From Sarcoidosis to Cytokine Storm: A Case Report of HLH Induced by Histoplasmosis and Epstein-Barr Virus

From Sarcoidosis to Cytokine Storm: A Case Report of HLH Induced by Histoplasmosis and Epstein-Barr Virus | 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 From Sarcoidosis to Cytokine Storm: A Case Report of HLH Induced by Histoplasmosis and Epstein-Barr Virus Zaraq Khan, Aditee Dash, Riya Shrestha, Tenzin Norphel Sherpa, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8254697/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Jan, 2026 Read the published version in Bulletin of the National Research Centre → Version 1 posted 10 You are reading this latest preprint version Abstract Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal inflammatory condition caused by uncontrolled activation of the immune system. It can be triggered by various factors and likely through infections particularly Epstein-Barr virus, while fungal infections such as histoplasmosis are less frequently implicated in its occurrence.We present a case of a middle-aged immunocompromised male patient who initially exhibited progressive hepatic dysfunction due to hepatic histoplasmosis. The patient subsequently developed severe multiorgan dysfunction and fulfilled 7 out of the 7 HLH-2024 diagnostic criteria. Bone marrow biopsy supported the diagnosis of hemophagocytosis. The patient was treated with intravenous dexamethasone and liposomal amphotericin B for disseminated histoplasmosis. This case illuminates the importance of considering HLH in patients with sudden and unexpected change in clinical status in chronic illness including but not limited to histoplasmosis. Early recognition and identification of the underlying etiology are crucial for initiating timely and targeted therapy. Histoplasmosis Ebstein-Barr Virus HLH sarcoidosis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 INTRODUCTION Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening hyperinflammatory syndrome characterized by excessive macrophage activation and the overproduction of cytokines 1 .HLH exists in two forms: primary HLH, which typically affects children and is associated with genetic defects in T-cells and natural killer (NK) cells such as PRF1, STXBP2, UNC13D, XIAP, SH2D1A etc 1 all resulting in impaired lymphocyte cytotoxicity; and secondary HLH, which is triggered by infections, malignancies, or autoimmune diseases 1 , 2 . Among infectious causes, herpesviruses particularly Epstein Barr virus (EBV), cytomegalovirus, and HIV are the most frequently implicated 3 . However, fungal infections, though rare, including Histoplasma capsulatum, have been identified as triggers 4 . While HLH is commonly seen in the pediatric population, it can also occur in adults, where hematologic malignancies are predominant, accounting for up to 50% of cases 5 . Its pathogenesis involves impaired cytotoxic function of T lymphocytes and NK cells, resulting in persistent immune activation, macrophage overactivity, and a cytokine storm that causes multi-organ tissue damage. Disseminated histoplasmosis, a systemic fungal infection caused by Histoplasma capsulatum, is another established inducer of secondary HLH, particularly in endemic regions such as the Mississippi and Ohio River valleys or in individuals with compromised cellular immunity 4 , 6 .Histoplasmosis-associated HLH has been reported in both HIV-positive and HIV-negative patients, complicating diagnosis and management 3 , 7 .Several case reports and reviews have documented HLH triggered by EBV or histoplasmosis, and occasionally both infections occur concurrently, increasing clinical severity and diagnostic complexity 3 , 8 – 10 . Although rare, such co-infections highlight the importance of maintaining a high index of suspicion for HLH in patients presenting with systemic inflammatory signs and multi-organ dysfunction. Case Presentation 51-year-old male patient with past medical history significant for hidradenitis suppurativa (on Adalimumab,80 mg every other week), granulomatous liver disease (being treated for hepatic sarcoidosis by Gastroenterology) was referred to our facility, intubated and sedated from an outside facility for high level acute care. The patient was not a particularly good historian, so most of the history was obtained from a chart check of electronic health records. The patient was initially found to have elevated liver function values 9 months prior to current hospital admission for which he was admitted to an outside facility. His total bilirubin at the time was found to be 6.4 mg/dl (0.3–1.2 mg/dl), alanine transaminase was 122 unit/liter (10–40 U/L), aspartate transaminase was 77 units/liter (0–39 U/L) and alkaline phosphatase was 1000 695 units/liter (25–100 U/L). His complete blood count was within normal range except for hemoglobin of 9.2 g/dl (12.9–16.6 g/dl). His gamma-glutamyl transferase was 928 units/liter (10–70 1U/L). A hepatitis panel was tested for Hepatitis A IgM antibodies, Hepatitis B surface antigen along with antibodies, Hepatitis B core antibodies and Hepatitis C IgG antibodies, which were negative. Ebstein Barr Virus serology panel was consistent with past infection. Antimitochondrial antibodies were found to be 5.7 U/ml (reference range < 20 U/ml). Angiotensin converting enzyme was 58 U/L (16–85 U/L). Magnetic resonance imaging cholangiogram (MRCP) was performed which showed normal liver and biliary structure with enlarged spleen measuring at 14.5 cm. He underwent core biopsy of liver which revealed granulomatous hepatitis characterized by well-formed non-necrotizing granuloma with negative GMS and AFB stains. Differentials on pathology included sarcoidosis versus infectious etiology. He was eventually discharged in stable condition with out-patient follow up with gastroenterology. He was admitted one month later for persistent vomiting. His liver functions on that admission had worsened with aspartate transaminase 228 U/L, alanine transaminase 222U/L, alkaline phosphatase 3,120 U/L and total bilirubin of 9.1 mg/dl. His complete blood count was within normal range except for hemoglobin, which was recorded at 10.6 gm/dl. MRCP was repeated which showed mild intrahepatic biliary ductal dilatation with mild worsening of splenomegaly along with development of hypo-enhancing lesions throughout the spleen. Infectious Diseases team was consulted who checked for histoplasma urine antigen which came back at 3.46 ng/ml (normal range is < 0.4 ng/ml). Histoplasma serological testing was also performed which came back as 1: 512 (normal is < 1:8). Both blastomycosis urine antigen and serologic testing, as well as cryptococcal serum antigen, were negative. Patient was subsequently initiated on prednisone (40mg daily) for possible hepatic sarcoidosis by Gastroenterology and was eventually discharged in a stable condition. 2 weeks later, the patient was seen in the Infectious Diseases clinic and was started on itraconazole 200mg twice daily. Unfortunately, the patient did not return for follow-up at the Infectious Diseases clinic, and no documentation of adherence to itraconazole was found in electronic medical record. Patient denied being on any antifungals. He had continued to follow up with Gastroenterology as an out-patient who continued him on steroids for presumptive diagnosis of hepatic sarcoidosis. His liver functions continued to improve over the course of his steroid therapy as checked on his follow up visits with Gastroenterology. Two weeks prior to the current hospital admission, the patient was admitted to another facility with fever, nausea, vomiting, and abdominal pain. Laboratory evaluation revealed worsening transaminitis, and hepatitis A IgM was positive. Patient was treated conservatively for hepatitis A with fluids and anti-emetics. Empiric antibiotic therapy with piperacillin-tazobactam was administered for five days for presumed cholecystitis, and the patient was discharged after seven days of hospitalization. At discharge his fever had subsided, and his vomiting had improved. Two days following discharge, the patient was readmitted with fever, tachycardia, tachypnea, and abdominal pain. Due to his altered mental status, he was intubated for airway protection. A computed tomography (CT) study of the head followed by Magnetic resonance imaging (MRI) of the brain without contrast were both unremarkable for any acute intracranial process. The patient also had a CT scan of the chest without contrast which revealed bilateral dense consolidation in lower bases along with pleural effusion (Fig. 1 ). This was followed by a bronchoscopy, but only aerobic cultures were sent which showed oral flora that was never worked up further by microbiology lab. Bronchoalveolar lavage fluid was sent for mycobacterium tuberculosis along with Pneumocystis Jirovecii PCRs which were both negative. For concern of cholecystitis/cholangitis, patient had an MRCP which showed gallbladder sludge with nonspecific gallbladder thickening. It also revealed splenomegaly with numerous tiny nodules consistent with benign versus infectious versus neoplastic processes. A small splenic infarct was also noted. The adrenal glands were normal. For further evaluation, a Hepatobiliary Iminodiacetic Acid (HIDA) scan was performed which demonstrated hepatic uptake without excretion into the biliary tree (Fig. 2 ). Patient was also tested for histoplasma urine antigen which was > 24 ng/ml (normal range is < 0.4 ng/ml). Beta D Glucan 1,3 was greater than 500 pg/ml (< 59 pg/ml is negative). Serum fibrinogen was 38 mg/dl (189–453 mg/dl), triglyceride was 484 mg/dl (0-149 mg/dl). His ferritin was markedly elevated at 72,333 ng/ml (22–322 ng/ml). He also had bicytopenia with Hb of 7.1 g/dl and platelets of 20,000/µL. IL-2(CD-25) levels, CXCL 9 and ADAMTS 13 were sent, which were 53250 pg/ml (532–1891 pg/ml), 99101 pg/ml (reference range 61%) respectively. Following transfer, the patient was received at our institution in an intubated and sedated state. Hematology service was consulted who performed bone marrow biopsy that revealed hypercellular bone marrow with left shifted erythroid maturation, hemophagocytosis, patchy necrosis, and rare EBV stain cells (Fig. 3 , 4 ). A GMS stain performed on bone marrow biopsy was positive for rare yeast cells consistent with histoplasma while PAS-D stain was unremarkable (Fig. 5 ).EBV DNA in the serum was 1050 IU/ml while serology showed EBV early antigen and IgM negative, and EBV nuclear antigen and IgG positive A follow up EBV DNA PCR one week into hospitalization showed 3680 IU/ml. CMV IgG and DNA PCR came back negative. He was rechecked for urine histoplasma antigen which came back as 24 ng/ml (normal range is < 0.4 ng/ml). The patient met 7 out of 7 criteria for diagnosis for hemophagocytic lymphohistiocytosis (HLH) 2024 modified criteria and his H-scoring for prediction of HLH was found to be greater than 99%. As such, he was started on intravenous (IV) dexamethasone 10mg twice daily. He was also started on IV liposomal amphotericin B 200mg every 24 hours for disseminated histoplasmosis. Hematology recommended against starting etoposide due to concerns that patient will have poor tolerability to it in his present clinical condition. His cognitive function improved over subsequent days and was extubated on day 4 of hospitalization. His liver function markers continued to get worsened following which GI was consulted who recommended ERCP which revealed findings consistent with sclerosing cholangitis. Post procedure, he developed lower GI bleed. Gradually over days, patient mentation dropped again leading to changing his care status to comfort care. The patient passed away after 3 hours of switching him to comfort care due to multiorgan failure secondary to HLH. Discussion This report details a case of secondary hemophagocytic lymphohistiocytosis in a middle-aged male, triggered by a combination of disseminated histoplasmosis and EBV infection. Unlike primary HLH, which is predominantly driven by genetic mutations affecting immune regulation, secondary HLH arises in response to external factors, with infections being the most frequently identified triggers 5 .In secondary HLH, cytotoxic T cells and natural killer (NK) cells fail to effectively eliminate infected or abnormal cells 11 . This defect leads to persistent activation of macrophages and lymphocytes, causing an uncontrolled release of pro-inflammatory cytokines a phenomenon often referred to as a "cytokine storm" 12 .Infectious triggers, particularly viruses like EBV, play a major role in promoting immune system overactivation 1 . EBV can remain latent in B lymphocytes and, upon reactivation, provoke an aggressive immune response that spirals out of control in predisposed individuals 5 . This is especially evident in secondary HLH, where EBV's ability to manipulate host immunity contributes significantly to pathogenesis 1 . In addition to viral causes, disseminated fungal infections, particularly Histoplasma capsulatum have emerged as increasingly recognized triggers of HLH, especially in immunosuppressed patients 4 . Histoplasma antigens may directly stimulate immune cells, and persistent fungal infection contributes to chronic immune activation 6 . The ongoing immune stimulation leads to excessive activation of macrophages, which begin engulfing blood cells (a process known as hemophagocytosis), along with widespread inflammation and tissue damage 11 . Without effective control, this systemic hyperinflammation can result in multi-organ failure and, if untreated, may be fatal 2 . Diagnosing HLH in adults is challenging due to its nonspecific clinical presentation. The HLH-2024 diagnostic criteria requires the presence of atleast five out of seven of the following: fever, splenomegaly, cytopenias affecting ≥ 2 lineages, hypertriglyceridemia and/or hypofibrinogenemia, hyperferritinemia, elevated soluble interleukin-2 receptor (sCD25), and histologic evidence of hemophagocytosis 13 .The recent HLH-criteria excludes NK cell function with inclusion of complementary cellular and genetic guidelines for the confirmatory diagnosis 13 .Additional diagnostic tools such as the H-Score and Optimized HLH Inflammatory (OHI) Index may enhance diagnostic precision, especially in adults or malignancy-associated HLH 2 . However, overlap with other hyperinflammatory conditions such as macrophage activation syndrome (MAS) in systemic diseases like adult-onset Still’s disease can complicate diagnosis, as features like lymphadenopathy, hyperferritinemia, and hepatosplenomegaly are common to both 12 .In our case presentation, the patient met seven of the seven HLH-2024 criteria, including prolonged fever, splenomegaly, elevated ferritin, hypofibrinogenemia, hypertriglyceridemia, bicytopenia, and bone marrow biopsy revealing hemophagocytosis. H-scoring was suggestive of greater than 99% probability of HLH. These findings helped distinguish HLH from other mimickers such as MAS and isolated disseminated histoplasmosis. Management of hemophagocytic lymphohistiocytosis (HLH) requires a dual approach: addressing the underlying cause and controlling the dysregulated immune response. When an infection is identified as the primary trigger, prompt initiation of targeted antimicrobial or antifungal therapy may be sufficient to resolve immune activation 11 , 14 . In cases of disseminated histoplasmosis, standard treatment consists of an induction phase with liposomal amphotericin B, followed by maintenance therapy with oral itraconazole 15 . However, in more severe or refractory cases particularly those involving Epstein-Barr virus (EBV) or underlying genetic predisposition additional immunosuppressive and cytotoxic therapy is warranted. The HLH-94 protocol, which includes an eight-week course of etoposide and dexamethasone, remains the cornerstone of treatment in these settings 1 .In our patient, disseminated histoplasmosis and reactivated EBV were identified as potential HLH triggers. He was initiated on IV liposomal amphotericin B (200 mg daily) and dexamethasone. Etoposide was withheld based on hematology consultation due to concerns about the patient's ability to tolerate aggressive cytotoxic therapy in his current clinical state. The prognosis for secondary HLH is often poor and largely depends on prompt diagnosis and effective management of the underlying trigger 16 . Mortality rates are high—typically between 40% and 80% especially in cases linked to malignancies or EBV infection (17,18) . Early initiation of immunosuppressive therapy, particularly etoposide-based regimens, can significantly improve outcomes by mitigating the cytokine storm 19 . Conversely, delayed recognition frequently leads to rapid clinical deterioration and multi-organ failure 16 .Poor prognostic indicators include central nervous system involvement, markedly elevated ferritin, and severe cytopenias, all of which suggest aggressive immune activation 20 . A lack of therapeutic response within the first two to three weeks further correlates with increased mortality 19 . Among secondary HLH subtypes, those associated with malignancy carry the highest mortality due to both disease burden and host immunosuppression 17 . In contrast, infection-related HLH, particularly when the pathogen is effectively treated, tends to have a more favorable prognosis especially with early intervention 18 .Despite advances in treatment protocols, survival in adult secondary HLH remains limited, highlighting the need for earlier diagnosis and the development of more targeted therapies 16 .Our patient passed away owing to multitude of factors primarily but not limiting to HLH. Conclusion This case emphasizes the need for early recognition and prompt intervention in secondary HLH, particularly in immunocompromised patients presenting with persistent fever, cytopenias, and organomegaly. While EBV remains the most common infectious trigger of HLH, clinicians should remain vigilant for rare fungal causes such as disseminated histoplasmosis, especially in those receiving TNF-α inhibitors or long-term corticosteroids. A multidisciplinary approach, incorporating timely infectious disease evaluation and hematology consultation, is critical to optimizing outcomes. Ultimately, this case highlights the complex interplay between immunosuppression, opportunistic infections, and immune dysregulation in the pathogenesis of secondary HLH. Declarations Ethics approval and consent to participate Ethical approval was not required for this case report. Written informed consent was obtained from the patient for participation and publication. Consent for publication Written informed consent for publication of this case report and any accompanying images was obtained from the patient. Competing interests The authors declare that they have no competing interests. Funding No funding was received for this study. Author Contribution ZK was one of the primary care holders of the patient, and helped with the manuscript writing, as well as article review at the end.AD was the attending physician responsible for this patient's care. She reviewed the article and helped with the literature search.RS helped with manuscript writing as well as preparing figures.TS assisted with manuscript writing and figure preparation.IM helped with manuscript writing as well as preparing figures. Acknowledgement Dr. Mustafa Al-kawaaz was the lead pathologist in the case, who helped us obtain clear histopathology images for this case report Availability of data and material Data sharing is not applicable to this article as no datasets were generated or analyzed during this case report. Author Bio I am currently working as an intern in the internal medicine department at Rochester Regional Hospital. I have previously completed my Infectious Diseases fellowship at University of Louisville Hospital. My area of interest is Infectious diseases particularly focusing on rare presentations of well-known or common clinical entities. References Xu L, Guo X, Guan H (2022) Serious consequences of Epstein-Barr virus infection: Hemophagocytic lymphohistocytosis. Int J Lab Hematol 44(1):74–81. https://doi.org/10.1111/ijlh.13736 Ruzicka M, Wimmer T, Stemmler HJ, Stecher SS, Schulze-Koops H, Hauck F, Subklewe M, von Bergwelt-Baildon M, Spiekermann K (2025) Clinical features, course, and risk factors of infection-associated secondary hemophagocytic lymphohistiocytosis. Infection . Advance online publication. https://doi.org/10.1007/s15010-025-02559-z . 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Cite Share Download PDF Status: Published Journal Publication published 30 Jan, 2026 Read the published version in Bulletin of the National Research Centre → Version 1 posted Editorial decision: Revision requested 07 Jan, 2026 Reviews received at journal 06 Jan, 2026 Reviewers agreed at journal 25 Dec, 2025 Reviewers agreed at journal 23 Dec, 2025 Reviews received at journal 16 Dec, 2025 Reviewers agreed at journal 10 Dec, 2025 Reviewers invited by journal 08 Dec, 2025 Editor assigned by journal 04 Dec, 2025 Submission checks completed at journal 04 Dec, 2025 First submitted to journal 01 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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15:39:19","extension":"xml","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":65024,"visible":true,"origin":"","legend":"","description":"","filename":"89fc9ea4294a4166b6bc0b8bcda32d251structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8254697/v1/9f2c20bb0065784e24659232.xml"},{"id":97898733,"identity":"b3a61b90-ce2d-4874-a3e4-3d4c23e82e67","added_by":"auto","created_at":"2025-12-10 15:39:31","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":71414,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8254697/v1/8ff4ccbeaa1bd73aa5a31aa8.html"},{"id":97832832,"identity":"62f9a98b-29f7-42d8-a24e-343bf8824d34","added_by":"auto","created_at":"2025-12-10 00:39:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":404960,"visible":true,"origin":"","legend":"\u003cp\u003eCT scan of the chest without contrast revealing bilateral dense consolidation in lower bases along with pleural effusion\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8254697/v1/bca89a2c8110723c8d01b99f.png"},{"id":97897295,"identity":"d901e8a0-f125-4419-84ba-fbdc726dd321","added_by":"auto","created_at":"2025-12-10 15:37:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":267926,"visible":true,"origin":"","legend":"\u003cp\u003eHepatobiliary Iminodiacetic Acid (HIDA) scan demonstrated hepatic uptake without excretion into the biliary tree\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8254697/v1/5ffd14786ba73ceb81c81c39.png"},{"id":97897273,"identity":"5296b0de-92d5-46e7-9eb7-e1c2cf038958","added_by":"auto","created_at":"2025-12-10 15:37:41","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":560965,"visible":true,"origin":"","legend":"\u003cp\u003eHematoxylin and Eosin stain displaying hemophagocytosis\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8254697/v1/7b8a41146596321e1c4df441.png"},{"id":97832833,"identity":"de81a63f-7dd7-407b-a6ec-3cf56d58c053","added_by":"auto","created_at":"2025-12-10 00:39:30","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":710158,"visible":true,"origin":"","legend":"\u003cp\u003eHematoxylin and Eosin stain displaying patchy necrosis within bone marrow tissue\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8254697/v1/f3fbc9fc759858ffa434c3df.png"},{"id":97898670,"identity":"cb692c97-f49f-4bad-960c-f0c9e6abc3fa","added_by":"auto","created_at":"2025-12-10 15:39:27","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":592006,"visible":true,"origin":"","legend":"\u003cp\u003eGMS staining showing budding yeasts\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8254697/v1/f7a2bad9fafe35f13f749844.png"},{"id":101690454,"identity":"0e800fcc-ce27-410f-9ab5-2b7395d8d8c5","added_by":"auto","created_at":"2026-02-02 16:03:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2713882,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8254697/v1/c63d7cba-d85a-4528-ae56-a452e07d49d7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"From Sarcoidosis to Cytokine Storm: A Case Report of HLH Induced by Histoplasmosis and Epstein-Barr Virus","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eHemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening hyperinflammatory syndrome characterized by excessive macrophage activation and the overproduction of cytokines\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.HLH exists in two forms: primary HLH, which typically affects children and is associated with genetic defects in T-cells and natural killer (NK) cells such as \u003cem\u003ePRF1, STXBP2, UNC13D, XIAP, SH2D1A\u003c/em\u003e etc\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eall resulting in impaired lymphocyte cytotoxicity; and secondary HLH, which is triggered by infections, malignancies, or autoimmune diseases\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Among infectious causes, herpesviruses particularly Epstein Barr virus (EBV), cytomegalovirus, and HIV are the most frequently implicated\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. However, fungal infections, though rare, including Histoplasma capsulatum, have been identified as triggers\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. While HLH is commonly seen in the pediatric population, it can also occur in adults, where hematologic malignancies are predominant, accounting for up to 50% of cases\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Its pathogenesis involves impaired cytotoxic function of T lymphocytes and NK cells, resulting in persistent immune activation, macrophage overactivity, and a cytokine storm that causes multi-organ tissue damage. Disseminated histoplasmosis, a systemic fungal infection caused by Histoplasma capsulatum, is another established inducer of secondary HLH, particularly in endemic regions such as the Mississippi and Ohio River valleys or in individuals with compromised cellular immunity\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.Histoplasmosis-associated HLH has been reported in both HIV-positive and HIV-negative patients, complicating diagnosis and management\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.Several case reports and reviews have documented HLH triggered by EBV or histoplasmosis, and occasionally both infections occur concurrently, increasing clinical severity and diagnostic complexity \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Although rare, such co-infections highlight the importance of maintaining a high index of suspicion for HLH in patients presenting with systemic inflammatory signs and multi-organ dysfunction.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003e51-year-old male patient with past medical history significant for hidradenitis suppurativa (on Adalimumab,80 mg every other week), granulomatous liver disease (being treated for hepatic sarcoidosis by Gastroenterology) was referred to our facility, intubated and sedated from an outside facility for high level acute care. The patient was not a particularly good historian, so most of the history was obtained from a chart check of electronic health records.\u003c/p\u003e\u003cp\u003eThe patient was initially found to have elevated liver function values 9 months prior to current hospital admission for which he was admitted to an outside facility. His total bilirubin at the time was found to be 6.4 mg/dl (0.3\u0026ndash;1.2 mg/dl), alanine transaminase was 122 unit/liter (10\u0026ndash;40 U/L), aspartate transaminase was 77 units/liter (0\u0026ndash;39 U/L) and alkaline phosphatase was 1000 695 units/liter (25\u0026ndash;100 U/L). His complete blood count was within normal range except for hemoglobin of 9.2 g/dl (12.9\u0026ndash;16.6 g/dl). His gamma-glutamyl transferase was 928 units/liter (10\u0026ndash;70 1U/L). A hepatitis panel was tested for Hepatitis A IgM antibodies, Hepatitis B surface antigen along with antibodies, Hepatitis B core antibodies and Hepatitis C IgG antibodies, which were negative. Ebstein Barr Virus serology panel was consistent with past infection. Antimitochondrial antibodies were found to be 5.7 U/ml (reference range\u0026thinsp;\u0026lt;\u0026thinsp;20 U/ml). Angiotensin converting enzyme was 58 U/L (16\u0026ndash;85 U/L). Magnetic resonance imaging cholangiogram (MRCP) was performed which showed normal liver and biliary structure with enlarged spleen measuring at 14.5 cm. He underwent core biopsy of liver which revealed granulomatous hepatitis characterized by well-formed non-necrotizing granuloma with negative GMS and AFB stains. Differentials on pathology included sarcoidosis versus infectious etiology. He was eventually discharged in stable condition with out-patient follow up with gastroenterology.\u003c/p\u003e\u003cp\u003eHe was admitted one month later for persistent vomiting. His liver functions on that admission had worsened with aspartate transaminase 228 U/L, alanine transaminase 222U/L, alkaline phosphatase 3,120 U/L and total bilirubin of 9.1 mg/dl. His complete blood count was within normal range except for hemoglobin, which was recorded at 10.6 gm/dl. MRCP was repeated which showed mild intrahepatic biliary ductal dilatation with mild worsening of splenomegaly along with development of hypo-enhancing lesions throughout the spleen. Infectious Diseases team was consulted who checked for histoplasma urine antigen which came back at 3.46 ng/ml (normal range is \u0026lt;\u0026thinsp;0.4 ng/ml). Histoplasma serological testing was also performed which came back as 1: 512 (normal is \u0026lt;\u0026thinsp;1:8). Both blastomycosis urine antigen and serologic testing, as well as cryptococcal serum antigen, were negative. Patient was subsequently initiated on prednisone (40mg daily) for possible hepatic sarcoidosis by Gastroenterology and was eventually discharged in a stable condition.\u003c/p\u003e\u003cp\u003e2 weeks later, the patient was seen in the Infectious Diseases clinic and was started on itraconazole 200mg twice daily. Unfortunately, the patient did not return for follow-up at the Infectious Diseases clinic, and no documentation of adherence to itraconazole was found in electronic medical record. Patient denied being on any antifungals. He had continued to follow up with Gastroenterology as an out-patient who continued him on steroids for presumptive diagnosis of hepatic sarcoidosis. His liver functions continued to improve over the course of his steroid therapy as checked on his follow up visits with Gastroenterology.\u003c/p\u003e\u003cp\u003eTwo weeks prior to the current hospital admission, the patient was admitted to another facility with fever, nausea, vomiting, and abdominal pain. Laboratory evaluation revealed worsening transaminitis, and hepatitis A IgM was positive. Patient was treated conservatively for hepatitis A with fluids and anti-emetics. Empiric antibiotic therapy with piperacillin-tazobactam was administered for five days for presumed cholecystitis, and the patient was discharged after seven days of hospitalization. At discharge his fever had subsided, and his vomiting had improved.\u003c/p\u003e\u003cp\u003eTwo days following discharge, the patient was readmitted with fever, tachycardia, tachypnea, and abdominal pain. Due to his altered mental status, he was intubated for airway protection. A computed tomography (CT) study of the head followed by Magnetic resonance imaging (MRI) of the brain without contrast were both unremarkable for any acute intracranial process. The patient also had a CT scan of the chest without contrast which revealed bilateral dense consolidation in lower bases along with pleural effusion (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This was followed by a bronchoscopy, but only aerobic cultures were sent which showed oral flora that was never worked up further by microbiology lab. Bronchoalveolar lavage fluid was sent for mycobacterium tuberculosis along with Pneumocystis Jirovecii PCRs which were both negative. For concern of cholecystitis/cholangitis, patient had an MRCP which showed gallbladder sludge with nonspecific gallbladder thickening. It also revealed splenomegaly with numerous tiny nodules consistent with benign versus infectious versus neoplastic processes. A small splenic infarct was also noted. The adrenal glands were normal. For further evaluation, a Hepatobiliary Iminodiacetic Acid (HIDA) scan was performed which demonstrated hepatic uptake without excretion into the biliary tree (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Patient was also tested for histoplasma urine antigen which was \u0026gt;\u0026thinsp;24 ng/ml (normal range is \u0026lt;\u0026thinsp;0.4 ng/ml). Beta D Glucan 1,3 was greater than 500 pg/ml (\u0026lt;\u0026thinsp;59 pg/ml is negative). Serum fibrinogen was 38 mg/dl (189\u0026ndash;453 mg/dl), triglyceride was 484 mg/dl (0-149 mg/dl). His ferritin was markedly elevated at 72,333 ng/ml (22\u0026ndash;322 ng/ml). He also had bicytopenia with Hb of 7.1 g/dl and platelets of 20,000/\u0026micro;L. IL-2(CD-25) levels, CXCL 9 and ADAMTS 13 were sent, which were 53250 pg/ml (532\u0026ndash;1891 pg/ml), 99101 pg/ml (reference range\u0026thinsp;\u0026lt;\u0026thinsp;647 pg/ml) and 28% (reference range\u0026thinsp;\u0026gt;\u0026thinsp;61%) respectively.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFollowing transfer, the patient was received at our institution in an intubated and sedated state. Hematology service was consulted who performed bone marrow biopsy that revealed hypercellular bone marrow with left shifted erythroid maturation, hemophagocytosis, patchy necrosis, and rare EBV stain cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e,\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). A GMS stain performed on bone marrow biopsy was positive for rare yeast cells consistent with histoplasma while PAS-D stain was unremarkable (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).EBV DNA in the serum was 1050 IU/ml while serology showed EBV early antigen and IgM negative, and EBV nuclear antigen and IgG positive A follow up EBV DNA PCR one week into hospitalization showed 3680 IU/ml. CMV IgG and DNA PCR came back negative. He was rechecked for urine histoplasma antigen which came back as 24 ng/ml (normal range is \u0026lt;\u0026thinsp;0.4 ng/ml). The patient met 7 out of 7 criteria for diagnosis for hemophagocytic lymphohistiocytosis (HLH) 2024 modified criteria and his H-scoring for prediction of HLH was found to be greater than 99%. As such, he was started on intravenous (IV) dexamethasone 10mg twice daily. He was also started on IV liposomal amphotericin B 200mg every 24 hours for disseminated histoplasmosis. Hematology recommended against starting etoposide due to concerns that patient will have poor tolerability to it in his present clinical condition. His cognitive function improved over subsequent days and was extubated on day 4 of hospitalization. His liver function markers continued to get worsened following which GI was consulted who recommended ERCP which revealed findings consistent with sclerosing cholangitis. Post procedure, he developed lower GI bleed. Gradually over days, patient mentation dropped again leading to changing his care status to comfort care. The patient passed away after 3 hours of switching him to comfort care due to multiorgan failure secondary to HLH.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis report details a case of secondary hemophagocytic lymphohistiocytosis in a middle-aged male, triggered by a combination of disseminated histoplasmosis and EBV infection. Unlike primary HLH, which is predominantly driven by genetic mutations affecting immune regulation, secondary HLH arises in response to external factors, with infections being the most frequently identified triggers\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.In secondary HLH, cytotoxic T cells and natural killer (NK) cells fail to effectively eliminate infected or abnormal cells\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. This defect leads to persistent activation of macrophages and lymphocytes, causing an uncontrolled release of pro-inflammatory cytokines a phenomenon often referred to as a \"cytokine storm\" \u003csup\u003e12\u003c/sup\u003e.Infectious triggers, particularly viruses like EBV, play a major role in promoting immune system overactivation\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. EBV can remain latent in B lymphocytes and, upon reactivation, provoke an aggressive immune response that spirals out of control in predisposed individuals\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. This is especially evident in secondary HLH, where EBV's ability to manipulate host immunity contributes significantly to pathogenesis\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. In addition to viral causes, disseminated fungal infections, particularly \u003cem\u003eHistoplasma capsulatum\u003c/em\u003e have emerged as increasingly recognized triggers of HLH, especially in immunosuppressed patients\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. \u003cem\u003eHistoplasma\u003c/em\u003e antigens may directly stimulate immune cells, and persistent fungal infection contributes to chronic immune activation\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. The ongoing immune stimulation leads to excessive activation of macrophages, which begin engulfing blood cells (a process known as hemophagocytosis), along with widespread inflammation and tissue damage\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Without effective control, this systemic hyperinflammation can result in multi-organ failure and, if untreated, may be fatal\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eDiagnosing HLH in adults is challenging due to its nonspecific clinical presentation. The HLH-2024 diagnostic criteria requires the presence of atleast five out of seven of the following: fever, splenomegaly, cytopenias affecting\u0026thinsp;\u0026ge;\u0026thinsp;2 lineages, hypertriglyceridemia and/or hypofibrinogenemia, hyperferritinemia, elevated soluble interleukin-2 receptor (sCD25), and histologic evidence of hemophagocytosis\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.The recent HLH-criteria excludes NK cell function with inclusion of complementary cellular and genetic guidelines for the confirmatory diagnosis\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.Additional diagnostic tools such as the H-Score and Optimized HLH Inflammatory (OHI) Index may enhance diagnostic precision, especially in adults or malignancy-associated HLH\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. However, overlap with other hyperinflammatory conditions such as macrophage activation syndrome (MAS) in systemic diseases like adult-onset Still\u0026rsquo;s disease can complicate diagnosis, as features like lymphadenopathy, hyperferritinemia, and hepatosplenomegaly are common to both\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.In our case presentation, the patient met seven of the seven HLH-2024 criteria, including prolonged fever, splenomegaly, elevated ferritin, hypofibrinogenemia, hypertriglyceridemia, bicytopenia, and bone marrow biopsy revealing hemophagocytosis. H-scoring was suggestive of greater than 99% probability of HLH. These findings helped distinguish HLH from other mimickers such as MAS and isolated disseminated histoplasmosis.\u003c/p\u003e\u003cp\u003eManagement of hemophagocytic lymphohistiocytosis (HLH) requires a dual approach: addressing the underlying cause and controlling the dysregulated immune response. When an infection is identified as the primary trigger, prompt initiation of targeted antimicrobial or antifungal therapy may be sufficient to resolve immune activation \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. In cases of disseminated histoplasmosis, standard treatment consists of an induction phase with liposomal amphotericin B, followed by maintenance therapy with oral itraconazole\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. However, in more severe or refractory cases particularly those involving Epstein-Barr virus (EBV) or underlying genetic predisposition additional immunosuppressive and cytotoxic therapy is warranted. The HLH-94 protocol, which includes an eight-week course of etoposide and dexamethasone, remains the cornerstone of treatment in these settings\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.In our patient, disseminated histoplasmosis and reactivated EBV were identified as potential HLH triggers. He was initiated on IV liposomal amphotericin B (200 mg daily) and dexamethasone. Etoposide was withheld based on hematology consultation due to concerns about the patient's ability to tolerate aggressive cytotoxic therapy in his current clinical state.\u003c/p\u003e\u003cp\u003eThe prognosis for secondary HLH is often poor and largely depends on prompt diagnosis and effective management of the underlying trigger\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Mortality rates are high\u0026mdash;typically between 40% and 80% especially in cases linked to malignancies or EBV infection \u003csup\u003e(17,18)\u003c/sup\u003e. Early initiation of immunosuppressive therapy, particularly etoposide-based regimens, can significantly improve outcomes by mitigating the cytokine storm\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Conversely, delayed recognition frequently leads to rapid clinical deterioration and multi-organ failure\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e.Poor prognostic indicators include central nervous system involvement, markedly elevated ferritin, and severe cytopenias, all of which suggest aggressive immune activation\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. A lack of therapeutic response within the first two to three weeks further correlates with increased mortality\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAmong secondary HLH subtypes, those associated with malignancy carry the highest mortality due to both disease burden and host immunosuppression\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. In contrast, infection-related HLH, particularly when the pathogen is effectively treated, tends to have a more favorable prognosis especially with early intervention\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.Despite advances in treatment protocols, survival in adult secondary HLH remains limited, highlighting the need for earlier diagnosis and the development of more targeted therapies\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e.Our patient passed away owing to multitude of factors primarily but not limiting to HLH.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case emphasizes the need for early recognition and prompt intervention in secondary HLH, particularly in immunocompromised patients presenting with persistent fever, cytopenias, and organomegaly. While EBV remains the most common infectious trigger of HLH, clinicians should remain vigilant for rare fungal causes such as disseminated histoplasmosis, especially in those receiving TNF-α inhibitors or long-term corticosteroids. A multidisciplinary approach, incorporating timely infectious disease evaluation and hematology consultation, is critical to optimizing outcomes. Ultimately, this case highlights the complex interplay between immunosuppression, opportunistic infections, and immune dysregulation in the pathogenesis of secondary HLH.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cp\u003eEthical approval was not required for this case report. Written informed consent was obtained from the patient for participation and publication.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003eWritten informed consent for publication of this case report and any accompanying images was obtained from the patient.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eNo funding was received for this study.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eZK was one of the primary care holders of the patient, and helped with the manuscript writing, as well as article review at the end.AD was the attending physician responsible for this patient's care. She reviewed the article and helped with the literature search.RS helped with manuscript writing as well as preparing figures.TS assisted with manuscript writing and figure preparation.IM helped with manuscript writing as well as preparing figures.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eDr. Mustafa Al-kawaaz was the lead pathologist in the case, who helped us obtain clear histopathology images for this case report\u003c/p\u003e\u003ch2\u003eAvailability of data and material\u003c/h2\u003e\u003cp\u003eData sharing is not applicable to this article as no datasets were generated or analyzed during this case report.\u003c/p\u003e\n\u003ch3\u003eAuthor Bio\u003c/h3\u003e\n\u003cp\u003eI am currently working as an intern in the internal medicine department at Rochester Regional Hospital. I have previously completed my Infectious Diseases fellowship at University of Louisville Hospital. 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Am J Med 127(11):1118\u0026ndash;1125. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.amjmed.2014.04.034\u003c/span\u003e\u003cspan address=\"10.1016/j.amjmed.2014.04.034\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bulletin-of-the-national-research-centre","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnrc","sideBox":"Learn more about [Bulletin of the National Research Centre](https://BNRC.springeropen.com)","snPcode":"42269","submissionUrl":"https://submission.springernature.com/new-submission/42269/3","title":"Bulletin of the National Research Centre","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Histoplasmosis, Ebstein-Barr Virus, HLH, sarcoidosis","lastPublishedDoi":"10.21203/rs.3.rs-8254697/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8254697/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal inflammatory condition caused by uncontrolled activation of the immune system. It can be triggered by various factors and likely through infections particularly Epstein-Barr virus, while fungal infections such as histoplasmosis are less frequently implicated in its occurrence.We present a case of a middle-aged immunocompromised male patient who initially exhibited progressive hepatic dysfunction due to hepatic histoplasmosis. The patient subsequently developed severe multiorgan dysfunction and fulfilled 7 out of the 7 HLH-2024 diagnostic criteria. Bone marrow biopsy supported the diagnosis of hemophagocytosis. The patient was treated with intravenous dexamethasone and liposomal amphotericin B for disseminated histoplasmosis. This case illuminates the importance of considering HLH in patients with sudden and unexpected change in clinical status in chronic illness including but not limited to histoplasmosis. Early recognition and identification of the underlying etiology are crucial for initiating timely and targeted therapy.\u003c/p\u003e","manuscriptTitle":"From Sarcoidosis to Cytokine Storm: A Case Report of HLH Induced by Histoplasmosis and Epstein-Barr Virus","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-10 00:39:25","doi":"10.21203/rs.3.rs-8254697/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-07T09:41:58+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-06T05:47:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"67694007730556316721877019979596797033","date":"2025-12-25T15:50:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"122093172077488058960401909015003100049","date":"2025-12-23T13:18:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-16T08:27:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"231463505034500920762515664366903429742","date":"2025-12-10T13:02:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-08T06:57:48+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-04T12:26:52+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-04T06:41:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bulletin of the National Research Centre","date":"2025-12-02T01:10:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bulletin-of-the-national-research-centre","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnrc","sideBox":"Learn more about [Bulletin of the National Research Centre](https://BNRC.springeropen.com)","snPcode":"42269","submissionUrl":"https://submission.springernature.com/new-submission/42269/3","title":"Bulletin of the National Research Centre","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c435d7c2-2f73-48d8-b1e3-6ebdeb072121","owner":[],"postedDate":"December 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-02T16:01:04+00:00","versionOfRecord":{"articleIdentity":"rs-8254697","link":"https://doi.org/10.1186/s42269-026-01402-1","journal":{"identity":"bulletin-of-the-national-research-centre","isVorOnly":false,"title":"Bulletin of the National Research Centre"},"publishedOn":"2026-01-30 15:58:15","publishedOnDateReadable":"January 30th, 2026"},"versionCreatedAt":"2025-12-10 00:39:25","video":"","vorDoi":"10.1186/s42269-026-01402-1","vorDoiUrl":"https://doi.org/10.1186/s42269-026-01402-1","workflowStages":[]},"version":"v1","identity":"rs-8254697","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8254697","identity":"rs-8254697","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}