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Fever of Unknown OriginFever of Unknown Origin

and Adult Onset Stills Disease (AOSD)and Adult Onset Stills Disease (AOSD)

AM Report AM Report

Eric Edwards, M.D.Eric Edwards, M.D.

September 4, 2007September 4, 2007

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Fever of Unknown Origin:Fever of Unknown Origin:

DefinitionDefinition NOT febrile illness without initially obviousNOT febrile illness without initially obvious

etiologyetiology

Classical definition (Petersdorf and Classical definition (Petersdorf andBeeson, 1961):Beeson, 1961):

Fever > 38.3 on several occasionsFever > 38.3 on several occasions

Duration>3 weeksDuration>3 weeks Failure to reach a diagnosis after one week of Failure to reach a diagnosis after one week of

inpatient investigation*inpatient investigation*

*or at least 3 outpatient visits (refined definition)

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Patient SubtypesPatient Subtypes

ClassicalClassical

Nosocomial (Hospitalized>24h, no fever PTA)Nosocomial (Hospitalized>24h, no fever PTA)

C. Difficile, PE, drugsC. Difficile, PE, drugs

Immune Deficient (ANC<500)Immune Deficient (ANC<500)

Bacteremia, Fungal, HSVBacteremia, Fungal, HSV

HIVHIV M. Avium, PCP, CMV, lymphoma, Kaposis, drugsM. Avium, PCP, CMV, lymphoma, Kaposis, drugs

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Differential DiagnosisDifferential Diagnosis

InfectionsInfections

MalignanciesMalignancies

Autoimmune Disease Autoimmune Disease

MiscellaneousMiscellaneous

DrugsDrugs

HepatitisHepatitis

DVTDVT

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Roth AR and Basello GM. Am Fam Physician. 2003 Dec 1;68(11):2223-8.

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Causes of FUOCauses of FUO(in India)(in India)

Infectious 53%Infectious 53%

#1: TB (45%)#1: TB (45%)

Neoplasm: 17%Neoplasm: 17% #1: NHL (47%)#1: NHL (47%)

Collagen Vasc.: 11%Collagen Vasc.: 11%

#1 SLE: 45%#1 SLE: 45%

Miscellaneous: 5%Miscellaneous: 5%

Undiagnosed: 14%Undiagnosed: 14%

Kejariwal D et al. J Postgrad Med. 2001 Apr-Jun; 47(2): 104-7.

TB

24%

Abscess

7%

Endocarditis

5%

Other ID

17%

NHL

8%

Other Onc

9%

SLE

5%

Other Rheum

6%

Misc.

5%

Unknown

14%

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FUO by the DecadesFUO by the Decades

Mourad O et al. Arch Int Med. 2003 Mar 10;163(5):545-51.

I nf e c t i ou s

2 4 %

M a l i gn a nc y

1 5 %

R he um

2 4 %

O t he r

8 %

U n k n o w n

2 9 %

I nf e c t i o us

2 9 %

M a l i g na n c y

1 6 %R h e u m

2 5 %

O t h e r

1 3 %

U n k n o w n

1 7 %

I n f e c t i o u s3 1 %

M a l i g n a nc y

2 4 %

R h e u m

1 5 %

O t he r

1 3 %

U n k n o w n

1 7 %

I nf e c t i ous

3 6 %

M a l i gna nc y1 9 %

R h e u m

1 8 %

O t h e r

1 8 %

U n k n o w n

9 %

1950s 1970s

1980s1990s

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Minimal Diagnostic CriteriaMinimal Diagnostic Criteria

H+PH+P

CBC & Diff CBC & Diff

Blood Cultures x 3Blood Cultures x 3

Chem10Chem10

LFTsLFTs

U/A and MicroscopyU/A and Microscopy

Urine cultureUrine culture

Chest X Chest X--rayray

Hepatitis serologies (if Hepatitis serologies (if

abnormal LFTs)abnormal LFTs)

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Other Basic TestsOther Basic Tests

ESR/CRPESR/CRP

Peripheral SmearPeripheral Smear

ANA ANA

Rheumatoid FactorRheumatoid Factor

HIVHIV

CMV IgMCMV IgM Mono Spot Mono Spot

PPDPPD

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Invasive ProceduresInvasive Procedures

Lumbar PunctureLumbar Puncture

Liver BiopsyLiver Biopsy

Temporal Artery BiopsyTemporal Artery Biopsy

Bone Marrow BiopsyBone Marrow Biopsy

Lymph Node BiopsyLymph Node Biopsy

Surgical Exploration of the AbdomenSurgical Exploration of the Abdomen

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Adult Onset Stills Disease Adult Onset Stills Disease

EpidemiologyEpidemiology Rare (0.16/100000)Rare (0.16/100000) ~60% female~60% female

Affects all ages Affects all ages PathogenesisPathogenesis Poorly understoodPoorly understood Genetic component?Genetic component? Infectious trigger?Infectious trigger?

CharacteristicsCharacteristics Daily, high spiking fevers (85Daily, high spiking fevers (85--100%)100%) Arthritis (68 Arthritis (68--94%)94%) Evanescent rash (51Evanescent rash (51--87%)87%)

No specific diagnostic studyNo specific diagnostic study Diagnosis is based on the presentation of characteristicDiagnosis is based on the presentation of characteristic

features and the exclusion of similar conditionsfeatures and the exclusion of similar conditions

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Diagnostic Criteria (Yamaguchi)Diagnostic Criteria (Yamaguchi)

MajorMajor Fever>39Fever>39°°, lasting >1, lasting >1

weekweek

Arthralgias or arthritis Arthralgias or arthritislasting >2 weekslasting >2 weeks

Typical rashTypical rash

WBC>10,000 withWBC>10,000 with

>80% PMNs>80% PMNs

MinorMinor Sore throat Sore throat

LymphadenopathyLymphadenopathyand/or splenomegalyand/or splenomegaly

Abnormal LFTs Abnormal LFTs

Negative ANA and RFNegative ANA and RF

ExclusionsExclusions InfectionsInfections

MalignancyMalignancy

Rheumatic DiseaseRheumatic Disease

Diagnosis: Five criteria, at least two major(83-91% sens., 90% spec., 70% PPV, 95% NPV)

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AOSD and Ferritin AOSD and Ferritin

Ferritin is an acute phase reactant Ferritin is an acute phase reactant

80% have >5x elevation in ferritin80% have >5x elevation in ferritin

NonNon--specificspecific

Low Glycosylated ferritin (GF) is moreLow Glycosylated ferritin (GF) is morespecificspecific

GF<20% + Ferritin >5x nl=93% specificGF<20% + Ferritin >5x nl=93% specific

Only 43% sensitiveOnly 43% sensitive

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Treatment Treatment

NSAIDsNSAIDs Monotherapy is effective in only ~10%Monotherapy is effective in only ~10%

SteroidsSteroids 75% will respond favorably75% will respond favorably

MethotrexateMethotrexate

TNF blocking agentsTNF blocking agents Etanercept Etanercept

InfliximabInfliximab

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PrognosisPrognosis

Three distinct patters (~1:1:1)Three distinct patters (~1:1:1)

Self limitedSelf limited

Most patients achieve remission within one yearMost patients achieve remission within one year Intermittent Intermittent

Recurrent flares with complete remission betweenRecurrent flares with complete remission between

Flares may be years apart Flares may be years apart

Recurrences tend to be milder than initial episodeRecurrences tend to be milder than initial episode

ChronicChronic

Articular manifestations can be severe Articular manifestations can be severe

2/3 may need at least one total joint replacement 2/3 may need at least one total joint replacement

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ReferencesReferences

1. Roth AR et al. Approach to the Patient with Fever of Unknown Origin.1. Roth AR et al. Approach to the Patient with Fever of Unknown Origin. Am Fam Am FamPhysician.Physician. 2003 Dec 1;68(11):22232003 Dec 1;68(11):2223--28.28.

2. Mourad O et al. A Comprehensive Evidence Based Approach to Fever of Unknown2. Mourad O et al. A Comprehensive Evidence Based Approach to Fever of UnknownOrigin.Origin. Arch Int Med. Arch Int Med. 2003 Mar 10;163:5452003 Mar 10;163:545--51.51.

3. Bor, DH. Approach to the Adult with Fever of Unknown Origin.3. Bor, DH. Approach to the Adult with Fever of Unknown Origin. www.utdol.comwww.utdol.com..

4. Kejariwal D et al. Pyrexia of Unknown Origin: A Prospective Study of 100 Cases.4. Kejariwal D et al. Pyrexia of Unknown Origin: A Prospective Study of 100 Cases. J J Postgrad Med.Postgrad Med. 2002 Apr2002 Apr--Jun;48(2):155 Jun;48(2):155--6.6.

5. Efthimiou P et al. Diagnosis and Management of Adult Onset Stills Disease.5. Efthimiou P et al. Diagnosis and Management of Adult Onset Stills Disease. Ann Ann

Rheum Dis.Rheum Dis. 2006 May;65:5642006 May;65:564--72.72.

6. Uppal SS et al. Ten Years of Clinical Experience with Adult Onset Stills Disease: Is6. Uppal SS et al. Ten Years of Clinical Experience with Adult Onset Stills Disease: Isthe Outcome Improving?the Outcome Improving? Clin Rheumatol.Clin Rheumatol. 2007 Jul;26(7):10552007 Jul;26(7):1055--60.60.

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