View source for Medicine:Fever of unknown origin

{{Infobox medical condition (new)
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| synonyms        = Pyrexia of unknown origin, ''febris e causa ignota''
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| types           = Various
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'''Fever of unknown origin''' ('''FUO''') refers to a condition in which the patient has an elevated temperature ([[Medicine:Fever|fever]]) but, despite investigations by one or more qualified [[Medicine:Physician|physician]]s, no explanation is found.<ref name="Mandell">
Mandell's Principles and Practices of Infection Diseases 6th Edition (2004) by Gerald L. Mandell MD, MACP, John E. Bennett MD, Raphael Dolin MD, {{ISBN|0-443-06643-4}} · Hardback · 4016 Pages Churchill Livingstone</ref><ref name="Harrison">[http://books.mcgraw-hill.com/medical/harrisons/ Harrison's Principles of Internal Medicine] {{Webarchive|url=https://web.archive.org/web/20120804162006/http://books.mcgraw-hill.com/medical/harrisons/ |date=2012-08-04 }} 16th Edition, The McGraw-Hill Companies, {{ISBN|0-07-140235-7}}</ref><ref name="Oxford">[http://www.oup.com/us/catalog/general/subject/Medicine/PrimaryCare/?ci=0192629220&view=usa The Oxford Textbook of Medicine] {{webarchive|url=https://web.archive.org/web/20060923174110/http://www.oup.com/us/catalog/general/subject/Medicine/PrimaryCare/?ci=0192629220&view=usa |date=2006-09-23 }} Edited by David A. Warrell, Timothy M. Cox and John D. Firth with Edward J. Benz, Fourth Edition (2003), [[Organization:Oxford University Press|Oxford University Press]], {{ISBN|0-19-262922-0}}</ref>

If the cause is found it is usually a [[Medicine:Diagnosis of exclusion|diagnosis of exclusion]], eliminating all possibilities until only the correct explanation remains.

==Causes==
Worldwide, infection is the leading cause of FUO with prevalence varying by country and geographic region.<ref name="Haidar" /> Extrapulmonary tuberculosis is the most frequent cause of FUO.<ref name="Harrison"/>
[[Medicine:Drug-induced hyperthermia|Drug-induced hyperthermia]], as the sole symptom of an [[Medicine:Adverse drug reaction|adverse drug reaction]], should always be considered. Disseminated granulomatoses such as [[Medicine:Tuberculosis|tuberculosis]], [[Medicine:Histoplasmosis|histoplasmosis]], coccidioidomycosis, [[Medicine:Blastomycosis|blastomycosis]] and [[Medicine:Sarcoidosis|sarcoidosis]] are associated with FUO. Lymphomas are the most common cause of FUO in adults. Thromboembolic disease (i.e. pulmonary embolism, deep venous thrombosis) occasionally shows fever. Although infrequent, its potentially lethal consequences warrant evaluation of this cause. Endocarditis, although uncommon, is possible. [[Biology:Bartonella|Bartonella]] infections are also known to cause fever of unknown origin.<ref name="Florin2008">{{cite journal|vauthors=Florin TA, Zaoutis TE, Zaoutis LB |title=Beyond cat scratch disease: widening spectrum of Bartonella henselae infection|journal=Pediatrics|volume=121|issue=5|pages=e1413–e1425 |year=2008|pmid=18443019|doi= 10.1542/peds.2007-1897|s2cid=14094482|url=http://pediatrics.aappublications.org/content/121/5/e1413.long}}</ref>

Human herpes viruses are a common cause of fever of unknown origin with one study showing [[Biology:Cytomegalovirus|Cytomegalovirus]], [[Biology:Epstein–Barr virus|Epstein–Barr virus]], human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7) being present in 15%, 10%, 14% and 4.8% respectively with 10% of people presenting with co-infection (infection with two or more human herpes viruses).<ref name="Haidar">{{cite journal |last1=Haidar |first1=Ghady |last2=Singh |first2=Nina |title=Fever of Unknown Origin |journal=New England Journal of Medicine |date=3 February 2022 |volume=386 |issue=5 |pages=463–477 |doi=10.1056/NEJMra2111003|pmid=35108471 |s2cid=246487696 }}</ref> [[Medicine:Infectious mononucleosis|Infectious mononucleosis]], most commonly caused by EBV, may present as a fever of unknown origin. Other symptoms of infectious mononucleosis vary with age with middle aged adults and the elderly more likely to have a longer duration of fever and [[Medicine:Leukopenia|leukopenia]], and younger adults and adolescents more likely to have splenomegaly, [[Medicine:Pharyngitis|pharyngitis]] and [[Medicine:Lymphadenopathy|lymphadenopathy]].<ref name="Haidar" />

Endemic mycoses such as [[Medicine:Histoplasmosis|histoplasmosis]], [[Medicine:Blastomycosis|blastomycosis]], coccidiomycosis and [[Medicine:Paracoccidioidomycosis|paracoccidioidomycosis]] can cause a fever of unknown origin in immunocompromised as well as immunocompetent people. These endemic mycoses may also present with pulmonary symptoms or extra-pulmonary symptoms such as B symptoms (such as fevers, chills, night sweats, unexplained weight loss).<ref name="Haidar" /> The endemic mycotic infection talaromycosis primarily affects those who are immunocompromised.<ref name="Haidar" /> Invasive opportunistic mycoses may also occur in immunocompromised people; these include [[Medicine:Aspergillosis|aspergillosis]], [[Medicine:Mucormycosis|mucormycosis]], [[Biology:Cryptococcus neoformans|Cryptococcus neoformans]].<ref name="Haidar" />

Cancer can also cause fever of unknown origin. This is thought to be due to release of pyrogenic cytokines from cancer cells as well as due to spontaneous tumor necrosis (sometimes with secondary infections).<ref name="Haidar" /> The cancer types most associated with fever of unknown origin include renal cell carcinoma, [[Medicine:Lymphoma|lymphoma]], [[Medicine:Liver cancer|liver cancer]], [[Medicine:Ovarian cancer|ovarian cancer]] atrial myxoma and [[Medicine:Castleman disease|Castleman disease]].<ref name="Haidar" />

In those with [[Biology:HIV|HIV]] currently being treated with antiretroviral therapy and with a low or undetectable viral load; causes of fever of unknown origin are usually not associated with HIV infection. But in those with AIDS, with high viral loads, viral replication and immune-compromise; cancers  and opportunistic infection are the most common cause of FUO.<ref name="Haidar" /> Approximately 2 weeks after initial HIV infection, with viral loads being high, an [[Medicine:Acute retroviral syndrome|acute retroviral syndrome]] can present with fevers, rash and mono-like symptoms.<ref name="Haidar" /> 

[[Medicine:Immune reconstitution inflammatory syndrome|Immune reconstitution inflammatory syndrome]] is a common cause of FUO when a previously suppressed immune system is re-activated. The newly active immune system often has an exaggerated response against opportunistic pathogens leading to a fever and other inflammatory symptoms. Immune reconstitution syndrome commonly presents as after microbiological control of infection (in cases of immune suppressing pathogens such as HIV) but the syndrome may also present after organ transplant, in the post-partum state, with formerly neutropenic hosts or withdrawing anti-TNF therapy.<ref name="Haidar" />

Auto-inflammatory and auto-immune disorders account for approximately 5-32% of fevers of unknown origin.<ref name="Haidar" /> These can be classified as purely auto-inflammatory disorders (disorders of innate immunity, with dysregulated interleukin 1 beta and/or IL-18 responses), purely auto-immune disorders (in which the adaptive immunity is dysregulated, with a dysregulated type 1 interferon response) or disorders with mixed features.<ref name="Haidar" /> [[Medicine:Rheumatoid arthritis|Rheumatoid arthritis]] or [[Medicine:Adult-onset Still's disease|adult-onset Still's disease]] have mixed features and are common causes of FUO.<ref name="Haidar" />

===Infection===

{| class="wikitable"
|-
! Infection cause !!
|-
| '''Localized pyogenic infections''' ||
{{colbegin}}
* Appendicitis<ref name="Harrisons 18th edition">{{cite book|last1=al.]|first1=ed. Dan L. Longo ... [et|title=Harrison's principles of internal medicine.|date=2012|publisher=McGraw-Hill|location=New York|isbn=978-0071748896|edition=18th}}</ref>
* [[Medicine:Cat-scratch disease|Cat-scratch disease]]<ref name="Harrisons 18th edition" />
* Cholangitis<ref name="Harrisons 18th edition" />
* [[Medicine:Cholecystitis|Cholecystitis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Dental abscess|Dental abscess]]<ref name="Harrisons 18th edition" />
* [[Medicine:Diverticulitis|Diverticulitis]]/[[Medicine:Abscess|abscess]]<ref name="Harrisons 18th edition" />
* Lesser sac abscess<ref name="Harrisons 18th edition" />
* Liver abscess<ref name="Harrisons 18th edition" />
* Mesenteric lymphadenitis<ref name="Harrisons 18th edition" />
* [[Medicine:Osteomyelitis|Osteomyelitis]]<ref name="Harrisons 18th edition" />
* Pancreatic abscess<ref name="Harrisons 18th edition" />
* [[Medicine:Pelvic inflammatory disease|Pelvic inflammatory disease]]<ref name="Harrisons 18th edition" />
* [[Medicine:Urinary tract infection|Perinephric/intrarenal abscess]]<ref name="Harrisons 18th edition" />
* [[Medicine:Acute prostatitis|Prostatic abscess]]<ref name="Harrisons 18th edition" />
* Renal [[Medicine:Malakoplakia|malakoplakia]]<ref name="Harrisons 18th edition" />
* [[Medicine:Sinusitis|Sinusitis]]<ref name="Harrisons 18th edition" />
* Subphrenic abscess<ref name="Harrisons 18th edition" />
* Suppurative [[Medicine:Thrombophlebitis|Thrombophlebitis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Tubo-ovarian abscess|Tubo-ovarian abscess]]<ref name="Harrisons 18th edition" />
{{colend}}
|-
| '''Intravascular infections''' ||
{{colbegin}}
* Bacterial [[Medicine:Aortitis|aortitis]]<ref name="Harrisons 18th edition" />
* Bacterial endocarditis<ref name="Harrisons 18th edition" />
* Vascular catheter infection<ref name="Harrisons 18th edition" />
{{colend}}
|-
| '''Systemic bacterial infections''' ||
{{colbegin}}
* [[Medicine:Bartonellosis|Bartonellosis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Brucellosis|Brucellosis]]<ref name="Harrisons 18th edition" />
* Campylobacter infection<ref name="Harrisons 18th edition" />
* [[Medicine:Cat-scratch disease|Cat-scratch disease]]/bacillary angiomatosis (B. henselae)<ref name="Harrisons 18th edition" />
* Gonococcemia<ref name="Harrisons 18th edition" />
* [[Medicine:Legionnaires' disease|Legionnaires' disease]]<ref name="Harrisons 18th edition" />
* [[Medicine:Leptospirosis|Leptospirosis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Listeriosis|Listeriosis]]<ref name="Harrisons 18th edition" />
* [[Unsolved:Lyme disease|Lyme disease]]<ref name="Harrisons 18th edition" />
* [[Medicine:Melioidosis|Melioidosis]]<ref name="Harrisons 18th edition" />
* Meningococcemia<ref name="Harrisons 18th edition" />
* [[Medicine:Rat-bite fever|Rat-bite fever]]<ref name="Harrisons 18th edition" />
* [[Medicine:Relapsing fever|Relapsing fever]]<ref name="Harrisons 18th edition" />
* [[Medicine:Salmonellosis|Salmonellosis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Syphilis|Syphilis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Tularemia|Tularemia]]<ref name="Harrisons 18th edition" />
* [[Medicine:Typhoid fever|Typhoid fever]]<ref name="Harrisons 18th edition" />
* Vibriosis<ref name="Harrisons 18th edition" />
* Yersinia infection<ref name="Harrisons 18th edition" />
{{colend}}
|-
| '''Mycobacterial infections''' ||
{{colbegin}}
* M. avium/M. intracellulare infections<ref name="Harrisons 18th edition" />
* Other atypical mycobacterial infections<ref name="Harrisons 18th edition" />
* [[Medicine:Tuberculosis|Tuberculosis]]<ref name="Harrisons 18th edition" />
{{colend}}
|-
| '''Other bacterial infections''' ||
{{colbegin}}
* [[Medicine:Actinomycosis|Actinomycosis]]<ref name="Harrisons 18th edition" />
* Bacillary angiomatosis<ref name="Harrisons 18th edition" />
* [[Medicine:Nocardiosis|Nocardiosis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Whipple's disease|Whipple's disease]]<ref name="Harrisons 18th edition" />
{{colend}}
|-
| '''Rickettsial infections''' ||
{{colbegin}}
* [[Medicine:Anaplasmosis|Anaplasmosis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Ehrlichiosis|Ehrlichiosis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Murine typhus|Murine typhus]]<ref name="Harrisons 18th edition" />
* [[Medicine:Q fever|Q fever]]<ref name="Harrisons 18th edition" />
* [[Medicine:Rickettsialpox|Rickettsialpox]]<ref name="Harrisons 18th edition" />
* [[Medicine:Rocky Mountain spotted fever|Rocky Mountain spotted fever]]<ref name="Harrisons 18th edition" />
* [[Medicine:Scrub typhus|Scrub typhus]]<ref name="Harrisons 18th edition" />
{{colend}}
|-
| '''Chlamydial infections''' ||
{{colbegin}}
* [[Medicine:Lymphogranuloma venereum|Lymphogranuloma venereum]]<ref name="Harrisons 18th edition" />
* [[Medicine:Psittacosis|Psittacosis]]<ref name="Harrisons 18th edition" />
* TWAR (C. pneumoniae) infection<ref name="Harrisons 18th edition" />
{{colend}}
|-
| '''Viral infections''' ||
{{colbegin}}
* Chikungunya fever<ref name="Harrisons 18th edition" />
* [[Medicine:Colorado tick fever|Colorado tick fever]]<ref name="Harrisons 18th edition" />
* [[Medicine:Coxsackie B virus|Coxsackie B virus]] infection<ref name="Harrisons 18th edition" />
* [[Biology:Cytomegalovirus|Cytomegalovirus]] infection<ref name="Harrisons 18th edition" />
* Dengue<ref name="Harrisons 18th edition" />
* [[Biology:Epstein–Barr virus|Epstein–Barr virus]] infection<ref name="Harrisons 18th edition" />
* [[Medicine:Hepatitis|Hepatitis]] A, B, C, D, and E<ref name="Harrisons 18th edition" />
* [[Biology:HIV|HIV]] infection<ref name="Harrisons 18th edition" />
* [[Biology:Human herpesvirus 6|Human herpesvirus 6]] infection<ref name="Harrisons 18th edition" />
* [[Medicine:Lymphocytic choriomeningitis|Lymphocytic choriomeningitis]]<ref name="Harrisons 18th edition" />
* Parvovirus B19 infection<ref name="Harrisons 18th edition" />
* [[Biology:Picornavirus|Picornavirus]]<ref name="Harrisons 18th edition" />
{{colend}}
|-
| '''Fungal infections''' ||
{{colbegin}}
* [[Medicine:Aspergillosis|Aspergillosis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Blastomycosis|Blastomycosis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Candidiasis|Candidiasis]]<ref name="Harrisons 18th edition" />
* Coccidioidomycosis<ref name="Harrisons 18th edition" />
* [[Medicine:Cryptococcosis|Cryptococcosis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Histoplasmosis|Histoplasmosis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Mucormycosis|Mucormycosis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Paracoccidioidomycosis|Paracoccidioidomycosis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Pneumocystis pneumonia|Pneumocystis pneumonia]]<ref name="Harrisons 18th edition" />
* [[Medicine:Sporotrichosis|Sporotrichosis]]<ref name="Harrisons 18th edition" />
{{colend}}
|-
| '''Parasitic infections''' ||
{{colbegin}}
* Amebiasis<ref name="Harrisons 18th edition" />
* [[Medicine:Babesiosis|Babesiosis]]<ref name="Harrisons 18th edition" />
* Chagas' disease<ref name="Harrisons 18th edition" />
* [[Medicine:Leishmaniasis|Leishmaniasis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Malaria|Malaria]]<ref name="Harrisons 18th edition" />
* [[Medicine:Strongyloidiasis|Strongyloidiasis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Toxocariasis|Toxocariasis]]<ref name="Harrisons 18th edition" />
* [[Medicine:Toxoplasmosis|Toxoplasmosis]]<ref name="Harrisons 18th edition" />
* Trichinellosis<ref name="Harrisons 18th edition" />
{{colend}}
|-
|}

===Neoplasm===
Although most neoplasms can present with fever, malignant lymphoma is by far the most common diagnosis of FUO among the neoplasms.<ref name="Harrisons 19th edition" /> In some cases the fever even precedes lymphadenopathy detectable by physical examination.<ref name="Harrisons 19th edition" />
{| class="wikitable"
|-
! [[Medicine:Neoplasm|Neoplasm]] cause !! Disease name
|-
| '''Hematologic malignancies''' ||
{{colbegin}}
* [[Medicine:Amyloidosis|Amyloidosis]]<ref name="Harrisons 19th edition" />
* Immunoblastic T-cell lymphoma<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Castleman's disease<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Hodgkin's lymphoma|Hodgkin's lymphoma]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Hypereosinophilic syndrome<ref name="Harrisons 19th edition" />
* [[Medicine:Leukemia|Leukemia]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Lymphomatoid granulomatosis<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Malignant histiocytosis<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Multiple myeloma|Multiple myeloma]]<ref name="Harrisons 19th edition" />
* [[Medicine:Myelodysplastic syndrome|Myelodysplastic syndrome]]<ref name="Harrisons 19th edition" />
* [[Medicine:Myelofibrosis|Myelofibrosis]]<ref name="Harrisons 19th edition" />
* Non-Hodgkin's lymphoma<ref name="Harrisons 18th edition" />
* Plasmacytoma<ref name="Harrisons 19th edition" />
* Systemic mastocytosis<ref name="Harrisons 19th edition" />
* [[Medicine:Vaso-occlusive crisis|Vaso-occlusive crisis]] in sickle cell disease<ref name="Harrisons 19th edition" />
{{colend}}
|-
| '''Solid tumors''' ||
{{colbegin}}
* Colon cancer<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Renal cell carcinoma<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Pancreatic cancer|Pancreatic cancer]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Hepatoma<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Sarcoma|Sarcoma]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Gall bladder [[Medicine:Carcinoma|carcinoma]]<ref name="Harrisons 18th edition" />
* Most of solid tumors and metastases can cause fever.
{{colend}}
|-
| '''Benign''' ||
{{colbegin}}
* Atrial myxoma<ref name="Harrisons 18th edition" />
* Renal Angiomyolipoma<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Biography:Cavernous hemangioma|Cavernous hemangioma]] of the liver<ref name="Harrisons 19th edition" />
* [[Medicine:Craniopharyngioma|Craniopharyngioma]]<ref name="Harrisons 19th edition" />
* Necrosis of dermoid tumor in Gardner syndrome<ref name="Harrisons 19th edition" />
{{colend}}
|-
|}

===Noninfectious inflammatory diseases===

{| class="wikitable"
|-
! Noninfectious inflammatory diseases !! Disease name
|-
| '''Systemic rheumatic and autoimmune diseases''' ||
{{colbegin}}
* [[Medicine:Ankylosing spondylitis|Ankylosing spondylitis]]<ref name="Harrisons 19th edition">{{cite book|title=Harrison's Principles of Internal Medicine|publisher=McGraw-Hill Education|location=US|isbn=978-0071802161|edition=19th|date=2015}}<!--|access-date=2 July 2015--></ref>
* [[Medicine:Antiphospholipid syndrome|Antiphospholipid syndrome]]<ref name="Harrisons 19th edition" />
* Autoimmune Hemolytic anemia<ref name="Harrisons 19th edition" />
* Autoimmune [[Medicine:Hepatitis|Hepatitis]]<ref name="Harrisons 19th edition" />
* [[Medicine:Behçet's disease|Behçet's disease]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Cryoglobulinemia|Cryoglobulinemia]]<ref name="Harrisons 19th edition" />
* [[Medicine:Dermatomyositis|Dermatomyositis]]<ref name="Harrisons 19th edition" />
* Felty syndrome<ref name="Harrisons 19th edition" />
* [[Medicine:Gout|Gout]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Mixed connective tissue disease|Mixed connective tissue disease]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Polymyositis|Polymyositis]]<ref name="Harrisons 19th edition" />
* Pseudogout<ref name="Harrisons 19th edition" />
* [[Medicine:Reactive arthritis|Reactive arthritis]]<ref name="Harrisons 19th edition" />
* [[Medicine:Relapsing polychondritis|Relapsing polychondritis]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Rheumatic fever|Rheumatic fever]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Rheumatoid arthritis|Rheumatoid arthritis]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Sjögren's syndrome<ref name="Harrisons 19th edition" />
* [[Medicine:Systemic lupus erythematosus|Systemic lupus erythematosus]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Vogt–Koyanagi–Harada disease|Vogt–Koyanagi–Harada disease]]<ref name="Harrisons 19th edition" />
{{colend}}
|-
| '''Vasculitis''' ||
{{colbegin}}
* Allergic vasculitis<ref name="Harrisons 19th edition" />
* [[Medicine:Eosinophilic granulomatosis with polyangiitis|Eosinophilic granulomatosis with polyangiitis]] (Churg–Strauss syndrome)<ref name="Harrisons 19th edition" />
* [[Medicine:Giant-cell arteritis|Giant-cell arteritis]]/polymyalgia rheumatica<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Granulomatosis with polyangiitis|Granulomatosis with polyangiitis]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Kawasaki disease|Kawasaki disease]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Hypersensitivity vasculitis<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Polyarteritis nodosa|Polyarteritis nodosa]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Takayasu's arteritis|Takayasu's arteritis]]<ref name="Harrisons 19th edition" />
* [[Medicine:Urticarial vasculitis|Urticarial vasculitis]]<ref name="Harrisons 19th edition" />
{{colend}}
|-
| '''Granulomatous diseases''' ||
{{colbegin}}
* [[Medicine:Idiopathic granulomatous hepatitis|Granulomatous hepatitis]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Sarcoidosis|Sarcoidosis]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Midline granuloma<ref name="Harrisons 18th edition" />
{{colend}}
|-
|-
| '''Autoinflammatory<br />syndromes''' ||
{{colbegin}}
* [[Medicine:Adult-onset Still's disease|Adult-onset Still's disease]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Blau syndrome|Blau syndrome]]<ref name="Harrisons 19th edition" />
* CAPS ([[Medicine:Cryopyrin-associated periodic syndrome|Cryopyrin-associated periodic syndrome]])<ref name="Harrisons 19th edition" />
* [[Medicine:Crohn's disease|Crohn's disease]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* DIRA ([[Medicine:Deficiency of the interleukin-1–receptor antagonist|Deficiency of the interleukin-1–receptor antagonist]])<ref name="Harrisons 19th edition" />
* Erythema multiforme<ref name="Harrisons 18th edition" />
* [[Medicine:Erythema nodosum|Erythema nodosum]]<ref name="Harrisons 18th edition" />
* Hemophagocytic syndrome<ref name="Harrisons 19th edition" />
* Hypersensitivity pneumonitis<ref name="Harrisons 18th edition" />
* [[Medicine:Juvenile idiopathic arthritis|Juvenile idiopathic arthritis]]<ref name="Harrisons 19th edition" />
* [[Medicine:PAPA syndrome|PAPA syndrome]] (pyogenic sterile arthritis, pyoderma gangrenosum, and acne)<ref name="Harrisons 19th edition" />
* [[Medicine:Periodic fever, aphthous stomatitis, pharyngitis and adenitis|PFAPA syndrome: periodic fever, adenitis, pharyngitis, aphthae]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Recurrent idiopathic [[Medicine:Pericarditis|Pericarditis]]<ref name="Harrisons 19th edition" />
* [[Medicine:SAPHO syndrome|SAPHO syndrome]] (synovitis, acne, pustulosis, hyperostosis, osteomyelitis)<ref name="Harrisons 19th edition" />
* [[Medicine:Schnitzler syndrome|Schnitzler syndrome]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Takayasu's arteritis|Takayasu's arteritis]]<ref name="Harrisons 18th edition" />
* Weber–Christian disease<ref name="Harrisons 18th edition" />
{{colend}}
|-
|}

===Miscellaneous conditions===

{{colbegin}}
* ADEM ([[Medicine:Acute disseminated encephalomyelitis|acute disseminated encephalomyelitis]])<ref name="Harrisons 19th edition" />
* Adrenal insufficiency<ref name="Harrisons 19th edition" />
* [[Medicine:Aneurysm|Aneurysm]]<ref name="Harrisons 19th edition" />
* Anomalous thoracic duct<ref name="Harrisons 19th edition" />
* [[Medicine:Aortic dissection|Aortic dissection]]<ref name="Harrisons 18th edition" />
* Aortic-enteral fistula<ref name="Harrisons 19th edition" />
* Aseptic meningitis (Mollaret's syndrome)<ref name="Harrisons 19th edition" />
* Atrial myxoma<ref name="Harrisons 19th edition" />
* Brewer's yeast ingestion<ref name="Harrisons 19th edition" />
* [[Medicine:Caroli disease|Caroli disease]]<ref name="Harrisons 19th edition" />
* Cholesterol emboli<ref name="Harrisons 19th edition" />
* [[Medicine:Complex partial status epilepticus|Complex partial status epilepticus]]<ref name="Harrisons 19th edition" />
* [[Medicine:Cyclic neutropenia|Cyclic neutropenia]]<ref name="Harrisons 19th edition" />
* Drug fever<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Erdheim–Chester disease|Erdheim–Chester disease]]<ref name="Harrisons 19th edition" />
* Extrinsic allergic alveolitis<ref name="Harrisons 19th edition" />
* Factitious disease<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Fire-eater's lung<ref name="Harrisons 19th edition" />
* Fraudulent fever<ref name="Harrisons 19th edition" />
* Gaucher's disease<ref name="Harrisons 19th edition" />
* Hamman–Rich syndrome (acute interstitial pneumonia)<ref name="Harrisons 19th edition" />
* Hashimoto's encephalopathy<ref name="Harrisons 19th edition" />
* Hematomas<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Hemoglobinopathies<ref name="Harrisons 18th edition" />
* Hypersensitivity pneumonitis<ref name="Harrisons 19th edition" />
* Hypertriglyceridemia<ref name="Harrisons 19th edition" />
* Hypothalamic hypopituitarism<ref name="Harrisons 19th edition" />
* Idiopathic normal-pressure hydrocephalus<ref name="Harrisons 19th edition" />
* Inflammatory pseudotumor<ref name="Harrisons 19th edition" />
* Kikuchi's disease<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Linear IgA dermatosis<ref name="Harrisons 19th edition" />
* Laennec's cirrhosis<ref name="Harrisons 18th edition" />
* Mesenteric fibromatosis<ref name="Harrisons 19th edition" />
* Metal fume fever<ref name="Harrisons 19th edition" />
* Milk protein allergy<ref name="Harrisons 19th edition" />
* Myotonic dystrophy<ref name="Harrisons 19th edition" />
* Nonbacterial osteitis<ref name="Harrisons 19th edition" />
* Organic dust toxic syndrome<ref name="Harrisons 19th edition" />
* Panniculitis<ref name="Harrisons 19th edition" />
* POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes)<ref name="Harrisons 19th edition" />
* Polymer fume fever<ref name="Harrisons 19th edition" />
* Post–cardiac injury syndrome<ref name="Harrisons 19th edition" />
* Postmyocardial infarction syndrome<ref name="Harrisons 18th edition" />
* Primary biliary cirrhosis <ref name="Harrisons 19th edition" />
* Primary hyperparathyroidism<ref name="Harrisons 19th edition" />
* [[Medicine:Pulmonary embolism|Recurrent pulmonary emboli]]<ref name="Harrisons 18th edition" />
* Pyoderma gangrenosum<ref name="Harrisons 19th edition" />
* Retroperitoneal fibrosis <ref name="Harrisons 19th edition" />
* Rosai-Dorfman disease<ref name="Harrisons 19th edition" />
* Sclerosing mesenteritis<ref name="Harrisons 19th edition" />
* Silicone embolization<ref name="Harrisons 19th edition" />
* Subacute thyroiditis (de Quervain's)<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Sweet syndrome (acute febrile neutrophilic dermatosis)<ref name="Harrisons 19th edition" />
* Thrombosis<ref name="Harrisons 19th edition" />
* Tubulointerstitial nephritis and uveitis syndrome (TINU)<ref name="Harrisons 19th edition" />
* Tissue infarction/necrosis<ref name="Harrisons 18th edition" />
* [[Medicine:Ulcerative colitis|Ulcerative colitis]]<ref name="Harrisons 19th edition" />
{{colend}}

===Inherited and metabolic diseases===
{{colbegin}}
* Adrenal insufficiency<ref name="Harrisons 18th edition" />
* [[Medicine:Cyclic neutropenia|Cyclic neutropenia]]<ref name="Harrisons 18th edition" />
* Deafness, urticaria, and amyloidosis<ref name="Harrisons 18th edition" />
* [[Medicine:Fabry disease|Fabry disease]]<ref name="Harrisons 18th edition" />
* Familial cold urticaria<ref name="Harrisons 18th edition" />
* [[Medicine:Familial Mediterranean fever|Familial Mediterranean fever]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Hyper-IgD syndrome|Hyperimmunoglobulinemia D and periodic fever]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Muckle–Wells syndrome|Muckle–Wells syndrome]]<ref name="Harrisons 18th edition" />
* [[Medicine:TNF receptor associated periodic syndrome|Tumor necrosis factor receptor–associated periodic syndrome (familial Hibernian fever)]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Type V Hypertriglyceridemia<ref name="Harrisons 18th edition" />
{{colend}}

===Thermoregulatory disorders===

{| class="wikitable"
|-
! Thermoregulatory disorders !! Location
|-
| '''Central''' ||
{{colbegin}}
* [[Medicine:Brain tumor|Brain tumor]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Cerebrovascular accident<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Encephalitis|Encephalitis]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* Hypothalamic dysfunction<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
{{colend}}
|-
| '''Peripheral''' ||
{{colbegin}}
* [[Medicine:Hypohidrotic ectodermal dysplasia|Anhidrotic ectodermal dysplasia]]<ref name="Harrisons 19th edition" />
* Exercise-induced [[Medicine:Hyperthermia|hyperthermia]]<ref name="Harrisons 19th edition" />
* [[Medicine:Hyperthyroidism|Hyperthyroidism]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
* [[Medicine:Pheochromocytoma|Pheochromocytoma]]<ref name="Harrisons 18th edition" /><ref name="Harrisons 19th edition" />
{{colend}}
|-
|}

===Habitual hyperthermia===
* Exaggerated [[Biology:Circadian rhythm|circadian rhythm]]<ref name="Harrisons 18th edition" />

===Other===
* “Afebrile” FUO [<38.3&nbsp;°C (100.9&nbsp;°F)]<ref name="Harrisons 18th edition" />

==Diagnosis==
A comprehensive and meticulous history (i.e. illness of family members, recent visit to the tropics, medication), repeated physical examination (i.e. skin rash, [[Biology:Eschar|eschar]], [[Medicine:Lymphadenopathy|lymphadenopathy]], [[Physics:Heart murmur|heart murmur]]) and myriad laboratory tests (serological, blood culture, immunological) are the cornerstone of finding the cause.<ref name="Mandell"/><ref name="Oxford"/>

Other investigations may be needed. Ultrasound may show cholelithiasis, [[Medicine:Echocardiography|echocardiography]] may be needed in suspected endocarditis and a CT-scan may show infection or malignancy of internal organs. Another technique is Gallium-67 scanning which seems to visualize chronic infections more effectively. Invasive techniques (biopsy and laparotomy for pathological and bacteriological examination) may be required before a definite diagnosis is possible.<ref name="Mandell"/><ref name="Oxford"/>

[[Physics:Positron emission tomography|Positron emission tomography]] using radioactively labelled fluorodeoxyglucose (FDG) has been reported to have a sensitivity of 84% and a specificity of 86% for localizing the source of fever of unknown origin.<ref>{{cite journal |vauthors=Meller J, Altenvoerde G, Munzel U, Jauho A, Behe M, Gratz S, Luig H, Becker W | title = Fever of unknown origin: prospective comparison of [18F]FDG imaging with a double-head coincidence camera and gallium-67 citrate SPET. | journal = Eur J Nucl Med. | volume = 27| issue = 11 | pages = 1617–1625 | year = 2000 | pmid = 11105817 | doi = 10.1007/s002590000341| s2cid = 6114482 }}</ref>

Despite all this, diagnosis may only be suggested by the therapy chosen. When a patient recovers after discontinuing medication it likely was drug fever, when antibiotics or antimycotics work it probably was infection. Empirical therapeutic trials should be used in those patients in which other techniques have failed.<ref name="Mandell"/>

===Definition===
There is no universal agreement with regards to time criteria or other diagnostic criteria to diagnose a fever of unknown origin and various definitions have been used.<ref name="Haidar" />

In 1961 Petersdorf and Beeson suggested the following criteria:<ref name="Mandell"/><ref name="Harrison"/>
* Fever higher than 38.3&nbsp;°C (101&nbsp;°F) on several occasions
* Persisting without diagnosis for at least 3 weeks
* At least 1 week's investigation in hospital

A new definition which includes the outpatient setting (which reflects current medical practice) is broader, stipulating:
* 3 outpatient visits or
* 3 days in the hospital without elucidation of a cause or
* 1 week of "intelligent and invasive" ambulatory investigation.<ref name="Harrison"/>

Presently FUO cases are codified in four subclasses.

====Classic====
This refers to the original classification by Petersdorf and Beeson. Studies show there are five categories of conditions:{{cn|date=March 2022}}
* [[Medicine:Infection|infection]]s (e.g.  abscesses, [[Medicine:Endocarditis|endocarditis]], [[Medicine:Tuberculosis|tuberculosis]], and complicated [[Medicine:Urinary tract infection|urinary tract infection]]s),
* [[Medicine:Neoplasm|neoplasm]]s (e.g. [[Medicine:Lymphoma|lymphoma]]s, leukaemias),
* connective tissue diseases (e.g. temporal arteritis and polymyalgia rheumatica, [[Medicine:Adult-onset Still's disease|Still's disease]], [[Medicine:Systemic lupus erythematosus|systemic lupus erythematosus]], and [[Medicine:Rheumatoid arthritis|rheumatoid arthritis]]),
* miscellaneous disorders (e.g.  [[Medicine:Alcoholic hepatitis|alcoholic hepatitis]], [[Medicine:Granuloma|granuloma]]tous conditions), and
* undiagnosed conditions.<ref name="Mandell"/><ref name="Oxford"/>

====Nosocomial====
Nosocomial FUO refers to pyrexia in patients that have been admitted to hospital for at least 24 hours. This is commonly related to hospital-associated factors such as surgery, use of a urinary catheter, intravascular devices (i.e. "drip", [[Medicine:Pulmonary artery catheter|pulmonary artery catheter]]), drugs (antibiotic-induced ''Clostridium difficile'' colitis, drug fever), and/or immobilization (decubitus ulcers). [[Medicine:Sinusitis|Sinusitis]] in the [[Medicine:Intensive care unit|intensive care unit]] is associated with nasogastric and orotracheal tubes.<ref name="Mandell"/><ref name="Harrison"/><ref name="Oxford"/> Other conditions that should be considered are deep-vein thrombophlebitis, [[Medicine:Pulmonary embolism|pulmonary embolism]], transfusion reactions, acalculous cholecystitis, [[Medicine:Thyroiditis|thyroiditis]], alcohol/drug withdrawal, adrenal insufficiency, and [[Medicine:Pancreatitis|pancreatitis]].<ref name="Harrison"/>

====Immune-deficient====
Immunodeficiency can be seen in patients receiving [[Medicine:Chemotherapy|chemotherapy]] or in hematologic malignancies. Fever is concomitant with [[Medicine:Neutropenia|neutropenia]] ([[Biology:Neutrophil|neutrophil]] <500/uL) or impaired cell-mediated immunity. The lack of immune response masks a potentially dangerous course. Infection is the most common cause.<ref name="Mandell"/><ref name="Harrison"/><ref name="Oxford"/>

====Human immunodeficiency virus (HIV)-associated====

HIV-infected patients are a subgroup of the immunodeficient FUO, and frequently have fever. The primary phase shows fever since it has a [[Medicine:Infectious mononucleosis|mononucleosis]]-like illness. In advanced stages of infection fever mostly is the result of a superimposed infections.<ref name="Mandell"/><ref name="Harrison"/><ref name="Oxford"/>

==Treatment==
Unless the patient is acutely ill, no therapy should be started before the cause has been found. This is because non-specific therapy is rarely effective and may delay the diagnosis. An exception is made for [[Medicine:Neutropenia|neutropenic]] (low white blood cell count) patients or patients who are severely immunocompromised in which delay could lead to serious complications.<ref name="Haidar" /> After blood cultures are taken this condition is aggressively treated with broad-spectrum antibiotics. Antibiotics are adjusted according to the results of the cultures taken.<ref name="Mandell"/><ref name="Harrison"/><ref name="Oxford"/>

HIV-infected people with pyrexia and [[Medicine:Hypoxia (medical)|hypoxia]] will be started on medication for possible [[Medicine:Pneumocystis pneumonia|''Pneumocystis jirovecii'' infection]]. Therapy is adjusted after a diagnosis is made.<ref name="Oxford"/>

==Prognosis==
Since there is a wide range of conditions associated with FUO, prognosis depends on the particular cause.<ref name="Mandell"/> If after six to twelve months no diagnosis is found, the chances of ever finding a specific cause diminish.<ref name="Oxford"/> Under those circumstances, the prognosis is good.<ref name="Harrison"/>

== See also ==
* [[Medicine:Chronic fatigue syndrome|Chronic fatigue syndrome]]
* [[Medicine:Encephalitis lethargica|Encephalitis lethargica]]
* Idiopathic chronic fatigue
* [[Medicine:Idiopathic disease|Idiopathic disease]]

==References==
{{Reflist}}

== External links ==
{{Medical resources
|   DiseasesDB     =
|   ICD10          = {{ICD10|R|50||r|50}}
|   ICD9           = {{ICD9|780.6}}
|   ICDO           =
|   OMIM           =
|   MedlinePlus    = 003090
|   eMedicineSubj  =
|   eMedicineTopic =
|   MeshID         = D005335
}}
{{General symptoms and signs}}

[[Category:Infectious diseases]]

{{Sourceattribution|Fever of unknown origin}}