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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