Infections in adults undergoing unrelated donor bone marrow transplantation

Infections in adultsundergoing unrelated donor bone marrow transplantation

EMMA C. M. WILLIAMSON,2 MICHAEL R. MILLAR,2 COLIN G. ST EWARD,1 JACQ UE LINE M. CORNI SH,1 ANNABEL B. M.FO OT,1 ANTHONY OAKHILL,1 DE RWOOD H. PAMPHIL ON,1 BARNABY REEVES,3 E. OWEN CAUL,4 DAVI D W. WARNOCK

4

AND DAVID I. MARKS1 1Bone Marrow Transplant Unit, Bristol Royal Hospital for Sick Children, United Bristol Healthcare

Trust, Bristol, 2Department of Microbiology, Bristol Royal Infirmary, Bristol, 3Surgical Epidemiology and Audit Unit,Lincoln’s Inn Fields, London, and 4Mycology Reference Laboratory, and Public Health Laboratory, Kingsdown, Bristol

Received 3 September 1998; accepted for publication 27 November 1998

Summary. This study retrospectively reviews infections overa 7-year period in 60 consecutive adults (median age 25years) undergoing their first unrelated donor bone marrowtransplant (UD-BMT). T-cell depletion was employed in 93%.More than half the patients had one or more severe,potentially life-threatening, infections. There was a highincidence of invasive fungal infections (Aspergillus 17,Candida four), despite the use of itraconazole or amphotericinprophylaxis. Ten Aspergillus infections occurred beyond 100d. Two patients (11%) with invasive aspergillosis survived.Clustering of infections was noted, with invasive fungalinfections significantly associated with bacteraemias (OR3·73, P ¼ 0·06) and multiple viral infections (OR 4·25,P ¼ 0·05). There were 21 severe viral infections in 16patients, with CMV disease occurring in four patients only;

viral pneumonitis was predominantly due to ‘communityrespiratory’ viruses. Most early bacteraemias (68%) weredue to Gram-positive organisms. The majority of episodes ofGram-negative sepsis were caused by non-fastidious non-fermentative bacteria, such as Pseudomonas spp. andAcinetobacterspp., historically regarded as organisms of lowpathogenicity. In patients with successful engraftment andminimal graft-versus-host disease, late infections suggestiveof continued immune dysfunction (shingles, recurrent lowerrespiratory infections, Salmonella enteritis and extensivewarts) were common.

Keywords: infection, aspergillosis, unrelated donor, bonemarrow transplantation, T-cell depletion.

Bone marrow transplantation has been increasingly used ascurative therapy for both children and adults with a varietyof haematological diseases over the last three decades. Sinceonly approximately 30% of the population have an HLA-matched sibling donor (Kernan et al, 1993), volunteerunrelated donor marrow represents an important alterna-tive source of stem cells. UD-BMT in adults appears to have agenerally poorer outcome than sibling allogeneic transplan-tation, but the difference is decreasing (Nademanee et al,1995). The difference may be partly explained becausepatients may be transplanted later in the course of theirdisease because of the time taken to search for suitabledonors. The rates of primary and secondary graft failure,frequency and severity of graft-versus-host disease (GVHD)and graft-versus-leukaemia effects may also differ (Armitage,1994). Infections are a major cause of morbidity andmortality in all BMT patients, but there is some evidence

that UD-BMT patients suffer more frequent and more severeinfections than sibling allograft patients (Atkinson et al,1993; Marks et al, 1993; Ochs et al, 1995; Takenaka et al,1997; Wald et al, 1997). The risk factors for infection withinthe population of UD-BMT patients have not been describedin detail, and the relative contributions of bacteria, fungi andviruses to morbidity and mortality have not been documen-ted. In this study we describe all microbiologically confirmedinfections in 60 consecutive adult BMT patients treated in asingle specialized unit, and analyse their outcome.

PATIENTS AND METHODS

Patients. We describe 60 consecutive adult patients (aged17 or older) with haematological diseases receiving a firsttransplant from an unrelated donor from June 1990 to June1997 at the Bone Marrow Transplant Unit, Royal Hospitalfor Sick Children, United Bristol Healthcare Trust. Patientswere considered to be of standard haematological risk if infirst or second complete remission with acute leukaemia, infirst chronic phase with chronic myeloid leukaemia (CML) or

British Journal of Haematology, 1999, 104, 560–568

560 q 1999 Blackwell Science Ltd

Correspondence: Dr D. I. Marks, Bone Marrow Transplant Unit,Bristol Royal Hospital for Sick Children, United Bristol HealthcareTrust, Bristol BS2 8BJ.

561Infections in Unrelated Donor BMT

q 1999 Blackwell Science Ltd, British Journal of Haematology 104: 560–568

with a diagnosis of refractory anaemia with excess blasts(RAEB). All other patients, including those with a diagnosisof acute leukaemia in third or greater remission or in relapse,CML in accelerated phase or blast crisis, chronic lymphocyticleukaemia (CLL) or aplastic anaemia, were considered to behigh risk. Six patients had previously undergone autologousbone marrow transplantation, and were classified as highrisk.

Conditioning regimens. The standard conditioning regimen,used for 51 patients, consisted of intravenous CAMPATH 1G(10 mg b.d.) on days ¹9 to ¹5, cyclophosphamide (60 mg/kg)on days ¹6 and ¹5 and total body irradiation (TBI)(14·4 Gy) given in eight fractions on days ¹3 to day 0(Oakhill et a;, 1996). Four additional patients with CML andmismatched donors also received thiotepa (2·5-5 mg/kg).Five patients who had previously undergone TBI or otherextensive radiotherapy had an alternative regimen consist-ing of CAMPATH, cyclophosphamide (200 mg/kg) andbusulphan (16 mg/kg).

Marrow and PBSC processing, GVHD prophylaxis andtreatment. The target dose harvested was 4 × 108 nucleatedcells per kg of recipient weight. Two patients received donorperipheral blood stem cells collected by leukapheresis on day5 after administration of 12 mg/kg of granulocyte-colonystimulating factor (G-CSF). Mononuclear cells were selectedfrom donor marrow using a Cobe Spectra which resulted inmost granulocytes and band neutrophils being excluded. 56donor marrows were T-cell depleted with CAMPATH anti-bodies. This was ex vivo with CAMPATH 1M and human ABserum as a source of complement in 38, and in vivo withintravenous CAMPATH IG in 18. The median degree of T-celldepletion achieved ex vivo was >98% (Oakhill et al, 1996;Chown et al, 1997). Cyclosporin A (CyA) was given to 59patients from day ¹1, then slowly tapered at 6 months in theabsence of GVHD. Whole blood CyA levels were regularlymeasured by immunoassay (TDx, Abbott), and the dosemodified to maintain levels of 100–225 nmol/l. Three dosesof intravenous methotrexate (15 mg/m2 on day 1 and10 mg/m2 on days 3 and 6) were also given to 20 patients.Patients whose conditioning included thiotepa (n ¼ 4)received CyA, plus additional methyl prednisolone startingon day ¹9. Acute GVHD was graded as stages I–IV usingstandard criteria (Glucksberg et al, 1974) and chronic GVHDwas assessed as being absent, limited or extensive (Shulmanet al, 1980). GVHD was treated initially with steroids, theirusage recorded as topical only or systemic. G-CSF was givenat 5 mg/kg, to all except the earliest two patientstransplanted, commencing on day 10, and continued untilthe absolute neutrophil count (ANC) remained above1 × 109/l for 3 consecutive days. The day of engraftmentwas defined as the first of 3 consecutive days on which theANC remained at 0·5 × 109/l or more.

Histocompatibility and immunogenetics. HLA-A and -Btyping was performed using standard serological techniques.HLA-DRB1 and -DQB1 typing was performed with restric-tion fragment length polymorphism analysis and later PCRsequence-specific primers (Oakhill et al, 1996; Marks et al,1998). Searches were initially conducted from the BritishBone Marrow and Platelet Donor Panel and the Anthony

Nolan Research Centre Panel. CMV-negative recipientspreferentially received marrow from CMV-negative donors.HLA typing was the major selection criterion, then CMVstatus, and finally preference was given to young maledonors.

Supportive care, infection prophylaxis and treatment of infection.All patients were transplanted in positive pressure singlerooms with air filtration by EU8-grade filters, and remainedin protective isolation from day 0 until engraftment. Patientswere free to leave the Unit during conditioning. All patientsreceived ‘clean’ diets which excluded fresh fruit andvegetables and tap water from day ¹3 until 30 d afterdischarge from isolation. Patients who were readmitted tothe Unit for management of complications were housed insingle rooms without air filtration. Intravenous access wasachieved by double-lumen tunnelled central venous catheter.In the absence of line infections and provided lumensremained patent, lines were left in situ for 3–6 months,depending on venous access. Patients received oral cipro-floxacin (250 mg b.d.) from day ¹3 until intravenousantibiotics were commenced. Co-trimoxazole (960 mgthrice weekly) was given as prophylaxis against Pneumocystiscarinii pneumonia (PCP) from day 28: this was replaced bynebulized pentamidine (300 mg every 3–4 weeks) in eightpatients with poor graft function or allergy. PCP prophylaxiswas used routinely for 6–12 months, but continued longerin patients with chronic GVHD. Phenoxy-methyl penicillin(250 mg b.d.) was commenced at 6 months and continuedfor life. Standard antifungal prophylaxis consisted ofitraconazole capsules, 400–600 mg orally daily. One patientreceived miconazole (prior to the availability of itraconazole)and six patients received amphotericin intravenously at0·5 mg/kg thrice weekly. Antifungal prophylaxis was givenfrom the day of admission (day ¹9) for 3 months, butcontinued longer if there was poor graft function or chronicGVHD. Patients at low risk of CMV disease (both patient anddonor seronegative) received low-dose oral aciclovir (400 mgt.d.s.) from day ¹4 and CMV seronegative blood products.Patients at high risk of CMV disease (patient, donor, or bothseropositive) received high-dose aciclovir (500 mg/m2 tdsintravenously) from day ¹4 to day 30, thereafter oralaciclovir (400 mg t.d.s.), and normal pooled humanimmunoglobulin (200 mg/kg) every 3 weeks, commencingon day ¹1. CMV prophylaxis was given routinely for 6months, but continued if there was severe chronic GVHD.If there was evidence of CMV reactivation in blood orbronchoalveolar lavage (BAL), ganciclovir was administeredfor at least 2 weeks at 5 mg/kg b.d. CMV disease was treatedwith ganciclovir plus intravenous immunoglobulin. Patientswere vaccinated against diphtheria, tetanus and polio (killedSalk vaccine) at 18 months post transplant using primaryimmunization schedules, and against measles at 2 years.Patients who received donor lymphocyte infusions (DLI) wererecommenced on aciclovir, co-trimoxazole and itraconazole.

Febrile neutropenia (defined as pyrexia of 388C on twooccasions within 1 h, or by a single episode of pyrexia of38·58C or more in a patient with ANC<1 × 109/l), wastreated with broad-spectrum intravenous antibiotics, withthe addition of intravenous amphotericin at 72 h for patients

with refractory fever. Patients received conventional ampho-tericin (Fungizone, Squibb) 0·5–1 mg/kg o.d., replaced by alipid formulation (Abelcet, Liposome Company or Ambisome,NeXstar) at 3–10 mg/kg o.d. if creatinine was >200 mmol/lor if there was a severe reaction to amphotericin. Patientswith proven aspergillosis were usually treated with a lipidformulation.

Microbiological methods and documentation of infection. Thecase records of the 60 patients and the computerized recordsof the Bristol Public Health Laboratory (PHL, U.K.) wereretrospectively reviewed for infective episodes, with correla-tion of laboratory results and clinical findings. Data werecollected on bacteraemias, invasive fungal infections, virae-mias, and gastrointestinal and respiratory infections ofproven aetiology. For a number of long-term survivorsattending the Unit every 2–6 months, their referringhaematologist was asked to complete a standard question-naire designed to assess late infections. Infections weredefined as early if occurring in the first 100 d, and as latethereafter.

Standard microbiological methods were used (PHLS,1997). Briefly, blood cultures were processed by anautomated system (Bactec, Becton Dickinson, until 1994,and BacT/Alert, Organon Teknika, thereafter). All bloodcultures were incubated for 5 d. For coagulase-negativestaphylococci, more than one culture positive with the sameantibiogram was required to diagnose bacteraemia and ruleout skin contamination (Garner et al, 1988). For all bloodculture isolates, organisms were excluded from the analysis ifthe patient was afebrile and C-reactive protein (CRP) was<10 mg/l. Coagulase-negative staphylococci were identifiedonly to species level if teicoplanin-resistant; all otherorganisms were fully identified using standard laboratorytests or API (Analytical Profile Index, bio-Merieux, Lyon,France). Organisms that could not be identified by thesemeans were sent to the Public Health Laboratory Servicereference laboratories.

Broncho-alveolar lavage (BAL) samples were subject to thefollowing analyses: microscopy for bacteria (Gram stain),mycobacteria (Ziehl Neelson stain) and fungi, quantitativeculture for bacteria, mycobacteria, legionella and fungi,direct immunofluorescence for Pneumocystis carinii, legionella,chlamydia, RSV, influenza A, influenza B, parainfluenzatypes 1–3, adeno, CMV, HSV I, HSV II, Deaff test for CMV andculture for viruses. For respiratory viruses, features includ-ing infiltrates on chest X-ray, oxygen desaturation, dyspnoeaor wheeze were considered diagnostic of lower respiratoryinvolvement, whereas symptoms restricted to sore throat,cough, coryza or sinusitis represented upper respiratoryinvolvement only.

Surveillance for CMV reactivation was performed in at-risk patients by weekly CMV antigenaemia tests on buffycoat and serology, and by BAL at 1, 2 and 3 months. CMVdisease was defined by (a) demonstration of CMV invisceral (lung, gastrointestinal) biopsy specimens byhistology or culture, (b) detection of CMV by Deaff testor culture of BAL in patients with pneumonitis, or (c)demonstration of CMV viraemia by antigenaemia orculture in patients with pancytopenia, fever and malaise.

CMV reactivation was defined as isolation of CMV orantigenaemia in patients with no clinical features of CMVdisease.

All stool samples were examined microscopically forCryptosporidium (modified Ziehl Neelson) and for otherparasites including Giardia lamblia (wet preparation orconcentrate). Stools were cultured for Salmonella, Shigella,Campylobacter and E. coli O157. Liquid stool samples werealso tested for Clostridium difficile toxin (tissue culture) andfor viruses (electron microscopy, ELISA for group A rotavirusand PCR for caliciviruses).

Serum was tested twice weekly for Aspergillus antigen,using Pastorex Latex agglutination test (Sanofi DiagnosticsPasteur, France) (until spring 1996) or Platelia Aspergillusenzyme-linked immunosorbent assay (ELISA, Sanofi Diag-nostics Pasteur). Both tests detect Aspergillus galactoman-nan. Microscopy for fungi was performed on all tissue biopsy,sputum and BAL samples using potassium hydroxide wetpreparations, and all samples were cultured for up to 2 weeksat 308C and 378C (Davey et al, 1996). Patients wereconsidered to have proven fungal infection if either histologywas positive, or a specimen with fungi isolated on culturealso had positive microscopy with hyphae seen. Patients withclinical features suspicious of fungal infection were con-sidered to have probable aspergillosis if either serologicaltesting was positive on two or more occasions within oneweek, or culture (of sputum, BAL or sinus lavage) waspositive in combination with suggestive radiological features(nodular or cavitating lesions on chest CT/roentogram, sinusopacification). Apparent clinical improvement on antifungaltreatment were not considered to be a sufficiently specificdiagnostic criterion for inclusion in this study.

Statistics. All data were assessed on 15 August 1997.Descriptive statistics were expressed as medians. Person-daysof survival were classified into three categories: 0–60 d, 61–240 d and >240 d. A single GVHD indicator variable wascreated to denote acute GVHD of >grade II or chronic GVHD.For some analyses the study population was divided intothose with and without an invasive fungal infection. Oddsratios (ORs) and 95% confidence intervals (CIs) describingassociations between other variables and invasive fungalinfections were calculated first by simple cross tabulationsand subsequently by multiple logistic regression modelling.The latter technique takes account of possible confoundingbetween variables of interest.

RESULTS

The clinical characteristics of the 60 patients are shown inTable I. The length of follow-up of surviving patients rangedfrom 70 d to 6·2 years, with a median of 26 months. Therewere over 30 000 patient-days of observation. 45 patientssurvived 100 d or more; microbiological data were obtainedon all long-term survivors by review of PHL records, patientnotes and questionnaire. 34 (57%) patients died during theperiod reviewed. Overall and event-free survival at 3 yearsfor the entire group were 42 6 6% and 27 6 6% (6SE)respectively. Six patients with CML who relapsed are in long-term cytogenetic and molecular remission after DLI.


562 Emma C. M. Williamson et al



Engraftment and GVHDFifty-four patients survived 21 d or more and were con-sidered evaluable. 48 patients (89%) engrafted primarily, ata median time of 16 d (range 11–41 d). Secondary graftfailure occurred in five patients (9%), two of whom hadautologous stem cell rescue and a third had a secondtransplant from the same unrelated donor. These threepatients all engrafted. Primary graft failure occurred in sixpatients, of whom three had autologous stem cell rescue(engraftment in one patient only), and a further patientengrafted after a second UD-BMT from a different donor.Acute GVHD grade I developed in 14 patients, grades II ormore in 13 (24%). Chronic GVHD developed in 18/45patients (40%) who survived more than 100 d.

InfectionsMore than half the patients had at least one severe,potentially life-threatening, infection, and infection contrib-uted to death in 23 patients (38%). 58% of patients (26/45)who survived >100 d were admitted to hospital for manage-ment of infections, and a third of these long-term survivors(15/45) had potentially life-threatening infections. Incidenceof infections (number of patients with one or more episodes),mortality (percentage of patients of those infected who diedwith infection directly contributing to death) and time ofonset (median and range) are shown in Table II.

BacteraemiasSixty-two percent of patients had at least one episode ofbacteraemia (61 episodes in 38 patients). The majority ofearly bacteraemias (68%) were caused by Gram-positiveorganisms, most frequently viridans streptococci. Only twoepisodes of early Gram-positive sepsis were associated withmortality: Listeria monocytogenes bacteraemia (in a patientwithout clinical evidence of meningitis), and Enterococcusfaecium (vancomycin-resistant: VRE) bacteraemia. Bothpatients died before engrafting. Early Gram-negative infec-tion due to Enterobacteriaceae, though uncommon (fivepatients, all with other significant pathologies, 8·3%), had acrude mortality of 60%. Two of the three isolates frompatients who died were ciprofloxacin-resistant; these patientswere on ciprofloxacin prophylaxis. One patient withdiarrhoea had Aeromonas bacteraemia, and responded totreatment. The remainder of the Gram-negative bacterae-mias (11 isolates from seven episodes) were due to non-fastidious non-fermenting organisms, all of which werethought to be secondary to intravascular line infection. Nonewas associated with mortality, except for one case ofS. maltophilia in a patient with extensive Stenotrophomonassoft tissue infection at an intravenous catheter exit site. Mostepisodes (14/17) of late bacteraemia were thought to beassociated with intravascular lines. None of these 14episodes was fatal. Organisms isolated were coagulase-negative staphylococci (eight), Corynebacterium spp. (three),Acinetobacter spp. (three), Pseudomonas aeruginosa (two) andan uncharacterized non-fermenting Gram-negative bacillus(one). Documented ‘late’ line-associated bacteraemiasresulted in removal of the line. Three additional patients,all with extensive GVHD, had bacteraemias due toEnterobacteriaceae all of which were fatal.

Fungal infectionsNearly one third of patients (n ¼ 19) developed invasivefungal infection. There were 17 cases of invasive aspergillosis(IA) (eight proven, nine probable), two of whom also hadinvasive non-albicans candidosis (blood isolate, one; multiplesterile sites at post mortem, one). A further patient hadcandidaemia, and another had biopsy-proven invasiveoesophageal candidosis. There was no peak period fordeveloping IA, and more than half the cases occurredbeyond 100 d. Two patients died of IA despite never having aneutrophil count <1 × 109/l. Other mycelial moulds wereisolated from two patients with IA: Paecilomyces variotii(lung) and Alternaria sp. (skin biopsy). Only two patientswith IA survived. These two patients were treated by surgicalresection of pulmonary masses (A. fumigatus isolated in onecase; no growth in one, who was antibody positive) andliposomal amphotericin. Both had recovered neutrophilfunction: one by autologous stem cell rescue after secondarygraft failure, and the other received a second transplant fromhis original donor. Multivariate analysis demonstratedclustering of infections, with an increased risk of invasivefungal infection in patients with two or more episodes ofbacteraemia (adjusted odds ratio 3·73, 95% CI 0·9–14·8,P ¼ 0·06) or in patients with two or more episodes of viralinfection (adjusted odds ratio 4·25, 95% CI 1·0–17·6,

Table I. Clinical characteristics of 60 adults undergoing UD-BMT.

Median age (years) 25 (17–49)

Sex (M/F) 35/25

DiagnosisChronic myeloid leukaemia 24Acute lymphoblastic leukaemia 14Acute myeloid leukaemia 16Myelodysplastic syndrome 4Chronic lymphocytic leukaemia 1Aplastic anaemia 1

Standard risk 36High risk 24

CMV statusDonor and recipient CMV positive 7Donor CMV positive/recipient CMV negative 9Donor CMV negative/recipient CMV positive 17Donor/recipient CMV negative 27

Matched 46Mismatched 14

T-cell depletionEx vivo 38In vivo 18None 4

GVHD prophylaxisNone 1Cyclosporin 35Cyclosporin þ methotrexate 20Cyclosporin þ methyl prednisolone 4

Female donor 28

P ¼ 0·05). There was no statistically significant associationbetween invasive fungal infection and patient age, HLAmatching, sex of donor or recipient, GVHD or systemicsteroid use. Two patients (3·3%), one of whom was takingco-trimoxazole prophylaxis, developed Pneumocystis cariniipneumonia. Mortality was 50%. Both patients had otherinvasive fungal infection (Aspergillus one, Candida one).

Viral infectionsMore than a quarter of patients had one or more episode ofsevere, potentially life-threatening, viral infection (21episodes in 16 patients). CMV disease was infrequent, butonly just over half the patients (33/60) were at risk. CMVreactivation occurred in 48% of these patients (16/33), butonly four patients developed CMV disease (pneumonitis,three; CMV viraemic syndrome, one), two of whom died. Fivepatients had severe infections with other herpes viruses:severe mucocutaneous Herpes simplex (HSV) infectioninvolving multiple sites in two patients who had extensiveGVHD and multiple other infective episodes, primaryVaricella infection in two patients (fatal in one patient whodeveloped visceral Varicella with hepatitis diagnosed byculture of rectal biopsy; Varicella pneumonitis in one patientwho survived), and EBV lymphoproliferative disease in afurther patient (fatal). Minor infections with herpes viruseswere common in this patient group: seven patients developedHSV infection limited to one mucosal site (oropharynx, six;genital, one), and nine patients had clinical reactivation ofVZV (shingles) limited to one dermatome. None of the

patients with either primary or reactivated VZV was takingaciclovir; the cumulative incidence of VZV disease in patientswho had discontinued prophylaxis (n ¼ 31) was 35%.Breakthrough HSV infection despite aciclovir occurred infour patients, including the two patients with severemucocutaneous infection. There were 11 episodes ofpneumonitis caused by non-herpes viruses, none of whichwas fatal. Pathogens isolated were: influenza A (fourpatients; associated with secondary graft failure in two,and bronchiolitis obliterans in a third), parainfluenza (fourpatients; associated with haemophagocytosis in one patient)and RSV (three patients, two transferred to the IntensiveTherapy Unit). In addition, parainfluenza was also isolatedfrom five patients with upper respiratory tract infections,influenza A from three patients with minor respiratorysymptoms, influenza B was retrospectively diagnosed sero-logically in one further patient, and two patients had upperrespiratory adenovirus infection. Disseminated adenovirus 4infection was diagnosed in one patient at post-mortem, 42 dafter first being isolated from a throat and rectal swabs. Afurther six patients had localized, gastrointestinal adeno-virus infection.

Other infectionsThere was one case of cerebral toxoplasmosis in a patientwith extensive cGVHD, who presented on day 334 withencephalopathy and visual impairment, who also hadpulmonary IA. Microbiologically confirmed gastrointestinalinfections occurred in 30% (n ¼ 18) of patients. Enteric



Table II. Infections and associated mortality.

Infection No. and % Onset: medianof patients (range) post-BMT Mortality

BacteraemiasGram-positive 31 (51·7%) Day 12 (1–652) 6·5%Gram-negative 14 (23·3%) Day 58 (1–1084) 28·6%

Fungal infectionsAspergillosis 17 (28·3%) Day 146 (3–668) 88·2%Candidosis 4 (6·7%) Day 46 (32–278) 25%Pneumocystis carinii pneumonia 2 (3·3%) Day 107 (84–130) 50%

Viral infectionsCMV 4 (6·7%) Day 86 (69–655) 50%VZV 11 (18·3%) Day 240 (120–839) 9·1%HSV 9 (15%) Day 90 (10–210) 0EBV lymphoproliferative disorder 1 (1·7%) Day 120 n/a 100%Adenovirus 9 (15%) Day 54 (3–228) 11·1%RSV 3 (5%) Day 56 (10–110) 0Influenza A, B 8 (13·3%) Day 175 (20–1440) 0Parainfluenza 9 (15%) Day 45 (6–376) 0Rota, small round structured virus 3 (5%) Day 250 (96–1090) 0

OtherToxoplasmosis 1 (1·7%) Day 334 n/a 100%Salmonella enteritis 3 (5%) Day 130 (¹2–178) 33%Giardia lamblia 1 (1·7%) Day 15 n/a 0Clostridium difficile 7 (11·7%) Day 56 (¹1–1560) 0



pathogens (n ¼ 22) documented were: Clostridium difficile(seven), Salmonella spp. (three), Giardia lamblia (one), adeno-virus (seven), rotavirus (two) and small round structuredvirus (SRSV) (one). Questionnaires revealed a high incidenceof late infections in patients with stable engraftment andabsent or limited cGVHD who were not taking anti-infectiveprophylaxis except oral penicillin. These included lowerrespiratory infections of presumed bacterial origin (fivepatients, of whom three had recurrent infections), extensivewarts (three patients), sinusitis (two patients), tonsillitisrequiring in-patient management (two patients, one also haderythema nodosum), Salmonella typhimurium enteritis (twopatients), otitis media (one patient), aseptic meningitis (onepatient) and seborrheic dermatitis (one patient).

DISCUSSION

This study systematically surveyed infection following UD-BMT in a patient population comprising >30 000 d at risk.More than half the patients had at least one serious,potentially life-threatening, infection. A number of factorsmay have predisposed to the high rate of infection seenincluding T-cell depletion, HLA mismatching (Keever et al,1989), past chemotherapy and high haematological risk. Allstudies of infection are potentially susceptible to problems ofover- and under-ascertainment. We have restricted our focusto laboratory-confirmed infections, and have excludedneutropenic fever and idiopathic pneumonitis. Tertiaryreferral centres will inevitably underestimate the incidenceof late infections. However, we believe that our frequentfollow-up and study methodology has enabled us to describerealistically the pattern of late infections in our patientgroup.

The striking feature of our study was the high incidence(28·3%) of invasive aspergillosis (IA). This disease has beenreported to have a mortality of >90% in BMT patients(Denning & Stevens, 1990), and has classically beendescribed as only responding to antifungal therapy inpatients who recover from neutropenia. The two survivors(with localized disease) in this study both had surgicalresection of pulmonary masses, and recovered neutrophilcounts only as the result of further infusions of stem cells.Other centres have also found pulmonary resection bene-ficial in selected patients (McWhinney et al, 1993; Robinsonet al, 1995). Strategies to prevent IA combine decreasingexposure using various methods of air filtration, andprophylactic use of antifungal drugs. The former will neverbe completely effective, partly because it will not preventcolonization pre-admission and it will also not prevent lateacquisition of Aspergillus: more than half our cases occurredbeyond 100 d. Oral absorption of itraconazole tablets isvariable, particularly in immunocompromised patients(Poirier et al, 1996). We have recently switched toitraconazole suspension, which is better absorbed (Prenticeet al, 1995). However, the efficacy of either itraconazole(Bohme et al, 1996) or low dose amphotericin in preventingIA is questionable. Trials of prophylactic fluconazole in BMTrecipients (Goodman et al, 1992; Slavin et al, 1995) havedemonstrated a decrease in invasive Candida infection. The

incidence of invasive candidosis in this study was low, so it ispossible that itraconazole was effective against this patho-gen. This study showed clusteringof infections, with significantassociations between multiple episodes of bacteraemia (OR3·73) or viral infections (OR 4·25) and invasive fungalinfection. This population was relatively small from astatistical point of view, but the odds ratios observedrepresent clinically important risks. Association betweenspecific viral infections in immunocompromised patientshave been described, for instance between CMV and IA inBMT recipients (Rotstein et al, 1985) and lung transplantrecipients (Husni et al, 1998). This is the first study todocument that factors that may be common to viralinfections in general may predispose patients to invasivefungal infection. Possible mechanisms whereby virusespredispose susceptible hosts to fungal infection would bemucosal damage from viral cytopathic effects or cytokinerelease, and immune dysregulation. Viral infections may beprofoundly immunosuppressive; there are reports of invasivepulmonary aspergillosis in patients with previously appar-ently normal immune systems who became lymphopenicduring influenza A pneumonitis (Fischer & Walker, 1979;Lewis et al, 1985). Viruses may also impair tracheobronchialciliary and pulmonary macrophage function, which wouldpredispose patients to aspergillosis. Additionally, herpesviruses have been associated with worsening of GVHD. Theassociation between bacteraemias and invasive fungalinfection is harder to explain. There is some evidence fromother patient groups with poor cell-mediated immunity, forexample premature neonates and HIV-positive adults, thatbacterial infections, even with organisms of low virulencesuch as coagulase-negative staphylococci, are immunosup-pressive and are associated with poorer outcomes such asprolonged hospital stay and weight loss (Gray et al, 1995;Macallan et al, 1995). However, the association betweenbacteraemias and invasive fungal infections is likely to becomplex. Other factors such as breakdown of mucosalbarriers may be the cause, as well as the result, of bacterialinfections, and antibiotic use may be an additional factorpredisposing to fungal infection both by disruptions ofbacterial ecology and immunomodulatory effects.

Since proven bacteraemic episodes are common in UD-BMT recipients, and are associated with morbidity as well asbeing a possible risk factor for invasive fungal infection, itmay be desirable to define better strategies to prevent theseinfections. Bacteraemias due to Enterobacteriaceae andPseudomonas aeruginosa are uncommon in patients receivingquinolone prophylaxis, but the emergence of ciprofloxacinresistance is of concern. The majority of early bacteraemiasin this study were due to Gram-positive organisms,particularly viridans streptococci in patients with mucositis.Possible preventive strategies would be the use of penicillin inaddition to ciprofloxacin or the use of a quinolone withenhanced Gram-positive cover such as sparfloxacin. Reportsof morbidity and mortality in association with viridansstreptococcal bacteraemia (Momin & Chandraseker, 1995)have led to trials of penicillin prophylaxis. A recent EORTCstudy (Anonymous, 1994) demonstrated a reduction infebrile neutropenic episodes and streptococcal bacteraemias

in patients receiving penicillin plus a quinolone, but theimpact on fungal infections was not clearly defined.Prophylactic use of vancomycin probably should be avoided.Use of broad-spectrum antibiotics with anti-anaerobeactivity disrupts so-called colonization resistance, vanco-mycin use is a major risk factor for acquisition of VRE.Trials of prophylactic vancomycin have yielded mixedresults, with some evidence of a decrease in Gram-positivebacteraemia but little evidence of improved patient survivalor of cost-effectiveness (Arns de Cunha et al, 1998; Brounet al, 1994).

The majority of Gram-negative isolates were non-fastidious non-fermentative bacteria. The emergence ofthese organisms, previously regarded as either environmen-tal contaminants or of low virulence, as significant causes ofnosocomial bacteraemia has recently been noted (Kiehn &Armstrong, 1990; Martino et al, 1996), particularly inassociation with central venous catheters (Martino et al,1996; Legrand & Ainaissie, 1992; Hulse et al, 1993). Currentmethods of identification and sensitivity testing of theseorganisms are poorly validated; in particular, cephalosporin-and carbapenem (meropenem/imipenem)-degrading enzymesmay not be expressed in vitro. Therefore patients may receivesuboptimal treatment, both in terms of use of antibiotics withpoor activity in vivo, and also unnecessary exposure to broad-spectrum agents.

Viral infections were common in this adult UD-BMTpopulation, and the so-called ‘community respiratory’viruses (RSV, parainfluenza, influenza A), often regarded asprimarily childhood pathogens of low virulence, haveemerged as significant causes of morbidity. The majority ofcases (79%) of documented viral pneumonitis were causedby these viruses, for which there is currently no proveneffective prophylaxis. It is difficult to compare the incidenceof pneumonitis in our patients due to these respiratoryviruses with published studies, since the latter are ofteneither reports of seasonal clustering or of nosocomialoutbreaks (Englund et al, 1991; Harrington et al, 1992).Parainfluenza, which is not seasonal, did appear to be morefrequent in our patients (pneumonitis 7%) than in otherstudies of allogeneic and autologous adult transplantpatients (0·5–2·3%: Wendt et al, 1992; Lewis et al, 1996;Whimbey et al, 1996), but patient numbers are small. Incontrast, herpes viruses, with the possible exception of HSV,appear to be no more problematic in this patient populationthan in other BMT recipients. CMV disease has historicallybeen regarded as one of the most important pathogens inallogeneic BMT patients, limiting the success of thisprocedure (Meyers et al, 1982; Schmidt et al, 1991) andprevious reports have suggested that it is more common inrecipients of UD-BMT (Marks et al, 1993; Takenaka et al,1997). The incidence of CMV disease in our patients was low(7%), but only 55% of transplants were at high risk.Aciclovir has been shown to reduce CMV disease in BMTpatients (Meyers et al, 1988; Prentice et al, 1994); and pre-emptive therapy with ganciclovir in BMT patients withevidence of CMV reactivation on surveillance cultures alsohas proven efficacy (Goodrich et al, 1991; Schmidt et al,1991). Both strategies were used in this study. A number of

BMT units are currently evaluating CMV PCR and althoughit appears that it can diagnose CMV reactivation earlier thanantigenaemia testing (unpublished observations), there areno data that demonstrate this translates into improvedoutcome. Some of the more sensitive techniques areassociated with a significant false positive rate (some PCR-positive patients do not go on to develop antigenaemia). VZVappears similar in incidence and clinical features in theseUD-BMT patients to published studies of both allogeneic andautograft recipients (Han et al, 1994), with a high incidence,predominantly of localized shingles, in patients not receivingaciclovir. Although aciclovir prophylaxis is prolonged inpatients with cGVHD, there would not appear to be ajustification for extended use in all patients. The lowincidence of EBV lymphoproliferative disease, compared toa published incidence of 5–30% (Smith et al, 1995), is ofnote. We presume this is due to use of CAMPATH antibodiesas the method for T-cell depletion (unpublished observa-tions), as they seem to deplete both T and B cells.

Better strategies are needed to prevent viral infections inall BMT recipients. Currently, there are few options beyondpharmacological prophylaxis for herpes viruses and generalinfection control measures to decrease transmission ofrespiratory and gastrointestinal viruses. The effectivenessof vaccination against influenza A in BMT recipients has notbeen evaluated, and not all our patients were vaccinated.Active Varicella vaccination appears promising in immuno-compromised patients (Redman et al, 1997), but has notbeen evaluated in an UD-BMT cohort.

Late infections with significant morbidity and mortalitywere common in our patients, more than half of whom werehospitalized with infection beyond 100 d, and a third ofwhom had severe infections. Although late aspergillosis iswell described (Wingard, 1994; Wald et al, 1997), toxoplas-mosis occurring beyond 6 months is extremely unusual(Derouin et al, 1992; Slavin et al, 1994), as is CMVpneumonitis. The spectrum of less severe infections seen inpatients with stable engraftment and absent or limitedcGVHD suggests continued immune dysfunction, and hassimilarities with infections seen in other patients with T-celldefects such as early HIV infection.

In summary, unrelated donor bone marrow transplanta-tion is frequently complicated by infection, and more thanhalf our patients experienced at least one severe, potentiallylife-threatening episode. Infections for which there existadequate prophylaxis (CMV disease, Candida albicans fungae-mia and bacteraemia due to Pseudomonas aeruginosa andEnterobacteriaceae) are now uncommon, but invasiveaspergillosis and pneumonitis due to ‘community’ respira-tory viruses are common, and are associated with sub-stantial morbidity and mortality. Efforts should be made toprovide better prophylaxis for these pathogens. Streptococciand non-fermenting Gram-negative bacilli have emerged asthe commonest agents of bacteraemia, but associatedmortality is low. Adult patients who have undergone UD-BMT remain at risk of severe infections for a prolongedperiod, and may need long-term anti-infective prophylaxis.The association between different classes of pathogenswarrants further study.





ACKNOWLEDGMENTS

Heather Hawkins collected many of these data and RobertThorne helped with data analysis. Dr David Grier reviewedrelevant radiological investigations. Dr Rosemary Barnesprovided valuable comments. We thank the nursing andmedical staff of the BMT unit for their excellent care of thesepatients.

REFERENCES

Anonymous (1994). Reduction of fever and streptococcal bacter-emia in granulocytopenic patients with cancer, a trial of oralpenicillin V or placebo combined with perfloxacin. InternationalAntimicrobial Therapy Cooperative Group of the EuropeanOrganization for Research and Treatment of Cancer. Journal ofthe American Medical Association, 272, 1183–1189.

Armitage, J.O. (1994) Bone marrow transplantation. New EnglandJournal of Medicine, 330, 827–838.

Arns de Cunha, C., Weisdorf, D., Sho, X.O., DeFor, T., Pastor, J.D. &Johnson, J.R. (1998) Early Gram-positive bacteremia in BMTrecipients, impact of three different approaches to antimicrobialprophylaxis. Bone Marrow Transplantation, 21, 173–180.

Atkinson, K., Dodds, A.J., Concannon, A.J., Milliken, S., Downs, K.,Marshall, G., Wilson, F. & Staniforth, D. (1993) Unrelatedvolunteer bone marrow transplantation, initial experience at StVincent’s Hospital, Sydney. Australian and New Zealand MedicalJournal, 23, 450–57.

Bohme, A., Just-Nubling, G., Bergmann, L., Shah, P.M., Stille, W. &Hoelzer, D. (1996) Itraconazole for prophylaxis of systemicmycoses in neutropenic patients with haematological malignan-cies. Journal of Antimicrobial Chemotherapy, 38, 953–961.

Broun, E.R., Wheat, J.L., Kneebone, P.H., Sundblad, K., Hromas, R.A.& Tricot, G. (1994) Randomized trial of the addition of Gram-positive prophylaxis to standard antimicrobial prophylaxis forpatients undergoing autologous bone marrow transplantation.Antimicrobial Agents and Chemotherapy, 38, 576–579.

Chown, S.R., Marks, D.I., Cornish, J.M., Pamphilon, D.H., Potter, M.N.,Steward, C.G. & Oakhill, A. (1997) Unrelated donor bone marrowtransplantation in children and young adults with acute myeloidleukaemia in remission. British Journal of Haematology, 99, 36–40.

Davey, K.G., Campbell, C.K. & Warnock, D.W. (1996) Mycologicaltechniques. Journal of Clinical Pathology, 49, 95–99.

Denning, D.W. & Stevens, D.A. (1990) Antifungal and surgicaltreatment of invasive aspergillosis, a review of 2121 publishedcases. Review of Infectious Diseases, 12, 1147–1201.

Derouin, F., Devergie, A., Auber, P., Gluckman, E., Beauvais, B.,Garin, Y.J.F. & Lariviere, M. (1992) Toxoplasmosis in bone marrowtransplant recipients; report of seven cases and review. ClinicalInfectious Diseases, 15, 267–270.

Englund, J.A., Anderson, L.J. & Rhame, F.S. (1991) Nosocomialtransmission of respiratory syncytial virus in immunocompro-mised adults. Journal of Clinical Microbiology, 29, 119–19.

Fischer, J.J. & Walker, D.H. (1979) Invasive pulmonary aspergillosisassociated with influenza. Journal of the American MedicalAssociation, 241, 1493–1494.

Garner, J.S., Jarvis, W.R., Emori, T.G., Horan, T.C. & Hughes, J.M.(1988) CDC definitions for nosocomial infections, AmericanJournal of Infection Control, 16, 128–140.

Glucksberg, H., Storb, R., Fefer, A., Buckner, C.D., Neiman, P.E., Clift,R.A., Lerner, R.G. & Thomas, E.D. (1974) Clinical manifestationsof graft versus host disease in human recipients of marrow fromHLA-matched sibling donors. Transplantation, 18, 295–304.

Goodman, J.L., Winston, D.J., Greenfield, R.A., Chandrasekar, P.H.,

Fox, B., Kaizer, H., Shadduck, R.K., Shea, T.C., Stiff, P., Freidman,D.J., Powderley, W.G., Silber, J.L., Horowitz, H., Lichtin, A., Wolff,S.N., Mangan, K.F., Silver, S.M., Welsdorf, D., Ho, W.G., Gilbert, G.& Buell, D. (1992) A controlled trial of fluconazole to preventfungal infections in patients undergoing bone marrow transplan-tation. New England Journal of Medicine, 326, 845–851.

Goodrich, J.M., Mori, M., Gleaves, C.A., Du Mond, C., Cays, M.,Ebeling, D.F., Buhles, W.C., DeArmond, B. & Meyers, J.D. (1991)Early treatment with ganciclovir to prevent cytomegalovirusdisease after allogeneic bone marrow transplantation. NewEngland Journal of Medicine, 325, 1601–1607.

Gray, J.E., Richardson, D.K., McCormick, M.C. & Goldman, D.A.(1995) Coagulase-negative staphylococcal bacteremia amongvery low birth weight infants, relation to admission illnessseverity, resource use, and outcome. Pediatrics, 95, 225–230.

Han, C.S., Miller, W., Haake, R. & Weisdord, D. (1994) Varicellazoster infection after bone marrow transplantation, incidence, riskfactors and complications. Bone Marrow Transplantation, 13, 277–283.

Harrington, R.D., Hooton, T.M., Hackman, R.C., Storch, G.A.,Osborne, B., Gleaves, C.A., Benson, A. & Meyers, J.D. (1992) Anoutbreak of respiratory syncytial virus in a bone marrowtransplant center. Journal of Infectious Diseases, 165, 987–993.

Hulse, M., Johnson, S. & Ferrieri, P. (1993) Agrobacterium infectionsin humans: experience at one hospital and review. ClinicalInfectious Diseases, 16, 112–117.

Husni, R.N., Gordon, S.M., Longworth, D.L., Arroliga, A., Stillwell,P.C., Avery, R.K., Maurer, J.R., Mehta, A. & Kirby, T. (1993) Cyto-megalovirus infection is a risk factor for invasive aspergillosis inlung transplant recipients. Clinical Infectious Diseases, 26, 753–755.

Keever, C.A., Small, T.N., Flomenberg, N., Heller, G., Pekle, K., Black,P., Pecora, A., Gillio, A., Kernan, N.A. & O’Reilly, R.J. (1989)Immune reconstitution following bone marrow transplantation:comparison of recipients of T-cell depleted marrow with recipientsof conventional marrow grafts. Blood, 73, 1340–1350.

Kernan, N.A., Bartsch, G., Ash, R.C., Beatty, P.G., Champlin, R.,Filipovich, A., Gajewski, J., Hansen, J.A., Hensley-Downey, J.,McCullough, J., McGlave, P., Perkins, H.A., Phillips, G.L., Sanders,J., Stroncek, D., Thomas, E.D. & Blume, K.G. (1993) Analysis of462 transplantations from unrelated donors facilitated by theNational Marrow Donor Program. New England Journal ofMedicine, 328, 593–602.

Kiehn, T.E., Armstrong, D. (1990) Changes in the spectrum oforganisms causing bacteremia and fungemia in immunocompro-mised patients due to venous access devices. European Journal ofClinical Microbiology and Infectious Diseases, 9, 869–872.

Legrand, C. & Anaissie, E. (1992) Bacteremia due to Achromobacterxylosoxidans in patients with cancer. Clinical Infectious Diseases, 14,479–84.

Lewis, M., Kallenbach, J., Ruff, P., Zaltzman, M., Abramowitz, J. &Zwi, S. (1985) Invasive pulmonary aspergillosis complicatinginfluenza A pneumonia in a previously healthy patient. Chest, 87,691–693.

Lewis, V.A., Champlin, R., Englund, J., Couch, R., Goodrich, J.M.,Rolston, K., Przepiorka, D., Mirza, N.Q., Yousuf, H.M., Luna, M.,Bodey, G.P. & Whimbey, E. (1996) Respiratory disease due toparainfluenza virus in adult bone marrow transplant recipients.Clinical Infectious Diseases, 23, 1033–1037.

Macallan, D.C., Noble, C., Baldwin, C., Jebb, S.A., Prentice, A.M.,Coward, W.A., Sawyer, M.B., McManus, T.J. & Griffin, G.E.(1995) Energy expenditure and wasting in human immuno-deficiency virus infection. New England Journal of Medicine, 333,83–8.

Marks, D.I., Bird, J.M., Cornish, J.M., Goulden, N.J., Jones, C.G.,

Knetchtli, C.J., Pamphilon, D.H., Steward, C.G. & Oakhill, A.(1998) Unrelated donor bone marrow transplantation forchildren and adolescents with Philadelphia-positive acute lym-phoblastic leukaemia. Journal of Clinical Oncology, 16, 931–936.

Marks, D.I., Cullis, J.O., Ward, K.N., Lacey, S., Szydlo, R., Hughes, T.P.,Schwarer, A.P., Lutz, E., Barrett, A.J., Hows, J.M., Batchelor, J.R. &Goldman, J.M. (1993) Allogeneic bone marrow transplantationfor chronic myeloid leukaemia using sibling and volunteerunrelated donors, a comparison of complications in the first 2years. Annals of Internal Medicine, 119, 207–2214.

Martino, R., Martinez, C., Pericas, R., Salazar, R., Sola, C., Brunet, S.,Sureda, A. & Domingo-Albos, A. (1996) Bacteraemia due toglucose non–fermenting Gram-negative bacilli in patients withhaematological malignancies and solid tumours. European Journalof Clinical Microbiology and Infectious Diseases, 15, 610–615.

McWhinney, P.H., Kibbler, C.C., Hamon, M.D., Smith, O.P., Gandhi,L., Berger, L.A., Walesby, R.K., Hoffbrand, A.V. & Prentice, H.G.(1993) Progress in the diagnosis and management of aspergillosisin bone marrow transplantation: 13 years’ experience. ClinicalInfectious Diseases, 17, 397–404.

Meyers, J.D., Flournoy, N. & Thomas, E.D. (1982) Nonbacterialpneumonia after allogeneic marrow transplantation: a review often years’ experience. Review of Infectious Diseases, 4, 1119–1132.

Meyers, J.D., Reed, E.C., Shepp, D.H., Thornquist, M., Dandliker, P.S.,Vicary, C.A., Flournoy, N., Kirk, L.E., Kersey, J.H., Thomas, E.D., etal (1988) Acyclovir for prevention of cytomegalovirus infectionand disease after allogeneic marrow transplantation. New EnglandJournal of Medicine, 318, 70–75.

Momin, F., Chandraseker, P.H. (1995) Antimicrobial prophylaxis inbone marrow transplantation. Annals of Internal Medicine, 123,205–215.

Nademanee, A., Schmidt, G.M., Parker, P., Dagis, A.C., Stein, A.,Snyder, D.S., O’Donnell, M., Smith, E.P., Stepan, D.E., Molina, A. etal (1995) The outcome of matched unrelated donor bone marrowtransplantation in patients with haematological malignanciesusing molecular typing for donor selection and graft-versus-hostdisease prophylaxis regimen of cyclosporine, methotrexate andprednisolone. Blood, 86, 1228–1234.

Oakhill, A., Pamphilon, D.H., Potter, M.N., Steward, C.G., Goodman, S.,Green, A., Goulden, P., Goulden, N.J., Hale, G., Waldman, H. &Cornish, J.M. (1996) Unrelated donor bone marrow transplantationfor children with relapsed acute lymphoblastic leukaemia in secondcomplete remission. British Journal of Haematology, 94, 574–578.

Ochs, L., Shu, X.O., Miller, J., Enright, H., Wagner, J., Filipovich, A.,Miller, W. & Weisdorf, D. (1995) Late infections after allogeneicbone marrow transplantations, comparison of the incidence inrelated and unrelated donor transplant recipients. Blood, 86,3976–3986.

PHLS Clinical Microbiology Standard Operating Procedures. Tech-nical Services Section, Public Health Laboratory Service, 1997.

Poirier, J.M., Berlioz, F., Isnard, F. & Cheymol, G. (1996) Markedintra- and inter-patient variability of itraconazole steady stateplasma concentrations. Therapie, 51, 163–167.

Prentice, A.G., Warnock, D.W., Johnson, S.A., Taylor, P.C. &Oliver, D.A. (1995) Multiple dose pharmacokinetics of an oralsolution of itraconazole in patients receiving chemotherapy foracute myeloid leukaemia. Journal of Antimicrobial Chemotherapy,36, 657–663.

Prentice, H.G., Gluckman, E., Powles, R.L., Ljungman, P., Milipied,N., Fernandez Ranada, J.M., Mandelli, F., Kho, P., Kennedy, L. &Bell, A.R. (1994) Impact of long-term acyclovir on cytomegalo-virus infection and survival after allogeneic bone marrowtransplantation. European Acyclovir for CMV Prophylaxis StudyGroup. Lancet, 343, 749–753.

Redman, R.L., Nader, S., Zerboni, L., Liu, C., Wong, R.M., Brown,B.W. & Arvin, A.M. (1997) Early reconstitution of immunity anddecreased severity of herpes zoster in bone marrow transplantrecipients immunized with inactivated Varicella vaccine. Journal ofInfectious Diseases, 176, 578–585.

Robinson, L.A., Reed, E.C., Galbraith, T.A., Alonso, A., Moulton, A.L.& Fleming, W.H. (1995) Pulmonary resection for invasiveAspergillus infections in immunocompromised patients. Journal ofThoracic and Cardiovascular Surgery, 109, 1182–1196.

Rotstein, C., Cummings, K.M., Tidingsm J., Killionm K, Powellm, E.,Gustafson, T.L. & Higby, D. (1985) An outbreak of invasiveaspergillosis among allogeneic bone marrow transplants: a case–control study. Infection Control, 6, 347–355.

Schmidt, G.M., Horak, D.A., Niland, J.C., Duncan, S.R., Forman, S.J.& Zaia, J.A. (1991) A randomized, controlled trial of prophylacticganciclovir for cytomegalovirus pulmonary infection in recipientsof allogeneic bone marrow transplants. New England Journal ofMedicine, 324, 1005–1011.

Shulman, H.M., Sullivan, K.M., Weiden, P.L., McDonaldmm, G.B.,Striker, G.E., Sale, G.E., Hackman, R., Tsoi, M., Storb, R. &Thomas, E.D. (1980) Chronic graft-versus-host syndrome in man:a long-term clinicopathologic study in 20 Seattle patients.American Journal of Medicine, 69, 204–217.

Slavin, M.A., Meyers, J.D., Remington, J.S. & Hackman, R.C.(1994) Toxoplasma gondii infection in marrow transplantpatients: a 20-year experience. Bone Marrow Transplantation,13, 549–557.

Slavin, M.A., Osborne, B., Adams, R., Levenstein, M.J., Schoch,H.G., Feldman, A.R., Meyers, J.D. & Bowden, R.A. (1995)Efficacy and safety of fluconazole prophylaxis for fungalinfections after marrow transplantation, a prospective, rando-mized, double-blind study. Journal of Infectious Diseases, 171,1545–1552.

Smith, C.A., Ng, C.Y., Heslop, H.E., Holladay, M.S., Richardson, S.,Turner, E.V., Loftin, S.K., Li, C., Brenner, M.K. & Rooney, C.M.(1995) Production of genetically modified Epstein-Barr virus-specific cytotoxic T cells for adoptive transfer to patients at highrisk of EBV-associated lymphoproliferative disease. Journal ofHematotherapy, 4, 73–79.

Takenaka, K., Gondo, H., Tanimoto, K., Nagafuji, K., Fujisaki, T.,Mizuno, S., Miyamoto, T., Okamura, T., Hayashi, S., Eto, T., Osaki,K., Yamasaki, K., Shibuya, T., Harada, N., Teshima, T., Matsuishi,E., Minematsu, T., Minamishima, Y., Harada, M. & Niho, Y. (1997)Increased incidence of cytomegalovirus (CMV) infection and CMV-associated disease after allogeneic transplantation from unrelateddonors. The Fukuoka Bone Marrow Transplantation Group. BoneMarrow Transplantation, 19, 241–287.

Wald, A., Leisenring, W., van Burick, J. & Bowden, R.A. (1997)Epidemiology of Aspergillus infections in a large cohort of patientsundergoing bone marrow transplantation. Journal of InfectiousDiseases, 175, 1459–1466.

Wendt, C.H., Weisdorf, D.J., Jordan, M.C., Balfour, H.H. & Hertz, M.I.(1992) Parainfluenza virus respiratory infection after bonemarrow transplantation. New England Journal of Medicine, 326,921–926.

Whimbey, E., Champlin, R.E., Couch, R.B., Englund, J.A., Goodrich,J.M., Raad, I., Przepiorka, D., Lewis, V.A., Mirza, N., Yousuf, H.,Tarrand, J.J. & Bodey, G.P. (1996) Community respiratory virusinfections among hospitalized adult bone marrow transplantrecipients. Clinical Infectious Diseases, 22, 778–82.

Wingard, J.R. (1994) Prevention and treatment of bacterial andfungal infections. Bone Marrow Transplantation (ed. by S. J. Forman,K. G. Blume and E. D. Thomas), pp. 363–375. Blackwell Science,Oxford.



Documents

Infections in adults undergoing unrelated donor bone marrow transplantation