Fever of unknown origin - clinical overview of classic_and_current concepts

Infect Dis Clin N Am 21 (2007) 917–936

Fever of Unknown Origin:Historical and Physical Cluesto Making the Diagnosis

Jill Tolia, MDa,b,*, Leon G. Smith, MDa

aDepartment of Infectious Diseases, St. Michael’s Medical Center,

111 Central Avenue, Newark, NJ 07104, USAbStaten Island University Hospital, Staten Island, NY, USA

‘‘Humanity has but three great enemies: fever, famine and war; of these by farthe greatest, by far the most terrible is fever’’

–Sir William Osler, MD, 1896 [1]

Fever of unknown origin (FUO), defined in 1961 by Petersdorf and Bee-son [2] as an illness of more than 3 weeks’ duration with a temperaturegreater than 101�F on several occasions with a diagnosis uncertain after 1week of study in the hospital, remains as elusive today as it did then nearly50 years ago [3]. There are no published guidelines on the approach to thediagnosis of FUO [4,5], which is not surprising considering some publishedstudies report as many as 200 different causes of FUO [5]. Numerous retro-spective case series and prospective studies report that a diagnosis is neverestablished in up to 30% of cases of FUO [6–8]. In addition, the definitionof FUO has changed over time, most notably in the revised definition of Du-rack and Street [9] with emphasis on four different types of FUO (Table 1).Specifically, the work-up of classical FUO has shifted from 1 week of studyin the hospital to 3 days or three outpatient visits. Notably, the advent ofHIV-AIDS and highly active antiretroviral therapy adds a new dimensionto the approach to FUO with infections and drug fever representing a higherproportion of cases and previously uncommon infections occurring fre-quently [10].

Historically, the ‘‘big three’’ causes of FUO have fallen into three cate-gories: (1) infection, (2) neoplasm, and (3) collagen vascular disease [2].

* Corresponding author. Department of Infectious Diseases, St. Michael’s Medical

Center, 111 Central Avenue, Newark, NJ 07104.

E-mail address: [email protected] (J. Tolia).

0891-5520/07/$ - see front matter � 2007 Elsevier Inc. All rights reserved.

doi:10.1016/j.idc.2007.08.011 id.theclinics.com

Table 1

New definitio

e-Deficient FUO HIV-Related FUO

Definition , O3 d, negative

res after 48 h

O38�C, O3 wk for

outpatients, O3 d for

inpatients, HIV infection

confirmed

Patient locat l or clinic Community, clinic, or

hospital

Leading caus used by infections,

ause documented in

40%–60%

HIV (primary infection),

typical and atypical

mycobacteria, CMV,

lymphomas,

toxoplasmosis,

cryptococcosis

History emph f chemotherapy,

administered,

rlying

nosuppressive

der

Drugs, exposures, risk

factors, travel, contacts,

stage of HIV infection

Examination lds, IV sites, lungs,

nal area

Mouth, sinuses, skin, lymph

nodes, eyes, lungs,

perianal area

918

TOLIA

&SMIT

H

ns for fever of unknown origin

Classic FUO Nosocomial FUO Immun

O38�C, O3 wk, O2 visits

or 3 d in hospital

O38�C, 3 d, not present or

including on admission

O38�Ccultu

ion Community, clinic, or

hospital

Acute care hospital Hospita

es Cancer, infections,

inflammatory conditions,

undiagnosed, habitual

hyperthermia

Nosocomial infections,

postoperative

complications, drug fever

Most ca

but c

only

asis Travel, contacts, animal

and insect exposure,

medications,

immunizations, family

history, cardiac valve

disorder

Operations and procedures,

devices, anatomic

considerations, drug

treatment

Stage o

drugs

unde

immu

disor

emphasis Fundi, oropharynx,

temporal artery,

abdomen, lymph nodes,

spleen, joints, skin, nails,

genitalia, rectum or

prostate, lower limb

deep veins

Wounds, drains, devices,

sinuses, urine

Skin fo

peria

Investigation emphasis Imaging, biopsies, Imaging, bacterial cultures CXR, bacterial cultures Blood and lymphocyte

count; serologic tests;

CXR; stool examination;

biopsies of lung, bone

marrow, and liver for

cultures and cytologic

tests; brain imaging

M situation Antimicrobial treatment

protocols

Antiviral and antimicrobial

protocols, vaccines,

revision of treatment

regiments, good nutrition

T Days Weeks to months

T Hours Days to weeks

, human immunodeficiency virus; IV, intravenous.

ll, Douglas and Bennett’s principles and practice of infectious diseases. 6th edition.

E

919

FEVER

OFUNKNOWN

ORIG

IN

sedimentation rate,

skin tests

anagement Observation, outpatient

temperature chart,

investigations, avoidance

of empirical drug

treatments

Depends on

ime course of disease Months Weeks

empo of investigation Weeks Weeks

Abbreviations: CMV, cytomegalovirus; CXR, chest radiograph; HIV

From Mackowiak P, Durack D. Fever of unknown origin. In: Mande

lsevier; 2005. p. 718–29; with permission.

920 TOLIA & SMITH

The percentage of cases of FUO in each of these three categories has shiftedover time, reflecting a change in diagnostic capabilities and disease preva-lence [6,11]. For example, many case series of FUO report a decrease inthe incidence of FUO caused by neoplasm, likely caused in part by earlierdiagnosis before the disease meets the criteria for FUO [6]. Other diseasesthat previously remained undiagnosed, such as Lyme disease, are now rou-tinely diagnosed because of the use of a previously unavailable diagnostictest [12]. A comprehensive history and physical is the key to establishing a di-agnosis in a patient with FUO. This article provides a systematic approachto the diagnosis of FUO by delineating the most important elements ofa comprehensive history and physical. In addition, shared anecdotes areequally valuable (Dr. Donald Louria, MD, personal communication,2007) and the body of this article and Box 1 contain numerous examplesof causes of FUO encountered in practice, which in addition to providingan interesting example of a case of FUO serve further to exemplify the ap-proach to diagnosis of FUO.

The history of presenting illness is of critical importance in the patientwith FUO and is often difficult to obtain because many symptoms relevantto the diagnosis are vague, intermittent, or seemingly insignificant [13]. Attimes, the patient with FUO may have forgotten early events and recallsthem only if specifically prodded. In some cases, it may be necessary on re-peat history and physical examination literally to start with the hair and sys-tematically move down the body to the toes (Dr. Donald Louria, MD,personal communication, 2007). In certain patient populations, notably el-derly patients, no symptoms related to the underlying illness are elicited inthe history of presenting illness. In the study by Esposito and Gleckman[14] of 111 patients greater than age 65 with FUO, intra-abdominal abscesswas the most common infectious etiology of FUO; however, in 13 of 41 pa-tients with this diagnosis no symptoms related to the abdomen were present[15]. In all patients, specific questions about constitutional symptoms includ-ing weight change, chills, and night sweats should be elicited. Questionsshould be asked about the true onset of symptoms, regardless of howmild or insidious. For example, in a patient with inflammatory bowel dis-ease, bowel symptoms may be intermittent or be of such long standing asto be accepted as normal [16]. No symptom should be regarded as irrelevant,keeping in mind that it is well regarded that most patients with FUO exhibitatypical manifestations of common illnesses [2].

In addition to a comprehensive list of all previously documented medicalconditions, the past medical history should include information about pre-viously treated chronic infections, such as tuberculosis (TB), endocarditis,and rheumatic fever. Any prior diagnosis of cancer, no matter how remote,with specific information about timing and type of therapy should be listed.Prior surgery with specific information about type of surgery performed,postoperative complications, and any indwelling foreign materials shouldalso be included. Questions about prosthetic devices should include

921FEVER OF UNKNOWN ORIGIN

Box 1. Clinical pearls for the diagnosis of feverof unknown origin

1. Alkaline phosphatase is the most important single laboratorytest; may be elevated in temporal arteritis, hypernephroma,thyroiditis, tuberculosis.

2. Thrombocytosis >600,000 mm3 suggests cancer or bonemarrow disease and less often tuberculosis or infections withyeasts or fungi.

3. Nucleated red cells in the periphery in the absence ofhemolysis suggests marrow invasion.

4. Free blood anywhere (pericardium, chest, abdomen, brain) canproduce FUOand this may last for weeks,sometimes with rigors.

5. Rectus sheath hematoma can produce FUO or shock.6. Trapezius soreness suggests subdiaphragmatic abscess.7. Up to 20% of FUO cases may be caused by cytomegalovirus

infection.8. Fever, leukopenia, and palpable spleen in middle-aged men

suggest either tuberculosis or lymphoma.9. With granulomatous hepatitis, liver function studies may be

normal; a liver biopsy or steroid trial may be needed.10. Tumors may produce fever for many months or even up to 7

or more years.11. Alcoholic hepatitis and hepatic cirrhosis can both be

associated with low-grade or substantial fever (up to 104�F).12. Juvenile rheumatoid arthritis should always be considered in

adults, especially if arthralgias or myalgias are present. Theerythrocyte sedimentation rate should be increased andthere may be a transient rash. There may also behepatosplenomegaly.

13. One or more liver abscesses can be present even withnormal liver function tests. If they are small enough,sonograms and CT scans can be negative.

14. Pulmonary emboli with or without a positive chestradiograph is an important cause of FUO; even angiogramscan be initially negative.

15. Bowel disease is an important cause of FUO; regional ileitis,colitis, and Whipple’s disease all can present as an FUO.

16. Sinusitis must be considered as a cause of FUO; the historymay be surprisingly negative.

17. In older patients with FUO, intra-abdominal infection shouldalways be considered carefully; a bowel leak, subacuteappendicitis, and cholecystitis may be very hard to diagnose.

922 TOLIA & SMITH

prosthetic valves, indwelling venous catheters, pacemakers and implantabledefibrillators, prosthetic joints, and cosmetic implants. Any history of psy-chiatric illness should be sought, because psychogenic or factitious fever isan important differential diagnosis. Prior history of intra-abdominal inflam-matory conditions even without surgical intervention, such as cholecystitisor diverticulitis, should be sought. Information about recent inpatient oroutpatient hospital stay is important for diagnosing nosocomial and iatro-genic causes of FUO.

A comprehensive list of all medications including over-the-counter andherbal remedies should be included. Drug fever is a well-documented causeof FUO and has been noted to occur with greater frequency in older patientsand patients with HIV. Certain medications highly associated with drug fe-ver are listed in Box 2. Drug fever can occur at any time during the course ofdrug therapy [17]. An absence of other signs of inflammation and relativebradycardia are seen with drug fever; however, relative bradycardia is a non-specific finding in drug fever, and has been described in association with a se-lected number of specific infections as shown in Box 3. Typically, the feverresolves within 2 days of discontinuation of the drug and persistence of feverbeyond 72 hours after the drug is removed allows one to conclude that thedrug is not the offending agent in producing the fever [5]. It should be keptin mind, however, that the disappearance of fever is related to the rate ofsecretion of metabolites of drug from the body and with certain slowly

18. Sarcoidosis can produce FUO if there is extensive centralnervous system or lung involvement.

19. Tender cartilage on the nose, ear, or sternum with episcleritisand Raynaud’s syndrome is polychondritis.

20. Pain on raising the arms over the head suggests Takayasu’sdisease.

21. Recurrent fever with erythema multiforme suggests herpessimplex.

22. Blindness, deafness, and central nervous system stuporsuggests Whipple’s disease.

23. Low-grade fever with anemia and abnormal liver functiontests suggests Wilson’s disease.

24. Recurrent fever with joint pain and petechial rash suggestschronic meningococcemia.

25. Recurrent shock and fever with abdominal trauma or sexsuggests anaphylaxis caused by leaking echinococcus.

26. Postprostate resection with fever and progressive dementiasuggests cryptococcus or tuberculosis.

27. Hectic fever, right upper quadrant tenderness, and elevatedalkaline phosphatase suggest Charcot’s fever.

923FEVER OF UNKNOWN ORIGIN

metabolized agents may take up to 1 week to be completely eliminated [18].Response of fever to naproxen has been shown in some case reports to besignificant; specifically, fevers caused by solid tumors subside promptly,whereas fevers caused by other entities may persist [11].

A history of previous allergic reactions to medications may again point toa diagnosis of drug fever when a related agent is used. Multiple drug and

Box 2. Commonly used medications that can cause feverof unknown origin

Antimicrobial agentsCarbapenemsCephalosporinsMinocycline HClNitrofurantoinPenicillinsRifampinSulfonamides

AnticonvulsantsBarbituratesCarbamazepinePhenytoin

Antihistamines

Cardiovascular drugsHydralazine HClProcainamide HClQuinidine

Histamine2 blockersCimetidineRanitidine HCl

Iodides

Herbal remedies

Nonsteroidal anti-inflammatory drugsIbuprofenSulindacPhenothiazinesSalicylates

From Amin K, Kauffman C. Fever of unknown origin: a strategic approach tothis diagnostic dilemma. Postgrad Med 2003;114:69–75; with permission.

924 TOLIA & SMITH

Box 3. Physical clues to diagnosing fever of unknown origin

Arthritis or joint painFamilial Mediterranean feverPseudogoutRat-bite feverRheumatoid arthritisSystemic lupus erythematosusLyme diseaseLymphogranuloma venereumWhipple’s diseaseBrucellosisHyperimmunoglobulinemia D syndrome

Band keratopathyAdult Still’s diseaseAdult juvenile rheumatoid arthritisSarcoidosis

Bruit over spineTumorArteriovenous fistula

Calf tendernessRocky Mountain spotted feverPolymyositisPneumococcal bacteremia

ConjunctivitisTuberculosisCat-scratch diseaseSystemic lupus erythematosusChlamydia infectionHistoplasmosis

Conjunctival suffusionLeptospirosisRelapsing feverRocky Mountain spotted fever

Costo-vertebral angle tendernessPerinephric abscessChronic pyelonephritis

Dry eyesRheumatoid arthritisSystemic lupus erythematosus

925FEVER OF UNKNOWN ORIGIN

Periarteritis nodosaSjogren’s syndrome

Epididymo-orchitisTuberculosisLymphomaBrucellosisLeptospirosisPeriarteritis nodosaInfectious mononucleosisBlastomycosisCarcinoma

EpistaxisRelapsing feverPsittacosisRheumatic fever

Heart murmurSubacute bacterial endocarditisAtrial myxoma (changes with position)

HepatomegalyLymphomaMetastatic carcinomaAlcoholic liver diseaseHepatomaRelapsing feverGranulomatous hepatitisQ feverTyphoid fever

LymphadenopathyLymphomaCat-scratch feverTuberculosisLymphomogranuloma venereumEpstein-Barr virus mononucleosisCytomegalovirus infectionToxoplasmosisHIV infectionAdult Still’s diseaseBrucellosisWhipple’s diseasePseudolymphomaKikuchi’s disease

926 TOLIA & SMITH

Orbital involvementLymphomaMetastatic carcinoma

Relative bradycardiaTyphoid feverMalariaLeptospirosisPsittacosisCentral feverDrug fever

Rose spotsTyphoidPsittacosis

Subconjunctival hemorrhageEndocarditisTrichinosis

Skin hyperpigmentationWhipple’s diseaseHypersensitivity vasculitisHemochromatosisAddison’s disease

Splenic abscessSubacute bacterial endocarditisBrucellosisEnteric fever

SplenomegalyLeukemiaLymphomaTuberculosisBrucellosisSubacute bacterial endocarditisCytomegalovirus infectionEpstein-Barr virus mononucleosisRheumatoid arthritisSarcoidosisPsittacosisRelapsing feverAlcoholic liver diseaseTyphoid fever

927FEVER OF UNKNOWN ORIGIN

Rocky Mountain spotted feverKikuchi’s disease

Spinal tendernessSubacute vertebral osteomyelitisSubacute bacterial endocarditisBrucellosisTyphoid fever

Sternal tendernessMyeloproliferative diseasesMetastatic carcinoma (marrow invasion)BrucellosisLeukemiaOsteomyelitis

Tender cartilageRaynaud’s syndromePolychondritisCytomegalovirus infection

Thigh tendernessBrucellosisPolymyositis

ThrombophlebitisPsittacosis

Tongue tendernessRelapsing feverGiant cell arteritisAmyloidosis

Trapezius tendernessSubdiaphragmatic abscess

Uveal tract involvementTuberculosisAdult juvenile rheumatoid arthritisToxoplasmosisSarcoidosisSystemic lupus erythematosus

UveitisTuberculosisAdult Still’s diseaseSarcoidosis

928 TOLIA & SMITH

environmental allergies may identify an atopic individual in whom certaininflammatory diseases may be more likely. Finally, an allergy history in a pa-tient with a seemingly unrelated and incongruous list of allergies may be themeans to identify an underlying psychiatric disorder contributing to eitherfactitious or psychogenic fever.

The portion of the history defined as the social history includes many im-portant aspects of a patient’s lifestyle that prove important in the diagnosisof FUO. Country of origin, prior countries of residence, and travel historyprovide important information about exposure to endemic diseases, such asmalaria and histoplasmosis (Figs. 1 and 2). Specific questions should beasked about travel, with details about activities during travel and prophylac-tic medications and vaccinations; vaccination status; occupation and volun-teer positions including history of contact with hospitalized patients, nursinghome residents, or young children; recreational drug use; recreational

Systemic lupus erythematosusBehcet’s syndrome

Watery eyesPeriarteritis nodosa

Data from References [13,19–21].

Fig. 1. Epidemiology of histoplasmosis. (From Mackowiak P, Durack D. Fever of unknown

origin. In: Mandell, Douglas and Bennett’s principles and practice of infectious diseases. 6th

edition. Elsevier; 2005. p. 718–29; with permission.)

929FEVER OF UNKNOWN ORIGIN

activities, such as gardening, swimming in lakes, or exploring caves; livingconditions and prior episodes of homelessness, unusual dietary habits,such as consumption of unpasteurized dairy products or rare meats; pets;animal and tick exposure; fresh water exposure; and sexual activity. In pa-tients with underlying immunologic compromise, questions about specificrecent travel are of limited perspective. For example, a patient with HIVcan present with FUO caused by disseminated histoplasmosis, even thoughthe last travel to an endemic histoplasma geographic area was 10 or 15 yearsearlier (Dr. Donald Louria, MD, personal communication, 2007). Some ex-amples of specific diagnoses that can be elicited in the social history areshown in Box 4.

The family history is important both for prior illnesses in family mem-bers, who may have a genetic link to the patient, and recent illnesses in fam-ily members to which the patient may have been exposed. Certain rarehereditary causes of FUO are listed in Table 2. Prior family history of canceris important in considering an occult cancer in the patient. A history of cur-rent similar symptoms in a family member may represent a shared exposure.

The importance of a good physical examination is exemplified by thestudy in which positive physical findings were directly related to the diagnosisin 26 (59%) of 44 patients in whom the diagnosis was made [22]. It is impor-tant to note that in most cases in this study, repeated physical examinationswere required before the findings pointing to the diagnosis were noted.

Much has been written about the measurement of fever and fever pat-terns in the diagnosis of FUO. Prior studies reveal that there is no significantrelationship between the pattern of fever and diagnosis [23]. Certain gener-alizations can be made based on anecdotal reports, however, which providesome guidance in the work-up of a patient with an obscure cause of fever.

Fig. 2. Distribution of drug-resistant malaria. (From Mackowiak P, Durack D. Fever of un-

known origin. In: Mandell, Douglas and Bennett’s principles and practice of infectious diseases.

6th edition. Elsevier; 2005. p. 718–29; with permission.)

930 TOLIA & SMITH

Box 4. Historical clues to diagnosing fever of unknown origin

Abdominal painPeriarteritis nodosaFamilial Mediterranean feverRelapsing fever

Animal contactPsittacosisLeptospirosisBrucellosisToxoplasmosisCat-scratch diseaseQ feverRat-bite fever

Back painBrucellosisSubacute bacterial endocarditisEnterococcal endocarditis, myeloma (in older patients)

Cardiovascular accidentSubacute bacterial endocarditisTakayasu’s arteritisPeriarteritis nodosaRocky Mountain spotted fever

Chronic conjunctivitisTuberculosisSystemic lupus erythematosusPolyarteritis nodosaCat-scratch diseaseSarcoidosis

FatigueCarcinomaLymphomaInfectious mononucleosisTyphoid feverSystemic lupus erythematosusRheumatoid arthritisToxoplasmosisAnicteric hepatitis

Foul breathLung abscessLiver failure

931FEVER OF UNKNOWN ORIGIN

Esophageal diverticulumRenal failure

HeadacheMalariaBrucellosisRelapsing feverRat-bite feverChronic meningitis-encephalitisMalariaBrucellosisCentral nervous system neoplasmRocky Mountain spotted fever

Headache and myalgiasPsittacosisQ feverStreptobacillary feverLeptospirosis

Medication and toxic substancesDrug feverFume fever

Mental confusionSarcoid meningitisTuberculous meningitisCryptococcal meningitisCarcinomatous meningitisCentral nervous system neoplasmBrucellosisTyphoid feverHIV infection

MyalgiasTrichinosisSubacute bacterial endocarditisPeriarteritis nodosaRheumatoid arthritisFamilial Mediterranean feverPolymyositisJuvenile rheumatoid arthritis

Neck painSubacute thyroiditisAdult Still’s disease

932 TOLIA & SMITH

Diurnal variation is absent in 50% of noninfectious conditions associatedwith fever [23]. Double quotidian fever defined as two peaks in 24 hoursis seen in 50% of cases of gonococcal endocarditis [23]. It has also been de-scribed in cases of leishmaniasis, malaria, miliary TB, and adult Still’s dis-ease [3]. A sustained fever occurs frequently in gram-negative pneumoniaor severe central nervous system damage [19]. Pel-Ebstein fever, a daily feverthat occurs for days to weeks then disappears and reappears later in thesame pattern (Fig. 3), has been associated with Hodgkin’s disease [15]. Pe-riodic or relapsing fever is seen in malaria, lymphoma, borrelia, cyclic neu-tropenia, and rat-bite fever. An early morning fever spike has been describedin TB, Nocardia, polyarteritis nodosa, brucellosis, and salmonellosis.

Other vital signs are important in the evaluation of FUO, specifically inrelation to the presence of fever. Relative bradycardia, shown in Fig. 4, hasbeen described in prior case reports in association with the following condi-tions: drug fever, leishmaniasis, typhoid fever, Legionnaire’s disease, psitta-cosis, leptospirosis, brucellosis, and Kikuchi’s disease. In general, thepatient’s blood pressure, pulse, and respiratory rate relative to the temper-ature are important in differentiating an acute infectious condition froma chronic indolent infectious or inflammatory condition or a long-standingnoninfectious condition.

Temporal arteritisRelapsing mastoiditisSeptic jugular phlebitis

Nonproductive coughTuberculosisQ feverTyphoid feverLegionnaires’ disease

Tick exposureRelapsing feverRocky Mountain spotted feverLyme disease

Vision disorders or eye painTemporal arteritisSubacute bacterial endocarditisRelapsing feverBrain abscessTakayasu’s arteritis

Data from References [13,19–21].

Table

Featu

Muckle-Wells syndrome

Age o mostly infancy or

od

Infancy or childhood

Mode

(au

Dominant

Chrom

gen

1 q

Durat 1–2 d

Abdo

Pains þDiarr �Chest �Skin i ul erythematous

(erysipelas-like)

þþ Urticaria

Arthr þ/þLymp l, inguinal, axillar �

Splen þRisk þTypic vitis, periorbital

testicular pain

Conjunctivitis, deafness later

in life

Effect roids None

Ab r syndrome; TRAPS, tumor necrosis factor recep-

tor-1–

Fr n. J Intern Med 2003;253:263–75; with permission.

933

FEVER

OFUNKNOWN

ORIG

IN

2

res of hereditary periodic fever syndromes

FMF HIDS TRAPS

f onset Variable !20–30 y Mostly !1 y Variable;

childho

of inheritance

tosomal)

Recessive Recessive Dominant

osomal location of

etic defect

16 p 12 q 12 q

ion of attacks 1–4 d 3–7 d 1–3 wk

minal symptoms

þ þþ þhea � þ �pain þ � �nvolvement Rather rare erysipelas-like

(only below the knee)

þþ Macules, papules þþ Painf

patches

algia or arthritis þ/þ þ/þ þ/�hadenopathy � þ Cervical, inguinal, axillar,

abdominal

þ Cervica

omegaly þ/� þ (childhood) �for amyloidosis þ Very rare Rare

al features Testicular pain (prepubertal) Conjuncti

edema,

ive treatment Colchicine None Corticoste

breviations: FMF, Familial Mediterranean fever; HIDS, hyperimmunoglobulin D and periodic feve

associated periodic syndrome.

om Knockaert DC, Vanderschueren S, Blockmans D. Fever of unknown origin in adults: 40 years o

934 TOLIA & SMITH

The physical examination of a patient with FUO should be thorough andconducted in systematic manner with attention to all body systems. Manyprior case series of FUO have established lists of physical examination find-ings and associated diagnosis of causes of FUO. A previously publishedcomprehensive list is shown in Box 3. In general, physical findings that ul-timately lead to a diagnosis of FUO can be categorized as follows: typicalfindings but an atypical presentation of a well-known disease, obscure phys-ical findings that are pathognomonic for a particular disease, physical find-ings in areas that are not extensively examined in a routine physicalexamination, and common physical findings of common causes of FUO.Representative examples of each category are outlined next.

An atypical presentation of awell-known disease is commonly seen in casesof FUO: isolated lymphadenopathy as the onlymanifestation of disseminatedTB; retroperitoneal lymphadenopathy in lymphoma that can easily be missedon physical examination; vascular findings (subconjunctival hemorrhages,

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

Days

106105104103102101

99100

98.69897

Tem

pera

ture

Copyright © 2005, 2004, 2000, 1995, 1990, 1985, 1979 by Elsevier Inc.

Fig. 3. Relative bradycardia (typhoid fever). (From Mackowiak P, Durack D. Fever of un-

known origin. In: Mandell, Douglas and Bennett’s principles and practice of infectious diseases.

6th edition. Elsevier; 2005. p. 718–29; with permission.)

170160150140130120110100908070605040

RespirationsStools

Pulse Temp.108107106105104103102101

9998979695

100

DateDay of disease

2nd week 3rd week 4th week1st week

Temperature

Pulse

1 2 3 4 5 6 7 8 9 10 12 13 14 15 16 17 18 2811 19 20 21 22 23 24 25 26 27

Copyright © 2005, 2004, 2000, 1995, 1990, 1985, 1979 by Elsevier Inc.

Fig. 4. Pel-Ebstein fever (Hodgkin’s disease). (From Mackowiak P, Durack D. Fever of un-

known origin. In: Mandell, Douglas and Bennett’s principles and practice of infectious diseases.

6th edition. Elsevier; 2005. p. 718–29; with permission.)

935FEVER OF UNKNOWN ORIGIN

Janeway lesions) in bacterial endocarditis; or bone pain or constitutionalsymptoms of metastatic cancer with no symptoms of the primary disorder.

Some obscure physical findings are so rare and yet so well associated withspecific diseases as to be significant. Relative bradycardia as previously out-lined is an important example. Some other examples include skin hyperpig-mentation and Whipple’s disease, a heart murmur that changes withposition and atrial myxoma, choroid lesions of the eyes and TB, rose spotsand salmonellosis, and Roth’s spots and bacterial endocarditis.

Physical findings that can be easily missed on routine physical examinationcan point to a diagnosis of FUO when a careful and thorough examination isconducted [24]. Some specific areas as presented by Tumulty [25] include eyegrounds, gums and oral cavity, clavicles, trapezius muscle, sternal tenderness,auscultation for bruits, rectal examination, testicular examination, and dia-phragmatic mobility. Uveitis could be the only finding in autoimmune diseaseor cotton wool spots may be the only manifestation of cytomegalovirus dis-ease in an immunocompromised patient. The list of eye findings and associ-ated diseases is extensive as shown in Box 3 and Table 2. Poor oral hygienecan point to the diagnosis of infective endocarditis or lung abscess. Tonguepain can be indicative of temporal arteritis or infiltrative diseases, such as am-yloid or sarcoid. Pain over the clavicles can be sign of localized painful lymphnodes caused by metastatic cancer from a remote location (gastrointestinal,ovarian). Pain over the trapezius muscle indicates an inflammatory process,which causes irritation of the diaphragm, such as a subdiaphragmatic abscessor pancreatic cancer. Sternal tenderness can be the result of anything thatcauses myeloproliferative changes of the bone marrow (metastatic tumor).Auscultation over the entire vascular system could elicit an occult vascular tu-mor or splenic infarct. Epididymitis can be seen as the only manifestation ofdisseminated TB. Sinus tenderness caused by chronic sinusitis can be easilyoverlooked if not examined specifically.

Some examples of common physical findings of well-known causes ofFUO include temporal artery tenderness in temporal arteritis, diffuse lymph-adenopathy in lymphoma, and heart murmur in bacterial endocarditis.

Despite changes in definition, categorization, and approach, FUO con-tinues to exist as a diagnostic dilemma. In this condition, unlike manyothers, the successful diagnosis depends on a thorough history and physicalexamination rather than modern diagnostic procedures. Attention to detail,recognition of certain patterns, and disregarding nothing increases the chan-ces of success. In addition, repetition of both history and physical examina-tion is often necessary to arrive at a diagnosis in this very difficult endeavor.

References

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[2] Petersdorf R, Beeson P. Fever of unexplained origin: report on 100 cases. Medicine 1961;40:

1–30.

936 TOLIA & SMITH

[3] Louria D. Fever of unknown etiology. Del Med J 1971;343–8.

[4] Larson E, Featherstone H, Petersdorf R. Fever of undetermined origin: diagnosis and fol-

low-up of 105 cases, 1970-1980. Medicine 1982;61(5):269–93.

[5] Mourad O, Palda V, Detsky A. A comprehensive evidence-based approach to fever of un-

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[6] Gaeta G, Fusco F, Nardiello S. Fever of unknown origin: a systematic review of the litera-

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