drug-induced fever, fever of unknown origin, workup for fever of unknown origin



  1. Holder, (Bonnie) M.A. PhD, APRN, BC
  2. Ledbetter, Carol PhD, APRN, BC, FAAN


Abstract: This article reviews the classification and etiology of fever of unknown origin (FUO) in the adult population. A systematic diagnostic approach is discussed, equipping the NP to follow a careful history and physical, as well as focused diagnostic tests and procedures to determine the underlying cause of FUO.


Article Content

Fever of unknown origin (FUO) describes an extended period of perplexing fevers that are difficult to diagnose, even for the most ardent provider. The FUO workup is directed by a careful history, physical exam, and focused diagnostic tests and procedures; to proceed otherwise would be ineffective, costly, time-consuming, and should be avoided.

Figure. No caption a... - Click to enlarge in new windowFigure. No caption available.

FUO is suspected when a patient presents with the following established criteria:


1. Illness lasting for at least 3 weeks


2. Illness accompanied by fever (temperature over 101[degrees] F [38.3[degrees] C] on several occasions)


3. No established diagnosis after 1 week of hospital investigation.1



The 3-week time frame eliminates viral illnesses that are generally difficult to diagnosis but which resolve within that time period. Due to the rising cost of hospitalization, as well as the availability of thorough diagnostic testing in the ambulatory setting, the third criterion has been modified. This updated and generally accepted criterion alters the duration of the evaluation to at least three outpatient visits, or 3 days of hospitalization.2-4


FUOs are typically uncommon presentations of common disorders, rather than rare diseases. A proper workup of FUO depends on the NP's attention to detail while obtaining a careful history. Determining the cause of FUO often involves pattern recognition. A thorough systematic approach often reveals a diagnosis that was obscured in the initial assessment.



FUO defies simplification. Reported causes exceed 200. Historically, FUO has been divided into four major categories: classic (including infectious, rheumatic-inflammatory, neoplastic, or miscellaneous disorders), nosocomial (healthcare acquired), immune deficient, and HIV-associated. Each group has a unique differential diagnosis based on characteristic and vulnerabilities (see Classification of FUO).5-8


The differential diagnosis of FUO is also generally broken into four major categories: infections, neoplastic, autoimmune, and miscellaneous causes (see Common etiologic categories of FUO).

Table. Classificatio... - Click to enlarge in new windowTable. Classification of FUO

"FUOs in adults are commonly caused by infections (30% to 40%), neoplasms (20% to 30%), collagen vascular diseases (10% to 20%), and numerous miscellaneous diseases (15% to 20%). Additionally, between 5% and 15% of FUO cases defy diagnosis, despite exhaustive studies."9


Patient history

Because FUOs are caused by a wide variety of disorders, the diagnostic approach is extensive and must be focused on the most likely cause for each individual patient. The hallmark of the FUO workup is a comprehensive history, physical exam, and appropriate lab testing. The initial workup should include daily monitoring of temperature (at 6 a.m. and 6 p.m. to rule out exaggerated circadian rhythm). With few exceptions, the exact pattern of fever is typically not useful. The most notable exceptions are cyclic neutropenia, malaria, and Hodgkin disease.6,10


Family history, ethnicity, medications, habits, travel history, social environment, sexual history, and psychiatric symptoms can yield valuable information. A careful review of past illnesses and any medical-surgical procedures including prosthetic devices and graft materials is essential.


When taking a history, the NP should focus on recent travel (of both the patient and recent contacts), exposure to pets and other animals, the work environment, alcohol intake, and recent contact with persons exhibiting similar symptoms. Family history must also be carefully scrutinized for hereditary causes of fever (Familial Mediterranean Fever).


If the patient has a history of conditions such as lymphoma, rheumatic fever, or previous abdominal disorder (such as inflammatory bowel disease), then the reoccurrence of such might have caused the fever. Histories of weight loss should be determined and animal or insect bites/scratches, particularly tick bites, is important. The NP should take care to note a history of exposure to infectious contacts (TB), visitors from abroad (typhoid), and sexual contacts. It is also important to document any blood transfusions or exposure to needles (accidental or otherwise) (see Historical clues to differential diagnosis of FUO).


When taking the history, the NP should question the patient as well as the family about current prescription and over-the-counter medications including supplements and herbals, and use of recreational drugs. This comprehensive history should be repeated at each visit; as often, potential diagnostic clues were overlooked or not remembered (particularly in children and the elderly). Clues may be subtle and not easily recognized.5,11-13


Drug-induced fever

Drug-induced fever (DIF) must be considered in patients who are taking medications. Drug fever is characterized by a temporary febrile illness that remits once the offending medication is discontinued. A vast number of agents can cause drug fever. However, the ones most frequently found in adult primary care fall into the following categories: antimicrobial; anticonvulsants; cardiovascular; antihistamines; histamine2 blockers; and herbal preparations (see Common drugs causing FUO).11,12


There is limited evidence regarding which group or population is at the highest risk for DIF. Individuals may be predisposed to DIF in the same manner that the sensitivity to one drug is associated with sensitivity to other drugs.11,12


Factitious fever

Studies have indicated that factitious fever is responsible for as many as 10% of FUO cases and is most commonly seen in young adults with healthcare experience or knowledge. Evidence of psychiatric problems or a history of multiple hospitalizations at different institutions is also 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 their thermometers, the most common cause of factitious fever.4,7,12


Alternatively, fever may be caused by injection of nonsterile material (such as feces or milk), resulting in atypically localized abscesses or polymicrobial infections. Therefore, NPs must consider factitious fever as a possibility in every patient with prolonged fever, especially in patients with one or more of the features described.9,14


Physical exam

A systematic exam should be conducted including the skin and nails, head, and neck; as well as the cardiovascular, respiratory, abdominal, musculoskeletal, and neurologic systems. The entire surface of the skin, including finger and toe nails, should be examined for signs of jaundice, rashes, and other skin lesions, which are often quite subtle. Care should be taken to remove all dressing, bandages that may conceal an infected wound. A thorough and comprehensive physical exam can and should serve as a guide to diagnostic testing, and can also prevent a "shotgun" approach for the FUO workup.


Diagnostic testing guided by clues presented in the physical findings include thyroid studies (slight thyroid enlargement), cardiac murmurs (atrial myxoma, or subacute bacterial endocarditis), widespread hyperpigmentation (Whipple disease), and thickened temporal artery (temporal arteritis).8,15-17 A repeated exam is often necessary because many illnesses have subacute presentations that may evolve over time.


Basic lab testing

Specific tests are commonly ordered for the evaluation of FUO. These include a complete blood cell count (CBC) with differential, basic chemistry profile, liver function test (LFT), measurement of lactate dehydrogenase level, erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA) rheumatoid factor (RF), C-reactive protein (CRP) level, tuberculosis skin test (PPD skin test), two to three sets of blood cultures, urinalysis, urine culture, and chest X-ray.7,8,12,13


Testing should be individualized and guided by clues from the history, presenting symptoms, exposures, any initial lab findings, and often repeated physical exams. All patients with FUO have fevers, so any diagnostic approach should be focused and relevant to the clinical presentation of the individual patient to determine the general category of FUO of the patient.


With infectious FUO, the clinician can expect a history of chills and night sweats and/or weight loss without loss of appetite. Patients with neoplastic FUOs often present with symptoms of fatigue and weight loss with dramatic loss of appetite. Night sweats are not uncommon. The clinical presentation of patient with FUOs caused by autoimmune disorders is commonly one of arthralgias, myalgias, or migratory chest or abdominal pain. Patients who do not have symptoms suggesting infectious, neoplastic, or autoimmune causes should be considered to have an FUO of a miscellaneous cause to guide further diagnostic studies.12,15-17

Table. Historical cl... - Click to enlarge in new windowTable. Historical clues to differential diagnosis of FUO

If the cause of the FUO has not been determined after the initial workup, then the NP should initiate a more focused diagnostic evaluation based on a more detailed, FUO-relevant history. The history and physical should be repeated, concentrating on areas that have high diagnostic significance of physical findings relevant to both infectious and noninfectious FUO disorders.8,10-13


Directed further studies and referrals based on further findings and information may include:

Table. Common drugs ... - Click to enlarge in new windowTable. Common drugs causing FUO

* FUO with headache should prompt exam of spinal fluid for pathogens, including Cryptococcus neoformans


* FUO with joint swelling indicates the need for sampling of the joint fluid for diagnostic studies


* FUO with elevated values in liver studies should prompt testing for viral hepatitis


* Risk of exposure for Q fever should prompt serologic testing for this infection


* In the absence of diagnostic clues consider computed tomography (CT) of chest, abdomen and pelvis (with contrast), or colonoscopy


* Echocardiography is useful in patients who meet Duke Criteria for endocarditis


* Temporal artery biopsy for older patients


* Lymph node biopsy.4,7,13



Exams utilizing nuclear medicine are often considered but have relatively low sensitivity in most studies of FUO. Liver biopsy has shown to have a reasonable yield in some studies but carries a high risk of complications.10,15


Nonspecific lab abnormalities and clinical symptoms, when evaluated together, may limit or eliminate various diagnoses from further diagnostic consideration and should be interpreted in the context of the FUO.


The NP should take an algorithmic approach to the FUO workup (see Diagnosis of FUO).


Empiric therapy

Many experts agree that empiric treatments, particularly in the early stages of evaluation, are not recommended.7,18 Continued observation and evaluation while searching for the underlying cause is thought to be the best strategy. Additionally, it is important to withhold therapy until the cause of the fever has been determined, so it can be tailored to a specific diagnosis. Most studies recommend empiric therapy for FUO in only four situations:


1. Antibiotics for culture-negative endocarditis


2. Low-dose corticosteroids for presumed temporal arteritis


3. Antituberculosis drugs for suspected miliary tuberculosis


4. Naproxen for suspected neoplastic fever.12,18,19



It is commonly accepted that diagnosis-defying cases of FUO carry favorable prognoses. Often, empiric therapy may only partially treat a process, making it difficult or impossible to determine subsequent optimal therapy by obscuring an actual diagnosis.


In the older patient with an FUO it is important to consider the patient's quality of life, overall health, and wishes. Neither the workup nor the treatment should compromise any of these elements, or be any worse than the disease itself.

Figure. Diagnosis of... - Click to enlarge in new windowFigure. Diagnosis of FUO


The ICD 9 code 780.60 Fever, unspecified, is used for FUO; chills with fever; never NOA (needs and outcome assessment); hyperpyrexia NOS (not otherwise specified); pyrexia NOA; or, pyrexia of unknown origin. When the underlying condition is determined, the ICD 9 code 780.61 is used, and for Fever presenting with conditions classified elsewhere; the underlying condition is coded first when associated fever is present such as neutropenia.19



FUO remains a great clinical challenge due to the fact that the differential diagnosis includes multiple disorders. These disorders can be either relatively common or rare. During the last two decades, the distribution of causes has changed toward infections, tumors, and autoimmune/inflammatory causes. Despite the sizable number of readily available diagnostic aids, the proportion of undiagnosed cases remains substantial. The care plan for a patient presenting with FUO must encompass a vigilant and systematic approach based on a comprehensive, and often repeated, history and physical exam.


The NP is well equipped to carry out this systematic-diagnostic approach, and can often determine the underlying cause of FUO. It is always important, however, to recognize when to initiate a referral(s) for specialized investigation and invasive diagnostic procedures.




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