Fever of Unknown Origin Workup

Laboratory and imaging findings vary according to the source of an FUO.^{[3, 4, 5]}

Tuberculosis

In tuberculosis, 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.

Urinary tract infections

For UTIs 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

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.

Osteomyelitis

In osteomyelitis, radiographs may not show changes for weeks after the development of symptoms. Radionucleotide studies (technetium Tc 99m [^99m Tc] 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.

Chlamydia

Chlamydia psittaci infection and, on rare occasions, Lymphogranuloma venereum infection can manifest as FUO. Serology is essential in 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. Researchers have also described systemic infections with Salmonella species, Neisseria meningitidis, and Neisseria gonorrhoeae as causes of FUO. Cultures and serologic tests establish the diagnosis of these infections.

Acquired immunodeficiency syndrome

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

Serologic testing can confirm the diagnosis of CMV or EBV 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

Candida albicans is the main culprit in disseminated fungal infections. Systemic infection in a patient may remain undiscovered, because blood cultures are negative in approximately 50% of the cases.

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.

Lymphomas

The correct diagnosis of Hodgkin or non-Hodgkin lymphoma 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 in these 2 forms of lymphoma.

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.

Collagen-vascular and autoimmune diseases

SLE is readily diagnosed in most cases by the demonstration of antinuclear antibodies.

Systemic-onset JRA is often difficult to diagnose. 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.

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. An elevated alkaline phosphatase level is the most consistent laboratory abnormality.

Kikuchi disease

Laboratory evidence of chronic inflammation, and, sometimes, liver function abnormalities can be found in Kikuchi disease.

Giant cell arteritis

Laboratory findings in GCA 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.

Polyarteritis nodosa

Any 3 of the following 10 findings is sufficient for the diagnosis of PAN (sensitivity 82%, 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
• Biopsy of small- or medium-sized arteries containing white blood cell infiltrate
• Peripheral eosinophilia (common and an important clue to PAN)

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.

Exclude UTIs and malignant tumors of the urinary tract; however, not all of them are consistently associated with pathologic findings in the urine.

At least 1 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.

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 are most helpful if paired samples show a significant, usually 4-fold, increase of antibodies specific to an infectious microorganism. Brucellosis, CMV infection, EBV infectious mononucleosis, HIV infection, amebiasis, toxoplasmosis, and chlamydial diseases are diagnosed with serology.

These diagnostic tests are of limited value in most patients with FUO, but they are appropriate for evaluation of the above illnesses in the correct clinical and epidemiologic setting.

Serum protein electrophoresis (SPEP) is useful in diagnosing atrial myxoma, SLE flares, and lymphomas.

Serum ferritin levels are useful in cases of FUO due to malignancies, SLE flare, and adult Still disease.

Frequently check antinuclear antibody 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 or PMR is 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).

Routinely obtain chest radiographs.

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.

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.

This can be very useful when osteomyelitis is suspected. MRI has also been used in the diagnosis of vasculitides.^[6]

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.

Perform ventilation and perfusion radionucleotide studies to document pulmonary emboli.

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.

Consider radionucleotide studies using gallium citrate or granulocytes labeled with indium In 111 (¹¹¹ In) for diagnosis of occult abscesses, neoplasms, or soft-tissue lymphomas.

Obtain pulmonary angiograms when, despite negative scanning studies, pulmonary emboli are suspected.

Positron emission tomography (PET) scanning has enhanced the detection of occult neoplasms, lymphomas, and vasculitides in patients with FUO.^[7]

This technique is highly sensitive in diagnosing endocarditis, particularly when transesophageal echocardiography is available.

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).^[8] 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).