Fever of unknown origin (FUO) refers to a condition in which the patient has an elevated temperature (

fever Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...

) but, despite investigations by a

physician A physician (American English), medical practitioner (Commonwealth English), medical doctor, or simply doctor, is a health professional who practices medicine, which is concerned with promoting, maintaining or restoring health through th ...

, no explanation has been found.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 McGraw Hill is an American educational publishing company and one of the "big three" educational publishers that publishes educational content, software, and services for pre-K through postgraduate education. The company also publishes referenc ...

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 Oxford University Press (OUP) is the university press of the University of Oxford. It is the largest university press in the world, and its printing history dates back to the 1480s. Having been officially granted the legal right to print books ...

, Cecil Textbook of Medicine
by Lee Goldman, Dennis Ausiello, 22nd Edition (2003), W.B. Saunders Company, Irwin and Rippe's Intensive Care Medicine
by Irwin and Rippe, Fifth Edition (2003),

Lippincott Williams & Wilkins Lippincott Williams & Wilkins (LWW) is an American imprint of the American Dutch publishing conglomerate Wolters Kluwer. It was established by the acquisition of Williams & Wilkins and its merger with J.B. Lippincott Company in 1998. Under the LW ...

, If the cause is found it is usually a

diagnosis of exclusion A diagnosis of exclusion or by exclusion (''per exclusionem'') is a diagnosis of a medical condition reached by a process of elimination, which may be necessary if presence cannot be established with complete confidence from history, examination or ...

, that is, by eliminating all possibilities until only one explanation remains, and taking this as the correct one.

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 An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. The meaning of this term ...

, should always be considered. Disseminated granulomatoses such as

tuberculosis Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in ...

histoplasmosis Histoplasmosis is a fungal infection caused by ''Histoplasma capsulatum''. Symptoms of this infection vary greatly, but the disease affects primarily the lungs. Occasionally, other organs are affected; called disseminated histoplasmosis, it can ...

coccidioidomycosis Coccidioidomycosis (, ), commonly known as cocci, Valley fever, as well as California fever, desert rheumatism, or San Joaquin Valley fever, is a mammalian fungal disease caused by ''Coccidioides immitis'' or ''Coccidioides posadasii''. Coccidio ...

blastomycosis Blastomycosis or blasto is a fungal infection caused by inhaling spores of a ''Blastomyces'' fungus. Only about half of people with the disease have symptoms, which can include fever, cough, night sweats, muscle pains, weight loss, chest pain, a ...

and

sarcoidosis Sarcoidosis (also known as ''Besnier-Boeck-Schaumann disease'') is a disease involving abnormal collections of inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph nodes. Less commonly af ...

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.

Bartonella ''Bartonella'' is a genus of Gram-negative bacteria. It is the only genus in the family Bartonellaceae. Facultative intracellular parasites, ''Bartonella'' species can infect healthy people, but are considered especially important as opportunis ...

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 ''Cytomegalovirus'' (''CMV'') (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order ''Herpesvirales'', in the family ''Herpesviridae'', in the subfamily ''Betaherpe ...

Epstein–Barr virus The Epstein–Barr virus (EBV), formally called ''Human gammaherpesvirus 4'', is one of the nine known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. EBV is a double-stranded DNA virus. It is b ...

, human herpesvirus 6 (

HHV-6 Human herpesvirus 6 (HHV-6) is the common collective name for ''human betaherpesvirus 6A'' (HHV-6A) and ''human betaherpesvirus 6B'' (HHV-6B). These closely related viruses are two of the nine known herpesviruses that have humans as their primar ...

), human herpesvirus 7 (

HHV-7 ''Human betaherpesvirus 7'' (HHV-7) is one of nine known members of the '' Herpesviridae'' family that infects humans. HHV-7 is a member of ''Betaherpesvirinae'', a subfamily of the ''Herpesviridae'' that also includes HHV-6 and '' Cytomegalovir ...

) being present in 15%, 10%, 14% and 4.8% respectively with 10% of people presenting with co-infection (infection with 2 or more human herpes viruses).

Infectious mononucleosis Infectious mononucleosis (IM, mono), also known as glandular fever, is an infection usually caused by the Epstein–Barr virus (EBV). Most people are infected by the virus as children, when the disease produces few or no symptoms. In young adult ...

, 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 Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...

, and younger adults and adolescents more likely to have

splenomegaly Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulating ...

pharyngitis Pharyngitis is inflammation of the back of the throat, known as the pharynx. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, difficulty swallowing, swollen lymph nodes, and a hoarse voice ...

and

lymphadenopathy Lymphadenopathy or adenopathy is a disease of the lymph nodes, in which they are abnormal in size or consistency. Lymphadenopathy of an inflammatory type (the most common type) is lymphadenitis, producing swollen or enlarged lymph nodes. In cli ...

. Endemic mycoses such as

coccidiomycosis Coccidioidomycosis (, ), commonly known as cocci, Valley fever, as well as California fever, desert rheumatism, or San Joaquin Valley fever, is a mammalian fungal disease caused by ''Coccidioides immitis'' or ''Coccidioides posadasii''. Coccidio ...

and

paracoccidioidomycosis Paracoccidioidomycosis (PCM), also known as South American blastomycosis, is a fungal infection that can occur as a mouth and skin type, lymphangitic type, multi-organ involvement type (particularly lungs), or mixed type. If there are mouth ulce ...

can cause a fever of unknown origin in immunocompromised as well as immunocompetent persons. These endemic mycoses may also present with pulmonary symptoms or extra-pulmonary symptoms such as

B symptoms B symptoms are a set of symptoms, namely fever, night sweats, and unintentional weight loss, that can be associated with both Hodgkin lymphoma and non-Hodgkin lymphoma. These symptoms are not specific to lymphomas, especially each one considere ...

(such as fevers, chills, night sweats, unexplained weight loss). The endemic mycotic infection

talaromycosis Talaromycosis is a fungal infection that presents with painless skin lesions of face and neck, fever, anaemia, large lymph glands and liver. It is caused by the fungus'' Talaromyces marneffei'', which is found in soil and decomposing organic ma ...

primarily affects those who are immunocompromised. Invasive opportunistic mycoses may also occur in immunocompromised people; these include

aspergillosis Aspergillosis is a fungal infection of usually the lungs, caused by the genus ''Aspergillus'', a common mould that is breathed in frequently from the air around, but does not usually affect most people. It generally occurs in people with lung di ...

mucormycosis Mucormycosis, also known as black fungus, is a serious fungal infection that comes under fulminant fungal sinusitis, usually in people who are immunocompromised. It is curable only when diagnosed early. Symptoms depend on where in the body the ...

Cryptococcus neoformans ''Cryptococcus neoformans'' is an encapsulated yeast belonging to the class Tremellomycetes and an obligate aerobe that can live in both plants and animals. Its teleomorph is a filamentous fungus, formerly referred to ''Filobasidiella neoformans' ...

. 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). The cancer types most associated with fever of unknown origin include

renal cell carcinoma Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, resp ...

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...

liver cancer Liver cancer (also known as hepatic cancer, primary hepatic cancer, or primary hepatic malignancy) is cancer that starts in the liver. Liver cancer can be primary (starts in liver) or secondary (meaning cancer which has spread from elsewhere to th ...

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...

atrial myxoma and

Castleman disease Castleman disease (CD) describes a group of rare lymphoproliferative disorders that involve enlarged lymph nodes, and a broad range of inflammatory symptoms and laboratory abnormalities. Whether Castleman disease should be considered an autoimmun ...

. In those with

HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

currently being treated with

antiretroviral therapy The management of HIV/AIDS normally includes the use of multiple Antiviral drug, antiretroviral drugs as a strategy to control HIV/AIDS, HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life- ...

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 Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual m ...

, 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 Immune reconstitution inflammatory syndrome (IRIS) is a condition seen in some cases of AIDS or immunosuppression, in which the immune system begins to recover, but then responds to a previously acquired opportunistic infection with an overwhel ...

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. 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 Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...

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 Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...

adult-onset Still's disease Adult-onset Still's disease (AOSD) is a form of Still's disease, a rare systemic autoinflammatory disease characterized by the classic triad of fevers, joint pain, and a distinctive salmon-colored bumpy rash. The disease is considered a diagnos ...

have mixed features and are common causes of FUO.

Infection

Neoplasm

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

Noninfectious inflammatory diseases

Miscellaneous conditions

* ADEM (

acute disseminated encephalomyelitis Acute disseminated encephalomyelitis (ADEM), or acute Demyelinating disease, demyelinating encephalomyelitis, is a rare autoimmune disease marked by a sudden, widespread attack of inflammation in the brain and spinal cord. As well as causing the ...

) * Adrenal insufficiency *

Aneurysm An aneurysm is an outward bulging, likened to a bubble or balloon, caused by a localized, abnormal, weak spot on a blood vessel wall. Aneurysms may be a result of a hereditary condition or an acquired disease. Aneurysms can also be a nidus (s ...

* Anomalous thoracic duct *

Aortic dissection Aortic dissection (AD) occurs when an injury to the innermost layer of the aorta allows blood to flow between the layers of the aortic wall, forcing the layers apart. In most cases, this is associated with a sudden onset of severe chest or ...

* Aortic-enteral fistula * Aseptic meningitis (Mollaret’s syndrome) * Atrial myxoma * Brewer’s yeast ingestion *

Caroli disease Caroli disease (communicating cavernous ectasia, or congenital cystic dilatation of the intrahepatic biliary tree) is a rare inherited disorder characterized by cystic dilatation (or ectasia) of the bile ducts within the liver. There are two patter ...

* Cholesterol emboli * Complex partial status epilepticus *

Cyclic neutropenia Cyclic neutropenia (CyN) is a rare hematologic disorder and form of congenital neutropenia that tends to occur approximately every three weeks and lasting for few days at a time due to changing rates of neutrophil production by the bone marrow. It ...

* Drug fever *

Erdheim–Chester disease Erdheim–Chester disease (ECD) is an extremely rare disease characterized by the abnormal multiplication of a specific type of white blood cells called histiocytes, or tissue macrophages (technically, this disease is termed a non- Langerhans-cel ...

* Extrinsic allergic alveolitis * Factitious disease * Fire-eater’s lung * Fraudulent fever * Gaucher’s disease * Hamman–Rich syndrome (acute interstitial pneumonia) * Hashimoto’s encephalopathy *

Hematomas A hematoma, also spelled haematoma, or blood suffusion is a localized bleeding outside of blood vessels, due to either disease or trauma including injury or surgery and may involve blood continuing to seep from broken capillaries. A hematoma is b ...

Hemoglobinopathies Hemoglobinopathy is the medical term for a group of inherited blood disorders and diseases that primarily affect red blood cells. They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits. There are t ...

* Hypersensitivity pneumonitis * Hypertriglyceridemia * Hypothalamic hypopituitarism * Idiopathic normal-pressure hydrocephalus * Inflammatory pseudotumor * Kikuchi’s disease * Linear IgA dermatosis *

Laennec's cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...

* 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 Subacute thyroiditis is a form of thyroiditis that can be a cause of both thyrotoxicosis and hypothyroidism. It is uncommon and can affect individuals of both sexes, occurring three times as often in women than in men. and people of all ages. The m ...

(de Quervain's) * Sweet syndrome (acute febrile neutrophilic dermatosis) * Thrombosis * Tubulointerstitial nephritis and uveitis syndrome (TINU) * Tissue

infarction Infarction is tissue death (necrosis) due to inadequate blood supply to the affected area. It may be caused by artery blockages, rupture, mechanical compression, or vasoconstriction. The resulting lesion is referred to as an infarct (from the ...

/necrosis *

Ulcerative colitis Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and a ...

Inherited and metabolic diseases

Adrenal insufficiency Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal gland normally secretes glucocorticoids (primarily cortisol), mineralocorticoids (primarily aldosterone), and androge ...

* Deafness, urticaria, and amyloidosis *

Fabry disease Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. T ...

Familial cold urticaria Cold urticaria (essentially meaning cold hives) is a disorder in large red welts called hives (''urticaria'') form on the skin after exposure to a cold stimulus. The hives are usually itchy and often the hands and feet will become itchy and swolle ...

Familial Mediterranean fever Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in Mediterranean fever gene, which encodes a 781–amino acid protein called pyrin. While all ethnic groups are sus ...

* Hyperimmunoglobulinemia D and periodic fever *

Muckle–Wells syndrome Muckle–Wells syndrome (MWS) is a rare autosomal dominant disease which causes sensorineural deafness and recurrent hives, and can lead to amyloidosis. Individuals with MWS often have episodic fever, chills, and joint pain. As a result, MWS is ...

* Tumor necrosis factor receptor–associated periodic syndrome (familial Hibernian fever) * Type V

Hypertriglyceridemia Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. Triglycerides are the most abundant fatty molecule in most organisms. Hypertriglyceridemia occurs in various physiologic conditions and in various diseases, and h ...

Thermoregulatory disorders

Habitual hyperthermia

* Exaggerated

circadian rhythm A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., Endogeny (biology), endogeno ...

Other

* “Afebrile” FUO 38.3 °C (100.9 °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 A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cr ...

eschar An eschar (; Greek: ''ἐσχάρᾱ'', ''eskhara''; Latin: ''eschara'') is a slough or piece of dead tissue that is cast off from the surface of the skin, particularly after a burn injury, but also seen in gangrene, ulcer, fungal infections, ...

heart murmur Heart murmurs are unique heart sounds produced when blood flows across a heart valve or blood vessel. This occurs when turbulent blood flow creates a sound loud enough to hear with a stethoscope. Turbulent blood flow is not smooth. The sound di ...

) and myriad laboratory tests (serological, blood culture, immunological) are the cornerstone of finding the cause. Other investigations may be needed. Ultrasound may show

cholelithiasis A gallstone is a stone formed within the gallbladder from precipitated bile components. The term cholelithiasis may refer to the presence of gallstones or to any disease caused by gallstones, and choledocholithiasis refers to the presence of migr ...

echocardiography An echocardiography, echocardiogram, cardiac echo or simply an echo, is an ultrasound of the heart. It is a type of medical imaging of the heart, using standard ultrasound or Doppler ultrasound. Echocardiography has become routinely used in t ...

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.

Positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in Metabolism, metabolic processes, and in other physiological activities including bl ...

using radioactively labelled

fluorodeoxyglucose 18F.html" ;"title="sup>18F">sup>18Fluorodeoxyglucose ( INN), or fluorodeoxyglucose F 18 (USAN and USP), also commonly called fluorodeoxyglucose and abbreviated 18F.html" ;"title="sup>18F">sup>18FDG, 2- 18F.html" ;"title="sup>18F">sup>18FDG or ...

(FDG) has been reported to have a sensitivity of 84% and a specificity of 86% for localizing the source of fever of unknown origin. 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.

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. In 1961 Petersdorf and Beeson suggested the following criteria: * 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. 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: *

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

s (e.g. abscesses,

endocarditis Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves. Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or the ...

, and complicated

urinary tract infection A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidney ...

s), *

neoplasm A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

s (e.g.

leukaemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...

s), *

connective tissue disease A connective tissue disease (collagenosis) is any disease that has the connective tissues of the body as a target of pathology. Connective tissue is any type of biological tissue with an extensive extracellular matrix that supports, binds togeth ...

s (e.g.

temporal arteritis Temporal may refer to: Entertainment * Temporal (band), an Australian metal band * ''Temporal'' (Radio Tarifa album), 1997 * ''Temporal'' (Love Spirals Downwards album), 2000 * ''Temporal'' (Isis album), 2012 * ''Temporal'' (video game), a 200 ...

and

polymyalgia rheumatica Polymyalgia rheumatica (PMR) is a syndrome experienced as pain or stiffness, usually in the neck, shoulders, upper arms, and Hip (anatomy), hips, but which may occur all over the body. The pain can be sudden or can occur gradually over a period. ...

, Still's disease,

systemic lupus erythematosus Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...

, and

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...

), * miscellaneous disorders (e.g.

alcoholic hepatitis Alcoholic hepatitis is hepatitis (inflammation of the liver) due to excessive intake of alcohol. Patients typically have a history of at least 10 years of heavy alcohol intake, typically 8-10 drinks per day. It is usually found in association wit ...

granuloma A granuloma is an aggregation of macrophages that forms in response to chronic inflammation. This occurs when the immune system attempts to isolate foreign substances that it is otherwise unable to eliminate. Such substances include infectious ...

tous conditions), and * undiagnosed conditions.

Nosocomial

Nosocomial FUO refers to

pyrexia Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...

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 In urinary catheterization a latex, polyurethane, or silicone tube known as a urinary catheter is inserted into the bladder through the urethra to allow urine to drain from the bladder for collection. It may also be used to inject liquids used ...

, intravascular devices (i.e. "

drip Drip or DRIP may refer to: * Mesomycetozoea, a class of eukaryotes also known as the DRIP clade * Drip gas, natural gas condensate * Drip irrigation, in agriculture and gardening * Dripping liquid * Drip email (campaign), the process of automati ...

pulmonary artery catheter A pulmonary artery catheter (PAC), also known as a Swan-Ganz catheter or right heart catheter, is a balloon-tipped catheter that is inserted into a pulmonary artery in a procedure known as pulmonary artery catheterization or right heart cathet ...

), drugs (antibiotic-induced '' Clostridium difficile'' colitis, drug fever), and/or immobilization (decubitus ulcers).

Sinusitis Sinusitis, also known as rhinosinusitis, is inflammation of the nasal mucosa, mucous membranes that line the paranasal sinuses, sinuses resulting in symptoms that may include thick Mucus#Respiratory system, nasal mucus, a nasal congestion, plugg ...

in the

intensive care unit 220px, Intensive care unit An intensive care unit (ICU), also known as an intensive therapy unit or intensive treatment unit (ITU) or critical care unit (CCU), is a special department of a hospital or health care facility that provides intensiv ...

is associated with nasogastric and orotracheal tubes. Other conditions that should be considered are deep-vein thrombophlebitis,

pulmonary embolism Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain p ...

transfusion reaction Blood transfusion is the process of transferring blood products into a person's Circulatory system, circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used w ...

s, acalculous cholecystitis,

thyroiditis Thyroiditis is the inflammation of the thyroid gland. The thyroid gland is located on the front of the neck below the laryngeal prominence, and makes hormones that control metabolism. Signs and symptoms There are many different signs and symptom ...

, alcohol/drug withdrawal,

adrenal insufficiency Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal gland normally secretes glucocorticoids (primarily cortisol), mineralocorticoids (primarily aldosterone), and androge ...

, and

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancr ...

Immune-deficient

Immunodeficiency can be seen in patients receiving

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

or in hematologic malignancies. Fever is concomitant with

neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...

(

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

<500/uL) or impaired cell-mediated immunity. The lack of immune response masks a potentially dangerous course. Infection is the most common cause.

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 Infectious mononucleosis (IM, mono), also known as glandular fever, is an infection usually caused by the Epstein–Barr virus (EBV). Most people are infected by the virus as children, when the disease produces few or no symptoms. In young adult ...

-like illness. In advanced stages of infection fever mostly is the result of a superimposed infections.

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

neutropenic Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...

(low white blood cell count) patients or patients who are severely immunocompromised 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. 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.

Prognosis

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

References

External links

{{General symptoms and signs Infectious diseases Fever Ailments of unknown cause