Fever of unknown origin
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 but despite investigations by a physician no explanation has been found.

If the cause is found it usually is a diagnosis of exclusion
Diagnosis of exclusion
A diagnosis of exclusion is a medical condition reached by a process of elimination, which may be necessary if presence cannot be established with complete confidence from examination or testing...

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


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 colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...

    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 even on intracardiac devices...

    , tuberculosis
    Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

    , and complicated urinary tract infection
    Urinary tract infection
    A urinary tract infection is a bacterial infection that affects any part of the urinary tract. Symptoms include frequent feeling and/or need to urinate, pain during urination, and cloudy urine. The main causal agent is Escherichia coli...

  • neoplasms (e.g. lymphoma
    Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...

    s, leukaemias),
  • connective tissue disease
    Connective tissue disease
    A connective tissue disease 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 together, and protects organs...

    s (e.g. temporal arteritis
    Temporal arteritis
    Giant-cell arteritis or Horton disease is an inflammatory disease of blood vessels most commonly involving large and medium arteries of the head...

     and polymyalgia rheumatica
    Polymyalgia rheumatica
    Polymyalgia rheumatica , abbreviated as PMR, is a syndrome with pain or stiffness, usually in the neck, shoulders, and hips. The pain can be very sudden, or can occur gradually over a period of time...

    , Still's disease
    Still's disease
    Still's disease can refer to:* Juvenile idiopathic arthritis* Adult-onset Still's disease...

    , systemic lupus erythematosus
    Systemic lupus erythematosus
    Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...

    , and rheumatoid arthritis
    Rheumatoid arthritis
    Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

  • miscellaneous disorders (e.g. alcoholic hepatitis
    Alcoholic hepatitis
    Alcoholic hepatitis is hepatitis due to excessive intake of alcohol. While distinct from cirrhosis, it is regarded as the earliest stage of alcoholic liver disease. Symptoms are jaundice, ascites , fatigue and hepatic encephalopathy...

    , granuloma
    Granuloma is a medical term for a tiny collection of immune cells known as macrophages. Granulomas form when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as bacteria and fungi as well as...

    tous conditions), and
  • undiagnosed conditions.


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 urinary catheter, intravascular devices (i.e. "drip
Peripheral venous catheter
In medicine, a peripheral venous catheter is a catheter placed into a peripheral vein in order to administer medication or fluids...

", pulmonary artery catheter
Pulmonary artery catheter
In medicine pulmonary artery catheterization is the insertion of a catheter into a pulmonary artery. Its purpose is diagnostic; it is used to detect heart failure or sepsis, monitor therapy, and evaluate the effects of drugs...

), drugs (antibiotics induced Clostridium difficile
Clostridium difficile
Clostridium difficile , also known as "CDF/cdf", or "C...

colitis, and drug fever), immobilization (decubitus ulcers). Sinusitis
Sinusitis is inflammation of the paranasal sinuses, which may be due to infection, allergy, or autoimmune issues. Most cases are due to a viral infection and resolve over the course of 10 days...

 in the intensive care unit
Intensive Care Unit
thumb|220px|ICU roomAn intensive-care unit , critical-care unit , intensive-therapy unit/intensive-treatment unit is a specialized department in a hospital that provides intensive-care medicine...

 is associated with nasogastric and orotracheal tubes. Other conditions that should be considered are deep-vein thrombophlebitis, and pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...

, transfusion reactions, 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.-Classification:...

, alcohol/drug withdrawal, adrenal insufficiency
Adrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...

, pancreatitis
Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...



Immunodeficiency can be seen in patients receiving chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

 or in hematologic malignancies. Fever is concommittent with neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...

 (neutrophil <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
Infectious mononucleosis is an infectious, widespread viral...

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

Some important causes

Extrapulmonary tuberculosis is the most frequent cause of FUO.
Drug-induced hyperthermia, as sole symptom of an adverse reaction to medication, should always be considered. Disseminated granulomatoses such as Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

, Histoplasmosis
Histoplasmosis is a disease caused by the fungus Histoplasma capsulatum. Symptoms of this infection vary greatly, but the disease primarily affects the lungs...

, Coccidioidomycosis
Coccidioidomycosis is a fungal disease caused by Coccidioides immitis or C. posadasii. It is endemic in certain parts of Arizona, California, Nevada, New Mexico, Texas, Utah and northwestern Mexico.C...

, Blastomycosis
Blastomycosis is a fungal infection caused by the organism Blastomyces dermatitidis...

 and Sarcoidosis
Sarcoidosis , also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells form as nodules in multiple organs. The cause of sarcoidosis is unknown...

 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 thing 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
Medical history
The medical history or anamnesis of a patient is information gained by a physician by asking specific questions, either of the patient or of other people who know the person and can give suitable information , with the aim of obtaining information useful in formulating a diagnosis and providing...



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
An eschar 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, necrotizing spider bite wounds, and exposure to cutaneous anthrax....

, lymphadenopathy
Lymphadenopathy is a term meaning "disease of the lymph nodes." It is, however, almost synonymously used with "swollen/enlarged lymph nodes". It could be due to infection, auto-immune disease, or malignancy....

, heart murmur
Heart murmur
Murmurs are extra heart sounds that are produced as a result of turbulent blood flow that is sufficient to produce audible noise. Most murmurs can only be heard with the assistance of a stethoscope ....

) and a myriad of laboratory tests (serological, blood culture, immunological) are the cornerstone of finding the cause.

Other investigations may be needed. Ultrasound may show cholelithiasis, echocardiography
An echocardiogram, often referred to in the medical community as a cardiac ECHO or simply an ECHO, is a sonogram of the heart . Also known as a cardiac ultrasound, it uses standard ultrasound techniques to image two-dimensional slices of the heart...

 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
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...

 using radioactively labelled fluorodeoxyglucose
Fludeoxyglucose or fluorodeoxyglucose , commonly abbreviated 18F-FDG or FDG, is a radiopharmaceutical used in the medical imaging modality positron emission tomography...

 (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.


Unless the patient is acutely ill, no therapy should be started before the cause has been found. This is because non-specific therapy rarely is 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.

HIV-infected persons with pyrexia and hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...

, will be started on medication for possible Pneumocystis jirovecii infection
Pneumocystis pneumonia
Pneumocystis pneumonia or pneumocystosis is a form of pneumonia, caused by the yeast-like fungus Pneumocystis jirovecii...

. Therapy is adjusted after a diagnosis is made.


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.
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