Fever of Unknown Origin - FUO

Definition

Fever of unknown origin (FUO) was defined in 1961 as [Petersdorf & Beeson]:

• Temperatures >38.3°C (101°F) on several occasions;

• A duration of fever of >3 weeks; and;

• Failure to reach a diagnosis despite 1 week of inpatient investigation.

This classification has stood for more than 30 years until the Durack & Street Classification [below - From: Harrison's]

Classification of FUO:

• Classic FUO - Classic FUO corresponds closely to the earlier definition of FUO, differing only with regard to the prior requirement for 1 week's study in the hospital. The new definition is broader, stipulating three outpatient visits or 3 days in the hospital without elucidation of a cause or 1 week of "intelligent and invasive" ambulatory investigation.

• Nosocomial FUO - In nosocomial FUO, a temperature of 38.3°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. Three days of investigation, including at least 2 days' incubation of cultures, is the minimum requirement for this diagnosis.

• Neutropenic FUO - Neutropenic FUO is defined as a temperature of 38.3°C (101°F) on several occasions in a patient whose neutrophil count is <500/L or is expected to fall to that level in 1 to 2 days. The diagnosis of neutropenic FUO is invoked if a specific cause is not identified after 3 days of investigation, including at least 2 days' incubation of cultures.

• FUO Associated with HIV - FUO associated with HIV infection is defined by a temperature 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. This diagnosis is invoked if appropriate investigation over 3 days, including 2 days' incubation of cultures, reveals no source.

• Neoplastic FUO - Caused by the malignant tumors listed below

Adoption of these categories of FUO on a wide scale in the literature would allow a more rational compilation of data regarding these disparate groups. In the remainder of this chapter, the discussion will focus on classic FUO unless otherwise specified.

Causes of Classic FUO

The ubiquitous use of microbiologic cultures and the widespread use of potent broad-spectrum antibiotics may have decreased the number of infections causing FUO. The wide availability of ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) has enhanced the detection of occult neoplasms and lymphomas in patients previously thought to have FUO. Likewise, the widespread availability of highly specific and sensitive immunologic testing has reduced the number of undetected cases of systemic lupus erythematosus and other autoimmune diseases.

Several generalizations can be made: Infections, especially extrapulmonary tuberculosis, remain the leading diagnosable cause of FUO. Prolonged mononucleosis syndromes caused by Epstein-Barr virus, cytomegalovirus (CMV), or HIV are conditions whose consideration as a cause of FUO is sometimes confounded by delayed antibody responses. Intraabdominal abscesses (sometimes poorly localized) and renal, retroperitoneal, and paraspinal abscesses continue to be difficult to diagnose. Renal malacoplakia, with submucosal plaques or nodules involving the urinary tract, may cause FUO and is often fatal if untreated. It is associated with coliform infection, is seen most often in patients with defects of intracellular bacterial killing, and is treated with fluoroquinolones or trimethoprim-sulfamethoxazole. Occasionally, other organs may be involved. Osteomyelitis, especially where prosthetic devices have been implanted, and infective endocarditis must be considered. Although true culture-negative infective endocarditis is rare, one may be misled by slow-growing organisms of the HACEK group (Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae; Chap. 150), Bartonella spp. (previously Rochalimaea), Legionella spp., Coxiella burnetii, Chlamydia psittaci, and fungi. Prostatitis, dental abscesses, sinusitis, and cholangitis continue to be sources of occult fever. Fungal disease, most notably histoplasmosis involving the reticuloendothelial system, may cause FUO. FUO with headache should prompt examination of spinal fluid for Cryptococcus neoformans. Malaria (which may result from transfusion, the failure to take a prescribed prophylactic agent, or infection with a drug-resistant strain) continues to be a cause, particularly of nonsynchronized FUO. A related protozoan species, Babesia, may cause FUO and is increasing in incidence. In most earlier series, neoplasms were the next most common cause of FUO after infections (Table 125-3). In the two most recent series, a decrease in the percentage of FUO cases due to malignancy was attributed to improvement in diagnostic technologies. This observation does not diminish the importance of considering neoplasia in the initial diagnostic evaluation of a patient with fever. A number of patients in these series had temporal arteritis, adult Still's disease, drug-related fever, and factitious fever. In recent series, approximately 25 to 30% of cases of FUO have remained undiagnosed. The general term noninfectious inflammatory diseases applies to systemic rheumatologic or vasculitic diseases such as polymyalgia rheumatica, lupus, and adult Still's disease as well as to granulomatous diseases such as sarcoidosis and Crohn's and granulomatous hepatitis.

Malignancies Commonly Associated with FUO:

In the elderly, multisystem disease is the most frequent cause of FUO, giant cell arteritis being the leading etiologic entity in this category. Tuberculosis is the most common infection causing FUO in the elderly, and colon cancer is an important cause of FUO with malignancy. Many diseases have been grouped in the various studies as "miscellaneous." On this list are drug fever, pulmonary embolism, factitious fever, familial Mediterranean fever, and Fabry's disease. A drug-related etiology must be considered in any case of prolonged fever. Any febrile pattern may be elicited by a drug, and both relative bradycardia and hypotension are uncommon. Eosinophilia and/or rash is found in only one-fifth of patients with drug fever, which usually begins 1 to 3 weeks after the start of therapy and remits 2 to 3 days after therapy is stopped. Virtually all classes of drugs cause fever, but antimicrobials (especially beta-lactam antibiotics), cardiovascular drugs (e.g., quinidine), antineoplastic drugs, and drugs acting on the central nervous system (e.g., phenytoin) are particularly common causes. It is axiomatic that, as the duration of fever increases, the likelihood of an infectious cause decreases. In a series of 347 patients referred to the National Institutes of Health from 1961 to 1977, only 6% had an infection. A significant proportion (9%) had factitious fevers-i.e., fevers due either to false elevations of temperature or to self-induced disease. A substantial number of these factitious cases were in young women in the health professions. It is worth noting that 8% of the patients with prolonged fevers (some of whom had completely normal liver function studies) had granulomatous hepatitis, and 6% had adult Still's disease. After prolonged investigation, 19% of cases still had no specific diagnosis. A total of 27% of patients either had no actual fever during the weeks of inpatient observation or had an exaggerated circadian temperature rhythm without chills, elevated pulse, or other abnormalities.

Causes of FUO Lasting >6 Months:

*No actual fever observed during 2 to 3 weeks of inpatient observation. Includes patients with exaggerated circadian rhythm (Aduan et al.).

Specialized Diagnostic Studies:

1. Classic FUO - Certain specific diagnostic maneuvers become critical in dealing with prolonged fevers. If factitious fever is suspected, electronic thermometers should be used, temperature-taking should be supervised, and simultaneous urine and body temperatures should be measured. Any tissue removed during prior relevant surgery should be reexamined; slides should be requested, and, if need be, paraffin blocks of fixed pathologic material should be reexamined and additional special studies performed. Relevant x-rays should be reexamined; reviewing of prior radiologic reports may be insufficient. Serum should be set aside in the laboratory as soon as possible and retained for future examination for rising antibody titers. Febrile agglutinins is a vague term that in most laboratories refers to serologic studies for salmonellosis, brucellosis, and rickettsial diseases. These studies are seldom useful, having low sensitivity and variable specificity. Rising titers of antibody to Brucella (Chap. 160) are usually diagnostic, but false-positive results may be obtained in typhoid fever, tularemia, and yersinial infections. Infection with Brucella canis may be missed with standard antibody tests for Brucella. Salmonella infection (Chap. 156) elevates antibody titers to the H and O antigens. High titers of antibody to the H antigen persist for years and may reflect previous infection or immunization. Serology for Yersinia enterocolitica may be useful. The measurement of specific antirickettsial titers should be requested for the diagnosis of Rocky Mountain spotted fever and Q fever. Multiple blood samples (no fewer than three, rarely more than six), including samples for anaerobic culture, should be cultured in the laboratory for at least 2 weeks to ensure that any HACEK-group organisms that may be present have ample time to grow (Chap. 150). Lysis-centrifugation blood culture techniques should be employed in cases where prior antimicrobial therapy or fungal or atypical mycobacterial infection is suspected. Blood culture media should be supplemented with L-cysteine or pyridoxal to assist in the isolation of nutritionally variant streptococci. It should be noted that sequential cultures positive for multiple organisms may reflect self-injection of contaminated substances. Urine cultures, including cultures for mycobacteria, fungi, and CMV, are indicated. Blood, urine, or cerebrospinal fluid (CSF) can now be tested for a variety of pathogens such as CMV or hepatitis C virus by using the polymerase chain reaction (PCR) to amplify and hence detect viral nucleic acid (Chap. 121). Liver biopsy, even when the results of liver function studies are normal, should be considered and pursued if the diagnosis remains elusive. Specimens should be cultured for mycobacteria and fungi. Likewise, bone marrow biopsy (not simple aspiration) should be used to obtain specimens for histology and culture. The blood smear should be examined for Plasmodium, Babesia, Trypanosoma, Leishmania, and Borrelia. In an FUO workup, 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 over 50 years of age. Still's disease is also suggested by elevations of ESR, leukocytosis, and anemia and is often accompanied by arthralgias, polyserositis (pleuritis, pericarditis), lymphadenopathy, splenomegaly, and rash. Antinuclear antibody, antineutrophil cytoplasmic antibody, rheumatoid factor, and serum cryoglobulins should be measured to rule out other collagen vascular diseases and vasculitis. Another cause of an extremely high ESR may be a false-positive value attributable to a cold agglutinin with a broad thermal amplitude. The ESR test is nonspecific, yielding values that depend on certain serum proteins (most notably fibrinogen) known to interfere with the zeta-potential that keeps erythrocytes from clumping. When fibrinogen levels go up, the zeta-potential is inhibited, erythrocytes clump, and the ESR is high. A cold agglutinin, by binding to erythrocytes, can produce a false-positive agglutinin that mimics an acute-phase response; cold agglutinins may be seen in Mycoplasma and Epstein-Barr virus infections and in lymphomas. With rare exceptions, the intermediate-strength purified protein derivative (PPD) skin test should be used to screen for tuberculosis in patients with classic FUO. Concurrent control tests, such as the CMI test (Connaught Labs, Swiftwater, PA), which is especially effective, should be employed. It should be kept in mind that both the PPD skin test and control tests may yield negative results in miliary tuberculosis, sarcoidosis, Hodgkin's disease, malnutrition, or AIDS. Noninvasive procedures should include an upper gastrointestinal contrast study with small-bowel follow-through and barium enema to include the terminal ileum and cecum. Chest x-rays should be repeated if new symptoms arise. In some cases, pulmonary function studies may be necessary. A diminished carbon monoxide diffusing capacity may indicate a restrictive lung disease such as sarcoidosis, even with a normal chest x-ray. In such cases, transbronchial biopsy may prove diagnostic. Flexible colonoscopy may be advisable, since colon carcinoma is a cause of FUO and easily escapes detection by ultrasound and CT. CT of the chest and abdomen should be performed. If a spinal or paraspinal lesion is suspected, however, MRI is preferred. MRI may be superior to CT in demonstrating intraabdominal abscesses and aortic dissection, but the relative utility of MRI and CT in the diagnosis of FUO is unknown. At present, it appears that abdominal CT, with oral and intravenous contrast, should be used unless MRI is specifically indicated. Arteriography may be useful for patients in whom systemic necrotizing vasculitis is suspected. Saccular aneurysms may be seen, most commonly in renal or hepatic vessels, and may permit diagnosis of arteritis when biopsy is difficult. Figure 125-1 shows a renal angiogram of a patient with polyarteritis nodosa. Ultrasonography of the abdomen is useful for the investigation of the hepatobiliary tract, kidneys, spleen, and pelvis. Echocardiography may be helpful in an evaluation for bacterial endocarditis, pericarditis, nonbacterial thrombotic endocarditis, and atrial myxomas. Transesophageal echocardiography is especially sensitive for these lesions. Radionuclide scanning procedures using technetium (Tc) 99m sulfur colloid, gallium (Ga) 67 citrate, or indium (In) 111-labeled leukocytes or immunoglobulin may be useful in identifying and/or localizing inflammatory processes. In a recent study, Ga scintigraphy yielded useful diagnostic information in almost one-third of cases, and it was suggested that this procedure might actually be used before other imaging techniques if no specific organ is suspected of being abnormal. Tc bone scan should be undertaken to look for osteomyelitis or bony metastases; 67Ga scan may be used to identify sarcoidosis (Chap. 318) or Pneumocystis carinii (Chap. 209) in the lungs or Crohn's disease (Chap. 287) in the abdomen. 111In-labeled white blood cell (WBC) scan may be used to locate abscesses; 111In-labeled immunoglobulin scan also shows promise in this regard. With 67Ga, 111In-WBC, and 111In-immunoglobulin scans, false-positive and false-negative findings are common. Biopsy of the liver and bone marrow should be considered routine in the workup of FUO if the studies mentioned above are unrevealing or if fever is prolonged. It goes without saying that areas of suspected abnormality should be sampled for pathologic examination whenever practical. When possible, a section of the tissue block should be retained for further sections or stains. PCR technology makes it possible to identify and speciate mycobacterial DNA in paraffin-embedded, fixed tissues. Thus, in some cases, it is possible to make a retrospective diagnosis based on studies of long-fixed pathologic tissues. In a patient over age 50 (or occasionally in a younger patient) with the appropriate symptoms and laboratory findings, "blind biopsy" of one or both temporal arteries may yield a diagnosis of arteritis. If noted, tenderness or decreased pulsation should guide the selection of a site for biopsy. Lymph node biopsy may be helpful if nodes are enlarged, but inguinal nodes are often palpable and are seldom diagnostically useful. Exploratory laparotomy has been performed when all other diagnostic procedures fail but has largely been replaced by modern imaging and guided-biopsy techniques. Laparoscopic biopsy may provide more adequate guided sampling of lymph nodes or liver.

2. Nosocomial FUO - The primary considerations in diagnosing nosocomial FUO are the underlying susceptibility of the patient coupled with the potential complications of hospitalization. The original surgical or procedural field is the place to begin a directed physical and laboratory examination for abscesses, hematomas, or infected foreign bodies. More than 50% of patients with nosocomial FUO are infected, and intravascular lines, septic phlebitis, and prostheses are all suspect. In this setting, the approach is to focus on sites where occult infections may be sequestered, such as the sinuses of intubated patients or a prostatic abscess in a man with a urinary catheter. Clostridium difficile colitis may be associated with fever and leukocytosis before the onset of diarrhea. In approximately 25% of patients with nosocomial FUO, the fever has a noninfectious cause. Among these causes are acalculous cholecystitis, deep vein thrombophlebitis, and pulmonary embolism. Drug fever, transfusion reactions, alcohol/drug withdrawal, adrenal insufficiency, thyroiditis, pancreatitis, gout, and pseudogout are among the many possible causes to consider. As in classic FUO, repeated meticulous physical examinations, coupled with focused diagnostic techniques, are imperative. Multiple blood, wound, and fluid cultures are mandatory. The pace of diagnostic tests is accelerated, and the threshold for procedures-CT scans, ultrasonography, 111In-WBC scans, noninvasive venous studies-is low. Even so, 20% of cases of nosocomial FUO may go undiagnosed. Like diagnostic measures, therapeutic maneuvers must be swift and decisive, as many patients are already critically ill. Intravenous lines must be changed (and cultured), drugs stopped for 72 h, and empirical therapy started if bacteremia is a threat. In many hospital settings, empirical antibiotic coverage for nosocomial FUO now includes vancomycin for methicillin-resistant Staphylococcus aureus as well as broad-spectrum gram-negative coverage with piperacillin/tazobactam, ticarcillin/clavulanate, imipenem, or meropenem. Practice guidelines covering many of these issues have been published jointly by the Infectious Diseases Society of America (IDSA) and the Society for Critical Care Medicine and can be accessed on the IDSA website ().

3. Neutropenic FUO - Neutropenic patients are susceptible to focal bacterial and fungal infections, to bacteremic infections, to infections involving catheters (including septic thrombophlebitis), and to perianal infections. Candida and Aspergillus infections are common. Infections due to herpes simplex virus or CMV are sometimes causes of FUO in this group. While the duration of illness may be short in these patients, the consequences of untreated infection may be catastrophic, with 50 to 60% infected, and 20% bacteremic. The IDSA has published extensive practice guidelines covering these critically ill neutropenic patients; these guidelines appear on the website cited in the previous section. In these patients, severe mucositis, quinolone prophylaxis, colonization with methicillin-resistant S. aureus, obvious catheter-related infection, or hypotension would dictate the use of vancomycin plus ceftazidime or imipenem to provide empirical coverage for bacterial sepsis.

4. HIV-Associated FUO - HIV infection alone may be a cause of fever. Infection due to Mycobacterium avium or Mycobacterium intracellulare, tuberculosis, toxoplasmosis, CMV infection, P. carinii infection, salmonellosis, cryptococcosis, histoplasmosis, non-Hodgkin's lymphoma, and (of particular importance) drug fever are all possible causes of FUO. Mycobacterial infection can be diagnosed by blood cultures and by liver, bone marrow, and lymph node biopsies. Chest CT should be performed to identify enlarged mediastinal nodes. Serologic studies may reveal cryptococcal antigen, and 67Ga scan may help identify P. carinii pulmonary infection. More than 80% of HIV patients with FUO are infected, but drug fever and lymphoma remain important considerations. Treatment of HIV-associated FUO depends on many factors and is discussed in Chap. 309.

Treatment

The emphasis in patients with classic FUO is on continued observation and examination, with the avoidance of "shotgun" empirical therapy. Empirical treatment for endocarditis, for example, should be avoided unless there are specific reasons beyond fever to invoke this diagnosis. Every patient with FUO should undergo an exhaustive examination for tuberculosis. If the PPD skin test is positive or if granulomatous hepatitis or other granulomatous disease is present with anergy (and sarcoid seems unlikely), then a therapeutic trial with isoniazid and rifampin (and possibly a third drug) should be undertaken, with treatment usually continued for up to 6 weeks. A failure of the fever to respond over this period suggests an alternative diagnosis. The response of rheumatic fever and Still's disease to aspirin and nonsteroidal anti-inflammatory agents (NSAIDs) may be dramatic. The effects of glucocorticoids on temporal arteritis, polymyalgia rheumatica, and granulomatous hepatitis are equally dramatic. Colchicine is highly effective in preventing attacks of familial Mediterranean fever but is of little use once an attack is well under way. 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 and unless inflammatory disease is both probable and debilitating or threatening. When no underlying source of FUO is identified after prolonged observation (>6 months), the prognosis is generally good, however vexing the fever may be to the patient. Under such circumstances, debilitating symptoms are treated with NSAIDs, and glucocorticoids are the last resort. The initiation of empirical therapy does not mark the end of the diagnostic workup; rather, it commits the physician to continued thoughtful reexamination and evaluation. Patience, compassion, equanimity, and intellectual flexibility are indispensable attributes for the clinician in dealing successfully with FUO.

Ex.: A patient with FUO: Renal arteriogram were performed and the arteriography showed a remarkable number of sacculated aneurysms associated with narrowing and tapering of the arteries, consistent with systemic vasculitis - in this particular case: polyarteritis nodosa.