A rare potentially fatal complication of a common virus: Epstein-Barr Virus-Induced Hemophagocytic Lymphohistiocytosis in Adolescence.

A rare potentially fatal complication of a common virus: Epstein-Barr Virus-Induced Hemophagocytic Lymphohistiocytosis in Adolescence. | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 8 August 2025 V1 Latest version Share on A rare potentially fatal complication of a common virus: Epstein-Barr Virus-Induced Hemophagocytic Lymphohistiocytosis in Adolescence. Authors : Bakr Alhayek , Xiaowei Malone [email protected] , Joelian Andrew Mislay , Maria Karla Sentmanat , Ryan T. Cardew , and Asha Ramsakal Authors Info & Affiliations https://doi.org/10.22541/au.175466539.96762146/v1 Published Cureus Version of record Peer review timeline 213 views 92 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Hemophagocytic Lymphohistiocytosis (HLH) is a rare, life-threatening condition requiring prompt recognition and treatment. We present a 19-year-old female with Graves’ disease and Epstein-Barr Virus (EBV) infection who developed severe pancytopenia and was diagnosed with EBV-induced HLH. This case highlights the importance of rapid HLH identification by maintaining a high clinical suspicion in patients with risk factors such as auto-immune disease and concomitant infection, as in our case. Equally important is identifying the underlying etiology of HLH, which may warrant novel treatment approaches such as the use of monoclonal antibodies instead of bone marrow suppressive agents typically employed in these patients. Introduction: Hemophagocytic Lymphohistiocytosis (HLH) is a rare but life-threatening syndrome of excessive immune activation that causes widespread tissue damage and multi-organ failure. Prompt treatment is crucial; however, delay in diagnosis often occurs due to the rarity of this syndrome, variable clinical presentation, and lack of specificity of the clinical and laboratory findings (1,2). We present a case of a 19-year-old female presenting with a sore throat as the initial symptom of Epstein-Barr Virus (EBV)-induced HLH. While EBV typically manifests with fever, tonsillopharyngitis, lymphadenopathy and hepatosplenomegaly, its progression to HLH in a healthy young adult is exceedingly uncommon and poses significant diagnostic challenges. Case Description: A 19-year-old White woman with a two-year history of Graves’ disease treated with methimazole 10 mg orally twice daily reported six weeks of waxing–waning sore throat, fever, and malaise. Approximately five weeks before the index admission (hospital Day −35) she received outpatient amoxicillin for presumed streptococcal pharyngitis. Five days later (Day −30) a contrast CT of the neck showed a 1.7‑cm left peritonsillar abscess with bilateral tonsillitis and cervical lymphadenopathy (Figure 1A); she completed seven days of IV clindamycin 900 mg q8h plus dexamethasone 6 mg q12h, followed by a 10‑day oral course of clindamycin 300 mg four times daily and a methylprednisolone taper. She was well at discharge (Day −5) but returned five days later (Day 0) with fever to 39.4 °C/103 °F, severe odynophagia, palpitations, and fatigue. On arrival she was tachycardic to 135 beats/ min, normotensive, and breathing comfortably. Examination showed 1 + symmetric erythematous tonsils without uvular deviation or trismus and mild splenomegaly; the remainder was unremarkable. Her laboratory workup on admission is shown in Table 1, Day 0. Repeat neck CT demonstrated near‑resolution of the abscess, sub‑centimeter bilateral cervical lymphadenopathy, and diffuse thyroid enlargement. Empiric IV vancomycin 1.5 g q12h and cefepime 2 g q8h were started; methimazole was discontinued because of cytopenias. Broad infectious and autoimmune work‑up including HIV, hepatitis A/B/C, HSV (Herpes Simplex Virus), VZV (Varicella-Zoster Virus), RPR (Rapid Plasma Reagin), Bartonella, Histoplasma, Blastomyces, Cryptococcus, ANA, and ANCA was negative. Over the next six days her fevers, cytopenias, and liver‑enzyme elevations worsened despite antibiotics (Table 1, Day 5). EBV PCR measured 19 700 copies/ mL (log 4.29). Ferritin peaked at 36 266 ng/ mL and soluble IL‑2 receptor (sCD25) at 9 117 pg/ mL (ref 175‑858). Flow cytometry of peripheral blood identified an aberrant CD8⁺ T‑cell subset lacking CD5 (6.6 % of events) with polyclonal T-Cell Receptors (TCR) β/γ rearrangements. Bone‑marrow biopsy revealed 95 % cellularity with numerous hemophagocytic histiocytes (Figure 1B), decreased granulopoiesis, left‑shifted erythropoiesis, < 1 % blasts by CD34/CD117, and positive EBV‑encoded RNA in‑situ hybridization; reticulin stain was Myelofibrosis Grade 1 (MF‑1) and cytogenetics were normal. These findings fulfilled HLH‑2004 criteria for EBV‑associated HLH. High‑dose dexamethasone 8 mg IV q6h, IVIG 1 g /kg daily × 2, and rituximab 640 mg weekly × 4 were initiated on Day 6. Because the ANC nadir reached 0.22 × 10³ µ/L, prophylactic acyclovir, fluconazole, and Trimethoprim-Sulfamethoxazole (TMP‑SMX) were given. The etoposide‑based HLH‑94 protocol was deferred owing to profound pancytopenia. On Day 25, emapalumab 1 mg/kg IV twice weekly was started, producing transient improvement (peak ANC 0.93 × 10³ µ/L; platelets 128 × 10³ µ/L) before drug shortages limited escalation. She was transferred on Day 32 to a regional HLH center; eight‑week telephone follow‑up confirmed resolution of cytopenias. Discussion: HLH was first described in 1939 by Scott and Robb-Smith. It is most common in infants up to 18 months of age however it can affect patients of any age (3). It is diagnosed based on the HLH-2004 criteria if five of the eight clinical criteria are met or if the patient has a molecular diagnosis of genetic HLH (4). It can be classified into primary HLH (pHLH) and secondary HLH (sHLH) (5). PHLH is caused by genetic mutations associated with immune dysfunction such as LYST, SH2D1A, PRF1, while sHLH is triggered by significant immune system insults such as infections (e.g., EBV), malignancies, or autoimmune diseases (6). Patients with secondary HLH tend to be older and develop the condition in response to strong immunologic triggers. However, our patient presents an atypical case, being just 19 years old (6) The main clinical manifestations of HLH include fever, hepatosplenomegaly, lymphadenopathy, cytopenias, hyperferritinemia, hypertriglyceridemia, and/or hypofibrinogenemia (7). In our case, our patient’s markedly elevated ferritin level served as the first clue leading to suspicion of HLH. HLH can rise as a complication of EBV infection, and recent advancements have clarified the pathophysiological mechanisms underlying EBV-induced HLH. EBV-infected B cells activate cytotoxic T lymphocytes, resulting in hypercytokinemia and subsequent histiocytic cell activation (8–10). Chronic EBV stimulation has also been implicated in the development of persistent HLH (8). Furthermore, EBV induces excessive activation of T and Natural Killer cells (NK), driving the dysregulated production of cytokines, including IL-2, IFN-α, and IL-6, which play a central role in the hyperinflammatory state. An additional mechanism involves the EBV-induced expression of latent membrane protein 1 (LMP-1), which promotes IFN-α secretion and macrophage activation, potentially leading to immune dysregulation and HLH development ((11,12). Once HLH has been diagnosed, therapy should be started as soon as possible. Of note, however, therapy should not be started until other hematological malignancies have been ruled out (13). In North America and most of Europe, the treatment of HLH generally includes dexamethasone and etoposide based on the HLH-1994 and HLH-2004 protocols (14,15). However, in our case this regimen was deferred due to profound pancytopenia. Anti-fungal prophylaxis, anti-pneumocystis jirovecii prophylaxis, anti-viral prophylaxis, and IVIG replacement should all be considered per the above protocols (13,16) in patients with EBV–HLH, the addition of rituximab has been shown to deplete EBV-harboring B cells and improve HLH (13,17). Interestingly, our case also presented with refractory HLH, for which the North American Consortium for Histiocytosis recommends the use of emapalumab, an anti-interferon-gamma antibody (18). Of note, antiviral therapy targets the lytic (rather than latent) phase of EBV infection, which has not been shown to be significantly contributory to the EBV related lymphoproliferative disorders and thus does not currently play a major role in most treatment protocols (18). Conclusion : Our case highlights the diagnostic challenges in HLH and emphasizes the importance of early recognition and tailored treatment, particularly in the context of EBV-associated triggers. Use of novel agents such as emapalumab can be helpful for the management of refractory disease, while avoiding the toxicities of conventional therapy. Conflict of Interest Statement: The authors declare that they have no relevant financial or non-financial conflicts of interest to disclose. Acknowledgements: The authors would like to thank the Department of Pathology for providing the histopathology images included in this report. References: 1. Filipovich A, McClain K, Grom A. Histiocytic disorders: recent insights into pathophysiology and practical guidelines. Biol Blood Marrow Transplant. 2010 Jan;16(1 Suppl):S82-9. 2. Jordan MB, Allen CE, Greenberg J, Henry M, Hermiston ML, Kumar A, et al. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO). Pediatr Blood Cancer. 2019 Nov;66(11):e27929. 3. George MR. Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med. 2014;5:69–86. 4. Henter J, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH‐2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb 25;48(2):124–31. 5. Hameed M, Garcia G, Cai Zhen K, Hartenstein B, De Jesus Herrera L, Hamad K, et al. Secondary Hemophagocytic Lymphohistiocytosis (HLH): A Systematic Review of Incidence and Prognostic Outcomes. Blood. 2024 Nov 5;144(Supplement 1):5374–5374. 6. Wu Y, Sun X, Kang K, Yang Y, Li H, Zhao A, et al. Hemophagocytic lymphohistiocytosis: current treatment advances, emerging targeted therapy and underlying mechanisms. J Hematol Oncol. 2024 Nov 7;17(1):106. 7. Tseng YT, Sheng WH, Lin BH, Lin CW, Wang JT, Chen YC, et al. Causes, clinical symptoms, and outcomes of infectious diseases associated with hemophagocytic lymphohistiocytosis in Taiwanese adults. Journal of Microbiology, Immunology and Infection. 2011 Jun;44(3):191–7. 8. Goudarzipour K, Kajiyazdi M, Mahdaviyani A. Epstein-barr virus-induced hemophagocytic lymphohistiocytosis. Int J Hematol Oncol Stem Cell Res. 2013;7(1):42–5. 9. Lee JS, Kang JH, Lee GK, Park HJ. Successful Treatment of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis with HLH-94 Protocol. J Korean Med Sci. 2005;20(2):209. 10. Imashuku S, Hibi S, Ohara T, Iwai A, Sako M, Kato M, et al. Effective control of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis with immunochemotherapy. Histiocyte Society. Blood. 1999 Mar 15;93(6):1869–74. 11. Lay JD, Tsao CJ, Chen JY, Kadin ME, Su IJ. Upregulation of tumor necrosis factor-alpha gene by Epstein-Barr virus and activation of macrophages in Epstein-Barr virus-infected T cells in the pathogenesis of hemophagocytic syndrome. J Clin Invest. 1997 Oct 15;100(8):1969–79. 12. Lay JD, Chuang SE, Rowe M, Su IJ. Epstein-barr virus latent membrane protein-1 mediates upregulation of tumor necrosis factor-α in EBV-infected T cells: Implications for the pathogenesis of hemophagocytic syndrome. J Biomed Sci. 2003 Jan;10(1):146–55. 13. Marsh RA. Epstein–Barr Virus and Hemophagocytic Lymphohistiocytosis. Front Immunol. 2018 Jan 8;8. 14. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011 Oct 13;118(15):4041–52. 15. 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 Jun 6;133(23):2465–77. 16. Zhang Y, Cheng Z, Hu Y, Tang L V. Management of Complex Infections in Hemophagocytic Lymphohistiocytosis in Adults. Microorganisms. 2023 Jun 29;11(7):1694. 17. Chellapandian D, Das R, Zelley K, Wiener SJ, Zhao H, Teachey DT, et al. Treatment of E pstein B arr virus‐induced haemophagocytic lymphohistiocytosis with rituximab‐containing chemo‐immunotherapeutic regimens. Br J Haematol. 2013 Aug 21;162(3):376–82. 18. Hines MR, Knight TE, McNerney KO, Leick MB, Jain T, Ahmed S, et al. Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome. Transplant Cell Ther. 2023 Jul;29(7):438.e1-438.e16. Table 1. Key laboratory values on Day 0 and Day 5 Test (units) Reference range Day 0 Day 5 WBC (×10³ µL) 4.0 – 11.0 1.73 1.15 ANC (×10³ µL) 0.90 - 4.5 0.37 0.18 Hemoglobin (g/dL) 12.0 – 16.0 9.8 9.6 Platelets (×10³ µL) 150 – 400 107 63 Sodium (mmol/L) 135 – 145 128 131 Creatinine (mg/dL) 0.60 – 1.20 0.40 0.30 AST (U/L) 5 – 40 316 322 ALT (U/L) 5 – 40 365 320 Alkaline phosphatase (U/L) 44 – 121 290 374 Total bilirubin (mg/dL) 0.2 – 1.0 1.0 3.40 Abbreviations: WBC – white blood cell count; ANC – absolute neutrophil count; AST / ALT – aspartate / alanine aminotransferase Figure 1. A. Acute tonsillitis with dominant left peritonsillar abscess measuring up to 1.7 cm (yellow circle). B. Bone-marrow aspirate demonstrating hemophagocytosis: activated histiocytes engulf hematopoietic elements, including erythrocytes—a key diagnostic feature of hemophagocytic lymphohistiocytosis (HLH). Information & Authors Information Version history V1 Version 1 08 August 2025 Peer review timeline Published Cureus Version of Record 19 Oct 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords bone marrow failure epstein barr virus hematology immune cytopenias Authors Affiliations Bakr Alhayek AdventHealth Tampa View all articles by this author Xiaowei Malone [email protected] AdventHealth Tampa View all articles by this author Joelian Andrew Mislay AdventHealth Tampa View all articles by this author Maria Karla Sentmanat Nova Southeastern University Dr Kiran C Patel College of Osteopathic Medicine View all articles by this author Ryan T. Cardew AdventHealth Tampa View all articles by this author Asha Ramsakal AdventHealth Tampa View all articles by this author Metrics & Citations Metrics Article Usage 213 views 92 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Bakr Alhayek, Xiaowei Malone, Joelian Andrew Mislay, et al. A rare potentially fatal complication of a common virus: Epstein-Barr Virus-Induced Hemophagocytic Lymphohistiocytosis in Adolescence.. Authorea . 08 August 2025. DOI: https://doi.org/10.22541/au.175466539.96762146/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); Cited by Bakr Alhayek, Xiaowei Malone, Joelian Andrew Mislay, Ryan T Cardew, Asha Ramsakal, A Rare, Potentially Fatal Complication of a Common Virus: Epstein-Barr Virus-Induced Hemophagocytic Lymphohistiocytosis in Adolescence, Cureus, (2025). https://doi.org/10.7759/cureus.94918 Crossref Loading... View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! Copying failed. Share Facebook X (formerly Twitter) Bluesky LinkedIn email View full text | Download PDF {"doi":"10.22541/au.175466539.96762146/v1","type":"Article"} Now Reading: Share Figures Tables Close figure viewer Back to article Figure title goes here Change zoom level Go to figure location within the article Download figure Toggle share panel Toggle share panel Share Toggle information panel Toggle information panel Go to previous graphic Go to next graphic Go to previous table Go to next table All figures All tables View all material View all material xrefBack.goTo xrefBack.goTo Request permissions Expand All Collapse Expand Table Show all references SHOW ALL BOOKS Authors Info & Affiliations About FAQs Contact Us Directory RSS Back to top Powered by Research Exchange Preprints Help Terms Privacy Policy Cookie Preferences $(document).ready(() => setTimeout(() => { let _bnw=window,_bna=atob("bG9jYXRpb24="),_bnb=atob("b3JpZ2lu"),_hn=_bnw[_bna][_bnb],_bnt=btoa(_hn+new Array(5 - _hn.length % 4).join(" ")); $.get("/resource/lodash?t="+_bnt); },4000)); (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a00e28a80d160db4',t:'MTc3OTY0NTE5NQ=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();