Current Diagnosis & Treatment in Infectious Diseases

Section II - Clinical Syndromes

18. Fever of Unknown Origin

Julie Brahmer MD

Merle A. Sande MD

Essentials of Diagnosis

• Fever is defined as a core body temperature above 38.3°C.
• Objective documentation of a fever is important in determining whether a patient is actually febrile.
• A thorough history and physical examination are necessary in order to focus diagnostic studies.
• Routine tests include chest x-ray, blood culture, chemistries, and a complete blood count.
• Knowing the most common causes of a fever of unknown origin (FUO) in each special population helps focus the diagnostic strategy.

General Considerations

Fever is defined as a core body temperature above the normal daily variation. Normal body temperature is 37–38°C and varies by as much as 0.6°C throughout the day. The core temperature, measured orally or rectally, is usually lowest in the morning and highest between 4:00 and 6:00PM.

Several endogenous and exogenous pyrogens can cause fever. Exogenous pyrogens, such as toxins, products of microbes, and microbes themselves, cause release of endogenous pyrogens called cytokines, including interleukin-1, interferon, tumor necrosis factor, interleukin-6, and interleukin-11.

Figure 18-1. Scheme for the pathogenesis of fever. IL, Interleukin; TNF, tumor necrosis factor; IFN, interferon; LIF, leukemia inhibitory factor; CNTF, ciliary neurotropic factor; OncM, oncostatin M.

Most of these cytokines are produced by macrophages in the reaction to exogenous pyrogens. These cytokines cause the hypothalamus to increase prostaglandin synthesis, which is thought to cause an upward shift of the normal core temperature set point (Figure 18-1).

Definitions of FUO

The classic definition of FUO is a fever of >3 weeks' duration that is >38.3°C on several occasions, the cause of which is not discovered after 1 week of evaluation in a hospital. This definition was a functional one because it eliminated acute causes of fevers, including acute viral infections, and, in > 90% of cases, the cause of the fever could be found. However, under current insurance guidelines and with newer technology available, a 1-week hospital stay is neither feasible nor practical. Therefore an updated version of the classic FUO definition has been proposed that defines it as documented fevers > 38.3°C for > 3 weeks' duration, when the source of the fever is not discovered during either 3 days of hospital investigation or 3 outpatient visits.

Additional definitions of FUO exist for different population subgroups, including HIV-positive patients, neutropenic patients (< 500 polymorphoneutrophils/mm³), the elderly, hospitalized patients, and pediatric patients. These definitions help the clinician direct the investigation to discover the most likely cause of the fever.

FUO in HIV-infected patients is defined as a fever ≥ 38.3°C for 4 weeks' duration in outpatients or > 3 days in inpatients whose HIV infection has been previously documented. In neutropenic patients, FUO is defined as a fever ≥ 38.3°C for 3 days with negative cultures after 2 days. In the elderly, the definition of FUOs is similar to the classic definition, except that the patients are elderly. In hospitalized patients, nosocomial FUO is defined as a fever > 38.3°C lasting 3 days, which was not present or incubating on admission and produces negative cultures after 2 days. Definite criteria for FUOs in children have not been established, but, according to Gartner, the best definition is a fever occurring for ≥ 8 days for which the history, physical examination, and laboratory data fail to reveal a cause (Tables 18-1,18-2, and 18-3).

Clinical Findings

To diagnose the cause of an FUO, the clinician should first document the presence of fever and its characteristics. Are there fevers, and how high do they get? Sometimes the presence of fever is only subjective (the patient feels warm but his or her temperature is normal). Although the fever pattern is rarely helpful in establishing a diagnosis, a history of periodic fever spikes suggests malaria, lymphoma, or cyclic neutropenia. Lymphoma (non-Hodgkin's and Hodgkin's) can present with the classic Pel-Ebstein fever, which is characterized by intermittent febrile periods lasting for days followed by days to weeks of afebrile periods. A reversal of the normal late-afternoon fever spike, that is, the presence of a morning fever spike, suggests tuberculosis, disseminated Salmonellainfection, and polyarteritis nodosum. Two fever spikes may occur in a 24-h period with tuberculosis or malaria. Periodic fevers (those that last for days to weeks and then abate or occur at regular intervals) in children include cyclic neutropenia, familial Mediterranean fever, and a syndrome of fever, pharyngitis, and aphthous stomatitis.

The history and physical examination are extremely important for the diagnosis of an FUO because they enable the physician to focus the diagnostic studies. The history should include family history, ethnic background, travel history, and animal exposures. The history and physical examination should be repeated periodically if no cause of the FUO is discovered during the first evaluation. It is also important to discontinue as many medications (prescription and over-the-counter) as the patient can tolerate since drug fevers are common.

Table 18-1. Historic clues to fever of unknown origin.1

Medication or toxic substances    Drug fever    Fume fever Tick exposure    Relapsing fever    Rocky Mountain spotted fever    Lyme disease Animal contact    Psittacosis    Leptospirosis    Brucellosis    Toxoplasmosis    Cat-scratch disease    Q fever    Rat-bite fever Myalgias    Trichinosis    Subacute bacterial endocarditis    Polyarteritis nodosa    Rheumatoid arthritis    Familial Mediterranean fever    Polymyositis Headache    Relapsing fever    Rat-bite fever    Chronic meningitis/encephalitis    Malaria    Brucellosis    CNS neoplasms    Rocky Mountain spotted fever Mental confusion    Sarcoid meningitis    Tuberculosis meningitis    Cryptococcal meningitis    Carcinomatous meningitis    CNS neoplasms    Brucellosis    Typhoid fever    HIV Cardiovascular accident    Subacute bacterial endocarditis    Takayasu's arteritis    Polyarteritis nodosa    Rocky Mountain spotted fever Nonproductive cough    Tuberculosis    Q fever    Psittacosis    Typhoid fever    Pulmonary neoplasms    Rocky Mountain spotted fever    Acute rheumatic fever Vision disorders or eye pain    Temporal arteritis (emboli)    Subacute bacterial endocarditis    Relapsing fever    Brain abscess    Takayasu's arteritis Fatigue    Carcinomas    Lymphomas    Cytomegalovirus mononucleosis    Typhoid fever    Systemic lupus erythematosus    Rheumatoid arthritis    Toxoplasmosis Abdominal pain    Polyarteritis nodosa    Abscesses    Familial Mediterranean fever    Porphyria    Relapsing fever    Cholecystitis Back pain    Brucellosis    Subacute bacterial endocarditis Neck pain    Subacute thryoiditis    Adult Still's disease    Temporal arteritis (angle of jaw)    Relapsing mastoiditis    Septic jugular phlebitis 1Source: Cunha BA: Fever of unknown origin (FUO). In Gorbach SL, Bartlett, JB, Blacklow NR: Infectious Diseases, 2nd ed. Philadelphia, WB Saunders, 1996.

Table 18-2. Physical clues to fever of unknown origin.1

Skin hyperpigmentation    Whipple's disease    Hypersensitivity vasculitis    Addison's disease Band keratopathy    Adult Still's disease Dry eyes    Rheumatoid arthritis    Systemic lupus erythematosus    Sjögren's syndrome Watery eyes    Polyarteritis nodosa Epistaxis    Relapsing fever    Psittacosis Conjunctivitis    Tuberculosis    Cat-scratch fever    Systemic lupus erythematosus Conjunctival suffusion    Leptospirosis    Relapsing fever    Rocky Mountain spotted fever Subconjunctival hemorrhage    Subacute bacterial endocarditis    Trichinosis Uveitis    Tuberculosis    Adult Still's diease    Sarcoidosis    Systemic lupus erythematosus Lymphadenopathy    Lymphomas    Cat-scratch fever    Tuberculosis    Lymphogranuloma venereum    Epstein-Barr virus mononucleosis    Cytomegalovirus    Toxoplasmosis    HIV    Adult Still's disease    Brucellosis    Whipple's disease    Pseudolymphoma    Kikuchi's disease    Mycobacterium avium complex Sternal tenderness    Metastatic carcinoma    Pre-leukemias Heart murmur    Subacute bacterial endocarditis Hepatomegaly    Hepatoma    Relapsing fever    Lymphomas    Metastatic carcinoma    Alcoholic liver disease    Granulomatous hepatitis    Q fever    Typhoid fever    Mycobacterium avium complex Splenomegaly    Leukemia    Lymphomas    Tuberculosis    Brucellosis    Subacute bacterial endocarditis    Cytomegalovirus    Epstein-Barr virus mononucleosis    Rheumatoid arthritis    Sarcoidosis    Psittacosis    Relapsing fever    Alcoholic liver disease    Typhoid fever    Rocky Mountain spotted fever    Kikuchi's disease    Mycobacterium avium complex Trapezius tenderness    Subdiaphragmatic abscess Thigh tenderness    Brucellosis    Polymyositis    Polymyositis rheumatica    Pyolnepositis Relative bradycardia    Typhoid fever    Malaria    Leptospirosis    Psittacosis    Central fever    Drug fever Splenic tenderness    Subacute bacterial endocarditis    Brucellosis    Salmonella Epididymo-orchitis    Tuberculosis    Lymphoma    Brucellosis    Leptospirosis    Polyarteritis nodosa    Epstein-Barr virus mononucleosis Spinal tenderness    Subacute vertebral osteomyelitis    Subacute bacterial endocarditis    Brucellosis    Typhoid fever Arthritis/joint pain    Familial Mediterranean fever    Pseudogout    Rat-bite fever    Rheumatoid arthritis    Systemic lupus erythematosus    Lyme disease    Brucellosis    Hyper IgD syndrome Calf tenderness    Rocky Mountain spotted fever    Polymyositis Thrombophlebitis    Psittacosis Abdominal tenderness    Cholecystitis 1Source: Cunha BA: Fever of unknown origin (FUO). In Gorbach SL, Bartlett JB, Blacklow NR: Infectious Diseases, 2nd ed. Philadelphia, WB Saunders, 1996.

Laboratory tests and evaluation should be focused by the history and physical examination and should not be used randomly. Serial blood cultures (three blood cultures over a 48-h period) should be drawn to detect a bacterial, fungal, or mycobacterial infectious cause (Table 18-3). A history of exposures to animals might warrant specific serological studies, for example, brucellosis. A history of travel to endemic areas might dictate the need for a malaria smear. The Mantoux test with a purified protein derivative should be done in all patients, since tuberculosis is a common cause of FUOs even without a history of exposure.

However, if the clinical suspicion of tuberculosis is high (as for HIV-positive patients), a negative purified protein derivative does not rule outtuberculosis as a cause of FUO, and appropriate biopsies and cultures are indicated. A screening chest x-ray should be obtained to rule out lung diseases.

Table 18-3. Laboratory clues to fever of unknown origin.1

Monocytosis    Tuberculosis    Polyarteritis nodosa    Cytomegalovirus    Sarcoidosis    Brucellosis    Subacute bacterial endocarditis    Systemic lupus erythematosus    Lymphomas    Carcinomas    Reginal enteritis    Myeloproliferative diseases Eosinophilia    Trichinosis    Lymphomas    Drug fever    Addison's disease    Polyarteritis nodosa    Hypersensitivity vasculitis    Hypernephroma    Myeloproliferative diseases Leukopenia    Miliary tuberculosis    Brucellosis    Systemic lupus erythematosus    Lymphomas    Pre-leukemias    Typhoid fever    Kikuchi's disease Basophilia    Carcinomas    Lymphomas    Pre-leukemias    Myeloproliferative diseases Lymphocytosis    Tuberculosis    Epstein-Barr virus mononucleosis    Cytomegalovirus    Toxoplasmosis    Non-Hodgkin's lymphoma    Pertussis Lymphocytopenia    HIV    Whipple's disease    Tuberculosis    Systemic lupus erythematosus    Sarcoidosis Atypical Lymphocytosis    Epstein-Barr virus mononucleosis    Cytomegalovirus    Brucellosis    Toxoplasmosis    Drug fever Thrombocytosis    Myeloproliferative diseases    Tuberculosis    Carcinomas    Lymphomas    Sarcoidosis    Vasculitis    Temporal arteritis    Subacute osteomyelitis    Hypernephroma Thrombocytopenia    Leukemias    Lymphomas    Myeloproliferative diseases    Relapsing fever    Epstein-Barr virus    Drug fever    Vasculitis    Systemic lupus erythematosus    HIV Rheumatoid factor    Subacute bacterial endocarditis    Chronic active hepatitis    Rheumatoid arthritis    Malaria    Hypersensitivity vasculitis ESR (>100 mm/h)    Adult Still's disease    Temporal arteritis    Hypernephroma    Subacute bacterial endocarditis    Drug fever    Carcinomas    Lymphomas    Myeloproliferative diseases    Abscesses    Subacute osteomyelitis    Polymyositis    Hyper IgD syndrome Elevated alkaline phosphatase    Hepatoma    Miliary tuberculosis    Lymphomas    Epstein-Barr virus mononucleosis    Cytomegalovirus    Adult Still's disease    Subacute thyroiditis    Temporal arteritis    Hypernephroma    Polyarteritis nodosa    Liver metastases    Granulomatous hepatitis    Mycobacterium avium complex Increased serum transaminases    Epstein-Barr virus mononucleosis    Cytomegalovirus    Q fever    Psittacosis    Drug fever    Leptospirosis    Toxoplasmosis    Brucellosis    Relapsing fever    Kikuchi's disease    Idiopathic granulomatosis    Alcoholic hepatitis Abnormal renal-function tests    Subacute bacterial endocarditis    Renal tuberculosis    Polyarteritis nodosa    Fabry's disease    Leptospirosis    Brucellosis    Lymphomas    Systemic lupus erythematosus    Hypernephroma    HIV    Malakoplakia 1Source: Cunha BA: Fever of unknown origin (FUO). In Gorbach SL, Bartlett JB, Blacklow NR: Infectious Diseases, 2nd ed. Philadelphia, WB Saunders, 1996.

In general, noninvasive testing should be performed first. If the cause of an FUO is not discovered by these tests, then invasive testing may be necessary to establish a diagnosis. Invasive testing may include computed tomography scans, bone marrow biopsies, liver biopsies, and, rarely, abdominal laporotomy. Advanced scanning technology has significantly diminished the role for abdominal laparotomy.

Differential Diagnosis

The differential diagnosis for FUO is broad. It is therefore best to categorize the potential causes into disease processes and then consider their likelihood within different subgroups of patients. The most common causes of classic FUOs (in nonhospitalized, ambulatory patients who do not fit into other subgroups) include infections, neoplasms, hypersensitivity, and autoimmune diseases (Table 18-4). In HIV-positive patients, the major causes of fever of unknown origin are infections such as tuberculosis, atypical mycobacterium such as Mycobacterium avium complex, and fungal infections. In contrast, the major causes of FUOs in elderly patients are malignancy and collagen vascular disorders, followed by occult infections.

In children, FUOs are rare. It is important to remember that normal mean temperatures increase with age until the child is 18 months old, after which they decrease. Therefore a temperature of 38.3°C is normal in an 18-month-old child. Infectious diseases account for 45% of all FUOs in children, and half of these are respiratory tract infections. Of FUOs in children, ~ 13% are caused by connective tissue diseases, and ~ 6% are caused by neoplasia.

Table 18-4. Diseases causing fever of unknown origin.1

Common Uncommon Rare Malignancy Lymphoma Metastases to liver/CNS Hypernephromas Hepatomas Pancreatic carcinoma Preleukemias Atrial myxomas CNS tumors Myelodysplastic diseases Infections Extrapulmonary tuberculosis (Renal TB, TB meningitis, Miliary TB) Intraabdominal abscesses (subdiaphragmatic abscesses:       Periappendiceal       Pericolonic       Hepatic) Pelvic abscesses Subacute bacterial endocarditis Mycobacterium avium complex (AIDS) Permanently placed central IV line Colon carcinoma Cytomegalovirus Toxoplasmosis Salmonella enteric fevers Intra/perinephric abscesses Dental abscesses HIV Cryptococcosis Small brain abcesses Chronic sinusitis Subacute vertebral osteomyelitis Chronic subacute vertebral osteomyelitis Listeria Yersinia Brucellosis Relapsing fever Rat-bite fever Chronic Q fever Cat-scratch fever Epstein-Barr virus (elderly) Malaria Leptospirosis Blastomycosis Histoplasmosis Coccidioidomycosis Infected aortic aneurysms Infected vascular graft Rocky Mountain spotted fever Lyme disease Leishmaniasis Trypanosomiasis Trichinosis Prosthetic device Relapsing mastoiditis Septic jugular phlebitis Rheumatologic Still's disease (adult juvenile rheumatoid arthritis) Temporal arteritis (elderly) Periarteritis nodosa Rheumatoid arthritis (elderly) Systemic lupus erythematosus Vasculitis (eg, Takayasu's arteritis, hypersensitive vasculitis) Felty's syndrome Pseudogout Acute rheumatic fever Sjögren's syndrome Behçet's disease Familial Mediterranean fever Miscellaneous causes Drug fever Cirrhosis Alcoholic hepatitis Granulomatous hepatitis Pulmonary emboli (multiple, recurrent) Regional enteritis Whipple's disease Fabry's disease Hyperthyroidism Hyperparathyroidism Pheochromocytomas Addison's disease Subacute thyroiditis Cyclic neutropenias Polymyositis Wegener's granulomatosis Occult hematomas Weber-Christian disease Sarcoidosis (eg, basilar meningitis, hepatic granulomas) Hypothalamic dysfunction Habitual hyperthermia Factitious fever Giant hepatic hemangiomas Mesenteric fibromatosis Pseudolymphomas Idiopathic granulomatosis Kikuchi's disease Malakoplakia Hyper IgD syndrome 1Source: Cunha BA: Fever of unknown origin (FUO). In Gorbach SL, Bartlett JB, Blacklow NR: Infectious Diseases, 2nd ed. Philadelphia, WB Saunders, 1996.

Table 18-5. Most common causes of fevers of unknown origin.1

Category Classic Neutropenic Elderly HIV Nosocomial Pediatric Definition Not in other categories— fever ≥ 3 weeks ANC < 500 Classic only in patients HIV-positive patients Hospitalized and not infected on admission Fevers ≥ 8 days in < 18-year-old patients Duration of investigation 3 Days as inpatient or 3 outpatient visits 3 Days as inpatient Same as classic FUO 3 Days as inpatient or 4 wks as outpatient 3 Days Not defined Most common causes Infection Malignancy Collagen-vascular diseases Drugs Fungal infection Perianal infection Bacterial infection Drugs Underlying disease Malignancy Infection Collagen-vascular diseases Drugs Infections (MAC, TB, & fungal) Lymphoma Drugs Infections (bacterial or fungal) Drugs Infection Collagen-vascular diseases Malignancy Drugs Abbreviations: ANC, absolute neutrophil count; HIV, human immunodeficiency virus; FUO, fever of unknown origin; MAC, Mycobacterium avium complex; TB, tuberculosis. 1Source: Mandell GL (ed): Mandell, Douglas, and Bennett's Principles and Practice of Infectious Disease, Churchill Livingstone, 1995.

By knowing the frequency of the different diagnoses in each subgroup of patients, the clinician can narrow the search for the cause of the fever (Table 18-5). If these investigations are done properly, in > 90% of patients the causes of an FUO will be diagnosed.

1. HIV-Positive Patients.In HIV-positive patients with an FUO, other specialized testing should be performed. The differential diagnosis for HIV-related FUOs consists of mainly infectious causes such as tuberculosis, Mycobacterium aviumcomplex, and disseminated fungal infections. Neoplasms such as lymphomas also cause FUOs in AIDS patients. Tuberculosis is a common cause, especially if the CD4 count is high. If the CD4 count is significantly decreased (< 100), atypical mycobacteria, mainly Mycobacterium avium, are the most common Mycobacterium species causing fever. Therefore work-ups of FUOs in AIDS patients should focus on those diagnoses.

Blood cultures should be done for bacteria, fungi, and mycobacteria. A serum cryptococcal antigen should also be ordered, because cryptococcal disease is also common in AIDS patients. Stool cultures should be obtained only if the patient has diarrhea. A chest x-ray should be obtained. A routine screening chest computed tomography scan to look for adenopathy may be useful, since M avium complex can cause isolated hilar and mediastinal adenopathy not seen on chest x-rays. Bone marrow biopsy and liver biopsy should be considered early in the evaluation if the above tests are negative. Of HIV patients with FUOs, 86% will have a diagnosis established.

1. Elderly Patients.In elderly patients, the differential diagnosis of FUOs varies slightly from the classical differential. Neoplasms such as lymphoma or malignancies metastatic to the liver are the most common causes. Collagen vascular diseases, especially temporal arteritis, are also more frequent in the elderly. The classic presentation of jaw claudication and vision loss for giant cell arteritis may be absent in the elderly. Occult infections, especially abdominal infections or prostatitis in elderly males, can cause FUOs because the classical physical findings may be absent and the leukocyte count normal. Tuberculosis is also a significant cause of FUOs in the elderly. Other diseases such as sarcoidosis, lupus, Still's disease, and factitious fevers are more common in younger patients.

Because of the increased incidence of temporal arteritis, a temporal artery biopsy should be considered as a diagnostic test along with the other routine studies. Because of the increased incidence of occult abdominal abscesses, a computed tomography scan of the abdomen should be part of the evaluation. If, after a thorough investigation, no explanation for the fever is found, the patient may be monitored closely, weekly to biweekly, as an outpatient.

Treatment

Empiric drug trials should be used with extreme caution and should not take the place of a thorough investigation for the cause of the FUO, especially if an infection is suspected. If malignancy is strongly suspected, a trial of naproxen can be tried. If investigations for an FUO in an HIV-positive patient are not successful in finding the cause, an empiric trial of antimycobacterial therapy may be useful. However, empiric treatment has not been evaluated scientifically. Neutropenic patients are the only group in which empiric broad-spectrum antibiotics should be started (see Chapter 26). Empiric therapy for neutropenic patients classically includes ceftazidime and an aminoglycoside; however, this may vary depending on gram-negative bacterial antibiotic susceptibilities in each hospital. Vancomycin can be added if a gram-positive infection is suspected or if the patient has persistent fevers. If fevers persist in this setting, antifungal agents should be added to the antibiotic regimen. Empiric antibiotic therapy should be started only after appropriate cultures have been done.

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