INTRODUCTION — Clinicians commonly refer to a febrile illness without an initially obvious etiology or without localizing signs as fever of unknown origin (FUO). This usage is not accurate. Most febrile illnesses either resolve before a diagnosis can be made or develop distinguishing characteristics that lead to a diagnosis. FUO refers to a prolonged febrile illness without an established etiology despite intensive evaluation and diagnostic testing.
Large case series of FUO applying this definition have been collected over a number of decades; these facilitate an approach to patients with FUO and an understanding of the changing patterns of FUO with time and newer diagnostic techniques.
The common and uncommon entities causing FUO in adults will be reviewed here. The definitions of this condition, an approach to the adult with FUO, and the etiology of FUO in children are discussed separately. (See "Approach to the adult with fever of unknown origin" and "Fever of unknown origin in children: Etiology".)
COMMON CAUSES — Three general categories of illness account for the majority of "classic" FUO cases and have been consistent through the decades (table 1A-B and figure 1) [1-10]:
●Infections
●Connective tissue diseases (eg, vasculitis, systemic lupus erythematosus, polymyalgia rheumatica)
●Malignancies
Worldwide, the proportion of FUO due to infection, connective tissue disease, malignancy, and other etiologies varies substantially, based on geography, patient-population, health care exposure, and other factors. Details regarding fever in specific groups of patients are available elsewhere. (See "Overview of neutropenic fever syndromes" and "Fever in the intensive care unit".)
The proportion of patients for whom no diagnosis is made has varied widely from 9 to 51 percent in studies published since 1990, and appears to be increasing over time (figure 1) [3-8,11]. The outcomes for such patients are discussed elsewhere (See "Approach to the adult with fever of unknown origin", section on 'Outcome'.)
Infections — Infectious etiologies vary by geography and are especially predominant in certain areas of the world, such as southeast Asia [12,13].
In a systematic review and meta-analysis that included 832 cases of FUO ultimately attributed to a specific infectious etiology, tuberculosis was the most common worldwide infectious cause (34 percent) [13]. Other common causes included brucellosis (10 percent; isolated to southern Europe, eastern Mediterranean, southeast Asia, and western Pacific), endocarditis (8 percent), and abscess (7 percent). Other notable causes were herpesviruses (eg, cytomegalovirus, Epstein-Barr virus), pneumonia, urinary tract infections, and enteric fever. The Americas and Africa were underrepresented in the studies included in the review.
Tuberculosis — Tuberculosis (TB) is the single most common infection in most FUO series [13]. Presentations of TB, which escape early detection, are either extrapulmonary, miliary, or occur in the lungs of patients with significant preexisting pulmonary disease or immunodeficiency. As an example, pulmonary tuberculosis in patients with AIDS is often subtle, and the chest radiograph is normal in 15 to 30 percent of cases [14,15]. (See "Diagnosis of pulmonary tuberculosis in adults".)
Disseminated (miliary) TB is readily treatable, while death can occur in patients who remain untreated. Thus, a vigorous search for this disorder should be pursued.
The purified protein derivative skin test is positive in fewer than 50 percent of patients with TB who present with an FUO, usually due to cutaneous anergy [16]. The interferon-gamma release assay also has low sensitivity for the diagnosis of active TB [17]. Sputum samples are positive in only one-quarter of cases. Because of these difficulties, establishing the diagnosis often requires biopsy of affected nodes, bone marrow, or liver.
Techniques for isolation of Mycobacterium tuberculosis from blood include isolator cultures and polymerase chain reaction (PCR) on BACTEC blood culture bottles with evidence of early growth [18,19]. Both of these methods have yielded positive results in approximately 16 days, although PCR may be more sensitive and specific [19].
Abscess — Occult abscesses are usually located in the abdomen or pelvis. Underlying conditions, which predispose to abscess formation, include cirrhosis, steroid or immunosuppressive medications, recent surgery, and diabetes. Abscesses arise when there has been disruption of a barrier such as the bowel wall in appendicitis, diverticulitis, or inflammatory bowel disease. The rupture often seals off spontaneously and local peritonitis is converted to an abscess by host defense mechanisms. Intraabdominal abscesses can develop in subphrenic, omental, pouch of Douglas, pelvic, and retroperitoneal locations in addition to visceral sites.
The source of infection in these abscesses can vary with the site of abscess formation:
●Pyogenic liver abscesses usually follow biliary tract disease or abdominal suppuration such as appendicitis or diverticulitis. Amebic liver abscesses cannot be distinguished on clinical grounds from pyogenic abscesses; amebic serology is positive in more than 95 percent of cases of extraintestinal disease.
●Hematogenous seeding rather than contiguous spread accounts for the majority of splenic abscesses, which are often missed prior to autopsy; endocarditis is the most common infection currently associated with splenic abscess.
●Perinephric or renal abscesses usually arise from existing infection in the urinary tract, although urine cultures may be negative or only intermittently positive. (See "Renal and perinephric abscess".)
Osteomyelitis — Osteomyelitis should be considered as a cause of FUO since localized symptoms in some sites may not be prominent. Examples include vertebral osteomyelitis and osteomyelitis of the mandible. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".)
Bacterial endocarditis — Cultures are negative in 2 to 5 percent of patients with infective endocarditis even when the utmost care is taken in obtaining the proper number and volume of blood cultures. The frequency of negative cultures is higher in patients who have already been treated with antimicrobials, such as intravenous drug users who frequently self-administer antibiotics [20].
Culture negativity is particularly likely with the following organisms, which are more difficult to isolate in culture:
●Coxiella burnetii (Q fever) and Tropheryma whipplei occasionally cause endocarditis but will not grow using cell free media. (See "Whipple's disease".)
●Brucella, Mycoplasma, Chlamydia, Histoplasma, Legionella, and Bartonella will not grow unless special media or microbiologic methods are employed.
●Haemophilus spp, Actinobacillus, Cardiobacterium, Eikenella, and Kingella (the so-called HACEK group) will not be detected unless blood cultures are incubated for 7 to 21 days.
The microbiology laboratory should be notified when endocarditis or other infections with such organisms are suspected, since most laboratories routinely discard blood cultures when there has been no growth after seven days of incubation. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)
Nonculture-based diagnostic modalities can be used to increase the diagnostic yield when culture-negative endocarditis is suspected (eg, serologic assays or polymerase chain reaction).
Peripheral manifestations are rarely detected in subacute endocarditis presenting as FUO. Endocarditis in intravenous drug users is often right sided and lacks murmurs, and self-administration of antimicrobials may obscure the detection of bacteremia.
Transesophageal echocardiography is positive in over 90 percent of cases of infective endocarditis presenting as FUO [16]. False-positive results may be due to anatomic abnormalities or noninfective vegetations; false-negative results occur with small vegetations or those that have already embolized. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis", section on 'Echocardiography'.)
Rarely, other endovascular infections (eg, mycotic aneurysms, septic thrombophlebitis) can be occult causes of fever. (See "Overview of infected (mycotic) arterial aneurysm" and "Catheter-related septic thrombophlebitis".)
Less common infections
Dental abscess — Apical dental abscesses are a rare cause of persistent fever that can be overlooked by the patient and physician. Among the 20 case reports in the literature, most individuals defervesced following removal of the decayed teeth, with or without antimicrobial therapy [21]. Other conditions linked to oral disease include brain abscesses, meningitis, mediastinal abscesses, and endocarditis; these are more common than dental FUO.
Opportunistic infections — The common occurrence of multiple concurrent opportunistic infections in FUO patients with AIDS confounds diagnosticians, particularly when CD4 counts are very low. These may include cytomegalovirus, Mycobacterium avium complex, Pneumocystis jirovecii, endemic fungi (eg, Histoplasma capsulatum), and gastrointestinal protozoa (eg, Cryptosporidium, Microsporidium).
Other types of immunocompromised hosts may also present with FUO caused by more than one infection. (See "Overview of infections following hematopoietic cell transplantation" and "Infection in the solid organ transplant recipient".)
Other infections — Tickborne illnesses are becoming more prevalent and more widely distributed in the United States. Organisms that cause babesiosis, Lyme disease, and anaplasmosis/ehrlichiosis, which have varying incubation periods and different susceptibilities to antimicrobial agents, may infect an individual concurrently or serially and present as FUOs or relapsing fever syndromes. Furthermore, emerging pathogens such as Borrelia miyamotoi may further confound diagnostic efforts.
A number of more obscure infections that are associated with FUO and usually have a pulmonary component include Q fever, leptospirosis, psittacosis, tularemia, and melioidosis. Other less common infections that cause FUO but do not have pulmonary manifestations include secondary syphilis, disseminated gonococcemia, chronic meningococcemia, visceral leishmaniasis, Whipple's disease, and yersiniosis. (See appropriate topic reviews.)
Connective tissue diseases — Adult-onset Still’s disease in young and middle-aged adults and giant cell arteritis (GCA) in older individuals are the most common rheumatologic disorders presenting as FUO. GCA accounts for approximately 15 percent of cases of FUO in older adults [16].
Adult-onset Still’s disease — Adult-onset Still’s disease is an inflammatory disorder characterized by quotidian (daily) fevers, arthritis, and an evanescent rash. Patients with adult-onset Still’s disease have features similar to children with systemic juvenile idiopathic arthritis. (See "Clinical manifestations and diagnosis of adult-onset Still's disease" and "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis".)
Giant cell arteritis — The diagnosis of GCA should be considered in a patient over the age of 50 who complains of headache, abrupt loss of vision, symptoms of polymyalgia rheumatica (which can occur without signs of vasculitis), unexplained fever or anemia, and a high erythrocyte sedimentation rate. The manifestations of GCA, however, can vary and may be transient. Jaw claudication, if present, is helpful in suspecting the diagnosis of GCA. Temporal artery biopsy is suggested in all cases of suspected GCA. (See "Clinical manifestations of giant cell arteritis".)
Other — Other rheumatic disorders also may present as an FUO, including polyarteritis nodosa [22], Takayasu's arteritis (which is common in Japan), granulomatosis with polyangiitis, and mixed cryoglobulinemia. (See appropriate topic reviews.)
Malignancy — The most common malignancies to present with FUO are as follows:
●Lymphoma, especially non-Hodgkin's
●Leukemia
●Renal cell carcinoma
●Hepatocellular carcinoma or other tumors metastatic to the liver
The most frequent occult malignancies to cause fever are of reticuloendothelial origin (eg, lymphoma and leukemia). Fever is most often evident in advanced lymphomas or in those with aggressive histologic patterns. Computed tomography or magnetic resonance imaging of the chest, abdomen, and pelvis and bone marrow biopsy usually identifies the sites of involvement.
Myelodysplastic syndromes occasionally present with fever and subtle evidence on blood smear of maturation arrest or dysplastic changes in one or several of the blood cell lines. Aleukemic leukemias are usually of the myeloid line. The diagnosis is made by bone marrow biopsy. Multiple myeloma has also been reported as a cause of FUO [23].
Renal cell carcinoma presents with fever in approximately 20 percent of cases. Microscopic hematuria and erythrocytosis may occur, but frequently there are no urine sediment abnormalities and the hematocrit is normal. Other adenocarcinomas also can cause fever, often but not invariably in the presence of hepatic metastases.
Atrial myxomas are uncommon but present with fever in approximately one-third of cases. Other findings include arthralgias, emboli, and hypergammaglobulinemia. The diagnosis is usually established by echocardiography. (See "Cardiac tumors".)
Drugs — Drugs can cause fever by stimulating an allergic or idiosyncratic reaction or by affecting thermoregulation. Eosinophilia and rash accompany drug fever in only 25 percent of cases; thus, the absence of these findings should not preclude a search for a possible offending drug [24]. Drug fever is discussed in detail elsewhere. (See "Drug fever".)
LESS COMMON CAUSES — Many other causes of FUO are listed in the table (table 2).
Factitious fever — Factitious fever is usually a manifestation of an underlying psychiatric condition that predominantly affects women and healthcare professionals. Patients with factitious fever feign illness for some secondary gain. They may also display evidence of self-mutilation and may have had multiple hospitalizations, invasive diagnostic tests (eg, cardiac catheterization), and surgery. The response to psychiatric intervention has been discouraging. (See "Factitious disorder imposed on self (Munchausen syndrome)".)
Fever elevations may be fabricated through manipulation of thermometers. Manipulated temperature elevations can be extreme, sometimes exceeding 41ºC, and the fever cycles may not be accompanied by the expected patient behavior and physical signs such as chills, covering with blankets, cool extremities, sweats, warm extremities, and tachycardia. Current widespread use of electronic thermometers diminishes the opportunity to manipulate or exchange thermometers.
Fever also can be induced by taking medications to which patients are allergic (eg, phenolphthalein) or by injecting foreign matter parenterally (eg, milk, urine, culture material, feces). The resulting illness may be associated with polymicrobial bacteremia, episodes of bacteremia caused by different pathogens, or recurrent soft tissue infections.
Disordered heat homeostasis — Disordered heat homeostasis occasionally follows hypothalamic dysfunction (eg, following a massive stroke or anoxic brain injury) or abnormal heat dissipation (from skin conditions such as ichthyosis). Excess heat production may also occur from illnesses such as hyperthyroidism.
Alcoholic hepatitis — The characteristic signs and symptoms of alcoholic hepatitis are fever, hepatomegaly, jaundice, and anorexia. Fever is typically modest (<38.3°C). There are several characteristic laboratory abnormalities in alcoholic hepatitis. The most typical is serum aminotransferase elevations to less than 500 international units/L with a disproportionate elevation of aspartate aminotransferase (serum glutamic oxaloacetic transaminase) compared with alanine aminotransferase (serum glutamic pyruvic transaminase); the ratio is usually greater than 2.0, a value that is rarely seen in other forms of liver disease [25]. (See "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and cirrhosis".)
Other — A number of other noninfectious disorders may present as an FUO:
●Venous thrombosis and thromboembolism, although more common presentations include dyspnea, pleuritic pain, cough, and hemoptysis. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)
●Hematoma (eg, from trauma, rupture of an aortic aneurysm, or spontaneously in an anticoagulated patient) with subsequent inflammation. The hip, pelvis, and retroperitoneum can hide a substantial amount of blood.
●Hyperthyroidism and subacute thyroiditis occasionally cause FUO, although these conditions most frequently are diagnosed clinically.
●Other endocrine causes of fever include pheochromocytoma and adrenal insufficiency [26].
●Hereditary periodic fever syndromes, such as familial Mediterranean fever, tumor necrosis factor receptor-1–associated periodic syndrome (also called TRAPS), hyper-IgD syndrome, Muckle-Wells syndrome, and familial cold autoinflammatory syndrome [27]. (See "Clinical manifestations and diagnosis of familial Mediterranean fever" and "New-onset urticaria".)
SUMMARY
●Etiology by category – Three general categories of illness account for the majority of "classic" fever of unknown origin (FUO) cases and have been consistent through the decades (table 1A-B). These categories are infections, connective tissue diseases, and malignancy. (See 'Common causes' above.)
•Infections – Among infections, tuberculosis and abscesses are among the most common etiologies presenting as FUO. (See 'Infections' above.)
•Connective tissue diseases – Systemic juvenile idiopathic arthritis (formerly called Still's disease) in younger patients and giant cell arteritis in older individuals are the most common rheumatologic disorders presenting as FUO. (See 'Connective tissue diseases' above.)
•Malignancies – The most common malignancies to present with FUO are lymphoma, especially non-Hodgkin's, leukemia, renal cell carcinoma, and hepatocellular carcinoma or other tumors metastatic to the liver. (See 'Malignancy' above.)
●Drug fever – Drug fever due to a variety of drugs is also a common cause of FUO. (See 'Drugs' above and "Drug fever".)
●Other etiologies – There are many other causes of FUO, including factitious fever and other systemic conditions (table 2). (See 'Less common causes' above.)
