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Fever of Unknown Origin (FUO)

Practice Essentials


Key features of fever of unknown origin (FUO), also known as pyrexia of unknown origin (PUO), are as follows:

  • Unexplained fevers are worrisome to patients and clinicians, but most persistent fevers are diagnosed, and often within one week of hospital evaluation or 3 outpatient visits.

  • Most fevers that persist beyond this period are caused by common conditions presenting uncommonly.

  • The upper limit of normal temperature in healthy outpatients and nonsurgical inpatients is 99.9º Fahrenheit (F) or 39º Celsius (C).

  • Hundreds of conditions may cause FUO. Although infections remain a significant cause, most FUOs in the developed world are caused by noninfectious inflammatory disorders, with malignancy a much smaller percentage. Infection is likely to evolve with increased global travel and the use of immunomodulating drugs.

  • The differential diagnoses of FUO depend on and continue to evolve based on regional factors, exposures, and available diagnostic tools.

  • A significant percentage of FUO cases are caused by miscellaneous conditions, and there is no standard algorithm for evaluating FUO. The approach to diagnostic study is best guided by ongoing assessment for historical, physical, and basic laboratory clues. Following clues, beginning with the least invasive evaluation, avoids unnecessary harm and cost to the patient.

  • Physical examination in FUO should pay special attention to skin, eyes, lymph nodes, liver, and spleen.

  • It is reassuring that most cases of FUO that remain undiagnosed despite intensive evaluations have good long-term prognoses and resolve within a year.

  • Historically, about 25-30% of cases remained undiagnosed despite extensive workup. A prospective multicenter study of cases from 2003 to 2005 in the Netherlands reported 51% of cases without a final diagnosis. [1] A systematic review of 18 papers published from 2005 to 2015 from regions across the globe found a lack of diagnostic outcome in 23%. [2] In light of considerable advances in diagnostics, this number seems surprisingly high and consistent.


Background

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. [3, 4] It is important to allow for flexibility in this definition, however. "Normal" core temperature in studies in developed nations has declined since the Industrial Revolution and may be inferred to peak at 99.9º F (37.7º C). [5, 6] The emergence of the human immunodeficiency virus (HIV) and the expanding use of immunomodulating therapies prompted Durack and Street to propose differentiating FUO into 4 categories: classical FUO (Petersdorf definition), hospital-acquired FUO, immunocompromised or neutropenic FUO, and HIV-related FUO. [7] 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. [7, 8, 9] 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.

Etiology

A baseline definition of "fever" is important in determining whether a patient's report of an elevated temperature warrants an FUO workup. The common assumption that "fever" is a temperature over 100.4 F (38 C) is obsolete. Large reviews of nonsurgical patients indicate that average temperature in uninfected individuals has been on the decline since the 1800s and ranges from 95.8 to an upper limit of 99.9 degrees Fahrenheit in both outpatients and inpatients. This may reflect multiple conditions, such as better sanitation and hygiene leading to reduced chronic diseases such as tuberculosis and gingivitis and increases in indoor and air-conditioned activities. Older individuals tend toward cooler temperatures. Most temperatures are measured orally for both practical and physiologic purposes. A "normal" core (internal) body temperature ranges from 96º F (35.6º C) to 99.9ºF (38ºC) in healthy persons. Core temperature in the afternoon is about 1ºF higher later in the day and may be a bit higher in women. [5, 6] 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. It is important to recognize that the use of infrared non-contact thermometers in adults may be fraught with error due to variations in user technique, known variations in detection range of these instruments, and environmental temperatures. The tympanic membrane correlates with core body temperature and is nearest to the hypothalamic center that regulates temperature, but accuracy is affected by user technique and whether the ear canal is obstructed (eg, by wax); cold weather also cools the tympanic membrane. [10] Both temporal artery and forehead thermometers are likely to underestimate core body temperature and should be verified with sublingual or other method if fever is suspected. In the author's 12-month institutional experience with entrance screening during the COVID-19 pandemic, infrared forehead thermometry results were highly variable and of low yield in detected infected individuals. [11, 12, 13] 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, infections lead the differential diagnoses, followed by collagen vascular diseases; malignancy is typically not heralded by fever alone in children. [14] 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. Realistically, it is difficult to define a set time frame or defined list of examinations to be performed before declaring "FUO". The duration of unsuccessful diagnosis varies widely because the diagnostic approach to fever is highly dependent upon the tools accessible in a given healthcare setting, including socioeconomic, and other disparities in healthcare. Similarly, local geography and epidemiology factor into diagnostics. How aggressive and prolonged the evaluation must be before declaring failure is also subjective and dependent on the setting. Reflecting this, Fusco et al found only 6 series out of 18 publications from across the globe predefined a minimum diagnostic workup. "In general, complete blood count, routine haematochemical tests, inflammatory indexes, including C-reactive protein and/or Erythrocyte Sedimentation Rate, urine analysis, blood and urine cultures, chest x-ray and abdominal and pelvic ultrasonography, were included." [2] Thus, declaring a case an FUO realistically depends on the standard-of-care approach to fever in a given geographic area or population. Causes of FUO may differ geographically based on regional exposures, economic development, and available diagnostic tools. For example, in developing countries, the baseline incidence of infection may be higher, whereas noninfectious inflammatory and malignant conditions are more common in developed countries. This article addresses FUO as approached from the lens of practitioners in developed countries; however, causes that may present from developing countries should not be missed and may be increasing with travel. Fusco et al observed the correlation of infections causing FUO in lower-medium income countries, versus neoplasias and non-infectious inflammatory diseases in higher-income nations in a systematic review of 18 case series. The majority of papers originated from countries considered high (6 countries) and upper-medium (8 countries) income. Four papers originated from Europe, 8 from Asia, and 6 from the Middle East. The final etiologies across the board were infections (nearly 40%), inflammatory diseases (20%), neoplasia (11%), and other (6.5%). [2] 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. 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, infections may yet regain their 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. [15] 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. Noninfectious Inflammatory Causes of FUO (Connective Tissue Diseases, Vasculitides, and Granulomatous Disorders) The most common noninfectious inflammatory causes of FUO include the following:

  • Giant cell (temporal) arteritis

  • Adult Still disease (juvenile rheumatoid arthritis)

Less-common noninfectious inflammatory causes of FUO include the following:

  • Systemic lupus erythematosus (SLE)

  • Periarteritis nodosa/microscopic polyangiitis (PAN/MPA)

  • Rheumatoid arthritis (RA)

The least common noninfectious inflammatory causes of FUO include the following:

  • Antiphospholipid syndrome (APS)

  • Gout

  • Pseudogout

  • Behçet disease

  • Sarcoidosis

  • Felty syndrome

  • Takayasu arteritis

  • Kikuchi disease

  • Periodic fever adenitis pharyngitis aphthous ulcer (PFAPA) syndrome

Infectious Causes of FUO The most common infectious causes of FUO include the following:

  • Tuberculosis (TB)

  • Q fever (parturient animals)

  • Brucellosis (hooved mammals, raw dairy)

Less common infectious causes of FUO include the following:

  • HIV infection

  • Abdominopelvic abscesses

  • Cat scratch disease (CSD)

  • Epstein-Barr virus (EBV) infection

  • Cytomegalovirus (CMV) infection

  • Enteric (typhoid) fever

  • Toxoplasmosis

  • Extrapulmonary TB

The least common infectious causes of FUO are listed below. Organ-based infectious causes of FUO are as follows:

  • Subacute bacterial endocarditis (SBE)

  • Tooth abscess

  • Chronic sinusitis/mastoiditis

  • Chronic prostatitis

  • Discitis

  • Vascular graft infections

  • Whipple disease

  • Multicentric Castleman disease (MCD)

  • Cholecystitis

  • Lymphogranuloma venereum (LGV)

Geographic and travel-related considerations for FUO are listed below. Tickborne infections, as follows:

  • Babesiosis, Ehrlichiosis (southeast and central United States)

  • Anaplasmosis (northeast and north-central United States)

  • Tickborne relapsing fever (rodent-infested cabins)

Regional infections, as follows:

  • Histoplasmosis (Midwest United States, Ohio and Mississippi River Valleys, Central and South America, bat/bird droppings)

  • Coccidiomycosis (southwest United States)

  • Leptospirosis (tropics, freshwater swimming, triathlons, "mud run" races)

  • Visceral leishmaniasis (Latin America, Middle East)

  • Rat-bite fever (rat bite, food, or water)

  • Louse-borne relapsing fever (East African migrants, refugee camps)

Malignant and Neoplastic Causes of FUO Malignant and neoplastic causes of FUO are as follows:

  • Most common: Lymphoma, renal cell carcinoma

  • Less common: Myeloproliferative disorder, acute myelogenous leukemia

  • Least common: Multiple myeloma, breast/liver/pancreatic/colon cancer, atrial myxoma, metastases to brain/liver, malignant histiocytosis

Miscellaneous Causes of FUO Miscellaneous Causes of FUO are as follows:

  • Most common: Cirrhosis (due to portal endotoxins), drug fever

  • Less common: Thyroiditis, Crohn disease (regional enteritis)

  • Least common: Pulmonary emboli, hypothalamic syndrome, familial periodic fever syndromes, cyclic neutropenia, factitious fever (especially in those experienced with the healthcare field)

Prognosis

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.


Clinical Presentation

History 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


Physical Examination 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

Differential Diagnoses

Diagnostic Considerations

Approximately 5%-15% of patients with fever of unknown origin (FUO) remain undiagnosed, even after extensive evaluations.


Hepatobiliary infections


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


The most common reason for misdiagnosis of osteomyelitis is the failure to consider the disease in a patient who is febrile with musculoskeletal symptoms.


Parasitic infections


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.


Drug fever


A history of allergy, skin rashes, or peripheral eosinophilia is often absent in cases of drug fever.


Tuberculosis


Tuberculosis (TB) is usually considered in the differential diagnoses; however, several factors may prevent a prompt diagnosis of TB. Miliary TB may initially manifest as constitutional symptoms that lack localizing signs.


Collagen-vascular and autoimmune diseases


Consider PAN, RA, and mixed connective-tissue diseases in patients with FUO, because of the potential for nonspecific presentations in these diseases. Rheumatic fever can be difficult to diagnose, because it is rare in the developed world.


Conditions to consider in the diagnosis of FUO

More than 200 conditions may cause FUO and include the following, as well as the disorders in the Differentials subsection, below:


Differential Diagnoses

Workup

Approach Considerations 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. [1, 16, 17, 18]

Laboratory Studies While a workup of FUO should emphasize clinical clues, the following, if not already performed, are essential laboratory and imaging tests that are of value in eliciting further diagnostic direction:

  • Complete blood cell (CBC) count with white blood cell (WBC) differential

  • Peripheral blood smear

  • Complete metabolic panel (CMP; provides data on electrolytes, glucose, acid-base, renal, liver, protein status)

  • C-reactive protein (CRP)

  • Erythrocyte sedimentation rate (ESR)

  • Urinalysis (used to detect glomerulonephritis, occult hematuria; pyuria is insensitive for detecting urinary tract infection in absence of suggestive symptoms, as asymptomatic bacteriuria is common) [19]

  • Blood cultures, preferably 3 blood draws from separate sites, performed at different times

  • HIV serology

  • Hepatitis A and B serology, and if epidemiologically applicable, Hepatitis E serology

  • Tuberculosis screening tests – Purified protein derivative (PPD, or Mantoux test); interferon gamma release assays (IGRA)

  • Posteroanterior and lateral chest radiography

Beyond the above essentials in early screening, some would add antinuclear antibody titers, rheumatoid factor, and thyroid stimulating hormone (TSH) and thyroxine level in diagnosing certain conditions (lupus, RA, thyroiditis, hyperthyroidism). Their diagnostic accuracy is limited in other autoimmune and collagen vascular diseases. Further examinations should be guided by historical and physical diagnostic clues, as well as clues from the initial results of the above. HIV serology 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. C-Reactive Protein Elevated CRP suggests an infectious or inflammatory process, but does not eliminate malignancy. Erythrocyte sedimentation rate 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. Complete blood count Eosinophilia may suggest polyarteritis nodosa, drug fever, or visceral leishmaniasis. Acute drop in hemoglobin or hematocrit may suggest occult hemorrhage or hematoma (often retroperitoneal). Complete metabolic profile 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. Urinalysis 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. [19] 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. [20] Blood cultures 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. Tuberculosis screening 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. Laboratory clues to specific causes of FUO 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. With Relapsing Fever/spirochetal diseases, it is best to obtain blood sample during febrile period for highest probablity of spirochetemia and direct observation. 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). Tissue analysis and cultures Assays, serology, and cultures 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.

Imaging Studies Chest radiography 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 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 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 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. FDG-PET/CT whole-body scanning 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. [9, 21, 22, 23] Radionucleotide studies 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. Bone scanning 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. [22, 24]

Other Tests Naproxen test 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.

Procedures FUO evaluations are best performed from least invasive to more invasive testing. Endoscopy 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. Biopsies and tissue sampling 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. [25] 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. [25] 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 entails an exploratory surgical procedure (eg, laparotomy). [26] 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 warranted, however, for the diagnosis of polyarteritis nodosa and giant cell arteritis, as these conditions may be disabling or life-threatening if left untreated; these are among the few conditions associated with an erythrocyte sedimentation rate of 100 mm/hour or greater. 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.


Treatment & Management

Approach Considerations 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:

  • Cases that meet criteria for culture-negative endocarditis

  • Cases in which findings or the clinical setting suggests cryptic disseminated TB (or, occasionally, other granulomatous infections)

  • Cases in which temporal arteritis with vision loss is suspected

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. Specific examples of 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.

Inpatient Treatment No evidence supports prolonged hospitalization of patients who are clinically stable and whose workup findings are unrevealing.

Outpatient Care Conduct close follow-up procedures and systematic reevaluation studies to prevent clinical worsening. Guide further workup studies on an outpatient basis.

Patient Transfer 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.

Consultations Appropriate consultations are indicated based on patient history, physical examination, laboratory data, and radiologic findings. Consultations include the following:

  • Infectious disease specialist

  • Hematologist/oncologist

  • Rheumatologist

  • Pulmonologist

  • Gastroenterologist

  • Endocrinologist

  • Interventional radiologist

  • Surgeon


Long-Term Monitoring 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.


References


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