Severe Transaminitis in SARS-CoV-2 and EBV Coinfection: A Case Report

Severe Transaminitis in SARS-CoV-2 and EBV Coinfection: A Case Report | 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 Severe Transaminitis in SARS-CoV-2 and EBV Coinfection: A Case Report Joseph H Kelly, Kenji Hamanaka, Abigail Polzin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6908136/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Aug, 2025 Read the published version in Virology Journal → Version 1 posted 9 You are reading this latest preprint version Abstract Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Epstein-Barr Virus (EBV) are each individually associated with mild hepatic injury and, rarely, with hyperbilirubinemia. SARS-CoV-2 and EBV coinfection is not well documented, but mild hepatic injury has been demonstrated. This case highlights a rare case of severe transaminitis and hyperbilirubinemia from SARS-CoV-2 and EBV coinfection. Case presentation: A 25-year-old man, with no significant past medical history, acquired severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Epstein-Barr virus (EBV) coinfection and developed severe transaminitis, moderate hyperbilirubinemia, and hepatosplenomegaly. The patient’s transaminitis returned to baseline over the course of weeks with no long-term sequelae. Conclusions: While SARS-CoV-2 and EBV are each independently associated with mild hepatic injury, this case highlights a rare presentation of severe liver injury, possibly due to synergistic viral effects. COVID-19 EBV Transaminitis Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is referred to as Coronavirus disease of 2019 or COVID-19. It is associated with a broad range of systemic complications, including hepatic dysfunction. Liver injury associated with COVID-19, otherwise known as COVID-19-associated liver injury (COVALI), is attributed to direct viral toxicity, systemic inflammation, and drug induced liver injury and occurs more often in patients with pre-existing hepatic conditions. 1 Abnormal liver function tests are reported in 14–53% of hospitalized patients with COVID-19, with a pooled incidence of 23.1%. 2,3 Mild transaminase elevations on admission are common, with peak aspartate aminotransferase (AST) range of 69–364 U/L and peak alanine aminotransferase (ALT) range of 52–220 U/L. 4,5 COVALI usually presents with AST predominance while viral hepatitis generally exhibits an ALT-predominant pattern. 4 – 6 Hyperbilirubinemia is rare in mild cases but is documented in severe disease, and it is associated with worse outcomes. 3 , 4 , 6 , 7 In contrast, Epstein-Barr Virus (EBV) infection is frequently accompanied by mild transaminitis, typically two to three times the upper limit of normal, in up to 90% of cases. 8 – 10 True EBV hepatitis, with transaminase levels five to ten times the upper limit, is uncommon; elevations greater than ten times the upper limit are unlikely to be due to EBV alone. 8 , 11 Hyperbilirubinemia and jaundice are rare, and when present, have been attributed to autoimmune hemolytic anemia, biliary duct obstruction due to abdominal lymphadenopathy, or cholestatic hepatitis. 10 , 12 – 17 Based on multiple case reports the incidence of cholestatic hepatitis is 5%. 18–21 Coinfection with SARS-CoV-2 and EBV is rare, and cases involving severe hepatitis in this context are even more limited. In a recent systematic review of 1,211 patients with SARS-CoV-2 and viral reactivation or coinfection, only 38 (3.14%) had EBV coinfection, with jaundice never reported, and only one case documenting transaminitis. 22 While EBV reactivation has been related to liver injury in SARS-CoV-2, the impact of coinfection with EBV on liver dysfunction is poorly understood. 22 – 24 We present a rare case of SARS-CoV-2 and EBV coinfection characterized by severe transaminitis, moderate hyperbilirubinemia, jaundice, and hepatosplenomegaly. This presentation exceeds the expected degree of hepatic injury from either virus alone and is more severe than prior reports of coinfection cases, raising the question of synergistic effect on hepatic dysfunction. Written consent was given by the patient, and Sanford Health’s Institutional Review Board waived approval. Case Presentation A 25-year-old male with no significant past medical history presented to his primary care physician with one day of severe headache, sore throat, fatigue, and myalgias. Physical examination was notable for pharyngeal erythema and left posterior cervical lymphadenopathy. Point-of-care testing was negative for Group A Streptococcus, Influenza A/B, and Respiratory Syncytial Virus. SARS-CoV-2 was detected via nucleic acid testing of a nasopharyngeal swab, and the patient was managed conservatively at home. Over the next five days, the patient developed progressive symptoms including worsening cough, congestion, persistent fevers, chills, night sweats, and right upper quadrant abdominal pain. Dark urine and scleral icterus followed, prompting re-evaluation. Laboratory studies revealed markedly elevated transaminases (ALT 1,414 U/L; AST 891 U/L), hyperbilirubinemia (total bilirubin 9.7 mg/dL), a mild leukocytosis, thrombocytopenia, and a slight elevation in alkaline phosphatase. Initial urinalysis was bright orange in color and uninterpretable microscopically due to pigment interference. He was referred to the Emergency Department for further evaluation. He denied alcohol use, recent travel, gastrointestinal symptoms, or relevant family history. Vital signs were within normal limits. Physical exam revealed jaundice, pharyngeal erythema, mild tonsillar enlargement, and palpable left posterior cervical lymphadenopathy. Laboratory investigation demonstrated normal creatine kinase, lipase, and coagulation studies (Protime and International Normalized Ratio). Acetaminophen and ethanol levels were undetectable. A comprehensive viral hepatitis panel was negative. Repeat urinalysis showed elevated specific gravity, 3 + bilirubin, and trace protein. Direct bilirubin was 7.6 mg/dL. Abdominal ultrasound demonstrated hepatomegaly and a contracted gallbladder without visible cholelithiasis; however, small stones could not be excluded “due to recent oral intake,” per the ultrasound read. Abdominal Computed tomography of the abdomen and pelvis revealed nonspecific gallbladder wall edema, hepatosplenomegaly, and trace ascites. The liver measured up to 22.9 cm craniocaudally, and the spleen up to 18.2 cm. Magnetic resonance imaging with and without contrast confirmed hepatomegaly without steatosis, mild periportal edema, contracted gallbladder with wall thickening, and splenomegaly. Magnetic resonance cholangiopancreatography was non-diagnostic due to motion artifact. A chest radiograph was unremarkable. The constellation of findings, including significant transaminitis, hepatosplenomegaly, and systemic symptoms, was deemed atypical for COVID-19 and the degree of transaminitis out of proportion for isolated COVALI. The patient was admitted for further workup and Hepatology consultation. Supportive care was initiated including IV fluids, tramadol for pain, and benzocaine-menthol lozenges for pharyngitis. The patient experienced progressive symptomatic improvement. Liver function tests including bilirubin levels improved during admission. The patient was discharged in stable condition with a presumptive diagnosis of acute viral hepatitis, suspected due to COVID-19. EBV serologies, HIV screening, blood cultures, and autoimmune hepatitis panels were pending at the time of hospital discharge. Later, Anti-EBV Viral Capsid Antigen Immunoglobulin M (anti-VCA IgM) returned strongly positive, with negative anti-Viral Capsid Antigen Immunoglobulin G (anti-VCA IgG). The patient was advised to avoid contact sports and strenuous activity for 3–4 weeks. At one-week follow-up, liver function tests and bilirubin levels had further declined to ALT 289 U/L, AST 126 U/L, and total bilirubin 3.3 mg/dL. At ten months, the patient had fully recovered with complete normalization of laboratory values and no evidence of long-term sequelae. Discussion and Conclusions It is important to distinguish the potential relationships between SARS-CoV-2 and EBV infections. When an EBV carrier is inoculated with SARS-CoV-2 and develops COVID-19 there is potential for reactivation of latent EBV infection. This has been documented and is attributed to severe immune modulation by SARS-CoV-2 infection. 22 Coinfection refers to simultaneous acute infection by SARS-CoV-2 and EBV. The phenomenon of reactivation is distinguishable from EBV and SARS-CoV-2 coinfection through serology. An EBV carrier’s serology testing would reveal the presence anti-VCA IgG and absence of anti-VCA IgM. Upon infection with SARS-CoV-2, EBV reactivation would be characterized by anti-VCA IgM conversion to positive. In contrast, when both infections are acute, and thus the patient is experiencing co-infection, baseline serology would indicate absence of both anti-VCA IgG and anti-VCA IgM. The possible baseline EBV serologies and coinfection versus reactivation serologies are summarized in Table 1 . As in the case presented, coinfection leads to anti-VCA IgM positivity, maintenance of anti-VCA IgG negativity and positive SARS-CoV-2 NAT. SARS-CoV-2 and EBV Serology Interpretation Table 1 This table outlines the serology results expected in both EBV naïve and EBV carrier patients, and the serology results expected in an EBV coinfection or reactivation. Baseline Serologies Acute SARS-CoV-2 Infection EBV IgM - - + + EBV IgG - + - + Interpretation EBV Naïve EBV Carrier Coinfection Reactivation SARS-CoV-2 and EBV coinfection is infrequently reported and remains poorly characterized. 22 – 24 Both viruses independently have been associated with mild transaminitis, typically no more than two to five times the upper limit of normal. 4 , 5 , 8 , 11 However, the severe transaminitis seen in this case, reaching thirty times the upper limit of normal, is not characteristic of either infection alone or previously reported coinfection. Based on the authors’ review of the literature, coinfection with this severe level of transaminitis has not previously been reported. 23 Furthermore, other causes of acute liver injury, including other viral hepatitis, autoimmune hepatitis, and drug-induced liver injury, were excluded through comprehensive workup. This case raises questions about a synergistic pathophysiological interaction between SARS-CoV-2 and EBV on liver function. It is plausible that the immune pathology of COVALI, characterized by direct action of the virus, hypoxic and endothelial injury, and the cytokine storm, was potentiated by concurrent EBV infection. 25 One report of severe EBV-hepatitis proposed that EBV infected T cells were responsible for the hepatocyte injury, yet the hepatocytes themselves were not infected with EBV on histologic examination. 26 This mechanism is in contrast to most viral hepatitis cases where virus-infected hepatocytes are destroyed by cytotoxic T lymphocytes through Fas/Fas ligand or perforin/granzyme B pathways. 27 This case presents the possibility of both types of destructive pathways being employed and the possible synergistic effect could be resulting from EBV infected T cells amplifying both the cytokine storm as well as hepatocyte destruction of SARS-CoV-2 infected cells, regardless of whether EBV had infiltrated hepatocytes themselves. This case contributes novel insight by underscoring the potential for SARS-CoV-2 and EBV coinfection to lead to severe hepatocellular injury even in immunocompetent patients. The transaminitis seen in this case demonstrates hepatocellular injury beyond the extend expected for either infection in isolation suggesting the possibility of synergistic effect of coinfection not yet elucidated. There is opportunity for further research into the mechanism of hepatic dysfunction in viral coinfections that could guide treatment courses in similar cases. Abbreviations SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 EBV Epstein-Barr virus COVID-19 Coronavirus disease of 2019 COVALI COVID-19 associated liver injury AST aspartate aminotransferase ALT alanine aminotransferase anti-VCA IgM Anti-EBV Viral Capsid Antigen Immunoglobulin M anti-VCA IgG anti-Viral Capsid Antigen Immunoglobulin G Declarations Ethics approval and consent to participate – Not applicable Consent for publication – Consent obtained in written form. Availability of data and materials – Not applicable Competing interests – The authors declare that they have no competing interests Funding – Not applicable Authors Contributions CrediT Statement (CRediT author statement | Elsevier) Joseph Kelly – resources, investigation, Writing – original draft, revised draft Kenji Hamanaka – Writing – review and editing, revised draft Abigail Polzin – conceptualization, Writing – review and editing, visualization Acknowledgements – Not applicable Footnotes – Not applicable References Ahmad A, Ishtiaq SM, Khan JA, Aslam R, Ali S, Arshad MI. COVID-19 and comorbidities of hepatic diseases in a global perspective. World J Gastroenterol. 2021;27(13):1296-310. Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017-32. Kulkarni AV, Kumar P, Tevethia HV, Premkumar M, Arab JP, Candia R, et al. Systematic review with meta-analysis: liver manifestations and outcomes in COVID-19. Aliment Pharmacol Ther. 2020;52(4):584-99. Bloom PP, Meyerowitz EA, Reinus Z, Daidone M, Gustafson J, Kim AY, et al. Liver Biochemistries in Hospitalized Patients With COVID-19. Hepatology. 2021;73(3):890-900. Hundt MA, Deng Y, Ciarleglio MM, Nathanson MH, Lim JK. Abnormal Liver Tests in COVID-19: A Retrospective Observational Cohort Study of 1,827 Patients in a Major U.S. Hospital Network. Hepatology. 2020;72(4):1169-76. Fu Y, Zhu R, Bai T, Han P, He Q, Jing M, et al. Clinical Features of Patients Infected With Coronavirus Disease 2019 With Elevated Liver Biochemistries: A Multicenter, Retrospective Study. Hepatology. 2021;73(4):1509-20. Saviano A, Wrensch F, Ghany MG, Baumert TF. Liver Disease and Coronavirus Disease 2019: From Pathogenesis to Clinical Care. Hepatology. 2021;74(2):1088-100. Crum NF. Epstein Barr virus hepatitis: case series and review. South Med J. 2006;99(5):544-7. Schechter S, Lamps L. Epstein-Barr Virus Hepatitis: A Review of Clinicopathologic Features and Differential Diagnosis. Arch Pathol Lab Med. 2018;142(10):1191-5. Herold J, Grimaldo F. Epstein-Barr Virus-induced Jaundice. Clin Pract Cases Emerg Med. 2020;4(1):69-71. Finkel M, Parker GW, Fanselau HA. The Hepatitis of Infectious Mononucleosis: Experience with 235 Cases. Mil Med. 1964;129:533-8. Fuhrman SA, Gill R, Horwitz CA, Henle W, Henle G, Kravitz G, et al. Marked hyperbilirubinemia in infectious mononucleosis. Analysis of laboratory data in seven patients. Arch Intern Med. 1987;147(5):850-3. Edoute Y, Baruch Y, Lachter J, Furman E, Bassan L, Assy N. Severe cholestatic jaundice induced by Epstein-Barr virus infection in the elderly. J Gastroenterol Hepatol. 1998;13(8):821-4. Paez-Guillan EM, Campos-Franco J, Alende R, Lazare H, Beceiro C, Gonzalez-Quintela A. Jaundice in relation to immune activation during Epstein-Barr virus-induced infectious mononucleosis. Am J Med Sci. 2023;365(3):270-8. Hinedi TB, Koff RS. Cholestatic hepatitis induced by Epstein-Barr virus infection in an adult. Dig Dis Sci. 2003;48(3):539-41. Salva I, Silva IV, Cunha F. Epstein-Barr virus-associated cholestatic hepatitis. BMJ Case Rep. 2013;2013. Agergaard J, Larsen CS. Acute acalculous cholecystitis in a patient with primary Epstein-Barr virus infection: a case report and literature review. Int J Infect Dis. 2015;35:67-72. Markin RS. Manifestations of Epstein-Barr virus-associated disorders in liver. Liver. 1994;14(1):1-13. Kofteridis DP, Koulentaki M, Valachis A, Christofaki M, Mazokopakis E, Papazoglou G, et al. Epstein Barr Virus hepatitis. European Journal of Internal Medicine. 2011;22(1):73-6. Shaukat A, Tsai HT, Rutherford R, Anania FA. Epstein-Barr virus induced hepatitis: An important cause of cholestasis. Hepatol Res. 2005;33(1):24-6. Irem Ceren Erbas CO, Hatice Karaoglu Asrak, Ayse Cakil Guzin, Nursen Belet. Cholestatic Hepatitis Secondary to Epstein-Barr Virus Infection in Children: Case Series and Review of the Literature. Journal of Pediatric Infectious Diseases. 2023;18(1):55-60. Kim JYH, Ragusa M, Tortosa F, Torres A, Gresh L, Mendez-Rico JA, et al. Viral reactivations and co-infections in COVID-19 patients: a systematic review. BMC Infect Dis. 2023;23(1):259. Garcia-Martinez FJ, Moreno-Artero E, Jahnke S. SARS-CoV-2 and EBV coinfection. Med Clin (Engl Ed). 2020;155(7):319-20. Nadeem A, Suresh K, Awais H, Waseem S. Epstein-Barr Virus Coinfection in COVID-19. J Investig Med High Impact Case Rep. 2021;9:23247096211040626. Zhang X, Yu Y, Zhang C, Wang H, Zhao L, Wang H, et al. Mechanism of SARS-CoV-2 Invasion into the Liver and Hepatic Injury in Patients with COVID-19. Mediterr J Hematol Infect Dis. 2022;14(1):e2022003. Kimura H, Nagasaka T, Hoshino Y, Hayashi N, Tanaka N, Xu JL, et al. Severe hepatitis caused by Epstein-Barr virus without infection of hepatocytes. Hum Pathol. 2001;32(7):757-62. Lau JY, Xie X, Lai MM, Wu PC. Apoptosis and viral hepatitis. Semin Liver Dis. 1998;18(2):169-76. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 21 Aug, 2025 Read the published version in Virology Journal → Version 1 posted Editorial decision: Revision requested 25 Jun, 2025 Reviews received at journal 25 Jun, 2025 Reviews received at journal 22 Jun, 2025 Reviewers agreed at journal 19 Jun, 2025 Reviewers agreed at journal 18 Jun, 2025 Reviewers invited by journal 17 Jun, 2025 Editor assigned by journal 17 Jun, 2025 Submission checks completed at journal 17 Jun, 2025 First submitted to journal 16 Jun, 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. 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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-6908136","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":473203318,"identity":"27ffd689-345f-4e77-b2f5-b8b1a74bf66e","order_by":0,"name":"Joseph H Kelly","email":"","orcid":"","institution":"University of South Dakota","correspondingAuthor":false,"prefix":"","firstName":"Joseph","middleName":"H","lastName":"Kelly","suffix":""},{"id":473203319,"identity":"65ebaa00-a2b6-4f36-80dc-16abfabfa36f","order_by":1,"name":"Kenji Hamanaka","email":"data:image/png;base64,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","orcid":"","institution":"Sanford USD Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Kenji","middleName":"","lastName":"Hamanaka","suffix":""},{"id":473203320,"identity":"16383b44-6f37-4843-89b7-780b67f6e8cf","order_by":2,"name":"Abigail Polzin","email":"","orcid":"","institution":"Sanford USD Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Abigail","middleName":"","lastName":"Polzin","suffix":""}],"badges":[],"createdAt":"2025-06-16 19:08:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6908136/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6908136/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12985-025-02865-w","type":"published","date":"2025-08-21T16:29:43+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89847275,"identity":"d93632e9-c033-40a5-b59d-bb6b83716b68","added_by":"auto","created_at":"2025-08-25 16:42:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":285476,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6908136/v1/e92f4065-46b0-4969-8363-2e2c78b182f1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Severe Transaminitis in SARS-CoV-2 and EBV Coinfection: A Case Report","fulltext":[{"header":"Background","content":"\u003cp\u003eSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is referred to as Coronavirus disease of 2019 or COVID-19. It is associated with a broad range of systemic complications, including hepatic dysfunction. Liver injury associated with COVID-19, otherwise known as COVID-19-associated liver injury (COVALI), is attributed to direct viral toxicity, systemic inflammation, and drug induced liver injury and occurs more often in patients with pre-existing hepatic conditions.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Abnormal liver function tests are reported in 14\u0026ndash;53% of hospitalized patients with COVID-19, with a pooled incidence of 23.1%.\u003csup\u003e2,3\u003c/sup\u003e Mild transaminase elevations on admission are common, with peak aspartate aminotransferase (AST) range of 69\u0026ndash;364 U/L and peak alanine aminotransferase (ALT) range of 52\u0026ndash;220 U/L.\u003csup\u003e4,5\u003c/sup\u003e COVALI usually presents with AST predominance while viral hepatitis generally exhibits an ALT-predominant pattern.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Hyperbilirubinemia is rare in mild cases but is documented in severe disease, and it is associated with worse outcomes.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIn contrast, Epstein-Barr Virus (EBV) infection is frequently accompanied by mild transaminitis, typically two to three times the upper limit of normal, in up to 90% of cases.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e True EBV hepatitis, with transaminase levels five to ten times the upper limit, is uncommon; elevations greater than ten times the upper limit are unlikely to be due to EBV alone.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Hyperbilirubinemia and jaundice are rare, and when present, have been attributed to autoimmune hemolytic anemia, biliary duct obstruction due to abdominal lymphadenopathy, or cholestatic hepatitis.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Based on multiple case reports the incidence of cholestatic hepatitis is 5%.\u003csup\u003e18\u0026ndash;21\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eCoinfection with SARS-CoV-2 and EBV is rare, and cases involving severe hepatitis in this context are even more limited. In a recent systematic review of 1,211 patients with SARS-CoV-2 and viral reactivation or coinfection, only 38 (3.14%) had EBV coinfection, with jaundice never reported, and only one case documenting transaminitis.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e While EBV reactivation has been related to liver injury in SARS-CoV-2, the impact of coinfection with EBV on liver dysfunction is poorly understood.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eWe present a rare case of SARS-CoV-2 and EBV coinfection characterized by severe transaminitis, moderate hyperbilirubinemia, jaundice, and hepatosplenomegaly. This presentation exceeds the expected degree of hepatic injury from either virus alone and is more severe than prior reports of coinfection cases, raising the question of synergistic effect on hepatic dysfunction.\u003c/p\u003e\n\u003cp\u003eWritten consent was given by the patient, and Sanford Health\u0026rsquo;s Institutional Review Board waived approval.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 25-year-old male with no significant past medical history presented to his primary care physician with one day of severe headache, sore throat, fatigue, and myalgias. Physical examination was notable for pharyngeal erythema and left posterior cervical lymphadenopathy. Point-of-care testing was negative for Group A Streptococcus, Influenza A/B, and Respiratory Syncytial Virus. SARS-CoV-2 was detected via nucleic acid testing of a nasopharyngeal swab, and the patient was managed conservatively at home.\u003c/p\u003e \u003cp\u003eOver the next five days, the patient developed progressive symptoms including worsening cough, congestion, persistent fevers, chills, night sweats, and right upper quadrant abdominal pain. Dark urine and scleral icterus followed, prompting re-evaluation. Laboratory studies revealed markedly elevated transaminases (ALT 1,414 U/L; AST 891 U/L), hyperbilirubinemia (total bilirubin 9.7 mg/dL), a mild leukocytosis, thrombocytopenia, and a slight elevation in alkaline phosphatase. Initial urinalysis was bright orange in color and uninterpretable microscopically due to pigment interference.\u003c/p\u003e \u003cp\u003eHe was referred to the Emergency Department for further evaluation. He denied alcohol use, recent travel, gastrointestinal symptoms, or relevant family history. Vital signs were within normal limits. Physical exam revealed jaundice, pharyngeal erythema, mild tonsillar enlargement, and palpable left posterior cervical lymphadenopathy.\u003c/p\u003e \u003cp\u003eLaboratory investigation demonstrated normal creatine kinase, lipase, and coagulation studies (Protime and International Normalized Ratio). Acetaminophen and ethanol levels were undetectable. A comprehensive viral hepatitis panel was negative. Repeat urinalysis showed elevated specific gravity, 3 + bilirubin, and trace protein. Direct bilirubin was 7.6 mg/dL. Abdominal ultrasound demonstrated hepatomegaly and a contracted gallbladder without visible cholelithiasis; however, small stones could not be excluded “due to recent oral intake,” per the ultrasound read. Abdominal Computed tomography of the abdomen and pelvis revealed nonspecific gallbladder wall edema, hepatosplenomegaly, and trace ascites. The liver measured up to 22.9 cm craniocaudally, and the spleen up to 18.2 cm. Magnetic resonance imaging with and without contrast confirmed hepatomegaly without steatosis, mild periportal edema, contracted gallbladder with wall thickening, and splenomegaly. Magnetic resonance cholangiopancreatography was non-diagnostic due to motion artifact. A chest radiograph was unremarkable.\u003c/p\u003e \u003cp\u003eThe constellation of findings, including significant transaminitis, hepatosplenomegaly, and systemic symptoms, was deemed atypical for COVID-19 and the degree of transaminitis out of proportion for isolated COVALI. The patient was admitted for further workup and Hepatology consultation. Supportive care was initiated including IV fluids, tramadol for pain, and benzocaine-menthol lozenges for pharyngitis. The patient experienced progressive symptomatic improvement. Liver function tests including bilirubin levels improved during admission.\u003c/p\u003e \u003cp\u003eThe patient was discharged in stable condition with a presumptive diagnosis of acute viral hepatitis, suspected due to COVID-19. EBV serologies, HIV screening, blood cultures, and autoimmune hepatitis panels were pending at the time of hospital discharge. Later, Anti-EBV Viral Capsid Antigen Immunoglobulin M (anti-VCA IgM) returned strongly positive, with negative anti-Viral Capsid Antigen Immunoglobulin G (anti-VCA IgG). The patient was advised to avoid contact sports and strenuous activity for 3–4 weeks. At one-week follow-up, liver function tests and bilirubin levels had further declined to ALT 289 U/L, AST 126 U/L, and total bilirubin 3.3 mg/dL. At ten months, the patient had fully recovered with complete normalization of laboratory values and no evidence of long-term sequelae.\u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003eIt is important to distinguish the potential relationships between SARS-CoV-2 and EBV infections. When an EBV carrier is inoculated with SARS-CoV-2 and develops COVID-19 there is potential for reactivation of latent EBV infection. This has been documented and is attributed to severe immune modulation by SARS-CoV-2 infection.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Coinfection refers to simultaneous acute infection by SARS-CoV-2 and EBV. The phenomenon of reactivation is distinguishable from EBV and SARS-CoV-2 coinfection through serology. An EBV carrier’s serology testing would reveal the presence anti-VCA IgG and absence of anti-VCA IgM. Upon infection with SARS-CoV-2, EBV reactivation would be characterized by anti-VCA IgM conversion to positive. In contrast, when both infections are acute, and thus the patient is experiencing co-infection, baseline serology would indicate absence of both anti-VCA IgG and anti-VCA IgM. The possible baseline EBV serologies and coinfection versus reactivation serologies are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. As in the case presented, coinfection leads to anti-VCA IgM positivity, maintenance of anti-VCA IgG negativity and positive SARS-CoV-2 NAT.\u003c/p\u003e\u003cp\u003eSARS-CoV-2 and EBV Serology Interpretation\u003c/p\u003e\u003cdiv class=\"gridtable\"\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\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\u003eThis table outlines the serology results expected in both EBV naïve and EBV carrier patients, and the serology results expected in an EBV coinfection or reactivation.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eBaseline Serologies\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eAcute SARS-CoV-2 Infection\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEBV IgM\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\u003e-\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+\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEBV IgG\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\u003e+\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+\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterpretation\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEBV Naïve\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEBV Carrier\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCoinfection\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReactivation\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003eSARS-CoV-2 and EBV coinfection is infrequently reported and remains poorly characterized.\u003csup\u003e\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e–\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Both viruses independently have been associated with mild transaminitis, typically no more than two to five times the upper limit of normal.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e However, the severe transaminitis seen in this case, reaching thirty times the upper limit of normal, is not characteristic of either infection alone or previously reported coinfection. Based on the authors’ review of the literature, coinfection with this severe level of transaminitis has not previously been reported.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e Furthermore, other causes of acute liver injury, including other viral hepatitis, autoimmune hepatitis, and drug-induced liver injury, were excluded through comprehensive workup.\u003c/p\u003e\u003cp\u003eThis case raises questions about a synergistic pathophysiological interaction between SARS-CoV-2 and EBV on liver function. It is plausible that the immune pathology of COVALI, characterized by direct action of the virus, hypoxic and endothelial injury, and the cytokine storm, was potentiated by concurrent EBV infection.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e One report of severe EBV-hepatitis proposed that EBV infected T cells were responsible for the hepatocyte injury, yet the hepatocytes themselves were not infected with EBV on histologic examination.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e This mechanism is in contrast to most viral hepatitis cases where virus-infected hepatocytes are destroyed by cytotoxic T lymphocytes through Fas/Fas ligand or perforin/granzyme B pathways.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e This case presents the possibility of both types of destructive pathways being employed and the possible synergistic effect could be resulting from EBV infected T cells amplifying both the cytokine storm as well as hepatocyte destruction of SARS-CoV-2 infected cells, regardless of whether EBV had infiltrated hepatocytes themselves.\u003c/p\u003e\u003cp\u003eThis case contributes novel insight by underscoring the potential for SARS-CoV-2 and EBV coinfection to lead to severe hepatocellular injury even in immunocompetent patients. The transaminitis seen in this case demonstrates hepatocellular injury beyond the extend expected for either infection in isolation suggesting the possibility of synergistic effect of coinfection not yet elucidated. There is opportunity for further research into the mechanism of hepatic dysfunction in viral coinfections that could guide treatment courses in similar cases.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eSARS-CoV-2 Severe acute respiratory syndrome coronavirus 2\u003c/p\u003e\n\u003cp\u003eEBV Epstein-Barr virus\u003c/p\u003e\n\u003cp\u003eCOVID-19 Coronavirus disease of 2019\u003c/p\u003e\n\u003cp\u003eCOVALI COVID-19 associated liver injury\u003c/p\u003e\n\u003cp\u003eAST aspartate aminotransferase\u003c/p\u003e\n\u003cp\u003eALT alanine aminotransferase\u003c/p\u003e\n\u003cp\u003eanti-VCA IgM Anti-EBV Viral Capsid Antigen Immunoglobulin M\u003c/p\u003e\n\u003cp\u003eanti-VCA IgG anti-Viral Capsid Antigen Immunoglobulin G\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate \u0026ndash; Not applicable\u003c/p\u003e\n\u003cp\u003eConsent for publication \u0026ndash; Consent obtained in written form.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials \u0026ndash; Not applicable\u003c/p\u003e\n\u003cp\u003eCompeting interests \u0026ndash; The authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003eFunding \u0026ndash; Not applicable\u003c/p\u003e\n\u003cp\u003eAuthors Contributions\u003c/p\u003e\n\u003cp\u003eCrediT Statement (CRediT author statement | Elsevier)\u003c/p\u003e\n\u003cp\u003eJoseph Kelly \u0026ndash; resources, investigation, Writing \u0026ndash; original draft, revised draft\u003c/p\u003e\n\u003cp\u003eKenji Hamanaka \u0026ndash; Writing \u0026ndash; review and editing, revised draft\u003c/p\u003e\n\u003cp\u003eAbigail Polzin \u0026ndash; conceptualization, Writing \u0026ndash; review and editing, visualization\u003c/p\u003e\n\u003cp\u003eAcknowledgements \u0026ndash; Not applicable\u003c/p\u003e\n\u003cp\u003eFootnotes \u0026ndash; Not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAhmad A, Ishtiaq SM, Khan JA, Aslam R, Ali S, Arshad MI. COVID-19 and comorbidities of hepatic diseases in a global perspective. World J Gastroenterol. 2021;27(13):1296-310.\u003c/li\u003e\n\u003cli\u003eGupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017-32.\u003c/li\u003e\n\u003cli\u003eKulkarni AV, Kumar P, Tevethia HV, Premkumar M, Arab JP, Candia R, et al. Systematic review with meta-analysis: liver manifestations and outcomes in COVID-19. Aliment Pharmacol Ther. 2020;52(4):584-99.\u003c/li\u003e\n\u003cli\u003eBloom PP, Meyerowitz EA, Reinus Z, Daidone M, Gustafson J, Kim AY, et al. Liver Biochemistries in Hospitalized Patients With COVID-19. Hepatology. 2021;73(3):890-900.\u003c/li\u003e\n\u003cli\u003eHundt MA, Deng Y, Ciarleglio MM, Nathanson MH, Lim JK. Abnormal Liver Tests in COVID-19: A Retrospective Observational Cohort Study of 1,827 Patients in a Major U.S. Hospital Network. Hepatology. 2020;72(4):1169-76.\u003c/li\u003e\n\u003cli\u003eFu Y, Zhu R, Bai T, Han P, He Q, Jing M, et al. Clinical Features of Patients Infected With Coronavirus Disease 2019 With Elevated Liver Biochemistries: A Multicenter, Retrospective Study. Hepatology. 2021;73(4):1509-20.\u003c/li\u003e\n\u003cli\u003eSaviano A, Wrensch F, Ghany MG, Baumert TF. Liver Disease and Coronavirus Disease 2019: From Pathogenesis to Clinical Care. Hepatology. 2021;74(2):1088-100.\u003c/li\u003e\n\u003cli\u003eCrum NF. Epstein Barr virus hepatitis: case series and review. South Med J. 2006;99(5):544-7.\u003c/li\u003e\n\u003cli\u003eSchechter S, Lamps L. Epstein-Barr Virus Hepatitis: A Review of Clinicopathologic Features and Differential Diagnosis. Arch Pathol Lab Med. 2018;142(10):1191-5.\u003c/li\u003e\n\u003cli\u003eHerold J, Grimaldo F. Epstein-Barr Virus-induced Jaundice. Clin Pract Cases Emerg Med. 2020;4(1):69-71.\u003c/li\u003e\n\u003cli\u003eFinkel M, Parker GW, Fanselau HA. The Hepatitis of Infectious Mononucleosis: Experience with 235 Cases. Mil Med. 1964;129:533-8.\u003c/li\u003e\n\u003cli\u003eFuhrman SA, Gill R, Horwitz CA, Henle W, Henle G, Kravitz G, et al. Marked hyperbilirubinemia in infectious mononucleosis. Analysis of laboratory data in seven patients. Arch Intern Med. 1987;147(5):850-3.\u003c/li\u003e\n\u003cli\u003eEdoute Y, Baruch Y, Lachter J, Furman E, Bassan L, Assy N. Severe cholestatic jaundice induced by Epstein-Barr virus infection in the elderly. J Gastroenterol Hepatol. 1998;13(8):821-4.\u003c/li\u003e\n\u003cli\u003ePaez-Guillan EM, Campos-Franco J, Alende R, Lazare H, Beceiro C, Gonzalez-Quintela A. Jaundice in relation to immune activation during Epstein-Barr virus-induced infectious mononucleosis. Am J Med Sci. 2023;365(3):270-8.\u003c/li\u003e\n\u003cli\u003eHinedi TB, Koff RS. Cholestatic hepatitis induced by Epstein-Barr virus infection in an adult. Dig Dis Sci. 2003;48(3):539-41.\u003c/li\u003e\n\u003cli\u003eSalva I, Silva IV, Cunha F. Epstein-Barr virus-associated cholestatic hepatitis. BMJ Case Rep. 2013;2013.\u003c/li\u003e\n\u003cli\u003eAgergaard J, Larsen CS. Acute acalculous cholecystitis in a patient with primary Epstein-Barr virus infection: a case report and literature review. Int J Infect Dis. 2015;35:67-72.\u003c/li\u003e\n\u003cli\u003eMarkin RS. Manifestations of Epstein-Barr virus-associated disorders in liver. Liver. 1994;14(1):1-13.\u003c/li\u003e\n\u003cli\u003eKofteridis DP, Koulentaki M, Valachis A, Christofaki M, Mazokopakis E, Papazoglou G, et al. Epstein Barr Virus hepatitis. European Journal of Internal Medicine. 2011;22(1):73-6.\u003c/li\u003e\n\u003cli\u003eShaukat A, Tsai HT, Rutherford R, Anania FA. Epstein-Barr virus induced hepatitis: An important cause of cholestasis. Hepatol Res. 2005;33(1):24-6.\u003c/li\u003e\n\u003cli\u003eIrem Ceren Erbas CO, Hatice Karaoglu Asrak, Ayse Cakil Guzin, Nursen Belet. Cholestatic Hepatitis Secondary to Epstein-Barr Virus Infection in Children: Case Series and Review of the Literature. Journal of Pediatric Infectious Diseases. 2023;18(1):55-60.\u003c/li\u003e\n\u003cli\u003eKim JYH, Ragusa M, Tortosa F, Torres A, Gresh L, Mendez-Rico JA, et al. Viral reactivations and co-infections in COVID-19 patients: a systematic review. BMC Infect Dis. 2023;23(1):259.\u003c/li\u003e\n\u003cli\u003eGarcia-Martinez FJ, Moreno-Artero E, Jahnke S. SARS-CoV-2 and EBV coinfection. Med Clin (Engl Ed). 2020;155(7):319-20.\u003c/li\u003e\n\u003cli\u003eNadeem A, Suresh K, Awais H, Waseem S. Epstein-Barr Virus Coinfection in COVID-19. J Investig Med High Impact Case Rep. 2021;9:23247096211040626.\u003c/li\u003e\n\u003cli\u003eZhang X, Yu Y, Zhang C, Wang H, Zhao L, Wang H, et al. Mechanism of SARS-CoV-2 Invasion into the Liver and Hepatic Injury in Patients with COVID-19. Mediterr J Hematol Infect Dis. 2022;14(1):e2022003.\u003c/li\u003e\n\u003cli\u003eKimura H, Nagasaka T, Hoshino Y, Hayashi N, Tanaka N, Xu JL, et al. Severe hepatitis caused by Epstein-Barr virus without infection of hepatocytes. Hum Pathol. 2001;32(7):757-62.\u003c/li\u003e\n\u003cli\u003eLau JY, Xie X, Lai MM, Wu PC. Apoptosis and viral hepatitis. Semin Liver Dis. 1998;18(2):169-76.\u003c/li\u003e\n\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":"virology-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"virj","sideBox":"Learn more about [Virology Journal](http://virologyj.biomedcentral.com/)","snPcode":"12985","submissionUrl":"https://submission.nature.com/new-submission/12985/3","title":"Virology Journal","twitterHandle":"@VirologyJ","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, EBV, Transaminitis","lastPublishedDoi":"10.21203/rs.3.rs-6908136/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6908136/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Epstein-Barr Virus (EBV) are each individually associated with mild hepatic injury and, rarely, with hyperbilirubinemia. SARS-CoV-2 and EBV coinfection is not well documented, but mild hepatic injury has been demonstrated. This case highlights a rare case of severe transaminitis and hyperbilirubinemia from SARS-CoV-2 and EBV coinfection.\u003c/p\u003e\n\u003cp\u003eCase presentation: A 25-year-old man, with no significant past medical history, acquired severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Epstein-Barr virus (EBV) coinfection and developed severe transaminitis, moderate hyperbilirubinemia, and hepatosplenomegaly. The patient’s transaminitis returned to baseline over the course of weeks with no long-term sequelae.\u003c/p\u003e\n\u003cp\u003eConclusions: While SARS-CoV-2 and EBV are each independently associated with mild hepatic injury, this case highlights a rare presentation of severe liver injury, possibly due to synergistic viral effects.\u003c/p\u003e","manuscriptTitle":"Severe Transaminitis in SARS-CoV-2 and EBV Coinfection: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-19 09:38:32","doi":"10.21203/rs.3.rs-6908136/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-25T11:43:08+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-25T11:30:11+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-23T01:34:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"98129700712027425442970976624309548412","date":"2025-06-19T08:13:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"283757112897811961543229915270514494031","date":"2025-06-18T16:08:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-17T21:20:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-17T21:17:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-17T13:35:58+00:00","index":"","fulltext":""},{"type":"submitted","content":"Virology Journal","date":"2025-06-16T18:55:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"virology-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"virj","sideBox":"Learn more about [Virology Journal](http://virologyj.biomedcentral.com/)","snPcode":"12985","submissionUrl":"https://submission.nature.com/new-submission/12985/3","title":"Virology Journal","twitterHandle":"@VirologyJ","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c56885ae-053a-402d-8166-242acef09a30","owner":[],"postedDate":"June 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-25T16:37:45+00:00","versionOfRecord":{"articleIdentity":"rs-6908136","link":"https://doi.org/10.1186/s12985-025-02865-w","journal":{"identity":"virology-journal","isVorOnly":false,"title":"Virology Journal"},"publishedOn":"2025-08-21 16:29:43","publishedOnDateReadable":"August 21st, 2025"},"versionCreatedAt":"2025-06-19 09:38:32","video":"","vorDoi":"10.1186/s12985-025-02865-w","vorDoiUrl":"https://doi.org/10.1186/s12985-025-02865-w","workflowStages":[]},"version":"v1","identity":"rs-6908136","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6908136","identity":"rs-6908136","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}