Fever of unknown origin predictors of outcome A prospective multicenter study on 164 patients

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1 Europen Journl of Internl Mediine 14 (2003) lote/ ejim Originl rtile Fever of unknown origin preditors of outome A prospetive multienter study on 164 ptients Cristin Bius *, Hortiu D. Bolosiu, Comn Tnsesu, And Bius, for the GSFONR,, d 1 Spitlul Colentin, Medil B, Soseu Stefn el Mre 19 21, set. 2, Buhrest, Romni Clinil Reserh Unit RECIF (Reseu d Epidemiologie Clinique Interntionl Frnophone), Buhrest, Romni Deprtment of Internl Mediine, Cluj County Hospitl, Cluj, Romni d I. Cntuzino Miroiology Institute, Buhrest, Romni Reeived 25 Novemer 2002; reeived in revised form 20 Ferury 2003; epted 11 Mrh 2003 Astrt Bkground: To dte, the studies tht hve een done on fever of unknown origin hve mostly een desriptive. Therefore, we know the etiogil spetrum nd how it hs hnged sine 1966 for mny regions of the world. However, we do not know if there re linil or lortory preditors of severe outome. Being le to estimte the severity of the disese erly on would llow one to determine how intensive the dignosti work-up should e. Methods: A multienter ohort study ws rried out on 164 onseutive ptients who met the lssi, modified riteri of fever of unknown origin. The study lsted 2 yers ( ) nd inluded follow-up period of nother 2 yers. The min outome mesured ws the finl dignosis estlished t the end of follow-up. Results: When the white ell ount ws norml, the reltive risk for serious disese ws 1.49 (CI: ; p50.004), when nemi ws present, the reltive risk ws 1.55 (CI: ; p50.003), nd for high lnine minotrnsferse (ALAT), iliruin, or ltte dehydrogense (LDH), the reltive risks were 1.57 (CI: ; p50.010), 1.57 (CI: ; p50.007), nd 3.43 (CI: ; p ), respetively. In multivrite nlysis, the odds rtios for serious diseses were 2.7 (CI: ; p50.02) for norml white ell ount, 2.8 (CI: ; p50.02) for nemi, 4.3 (CI: ; p50.003) for high serum iliruin, nd 5.3 ( ; p50.009) for high serum ALAT. Conlusions: In ptients hving fever of unknown origin, nemi, norml white ell ount, nd high ALAT nd iliruin re independent preditors of severe outome Elsevier B.V. All rights reserved. Keywords: Multienter ohort study; Prognosis; Fever of unknown origin; Biliruin; Alnine minotrnsferse; Ltte dehydrogense; Anemi; Leukoytosis 1. Introdution *Corresponding uthor. E-mil ddress: ius@fx.ro (C. Bius). Fever of unknown origin (FUO) is extremely diffiult to 1 Grupul pentru Studiul Ferei de Origine Neunosut in Romni (The dignose. It hs een defined s n illness with retl Group for the Study of the Fever of Unknown Origin in Romni): Buhrest: C. Bius, C. Tnsesu, I. Mtei, A. Hidr, R. Voiosu, temperture exeeding C on t lest three osions, Colentin Hospitl; E. Ceusu, P. Clistru, C. Criste, Infetious Diseses lsting t lest 3 weeks, nd with no dignosis rehed Hospitl; A. Bius, I. Cntuzino Miroiology Institute; Cluj: H. fter 1 week of intensive investigtions [1]. Mny prospe- Bolosiu, M. Stoiesu, County Hospitl; Isi: V. Lu, Infetious Diseses tive studies [2 10] of ptients with FUO hve een Hospitl; A. Cosovnu, St. Spiridon Hospitl; Timisor: D. Stnesu, performed round the world using this definition, while Infetious Diseses Hospitl; Siiu: M. De, C. Be, C. Cipin, M. Greu, D. Vulu, County Hospitl; Brsov: E. Gheorghit, I. Brumru, G. other series hve used different riteri. The spetrum of Vuln, County Hospitl; Trgu Mures: E. Crs, D. Pop Petre, County diseses seems to e determined y geogrphi nd Hospitl. eonomi ftors, nd it ppers to hnge with time. With / 03/ $ see front mtter 2003 Elsevier B.V. All rights reserved. doi: / S (03)00075-X

2 250 C. Bius et l. / Europen Journl of Internl Mediine 14 (2003) the exeption of smll retrospetive study performed in tionnires, the medil history of eh ptient ws tken ounty hospitl in Hungry [11], no other study on FUO nd thorough physil exmintion given. hs een performed in Centrl or Estern Europe. Medil history, physil exmintion, nd the results of The question of how fr we should proeed with lortory investigtions were prospetively registered in invsive nd/ or expensive investigtions when fing this strutured dt olletion form. In se of no dignosti dignosti prolem remins unnswered euse of the hypothesis, the tests listed in the two series of invesdesriptive nture of pst studies, whih ssessed the tigtions (Tle 3) were reommended. spetrum of diseses using FUO; none tried to determine At the end of follow-up, the ptients were lssified s whether it ws possile to predit the severity of the hving severe or mild illness. The inlusion riteri in the outome. Only one study developed guide to predit the severe illness group were: () deth due to the disese tht proility of rehing dignosis [12]. We therefore hd used the FUO; () ny neoplsti disese; () onduted multienter ohort study with 2-yer follow- infetions whih, left untreted, invrily led to deth up to determine the preditors of outome of FUO in (septiemi, infetious endorditis); nd (d) severely Romni. ltered generl stte nd/ or weight loss.5 kg. Continuous vriles were sttistilly nlyzed nd groups of ptients (severe nd mild illness) were first ompred using the Mnn Whitney U-test. When the 2. Mterils nd methods differenes were sttistilly signifint, the vriles were trnsformed into dihotomous groups (e.g. norml/ nor- Of 37 deprtments of internl mediine nd infetious ml ALAT, LDH, hemogloin). A two-tiled Fisher s diseses of university hospitls (seondry nd tertiry ext test ws used for ll dihotomous vriles in re) from ll regions of Romni tht hd een invited to univrite nlysis, nd vriles signifint t the 0.1 prtiipte in our study, nine eventully greed to do so. A level were then inorported into logisti regression totl of 164 ptients were inluded in the 2-yer study model for multivrite nlysis, with severity of disese (Jnury 1997 Deemer 1998), s well s in the 2-yer (severe/ mild) s the dependent vrile. We used SPSS follow-up, whih ws onduted y telephone from the 11.0 softwre (SPSS, Chigo, IL, USA). The signifine oordinting enter to oth the treting physiins nd the level ( p) ws set t ptients themselves. The inlusion riteri were: () ge.18 yers; () fever for t lest 3 weeks; () fever C t lest twie; (d) 3. Results sene of dignosti suggestions (dignosti hypothesis) fter history, linil exmintion, nd series of sreen- A totl of 164 ptients (85 femles, 79 mles) meeting ing investigtions (Tle 1); nd (e) initil dignosti our riteri for FUO were inluded in our 2-yer study. hypothesis (rised fter the history, linil exmintion, Their men ge ws yers (medin 46 yers, rnge nd series of sreening investigtions) not onfirmed fter yers). the pproprite investigtions ( suggestions list ws A totl of 93 ptients (57%) were referred y generl provided; Tle 2). In order to e inluded, ptients hd to prtitioners nd 71 (43%) hd lredy undergone extenmeet riteri () () nd either (d) or (e). sive investigtions efore referrl. The ptients rrived The exlusion riteri were: () immunosuppressive fter men of dys from the eginning of their 9 tretment within 2 months or grnuloyte ount,10 / l for FUO (medin 49 dys, rnge 3 dys 3 yers). ny reson; () known infetion with HIV; () onfirmtion The men follow-up ws months (medin 22 of the initil dignosti hypothesis rised fter history, months, rnge 1 24 months). Some 124 ptients (75.6%) linil exmintion, nd/ or sreening investigtions. were followed for 24 months. For 33 ptients (20.1%), the Following the ompletion of some stndrd ques- follow-up ws less thn 6 months. The follow-up of the 38 ptients who died (23%) ws onsidered to e 24 months. Tle 1 Ptients were hospitlized for totl of 3343 dys, with Sreening investigtions men of dys per ptient (medin 19 dys, rnge 1. Blood ell ount1lood smer 5 69 dys). The durtion of hospitl sty ws not ssoi- 2. Erythroyte sedimenttion rte ted with the outome ( p.0.05). 3. Serum retinine, protein, lumin, gluose, iliruin, lkline A totl of 133 ptients (83%) hd ontinuous fever nd phosphtse, minotrnsferses, ltte dehydrogense 27 (17%) hd reurrent fever, the ltter defined s t lest 4. Urinry nlysis 5. Urine ulture two episodes of fever with intervls of t lest 48 h 6. Chest X-ry without fever. 7. Three lood ultures (eroi1neroi) As for the etiology, 74 ptients (45.1%) hd infetions, 8. Serum protein eletrophoresis 41 (25%) neoplsms, 30 (18.3%) non-infetious inflmm- 9. C-retive peptide tory diseses, three (1.8%) drug fever, nd four (2.1%)

3 C. Bius et l. / Europen Journl of Internl Mediine 14 (2003) Tle 2 Investigtions performed for the dignosti hypothesis rised y the history, linil exmintion, nd/ or sreening investigtions suggesting: Gint ell rteritis, polymylgi rheumti: temporl rtery iopsy. Infetious endorditis: ehordiogrphy (trnsthori, trnsesophgel). Hemtologi disese: one mrrow punture with or without ulture (in se of suspeted tuerulosis), one mrrow iopsy. Pulmonry or medistinl disese: tuerulin test, sputum ulture for tuerulosis, pulmonry firosopy (ronho-lveolr lvge with ultures, ytologi exm), CT of hest. Dirrhe: stools for worms, eggs, ysts, ultures; olonosopy. Adominl disese: gyneologi exm, ultrsonogrphy nd/ or CT of domen nd pelvis. Adenomegly: iopsy, serologies for toxoplsm, CMV, HIV. Thyroid disese: thyroid-stimulting hormone (TSH), T4; thyroid ultrsonogrphy, ntimirosoml ntiodies. Collgen-vsulr disese (skin mnifesttion, rthritis, serositis): ntinuler ntiodies, rheumtoid ftor, ntineutrophil ytoplsmi utontiodies (ANCA), 24-h proteinuri, nti-doule strined DNA (nti-dsdna), ryogloulins. Liver disese: ultrsonogrphy or CT, heptitis B nd C serologies, nti-smooth musle nd LKM ntiodies, liver iopsy. Sinus disese: rdiogrph of sinus nd teeth. Tooth disese: orthopntomogrm. Neuromusulr disese: lumr punture, rin CT, eletromyogrm (EMG), musulr iopsy, retine phosphokinse. Skin eruption: dermtologi exm, skin iopsy. Pludism: thik lood smer. Urinry disese: urinry quntittive nd qulittive ytology, intrvenous pyelogrphy, urine ultures for tuerulosis. Bilio-pnreti disese: dominl ultrsonogrphy, CT, endosopi retrogrde olngiogrphy. Tle 3 Proposed miniml investigtions for ptients with fever of unknown origin First series Tuerulin test 24-h Proteinuri Antinuler ntiodies, nti-dsdna Bene-Jones proteinuri Adomino-pelvi ultrsonogrphy Sinus X-ry Orthopntomogrm Temporl rtery iopsy (if ge.60) Bone mrrow punture (if hemtologil perturtion: leukopeni, thromoytopeni, nemi, peripherl norml ells) B nd C heptitis, HIV, CMV serologies Thyroid-stimulting hormone Trnsthori ehordiogrphy Gyneologi exm Seond series (if exmintions of first series re negtive): Chest, dominl, nd pelvi CT sn Liver iopsy (if high minotrnsferses) Bone mrrow punture Bone mrrow iopsy (in se of hemtologil perturtion nd/ or high LDH) Colonosopy Smll intestine rdiologil exm

4 252 C. Bius et l. / Europen Journl of Internl Mediine 14 (2003) other uses. The etiology remined osure for 12 The eqution of the logisti regression ws: ptients (7.3%); the fever disppered spontneously in nine ptients, one ptient still hd fever t the end of LOGODDS (severe illness) follow-up, nd the fever disppered in two ptients fter 3 (iliruin) empiril tretment with ortiosteroids, whih ws 3 (ALAT) initited euse of the severity of their illness. 3 (nemi) The most frequent etiologies were tuerulosis (n527, 16.5%), mlignnt lymphom (n521, 13%), nd ollgenvsulr 3 (leukoytosis). diseses (n517, 10.3%). Using the riteri presented in the Mterils nd methsevere Estimted from this eqution, the ptient s risk for ods setion t the end of follow-up, 93 ptients (56.7%) illness ws equl to 24% when ll vriles (red ell were lssified s hving severe illness nd 71 ptients nd white ell ount, ALAT, nd iliruin) were within the (43.3%) s hving mild illness (Tle 4). norml rnge, nd equl to 98% when ll vriles were In univrite nlysis, nemi, norml white lood pthologi. ell ount, nd inresed lnine minotrnsferse (ALAT), ltte dehydrogense (LDH), nd totl iliruin were ssoited with n inresed risk of severe illness 4. Disussion (Tle 5), wheres the ge of ptients, durtion of fever, serum lumin, nd erythroyte sedimenttion rte (ESR) We performed multienter ohort study in order to were not. otin representtive smple of ptients with FUO in our In multivrite nlysis y logisti regression, the model ountry. We did not sueed in inluding ll ptients with retined four independent vriles: nemi, leukoytosis, FUO, lthough ll university hospitls were invited to high ALAT, nd high totl iliruin (smple size: 120 prtiipte. However, this is the first multientri, prospeptients; Tle 6). Unfortuntely, LDH ould not e tive study on the sujet in Romni, nd ptients from ll introdued into the model euse of the high numer of regions of the ountry were inluded. missing vlues. Beuse of the impreision of Petersdorf s third riterion [1], whih ould led to seletion is, we tried to hnge it from time-relted to qulity-relted riterion. Our study hd lredy egun when newer definitions of FUO Tle 4 were disussed [13,14]. Clssifition of outomes in severe nd not severe disese The etiology of FUO in Romni respeted the lssil Severe outome Mild outome trid (infetions, neoplsms, nd non-infetious inflmm- Lymphom 21 Tuerulosis 16 tions) present in other studies, with the proportions eing Solid neoplsm 12 FUO 10 equivlent to those in older Western series [1,3], in series, Collgen-vsulr disese 11 Chroni pyelonephritis 7 from ommunity hospitls [6], nd in the newer series Tuerulosis 11 Gint ell rteritis 6 from the developing world [10]. We found lrge propor- Infetious endorditis 8 Collgen-vsulr disese 5 tion of infetions dominted y tuerulosis, due to its Leukemi 8 Adult Still s disese 4 AIDS 4 Drug fever 3 high inidene in Romni, nd n importnt proportion of Typhoid fever 4 Dentl infetion 3 solid neoplsms nd systemi lupus erythemtosus, prtly Aute pyelonephritis 3 Toxoplsmosis 2 due to the low ess to imging tehniques (ultrsonog, FUO 2 Cytomeglovirus infetion 2 rphy nd omputed tomogrphy) nd speifi serologi Choleystitis 2 Myoplsm pneumonie 2 proedures during the first week of investigtions. Chroni pyelonephritis 2 Cryogloulinemi 2 All of the existing studies were purely desriptive, Septiemi 2 Hyperthyroidism 2 Enephlitis 2 Pneumoni 2 exept for one [12], whih developed guide for preditd Gint ell rteritis 1 e Neurosis 2 ing the proility of rehing dignosis. Aording to f Proly infetious FUO 2 this guide, the proility of rehing dignosis is higher Rheumtoid rthritis 1 when the ptient hs ontinuous rther thn periodi fever Totl 93 Totl 71 nd/ or nemi nd/ or norml serum protein eletro Altered generl stte nd/or weight loss.5 kg. phoresis. Systemi lupus erythemtosus, polymyositis, dermtomyositis, over- We onsidered tht when ptient with n FUO is seen lp syndrome. for the first time, it is most importnt to predit the severity Undignosed FUO. of the outome. Depending on the potentil preditors, the The ptient hd murosis nd weight loss.5 kg. e The ptients hd norml linil nd lortory exmintions (exeptwith more nd more expensive nd invsive investigtions liniin should deide () whether he should ontinue ing neurosis) nd the fever disppered fter sedtive therpy. f Undignosed FUO tht resolved with ntiiotherpy. or () if he n onfine himself to linil exmintion nd

5 Tle 5 Preditors of severe outome (univrite nlysis) C. Bius et l. / Europen Journl of Internl Mediine 14 (2003) Prmeter Severe Mild Reltive risk Test p (two Smple, outome outome with onfidene sided) n intervl Age (yers) Mnn Whitney U (18 78) (18 77) Durtion of Mnn Whitney U fever (dys) (3 700) (4 1000) ESR (mm/ h) Mnn Whitney U (5 175) (2 150) Serum lumin (g/ dl) Mnn Whitney U ( ) ( ) Anemi 35/ 91 11/ ( ) Fisher s ext test (H,10 g/dl) (38.4%) (15.9%) High ALAT 18/ 87 4/ ( ) Fisher s ext test (20.7%) (6%) High LDH 12/ 20 2/ ( ) Fisher s ext test (60%) (7.7%) High iliruin 26/ 68 8/ ( ) Fisher s ext test (38.2%) (15.4%) Leukoytosis 46/ 91 19/ ( ) Fisher s ext test (.10 /l) (50.5%) (27.5%) Chills 26/ 93 23/ ( ) Fisher s ext test (28%) (32.4%) Perspirtion 69/ 93 47/ ( ) Fisher s ext test (74.2%) (67.1%) Continuous vs. 15/ 91 12/ ( ) Fisher s ext test reurrent fever (16.5%) (17.4%) Without missing vlues. Medin. Rnge. ty, s there ws no orreltion etween them (the orrel- tion mtrix ws performed to exlude multiollinerity). Therefore, we nnot reple ALAT nd iliruin with hepti dmge s n independent vrile. In multivrite nlysis, prt of the onstnt my e explined y LDH, whih in univrite nlysis ws si series of investigtions, nd then wit for new linil lues to pper. In this study, nemi, leukoytosis, norml ALAT, nd norml iliruin predited severe illness s the use of FUO, oth in univrite nd multivrite nlysis. ALAT nd iliruin were independent preditors of severi- Tle 6 Ftors ssoited with severe outome of FUO (multiple logisti regression) Vrile Coeffiient Stndrd error p-vlue Odds rtio Upper 95% Lower 95% onfidene onfidene intervl intervl High totl iliruin High ALAT Hemogloin,10 g/ dl Leukoytes.10 / l Likelihood rtio test: P ; Hosmer-Lemeshow goodness-of-fit test: P

6 254 C. Bius et l. / Europen Journl of Internl Mediine 14 (2003) ssoited with the highest reltive risk for severe Referenes outome (LDH ould not e introdued into the multivrite model euse of the importnt numer of missing [1] Petersdorf RG, Beeson P. Fever of unexplined origin: report of 100 vlues). On the other hnd, multivrite nlysis y logisti ses. Mediine 1961;40:1 30. regression suggests tht when ll the vriles of the [2] Glekmn RA, Crowley M, Esposito A. Fever of unknown origin: view from the ommunity hospitl. Am J Med Si 1977;274:21 5. multivrite model re pthologi, the proility of [3] Howrd P, Hhn H, Plmer RL, Hrdin WJ. Fever of unknown severe outome is 98%; therefore, the dditive preditive origin: prospetive study of 100 ptients. Texs Med 1977;73:56 vlue of elevted LDH my e of little relevne. 9. When the ptient hs norml hemogloin, norml [4] Lrson EB, Fetherstone HJ, Petersdorf RG. Fever of undetermined white ell ount, nd norml ALAT, LDH, nd iliruin, origin: dignosis nd follow-up of 105 ses, Mediine 1982;61: the proility of hving severe disese is low. There- [5] Brdo FJ, Vzquez JJ, Pen JM, Arnlih F, Ortiz-Vzquez J. fore, we propose tht, t the first visit, the physiin should Pyrexi of unknown origin: hnging spetrum of diseses in two onfine himself to linil exmintion, few investig- onseutive series. Postgrd Med J 1992;68: tions (those in Tle 1 plus dominl ultrsonogrphy [6] Kznjin PH. Fever of unknown origin: review of 86 ptients nd ntinuler ntiodies), nd the ptient s follow-up. In treted in ommunity hospitls. Clin Infet Dis 1992;15(6): [7] Knokert DC, Vnneste LJ, Vnneste SB, Boers HJ. Fever of ontrst, nemi, n norml white lood ount, nd unknown origin in the 1980s. An updte of the dignosti spetrum. espeilly high LDH, ALAT, nd iliruin re preditors Arh Int Med 1992;153:52 5. of severe disese, nd intensive dignosti work-up is [8] Shoji S, Immur A, Imi Y et l. Fever of unknown origin: neessry when these normlities re present. Bsed on review of 80 ptients from the Shin etsu re of Jpn from these rules, we pln to implement seond prospetive Int Med 1994;33(2):74 6. [9] The Netherlnds FUO Study Group, de Kleijn EMHA, Vndenstudy nd to ssess the vlidity of these reommendtions rouke JP, vn der Meer JWM. Fever of unknown origin (FUO) I. in linil prtie. A prospetive multienter study of 167 ptients with FUO, using In onlusion, our results indite tht, in ptients fixed epidemiologi entry riteri. Mediine 1997;76: presenting with FUO, nemi, n norml white ell [10] Kejriwl D, Srkr N, Chkrorti SK, Agrwl V, Roy S. Pyrexi ount, nd high ALAT nd iliruin re independent of unknown origin: prospetive study of 100 ses. J Postgrd Med 2001;47(2): preditors of severe outome. [11] Almsi I, Ternk G. Differentil dignosis in ptients with fever t the deprtment for infetious diseses of ounty hospitl. Orv Hetil 1993;133: Aknowledgements [12] The Netherlnds FUO Study Group, de Kleijn EMHA, vn Lier HJ, vn der Meer JWM. Fever of unknown origin (FUO) II. Dignosti proedures in prospetive multienter study of 167 ptients. We thnk Pierre Duhut from RECIF (Reseu d E- Mediine 1997;76: pidemiologie Clinique Interntionl Frnophone) Amiens, [13] Arnow PM, Flherty JP. Fever of unknown origin. Lnet Frne, whom we onsulted from the very eginning of the 1997;350: projet (design of the study) to the end (editing of the [14] de Kleijn EMHA, Knokert DC, vn der Meer JWM. Fever of pper). Funding ws provided y STIZO SA, Herules Srl unknown origin: new definition nd proposl for dignosti work- up. Eur J Int Med 2000;11:1 3. (onstrution ompnies) nd ASTA Medi.