Fever of Unknown Origin (FUO)

Definition and EtiologyTop

Fever of unknown origin (FUO) is a clinical entity that may have various causes. Its key feature is fever that does not resolve spontaneously, persists longer than an average infectious disease, and whose cause remains unknown despite routine investigations.

Classic FUO is diagnosed if all of the 3 following criteria are met:

1) Fever >38.3 degrees Celsius that persists or recurs on several occasions.

2) Duration of fever >3 weeks.

3) The cause has not been established or remains uncertain despite routine diagnostic investigations continued for ~1 week (≥3 days in the hospital or ≥3 outpatient visits).

In hospitalized patients (after ≥2 days of hospitalization) as well as patients with neutropenia or HIV infection, FUO is diagnosed if the following criteria are met:

1) Fever >38.3 degrees Celsius that persists or recurs on several occasions.

2) The cause has not been established or diagnosis remains uncertain despite routine inpatient diagnostic investigations continued for 3 to 5 days.

CausesTop

1. The most important causes of classic FUO:

1) Infection (the longer the duration of FUO, the more unlikely the infectious etiology): Most frequently pulmonary and extrapulmonary tuberculosis (TB), abscess (intraabdominal, subphrenic, perinephric, pelvic), infectious endocarditis, cytomegalovirus (CMV) infection, toxoplasmosis, typhoid fever, paratyphoid fever, chronic prostatitis; less frequently systemic fungal infection or zoonotic diseases (mostly travel-associated infections, particularly those linked to travelling to tropical countries), such as malaria, leptospirosis, brucellosis, tularemia, psittacosis, rickettsial infections (spotted fevers, typhus), Q fever, anaplasmosis, ehrlichiosis, bartonellosis, and cat-scratch disease.

2) Inflammatory diseases: Systemic connective tissue diseases (most frequently adult-onset Still disease, polyarteritis nodosa, systemic lupus erythematosus) and inflammatory bowel disease (particularly Crohn disease). In elderly patients more frequent causes are temporal arteritis, polymyalgia rheumatica, and rheumatoid arthritis.

3) Cancer: Most frequently hematologic and lymphatic malignancies (Hodgkin lymphoma, non-Hodgkin lymphoma, leukemia, myelodysplastic syndrome), clear cell renal cell carcinoma, hepatic adenoma, liver cancer, pancreatic cancer, colorectal cancer, primary central nervous system (CNS) malignancies.

4) Drugs (usually polytherapy): Most frequently penicillins, sulfonamides, vancomycin, amphotericin B, salicylates, bleomycin, interferons, quinidine derivatives, phenothiazine derivatives (promethazine, thiethylperazine), barbiturates, phenytoin, methyldopa, haloperidol (neuroleptic malignant syndrome), tricyclic antidepressants, and lithium. Drug-induced fever is more frequent in the elderly. It usually develops within 1 to 2 weeks of starting treatment (although it may occur at any point of treatment) and resolves spontaneously within 48 to 72 hours (later in patients with liver disease or renal failure). Fever may be accompanied by erythematous, macular, or maculopapular rash and increased eosinophil counts. The pattern of fever is not significant. Relative bradycardia is often present.

5) Other: Alcoholic hepatitis, thyroiditis, pulmonary embolism (generally recurrent and undetected, without severe clinical symptoms), hematomas, factitious fever.

2. Causes of FUO based on the risk group:

1) FUO in a hospitalized patient: Most frequently caused by abscess (intra-abdominal or pelvic), sinusitis (due to prolonged presence of a nasotracheal tube), catheter-associated bloodstream infection (long-term indwelling catheter in a large vessel), infective endocarditis (associated with invasive diagnostic procedures, catheterization of large vessels, or surgery), pseudomembranous colitis (Clostridioides difficile), drugs, septic thrombophlebitis, pulmonary embolism, pancreatitis, retroperitoneal hematoma.

2) FUO in a patient with neutropenia: Primary bacteremia, catheter-associated bloodstream infections (long-term indwelling catheter in a large vessel), fungemia (eg, Candida spp), hepatosplenic candidiasis, invasive fungal infection (eg, Aspergillus spp), pelvic abscess (perirectal or located between the rectum and sacral bone), drugs, metastases to the CNS or liver.

3) FUO in a patient with HIV infection: TB and non-TB mycobacterial infection are the most common causes. Less frequent are pneumocystosis, CMV infection, herpes simplex virus (HSV) infection, toxoplasmosis, salmonellosis, fungal infection, lymphoma, Kaposi sarcoma, and drugs (eg, trimethoprim/sulfamethoxazole). HIV alone is rarely responsible for FUO.

4) FUO in a patient returning from tropical regions: Malaria (incubation period up to 6 weeks, although in cases of Plasmodium vivax and Plasmodium ovale it may be up to several months or years); other tropical parasitic infestations (amebiasis, leishmaniasis, trypanosomiasis, cryptosporidiosis, filariasis, tropical pulmonary eosinophilia, schistosomiasis, paragonimiasis); typhoid fever (incubation period up to 6 weeks); rickettsial diseases; viral hemorrhagic fevers, most frequently dengue fever (incubation period 3-8 days).

DiagnosisTop

Basic diagnostic studies used in the evaluation of FUO:

1) Laboratory tests: Complete blood count (CBC) with differential count; erythrocyte sedimentation rate (ESR); serum levels of electrolytes, bilirubin, liver enzymes, urea/blood urea nitrogen (BUN), creatinine, and uric acid; urinalysis; rheumatoid factor; antinuclear antibodies; microbiologic studies: blood cultures (2-3 cultures in a patient not treated with antibiotics), urine cultures, tuberculin skin test or interferon gamma release assay (IGRA), serologic studies (HIV, CMV, Epstein-Barr virus [EBV]). Some clinicians use procalcitonin as an aid in differentiation between bacterial infections and other causes of fever, but the clinical utility of the test in this setting is unclear.

2) Imaging studies: Abdominal ultrasonography, chest radiography, abdominal and pelvic computed tomography (CT) or magnetic resonance imaging (MRI); if necessary (symptoms or signs of CNS involvement), also CT or MRI of the head.

Take a detailed history and repeatedly perform thorough physical examinations. Make sure that body temperature is measured and interpreted correctly (see below). The combination of localizing signs and symptoms accompanying FUO (potential diagnostic clues) together with the results of key diagnostic studies provide the basis for preliminary diagnosis and guide further investigations. If the patient’s condition is stable, the preliminary diagnostic workup may be performed in an outpatient setting.

If the condition is not life-threatening and the patient is hospitalized, you may consider watchful waiting and use targeted diagnostic studies to confirm or exclude the most probable causes in a given risk group (eg, patients returning from a tropical country; hospitalized patients; patients with neutropenia; patients with HIV infection; patients aged >50 years). Start with noninvasive studies and add invasive studies when necessary. If the patient is severely ill, simultaneously exclude probable causes. In febrile patients with a recent history of travel to areas endemic for malaria, promptly exclude malaria (prophylactic treatment with antimalarial agents during travel does not exclude the possibility of infection).

If drug-induced fever is suspected, start by discontinuing all drugs used by the patient (including over-the-counter agents) or reduce their number to the necessary minimum. Check if the patient has used drugs of abuse (including designer drugs) or unapproved weight-loss products. Drug-induced fever usually resolves within 48 to 72 hours following discontinuation of the offending agent.

In justified cases some experts suggest empiric treatment if specific but unconfirmed diseases are suspected; most frequently, this involves TB (if clinically suspected, start TB treatment after obtaining specimens for culture), infective endocarditis (if suspected based on the Duke criteria [see Table: Duke criteria in Infective Endocarditis], start antimicrobial therapy after obtaining appropriate blood cultures), temporal arteritis, or other systemic connective tissue diseases (exclude infection, then consider glucocorticoids and nonsteroidal anti-inflammatory drugs [NSAIDs]). Resolution of fever and other symptoms in response to therapy confirms the preliminary diagnosis. In the case of transient improvement, consider investigation for malignancy, particularly if low-grade or high-grade fever is accompanied by systemic manifestations or lymphadenopathy.

Differential Diagnosis

1. Incorrect measurement of body temperature: To meet the criterion of a body temperature elevation >38.3 degrees Celsius, it is necessary to establish how the measurement was made, including the type of thermometer (mercury, electronic, LCD, infrared), site of measurement (mouth, forehead, axilla, ear, rectum), time of day, frequency of measurements, and conditions and technique of measurement. You may ask patients to demonstrate how they measure their temperature and handle the thermometer. The least accurate measurements are made in the axilla (results are ~0.8 degrees Celsius lower than the core body temperature) and ear (results are highly variable, depending on the presence of cerumen and other factors). Oral temperature is ~0.5 degrees Celsius lower and rectal temperature is ~0.5 degrees Celsius higher than the core temperature. Chewing gum immediately before the measurement increases temperatures measured in the mouth or ear, while smoking has a similar effect on the temperature measured in the mouth. Measure body temperature preferably several times a day over a few days of diagnostic hospitalization with monitoring of pulse rate, which eliminates measurement errors and may be used to assess the patterns of fever and pulse. Note that the reference ranges for body temperatures are variable and change depending on the time of day, season, phase of the menstrual cycle, and nutrition status.

2. Factitious fever: It is generally chronic and accompanied by varied changing symptoms. The course is inconsistent. The patient’s history reveals numerous hospitalizations. A chronic fever of this type is generally not accompanied by weight loss and patients are in good general condition. Antipyretic drugs are usually ineffective. Most patients have psychiatric or personality disorders; somatic disorders are often seen. Hospitalized patients generally refuse their consent for supervised body temperature measurements and certain diagnostic tests. If body temperature is taken using a mercury thermometer, the recorded values are usually very high and show no diurnal variation. The skin is cold. Relative bradycardia is present. You may ask the patient to provide a urine sample after body temperature measurement and immediately measure the sample’s temperature (it is always slightly higher than the oral or axillary temperature).

TreatmentTop

Symptomatic Treatment

1. Antipyretic agents:

1) First-line agents: Oral or rectal acetaminophen (INN paracetamol) 500 to 1000 mg, repeated if necessary every 6 hours (up to 4 g/d). If oral or rectal administration is not possible, 500 to 1000 mg may be administered IV every 6 hours (maximum, 4 g/d). In patients with severe renal failure (creatinine clearance <10 mL/min), increase the dosing interval to every 8 hours. In patients with cirrhosis, limit acetaminophen to a maximum dose of 2 g/d. Acetaminophen overdose leads to acute liver failure (this may occur even with 8 g/d; the risk is highest in patients who are fasting or abuse alcohol). Management of acetaminophen overdose: see Acetaminophen.

2) Alternative antipyretics: NSAIDs:

a) Oral ibuprofen 200 to 400 mg, repeated if necessary every 5 to 6 hours (maximum, 2 g/d).

b) Oral acetylsalicylic acid 500 mg, repeated if necessary every 5 to 6 hours (maximum, 2.5 g/d). Contraindicated in patients with peptic ulcer disease, bleeding disorder, or aspirin-induced asthma.

2. Techniques of physical cooling: These are used in patients with a very high fever (>40 degrees Celsius) not responding to antipyretic agents.