Fever of unknown origin

Fever of unknown origin
Classification and external resources
ICD-10	R50
ICD-9-CM	780.6
MedlinePlus	003090
MeSH	D005335

Fever of unknown origin (FUO), pyrexia of unknown origin (PUO) or febris e causa ignota (febris E.C.I.) refers to a condition in which the patient has an elevated temperature (fever) but despite investigations by a physician no explanation has been found.^{[1][2][3][4][5]}

If the cause is found it is usually a diagnosis of exclusion, that is, by eliminating all possibilities until only one explanation remains, and taking this as the correct one.

Definition

In 1961 Petersdorf and Beeson suggested the following criteria:^[1][2]

• Fever higher than 38.3 °C (101 °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.^[2]

Presently FUO cases are codified in four subclasses.

Classic FUO

This refers to the original classification by Petersdorf and Beeson. Studies show there are five categories of conditions:

• infections (e.g. abscesses, endocarditis, tuberculosis, and complicated urinary tract infections),
• neoplasms (e.g. lymphomas, leukaemias),
• connective tissue diseases (e.g. temporal arteritis and polymyalgia rheumatica, Still's disease, systemic lupus erythematosus, and rheumatoid arthritis),
• miscellaneous disorders (e.g. alcoholic hepatitis, granulomatous conditions), and
• undiagnosed conditions.^[1][3]

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", pulmonary artery catheter), drugs (antibiotic-induced Clostridium difficile colitis, drug fever), and/or immobilization (decubitus ulcers). Sinusitis in the intensive care unit is associated with nasogastric and orotracheal tubes.^[1][2][3] Other conditions that should be considered are deep-vein thrombophlebitis, pulmonary embolism, transfusion reactions, acalculous cholecystitis, thyroiditis, alcohol/drug withdrawal, adrenal insufficiency, and pancreatitis.^[2]

Immune-deficient

Immunodeficiency can be seen in patients receiving chemotherapy or in hematologic malignancies. Fever is concomitant with neutropenia (neutrophil <500/uL) or impaired cell-mediated immunity. The lack of immune response masks a potentially dangerous course. Infection is the most common cause.^[1][2][3]

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 mononucleosis-like illness. In advanced stages of infection fever mostly is the result of a superimposed infections.^[1][2][3]

African hantavirus (Sangassou virus)

In 2010, the first indigenous African hantavirus, Sangassou virus (SANGV) was isolated from an African wood mouse in a forest in Guinea, West Africa. A retrospective seroepidemiological analysis revealed the presence of Sangassou virus-specific neutralizing antibodies in the sera of patients suffering from fever of unknown origin.^[6][7]

Causes

Extrapulmonary tuberculosis is the most frequent cause of FUO.^[2] Drug-induced hyperthermia, as the sole symptom of an adverse drug reaction, should always be considered. Disseminated granulomatoses such as tuberculosis, histoplasmosis, coccidioidomycosis, blastomycosis and 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 another important etiology to consider. An underestimated reason is factitious fever. Patients frequently are women that work, or have worked, in the medical field and have complex medical histories.^[1][8] Bartonella infections are also known to cause fever of unknown origin.^[9]

Here are the known causes of FUO.^[10]

Infection

Infection cause	Disease name
Localized pyogenic infections	Appendicitis[10] Cat-scratch disease[10] Cholangitis[10] Cholecystitis[10] Dental abscess[10] Diverticulitis/abscess[10] Lesser sac abscess[10] Liver abscess[10] Mesenteric lymphadenitis[10] Osteomyelitis[10] Pancreatic abscess[10] Pelvic inflammatory disease[10] Perinephric/intrarenal abscess[10] Prostatic abscess[10] Renal malakoplakia[10] Sinusitis[10] Subphrenic abscess[10] Suppurative Thrombophlebitis[10] Tubo-ovarian abscess[10]
Intravascular infections	Bacterial aortitis[10] Bacterial endocarditis[10] Vascular catheter infection[10]
Systemic bacterial infections	Bartonellosis[10] Brucellosis[10] Campylobacter infection[10] Cat-scratch disease/bacillary angiomatosis (B. henselae)[10] Gonococcemia[10] Legionnaires' disease[10] Leptospirosis[10] Listeriosis[10] Lyme disease[10] Melioidosis[10] Meningococcemia[10] Rat-bite fever[10] Relapsing fever[10] Salmonellosis[10] Syphilis[10] Tularemia[10] Typhoid fever[10] Vibriosis[10] Yersinia infection [10]
Mycobacterial infections	M. avium/M. intracellulare infections[10] Other atypical mycobacterial infections[10] Tuberculosis[10]
Other bacterial infections	Actinomycosis[10] Bacillary angiomatosis[10] Nocardiosis[10] Whipple's disease[10]
Rickettsial infections	Anaplasmosis[10] Ehrlichiosis[10] Murine typhus[10] Q fever[10] Rickettsialpox[10] Rocky Mountain spotted fever[10] Scrub typhus[10]
Chlamydial infections	Lymphogranuloma venereum[10] Psittacosis[10] TWAR (C. pneumoniae) infection[10]
Viral infections	Chikungunya fever[10] Colorado tick fever[10] Coxsackie B virus infection[10] Cytomegalovirus infection[10] Dengue[10] Epstein-Barr virus infection[10] Hepatitis A, B, C, D, and E[10] HIV infection[10] Human herpesvirus 6 infection[10] Lymphocytic choriomeningitis[10] Parvovirus B19 infection[10] Picornavirus[10]
Fungal infections	Aspergillosis[10] Blastomycosis[10] Candidiasis[10] Coccidioidomycosis[10] Cryptococcosis[10] Histoplasmosis[10] Mucormycosis[10] Paracoccidioidomycosis[10] Pneumocystis pneumonia[10] Sporotrichosis[10]
Parasitic infections	Amebiasis[10] Babesiosis[10] Chagas' disease[10] Leishmaniasis[10] Malaria[10] Strongyloidiasis[10] Toxocariasis[10] Toxoplasmosis[10] Trichinellosis[10]

Neoplasm

Although most neoplasms can present with fever, malignant lymphoma is by far the most common diagnosis of FUO among the neoplasms.^[11] In some cases the fever even precedes lymphadenopathy detectable by physical examination.^[11]

Neoplasm cause	Disease name
Hematologic malignancies	Amyloidosis[11] Immunoblastic T-cell lymphoma[10][11] Castleman's disease[10][11] Hodgkin's lymphoma[10][11] Hypereosinophilic syndrome[11] Leukemia[10][11] Lymphomatoid granulomatosis[10][11] Malignant histiocytosis[10][11] Multiple myeloma[11] Myelodysplastic syndrome[11] Myelofibrosis[11] Non-Hodgkin's lymphoma[10] Plasmacytoma[11] Systemic mastocytosis[11] Vaso-occlusive crisis in sickle cell disease[11]
Solid tumors	Colon cancer[10][11] Renal cell carcinoma[10][11] Pancreatic cancer[10][11] Hepatoma[10][11] Sarcoma[10][11] Gall bladder carcinoma[10] Most of solid tumors and metastases can cause fever. Those most commonly causing FUO are: breast, colon, hepatocellular, lung, pancreatic, and renal cell carcinomas.[11]
Benign	Atrial myxoma[10] Renal Angiomyolipoma[10][11] Cavernous hemangioma of the liver[11] Craniopharyngioma[11] Necrosis of dermoid tumor in Gardner syndrome[11]

Noninfectious inflammatory diseases

Noninfectious inflammatory diseases	Disease name
Systemic rheumatic and autoimmune diseases	Ankylosing spondylitis [11] Antiphospholipid syndrome [11] Autoimmune Hemolytic anemia[11] Autoimmune Hepatitis[11] Behçet's disease[10][11] Cryoglobulinemia[11] Dermatomyositis[11] Felty syndrome[11] Gout[10][11] Mixed connective tissue disease[10][11] Polymyositis[11] Pseudogout[11] Reactive arthritis[11] Relapsing polychondritis[10][11] Rheumatic fever[10][11] Rheumatoid arthritis[10][11] Sjögren’s syndrome[11] Systemic lupus erythematosus[10][11] Vogt-Koyanagi-Harada syndrome[11]
Vasculitis	Allergic vasculitis[11] Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)[11] Giant-cell arteritis/polymyalgia rheumatica[10][11] Granulomatosis with polyangiitis[10][11] Kawasaki's disease[10][11] Hypersensitivity vasculitis[10][11] Polyarteritis nodosa[10][11] Takayasu arteritis[11] Urticarial vasculitis[11]
Granulomatous diseases	Granulomatous hepatitis[10][11] Sarcoidosis[10][11] Midline granuloma[10]
Autoinflammatory syndromes	Adult-onset Still's disease[10][11] Blau syndrome[11] CAPS (Cryopyrin-associated periodic syndrome)[11] Crohn's disease[10][11] DIRA (Deficiency of the interleukin-1–receptor antagonist)[11] Erythema multiforme[10] Erythema nodosum[10] Hemophagocytic syndrome[11] Hypersensitivity pneumonitis[10] Juvenile idiopathic arthritis[11] PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne)[11] PFAPA syndrome: periodic fever, adenitis, pharyngitis, aphthae[10][11] Recurrent idiopathic Pericarditis[11] SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteomyelitis)[11] Schnitzler's syndrome[10][11] Takayasu's arteritis[10] Weber-Christian disease[10]

Miscellaneous conditions

• ADEM (acute disseminated encephalomyelitis)^[11]
• Adrenal insufficiency^[11]
• Aneurysm^[11]
• Anomalous thoracic duct^[11]
• Aortic dissection^[10]
• Aortic-enteral fistula^[11]
• Aseptic meningitis (Mollaret’s syndrome)^[11]
• Atrial myxoma^[11]
• Brewer’s yeast ingestion^[11]
• Caroli disease^[11]
• Cholesterol emboli^[11]
• Complex partial status epilepticus^[11]
• Cyclic neutropenia^[11]
• Drug fever^[10][11]
• Erdheim-Chester disease^[11]
• Extrinsic allergic alveolitis^[11]
• Factitious disease^[10][11]
• Fire-eater’s lung^[11]
• Fraudulent fever^[11]
• Gaucher’s disease^[11]
• Hamman-Rich syndrome (acute interstitial pneumonia)^[11]
• Hashimoto’s encephalopathy^[11]
• Hematomas^[10][11]
• Hemoglobinopathies^[10]
• Hypersensitivity pneumonitis^[11]
• Hypertriglyceridemia^[11]
• Hypothalamic hypopituitarism^[11]
• Idiopathic normal-pressure hydrocephalus^[11]
• Inflammatory pseudotumor^[11]
• Kikuchi’s disease^[10][11]
• Linear IgA dermatosis^[11]
• Laennec's cirrhosis^[10]
• Mesenteric fibromatosis^[11]
• Metal fume fever^[11]
• Milk protein allergy^[11]
• Myotonic dystrophy^[11]
• Nonbacterial osteitis^[11]
• Organic dust toxic syndrome^[11]
• Panniculitis^[11]
• POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes)^[11]
• Polymer fume fever^[11]
• Post–cardiac injury syndrome^[11]
• Postmyocardial infarction syndrome^[10]
• Primary biliary cirrhosis ^[11]
• Primary hyperparathyroidism^[11]
• Recurrent pulmonary emboli^[10]
• Pyoderma gangrenosum^[11]
• Retroperitoneal fibrosis ^[11]
• Rosai-Dorfman disease^[11]
• Sclerosing mesenteritis^[11]
• Silicone embolization^[11]
• Subacute thyroiditis (de Quervain's)^[10][11]
• Sweet syndrome (acute febrile neutrophilic dermatosis)^[11]
• Thrombosis^[11]
• Tubulointerstitial nephritis and uveitis syndrome (TINU)^[11]
• Tissue infarction/necrosis^[10]
• Ulcerative colitis^[11]

Inherited and metabolic diseases

• Adrenal insufficiency^[10]
• Cyclic neutropenia^[10]
• Deafness, urticaria, and amyloidosis^[10]
• Fabry disease^[10]
• Familial cold urticaria^[10]
• Familial Mediterranean fever^[10][11]
• Hyperimmunoglobulinemia D and periodic fever^[10][11]
• Muckle-Wells syndrome^[10]
• Tumor necrosis factor receptor–associated periodic syndrome (familial Hibernian fever)^[10][11]
• Type V Hypertriglyceridemia^[10]

Thermoregulatory disorders

Thermoregulatory disorders	Location
Central	Brain tumor[10][11] Cerebrovascular accident[10][11] Encephalitis[10][11] Hypothalamic dysfunction[10][11]
Peripheral	Anhidrotic ectodermal dysplasia[11] Exercise-induced hyperthermia[11] Hyperthyroidism[10][11] Pheochromocytoma[10][11]

Habitual hyperthermia

• Exaggerated circadian rhythm^[10]

Other

• “Afebrile” FUO [<38.3 °C (100.94 °F)]^[10]

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, eschar, lymphadenopathy, heart murmur) and myriad laboratory tests (serological, blood culture, immunological) are the cornerstone of finding the cause.^[1][3]

Other investigations may be needed. Ultrasound may show cholelithiasis, 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.^[1][3]

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.^[12]

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.^[1]

Therapy

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 mostly delays diagnosis. An exception is made for neutropenic patients in which delay could lead to serious complications. 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.^[1][2][3]

HIV-infected persons with pyrexia and hypoxia will be started on medication for possible Pneumocystis jirovecii infection. Therapy is adjusted after a diagnosis is made.^[3]

Prognosis

Since there is a wide range of conditions associated with FUO, prognosis depends on the particular cause.^[1] If after 6 to 12 months no diagnosis is found, the chances diminish of ever finding a specific cause.^[3] However, under those circumstances prognosis is good.^[2]

References

1. 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
2. Harrison's Principles of Internal Medicine 16th Edition, The McGraw-Hill Companies, ISBN 0-07-140235-7
3. The Oxford Textbook of Medicine Edited by David A. Warrell, Timothy M. Cox and John D. Firth with Edward J. Benz, Fourth Edition (2003), Oxford University Press, ISBN 0-19-262922-0
4. Cecil Textbook of Medicine by Lee Goldman, Dennis Ausiello, 22nd Edition (2003), W.B. Saunders Company, ISBN 0-7216-9652-X
5. Irwin and Rippe's Intensive Care Medicine by Irwin and Rippe, Fifth Edition (2003), Lippincott Williams & Wilkins, ISBN 0-7817-3548-3
6. Klempa B, Koivogui L, Sylla O et al. Serological evidence of human hantavirus infections in Guinea, West Africa. J Infect Dis 2010; 201: 1031–1034.
7. Strecker, Jan ter Meulen and Detlev H. KrügerAuste, et al. Sangassou virus, the first hantavirus isolate from Africa. Journal of Virology2012, 86(7):3819. doi:10.1128/JVI.05879-11
8. Fever of Unknown Origin at Mount Sinai Hospital
9. Florin TA, Zaoutis TE, Zaoutis LB (2008). "Beyond cat scratch disease: widening spectrum of Bartonella henselae infection". Pediatrics. 121 (5): e1413–25. doi:10.1542/peds.2007-1897. PMID 18443019.
10. al.], ed. Dan L. Longo ... [et (2012). Harrison's principles of internal medicine. (18th ed.). New York: McGraw-Hill. ISBN 978-0071748896.
11. Harrison'sTM Principles of Internal Medicine (19th ed.). USA: McGraw-Hill Education. ISBN 978-0-07-1802161.
12. Meller J, Altenvoerde G, Munzel U, Jauho A, Behe M, Gratz S, Luig H, Becker W (2000). "Fever of unknown origin: prospective comparison of [18F]FDG imaging with a double-head coincidence camera and gallium-67 citrate SPET.". Eur J Nucl Med. 27 (11): 1617–25. doi:10.1007/s002590000341. PMID 11105817.