Fever of Unknown Origin AIMGP Seminar Series Dr. Katina Tzanetos February 2007.
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Transcript of Fever of Unknown Origin AIMGP Seminar Series Dr. Katina Tzanetos February 2007.
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