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and changes in disease states, such as the emer-gence of human immunodeficiency virus(HIV) infection and an increasing number ofpatients with neutropenia. Others contend thataltering the definition would not benefit theevaluation and care of patients with FUO.4

The four categories of potential etiology ofFUO are centered on patient subtype—clas-sic, nosocomial, immune deficient, and HIV-associated. Each group has a unique differen-tial diagnosis based on characteristics andvulnerabilities and, therefore, a differentprocess of evaluation (Table 1).5

CLASSIC

The classic category includes patients whomeet the original criteria of FUO, with a newemphasis on the ambulatory evaluation ofthese previously healthy patients.6 The revisedcriteria require an evaluation of at least threedays in the hospital, three outpatient visits, orone week of logical and intensive outpatienttesting without clarification of the fever’scause.5 The most common causes of classicFUO are infection, malignancy, and collagenvascular disease.

NOSOCOMIAL

Nosocomial FUO is defined as fever occur-ring on several occasions in a patient who hasbeen hospitalized for at least 24 hours and has

Adult patients frequently pre-sent to the physician’s officewith a fever (temperaturehigher than 38.3°C [100.9°F]).1

Most febrile conditions arereadily diagnosed on the basis of presentingsymptoms and a problem-focused physicalexamination. Occasionally, simple testingsuch as a complete blood count or urine cul-ture is required to make a definitive diagnosis.Viral illnesses (e.g., upper respiratory infec-tions) account for most of these self-limitingcases and usually resolve within two weeks.2

When fever persists, a more extensive diagnos-tic investigation should be conducted.Although some persistent fevers are manifes-tations of serious illnesses, most can be readilydiagnosed and treated.

Definitions and ClassificationsThe definition of fever of unknown origin

(FUO), as based on a case series of 100 pa-tients,3 calls for a temperature higher than38.3°C on several occasions; a fever lastingmore than three weeks; and a failure to reach adiagnosis despite one week of inpatient investi-gation. This strict definition prevents commonand self-limiting medical conditions frombeing included as FUO. Some experts haveargued for a more comprehensive definition ofFUO that takes into account medical advances

Fever of unknown origin (FUO) in adults is defined as a temperature higher than38.3°C (100.9°F) that lasts for more than three weeks with no obvious source despiteappropriate investigation. The four categories of potential etiology of FUO are classic,nosocomial, immune deficient, and human immunodeficiency virus–related. The foursubgroups of the differential diagnosis of FUO are infections, malignancies, autoim-mune conditions, and miscellaneous. A thorough history, physical examination, andstandard laboratory testing remain the basis of the initial evaluation of the patientwith FUO. Newer diagnostic modalities, including updated serology, viral cultures,computed tomography, and magnetic resonance imaging, have important roles in theassessment of these patients. (Am Fam Physician 2003;68:2223-8. Copyright© 2003American Academy of Family Physicians.)

Approach to the Adult Patient with Fever of Unknown OriginALAN R. ROTH, D.O., and GINA M. BASELLO, D.O., Jamaica Hospital Medical Center,Mount Sinai School of Medicine Family Practice Residency Program, Jamaica, New York

See page 2113 fordefinitions of strength-of-evidence levels.

Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright© 2003 American Academy ofFamily Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved.

not manifested an obvious source of infection that couldhave been present before admission. A minimum of threedays of evaluation without establishing the cause of fever isrequired to make this diagnosis.5 Conditions causing noso-comial FUO include septic thrombophlebitis, pulmonaryembolism, Clostridium difficile enterocolitis, and drug-induced fever. In patients with nasogastric or nasotrachealtubes, sinusitis also may be a cause.7,8

IMMUNE DEFICIENT

Immune-deficient FUO, also known as neutropenicFUO, is defined as recurrent fever in a patient whose neu-trophil count is 500 per mm3 or less and who has been

assessed for three days without establishing an etiology forthe fever.5 In most of these cases, the fever is caused byopportunistic bacterial infections. These patients are usu-ally treated with broad-spectrum antibiotics to cover themost likely pathogens. Occult infections caused by fungi,such as hepatosplenic candidiasis and aspergillosis, mustbe considered.9 Less commonly, herpes simplex virus maybe the inciting organism, but this infection tends to presentwith characteristic skin findings.

HIV-ASSOCIATED

HIV-associated FUO is defined as recurrent fevers over afour-week period in an outpatient or for three days in a hos-pitalized patient with HIV infection.5 Although acute HIVinfection remains an important cause of classic FUO, thevirus also makes patients susceptible to opportunistic infec-tions. The differential diagnosis of FUO in patients who areHIV positive includes infectious etiologies such as Mycobac-terium avium-intracellulare complex, Pneumocystis cariniipneumonia, and cytomegalovirus. Geographic considera-tions are especially important in determining the etiology ofFUO in patients with HIV. For example, a patient with HIVwho lives in the southwest United States is more susceptibleto coccidioidomycosis. In patients with HIV infection, non-infectious causes of FUO are less common and include lym-phomas, Kaposi’s sarcoma, and drug-induced fever.9,10

Differential DiagnosisThe differential diagnosis of FUO generally is broken

into four major subgroups: infections, malignancies,autoimmune conditions, and miscellaneous (Table 2). Sev-

2224 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 68, NUMBER 11 / DECEMBER 1, 2003

TABLE 1

Classification of Fever of Unknown Origin (FUO)

Category of FUO Definition Common etiologies

Classic Temperature >38.3°C (100.9°F) Infection, malignancy, collagen vascular disease Duration of >3 weeksEvaluation of at least 3 outpatient visits or 3 days

in hospital

Nosocomial Temperature >38.3°C Clostridium difficile enterocolitis, drug-induced, Patient hospitalized ≥ 24 hours but no fever or pulmonary embolism, septic thrombophlebitis,

incubating on admission sinusitisEvaluation of at least 3 days

Immune deficient Temperature >38.3°C Opportunistic bacterial infections, aspergillosis, (neutropenic) Neutrophil count ≤ 500 per mm3 candidiasis, herpes virus

Evaluation of at least 3 days

HIV-associated Temperature >38.3°C Cytomegalovirus, Mycobacterium avium-intracellulareDuration of >4 weeks for outpatients, >3 days complex, Pneumocystis carinii pneumonia,

for inpatients drug-induced,Kaposi’s sarcoma, lymphoma HIV infection confirmed

HIV = human immunodeficiency virus.

Adapted with permission from Durack DT, Street AC. Fever of unknown origin—reexamined and redefined. Curr Clin Top Infect Dis 1991;11:37.

The Authors

ALAN R. ROTH, D.O., is chairman and program director of the JamaicaHospital Medical Center, Mount Sinai School of Medicine Family Prac-tice Residency Program, Jamaica, N.Y. He is also associate professor ofcommunity and preventive medicine at Mount Sinai School of Medi-cine. Dr. Roth received his medical degree from the New York Collegeof Osteopathic Medicine, Old Westbury, N.Y., and completed a familymedicine residency at the Jamaica Hospital Medical Center.

GINA M. BASELLO, D.O., is assistant director of the Jamaica HospitalMedical Center, Mount Sinai School of Medicine Family Practice Resi-dency Program, and clinical instructor of community and preventive med-icine at the Mount Sinai School of Medicine. She received her medicaldegree from the New York College of Osteopathic Medicine and com-pleted a family medicine residency at Jamaica Hospital Medical Center.

Address correspondence to Alan R. Roth, D.O., Jamaica Hospital Med-ical Center, Family Practice Residency Program, 89-06 135th Street,Suite 3C, Jamaica, NY 11418 (e-mail: [email protected]) Reprintsare not available from the authors.

eral factors may limit the applicability of research literatureon FUO to everyday medical practice. These factorsinclude the geographic location of cases, the type of insti-tution reporting results (e.g., community hospital, univer-sity hospital, ambulatory clinic), and the specific subpopu-lations of patients with FUO who were studied. Despitethese limiting factors, infection remains the most commoncause of FUO in study reports.3,11,12

INFECTIONS

Of the many infectious diseases that are associated withFUO, tuberculosis (especially in extrapulmonary sites) andabdominal or pelvic abscesses are the most common.13

Intra-abdominal abscesses are associated with perforatedhollow viscera (as occurs in appendicitis), diverticulitis,malignancy, and trauma. Other common infections thatshould be considered as the source of FUO include suba-cute bacterial endocarditis, sinusitis, osteomyelitis, anddental abscess.11,13 As the duration of fever increases, thelikelihood of an infectious etiology decreases. Malignancyand factitious fever are more common diagnostic consid-erations in patients with prolonged FUO.14

MALIGNANCIES

Because of a substantial increase in the elderly population,as well as advances in the diagnosis and treatment of diseases

common in this population, malignancy has become a com-mon etiologic consideration in elderly patients. Malignan-cies that sometimes are difficult to diagnose, such as chronicleukemias, lymphomas, renal cell carcinomas, and meta-static cancers, often are found in patients with FUO.12

AUTOIMMUNE CONDITIONS

Rheumatoid arthritis and rheumatic fever are inflam-matory diseases that used to be commonly associated withFUO, but with advances in serologic testing, these condi-tions usually are diagnosed more promptly. At this time,adult Still’s disease and temporal arteritis have become themost common autoimmune sources of FUO because theyremain difficult to diagnose even with the help of labora-tory testing.

Multisystem inflammatory diseases such as temporalarteritis and polymyalgia rheumatica have emerged as theautoimmune conditions most frequently associated withFUO in patients older than 65 years.15 Elderly patients whopresent with symptoms consistent with temporal arteritisassociated with an elevation of the erythrocyte sedimenta-tion rate should be referred for temporal artery biopsy.16

MISCELLANEOUS

Many unrelated pathologic conditions can present asFUO, with drug-induced fever being the most com-mon.11,14 This condition is part of a hypersensitivity reac-tion to specific drugs such as diuretics, pain medications,antiarrhythmic agents, antiseizure drugs, sedatives, certainantibiotics, antihistamines, barbiturates, cephalosporins,salicylates, and sulfonamides (Table 3).

Complications from cirrhosis and hepatitis (alcoholic,granulomatous, or lupoid) are also potential causes ofFUO.12,13 Deep venous thrombosis, although a rare causeof FUO, must be considered in relevant patients, andvenous Doppler studies should be obtained.17 Factitiousfever has been associated with patients who have somemedical training or experience and a fever persistinglonger than six months.18 Failure to reach a definitive diag-nosis in patients presenting with FUO is not uncommon;20 percent of cases remain undiagnosed. Even if an exten-sive investigation does not identify a cause for FUO, thesepatients generally have a favorable outcome.19

Evaluation of the Patient with FUOThe initial approach to the patient presenting with fever

should include a comprehensive history, physical examina-

Fever of Unknown Origin

DECEMBER 1, 2003 / VOLUME 68, NUMBER 11 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2225

TABLE 2

Common Etiologies of Fever of Unknown Origin

InfectionsTuberculosis (especially

extrapulmonary)Abdominal abscessesPelvic abscessesDental abscessesEndocarditisOsteomyelitisSinusitisCytomegalovirusEpstein-Barr virusHuman immunodeficiency virusLyme diseaseProstatitisSinusitisMalignanciesChronic leukemiaLymphomaMetastatic cancersRenal cell carcinomaColon carcinomaHepatomaMyelodysplastic syndromesPancreatic carcinomaSarcomas

Autoimmune conditionsAdult Still’s diseasePolymyalgia rheumaticaTemporal arteritisRheumatoid arthritisRheumatoid feverInflammatory bowel diseaseReiter’s syndromeSystemic lupus erythematosusVasculitidesMiscellaneousDrug-induced feverComplications from cirrhosisFactitious feverHepatitis (alcoholic,

granulomatous, or lupoid)Deep venous thrombosisSarcoidosis

tion, and appropriate laboratory testing. As the underlyingprocess develops, the history and physical assessmentshould be repeated. The first step should be to confirm ahistory of fever and document the fever pattern. Classicfever patterns such as intermittent, relapsing sustained,and temperature-pulse disparity may prove to be usefulbut rarely are diagnostic.20

In taking a history from a patient with FUO, particularattention should be given to recent travel, exposure to petsand other animals, the work environment, and recent con-tact with persons exhibiting similar symptoms. In patientsreturning from areas where tuberculosis and malaria arecommon, the index of suspicion for these diseases shouldbe elevated. In patients who have had contact with pets orother animals, diseases common to animal handlers mustbe suspected.

The family history should be carefully scrutinized forhereditary causes of fever, such as familial Mediterraneanfever. The medical history also must be examined for con-ditions such as lymphoma, rheumatic fever, or a previousabdominal disorder (e.g., inflammatory bowel disease), thereactivation of which might account for the fever. Finally,drug-induced fever must be considered in patients who aretaking medications.19

Diagnostic clues often are not readily apparent on phys-ical examination; repeated examination may be essential.Careful attention to the skin, mucous membranes, andlymphatic system, as well as abdominal palpation formasses or organomegaly, is important. The physician’schoice of imaging should be guided by findings from athorough history and physical examination21 (e.g., a car-diac murmur in the presence of negative blood culturesshould be investigated with a transthoracic echocardio-gram or, if needed, transesophageal echocardiogram)rather than strictly following the stepwise approach out-lined in Figure 1. Also, Duke’s clinical criteria include twomajor and six minor criteria that help determine the like-lihood of endocarditis.22 [Evidence level A, validated clini-cal decision tool] A cost-effective individualized approachis essential to the evaluation of these patients, and without

a thoughtful and focused investigation, inappropriate testsmight be performed.

The preliminary evaluation helps in the formulation ofa differential diagnosis and guides further studies that aremore invasive or expensive. These preliminary investiga-tions should include a complete blood count, liver func-tion test, erythrocyte sedimentation rate, urinalysis, andbasic cultures. Simple clues found during initial testingoften will guide the clinician toward one of the major sub-groups of FUO. The decision to obtain further diagnosticstudies should be based on abnormalities found in the ini-tial laboratory work-up and not represent a haphazard useof costly or invasive modalities.

Skin testing for tuberculosis with purified protein deriv-ative (PPD) is an inexpensive screening tool that should beused in all patients with FUO who do not have a knownpositive PPD reaction. However, a positive PPD reactionalone does not prove the presence of active tuberculosis. Achest radiograph also should be obtained in all patients toscreen for possible infection, collagen vascular disease, ormalignancy. If this initial assessment does not disclose thesource of fever, more specific investigatory techniques,such as serology, sonography, computed tomography(CT), magnetic resonance imaging (MRI), and nuclearmedicine scanning should be conducted, based on clinicalsuspicion.

Abdominal sonography, pelvic sonography, or CT scan-ning should be performed early in the diagnostic process torule out such common causes of FUO as intra-abdominalabscess or malignancy, depending on the primary evalua-tion.17 This testing, including directed biopsies, has greatlyreduced the need for more invasive operative studies.23

MRI should be reserved for clarifying conditions foundthrough the use of other techniques or when the diagnosisremains obscure. The use of radionucleotide scanning,such as gallium 67, technetium Tc 99m, or indium-labeledleukocytes, is warranted for detecting inflammatory condi-tions and neoplastic lesions that often are underdiagnosedby CT scans; however, these tests tend not to detect colla-gen vascular disease and other miscellaneous conditions24

(Table 4).Endoscopic procedures may be helpful in the diagnosis

of disorders such as inflammatory bowel disease and sar-coidosis. The newest diagnostic technique in the evaluationof the patient with FUO is positron emission tomography(PET). This modality appears to have a very high negativepredictive value in ruling out inflammatory causes of fever.


TABLE 3

Agents Commonly Associated with Drug-Induced Fever

Allopurinol (Zyloprim)Captopril (Capoten)Cimetidine (Tagamet)Clofibrate (Atromid-S)ErythromycinHeparinHydralazine (Apresoline)Hydrochlorothiazide (Esidrix)Isoniazid

Meperidine (Demerol)Methyldopa (Aldomet)Nifedipine (Procardia)Nitrofurantoin (Furadantin)PenicillinPhenytoin (Dilantin)Procainamide (Pronestyl)Quinidine


DECEMBER 1, 2003 / VOLUME 68, NUMBER 11 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2227

Diagnosis of Fever of Unknown Origin

InfectionUrine and sputum cultures

for AFB, VDRL, HIV test;serology for CMV, EBV,ASO titer (geographicallyspecific testing)

Diagnosis clear?

HematologicPeripheral smear,

serum proteinelectrophoresis

Diagnosis clear?

NonhematologicMammography, chest

CT with contrast,upper/lowerendoscopy, bonescan, gallium 67 scan

Diagnosis clear?

Autoimmune conditionsRheumatoid factor, ANA

Diagnosis clear?

MiscellaneousOrder appropriate

diagnostic tests based on information from the history.

Complete history and physical assessment

Positive findings Yes Order appropriate and specificdiagnostic testing.

Yes Order appropriate follow-updiagnostic testing.

No

No

No

CBC, electrolytes, LFT, blood culture, urinalysis,urine culture, ESR, PPD skin test, chest radiograph

TTE/TEE, lumbar puncture,gallium 67 scan, sinusfilms (radiography or CT)

No

Bone marrow biopsyNo

MRI of the brain, biopsy of suspiciousskin lesions or lymph nodes, liverbiopsy, diagnostic laparoscopy

No

Temporal artery biopsy,lymph node biopsy

Positive results

Malignancies

CT of abdomen/pelvis with contrast

Assign to most likely category.

FIGURE 1. Algorithm for the diagnosis of fever of unknown origin. (CBC = complete blood count; LFT = liver function test;ESR = erythrocyte sedimentation rate; PPD = purified protein derivative; CT = computed tomography; AFB = acid-fastbacilli; HIV = human immunodeficiency virus; CMV = cytomegalovirus; EBV = Epstein-Barr virus; ASO = antistreptolysin-Oantibodies; ANA = antinuclear antibody; TTE = transthoracic echocardiography; TEE = transesophageal echocardiography;MRI = magnetic resonance imaging)

However, because of its limited availability it is too early todetermine if PET scans will prove to be a useful diagnostictool in the evaluation of these patients.25,26

More invasive testing, such as lumbar puncture orbiopsy of bone marrow, liver, or lymph nodes, should beperformed only when clinical suspicion shows that thesetests are indicated or when the source of the fever remainsunidentified after extensive evaluation. When the definitivediagnosis remains elusive and the complexity of the caseincreases, an infectious disease, rheumatology, or oncologyconsultation may be helpful.

The authors indicate that they do not have any conflicts of inter-ests. Sources of funding: none reported.

REFERENCES

1. Cherry DK, Woodwell DA. National Ambulatory Medical Care Sur-vey: 2000 summary. Adv Data 2002;328:1-32.

2. Dykewicz MS. Rhinitis and sinusitis. J Allergy Clin Immunol2003;111(suppl 2):S520-9.

3. Petersdorf RG, Beeson PB. Fever of unexplained origin: report on100 cases. Medicine 1961;40:1-30.

4. Cunha BA. Fever of unknown origin. Infect Dis Clin North Am1996;10:111-27.

5. Durack DT, Street AC. Fever of unknown origin—reexamined andredefined. Curr Clin Top Infect Dis 1991;11:35-51.

6. Durack DT. Fever of unknown origin. In: Mackowiak PA, ed. Fever:basic mechanisms and management. 2d ed. Philadelphia: Lippin-cott-Raven, 1997:237-49.

7. Konecny P, Davidson RN. Pyrexia of unknown origin in the 1990s:time to redefine. Br J Hosp Med 1996;56:21-4.

8. Kountakis SE, Burke L, Rafie J J, Bassichis B, Maillard AA, Stiern-berg CM. Sinusitis in the intensive care unit patient. OtolaryngolHead Neck Surg 1997;117:362-6.

9. Hughes WT, Armstrong D, Bodey GP, Feld R, Mandell GL, MeyersJD, et al. From the Infectious Diseases Society of America. Guide-lines for the use of antimicrobial agents in neutropenic patientswith unexplained fever. J Infect Dis 1990;161:381-96.

10. Armstrong WS, Katz JT, Kazanjian PH. Human immunodeficiencyvirus–associated fever of unknown origin: a study of 70 patientsin the United States and review. Clin Infect Dis 1999;28:341-5.

11. De Kleijn EM, Vandenbroucke JP, van der Meer JW. Fever of unknownorigin (FUO). I. A prospective multicenter study of 167 patients withFUO, using fixed epidemiologic entry criteria. The Netherlands FUOStudy Group. Medicine [Baltimore] 1997;76:392-400.

12. Knockaert DC, Vanneste L J, Bobbaers HJ. Recurrent or episodicfever of unknown origin. Review of 45 cases and survey of the lit-erature. Medicine [Baltimore] 1993;72:184-96.

13. Kazanjian PH. Fever of unknown origin: review of 86 patientstreated in community hospitals. Clin Infect Dis 1992;15:968-73.

14. Aduan RP, Fauci AS, Dale DC, Wolff SM. Prolonged fever ofunknown origin (FUO): a prospective study of 347 patients. ClinRes 1978;26:558.

15. Knockaert DC, Vanneste LJ, Bobbaers HJ. Fever of unknown ori-gin in elderly patients. J Am Geriatr Soc 1993;41:1187-92.

16. Epperly TD, Moore KE, Harrover JD. Polymyalgia rheumatica andtemporal arteritis. Am Fam Physician 2000;62:789-96.

17. Mourad O, Palda V, Detsky A. A comprehensive evidence-basedapproach to fever of unknown origin. Arch Intern Med 2003;163:545-51.

18. Mackowiak P, Durack D. Fever of unknown origin. In: Mandell GL,Douglas RG, Bennett JE, Dolin R, eds. Mandell, Douglas, and Ben-nett’s Principles and practice of infectious diseases. 5th ed.Philadelphia: Churchill Livingstone; 2000:623-31.

19. Arnow PM, Flaherty JP. Fever of unknown origin. Lancet 1997;350:575-80.

20. Mackowiak PA. Commentary. Fever patterns. Infectious DiseaseClinical Practice 1997;6:308-9.

21. Kupferwasser LI, Darius H, Muller AM, Martin C, Mohr-Kahaly S,Erbel R, et al. Diagnosis of culture-negative endocarditis: the roleof the Duke criteria and the impact of transesophageal echocar-diography. Am Heart J 2001;142:146-52.

22. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis ofinfective endocarditis: utilization of specific echocardiographicfindings. Am J Med 1994;96:200-9.

23. Hirschmann JV. Fever of unknown origin in adults. Clin Infect Dis1997;24:291-300.

24. Suga K, Nakagi K, Kuramitsu T, Itou K, Tanaka N, Uchisato H, etal. The role of gallium-67 imaging in the detection of foci in recentcases of fever of unknown origin. Ann Nucl Med 1991;5:35-40.

25. Lorenzen J, Buchert R, Bohuslavizki KH. Value of FDG PET inpatients with fever of unknown origin. Nucl Med Commun2001;22:779-83.

26. Knockaert DC, Vanderschueren S, Blockmans D. Fever of unknownorigin in adults: 40 years on. J Intern Med 2003;253:263-75.


TABLE 4

Diagnostic Imaging in Patients with FUO

Imaging Possible diagnoses

Chest radiograph Tuberculosis, malignancy, Pneumocystis carinii pneumonia

CT of abdomen or pelvis Abscess, malignancywith contrast agent

Gallium 67 scan Infection, malignancyIndium-labeled leukocytes Occult septicemiaTechnetium Tc 99m Acute infection and inflammation

of bones and soft tissueMRI of brain Malignancy, autoimmune

conditionsPET scan Malignancy, inflammationTransthoracic or Bacterial endocarditis

transesophageal echocardiography

Venous Doppler study Venous thrombosis

FUO = fever of unknown origin; CT = computed tomography; MRI =magnetic resonance imaging; PET = positron emission tomography.


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