Fever of unknown origin

Fever of unknown origin (FUO) refers to a condition in which the patient has an elevated temperature (fever) for which no cause can be found despite investigations by one or more qualified physicians.Mandell's Principles and Practices of Infection Diseases 6th Edition (2004) by Gerald L. Mandell MD, MACP, John E. Bennett MD, Raphael Dolin MD, · Hardback · 4016 Pages Churchill LivingstoneHarrison's Principles of Internal Medicine 16th Edition, The McGraw-Hill Companies, 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, If the cause is found, it is usually a diagnosis of exclusion, eliminating all possibilities until only the correct explanation remains.

In the West, the classical medical definition of the FUO required a clinician-verified measurement of temperature of ≥ at any site on several (varied) occasions over 3 weeks, though in the recent years the threshold of ≥ has been becoming increasingly more prevalent.

Causes Worldwide, infection is the leading cause of FUO, with prevalence varying by country and geographic region. Extrapulmonary tuberculosis is the most frequent cause of FUO. 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 causes a fever. Although infrequent, its potentially lethal consequences warrant evaluation of this cause. Infective endocarditis, although uncommon, is possible. Bartonella infections are also known to cause fever of unknown origin.

Human herpes viruses are a common cause of fever of unknown origin with one study showing Cytomegalovirus, 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). 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 leukopenia, and younger adults and adolescents more likely to have splenomegaly, pharyngitis and lymphadenopathy.

Endemic mycoses such as histoplasmosis, blastomycosis, coccidioidomycosis, and 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, and unexplained weight loss). The endemic mycotic infection talaromycosis primarily affects those who are immunocompromised. Invasive opportunistic mycoses may also occur in immunocompromised people; these include aspergillosis, mucormycosis, Cryptococcus neoformans.

Cancer can also cause a 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). The cancer types most associated with fever of unknown origin include renal cell carcinoma, lymphoma, liver cancer, ovarian cancer atrial myxoma and Castleman disease.

In those with HIV currently being treated with antiretroviral therapy and with a low or undetectable viral load, the 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. Approximately 2 weeks after initial HIV infection, with viral loads being high, an acute retroviral syndrome can present with fevers, rash and mono-like symptoms.

Immune reconstitution inflammatory syndrome is a common cause of FUO when a previously suppressed immune system is reactivated. 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 after microbiological control of infection (in cases of immunosuppressing pathogens such as HIV), but the syndrome may also present after organ transplant, in the post-partum state, with formerly neutropenic hosts, or after withdrawing anti-TNF therapy.

Auto-inflammatory and auto-immune disorders account for approximately 5-32% of fevers of unknown origin. 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. Rheumatoid arthritis or adult-onset Still's disease have mixed features and are common causes of FUO.

Infection

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

Neoplasm Although most neoplasms can present with fever, malignant lymphoma is by far the most common diagnosis of FUO among neoplasms. In some cases, the fever even precedes lymphadenopathy detectable by physical examination. Neoplasm cause Disease name Hematologic malignancies Amyloidosis Immunoblastic T-cell lymphoma Castleman's disease Hodgkin's lymphoma Hypereosinophilic syndrome Leukemia Lymphomatoid granulomatosis Malignant histiocytosis Multiple myeloma Myelodysplastic syndrome Myelofibrosis Non-Hodgkin's lymphoma Plasmacytoma Systemic mastocytosis Vaso-occlusive crisis in sickle cell disease Solid tumors Colon cancer Renal cell carcinoma Pancreatic cancer Hepatoma Sarcoma Gall bladder carcinoma Most solid tumors and metastases can cause fever. Benign Atrial myxoma Renal Angiomyolipoma Cavernous hemangioma of the liver Craniopharyngioma Necrosis of dermoid tumor in Gardner syndrome

Noninfectious inflammatory diseases

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

Miscellaneous conditions

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

Inherited and metabolic diseases

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

Thermoregulatory disorders

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