Bone Marrow Transplantation (2003) 32, 709–714 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00 www.nature.com/bmt

Nontuberculous mycobacterial infections in Chinese hematopoietic stem cell transplantation recipients

WY Au1, VCC Cheng2,PLHo2, KY Yuen2, I Hung1,SYMa1, AKW Lie1, R Liang1 and YL Kwong1

1Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong; and 2Department of Microbiology, Queen Mary Hospital, University of Hong Kong, Hong Kong

Summary: nistic non-tuberculous mycobacteria (NTM). Elaborate but empirical clinical, radiological and microbiological criteria Between 1995 and 2002, nine cases of nontuberculous have been developed in an attempt to distinguish between mycobacterium (NTM) were isolated from 462 allogeneic infection and colonization by NTM.1 In Oriental countries stem cell transplant (SCT) recipients (1.9%), and none such as Hong Kong, both MTB and NTM infections from 139 autologous cases. They included three cases each are commonly found in chronic lung disease and immuno- of Mycobacterium fortuitum and M. chelonae, and single suppressed patients.2 The clinical feature of MTB infection cases of M. scrofalaceum, M. gordonnae and M. avium in HSCT recipients in Oriental and Western patients has complex. Seven cases were respiratory, including five been extensively reviewed.3–7 However, few series of NTM cases requiring treatment, and two involved infected after HSCT have been published.8–12 Furthermore, data catheters and vascular conduits. Compared with nine from regions of high MTB prevalence have not been cases of mycobacterium tuberculosis (MTB) isolated in reported. the same period, NTM isolation occurred later after HSCTand involved more unrelated donors. Important Material and methods risk factors for NTM infection included significant aGVHD (P ¼ 0.043), leukemia relapse (P ¼ 0.022), MUD Patients andmismatchSCT(Po0.001) and existence of BO (Po0.001). Coinfection with aspergillus was common. Clinical and microbiological records of consecutive cases of Invasive NTM disease required prolonged antimicrobial adult HSCT were reviewed. Standard conditioning regi- treatment in five cases due to M. fortuitum and M. chelonae. mens were used as reported,13–16 and cyclosporine (2 mg/ With better MTB prophylaxis, intensive immuno- kg) and methotrexate were the standard graft-versus-host suppression and better awareness, NTM has become an disease (GVHD) prophylaxis. GVHD incidence and emerging threat in oriental allogeneic HSCTrecipients. survival have been previously reported,13–16 and were The cutoff between colonization and infection, and the comparable with reported Caucasian series. Pre-HSCT threshold for starting treatment is unclear. NTM isolation screening included chest X-ray (CXR), history and is a marker for severe immunosuppression and poor surveillance sputum culture in all cases. Patients with a prognosis. When there is doubt over species identity or radiological or clinical history of MTB infection were given extent of infection, broad-spectrum cover may be prudent. isoniazid prophylaxis (300 mg) for 6 months.17 All patients Bone Marrow Transplantation (2003) 32, 709–714. received oral ciprofloxacin (500 mg  2/day), fluconzatole doi:10.1038/sj.bmt.1704210 (200 mg/day) and acyclovir (200 mg  3/day) prophylaxis Keywords: nontuberculous mycobacterium; allogeneic from conditioning until engraftment. In addition, mis- stem cell transplantation matched or unrelated HSCT recipients (MUD) were given total gut decontamination (nystatin 1 : 10 000 5 ml  4/day, tobramycin 125 mg  2/day and vancomycin 250 mg  4/ day until engraftment), and ganciclovir (250 mg/day 3  / Hematopoietic stem cell transplant (HSCT) recipients are week until day 120), as reported.18 Broadspectrum anti- at risk of opportunistic infections, including mycobacterial biotics and amphotericin B were administered for neutro- infections. The specific spectrum of infections has varied penic fever. Twice weekly surveillance sputum, blood and with type of HSCT and local prevalence of mycobacterial urine microscopy and culture, cytomegalovirus surveillance species. In Caucasians, pathogenic Mycobacterium tubercu- and CXR were performed for all in-patients. The tests were losis (MTB) is uncommon and most isolates are opportu- repeated for fever or respiratory symptoms in outpatients.

Correspondence: Dr WY Au, University Department of Medicine, Microbiological tests Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong. E-mail: [email protected] Mycobacterial cultures and species identification were Received 5 March 2003; accepted 9April 2003 performed according to standard procedures.19 Briefly, Mycobacteria and stem cell transplantation in Chinese WY Au et al 710 sterile specimens (eg body fluids) were inoculated directly incidence of NTM and MTB isolation after allogeneic into an egg-based medium, Lowenstein–Jensen medium, HSCT were 1.9% (n ¼ 9) and 1.5% (n ¼ 7), while the crude while nonsterile specimens (eg sputum) were decontami- incidences after MUD SCT were 5.4% (n ¼ 4) and 1.4% nated first. Cultures were kept at 30 and 351C for 6 weeks, (n ¼ 2), respectively. NTM was not isolated from 139 and visible colonies were identified by conventional autologous HSCT cases. The median latency of NTM biochemical tests. Isolates of MTB were confirmed by isolation after HSCT was longer than MTB (16.9months vs manual one-tube nested polymerase chain reaction (PCR) 8.1 months). Smear positivity was reported in five cases for the IS6110 gene sequence.20 Ambiguous isolates were (two MTB, three NTM) and the median times taken for referred to reference laboratories. Antimicrobial suscepti- culture identification were 23 (3–86) days for NTM and 53 bility was tested by agar proportion technique using (14–79) days for MTB. Nine patients (five NTM and four Middlebrook 7H10 agar for M. tuberculosis. Susceptibility MTB) died of the underlying malignancy or sepsis. testing of NTB included agar disk diffusion and the E test according to specific isolates. Case reports Suspected colonization. UPN 258 underwent matched Statistical analysis sibling SCT for c-ALL in CR1 8 months after successful Published and possible risk factors associated with induction with the linker protocol. Pre-SCT CXR and increased risk of mycobacterial infection after SCT were sputum screening were normal. However, pre-SCT sputum analyzed separately for MTB and SCT cases. These screening was smear positive for AFB. The patient was included allogeneic vs autologous SCT, unrelated/mis- asymptomatic and microscopic morphology suggested match SCT vs matched sibling SCT, use of total body NTM, confirmed by positive culture of M. avium intra- irradiation (TBI) in conditioning, severe (Gluckberg grade cellulare. He underwent Cy-TBI conditioning in the III or IV) acute GVHD, significant chronic GVHD, relapse absence of specific antituberculous therapy and engrafted of malignancy after SCT and bronchiolitis obliterans on day 22 without pulmonary complications. There was no GVHD, but he suffered from leukemia relapse 5 years later (o75% pre-SCT FEV1). Kaplan–Meier analysis with Log-rank modeling was performed and cases were censored and was successfully treated twice with chemotherapy and on the day of MTB/NTM infection, death or last follow- stem cell infusion. He died of second relapse at 68 months, up. Cox model logistic regression was performed for without any subsequent radiological or microbiological multivariate analysis for the same factors. Calculations evidence of NTM. were performed using SPSS 10.0 software (SPSS, Chicago, UPN 323 underwent sibling SCT for myeloma and IL, USA). achieved complete remission with BO and bilateral bronchiectasis, requiring cyclosporin, azathioprine and regular antibiotic treatment. At 68 months follow-up, M. scrofulaceum was isolated from sputum culture 80 days Results after resolution of a respiratory exacerbation. His clinical course and lung function remained stable 12 months later Patients with no further NTM isolation. The cohort included 601 cases of HSCT with 111 cases transplanted before 1995 and 490 cases transplanted from Catheter-related infections. UPN 293 had Takayasu arter- 1995 to 2002. They consisted of 462 allogeneic HSCT (261 itis with an aortofemoral Teflon inverted Y vascular graft men, 201 women, median age 35 (15–65) years, 74 performed 6 years before SCT for CML. Mild chronic unrelated/mismatched cases) and 139autologous HSCT GVHD developed after successful donor lymphocyte recipients (72 men, 67 women, median age 46 (14–67) infusion for molecular relapse at 14 months and was years). The median follow-up time was 40 (1–146) months. treated conservatively. She suffered from prolonged fever Isoniazid prophylaxis was administered to 14 cases in and malaise at 54-month follow-up. Extensive mid-graft whom mycobacteria was not found. Mycobaterium was thrombosis and inflammation was shown on angiogram isolated in 18 cases, including nine cases of pulmonary and computerized tomography. An open debridement MTB (data not shown) and nine cases of NTM (Table 1). showed M. chelonae infection, and she underwent graft These included three cases each of M. fortuitum and M. removal and 3 months treatment with amikacin, linezolid, chelonae, and single cases of M. scrofalaceum, M. azithromycin, with clarithromcyin maintenance. gordonnae and M. avium complex (MAC). Two patients UPN 823 suffered from fever after Hickman flushing and suffered from an infected catheter or vascular graft. Of exit site inflammation 3 months after HSCT. Blood and seven other NTM isolates, two were classified as coloniza- swab cultures grew M. gordonae and symptoms subsided tion and were not treated specifically (see below). Only one with catheter removal, without antibiotic treatment. patient fulfilled the American Thoracic Society (ATS) bacteriologic criteria of definite pulmonary disease with Pulmonary infection without leukemia. UPN 152 under- repeated isolates, while four were labeled as probable went MUD SCT for AML in CR2 and suffered from severe infections.21 Notably, concomitant fungal infection was aGVHD followed by cGVHD affecting the skin and lungs. present in all five cases. One case each died before and Despite CsA, azathioprine and inhaled steroids, her FEV1 during treatment, while NTM eradication was unsuccessful decreased to 60% at 12-month follow-up. A bronchio- despite 18 months of treatment in one late death. The crude alveolar lavage (BAL) performed for fever and left lower

Bone Marrow Transplantation Table 1 Clinical characteristics of nine cases of nontuberculous mycobacterium isolation

UPN Sex/age SCT and Sequential comorbidity Site of NTM CXR lesion Latency Species Treatment Outcome (clinical and conditioning up to NTM infection isolation (months) mycobacterial)

258 M/15 Sib  ALL-CR1 Nil Sputum Nil 0 M. avium Nil Died 68 months VP16-Cy-TBI (smear+ve) intracellulare (disease) NTM–ve (colonize) 323 M/50 Sib  MM-PR1 Paraparesis, aGVHD Sputum Bronchiectasis 68 M. scrofulaceum Nil Alive 12+months Bu-Cy (III), cGVHD, BO(56%) L+R (colonize) NTM–ve 293 F/47 Sib  CML-CP Takayasu arteritis, Aortofemoral graft Nil 54 M. chelonae Explant, (AMI+LIN+ Alive 6+months Bu-Cy BO(72%), molecular AZI)  3 (CLA)  3+ NTM–ve relapse 823 F/43 Sib  CML-CP Nil Hickman Nil 4 M. gordonae Explant Alive 2+months Bu-Cy NTM–ve 152 F/30 MUD  AML-CR2 aGVHD (IV), Sputum Lower lobe L 15 M. fortuitum (AMI+OFL+RIF+ Died 18 months Bu-Cy-TBI cGVHD, BO(60%), (smear+ve) (definite infection) AZI+ETH)  18 (sepsis) NTM+ve aspergillus, norcardia,

pseudomonas Chinese in Au transplantation WY cell stem and Mycobacteria 703 M/27 MUD Â AML-CR2 aGVHD (III), BAL Lower lobe L+R 16 M. chelonae (IMI+CLA+OFL) Â 2 Alive 3+months

Bu-Cy BO(28%), aspergillus (possible infection) NTM–ve al et 604 M/19MUD  ALL-CR1 Relapse, aGVHD Sputum Lower lobe L 11 M. fortuitum Nil (undiagnosed) Died 0 month (sepsis) Cy-TBI (IV), aspergillus (possible infection) NTM+ve 593 F/21 MUD  AML-CR1 Relapse, aGVHD Sputum Mid zone R 17 M. chelonae (ETH+PZA+INH+ Died 1 month (sepsis) Bu-Cy (IV), BO(30%), (smear+ve) (possible infection) RIF)  0.5 NTM+ve cGVHD, aspergillus 375 F/56 Sib  CML-CP cGVHD, BO (62%), EM Urine, Lower lobe L+R 38 M. fortuitum (ETH+PZA)  2 Died 29months (2nd ca) Bu-Cy aspergillus, donor skin, sputum (possible infection) (INH+RIF)  9 NTM–ve leukaemia

UPN: unique progression number; SCT: stem cell transplant; MUD: matched unrelated donor, CR: complete remission; CP: chronic phase; AML: acute myeloid leukemia; ALL: acute lymphoblastic leukemia; CML: chronic myeloid leukemia; lymph: lymphoma; Auto: autologous transplantaiton; M: male; F: female; BAL: bronchioalveolar lavage; L: left; R: right; +ve: positive; –ve: negative; EM: early morning; BO: bronchiolitis obliterans (forced expiratory rate % of normal); GVHD: graft-versus-host disease (Gluckberg grade); ETH; ethambutol; PZA: pyrazinamide; INH: isoniazid; RIF: rifampicin; OFL: ofloxacin; AMI: amikacin; IMI: imipenam; KLA: clarithromycin; LIN: linezolid; AZI: azithromycin; x: months of treatment; NTM: non-tuberculous mycobacterium; 2nd ca: second unrelated malignancy; AFB: acid-fast bacillus. oeMro Transplantation Marrow Bone 711 Mycobacteria and stem cell transplantation in Chinese WY Au et al 712 lobe infiltrate grew M. Fortuitum. She was treated with pulmonary infiltrates. Subsequent investigations confirmed multiple antituberculous agents but remained sputum AML of donor origin, while sputum and urine specimen culture and smear positive. She also received prolonged grew M. fortuitum and A. fumigatus. She achieved CR for 6 treatment for pulmonary aspergillosis and nocardia, and months with three courses of intensive chemotherapy, died of respiratory failure 18 months later. supported with antimycobacterium drugs and ambisome. UPN 703 received an overseas MUD SCT for AML in Although there was no recurrence of severe infection, she CR2, with mild aGVHD. He suffered from sudden rapid died of refractory donor AML relapse. onset of BO at 11 months, unresponsive to azathioprine and inhalational steroids. At 16 months he suffered from Risk factors for mycobacterial infection. The distribution fever, hypoxia and bilateral lung infiltrates requiring of clinical risk factors among background, NTM and MTB intubation and ventilatory support. A BAL showed M. cases are shown in Table 2. The significant risk factors for chelonae and Aspergillus, and he was treated aggressively NTM infection included significant aGVHD (P ¼ 0.043), with ambisome, caspofungin and broadspectrum antibio- leukemia relapse (P ¼ 0.022), MUD and mismatch SCT tics with NTM coverage. He recovered after 1 month and (Po0.001) and existence of BO (Po0.001). On multi- was maintained on oral NTM drugs and itraconazole for 3 variate analysis, only unrelated or mismatch SCT and BO months, without fever or respiratory deterioration. remained significant. On the other hand, risk factors for MTB appeared to be slightly different in our latest cohort. Pulmonary infection with leukemia. UPN 604 relapsed 10 On univariate analysis, pronounced cGVHD (P ¼ 0.049) months after MUD BMT for ALL, without GVHD. He and BO (P ¼ 0.032) were significant factors. Interestingly, achieved CR2 with chemotherapy with stem cell support the use of TBI conditioning (mainly for ALL cases) was from the same donor, but suffered from grade IV aGVHD associated with reduced risk of MTB (P ¼ 0.037). On with erythroderma, diarrhea and CMV reactivation. This multivariate analysis, however, the effect of TBI dis- was treated with ATG, gancyclovir, prophylatic ambisome appeared, while mismatch and unrelated SCT become a and steroids, but he developed rapid onset of pulmonary significant risk factor. infiltrates and died of septicemia. Sputum samples grew Aspergillus fumigatus and M. fortuitum post mortem. Similarly, UPN 593 suffered from AML relapse 5 Discussion months after MUD SCT. She achieved CR after intensive chemotherapy and stem cells from same donor but suffered The incidence of pulmonary MTB and NTM isolation in from grade IV aGVHD and rapid onset of BO, controlled the Hong Kong general population has remained stable for with steroids, CsA and mycophenolate mofeteil. After 1 the past three decades at 112.3 and 10.7 per 100 000/year, year, she was admitted with acute respiratory failure and respectively.23 Among NTM isolates, only 16.7 and 2.3% bilateral lung infiltrates, requiring mechanical ventilation. represented progressive disease and persistent carriage.24 A BAL showed smear-positive Aspergillus and AFB, but Among 1798 registered HIV carriers, the incidences of she died despite empirical ambisome and anti-TB treat- MTB and NTM from 1985 to 2001 were 126 (7%) and 19 ment. M. chelonae was identified post mortem. (1%) cases, respectively.25 Unlike with HIV carriers and The unique leukemia course of UPN 375 has been normal hosts, the incidence of NTM isolation in HSCT reported.22 She underwent SCT for CML with moderate recipients was comparable to that of MTB. This may be cGVHD. At 3-year FU, she suffered from fever and skin related to improved MTB prophylaxis and distinct predis- infiltrations. A skin biopsy showed granuloma annulare. posing factors for NTM growth, including prolonged Empirical mycobacterial treatment was commenced. This recurrent neutropenia and chronic lung damage due to was followed by cytopenia, with circulating blasts and GVHD. Our group previously reported a crude incidence

Table 2 Kaplan–Meier comparison of clinical risk factors for NTM and MTB infection against background stem cell transplant recipient population (1996–2002)

Factor (yes vs no) Nil (n=583) NTM (n=9) P-value MTB (n=9) P-value Sex (M : F) 322 vs 261 4 vs 5 0.52 (NS) 9 vs 00.12(NS) Age (median) 36.2 29.8 NS 34.2 NS Autologous SCT 137 vs 446 0 vs 90.11 (NS) 2 vs 70.93(NS) Mismatch or unrelateda 68 vs 378 4 vs 5 o0.001 (0.006) 2 vs 5 0.65 (0.028) TBI 199 vs 384 3 vs 6 0.95 (NS) 0 vs 90.037 (0.96) aGVHDa 67 vs 3795 vs 4 0.043 (0.14) 3 vs 60.18(NS) cGVHDa 130 vs 316 4 vs 5 0.79(NS) 6 vs 1 0.013 (0.049) BOa 44 vs 401 6 vs 3 o0.001 (o0.001) 4 vs 3 0.0022 (0.032) Relapseb 167 vs 416 4 vs 5 0.022 (0.056) 3 vs 6 0.74 (0.105)

M: men; F: women; SCT: stem cell transplantation; TBI: total body irradiation; aGVHD: acute graft-versus-host disease; cGVHD: chronic graft-versus-host disease; BO: bronchiolitis obliterans; NTM: nontuberculous mycobacterium; MTB: mycobacterium tuberculosis; Nil: no infection; P-value: Kaplan–Meier level of significance based on Cox’s model (multivariate analysis P-value in brackets); NS: not significant. aOnly applicable to allogeneic cases. bInclude molecular relapses.

Bone Marrow Transplantation Mycobacteria and stem cell transplantation in Chinese WY Au et al 713 Table 3 Comparison between oriental and Caucasian reported series of mycobacterium infection

Author (year/site) Cases (Yr) Incidence NTM Infections Isolatesa Infection sites Outcomeb (vs TB) (species) (species) Au (2003/Hong Kong) 601 (9) 1.16% (1.16%) 7 (3F, 3C, 1G) 2 (1 M, 1S) 2 catheter/7 lung 3 died (lung) Roy (1997/Minnesota) 2241 (20) 0.4% (0.089%) 9 (5F, 3C, 2 M) 10 (4F and C, 6 catheter/1 lung 2 died (1 catheter, 1 lung) 3 M, 1 T, 1G) Gaviria (2000/Seattle) 6259(20) 0.64% (0.048%) 28 (6F, 5C, 3M, 12 (10M, 2G) 23 catheter/15 lung 9died (2 catheter, 7 lung) 10Abs, 2G, 1Mu)

Yr: number of years of study; NTM: nontuberculous mycobacterium; TB: tuberculosis. aCases classified as isolates were all from lung; F: M. fortuitum;C:M. chelonae;M:M. avium intraceullare; Abs: M. abscessus;G:M. gordonae; Mu: M. mucogenicum;S:M. scrofulaceum;T:M. terrae. bInclude cases clinically classified as isolates and excluding unrelated deaths. of 5.5% of MTB among 183 HSCT cases from 1991 to tion associated with chronic lung disease. Our incidence of 1994, with a median onset of 5 months and increased risks catheter infection appeared to be lower compared with with allogeneic HSCT, GVHD and pulmonary irradia- Caucasian studies, possibly related to our practice of early tion.17 Retrospectively, the association with TBI may be removal of central venous catheters, and the availability of related to the routine use of Bu-Cy-TBI for unrelated/ a comprehensive community nurse home-care of catheter mismatch conditioning, which was abandoned after 1997. hygiene in Hong Kong. The removal of infected foreign This update showed an apparently reduced crude incidence material is essential and for deep implants, extensive of MTB, and confirmed the importance of GVHD. It also surgery, and prolonged antibiotic treatment may be needed. showed that even with vigorous pre-HSCT screening and For pulmonary isolates, colonization and infection may be prophylaxis, late-onset MTB infection may still complicate indistinguishable in the bronchiectatic and scar tissues in chronic BO and may be more common among unrelated/ BO patients. The Seattle and Minnesota series reported mismatch SCT recipients. 30% and 52% of isolates as colonization, mainly involving There are few studies on the relative significance of NTM M. avium. The issue was further complicated by the among mycobacterial infections in HSCT patients. The commencement of NTM treatment in 25% and septic problem was first reported in four cases published 20 years death in 50% of ‘colonization’ cases in the former series. It ago.11,26 In two subsequent series from Minneapolis and must be recognized that clinical definitions of infection and Seattle, 59cases of NTM were reported among 8500 HSCT colonization for immunocompromised and immunocompe- recipients over 20 years (incidence 0.4–1.11%). The tent hosts21 are empirical, and mainly apply to the M. incidence was 5–10 times higher than that of MTB infection avium, M. abscessus and M. kansasii species. In Chinese (Table 3). Approximately equal numbers of catheter-related patients, M. fortuitum/chelonae appeared to be more infections (usually due to M. fortunitum/chelonae) and prevalent. Similar to Western experience, this is rarely a pulmonary isolates (M. avium intracellulare, M. fortuitum/ benign finding. Our statistical analysis suggested that the chelonae) were reported. Four Oriental series involving presence of BO and mismatched/unrelated SCT are 1200 patients did not report any NTM cases among 14 independent risks factors for NTM infection, while disease positive isolates,4–7 although recent case reports have relapse and aGVHD might also be implicated. Hence, appeared from the region.9 This could be due to increased NTM infections after autologous HSCT are rarely in- recognition and improved mycobacterial identification.27 volved.30 Furthermore aspergillus and other pathogens are Our present cohort showed both similarities and concurrently present in up to 80% of cases.10 Hence, in the differences compared with those of Caucasian NTM appropriate clinical setting, single isolates (especially for reports, and illustrated some practical points in clinical more virulent NTM species) warrant prompt treatment. management. In our area of high MTB prevalence, Eradication of NTM may be impossible and mycobacteria isolation of NTM and MTB occurs at roughly equal may contribute to continued pulmonary destruction. Even frequencies. Furthermore, as illustrated, the clinical factors with adequate treatment, the death rates in these respira- predisposing to NTM and MTB infections showed much tory cripples remained high.10 It remains to be seen if our similarity and overlap. Hence, the finding of a positive acid- NTM experience is reproduced by other Oriental centers, fast bacillus smear or mycobacterium culture in an Oriental and whether more vigorous treatment will change the HSCT recipient presents a treatment dilemma, since MTB natural history of the disease. is still highly probable. The use of the tuberculin skin test is limited by universal BCG vaccination, while the use of PCR to confirm MTB is not always reliable.28 For critically ill cases, empirical treatment for MTB is warranted, and References can be modified or stopped after NTM species isolation.29 1 Patel R, Roberts GD, Keating MR, Paya CV. Infections due In the absence of fever and respiratory symptoms, however, to nontuberculous mycobacteria in kidney, heart, and liver observation and repeated sampling may also be appro- transplant recipients. Clin Infect Dis 1994; 19: 263–273. priate. 2 Chan JC, So SY, Lam WK, Ip MS. High incidence of Clinical infections by NTM fall into two main categories: pulmonary tuberculosis in the non-HIV infected immunocom- early-onset catheter-related infection and late-onset infec- promised patients in Hong Kong. Chest 1989; 96: 835–839.

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