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Nuoro; (10) L Tasso, Div. Malattie Infettive, Ist. G Gaslini,. Genova; (11) F Narni, Sez. Emato-Oncologia, Univ. Modena;. (12) E Pogliani, Ematologia, Osp. S ...

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Viral infections Hepatitis reactivation and liver failure in haemopoietic stem cell transplants for hepatitis B virus (HBV)/hepatitis C virus (HCV) positive recipients: a retrospective study by the Italian group for blood and marrow transplantation A Locasciulli1, B Bruno2, EP Alessandrino3, G Meloni4, W Arcese4, G Bandini5, V Cassibba6, B Rotoli7, E Morra8, I Majolino1, A Alberti9 and A Bacigalupo2 1 Ematologia e Trapianto di Midollo, Ospedale S Camillo-Forlanini, Roma, Italy; 2Ematologia II, Centro Trapianto di Midollo, Ospedale S. Martino, Genova, Italy; 3Ematologia e Trapianto di Midollo, Policlinico S. Matteo IRCCS, Pavia, Italy; 4Dip. Biotecnologie Cellulari e Ematologia, Univ. ‘La Sapienza’, Roma, Italy; 5Istituto Ematologia ‘Seragnoli’, Ospedale S Orsola, Bologna, Italy; 6Ematologia e TMO, Osp. Generale Regionale, Bolzano, Italy; 7Div. Ematologia, Univ. ‘Federico II’, Napoli, Italy; 8 Div. Ematologia, Ospedale Niguarda, Milano, Italy; and 9Clinica Medica V, Policlinico Univ. Padova, Italy

Summary: Hepatitis B virus/hepatitis C virus (HBV/HCV) positive patients undergoing haemopoietic stem cell transplantation (HSCT) are at risk of hepatitis reactivation and fatal liver failure: we have conducted a retrospective study to assess the risk in 20 Italian transplant centres. A total of 90 patients infected with HBV (n ¼ 33) or HCV (n ¼ 57) receiving allogeneic (n ¼ 36) or autologous (n ¼ 54) haemotopoietic stem cell transplant (HSCT) between 1996 and 2000 were reviewed. The biochemical profiles and outcomes of infection-related liver disease were also analysed. The risk of death at 2 years was comparable when considering type of infection (3% for HBV vs 8% for HCV, P ¼ 0.6) or type of HSCT (7% for allogeneic vs 5% for autologous HHSCT, P ¼ 0.34). Hepatitis reactivation followed by resolution was more frequent in HCV+ than in HBV+ patients receiving an allograft (100% vs 16%, P ¼ 0.004). In HBV+ cases, risk of reactivation was comparable after autologous or allogeneic transplantation (66 vs 81%, P ¼ 0.3), but liver disease was more severe and occurred earlier in the autologous group. Our results indicate that HBV and HCV infection should not be taken as an absolute contraindication for HSCT and the risk of life-threatening liver complications are similar after allogeneic or autologous transplants. Bone Marrow Transplantation (2003) 31, 295–300. doi:10.1038/sj.bmt.1703826 Keywords: HSCT; HBV; HCV

Correspondence: Dr A Locasciulli, Ematologia e Trapianto di Midollo, Ospedale S Camillo-Forlanini, Circonvallazione Gianicolense 87, 00152 Roma, Italy Received 8 April 2002; accepted 14 September 2002

Prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection is estimated to be around 2–5% in the general population worldwide. Patients who are candidates for a haemopoietic stem cell transplant (HSCT) are at higher risk for HBV and HCV infection due to the underlying disease and the profound immunodeficiency. In a prospective study recently conducted by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation, in patients transfused in the ‘postscreening’ era, the prevalence of HBV and HCV infection before transplant was 3.1 and 6%, respectively.1 Thus, viral hepatitis is still seen in a consistent number of HSCT candidates, regardless of currently available blood screening procedures. Liver disease is a well-known major complication after HSCT, with mortality rates ranging from 4 to 15%:2–4 the risk is increased in HBV/HCV positive recipients.5,6 For this reason, some centres consider HBV/ HCV-infected patients ineligible for transplant.2 In other reports the presence of pretransplant hepatitis B surface antigen (HBsAg) or anti-Hepatitis C virus (antiHCV) antibodies did not significantly influence the shortterm clinical outcome, even though a significant proportion of infected patients developed biochemical evidence of hepatitis reactivation post-transplant.7–10 In our own prospective study of 193 unselected consecutive patients undergoing allogeneic BMT, liver failure was the primary cause of death during the first 6 months after transplant: it was mainly related to veno-occlusive disease (VOD) of the liver, while pretransplant HBV and/or HCV infection, with or without abnormal transaminase levels, did not increase the risk of severe liver disease post-transplant.1 In this study, as in others, the number of HBV- and HCV-infected patients was small: it was therefore difficult to make a comprehensive description of the clinical profile and outcome of liver disease after BMT. Furthermore, while several studies have reported patients receiving allogeneic HSCT, little information is

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available on HBV and HCV carriers undergoing autologous HSCT. On behalf of GITMO (Italian Group for Blood and Marrow Transplantation) we have therefore conducted a multicentre retrospective study of HBV- or HCV-infected patients who received allogeneic or autologous HSCT in 20 Italian BMT Units between 1996 and 2000. The aim of the study was to assess liver-related mortality and morbidity rates according to the type of infection (HBV or HCV) and transplant (allogeneic or autologous). We also investigated the biochemical profiles and outcomes of HBV- or HCVrelated liver disease, focusing on the frequency of post transplant hepatitis reactivation and resolution.

Patients and methods Design of the study and patient recruitment This study, promoted by the GITMO, (Italian Cooperative Group for Blood and Marrow Transplantation) was designed as a retrospective survey of hepatic complications in a cohort of patients infected with HBV or HCV and undergoing allogeneic or autologous HSCT from January 1996 to January 2000 in 20 Italian Units. For every subject included in the study, a data collection form was completed, so as to provide detailed information on the pretransplant status of the underlying haematological or malignant disease and liver disease, type of viral infection (HBV and/or HCV) and post-transplant follow-up to June 2000 or to patient death if this occurred earlier.

Patients The patient population consisted of 90 subjects undergoing allogeneic (n ¼ 36) or autologous (n ¼ 54) HSCT. In all, 33 were HBsAg positive and 57 were anti-HCV positive: of these, 38 were also tested for viraemia, and 32 (84%) were HCV-RNA positive. The main clinical characteristics in the two groups of patients, undergoing allogeneic or autologous HSCT, are listed in Table 1. The two groups differed in clinical characteristics: the majority of patients undergoing allogeneic HSCT had acute or chronic leukaemia, while in the autologous group, nonHodgkin lymphoma and solid tumours were the commonest diseases. Mean age at transplant was higher in the autologous group. As to the status of the underlying disease, 37 patients (autologous ¼ 20, allogeneic ¼ 17) were transplanted in first complete remission, first chronic phase or with stable disease, 25 in second or subsequent remission (autologous ¼ 12, allogeneic ¼ 13), while in 28 cases, HSCT was performed with resistant or advanced disease (autologous ¼ 22, allogeneic ¼ 6). Allogeneic bone marrow was obtained from a HLA identical sibling in 28 cases, from a twin in one case, from a relative other than identical sibling in one and from an unrelated donor in six cases. Stem cell source was bone marrow in all allogeneic and in four autologous transplants, while in the other 50 patients, peripheral blood stem cell infusions were performed. Of the 90 patients included in the study, 88 were evaluated after a single HSCT and six after their second allogeneic BMT. Bone Marrow Transplantation

Table 1 Clinical characteristics in 90 patients with HBV or HCV infection undergoing allogeneic or autologous HSCT

No. patients Gender: M/F Age (years): mean7s.d. Stem cell source: BM/PB

Autologous

Allogeneic

54 31/23 44.4714.1 4/50

36 26/10 37.1716.3 36/0

SC donor relation: HLA identical sibling Related nonidentical Unrelated Twin

28 1 6 1

Underlying disease Acute lymphoblastic leukaemia Acute myeloid leukaemia Chronic lymphocytic leukaemia Chronic myeloid leukaemia Myelodysplastic syndrome Multiple myeloma Non-Hodgkin lymphoma Aplastic anaemia Thalassaemia Solid tumour

1 10 1 0 1 7 27 0 0 7

10 7 0 10 2 2 2 2 1 0

Status First complete remission or stable disease XSecond remission Resistant/advanced disease

20 12 22

17 13 6

Transplant protocols varied widely, according to the different HSCT Units, type of transplant and underlying disease. Briefly, total body irradiation was administered to four out of 54 patients undergoing autologous HSCT and in 22 out of 36 patients receiving an allograft (Po 0.0001). In the latter group, conditioning was more homogenous, consisting mainly of cyclophosphamide alone or with busulfan (28 and 10 vs 15 and 8 in the autologous group, Po0.0001 and ¼ 0.017, respectively). Graft-versus-host disease (GVHD) prophylaxis was with cyclosporin and methotrexate in the 36 patients undergoing allogeneic BMT. In nine cases, steroids were added, and in one patient antilymphocyte globulin (ALG) was also administered.

Assessment of liver disease Alanine aminotransferase (ALT), bilirubin and albumin serum levels were evaluated before the conditioning regimen, at HSCT (day 0: day of stem cell infusion), at weekly intervals during the first month after transplant, and then at 1–3 month intervals up to the end of follow-up, relapse of the underlying disease or death. At the same time points, all patients underwent clinical evaluation for symptoms and signs of liver disease. A diagnosis of VOD and GVHD was made according to published criteria11,12

Definition criteria for clinical outcome of liver disease Fulminant hepatic failure (FHF) was defined according to Bernuau et al.13 ALT profile and outcome of liver disease were assessed by serial enzyme evaluations. Hepatitis reactivation was defined as a three-fold elevation of ALT levels compared to pretransplant values, on at least two

HSCT in HBV- or HCV-infected patients A Locasciulli et al

consecutive determinations 1 week apart, in the absence of clinical features of VOD or GVHD. Hepatitis reactivation episodes were classified as mild (ALT o200, normal values p40 IU/l), moderate (ALT: 200–400 IU/l) and severe (ALT4400 IU/l). Stable hepatitis remission was defined as persistent ALT normalisation. Hepatitis B was considered as resolved in patients who cleared HBsAg.

Assessment of stem cell donors As part of the work-up before marrow harvesting, marrow donors were evaluated for transaminase levels, serum markers for HBV (HBsAg, anti-HBs, anti-HBc) and HCV (anti-HCV with or without HCV-RNA). Blood components administered to the patients were obtained from HBsAg-negative, anti-HCV-negative volunteer donors in all the participating centres.

Patient 1: A 54-year-old HBsAg and anti-HBe-positive female with an ALT of 155 U/l before transplant, died at day +33 after autologous HSCT with a clinical picture suggesting hepatitis reactivation and VOD. Patient 2: A 51-year-old anti-HCV-positive male with decompensated cirrhosis before transplant died of liver failure on day +180 after autologous HSCT. Patients 3 and 4: Two anti-HCV-positive males (13 year old and 43 year old) with pretransplant ALT levels of 69 and 96, respectively, died of liver failure 60 and 180 days after allogeneic BMT. The risk of death for liver failure was not significantly different between HBsAg and anti-HCV-positive patients, being 3 and 8% at 24 months, respectively (P ¼ 0.6) (Figure 1), or between recipients of autologous (5%) or allogeneic (7%) HSCT (P ¼ 0.34) (Figure 2).

297

Liver disease after HSCT HBV markers, including HBsAg, HBeAg, anti-HBs, antiHBc and anti-HBe were tested in serum by commercially available assays. Antibodies to HCV (anti-HCV) were detected by second- or third-generation ELISA (Ortho Diagnostic Systems, Raritan, NJ, USA). HCV-RNA was tested in serum by nested polymerase chain reaction (PCR) according to previously described methods.14 Patients were evaluated for HBV and HCV markers before and at least once after transplant.

Statistical analysis Data were analysed by contingency tables, log rank, rank sum Mann–Whitney and Fisher tests, when appropriate. Survival curves were calculated according to Kaplan and Meier.

Table 2 summarises the biochemical outcome of the 90 patients, according to the type of HSCT. Liver enzyme 100 90 % risk of death for LF

Hepatitis B and C serum markers

80 70 60 50

a=HBV n=33 3% b=HCV n=57 8%

40 30

P=0.6

20 b a

10 0

Of the 90 patients included in the study, 33 were HBsAg positive(autologous HSCT ¼ 18, allogeneic BMT ¼ 15) and 57 anti-HCV positive (autologous HSCT ¼ 36, allogeneic BMT ¼ 21) before transplant. Pretransplant ALTs were abnormal in 12 (36%) HBV- and in 28 (49%) HCVinfected cases, respectively. Median follow-up post-HSCT was 210 (range: 5–1300) and 385 days (range: 7–1170) in autologous and allogeneic transplants, respectively. In all, 29 patients (32%) (autologous ¼ 15, allogeneic ¼ 14) died during follow-up. Causes of death after autologous HSCT were as follows: progression of the underlying disease (n ¼ 9), infection (n ¼ 2), liver failure (n ¼ 2), heart failure (n ¼ 1) and interstitial pneumonia (IP) (n ¼ 1). Causes of death after allogeneic HSCT were as follows: disease progression (n ¼ 5), IP (n ¼ 3), liver failure (n ¼ 2), heart failure (n ¼ 1), GVHD (n ¼ 1), multiorgan failure primarily involving kidney, heart and lungs (n ¼ 2).

Mortality due to liver failure Four patients (one HBsAg positive and three anti-HCV positive before BMT) died of liver failure; two had received an allogeneic HSCT and two autologous HSCT.

24

12 Months from HSCT

Results

Figure 1 Death from liver failure in patients undergoing allogeneic and autologous HSCT: actuarial risk in HBV (a) vs HCV (b) infection before transplant.

10 9 8 7 6 5 4 3 2 b a

1 12

24

Months from HSCT Figure 2 Death from liver failure in HBV- and HCV-infected patients undergoing HSCT: actuarial risk with autologous (a) vs allogeneic (b) transplant. Bone Marrow Transplantation

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298 Table 2 transplant

Biochemical parameters of liver disease after HSCT in 90 patients according to the type of Autologous

Allogeneic

P

No. patients ALTa: median (range): Before conditioning regimen First abnormal value post-HSCT Timing(days post-HSCT)a

54

36

33 (10–683) 75 (45–1588) +21 (+2 to +370)

48.5 (16–818) 104 (47–382) +15 (+1 to +210)

0.035 0.012 0.01

ALTa Peak value Timing (days post-HSCT)b Duration (days)

178 (49–2729) +60 (+20 to +370) 90 (1–1300)

196.5 (48–1708) +105 (+7 to +1095) 226.5 (+2 to +1170)

0.04 0.006 0.22

1.7 (1.2–7.2) +7 (0 to +90)

2.25 (1.3–20) +18 (0 to +210)

0.02 o0.0001

7.45 (1.9–23) +34 (0 to +330) 50 (7–420)

3.35 (1.3–45) +18 (0 to +210) 30 (1–180)

0.01 0.53 0.014

Total bilirubinc: median (range) First abnormal value post-HSCT Timing (days post-HSCT)b Bilirubina Peak value Timing (days post-HSCT)b Duration (days)

ALT=alanine aminotransferase, normal values p40 IU/l. Day 0=day of stem cell infusion. Normal value p1 mg/dl.

a

b c

100

10

90

9

80

8

70

7

60

6

50

5

40

4

30

3

20

2

10

1

% %

0 12 Months from HSCT

24

Figure 3

12 Months from HSCT

24

Risk of hepatitis reactivation in HBV-infected patients undergoing allogeneic (a) vs autologous (b) HSCT.

Figure 4 Risk of hepatitis reactivation in HCV-infected patients under-

deterioration occurred earlier in the allogeneic group (day+15 vs day +21), while peak values were observed significantly later, when compared to the autologous group (day+105 vs day+60; P ¼ 0.006). The opposite was seen in the behaviour of bilirubin values, which deteriorated earlier (day+7 vs day+18; Po0.0001) and reached a higher peak (7.45 vs 3.35 mg/dl) in the autologous group.

timing, the majority of patients had a clinical exacerbation of liver damage within the first year post-transplant. Interestingly, in the autologous group the majority of patients showed ALT peaks within 6 months after HSCT, while most patients undergoing allogeneic transplant did so later on. In cases infected with HCV, the liver disease displayed different patterns in the two sets of transplant patients. Indeed, patients undergoing with autologous HSCT had a significantly lower risk of reactivation post-transplant, compared to the allogeneic group (16% vs 100%, P ¼ 0.004, Figure 4). In the latter, all reactivation episodes occurred during the first year of follow-up, mainly within the first 6 months. The few episodes of reactivation observed in the autologous group were seen within the first 3 months post-transplant.

Hepatitis after HSCT: reactivation, severity and outcome Risk of reactivation in HBV- and HCV-infected patients was calculated and compared, according to the type of HSCT. HBsAg-positive patients: the risk of hepatitis B reactivation at 24 months after HSCT was 81% for allogeneic and 66% for autologous cases (P ¼ 0.3; Figure 3). As to the Bone Marrow Transplantation

going allogeneic (a) vs autologous (b) HSCT.

HSCT in HBV- or HCV-infected patients A Locasciulli et al

Severity and outcome of viral hepatitis following posttransplant reactivation were studied in detail in those cases with available serial enzyme measurements for at least 1 year after transplant. In patients undergoing allogeneic marrow transplant, donor serology was also considered (Table 3). HBsAg-positive patients: The allogeneic group consisted of nine patients; BMT donors were also HBsAg positive in four of them. Reactivation episodes were mild in three, severe in three (including two with HBsAg-positive donor in each group) and moderate in three. A stable hepatitis remission was documented in four cases (44%) (including one with a positive donor). Of 10 autologous patients, reactivation was mild in two, moderate in one and severe in seven. Nine (90%) showed a stable biochemical remission, including the seven cases with severe hepatitis: the probability of stable hepatitis remission was significantly higher in the autologous group (P ¼ 0.01). Anti-HCV-positive patients: Among 13 allogeneic cases considered for the analysis, six had a mild reactivation (including one patient with a HCV-positive donor), four had a moderate, and three a severe hepatitis exacerbation. Stable biochemical remission occurred in seven of them, including the patient with the anti-HCV-positive donor. In the autologous group, 13 patients were studied: reactivation was mild in nine, moderate in two and severe in two. A stable biochemical remission was documented in six cases. Among HCV-infected patients, the probability of hepatitis resolution was therefore higher (autologous 48% vs allogeneic 67%), but not significantly so (P ¼ 0.99) in the allogeneic setting.

Resolution of HBV infection Of the 15 HBsAg-positive patients unergoing allogeneic BMT, one (7%) cleared the antigenemia over time; two out of 17 cases (12%) with available serologic follow-up did so in the autologous group.

Table 3 Severity and outcome of hepatitis reactivation following HSCT in patients with HBV and HCV infection No. patients

ALT: o200a

200–400

>400

10

2 (1)

1 (1)

7 (7)

4 5

2 (0) 1 (1)

— 3 (1)

2 (1) 1 (1)

13

9 (6)

2 (0)

2 (0)

1 12

1 (1) 5 (4)

— 4 (2)

— 3(1)

Type of infection HBV Autologous Allogeneic: Donor/patient +/+ /+ HCV Autologous Allogeneic: Donor/patient +/+ /+

ALT: normal values p42 U/l. Numbers in parentheses indicate the number of patients with subsequent persistent normal values of ALT.

a

299

Discussion The risk of severe hepatic complications after stem cell transplantation is thought to be increased in the presence of pretransplant HBV or/and HCV infection and such condition has been considered a contraindication to performing these procedures.2 The magnitude of such a risk, in the contest of autologous and allogeneic HSCT, has not yet been precisely defined. We therefore studied a large series of HBV- or HCVinfected patients who underwent HSCT in Italy between 1996 and 2000. Fatal liver failure occurred in 3% of HBsAg-positive patients, and in 8% of anti-HCV-positive patients. These rates are not significantly different between the two groups and suggest that additional risk factors for hepatic complications after HSCT should be taken into consideration. When HBV- and HCV-positive patients were compared, some interesting differences in the ALT profiles following autologous and allogeneic HSCT were observed. In HCV-positive cases, ALT elevation was more frequent, severe and protracted following allogeneic grafting compared to autologous transplantation. Interestingly, all HCV-positive patients showed post-transplant hepatitis reactivation, characterised by a sharp enzyme elevation during the first year (Figure 4). These episodes were not clinically related to acute or chronic GVHD. When the course of reactivation was benign, recovery from liver disease was more frequently seen with allogeneic compared to autologous HSCT. However, it has to be noted that these interesting observations should be considered with caution, as they are derived from data obtained retrospectively. Other factors may influence the profile of liver disease besides GVHD, such as drug toxicity, immune suppression, donor immunity or other infectious agents. Indeed, a prospective study, also including quantitative viraemia, tests for other viruses and histologic evaluation is in progress. On the other hand, in HBV-infected patients, liver disease was more severe following autologous rather than allogeneic HSCT, suggesting that in these patients changes in the virus–host interaction induced by immune restoration had a marked effect on the activity and severity of liver damage. These results are likely to reflect the natural course of HBV infection following HSCT, considering that they were obtained retrospectively, and none of these patients was treated with prophylactic or therapeutic measures, such as Lamivudine (alone or in combination with anti-HBs immunoglobulins), as was recently the care in some studies.15–17 In conclusion, this study defines the actual risk of severe liver disease after allogeneic and autologous HSCT in HBV- and HCV-infected patients and describes not only the severity but also the possible resolution of liver disease in these cases. Our results also indicate the need for further studies to identify the best approach for HBV- and HCVinfected patients who are in need of HSCT. The importance of immune response in promoting and sustaining liver disease must be taken into account, especially when nonmyeloablative conditioning regimens, based on less

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toxic but intensely immunosuppressive protocols, are administered, both in the autologous and the allogeneic setting.

Acknowledgements We are grateful to the following GITMO Members and Centres contributing patients to the Study: (1) G Meloni, G Arcese, Dip. Biol cellulari e Ematologia, Univ ‘La Sapienza’ Roma; (2) I Majolino, Div. Ematologia e TMO, Osp. San Camillo, Roma; (3) G De Rosa, C Selleri Div. Ematologia, Univ. ‘Federico II’, Napoli, (4) S Cesaro, Clinica Oncoematologia Pediatrica e Centro Leucemie Infantili, Padova; (5) EP Alessandrino, Dip. Ematologia e TMO, Policlinico S Matteo, Pavia; (6) C Cesana, Istituto Clinico Humanitas, Rozzano, Milano; (7) V Cassibba, Ematologia e TMO, Osp. Generale Regionale Bolzano; (8) IM Liberati, Med. Int e Scienze Oncologiche, Policlinico Monteluce, Perugia; (9) A Palmas, Div. Ematologia Osp. S Francesco, Nuoro; (10) L Tasso, Div. Malattie Infettive, Ist. G Gaslini, Genova; (11) F Narni, Sez. Emato-Oncologia, Univ. Modena; (12) E Pogliani, Ematologia, Osp. S Gerardo, Univ. MilanoBicocca, Monza (Mi); (13) A Rovelli, Emat. Pediatrica e TMO, Osp. S. Gerardo, Univ. Milano-Bicocca, Monza (Mi) (14) E Morra, P Marenco, Ematologia e TMO, Osp. Niguarda, Milano; (15) A Bacigalupo, Dip. Ematologia, Osp. S Martino, Genova; (16) R Raimondi, div. Ematologia, Osp. S Bartolo, Vicenza; (17) C Bergonzi, Sez. Ematologia e TMO, Medicina II, Cremona; (18) G Irrera, Osp. ‘Bianchi-Melacrino-Morelli’, Reggio Calabria; (19) S Ceppi, Oncoematologia Pediatrica, Osp. Silvestrini, Perugia; (20) G Bandini, Ist. Ematologia ‘Seragnoli’, Osp. S. Orsola, Bologna. Partially supported by a grant of AIRC (Associazione Italiana Ricerca Cancro).

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