{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T06:21:15Z","timestamp":1782195675768,"version":"3.54.5"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"1082","license":[{"start":{"date-parts":[[2015,10,21]],"date-time":"2015-10-21T00:00:00Z","timestamp":1445385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,12,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>In 1925, Sir Thomas Horder, a leading physician of his day, gave a lecture, published in this journal, entitled \u2018Some cases of pyrexia without physical signs\u2019. The paper highlighted what was already a familiar clinical presentation \u201cwhich taxes our resources to the utmost\u201d. Fast-forward through 90\u2005years of careful clinical description, technological innovation in diagnosis and treatment, emergent infections, novel diagnoses, demographic shifts, and radical changes in the health economy. Sir Thomas would find certain aspects familiar, and others revolutionary, in the differential diagnosis and management of the 21st century patient with pyrexia of unknown origin (PUO). Within high-income settings, the proportion of cases due to infection has declined, albeit unevenly. The era of untreated HIV, and the consequences of iatrogenic intervention and immunosuppression, led to Durack and Street\u2019s subclassification of the condition in the early 1990s into classic, nosocomial, neutropenic and HIV-associated PUO. Shifts towards ambulatory care have driven a change in the definition of many diseases. An era of observant clinicians, who lent their names to eponymous syndromes, followed by meticulous serological, genetic and clinicopathological correlation, generated a battery of diagnoses that, along with malignancy, form a large proportion of diagnoses in more recent clinical care. In the current era, universal access to cross-sectional imaging and an infinite array of laboratory tests has undermined the attention paid to history and examination. In some areas of the clinical assessment, such as assessing the fever pattern, this shift is supported by research evidence. The issues that need to be addressed in the next 90\u2005years of technological innovation, information sharing and health service transformation are likely to include: transcriptomic approaches to diagnosis; the place of positron emission tomography (PET) in the diagnostic pathway; the optimal management of high ferritin states; and the most cost-effective diagnostic environment, in the face of this era of specialisation and fragmentation of care. In the meantime, this review covers some important early 21st century lessons to be shared in avoiding diagnostic pitfalls and choosing empirical therapy.<\/jats:p>","DOI":"10.1136\/postgradmedj-2015-133554","type":"journal-article","created":{"date-parts":[[2015,10,22]],"date-time":"2015-10-22T02:58:27Z","timestamp":1445482707000},"page":"665-669","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Pyrexia of unknown origin 90\u2005years on: a paradigm of modern clinical medicine"],"prefix":"10.1093","volume":"91","author":[{"given":"Michael","family":"Brown","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,10,21]]},"reference":[{"key":"2023041905523838700_R1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1136\/pgmj.1.2.17","article-title":"Some cases of pyrexia without physical signs","volume":"1","author":"Horder","year":"1925","journal-title":"Postgrad Med J"},{"key":"2023041905523838700_R2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/00005792-196102000-00001","article-title":"Fever of unexplained origin: report on 100 cases","volume":"40","author":"Petersdorf","year":"1961","journal-title":"Medicine (Baltimore)"},{"key":"2023041905523838700_R3","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1097\/MD.0b013e31802fe858","article-title":"A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol","volume":"86","author":"Bleeker-Rovers","year":"2007","journal-title":"Medicine (Baltimore)"},{"key":"2023041905523838700_R4","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1097\/00005792-199711000-00002","article-title":"Fever of unknown origin (FUO). I. A prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria. The Netherlands FUO Study Group","volume":"76","author":"De Kleijn","year":"1997","journal-title":"Medicine (Baltimore)"},{"key":"2023041905523838700_R5","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1001\/archinte.163.9.1033","article-title":"From prolonged febrile illness to fever of unknown origin: the challenge continues","volume":"163","author":"Vanderschueren","year":"2003","journal-title":"Arch Intern Med"},{"key":"2023041905523838700_R6","first-page":"35","article-title":"Fever of unknown origin--reexamined and redefined","volume":"11","author":"Durack","year":"1991","journal-title":"Curr Clin Top Infect Dis"},{"key":"2023041905523838700_R7","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3389\/fcimb.2014.00025","article-title":"The diagnosis of infectious diseases by whole genome next generation sequencing: a new era is opening","volume":"4","author":"Lecuit","year":"2014","journal-title":"Front Cell Infect Microbiol"},{"key":"2023041905523838700_R8","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1101\/gr.171934.113","article-title":"A cloud-compatible bioinformatics pipeline for ultrarapid pathogen identification from next-generation sequencing of clinical samples","volume":"24","author":"Naccache","year":"2014","journal-title":"Genome Res"},{"key":"2023041905523838700_R9","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1093\/cid\/ciu912","article-title":"Diagnosis of neuroinvasive astrovirus infection in an immunocompromised adult with encephalitis by unbiased next-generation sequencing","volume":"60","author":"Naccache","year":"2015","journal-title":"Clin Infect Dis"},{"key":"2023041905523838700_R10","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1093\/cid\/ciu940","article-title":"Astrovirus VA1\/HMO-C: an increasingly recognized neurotropic pathogen in immunocompromised patients","volume":"60","author":"Brown","year":"2015","journal-title":"Clin Infect Dis"},{"key":"2023041905523838700_R11","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1136\/bmj.39003.640567.AE","article-title":"Googling for a diagnosis--use of Google as a diagnostic aid: internet based study","volume":"333","author":"Tang","year":"2006","journal-title":"BMJ"},{"key":"2023041905523838700_R12","doi-asserted-by":"crossref","first-page":"e35290","DOI":"10.1371\/journal.pone.0035290","article-title":"Peripheral T cell cytokine responses for diagnosis of active tuberculosis","volume":"7","author":"Nemeth","year":"2012","journal-title":"PLoS ONE"},{"key":"2023041905523838700_R13","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1086\/515143","article-title":"Relative bradycardia is not a feature of enteric fever in children","volume":"28","author":"Davis","year":"1999","journal-title":"Clin Infect Dis"},{"key":"2023041905523838700_R14","doi-asserted-by":"crossref","first-page":"728","DOI":"10.7326\/0003-4819-106-5-728","article-title":"Drug fever: a critical appraisal of conventional concepts. An analysis of 51 episodes in two Dallas hospitals and 97 episodes reported in the English literature","volume":"106","author":"Mackowiak","year":"1987","journal-title":"Ann Intern Med"},{"key":"2023041905523838700_R15","volume-title":"RCP comment on Commission on Generalism report. Guiding","author":"Royal College of General Practitioners and the Health Foundation","year":"2011"},{"key":"2023041905523838700_R16","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.ejim.2009.01.002","article-title":"Inflammation of unknown origin versus fever of unknown origin: two of a kind","volume":"20","author":"Vanderschueren","year":"2009","journal-title":"Eur J Intern Med"},{"key":"2023041905523838700_R17","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1001\/archinte.163.5.545","article-title":"A comprehensive evidence-based approach to fever of unknown origin","volume":"163","author":"Mourad","year":"2003","journal-title":"Arch Intern Med"},{"key":"2023041905523838700_R18","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1179\/2295333714Y.0000000070","article-title":"Tackling fever and inflammation of unknown origin: the do's and don'ts","volume":"69","author":"Vanderschueren","year":"2014","journal-title":"Acta Clin Belg"},{"key":"2023041905523838700_R19","doi-asserted-by":"crossref","first-page":"e233","DOI":"10.1016\/j.lpm.2014.02.026","article-title":"Fever of unknown origin in the 2000s: evaluation of 103 cases over eleven years","volume":"43","author":"Robine","year":"2014","journal-title":"Presse M\u00e9d"},{"key":"2023041905523838700_R20","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/1471-2334-9-105","article-title":"Use of a T cell interferon gamma release assay in the investigation for suspected active tuberculosis in a low prevalence area","volume":"9","author":"Winqvist","year":"2009","journal-title":"BMC Infect Dis"},{"key":"2023041905523838700_R21","doi-asserted-by":"crossref","first-page":"5486","DOI":"10.1128\/IAI.01436-08","article-title":"Frequencies of region of difference 1 antigen-specific but not purified protein derivative-specific gamma interferon-secreting T cells correlate with the presence of tuberculosis disease but do not distinguish recent from remote latent infections","volume":"77","author":"Hinks","year":"2009","journal-title":"Infect Immun"},{"key":"2023041905523838700_R22","doi-asserted-by":"crossref","first-page":"91","DOI":"10.4103\/0970-2113.148467","article-title":"Interferon gamma release assay and tuberculin skin test positivity in sarcoidosis","volume":"32","author":"Vyas","year":"2015","journal-title":"Lung India"},{"key":"2023041905523838700_R23","first-page":"298405","article-title":"Ferritin in adult-onset Still's disease: just a useful innocent bystander?","volume":"2012","author":"Mehta","year":"2012","journal-title":"Int J Inflamm"},{"key":"2023041905523838700_R24","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.mayocp.2011.08.002","article-title":"Predictive parameters for a diagnostic bone marrow biopsy specimen in the work-up of fever of unknown origin","volume":"87","author":"Ben-Baruch","year":"2012","journal-title":"Mayo Clin Proc"},{"key":"2023041905523838700_R25","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1001\/archinternmed.2009.401","article-title":"Yield of bone marrow examination in diagnosing the source of fever of unknown origin","volume":"169","author":"Hot","year":"2009","journal-title":"Arch Intern Med"},{"key":"2023041905523838700_R26","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.ejrad.2010.11.018","article-title":"A meta-analysis of the value of fluorodeoxyglucose-PET\/PET-CT in the evaluation of fever of unknown origin","volume":"80","author":"Dong","year":"2011","journal-title":"Eur J Radiol"},{"key":"2023041905523838700_R27","doi-asserted-by":"crossref","first-page":"654","DOI":"10.12968\/hmed.2013.74.11.654","article-title":"Use of CT-PET imaging investigation of pyrexia of unknown origin","volume":"74","author":"Bharucha","year":"2013","journal-title":"Br J Hosp Med (Lond)"},{"key":"2023041905523838700_R28","first-page":"51","article-title":"FDG-PET in patients with fever of unknown origin: the importance of diagnosing large vessel vasculitis","volume":"53","author":"Meller","year":"2009","journal-title":"Q J Nucl Med Mol Imaging"},{"key":"2023041905523838700_R29","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1002\/jhm.463","article-title":"The devil is in the details","volume":"4","author":"Jenkins","year":"2009","journal-title":"J Hosp Med"},{"key":"2023041905523838700_R30","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.3899\/jrheum.111549","article-title":"Beneficial effect of interleukin 1 inhibition with anakinra in adult-onset Still's disease. An open, randomized, multicenter study","volume":"39","author":"Nordstr\u00f6m","year":"2012","journal-title":"J Rheumatol"}],"container-title":["Postgraduate Medical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/pmj\/article-pdf\/91\/1082\/665\/49967447\/postgradmedj-91-665.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/pmj\/article-pdf\/91\/1082\/665\/49967447\/postgradmedj-91-665.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,19]],"date-time":"2023-04-19T05:53:00Z","timestamp":1681883580000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/pmj\/article\/91\/1082\/665\/6994949"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10,21]]},"references-count":30,"journal-issue":{"issue":"1082","published-online":{"date-parts":[[2015,10,21]]},"published-print":{"date-parts":[[2015,12,1]]}},"URL":"https:\/\/doi.org\/10.1136\/postgradmedj-2015-133554","relation":{},"ISSN":["1469-0756","0032-5473"],"issn-type":[{"value":"1469-0756","type":"electronic"},{"value":"0032-5473","type":"print"}],"subject":[],"published-other":{"date-parts":[[2015,12]]},"published":{"date-parts":[[2015,10,21]]}}}