AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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 one week of inpatient investigation.¹

This article provides a review of the etiologies of FUO and a rational approach to investigating a patient with this interesting condition.

Pathophysiology

FUOs are caused by infections (30-40%), neoplasms (20-30%), collagen vascular diseases (10-20%), and numerous miscellaneous diseases (15-20%). The literature also reveals that between 5 and 15% of FUO cases defy diagnosis, despite exhaustive studies.

Variations in FUO, as found in the literature, reflect the populations and periods studied. In children, infections are the most common cause of FUO, whereas neoplasms and connective-tissue disorders are more common in elderly persons. FUOs that persist for more than one year are less likely to be caused by infections and neoplasms and much more likely to be due to granulomatous diseases (the most common cause in these cases).

Diagnostic advances continuously modify the spectrum of FUO-causing diseases; for example, serologic tests have reduced the importance of HIV and numerous rheumatic diseases (eg, systemic lupus erythematosus [SLE], juvenile rheumatoid arthritis [JRA], rheumatoid arthritis [RA]) as causes of FUO. Modern imaging techniques (eg, ultrasonography, CT scanning, MRI) enable early detection of abscesses and solid tumors that were once difficult to diagnose.

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.

Age

More than 30% of FUO cases in persons older than 50 years are related to connective-tissue disorders and vasculitic disorders. Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are the two principal connective-tissue etiologies, accounting for 50% of the cases.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Diagnostic approach to fever of unknown origin (FUO) in adults
• • Inquire about symptoms involving all major organ systems, including a detailed history of general symptoms (eg, fever, weight loss, night sweats, headaches, rashes).
  • Record all symptoms, even if they disappeared before the examination. Previous illnesses are important, including surgeries and psychiatric illnesses.
  • Provide a detailed evaluation including the following:
  • • Family history
    • Immunization status
    • Occupational history
    • Travel history
    • Nutrition (including consumption of dairy products)
    • Drug history (over-the-counter medications, prescription medications, illicit substances)
    • Sexual history
    • Recreational habits
    • Animal contacts (including possible exposure to ticks and other vectors)

Physical

• Definitive documentation of fever and exclusion of factitious fever are essential early steps in the physical examination.
• • Measure the fever more than once and in the presence of a nurse to exclude manipulation of thermometers.
  • Electronic thermometers facilitate the rapid and unequivocal documentation of fever.
• The pattern of fever (continuous, remittent, intermittent) is usually of little help in the evaluation.
• • In general, specific fever patterns do not correlate strongly with specific diseases. Notable exceptions include tertian and quartan malaria. However, most people who are naive about malaria are not diagnosed with FUO because they are usually diagnosed with malaria before 3 weeks have elapsed.
  • Other diseases (eg, brucellosis, borreliosis, Hodgkin disease) tend to cause recurrent episodes of fever.
• Repeat a regular physical examination daily while the patient is hospitalized. Pay special attention to rashes, new or changing cardiac murmurs, signs of arthritis, abdominal tenderness or rigidity, lymph node enlargement, funduscopic changes, and neurologic deficits.

Causes

• Bacterial diseases
• • Abscesses: FUO should prompt consideration of abscesses, which are usually located intra-abdominally, even in the absence of localizing symptoms. Previous abdominal operations, trauma, or histories of diverticulosis, peritonitis, endoscopy, and gynecologic procedures increase the likelihood of an occult intra-abdominal abscess. The most common abscess locations include the subphrenic space, liver, right lower quadrant, retroperitoneal space, and the female pelvis.
  • Tuberculosis (TB): This is usually considered in the FUO differential diagnoses²; however, several factors may prevent a prompt diagnosis of TB. Dissemination, which usually occurs in immunocompromised patients, may initially manifest as constitutional symptoms that lack localizing signs. Chest radiography findings may be normal. Results from purified protein derivative (PPD) tests may be negative, and culture findings may not become positive for 4-6 weeks. TB of the kidney or mesenteric lymph nodes tends to manifest as FUO by lacking characteristic localized manifestations. Disseminated visceral infections with atypical mycobacteria (Mycobacterium avium being the prototype) also cause FUO; however, most of these patients have some other underlying hematologic malignancy or are infected with HIV.
  • Urinary tract infections (UTIs): These rarely cause FUO because urinalysis is an easily performed routine test that is used to detect most cases of UTIs. However, in young children, the collection of clean-catch urine specimens may be difficult; furthermore, perinephric abscesses occasionally fail to communicate with the urinary system, resulting in normal urinalysis findings. Occult UTI is possible in a patient with anatomic abnormalities of the urinary tract and FUO.
  • Endocarditis: This is now a rare cause of FUO. Failure to diagnose endocarditis may be due to the absence of a murmur or the failure of blood cultures to yield the organism. Culture-negative endocarditis is reported in 5-10% of endocarditis cases. Prior antibiotic therapy is the most common reason for negative blood cultures.
  • Hepatobiliary infections: In patients with hepatobiliary infections, cholangitis can occur without local signs and with only mildly elevated or normal findings on liver function tests. Similarly, 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.
  • Osteomyelitis: This usually causes localized pain or discomfort, at least intermittently. The most common reason for misdiagnosis of osteomyelitis is the failure to consider the disease in a patient who is febrile with musculoskeletal symptoms. Consider vertebral osteomyelitis in patients with low-grade fever or a history of UTIs. Radiographs may not show changes for weeks after the development of symptoms. Radionucleotide studies (technetium Tc 99m bone scanning) are more sensitive than plain radiography, and MRI is also an extremely useful test for the diagnosis of osteomyelitis.
  • Rickettsia: Chronic infections with Coxiella burnetii, chronic Q fever, and Q fever endocarditis have been identified in patients with FUO. Signs of hepatic involvement are common, and the infection is transmitted from cattle and sheep. Perform serologic tests in suspected cases.³
  • Chlamydia: Consider Chlamydia psittaci infection, the cause of psittacosis, in patients with FUO who have a history of contact with birds. On rare occasions, Lymphogranuloma venereum infection manifests as FUO. Serology is essential for the diagnosis of these chlamydial infections.
  • Systemic bacterial illnesses: Some systemic bacterial illnesses can manifest as FUOs. Brucellosis, still prevalent in Latin America and the Mediterranean, is very important. Consider this disease in patients with persistent fever and a history of contact with cattle, swine, goats, and/or sheep or in patients who consume raw milk products. Researchers have also described systemic infections with Salmonella species, Neisseria meningitidis, and Neisseria gonorrhoeae as causes of FUO. Cutaneous changes may be the only sign other than fever in neisserial infections. Cultures and serologic tests establish the diagnosis of these infections.
  • 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.
• Viral diseases
• • HIV: Prolonged febrile episodes are common in patients with advanced HIV infection. Approximately 75% of the cases are infectious in nature, about 20-25% are due to lymphomas, and a small fraction (0-5%) are due to HIV itself. Typical and atypical mycobacteria and cytomegalovirus (CMV) are opportunistic infections 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.
  • AIDS: More than 80% of patients with AIDS and lymphomas have involvement of extranodal sites (usually the brain). However, lymphomas are occasionally difficult to diagnose promptly. Perform extensive diagnostic workup studies (eg, 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.
  • Herpes viruses: CMV and Epstein-Barr virus (EBV) can cause prolonged febrile illnesses with constitutional symptoms and no prominent organ manifestations, particularly in elderly persons. Infections with these viruses usually cause lymphadenopathies, which may be missed on physical examination if the lymph nodes are not prominently enlarged. Serologic testing can confirm the correct diagnosis when the patient presents with lymphocytosis with atypical lymphocytes. The results of these tests may initially be negative; therefore, repeat them in suspected cases 2-3 weeks after the onset of illness.
• Fungal infections: Immunosuppression, the use of broad-spectrum antibiotics, the presence of intravascular devices, and total parenteral nutrition all predispose to disseminated fungal infections, and Candida albicans is the main culprit. Systemic infection may remain undiscovered in these patients because blood cultures are negative in approximately 50% of the cases. Malassezia furfur infection can cause FUO and line infections in patients on total parenteral nutrition who receive intravenous lipid preparations. In some cases, fever is the most prominent symptom in patients with reticuloendothelial involvement by histoplasmosis without clinical manifestations in other organs.
• Parasitic infections: Consider toxoplasmosis in patients who are febrile with lymph node enlargement; however, the diagnosis may be difficult to establish because the lymph nodes may be small. Rising antibody titers and immunoglobulin M (IgM) antibodies confirm the diagnosis. 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. Other parasites that cause FUO in rare cases include Trypanosoma, Leishmania, and Amoeba species.
• Neoplasms
• • Lymphomas: Hodgkin and non-Hodgkin lymphomas frequently cause fever, night sweats, and weight loss. The correct diagnosis can be delayed if the tumor is difficult to detect (eg, when the disease is confined to the retroperitoneal lymph nodes). Anemia may be the most prominent laboratory abnormality.
  • Leukemias: Acute leukemias are another important neoplastic group that can cause FUO. In preleukemic states, the peripheral blood smear and bone marrow aspirate may not reveal the correct diagnosis; therefore, perform a bone marrow biopsy.
  • Solid tumors: Among solid tumors, renal cell carcinoma is most commonly associated with FUO, with fever being the only presenting symptom in 10% of cases. Hematuria may be absent in approximately 40% of cases, whereas anemia and a highly elevated sedimentation rate are common.
  • Other solid tumors: Solid tumors such as adenocarcinomas of the breast, liver, colon, or pancreas and liver metastases from any primary site may manifest as fever.
  • Malignant histiocytosis: This is a rare rapidly progressive malignant disease that manifests as high fevers, weight loss, enlarged lymph nodes, and hepatosplenomegaly. It is an occasional cause of FUO.
• Collagen vascular and autoimmune diseases
• • Collagen vascular and autoimmune diseases can manifest as FUO if the fever precedes other more specific manifestations (eg, arthritis, pneumonitis, renal involvement).
  • SLE was a relatively common cause of FUO 20 years ago; currently, it is readily diagnosed in most cases by the demonstration of antinuclear antibodies.
  • Systemic-onset JRA is a cause of FUO and is often difficult to diagnose. High-spiking fevers, nonpruritic rashes, arthralgias and myalgias, pharyngitis, and lymphadenopathy are common. Laboratory abnormalities include pronounced leukocytosis, an elevated erythrocyte sedimentation rate (ESR), anemia, and abnormal liver function tests. These findings usually trigger a search for an infectious cause; thus, they delay the correct diagnosis.
  • Consider polyarteritis nodosa (PAN), RA, and mixed connective-tissue diseases (ie, other collagen vascular diseases) because of their potential for nonspecific presentations. Rheumatic fever can be difficult to diagnose because it is rare in the developed world.
• Granulomatous diseases
• • Sarcoidosis: Given its multiorgan involvement, sarcoidosis rarely manifests as fever and malaise without evidence of lymph node and pulmonary involvement. Erythema nodosum is occasionally present, and the finding of noncaseous granulomas in the liver should raise concern.
  • Regional enteritis: Crohn disease is the most common gastrointestinal cause of FUO. Diarrhea and other abdominal symptoms are occasionally absent, particularly in young adults. The diagnosis is established with endoscopy and biopsy.
  • Granulomatous hepatitis: In some patients with hepatic granulomas, none of the diseases usually associated with FUO (eg, TB, syphilis, brucellosis, sarcoidosis, Crohn disease, Hodgkin disease) are found. These patients often have fever that may be accompanied by slight hepatomegaly, asthenia, and, sometimes, arthralgias and myalgias for many months or years. An elevated alkaline phosphatase level is the most consistent laboratory abnormality. The long-term prognosis is excellent; approximately 50% of patients recover spontaneously, and the other 50% respond to corticosteroid treatment (duration of therapy ranging from a few weeks to several years).
• 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. A history of allergy, skin rashes, 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. When suspecting drug fever, discontinue the implicated drug. Stopping the causative drug generally leads to defervescence within 2 days
• Inherited diseases: In patients of Mediterranean descent with FUO, familial Mediterranean fever is most often the cause. Recurrent febrile episodes at varying intervals are associated with pleural, abdominal, or joint pain due to polyserositis. This is a diagnosis of exclusion.
• Endocrine disorders
• • Hyperthyroidism and subacute thyroiditis⁴ are the 2 most common endocrinologic causes of FUO. In fact, fever is often the major clinical sign, in addition to weight loss.
  • Adrenal insufficiency is a rare, potentially fatal, very treatable endocrine cause of FUO. Consider this diagnosis in patients with nausea, vomiting, weight loss, skin hyperpigmentation, hypotension, hyponatremia, and hyperkalemia.
• Peripheral pulmonary emboli and occult thrombophlebitis: These have been known to cause FUO. Consider these diagnoses in patients with predisposing conditions, particularly previous surgery, traumas, or prolonged bed rest. Another possible cause of fever after surgery or trauma is an undiscovered hematoma, usually located intra-abdominally.
• Kikuchi disease: A self-limiting necrotizing lymphadenitis known as Kikuchi disease was recently described as a cause of FUO. Kikuchi disease causes prolonged fever, constitutional symptoms, laboratory evidence of chronic inflammation, and, sometimes, liver function abnormalities. The etiology of Kikuchi disease is unknown.
• 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. Evidence of psychiatric problems or a history of multiple hospitalizations at different institutions is common. Rapid changes of body temperature without associated shivering or sweating, large differences between rectal and oral temperature, and discrepancies between fever, pulse rate, or general appearance are typically observed among patients who manipulate or exchange their thermometers, the most common cause of factitious fever. Alternatively, fever may be caused by injection of nonsterile material (eg, feces, milk), resulting in atypically localized abscesses or polymicrobial infections. Therefore, consider factitious fever as a possibility in every patient with prolonged fever, especially in patients with one or more of the features described.
• Other vasculitides
• • Giant cell arteritis
  • • Classic symptoms of GCA include temporal headache, jaw claudication, fever, visual disturbances (visual loss, blurred vision, diplopia, amaurosis fugax), weight loss, anorexia, fatigue, and cough. Polymyalgia (aching and stiffness of the proximal muscles and the trunk) occurs in 40% of these patients. During the examination, the physician may observe temporal artery tenderness or decreased pulsation. Laboratory findings include an elevated ESR, mild-to-moderate normochromic normocytic anemia, elevated platelet counts, and abnormal liver function tests (25% of cases). Perform a biopsy of a temporal artery to obtain a definitive diagnosis. Pathologic review shows vasculitis and a mononuclear cell infiltrate.
    • Treat the patient with high doses of steroids, and use intravenous steroids if the patient is very ill or has significant ocular compromise. Carefully monitor the patient because inadequate treatment and steroid toxicities (eg, hypertension, diabetes, dyspepsia, bone loss, psychosis, cataracts) can cause significant morbidity.
  • Polymyalgia rheumatica
  • • PMR is characterized by symmetrical pain and stiffness involving the lumbar spine and large proximal muscles, most notably the neck, shoulders, hips, and thighs. Symptoms are usually worse in the morning. Constitutional symptoms (eg, fever, malaise, depression, weight loss) are also observed. Symptoms may worsen relentlessly over weeks to months without treatment. Physical examination is notable for normal muscle strength. Carefully perform a history and physical examination because such protean symptoms may evade diagnosis.
    • The diagnosis of PMR is clinical, and treatment is 2-fold, consisting of (1) amelioration of symptoms with steroid therapy and (2) close monitoring for possible development of GCA.
  • PAN: This ranks a distant third behind GCA and PMR among the vasculitides that cause FUO in patients older than 50 years. PAN involves the medium- and small-sized muscular arteries. The male-to-female incidence ratio is 2:1. Incidence increases in patients with hepatitis B or C. Any 3 of the following 10 findings is sufficient for the diagnosis of PAN (sensitivity 82%, specificity 86%), and therapy consists of prednisone (cyclophosphamide is used in refractory cases):
  • • 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
    • Biopsy of small- or medium-sized arteries containing white blood cell infiltrate
  • Other vasculitides that cause FUO include Wegener granulomatosis, Takayasu arteritis, and cryoglobulinemia. These are uncommon causes of FUO.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Atypical mycobacterial infection
Bubonic plague
Clostridial necrotizing fasciitis
Eosinophilic toxocariasis
Fungal infections of the genitourinary tract
Gallbladder gangrene
Heroin abuse
Lung cancer
Lyssavirus infection
Picornavirus infection
Pneumoconiosis
Retroviral infections
Rhinocerebral phycomycosis
Sepsis
Sphenoid sinusitis
Thrombophlebitis
Thyroid carcinoma
Trypanosoma infection
TB of the genitourinary tract
UTI
Venereal warts
Osteomyelitis
Rat-bite fever (S minor)
Malassezia furfur infection
C burnetii infection
Malignant histiocytosis
Drug fever
Factitious fever
Kikuchi disease

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC count and microscopic examination
• • Anemia is an important finding and suggests a serious underlying disease.
  • Ensure that leukemias are not missed in aleukemic or preleukemic cases.
  • Suspect herpesvirus infection if the patient has lymphocytosis with atypical cells.
  • A leukocytosis with an increase in bands suggests an occult bacterial infection.
  • Diagnose malaria and spirochetal diseases with the aid of direct examination of the peripheral blood smear; however, repeated examinations are often necessary.
• Urinalysis: Exclude UTIs and malignant tumors of the urinary tract; however, not all of them are consistently associated with pathologic findings in the urine.
• Serum chemistry
• • At least one liver function test result is usually abnormal, with an underlying disease originating in the liver or a disease that causes nonspecific alterations of the liver (eg, granulomatous hepatitis).
  • Most other chemistry tests rarely contribute to the diagnosis, although they are frequently ordered.
• Cultures
• • Blood cultures for aerobic and anaerobic pathogens are essential in the evaluation; however, no more than 6 sets of blood cultures are required. Routinely culture the patients' urine.
  • Cultures of sputum and stool may be helpful in the presence of signs or symptoms suggestive of pulmonary or gastrointestinal disease, respectively.
  • Obtain cultures for bacteria, mycobacteria, and fungi in all normally sterile tissues and liquids that are sampled during further workup. These tissues and fluids include cerebrospinal fluid (CSF), pleural or peritoneal fluid, and fluid from the liver, bone marrow, and lymph nodes.
• Serologies
• • Serologies are most helpful if paired samples show a significant, usually 4-fold, increase of antibodies specific to an infectious microorganism. Brucellosis, CMV infection, infectious mononucleosis, HIV infection, amebiasis, toxoplasmosis, and chlamydial diseases are diagnosed with serology.
  • These diagnostic tests are of limited value in most patients with fever of unknown origin (FUO), but they are appropriate for evaluation of the above illnesses in the correct clinical and epidemiological setting.
• Other tests
• • Frequently check antinuclear antibody (ANA) titers, rheumatologic factor, thyroxine level, and ESR because they are helpful in diagnosing certain conditions (lupus, RA, thyroiditis, hyperthyroidism, GCA, PMR). Their diagnostic accuracy is limited in other autoimmune and collagen vascular diseases.
  • In patients in whom GCA and PMR are suspected, checking the ESR may be particularly useful because the ESR is nearly always greater than 60 mm/h (and often is much higher, especially in GCA).

Imaging Studies

• Chest radiography: Routinely obtain chest radiography.
• Abdominal ultrasonography: Routine abdominal ultrasonography may also be justified, even in the absence of signs of an intra-abdominal process. However, negative ultrasonographic findings and absent symptoms suggestive of an intra-abdominal process do not exclude such a process.
• CT scanning
• • If ultrasonography fails to help reveal the diagnosis, obtain CT scans of the abdomen in all patients with symptoms suggesting an intra-abdominal process, in patients with suspected retroperitoneal tumors or infections, and in those with abnormal findings on liver function tests.
  • Intravenous pyelography may be more sensitive than CT scanning in detecting processes involving the descending urinary tract, but CT scanning is preferred for most other processes of the retroperitoneal space.
• MRI: This can be very useful when osteomyelitis is suspected. MRI has also been used in the diagnosis of vasculitides.

Other Tests

• Endoscopic examination
• • Perform an endoscopic examination of the upper and lower gastrointestinal tract, including retrograde cholangiography when indicated or when searching for Crohn disease, Whipple disease, biliary tract disease, and gastrointestinal tumors.
  • Occasionally, complementing endoscopic studies with barium enemas or upper gastrointestinal series is necessary.
• Radionucleotide studies
• • Perform ventilation and perfusion radionucleotide studies to document pulmonary emboli.
  • Obtain a pulmonary angiography when suspecting pulmonary emboli, despite negative scanning studies.
  • A technetium bone scan may be a more sensitive method for documenting skeletal involvement when suspecting osteomyelitis in a patient without compatible changes in conventional radiography.
  • Consider radionucleotide studies using gallium citrate or granulocytes labeled with indium In 111 for diagnosis of occult abscesses, neoplasms, or soft-tissue lymphomas.
• Positron emission tomography (PET) scanning: This has enhanced the detection of occult neoplasms, lymphomas, and vasculitides in patients with FUO.
• Echocardiography: This technique is highly sensitive in diagnosing endocarditis, particularly when transesophageal echocardiography is available.

Procedures

• The final diagnosis is obtained during direct biopsy examination of involved tissue. Biopsies are easily performed in enlarged accessible lymph nodes, other peripheral tissues, and bone marrow.
• The decision to biopsy is more difficult if it necessitates an exploratory surgical procedure (eg, laparotomy). This is rarely indicated (eg, when imaging techniques are nondiagnostic and an intra-abdominal source is suspected).
• Liver biopsy rarely yields helpful data in patients without abnormal liver function tests or abnormal liver findings (observed on CT scan or ultrasonography).

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• In general, empiric therapy has little or no role in cases of classic fever of unknown origin (FUO).
• Treatment should be directed toward the underlying cause, as needed, once a diagnosis is made.
• Some studies suggest a few exceptions to this general approach, including the following:
• • Cases that meet criteria for culture-negative endocarditis
  • Cases in which findings or the clinical setting suggests cryptic disseminated TB (or, occasionally, other granulomatous infections)
  • Cases in which temporal arteritis with vision loss is suspected.
• Several studies have found that prolonged undiagnosed FUO generally carries a favorable prognosis.

Surgical Care

Because of a better understanding of the etiologies and careful diagnostic approaches, patients with FUO rarely need surgical treatment.

Consultations

Appropriate consultations are indicated based on patient history, physical examination, laboratory data, and radiologic findings, including the following:

• Infectious disease specialist
• Hematologist/oncologist
• Rheumatologist
• Pulmonologist
• Gastroenterologist
• Endocrinologist
• Interventional radiologist
• Surgeon

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The medications used depend on the etiology of the fever of unknown origin (FUO).

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Approximately 5-15% of patients with fever of unknown origin (FUO) remain undiagnosed, even after extensive evaluations.
• Careful review of the literature shows that patients with FUO usually have a benign long-term course, especially in the absence of substantial weight loss or other signs of a serious underlying disease.
• No evidence supports prolonged hospitalization in patients who are clinically stable and whose workup findings are unrevealing.

Further Outpatient Care

• Conduct close follow-up procedures and systematic re-evaluation studies to prevent clinical worsening. Guide further workup studies on an outpatient basis.

In/Out Patient Meds

• The medications used to treat FUO are case-dependent.

Transfer

• Indications for transfer include the following:
• • The current facility is unable to establish a diagnosis.
  • Diagnostic tests are unavailable at the existing facility.
  • The patient deteriorates clinically.

Complications

• Complications of FUO, if they occur, are case dependent.

Prognosis

• The prognosis of FUO depends on the underlying cause and varies from patient to patient.

Patient Education

• For excellent patient education resources, visit eMedicine's Cold and Flu Center and Children's Health Center. Also, see eMedicine's patient education articles Fever in Adults and Fever in Children.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Problems may arise in the 5-15% of patients whose fever of unknown origin (FUO) remains undiagnosed, even after extensive evaluations. These patients usually have a benign long-term course, but close follow-up and systematic re-evaluation studies are essential to avoid missing potential etiologies.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore). Feb 1961;40:1-30. [Medline].
2. Bofinger JJ, Schlossberg D. Fever of unknown origin caused by tuberculosis. Infect Dis Clin North Am. Dec 2007;21(4):947-62, viii. [Medline].
3. Botelho-Nevers E, Raoult D. Fever of unknown origin due to rickettsioses. Infect Dis Clin North Am. Dec 2007;21(4):997-1011, ix. [Medline].
4. Cunha BA, Thermidor M, Mohan S, et al. Fever of unknown origin: subacute thyroiditis versus typhoid fever. Heart Lung. Mar-Apr 2005;34(2):147-51. [Medline].
5. Amberger CC, Dittmann H, Overkamp D, et al. [Large vessel vasculitis as cause of fever of unknown origin (FUO) or systemic inflammation. Diagnosis using 18-F-fluor-2-deoxy-D-glucose positron emission tomography ((18)F-FDG-PET)]. Z Rheumatol. Feb 2005;64(1):32-9. [Medline].
6. Antoniadou A, Giamarellou H. Fever of unknown origin in febrile leukopenia. Infect Dis Clin North Am. Dec 2007;21(4):1055-90, x. [Medline].
7. Argibay S, DĂ­az J, Nunez I, et al. [Hepatic abscess demonstrated by 67Ga-citrate scintigraphy within a diagnosis of fever of unknown origin]. Rev Esp Med Nucl. Nov-Dec 2004;23(6):417-20. [Medline].
8. Barbado FJ, Vazquez JJ, Pena JM, et al. Pyrexia of unknown origin: changing spectrum of diseases in two consecutive series. Postgrad Med J. Nov 1992;68(805):884-7. [Medline].
9. Bissuel F, Leport C, Perronne C, et al. Fever of unknown origin in HIV-infected patients: a critical analysis of a retrospective series of 57 cases. J Intern Med. Nov 1994;236(5):529-35. [Medline].
10. Bouza E, Loeches B, Munoz P. Fever of unknown origin in solid organ transplant recipients. Infect Dis Clin North Am. Dec 2007;21(4):1033-54, ix-x. [Medline].
11. Cleri DJ, Ricketti AJ, Vernaleo JR. Fever of unknown origin due to zoonoses. Infect Dis Clin North Am. Dec 2007;21(4):963-96, viii-ix. [Medline].
12. Cunha BA. Fever of unknown origin (FUO): diagnostic importance of serum ferritin levels. Scand J Infect Dis. 2007;39(6-7):651-2. [Medline].
13. Cunha BA. Fever of unknown origin caused by adult juvenile rheumatoid arthritis: the diagnostic significance of double quotidian fevers and elevated serum ferritin levels. Heart Lung. Nov-Dec 2004;33(6):417-21. [Medline].
14. Cunha BA. Fever of unknown origin. Infect Dis Clin North Am. Mar 1996;10(1):111-27. [Medline].
15. Cunha BA. Fever of unknown origin: clinical overview of classic and current concepts. Infect Dis Clin North Am. Dec 2007;21(4):867-915, vii. [Medline].
16. Cunha BA. Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination, and laboratory tests. Infect Dis Clin North Am. Dec 2007;21(4):1137-87, xi. [Medline].
17. de Kleijn EM, van der Meer JW. Fever of unknown origin (FUO): report on 53 patients in a Dutch university hospital. Neth J Med. Aug 1995;47(2):54-60. [Medline].
18. Ergönül O, Willke A, Azap A, et al. Revised definition of 'fever of unknown origin': limitations and opportunities. J Infect. Jan 2005;50(1):1-5. [Medline].
19. Cunha BA. Fever of Unknown Origin. New York, NY: Informa Healthcare; 2007.
20. Gaeta GB, Fusco FM, Nardiello S. Fever of unknown origin: a systematic review of the literature for 1995-2004. Nucl Med Commun. Mar 2006;27(3):205-11. [Medline].
21. Hirschmann JV. Fever of unknown origin in adults. Clin Infect Dis. Mar 1997;24(3):291-300; quiz 301-2. [Medline].
22. Hot A, Schmulewitz L, Viard JP, et al. Fever of unknown origin in HIV/AIDS patients. Infect Dis Clin North Am. Dec 2007;21(4):1013-32, ix. [Medline].
23. Kazanjian PH. Fever of unknown origin: review of 86 patients treated in community hospitals. Clin Infect Dis. Dec 1992;15(6):968-73. [Medline].
24. Klastersky J, Weerts D, Hensgens C, et al. Fever of unexplained origin in patients with cancer. Eur J Cancer. Sep 1973;9(9):649-56. [Medline].
25. Knockaert DC. Recurrent fevers of unknown origin. Infect Dis Clin North Am. Dec 2007;21(4):1189-211, xi. [Medline].
26. Knockaert DC, Dujardin KS, Bobbaers HJ. Long-term follow-up of patients with undiagnosed fever of unknown origin. Arch Intern Med. Mar 25 1996;156(6):618-20. [Medline].
27. Knockaert DC, Vanneste LJ, Vanneste SB, et al. Fever of unknown origin in the 1980s. An update of the diagnostic spectrum. Arch Intern Med. Jan 1992;152(1):51-5. [Medline].
28. Larson EB, Featherstone HJ, Petersdorf RG. Fever of undetermined origin: diagnosis and follow-up of 105 cases, 1970-1980. Medicine (Baltimore). Sep 1982;61(5):269-92. [Medline].
29. Lopez Rodriguez M, Vazquez Munoz E, Gomez Cerezo J, et al. [Cost-effectiveness of computerized axial tomography in the diagnosis of traditional clinical picture of fever of unknown origin]. Rev Clin Esp. Jan 2005;205(1):19-23. [Medline].
30. Lortholary O, Guillevin L, Bletry O. Fever of unknown origin: a retrospective multicenter study of 103 cases, 1980-1988. Eur J Intern Med. 1992;3:109-20.
31. Luft FC, Rissing JP, White A, et al. Infections or neoplasm as causes of prolonged fever in cancer patients. Am J Med Sci. Jul-Aug 1976;272(1):65-74. [Medline].
32. Mert A, Ozaras R. Clinical importance of miliary pattern in the chest X-ray of a patient with fever of unknown origin. Intern Med. Feb 2005;44(2):161. [Medline].
33. Miralles P, Moreno S, Perez-Tascon M, et al. Fever of uncertain origin in patients infected with the human immunodeficiency virus. Clin Infect Dis. Apr 1995;20(4):872-5. [Medline].
34. Moret Ch, Meier P, Rotman S, et al. [Fever of unknown origin with granulomatous hepatitis, uveitis and acute renal failure]. Schweiz Rundsch Med Prax. Jan 12 2005;94(1-2):25-30. [Medline].
35. Niamane R, Karim Moudden M, Zyani M, et al. Protracted fever of unknown origin as the presenting symptom of Behçet's disease. Report of a case. Joint Bone Spine. Mar 2005;72(2):175-6. [Medline].
36. Norman DC, Wong MB, Yoshikawa TT. Fever of unknown origin in older persons. Infect Dis Clin North Am. Dec 2007;21(4):937-45, viii. [Medline].
37. Ozaras R, Celik AD, Zengin K, et al. Is laparotomy necessary in the diagnosis of fever of unknown origin?. Acta Chir Belg. Feb 2005;105(1):89-92. [Medline].
38. Petersdorf RG. Fever of unknown origin. An old friend revisited. Arch Intern Med. Jan 1992;152(1):21-2. [Medline].
39. Petersdorf RG, Wallace JF. Fever of unknown origin. In: Barondess J, ed. Diagnostic Approach to Presenting Symptoms. 1971:301-32.
40. Salinas F, Mulero F, Marín M, et al. [Fever of unknown origin (FUO), scintigraphy with Gallium 67 citrate scintigraphy and malignant lymphoma of soft tissues]. Rev Esp Med Nucl. Nov-Dec 2004;23(6):427-8. [Medline].
41. Schattner A. The patient's history remains a powerful tool in the diagnosis of fever of unknown origin. Eur J Intern Med. Feb 2005;16(1):63. [Medline].
42. Shoji S, Imamura A, Imai Y, et al. Fever of unknown origin: a review of 80 patients from the Shin'etsu area of Japan from 1986-1992. Intern Med. Feb 1994;33(2):74-6. [Medline].
43. Smith JW. Fever of undetermined origin: not what it used to be. Am J Med Sci. Jul 1986;292(1):56-64. [Medline].
44. Speil C, Mushtaq A, Adamski A, Khardori N. Fever of unknown origin in the returning traveler. Infect Dis Clin North Am. Dec 2007;21(4):1091-113, x. [Medline].
45. Tolia J, Smith LG. Fever of unknown origin: historical and physical clues to making the diagnosis. Infect Dis Clin North Am. Dec 2007;21(4):917-36, viii. [Medline].
46. Wagner AD, Andresen J, Raum E, et al. Standardised work-up programme for fever of unknown origin and contribution of magnetic resonance imaging for the diagnosis of hidden systemic vasculitis. Ann Rheum Dis. Jan 2005;64(1):105-10. [Medline].
47. Zenone T. Fever of unknown origin in rheumatic diseases. Infect Dis Clin North Am. Dec 2007;21(4):1115-35, x-xi. [Medline].

Article Last Updated: Sep 23, 2008