Tender subcutaneous nodules on the anterior shin and foot in an individual with polyarteritis nodosa
Key features of fever of unknown origin (FUO), also known as pyrexia of unknown origin (PUO), are as follows:
The syndrome of 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, 2] However, it is important to allow for flexibility in this definition. The emergence of human immunodeficiency virus (HIV) and the expanding use of immunomodulating therapies prompted Durack and Street to propose differentiating FUO into four categories: classical FUO (Petersdorf definition), hospital-acquired FUO, immunocompromised or neutropenic FUO, and HIV-related FUO.[3]
Emerging techniques such as molecular diagnostics, expanding use of immunocompromising therapies and organ transplantation, and the advent of globally mobile populations demand an evolving approach to defining and evaluating FUO.[4, 3, 5] Modern imaging techniques (eg, ultrasonography, computed tomography [CT] scanning, magnetic resonance imaging [MRI], positron emission tomography [PET]) enable early detection of abscesses and solid tumors that were once difficult to diagnose.
A baseline definition of "fever" is important in determining whether a patient's report of an elevated temperature warrants an FUO workup. Most temperatures are measured orally for both practical and physiologic purposes. A "normal" core (internal) body temperature ranges from 96º Fahrenheit (F) (35.6º Celsius [C]) to 100.8ºF (38.2ºC) in healthy persons, with a mean of 98.2ºF (36.8ºC). Core temperature in the afternoon is about 1ºF higher later in the day and may be a bit higher in women.
The temperature of the sublingual fossa correlates most closely, and changes most consistently, with core body temperature, which is fairly constant; the rectum and axilla do not, especially during sepsis. The tympanic membrane also correlates with core body temperature and is nearest to the hypothalamic center that regulates temperature, but accuracy depends on user technique and whether the ear canal is obstructed (eg, by wax); cold weather also cools the tympanic membrane.[6]
For the purposes of this article, the term FUO refers to the classic category, which focuses on the adult population. The definition of FUO in the pediatric age group varies, with a time frame ranging from 1-3 weeks in the literature. In this age group, the differential diagnoses are led by infections, followed by collagen vascular diseases; malignancy is typically not heralded by fever alone in children.[7] This article excludes FUO in the setting of impaired immunity such as HIV disease, solid-organ and bone marrow transplantation, and neutropenia. Disease-specific diagnostic algorithms in these conditions are described elsewhere. Regardless of age group, most clinicians define FUO as a persisting conundrum with few or no objective clues.
Causes of FUO may differ geographically based on regional exposures, economic development, and available diagnostic tools. For example, in developing countries, infection may predominate, while noninfectious inflammatory and malignant conditions are more common in developed countries. The focus of this article is FUO in developed countries; however, travel-associated causes that may present from developing countries should not be missed.
The list of etiologic possibilities is extensive, and it is helpful to break the differential diagnoses into broader categories, such as infection, noninfectious inflammatory conditions, malignancies, and miscellaneous. In recent years, noninfectious inflammatory disorders predominate, with infection now second.
A prospective review of FUO in 290 subjects between 1990 and 1999 found noninfectious inflammatory diseases in 35.2% of cases, infections in 29.7%, miscellaneous causes in 19.8%, and malignancies in 15.1%. Most were diagnosed within 3 visits or 3 hospital days. This differs from prior estimates, in which infections dominated, followed by malignancies, collagen vascular diseases, and numerous miscellaneous conditions. With the increasing use of immunomodulators used to treat an expanding range of conditions, infection may yet regain its lead as the cause of FUO. Interestingly, the rate of unknown causes is higher in this report than in prior estimates, with 33.8% remaining undiagnosed beyond 7 days. The short time frame may overestimate the number of undiagnosed cases. Evaluations in the past may not have proceeded as quickly, and, even now, newer tests may require transport to specialty laboratories, and diagnosis may still take longer than 7 days.[8]
The causes of FUO are often common conditions presenting atypically. Listed below are the most common, less common, and least common in their respective categories, but by no means the only causes.
The most common noninfectious inflammatory causes of FUO include the following:
Less-common noninfectious inflammatory causes of FUO include the following:
The least common noninfectious inflammatory causes of FUO include the following:
The most common infectious causes of FUO include the following:
Less-common infectious causes of FUO include the following:
The least common infectious causes of FUO are listed below.
Organ-based infectious causes of FUO are as follows:
Geographic and travel-related considerations for FUO are listed below.
Tickborne infections, as follows:
Regional infections, as follows:
Malignant and neoplastic causes of FUO are as follows:
Miscellaneous Causes of FUO are as follows:
For patient education information, see Fever in Adults and Fever in Children.
Despite extensive differential diagnoses, patients with FUO that remains undiagnosed after an intensive and rational diagnostic evaluation generally have a reassuringly benign long-term course.
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:
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:
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:
Clues and etiologic associations are as follows:
Animal and animal product exposures
A history of exposure to unpasteurized dairy (eg, swine, cattle, goats, camels, sheep) may suggest the following:
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:
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).
Historical clues to malignant causes of FUO are as follows:
Historical clues to miscellaneous causes of FUO are as follows:
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:
Laboratory and imaging findings vary according to the source of an fever of unknown origin (FUO). Imaging should be directed by historical, physical, and basic laboratory clues.[9, 10, 11]
While a workup of FUO should emphasize clinical clues, the following are essential laboratory and imaging tests that are of value in eliciting further diagnostic direction:
Beyond the above essentials in early screening, some would add antinuclear antibody titers, rheumatoid factor, and thyroxine level in diagnosing certain conditions (lupus, RA, thyroiditis, hyperthyroidism). Their diagnostic accuracy is limited in other autoimmune and collagen vascular diseases.
If any test should be routinely included in the evaluation of FUO, HIV antigen-antibody assay should. Antigen-antibody assay results are positive early in infection, thus eliminating need for HIV viral load screening because of lag in antibody seroconversion.
An ESR of more than 100 seconds in the absence of anemia may indicate giant cell arteritis, multiple myeloma, or osteomyelitis.
A very low ESR with myalgias suggests trichinosis.
Eosinophilia may suggest polyarteritis nodosa, drug fever, or visceral leishmaniasis.
Acute drop in hemoglobin or hematocrit may suggest occult hemorrhage or hematoma (often retroperitoneal).
Alkaline phosphatase elevation suggests lymphoma or granulomatous hepatitis.
Transaminitis may result from multiple causes.
Elevated total protein or calcium (look for monoclonal gammopathy) may suggest multiple myeloma.
Hematuria may indicate renal cell carcinoma, tuberculosis, endocarditis, brucellosis, lymphoma, or periarteritis nodosa.
Asymptomatic pyuria and bacteriuria are common with advancing age and comorbidities, and these findings may offer little diagnostic direction.[12]
Normal urinalysis or urine culture results do not necessarily suggest or eliminate perinephric abscess. Approximately 30% of patients with perinephric abscess have normal urinalysis results, and up to 40% have sterile urine cultures.[13]
Blood cultures for aerobic and anaerobic pathogens are essential in the evaluation; however, no more than 6 sets of blood cultures are required. Sampling 2-3 peripheral blood samples may suffice given modern culture techniques.
PPD or Mantoux screening is inexpensive and sensitive but requires placement by clinical staff and interpretation 48-72 hours later of induration size, a type IV hypersensitivity reaction (indicating prior tuberculosis exposure).
Interferon gamma release assay (IGRA) offers higher sensitivity and, where readily available and quickly processed, faster turnaround.
Anemia is an important finding and suggests a serious underlying disease.
Suspect herpesvirus infection if the patient has lymphocytosis with atypical cells.
Leukocytosis with an increase in bands suggests an occult bacterial infection, as well as occult hemorrhage, hematoma, or thromboembolic process.
Diagnose malaria and spirochetal diseases with the aid of direct examination of the peripheral blood smear; however, repeated examinations by an experienced technologist are often necessary. Preleukemic states may not manifest in the peripheral blood smear, and bone marrow aspirate may not reveal the correct diagnosis; bone marrow biopsy may be necessary for diagnosis.
Adult-onset Still disease is often difficult to diagnose. Laboratory abnormalities include pronounced leukocytosis, an elevated erythrocyte sedimentation rate (ESR), anemia, and abnormal liver function test results.
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.
Laboratory findings in giant cell arteritis (GCA) include an elevated ESR, mild to moderate normochromic normocytic anemia, elevated platelet counts, and abnormal liver function test results (25% of cases). Perform a biopsy of a temporal artery to obtain a definitive diagnosis. Pathologic review shows vasculitis and a mononuclear cell infiltrate.
At least one liver function test result is usually abnormal in an underlying disease that originates in the liver or a disease that causes nonspecific alterations of the liver (eg, granulomatous hepatitis).
Aside from HIV screening, other assays, serology, and cultures should be directed by findings of the history, physical, and laboratory screening, as well clinical reevaluation for more diagnostic clues. The specifics of testing for individual conditions is deferred to other more detailed sources.
Routinely perform chest radiography. Posteroanterior and lateral chest radiography is usually readily available and relatively inexpensive. It may rapidly detect abnormalities missed on physical examination, and may direct further diagnostic imaging with computed tomography (CT) of the thorax.
Thoracic CT angiography is more sensitive than ventilation-perfusion scanning when pulmonary emboli are suspected in spite of negative findings on venous ultrasonography of the extremities. Arteriography demonstrates small and large aneurysms and focal constrictions between dilated segments in polyarteritis nodosa.
Echocardiography is highly sensitive in diagnosing endocarditis, particularly when transesophageal echocardiography is available. Culture-negative endocarditis is reported in 5%-10% of endocarditis cases. Prior antibiotic therapy is the most common reason for negative blood culture results.
CT scanning of the abdomen and pelvis with intravenous and oral contrast is useful in the setting of hepatosplenomegaly looking for adenopathy, intraabdominal or psoas muscle hematoma or abscess, perinephric abscess, cholecystitis, or neoplasia. Plain abdominal films and ultrasonography are relatively insensitive in the diagnosis of FUO. In patients with hepatobiliary infections, cholangitis can occur without local signs and with only mildly elevated or normal findings on liver function tests.
Positron emission tomography (PET) scanning alone was once fraught with excessive false-positive findings; however, PET combined with CT improves diagnostic capabilities, especially as the causes of FUO have evolved in the past decade. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), in which radiolabeled glucose marks foci of increased glucose metabolism, has been used successfully in oncology diagnostics and can also be used to diagnose infectious and noninfectious inflammatory foci. Recent studies recommend using FDG-PET early in the workup of FUO and suggest that including FDG-PET/CT yields a correct diagnosis in 60% to more than 80% of cases. Furthermore, the time to diagnosis may be shortened and invasive procedures reduced, potentially leading to reduced costs and morbidity. Nonetheless, the possibility of false-positive results should be kept in mind.[14, 15, 16, 5]
Radionucleotide studies using gallium citrate are used to detect chronic inflammation and may be more sensitive in detecting occult abscesses, neoplasms, or soft-tissue lymphomas in FUO of more than 2 weeks’ duration. Indium WBC scan, using granulocytes labeled with indium In 111 (111In), can be cumbersome and often insensitive in chronic inflammatory states.
Whereas plain radiographs may not show changes for weeks after the onset of infection, technetium bone scan may be a more sensitive method for documenting skeletal involvement when osteomyelitis is suspected. Magnetic resonance imaging (MRI) is considered the criterion standard for detection of acute osteomyelitis and delineating structural abnormalities; however, it is less sensitive in the setting of chronic osteomyelitis and prosthetic joint infection. While potentially a greater cost upfront, positron emission tomography-computed tomography (PET-CT) full-body scans are increasingly recognized as useful early in efficiently localizing abnormalities and may save other healthcare costs in the FUO workup. PET-CT is especially sensitive in localizing and detecting small foci of inflammation and metabolic activity. It is particularly superior to MRI and other nuclear imaging studies in localizing foci of osteomyelitis of the hip, vertebrae, or prosthetic devices, as well as endovascular graft infection, neoplasia, and vasculitides.[15, 17]
Simple, noninvasive, and inexpensive, a naproxen test may rapidly screen out infection versus neoplastic disease and significantly narrow the differential diagnoses. In this test, naproxen sodium 250 mg is given orally every 8 hours for 3 days. A sharp decline or resolution in fever within 24 hours directs the workup away from infection and suggests a neoplastic disorder.
FUO evaluations are best performed from least invasive to more invasive testing.
Perform an endoscopic examination of the upper and lower gastrointestinal tract, including retrograde cholangiography when indicated or when searching for Crohn disease, Whipple disease, biliary tract disease, and gastrointestinal tumors. Crohn disease is the most common gastrointestinal cause of FUO. Diarrhea and other abdominal symptoms are occasionally absent, particularly in young adults.
Obtain cultures for bacteria, mycobacteria, and fungi in all normally sterile tissues and liquids that are biopsied. This may include cerebrospinal fluid (CSF), pleural or peritoneal fluid, and fluid from the liver, bone marrow, and lymph nodes.
Biopsies are easily performed in enlarged accessible lymph nodes, other peripheral tissues, and bone marrow. Superficial enlarged lymph nodes of highest yield on biopsy include posterior cervical, supraclavicular or infraclavicular, and epitrochlear nodes. Deep nodes of highest yield are the hilar, mediastinal, or retroperitoneal lymph nodes.[18]
Bone marrow biopsy is of highest yield with unexplained abnormality of the CBC count (hematologic malignancy) and granulomatous disease such as sarcoidosis, tuberculosis, or histoplasmosis.[18]
Liver biopsy rarely yields helpful data in patients without abnormal liver function test results or abnormal liver findings (observed on CT scan or ultrasonography). Liver biopsy may be necessary to characterize granulomatous or autoimmune hepatitis.
The decision to biopsy is more difficult if it necessitates an exploratory surgical procedure (eg, laparotomy).[19] This is rarely indicated (eg, when imaging techniques are nondiagnostic and an intra-abdominal source is suspected), particularly considering the generally benign course of FUO that remains undiagnosed after extensive workup.
Arterial biopsy is rarely associated with hematoma, ischemic complications, or nerve damage, given that nerves and vessels often follow a similar course. This may be necessary, however, for polyarteritis nodosa and giant cell arteritis. Biopsy of small- or medium-sized arteries demonstrate white blood cell infiltrate in polyarteritis nodosa. Temporal artery biopsy is necessary for definitive diagnosis of giant cell arteritis, provided a sufficient length of artery is excised.
In general, empiric therapy has little or no role in cases of classic fever of unknown origin (FUO).
Treatment should be directed toward the underlying cause, as needed, once a diagnosis is made.
Some studies suggest a few exceptions to this general approach, including the following:
Several studies have found that prolonged undiagnosed FUO generally carries a favorable prognosis.
Because of a better understanding of the etiologies and careful diagnostic approaches, patients with FUO rarely need surgical treatment.
In patients with hepatic granulomas, approximately 50% of patients recover spontaneously, while the other 50% respond to corticosteroid treatment (duration of therapy ranging from a few weeks to several years).
Patients with giant cell arteritis should be treated with high doses of steroids, and intravenous steroids should be administered if the patient is very ill or has significant ocular compromise. Carefully monitor the patient, since inadequate treatment and steroid toxicities (eg, hypertension, diabetes, dyspepsia, bone loss, psychosis, cataracts) can cause significant morbidity.
In polymyalgia rheumatica, the treatment consists of amelioration of symptoms with steroid therapy and close monitoring for possible development of GCA.
When drug fever is suspected, discontinue the implicated drug. Stopping the causative drug generally leads to defervescence within 2 days.
No evidence supports prolonged hospitalization of patients who are clinically stable and whose workup findings are unrevealing.
Conduct close follow-up procedures and systematic reevaluation studies to prevent clinical worsening. Guide further workup studies on an outpatient basis.
The need for transfer is indicated if (1) the current facility is unable to establish a diagnosis, (2) diagnostic tests are unavailable at the existing facility, or (3) the patient deteriorates clinically such that necessary level of care or consultations is unavailable.
Appropriate consultations are indicated based on patient history, physical examination, laboratory data, and radiologic findings. Consultations include the following:
The 5%-15% of patients whose FUO remains undiagnosed, even after extensive evaluations, usually have a benign long-term course, but close follow-up and systematic reevaluation studies are essential to avoid missing potential etiologies.
The choice of medications administered to patients depends on the etiology of the fever of unknown origin (FUO).
Tender subcutaneous nodules on the anterior shin and foot in an individual with polyarteritis nodosa
Early rash of systemic lupus erythematosis. Rashes occurring the setting of FUO may be biopsied for diagnosis.[ From eMedicine article, Subacute Cutaneous Lupus Erythematosis]
Sweet syndrome may herald a hematologic malignancy
Psoas abscess may cause fevers, but it may be secondary to another condition that may cause FUO, including endocarditis, gastrointestinal or urologic malignancy or infection, vertebral osteomyelitis, or occult intravenous drug use. In this case, an enteric fistula due to underlying Crohn's disease was the culprit.
