012711 Fever of Unknown Origin [Team 2]

8/6/2019 012711 Fever of Unknown Origin [Team 2]

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OUTLINE:Case PresentationPerspectives

Primary Attending Physicians IntroductionInfectious Disease Specialists PerspectiveHematologists PerspectiveOncologists PerspectiveRheumatologists PerspectiveCardiologists PerspectiveDermatologists PerspectiveNeurologists PerspectivePulmonologists Perspective

Final DiagnosisFever of Unknown Origin Lecture ProperSummary Table for the Four Classifications of FeverAppendix

CASE PRESENTATIONPatient Profile

MaleMiddle-agedFrom Antipolo, RizalMarried

Anxious and SadClinical History

Feeling achy and tiredUnusual fever patternElevated pinkish colored rash

Disappeared after some timeCough with mild shortness of breathHeadache

Physical ExaminationPainful joints

Red but not swollenSeveral swollen tender neck lymph nodesStiff and sore, especially when feverish

LabsElevated white blood cell count

Mildly abnormal liver enzymesPERSPECTIVES

Primary Attending Physicians Introduction

SHAPE \* MERGEFORMAT

Main Causes of FUO

Undiagnosed

Infectious (TB)

Non-infectious inflammatory diseases

Neoplasms

Inflammatory Causes

MiscellaneousDrug-related, Pulmonary Fever, Factitious Fever, Hereditary Periodic Fever Syndromes, and Fabry

Disease

Fever without a Source

Fever of 1 week or less

Careful History and PE yields no possible source

3 main considerations:InfectiousRheumatologicMalignant

Infectious Disease Specialists Perspective


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Salient Features

Salient feature Rationale Other questions to ask

Identifying data

51 y.o previously healthy male, married

from Antipolo, Rizal

Predisposition for diseases (infectious

and non-infectious)in certain age

groups, sex, country/region

History of present illnessFever of 1 week duration which is

more prominent in the afternoon

Fever with an unusual pattern such as

that occurring in the afternoon with

resolution by morning is usually

associated with pulmonary tuberculosis

among other diseases.

Were there any medications taken for

the fever?

Others in the household or neighborhood

with the same symptoms?

Bodymalaise Usuallyassociatedwithfever A c6vi6esofdailylivingimpaired?


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Chills Notallfeverpresentwithchills;may

helpinthedifferen6aldiagnosis.

Maybepresentinurinarytractinfec6on

andpulmonarytuberculosis.

Nightsweats Therearefewdiseaseswhichpresents

withnightsweats,suchaspulmonary

tuberculosis.

Nightsweats Therearefewdiseaseswhichpresents

withnightsweats,suchaspulmonary

tuberculosis.

Unresponsivetoan6bio6cs Historyofpreviousan6bio6ctherapy

willaffectthemanagement.Eitherthe

previouslyusedan6bio6cwillnolonger

beusedorthereisshiFingtoan

an6bio6cwithwidermicrobialcoverage.

Whatan6bio6cs?orwhat?Dosingor

frequency?Compliance?Sideeffects?

Patchesofrash Mayalsobeassociatedwiththefever;

reac6ontotheincreaseinbodyheat

Istheresolu6onofthesymptom

togetherwithfeverlysis?Pruri6c?

Cough Coughwouldpointtoapossiblefocusof

infec6onorpossibleaffectedorgan

system

Wasthecoughproduc6ve?Whatcolor?

Dura6on?Medica6onstaken?

Headache Usuallyassociatedwithfever

Myalgia Maybeassociatedwiththefeveror

maypointtoadifferentdiseaseen6ty

suchasinfluenza

Generalized?Localized?Timing?

Relievedby?

PastMedicalHistory

Elevatedbloodpressureandcholesterol

withregularintakeofmedica6ons

Mayaffectmanagementop6ons

especiallyiftherearepossibledrugdrug

interac6onsbetweenproposed

treatmentandcurrentmedica6ons

Whatarethemedica6onsbeingtaken

forthesecondi6ons?Whatwasthe

highestandusualBP?Associa6ng

symptoms?

PhysicalExamina5onTachycardia Usuallyassociatedwithfeverwherein

anincreasein1degreeCelsiuswill

increasetheusualheartrateofthe

pa6entto10morebeatsperminute.

Definition of FUO

Petersdorf and Beeson (1961)temperatures of 38.3C (101F) on several occasions;a duration of fever of >3 weeks; andfailure to reach a diagnosis despite 1 week of inpatient investigation.

Durack and Street (new system for FUO classification)classic FUO;

nosocomial FUO;neutropenic FUO; andFUO associated with HIV infection

Diagnostic Algorithm

Comprehensive history

confirm a history of fever and document the fever pattern

Thorough physical examination

Appropriate laboratory testingRule out drug fever


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Suspected drug is not the cause if fever persists beyond 72 hours after its removalAfter ruling out drug fever, do preliminary laboratory evaluationcomplete blood count/diff countelectrolytesliver function testerythrocyte sedimentation rateurinalysisPPD skin testChest X-ray

basic cultures: blood, urine

Differentials

Differen5al ReasonsforRulingin ReasonsforRulingout

Tuberculosis Cough

ever

NightSweats

Tachycardia

Lymphadenopathy:ofTBisusually

painless

Malaria lulikesymptomsoffever,headache,

malaise,fa6gue,muscleaches.

Paroxysmalcycle:chills1-2hrsfollowed

byhighfever3-4hrsandthen2-4hrsof

profusediaphoresis

Somepa6entsmaypresentwith

diarrheaandGIsymptoms.

Nohistoryofexposure

Typhoidever ever pa\ernisstepwise,characterized

byarisingtemperatureoverthecourse

ofeachdaythatdropsbythe

subsequentmorning;peaksandtroughs

riseprogressivelyover6me

Cough,dullfrontalheadache,malaise

Mostdocumentedtyphoidfevercases

involvedschool-agedchildrenandyoung

adults

Influenza evermayvarywidelyamongpa6ents:

low(100)tohigh(104).Some

pa6entsreportfeelingfeverishanda

feelingofchills

Myalgiasarecommonandrangefrom

mildtosevererontal/retro-orbitalheadacheis

commonandisusuallysevere

Weaknessandseverefa6guemay

preventpa6entsfromperformingtheir

normalac6vi6esorwork

Coughandotherrespiratorysymptoms

maybeini6allyminimalbutfrequently

progressastheinfec6onevolves;may

reportnonproduc6vecough,cough-

relatedpleuri6cchestpain,anddyspnea

Tachycardiamostlikelyresultsfrom

hypoxia,fever,orboth.

Noocularsymptoms:photophobia,

burningsensa6ons,and/orpainupon

mo6on

DiagnosticsDifferen5al Diagnostic Examinations to be Requested


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Tuberculosis CXR

miliary reticulonodular pattern, large infiltrates with pleural

effusion, or interstitial infiltrates with pleural effusion

noradioabnormalityearlyinthecourseandamongHIV

pa6ents

PPDskintest

whealandflare(willnotindicatewhetherac6veinfec6on,inac6veinfec6on,orjustexposure)

maybenega6veinuptohalfofcases

CBC/Diffcount

anemia(ACD)withleukopenia,neutrophilicleukocytosis,

leukemoidreac6onandpolycythemia

LT

elevatedALP,ALTandAST

couldalsobesecondarytolong-standingcholesterol

problemifwithhepa6cinvolvement

SputumAB/culture

demonstra6onofacid-fastmycobacterium

Bronchoscopy/alveolarlavage

higheryieldforculture

CSanalysis

Cultures:blood,urine,CS

Malaria Thicksmear

demonstra6onofplasmodiabutspecia6onisnotpossible

doneduringorsoonaFerfeverspikes

Thinsmear

lesssensi6vethanthicksmearbutspecia6oncanbedone

Typhoidever Clinicaldiagnosis

Serologic:Indirecthemagglu6na6on/indirectfluorescentVi

an6body/typhidot(ELISA)

Culture:(blood/urine/stool)

isola6onoforganism;mul6pleculturesInfluenza Clinicaldiagnosis

CBC

leukopeniawith/withoutlymphocytosis

CXR

shouldbecleartoexcludepneumonia

Cultureisanop6on(nasopharyngeal/throatswab)

Primary Diagnosis: Disseminated Tuberculosis

The Philippines ranks ninth on the list of 22 high-burden tuberculosis (TB) countries in the world,

according to WHOs Global TB Report 2009

In 2007, approximately 100 Filipinos died each day from the disease.

In 2004, the country achieved a TB case detection rate of 72 percent, exceeding WHOs target of 70

percent, and reached 75 percent in 2007. The DOTS (the internationally recommended strategy for TBcontrol) treatment success rate has remained around 88 percent since 1999

However, while the national performance levels are already high, many provinces are still below target

levels due to various systemic and social factors, including:

Problem in seeking care due to the stigma of TB

The expanding multidrug-resistant (MDR) TB. WHO has reported extensively drugresistant TB in the

Philippines. The availability of over-the-counter TB drugs and selfmedication by patients continue

to contribute to the emergence of TB drug resistance.

Disseminated TB is life-threatening if not treated promptly and especially for the elderly, infants,and


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people with a compromised immune system.

Treatment Options

Hospital admissionclose observationfollow-up every potential lead

As a general rule, antibiotics should not be given empirically as a diagnostic measure.

Treatment should be directed against the underlying pathology.While waiting for the results of laboratory tests, symptoms may be addressed.

Supportive TreatmentPharmacologic:

Acetaminophen, Aspirin, or NSAIDsNon-pharmacologic

Ensure adequate hydration

Proper nutrition

Sponge bath

Hydrotherapy

Use of wet socks

Treatment for disseminated TBTreatment Goal: eradicate the infection with drugs that target TB.Main Pharmacologic Treatment: (4 drugs)

Isoniazid

Rifampicin,

Pyrazinamide

EthambutolOther drugs: Amikacin, Ethionamide, Moxifloxacin, Para-aminosalicylic acid and streptomycin.Refer to TB-DOTS

Prognosis

Most disseminated forms of TB respond well to treatment.

Complications of disseminated TV can include:Adult respiratory distress syndrome (ARDS)Lung failureRelapse of the disease

Medicines used to treat TB may cause side effects, including liver problems.Other side effects include:

Changes in vision

Orange- or brown-colored tears and urine

Rash

Public Health and Psychosociocultural Issues

For the patient, tuberculosis and malaria are differentials.These two disease entities are endemic in the Philippines and may remain undiagnosed for a long

time.For TB, the DOTS has gained significant improvements in treating TB patients

Research-oriented countries are focusing on chronic diseases and their complications (e.g. CVD, CA,

DM). Furthermore, HIV is now taking the limelight.This causes diseases like TB and Malaria to be relegated to the background although they are still

taking many lives each year.

Hematologists PerspectiveWorking Diagnosis: Malaria

Pathophysiology (from Best Practice):During a blood meal, an infected female Anopheles mosquito injects thousands of malarial

sporozoites, which rapidly enter hepatocytes. Reproduction by asexual fission (tissue schizogony)takes place to form a pre-erythrocytic schizont. This part of the life-cycle produces no symptoms.After a period of time, thousands of merozoites are released into the blood stream to penetrateerythrocytes after attaching via receptors. The time period before merozoites enter the blood isdesignated the pre-patent period; this is between 7 and 30 days forP falciparum, but may be much


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longer forP vivax orP ovale because of the possible development of an inactive hypnozoite stage inthe liver. HYPERLINK "http://bestpractice.bmj.com/best-practice/monograph/161/resources/references.html" \l "ref-16" Most merozoites undergo blood schizogony to form trophozoites,evolving to schizonts, which rupture to release new merozoites. These then invade new erythrocytesand the 48-hour cycle continues, sometimes resulting in periodicity of fever. The rupture oferythrocytes releases toxins that induce the release of cytokines from macrophages, resulting in thesymptoms of malaria. HYPERLINK "http://bestpractice.bmj.com/best-practice/monograph/161/resources/references.html" \l "ref-17" Some merozoites mature into larger forms called gametocytes,which reproduce sexually if they are ingested by a mosquito.

Differentials

Disease Characteris5cs Notes

Influenza influenzavirus,worldwidedistribu6on,

fever,headache,drycough,runnynose,

sorethroat,myalgia,malaise

Influenzacanbediagnosedserologically

orbyisola6ngthevirus

Dengueever ever,headache,nausea,malaise,

anorexia,sorethroat,severemyalgias.

Rash(centrifugal),petechiae,

lymphadenopathy,conjunc6val

injec6on,pharyngealerythema,

rela6vebradycardia

Denguecanbediagnosedserologically

Typhoidfever fever(stepladdertemperature)

Headache

Chills

abdominalandchestrash(rosespots)

jointpains

Per6nentNega6ves:

abdominaltenderness

diarrhea(possiblebloody)

splenomegaly,hepatomegaly

Bradycardia

proteinuria(ruleoutinlabs)

TB ever,headache,nausea,malaise,

anorexia,sorethroat,severemyalgias.

Incidenceishighinthecountry

Diagnostics

Diagnos5cs ExpectedResults ClinicalDecisions

ThickBloodSmear

(Quan6ta6vetest)

Shoulddemonstrateparasites

insideRBCs

Parasitemiacanbecalculatedbased

onthenumberofinfectedRBCs

ThinBloodSmear

(Qualita6vetest)

Shoulddemonstrateparasites

insideRBCs

Treatmentgreatlydependsonthe

iden6fica6onofthePlasmodium

speciesresponsibleforthe

infec6on.

LDHTest ElevatedLDHlevels(partoftriadof

malaria:thrombocytopenia,elevated

LDHandatypicallymphocytes)

Indica6veofhaemoly6canemiadue

toRBCdamage

CBCandWBCDifferen6al,Peripheralbloodsmear

Normochromic,normocy6canemiaThrombocytopeniaandAtypical

lymphocytes

slightmonocytosis,lymphopenia

andeosinopenia,withreac6ve

lymphocytosisandeosinophiliain

theweeksaFertheacuteinfec6on

Indica6veofplateletdysfunc6on

Additional diagnostic exams to be requested:Chest X-ray: To see infiltrates


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AFB smear and culture: demonstration of the inciting organism

Treatment

Chloroquine

Mefloquine

Primaquine

Quinine

Pyrimethamine-Sulfadoxine (Fansidar)

Doxycycline


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Immunohistochemistry studies Tissue was not enough to do immunohistochemistry stains

Pulmonary Function Test Not done

Hepatitis Panel for Hepatocellular CA Positive antibodies for Hep A, B and C

Bone Scan for Bone Metastasis Deferred

MRI of the brain for head and neck CA Not done until seen by a neurologist

Expectedfindings

0%ofCUPsarefoundtobeadenocarcinoma

5%Squamouscellcarcinoma

25%Poorlydifferen6ated

Hodgkins Lymphoma

Diagnostic Exam Information Provided

Erythrocyte Sedimentation Rate 5xelevated

orHodgkinsLymphoma,itisexpectedtobeelevated

whichconfersworseprognosis

Notspecific

Lactate dehydrogenase 10xelevated

orHodgkinsLymphoma,itisexpectedtobeelevated

CBC LeukocytosisorHodgkinsLymphoma,cytopeniaisexpected.

Plateletscanbeincreasedordecreased.

Alkaline Phosphatase Elevated

Increasedwithliverorboneinvolvement

Clinicalpresenta6onandhistoryandriskfactorsmustbeassessedbeforeaskingforspecifictestsfor

Cancer

Un6ltheresultsoftheexcisionalbiopsythenwecanaskforthetests

Whichcancerpresentswithdermatologicmanifes6on

HodgkinsLymphomahypersensi6vityofexaggeratedpropor6onsTherapy

Chemotherapy

SurgeryRadiotherapy

Immunotherapy

Palliative treatment


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Rheumatologists Perspective - DIfferentialsAcute Rheumatic Fever

Consideredasaclinicalsyndrome

Causedbyastreptococcalinfec6on

Usuallypresentinpediatricpa6ents(5-12)

Rule In Rule OutFever

Arthralgia

Rash

Pharyngitis possible / Evidence of Streptoccocal

infection

Pleuritis possible

Not common for a middle-aged patient in an acute

setting

Rash

Does not fully satisfy the Jones Criteria for ARF

ARF RARELY presents with lymphadenopathy

ARF usually occur two to four weeks after group A

beta-hemolytic streptococcal infection of the

pharynx

Does not normally present with elevated white-

blood-cell count and mildly abnormal liver enzymes

Jones Criteria

2 Major + 1 Minor OR1 Major +2 minor

With evidence of Streptococcal infection

Minor

ProlongedP-RInterval

Noprolonga6on

Sinustachycardia

Arthralgia

ever

Supporting evidence

Laboratory Findings: elevated ESR and CRP

Supporting evidence

Throat culture

(+)alphahemoly6cstrep

ASO titer

200(twiceelevated)

Treatment

Penicillin

High dose salicylates (4-8 g/ day)

NSAIDS

Steroids

Public Health

Developing countries:

Affectnearly20millionpeople

Oneoftheleadingcausesofcardiovasculardeathduringthefirst5yearsoflife

470,000 new cases of ARF worldwide

Mostindevelopingcountriesandusuallyamongindigenousgroups

Mean incidence 19:100,000

Rheumatoid Arthritis


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Spiking quotidian Fevers

Overt Arthritis

Characteristic fleeting rash most apparent with fever

spikes

Lymphadenopathy

Increased white blood cell count

Hepatic dysfunction seen in chronically ill patients

Need to check ESR if highly elevated

Need to check peripheral smear for microcytosis

Clinical Manifestations

ever

Anemia

HighESR

Headaches

Age:over50yearsoldwithothermanifesta6ons

i.e.malaise,fa6gue,anorexia,weightloss,sweats,arthralgias,andassociatedpolymyalgiarheuma6c

Laboratory

Markersofinflamma6on(ESR)

Hematologicparameters(CBC)

Liverfunc6ontests

Kidneyfunc6ontests(crea6nine)

Immunologicparameters(IgG,complementlevels)

Biopsy

NeutrophilcountshiFtotheleF

R(-)andANA(-)ruleinS6llsdisease

Alkalinephosphataseisnormal

Immunologicparameters

IgGelevated

Complementlevel

Treatment

NSAIDs

Steroids(i.e.prednisone)

An6-rheuma6cagents(i.e.cyclophosphamide,methotrexate)

Intravenousgammaglobulin(IVIG)

Monoclonalchimerican6-TN(i.e.infliximab)

IL-1blockade

Public Health

Veryrareinadults

Usually:20-35yearsofage

Presentwithhighintermi\entfever,jointinflamma6onandpain,musclepainwithfeversanddevelops

persistentchronicarthri6s

95%ofpa6entshavefaintsalmoncoloredskinrashes

Giant Cell Arteritis

Mononuclearinfiltra6onofbloodvessels

Inflamma6onhardeningofarteri6es

Rule In Rule Out


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Fever

Headache

Patient is over 50 yo

Malaise

Fatigue

Sweats

PolymyalgiaHepatic Dysfunction

Male

Need to demonstrate:

High ESR

Normochromic/slightly hypochromic anemia

Need to measure:

Serum creatinine kinase

Levels of IgG and complementConfirm diagnosis via biopsy of the temporal artery

Treatment

Prednisone40-0mg/dLfor1month(withgradualtapering)

Aspirin(lowdose,100mgPO1x/day)

Public Health

IntheUS

Incidence:0.5-27casesper100,000peopleage50andabove

Scandinaviancountrieshavethehighestincidence

IncidenceratesarehigherinCaucasiansofEuropeandescent

LesscommoninAsians

MorecommoninwomenCardiologists Perspective


DifferentialsInfective Endocarditis

Aninfec6on(usuallybacterial)oftheendocardialsurfaceoftheheartwhichproducesseverevalvular

insufficiencyandmayleadtointractableconges6veheartfailureandmyocardialabscesses.

Acuteendocardi6sisafebrileillnessthatrapidlydamagesstructures,hematogenouslyseeds

extracardiacsites,and,ifleFuntreated,progressestodeathwithinweeks.

Epidemiology

ThereisnoPhilippinedataontheprevalenceofIE.However,intheUS,thereareabout10,000to15,000new

casesdiagnosed.

Thereisamalepredominanceofpa6entshavingIEwithmale-to-femalera6orangingfrom3:2to9:1.

ThereisanincreasedriskofhavingIEasoneages,with25-50%ofcaseshappeningattheageof0yearsand

above

Pathogenesis

Bacteremia(nosocomialorspontaneous)thatdeliverstheorganismtothesurfaceofthevalve

Adherenceoftheorganism

Eventualinvasionofthevalvularleaflets

StaphylococcusaureusandEnterococcusfaecalisarethepredominantmicroorganisms.

ClinicalManifesta6ons

Bacteremia(nosocomialorspontaneous)thatdeliverstheorganismtothesurfaceofthevalve

Adherenceoftheorganism

Eventualinvasionofthevalvularleaflets

StaphylococcusaureusandEnterococcusfaecalisarethepredominantmicroorganisms.

Rule In Rule Out

Symptoms of fever, chills and sweats, malaise,

arthralgias

Shortness of breath, cough and tachycardia may be

symptoms of CHF

Laboratory manifestations include leukocytosis

There was no heart murmur.

Does not explain the rash and the CLAD.

Cannot be ruled out fully without proper diagnostic

procedures to fulfill the Dukes Criteria.

DukesCriteria


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MajorCriteria

1. Posi6vebloodculture

Typicalmicroorganismforinfec6veendocardi6sfromtwoseparatebloodcultures

Viridansstreptococci, Streptococcusbovis ,HACEKgroup,Staphylococcusaureus,orCommunity-

acquiredenterococciintheabsenceofaprimaryfocus,orPersistentlyposi6vebloodculture,defined

asrecoveryofamicroorganismconsistentwithinfec6veendocardi6sfrom:

Bloodculturesdrawn>12hapart;orAllofthreeoramajorityoffourormoreseparatebloodcultures,withfirstandlastdrawnatleast1hapart.Singleposi6vebloodcultureforCoxiellaburne5iorphaseI

IgGan6body6terof>1:800

2. Evidenceofendocardialinvolvement

Posi6veechocardiograma

Oscilla6ngintracardiacmassonvalveorsuppor6ngstructuresorinthepathofregurgitantjetsorin

implantedmaterial,intheabsenceofanalterna6veanatomicexplana6on,or

Abscess,ornewpar6aldehiscenceofprosthe6cvalve,or

Newvalvularregurgita6on(increaseorchangeinpreexis6ngmurmurnotsufficient)

MinorCriteria

1. Predisposi6on:predisposingheartcondi6onorinjec6ondruguse

2. ever38.0C(100.4)3. Vascularphenomena:majorarterialemboli,sep6cpulmonaryinfarcts,myco6caneurysm,intracranial

hemorrhage,conjunc6valhemorrhages,Janewaylesions

4. Immunologicphenomena:glomerulonephri6s,Osler'snodes,Roth'sspots,rheumatoidfactor

5. Microbiologicevidence:posi6vebloodculturebutnotmee6ngmajorcriterionasnotedpreviouslybor

serologicevidenceofac6veinfec6onwithorganismconsistentwithinfec6veendocardi6s

JonesCriteria(refertopreviousgroups)

LaboratoryTests

CBC

LT

KT

Metabolicprofile

ESRorCRP

R,ANA

ASOTiters

ImagingModali6es

ChestX-ray

2DEcho

Checkforvegeta6ons

Nodomingofventricularwalls,mildflu\erofaor6cvalve(sugges6veofsclerosis),leF

ventricularwallhypertrophyhencenotIE

TB Pericarditis

Themostcommoninfec6ouse6ologyofconstric6vepericardi6s

Constric6vepericardi6spresentswithamyriadofsymptomsthatmaydevelopslowlyoveranumberof

yearssuchthatpa6entsmaynotbeawareofalltheirsymptomsun6lques6oned.

Dueto:

Directprogressionofaprimaryfocuswithinthepericardium,or

Toreac6va6onofalatentfocus

Ruptureofanadjacentsubcarinallymphnode

Onsetmaybesubacute

Anacutepresenta6onmaybepossible,withdyspnea,fever,dullretrosternalpain,andapericardialfric6on

rub.

Aneffusiondevelopsinmanycases

Signsofcardiactamponademayeventuallyappear.

Suspectifthepa6entisinahigh-riskpopula6on(HIV-infected,orwithinhigh-prevalencecountry);if


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thereisevidenceofpreviousTBinotherorgans

Suspectif2DEcho,CTorMRIshowseffusionandthicknessalongthepericardialspace.

SternalpainnecessaryforTBpericardi6s,butnotpresenttothepa6ent

Rule In Rule Out

Acute pericarditis may present with fever, dyspnea,

shortness of breath, fatigue, and CLAD.Abnormal liver enzymes may indicate liver

congestion

No elevated JVP, ascites, and lower extremity edema.

No pericardial friction rubDoes not explain the rash and the painful joints.

Dermatologists PerspectiveAdditional Questions/Information

Type of Lesion:

Shape & size: Maculopapular, poorly defined

Location: localized to the trunk

Color: light pink

Timing: manifesting at the height of fever & spontaneously disappears

Associated symptoms: (-) pain, pruritus

(-) asthma

(-) pet exposure(+) allergy to cheese cake

Differentials

Cholinergic urticaria

In cholinergic urticaria, physical stimulus is usually heat or sweat

usually found in men and people aged 10- 30 years

appears rapidly; mean duration of 80 minutes

POSSIBLE STIMULUS: the sponge bath

Drug eruptions

Can be due to a hypersensitivity reaction to the drug, or due to adverse effects of the drugs (such as

release of cell mediators)

Consider medications of the patient:

Hypertensive medications

Antibiotics given

Drugs that can cause urticaria:

Aspirin

Barbiturates

Captopril

Enalapril

Penicillins

Sulfonamides

Inflammatory

Transient rashes occur in inflammatory conditions, such as Stills Disease

Urticarial Rash secondary to Hep B

Rule In Rule Out


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BASED ON HX patterned fever occurring in the night up

to dawn

Antibiotics did not relieve symptoms

Night sweats--feature of Hep B infections

PE/ Diagnostics--> slightly elevated patched pinkish colored

rash, which disappeared after a while

TachycardiaElevated WBC count

Mildly abnormal liver enzymes (indicate hepatic pathology)

History: There is cough with shortness of breath--> may

indicate a pulmonary focus instead

On PE: stiffness and soreness during fever, not usually seen

in Hepatitis B infections

Infectious Mononucleosis

Rule In Rule Out

Fatigue/ prolonged malaise on History

Fever and lymphadenopathy are seen in some patients

Maculopapular generalized rash that is usually faint,

evanescent and RAPIDLY DISAPPEARS. Rash is

nonpruritic

Arthralgias and myalgias may occur

Headaches and night sweats on history

Diagnostics--> leukocytosis is seen in infectious

mononucleosis

May also present with elevated liver enzymes

Chills are not common

Although chills can still occur

Following are not seen in the patient:

nausea, anorexia without vomiting (common in IM)

pulmonary involvement is NOT a feature of EBV

mononucleosis

Palatal petechiae of the posterior oropharynx

Primary Impression: Stills Disease

Rule In Rule Out

BASED ON HISTORY

Fever that comes and goes--usually theres fever in the

evening

Arthralgia, myalgia

Skin rashes--usually comes and goes in the fever, not itchy,

transient, salmon pink

Swollen lymph nodesWeight loss, 30% within 3 weeks

Sore throat

Can present with pulmonary symptoms

LAB: leukocytosis, high ESR and CRP, liver enzymes high,

negative rheumatoid factor

Abdominal pain, swelling

No hepatosplenomegaly

Pain when taking a deep breath

More common among women

very rare, 1 in 100,000

Neurologists PerspectiveAdditional Questions/Information

(+) lethargy, irritability, neck pain, progressive worsening headache

(-) drowziness, seizures, confusion, papilledema, rigidity, CN deficits, apasia, vomiting, motor changes,

psychosis, paralysis, disorientation

Lumbar puncture:

Opening pressure: normal, clear, colorless

CSF analysis: normal sugar, elevated protein, few white cells (0-1)

(-) G/S, antigen detection, CALAS

Culture pending

Brain CT:

(-) vegetations, infarction, abcess, edema

Differentials

TB Meningitis

Rule In Rule Out


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Fatigue/ prolonged malaise on History

Fever and lymphadenopathy are seen in some patients

Maculopapular generalized rash that is usually faint,

evanescent and RAPIDLY DISAPPEARS. Rash is

nonpruritic

Arthralgias and myalgias may occur

Headaches and night sweats on historyDiagnostics--> leukocytosis is seen in infectious

mononucleosis

May also present with elevated liver enzymes

Chills are not common

Following are not seen in the patient:

nausea, anorexia without vomiting (common in IM)

pulmonary involvement is NOT a feature of EBV

mononucleosis

Palatal petechiae of the posterior oropharynx

Viral EncephalitisCommon viral agents: Enteroviruses, HSV, arthropod-borne viruses, HIVManifestations:

Headache (Frontal or retroorbital)Fever

Nuchal RigidityConstitutional signs: malaise, myalgia, anorexia, nausea and vomiting, abdominal pain, diarrheaMild lethargy and drowsiness

Rule In Rule Out

Philippines classified as an endemic country

Acute onset of febrile illness w/ the ff. signs &

symptoms:

Lethargy

Headache

Fever

Focal neurologic disturbances have to be observed

Aphasia

Ataxia

Upper or lower motor neuron patterns of weakness

Involuntary movements (myoclonic jerks, tremors)

Cranial nerve deficits (ocular palsy, facial weakness)

SSx reflect foci of infection or inflammation in the

brain

Diagnostics

Differen5al Diagnostic Examinations to be Requested

TBMeningi6s CSAnalysis:

Elevatedopeningpressure

lymphocy6cpleocytosis(10500cells/L),

elevatedproteinconcentra6onintherangeof15g/L

(10500mg/dL)

decreasedglucoseconcentra6onintherangeof1.1

2.2mmol/L(2040mg/dL).

Viralencephali6s CSAnalysis:

Lymphocy6cpleocytosis(250-500cells)

Elevatedprotein(0.2-0.8g/L)

Normalglucose

Normal/mildlyelevatedopeningpressure

(100-350mmHg)

CSculture(poorsensi6vity)

Primary Impression: Non-neurologic Disease

Pulmonologists PerspectiveAdditional Questions/Information

Normal ABG

Normal BUN, Creatinine

Normal C-ANCA

G/S:

Epithelial Cell < 10


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White Cell > 20

(+) cocci in pairs, cocci in chains, GPB

Sputum Culture showed normal flora

Blood Culture was negative after 48 hrs

Tests requested but not done:

PFT

Bronchoalveolar lavage

Differentials

Tuberculosis

Rule In Rule Out

Cough

Intermittent Fever

Fatigue

Night sweats

Shortness of breath

Lymphadenopathy

Abnormal liver enzymes

Endemicity

Acute cough

No mention of hemoptysis

No mention of weight loss


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Pneumonia (may be bacterial, viral or fungal)

Rule In Rule Out

Cough

Fever

Shortness of breath

Lymphadenopathy

Elevated WBC

joint pain

fever pattern

rash

Pulmonary Symptoms secondary to a primary disease

Rule In Rule Out

Cyclical pattern of fever

Feeling of coldness followed by fever and sweating

Stiffness

Headache

Myalgia

Arthralgia

Elevated liver enzymes

Travel history not indicated

No vomiting

No convulsions

Primary Impression: Pulmonary Tuberculosis t/c Atypical Pneumonia

Final Diagnosis

Considering everything, the primary physician decides to order the following tests:

Blood culture

CBC

Sputum smear and culture

Excisional biopsy of lymph node

Abdominal CT Scan

Patient finally agreed to an excision biopsy of the lymph node.

Histopathology:

Figure 1. Histopathologic picture of the biopsy:

Abundant histiocytes, necrosis without neutrophils.

FINAL DIAGNOSIS:Kikuchi Disease

From Medscape: Kikuchi disease, also called histiocytic necrotizing lymphadenitis or Kikuchi-

Fujimoto disease, is an uncommon, idiopathic, generally self-limited cause of HYPERLINK "http://

emedicine.medscape.com/article/960858-overview" lymphadenitis. Kikuchi first described the

disease in 1972 in Japan. Fujimoto and colleagues independently described Kikuchi disease in the

same year.

FEVER OF UNKNOWN ORIGIN LECTURE PROPER

Definitions

FeverA state of elevated core temperature which is often but not necessarily part of defensive responses of

multi cellular organism (host) to invasion of live or inanimate matter recognized as pathogenic or

alien by the host.

Pyrogen mediated

Hyperthermia

Unregulated rise in body temperature

Represents failure of homeostasis pyrogens not involved

Petersdorf & Beeson chose 1 week work-up to r/o self-limiting viral illnesses and to allow for sufficient


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time for initial investigations to be completed.

Over the past 40 years, health care has shifted from inpatient to the ambulatory setting. It has now

become widely accepted that the 1-week inpatient investigation be modified to allow for evaluations

to be completed in an outpatient setting.

There are more than 200 causes of FUO reported in the literature

Classification of FeverAcute Febrile Illness

Prolonged Febrile Illness (see table in the Appendix)

Classic FUO in the immunocompetent

Nosocomial FUO

Neutropenic FUO

HIV associated FUO

Classification of Fever of Unknown Origin

Classical Definition (Durack & Street, 1991; Durack & Street, 1991)

T > 38.3oC on several occasions

> 3 weeks duration

Diagnosis uncertain after 3 days in-house or 3 outpatient visits

Validation of New Definition (Vanderschueren et al. Arch Intern Med2003; 163:1033-41)

Prolonged febrile illness (PFI)in immunocompetent patients (n = 290)

Illness of at least 3 weeks duration before diagnosis

Temperature > 38.3C on >3 occasions

No diagnosis at referral

Subgroups of PFI according to the time of diagnosis

Early diagnosis within 3 days

Intermediate diagnosis: between 4 and 7 days

Late diagnosis: after Day 7: 30%

No diagnosis: 33.8%

FUO as defined by Durack & Street includes subgroups B to D. 13.1%

FUO as defined by Petersdorf &Beeson includes subgroups C to D.

Prolonged febrile illness is 23.1%

Case-mix of Vanderschueren study cohort (2003) based on FUO definition used

Nosocomial FUO

Hospitalized

T > 38.3oC

Infection not present on admission

Diagnosis unclear after 3 days with at least 2 days for blood cultures

FUO in the immunocompromised

ANC < 500/mm3

T > 38.3oCDiagnosis unclear after 3 days with at least 2 days for blood cultures

HIV associated FUO

HIV positive

T > 38.3oC on several occasions

Duration > 4 wks OP or 3 days IP

Diagnosis unclear after 3 days with at least 2 days for blood cultures


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FUO: Diagnostic Entities (from 11 case series reporting over 1000 pts.)


Best predictor of survival is disease category. Increase in CA; decrease in Infectious Diseases

Overall, 12-35% of pts with FUO will die from FUO-related causes.

52 100% of pts. with a dx of malignancy will die within 5 years of dx

8 22% mortality among ID causes

Changing Spectrum of FUO

EMBED Excel.Chart.8 \s

Over past 40 yrs, proportion due to ID and CA have decreased. The easy detection of solid tumors and abn.

lymph nodes via UTZ and computed tomography (CT) has resulted in a decline of tumors as a common

cause of FUO.

Pts with undiagnosed FUO used to make up the smallest proportion. At present, the largest proportion who

present with FUO never have a cause identified.

The most common ID causes: TB, intra-abdl abscesses

Malignancies: Hodgkins and non-Hodgkins lymphoma

Temporal arteritis: accts for 16-17% of FUO in the elderly

FUO patients at UST Hospital, 1980 1991 (n=72)

Dy E, et al. JPSMID, 1992;22:35-40


Major Evolutionsin Causes of FUO from Original Article to Present Day

Shift to less infection, less cancer, more inflammatory disease and more unknown

Much less common for some infections (i.e., abdominal abscess) and tumors (i.e., lymphoma) to go

undetected due to UTZ, TEE, CT, etc.

New infections: CMV, HIV, Parvo B19, HHV8, PCP,Brucella, Bartonella, Babesia, B. burgdorferi,

Yersinia, SARS

HHV8: human herpesvirus8the most recently identified human oncogenic herpesvirus. Associated

with Kaposis sarcoma, and human lymphoproliferative diseases, such as pleural effusion lymphomas

and multicentric Castlemans disease.

But first, dont forget the obvious

Confirm that a true fever exists.

Daily record of temperatures

Fever pattern: not very helpful

Rule out drug fever.

If possible, D/C all medications early in the evaluation

Suspected drug is not the cause: if fever persists beyond 72 hours after removal of the suspected

drug

Drugs Implicated as a cause of fever

Recommended Diagnostic Tests for which Evidence Exists & are Relatively High Yield

Abdominal CT: 19%one of the first investigations (after basic work-up)

likely to identify 2 of the most common causes of FUO: intra-abdominal abscess, lymphoproliferative

disorders

Nuclear imaging: as second-step investigation

Positron Emission Tomography: [18 F]fluoro deoxyglucose PET:

total body scintigraphy

high specificity; diagnostically useful in 41 69% in 3 FUO case series

very good tracer for inflammatory diseases, esp. temporal arteritis

Technetium-based studies: sensitivity: 40 75%; specificity 93 - 94%


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Inferior: Gallium 67, Indium 111 IgG, Indium 111-labeled wbc scans

Ultrasonography

Sensitivity of 80-85% (vs. 90-100% for CT)UTZ images may be obscured by overlying gas patterns

CT provides better imaging of the retroperitoneum

Duke criteria for IE

IE accounts for ~ 1-5% of all causes of FUO

Duke criteria: specificity in FUO: 99%; sensitivity in non-FUO cases: 82%

TEE (sensitivity: 100%, specificity: 98%) for early detection of valvular vegetations in IE, esp. culture-

negative IE

TTE (sensitivity: 63%, specificity: 98%)

Liver biopsy

Yield of 14 17% (in a selected group of FUO patients)

Complications (in pts. w/o FUO): 0.06 0.32%Deaths: 0.009 0.12%

Temporal artery biopsy

preferred strategy when likelihood of disease is intermediate

In all patients > 60 with ESR or alkaline phosphatase

Rare complications: damage of the facial nerve, skin necrosis, drooping of the eyebrow

Leg Doppler imaging

when deep vein thrombosis is suspected as cause of fever (2 6% of patients

safe procedure; identifies a treatable cause

NOT RECOMMENDED

Bone marrow cultures

Yield in immunocompetent persons: 0 2%

use at your discretion based on circumstances

Uncertain:

Surgical exploration of the abdomen

poor methodological quality of studies

mortality: 4%; post-op complications: 12%

laparoscopy: 44% yield in pre-CT area

role in post-CT era: unclear

Empiric therapy

utility in FUO not studies

may obscure or confuse the diagnosis

Commonly Performed Tests where No Systematic Evidence for FUO Diagnosis Exists to Date

ESR

CRP

PCR

Bone scan

MRI


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APPENDIX

SUMMARY TABLE OF THE CLASSIFICATION OF PROLONGED FEBRILE ILLNESS


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Summary Classic FUO Nosocomial FUO Immune-deficient FUO HIV-related FUO Definition

>38C

> 3 wk

> 2 visits or 3d in

hospitals

> 38C

3 days

not present or incubating

on admission

> 38C

> 3 days

negative cultures after

48h

38C

> 3 wk for outpatient

> 3day inpatient

HIV infection

Patient Location Community, clinic,

or hospital

Acute care hospital Hospital or clinic Community, clinic

or hospital

Leading causes Cancer, infections,

inflammatory

conditions,

undiagnosed,

habitual

hyperthermia

Nosocomial

infections,

postoperative

complications,

drug fever

Majority due to

infections, but

cause documented

in only 40-60%

HIV (primary

infection), typical

and atypical

mycobacteria,

CMV, lymphomas,

toxoplasmosis,

cryptococcosis

History emphasis Travel, contacts,

animal and insect

exposure,

medications,

immunizations,

family history,

cardiac valve

disorder

Operations and

procedures,

devices, anatomic

considerations,

drug treatment

Stage of

chemotherapy,

drugs

administered,

underlying

immunosuppressiv

e disorder

Drugs, exposures,

risk factors, travel,

contacts, stage of

HIV infection

Examination

emphasis

Fundi, oropharynx,

temporal artery,

abdomen, lymph

nodes, spleen,

joints, skin, nails,

genitalia, rectum or

prostate, lower

limb deep veins

Wounds, drains,

devices, sinuses,

urine

Skin folds, IV sites,

lungs, perianal area

Mouth, sinuses,

skin, lymph nodes,

eyes, lungs,

perianal area

Investigation

emphasis

Imaging, biopsies,

sed rates, skin tests

Imaging, bacterial

cultures

CXR, bact cultures CBC, serologic

tests, CXR, stool,

biopsies, cultures,

imaging


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Management Observation, OP

temp chart,

avoidance of

empirical drug

treatments

Depends on

situation

Antimicrobial

treatment protocols

Antiviral and

antimicrobial

protocols,

vaccines, revision

of treatment

regimens, good

nutrition

Time course Months Weeks Days Weeks to Months

Tempo of

Investigation

Weeks Days Hours Days to weeks


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Algorithm for FUO Diagnosis

Categories of FUO

Feature Nosocomial Neutropenic HIV-Associated Classic

Patients situation Hospitalized,

acute care, no

infection when

admitted

Neutrophil count

either 3 weeks

Duration of illness

while under

investigation

visits

3 daysb

3 daysb

3 daysb

(or 4

weeks as

outpatient)

3 daysb

or three

outpatient

Examples of cause Septic

thrombophlebitis,

sinusitis,

Clostridium

difficile colitis,drug fever

Perianal infection,

aspergillosis,

candidemia

MAIc

infection,

TB, non-

Hodgkins

lymphoma, drug

fever

Infections,

malignancy,

inflammatory

diseases,

drug fever

a All require temperatures of >38.3C (>101F) on several occasions.

b Includes at least 2 days incubation of microbiology cultures.

cM. avium/M. intracellulare.

Source: Modified from DT Durack, AC Street, in JS Remington, MN Swartz (eds): Current

Clinical Topics in Infectious Diseases. Cambridge, MA, Blackwell, 1991.

FEVEROF UNKNOWN ORIGIN (FUO)Year Level 7 [Module 19: Infectious Module]|January 27, 2011

Team 2|

Page PAGE 15 of NUMPAGES 15

Year Level 7 [Module 19: Infectious Module]


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FEVEROF UNKNOWN ORIGIN (FUO)

Class Presentation and Lecture by Raul Destura,

M.D.

January 27, 2011

Team 2|Anna, Gabe, Janka, Stef, Ven, Robert, Claire, Miah, Kim



Additional Information ProvidedRash transient, with a questionable historyCough intermittently productive, sometimes with scratchy throat

Chest X-Ray on admissionNormal vascular marking & cardiothoracic ratioNo blunting of costophrenic sulci

(+) PPD test at 15mmCBC Leucocytosis of 23,000 deviated to the leftLiver function 2x elevatedAFB smear is 3 of 3 negativeCCulture still pending until 8th week of admission

No consent for bronchoscopy and of CSF analysis

Blood cultures remain negative until 24th hour of admissionUrine is clean, clean catchTB PCR no amplifications of microbial DNAMalarial smear always a consider because of location

3 collections- normochromic or normocytic(-) malaria parasite

(+)Typhidot possible false positive due to cross-linking(-) Blood, urine, stool exams for enteric pathogens

Addi6onalQues6onsAskedandResponses

amilyhistoryofCancer

None

Previousinfec6on

Previoushistoryofinfluenzamonthsprior

Historyofsmoking

packyears,stoppedwhen35yearsWeightloss

30%weightloss,inama\erof3weeks

Occupa6on

ormerCEOofSMC

From 1952 to 1994 series:

Infections: 28%


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Inflammatory d iseases: 21%

Malignancies: 17%

Undetermined: 19%

Infections 61%

Neoplasms 13%

Connective Tissue Diseases 6%

Miscellaneous 4%

Unknown 17%

Additional Information Provided

DentalprocedureanddentalcariespresentNopharyngi6s

Nosurgicalimplants

NohistoryofIVdruguse

Norecordofvalvularheartdefectsorcongenitaldefects

27yearshypertensive

10-170systolicand90-100diastolic

Hypercholesteremiabeingtreatedfor8mos

amilyhistoryofCVD,ischemicinfarctandconges6veheartfailure

Sinustachycardia

NormalBMI

NormalJVP,caro6dbruitonthe(R)

Heartsoundsarenormal

NormalPMI

Noorganomegaly

Onymycosisonthebigtoe

Criteria for Fever of Unknown Origin (Durack and Street (1991))Classical FUO

Fever >= 3.83 degrees celcius on several occasionsIllness >= 3 weeks durationDiagnosis uncertain after 3 days of in-hospital investigation o 3 out-patient visits

012711 Fever of Unknown Origin [Team 2]

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