Fever of Unknown Origin Clinical Presentation

In adults with FUO, inquire about symptoms involving all major organ systems and get a detailed history of general symptoms (eg, fever, weight loss, night sweats, headaches, rashes).

The history can provide important clues to FUO due to surgery, zoonoses, malignancies, and inflammatory/immune disorders.

Record all symptoms, even those that disappeared before the examination. Previous illnesses (including psychiatric illnesses) and surgeries are important.

Make a detailed evaluation that includes the following:

• Family history
• Immunization status
• Occupational history
• Travel history
• Nutrition (including consumption of dairy products)
• Drug history (over-the-counter medications, prescription medications, illicit substances)
• Sexual history
• Recreational habits
• Animal contacts (including possible exposure to ticks and other vectors)

Abscesses

Previous abdominal surgery, trauma, or a history of diverticulosis, peritonitis, endoscopy, or gynecologic procedures increase the likelihood of an occult intra-abdominal abscess.

Osteomyelitis

Osteomyelitis usually causes localized pain or discomfort, at least intermittently. Consider vertebral osteomyelitis in patients with low-grade fever or a history of UTIs.

Rickettsia

Chronic infections with Coxiella burnetii, chronic Q fever, and Q fever endocarditis have been identified in patients with FUO. Signs of hepatic involvement are common, and the infection is transmitted from cattle and sheep.

Chlamydia

Consider Chlamydia psittaci infection, the cause of psittacosis, in patients with FUO who have a history of contact with birds.

Systemic bacterial illnesses

Consider brucellosis in patients with persistent fever and a history of contact with cattle, swine, goats, and/or sheep or in patients who consume raw milk products.

Human immunodeficiency virus

Prolonged febrile episodes are common in patients with advanced HIV infection.

Herpes viruses

CMV and Epstein-Barr virus (EBV) can cause prolonged febrile illnesses with constitutional symptoms and no prominent organ manifestations, particularly in elderly persons.

Fungal infections

Immunosuppression, the use of broad-spectrum antibiotics, the presence of intravascular devices, and total parenteral nutrition all predispose to disseminated fungal infections, and Candida albicans is the main culprit.

Malassezia furfur infection can cause FUO and line infections in patients on total parenteral nutrition who receive intravenous lipid preparations. In some cases, fever is the most prominent symptom in patients with reticuloendothelial involvement by histoplasmosis without clinical manifestations in other organs.

Lymphomas

Hodgkin and non-Hodgkin lymphomas frequently cause fever, night sweats, and weight loss.

Malignant histiocytosis

This is a rare, rapidly progressive, malignant disease that manifests as high fevers, weight loss, enlarged lymph nodes, and hepatosplenomegaly.

Collagen vascular and autoimmune diseases

Collagen vascular and autoimmune diseases can manifest as FUO if the fever precedes other, more specific manifestations (eg, arthritis, pneumonitis, renal involvement). Systemic-onset JRA is a cause of FUO and is often difficult to diagnose. High-spiking fevers, nonpruritic rashes, arthralgias and myalgias, pharyngitis, and lymphadenopathy are common.

Sarcoidosis

Given its multiorgan involvement, sarcoidosis rarely manifests as fever and malaise without evidence of lymph node and pulmonary involvement. Erythema nodosum is occasionally present, and the finding of noncaseous granulomas in the liver should raise concern.

Regional enteritis

Crohn disease is the most common gastrointestinal cause of FUO. However, diarrhea and other abdominal symptoms are occasionally absent, particularly in young adults.

Granulomatous hepatitis

In some patients with hepatic granulomas, none of the diseases usually associated with FUO (eg, TB, syphilis, brucellosis, sarcoidosis, Crohn disease, Hodgkin disease) is found. These patients often have fever that may be accompanied by slight hepatomegaly, asthenia, and, sometimes, arthralgias and myalgias for many months or years.

Inherited diseases

Recurrent febrile episodes at varying intervals are associated with pleural, abdominal, or joint pain due to polyserositis. This is a diagnosis of exclusion.

Endocrine disorders

Hyperthyroidism and subacute thyroiditis are the 2 most common endocrinologic causes of FUO. In fact, fever is often the major clinical sign, in addition to weight loss.

Adrenal insufficiency is a rare, potentially fatal, very treatable endocrine cause of FUO. Consider this diagnosis in patients with nausea, vomiting, weight loss, skin hyperpigmentation, hypotension, hyponatremia, and hyperkalemia.

Peripheral pulmonary emboli and occult thrombophlebitis

Consider these diagnoses in patients with predisposing conditions, particularly previous surgery, trauma, or prolonged bed rest. Another possible cause of fever after surgery or trauma is an undiscovered hematoma, usually located intra-abdominally.

Kikuchi disease

Kikuchi disease causes prolonged fever and constitutional symptoms.

Factitious fever

Evidence of psychiatric problems or a history of multiple hospitalizations at different institutions is common in patients with factitious fever.

Rapid changes of body temperature without associated shivering or sweating, large differences between rectal and oral temperature, and discrepancies between fever, pulse rate, or general appearance are typically observed in patients who manipulate or exchange their thermometers, the most common cause of factitious fever. Alternatively, fever may be caused by injection of nonsterile material (eg, feces, milk), resulting in atypically localized abscesses or polymicrobial infections.

Therefore, consider factitious fever as a possibility in every patient with prolonged fever, especially in patients with 1 or more of the above-described features described.

Giant cell arteritis

Classic symptoms of GCA include temporal headache, jaw claudication, fever, visual disturbances (visual loss, blurred vision, diplopia, amaurosis fugax), weight loss, anorexia, fatigue, and cough. Polymyalgia (aching and stiffness of the proximal muscles and the trunk) occurs in 40% of these patients.

Polymyalgia rheumatica

PMR is characterized by symmetrical pain and stiffness involving the lumbar spine and large proximal muscles, most notably the neck, shoulders, hips, and thighs. Symptoms are usually worse in the morning. Constitutional symptoms (eg, fever, malaise, depression, weight loss) are also observed. Symptoms may worsen relentlessly over weeks to months without treatment.

Polyarteritis nodosa

Any 3 of the following 10 findings is sufficient for the diagnosis of PAN (sensitivity 82%, specificity 86%):

• Mononeuritis multiplex
• Myalgias with muscle tenderness
• Livedo reticularis
• Testicular pain or tenderness
• Renal impairment (elevated BUN [blood urea nitrogen] and creatinine levels)
• Weight loss of 4 kg or more
• Diastolic blood pressure greater than 90 mm Hg
• Hepatitis-B positive
• Arteriography showing small and large aneurysms and focal constrictions between dilated segments
• Biopsy of small- or medium-sized arteries containing white blood cell infiltrate
• Peripheral eosinophilia (common and an important clue to PAN)

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 a nurse to exclude manipulation of thermometers. Electronic thermometers facilitate the rapid and unequivocal documentation of fever.

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

Pulse-temperature relationships (ie, relative bradycardia) are useful in evaluating for typhoid fever, Q fever, psittacosis, lymphomas, and drug fevers.

The pattern of fever (continuous, remittent, intermittent) is usually of little help in the evaluation. In general, specific fever patterns do not correlate strongly with specific diseases. Notable exceptions include tertian and brucellosis, borreliosis, Hodgkin disease) tend to cause recurrent episodes of fever.

Fever curves are useful in FUO and are helpful in evaluating for adult Still disease, visceral leishmaniasis, and zoonotic infections.

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.

Systemic bacterial illnesses

Cutaneous changes may be the only sign other than fever in neisserial infections.

Herpes viruses

CMV and Epstein-Barr virus (EBV) infections usually cause lymphadenopathies, which may be missed on physical examination if the lymph nodes are not prominently enlarged.

Parasitic infections

Consider toxoplasmosis in patients who are febrile with lymph node enlargement; however, the diagnosis may be difficult to establish, because the lymph nodes may be small.

Solid tumors

Among solid tumors, renal cell carcinoma is most commonly associated with FUO, with fever being the only presenting symptom in 10% of cases.

Giant cell arteritis

During the examination in patients with GCA, the physician may observe temporal artery tenderness or decreased pulsation.

Polymyalgia rheumatica

The diagnosis of PMR is clinical. Physical examination is notable for normal muscle strength. Carefully perform a history and physical examination, because such protean symptoms may evade diagnosis.