Fever of Unknown OriginAIMGP Seminar SeriesDr. Katina TzanetosFebruary 2007

References Mourad, O., et al. A Comprehensive Evidenced-Based Approach to Fever of Unknown Origin. Arch Inter Med 163: March 10, 2003.Roth, A. and Basello, G. Approach to the Adult Patient with Fever of Unknown Origin. American Family Physician 68 (11), 2223.Up To Date.Approach to the adult with fever of unknown originEtiologies of fever of unknown origin in adults

* Much of this talk based on very helpful article by Mourad et al. Highly recommended

Case Discussion Based on Real Patient28-year old female, born in Canada, parents from Hong Kong2.5 week history of fever 40.0C or higherOnly other symptom is possible rash on lower legs intermittent, tender, red nodules Works in bankNon-smoker, non-drinkerOnly medication is OCP

Take a minute to discussDoes she fit the criteria for Fever of Unknown Origin

Why or why not?

Fever of Unknown Origin - DefinitionClassic definitionTemperature higher than 38.3CSeveral occasionsCause obscure after 1-week of in-patient evaluationCurrent definition recognizes acceptability of out-patient in place of in-patient investigations

Case DiscussionBased on short duration and absence of investigations patient does not fit diagnostic criteriaIf fever persists, should pursue diagnosisHer fever persistsWhat aspects of the history and physical examination do you focus on during this initial visit?

Four Proposed Categories of FUOBased on potential etiology of FUOAll require temperature > 38.3C Categorization be especially helpful in organizing an approach to patient evaluationClassicNosocomialImmune-deficient (neutropenic)HIV-related

Classic Category of FUODefinition: Duration > 3 weeks, evaluation of at least 3 outpatient visits or 3 days in-hospitalCommon etiologies:Infection, malignancy, CVD

This category will be the focus of this talk

Nosocomial Category of FUODefinition:Hospitalization of at least 24 hrs with no fever on admission, evaluation of at least 3 daysCommon etiologies:C.Difficile, drugs, PE, septic thrombophlebitis, sinusitis (intubated patients)

Immune-deficient (neutropenic) Category of FUODefinition:Neutrophil count < 500/mm3, evaluation of at least 3 daysEtiologies:Opportunistic bacterial infections, aspergillosis, candidiasis, herpes virus

HIV-Associated Category of FUODefinition:Duration of at least 4 weeks for outpatients and 3 days for inpatients, HIV confirmedEtiologies:Cytomegalovirus, MAI, Pneumocystis, drugs, Kaposis, lymphoma

Etiology and Epidemiology of Classic FUOInfections: Most common cause accounting for 1/3 of cases TB; Most common infection in non-elderly adultsPPD positive in less than 50% of pts with TB and FUO, Sputum samples positive in only of patientsAbscessesUsually in abdomen or pelvis with some pre-disposing cause (e.g. recent surgery, diabetes, biliary tract disease, recent UTI)Other infections: Osteomyelitis, endocarditis (esp. in pts with recent antibiotic use or HACEK organisms)Malignancy: Second most common cause Lymphoma (esp. non-Hodgkins), Leukemia, Renal cell, HCC, other metastasis to liverCVD: Third most common causeAdult Stills disease in younger patients and giant cell arteritis in older patients

Diagnostic Approach - HistoryHistoryTravelExposures to toxins, sick persons, animalsImmunosuppressionLocalizing symptomsLook for subtle findings: eg. Jaw claudication, nocturia with prostatitisDegree of fever, nature of fever curve, apparent toxicity, and response to antipyretics not specific enough to guide management

Diagnostic Approach Physical ExaminationRepeated examination may be neededCareful attention to skin, mucous membranes, lymph and abdominal systemAsk pts to record and measure temperature dailyYield from history and physical examination unknown

Back to the caseThorough history and physical non-contributory except for intermittent skin lesions

Given what you know thus far, what investigations would you order?

Diagnostic Approach Laboratory InvestigationsSuggested minimal diagnostic work-up to qualify as FUO has varied over the yearsRecent article by Mourad et al suggests following as minimal:History and physical examinationCBC and differentialBlood film reviewed by hematopathologistRoutine chemistry including LDH, bilirubin, liver enzymesUrinalysis and microscopyANA, RH factorHIVCMV IgM; heterophil test if suspicious for MononucleosisQ-fever serology (if risk exists)CXRHepatitis serology (if abnormal liver enzymes)

Diagnostic Approach Investigations and the EvidenceAbdominal CTUseful to look for abdominal lymphoma and abscessDiagnostic yield in case series 19%Clinical follow-up showed that only 1/32 patients with normal scans had an intra-abdominal cause for FUO

Diagnostic Approach Investigations and the EvidenceNuclear Imaging: For localizing inflammatory or infectious focusTechnetium scans likely have best test characteristics overall and should be test of choiceTechnetium studies: specificity 93%, sensitivity 40-75%; PLR 5.7-12.5Indium-labeled WBC scans: specificity 69%-86%, sensitivity 45%-82%Gallium scans: (limited studies)

Diagnostic Approach Investigations and the EvidenceDuke criteria for endocarditis: Endocardities: 1-5% of all cases of FUOSensitivity 82%, specificity 99%

Liver Biopsy: Diagnostic yield 14%-17% regardless of whether abnormal physical exam or liver enzymes existComplications in FUO from biopsy only 0.32% at mostRecommended

Diagnostic Approach Investigations and the EvidenceTemporal artery biopsy Large studies comprised of elderly with FUO lackingArteritis cause of FUO ~16% of pts (All comers)Safe, recommended in elderly with FUO

Leg dopplersDVT cause of FUO ~ 2-6% of ptsSafe, easy to do, recommended

Diagnostic Approach Investigations and the EvidenceBone Marrow ExaminationDiagnostic yield of culture 0-2%Not recommended in immunocompetent ptsAbdominal explorationRole of surgery in post-CT era uncertainEmpiric Therapy (antibiotics, anti-TB, steroids)Not studied Not recommended

Proposed Diagnostic AlgorithmMourad, O. et al. Arch Intern Med 2003;163:545-551.

Back to the caseCBC and differential, electrolytes, BUN, creatinine, Ca/Mg/Ph all normalLiver enzymes very slightly elevated then normalized (AST 68normal, ALT 78normal), bilirubin, ALP normalMultiple blood cultures: no growthESR 39Hepatitis, Lyme, PPD, Mononucleosis, Q-fever, HIV serology all negative, ANA, RF negativeCT thorax and abdomen normal2D Echo normalLeg dopplers negativeSkin biopsy: unremarkable epidermis and dermis, no subcutaneous material obtained; lesions resolved

Back to the caseFever of > 40C continued for more than 4 weeksNo diagnosis despite multiple out-pt visits and a short in-hospital stayDebated about going to bone marrow biopsy versus liver biopsyDecided on nuclear scanHowever, pt was given short course of oral antibiotics by family MD, symptoms resolved, pt cancelled all further tests and follow-up appointments with us and is doing fine

Conclusions from CaseGiven our modern-day advances, prognosis in patients who truly have no diagnosis after extensive recommended work-up is very good (most sinister diagnoses are discovered)In some cases, spontaneous resolution occurs, in others, watchful waiting is necessary (but often frustrating) 1930s: > 30% of FUO with no diagnosis diedToday: 50-90% or more recover spontaneously