{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T14:01:59Z","timestamp":1780495319581,"version":"3.54.1"},"reference-count":48,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Murine typhus (also called flea-borne or endemic typhus) is an undifferentiated febrile illness caused by the bacterium Rickettsia typhi. The disease, transmitted by rat and cat fleas, is endemic to seaboard regions worldwide. Recently, murine typhus has reemerged as an increasingly recognized cause of febrile illness in the United States, especially in Texas and Southern California. In addition to fever, manifestations often include headache, malaise, myalgias, and a maculopapular rash in approximately half of cases. Although usually considered a mild illness, when untreated, symptoms can last up to 3 weeks. Severe manifestations such as pneumonitis, acute kidney injury, and meningoencephalitis may occur. Historically, death has occurred in 0.4%, but in Southern California, the case fatality rate has been recently recorded at 1.8%. As murine typhus has reemerged, there have been growing reports that this infection has triggered hemophagocytic lymphohistiocytosis, a life-threatening hyperinflammatory syndrome. We herein report two fatal cases of hemophagocytic lymphohistiocytosis secondary to murine typhus. Autopsy revealed typhus group rickettsial antigen in tissues via immunohistochemistry, along with hemophagocytosis. Interestingly, the classic vascular and perivascular histopathologic findings associated with disseminated rickettsial infection were absent. These findings highlight an aberrant inflammatory cascade leading to hemophagocytic lymphohistiocytosis.<\/jats:p>","DOI":"10.3390\/pathogens15020230","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T08:51:09Z","timestamp":1771491069000},"page":"230","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Paucity of Typical Pathology: An Autopsy Series of Typhus Group Rickettsiosis-Associated Hemophagocytic Lymphohistiocytosis"],"prefix":"10.3390","volume":"15","author":[{"given":"Joshua","family":"Klinnert","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0514-4076","authenticated-orcid":false,"given":"Vasily","family":"Ovechko","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0872-5113","authenticated-orcid":false,"given":"Michelle M.","family":"Felicella","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1581-5793","authenticated-orcid":false,"given":"April","family":"McDougal","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3906-312X","authenticated-orcid":false,"given":"Sarah E.","family":"Muir","sequence":"additional","affiliation":[{"name":"John Sealy School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2079-0076","authenticated-orcid":false,"given":"Patricia A.","family":"Crocquet-Valdes","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3309-4360","authenticated-orcid":false,"given":"David H.","family":"Walker","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4653-2323","authenticated-orcid":false,"given":"Lucas S.","family":"Blanton","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"key":"ref_1","first-page":"96","article-title":"Family I. Rickettsiaceae","volume":"Volume 2","author":"Brenner","year":"2005","journal-title":"Bergey\u2019s Manual of Systematic Bacteriology"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Gillespie, J.J., Williams, K., Shukla, M., Snyder, E.E., Nordberg, E.K., Ceraul, S.M., Dharmanolla, C., Rainey, D., Soneja, J., and Shallom, J.M. (2008). Rickettsia phylogenomics: Unwinding the intricacies of obligate intracellular life. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0002018"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"319","DOI":"10.3201\/eid0303.970308","article-title":"Flea-borne rickettsioses: Ecologic considerations","volume":"3","author":"Azad","year":"1997","journal-title":"Emerg. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"412","DOI":"10.3201\/eid1603.091028","article-title":"Murine typhus in Austin, Texas, USA, 2008","volume":"16","author":"Adjemian","year":"2010","journal-title":"Emerg. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"311","DOI":"10.4269\/ajtmh.1970.19.311","article-title":"The changing ecology of murine (endemic) typhus in Southern California","volume":"19","author":"Adams","year":"1970","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"457","DOI":"10.4269\/ajtmh.16-0197","article-title":"Opossums and cat fleas: New insights in the ecology of murine typhus in Galveston, Texas","volume":"95","author":"Blanton","year":"2016","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1086\/527443","article-title":"Murine typhus: An unrecognized suburban vectorborne disease","volume":"46","author":"Civen","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.actatropica.2016.10.018","article-title":"Clinical and laboratory characteristics, epidemiology, and outcomes of murine typhus: A systematic review","volume":"166","author":"Tsioutis","year":"2017","journal-title":"Acta Trop."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.4269\/ajtmh.16-0465","article-title":"Fatal flea-borne typhus in Texas: A retrospective case series, 1985\u20132015","volume":"96","author":"Pieracci","year":"2017","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Doppler, J.F., and Newton, P.N. (2020). A systematic review of the untreated mortality of murine typhus. PLoS Negl. Trop. Dis., 14.","DOI":"10.1371\/journal.pntd.0008641"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"838","DOI":"10.15585\/mmwr.mm7231a1","article-title":"Fleaborne typhus-associated deaths\u2014Los Angeles County, California, 2022","volume":"72","author":"Alarcon","year":"2023","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e01955","DOI":"10.1016\/j.idcr.2024.e01955","article-title":"Severe flea-borne typhus complicated by hemophagocytic lymphohistiocytosis: A case report and review of literature","volume":"36","author":"Mayo","year":"2024","journal-title":"IDCases"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"507","DOI":"10.5858\/arpa.2020-0802-RA","article-title":"Hemophagocytic lymphohistiocytosis","volume":"146","author":"Ponnatt","year":"2022","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1056\/NEJMra2314005","article-title":"Hemophagocytic lymphohistiocytosis","volume":"392","author":"Henter","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e51","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":"ref_16","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1111\/joim.20065","article-title":"Multicenter validation of secondary hemophagocytic lymphohistiocytosis diagnostic criteria","volume":"297","author":"Lachmann","year":"2025","journal-title":"J. Intern. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"ofaa355","DOI":"10.1093\/ofid\/ofaa355","article-title":"A Case of hemophagocytic lymphohistiocytosis associated with Mediterranean spotted fever in a healthy 29-year-old female","volume":"7","author":"Karra","year":"2020","journal-title":"Open Forum Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Naoi, T., Morita, M., Kawakami, T., and Fujimoto, S. (2018). Hemophagocytic lymphohistiocytosis associated with scrub typhus: Systematic review and comparison between pediatric and adult cases. Trop. Med. Infect. Dis., 3.","DOI":"10.3390\/tropicalmed3010019"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"132","DOI":"10.3390\/idr15010014","article-title":"Flea-borne typhus causing hemophagocytic lymphohistiocytosis: An autopsy case","volume":"15","author":"Chandramohan","year":"2023","journal-title":"Infect. Dis. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.bcmd.2015.06.009","article-title":"Ehrlichia-induced hemophagocytic lymphohistiocytosis: A case series and review of literature","volume":"55","author":"Otrock","year":"2015","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"ofad213","DOI":"10.1093\/ofid\/ofad213","article-title":"Anaplasmosis-induced hemophagocytic lymphohistiocytosis: A case report and review of the literature","volume":"10","author":"Scribner","year":"2023","journal-title":"Open Forum Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1002\/jha2.405","article-title":"Secondary hemophagocytic lymphohistiocytosis associated with Rocky Mountain spotted fever in a toddler: A case report","volume":"3","author":"Lim","year":"2022","journal-title":"EJHaem"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.jare.2018.05.007","article-title":"Clinical characteristics and effective treatments of scrub typhus-associated hemophagocytic lymphohistiocytosis in children","volume":"15","author":"Jin","year":"2019","journal-title":"J. Adv. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"108115","DOI":"10.1016\/j.ijid.2025.108115","article-title":"Scrub typhus-associated hemophagocytic lymphohistiocytosis among healthy children: A case series from northern Thailand","volume":"161","author":"Kunanitthaworn","year":"2025","journal-title":"Int. J. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.4269\/ajtmh.2012.11-0794","article-title":"Murine typhus in returned travelers: A report of thirty-two cases","volume":"86","author":"Walter","year":"2012","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_26","first-page":"613","article-title":"Murine typhus in Tenerife. Clinicoepidemiological study and differential clinical features with Q fever","volume":"121","author":"Miguelez","year":"2003","journal-title":"Med. Clin."},{"key":"ref_27","first-page":"122","article-title":"Hemophagocytic lymphohistiocytosis secondary to murine typhus: A case report","volume":"27","author":"Mandell","year":"2025","journal-title":"Isr. Med. Assoc. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1093\/ajcp\/91.6.720","article-title":"Histopathology and immunohistologic demonstration of the distribution of Rickettsia typhi in fatal murine typhus","volume":"91","author":"Walker","year":"1989","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"306","DOI":"10.4269\/ajtmh.18-0084","article-title":"Case Report: Fulminant murine typhus presenting with status epilepticus and multi-organ failure: An autopsy case and a review of the neurologic presentations of murine typhus","volume":"99","author":"Stephens","year":"2018","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1093\/ajcp\/17.10.797","article-title":"Endemic (murine) typhus; report of autopsy findings in three cases","volume":"17","author":"Binford","year":"1947","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.3201\/eid2411.171373","article-title":"Rickettsia typhi as cause of fatal encephalitic typhus in hospitalized patients, Hamburg, Germany, 1940\u20131944","volume":"24","author":"Rauch","year":"2018","journal-title":"Emerg. Infect. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1038\/labinvest.3780144","article-title":"Establishment of a novel endothelial target mouse model of a typhus group rickettsiosis: Evidence for critical roles for gamma interferon and CD8 T lymphocytes","volume":"80","author":"Walker","year":"2000","journal-title":"Lab. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.3201\/eid2407.180093","article-title":"Typhus group rickettsiosis, Germany, 2010\u20132017 (1)","volume":"24","author":"Rauch","year":"2018","journal-title":"Emerg. Infect. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1111\/j.1469-0691.2011.03717.x","article-title":"Coagulation and inflammation in scrub typhus and murine typhus--a prospective comparative study from Laos","volume":"18","author":"Paris","year":"2012","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/nrmicro1866","article-title":"Emerging and re-emerging rickettsioses: Endothelial cell infection and early disease events","volume":"6","author":"Walker","year":"2008","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.3201\/eid2708.203661","article-title":"Spotted fever group rickettsioses in Israel, 2010\u20132019","volume":"27","author":"Cohen","year":"2021","journal-title":"Emerg Infect Dis"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1086\/590211","article-title":"Host- and microbe-related risk factors for and pathophysiology of fatal Rickettsia conorii infection in Portuguese patients","volume":"198","author":"Sousa","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"237","DOI":"10.35946\/arcr.v37.2.08","article-title":"The role of innate immunity in alcoholic liver disease","volume":"37","author":"Nagy","year":"2015","journal-title":"Alcohol. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"185","DOI":"10.35946\/arcr.v37.2.04","article-title":"Impact of alcohol abuse on the adaptive immune system","volume":"37","author":"Pasala","year":"2015","journal-title":"Alcohol. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1128\/CVI.05029-11","article-title":"Ethanol inhibits antigen presentation by dendritic cells","volume":"18","author":"Eken","year":"2011","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1189\/jlb.1A0716-298RR","article-title":"Chronic alcohol consumption inhibits peripheral NK cell development and maturation by decreasing the availability of IL-15","volume":"101","author":"Zhang","year":"2017","journal-title":"J. Leukoc. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"21536","DOI":"10.5070\/D3202021536","article-title":"Why sulfonamides are contraindicated in Rocky Mountain spotted fever","volume":"20","author":"Ren","year":"2014","journal-title":"Dermatol. Online J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1111\/j.1749-6632.1952.tb22662.x","article-title":"Treatment of Rocky Mountain spotted fever with antibiotics","volume":"55","author":"Harrell","year":"1952","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1182\/blood.2018894618","article-title":"Recommendations for the management of hemophagocytic lymphohistiocytosis in adults","volume":"133","author":"Horne","year":"2019","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1097\/CCM.0000000000005361","article-title":"Consensus-based guidelines for the recognition, diagnosis, and management of hemophagocytic lymphohistiocytosis in critically ill children and adults","volume":"50","author":"Hines","year":"2022","journal-title":"Crit. Care Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e1137","DOI":"10.1097\/CCM.0000000000004581","article-title":"Treatment and mortality of hemophagocytic lymphohistiocytosis in adult critically ill patients: A systematic review with pooled analysis","volume":"48","author":"Knaak","year":"2020","journal-title":"Crit. Care Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Eslami, A., Alimoghadam, S., Khodadadi, S., Allahverdi, H., Alimoghadam, R., Kasaeian, A., Mansouri, D., Alimoghaddam, K., and Alavi Darazam, I. (2024). Comprehensive insights into tuberculosis-associated hemophagocytic lymphohistiocytosis: A systematic review. BMC Infect. Dis., 24.","DOI":"10.1186\/s12879-024-10220-7"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1016\/j.amjmed.2025.06.005","article-title":"Murine typhus\u2014A horse in zebra\u2019s clothing","volume":"138","author":"Blanton","year":"2025","journal-title":"Am. J. Med."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/2\/230\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T09:01:32Z","timestamp":1771491692000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/2\/230"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,19]]},"references-count":48,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["pathogens15020230"],"URL":"https:\/\/doi.org\/10.3390\/pathogens15020230","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,19]]}}}