Fever of Unknown Origin (FUO) Workup

Laboratory and imaging findings vary according to the source of an fever of unknown origin (FUO). Imaging should be directed by historical, physical, and basic laboratory clues. ^{[1, 16, 17, 18]}

While a workup of FUO should emphasize clinical clues, the following, if not already performed, are essential laboratory and imaging tests that are of value in eliciting further diagnostic direction:

• Complete blood cell (CBC) count with white blood cell (WBC) differential
• Peripheral blood smear
• Complete metabolic panel (CMP; provides data on electrolytes, glucose, acid-base, renal, liver, protein status)
• C-reactive protein (CRP)
• Erythrocyte sedimentation rate (ESR)
• Urinalysis (used to detect glomerulonephritis, occult hematuria; pyuria is insensitive for detecting urinary tract infection in absence of suggestive symptoms, as asymptomatic bacteriuria is common) ^[19]
• Blood cultures, preferably 3 blood draws from separate sites, performed at different times
• HIV serology
• Hepatitis A and B serology, and if epidemiologically applicable, Hepatitis E serology
• Tuberculosis screening tests – Purified protein derivative (PPD, or Mantoux test); interferon gamma release assays (IGRA)
• Posteroanterior and lateral chest radiography

Beyond the above essentials in early screening, some would add antinuclear antibody titers, rheumatoid factor, and thyroid stimulating hormone (TSH) and thyroxine level in diagnosing certain conditions (lupus, RA, thyroiditis, hyperthyroidism). Their diagnostic accuracy is limited in other autoimmune and collagen vascular diseases.

Further examinations should be guided by historical and physical diagnostic clues, as well as clues from the initial results of the above.

HIV serology

If any test should be routinely included in the evaluation of FUO, HIV antigen-antibody assay should. Antigen-antibody assay results are positive early in infection, thus eliminating need for HIV viral load screening because of lag in antibody seroconversion.

C-Reactive Protein

Elevated CRP suggests an infectious or inflammatory process, but does not eliminate malignancy.

Erythrocyte sedimentation rate

An ESR of more than 100 seconds in the absence of anemia may indicate giant cell arteritis, multiple myeloma, or osteomyelitis.

A very low ESR with myalgias suggests trichinosis.

Complete blood count

Eosinophilia may suggest polyarteritis nodosa, drug fever, or visceral leishmaniasis.

Acute drop in hemoglobin or hematocrit may suggest occult hemorrhage or hematoma (often retroperitoneal).

Complete metabolic profile

Alkaline phosphatase elevation suggests lymphoma or granulomatous hepatitis.

Transaminitis may result from multiple causes.

Elevated total protein or calcium (look for monoclonal gammopathy) may suggest multiple myeloma.

Urinalysis

Hematuria may indicate renal cell carcinoma, tuberculosis, endocarditis, brucellosis, lymphoma, or periarteritis nodosa.

Asymptomatic pyuria and bacteriuria are common with advancing age and comorbidities, and these findings may offer little diagnostic direction. ^[19]

Normal urinalysis or urine culture results do not necessarily suggest or eliminate perinephric abscess. Approximately 30% of patients with perinephric abscess have normal urinalysis results, and up to 40% have sterile urine cultures. ^[20]

Blood cultures

Blood cultures for aerobic and anaerobic pathogens are essential in the evaluation; however, no more than 6 sets of blood cultures are required. Sampling 2-3 peripheral blood samples may suffice given modern culture techniques.

Tuberculosis screening

PPD or Mantoux screening is inexpensive and sensitive but requires placement by clinical staff and interpretation 48-72 hours later of induration size, a type IV hypersensitivity reaction (indicating prior tuberculosis exposure).

Interferon gamma release assay (IGRA) offers higher sensitivity and, where readily available and quickly processed, faster turnaround.

Laboratory clues to specific causes of FUO

Anemia is an important finding and suggests a serious underlying disease.

Suspect herpesvirus infection if the patient has lymphocytosis with atypical cells.

Leukocytosis with an increase in bands suggests an occult bacterial infection, as well as occult hemorrhage, hematoma, or thromboembolic process.

Diagnose malaria and spirochetal diseases with the aid of direct examination of the peripheral blood smear; however, repeated examinations by an experienced technologist are often necessary. With Relapsing Fever/spirochetal diseases, it is best to obtain blood sample during febrile period for highest probablity of spirochetemia and direct observation. Preleukemic states may not manifest in the peripheral blood smear, and bone marrow aspirate may not reveal the correct diagnosis; bone marrow biopsy may be necessary for diagnosis. 

Adult-onset Still disease is often difficult to diagnose. Laboratory abnormalities include pronounced leukocytosis, an elevated erythrocyte sedimentation rate (ESR), anemia, and abnormal liver function test results.

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.

Laboratory findings in giant cell arteritis (GCA) include an elevated ESR, mild to moderate normochromic normocytic anemia, elevated platelet counts, and abnormal liver function test results (25% of cases). Perform a biopsy of a temporal artery to obtain a definitive diagnosis. Pathologic review shows vasculitis and a mononuclear cell infiltrate.

At least one liver function test result is usually abnormal in an underlying disease that originates in the liver or a disease that causes nonspecific alterations of the liver (eg, granulomatous hepatitis).

Tissue analysis and cultures

See Procedures. 

Assays, serology, and cultures

Aside from HIV screening, other assays, serology, and cultures should be directed by findings of the history, physical, and laboratory screening, as well clinical reevaluation for more diagnostic clues. The specifics of testing for individual conditions is deferred to other more detailed sources.

 

Chest radiography

Routinely perform chest radiography. Posteroanterior and lateral chest radiography is usually readily available and relatively inexpensive. It may rapidly detect abnormalities missed on physical examination, and may direct further diagnostic imaging with computed tomography (CT) of the thorax.

Thoracic CT angiography

Thoracic CT angiography is more sensitive than ventilation-perfusion scanning when pulmonary emboli are suspected in spite of negative findings on venous ultrasonography of the extremities. Arteriography demonstrates small and large aneurysms and focal constrictions between dilated segments in polyarteritis nodosa.

Echocardiography

Echocardiography is highly sensitive in diagnosing endocarditis, particularly when transesophageal echocardiography is available. Culture-negative endocarditis is reported in 5%-10% of endocarditis cases. Prior antibiotic therapy is the most common reason for negative blood culture results.

CT scanning of the abdomen and pelvis

CT scanning of the abdomen and pelvis with intravenous and oral contrast is useful in the setting of hepatosplenomegaly looking for adenopathy, intraabdominal or psoas muscle hematoma or abscess, perinephric abscess, cholecystitis, or neoplasia. Plain abdominal films and ultrasonography are relatively insensitive in the diagnosis of FUO. In patients with hepatobiliary infections, cholangitis can occur without local signs and with only mildly elevated or normal findings on liver function tests.

FDG-PET/CT whole-body scanning

Positron emission tomography (PET) scanning alone was once fraught with excessive false-positive findings; however, PET combined with CT improves diagnostic capabilities, especially as the causes of FUO have evolved in the past decade. ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET), in which radiolabeled glucose marks foci of increased glucose metabolism, has been used successfully in oncology diagnostics and can also be used to diagnose infectious and noninfectious inflammatory foci. Recent studies recommend using FDG-PET early in the workup of FUO and suggest that including FDG-PET/CT yields a correct diagnosis in 60% to more than 80% of cases. Furthermore, the time to diagnosis may be shortened and invasive procedures reduced, potentially leading to reduced costs and morbidity. Nonetheless, the possibility of false-positive results should be kept in mind. ^{[9, 21, 22, 23]}

Radionucleotide studies

Radionucleotide studies using gallium citrate are used to detect chronic inflammation and may be more sensitive in detecting occult abscesses, neoplasms, or soft-tissue lymphomas in FUO of more than 2 weeks’ duration. Indium WBC scan, using granulocytes labeled with indium In 111 (¹¹¹In), can be cumbersome and often insensitive in chronic inflammatory states.

Bone scanning

Whereas plain radiographs may not show changes for weeks after the onset of infection, technetium bone scan may be a more sensitive method for documenting skeletal involvement when osteomyelitis is suspected. Magnetic resonance imaging (MRI) is considered the criterion standard for detection of acute osteomyelitis and delineating structural abnormalities; however, it is less sensitive in the setting of chronic osteomyelitis and prosthetic joint infection. While potentially a greater cost upfront, positron emission tomography-computed tomography (PET-CT) full-body scans are increasingly recognized as useful early in efficiently localizing abnormalities and may save other healthcare costs in the FUO workup. PET-CT is especially sensitive in localizing and detecting small foci of inflammation and metabolic activity. It is particularly superior to MRI and other nuclear imaging studies in localizing foci of osteomyelitis of the hip, vertebrae, or prosthetic devices, as well as endovascular graft infection, neoplasia, and vasculitides. ^{[22, 24]}

Naproxen test

Simple, noninvasive, and inexpensive, a naproxen test may rapidly screen out infection versus neoplastic disease and significantly narrow the differential diagnoses. In this test, naproxen sodium 250 mg is given orally every 8 hours for 3 days. A sharp decline or resolution in fever within 24 hours directs the workup away from infection and suggests a neoplastic disorder. 

FUO evaluations are best performed from least invasive to more invasive testing.

Endoscopy

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. Crohn disease is the most common gastrointestinal cause of FUO. Diarrhea and other abdominal symptoms are occasionally absent, particularly in young adults.

Biopsies and tissue sampling

Obtain cultures for bacteria, mycobacteria, and fungi in all normally sterile tissues and liquids that are biopsied. This may include cerebrospinal fluid (CSF), pleural or peritoneal fluid, and fluid from the liver, bone marrow, and lymph nodes.

Biopsies are easily performed in enlarged accessible lymph nodes, other peripheral tissues, and bone marrow. Superficial enlarged lymph nodes of highest yield on biopsy include posterior cervical, supraclavicular or infraclavicular, and epitrochlear nodes. Deep nodes of highest yield are the hilar, mediastinal, or retroperitoneal lymph nodes. ^[25]

Bone marrow biopsy is of highest yield with unexplained abnormality of the CBC count (hematologic malignancy) and granulomatous disease such as sarcoidosis, tuberculosis, or histoplasmosis. ^[25]

Liver biopsy rarely yields helpful data in patients without abnormal liver function test results or abnormal liver findings (observed on CT scan or ultrasonography). Liver biopsy may be necessary to characterize granulomatous or autoimmune hepatitis.

The decision to biopsy is more difficult if it entails an exploratory surgical procedure (eg, laparotomy). ^[26] This is rarely indicated (eg, when imaging techniques are nondiagnostic and an intra-abdominal source is suspected), particularly considering the generally benign course of FUO that remains undiagnosed after extensive workup.

Arterial biopsy is rarely associated with hematoma, ischemic complications, or nerve damage, given that nerves and vessels often follow a similar course. This may be warranted, however, for the diagnosis of polyarteritis nodosa and giant cell arteritis, as these conditions may be disabling or life-threatening if left untreated; these are among the few conditions associated with an erythrocyte sedimentation rate of 100 mm/hour or greater. Biopsy of small- or medium-sized arteries demonstrate white blood cell infiltrate in polyarteritis nodosa. Temporal artery biopsy is necessary for definitive diagnosis of giant cell arteritis, provided a sufficient length of artery is excised.