Fever of Unknown Origin (FUO) Clinical Presentation

The history can provide important clues to fever of unknown origin (FUO) due to zoonoses, malignancies, and inflammatory/immune disorders. In adults with FUO, inquire about symptoms involving all major organ systems and obtain a detailed history of general symptoms (eg, fever, weight loss, night sweats, headaches, rashes). Record all symptoms, even those that disappeared before the examination. Previous illnesses (including psychiatric illnesses) are important. Look for patterns of symptoms and relapsing fevers.

Make a detailed history evaluation that includes the following:

• Family history
• Immunization status
• Dental history
• Occupational history
• Travel history, especially within the prior year
• Nutrition and weight history (including consumption of dairy products); note changes in the fit of clothing if the patient does not monitor weight
• Drug history (over-the-counter medications, prescription medications, illicit substances)
• Sexual history
• Recreational habits
• Animal contacts (including possible exposure to ticks and other vectors)
• Surgery, invasive procedures, trauma

Fever pattern

Fever with rigors or shaking chills is most suggestive of infection, as opposed to noninfectious inflammatory conditions.

In general, specific fever patterns do not correlate strongly with specific diseases. Notable exceptions include classic recurrent fevers, as follows:

• Tertian fever in prolonged malaria (occurring every third day)
• Undulant fever in brucellosis (evening fevers and sweats resolving by morning)
• Tick-borne relapsing fever ( Borrelia hermsii, B parkeri, B duttonii; fever lasting 1-3 days followed by up to 2 weeks without fever followed by another 1-3 days of fever) ^[27]
• Louse-borne relapsing fever ( Borrelia recurrentis; fever lasting roughly 3-6 days followed by up to 2 weeks without fever followed by 1-5 febrile episodes that decrease in severity) ^[28]
• Pel-Ebstein (cyclical) fever in Hodgkin disease (week-long high fevers with week-long remissions)
• Periodic fevers in cyclic neutropenia
• Double quotidian fever (two fever spikes a day) in adult Still disease; also seen in malaria, typhoid, and other infections
• Morning fevers in polyarteritis nodosa, tuberculosis, and typhoid

Historical clues to likely noninfectious inflammatory causes of FUO

Collagen vascular and autoimmune diseases can manifest as FUO if the fever precedes other, more specific manifestations (eg, arthritis, pneumonitis, renal involvement). Weight loss is not unusual.

Clues and etiologic associations are as follows:

• Headache, jaw claudication, and visual disturbances (visual loss, blurred vision, diplopia, amaurosis fugax): Giant cell or temporal arteritis
• Symmetrical pain and stiffness of lumbar spine and large proximal muscles (neck, shoulders, hips, thighs): Polymyalgia rheumatica; also myalgias, tender muscles, lacelike rash (livedo reticularis), testicular pain
• High-spiking fevers, nonpruritic morbilliform rash that follows the fever curve, arthralgias: Adult-onset Still disease, lymphadenopathy
• Facial rash: SLE
• Right lower quadrant pain, diarrhea (or none): Crohn disease (regional enteritis); Yersinia enteritis may mimic Crohn disease or appendicitis
• Erythema nodosum, painful nodules on shins: Idiopathic erythema nodosum may itself cause fever sarcoidosis; Crohn disease; ulcerative colitis; Behçet disease
• CNS disorders, specifically subarachnoid haemorrhage, cerebral trauma, ischemic or haemorrhagic stroke: Central fever with disorder of thermoregulation

Historical clues to likely infectious causes of FUO

Clues and etiologic associations are as follows:

• Previous abdominal surgery, trauma, or a history of diverticulosis, peritonitis, endoscopy, urologic or gynecologic procedures: Intraabdominal abscess, perinephric abscess, psoas abscess
• Erythema nodosum, painful nodules on shins: Granulomatous fungal infections, histoplasmosis, coccidioidomycosis, Yersinia enteritis, tuberculosis

Animal and animal product exposures

A history of exposure to unpasteurized dairy (eg, swine, cattle, goats, camels, sheep) may suggest the following:

• Brucellosis
• Coxiella burnetii ( chronic Q fever, Q fever endocarditis; parturient animals aerosolize Coxiella from the placenta)
• Yersinia enterocolitica/ Yersinia pseudotuberculosis: Mesenteric adenitis, pseudoappendicitis, with or without diarrhea

Exposure to birds (especially new pets, sick birds) may suggest Chlamydia psittaci infection.

Exposure to cats or cat litter may suggest toxoplasmosis or cat scratch disease (especially kittens).

Exposure to undercooked or undersmoked game meats, especially bear, cougar, wild hog, may suggest trichinosis (diffuse myalgias).

Travel-related and other environmental exposures

Travel-related and other environmental exposures are as follows:

• Desert areas of the southwest United States, California: Coccidioides immitis infection
• River valleys (Ohio, Mississippi, Central/South America): Histoplasma, Blastomyces infection
• Caves (bats): Histoplasma infection
• Swimming in rivers, fresh water, especially with rains: Leptospirosis
• Rural Central/South America, Africa, Asia: Tuberculosis, especially extrapulmonary; malaria (in malaria-prone areas; travelers of developed countries may not seek pretravel advice or take malaria prophylaxis; malaria may manifest weeks to months after return home)
• Mediterranean, tropics: Visceral leishmaniasis
• United States, rodent-infested cabins: Borrelia hermsii (tick-borne relapsing fever), week-long fevers interrupted by week-long remissions
• North America, Eurasia, tick-infested brush and forest: Borrelia miyamoto i
• Middle East, Latin America, refugees, disrupted civil services in disaster or war, humanitarian aid workers: Borrelia recurrentis/Brucella melitensis (louse-borne relapsing fever)
• Uncertain sanitation, adventurous eating: Salmonella typhi (typhoid)

Sexual encounters without barrier precautions

Travelers are especially likely to experience unanticipated encounters out of their usual norm; consider HIV, disseminated gonorrhea.

Childcare, daycare, grandchildren

Acute Epstein-Barr virus (EBV) infection is easily spread, and a small percentage of adults are not immune; fever for several weeks with or without organomegaly may be the only symptom in older adults.

Acute cytomegalovirus (CMV) is similarly easy to acquire and may cause several weeks of fever in adults (reactivation is also possible, with manifestations in several organ systems).

Acute Parvovirus B19 infection can manifest with fever, arthralgias, rash, fatigue with fever being one of the most common symptoms of adults. 

Historical clues to malignant causes of FUO

Historical clues to malignant causes of FUO are as follows:

• Pel-Ebstein (cyclical) fever in Hodgkin disease (week-long high fevers with week-long remissions)
• Lymphadenopathy, painless: Lymphoma, leukemia
• Weight loss with anorexia
• Itching after a hot bath: Lymphoma
• Erythema nodosum, painful nodules on shins: Lymphoma

Historical clues to miscellaneous causes of FUO

Historical clues to miscellaneous causes of FUO are as follows:

• Prolonged immobility, car trips, flights: Thromboembolic disease
• Ethanol abuse: Alcoholic hepatitis, cirrhosis (endotoxemia of portal circulation)
• Medication list review: Drug fever
• Anticoagulant use: Hematoma, occult hemorrhage

Definitive documentation of fever and exclusion of factitious fever are essential early steps in the physical examination. Measure the fever more than once and in the presence of healthcare personnel to exclude manipulation of thermometers.

On physical examination, pay special attention to the eyes, skin, lymph nodes, spleen, heart, abdomen, and genitalia.

Repeat a regular physical examination daily while the patient is hospitalized. Pay special attention to rashes, new or changing cardiac murmurs, signs of arthritis, abdominal tenderness or rigidity, lymph node enlargement, funduscopic changes, and neurologic deficits.

Physical examination clues to causes of FUO are as follows:

• Pulse-temperature deficit or relative bradycardia (inappropriately low pulse rate for degree of fever, in the absence of beta blockade): Typhoid fever, Q fever, psittacosis, legionellosis, lymphoma, drug fever
• Unequal pulse in upper extremities: Takayasu arteritis
• Eyes - Roth spots, retinal artery occlusion: SLE, vasculitis, bacterial endocarditis, cat scratch disease (stellate retinitis)
• Oral ulcers: SLE, Behçet disease, histoplasmosis
• Tender tooth on percussion, caries/gingivitis: Dental abscess
• Enlarged or tender thyroid: Thyroiditis
• Lymphadenopathy: Sarcoidosis, SLE, adult-onset Still disease, granulomatous infections, hematologic malignancies
• Cardiac murmur: SLE (Libman-Sacks endocarditis), bacterial endocarditis
• Hepatomegaly without splenomegaly: Granulomatous hepatitis, primary liver cancer, renal cell carcinoma, or liver metastases; excludes collagen vascular disease and hematologic malignancy
• Splenomegaly without hepatomegaly: Bacterial endocarditis, EBV/CMV infection, typhoid, tuberculosis, histoplasmosis, brucellosis, malaria, Q fever, borreliosis (relapsing fevers), cirrhosis
• Tenderness to palpation of sternum: Hematologic malignancy
• Tenderness to percussion over a vertebra: Vertebral osteomyelitis, tuberculosis, typhoid, brucellosis
• Epididymitis or nodules: Sarcoid, SLE, polyarteritis nodosa
• Tender red nodules on shins: Idiopathic erythema nodosum (EN), collagen vascular disease, granulomatous infections, EBV infection, typhoid, bartonellosis, drug fever