{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:05:37Z","timestamp":1790017537864,"version":"4.0.1"},"reference-count":17,"publisher":"American Diabetes Association","issue":"10","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>Teplizumab delays progression from stage 2 to stage 3 type 1 diabetes (T1D). Epstein-Barr virus (EBV) reactivation after teplizumab is usually transient and mild. We report EBV reactivation-associated secondary hemophagocytic lymphohistiocytosis (HLH) in an adult with trisomy 21 who was treated with teplizumab.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>We describe the clinical course, virologic testing, histopathology, treatment, and follow-up of a 44-year-old man with trisomy 21 and stage 2 T1D after a 14-day teplizumab course.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Six days after completion of the 14-day teplizumab course, he developed respiratory, hepatic, and renal failure. EBV PCR peaked at &amp;gt;2,000,000 copies\/mL; serology confirmed reactivation. Lymph node biopsy showed EBV-associated lymphoproliferation, and criteria for secondary HLH were fulfilled (HScore 238). Dexamethasone and four weekly rituximab doses were associated with clinical, biochemical, and virologic recovery. At 12 months, he remained clinically stable with stage 2 T1D and no insulin treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>This case documents EBV reactivation-associated secondary HLH after teplizumab treatment in a patient with trisomy 21. Causality cannot be established, and the absence of pretreatment EBV PCR limits assessment of whether preexisting EBV DNAemia at treatment initiation contributed to the poor outcome. The observation raises a plausible but unproven host-virus-drug interaction and supports early EBV PCR and HLH evaluation after severe inflammatory deterioration after teplizumab.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/dc26-0543","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T17:27:52Z","timestamp":1785259672000},"page":"1790-1794","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":0,"title":["Fulminant Secondary HLH Following EBV Reactivation in an Adult With Trisomy 21 After Teplizumab Treatment for Stage 2 Type 1 Diabetes"],"prefix":"10.2337","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5639-8690","authenticated-orcid":false,"given":"Christian","family":"Klemann","sequence":"first","affiliation":[{"name":"Department for Pediatric Immunology, Rheumatology & Infectiology, Hospital for Children and Adolescents, Leipzig University 1 , Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9563-3537","authenticated-orcid":false,"given":"Olga","family":"Kordonouri","sequence":"additional","affiliation":[{"name":"Auf der Bult Children\u2019s Hospital 2 , Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"2026092114525571900_B1","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1056\/NEJMoa1902226","article-title":"An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes","volume":"381","author":"Herold","year":"2019","journal-title":"N Engl J Med"},{"key":"2026092114525571900_B2","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.2337\/dc15-1419","article-title":"Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association","volume":"38","author":"Insel","year":"2015","journal-title":"Diabetes Care"},{"key":"2026092114525571900_B3","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.2337\/dc25-S002","article-title":"Classification and diagnosis of diabetes: Standards of Care in Diabetes\u20142025","volume":"48","author":"American Diabetes Association","year":"2025","journal-title":"Diabetes Care"},{"key":"2026092114525571900_B4","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1128\/JCM.42.8.3381-3387.2004","article-title":"Routine Epstein-Barr virus diagnostics from the laboratory perspective: still challenging after 35 years","volume":"42","author":"Hess","year":"2004","journal-title":"J Clin Microbiol"},{"key":"2026092114525571900_B5","doi-asserted-by":"crossref","first-page":"31","DOI":"10.5501\/wjv.v1.i1.31","article-title":"Serological diagnosis of Epstein-Barr virus infection: problems and solutions","volume":"1","author":"De Paschale","year":"2012","journal-title":"World J Virol"},{"key":"2026092114525571900_B6","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1002\/art.38690","article-title":"Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome","volume":"66","author":"Fardet","year":"2014","journal-title":"Arthritis Rheumatol"},{"key":"2026092114525571900_B7","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1111\/bjh.12386","article-title":"Treatment of Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis with rituximab-containing chemoimmunotherapeutic regimens","volume":"162","author":"Chellapandian","year":"2013","journal-title":"Br J Haematol"},{"key":"2026092114525571900_B8","doi-asserted-by":"crossref","first-page":"365","DOI":"10.2337\/dci25-0066","article-title":"Toward disease-modifying therapies in type 1 diabetes: focus on teplizumab","volume":"49","author":"Mathieu","year":"2026","journal-title":"Diabetes Care"},{"key":"2026092114525571900_B9","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.2337\/dc23-0675","article-title":"Teplizumab: a disease-modifying therapy for type 1 diabetes that preserves \u03b2-cell function","volume":"46","author":"Herold","year":"2023","journal-title":"Diabetes Care"},{"key":"2026092114525571900_B10","doi-asserted-by":"crossref","first-page":"e16220","DOI":"10.7554\/eLife.16220","article-title":"Trisomy 21 consistently activates the interferon response","volume":"5","author":"Sullivan","year":"2016","journal-title":"Elife"},{"key":"2026092114525571900_B11","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1007\/s10875-020-00803-9","article-title":"Three copies of four interferon receptor genes underlie a mild type I interferonopathy in Down syndrome","volume":"40","author":"Kong","year":"2020","journal-title":"J Clin Immunol"},{"key":"2026092114525571900_B12","doi-asserted-by":"crossref","first-page":"73","DOI":"10.3389\/fped.2020.00073","article-title":"Immune dysregulation in children with Down syndrome","volume":"8","author":"Huggard","year":"2020","journal-title":"Front Pediatr"},{"key":"2026092114525571900_B13","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.3389\/fimmu.2017.01902","article-title":"Epstein-Barr virus and hemophagocytic lymphohistiocytosis","volume":"8","author":"Marsh","year":"2017","journal-title":"Front Immunol"},{"key":"2026092114525571900_B14","doi-asserted-by":"crossref","first-page":"e177492","DOI":"10.1172\/JCI177492","article-title":"Teplizumab induces persistent changes in the antigen-specific repertoire in individuals at risk for type 1 diabetes","volume":"134","author":"Lled\u00f3-Delgado","year":"2024","journal-title":"J Clin Invest"},{"key":"2026092114525571900_B15","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1007\/s00125-025-06646-6","article-title":"Teplizumab treatment for stage 2 type 1 diabetes: a real-world evaluation of metabolic and immunological outcomes","volume":"69","author":"Karakus","year":"2026","journal-title":"Diabetologia"},{"key":"2026092114525571900_B16","doi-asserted-by":"crossref","first-page":"5033","DOI":"10.1038\/s41467-025-60276-5","article-title":"Latent EBV enhances the efficacy of anti-CD3 mAb in type 1 diabetes","volume":"16","author":"Lled\u00f3-Delgado","year":"2025","journal-title":"Nat Commun"},{"key":"2026092114525571900_B17","unstructured":"Provention Bio, Inc\n          . TZIELD (teplizumab-mzwv) prescribing information. 2026. Accessed 23 July 2026. Available from products.sanofi.us\/tzield\/tzield.pdf"}],"container-title":["Diabetes Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/49\/10\/1790\/889491\/dc260543.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/49\/10\/1790\/889491\/dc260543.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:53:04Z","timestamp":1790016784000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/care\/article\/49\/10\/1790\/172248\/Fulminant-Secondary-HLH-Following-EBV-Reactivation"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":17,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,7,28]]},"published-print":{"date-parts":[[2026,10,1]]}},"URL":"https:\/\/doi.org\/10.2337\/dc26-0543","relation":{},"ISSN":["0149-5992","1935-5548"],"issn-type":[{"value":"0149-5992","type":"print"},{"value":"1935-5548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]}}}