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Fever of Unknown Origin

Author: Kirk M Chan-Tack, MD, Fellow, Division of Infectious Disease, University of Maryland School of Medicine
Coauthor(s): John Bartlett, MD, Chief of Division of Infectious Diseases, Chief of HIV Care Service, Professor, Department of Internal Medicine, Johns Hopkins University School of Medicine
Contributor Information and Disclosures

Updated: Sep 23, 2008

Introduction

Background

Fever of unknown origin (FUO) was defined in 1961 by Petersdorf and Beeson as the following: (1) a temperature greater than 38.3°C (101°F) on several occasions, (2) more than 3 weeks' duration of illness, and (3) failure to reach a diagnosis despite one week of inpatient investigation.¹

This article provides a review of the etiologies of FUO and a rational approach to investigating a patient with this interesting condition.

Pathophysiology

FUOs are caused by infections (30-40%), neoplasms (20-30%), collagen vascular diseases (10-20%), and numerous miscellaneous diseases (15-20%). The literature also reveals that between 5 and 15% of FUO cases defy diagnosis, despite exhaustive studies.

Variations in FUO, as found in the literature, reflect the populations and periods studied. In children, infections are the most common cause of FUO, whereas neoplasms and connective-tissue disorders are more common in elderly persons. FUOs that persist for more than one year are less likely to be caused by infections and neoplasms and much more likely to be due to granulomatous diseases (the most common cause in these cases).

Diagnostic advances continuously modify the spectrum of FUO-causing diseases; for example, serologic tests have reduced the importance of HIV and numerous rheumatic diseases (eg, systemic lupus erythematosus [SLE], juvenile rheumatoid arthritis [JRA], rheumatoid arthritis [RA]) as causes of FUO. Modern imaging techniques (eg, ultrasonography, CT scanning, MRI) enable early detection of abscesses and solid tumors that were once difficult to diagnose.

Patients with undiagnosed FUO (5-15% of cases) generally have a benign long-term course, especially when the fever is not accompanied by substantial weight loss or other signs of a serious underlying disease. These findings suggest that the underlying cause is one of the more serious diseases that initially manifest as FUOs. Such underlying diseases are usually diagnosed after an intensive and rational diagnostic evaluation.

Age

More than 30% of FUO cases in persons older than 50 years are related to connective-tissue disorders and vasculitic disorders. Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are the two principal connective-tissue etiologies, accounting for 50% of the cases.

Clinical

History

• Diagnostic approach to fever of unknown origin (FUO) in adults
  • Inquire about symptoms involving all major organ systems, including a detailed history of general symptoms (eg, fever, weight loss, night sweats, headaches, rashes).
  • Record all symptoms, even if they disappeared before the examination. Previous illnesses are important, including surgeries and psychiatric illnesses.
  • Provide a detailed evaluation including 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)

Physical

• 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.
• 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 quartan malaria. However, most people who are naive about malaria are not diagnosed with FUO because they are usually diagnosed with malaria before 3 weeks have elapsed.
  • Other diseases (eg, brucellosis, borreliosis, Hodgkin disease) tend to cause recurrent episodes of fever.
• 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.

Causes

• Bacterial diseases
• Abscesses: FUO should prompt consideration of abscesses, which are usually located intra-abdominally, even in the absence of localizing symptoms. Previous abdominal operations, trauma, or histories of diverticulosis, peritonitis, endoscopy, and gynecologic procedures increase the likelihood of an occult intra-abdominal abscess. The most common abscess locations include the subphrenic space, liver, right lower quadrant, retroperitoneal space, and the female pelvis.
• Tuberculosis (TB): This is usually considered in the FUO differential diagnoses² ; however, several factors may prevent a prompt diagnosis of TB. Dissemination, which usually occurs in immunocompromised patients, may initially manifest as constitutional symptoms that lack localizing signs. Chest radiography findings may be normal. Results from purified protein derivative (PPD) tests may be negative, and culture findings may not become positive for 4-6 weeks. TB of the kidney or mesenteric lymph nodes tends to manifest as FUO by lacking characteristic localized manifestations. Disseminated visceral infections with atypical mycobacteria (Mycobacterium avium being the prototype) also cause FUO; however, most of these patients have some other underlying hematologic malignancy or are infected with HIV.
• Urinary tract infections (UTIs): These rarely cause FUO because urinalysis is an easily performed routine test that is used to detect most cases of UTIs. However, in young children, the collection of clean-catch urine specimens may be difficult; furthermore, perinephric abscesses occasionally fail to communicate with the urinary system, resulting in normal urinalysis findings. Occult UTI is possible in a patient with anatomic abnormalities of the urinary tract and FUO.
• Endocarditis: This is now a rare cause of FUO. Failure to diagnose endocarditis may be due to the absence of a murmur or the failure of blood cultures to yield the organism. Culture-negative endocarditis is reported in 5-10% of endocarditis cases. Prior antibiotic therapy is the most common reason for negative blood cultures.
• Hepatobiliary infections: In patients with hepatobiliary infections, cholangitis can occur without local signs and with only mildly elevated or normal findings on liver function tests. Similarly, acute cholecystitis and gallbladder empyema can lead to a diagnosis of FUO because of the lack of right upper quadrant pain or jaundice, especially in elderly patients.
• Osteomyelitis: This usually causes localized pain or discomfort, at least intermittently. The most common reason for misdiagnosis of osteomyelitis is the failure to consider the disease in a patient who is febrile with musculoskeletal symptoms. Consider vertebral osteomyelitis in patients with low-grade fever or a history of UTIs. Radiographs may not show changes for weeks after the development of symptoms. Radionucleotide studies (technetium Tc 99m bone scanning) are more sensitive than plain radiography, and MRI is also an extremely useful test for the diagnosis of osteomyelitis.
• 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. Perform serologic tests in suspected cases.³
• Chlamydia: Consider Chlamydia psittaci infection, the cause of psittacosis, in patients with FUO who have a history of contact with birds. On rare occasions,Lymphogranuloma venereum infection manifests as FUO. Serology is essential for the diagnosis of these chlamydial infections.
• Systemic bacterial illnesses: Some systemic bacterial illnesses can manifest as FUOs. Brucellosis, still prevalent in Latin America and the Mediterranean, is very important. Consider this disease 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. Researchers have also described systemic infections with Salmonella species, Neisseria meningitidis, and Neisseria gonorrhoeae as causes of FUO. Cutaneous changes may be the only sign other than fever in neisserial infections. Cultures and serologic tests establish the diagnosis of these infections.
• Spirochetal diseases: The most important spirochete is Borrelia recurrentis, which is transmitted by ticks and is responsible for sporadic cases of relapsing fever. Rat-bite fever (Spirillum minor), Lyme disease (Borrelia burgdorferi), and syphilis (Treponema pallidum) are other spirochetal diseases that can cause FUO.
• Viral diseases
• HIV: Prolonged febrile episodes are common in patients with advanced HIV infection. Approximately 75% of the cases are infectious in nature, about 20-25% are due to lymphomas, and a small fraction (0-5%) are due to HIV itself. Typical and atypical mycobacteria and cytomegalovirus (CMV) are opportunistic infections that frequently cause prominent constitutional symptoms, including fever, with few localizing or specific signs. Other opportunistic infections (eg, salmonellosis, histoplasmosis, toxoplasmosis) can also present as FUO and elude rapid diagnosis in patients who are febrile with AIDS.
• AIDS: More than 80% of patients with AIDS and lymphomas have involvement of extranodal sites (usually the brain). However, lymphomas are occasionally difficult to diagnose promptly. Perform extensive diagnostic workup studies (eg, imaging studies) to exclude these opportunistic diseases in patients with HIV fever who have a prolonged fever before attributing the fever to the 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. Infections with these viruses usually cause lymphadenopathies, which may be missed on physical examination if the lymph nodes are not prominently enlarged. Serologic testing can confirm the correct diagnosis when the patient presents with lymphocytosis with atypical lymphocytes. The results of these tests may initially be negative; therefore, repeat them in suspected cases 2-3 weeks after the onset of illness.
• 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. Systemic infection may remain undiscovered in these patients because blood cultures are negative in approximately 50% of the cases. 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.
• 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. Rising antibody titers and immunoglobulin M (IgM) antibodies confirm the diagnosis. If the physician is unaware of a history of recent travel to an endemic area and if the fever pattern is nonsynchronized, malaria can be missed as a cause of fever. Other parasites that cause FUO in rare cases include Trypanosoma, Leishmania, and Amoeba species.
• Neoplasms
• Lymphomas: Hodgkin and non-Hodgkin lymphomas frequently cause fever, night sweats, and weight loss. The correct diagnosis can be delayed if the tumor is difficult to detect (eg, when the disease is confined to the retroperitoneal lymph nodes). Anemia may be the most prominent laboratory abnormality.
• Leukemias: Acute leukemias are another important neoplastic group that can cause FUO. In preleukemic states, the peripheral blood smear and bone marrow aspirate may not reveal the correct diagnosis; therefore, perform a bone marrow biopsy.
• 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. Hematuria may be absent in approximately 40% of cases, whereas anemia and a highly elevated sedimentation rate are common.
• Other solid tumors: Solid tumors such as adenocarcinomas of the breast, liver, colon, or pancreas and liver metastases from any primary site may manifest as fever.
• Malignant histiocytosis: This is a rare rapidly progressive malignant disease that manifests as high fevers, weight loss, enlarged lymph nodes, and hepatosplenomegaly. It is an occasional cause of FUO.
• 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).
• SLE was a relatively common cause of FUO 20 years ago; currently, it is readily diagnosed in most cases by the demonstration of antinuclear antibodies.
• 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. Laboratory abnormalities include pronounced leukocytosis, an elevated erythrocyte sedimentation rate (ESR), anemia, and abnormal liver function tests. These findings usually trigger a search for an infectious cause; thus, they delay the correct diagnosis.
• Consider polyarteritis nodosa (PAN), RA, and mixed connective-tissue diseases (ie, other collagen vascular diseases) because of their potential for nonspecific presentations. Rheumatic fever can be difficult to diagnose because it is rare in the developed world.
• Granulomatous diseases
• 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. Diarrhea and other abdominal symptoms are occasionally absent, particularly in young adults. The diagnosis is established with endoscopy and biopsy.
• 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) are found. These patients often have fever that may be accompanied by slight hepatomegaly, asthenia, and, sometimes, arthralgias and myalgias for many months or years. An elevated alkaline phosphatase level is the most consistent laboratory abnormality. The long-term prognosis is excellent; approximately 50% of patients recover spontaneously, and the other 50% respond to corticosteroid treatment (duration of therapy ranging from a few weeks to several years).
• Drug fever: Although a wide variety of drugs can cause drug fever, the most common are beta-lactam antibiotics, procainamide, isoniazid, alpha-methyldopa, quinidine, and diphenylhydantoin. A history of allergy, skin rashes, or peripheral eosinophilia is often absent in cases of drug fever. Neither the fever pattern nor the duration of previous therapy is helpful in establishing the diagnosis. When suspecting drug fever, discontinue the implicated drug. Stopping the causative drug generally leads to defervescence within 2 days
• Inherited diseases: In patients of Mediterranean descent with FUO, familial Mediterranean fever is most often the cause. 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 thyroiditis⁴ 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: These have been known to cause FUO. Consider these diagnoses in patients with predisposing conditions, particularly previous surgery, traumas, or prolonged bed rest. Another possible cause of fever after surgery or trauma is an undiscovered hematoma, usually located intra-abdominally.
• Kikuchi disease: A self-limiting necrotizing lymphadenitis known as Kikuchi disease was recently described as a cause of FUO. Kikuchi disease causes prolonged fever, constitutional symptoms, laboratory evidence of chronic inflammation, and, sometimes, liver function abnormalities. The etiology of Kikuchi disease is unknown.
• Factitious fever: This is responsible for as many as 10% of FUO cases in some series and is most commonly encountered among young adults with health care experience or knowledge. Evidence of psychiatric problems or a history of multiple hospitalizations at different institutions is common. 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 among 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 one or more of the features described.
• Other vasculitides
• 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. During the examination, the physician may observe temporal artery tenderness or decreased pulsation. Laboratory findings include an elevated ESR, mild-to-moderate normochromic normocytic anemia, elevated platelet counts, and abnormal liver function tests (25% of cases). Perform a biopsy of a temporal artery to obtain a definitive diagnosis. Pathologic review shows vasculitis and a mononuclear cell infiltrate.
• Treat the patient with high doses of steroids, and use intravenous steroids if the patient is very ill or has significant ocular compromise. Carefully monitor the patient because inadequate treatment and steroid toxicities (eg, hypertension, diabetes, dyspepsia, bone loss, psychosis, cataracts) can cause significant morbidity.
• 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. Physical examination is notable for normal muscle strength. Carefully perform a history and physical examination because such protean symptoms may evade diagnosis.
• The diagnosis of PMR is clinical, and treatment is 2-fold, consisting of (1) amelioration of symptoms with steroid therapy and (2) close monitoring for possible development of GCA.
• PAN: This ranks a distant third behind GCA and PMR among the vasculitides that cause FUO in patients older than 50 years. PAN involves the medium- and small-sized muscular arteries. The male-to-female incidence ratio is 2:1. Incidence increases in patients with hepatitis B or C. Any 3 of the following 10 findings is sufficient for the diagnosis of PAN (sensitivity 82%, specificity 86%), and therapy consists of prednisone (cyclophosphamide is used in refractory cases):
• Mononeuritis multiplex
• Myalgias with muscle tenderness
• Livedo reticularis
• Testicular pain or tenderness
• Renal impairment (elevated BUN 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
• Other vasculitides that cause FUO include Wegener granulomatosis, Takayasu arteritis, and cryoglobulinemia. These are uncommon causes of FUO.

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