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