{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T08:22:08Z","timestamp":1772180528719,"version":"3.50.1"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:00:00Z","timestamp":1772150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>This case report describes a 42-year-old male with chronic hepatitis B (CHB) who developed hemophagocytic lymphohistiocytosis (HLH) following treatment with peginterferon alfa-2b (PegIFN-\u03b1-2b). The patient tolerated the initial injections well. After the 16th injection in February 2025, laboratory tests revealed cytopenia, prompting discontinuation of PegIFN-\u03b1-2b. The onset of a high-grade fever approximately three weeks after drug cessation coincided with the timeframe for the drug\u2019s clearance, suggesting a continued immunostimulatory effect. HLH was diagnosed based on hyperferritinemia (&amp;gt;50,000 ng\/mL), elevated soluble interleukin-2 receptor (sCD25), and hemophagocytosis on bone marrow biopsy. He responded well to etoposide and dexamethasone. However, his course was complicated by sequential opportunistic infections: severe anemia due to parvovirus B19 (confirmed by plasma metagenomic next-generation sequencing, mNGS) and subsequent herpes simplex virus (HSV) encephalitis (diagnosed via CSF mNGS). Both complications were managed successfully with intravenous immunoglobulin and acyclovir, respectively. This case highlights PegIFN-\u03b1-2b as a rare direct trigger of HLH in CHB and underscores the critical risk of opportunistic infections during immunosuppressive therapy, demonstrating the pivotal role of mNGS in diagnosing elusive infections in immunocompromised hosts.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1760610","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:50:43Z","timestamp":1772175043000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Hemophagocytic lymphohistiocytosis directly triggered by peginterferon alfa-2b in a patient with chronic hepatitis B"],"prefix":"10.3389","volume":"17","author":[{"given":"Peipei","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahui","family":"Pang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiming","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Menglan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenxing","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Third Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dayang","family":"Hui","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingxian","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Shenzhen Third People\u2019s Hospital","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xudong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Third Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianyun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1146\/annurev-pathol-020117-043625","article-title":"Hemophagocytic lymphohistiocytosis","volume":"13","author":"Al-Samkari","year":"2018","journal-title":"Annu Rev Pathol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2020.101515","article-title":"Hemophagocytic lymphohistiocytosis: An update on pathogenesis, diagnosis, and therapy","volume":"34","author":"Griffin","year":"2020","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/apa.15973","article-title":"Virus-triggered secondary hemophagocytic lymphohistiocytosis","volume":"110","author":"Imashuku","year":"2021","journal-title":"Acta Paediatr"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.hoc.2025.02.007","article-title":"Recognizing and managing secondary hemophagocytic lymphohistiocytosis in adults: A practical clinical guide","volume":"39","author":"Zoref-Lorenz","year":"2025","journal-title":"Hematol Oncol Clin North Am"},{"key":"B5","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1186\/s13023-025-03698-0","article-title":"Perspectives on the current diagnostic and treatment paradigms in secondary hemophagocytic lymphohistiocytosis (HLH)","volume":"20","author":"Naymagon","year":"2025","journal-title":"Orphanet J Rare Dis"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2023.105782","article-title":"Mechanism of interferon alpha therapy for chronic hepatitis B and potential approaches to improve its therapeutic efficacy","volume":"221","author":"Zhao","year":"2024","journal-title":"Antiviral Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1223062","article-title":"IFN-\u03b1 induced systemic lupus erythematosus complicated with hemophagocytic lymphohistiocytosis: a case report and literature review","volume":"14","author":"Zeng","year":"2023","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-005-0289-3","article-title":"Strategies to improve plasma half life time of peptide and protein drugs","volume":"30","author":"Werle","year":"2006","journal-title":"Amino Acids"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nri3133","article-title":"Immunomodulatory functions of type I interferons","volume":"12","author":"Gonz\u00e1lez-Navajas","year":"2012","journal-title":"Nat Rev Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2257.2005.00728.x","article-title":"Haemophagocytic syndrome associated with hepatitis-B virus infection responding to etoposide","volume":"27","author":"Aleem","year":"2005","journal-title":"Clin Lab Haematol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1069752","article-title":"Study on liver histopathology of chronic HBV infected patients with different normal ALT values","volume":"13","author":"Zeng","year":"2022","journal-title":"Front Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0000000000003807","article-title":"The liver in hemophagocytic lymphohistiocytosis: not an innocent bystander","volume":"77","author":"Diamond","year":"2023","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.53854\/liim-2904-4","article-title":"Tenofovir alafenamide (TAF) clinical pharmacology","volume":"29","author":"Di Perri","year":"2021","journal-title":"Infez Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(23)00273-4","article-title":"Diagnosis and investigation of suspected haemophagocytic lymphohistiocytosis in adults: 2023 Hyperinflammation and HLH Across Speciality Collaboration (HiHASC) consensus guideline","volume":"6","author":"Cox","year":"2024","journal-title":"Lancet Rheumatol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3851\/IMP3018","article-title":"Herpes simplex virus type-1: replication, latency, reactivation and its antiviral targets","volume":"21","author":"Pires de Mello","year":"2016","journal-title":"Antivir Ther"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.2174\/187152611795768088","article-title":"Herpes simplex encephalitis: from virus to therapy","volume":"11","author":"Rozenberg","year":"2011","journal-title":"Infect Disord Drug Targets"},{"key":"B17","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1128\/CMR.15.3.485-505.2002","article-title":"Human parvovirus B19","volume":"15","author":"Heegaard","year":"2002","journal-title":"Clin Microbiol Rev"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2018.11.050","article-title":"Hemophagocytic lymphohistiocytosis: clinical presentations and diagnosis","volume":"7","author":"Risma","year":"2019","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-788349","article-title":"Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study","volume":"130","author":"Bergsten","year":"2017","journal-title":"Blood"},{"key":"B20","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1186\/s13045-024-01621-x","article-title":"Hemophagocytic lymphohistiocytosis: current treatment advances, emerging targeted therapy and underlying mechanisms","volume":"17","author":"Wu","year":"2024","journal-title":"J Hematol Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1080\/10245332.2018.1491093","article-title":"Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults and adolescents-a life-threatening disease: analysis of 133 cases from a single center","volume":"23","author":"Lai","year":"2018","journal-title":"Hematology"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(06)70524-2","article-title":"Tuberculosis-associated haemophagocytic syndrome","volume":"6","author":"Brastianos","year":"2006","journal-title":"Lancet Infect Dis"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/idr16020012","article-title":"Hemophagocytic lymphohistiocytosis (HLH) in patients with tick-borne illness: A scoping review of 98 cases","volume":"16","author":"Jevtic","year":"2024","journal-title":"Infect Dis Rep"},{"key":"B24","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s40425-019-0598-9","article-title":"Haemophagocytic lymphohistiocytosis in patients treated with immune checkpoint inhibitors: analysis of WHO global database of individual case safety reports","volume":"7","author":"Noseda","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2021.100906","article-title":"Diagnosis of infectious diseases in immunocompromised hosts using metagenomic next generation sequencing-based diagnostics","volume":"53","author":"Casto","year":"2022","journal-title":"Blood Rev"},{"key":"B26","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1007\/s13311-016-0433-7","article-title":"Herpes simplex virus-1 encephalitis in adults: pathophysiology, diagnosis, and management","volume":"13","author":"Bradshaw","year":"2016","journal-title":"Neurotherapeutics"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jocn.2025.111230","article-title":"Acyclovir dosing strategies in herpes encephalitis: A retrospective charts review","volume":"136","author":"Aboelezz","year":"2025","journal-title":"J Clin Neurosci"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e0114321","DOI":"10.1128\/mBio.01143-21","article-title":"Enhanced virus detection and metagenomic sequencing in patients with meningitis and encephalitis","volume":"12","author":"Piantadosi","year":"2021","journal-title":"mBio"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1760610\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:50:44Z","timestamp":1772175044000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1760610\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,27]]},"references-count":28,"alternative-id":["10.3389\/fimmu.2026.1760610"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1760610","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,27]]},"article-number":"1760610"}}