Topic Editor: Grant E. Fraser, M.D., FRACGP, FACRRM, ASTEM
Review Date: 9/30/2012
Definition
The classic definition of Fever of Unknown Origin (FUO), developed in 1961, required both:
- An elevation of body temperature =38.3°C (100.9°F) on several occasions for more than 3 weeks
- Failure to diagnosis after 1 week of investigation in the hospital
Newer definitions include:
- Elevation of body temperature =38°C (100.4°F)
- Outpatient:
- Present after 3 outpatient visits
- Failure to diagnose despite 1 week of 'intelligent and invasive' efforts
- Inpatient:
- Present after 3 days in hospital
- Failure to diagnose despite 3 days of 'intelligent and invasive' efforts
Description
- FUO can be caused by a wide range of conditions; however, the most common causes are infections, malignancies and auto-immune diseases
- A longer duration of FUO decreases the likelihood of an infectious etiology
- FUO can be classified into 4 types:
- Classic FUO
- Classic FUO refers to an elevated temperature >38°C (100.4°F) with no diagnosis, which has occurred on several occasions, with illness duration of >3 weeks. Failure to diagnose must include a 'intelligent and invasive' evaluation and depending on setting include:
- Outpatient: 3 or more visits and 1 week of evaluation
- Inpatient: 3 days in hospital
- Nosocomial FUO
- Nosocomial FUO refers to fever >38°C (100.4°F) occurring in patients hospitalized for acute care with no infection at admission, and no infection diagnosed after 3 days of investigation, including at least 2 days incubation of cultures
- Neutropenic FUO
- Neutropenic FUO refers to fever >38°C (100.4°F) occurring in patients with a neutrophil count of 1000/ µL (1.0 x 109/L) or expected to reach that level in 2 days, with no diagnosis despite 3 days of investigation, including at least 2 days' incubation of cultures [Note that some will define neutropenia as 500/µL (0.5 x109/L) ]
- HIV-associated FUO
- HIV-associated FUO refers to fever >38°C (100.4°F) in a patient with confirmed HIV, over a period of >4 weeks as an outpatient or >3 days as an inpatient, with no diagnosis after 3 days of investigation, including at least 2 days of culture incubation
Epidemiology
Incidence/prevalence
- No data are available regarding actual incidence in the general population
- The prevalence among hospitalized patients is 2.9% according to one 2003 study
Age
- There is a variation in the causes of FUO by age
- Self-limiting viral syndromes are more common in pediatric FUO
- Infection, neoplasm and inflammatory conditions (such as rheumatic diseases, connective tissue disorders, vasculitis, giant cell arteritis, polymyalgia rheumatica and sarcoidosis) are common with FUO in the elderly (> 65 years)
Risk factors
- Drug abuse (especially IV use)
- Elderly
- Exposure to biologic or chemical agents
- HIV-infected/AIDS patients, especially with low CD4 counts
- Malignancy
- Recent travel to endemic areas for infectious agents (most common in tropical areas or peri-equatorial)
Etiology
Common etiologies of FUO include
- Infection [Most common cause]
- Abscess (abdominal, dental, pelvic)
- Brucellosis
- Chlamydia
- Cytomegalovirus (often associated with HIV)
- Endocarditis
- Epstein-Barr virus
- Fungal infections
- Hepatobiliary infections
- Herpes viruses
- Human immunodeficiency virus (HIV)
- Malaria
- Osteomyelitis
- Parasitic infections (toxomplasmosis and infections caused by Trypanosoma, Leishmania, Ameoba)
- Prostatitis
- Rickettsial infections
- Sinusitis
- Spirochetal infections (Lyme disease, syphilis)
- Systemic bacterial infections (brucellosis, infections caused by Salmonella, Neisseria meningitidis and Neisseria gonorrhoeae)
- Tuberculosis (especially extrapulmonary)
- Urinary tract infection
- Malignancy [Second most common cause of FUO]
- Colon cancer
- Hepatoma
- Leukemia
- Lymphoma
- Malignant histiocytosis
- Metastatic cancers
- Pancreatic carcinoma
- Renal cell carcinoma
- Sarcomas
- Autoimmune disease [Another cause of FUO]
- Adult Still's disease (a rare condition with inflammatory arthritis)
- Inflammatory bowel conditions (Crohn's disease, ulcerative colitis)
- Polyarteritis nodosa
- Polymyalgia rheumatica
- Rheumatoid arthritis
- Rheumatoid fever
- Systemic lupus erythematosus
- Temporal arteritis/Giant cell arteritis (GCA)
- Miscellaneous
- CNS disorders
- Deep vein thrombosis
- Drug-induced fever
- Endocrine disorders (Hyperthyroidism and subacute thyroiditis)
- Factitious fever
- Hepatitis
- Inherited diseases (Familial Mediterranean fever)
- Kikuchi disease (Self-limited necrotizing lymphadenitis)
- Myositis
- Pulmonary embolism
- Rhabdomyolysis
- Sarcoidosis
- Thrombophlebitis
History
- Evaluation of past medical history, family history, travel history, occupational history, sexual history, and drug history
- Exposure to pets, animals or insect vectors
- Fever duration and pattern
- Nutrition (including consumption of dairy products)
- Recreational habits
- Vaccination status
Some symptoms are variable depending on the underlying cause. These include:
- Altered mental status
- Anorexia
- Arthralgia and/or myalgia
- Chills, sweats and rigors
- Cough and dyspnea
- Headaches
- Localized pain
- Nausea, vomiting, diarrhea
- Rash
- Weight loss
Physical findings on examination
Physical findings are variable depending on the underlying cause:
- Abdominal rigidity or tenderness
- Fundoscopic changes
- Hepatomegaly and/or splenomegaly
- Hypertension and/or tachycardia
- Lymphadenopathy
- Muscle rigidity or tenderness
- New or changed cardiac murmurs
- Neurologic deficits
- Rash
- Signs of arthritis
- Temporal artery tenderness
Blood test findings
- Complete blood count (CBC): Presence of anemia is non-specific, but can suggest chronic disease or an acute process. Leukocytosis may be due to an occult bacterial infection or a non-specific stress reaction. Abnormally low or high leukocyte counts and abnormal cells such as blasts can suggest hematologic malignancy
- An unusual differential on a CBC such as profound lymphocytosis can indicate pertussis or viral infection. Monocytosis can occur with viral infections, eosinophilia may occur with parasitic infection or allergic etiology
- Peripheral blood smears for malaria and spirochete infections
- ESR or CRP: Non-specific markers, which may be elevated due to infection (viral, bacterial, parasitic), autoimmune disease or malignancy. These tests need to put in context with a careful clinical evaluation. These tests are highly non-specific but are reassuring if normal. There is almost never a reason to perform both tests. CRP is significantly more sensitive and specific
- Comprehensive panel : Abnormal liver function tests may indicate an underlying cause of hepatic origin (e.g. granulomatous hepatitis); although almost any infectious process will result in some elevation of liver transaminases (as will rhabdomyolysis or myositis)
- Cultures: Blood cultures for aerobic and anaerobic pathogens should be performed. Sputum and stool cultures where symptoms might relate to these body systems can be helpful in evaluating for a pulmonary or GI cause. Fluid (e.g. ascites, joint fluid, pleural fluid, CSF, etc) and tissue specimens should be evaluated for the presence of pathogens such as bacteria, mycobacteria, and fungi on a case by case basis as clinically indicated
- Serology: Serology may be used for diagnosis of many conditions such as brucellosis, HSV, CMV, EBV, HIV, legionella, lyme, rickettsial diseases, amebiasis, toxoplasmosis, chlamydial diseases, dengue, barmah forest virus, ross river virus, murray valley encephalitis, yellow fever, and other mosquito/tick borne pathogens (specific by world region and where patient has travelled)
- Autoimmune conditions such as rheumatoid arthritis and rheumatic fever can be diagnosed more promptly using serologic testing
Other laboratory test findings
- Urinalysis and urine culture can effectively rule in or out UTI. Abnormalities may be present with urinary tract malignancy (may also have normal urinalysis)
Radiographic test findings
- Chest radiography: The FUO evaluation should include a chest radiograph as a part of the initial investigation to screen for chest infection, some types of collagen vascular disease and malignancy
- Ultrasonography: Ultrasonography of the abdomen is useful for evaluating causes associated with hepatobiliary tract, spleen, kidneys, and the pelvis. Negative results do not, however, exclude the presence of an intra-abdominal pathology. If DVT is suspected, duplex ultrasonography of the suspect limb or region should be performed
- CT scan: CT scan of the abdomen with IV and oral contrast (often with pelvis and chest also) should be performed when results of ultrasonography and liver function tests are inconclusive. CT can be helpful in diagnosis of intra-abdominal, pelvic or chest tumors or infections
- MRI scan: MRI imaging is highly useful in the detection of osteomyelitis and vasculitides
- PET scan: PET scan can be used to detect occult neoplasms and lymphomas
- Radionucleotide Studies: Radionucleotide scanning, using gallium 67, technetium (Tc) 99m, or indium-labeled leukocytes can detect occult neoplasm, abscess and inflammatory conditions, which may remain undetected by CT scans. Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography scanning is both more rapid and sensitive than other nuclear resonance techniques due to the ability of FDG to reliably accumulate in both tumor and inflammatory sites
- Angiography: If pulmonary embolism is suspected, CT pulmonary angiogram (CTPA) can be obtained (in low risk patients, a negative D-dimer is sufficient to rule out this diagnosis)
Other diagnostic test findings
- Endoscopy: Endoscopic evaluation, including retrograde cholangiography, if needed, can be used to detect Crohn's, Ulcerative Colitis, Whipple's disease, biliary tract disease or tumors of the GI tract. Barium enema may be used in certain cases to aid evaluation
- Echocardiography may be helpful in diagnosis of endocarditis as a potential cause of FUO in patients who meet Dukes criteria
- Biopsy: Biopsy of abnormal tissue is often useful. Indication for biopsy of tissues, such as liver, lymph nodes or bone marrow should be guided by a strong clinical suspicion of abnormality, or a diagnostic test supporting a specific area of abnormality
- Liver biopsy may be helpful in diagnosis of hepatic conditions such as granulomatous hepatitis
- Lymph node biopsy is often indicated when there are enlarged, palpable lymph nodes
- Exploratory laparotomy is rarely performed and only when all other methods of diagnosis fail to provide conclusive results
General treatment items
- The primary aim of therapy is the treatment of the underlying cause after diagnosis
- Empiric therapy with antibiotics is not usually indicated in cases of classic FUO. However, in cases of nosocomial and neutropenic FUO, empiric therapy is usually recommended. In cases where there is clinical evidence of septicemia (hypotension, organ dysfunction, etc), neutropenia, asplenia, or immunosuppression, empiric therapy is recommended
- Antipyretics are not recommended until a diagnosis is made, as they can mask significant clinical signs of disease (e.g. typical fever patterns in malaria and typhoid). NSAIDs may be used after diagnosis is established
- Glucocorticoids may be beneficial in conditions such as temporal arteritis or polymyalgia rheumatic; but may mask other conditions
- There is no evidence to support the benefit of other therapies such as external cooling
- Treatment of neutropenic FUO
- Empirical antibiotic treatment is recommended in cases of neutropenic FUO
- Monotherapy: Ceftazidime, cefepime or a carbapenem can be considered
- Combination therapy: Extended-spectrum beta-lactam such as ceftazidime or piperacillin/tazobactam, plus an aminoglycoside (gentamicin or tobramycin) should be used
- For patients with an indwelling IV line, adding vancomycin to the regimen above is usually recommended
- Treatment of nosocomial FUO
- Empiric antibiotic treatment is recommended in cases of nosocomial FUO
- In critically-ill patients treatment with vancomycin (with MRSA coverage) should be part of the treatment regimen along with other antibiotics
- Other broad spectrum antibiotics such as piperacillin/tazobactam, ticarcillin/clavulanate, and meropenem are usually recommended
Medications indicated with specific doses
Aminoglycosides
CarbapenamsCephalosporins- Cefepime (4th generation)
- Ceftazidime (3rd Generation)
Penicillins- Clavulanate/ticarcillin (4th generation-extended spectrum)
- Piperacillin/tazobactam (4th generation-extended spectrum)
OthersDietary and Activity restrictions
- Patients may require greater calorie and fluid intake during illness
Disposition
Admission criteria
- Patients with unstable vital signs need hospitalization and resuscitation
- High-risk patients with FUO such as neutropenic patients, immunocompromised patients, asplenic patients or IV drug abusers generally require hospitalization
Discharge criteria
- Clinically stable patients with inconclusive diagnostic findings usually do not benefit from hospitalization
- Patients may be safely discharged following stabilization of vital signs and identification of the underlying cause
Prevention
- No specific measures are available to prevent FUO
- Neutropenic FUO may be prevented by prophylactic antimicrobial treatment in selected cases
Prognosis
- Prognosis of FUO is variable and depends on the underlying cause
- Overall mortality of FUO is around 12-35%
- The underlying disease may be the best predictor of mortality for classic FUO: Malignancy (52-100%), infection (8-22%).
- Patients with HIV have high mortality
- The prognosis of FUO is usually good if no identifiable source is found within 6 months
- Neutropenic FUO has a poor prognosis if the underlying infection is not treated
Pregnancy/Pediatric effects on condition
- FUO occurring during pregnancy may be associated with an increased risk of neural tube defects and preterm labor
Synonyms
- Pyrexia of unknown origin
Abbreviation
ICD-9-CM
- 780.6 Fever of unknown origin
ICD-10-CM
- R50.9 FUO (fever of unknown origin)
