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Fever of unknown origin (FUO) was defined in 1961 by Petersdorf and Beeson as the following:
(1) a temperature greater than 38.3°C (101°F) on several occasions, (2) more than 3 weeks'
duration of illness, and (3) failure to reach a diagnosis despite 1 week of inpatient investigation.[1,

Diagnostic advances continuously modify the spectrum of FUO-causing diseases; for example,
serologic tests have reduced the importance of the human immunodeficiency virus (HIV) and
numerous rheumatic diseases (eg, systemic lupus erythematosus [SLE], juvenile rheumatoid
arthritis [JRA], rheumatoid arthritis [RA]) as causes of FUO. (See Etiology and Serology.)
Modern imaging techniques (eg, ultrasonography, computed tomography [CT] scanning,
magnetic resonance imaging [MRI]) enable early detection of abscesses and solid tumors that
were once difficult to diagnose. (See Computed Tomography Scanning and Magnetic Resonance
Patients with undiagnosed FUO (5-15% of cases) generally have a benign long-term course,
especially when the fever is not accompanied by substantial weight loss or other signs of a
serious underlying disease. These findings suggest that the underlying cause is one of the more
serious diseases that initially manifest as FUOs. Such underlying diseases are usually diagnosed
after an intensive and rational diagnostic evaluation. (See Prognosis, History, and Diagnostic

FUOs are caused by infections (30-40%), neoplasms (20-30%), collagen vascular diseases (1020%), and numerous miscellaneous diseases (15-20%). The literature also reveals that, as
previously mentioned, between 5 and 15% of FUO cases defy diagnosis, despite exhaustive
FUOs that persist for more than 1 year are less likely to be caused by an infection or neoplasm
and are much more likely to be the result of a granulomatous disease (the most common cause in
these cases).
The following conditions are sources of FUO:



Urinary tract infections


Hepatobiliary infections




Systemic bacterial illnesses

Spirochetal diseases


Acquired immunodeficiency syndrome (AIDS)

Herpes viruses

Fungal infections

Parasitic infections



Solid tumors

Malignant histiocytosis

Collagen vascular and autoimmune diseases


Regional enteritis

Granulomatous hepatitis

Drug fever

Inherited diseases

Endocrine disorders

Peripheral pulmonary emboli and occult thrombophlebitis

Kikuchi disease

Factitious fever

Giant cell arteritis (GCA)

Polymyalgia rheumatica (PMR)

Polyarteritis nodosa (PAN)

FUO should prompt consideration of abscesses, which are usually located intra-abdominally,
even in the absence of localizing symptoms. The most common abscess locations include the
subphrenic space, liver, right lower quadrant, retroperitoneal space, and the female pelvis.

Tuberculosis (TB) is usually considered in the FUO differential diagnoses. (See Differentials,

Urinary tract infections
These rarely cause FUO, because urinalysis is an easily performed routine test that is used to
detect most cases of urinary tract infection (UTI).

Endocarditis is now a rare cause of FUO.

Systemic bacterial illnesses
Some systemic bacterial illnesses can manifest as FUOs. Brucellosis, still prevalent in Latin
America and the Mediterranean, is very important. Researchers have also described systemic
infections with Salmonella species, Neisseria meningitidis, and Neisseria gonorrhoeae as causes
of FUO.

Spirochetal diseases
The most important spirochete is Borrelia recurrentis, which is transmitted by ticks and is
responsible for sporadic cases of relapsing fever. Rat-bite fever (Spirillum minor), Lyme disease
(Borrelia burgdorferi), and syphilis (Treponema pallidum) are other spirochetal diseases that can
cause FUO.

Human immunodeficiency virus
Typical and atypical mycobacteria and cytomegalovirus (CMV) are opportunistic infections in
persons with HIV infection that frequently cause prominent constitutional symptoms, including
fever, with few localizing or specific signs. Other opportunistic infections (eg, salmonellosis,
histoplasmosis, toxoplasmosis) can also present as FUO and elude rapid diagnosis in patients
who are febrile with AIDS.

Parasitic infections
Consider toxoplasmosis in patients who are febrile with lymph node enlargement; Malaria can
also be a cause of fever. Other parasites that cause FUO, albeit in rare cases, include
Trypanosoma,Leishmania, and Amoeba species.

Acute leukemias are another important neoplastic group that can cause FUO.

Solid tumors
Among solid tumors, renal cell carcinoma is most commonly associated with FUO.
Other solid tumors, such as adenocarcinomas of the breast, liver, colon, or pancreas, as well as
liver metastases from any primary site, may also manifest as fever.

Malignant histiocytosis
This rare, rapidly progressive malignant disease is an occasional cause of FUO.

Collagen-vascular and autoimmune diseases
SLE was once a relatively common cause of FUO. Systemic-onset JRA is another cause of FUO
and is often difficult to diagnose.
PAN, RA, rheumatic fever, and mixed connective-tissue diseases (ie, other collagen vascular
diseases), also cause FUO.

Regional enteritis
Crohn disease is the most common gastrointestinal cause of FUO.

Drug fever
Although a wide variety of drugs can cause drug fever, the most common are beta-lactam
antibiotics, procainamide, isoniazid, alpha-methyldopa, quinidine, and diphenylhydantoin.

about 20-25% of cases are due to lymphomas. .Inherited diseases In patients of Mediterranean descent with FUO. accounting for 50% of the cases. as one of the vasculitides that causes FUO in patients older than age 50 years. Variations in FUO. potentially fatal. Incidence increases in patients with hepatitis B or C. the male-to-female incidence ratio is 2:1. whereas neoplasms and connectivetissue disorders are more common in elderly persons. Endocrine disorders Hyperthyroidism and subacute thyroiditis are the 2 most common endocrinologic causes of FUO. Among patients with HIV infection. PAN involves the medium. Uncommon causes of FUO include Wegener granulomatosis. very treatable endocrinologic source of FUO. Adrenal insufficiency is a rare. familial Mediterranean fever is most often the cause. Epidemiology More than 30% of FUO cases in persons older than 50 years are related to connective-tissue disorders and vasculitic diseases. and 0-5% of cases are due to the HIV itself. and cryoglobulinemia. behind GCA and PMR. Factitious fever This is responsible for as many as 10% of FUO cases in some series and is most commonly encountered among young adults with health care experience or knowledge. In PAN.and small-sized muscular arteries. GCA and PMR are the 2 principal connective-tissue etiologies. Its etiology is unknown. approximately 75% of cases of FUO are infectious in nature. as found in the literature. necrotizing lymphadenitis. infections are the most common cause of FUO. Kikuchi disease Kikuchi disease is a self-limiting. Polyarteritis nodosa This condition ranks a distant third. Takayasu arteritis. reflect the populations and periods studied. In children.

rashes). fever. Previous illnesses (including psychiatric illnesses) and surgeries are important. careful review of the literature shows that patients with FUO usually have a benign long-term course. inquire about symptoms involving all major organ systems and get a detailed history of general symptoms (eg. are case dependent. The history can provide important clues to FUO due to surgery. weight loss. prescription medications. zoonoses. Complications of FUO. even those that disappeared before the examination. if they occur. headaches. night sweats. Patient Education For patient education information. see Fever in Adults and Fever in Children. However. especially in the absence of substantial weight loss or other signs of a serious underlying disease. malignancies. and inflammatory/immune disorders.The prognosis of FUO depends on the underlying cause and varies from patient to patient. illicit substances)  Sexual history  Recreational habits  Animal contacts (including possible exposure to ticks and other vectors) . Make a detailed evaluation that includes the following:  Family history  Immunization status  Occupational history  Travel history  Nutrition (including consumption of dairy products)  Drug history (over-the-counter medications. Record all symptoms. Proceed to Clinical Presentation History In adults with FUO.

fever is the most prominent symptom in patients with reticuloendothelial involvement by histoplasmosis without clinical manifestations in other organs. Rickettsia Chronic infections with Coxiella burnetii. peritonitis. Fungal infections Immunosuppression. Chlamydia Consider Chlamydia psittaci infection. Consider vertebral osteomyelitis in patients with low-grade fever or a history of UTIs. trauma. or gynecologic procedures increase the likelihood of an occult intra-abdominal abscess. the cause of psittacosis. . or a history of diverticulosis. at least intermittently. particularly in elderly persons.Abscesses Previous abdominal surgery. In some cases. in patients with FUO who have a history of contact with birds. chronic Q fever. Signs of hepatic involvement are common. goats. and/or sheep or in patients who consume raw milk products. Osteomyelitis Osteomyelitis usually causes localized pain or discomfort. and Q fever endocarditis have been identified in patients with FUO. and the infection is transmitted from cattle and sheep. and total parenteral nutrition all predispose to disseminated fungal infections. Human immunodeficiency virus Prolonged febrile episodes are common in patients with advanced HIV infection. Systemic bacterial illnesses Consider brucellosis in patients with persistent fever and a history of contact with cattle. Malassezia furfur infection can cause FUO and line infections in patients on total parenteral nutrition who receive intravenous lipid preparations. Herpes viruses CMV and Epstein-Barr virus (EBV) can cause prolonged febrile illnesses with constitutional symptoms and no prominent organ manifestations. and Candida albicans is the main culprit. endoscopy. swine. the use of broad-spectrum antibiotics. the presence of intravascular devices.

brucellosis. sarcoidosis. more specific manifestations (eg. TB. night sweats. Granulomatous hepatitis In some patients with hepatic granulomas. pneumonitis. particularly in young adults. enlarged lymph nodes. arthritis. syphilis. and weight loss. pharyngitis. Inherited diseases Recurrent febrile episodes at varying intervals are associated with pleural. arthralgias and myalgias for many months or years. Malignant histiocytosis This is a rare. sometimes. Sarcoidosis Given its multiorgan involvement. However. fever is often the major clinical sign. Erythema nodosum is occasionally present. rapidly progressive. weight loss.Lymphomas Hodgkin and non-Hodgkin lymphomas frequently cause fever. malignant disease that manifests as high fevers. abdominal. or joint pain due to polyserositis. and the finding of noncaseous granulomas in the liver should raise concern. nonpruritic rashes. Collagen vascular and autoimmune diseases Collagen vascular and autoimmune diseases can manifest as FUO if the fever precedes other. and hepatosplenomegaly. High-spiking fevers. Regional enteritis Crohn disease is the most common gastrointestinal cause of FUO. none of the diseases usually associated with FUO (eg. arthralgias and myalgias. renal involvement). and lymphadenopathy are common. These patients often have fever that may be accompanied by slight hepatomegaly. Endocrine disorders Hyperthyroidism and subacute thyroiditis are the 2 most common endocrinologic causes of FUO. Crohn disease. Systemic-onset JRA is a cause of FUO and is often difficult to diagnose. in addition to weight loss. sarcoidosis rarely manifests as fever and malaise without evidence of lymph node and pulmonary involvement. In fact. and. . This is a diagnosis of exclusion. diarrhea and other abdominal symptoms are occasionally absent. asthenia. Hodgkin disease) is found.

weight loss) are also observed. fever. and hyperkalemia.Adrenal insufficiency is a rare. Therefore. milk). malaise. hypotension. Rapid changes of body temperature without associated shivering or sweating. particularly previous surgery. especially in patients with 1 or more of the above-described features described. Polymyalgia rheumatica PMR is characterized by symmetrical pain and stiffness involving the lumbar spine and large proximal muscles. fatigue. Factitious fever Evidence of psychiatric problems or a history of multiple hospitalizations at different institutions is common in patients with factitious fever. Kikuchi disease Kikuchi disease causes prolonged fever and constitutional symptoms. Peripheral pulmonary emboli and occult thrombophlebitis Consider these diagnoses in patients with predisposing conditions. anorexia. trauma. resulting in atypically localized abscesses or polymicrobial infections. and cough. pulse rate. Symptoms are usually worse in the morning. shoulders. very treatable endocrine cause of FUO. or general appearance are typically observed in patients who manipulate or exchange their thermometers. weight loss. feces. amaurosis fugax). Symptoms may worsen relentlessly over weeks to months without treatment. or prolonged bed rest. weight loss. potentially fatal. skin hyperpigmentation. Polymyalgia (aching and stiffness of the proximal muscles and the trunk) occurs in 40% of these patients. jaw claudication. Consider this diagnosis in patients with nausea. diplopia. depression. hyponatremia. Alternatively. and discrepancies between fever. blurred vision. hips. usually located intra-abdominally. consider factitious fever as a possibility in every patient with prolonged fever. vomiting. fever may be caused by injection of nonsterile material (eg. Polyarteritis nodosa . visual disturbances (visual loss. fever. most notably the neck. large differences between rectal and oral temperature. Giant cell arteritis Classic symptoms of GCA include temporal headache. the most common cause of factitious fever. Another possible cause of fever after surgery or trauma is an undiscovered hematoma. Constitutional symptoms (eg. and thighs.

borreliosis. Notable exceptions include tertian and brucellosis. In general.or medium-sized arteries containing white blood cell infiltrate  Peripheral eosinophilia (common and an important clue to PAN) Physical Examination Definitive documentation of fever and exclusion of factitious fever are essential early steps in the physical examination. On physical examination. Hodgkin disease) tend to cause recurrent episodes of fever. relative bradycardia) are useful in evaluating for typhoid fever. Measure the fever more than once and in the presence of a nurse to exclude manipulation of thermometers. specificity 86%):  Mononeuritis multiplex  Myalgias with muscle tenderness  Livedo reticularis  Testicular pain or tenderness  Renal impairment (elevated BUN [blood urea nitrogen] and creatinine levels)  Weight loss of 4 kg or more  Diastolic blood pressure greater than 90 mm Hg  Hepatitis-B positive  Arteriography showing small and large aneurysms and focal constrictions between dilated segments  Biopsy of small. skin. Electronic thermometers facilitate the rapid and unequivocal documentation of fever. Pulse-temperature relationships (ie. psittacosis. The pattern of fever (continuous. abdomen. lymphomas. remittent. and drug fevers. intermittent) is usually of little help in the evaluation. lymph nodes. spleen.Any 3 of the following 10 findings is sufficient for the diagnosis of PAN (sensitivity 82%. and genitalia. pay special attention to the eyes. . Q fever. specific fever patterns do not correlate strongly with specific diseases. heart.

Proceed to Differential Diagnoses Diagnostic Considerations Approximately 5-15% of patients with fever of unknown origin (FUO) remain undiagnosed. abdominal tenderness or rigidity. because the lymph nodes may be small. with fever being the only presenting symptom in 10% of cases. Pay special attention to rashes. Repeat a regular physical examination daily while the patient is hospitalized. new or changing cardiac murmurs. renal cell carcinoma is most commonly associated with FUO. the diagnosis may be difficult to establish. Herpes viruses CMV and Epstein-Barr virus (EBV) infections usually cause lymphadenopathies. lymph node enlargement. and neurologic deficits. the physician may observe temporal artery tenderness or decreased pulsation. visceral leishmaniasis. Systemic bacterial illnesses Cutaneous changes may be the only sign other than fever in neisserial infections. Polymyalgia rheumatica The diagnosis of PMR is clinical. Solid tumors Among solid tumors.Fever curves are useful in FUO and are helpful in evaluating for adult Still disease. funduscopic changes. and zoonotic infections. however. Parasitic infections Consider toxoplasmosis in patients who are febrile with lymph node enlargement. Physical examination is notable for normal muscle strength. which may be missed on physical examination if the lymph nodes are not prominently enlarged. even after extensive evaluations. because such protean symptoms may evade diagnosis. Giant cell arteritis During the examination in patients with GCA. Carefully perform a history and physical examination. . signs of arthritis.

because of the potential for nonspecific presentations in these diseases. Rheumatic fever can be difficult to diagnose. or peripheral eosinophilia is often absent in cases of drug fever. Neither the fever pattern nor the duration of previous therapy is helpful in establishing the diagnosis. Parasitic infections If the physician is unaware of a history of recent travel to an endemic area and if the fever pattern is nonsynchronized. malaria can be missed as a cause of fever. Drug fever A history of allergy.Hepatobiliary infections Acute cholecystitis and gallbladder empyema can lead to a diagnosis of FUO because of the lack of right upper quadrant pain or jaundice. especially in elderly patients. Collagen-vascular and autoimmune diseases Consider PAN. Tuberculosis Tuberculosis (TB) is usually considered in the FUO differential diagnoses. and mixed connective-tissue diseases in patients with FUO. however. below:  Abdominal Abscess  Actinomycosis  Acute Lymphoblastic Leukemia  Acute Myelogenous Leukemia . which usually occurs in immunocompromised patients. as well as the disorders in the Differentials subsection. several factors may prevent a prompt diagnosis of TB. because it is rare in the developed world. In TB. RA. may initially manifest as constitutional symptoms that lack localizing signs. Conditions to consider in the diagnosis of FUO Diseases to consider in patients with symptoms of FUO include the following. Osteomyelitis The most common reason for misdiagnosis of osteomyelitis is the failure to consider the disease in a patient who is febrile with musculoskeletal symptoms. skin rashes. dissemination.

 Adenoviruses  Adrenal Carcinoma  Adrenal Insufficiency  Amebiasis  Amebic Hepatic Abscesses  Atrial Myxoma  Atypical Mycobacterial Infection  Bacillary Angiomatosis  Bacteroides Infection  Bartonellosis  Blastomycosis  Brain Abscess  Brucellosis  California Encephalitis  Campylobacter Infections  Candidiasis  Carcinoid Tumor. Intestinal  C burnetii infection  Chagas Disease (American Trypanosomiasis)  Cholangitis  Cholecystitis  Choledocholithiasis .

Gallbladder  Empyema. Chronic Bacterial Prostatitis  Chronic Lymphocytic Leukemia  Chronic Mesenteric Ischemia  Chronic Myelogenous Leukemia  Clostridial necrotizing fasciitis  Colon Cancer. Adenocarcinoma  Coxsackieviruses  Cryptococcosis  Cytomegalovirus  Cytomegalovirus Colitis  Dengue Fever  Diabetic Ulcers  Drug Fever  Eastern Equine Encephalitis  Echoviruses  Emphysematous Pyelonephritis  Empyema. Pleuropulmonary  Enteroviruses  Eosinophilic Pneumonia  Eosinophilic Toxocariasis  Epididymal Tuberculosis .

Viral  Giardiasis  Graves Disease  Hairy Cell Leukemia  Hepatitis A-E  Hepatoma  Herpes Simplex  Histoplasmosis  Human Immunodeficiency Virus  Human Herpesvirus Type 6  Hypersensitivity Pneumonitis  Hyperthyroidism  Inflammatory Bowel Disease  Intra-abdominal Sepsis  Japanese Encephalitis  Kikuchi Disease  Legionnaires Disease . Epididymitis  Epidural Abscess  Erythema Multiforme (Stevens-Johnson Syndrome)  Factitious Fever  Gallbladder Gangrene  Gastroenteritis.

 Leishmaniasis  Leptospirosis  Leukocytoclastic Vasculitis  Libman-Sacks Endocarditis  Listeria Monocytogenes  Liver Abscess  Lung Abscess  Lymphocytic Choriomeningitis  Lyssavirus Infection  Malaria  Malassezia furfur Infection  Malignant histiocytosis  Mastocytosis. Familial  Mediterranean Spotted Fever  Meningococcemia  Miliary Tuberculosis  Mucormycosis  Mycoplasma Infections  Naegleria Infection  Neuroleptic Malignant Syndrome  Nocardiosis . Systemic  Mediterranean Fever.

Viral  Prostatic Abscess  Psittacosis  Q Fever  Rat-bite Fever (S minor)  Rhinocerebral Phycomycosis  Sphenoid Sinusitis  Thrombophlebitis  Trypanosoma Infection Differential Diagnoses  Appendicitis  Arenaviruses  Aspergillosis . Nonarticular Rheumatism/Regional Pain Syndrome  Nonbacterial Prostatitis  Norwalk Virus  Onchocerciasis  Osteomyelitis  Pancreatitis. Viral  Pneumonia. Acute  Pelvic Inflammatory Disease  Pericholangitis  Pharyngitis.

the collection of clean-catch urine specimens may be difficult. pulmonary emboli are suspected. Endocarditis . resulting in normal urinalysis findings. 4.[6.[3. Constrictive Proceed to Workup Approach Considerations Laboratory and imaging findings vary according to the source of an FUO. Positron emission tomography (PET) scanning has enhanced the detection of occult neoplasms. perinephric abscesses occasionally fail to communicate with the urinary system. 5] Routinely obtain chest radiographs. chest radiography findings may be normal. Results from purified protein derivative (PPD) tests may be negative. 7. furthermore. lymphomas. despite negative scanning studies. and culture findings may not become positive for 4-6 weeks. Tuberculosis In tuberculosis. Occult UTI is possible in a patient with anatomic abnormalities of the urinary tract and FUO. Urinary tract infections For UTIs in young children. particularly when transesophageal echocardiography is available. Acute  Pericarditis. 8] Echocardiography is highly sensitive in diagnosing endocarditis. and vasculitides in patients with FUO. Obtain pulmonary angiograms when. Catscratch Disease  Celiac Sprue  Gout  Graft Versus Host Disease  Myocarditis  Pericarditis.

and Neisseria gonorrhoeae as causes of FUO. Prior antibiotic therapy is the most common reason for negative blood cultures. and Q fever endocarditis have been identified in patients with FUO.Culture-negative endocarditis is reported in 5-10% of endocarditis cases. radiographs may not show changes for weeks after the development of symptoms. Cultures and serologic tests establish the diagnosis of these infections. However. Researchers have also described systemic infections with Salmonella species. and MRI is also an extremely useful test for the diagnosis of osteomyelitis. Osteomyelitis In osteomyelitis. still prevalent in Latin America and the Mediterranean. chronic Q fever. Rickettsia Chronic infections with Coxiella burnetii. is very important. lymphomas are occasionally difficult to diagnose promptly. Systemic bacterial illnesses Some systemic bacterial illnesses can manifest as FUOs. Perform extensive diagnostic workup studies (eg. and the infection is transmitted from cattle and sheep. Hepatobiliary infections In patients with hepatobiliary infections. on rare occasions. Neisseria meningitidis. Signs of hepatic involvement are common. Perform serologic tests in suspected cases. Acquired immunodeficiency syndrome More than 80% of patients with AIDS and lymphomas have involvement of extranodal sites (usually the brain). cholangitis can occur without local signs and with only mildly elevated or normal findings on liver function tests. Serology is essential in the diagnosis of these chlamydial infections. Radionucleotide studies (technetium Tc 99m [99m Tc] bone scanning) are more sensitive than plain radiography. imaging studies) to exclude these opportunistic diseases in patients with HIV fever who have a prolonged fever before attributing the fever to the HIV infection. Lymphogranuloma venereum infection can manifest as FUO. Brucellosis. Herpes viruses . Chlamydia Chlamydia psittaci infection and.

the peripheral blood smear and bone marrow aspirate may not reveal the correct diagnosis. anemia. therefore. The results of these tests may initially be negative. because blood cultures are negative in approximately 50% of the cases. Systemic-onset JRA is often difficult to diagnose. Collagen-vascular and autoimmune diseases SLE is readily diagnosed in most cases by the demonstration of antinuclear antibodies. with fever being the only presenting symptom in 10% of cases. Hematuria may be absent in approximately 40% of cases. Regional enteritis . In preleukemic states. when the disease is confined to the retroperitoneal lymph nodes). Lymphomas The correct diagnosis of Hodgkin or non-Hodgkin lymphoma can be delayed if the tumor is difficult to detect (eg. Anemia may be the most prominent laboratory abnormality in these 2 forms of lymphoma. the diagnosis may be difficult to establish because the lymph nodes may be small. however. Parasitic infections Consider toxoplasmosis in patients who are febrile with lymph node enlargement.Serologic testing can confirm the diagnosis of CMV or EBV when the patient presents with lymphocytosis with atypical lymphocytes. Laboratory abnormalities include pronounced leukocytosis. renal cell carcinoma is most commonly associated with FUO. they delay the correct diagnosis. Solid tumors Among solid tumors. repeat them in suspected cases 2-3 weeks after the onset of illness. an elevated erythrocyte sedimentation rate (ESR). Rising antibody titers and immunoglobulin M (IgM) antibodies confirm the diagnosis. thus. therefore. perform a bone marrow biopsy. These findings usually trigger a search for an infectious cause. Systemic infection in a patient may remain undiscovered. and abnormal liver function tests. whereas anemia and a highly elevated sedimentation rate are common. Leukemias Acute leukemias are another important neoplastic group that can cause FUO. Fungal infections Candida albicans is the main culprit in disseminated fungal infections.

Giant cell arteritis Laboratory findings in GCA include an elevated ESR. Crohn disease. The diagnosis is established with endoscopy and biopsy. and. liver function abnormalities can be found in Kikuchi disease. Perform a biopsy of a temporal artery to obtain a definitive diagnosis. sometimes. Hodgkin disease) are found. Kikuchi disease Laboratory evidence of chronic inflammation. mild to moderate normochromic normocytic anemia. and abnormal liver function tests (25% of cases). sarcoidosis. specificity 86%):  Mononeuritis multiplex  Myalgias with muscle tenderness  Livedo reticularis  Testicular pain or tenderness  Renal impairment (elevated BUN and creatinine levels)  Weight loss of 4 kg or more  Diastolic blood pressure greater than 90 mm Hg  Hepatitis B positive  Arteriography showing small and large aneurysms and focal constrictions between dilated segments . Diarrhea and other abdominal symptoms are occasionally absent. particularly in young adults. Granulomatous hepatitis In some patients with hepatic granulomas. TB. Pathologic review shows vasculitis and a mononuclear cell infiltrate. Polyarteritis nodosa Any 3 of the following 10 findings is sufficient for the diagnosis of PAN (sensitivity 82%. brucellosis. elevated platelet counts. none of the diseases usually associated with FUO (eg. syphilis. An elevated alkaline phosphatase level is the most consistent laboratory abnormality.Crohn disease is the most common gastrointestinal cause of FUO.

 Biopsy of small. Cultures Blood cultures for aerobic and anaerobic pathogens are essential in the evaluation. Obtain cultures for bacteria. These tissues and fluids include cerebrospinal fluid (CSF). and lymph nodes. granulomatous hepatitis). Suspect herpesvirus infection if the patient has lymphocytosis with atypical cells. Diagnose malaria and spirochetal diseases with the aid of direct examination of the peripheral blood smear. bone marrow. however. A leukocytosis with an increase in bands suggests an occult bacterial infection. and fungi in all normally sterile tissues and liquids that are sampled during further workup. Cultures of sputum and stool may be helpful in the presence of signs or symptoms suggestive of pulmonary or gastrointestinal disease. Urinalysis Exclude UTIs and malignant tumors of the urinary tract. no more than 6 sets of blood cultures are required. Ensure that leukemias are not missed in aleukemic or preleukemic cases. with an underlying disease originating in the liver or a disease that causes nonspecific alterations of the liver (eg.or medium-sized arteries containing white blood cell infiltrate  Peripheral eosinophilia (common and an important clue to PAN) Complete Blood Count (CBC) Anemia is an important finding and suggests a serious underlying disease. Serum Chemistry At least 1 liver function test result is usually abnormal. Serology . mycobacteria. however. respectively. Most other chemistry tests rarely contribute to the diagnosis. although they are frequently ordered. repeated examinations are often necessary. not all of them are consistently associated with pathologic findings in the urine. however. and fluid from the liver. Routinely culture the patients' urine. pleural or peritoneal fluid.

Serologies are most helpful if paired samples show a significant. Serum ferritin levels are useful in cases of FUO due to malignancies. and adult Still disease. thyroxine level. RA. Frequently check antinuclear antibody titers. CMV infection. SLE flares. PMR). toxoplasmosis. HIV infection. Serum protein electrophoresis (SPEP) is useful in diagnosing atrial myxoma. in patients with suspected retroperitoneal tumors or infections. Brucellosis. but they are appropriate for evaluation of the above illnesses in the correct clinical and epidemiologic setting. MRI has also been used in the diagnosis of vasculitides. and chlamydial diseases are diagnosed with serology. but CT scanning is preferred for most other processes of the retroperitoneal space. amebiasis.[9] . and ESR. EBV infectious mononucleosis. SLE flare. However. even in the absence of signs of an intra-abdominal process. GCA. and lymphomas. Computed Tomography Scanning If ultrasonography fails to help reveal the diagnosis. These diagnostic tests are of limited value in most patients with FUO. usually 4-fold. Their diagnostic accuracy is limited in other autoimmune and collagen vascular diseases. obtain CT scans of the abdomen in all patients with symptoms suggesting an intra-abdominal process. In patients in whom GCA or PMR is suspected. especially in GCA). because the ESR is nearly always greater than 60 mm/h (and often is much higher. hyperthyroidism. checking the ESR may be particularly useful. increase of antibodies specific to an infectious microorganism. and in those with abnormal findings on liver function tests. thyroiditis. because they are helpful in diagnosing certain conditions (lupus. Abdominal Ultrasonography Routine abdominal ultrasonography may also be justified. rheumatologic factor. Magnetic Resonance Imaging This can be very useful when osteomyelitis is suspected. negative ultrasonographic findings and absent symptoms suggestive of an intra-abdominal process do not exclude such a process. Intravenous pyelography may be more sensitive than CT scanning in detecting processes involving the descending urinary tract.

Treatment should be directed toward the underlying cause. A technetium bone scan may be a more sensitive method for documenting skeletal involvement when osteomyelitis is suspected in a patient in whom conventional radiography has shown no compatible changes. accessible lymph nodes. and gastrointestinal tumors. when imaging techniques are nondiagnostic and an intra-abdominal source is suspected).Endoscopic Examination Perform an endoscopic examination of the upper and lower gastrointestinal tract. laparotomy). Occasionally. and bone marrow. including the following:  Cases that meet criteria for culture-negative endocarditis . Radionucleotide Studies Perform ventilation and perfusion radionucleotide studies to document pulmonary emboli. Some studies suggest a few exceptions to this general approach.[10] This is rarely indicated (eg. biliary tract disease. once a diagnosis is made. complementing endoscopic studies with barium enemas or upper gastrointestinal series is necessary. Liver biopsy rarely yields helpful data in patients without abnormal liver function tests or abnormal liver findings (observed on CT scan or ultrasonography). or soft-tissue lymphomas. Biopsies are easily performed in enlarged. The decision to biopsy is more difficult if it necessitates an exploratory surgical procedure (eg. Whipple disease. empiric therapy has little or no role in cases of classic fever of unknown origin (FUO). other peripheral tissues. Proceed to Treatment & Managemen Approach Considerations In general. Consider radionucleotide studies using gallium citrate or granulocytes labeled with indium In 111 (111 In) for diagnosis of occult abscesses. Biopsy The final diagnosis is obtained during direct biopsy examination of involved tissue. including retrograde cholangiography when indicated or when searching for Crohn disease. as needed. neoplasms.

Several studies have found that prolonged. or (3) the patient deteriorates clinically. laboratory data. Outpatient Care Conduct close follow-up procedures and systematic reevaluation studies to prevent clinical worsening. physical examination. Cases in which findings or the clinical setting suggests cryptic disseminated TB (or. patients with FUO rarely need surgical treatment. Consultations Appropriate consultations are indicated based on patient history. Guide further workup studies on an outpatient basis. and radiologic findings. (2) diagnostic tests are unavailable at the existing facility. Inpatient Treatment No evidence supports prolonged hospitalization in patients who are clinically stable and whose workup findings are unrevealing. Consultations include the following:  Infectious disease specialist  Hematologist/oncologist  Rheumatologist  Pulmonologist  Gastroenterologist  Endocrinologist . occasionally. Because of a better understanding of the etiologies and careful diagnostic approaches. undiagnosed FUO generally carries a favorable prognosis. Patient Transfer The need for transfer is indicated if (1) the current facility is unable to establish a diagnosis. other granulomatous infections)  Cases in which temporal arteritis with vision loss is suspected.

approximately 50% of patients recover spontaneously. bone loss. while the other 50% respond to corticosteroid treatment (duration of therapy ranging from a few weeks to several years). psychosis. diabetes. Interventional radiologist  Surgeon Long-Term Monitoring Problems may arise in the 5-15% of patients whose FUO remains undiagnosed. Specific examples of treatment In patients with hepatic granulomas. hypertension. In polymyalgia rheumatica. When drug fever is suspected. discontinue the implicated drug. and use intravenous steroids if the patient is very ill or has significant ocular compromise. Carefully monitor the patient. In giant cell arteritis. the treatment consists of amelioration of symptoms with steroid therapy and close monitoring for possible development of GCA. Stopping the causative drug generally leads to defervescence within 2 days. because inadequate treatment and steroid toxicities (eg. dyspepsia. These patients usually have a benign long-term course. cataracts) can cause significant morbidity. even after extensive evaluations. Proceed to Medication Medication Summary The choice of medications administered to patients depends on the etiology of the FUO. but close followup and systematic reevaluation studies are essential to avoid missing potential etiologies. treat the patient with high doses of steroids. .

(2) a duration of fever of >3 weeks. (3) neutropenic FUO. improved diagnostic technologies. While this classification has stood for more than 30 years. This updated classification includes (1) classic FUO. (2) nosocomial FUO.3°C (>101°F) on several occasions. Durack and Street have proposed a revised system for classification of FUO that better accounts for nonendemic and emerging diseases. and adverse reactions to new therapeutic interventions. and (4) FUO associated . and (3) failure to reach a diagnosis despite 1 week of inpatient investigation.Fever of unknown origin (FUO) was defined by Petersdorf and Beeson in 1961 as (1) temperatures of >38.

3°C (≥101°F) on several occasions over a period of >4 weeks for outpatients or >3 days for hospitalized patients with HIV infection.with HIV infection. Adoption of these categories of FUO in the literature has allowed a more rational compilation of data regarding these disparate groups. The diagnosis of neutropenic FUO is invoked if a specific cause is not identified after 3 days of investigation.3°C (≥101°F) develops on several occasions in a hospitalized patient who is receiving acute care and in whom infection was not manifest or incubating on admission. HIV-associated FUO is defined by a temperature of ≥38. In the remainder of this chapter. including at least 2 days’ incubation of cultures. Classic FUO corresponds closely to the earlier definition of FUO. . is the minimum requirement for this diagnosis. Three days of investigation. the discussion will focus on classic FUO in the adult patient unless otherwise specified. In nosocomial FUO . stipulating three outpatient visits or 3 days in the hospital without elucidation of a cause or 1 week of “intelligent and invasive” ambulatory investigation. This diagnosis is invoked if appropriate investigation over 3 days. differing only with regard to the prior requirement for 1 week’s study in the hospital. including 2 days’ incubation of cultures. The newer definition is broader. Neutropenic FUO is defined as a temperature of ≥38. a temperature of ≥38. reveals no source.3°C (≥101°F) on several occasions in a patient whose neutrophil count is <500/μL or is expected to fall to that level in 1–2 days. including at least 2 days’ incubation of cultures.

including a prospective study of 167 adult patients with FUO encompassing all eight university hospitals in the Netherlands and using a standardized protocol in which the first author reviewed every patient’s case. The wide availability of ultrasonography. systemic lupus erythematosus. Newer studies reflect not only changing patterns of disease but also the impact of diagnostic techniques that make it possible to eliminate many patients with specific illness from the FUO category. MRI. The ubiquitous use of potent broad-spectrum antibiotics may have decreased the number of infections causing FUO. and positron emission tomography (PET) scanning has enhanced the detection of localized infections and of occult neoplasms and lymphomas in patients previously thought to have FUO. Prolonged mononucleosis syndromes caused by Epstein-Barr virus. or HIV are conditions whose consideration as a cause of FUO are sometimes confounded . Infections such as extrapulmonary tuberculosis and—in endemic areas—typhoid fever and malaria remain a leading diagnosable cause of FUO.CAUSES OF CLASSIC FUO Table 18-1 summarizes the findings of several large studies of FUO carried out since the advent of the antibiotic era. Coincident with the widespread use of antibiotics. increasingly useful diagnostic technologies—both noninvasive and invasive—have been developed. cytomegalovirus (CMV). radionuclide scanning. and polyarteritis nodosa. Likewise. CT. the widespread availability of highly specific and sensitive immunologic testing has reduced the number of undetected cases of adult Still’s disease.

Osteomyelitis. one may be misled by cryptic endocarditis caused by indolent. (previously Rochalimaea ). retroperitoneal. Fungal diseases. with submucosal plaques or nodules involving the urinary tract. is seen in patients with defects of intracellular bacterial killing. Coxiella burnetii . Cardiobacterium hominis . may cause fatal FUO if untreated. Although true culturenegative infective endocarditis is rare. Prostatitis. slow-growing microorganisms of the HACEK group ( Haemophilus aphrophilus . particularly outside of the endemic regions where these diseases may be more readily recognized . The rising popularity of adventure travel among citizens of Western countries has increased the incidence in these nations of presentation for FUO due to otherwise uncommon .by delayed antibody responses. should prompt evaluation for paracoccidioidomycosis and coccidioidomycosis. sinusitis. dental abscesses. may cause FUO. and is treated with fluoroquinolones or trimethoprim-sulfamethoxazole. Legionella spp.. respectively. it is associated with intracellular bacterial infection. most notably histoplasmosis involving the reticuloendothelial system. Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans . especially where prosthetic devices have been implanted. B artonella spp. Intraabdominal abscesses (sometimes poorly localized) and renal. Renal malacoplakia. must be considered. and fungi. Chlamydophila psittaci . even for very limited periods. E ikenella corrodens . and paraspinal abscesses continue to be difficult to diagnose. and cholangitis continue to be sources of occult fever. other organs may be involved. and K ingella kingae ). FUO following travel to neotropical regions and the desert southwest of the United States. Occasionally.

babesiosis. a decrease in the percentage of FUO cases due to malignancy was attributed to improvement in diagnostic technologies—in particular. In the elderly. ~25–50% of cases of FUO have remained undiagnosed. The general term noninfectious inflammatory diseases applies to systemic rheumatologic or vasculitic diseases such as polymyalgia rheumatica. particularly of the asynchronous variety. Malaria (which may result from transfusion. lupus. multisystem disease is the most frequent cause of FUO. notably Chikungunya fever and scrub typhus. A number of patients in these series had temporal arteritis. may cause FUO and is increasing in geographic distribution and in incidence. . In recent series. PET scanning. adult Still’s disease. or infection with a drug-resistant Plasmodium strain) continues to be a cause of FUO. and adult Still’s disease as well as to granulomatous diseases such as sarcoidosis. MRI.endemic vector-borne infections. In more recent series. and tumor antigen assays. high-resolution tomography. This observation does not diminish the importance of considering neoplasia in the initial diagnostic evaluation of a patient with fever. FUO with headache should prompt examination of spinal fluid for Cryptococcus neoformans. neoplasms were the next most common cause of FUO after infections ( Table 18-1 ). drug-related fever. failure to take a prescribed prophylactic agent. and factitious fever. Mycobacterium tuberculosis . especially among the elderly and the immunosuppressed. A related protozoan infection. In most earlier series. and travel-acquired trypanosomes. giant-cell arteritis being the leading etiologic entity in this category. Crohn’s disease. and granulomatous hepatitis.

. and the Muckle-Wells syndrome)]. factitious fever. even for the more indolent infectious etiologies (e. phenytoin) are particularly common causes. The use of TNF inhibitors for treatment of inflammatory diseases has led to atypical presentations of tuberculosis. cardiovascular drugs (e. Virtually all classes of drugs can cause fever. and drugs acting on the central nervous system (e. but antimicrobial agents (especially β-lactam antibiotics). histoplasmosis. antineoplastic drugs. and congenital lysosomal storage diseases such as Gaucher’s and Fabry’s disease. familial cold urticaria. and colon cancer is an important cause of FUO with malignancy in this age group. tumor necrosis factor (TNF) receptor–associated periodic syndrome (also known as TRAPS or familial Hibernian fever). It is axiomatic that. paracoccidioidomycosis. and JC virus infection associated with FUO.” On this list are drug fever.g. Any febrile pattern may be elicited by a drug. A drug-related etiology must be considered in any case of prolonged fever. quinidine). Many diseases have been grouped in the various studies as “miscellaneous. .In patients >50 years of age. as the duration of fever increases.g. brucellosis.g. pulmonary embolism. In a series of 347 patients referred to the National Institutes of Health from 1961 to 1977.. malaria due to Plasmodium malariae ).. hyper-IgD syndrome. Tuberculosis is the most common infection causing FUO in the elderly. this disease accounts for 15–20% of FUO cases. the likelihood of an infectious cause decreases. the hereditary periodic fever syndromes [familial Mediterranean fever. coccidioidomycosis.

are undergoing diseasemodifying interventions such as TNF-α suppression. and safaris). This list applies predominantly to Western nations such as the United States. A significant proportion (9%) had factitious fevers—i. unusual environmental exposures associated with travel or hobbies (e. GLOBAL CONSIDERATIONS More than 200 conditions may be considered in the differential diagnosis of classic FUO in adults. A total of 27% of patients had no actual fever during inpatient observation or had an exaggerated circadian temperature rhythm without chills. and pets. The workup of FUO must take into careful consideration the patient’s country of origin.only 6% had an infection ( Table 18-2 ) . It is worth noting that 8% of the patients with prolonged fevers (some of whom had completely normal liver function studies) had granulomatous hepatitis. or have recently reconstituted immunity. or other abnormalities. 19% of cases still had no specific diagnosis. elevated pulse. recent and remote travel (including past service in foreign wars). The increasing number of returning sojourners with exotic travel itineraries underscores the need for a detailed history of travel and associated activities in the setting of undiagnosed fever. increasing numbers of travelers are immunosuppressed. For example..g. as do the changing demographics of the travelers themselves. Immigrants with unexplained . the most common of these are listed in Table 18-3 . A substantial number of these factitious cases were in young women in the health professions.. caving. fevers due either to false elevations of temperature or to self-induced disease. and 6% had adult Still’s disease After prolonged investigation.e. hunting.

Moreover. Patients. subclinical infections may be unmasked decades after exposure by new malignancies or immunosuppressive conditions. In both foreign-born individuals and veterans of foreign wars.g. If specialized laboratory and imaging studies cannot be conducted. culture of lysed. diagnosis may be facilitated by maximizing the quality and precision of locally available approaches (e. insight may be gained from contacting local epidemiologists. including immunization with nonstandard or unidentified live vaccines. family members. Emerging infectious diseases may include FUO first presenting as clusters of cases in remote regions. centrifuged blood cultures. underscores the need for obtaining an insightful environmental. 221 ). with early notification of public health authorities in cases of suspicious etiology ( Chap. The differential diagnosis of FUO must also take into account changes in the range of arthropod vectors or the possibility that local permissive vectors have become infected with previously nonendemic pathogens. should be carefully interviewed with regard to childhood exposures. many of which cause illnesses presenting with prolonged fever. and professional history. including naturalized citizens who have left their countries of origin decades previously. The possibility of international and domestic terrorist activity involving the intentional release of infectious agents..fever. occupational. and close occupational contacts may need to be interviewed. . Evaluation of FUO in underresourced medical settings requires increased reliance on history and clinical examination. and microscopic examination by an experienced technician).

Leptospira .. B. and simultaneous urine and body temperatures should be measured. paraffin blocks of fixed . and. reference is made to “potentially diagnostic clues.” as outlined by de Kleijn and colleagues. and the inclusion bodies of ehrlichiosis and anaplasmosis . and C agents. 18-1 . localizing signs. slides should be requested. Specialized staining of mononuclear cells and granulocytes can help to identify intracellular bacteria. see Table 221-2 )—that circumvent vaccine-acquired immunity could be developed or that novel recombinant organisms could be engineered to produce clinical or laboratory responses that defy current diagnostic approaches. temperature-taking should be supervised. and Borrelia . thin blood smears. these clues may be key findings in the history (e.g. Any tissue removed during prior relevant surgery should be reexamined. Certain specific diagnostic maneuvers become critical in dealing with prolonged fevers. prepared with proper technique and quality stains and subjected to expert microscopy. should be used to speciate Plasmodium and to identify Babesia . Thick blood smears should be examined for Plasmodium .the global spread of genetic engineering technologies raises the possibility that traditional agents—including Centers for Disease Control Categories A. In this flow chart. if necessary. or key symptoms. protozoal amastigotes. If factitious fever is suspected. SPECIALIZED DIAGNOSTIC STUDIES Classic FUO A stepwise flow chart depicting the diagnostic workup and therapeutic management of FUO is provided in Fig. travel). Rickettsia . Leishmania . Trypanosoma .

review of prior radiologic reports may be insufficient. Relevant x-rays should be reexamined. 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 . Serum should be set aside in the laboratory as soon as possible and retained for future examination for rising antibody titers. 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 malacoplakia Sinusitis Subphrenic abscess Suppurative thrombophlebitis Tuboovarian abscess Intravascular infections Bacterial aortitis Bacterial endocarditis Vascular catheter infection Systemic bacterial infections Bartonellosis Brucellosis Campylobacter infection Cat-scratch disease/bacillary angiomatosis (B.pathologic material should be reexamined and additional special studies performed.

and E HIV infection Human herpesvirus 6 infection Lymphocytic choriomeningitis Parvovirus B19 infection Picornavirus infection Fungal infections Aspergillosis Blastomycosis Candidiasis Coccidioidomycosis Cryptococcosis Histoplasmosis Mucormycosis Paracoccidioidomycosis Pneumocystis infection Sporotrichosis Parasitic infections Amebiasis Babesiosis Chagas’ disease Leishmaniasis Malaria Strongyloidiasis Toxocariasis Toxoplasmosis Trichinellosis Presumed infections.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 Mycoplasmal infections Chlamydial infections Lymphogranuloma venereum Psittacosis TWAR (C. pneumoniae) infection Viral infections Chikungunya fever Colorado tick fever Coxsackievirus group B infection Cytomegalovirus infection Dengue Epstein-Barr virus infection Hepatitis A. B. C. D. avium/M. agent undetermined Kawasaki’s disease (mucocutaneous lymph node syndrome) Kikuchi’s necrotizing lymphadenitis Neoplasms Malignant .

aphthae Postmyocardial infarction syndrome Recurrent pulmonary emboli Subacute thyroiditis (de Quervain’s) Tissue infarction/necrosis Inherited and Metabolic Diseases Adrenal insufficiency Cyclic neutropenia Deafness. and amyloidosis Fabry disease Familial cold urticaria .Colon cancer Gall bladder carcinoma Hepatoma Hodgkin’s lymphoma Immunoblastic T-cell lymphoma Leukemia Lymphomatoid granulomatosis Malignant histiocytosis Non-Hodgkin’s lymphoma Pancreatic cancer Renal cell carcinoma Sarcoma Benign Atrial myxoma Castleman’s disease Renal angiomyolipoma TABLE 18-3 Causes of FUO in Adults in the United States Habitual Hyperthermia (Exaggerated circadian rhythm) Collagen Vascular/Hypersensitivity Diseases Adult Still’s disease Behçet’s disease Erythema multiforme Erythema nodosum Giant-cell arteritis/polymyalgia rheumatica Hypersensitivity pneumonitis Hypersensitivity vasculitis Mixed connective-tissue disease Polyarteritis nodosa Relapsing polychondritis Rheumatic fever Rheumatoid arthritis Schnitzler’s syndrome Systemic lupus erythematosus Takayasu’s aortitis Weber-Christian disease Granulomatosis with polyangiitis (Wegener’s) Granulomatous Diseases Crohn’s disease Granulomatous hepatitis Midline granuloma Sarcoidosis Miscellaneous Conditions Aortic dissection Drug fever Gout Hematomas Hemoglobinopathies Laennec’s cirrhosis PFPA syndrome: periodic fever. pharyngitis. adenitis. urticaria.

It is critical to inform the laboratory of the intent to test for unusual organisms.94°F)] Febrile agglutinins is a vague term that. having low sensitivity and variable specificity. and rickettsial diseases. Multiple blood samples (no fewer than three and rarely more than six. or Tropheryma whipplei .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 Central Brain tumor Cerebrovascular accident Encephalitis Hypothalamic dysfunction Peripheral Hyperthyroidism Pheochromocytoma Factitious Fevers “Afebrile” FUO [<38. Blood culture media should be supplemented with l-cysteine or pyridoxal to assist in the isolation of nutritionally variant streptococci. Bartonella . Mycoplasma . Coxiella . Cultures of sinus fluid and pulmonary secretions on . such as Histoplasma .3°C (100. brucellosis. Chlamydophila . It should be noted that sequential cultures positive for multiple organisms may reflect self-injection of contaminated substances. in most laboratories. including samples for anaerobic culture) should be cultured in the laboratory—with and without increased CO 2 —for 2 to 3 weeks to ensure ample growth time for any HACEK organisms ( Chap. These studies are seldom useful. Lysis-centrifugation blood culture techniques should be employed when prior antimicrobial therapy or fungal or atypical mycobacterial infection is suspected. Specialized media should be used if an exposure or travel history suggests uncommon causes of endocarditis. refers to serologic studies for salmonellosis. 146 ).

splenomegaly. are indicated. and rash.multiple permissive cell lines may prove helpful in identifying new respiratory viruses implicated in FUO. and anemia and is often accompanied by arthralgias. Antinuclear antibody. 179 ). The C-reactive protein level may be a useful cross-reference for the ESR and is a more sensitive and specific indicator of an “acute-phase” inflammatory metabolic response. fungi. rheumatoid factor. lymphadenopathy. and serum cryoglobulins should be measured to rule out other collagen vascular diseases and vasculitis. cerebrospinal fluid can be tested for herpesvirus. polyserositis (pleuritis. A highly multiplexed oligonucleotide microarray using PCR amplification and containing probes for all recognized virus species hosted by vertebrates and up to 135 bacterial. antineutrophil cytoplasmic antibody. leukocytosis. Elevated levels of . 73 fungal. In any FUO workup. and 63 parasitic genera and species has been developed but has not yet been approved for clinical use. The continued clinical validation of such microarrays will further diminish rates of undiagnosed FUO of infectious etiology. the erythrocyte sedimentation rate (ESR) should be determined. Striking elevation of the ESR and anemia of chronic disease are frequently seen in association with giant cell arteritis or polymyalgia rheumatica—common causes of FUO in patients >50 years of age. Still’s disease is suggested by elevations of ESR. and CMV. pericarditis). Urine cultures. In the setting of recurrent fevers with lymphocytic meningitis (Mollaret’s meningitis). including cultures for mycobacteria. with use of the polymerase chain reaction (PCR) to amplify and detect viral nucleic acid ( Chap.

angiotensin-converting enzyme in serum may point to sarcoidosis. sarcoidosis. tuberculosis. Hodgkin’s disease. Negative results in the QFT-GIT test—as in the TST—do not definitively exclude a diagnosis of tuberculosis. the sensitivity of the QFT-GIT test was statistically similar to that of the TST for detecting infection in persons with untreated.S. should be employed. or AIDS. . primarily in persons who have been infected with nontuberculous mycobacteria or vaccinated with BCG. These tests—the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay and the T-SPOT TB assay—measure the production of interferon γ by T lymphocytes upon exposure to antigens of M. culture-confirmed tuberculosis. PA). the intermediate-strength purified protein derivative (PPD) skin test should be used to screen patients with classic FUO for tuberculosis. is less influenced by previous infection with nontuberculous mycobacteria. and is not affected by prior vaccination with bacille Calmette-Guérin (BCG). Swiftwater. such as the mumps skin test antigen (Aventis-Pasteur. With rare exceptions. It should be kept in mind that both the PPD tuberculin skin test (TST) and control tests may yield false-negative results in patients with miliary tuberculosis. In direct comparisons. Repeating the QFT-GIT test does not boost the in vitro response. Concurrent control tests. Food and Drug Administration for the diagnosis of tuberculosis. TSTs are variably affected by these factors. Two interferon γ–release assays have been approved by the U. while injection of PPD for the TST can boost subsequent TST responses. The QFT-GIT test is more specific. malnutrition.

Radionuclide scanning procedures using technetium (Tc) 99m . MRI is preferred. spleen. however. At present. but the comparative utility of MRI and CT in the diagnosis of FUO is unknown. Echocardiography may be helpful in an evaluation for bacterial endocarditis. Saccular aneurysms may be seen. Sputum should be induced with an ultrasonic nebulizer for cultures. nonbacterial thrombotic endocarditis. Ultrasonography of the abdomen is useful for investigation of the hepatobiliary tract. kidneys. abdominal CT with contrast should be used unless MRI is specifically indicated. Arteriography may be useful for patients in whom systemic necrotizing vasculitis is suspected. and molecular diagnostic testing. pericarditis. cytology. If there are pulmonary signs or symptoms. and may permit diagnosis of arteritis when biopsy is difficult. and pelvis. Transesophageal echocardiography is preferred for these lesions. and atrial myxomas.Noninvasive procedures should include an upper gastrointestinal contrast study with small-bowel follow-through and colonoscopy to examine the terminal ileum and cecum for early evidence of lymphoma or subclinical Crohn’s disease. and cytology should be considered. most commonly in renal or hepatic vessels. bronchoscopy with bronchoalveolar lavage for cultures. If a spinal or paraspinal lesion is suspected. MRI may be superior to CT in demonstrating intraabdominal abscesses and aortic dissection. PCR. Chest x-rays should be repeated if new symptoms arise. Colonoscopy is especially strongly indicated in the elderly. High-resolution spiral CT of the chest and abdomen should be performed with both IV and oral contrast.

or indium (In) 111–labeled leukocytes may be useful in identifying and/or localizing inflammatory processes such as aortitis or abscess. FDG PET scanning should therefore be chosen over 67 Ga scanning in the diagnosis of FUO. 329 ) or Pneumocystis infection ( Chap. Fluorodeoxyglucose F18 (FDG) PET scanning appears to be superior to other forms of nuclear imaging. false-positive and false-negative findings are common. The FDG used in PET scans accumulates in tumors and at sites of inflammation and has even been shown to accumulate reliably at sites of vasculitis. 111 In-labeled white blood cell (WBC) scan may be used to locate abscesses. In one study. Biopsy of the liver and bone marrow should be considered in the workup of FUO if the studies mentioned above are unrevealing and if fever is prolonged. 295 ) in the abdomen. even when liver enzymes are normal and no other diagnostic clues point to liver disease. With these scans. 207 ) in the lungs or Crohn’s disease ( Chap. All biopsy specimens . Ga scintigraphy yielded useful diagnostic information in almost one-third of cases. 67 Ga scan may be used to identify sarcoidosis ( Chap. 99m Tc bone scan should be undertaken to look for osteomyelitis or bony metastases. Where available. It is likely that PET scanning. Granulomatous hepatitis has been diagnosed by liver biopsy. and it was suggested that this procedure might actually be used before other imaging techniques if no specific organ is suspected of being abnormal. which provides quicker results (hours vs days). will prove even more sensitive and specific than 67 Ga scanning in FUO.sulfur colloid. gallium (Ga) 67 citrate.

a retrospective diagnosis can sometimes be made on the basis of studies of long-fixed pathologic tissues. Exploratory laparotomy has been performed when all other diagnostic procedures fail but has largely been replaced by imaging and guided-biopsy techniques. but inguinal nodes are often palpable and are seldom diagnostically useful. with less invasive morbidity. and fungi. Nosocomial FUO (See also Chap. Lymph node biopsy may be helpful if nodes are enlarged. Peritoneal lavage may be used as a minimally invasive approach to peritoneal cytology studies. fixed tissues. The . Likewise.should be cultured for bacteria. in the absence of clues pointing to the bone marrow. In a patient over age 50 (or occasionally in a younger patient) with the appropriate symptoms and laboratory findings. mycobacteria. When possible. At some research centers. Tenderness or decreased pulsation. 131 ) The primary considerations in diagnosing nosocomial FUO are the underlying susceptibility of the patient coupled with the potential complications of hospitalization. PCR technology makes it possible in some cases to identify and speciate mycobacterial DNA in paraffin-embedded. should guide the selection of a site for biopsy. if noted. “blind biopsy” of one or both temporal arteries may yield a diagnosis of arteritis. bone marrow biopsy (not simple aspiration) for histology and culture has yielded diagnoses late in the workup. Laparoscopic biopsy may provide more adequate guided sampling of lymph nodes or liver. Thus. a section of the tissue block should be retained for further sections or stains.

empirical . alcohol/drug withdrawal. and pseudogout are among the many possible causes to consider. Drug fever. As in classic FUO. pancreatitis. as many patients are already critically ill. The pace of diagnostic tests is accelerated. hematomas. and fluid cultures are mandatory. are imperative. Multiple blood. Like diagnostic measures. or infected foreign bodies. thyroiditis. and the threshold for procedures—CT scans. adrenal insufficiency. Among these causes are acalculous cholecystitis. septic phlebitis. or persistently high virus loads are a threat. wound. In this setting. Even so. the best approach is to focus on sites where occult infections may be sequestered. and prostheses are all suspect. the fever has a noninfectious cause. ultrasonography. IV lines must be changed (and cultured). Intravascular lines. More than 50% of patients with nosocomial FUO are infected. drugs stopped for 72 hours. noninvasive venous studies—is low. fungemia. In ~25% of patients with nosocomial FUO. and empirical therapy started if bacteremia. 20% of cases of nosocomial FUO may go undiagnosed. transfusion reactions. such as the sinuses of intubated patients or a prostatic abscess in a man with a urinary catheter. deep-vein thrombophlebitis. 111 In WBC scans. and pulmonary embolism. Clostridium difficile colitis may be associated with fever and leukocytosis before the onset of diarrhea. repeated meticulous physical examinations. In many hospital settings. gout. coupled with focused diagnostic techniques. therapeutic maneuvers must be swift and decisive.original surgical or procedural field is the place to begin a directed physical and laboratory examination for abscesses.

edu/IDSA/guidelines ). Infections due to herpes simplex virus or CMV are sometimes causes of FUO in this group.journals. Candida and Aspergillus infections are common. Neutropenic FUO (See also Chap. aureus .uchicago. to infections involving catheters (including septic thrombophlebitis). imipenem. In these patients. and to perianal infections. to bacteremic infections. cefepime. Practice guidelines covering many of these issues have been published jointly by the Infectious Diseases Society of America (IDSA) and the American College of Critical Care Medicine and can be accessed on the IDSA website ( www. While the duration of illness may be short in these patients. or meropenem.antibiotic therapy for nosocomial FUO now includes vancomycin for coverage of methicillin-resistant Staphylococcus aureus as well as broad-spectrum gram-negative coverage with piperacillin/ tazobactam. quinolone prophylaxis. the consequences of untreated infection may be catastrophic. . ticarcillin/clavulanate. 86 ) Neutropenic patients are susceptible to focal bacterial and fungal infections. or hypotension dictates the use of vancomycin plus ceftazidime. colonization with methicillin-resistant S. severe mucositis. 50–60% of febrile neutropenic patients are infected. or a carbapenem with or without an aminoglycoside to provide empirical coverage for bacterial IDSA/guidelines ). The IDSA has published extensive practice guidelines covering these critically ill neutropenic patients ( www.uchicago. obvious catheter-related infection.journals. and 20% are bacteremic.

Pneumocystis infection. The age and physical state of the patient are factors as well: the frail. Serologic studies may reveal cryptococcal antigen. histoplasmosis. salmonellosis. and (of particular importance) drug fever are all possible causes of FUO. toxoplasmosis. a nosocomial setting—all vastly affect the risk equation and dictate therapy based on the probability of various causes of fever and on the calculated risks and benefits of a guided empirical approach. Mycobacterial infection can be diagnosed by blood cultures and by liver. and 67 Ga scan may help identify Pneumocystis pulmonary infection. cryptococcosis. strongyloidiasis. FUO has an infectious etiology in >80% of HIV-infected patients. elderly patient may merit a trial of empirical therapy earlier than the robust young adult. but drug fever and lymphoma remain important considerations. and lymph node biopsies. Other modifiers of FUO— neutropenia. Infection due to Mycobacterium avium or M. Treatment of HIV-associated FUO depends on many factors and is discussed TREATMENT Fever of Unknown Origin The focus here is on classic FUO. Chest CT should be performed to identify enlarged mediastinal nodes.HIV-Associated FUO HIV infection alone may be a cause of fever. CMV infection. bone marrow. The infectious etiology varies with the extent of immunosuppression and the geographic region. tuberculosis. non-Hodgkin’s lymphoma. intracellulare . The emphasis in patients with classic FUO is on continued . HIV infection.

vitalsign instability or neutropenia is an indication for empirical therapy with a fluoroquinolone plus piperacillin or the regimen mentioned above (see “Nosocomial FUO”). The effects of glucocorticoids on temporal arteritis. disease-modifying biologic therapy. The ability of glucocorticoids and NSAIDs to mask fever while permitting the spread of infection dictates that their use be avoided unless infection has been largely ruled out . for example. then a therapeutic trial for tuberculosis should be undertaken.. asplenia. cave interiors) may all tip the balance toward earlier empirical anti-infective therapy. The response of rheumatic fever and Still’s disease to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) may be dramatic. A failure of the fever to respond over this period suggests an alternative diagnosis. However. with the avoidance of “shotgun” empirical therapy.g. If the TST is positive or if granulomatous hepatitis or other granulomatous disease is present with anergy (and sarcoid seems unlikely). and granulomatous hepatitis are equally dramatic. polymyalgia rheumatica. Colchicine is highly effective in preventing attacks of familial Mediterranean fever but is of little use once an attack is well under way. or exotic travel or environmental exposures (e. with treatment usually continued for up to 6 weeks. intercurrent immunosuppressive drug use. Cirrhosis. Antibiotic therapy (even that for tuberculosis) may irrevocably alter the ability to culture fastidious bacteria or mycobacteria and delineate ultimate cause.observation and examination.

it commits the physician to continued thoughtful reexamination and evaluation. When no underlying source of FUO is identified after prolonged observation (>6 months). vigilance.and unless inflammatory disease is both probable and debilitating or threatening. compassion. The initiation of empirical therapy does not mark the end of the diagnostic workup. and intellectual flexibility are indispensable attributes for the clinician in dealing successfully with FUO. . the prognosis is generally good. debilitating symptoms are treated with NSAIDs. rather. and glucocorticoids are the last resort. Under such circumstances. equanimity. Patience. however vexing the fever may be to the patient.