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s ca ns (7 11)a nd I I In -la be le dhuman immunogl obulin (HIG )scintig rap hy (1 2) in FUO pa tien ts.The murine monoclonal antibody BW 250/I 83 has beensuccessfully used to diagnose musculoskeletal infection(13,14), inflammatory bowel disease (15,16) and infectiveendocarditis (1 7). Recently, Becker et al. (18) published thefirst results of using the monoclonal antibody 99mTc@BW250/183 in patients with FUO using planar scintigraphy. InBecker's patients, the diagnostic value of photopenic lesionsw as n ot e xam ined .The aim of our study, using the sam e m onoclonal antibody,w as to gather m ore inform ation about the clinical value of thism ethod for FU O patients, including the use ofSP EC T and usinga different approach to interpret photopenic bone marrowlesions in a series of patients with FUO who had an intermed iate p rev alen ce (3 5% ) o f p yo gen ic in fection s.MAT ERIA LS AND MET hODST his stu dy is a retro sp ective ana lysis of 5 1 p atien ts (a ge ran ge2 7 5r; m ed ia n a ge 4 1 y r) w ho u nd erw en t immunos cin tig ra ph y o fin flammation b etw een Jan uary 1 98 9 a nd Ju ly 1 99 5.The patients were referred with the diagnosis of FUO by thed ep artm en t o f in te rn al m ed ic in e (n = 3 9), th e p ed ia tric d ep artm en t(n = 6) and other departments (n 2) of our university. Fourp at ie nts wer e r ef err ed f rom o th er hos pi ta ls . C rit eri a f or in clu sio n i nthis stu dy w ere: m on osymp tomatic fev er of a 3 8.3 Cor g reaterla stin g m ore th an 2 w k an d n o estab lish ed d iag no sis after at least1 w k in the h osp ita l.T h e dura tio n o ff ev er was 22 day s l5y r (media n dur atio n 8 wk ).Tw elv e o f th e 5 1 p atie nts re ce iv ed a ntib io tic o r immunos up pre ss iv e th era py fo r more th an 1 wk b efo re immunosc in tig ra ph y.T he diag no stic ev alu atio n o f the pa tien ts b efo re scintig rap hyinclud ed a t lea st ro utin e bloo d ch em istry , rad io gra ph ic stu dies,s ero lo gic al a nd b ac te rio lo gic te sts a nd a bd om in al u ltra so un d e xamin atio n. F in al d ia gn os is w as e sta blis he d b y c lin ic al fo llow-u p,ra dio grap hy , C T, MRI, ech oc ard io grap hy , en dosco py , b io psy ,su rg ery , cu ltu re o r sero lo gical tests. F ull h osp ital reco rd s an d afo llo w-u p o f at least 6 m o w ere av ailable for all pa tien ts. T hirtyfiv e p erc ent ( 18 of 5 1) o f th e p atien ts ha d in fectio n, 16% (8 o f 51 )autoimmune diseases, 14% (7 of 5 1) neoplasm s and 8% (4 of 51)other diseases. Fever rem ained unexplained in 27% (14 of 51) ofthe patients.T he mun ne mon oc lo na l a ntib od y BW 250 /1 83 (B eh rin gw erk e,M arburg, Germ any) was used for im munoscintigraphy. BW 250/183 is an immunoglobulin G 1 subtype that binds to the antigenNCA -9 5, a su rface g lyco pro tein w ith a m olecu la r w eig ht o f 95 kDth at a pp ea rs e arly in th e d iffe re ntia tio n o f g ra nu lo po ie tic c ells a ndis expressed on the cell m em brane surface of alm ost all hum ang ra nu lo cy te s a nd th eir mo re ma tu re p re cu rs or s.A c co rd ing to t he manu fa ctu re r's r ec ommenda tio n, 250500pgo f th e in ta ct a ntib od y w ere la be le d w ith 5 50 MBq 99mT c..p erte ch ..n eta te a nd in je ct ed in tr av enou sly . I n a ll p atie nts , s cin tig ra phy wa s

The a im of ours tudywas to evalua tethe c lin ica lvalueo f immun osc in tig ra ph y w ith th e mon oc lo na l a ntib od y @@T c-BW50/1 8 3 inpatients w ith fever of unknow n origin (F UO ). T he antibody BW250/183 is an immunoglobulin G1 subtype that binds to the antigenNCA-95,whichis expressedn the cell membraneurfaceofg ran uloc ytes. M eth ods W e stu died 5 1 p atients w ho w ere referredw ith the diagnosis of F UO . T hirty-five percent of the patientssuffered from infection, 17% had autoim mune diseases, 14% hadneoplasm s and 8% had other diseases. T he rem aining 28% of thepatients did not have a diagnosis. P lanar im aging w as perform ed ina ll p a ti en ts , a nd 19 patie nts underwent SPECT . I nour a na ly sis , b othc old a nd h ot s po ts w ere c on sid ere d d ia gn os tic . R es ults: P yo ge nicinfections were visualized correctly in 13 foci. The diagnosis ofendocarditis (n = 4) could be determined only by SPECT. Falsenegative results w ere found in 4 patients and false-positive uptakewas s ee n in 2 p atie nts. N o fa ls e-p os itiv e u pta ke o r c old s po ts in th ec en tra l b on e m arrow w ere fo un d in p atie nts w ith v ira l, g ra nu lomato us a nd a uto immun e d ise as es o r in t ho se p atie nts inw h om no FUOcau se w as fou nd in a 6 -m o fo llo w-u p. In t hese p atients, a neg ativescan did not change their diagnostic work-up. Cold spots in thecen tral b on e m arrow w ere co rre ctly in terp re ted in 5 o f 6 p atien ts.Sensitivity in detecting pyogenic foci w as 73% and specificity w as97%. P ositiv e an d n eg ativ e p red ictive v alu es w ere 93% an d 8 7% ,re sp ec tiv ely . In clu din g a re as o f d ec re as ed u pta ke in th e a na ly sis,s en si tiv ity f or d et ec tin g an under ly ing in flamma to ry o r ma lig nantprocess for F UO w as 81% and specificity w as 87% . P ositive andn eg ativ e p re dic tiv e v alu es w ere 8 1% a nd 8 7% , re sp ec tiv ely . C onc lus ion : Immunosc in ti graphy ith @Tc-BW50/183 in patientsw ith FUO h as clin ical p oten tial fo r th e d iag no sis an d ex clu sion o fpy og enic cau se s o f FUO . M eta static m alig nan t d ise ase an d highgrade spondylodiskitis could be diagnosed early in a diagnosticwork -u p b y a ch aracte ristic c old spo t p attern in the b on e m arrow.SPECT i s i nd ispensi bl e for s ci nt ig raphi c imag ing of endoca rd it is .K ey W ords fever of unknow n origin; immunoscintigraphy; technet ium-99m-an ti gr anu locyt e- an ti body; monoc lonal an ti body; SPECT;iterative reconstructionJ Nuci Med 1998 39I2 48 -1253FeverfunknownriginFUO)sdefinedsrecurrenteverf3 8.3 C o r g reater, lastin g 2 3w k or lo ng er a nd un diag no sedafter 1 w k of hospital evaluation (1 ). Prolonged undiagnosedfever is usually an atypical manifestation of more commondiseases rather than a m anifestation of an exotic illness.The three most common causes of fever are infection,n eo plasm an d au to immu ne o r co llag en v ascu lar diseases (1,2 ).M alignant diseases have now replaced infection as a leadingcause of FUO. N evertheless, in som e larger studies, the preyalence of infection in patients with FUO is up to 50% (2).P re vio us stu die s u se d 6 7G a (3 6 ), I 1 In w hite b lo od c ell (WBC)ReceivedMar.12,1997;revisionaccepted Oct. 13, 1997.For correspondence or reprints contact: W olfgang Becker, M D, D epartm ent ofN uc lea r M ed ic in e, U niv er sity o f G ottin ge n, R ob er t K och -S tr . 4 0, 0 -3 70 75 G Ottin gen ,Germany.

1248 THEOURNALFNUCLEAREDIC INEol.39 o.7 . July1998

Clinical Value of Immunoscintigraphy in Patientswith Fever of Unknown OriginJohannes M eller, V elem ir Ivancevic, M onika C onrad, Stefan G ratz, D ieter L udw ig M unz and W olfgang B eckerD ep artm en t o fN uclear M edicin e, G eo rg A ugu st U niversity o f G ttin gen , G ttin gen ; a nd C linic a nd P oliclin ic of N uclearMedic in e, Char it ,Humbold t Un iv er si ty , B er lin , G ermany

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Patientno.Age &r)SexScintigraphic findings@ncreasedptake)Scintigraphic diagnosisFinal diagnosesDiagnosia verifiedy122FLeftsacroiliac jointPyogenic s ac ro ile itisP yo ge nk@ s ac ro ile itisMR I,28FRight max illarysinusS inusitisSinu sitisS,375Flip o f p ac ema ke r le ad In fe ct iv e e nd oc ard ftisIn fe ctiv e e nd oc ard itis TEE, C,448MHeart valvesInfective endocarditislnfectNe endocardttisTEE, C,550FHeart valvesInfective endocarditisInfective endOcarditiSTEE ,62MTerminal ileumIlethsSalmonellosisC,E710FRight ascending co lonCol it isSalmonel lo s isC,E84MPeMsAbscessAbscess,

salmonellosisC, 5,T963FLiver, Sheldon ca the terHepati c abscess,catheter infectionHepatic abscess,sepsis, catheterinfection,(Candidaalbicans)C,US ,E1060FColonColitisUlcerative

colitisEN1158MUpper abdomenAbscessParacolonic abscessdue to colorecta lcancer5,C1267FPeMsAbscessCarcinoma

of thesigmoidS1327MMediastinumMediastinitisTeratomaS1474MHeartvalvesInfective endOCa rd itiS In fe ct iv e e ndoc ar ditis TEE ,C

= cu lt ur e;S =surge ry ; TEE = t rans es ophageal echocardiography;SE= serology; US = ultrasound; EN = endoscopy.

TABLE IPatie nts w ith I nc re as ed T ra ce r Up ta ke

perform ed between (m ean s.d.) 4 1 hr and 22 2 hr afterinjection.P lan ar scan s o f th e h ead , ch est, ab domen an d ex trem ities w erep erfo rm ed in th e a nte rio r a nd p os te rio r p ro je ctio ns u sin g a s in glehead (SX 100; Picker International, Ohio) or a double-head(PRISM 20 00 ; P ick er) g amma cam era fitted w ith a p aralle l-ho le,high-resolution and low -energy (L EH R) collim ator (128 X 128matrix , 3 00 5 00 kc ts/im ag e; w ho le -b od y sc an s w ere p erfo rm edw ith an acq uisition tim e o f 30 mm). In 1 9 p atien ts, S PE CT im ag esofthe thorax (n = 17) or abdom en/pelvis (n = 2) w ere obtained 24hr p ostin jectio n usin g a sin gle-h ead (E CAT; P ick er) or a d ou blehe ad (PRISM 2 00 0) g amma c am era fitted w ith L EHR co llim ato rs(360 circular orbit, 60 stops at 30 sec per stop, 64 X 64 or 128 X128 matrix ). S PECT re co nstru ctio n u sin g a n Ody sse y 2 00 0 (P ic ke r) c ompu te r sy stem was d on e b oth b y filte re d b ac kp ro je ctio n (lowp ass/ram p) an d b y iterativ e rec on structio n (ISA) d escrib ed elsew he re ( 1 9) u sin g e ig ht ite ra tiv e ste ps a nd a tte nu atio n c orre ctio n.In th e firs t ste p o f a na ly sis , a sc an w as c on sid ere d tru e-p os itiv ewhen abnormal accumulation of the tracer outside organs ofphysiologic uptake (liver, spleen, bone m arrow , kidneys andb la dd er) w as c on firm ed b y fu rth er in ve stig atio n a s re pre se ntin g apyogenic cause of fever. A scan w as considered false-positivew hen abnorm al uptake represented a noninfectious process. Atru e-n eg ative scan w as a no rm al immu no scintig rap hic stu dy , inw hich noninfective causes of F UO w ere established by furtherinvestigations. A false-negative scan was a normal study, inwhich a pyogenic cause for FUO was demonstrated subsequently.In th e seco nd step o f an aly sis, p hoto pen ic lesio ns in th e ce ntralbone m arrow w ere included in the analysis using the follow inginterpretation: M ultiple cold spots in the bone marrow werec on sid ere d to re pre se nt m alig na nt d ise ase (2 0 22 ). D ec re ase duptake in two adjacent segm ents of the spine was considered to besp on dy lo disk itis. T his interpretatio n w as ad op ted b ecau se o f th ew ay infection norm ally spreads from the intervertebral disk toadjacent vertebral bodies due to the special blood supply of thevertebral colum n (23 ). A single cold spot in the bone m arrow w as

c on sid ere d to re pre se nt a n in fe ctiv e ra th er th an a m alig na nt c au se(1 4). A sca n w as re ga rded a s tru e-po sitive if a bno rm al a ccumu latio n o f th e tra ce r o uts id e o rg an s o f p hy sio lo gic u pta ke re pre se nte da p yo gen ic cau se fo r fev er o r d ecreased u ptak e in the b on e m arroww as co rrectly inte rp reted to rep resent eith er a n infla mm ato ry o rma lig nant p ro ce ss w ith r ef er en ce to th e c rit er ia c it ed e ar lie r. A s canw as re ga rd ed a s fa lse -p ositiv e w he n a bn orm al u pta ke re pre se nte d an on in fe ctio us p ro ce ss o r if n o c orre ct in te rp re ta tio n o f d ec re as eduptake in the bone m arrow could be given. A true-negative scanw as a n orm al immunosc in tig ra ph ic s tu dy in w hic h n on in fe ctio uscauses of FUO were established by further investigations. Afa ls e-n eg ativ e s ca n w as a n orm al stu dy in w hic h fu rth er e va lu atio nre ve ale d p yo ge nic in flammatio n o r m eta sta tic d is ea se in th e b on emarrow as a cause of FUO.RESULTSThe patient data including scintigraphic findings and theirinterpretation compared with final diagnoses are shown inT ables 1 3 .A 35% prevalence of pyogenic inflam mation wasfound in our series.Pyogenic infections as a cause of FUO were correctlyvisualized in 12 patients (13 foci). Infective endocarditis w assuccessfully imaged in 4 of 5 patients. Vegetations were >8m m in diameter, and the diagnosis w as proven by transesophageal echocardiography (TEE) culture, clinical course andsurgery in 2 patients. The diagnosis of endocarditis could bemade only using SPECT. Filtered backprojection and ISArevealed full concordance w ith the results. Three of 5 abdomin al ab sc esses co uld b e co rrectly d iag no sed b y immu no scin tigraphy. In 1 patient (Patient 9, Table 1), hepatic abscess wasobserved by scintigraphy 5 days before ultrasound showed ananechoic lesion at the inflammation site. In other patients w howere true-positive by scintigraphy, their ultrasounds and CTs ca ns w ere fa ls e-n eg ativ e o r m is le ad in g. F or e xamp le , p ara co lica bscess (P atien t 3 , T ab le 1 ) in filtratin g th e sp leen w as regard edas a splenic infarction by CT. In 3 patients, inflammatory boweldisease as a cause of FUO was correctly imaged by immu

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Age Sdntigraphic findings ScintigraphiciagnosisPatientno. (yr) Sex (decreased u ptake) diagnosis Final diagnoses verifiedy1540 F Rightsacroiliacjoint Pyogenicsacroileitis Pyogenk@acroileitis BS,1674 M Thoracic vertebrae (18-9) Spondylodiskitis H igh-grade spondylodiskitis S, H ,17 64 F Multiplefoci of Neoplasm Non-Hodgkin'slymphomadecreaseduptake18 67 F Muttiplefoci of Neoplasm Bone marrowmetastases,RIdecreaseduptake small-cell lungancer19 50 M Muftip@oci of Neoplasm Bone marrowmetastases H ,RIdecreased

uptake (carcinoma ofhesigmoid)2024 M Thoracicvertebra (19) Spondylitis Fatty infiltrationof the boneRImarrowBS

= b on e scin tig rap hy; H = histo lo gy ; C = c ulture ; S =urgery.noscintigraphy22 2 hr after injection of the radiopharma- Decreased activity in the central bone marrow was verifiednceutical. In one patient, ulcerative colitis already was diag- 6 patients. The underlying process w as correctly interpretednnosed,but neither a barium enema nor endoscopy, including 5 patients (malignant disease in 3 patients, inflammation inbiopsy, could show current inflam matory processes. In contra- patients). In 1 patient, a focal cold spot in the thoracic spine,distinction to these findings, im munoscintigraphy detected w hich represented a fatty infiltration of the bone m arrow, wasgranulocytic infiltration of the w hole colon. T he clinical course m isinterpreted assteomyelitis.afterimmunosuppressive medication revealed that in this pa- Results of SPECT reconstruction done either byilteredtient

highly acute ulcerative colitis was the only cause of backprojection or ISA algorithm were fully concordant inllmonosymptomatic fever. patients. Five true-positive, 2 false-negative and 12 t rue-negaFalse-negative results w ere obtained in 4 patients (endocar- tive scans w ere obtained. These results includedndocarditisditis,h ep atic ab scess, p an creatic ab scess an d p yog en ic in tersti- (tru e-p ositive : 4 patien ts, false-ne gativ e: I p atie nt) an d ab domtial nephritis). In 2 patients, a false-positive accum ulation ofthe inal abscesses (true-positive: 1 patient, false-negative: I patracer w as seen in m align an t disease (m ed iastin al teratoma an dient).sigmoidcarcinoma). No false-positive uptake occurred in viral, W ith reference to the analysis proposed previously, sensitivgranulomatous and autoimmune diseases. Furthermore, no ity for detecting pyogenic foci was 73% and specificityasfalse-positiveuptake or cold spots in the central bone marrow 97%. Positive and negative predictive values were 93%ndoccurredin those patients in whom no cause of FUO could be 87%,espectively.foundat a 6-mo follow-up. In these patients, the fever resolved W hen areas of decreased uptake were included in the analyw ithout any specific therapy. N egative scans did not change the sis, sensitivity for detecting underlying inflammatory or m aligdiagnostic work-up in these patients because the referring nant processes, as causes of FUO, was 8 1 % and specificityasphysicianswere aware that a scan could be helpful, but it would 87%. Positive and negative predictive values were 81%ndnotdefinitively exclude pyogenic inflammation. 87%,espectively.TABLE3Patientsw i th Norma lcansSexDisease

(no. (no.of Diagnosisverifiedyo fpatients) Age(yr@ patients) F inald iagnoses (no.of patients)10-59

C = culture ;S = surgery;EN = endoscopy;SE = serology;BS = bone scint igraphy;US = ul trasound;TEE= transoesophagealechocardiography;H =histology;CL = clinicalcourse.

T ABL E 2Patients w ith D ecreased Tracer U ptake in C entral Bone M arrow

M (1 )F(3)M (6 )F (2)

M (2 )F ( 6 )M(?)F(7)

Infectiveendocarditis(n = 1),hepatic abscess( n = 1 ), p an cre atic a b sc es s ( n = 1 ),pyogenic interstitialnephritis(n = 1)Tuberculosis(n = 1),prolongedvirusinfection(n = 1) ,cytomegalicinfection(n = 1) ,brucellosis(n = 1),foreignbody reaction( n = 1 ), g ra nu loma to us h ep ati ti s (n = 1 ),self- inducedfever(n = 1),renalcel lc ar cin oma ( n = 1 )Autoimmunehemolyticanemia (n = 1),chronicr el ap si ng n eu ro pa th y ( n = 1 ), S t i ll 's d is ea se( n= 4 ),Ho rton's d is ea se ( n= 1 ),rheumatoidarthrftls(n = 1)No cause foundfo rFUO

TEE(1),C (3),5 (1),SE( 1) ,T ( 1) , ( 1)

CL (3),5 (2),SE(2),H (1)

US (14), CT (13), SE (14),TEE(3),EN(8),H (3),C (13),MRI(2)

Pyogenicdisease (4)Various 40-57diseases (8)

Autoimmune 2-67disease (8)FUO(14) 272

CL (6),-ray(1), (8)

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DISCUSSIONThe ideal radiolabeled agent for imaging inflammation inpatients with FUO should, despite a high photon flux, have aradiation burden as low as possible and the diagnosis should beavailable as soon as possible. In the FUO context, that show s aw ide range of underlying diseases. It w ould not be disadvantag eou s if th e rad io tracer w as trap ped in o th er than in flammato ry(e.g., m alignant) foci. E ven the absence of accum ulation of theradiop harm aceu tica l at sites th at no rm ally show a p hy sio lo gicuptake of the tracer can give further information about theunde rl yi ng pa tho logy.F or ex am ple, 6 7G a im age s ac ute, ch ro nic an d g ranu lomato usinflammation, but it also accumulates in various malignantdiseases (24) that are know n to be potential F UO causes. O n theother hand, 67Ga yields a considerable radioactive burden forthe patient and is excreted into the bowel with possiblesu perim positio n an d patho lo gic fo ci in p lan ar scan s.Scans with I IIIn W BC are highly sensitive and specific fordiagnosing acute and chronic inflam mations (25,26). O ccasional accumulation of the tracer can be found in malignantd isea se, co ntrib utin g to th e fina l diagn osis in pa tien ts w ith FUO(11 ). Although cold spots in the central bone marrow areconsidered an unspecific finding in I I1In W BC scintigraphy(27), they should not be rejected as nondiagnostic iftheir valuein detecting metastatic or chronic inflammatory disease is

c on sid ere d. U nfo rtu na te ly , la be lin g b lo od c ells w ith I I In -o xin eis time-consuming and the photon flux In WBC is too lowto en ab le S PE CT acq uisitio n.Scans w ith I IIn-labeled HIG (12), which has not beencom mercially available until recently, could be useful in particular patient subgroups (e.g., granulocytopenic patients orHIV-posi ti ve pa ti en ts ).Com pared to other com pounds, 99m Tc@BW250/183 has thead va nta ge o f rap id av ailab ility . S PE CT acqu isition is p ossib le,even 24 hr postinjection due to the high photon flux of 99mTc.Furtherm ore, the low background activity enables im aging ofinflammatory foci with a high target-to-background ratio. Dueto superior targeting of the central bone m arrow , w here approximately 55% of the radiolabeled antibodies are bound, coldspots can be detected with higher accuracy than with otherte chnique s ( 21 ).In our series, 13 foci in 12 patients were correctly im aged byim munoscintigraphy. In all of these patients, granulocyticinfiltration either had been assum ed or was proven by furtherevaluation (Figs. 1 and 2). Infective endocarditis could bediagnosed using only SPECT, which is concordant with thefindings of M orguet et al. (1 7 ). Infective endocarditis acc ou nte d fo r th e h ig h ra te o f fa ls e-n eg ativ e immunosc in tig ra ph icscans in the series examined by Becker et al. (18) who usedplanar scintigraphy in their patients w ith F UO . A n ISA that hasproved Superior to filtered backprojection in various circumstances (28,29 ) showed no advantage in showing infectiveen do card itis (F ig. 3 ). In o ur p atien ts, 3 of5 ab domin al ab scesseswere correctly diagnosed by immunoscintigraphy. In thesep atien ts, ultraso un d an d C T w ere false-n eg ativ e o r m islead in gin the diagnosis. These observations support the results ofprevious studies that compared InW BC scans with ultrasound and CT (25,26). In our series, inflammatory boweldisease as a cause of FUO was correctly imaged in 3 patients22 2 hr after injection of the radiopharm aceutical. Im mun oscin tig rap hy pro ved u sefu l esp ecially in child re n w ith salm onellosis and ulcerative colitis w ith an atypical clinical course.These findings are concordant with previous data in whichimmu no scin tig rap hy w as u seful fo r d iag nosin g in flammato rybow el disease, although its accuracy was low er than w ith I I IIn

FIGURE1.P lana r canofpelvk@bsces sausedbysa lmo nello sisn4-yr-oldchild ,whichw as observed 4 hr af ter inject ion.WBC s cin tig ra ph y a nd im ag in g w ith 9 9mT c@ la be le d le uk oc yte s(15,16).Cold spots in the central bone m arrow found by I I InW BCscintigraphy are associated w ith a w ide range of pathological

Iht

FIGURE2. WhO le-bO dycans howsmultipleco ldspotsin tho rac icandlumbarspine indicatingbone marrowm etastasis. False-poaltiveaccumulat ion of t racer was ins igmoidcarc inoma.

LIft

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marrow. This may be due to delayed scintigraphy when theinitial granulocytic response has been replaced by a lym phocytic/monocytic response. Destruction of the central bonem arrow by septic infarction, reduced influx of labeled granulocytes and circulating free antibodies, as a result of disturbedmicrocirculation, also has been proposed as the underlyingprocess (31 ). D ecreased uptake in tw o adjacent segm ents of thespine, as seen in one patient, although highly predictive ofvertebral osteom yelitis (33), is an infrequent pattern of spondy litis on immu noscin tig rap hy. In o ur series, p yo gen ic sacro ileitis show ed the sam e scintigraphic pattern as vertebral osteomyelitis. The diagnosis was made in one patient (duration offever: 3 wk) who had increased uptake in the left sacroiliacjoint, whereas another patient (duration of fever: >4 wk)presented w ith decreased uptake in the right sacroiliac joint.D espite a lack of published im munoscintigraphic data, especially for sacroileitis, these observations are in concordancew ith the findings of Schauw ecker (34), w ho dem onstrated thatsen sitiv ity o f I nWBC scin ti gr aphy in chr on ic o st eomye li tisw as significantly lower in the central skeleton (containingactive bone marrow) than in the peripheral bones because ofincreasin g in cid en ce o f p hotop en ic lesio ns. T he sam e o bserv ations were made by Reuland et al. (14) using 99mTc..BW250/1 83. The instance of a false-positive interpretation of afocal cold spot in a thoracic vertebra as osteomyelitis in apatient, w hich w as proven to represent fatty infiltration of thebone marrow by M RI, underlines the difficulties that mayap pear ifan u nsp ecific fin din g lik e p ho to pen ia is in clud ed in thesci nt ig raphi c anal ys is .Immunoscintigraphy failed to detect histologically provenpyogenic interstitial nephritis and one hepatic abscess. T hesefalse-negative findings are probably because of the high physiologic accum ulation of radiotracer in the kidneys and liver. Inaddition, a chronic pancreatic abscess could not be detected byimmu no scin tigrap hy ev en u sin g S PE CT (filtered b ack pro je ction and ISA). In this patient, labeled granulocytes or freecirculating antibodies w ere probably not able to pass throughthe thick w all o f th e ch ro nic a bscess fo rm atio n. F alse-po sitiv euptake w as seen in a m ediastinal teratom a infiltrated by a largeam ount of eosinophiles, possibly cross-reacting w ith the antibody, and in a carcinoma of the sigmoid (Fig. 2). This wasprobably caused by granulocytic infiltration of the tum or, anobservation also known from 1nWBC scin tigrap hy (35 ).S tu dies in FUO patien ts p erfo rm ed w ith e ith er 6 7G a (3 ) o r1 1 In-labeled WBC ( 7 1 1 ) revealed a wide range of sensitivities (34% to 75% and 17% to 85%, respectively). Thesediscrepancies may be explained by the small and differentpatient populations, generally including no more than 35patients w ho suffered from a wide spectrum of diseases. In thestudy recently published by B ecker et al. (18), w ho perform edimmunoscintigraphy with 99mTc..BW 250/183 in 34 patientswith FUO, the overall diagnostic sensitivity was low (40%)despite a 58.8% prevalence of inflam matory causes for FU O.T his strik in g d ifferen ce, comp ared to o ur resu lts, m ay be p artlyexplained by the fact that SPECT was not performed in thesepatients. Therefore, diagnoses in 6 patients suffering fromen doca rd itis w ere m issed . It is d eb atab le if the v eg etation s w ere> 5 mm in diameter, as was common in these patients, that theywould have been detected by SPECT.c@ONCLUSIONImmunoscintigraph@ ' perform ed w ith the m onoclonal antigranulocyte antibody 9m Tc@ BW 250/183 is a useful diagnostictool in patients with FUO in the following conditions: inendocarditis, scintigraphy could contribute to the final diag

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FIGURE3. Who le-bo dycanobtaln ed2 hra fterinjec tionn8 -yr-oldch ildshows sinusitisin rightsinus maxil laris .conditions including infection, m etastatic disease, fracture,po stradiatio n th erap y ch ang es, su rg ical in terv en tio ns, P aget'sdisease and degenerative disk disease (27,30,31 ). This alsoproved true for immunoscintigraphy with M Ab 99mTc@ BW250/183 (13,21 ). D ecreased uptake is usually considered nondiagnostic. In these patients, dual-isotope im aging w ith 11InW BC and 99mTcsulfur colloid (32) could be helpful in thed ia gn osis. C ombin ed s cin tig ra ph y w ith 9 9mT c..BW 250 /1 83 a nd9 9mT cs ulfu r c ollo id h as th e p ote ntia l fo r re du cin g n on dia gn ostic studies, but data about this topic are not available. On theother hand, the amount and configuration of cold spots in thec entra l b on e m arrow rep resen t im po rtan t in form ation abo ut th eunderlying process, especially w hen screening patients w ithFUO. In our patients, w idespread photopenic bone marrowlesions w ere correctly interpreted as representing m alignantdisease (Fig. 4). In these patients, immunoscintigraphy establish ed th e diagn osis of m align an t d isease early in th eir d iag no stic work-up. As known from InWBC scin tig rap hy andrecently shown in immunoscintigraphy with @ Tc-BW250/I 83 (33), spondylitis predom inantly presents as a photopenicdefect rather than as increased uptake in the central bone

FiGURE4. Colonelsl ices of imageshow infectiveendOcardit iSn project iont o t ip o f pacemakerw i th lead shownw i th ISA ( top)and f il te redbackreconstruction(bottom).SPET was performed24 hr after inject ion.

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a cc u ra te a s se ssmen t o f u lc er at iv e c ol it is w i th e xamet az ime -l ab el le d l eukoc yt es t ha nw it h a nt ig ra nu lo cy te a nti bo die s. E ur J N uc ! M e d l 99 6; 23 :2 47 2 55 .1 6. S eg ar ra I , R oc a M , B aliella s C , e t a l. G ra nu lo cy te- sp ecif ic m on oc lo na l a nt ib od yt ec hn et ium -9 9m -BW 250 /1 8 3 and i nd ium -I I I o x in e -l ab el ed l eukoc yt e s ci nt ig ra phy i ni n fl ammato ry bowel d isease . Eur J Nuc!Med 199l ;l 8:7 l57 l9 .17. M orguet A J, M un z D L, Ivancevic V . et al. Im mun oscintigraphy using technetium99m-labeled ant inca-95 ant igranulocyte ant ibodies as an adjunct to echocardiographyi n s ub ac ute i nf ec ti ve e nd oc ar dit is . J Am C o! ! C ar di o! I 99 4;2 3: I 7 71 1 77 8.1 8. B ec ke r W , D lk em ey erU . G ra ma tzk i MU , S ch ne id er MU , S ch ee le J . W o lf F . U se o fim muno scintigraphy in the diagnosis of fever of unkn ow n origin. E ur J N uc! M ed1993;20:I078l083.19. Luig H, Eschner W , Bhre M , Voth E, Nolte G. Eine iterative Strategic zurB es tim mu ng d er Q uellen verte ilu ng b ei d er E in zelp ho to nen -T om og ra ph ie m it e in err ot ie re nd en Gammakamer a ( SPECT). Nukl ea rme di :i n l 98 8 ;2 7 :l 40 I 46 .2 0. B at hm an n J , Mo se r E . V er gl ei ch v on S ke le tt sz in tig ra ph ie u nd K no ch enma rk ss zi nt igr ap hi e b eim Na chwei s o ssr erMet as ta se n. R a di o! og e l 99 5; 35 :8 l 4.2 1. M un z D L. K no ch en ma rk sz in tig ra ph ie P rin zip ie n, k lin is ch e E rg eb nis se u nd In dik at ionen . Rad io !oge 1992 ;32 :485494 .2 2. R es ke S N, K ar ste ns J H, H en ric h MM , e t a l. N ac hw eis d es S ke le ttb efa lls m alig ne rErkrankungen durch Immunszin t ig raph ie des K.nochenmarks .Nuk!earmed i: in 1993;32:111-119.23. Bahk YW. C om bined scintigraphic and radiographic diagno sis of bone and jointd is ea se s. B e rl in : S p ri ng er Ve rl ag ; 1 99 4: 47 4 9.24. L avender JP, Low e J. Barker JR. Burn JI, Chaudhri M A. 67G a citrate scanning inn eop la st ic a nd i nf lammat or y l es io ns . Br J Radi o! 1 97 l ;4 4: 36 I 36 6.2 5. C arr oll B , S ilv erm an PM, G oo dw in D A. D ou gall I R. U ltr as on og rap hy an d in diu m- I I Iwhi te b lo od c el l s ca nn in g f or t he d et ec ti on o f i nt ra -a bd om in al a bs ce ss es . R ad io !o gy1981;140 :55-16 0.2 6. K no ch el J Q, K oe hler P R, L ee T G, W elc h DM. D ia gn os is o fab do min al ab sc es se s w ithCT, u lt ra s ound, a nd i nd ium -l I 1 l eukoc yt e s ca n s. R adi o! og y l 98 0; l3 7: 42 5 43 2 .2 7. D atz F L, T ho rn e D A. C au se. s ig nific an ce o fc old b on e d efe cts o n in diu m-I I I lab eledl eukocy te imaging. J Nuc!Med l987 ;28 :820823.28. M eller J, Con rad M , Behr 1, G ratz 5, L uig H , B ecker W . S tellenw ert der iterativenR e ko ns tr uk ti on b ei d er D ia gn os ti k v on Le be rhma ng iomen . Nukl ea rme di :i n 1 99 7; 36 :6570.29. Reuland P, M flller-Schauenburg W , Luig H , E schner W , Feine U . V ergleich derk lin is ch en W er ti gk ei t e in es i te ra ti ve n R ek on st ru kt io ns ve rf ah re ns m it d er g ef il te rt enRuckp ro je k ti on b ei d er SPECT der Le be r. Nuki ea rmedi zi n l 98 9; 28 :l 39 l 44 .3 0. Mo k YP , C ar ne y WH , F er di na nd ez -U ll oa M . S ke le ta l p ho to pe nic l es io ns in i nd iumI11 WBC imaging. Nuc!Med 1984;25:3221326.3 1. Palestro CJ, Kim CK, Swyer A J, V allabhajosula S. Goldsmith Si. Radionuclided iag no sis o f v erteb ral o steo my elitis : in diu m-l I 1 - le uk oc yte an d te ch netiu m-9 9m -methy lene d iphosphonate bone sc in tig raphy . J Nuc!M ed I991 ;32 : I861865 .3 2. P alestro C , R oum anas P . Sw yer A J, C hun K K, G oldsm ith Si. D iagnosis of m usku los ke le ta l in fe cti on u si ng c ombi ne d I n- I I I l ab ele d le uk oc yte a nd @TcC mar rowim ag in g. C li ii N u c! Me d l 99 2; 17 :2 69 2 73 .3 3. G ra tz 5 , B rau n H G, B eh r TM , et a l. P ho to pen ia in ch ro nic v er te bra l o steo my elitis w ithtec hn etiu m-9 9m an tig ran ulo cy te an tib od y (BW 2 50 /1 83 ). J N uc! M ed l9 97 ;3 8:2 1 I216.3 4. 5 ch auwe ck er D S. O st eomy el it is . D ia gn os is w it h I n- l I I -l ab el ed l eu ko cy te s. R ad io !o gy1989;l71:141146.35. Saverymuttu SH, M altby P. Batman P. ioseph AE, Maxwell D . False-positivel oc al is ati on o fi nd ium- Il l g ra nu lo cy te s i n c ol on ic c ar ci noma . B rJ Ra d l9 86 ;5 9: 77 3 777.

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noses if SPECT was perform ed in cases of doubtful findings inTEE. Immunoscintigraphy was superior to sonography and CTin th e early d etec tio n of ab dom ina l ab scesse s. Immun osc in tigraphy was able to exclude pyogenic processes with highaccuracy in those patients w ith autoimmune disease, w hich is ofp articu lar in terest in sy ndromes lik e S till's d isease, in w hich n oestablished serologic m arker of diagnosis existed until now.M etastatic malignant disease as a common cause of FUO mayb e d iag no sed and differen tia ted from othe r u nd erly in g d ise asesby a characteristic pattern of m ultiple cold spots in the centralbone marrow early in diagnostic work-up. A differentiatedanalysis of photopenic defects in the bone marrow should bein clu de d in th e fin al s cin tig ra ph ic in te rp re ta tio n.REFERENCESI . P et er sd or f RG, B ee so n PB. F ev er o f u ne xp la in ed o ri gi n: r ep or t o n 1 00 c as es . M ed ic in e1961;40: 130.2 . Sm it h JW . Sout hwest er n i nt er na l medi ci ne con fe rence : f ev e r o f unde te rm i ned o ri gi n:n ot w hat it u sed to b e. A m J M ed S ci l9 86 ;2 92 :5 6 6 4.3. Hilson AJW , M aisey M N. Gallium -67 scanning in pyrexia of unknown origin. Br

Medi l979;4:1330133l.4. K nockaert D C, M ortelm ans L A, D c Roo M C, B obbaers A D. Clinical value of 67G asc in tig raphy in invest iga tionof fevero r in fl ammat ionof unknown or ig in in u lt rasounda nd c om pu te d a re a. A cta C li n B ei g l 98 9; 44 :9 l 98 .5 . M c N ei l B J , S a nd e rsR , A l de r so n P 0 , e t a l . A p r os p ec ti ves tu d y of C T, u lt ra s ou n d ,a n dgall ium imaging in pati ent s wi th fever . Rad io logy 198I ;l39 :647653 .6 . S fa ki an ak is GN , A I- Sh ei kh W , H ea l A , R odman G , Z ep pa R , S er af in i A . C omp ar is on so fs ci nt ig ra ph y w it h i nd ium- I I I le uk oc yt es a nd 6 7G a i n th e d ia gn os is o fo cc ul t s ep si s.J Nucl Me d l 98 2; 23 :6 I 8 62 6.

7 . D avies 5G . G arv ie N W. T he role of indium -labeled leu kocyte im aging in pyrexia ofunknown o ri gi n. Br J Radi o! l 99 0 ;6 3: 85 0 85 4 .8. Haentjens M , Piepsz A, ScheIl-Frederick E, Perlm utter-Crem er N , FrU .hling J.L im ita tio ns in th e u se o f in diu m-l I 1 -o xin e-la bele d leu ko cy te s fo r th e d ia gn os is o foccu l t i nfect ion in ch ildren. Ped ia t r Rad io ! l987 ;17 :139I42.9. Hawker Ri, Hall CE, Drolc Z. Rhys-Evans PH. Indium leukocyte im aging in truep yr ex ia o f u nk nown o ri gi n. E ur J N uc ! M ed I 98 5; l0 :1 72 l 74 .10. S chm idt K G, R asm ussen JW , S orensen P G. W edebye IM . Ind ium -I I I granu lo cytes cin tig ra ph y in th e ev alu atio n o f p atie nts w ith f ev er o f u nd ete rm in ed o rig in . S ca ndJ !n tctD i s l987 ; I9 :339345 .I I . Syrjal M T. Valtonen V . Liewendahl K, M yllylS G . Diagnostic significance ofi nd ium- I 1 1 g r an ul oc yt e s ci nt ig ra ph y i n f eb ri le p at ie nt s. J N uc ! M ed 1 98 7; 28 : 1 55 1 60 .12. O yen W J, C laessens RA , R aem aekers JM , de P au w B E, van der M eer JW , C orstensFH . D ia gno si ng i nf ec ti on i n f eb ri le g ra nul oc yt op en ic p a ti en ts w it h i nd ium -I 1 1 l ab el edhuman immunog lo bul in . J C ! in Onco ! 1 99 2; I0 :6 1 6 8.13. H otze A , B ride B . O verbeck B , et al. T echnetium -99m -labeled antigranulocy tean tibod ies in suspected bone infect ions. J Nuc!Med l992 ;33 :52653.14. R euland P . W ink er K H, H euchert 1, et al. D etection of infection in postoperativeorthopedic pat ients with technet ium-99m-labeled monoclonal ant ibodies against granulocytes.Nuc!Med I99I;32:220922l4.I 5. A lm ers 5, G ranerus G , F ranzen L , Strom M . T echnetium -99m scintigraphy: m ore