C ytomegalovirus (CMV) pneumonia is a major complication

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1 Long-term Sequele fter Recovery from ytomeglovirus Pneumoni in Allogeneic Bone Mrrow Trnsplnt Recipients* Sin-Ming hien, M.D., Ph.D.;t hrles K. hn, M.D., Ph.D., F...P; George Ksupski, Ph.D; Den hmberlin, M.D.; Gillin Fyles, M.D.; nd Hns Messner, M.D., Ph.D. The clinicl course of cytomeglovirus (MV) pneumoni in seven consecutive bone mrrow trnsplnt (BMT) recipients during 24-month period ws studied. Retrospective nlysis of clinicl dt on the recipients with MV pneumoni during the illness nd prospective follow-up of those who recovered from the pneumoni ws performed. Those who hd MV s the sole pthogen nd with lymphocytosis in the BAL or the peripherl blood during the illness recovered from the pneumoni. On the contrry, those who hd mixed bcteril or fungl infection with peripherl lymphopeni died. Persistent lymphocytosis in the BAL nd the peripherl blood, in the bsence of MV infection, ws observed in the survivors. Two subsequently developed restrictive lung disese nd two hd relpse of their primry mlignncy. These dt suggest tht MV pneumoni in BMT ptients is ssocited with significnt long-term sequle. The phenomenon of persistent lymphocytosis in the BAL nd the peripherl blood, in the bsence of MV infection, supports Grundy s hypothesis tht MV pneumoni in BMT recipients is n immunopthologic condition. (hest 1992; 11:1-4) AML = cute myelogenous leukemi; BMT bone mrrow trnsplnttion; BOOP bronchiolitis obliterns orgnizing pneumoni; DHPG dihydroxy-2-propoxymethyl-gunine; GlGgmmimmunoglobulin; GVHDgrft-vs-host disese ytomeglovirus (MV) pneumoni is mjor compliction following llogeneic bone mrrow trnsplnttion (BMT), 2 nd it crries mortlity rte of pproximtely 5 percent.3 Tretment with n ntivirl gent, such s dihydroxy-2-propoxymethyl-gunine (DHPG), hs no significnt impct on the outcome.4 However, the ddition of MV hyper-gmmimmunoglobulin (GG) hs improved the survivl rte to 5 percent.5 6 This lso supports the hypothesis of Grundy et l tht MV pneumoni in trnsplnt recipients is n immunopthologic process due to the host T-cell response to the presence of virl ntigens in the lung. To our knowledge, there re no published dt on the long-term outcome of BMT recipients who recovered from MV pneumoni. n view ofthe hypothesis of Grundy et l, we followed the clinicl course of seven consecutive BMT recipients with MV pneumoni during 24-month period t our center. The results indicte tht there could be significnt longterm complictions following n pprent recovery from the pneumoni nd lend support to the their *From the Deprtments of Medicine nd Virology, the Wellesley nd Princess Mrgret Hospitls, nd the Deprtment of Pthology, the Toronto Hospitl, University of Toronto, Toronto, Ontrio, nd. Supported in prt by grnts from the Ministry ofhelth of Ontrio nd the onnught Fund. Presented in prt s n bstrct t the Americn Thorcic Society Annul Scientific Meeting, Boston, Mss, My 2-23, 199. tfellow of the Medicl Reserch ouncil of nd. Mnuscript received April ; revision ccepted August 5. Reprint requests: Dt /sn, 16 Wellesley Street, 242 Jones Bldg. Toronto, Ontrio, nd M4Y 1J3 immunologic hypothesis. MATERAL AND METHODS From July 196 to June 19, fiberoptic bronchoscopy (FOB) with broncholveolr lvge (BAL) ws performed on 23 BMT recipients t our center. ndictions for the procedure included progressive dyspne nd/or pulmonry infiltrtes on chest roentgenogrm (XR) fter BMT All BALS were processed for detecting the presence of bcteri, including Legionell, mycobcterium, fungus, protozo, nd viruses. n prticulr, immunofluorescence studies using monoclonl ntibody directed ginst n erly nucler ntigen of MV in shell vil cell culture ssy ws used for detecting the presence ofmv in the BAL fluid. Briefly, monolyers of fibroblst in shell vils were inoculted with the BAL fluid, the cells were then exmined 16 h lter with the immunofluorescent ntibody directed ginst MV. Dignosis of MV pneumoni ws bsed on the presence of MV in the BAL using this shell vil culture-immunofluorescent detection system. Differentil cell count ofthe BAL fluid ws lso obtined. Recipients who recovered from MV pneumoni were followed up t regulr intervls with complete blood cell count, sputum nd urine cultures, XR, nd pulmonry function tests (PFT). Bronchoscopy with BAL ws performed whenever indicted. RESULTS During the 24-month period, FOB with BAL ws performed on 23 BMT recipients who presented with cute respirtory illness. Seven of them were dignosed s hving MV pneumoni. The clinicl chrcteristics of these ptients re summrized in Tble 1. These include their primry dignosis, the conditioning regimens, pretrnsplnt MV serologic study s well s the durtion fter BMT when MV pneu- 1 Long-term Sequele fter Recovery from MV Pneumoni (hien et 1 Downloded From: on 4/2/217

2 Tble 1-linicl hrcteristics ofbmt Recipients with MV Pneumoni se No.! Sex!Age, yr Primry Disese onditioning Regimen Pre-BMT MV Serologic Study Donor MV Serologic Study MV Pneumoni: lime of Onset JMJ4O ML Ar-, P, TB Negtive Negtive 3.5 y 2/W31 AML Are-, M, TB! Negtive Negtive 6 dys 3f1/26 ALL Ar-, P, Th Ebsitive Negtive 25 dys 4/Mi26 AML M-, VP16, TB Negtive Negtive 5 mo MJ44 AML M-, P, TB Positive Negtive 7 dys 6//47 AML Am-, P, TB Positive Negtive 3 dys 71F/33 MF Am-, P, TB Negtive Negtive 45 dys *BMTbone mrrow trnsplnt; MV=cytomeglovirus; pneum=pneumoni ML=chronic myelogenous leukemi; AML cute myelogenous leukemi; ALL=cute lymphocytic leukemi; MF=myelofibrosis; Ar- cytrbine; P=cyclophosphmide; M mitoxntrone; VP16 etoposide; TB totl body irrdition. moni ws dignosed. As shown in Tble i, with the exception of cse i, ll ptients presented within the first six months fter BMT. The clinicl presenttion of MV pneumoni s well s the outcome in ech cse ws presented in Tble 2. All ptients were symptomtic on presentlion; symptoms include dry cough, dyspne, nd fever. All except one ptient (cse i) hd bilterl infiltrtes on XR. ytomeglovirus ws the sole pthogen in four cses, nd the rest hd concomitnt bcteril or fungl infection. The incidence ofmv pneumoni in this cohort is 31 percent, which is comprble with other studies. #{176} All, except one ptient (cse 3), were treted with DHPG nd GG. Those ptients who hd MV s the sole pthogen nd with peripherl lymphocytosis during the illness recovered from the pneumoni (cses i through 4). At the time of presenttion, the men lymphocyte counts from these four ptients were 1.55 x 1fL, with the percentge of lymphocytes rnging from 35 percent to 73 percent (Tble 2). On the contrry, ftl outcome ws observed in the three ptients with mixed infection nd with peripherl lymphopeni. The men lymphocyte counts from these three ptients were. i9 x i/l, with the percentge of lymphocytes rnging from 2 percent to percent (Tble 2). The four ptients who survived the MV pneumom were followed up t regulr intervls. At the end ofthe two-yer period, two developed restrictive lung disese nd two died of relpse from the primry hemtologic disorder. Thus, in this cohort, the outcome of MV pneumoni in BMT recipients cn be divided into three subgroups: (1) survived the pneumoni but subsequently developed restrictive lung disese; (2) recovered from the pneumoni but followed with relpse oftheprimry mlignncy; nd (3) ftlity. Restrictive Lung Disese n cses i nd 2 (Fble 1), both ptients were seronegtive to MV pre-bmt nd hd cute grft- Tble 2-linicl Presenttion nd Outcome OJMV Pneutnoni se No. Presenting Symptoms XR Findings oncurrent nfection Peripherl Blood Differentils (Neu Lym Mono) (AL) Outcome Long-term Sequele 1 Dyspne, dry Norml Negtive 39% 44% 5% Alive BD cough, mild fever (2.33 x 1 ) 2 Dry cough, mild Bi-bsilr infiltrtes Negtive 21% 73% 3% Alive BD fever (2.33 x 1 ) 3 Dyspne, fever Bilterl interstitil infiltrtes Negtive 22% 7% 6% (.63x1) Alive Relpse of ALL 4 Dyspne dry cough Bilterl interstitil infiltrtes Negtive 63% 35% 2% Alive Relpse ofaml fever (O.91x1) 5 Dyspne Diffuse interstitil Klebsiell nd 94% 2% 3% Died... fever infiltrtes Enterobcter (.12 X 1) 6 Fever, dysphgi, Bilterl infiltrtes Legionell 6% % 6% Died... respirtory + RUL&LUL consolidtion (.14 X 1 ) 7 Progressive dyspne Bibsilr interstitil infiltrtes Aspergillus 95% 4% 1% (.32x 1 ) Died... BMTbone mrrow trnsplnt; MV=cytomeglovirus; pneum=pneumoni XR=chest roentgenogrm; ML=chronic myelogenous leukemi AML cute myelogenous leukemi; ALL=cute lymphocytic leukemi MF= myelofibrosis; BD =restrictive lung disese; AL bsolute lymphocyte count; RUL right upper lobe; LUL left upper lobe HEST 11 4 APRL Downloded From: on 4/2/217

3 Tble 3-Seril Pulmonry Function Tests (PFT) on se 1 nd Differentil ell ount ofbroncholveolor Lvge (BAL)5 lime, mo Post-MV Pvr TL, % predicted RV, % predicted FV, % predicted Dco, % predicted BAL cellulr differentil Mcrophges, % Lymphocytes, % Neutrophils, % Mediction Prednisone, mg/dy *BMT = bone mrrow trnsplnt; MV cytomeglovirus; T = totl lung cpcity; RV residul volume; FV = forced vitl cpcity; Den diffusing corrected for hemoglobin. vs-host disese (GVHD) post-bmt Within six to nine months fter recovery from the MV pneumoni, both presented with progressive dyspne. The BALs reveled no pthogen. The PFTs showed restrictive defect with reduction in lung volumes nd diffusing cpcity (Tbles 3 nd 4). n cse 2, dignosis of bronchiolitis obliterns with orgnizing pneumoni ws mde on open lung biopsy specimen. The ptient ws treted with methylprednisolone (1 g/dy) for five dys nd with symptomtic improvement. Methylprednisolone ws then switched to orl prednisone nd the dosge ws grdully tpered. Repeted PFTs obtined three months lter showed improvement in lung volumes s well s diffusing cpcity (Tble 4). n cse i, the chnges in the PFT results were not s severe s in cse 2. After infectious cuse ws ruled out by bronchoscopy, the ptient s Tble 4-Seril Pulmonry Function Tests (PFT) on se 2 nd ThJJ#{232}Tentilell ount ofbroncholveolr Lvge (BAL)5 Time, mo Post-MV PFT TL, % predicted BAL RV, % predicted FV, % predicted Dco, % predicted differentil cellulr Mcrophges, % Lymphocytes, % Neutrophils, % Mediction Methylprednisolone, g/dy *BMT = bone mrrow trnsplnt; MV cytomeglovirus; TL = totl lung cpcity; RV residul volume; FV forced vitl cpcity; Dco= diffusing cpcity corrected for hemoglobin. Tble 5-dmonry Function Tests in Asymptomtk BMT Recipients before nd 1 Yer fter Trnsplonttion PFr lime, mo Pre-BMT TL, % predicted 15± ± 11 RV,%predicted 4±16 96±23 FV, % predicted 17± 14 17±14 Den, % predicted 99±2 7± 27 *BMTbone mrrow trnsplnt; TL=totl lung cpcity; RV = residul volume; FV = forced vitl cpcity; Dco= diffusing cpcity corrected for hemoglobin prednisone dose ws incresed from the mintennce dose of 7.5 mg/dy to 15 mg/dy. Symptomtic im provement ws observed nd repeted PFT three months However, lter the diffusing showed mild cpcities increseofbothin lung ptientsvolumes. were persistently lower thn before MV pneumoni. As shown in Tble 5, dt obtined from ten symptomtic recipients from the sme er showed no significnt chnge in lung volumes, with mild reduction in diffusion cpcity (though still within the norml limits) yer fter BMT However, the diffusing cpcities obtined from both ptients fter recovery from MV pneumoni were lower thn the men vlue obtined from those who did not hve MV pneumoni yer fter trnsplnttion. Both ptients re live t the time of reporting. Seril BALS were obtined from both ptients during the follow-up period. Persistent lymphocytosis, in the bsence of detectble virus by the shell vil culture technique ws found in the BALs in both ptients (Tbles 2 nd 3). The percentge of lymphocytes in the BAL fluids ws significntly higher thn the norml rnges t our institute. The men profile of BAL differentil obtined from seven symptomtic BMT recipients t our institute up to ioo dys fter BMT is mcrophges percent, neutrophils 3 percent, nd lymphocytes 9 percent (unpublished dt). Anlysis of peripherl blood lso showed reltive lymphocytosis during the cute illness nd persisted into the recovery phse until the presenttion of restrictive lung disese (Fig 1, left) Recurrence ofprimry Hemtologic Mlignncies Two ptients, cses 3 nd 4 hd relpse of the pmry hemtologic disese fter recovery from me MV pneumoni. n cse 3, the ptient ws seropositive to MV pre-bmt During the episode of MV pneumoni, disseminted virl repliction nd shedding ws shown by positive shell-vil cultures from urme nd orophrynx. Anlysis ofthe penphe gin showed reltive lymphocytosis, both during the cute illness nd persisted into recovery period the without positive virl culture. n cse 3, the pek percentge of lymphocyte t the time of presenttion ws 7 percent. The lymphocytosis persisted for three 12 Long-term See fter Recovery from MV Pneumoni (Nn stt) Downloded From: on 4/2/217

4 1.1 MV in BAL DHPG BOOP GG Steroids First Relpse Second Relpse 1-4. E >. -J w ) ) Months Months Months Post-MV Pneumoni Months Post-MV Pneumoni FGURE 1. Schemtic digrm showing the presence of peripherl lymphocytosis in cses 2 through 4 fter cytomeglovirus (MV) pneumoni. n ll three cses, the percentge of lymphocytes in the peripherl blood ws plotted ginst the durtion fter bone mrrow trnsplnttion (BMT) s well s fter MV pneumoni. Figure 1A (left) shows the peripherl lymphocytosis during MV pneumoni s well s prior to the presenttion of BOOP in cse 2. Similr pttern ws obtined in cse 1. n lb (cse 3) nd 1 (upper nd lower right) (cse 4), the blck dots represent the percentge of lymphocytes in the peripherl blood. n both cses, the percentge of lymphocytes is persistently bove the norml rnge (2 percent) until relpse ofthe primry mlignncy. n lb (cse 3), the totl white blood cell count during the sme period ws lso shown (the white dot). #{149}.... E -J ). MV Relpse of AML,, Months Months Post-MV Pneumoni months nd declined on relpse of the hemtologic mlignncy (Fig i, upper right). The ptient subsequently died of cute myelogenous leukemi (AML) fter second relpse. Similr phenomenon ws observed in cse 4, who ws seronegtive to MV pre-bmt. Peripherl lymphocytosis ws observed during MV pneumoni nd persisted prior to the relpse of cute leukemi (Fig 1, lower right). Ptients with Mixed nfection The BALs obtined from cses 5, 6, nd 7 during the cute illness showed evidence of mixed bcteril or fungl infection with MV. Klebsiell nd Enterobcter were identified in one cse, Legionell in the second, nd Aspergillus in the third cse (Tble 2). All were treted with DHPG nd GG, with pproprite ntibiotics or ntifungl gents. None survived the cute illness. Anlysis of peripherl blood found profound lymphopeni in ll three ptients t the time of illness (.i2,.i4, nd.32 x i/l, respectively) (Tble 2). Thus, concurrent bcteril or fungl infection in BMT recipients with MV pneumoni nd lymphopeni crried n extremely poor prognosis. DSusSON n the pst, MV pneumoni in BMT recipients crried high mortlity rte. ombintion therpy of DHPG nd GG hs improved the survivl rte to 5 percent. Similr success rte ws observed in our study. Grundy et l hve proposed tht MV pneumoni in BMT recipients is n immunologic disese, with the primry pthologic process being n ctivted host immune response to the presence of virl ntigen(s) in the lung. The consequence of this ctivted host immune system is not known, s there re no published dt on the long-term sequele of BMT recipients who recovered from MV pneumoni (to our knowledge). n the present study, four ptients recovered from the pneumoni. Two developed restrictive lung disese within six to nine months nd HEST 11 4 APRL Downloded From: on 4/2/217

5 two died of relpse from the primry mlignnt neoplsm within five months fter recovery from MV pneumoni. Thus, our results seem to suggest tht there is significnt morbidity nd mortlity ssocited with BMT recipients who recovered from MV pneumoni. During the cute illness, lymphocytosis ws found in the BAL fluid obtined from both ptients who subsequently developed restrictive lung disese, suggestive of n ctivted host immune system induced by the virl infection. More importntly, the BAL lymphocytosis persisted in both ptients in the bsence ofpositive virl culture, following recovery from MV pneumoni. This indictes tht the ctivted immune system might not subside with the elimintion of MV from the body. The fct tht both ptients developed restrictive lung disese, in the presence of the BAL lymphocytosis, within six to nine months fter recovery from MV pneumoni suggests cuse nd effect reltionship between the two observtions. This would support the hypothesis tht MV pneumoni iii BMT recipients in n immunopthologic condition, nd suggests MV pneumoni in BMT recipients cn be ssocited with short-term mortlity s well s long-term sequele. Two ptients who survived the MV pneumoni hd recurrence of the primry mlignncy. Peripherl lymphocytosis ws noted in both ptients during the illness nd persisted into the recovery phse (Fig 1, upper nd lower right). Recently, Milburn et l reported nonspecific polyclonl B-cell ctivtion in BMT recipients who hd MV pneumoni. These dt suggest tht MV infection results in nonspecific polyclonl ctivtion of hemtopoietic cell lines, including mlignnt ones, nd my ply role in relpse ofthe primry disese in these two ptients. However, it should be emphsized tht this remins hypothesis t present nd more dt re needed to support this )ostultion. Peripherl lymphocytosis ws observed in ll ptients who hd MV s the sole pthogen (cses 1 through 4) nd recovered from the illness, wheres ll three ptients who hd mixed infections nd died of the pneumoni hd substntilly lower lymphocyte counts in peripherl blood. (The men bsolute lymphocyte count ws 1.55 x 1/L vs. 19 x 1fL.) These dt suggest tht the immunocompetency of the host is n importnt fctor in determining the outcome of MV pneumoni in BMT recipients, nd peripherl lymphocytosis t the time of illness my be used s prognostic fctor for recovery. n summry, the following conclusions cn be drwn from the results of this study. First, there re longterm sequele in BMT recipients who recovered from MV pneumoni. n our study, these ptients either developed restrictive lung disese or hd relpse of the primry mlignncy. Second, the phenomenon of persistent lymphocytosis in the BAL nd the peripherl blood, in the bsence of positive virl culture, supports Grundy s hypothesis tht MV pneumoni in BMT ptients is n immunopthologic condition. Third, peripherl lymphocytosis during MV pneumoni my be used s prognostic fctor for recovery from the illness, s recovery occurs only in ptients who were ble to mount the response in the peripherl blood during the illness. AKNOWLEDGMENT: The uthors wish to thnk Mr.s Fehmid Numohmed for prepring the mnuscript. REFERENES 1 Krowk MJ, Bosenow E, Hoglnd H. Pulmonry cornplictions of bone mrrow trnsplnttion. hest 195; 7: hn K, Hylnd RH, Hutcheon MA. Pulmonry complictions following bone mrrow trnsplnttion. lin hest Med 199; 11: Shepp DH, Dndliker PS, demirnd P. Thimyst B, ederberg DM, Kirk LE. Activity of 9-[2-hydroxy-1-9hydroxymethylOethoxymethyl]gunine in the tretment of cytomeglovirus pneumoni. Ann ntern Med 195; 13: Myers JD, Flourney N, Thoms ED. Nonbcteril pneumoni fter llogeneic mrrow trnsplnttion. J nfect Dis 196; 153: Emnuel D, unninghm L, Jules-Elysee K, Brochstein JA, Kernn NA, Lyer J, et l. ytomeglovirus pneumoni fter bone mrrow trnsplnttion successfully treted with the combintion of gnciclovir nd high dose intrvenous immune globulin. Ann ntern Med 19; 19: Reed E, Bowden RA, Dndliker PS, Lilleby KE, Meyers JD. Tretment of cytomeglovirus pneumoni with gnciclovir nd intrvenous cytomeglovirus immunoglobulin in ptients with bone mrrow trnsplnts. Ann ntern Med 19; 19:73-7 Grundy JE, Shnley JD, Griffith PD. s cytomeglovirus interstitil pneumonitis in trnsplnt recipients n immunopthologicl conditions? Lncet 197; 2: Mrtin WJ, Smith TF. Rpid detection ofcytomeglovirus in broncholveolr lvge by monoclonl ntibody method. J lin Microbiol 196; 23:16-9 rwford SW, Bowden BA, Hckmn R, Gleves A, Meyers JD, lrk JG. Rpid detection of cytomeglovirus pulmonry infection by broncholveolr lvge nd centrifugtion culture. Ann ntern Med 19; 1:1-5 1 Meyers JD, Flourney N, Thoms ED. Risk fctors for cytomeglovirus infection fter bone mrrow trnsplnttion. J nfect Dis 196; 153: Milburn HJ, Grundy JE, Dubois RM, Prentice HG, Griffith GD. s the mesurement ofvirus-speciflc ntibody in the lungs of trnsplnt recipients with cytomeglovirus pneumonitis of dignostic or prognostic vlue? J Med Virol 19; 26: Long4erm Sequele fter Recovery from MV Pneumoni (hlen et!) Downloded From: on 4/2/217