Fever of Unknown OriginFever of Unknown Origin

AIMGP Seminar Series

Dr. Katina Tzanetos

February 2007

References 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 origin– Etiologies of fever of unknown origin in adults

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

Case Discussion – Based on Real PatientCase Discussion – Based on Real Patient

28-year old female, born in Canada, parents from Hong Kong

2.5 week history of fever 40.0C or higher Only other symptom is possible rash on lower legs

– intermittent, tender, red nodules Works in bank Non-smoker, non-drinker Only medication is OCP

Take a minute to discuss…Take a minute to discuss…

Does she fit the criteria for Fever of Unknown Origin

Why or why not?

Fever of Unknown Origin - DefinitionFever of Unknown Origin - Definition

Classic definition– Temperature higher than 38.3C– Several occasions– Cause obscure after 1-week of in-patient

evaluation

Current definition – recognizes acceptability of out-patient in place

of in-patient investigations

Case DiscussionCase Discussion

Based on short duration and absence of investigations patient does not fit diagnostic criteria

If fever persists, should pursue diagnosisHer fever persists

– What aspects of the history and physical examination do you focus on during this initial visit?

Four Proposed Categories of FUOFour Proposed Categories of FUO

Based on potential etiology of FUO All require temperature > 38.3C Categorization be especially helpful in organizing

an “approach” to patient evaluation– Classic– Nosocomial– Immune-deficient (neutropenic)– HIV-related

Classic Category of FUOClassic Category of FUO

Definition: – Duration > 3 weeks, evaluation of at least 3

outpatient visits or 3 days in-hospital

Common etiologies:– Infection, malignancy, CVD

This category will be the focus of this talk

Nosocomial Category of FUONosocomial Category of FUO

Definition:– Hospitalization of at least 24 hrs with no fever

on admission, evaluation of at least 3 days

Common etiologies:– C.Difficile, drugs, PE, septic thrombophlebitis,

sinusitis (intubated patients)

Immune-deficient (neutropenic) Immune-deficient (neutropenic) Category of FUOCategory of FUO

Definition:– Neutrophil count < 500/mm3, evaluation of at

least 3 days

Etiologies:– Opportunistic bacterial infections, aspergillosis,

candidiasis, herpes virus

HIV-Associated Category of FUOHIV-Associated Category of FUO

Definition:– Duration of at least 4 weeks for outpatients and

3 days for inpatients, HIV confirmed

Etiologies:– Cytomegalovirus, MAI, Pneumocystis, drugs,

Kaposi’s, lymphoma

Etiology and Epidemiology Etiology and Epidemiology of of Classic Classic FUOFUO

Infections: Most common cause accounting for 1/3 of cases – TB; Most common infection in non-elderly adults

– PPD positive in less than 50% of pts with TB and FUO, Sputum samples positive in only ¼ of patients

– Abscesses Usually 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-Hodgkin’s), Leukemia, Renal cell, HCC, other metastasis to liver

CVD: Third most common cause– Adult Still’s disease in younger patients and giant cell arteritis in older

patients

Diagnostic Approach - HistoryDiagnostic Approach - History

History– Travel– Exposures to toxins, sick persons, animals– Immunosuppression– Localizing symptoms– Look for subtle findings: eg. Jaw claudication, nocturia

with prostatitis Degree of fever, nature of fever curve, apparent

toxicity, and response to antipyretics not specific enough to guide management

Diagnostic Approach – Diagnostic Approach – Physical ExaminationPhysical Examination

Repeated 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 case…Back to the case…

Thorough history and physical non-contributory except for intermittent skin lesions

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

Diagnostic Approach – Diagnostic Approach – Laboratory InvestigationsLaboratory Investigations

Suggested minimal diagnostic work-up to qualify as FUO has varied over the years

Recent article by Mourad et al suggests following as minimal:

– History and physical examination– CBC and differential– Blood film reviewed by hematopathologist– Routine chemistry including LDH, bilirubin, liver enzymes– Urinalysis and microscopy– ANA, RH factor– HIV– CMV IgM; heterophil test if suspicious for Mononucleosis– Q-fever serology (if risk exists)– CXR– Hepatitis serology (if abnormal liver enzymes)

Diagnostic Approach – Diagnostic Approach – Investigations and the EvidenceInvestigations and the Evidence

Abdominal CT– Useful to look for abdominal lymphoma and

abscess– Diagnostic 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 – Diagnostic Approach – Investigations and the EvidenceInvestigations and the Evidence

Nuclear Imaging: – For localizing inflammatory or infectious focus– Technetium scans likely have best test

characteristics overall and should be test of choice

Technetium studies: specificity 93%, sensitivity 40-75%; PLR 5.7-12.5

Indium-labeled WBC scans: specificity 69%-86%, sensitivity 45%-82%

Gallium scans: (limited studies)

Diagnostic Approach – Diagnostic Approach – Investigations and the EvidenceInvestigations and the Evidence

Duke criteria for endocarditis: – Endocardities: 1-5% of all cases of FUO– Sensitivity 82%, specificity 99%

Liver Biopsy: – Diagnostic yield 14%-17% regardless of whether

abnormal physical exam or liver enzymes exist– Complications in FUO from biopsy only 0.32% at most– Recommended

Diagnostic Approach – Diagnostic Approach – Investigations and the EvidenceInvestigations and the Evidence

Temporal artery biopsy – Large studies comprised of elderly with FUO lacking– Arteritis cause of FUO ~16% of pts (All comers)– Safe, recommended in elderly with FUO

Leg dopplers– DVT cause of FUO ~ 2-6% of pts– Safe, easy to do, recommended

Diagnostic Approach –Diagnostic Approach –Investigations and the EvidenceInvestigations and the Evidence

Bone Marrow Examination– Diagnostic yield of culture 0-2%– Not recommended in immunocompetent pts

Abdominal exploration– Role of surgery in post-CT era uncertain

Empiric Therapy (antibiotics, anti-TB, steroids)– Not studied – Not recommended

Proposed Diagnostic AlgorithmProposed Diagnostic Algorithm

Mourad, O. et al. Arch Intern Med 2003;163:545-551.

Back to the case…Back to the case…

CBC and differential, electrolytes, BUN, creatinine, Ca/Mg/Ph all normal

Liver enzymes very slightly elevated then normalized (AST 68normal, ALT 78normal), bilirubin, ALP normal

Multiple blood cultures: no growth ESR 39 Hepatitis, Lyme, PPD, Mononucleosis, Q-fever, HIV serology all

negative, ANA, RF negative CT thorax and abdomen normal 2D Echo normal Leg dopplers negative Skin biopsy: unremarkable epidermis and dermis, no subcutaneous

material obtained; lesions resolved

Back to the case…Back to the case… Fever of > 40C continued for more than 4 weeks No diagnosis despite multiple out-pt visits and a

short in-hospital stay Debated about going to bone marrow biopsy

versus liver biopsy Decided on nuclear scan However, 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 CaseConclusions from Case

Given 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 died– Today: 50-90% or more recover spontaneously