic abnormalities such as anemia and leukopenia are relatively common, hemophagocytic lymphohistiocytosis (HLH) secondary to brucellosis is rare and potentially life-threatening ( 2 ). HLH represents a hyperinflammatory syndrome characterized by uncontrolled activation of macrophages and cytotoxic T cells, leading to cytokine storm, cytopenia, and multi-organ dysfunction ( 3 ). Early detection and treatment are essential, as delayed diagnosis can result in fatal outcomes. We report a fatal case of HLH complicating incompletely treated brucellosis in a 75-year-old man from an endemic area of Iran. This case underscores the lethal potential of this complication and illustrates that even aggressive immunomodulatory therapy may fail without prompt immune control of the underlying trigger. Case Presentation Clinical Presentation A 75-year-old male from northwest Iran, a region endemic for brucellosis, presented to our hospital with hematochezia a day prior to admission. The patient presented a history of knee pain and a notable weight loss of approximately 20 kilograms over the past two months. Additionally, the patient reported malaise, intermittent episodes of fever accompanied by chills, and nausea and vomiting over the past month. Approximately 40 days prior to admission, given his chronic knee pain, high risk occupation as a farmer and residence in a brucellosis-endemic area, serological testing for brucellosis was performed. Serological testing for Brucella species revealed a standard tube agglutination (Wright) titer of 1:128, Coombs Wright test titer of 1:256, and a 2-mercaptoethanol (2ME) test titer of 1:128. These values are consistent with active brucellosis infection, particularly in the clinical context of endemic exposure and symptomatology and excluding other differential diagnosis. The patient received doxycycline and rifampin which palliated his joint pain but stopped taking his medications after less than 4 weeks due to gastrointestinal adverse reactions, not completing the treatment. A week prior to admission the patient visited another hospital in his hometown due to nausea and vomiting and was admitted for 3 days. The endoscopy revealed erythematous gastritis without evidence of ulceration, bleeding or other abnormalities. He was given pantoprazole and domperidone and discharged. Upon admission, the laboratory tests revealed that the patient had iron deficiency anemia, hypoalbuminemia, hematuria, hypokalemia and elevated levels of C-reactive protein, alkaline phosphatase, direct and total bilirubin and during the hospitalization the patient developed pancytopenia, increased levels of liver enzymes, hypertriglyceridemia and hyperferritinemia (Table 1 ). Table 1 Major laboratory test results of the patient during hospitalization. Upon admission At the time of diagnosis After treatment Normal range Unit HGB 8.9 9 7.9 13.5–17.5 g/dL WBC 4.9 9.6 1.3 4.5–11 ×10 3 /µL PLT count 177 72 63 150–450 ×10 3 /µL Albumin 2.2 1.8 2.6 3.5–5.3 g/dL Alkaline phosphatase 382 610 688 80–306 U/L Aspartate aminotransferase 28 43 87 Up to 43 U/L Alanine aminotransferase 17 15 32 Up to 40 U/L TG - 300 - < 150 mg/dL Ferritin - 6022 - 20–300 µg/L Total bilirubin 2 4.2 5.3 0.1–1.2 mg/dL Direct bilirubin 1.4 3.3 2.8 < 0.3 mg/dL LDH 1312 1774 1163 Up to 350 U/L WBC, white blood cell; HGB, hemoglobin; PLT, platelet; TG, triglycerides; LDH, Lactate dehydrogenase He was first admitted to gastroenterology ward for workup on his hematochezia and later moved to infectious disease ward due to possibility of his complications being related to his untreated brucellosis. There was no history of tuberculosis, blood transfusions, alcohol consumption, smoking or other relevant factors. Additionally, there was no family history of similar conditions. Diagnostics and examinations On admission, neck ultrasonography revealed oval-shaped lymph nodes in bilateral jugular chains, some having preserved hila and others showing cortical thickening, with a maximum short-axis diameter of 8mm on the right side. During the evaluation minimal perihepatic fluid and periportal cuffing, also splenomegaly (a span of 160mm was reported) and peri-splenic fluid was seen as well mild to moderate pleural effusion was seen on the left side. A later CT scan confirmed sonographic findings including splenomegaly, also reporting moderate ascites, enhancement of peritoneum, pleural effusion on both sides with the left side being dominant, a simple kidney cyst, and paraaortic lymphadenopathy (Fig. 1 ). Signs of disc space narrowing and degenerative changes in spine was seen which was later confirmed by MRI in L3-L5 (Fig. 2 ). The patient underwent endoscopy and colonoscopy in gastrointestinal disease ward but no abnormalities that could explain iron deficiency anemia was found. He received gentamicin, rifampin and doxycycline for brucellosis and was transferred to the infectious disease ward 8 days after admission as there was no gastrointestinal finding that could justify the patient’s symptoms. Upon admission to infectious disease ward, the patient was ill-looking and complained of episodes of fever and chills. He barely tolerated oral intake due to nausea and appeared cachectic. Laboratory investigations revealed hypertriglyceridemia and elevated ferritin levels. These findings, meeting several HLH-2004 criteria (fever, splenomegaly, bi-cytopenia, hyperferritinemia, and hypertriglyceridemia), raised strong suspicion for HLH. Bone marrow biopsy was performed which further confirmed the diagnosis (Fig. 3 ). Initially the patient was initiated on corticosteroid therapy following the diagnosis which led to transient clinical improvement. However, his condition subsequently deteriorated; his mental status started to alter, leading to disorientation and confusion, and his pleural effusion worsened as well, leading to intensive care unit admission and a switch to etoposide which yielded minimal response. The patient received two doses of etoposide 100 mg on days 14 and 18 after admission. G-CSF was administered to help with his leukopenia. The patient was given multiple transfusions of packed red blood cells (PRBCs), platelets, and fresh frozen plasma (FFP) during hospitalization to help treat his symptoms. As a last resort, he received intravenous immunoglobin (IVIG). During this time, he developed rapid atrial fibrillation and a significant decrease in Glasgow Coma Scale (GCS) score, necessitating intubation. Despite aggressive supportive measures, the patient ultimately expired Discussion Our case illustrates a tragic but instructive sequence: incomplete treatment of a common endemic infection leading to a catastrophic hyperinflammatory syndrome that proved unresponsive to standard HLH therapy. Brucellosis-associated HLH is a rare but life-threatening complication, with few cases reported worldwide. The pathophysiology involves persistent antigenic stimulation by Brucella organisms, leading to excessive activation of immune system and hemophagocytosis. This hyperinflammatory state can be triggered by untreated, relapsed, or inadequately treated infection, as in our patient who did not complete his antibiotic regimen. The clinical presentation of HLH overlaps with brucellosis itself, including fever, hepatosplenomegaly, cytopenia, and elevated liver enzymes, which can mask the diagnosis ( 2 , 4 ). Laboratory evaluation using the HLH-2004 criteria including cytopenia in ≥ 2 lineages, hyperferritinemia, hypertriglyceridemia, and demonstration of hemophagocytosis in bone marrow is indeed essential for accurate identification but may delay the diagnosis as some features, such as hypertriglyceridemia or hemophagocytosis, develop over days ( 5 ). In this patient, the initial workup for hematochezia delayed the recognition of the systematic inflammatory process as some of the symptoms were contributed to GI blood loss and severe anemia; progressive loss of consciousness was a prominent early indicator of severe HLH, emphasizing the need for treatment based on clinical suspicion rather than relying solely on HLH-2004 criteria. The management of our patient was further complicated by the lack of high-quality evidence, forcing clinicians to rely on protocols (HLH-94/2004) designed for familial HLH, which may not be optimal for all cases of secondary, infection-driven HLH. HLH can occur secondary to a wide range of infections, with viral triggers being the most frequent. Epstein–Barr virus (EBV) remains the most common cause worldwide, often associated with severe and rapidly progressive disease. Other viral agents such as cytomegalovirus (CMV), herpes simplex virus (HSV), human immunodeficiency virus (HIV), influenza, and SARS-CoV-2 have also been implicated ( 6 ). Among bacterial infections, Mycobacterium tuberculosis , Brucella spp., and Salmonella species are the most frequently reported triggers. Parasitic and fungal infections are also recognized causes, particularly in immunocompromised individuals ( 7 , 8 ). A recent adult review found only a few published cases of brucellosis-associated HLH to date, underscoring the extreme rarity of this complication ( 2 ). Although the documented cases are few, this might be due to overlapping manifestations of HLH and other complications secondary to brucellosis, especially in endemic areas where the number of cases is high but they remain either underreported or the symptoms remain attributed to brucellosis itself ( 9 , 10 ). The rarity of this complication can’t be a reason to underestimate it as HLH can be fatal especially to the elderly population. A 2019 literature review reported an overall mortality of 62% in patients > 50 years old who were diagnosed with acquired HLH ( 11 ). The pathophysiology is believed to involve excessive immune activation and cytokine release due to uncontrolled infection-driven macrophage and T-cell stimulation ( 3 ). Recognizing HLH in the context of infection is challenging, as symptoms often overlap with sepsis; however, persistence of fever, cytopenia, hepatosplenomegaly, and hyperferritinemia despite appropriate antimicrobial therapy should raise suspicion for infection-associated HLH ( 12 ). Management of HLH secondary to brucellosis is particularly challenging. Immunosuppressive therapy required for HLH may exacerbate the underlying infection, while antibiotics for brucellosis can induce cytopenias and hepatotoxicity, further complicating disease course ( 12 , 13 ). In this patient, corticosteroids provided only transient improvement, etoposide showed minimal response, and IVIG was used as salvage therapy, highlighting the difficulty of treatment and poor prognosis in severe, multi-organ disease. Despite recognition of HLH and initiation of appropriate therapy, the disease can progress rapidly and be fatal, particularly in elderly patients or those with comorbidities ( 11 ). Our patient’s course emphasizes the importance of early suspicion and aggressive management, including complete and timely antimicrobial therapy, with consideration of immunomodulatory treatment in severe cases. One of the major challenges in advancing the management of hemophagocytic lymphohistiocytosis (HLH) is the lack of randomized clinical trials. Because HLH is a rapidly progressive and often fatal condition, withholding potentially life-saving treatment for the purpose of randomization raises serious ethical concerns. As a result, most available data on therapeutic strategies such as corticosteroids, etoposide, cyclosporine, and intravenous immunoglobulin (IVIG) come from retrospective analyses, case reports, and small case series rather than controlled trials ( 5 ). This limitation makes it difficult to establish standardized treatment protocols or to evaluate the comparative effectiveness and safety of newer therapeutic agents. Consequently, management decisions often rely on clinical judgment, disease severity, and individual response rather than robust evidence-based guidelines. Conclusion This fatal case underscores that hemophagocytic lymphohistiocytosis is a critical and often missed complication of brucellosis. It serves as a critical reminder for clinicians in endemic regions that in a patient with known infection, the emergence of persistent fever, cytopenias, and hepatosplenomegaly should immediately raise the alarm for secondary HLH. While early, aggressive immunomodulatory therapy is essential, this case clearly illustrates that its success is entirely contingent on the simultaneous and definitive control of the underlying infectious trigger. Ultimately, the most effective strategy remains prevention through ensuring complete adherence to appropriate antimicrobial regimens, as the prognosis of established HLH, particularly in the elderly, remains devastatingly poor. Future efforts must focus on rapid diagnostic algorithms and novel therapies that can more effectively quell the cytokine storm without compromising infection control. Abbreviations 2ME 2-mercaptoethanol ALT Alanine aminotransferase AST Aspartate aminotransferase CMV Cytomegalovirus Coombs Coombs Wright test CT Computed tomography EBV Epstein–Barr virus FFP Fresh frozen plasma G-CSF Granulocyte-colony stimulating factor GCS Glasgow Coma Scale HLH Hemophagocytic lymphohistiocytosis HIV Human immunodeficiency virus HSV Herpes simplex virus IVIG Intravenous immunoglobulin MRI Magnetic resonance imaging PRBC Packed red blood cells WBC White blood cell Declarations Ethics approval and consent to participate: This case report was approved by the Ethics Committee of Shahid Beheshti University of Medical Sciences and was conducted in accordance with the principles of the Declaration of Helsinki. Consent for publication Written informed consent for publication of this case report and accompanying clinical details was obtained from the patient’s legal representative. Availability of data and materials Available upon request. Competing interests The authors declare that they have no competing interests. Funding No funding was received for this work. Authors’ contributions Clinical evaluation and disease management: IAD, RN, AT, and SHH were involved in the clinical assessment, diagnostic evaluation, and management of the patient. Pathology assessment: SS reviewed and interpreted the bone marrow pathology and confirmed hemophagocytosis. Data collection and information retrieval: NK and SHH collected clinical data, laboratory information, and relevant patient details. NK performed the literature review and retrieved supporting evidence for the manuscript. Manuscript drafting and editing: NK prepared the initial draft of the manuscript. IAD critically reviewed the manuscript and provided major revisions. SS, RN, and AT reviewed the manuscript and contributed to editing and refinement. Conceptualization and supervision: IAD conceptualized the report, supervised all stages of manuscript preparation, and approved the final version. All authors read and approved the final manuscript. Acknowledgements The authors extend their gratitude to the Clinical Research Development Unit at Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences in Tehran, Iran, for their invaluable assistance and support throughout this study. Clinical trial registration Not applicable. References Bergsten E, Horne A, Aricó M, Astigarraga I, Egeler RM, Filipovich AH, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728-38. Shi L, Wang B, Peng D, Zhang K, Wang Y. Brucella-associated hemophagocytic syndrome: case report of a potentially life-threatening condition and literature review. Front Immunol. 2025;16:1592089. Wu Y, Sun X, Kang K, Yang Y, Li H, Zhao A, Niu T. Hemophagocytic lymphohistiocytosis: current treatment advances, emerging targeted therapy and underlying mechanisms. J Hematol Oncol. 2024;17(1):106. Jiang S, Xia B, Wu H, Zhang P, Li X, Zhang K. Brucellosis-associated hemophagocytic lymphohistiocytosis: a case report and literature review. Front Med (Lausanne). 2025;12:1609644. La Rosée P, Horne A, Hines M, von Bahr Greenwood T, Machowicz R, Berliner N, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465-77. Imashuku S, Morimoto A, Ishii E. Virus-triggered secondary hemophagocytic lymphohistiocytosis. Acta Paediatr. 2021;110(10):2729-36. Chiu CY, Hicklen RS, Kontoyiannis DP. Fungal-Induced Hemophagocytic Lymphohistiocytosis: A Literature Review in Non-HIV Populations. J Fungi (Basel). 2025;11(2). Chesshyre E, Ramanan AV, Roderick MR. Hemophagocytic Lymphohistiocytosis and Infections: An Update. The Pediatric Infectious Disease Journal. 2019;38(3):e54-e6. Park D, Yoon K, Lo A, Bolos D. Hemophagocytic Lymphohistiocytosis Induced by Brucellosis: A Case Report. Cureus. 2024;16(7):e64287. Fernandez-Georges IK, Manalo SM, Arede M, Ciaravino G, Beltrán-Alcrudo D, Casal J, et al. Ruminant and human brucellosis situation in Türkiye and the Caucasus. Trop Anim Health Prod. 2025;57(6):296. Altook R, Ruzieh M, Singh A, Alamoudi W, Moussa Z, Alim H, et al. Hemophagocytic Lymphohistiocytosis in the Elderly. Am J Med Sci. 2019;357(1):67-74. Eslami A, Alimoghadam S, Khodadadi S, Allahverdi H, Alimoghadam R, Kasaeian A, et al. Comprehensive insights into tuberculosis-associated hemophagocytic lymphohistiocytosis: a systematic review. BMC Infectious Diseases. 2024;24(1):1341. Huang S, Wang H, Li F, Du L, Fan W, Zhao M, et al. Better efficacy of triple antibiotics therapy for human brucellosis: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2023;17(9):e0011590. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 24 Feb, 2026 Reviews received at journal 24 Feb, 2026 Reviews received at journal 22 Feb, 2026 Reviewers agreed at journal 12 Feb, 2026 Reviewers agreed at journal 11 Feb, 2026 Reviewers agreed at journal 10 Feb, 2026 Reviews received at journal 10 Feb, 2026 Reviewers agreed at journal 10 Feb, 2026 Reviewers agreed at journal 10 Feb, 2026 Reviewers invited by journal 10 Feb, 2026 Editor assigned by journal 22 Dec, 2025 Submission checks completed at journal 22 Dec, 2025 First submitted to journal 11 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8338379","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":591663608,"identity":"0d8ba0b3-7b5e-4cfb-8b22-ad7de2b18b5a","order_by":0,"name":"Nahal Khoshdel","email":"","orcid":"","institution":"Shahid Beheshti University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Nahal","middleName":"","lastName":"Khoshdel","suffix":""},{"id":591663609,"identity":"babe3194-3d44-47f4-bee2-a4a9bb16f2e4","order_by":1,"name":"Shahram Sabeti","email":"","orcid":"","institution":"Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences Tehran","correspondingAuthor":false,"prefix":"","firstName":"Shahram","middleName":"","lastName":"Sabeti","suffix":""},{"id":591663610,"identity":"9c73ee26-8dca-49a6-a838-3e8b8aff8111","order_by":2,"name":"Ronak Nalini","email":"","orcid":"","institution":"Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ronak","middleName":"","lastName":"Nalini","suffix":""},{"id":591663611,"identity":"cf0667b4-ef26-4627-80f4-18f61aa6dd4a","order_by":3,"name":"Seyed Hamid Hosseini","email":"","orcid":"","institution":"Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Seyed","middleName":"Hamid","lastName":"Hosseini","suffix":""},{"id":591663612,"identity":"68edc2db-50af-43a2-a5f7-6cbc54093c4b","order_by":4,"name":"Adineh Taherkhani","email":"","orcid":"","institution":"Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Adineh","middleName":"","lastName":"Taherkhani","suffix":""},{"id":591663613,"identity":"3c71c351-87f1-4836-b804-cbdbd17c4e4d","order_by":5,"name":"Ilad Alavi Darazam","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtklEQVRIiWNgGAWjYBACNnYGBomEHzZAkmgtzEDFD3vSSNDCANQi+YDtMAla+JiZH95I4Dmf2D+7+eADhhqbaCIcxmZskWBxO3HGnWPJBgzH0nIbCGthMJNI4Lmd2HAjx0yCseEwMVrYv0kksJ1LnE+CFh6gLWwHEjeQoqXYIrEn2XjjjbRkgwRi/CLf3r7x5o8fdrLzbiQffPChxoawFhhwBKtMIFY5CNiTongUjIJRMApGGAAAH0I8HAZrpwYAAAAASUVORK5CYII=","orcid":"","institution":"Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Ilad","middleName":"Alavi","lastName":"Darazam","suffix":""}],"badges":[],"createdAt":"2025-12-11 15:38:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8338379/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8338379/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102739701,"identity":"15b744e2-6c83-443f-bf14-5ba8d8dd6204","added_by":"auto","created_at":"2026-02-16 07:11:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":352613,"visible":true,"origin":"","legend":"\u003cp\u003eFollow up CT scan showing pleural effusion, splenomegaly and degenerative changes in spine\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8338379/v1/021b48e2b53145fa14c3fe1a.png"},{"id":102739729,"identity":"f74772b0-6ccb-4c8d-99d9-d38978ed9eda","added_by":"auto","created_at":"2026-02-16 07:11:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":442245,"visible":true,"origin":"","legend":"\u003cp\u003eMRI confirming degenerative changes in spine\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8338379/v1/fcfe52845d23c58df99b0f93.png"},{"id":102739710,"identity":"2dc2cdba-cbca-49b6-8e02-34669403ccd7","added_by":"auto","created_at":"2026-02-16 07:11:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1070423,"visible":true,"origin":"","legend":"\u003cp\u003eBone marrow aspirate smear showing hemophagocytosis (green arrow) at ×40 magnification. A macrophage is seen actively engulfing a hematopoietic cell within a background of adipocytes and marrow elements (Giemsa stain).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8338379/v1/70e3c08c4c14e04df31480ca.png"},{"id":102739747,"identity":"8881aa21-01ca-4f00-8da0-4d3278c1807e","added_by":"auto","created_at":"2026-02-16 07:11:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2756031,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8338379/v1/c6dadefd-66e2-4cf0-86fc-82b864c7e599.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Fatal Hemophagocytic Lymphohistiocytosis Triggered by Incompletely Treated Brucellosis: A Case Report and Warning from an Endemic Region","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBrucellosis remains a major zoonotic infection in endemic regions transmitted primarily through unpasteurized dairy products or direct contact with infected animals. The disease exhibits a wide clinical spectrum, ranging from mild episodic fever to severe multisystem involvement (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Although hematologic abnormalities such as anemia and leukopenia are relatively common, hemophagocytic lymphohistiocytosis (HLH) secondary to brucellosis is rare and potentially life-threatening (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). HLH represents a hyperinflammatory syndrome characterized by uncontrolled activation of macrophages and cytotoxic T cells, leading to cytokine storm, cytopenia, and multi-organ dysfunction (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Early detection and treatment are essential, as delayed diagnosis can result in fatal outcomes.\u003c/p\u003e \u003cp\u003eWe report a fatal case of HLH complicating incompletely treated brucellosis in a 75-year-old man from an endemic area of Iran. This case underscores the lethal potential of this complication and illustrates that even aggressive immunomodulatory therapy may fail without prompt immune control of the underlying trigger.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eClinical Presentation\u003c/p\u003e \u003cp\u003eA 75-year-old male from northwest Iran, a region endemic for brucellosis, presented to our hospital with hematochezia a day prior to admission. The patient presented a history of knee pain and a notable weight loss of approximately 20 kilograms over the past two months. Additionally, the patient reported malaise, intermittent episodes of fever accompanied by chills, and nausea and vomiting over the past month.\u003c/p\u003e \u003cp\u003eApproximately 40 days prior to admission, given his chronic knee pain, high risk occupation as a farmer and residence in a brucellosis-endemic area, serological testing for brucellosis was performed. Serological testing for \u003cem\u003eBrucella\u003c/em\u003e species revealed a standard tube agglutination (Wright) titer of 1:128, Coombs Wright test titer of 1:256, and a 2-mercaptoethanol (2ME) test titer of 1:128. These values are consistent with active brucellosis infection, particularly in the clinical context of endemic exposure and symptomatology and excluding other differential diagnosis.\u003c/p\u003e \u003cp\u003eThe patient received doxycycline and rifampin which palliated his joint pain but stopped taking his medications after less than 4 weeks due to gastrointestinal adverse reactions, not completing the treatment.\u003c/p\u003e \u003cp\u003eA week prior to admission the patient visited another hospital in his hometown due to nausea and vomiting and was admitted for 3 days. The endoscopy revealed erythematous gastritis without evidence of ulceration, bleeding or other abnormalities. He was given pantoprazole and domperidone and discharged.\u003c/p\u003e \u003cp\u003eUpon admission, the laboratory tests revealed that the patient had iron deficiency anemia, hypoalbuminemia, hematuria, hypokalemia and elevated levels of C-reactive protein, alkaline phosphatase, direct and total bilirubin and during the hospitalization the patient developed pancytopenia, increased levels of liver enzymes, hypertriglyceridemia and hyperferritinemia (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMajor laboratory test results of the patient during hospitalization.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUpon admission\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the time of diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAfter treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNormal range\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUnit\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHGB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.5\u0026ndash;17.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eg/dL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.5\u0026ndash;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026times;10\u003csup\u003e3\u003c/sup\u003e/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e177\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e150\u0026ndash;450\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026times;10\u003csup\u003e3\u003c/sup\u003e/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.5\u0026ndash;5.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eg/dL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlkaline phosphatase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e382\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e610\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e688\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e80\u0026ndash;306\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eU/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAspartate aminotransferase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUp to 43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eU/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlanine aminotransferase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUp to 40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eU/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003emg/dL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerritin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20\u0026ndash;300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026micro;g/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal bilirubin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.1\u0026ndash;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003emg/dL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDirect bilirubin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003emg/dL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1312\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1774\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1163\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUp to 350\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eU/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cem\u003eWBC, white blood cell; HGB, hemoglobin; PLT, platelet; TG, triglycerides; LDH, Lactate dehydrogenase\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHe was first admitted to gastroenterology ward for workup on his hematochezia and later moved to infectious disease ward due to possibility of his complications being related to his untreated brucellosis.\u003c/p\u003e \u003cp\u003eThere was no history of tuberculosis, blood transfusions, alcohol consumption, smoking or other relevant factors. Additionally, there was no family history of similar conditions.\u003c/p\u003e \u003cp\u003eDiagnostics and examinations\u003c/p\u003e \u003cp\u003eOn admission, neck ultrasonography revealed oval-shaped lymph nodes in bilateral jugular chains, some having preserved hila and others showing cortical thickening, with a maximum short-axis diameter of 8mm on the right side. During the evaluation minimal perihepatic fluid and periportal cuffing, also splenomegaly (a span of 160mm was reported) and peri-splenic fluid was seen as well mild to moderate pleural effusion was seen on the left side.\u003c/p\u003e \u003cp\u003eA later CT scan confirmed sonographic findings including splenomegaly, also reporting moderate ascites, enhancement of peritoneum, pleural effusion on both sides with the left side being dominant, a simple kidney cyst, and paraaortic lymphadenopathy (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Signs of disc space narrowing and degenerative changes in spine was seen which was later confirmed by MRI in L3-L5 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe patient underwent endoscopy and colonoscopy in gastrointestinal disease ward but no abnormalities that could explain iron deficiency anemia was found.\u003c/p\u003e \u003cp\u003eHe received gentamicin, rifampin and doxycycline for brucellosis and was transferred to the infectious disease ward 8 days after admission as there was no gastrointestinal finding that could justify the patient\u0026rsquo;s symptoms.\u003c/p\u003e \u003cp\u003eUpon admission to infectious disease ward, the patient was ill-looking and complained of episodes of fever and chills. He barely tolerated oral intake due to nausea and appeared cachectic. Laboratory investigations revealed hypertriglyceridemia and elevated ferritin levels. These findings, meeting several HLH-2004 criteria (fever, splenomegaly, bi-cytopenia, hyperferritinemia, and hypertriglyceridemia), raised strong suspicion for HLH. Bone marrow biopsy was performed which further confirmed the diagnosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Initially the patient was initiated on corticosteroid therapy following the diagnosis which led to transient clinical improvement. However, his condition subsequently deteriorated; his mental status started to alter, leading to disorientation and confusion, and his pleural effusion worsened as well, leading to intensive care unit admission and a switch to etoposide which yielded minimal response. The patient received two doses of etoposide 100 mg on days 14 and 18 after admission. G-CSF was administered to help with his leukopenia. The patient was given multiple transfusions of packed red blood cells (PRBCs), platelets, and fresh frozen plasma (FFP) during hospitalization to help treat his symptoms. As a last resort, he received intravenous immunoglobin (IVIG).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDuring this time, he developed rapid atrial fibrillation and a significant decrease in Glasgow Coma Scale (GCS) score, necessitating intubation. Despite aggressive supportive measures, the patient ultimately expired\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur case illustrates a tragic but instructive sequence: incomplete treatment of a common endemic infection leading to a catastrophic hyperinflammatory syndrome that proved unresponsive to standard HLH therapy.\u003c/p\u003e \u003cp\u003eBrucellosis-associated HLH is a rare but life-threatening complication, with few cases reported worldwide. The pathophysiology involves persistent antigenic stimulation by \u003cem\u003eBrucella\u003c/em\u003e organisms, leading to excessive activation of immune system and hemophagocytosis. This hyperinflammatory state can be triggered by untreated, relapsed, or inadequately treated infection, as in our patient who did not complete his antibiotic regimen.\u003c/p\u003e \u003cp\u003eThe clinical presentation of HLH overlaps with brucellosis itself, including fever, hepatosplenomegaly, cytopenia, and elevated liver enzymes, which can mask the diagnosis (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Laboratory evaluation using the HLH-2004 criteria including cytopenia in \u0026ge;\u0026thinsp;2 lineages, hyperferritinemia, hypertriglyceridemia, and demonstration of hemophagocytosis in bone marrow is indeed essential for accurate identification but may delay the diagnosis as some features, such as hypertriglyceridemia or hemophagocytosis, develop over days (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In this patient, the initial workup for hematochezia delayed the recognition of the systematic inflammatory process as some of the symptoms were contributed to GI blood loss and severe anemia; progressive loss of consciousness was a prominent early indicator of severe HLH, emphasizing the need for treatment based on clinical suspicion rather than relying solely on HLH-2004 criteria. The management of our patient was further complicated by the lack of high-quality evidence, forcing clinicians to rely on protocols (HLH-94/2004) designed for familial HLH, which may not be optimal for all cases of secondary, infection-driven HLH.\u003c/p\u003e \u003cp\u003eHLH can occur secondary to a wide range of infections, with viral triggers being the most frequent. Epstein\u0026ndash;Barr virus (EBV) remains the most common cause worldwide, often associated with severe and rapidly progressive disease. Other viral agents such as cytomegalovirus (CMV), herpes simplex virus (HSV), human immunodeficiency virus (HIV), influenza, and SARS-CoV-2 have also been implicated (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Among bacterial infections, \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e, \u003cem\u003eBrucella\u003c/em\u003e spp., and \u003cem\u003eSalmonella\u003c/em\u003e species are the most frequently reported triggers. Parasitic and fungal infections are also recognized causes, particularly in immunocompromised individuals (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). A recent adult review found only a few published cases of brucellosis-associated HLH to date, underscoring the extreme rarity of this complication (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Although the documented cases are few, this might be due to overlapping manifestations of HLH and other complications secondary to brucellosis, especially in endemic areas where the number of cases is high but they remain either underreported or the symptoms remain attributed to brucellosis itself (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The rarity of this complication can\u0026rsquo;t be a reason to underestimate it as HLH can be fatal especially to the elderly population. A 2019 literature review reported an overall mortality of 62% in patients\u0026thinsp;\u0026gt;\u0026thinsp;50 years old who were diagnosed with acquired HLH (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). The pathophysiology is believed to involve excessive immune activation and cytokine release due to uncontrolled infection-driven macrophage and T-cell stimulation (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Recognizing HLH in the context of infection is challenging, as symptoms often overlap with sepsis; however, persistence of fever, cytopenia, hepatosplenomegaly, and hyperferritinemia despite appropriate antimicrobial therapy should raise suspicion for infection-associated HLH (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eManagement of HLH secondary to brucellosis is particularly challenging. Immunosuppressive therapy required for HLH may exacerbate the underlying infection, while antibiotics for brucellosis can induce cytopenias and hepatotoxicity, further complicating disease course (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In this patient, corticosteroids provided only transient improvement, etoposide showed minimal response, and IVIG was used as salvage therapy, highlighting the difficulty of treatment and poor prognosis in severe, multi-organ disease.\u003c/p\u003e \u003cp\u003eDespite recognition of HLH and initiation of appropriate therapy, the disease can progress rapidly and be fatal, particularly in elderly patients or those with comorbidities (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Our patient\u0026rsquo;s course emphasizes the importance of early suspicion and aggressive management, including complete and timely antimicrobial therapy, with consideration of immunomodulatory treatment in severe cases.\u003c/p\u003e \u003cp\u003eOne of the major challenges in advancing the management of hemophagocytic lymphohistiocytosis (HLH) is the lack of randomized clinical trials. Because HLH is a rapidly progressive and often fatal condition, withholding potentially life-saving treatment for the purpose of randomization raises serious ethical concerns. As a result, most available data on therapeutic strategies such as corticosteroids, etoposide, cyclosporine, and intravenous immunoglobulin (IVIG) come from retrospective analyses, case reports, and small case series rather than controlled trials (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). This limitation makes it difficult to establish standardized treatment protocols or to evaluate the comparative effectiveness and safety of newer therapeutic agents. Consequently, management decisions often rely on clinical judgment, disease severity, and individual response rather than robust evidence-based guidelines.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis fatal case underscores that hemophagocytic lymphohistiocytosis is a critical and often missed complication of brucellosis. It serves as a critical reminder for clinicians in endemic regions that in a patient with known infection, the emergence of persistent fever, cytopenias, and hepatosplenomegaly should immediately raise the alarm for secondary HLH. While early, aggressive immunomodulatory therapy is essential, this case clearly illustrates that its success is entirely contingent on the simultaneous and definitive control of the underlying infectious trigger. Ultimately, the most effective strategy remains prevention through ensuring complete adherence to appropriate antimicrobial regimens, as the prognosis of established HLH, particularly in the elderly, remains devastatingly poor. Future efforts must focus on rapid diagnostic algorithms and novel therapies that can more effectively quell the cytokine storm without compromising infection control.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e2ME\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e2-mercaptoethanol\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eALT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAlanine aminotransferase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAST\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAspartate aminotransferase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCMV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCytomegalovirus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCoombs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCoombs Wright test\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eComputed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEBV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEpstein\u0026ndash;Barr virus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFFP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFresh frozen plasma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eG-CSF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGranulocyte-colony stimulating factor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGCS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGlasgow Coma Scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHLH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHemophagocytic lymphohistiocytosis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHIV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHuman immunodeficiency virus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHSV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHerpes simplex virus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIVIG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntravenous immunoglobulin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMagnetic resonance imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePRBC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePacked red blood cells\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWBC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWhite blood cell\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case report was approved by the Ethics Committee of Shahid Beheshti University of Medical Sciences and was conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of this case report and accompanying clinical details was obtained from the patient\u0026rsquo;s legal representative.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAvailable upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical evaluation and disease management: IAD, RN, AT, and SHH were involved in the clinical assessment, diagnostic evaluation, and management of the patient.\u003c/p\u003e\n\u003cp\u003ePathology assessment: SS reviewed and interpreted the bone marrow pathology and confirmed hemophagocytosis.\u003c/p\u003e\n\u003cp\u003eData collection and information retrieval: NK and SHH collected clinical data, laboratory information, and relevant patient details. NK performed the literature review and retrieved supporting evidence for the manuscript.\u003c/p\u003e\n\u003cp\u003eManuscript drafting and editing: NK prepared the initial draft of the manuscript. IAD critically reviewed the manuscript and provided major revisions. SS, RN, and AT reviewed the manuscript and contributed to editing and refinement.\u003c/p\u003e\n\u003cp\u003eConceptualization and supervision: IAD conceptualized the report, supervised all stages of manuscript preparation, and approved the final version.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors extend their gratitude to the Clinical Research Development Unit at Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences in Tehran, Iran, for their invaluable assistance and support throughout this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBergsten E, Horne A, Aric\u0026oacute; M, Astigarraga I, Egeler RM, Filipovich AH, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728-38.\u003c/li\u003e\n\u003cli\u003eShi L, Wang B, Peng D, Zhang K, Wang Y. Brucella-associated hemophagocytic syndrome: case report of a potentially life-threatening condition and literature review. Front Immunol. 2025;16:1592089.\u003c/li\u003e\n\u003cli\u003eWu Y, Sun X, Kang K, Yang Y, Li H, Zhao A, Niu T. Hemophagocytic lymphohistiocytosis: current treatment advances, emerging targeted therapy and underlying mechanisms. J Hematol Oncol. 2024;17(1):106.\u003c/li\u003e\n\u003cli\u003eJiang S, Xia B, Wu H, Zhang P, Li X, Zhang K. Brucellosis-associated hemophagocytic lymphohistiocytosis: a case report and literature review. Front Med (Lausanne). 2025;12:1609644.\u003c/li\u003e\n\u003cli\u003eLa Ros\u0026eacute;e P, Horne A, Hines M, von Bahr Greenwood T, Machowicz R, Berliner N, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465-77.\u003c/li\u003e\n\u003cli\u003eImashuku S, Morimoto A, Ishii E. Virus-triggered secondary hemophagocytic lymphohistiocytosis. Acta Paediatr. 2021;110(10):2729-36.\u003c/li\u003e\n\u003cli\u003eChiu CY, Hicklen RS, Kontoyiannis DP. Fungal-Induced Hemophagocytic Lymphohistiocytosis: A Literature Review in Non-HIV Populations. J Fungi (Basel). 2025;11(2).\u003c/li\u003e\n\u003cli\u003eChesshyre E, Ramanan AV, Roderick MR. Hemophagocytic Lymphohistiocytosis and Infections: An Update. The Pediatric Infectious Disease Journal. 2019;38(3):e54-e6.\u003c/li\u003e\n\u003cli\u003ePark D, Yoon K, Lo A, Bolos D. Hemophagocytic Lymphohistiocytosis Induced by Brucellosis: A Case Report. Cureus. 2024;16(7):e64287.\u003c/li\u003e\n\u003cli\u003eFernandez-Georges IK, Manalo SM, Arede M, Ciaravino G, Beltr\u0026aacute;n-Alcrudo D, Casal J, et al. Ruminant and human brucellosis situation in T\u0026uuml;rkiye and the Caucasus. Trop Anim Health Prod. 2025;57(6):296.\u003c/li\u003e\n\u003cli\u003eAltook R, Ruzieh M, Singh A, Alamoudi W, Moussa Z, Alim H, et al. Hemophagocytic Lymphohistiocytosis in the Elderly. Am J Med Sci. 2019;357(1):67-74.\u003c/li\u003e\n\u003cli\u003eEslami A, Alimoghadam S, Khodadadi S, Allahverdi H, Alimoghadam R, Kasaeian A, et al. Comprehensive insights into tuberculosis-associated hemophagocytic lymphohistiocytosis: a systematic review. BMC Infectious Diseases. 2024;24(1):1341.\u003c/li\u003e\n\u003cli\u003eHuang S, Wang H, Li F, Du L, Fan W, Zhao M, et al. Better efficacy of triple antibiotics therapy for human brucellosis: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2023;17(9):e0011590.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"tropical-diseases-travel-medicine-and-vaccines","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tdtm","sideBox":"Learn more about [Tropical Diseases, Travel Medicine and Vaccines](http://tdtmvjournal.biomedcentral.com)","snPcode":"40794","submissionUrl":"https://submission.nature.com/new-submission/40794/3","title":"Tropical Diseases, Travel Medicine and Vaccines","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Hemophagocytic Lymphohistiocytosis (HLH), Brucellosis, Infection-associated HLH","lastPublishedDoi":"10.21203/rs.3.rs-8338379/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8338379/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Brucellosis, a common zoonosis in endemic areas, can rarely precipitate the life-threatening hyperinflammatory syndrome, hemophagocytic lymphohistiocytosis (HLH). This complication carries a high mortality rate, especially when diagnosis and treatment are delayed.\u003c/p\u003e\n\u003cp\u003eCase Presentation: A 75-year-old male farmer from a brucellosis-endemic region in Iran presented with hematochezia, fever, weight loss, and pancytopenia. He had been diagnosed with active brucellosis 40 days prior but discontinued antibiotic therapy after four weeks. During hospitalization, he developed progressive cytopenias, hyperferritinemia (6,022 ng/mL), hypertriglyceridemia, and splenomegaly. A bone marrow biopsy confirmed hemophagocytosis, leading to a diagnosis of secondary HLH. Despite initiating treatment per HLH-2004 protocols with corticosteroids, etoposide, and intravenous immunoglobulin, his condition deteriorated rapidly. He developed altered mental status, required intubation, and succumbed to the illness.\u003c/p\u003e\n\u003cp\u003eConclusion: This case underscores brucellosis as a potential trigger for HLH. It highlights the critical importance of ensuring complete treatment for brucellosis and maintaining a high index of suspicion for HLH in patients with persistent fever, cytopenias, and hepatosplenomegaly, even in the context of a known infection. Early, aggressive immunomodulatory therapy alongside appropriate antimicrobials is essential, though outcomes can remain poor, particularly in elderly patients.\u003c/p\u003e","manuscriptTitle":"Fatal Hemophagocytic Lymphohistiocytosis Triggered by Incompletely Treated Brucellosis: A Case Report and Warning from an Endemic Region","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-16 07:08:23","doi":"10.21203/rs.3.rs-8338379/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-24T16:18:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-24T15:55:59+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-22T14:33:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"217852071035804743282634802902840128986","date":"2026-02-12T14:44:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"231463505034500920762515664366903429742","date":"2026-02-11T08:56:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"287199267793076390796675386344361820531","date":"2026-02-11T04:03:29+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-10T16:10:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"321152536872396384063567540934948771882","date":"2026-02-10T16:01:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"134826109581903176750154822943257464982","date":"2026-02-10T14:50:02+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-10T14:36:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-22T16:34:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-22T16:33:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"Tropical Diseases, Travel Medicine and Vaccines","date":"2025-12-11T15:26:08+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"tropical-diseases-travel-medicine-and-vaccines","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tdtm","sideBox":"Learn more about [Tropical Diseases, Travel Medicine and Vaccines](http://tdtmvjournal.biomedcentral.com)","snPcode":"40794","submissionUrl":"https://submission.nature.com/new-submission/40794/3","title":"Tropical Diseases, Travel Medicine and Vaccines","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"dccaec64-6780-4e31-bd29-47fedc4f4048","owner":[],"postedDate":"February 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-08T15:51:50+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-16 07:08:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8338379","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8338379","identity":"rs-8338379","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}