Fever of Unknown Origin- A Practical Approach Library Lecture

Fever of Unknown Origin-A Practical Approach

Dr.Murat AkovaHacettepe University School of MedicineSection of Infectious DiseasesAnkara, Turkey

ESCMID Online Lecture Library

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Definitions•Classical FUO

– 3 w persisting fever, >38 ºC – >2 hospital visiting or 3 d in hospital evaluation

•Nosocomial FUO– Fever absent at admission and persisting in

hospital >3 d, >38 ºC

•Immundeficiency-related FUO– 3 d persisting fever, >38 ºC – Cultures negative at 48 h

•HIV-related FUO– Outpatient >3 w, in patient >3 d persisting fever,

>38 ºC– Confirmed HIV-positive patient

Infect Dis Clin N Am 2007;21:917


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Causes of FUO 12 Centers, 154 Patients

Küçükardalı Y, et al. Int J Infect Dis 2008; 12: 71


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Distribution of Diagnosis

Küçükardalı Y, et al. Int J Infect Dis 2008; 12: 71


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FUO in Elderly

•Collagen tissue diseases are more frequent–Polmyalgia rheumatica–Temporal arteritis

•Most frequent infectious diseases–Intraabdominal abscesses–Complicated UTI–Tuberculosis–Endocarditis

Clin Geriatr Med 2007;23:649


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Causes of FUO

Elderly, n=204 Young, n=152

Knockaert DC et al. J Am Geriatr Soc 1993;41:1187Knockaert DC et al. J Am Geriatr Soc 1993;41:1187


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Fever of Unknown OriginFever of Unknown OriginChanging SpectrumChanging Spectrum


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Rare and Emerging Causes of Rare and Emerging Causes of FUOFUO

•Babesiosis, Erlichiosis, Bartonellosis, Lyme disease

•Persistant Yersinia infection

•Parvovirus infections

•HHV-8

•Pneumocystis jirovecii infection

•Kikuchi necrotizing lymphaadenitis

•Inflammatory pseudotumor of lymph nodes

•Castleman disease

•Macrophage activation syndromeESCMID Online Lecture Library

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•Schnitzler disease

•B12 vitamin deficiency

•Occult haematoma

•Aortic dissection

•Lineer IgA dermatosis

•Chronic fatigue syndrome

•Anticonvulsant hypersensitivity

•Minocycline hypersensitivity

Rare and Emerging Causes of Rare and Emerging Causes of FUOFUO


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Hereditary Periodic Fever SyndromesHereditary Periodic Fever Syndromes


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A Patient with Fever and Lymphadenopathy

•25 y, male, from an eastern city of Turkey

•Fever, >39 C, persisting >1 month

•Axiller lymphanedopathy

•Multiple skin nodules, some pustulating

•Patchy infiltration in both lungs ESCMID Online Lecture Library

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Cont…

•He was given parenteral sulbactam-ampicillin in another hospital w no success

• Thoracoabdominal CT scan revelaed multiple abscesses in both liver and spleen and multiple noduler infiltration in both lungs

•Axillary lymph node biopsy reveals microabscesses with diffuse PMNL infiltration


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Cont…

•The patient reports working in a horse farm–Several horses recently dying due to an

unknown disease

•Micro lab reports Burkholderia cepacia growing in the blood cultures


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Cont…

•Upon being informed by the history of the patient Burkholderia mallei as confirmed in the cultures• Phenotypic testing

• 16S ribosomal RNA-gene sequencing

–He was given iv cefatzidim for two weeks, then po cipro for 6 months w complete recoveryESCMID Online Lectu

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Sites of Infection in Granulocytopenic Patient

Mouth & pharynx Vascular

catheter

LungsDistalesophagus

Colon

Perianalregion

Bone marrowaspiration site

Nose & sinuses


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Single Agent Bacteremia in EORTC-IATG Trials

Periods of EORTC Trials

% B

ac

tere

mia

Viscoli C. Eur J Cancer 2002;38(suppl 4):S82


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Distribution of BSI in 2652 Cancer Patients- SCOPE Project%

o

f p

atie

nts

Wisplinghoff, et al. Clin Infect Dis 2003;36:1103

* ** P<.001


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Etiology of MicrobiologicallyDocumented Secondary Infections

Akova M, et al. Clin Infect Dis 2005;40:239

Microbiologically documentedInfections, n=50

Gram-positive bacteria,n=25

n=129 secondary inf.


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Initial Empirical Approach

IDSA. Clin Infect Dis 2002;34:730


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No Guidelines or Evidence-based Recommendations are Available for the

Management of FUO


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Evaluation in Patient with FUO

• Detailed history and PE

• CBC, biochemistry• Urinalysis• Chest X-ray• Acute phase reactants• ANA, RF• Blood cultures

•CMV IgM

•Heterophil antibodies

•PPD

•Abdominopelvic CT

•Radyonuclear scan

•HIV antibodies

•Lower extremity Doppler angiography

Arrow PM, Flaherty JP. Lancet 1997;350:575


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Tests for Which Evidence ExistsTests for Which Evidence Exists

••Abdominal CTAbdominal CT

••Nuclear imagingNuclear imaging

••Duke criteriaDuke criteria

••Liver biopsyLiver biopsy

••Temporal arterial biopsyTemporal arterial biopsy

••Lower extremity Doppler Lower extremity Doppler

ultrasound imagingultrasound imaging


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Nuclear ImagingNuclear Imaging

TcTc--based tests(99mbased tests(99m--Tc BW Tc BW 250/183) 250/183)

Sensitivity Specificity

9393--94%94% 4040--7575%%

Indium 111 IgGIndium 111 IgGIndium 111Indium 111--labeled leucocyteslabeled leucocytes 4545--82%82% 69-86%

GaGa--67 scintigraphy67 scintigraphy 67%67% 78%78%

Fluodeoxyglucose PETFluodeoxyglucose PET 84%84% 86%86%

Semin Nucl Med 2009;39:81-87


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Liver BiopsyLiver Biopsy

Diagnostic yield in FUO 14Diagnostic yield in FUO 14--17%17%

No correlation with No correlation with hepatomegaly or alterations in hepatomegaly or alterations in liver function testsliver function tests

Complication:Complication: 0.0670.067--0.32 %0.32 %Mortality: Mortality: 0.0090.009--0.12 %0.12 %ESCMID Online Lectu

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TTeemporal Arterial Biopsymporal Arterial Biopsy

Incidence in FUO 16Incidence in FUO 16--17%17%

Complications are rare (facial nerve paralysis, skin necrosis)

Temporal arterial duplex ultrasonographyTemporal arterial duplex ultrasonography

HaloStenosisOcclusion

SSensitivity and specificity 93%ensitivity and specificity 93%ESCMID Online Lecture Library

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Prognosis in FUO

•Variable depending on the cause of FUO– Worse in elderly and patients with malignancy

•Delay in diagnosis is related with worse outcome– Intraabdominal infection– Miliary tuberculosis– Disseminated fungal infection– Recurrant pulmoner emboli

•Fever subsides within >4 weeks w/o sequela in patients w/o a diagnosis– 5-year mortality 3.2%ESCMID Online Lectu

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1st Evaluation

>>3 w fever3 w fever

FUOFUO

Stop all medications

>>72 h persisting fever72 h persisting fever

Documentation of fever

<<72 h defervescence72 h defervescence

Drug feverDrug fever

Diagnostic AlgorithmDiagnostic Algorithm


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Abdominal CT

Tc-based scintigraphyPET scan

(+) foci(+) foci

Tissue sample for confirming diagnosis

YesYes Duke criteria

NoNo

Suspected infective endocarditis


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Lower extremityDoppler

DVT (+)DVT (+)

LMWHLMWH

Fever persistsFever persists

YesYesTemporal arterybiopsy

NoNo

Liverbiopsy

LaparoscopyUndiagnosed FUOUndiagnosed FUOClinical

follow-up

Age >50

Clinicaldeterioration?

NoNo

YesYes


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••The most frequent cause are infectionsThe most frequent cause are infections

••>200 causes have been desccribed in the >200 causes have been desccribed in the literatureliterature

••80% of patients can be diagnosed within 3 80% of patients can be diagnosed within 3 weeksweeks

••Clinical evaluation guides complex diagnostic Clinical evaluation guides complex diagnostic toolstools

ConclusionsConclusions--11


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Conlusions-2

••Unjustified, blind diagnostic tools are Unjustified, blind diagnostic tools are ineffective and expose patients to ineffective and expose patients to unnecessary invasive proceduresunnecessary invasive procedures

••Mortality at the 1st year is highMortality at the 1st year is high

••LongLong--term prognosis are favorable in term prognosis are favorable in patients with an undiagnosed cause patients with an undiagnosed cause of FUOof FUOESCMID Online Lectu

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Fever of Unknown Origin- A Practical Approach Library Lecture