Diagnostic aspects of invasive Aspergillus infections in allogeneic BMT recipients

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1 (2000) 25, Mcmilln Publishers Ltd All rights reserved /00 $ Dignostic spects of invsive Aspergillus infections in llogeneic BMT recipients E Jntunen 1,2, A Piilonen 3, L Volin 1, T Prkkli 1, P Koukil-Kähkölä 4, T Ruutu 1 nd P Ruutu 5 1 Deprtment of Medicine, Helsinki University Centrl Hospitl; 2 Deprtment of Medicine, Kuopio University Hospitl; 3 Deprtment of Rdiology, Helsinki University Centrl Hospitl; 4 Mycologicl Lbortory, Helsinki University Centrl Hospitl; nd 5 Ntionl Public Helth Institute, Helsinki, Finlnd Summry: To investigte dignostic spects of invsive spergillosis (IA) in llogeneic BMT recipients, the chrts of 22 consecutive ptients with IA trnsplnted in were reviewed. IA ws dignosed dys (medin 131 dys) post BMT. In 16 ptients (73%), definite or probble dignosis of IA ws mde during life. Respirtory symptoms were the presenting feture in hlf of the ptients followed by neurologicl symptoms (27%). Chest X-ry reveled single or multiple nodulr lesions in 10 ptients; cvittion ws observed in five ptients. Tissue biopsy ws the most common method of dignosis (nine ptients: lungs 6, liver 1, subcutneous tissue 1, brin 1). Five IA cses were detected by nine guided fine needle lung biopsies in eight ptients nd without complictions. Broncholveolr lvge ws performed in 14 ptients with findings suggestive of invsive pulmonry spergillosis in eight cses. Lungs were the most common orgn ffected (90%) followed by centrl nervous system (41%). The dignosis of IA is still difficult, nd lrge number of ptients hve dvnced infection t dignosis. Methods for erly dignosis re needed. Ptients with clinicl suspicion of IA should be treted vigorously with ntifungl gents during the dignostic work-up. (2000) 25, Keywords: Aspergillus infection; llogeneic BMT; dignosis; rdiology; biopsy; broncholveolr lvge Invsive spergillosis (IA) is n importnt clinicl problem in llogeneic BMT recipients. In previous studies, the incidence of IA hs rnged from 4 to 10% 1 5 nd my be incresing. 6 Aspergillus infections hve been considered difficult to dignose. 7 9 They often present with non-specific symptoms nd signs. In the llogeneic setting other opportunistic infections my mke the dignosis of IA even more difficult. Due to frequent coloniztion of the upper respirtory trct with Aspergillus sp, tissue biopsy is needed for definitive dignosis. Correspondence: Dr E Jntunen, Deprtment of Medicine, Kuopio University Hospitl, PO Box 1777, SF Kuopio, Finlnd Received 9 August 1999; ccepted 24 November 1999 Knowledge of the spectrum of clinicl presenttion of IA is essentil both for rising clinicl suspicion nd for guiding dignostic ttempts. Furthermore, informtion on the yield of different dignostic methods is needed in choosing rtionl dignostic strtegies. We hve therefore nlyzed our experience on the dignostic spects of IA in recent cohort of llogeneic BMT recipients. Ptients nd methods From Jnury 1989 to December 1995, 205 dult ptients ( 16 yers) received their first llogeneic BMT t the Deprtment of Medicine, Helsinki University Centrl Hospitl. One hundred nd seventy-three ptients hd n HLAmtched sibling donor, in one cse there ws one-ntigen mismtch, nd 31 ptients hd n HLA-mtched unrelted donor. All ptient chrts were screened for bseline dt, post-trnsplnt course, nd occurrence of Aspergillus infection. Autopsy dt were lso reviewed when vilble. All ptients were cred for in single rooms with HEPA filters from the beginning of the conditioning therpy until engrftment. No systemic ntifungl prophylxis ws used. Systemic ntifungl gents, primrily mphotericin B (0.5 mg/kg/dy), were given empiriclly for neutropenic fever unresponsive to brod-spectrum ntibiotics given for t lest 4 dys. In cses of suspected lung problems, conventionl chest X-ry ws usully followed by computed tomogrphy (CT). In ptients with pulmonry infiltrtes, fiberoptic bronchoscopy with broncholveolr lvge (BAL) nd brushing ws crried out, especilly in ptients with diffuse pulmonry infiltrtes. In ptients with focl pulmonry lesions rdiologiclly guided fine needle biopsy (FNB) ws considered the first-line dignostic tool. Microbiologicl methods Stndrd microbiologicl methods for direct microscopy, culture nd identifiction of fungi were used. 10,11 Neither ntigen tests nor culture or microscopy of sputum 17,18 were used for the dignostics of Aspergillus infections during the study period. Dignostic criteri for invsive spergillosis Definite IA ws defined s the demonstrtion of filmentous fungi with microscopy from tissue smples tken during

2 868 life or t utopsy with or without positive culture for Aspergillus sp. Probble invsive pulmonry spergillosis (IPA) ws defined s the demonstrtion of filmentous fungi comptible with the morphology of Aspergillus nd/or positive culture for Aspergillus sp from specimen tken t BAL in ptients with rdiologicl findings suggestive of pulmonry fungl infection Dt collection In ptients with definite IA or probble IPA, dt of clinicl history, lbortory, nd rdiologicl findings before the dignosis of IA were recorded from the ptient chrts. Dignostic ttempts (rdiologicl studies, BAL studies, biopsies) performed within 30 dys prior to the dignosis of IA were lso included. The ptient ws considered febrile if the xillry temperture ws 38 C t lest once within week preceding the dignosis of IA. GVHD ws clssified ccording to published criteri 22,23. Autopsy dt were lso recorded when vilble. Results Of the 205 consecutive ptients trnsplnted in , 22 (11%) were dignosed s hving IA. A definitive dignosis of IA ws mde in 18 ptients, wheres four ptients hd probble IPA. The medin time to dignosis ws 131 dys post-trnsplnt (rnge dys). There were 10 femles nd 12 mles with medin ge of 42 yers (rnge yers). Underlying hemtologicl dignoses included AML (n = 5), MDS (n = 5), ALL (n = 4), CML (n = 3) nd others (n = 5). The mrrow donor ws n HLA-identicl sibling in 16 cses; six ptients hd n unrelted donor. Post-trnsplnt course before the dignosis of IA All ptients engrfted (ANC /l) t medin of 17 dys (rnge dys) post BMT. However, 13 out of 22 ptients (59%) developed lte neutropeni (ANC /l) for medin of 5 dys (rnge 2 28 dys). A gret mjority of the ptients hd GVHD (Tble 1); only Tble 1 Incidence nd tretment of GVHD in 22 ptients with invsive spergillosis prior to the dignosis of fungl infection No. of ptients (%) Acute GVHD grde no 5 (23) I 3 (14) II 5 (23) III 6 (26) gr II IV 14 IV 3 (14) (63%) Chronic GVHD no 7 (35) limited 1 (5) extensive 12 (60) Tretment of GVHD high-dose MP 18 (82) + ATG 12 (55) Ptients who survived 100 dys fter BMT. MP = methylprednisolone; ATG = ntithymocyte globulin. three ptients with IA hd no GVHD nd/or extensive cgvhd. Thirteen ptients (59%) were on CsA nd ll were tking methylprednisolone ( mg/kg/dy, medin 0.6 mg/kg/dy) t the time of the dignosis of IA. Fourteen ptients (64%) received mphotericin B (AmB) on n empiricl bsis fter BMT. The medin cumultive dose of AmB before the dignosis of IA ws 5 mg/kg (rnge 1 20 mg/kg). One ptient with history of IPA before BMT received liposoml AmB fter BMT. Clinicl nd lbortory fetures t dignosis of IA Respirtory symptoms were the most common presenting clinicl fetures of IA followed by neurologicl symptoms (Tble 2). No ptient presented with hemoptysis. Only seven ptients (32%) were febrile ( 38 C) within week preceding the dignosis. The medin ANC count ws /l (rnge /l). In seven ptients (32%), the ANC ws /l. The serum C-rective protein (CRP) rnged from 5 mg/l to 384 mg/l (medin 58 mg/l, reference vlue 10 mg/l). In five ptients (23%), CRP ws 20 mg/l t dignosis. On the other hnd, ll ptients dignosed to hve IA for the first time t utopsy hd high CRP vlues just prior to deth ( mg/l, medin 320 mg/l). Rdiologicl findings in the lungs Chest X-ry hd been tken within 30 dys prior to the dignosis in 21 ptients; in one ptient rdiologicl ssessment ws bsed only on CT. Out of 17 ptients with bnorml findings (Tble 3), single or multiple nodulr pulmonry lesions were observed initilly in 10 ptients (47% of ll). Single or multiple cvittions were observed in five ptients (23%). Thorcic computed tomogrphy (CT) ws performed t lest once on 16/22 ptients within 30 dys prior to the dignosis of IA. In 12 ptients (75%) single or multiple pulmonry focl lesions corresponding to the findings in the chest X-ry were lso observed on CT (Tble 3). One ptient with norml chest X-ry hd multiple smll nodulr lesions on the subsequent CT, nd in nother ptient the findings on CT were more widespred thn on chest X-ry. Tble 2 Presenting symptoms in ptients with invsive spergillosis Respirtory symptoms (11 ptients, 50%) dyspne 6 dyspne nd cough 3 cough 1 chest pin 1 Neurologicl symptoms (6 ptients, 27%) seizures nd hemipresis 3 seizures 1 hemipresis 1 stupor 1 Fever (7 ptients, 32%) Axillry temperture 38 C within 7 dys before the dignosis of Aspergillus infection.

3 Tble 3 Summry of rdiologicl findings (chest X-ry, thorcic CT) within 30 dys prior to the dignosis of Aspergillus infection No. of ptients (%) Chest X-ry (21 ptients) (%) nodulr lesions 10 (47) single 5 multiple 5 diffuse infiltrtes 5 (23) pulmonry oedem 2 (10) norml 4 (20) Thorcic computed tomogrphy (16 ptients) (%) single or multiple lesions corresponding to chest 12 (75) X-ry nodulr lesions, norml chest X-ry 1 (6) findings more widespred thn in chest X-ry 1 (6) nodulr lesions (no X-ry for comprison) 1 (6) no inflmmtory lesions 1 (6) Cvittion of single or multiple nodulr lesions in five ptients. Dignosis of Aspergillus infections Definite or probble IA ws dignosed during life in 16/22 ptients (73%) (definite IA in nine ptients, probble IPA in seven ptients with subsequent confirmtion t utopsy in three). Altogether, 13 tissue biopsies were performed on 11 ptients within 30 dys prior to the dignosis of IA. The medin time from n bnorml rdiologicl finding to tissue biopsy ws 3 dys (rnge 1 22 dys). Nine rdiologiclly guided fine needle lung biopsies (FNB) were performed on eight ptients without complictions. The findings were suggestive of IA in five ptients. In one of these ptients only the second ttempt yielded positive result. In two ptients IA ws found t utopsy lthough n FNB with negtive result hd been performed 2 nd 23 dys prior to deth, respectively. In three other ptients biopsy of subcutneous bscess, brin, nd liver yielded the dignosis of IA. In ddition, definitive dignosis of IA ws estblished in one ptient on open lung biopsy fter negtive finding from prior FNB. Broncholveolr lvge (BAL) ws performed t lest once on 14 ptients 30 dys preceding the dignosis of IA. The medin time from the first bnorml rdiologicl finding to BAL ws 1 dy (rnge 0 21 dys). The findings on microscopy nd culture of bronchil brush nd lvge smples were suggestive of IPA in eight ptients (57%). Aspergillus sp ws isolted in six ptients (A. fumigtus in ll), nd microscopic identifiction of filmentous fungi ws ccomplished in five ptients. Of the eight ptients with findings suggestive of IA in BAL, the finl dignosis ws probble IPA in four. In nother four ptients, dignosis of definite IA ws subsequently mde by either FNB (one ptient) or utopsy (three ptients). However, in six ptients (eight BAL procedures) with definitive IA (biopsy 3, utopsy 3), BAL ws either negtive or yielded unrelted findings (Pneumocystis crinii 2, cytomeglovirus 1, Xnthomons mltophili 1). The mycologicl species identifiction ws A. fumigtus in ll 16 ptients with fungl isoltion. In ddition, A. flvus ws isolted in one ptient from BAL fluid nd A. niger in nother ptient from the mxillry sinus. One ptient hd concomitnt invsive Cndid infection. In six ptients, no fungl isoltion ws mde, nd the dignosis of Aspergillus infection ws bsed only on the morphologicl identifiction of filmentous fungl elements. Autopsy ws performed in 15 ptients. Six ptients were dignosed s hving IA on the bsis of the utopsy findings; five of these ptients were lredy receiving mphotericin B. In three ptients with dignosis of probble IPA, definite dignosis ws mde t utopsy. Ten ptients were utopsied t the Deprtment of Pthology, University of Helsinki with n identicl utopsy protocol. Pulmonry involvement ws found in nine ptients (90%) nd CNS involvement in seven ptients (70%) followed by the involvement of hert (four ptients), thyroid glnd (three ptients), gut (two ptients) nd liver, kidneys nd pncres (one ptient ech). On the bsis of the vilble evidence, IPA ws found in nine ptients (41%), nd 13 ptients were found to hve disseminted spergillosis (involvement of t lest two noncontinuous orgns). The most common orgns ffected by spergillosis were lungs (20 ptients, 90%) followed by CNS (definite eight ptients, probble one ptient, 41%). Discussion In the present retrospective study we nlyzed the dignostic spects of invsive spergillosis in 22 llogeneic BMT recipients. Lte onset, non-specific symptoms, often febrile onset nd frequent disseminted disese type with CNS involvement highlight dignostic problems in these ptients who often hve concomitnt GVHD nd mixed infections. The bove spects seem to differ from the experiences gined in, for exmple, hemtologicl ptients with Aspergillus infections fter conventionl chemotherpy. 8,24 Few ttempts hve been mde to describe the clinicl fetures of IA in BMT recipients. In our nlysis, more thn hlf of the ptients were febrile t dignosis, thus mking clinicl suspicion of potentilly ftl infection less likely. An explntion for this might be the use of corticosteroids in ll ptients t the time of the dignosis of IA. Only hlf of the ptients reported respirtory symptoms, though this is difficult to scertin retrospectively. A significnt proportion of the ptients presented with neurologicl symptoms nd signs, which is in ccordnce with the findings reported by Sugier-Veber nd co-workers. 3 The serum level of CRP, vluble indictor of systemic inflmmtory response, hs not been nlyzed in previous studies of IA fter BMT. We observed unexpectedly low levels for CRP in mny ptients dignosed s hving IA during life. This suggests tht in these ptients the degree of tissue invsion nd necrosis cused by Aspergillus sp might be low. On the other hnd, very high CRP levels were found in the mjority of the ptients with n utopsy dignosis of disseminted IA. Thus, CRP seems to hve only limited dignostic vlue in this context. Rdiologicl findings were suggestive of IPA in bout hlf of the ptients just prior to dignosis. However, significnt proportion of ptients presented with diffuse pul- 869

4 870 monry infiltrtes, which could hve been cused by mny other pthogenic orgnisms besides Aspergillus sp. In some ptients, concomitnt bcteril or virl infection ws, in fct, dignosed simultneously with IA. It hs been shown tht thorcic CT is useful in some neutropenic ptients with norml chest X-ry 25,26 or fter BMT 20,27 in the erly detection nd mngement of IPA. In this study, thorcic CT performed shortly fter chest X-ry yielded, in most cses, comprble findings, but in some ptients CT disclosed pulmonry pthology more clerly thn did chest X-ry. In this retrospective nlysis, the contribution of CT to the erly dignosis of pulmonry spergillosis ws perhps less impressive when compred to prospective study, where seril CT studies using high-resolution techniques hve been used. 26 An dditionl dvntge of thorcic CT in this context is tht CT shows the exct locliztion of lesions nd is helpful in choosing the best method (BAL or biopsy) nd site for dignostic smpling. Fine needle biopsy of the lungs hs not been widely used in BMT ptients. In the present series, severl rdiologiclly guided FNBs were performed with rther high dignostic yield nd without complictions. We hd, however, four flse negtive findings on single FNBs, suggesting tht therpeutic decisions cnnot be mde solely on this bsis. Open lung biopsy, especilly vi thorcoscopy, is n lterntive dignostic method if techniclly fesible nd my offer more representtive tissue smples for culture nd microscopy. Broncholveolr lvge hs been widely used in the dignosis of lung problems in immunocompromised ptients. In the present mteril, BAL yielded the dignosis of probble IPA in 57% of ptients. This figure is the sme s in recent multi-institutionl prospective survey of hemtologicl ptients conducted by EORTC. 8 In BMT recipients with pulmonry pthology, finding of Aspergillus from BAL specimen either by culture or microscopy is suggestive of IPA 2,3 nd n indiction for therpy. In our study, BAL ws non-dignostic in some ptients just before the dignosis of IPA. On the other hnd, BAL my lso offer useful microbiologicl informtion regrding other pulmonry pthogens, which ws lso observed in this study. The dignostic pproch used in this ptient cohort resulted in reltively high percentge of dignoses of IA (73%) mde during life. In ddition, five out of six ptients dignosed s hving IA for the first time t utopsy received AmB bsed on clinicl suspicion of fungl infection. In report by Sugier-Veber et l, 3 the dignosis of IA ws mde during life in 61% of ptients. McWhinney nd coworkers 2 reported n even higher percentge of dignosis during life (80%). Dignosis of invsive Aspergillus infection in llogeneic BMT recipients still seems to be difficult tsk, nd mny ptients hve n dvnced infection t the time of dignosis. Erly dignosis of IA is essentil, s the infection is difficult to tret nd the costs of therpy re high. Since the clinicl nd rdiologicl fetures of IA re often nonspecific, erly empiricl therpy with mphotericin B is suggested long with pproprite dignostic studies. Newer methods for erly dignosis including Aspergillus ntigen studies or polymerse chin rection techniques my llow erlier dignosis nd improved mngement of IA in llogeneic BMT recipients. References 1 Wingrd JR, Bels SU, Sntos GW et l. Aspergillus infections in bone mrrow trnsplnt recipients. Bone Mrrow Trnsplnt 1987; 2: McWhinney PHM, Kibbler CC, Hmon MD et l. Progress in the erly dignosis nd mngement of spergillosis in bone mrrow trnsplnttion: 13 yers experience. Clin Infect Dis 1993; 17: Sugier-Veber P, Devergie A, Sulhin A et l. Epidemiology nd dignosis of invsive pulmonry spergillosis in bone mrrow trnsplnt ptients: results of 5-yer retrospective study. Bone Mrrow Trnsplnt 1993; 12: Morrison VA, Hke RJ, Weisdorf DJ. Non-Cndid fungl infections fter bone mrrow trnsplnttion: risk fctors nd outcome. Am J Med 1994; 86: Jntunen E, Ruutu P, Nisknen L et l. Incidence nd risk fctors for invsive fungl infections in llogeneic BMT recipients. Bone Mrrow Trnsplnt 1997; 19: Wld A, Leisenring W, vn Burik J-A, Bowden RA. Epidemiology of Aspergillus infections in lrge cohort of ptients undergoing bone mrrow trnsplnttion. J Infect Dis 1997; 175: Ruutu P, Vltonen V, Elonen E et l. Invsive pulmonry spergillosis: dignostic nd therpeutic problem. Scnd J Infect Dis 1987; 19: Denning DW, Mrinus A, Cohen J et l. An EORTC multicentre prospective survey of invsive spergillosis in hemtologicl ptients: dignosis nd therpeutic outcome. J Infect 1998; 37: Richrdson M, Kokki M. Antifungl therpy in bone mrrow filure. Br J Hemtol 1998; 100: Evns EGV, Richrdson MD. Medicl Mycology A Prcticl Approch. Oxford University Press: Oxford, Richrdson MD, Wrnock DW. Fungl Infection. Dignosis nd Mngement. Blckwell Scientific: Oxford, Rogers TR, Hynes KA, Brnes RA. Vlue of ntigen detection in predicting invsive pulmonry spergillosis. Lncet 1990; 336: Mnso E, Montillo M, De Sio G et l. Vlue of ntigen nd ntibody detection in the serologicl dignosis of invsive Aspergillosis in ptients with hemtologicl mlignncies. Eur J Clin Microbiol Infect Dis 1994; 13: Bretgne S, Mrmort-Khuong A, Kuentz M et l. Serum spergillus glctomnnn ntigen testing by sndwich ELISA: prcticl use in neutropenic ptients. J Infect 1997; 35: Verweij PE, Dompeling EC, Connelly JP et l. Seril monitoring of Aspergillus ntigen in the erly dignosis of invsive spergillosis. Preliminry investigtions with two exmples. Infection 1997; 25: Mchetti M, Fesi M, Mordini N et l. Comprison of n enzyme immunossy nd ltex gglutintion system for the dignosis of invsive spergillosis in bone mrrow trnsplnt recipients. Bone Mrrow Trnsplnt 1998; 21: Horvth JA, Dummer S. The use of respirtory trct cultures in the dignosis of invsive pulmonry spergillosis. Am J Med 1996; 100: Yeun K-Y, Woo PCY, Ip MSM et l. Stge-specific mnifesttions of mold infections in bone mrrow trnsplnt recipients: risk fctors nd significnce of positive concentrted smers. Clin Infect Dis 1997; 25:

5 19 Kuhlmn JE, Fishmn EK, Siegelmn SS. Invsive pulmonry spergillosis in cute leukemi: chrcteristic findings on CT, the CT hlo sign, nd the role of CT in erly dignosis. Rdiology 1985; 157: Mori M, Glvin JR, Brloon TJ et l. Fungl pulmonry infections fter mrrow trnsplnttion: evlution with rdiogrphy nd CT. Rdiology 1991; 178: Blum U, Windfuhr M, Buitrgo-Tellez C et l. Invsive pulmonry spergillosis. MRI, CT, nd plin rdiogrphic findings nd their contribution to erly dignosis. Chest 1994; 106: Thoms ED, Storb R, Clift RA et l. Bone mrrow trnsplnttion. New Engl J Med 1975; 292: Schulmn HM, Sullivn KM, Storb R et l. Chronic grftversus-host disese in 52 ptients. Adverse nturl course nd successful tretment with combintion immunosuppression. Blood 1981; 57: Fisher BD, Armstrong D, Yu B, Gold JWM. Invsive spergillosis: progress in erly dignosis nd therpy. Am J Med 1981; 71: Kuhlmn JE, Fishmn EK, Burch PA. Invsive pulmonry spergillosis in cute leukemi. The contribution of CT to erly dignosis nd ggressive mngement. Chest 1987; 92: Cillot D, Cssnovs O, Bernrd A et l. Improved mngement of invsive pulmonry spergillosis in neutropenic ptients using erly thorcic computed tomogrphic scn nd surgery. J Clin Oncol 1997; 15: Brloon TJ, Glvin JR, Mori M et l. High-resolution ultrfst chest CT in the clinicl mngement of febrile bone mrrow trnsplnt ptients with norml or nonspecific chest roentgenogrms. Chest 1991; 99: Cordonnier C, Bernudin JF, Bierling P et l. Pulmonry complictions occurring fter llogeneic bone mrrow trnsplnttion: study of 130 consecutive trnsplnted ptients. Cncer 1986; 58: Heurlin N, Lönnqvist B, Tollemr J, Ehrnst A. Fiberoptic bronchoscopy for dignosis of opportunistic pulmonry infections fter bone mrrow trnsplnttion. Scnd J Infect Dis 1989; 21: Sito H, Anissie EJ, Morice RC et l. Broncholveolr lvge in the dignosis of pulmonry infiltrtes in ptients with cute leukemi. Chest 1988; 94: