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ORIGINAL ARTICLE

Risk factors for fatal infectious complications developing late after allogeneic stem cell transplantation A Bjorklund1, J Aschan1,3, M Labopin2, M Remberger3, O Ringden3, J Winiarski4 and P Ljungman1 1 Hematology Center, Karolinska University Hospital, and Department of Medicine, Karolinska Institute, Stockholm, Sweden; 2The European Group for Blood and Marrow Transplantation Acute Leukemia Working Party, Hopital Saint-Antoine Asistance Publique Hopitaux de Paris and Universite´ Paris 6, Pierre et Marie Curie, Paris, France; 3Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, and Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden and 4Department of Pediatrics, Karolinska University Hospital, and Department of Clinical Science, Intervention and Technology, Karolinska Institue, Stockholm, Sweden

Infectious complications remain a major problem contributing to significant mortality after hematopoietic allogeneic stem cell transplantation (HSCT). Few studies have previously analyzed mortality due to late infections. Forty-four patients dying from an infectious complication were identified from a cohort of 688 consecutive patients surviving more than 6 months without relapse. A control group of 162 patients was selected using the year of HSCT as the matching criterion. Out of 44 patients, 30 (68%) died from pneumonia, 7/44 (16%) from sepsis, 5/44 (11%) from central nervous system infection and 2/44 (4.5%) from disseminated varicella. The cumulative incidences of different types of infection were 1.6% for viral, 1.5% for bacterial and 1.3% for fungal infections and 0.15% for Pneumocystis jirovecii pneumonia. The majority (66%) of the lethal infections occurred within 18 months after HSCT. Acute GVHD (relative risk (RR): 7.19, Po0.0001), chronic GVHD (RR: 6.49, Po0.001), CMV infection (RR: 4.69, P ¼ 0.001), mismatched or unrelated donor (RR: 3.86, P ¼ 0.004) and TBI (RR: 2.65, P ¼ 0.047) were independent risk factors of dying from a late infection. In conclusion, infections occurring later than 6 months after HSCT are important contributors to late non-relapse mortality after HSCT. CMV infection or acute GVHD markedly increase the risk. Bone Marrow Transplantation (2007) 40, 1055–1062; doi:10.1038/sj.bmt.1705856; published online 24 September 2007 Keywords: hematopoietic stem cell transplantation; late complications; infection; risk factors; mortality

Correspondence: Dr A Bjorklund, Hematology Center, M54, Huddinge, Institute of Medicine, Karolinska University Hospital, Stockholm S-14186, Sweden. E-mail: [email protected] Received 1 May 2007; revised 9 August 2007; accepted 9 August 2007; published online 24 September 2007

Introduction The procedure of hematopoietic allogeneic stem cell transplantation (HSCT) has evolved in recent decades. Great progress has been made in improving the outcome by better matching of donor and recipient, prevention of GVHD and supportive care. Infectious complications are still a major problem contributing to transplantationrelated mortality. In a recent paper, Gratwohl et al.1 showed that the risk of death from infection has been reduced in recent years but that it does occur for several years after HSCT.1 However, the risk factors regarding death from infection in long-term survivors have not been thoroughly studied. The main causes of late death in HSCT recipients are leukemic relapse and chronic GVHD. Socie et al.2 showed that 6% of patients dying more than 2 years after HSCT died from infection, excluding those who had severe chronic GVHD.2 The epidemiology and outcome of early infections after HSCT have been well described earlier.3–6 Thus, the aim of this study was to determine risk factors for fatal infections occurring later than 6 months after allogeneic HSCT.

Patients and methods Cases and controls A total of 938 patients underwent HSCT from 1976 to 2002 at Karolinska University Hospital, Huddinge (formerly Huddinge University Hospital), of whom 250 died during the first 6 months. Among the surviving 688 consecutive patients, 44 died from an infectious complication (cases). The charts were reviewed, and information registered before the end of 2003 was included. A control group of 162 patients (3–4 controls per case, depending on availability) was derived from the remaining population, using the year of HSCT as the matching criterion. Data on the controls were collected until the time of relapse, until death from causes other than infection, until the time of ‘lost to follow-up’ or until the end of 2003, depending on which event occurred first. The mean

Risk factors for fatal infections after HSCT A Bjorklund et al

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follow-up period was 1.0 year (195–4865 days) among the cases and 8.9 years (217–8782 days) in the control group. Patients who experienced relapse of their original disease were excluded unless the relapse had been well controlled by donor lymphocyte infusions. Patients suffering from severe GVHD were included only if the infection significantly impacted the outcome, that is, if the GVHD was in a stable phase and the infection was clinically evident and led to rapid deterioration of the patients condition. An infection occurring later than 6 months after transplantation was defined as a late infection. The following definitions of fatal infections were used: the infection had to be clinically evident and ongoing at the time of death. Pneumonia was defined as symptoms of a lower respiratory tract infection (fever, cough) combined with hypoxia, or a positive chest X-ray or computed tomography scan. Sepsis was defined as a positive blood culture together with fever or a septic shock. A central nervous system infection was defined as symptoms or signs compatible with a central nervous system infection combined with a positive computed tomography scan, an autopsy finding or a test result in spinal fluid typical of an infectious cause (positive culture, positive antigen test or a test for viral DNA).

Conditioning regimens The SCTs were performed as described previously.7–9 Nearly all patients with malignancies were treated by means of myeloablative conditioning consisting of either 10 Gy TBI, 12 Gy fractionated TBI (3 Gy/day on 4 consecutive days) or Bu at 4 mg/kg/day on 4 consecutive days, in combination with Cy at 60 mg/kg/day for 2 consecutive days. In patients receiving unrelated donor transplants, antithymocyte globulin (ATG) or muromonab CO3 (OKT-3) was added before HSCT. Patients with severe aplastic anemia received Cy at 50 mg/kg on 4 consecutive days and after 1988, in combination with ATG at 2–5 mg/kg for 2–5 days. Patients with metabolic disorders were given Cy at 2 g/m2 in combination with Bu at 80 mg/m2 or TBI.9 The standard non-myeloablative regimen was fludarabine (30 mg/m2/day) for 6 days, combined with Bu at 4 mg/kg/day for 2 days and ATG (2 mg/kg/day) for 4 days, but other regimens were also used.8 Prophylaxis and therapy of GVHD Several different protocols were used for GVHD prophylaxis during the study period. The most commonly used regimens were monotherapy with either Mtx or cyclosporin,10 a combination of cyclosporin and Mtx, or T-cell depletion with monoclonal antibodies.11 Acute and chronic GVHD were diagnosed on the basis of clinical symptoms and verified by study of biopsy specimens (skin, liver, gastrointestinal tract or oral mucosa). Acute GVHD was graded on a scale of 0 (absent) to IV (severe), according to previously published criteria.12,13 The severity of chronic GVHD was defined as mild, moderate or severe, according to previously published criteria14 and was classified by the treating physician. Bone Marrow Transplantation

Acute GVHD grade I was treated with prednisone at 2 mg/kg/day and when possible gradually tapered after 1 week of treatment. In severe cases, ATG, methylprednisolone, Mtx or psoralen in combination with UV light A (PUVA) was added, alone or in combination. Chronic GVHD was treated according to several different strategies, depending on severity and clinical appearance. The strategies included treatment with prednisone, cyclosporin and azathioprine,15 PUVA,16 thalidomide17 or extracorporeal photopheresis.18

Diagnosis, prophylaxis and treatment of infections Antimicrobial prophylaxis was given as described previously.8 Pneumocystis prophylaxis (cotrimoxazole or pentamidine) was given to all patients for 6 months, and the treatment was prolonged if chronic GVHD occurred. Penicillin V was added to pentamidine in patients with chronic GVHD. Fluconazole and acyclovir were given on individual basis. Vaccinations of long-term survivors were given as described previously.19 Over the study period, various CMV diagnostic monitoring techniques have been used. Before 1988, CMV infection was detected by a standard viral culture technique. Between 1988 and November 1991, a rapid isolation technique20 was used.21 From December 1991, a semiquantitative leukocyte-based PCR technique was used22 and after November 2000 a quantitative, real-time PCR method.23 The strategy of preemptive therapy with either ganciclovir or foscarnet for patients with CMV detected in the blood has been used since 1990.24,25 Cytomegalovirus viremia, infection, disease, reactivation and acute infection were defined according to Ljungman et al.26 Patients were treated for CMV infection as previously published.27,28 Obliterative bronchiolitis Definitive diagnosis of obliterative bronchiolitis is based on histological examination of lung biopsies, and this was not routinely carried out. In this study, we chose to estimate the severity of respiratory dysfunction (RD) on the basis of pulmonary function tests and clinical symptoms. Patients with values of mild obstructive disease in combination with clinical symptoms and all patients with moderate to severe obstructive or restrictive dysfunction were classified as having RD. Only patients who developed their dysfunction after HSCT were taken into consideration. The routine follow-up of HSCT patients included pulmonary function tests before transplantation, at 3, 6 and 12 months, and then yearly up to 5 years. Statistics Patient-, disease- and transplant-related variables of cases and controls were compared, using the w2 statistic for categorieal variables, and the Mann–Whitney test for continuous variables. The following factors were evaluated: donor (matched or mismatched family/unrelated), conditioning regimen (TBI, yes/no), ATG/OKT-3 (yes/no), serological CMV status of the donor and recipient (positive/negative), age (as a continuous variable), CMV infection (yes/no), respiratory impairment (yes/no), acute


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GVHD (grades II–IV vs 0–I), chronic GVHD of any grade (yes/no) and severe chronic GVHD (yes/no). Factors differing in distribution between the two groups with a P-value o0.10 and factors associated with fatal infectious complications in univariate analysis were included in the final models. Associations of each potential prognostic factor with fatal infectious complications were evaluated by using the proportional subdistribution hazard regression model of Fine and Gray29 in a competing risks setting, death due to relapse or other causes being treated as a competing event. To study the impact of chronic GVHD as a time-dependent variable, multivariate analysis was performed using Cox’s proportional hazards model including a time-dependent variable. All analyses were stratified according to the year of transplantation, used to match cases and controls. All P-values are two-sided with type I error rate fixed at 0.05. Statistical analyses were performed with SPSS (SPSS Inc., Chicago, IL, USA) and Splus (MathSoft Inc., Seattle, WA, USA) software packages.

Results Pretransplant characteristics of cases and controls Comparison of the pretransplant characteristics of the patients and controls is shown in Table 1. The cases had more often been conditioned with TBI than the controls and had more often received grafts from mismatched or unrelated donors. Peripheral stem cell grafts, reduced conditioning and asplenia due to splenectomy were equally common in the two groups. Types of fatal infection in the cases Forty-four of the 688 patients (6.4%) surviving for more than 6 months died from infection. Details of the fatal infections occurring in the cases are shown in Table 2. Thirty-one of 44 patients (70%) developed their fatal infection within 2 years and 39 (89%) within 5 years after HSCT (Figure 1). Thirty of the cases (68%) died from pneumonia, representing 30 of all 688 (4.4%) patients surviving for 6 months after HSCT. A pathogen could be identified in 17/30 (57%) of the cases of pneumonia. All patients who developed fatal pneumonia later than 14 months after HSCT had RD (data not shown). Seven patients (16% of cases; 1.0% of all patients) died from sepsis, five (11%; 0.7%) from central nervous system infection and two from disseminated varicella infection. The time after HSCT associated with the different types of fatal infection is shown in Figure 2. All fungal infections were diagnosed during the first year after HSCT. Most viral infections (9 of 11 cases) and all CMV pneumonias (5 cases) were diagnosed within 15 months. Four of the five lethal bacterial infections developing later than 9 months after HSCT occurred in patients without chronic GVHD or immunosuppression. The spectrum of lethal infections did not change over time (data not shown). Post transplant complications in cases and controls Forty-seven of the 162 controls (29%) died later than 6 months after HSCT. The most frequent cause of death

Table 1

Pretransplant characteristics of the study population

No. Median age (years)

Cases

Controls

P-values

44 32 (2–56)

162 23 (0.5–60)

0.12

13 6 17 1 3

40 27 39 9 7

2 1 1

6 17 17

8 10 11 15

30 39 44 58

Diagnosis ALL AML CML Lymphoma and CLL MDS or myeloproliferative disorder Myeloma Severe aplastic anemia Other Year of transplant 1976–1985 1986–1990 1991–1995 1996–2002 Reduced-intensity conditioning TBI Peripheral stem cell graft Previous splenectomy

(3) (64) (16) (3)

0.64 0.02 0.24 0.64

22 (50) 22 (50)

109 (67) 53 (33)

0.03

15 (32)

47 (29)

CMV serological status (patient) Negative 11 (25) Positive 33 (75)

56 (35) 106 (65)

0.23

64 (40) 95 (60)

0.52

Donor type HLA-identical sibling Family mismatch or unrelated donor Unrelated donor

CMV serological status (donor) Negative Positive

2 36 4 2

(5) (82) (9) (5)

5 103 26 5

15 (35) 27 (65)

Abbreviation: MDS ¼ myelodysplastic syndrome.

(27/47) among the controls was recurrence of the original disease. Other causes included respiratory insufficiency (7/47), chronic GVHD (3/47), cardiac arrest/failure (3/47), secondary malignancy (2/47) and other (5/47) (thrombotic thrombocytopenic purpura (TTP), suicide, unknown, degenerative neurological disease, hepatic failure). Comparison of post transplant complications is shown in Table 3. The cases were more likely to have had CMV infection, acute GVHD grades II–IV, RD and either ongoing or previous chronic GVHD than the controls. Thirty-six patients (80%) of the cases had ongoing immunosuppressive therapy in one of the following combinations at the time of death: prednisolone or cyclosporine (16/44), prednisolone and cyclosporine (16/44), 42 immunosuppressive (IS) drugs (3/44).

Analyses of risk factors In univariate competing risk factor analysis of fatal late infections, the strongest risk factors were acute and chronic GVHD, and CMV disease (Table 4). Two multivariate models were constructed. In a competing risk model (excluding chronic GVHD), acute GVHD (relative risk (RR): 6.7; 95% confidence interval (CI): 3.7–12; Bone Marrow Transplantation


1058 Types of late fatal infection

Table 2

Viral

Agent

Pneumonias

No. Cumulative (44 cases) incidence (%) (688 patients)

Unidentifiable Aspergillus CMV Adenovirus Influenza A Mycobacterium tuberculosis Pneumocystis jirovecii Pneumococcus Klebsiella Total

Sepsis

13 6 5 1 1 1 1 1 1 30

Bacterial

Unknown

4.4

1

2 1 1 1 1 1 7

CNS infection Aspergillus Human T-cell leukemia virus-1 Neisseria meningitidis Streptococcus pneumoniae Herpes simplex Total

1 1 1 1 1 5

0.7

Other

2 2

0.3

4

6

8

10

12

14

Figure 2 Time points of different groups of lethal infection developing later than 6 months after HSCT. Infections divided into four groups: viral (11 cases), fungal (8 cases), bacterial (10 cases) and unknown (14 cases). The only case caused by Pneumocystis jirovecii pneumonia occurring after 8 months is not included. HSCT ¼ hematopoietic allogeneic stem cell transplantation

1.0

Table 3

Post transplant complications in cases and controls

Complication Acute GVHD Grades 0–I Grades II–IV

44 40

Number of patients

2 2

Years after transplantation

Pseudomonas Klebsiella Streptococcus pneumoniae Staphylococcus aureus Candida Unknown Total

Varicella zoster Total

Fungal

Cases (%)

Controls (%)

P-values

24 (55) 20 (45)

146 (90) 16 (10)

o0.0001

CMV infection CMV disease Treatment with donor lymphocyte infusion Respiratory dysfunction

33 (75) 11 (25) 3 (7)

81 (50) 6 (4) 24 (15)

0.003 o0.0001 0.21

21 (48)

46 (28)

0.02

Chronic GVHD No Mild Moderate Severe

4 13 13 14

65 63 26 8

(9) (29) (29) (32)

(40) (39) (16) (5)

o0.0001

30

Discussion 20

10

0.5 1

2

3

4

5

6

7

8

9

10

11

12

13

14

Years

Figure 1

The solid curve represents the cumulative number of lethal infections developing later than 6 months after HSCT. HSCT ¼ hematopoietic allogeneic stem cell transplantation.

Po0.0001), CMV disease (RR: 4.2; 95% CI: 1.9–8.9; Po0.001) and the use of a mismatched or unrelated donor (RR: 2.9; 95% CI: 1.4–6.1; P ¼ 0.004) were significant risk factors for the development of a fatal infectious complication. A Cox model was also constructed with chronic GVHD included as a time-dependent variable (Table 4). Here, the same risk factors as in the competing risk analysis (severe chronic GVHD and the use of TBI in the conditioning regimen) had a significant impact on the risk of late fatal infections. Bone Marrow Transplantation

Infections remain a threat to long-term survivors for many years after HSCT. This fits with previously published data.1,2,30,31 In our single center study, the cumulative incidences of different types of infection were 1.6% for viral, 1.5% for bacterial, 1.3% for fungal infections and 0.15% for Pneumocystis jirovecii pneumonia. Although directly comparable data are lacking, extrapolation of results from other studies indicates a similar pattern.1,30,32,33 The patients in the study were transplanted over a long time during which many developments in transplantation technology occurred such as the increasing use of unrelated donors and peripheral blood stem cells, better diagnostic methods for diagnosis of infection and introduction of new antibacterial, antifungal and antiviral agents. Furthermore, most were given myeloablative conditioning. On the other hand, the two largest cohorts both among cases and controls were identified during the two most recent periods and GVHD remains one of the major risk factors for late complications also today. Therefore, although there are limitations due to the time factor, we believe that our results are relevant also to today’s practice.


1059 Table 4 Univariate competing risk analysis of risk factors, comparing cases and controls, and multivariate analysis of risk factors of fatal late infectious complications (Cox model) Factor

RR

95% CI

P-values

Univariate analysis Median age Mismatch or unrelated donor vs HLA-identical sibling TBI ATG CMV-positive recipient CMV-positive donor CMV infection CMV disease Respiratory dysfunction Acute GVHD grades II–IV (vs 0–I) Moderate to severe chronic GVHD Chronic GVHD—not time-dependent

1.52 2.29 2.4 0.81 1.57 1.13 2.78 4.97 1.95 6.5 4.62 5.3

0.85–2.72 1.12–4.7 1.14–5 0.39–1.7 0.8–3.1 0.94–1.35 1.43–5.4 2.62–9.43 1.09–3.5 3.53–12 2.53–8.4 1.9–14.9

0.16 0.02 0.02 0.58 0.19 0.19 0.003 o0.0001 0.03 o0.0001 o0.0001 0.002

6.49 3.86 2.65 4.69

2.6–16.5 1.6–9.6 1.02–6.9 1.9–11.4

7.19

3.07–16.8

o0.0001 0.004 0.047 0.001 NS o0.0001

Multivariate analysis Moderate to severe chronic GVHD Mismatch vs match TBI CMV infection Respiratory dysfunction Acute GVHD grade XII

Abbreviations: ATG ¼ antithymocyte globulin; CI ¼ confidence interval; RR ¼ relative risk.

The risk of late death resulting from CMV was low (0.7%) compared with that reported in other studies. Although the various studies are not directly comparable, Boeckh et al.34 showed the frequency of CMV disease occurring more than 3 months after HSCT to be 17.8%, with a median time to diagnosis of approximately 6 months and a mortality rate in late CMV disease of 46%. Junghanss and Marr3 compared the risk of CMV disease in patients receiving standard or reduced-intensity conditioning (RIC) and showed that the risk of late CMV disease was higher in the reduced-intensity group, something that we were unable to investigate owing to the low number of RIC transplants in our study. Since late fatal infections are relatively rare events, it is important to know the predisposing risk factors in order to give appropriate prophylaxis to high-risk patients. Both acute and severe chronic GVHD were independent risk factors for late death caused by infections. The immune defects associated with chronic GVHD include delayed immune reconstitution of all lymphocytic subsets (B, T and NK cells)31,35 and impaired thymic and splenic function.36,37 These defects in combination with the ongoing immunosuppressive treatment in 80% of the patients could therefore explain the increased risk for developing a late fatal infection. Acute GVHD grades II–IV is strongly correlated to chronic GVHD.38–40 However, it was somewhat surprising when correcting for severe chronic GVHD that acute GVHD remained a strong predictive factor as regards late fatal infection, since Maury et al.31 have shown that patients with acute GVHD not followed by chronic GVHD have near normal immune reconstitution with only slightly lowered CD8 þ levels late after transplantation.31 One explanation for increased susceptibility to infection could be a persistent immune defect after high doses of steroids.41 Furthermore, use of a mismatched or unrelated stem cell

donor was an independent risk factor, showing that immunologic incompatibilities between donor and recipient influence immune reconstitution for a long time after HSCT. This finding is supported by other results showing delayed recovery of CD3 þ , CD4 þ and CD8 þ cell numbers as well as decreased T-cell proliferative responses31,42 in patients with non-sibling donors. Infection with CMV was also a predisposing factor as regards late death. CMV has been shown to suppress T cells, NK cells, macrophages, neutrophils and dendritic cells38,43–45 and is clinically associated with death in cases of bacterial and fungal infection.32,38,46 It was somewhat surprising, however, that the impact of a CMV infection lasts for such a long time after HSCT. Although several patients experienced repeated reactivation during the early phase after HSCT, we did not routinely monitor CMV for longer than 6 months after HSCT, so we do not know if the patients experienced repeated and/or prolonged CMV reactivation contributing to the long-term risk of fatal infections. Marr et al.32 speculate that the ability of CMV to increase the incidence of late aspergillus disease could be a marker of some unknown immunologic defect independent of ganciclovir-associated neutropenia or corticosteroid therapy.32 No mortality due to fungal infections was seen beyond 11 months after HSCT, indicating that a more profound immune defect would be required for such infections to occur. Death due to bacterial infections was seen at all time points. Nine of the ten patients dying from bacterial infections had received TBI. We show in the multivariate analysis that TBI is a risk factor as regards a late-occurring fatal infection (RR: 2.65). One possible explanation for this could be an increase in lung complications47 and another, the lifelong splenic impairment caused by TBI.48,49 Many patients developed the infection at home and were evaluated at their local hospitals where advanced Bone Marrow Transplantation


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diagnostic procedures such as bronchoscopy with bronchoalveolar lavage were frequently not available explaining a somewhat high number of pneumonias with unknown origin. RD was a risk factor in univariate but not multivariate analysis, suggesting interactions with other variables, most likely chronic GVHD and the use of TBI. However, all fatal cases of pneumonia occurring later than 14 months after HSCT were seen in patients with pulmonary dysfunction. We were unable to show an impact on late infectious disease mortality brought about by RIC or the use of PBSC transplantation. The number of RIC transplant patients among both the cases and the controls was low, limiting the power of the analysis. However, it has been shown that the risk of infectious disease mortality associated with RIC is most pronounced early after HSCT.3,50,51 The lack of impact of stem cell source (bone marrow vs peripheral blood) is somewhat in conflict with results from other studies showing an increased incidence of chronic GVHD after PBSC transplantation,52 resulting in a subsequent increase of late infections.53 The main aspect of the risk factors for late infectious death seems to be the impact on immune reconstitution. Several of the identified risk factors have previously been shown to be correlated. Acute GVHD increases the risk of CMV infection,54,55 the CMV viral load56 and subsequent chronic GVHD.38,40 The use of alternative donors increases the risk of CMV infection and acute GVHD. CMV infection has been associated with an increased risk of chronic GVHD,20,57,58 and chronic GVHD has been associated with late CMV infection.34 Despite these interactions, our results show that these factors have independent impacts on the risk of late death from infectious disease. The common theme of these risk factors is their impact on immune reconstitution showing that even early events might have far-reaching consequences. The main options in prophylaxis are vaccinations and antimicrobial chemoprophylaxis. Five of our patients died from infections potentially preventable by vaccination, and vaccination recommendations for long-term survivors have been published earlier.51,59 However, many of the most severely immunocompromised patients respond poorly to some vaccines such as pneumococcal polysaccharide and influenza vaccines.60,61 New vaccines such as the pneumococcal conjugate vaccine have been introduced that might induce better responses in high-risk patients, but additional studies are needed. Antimicrobial chemoprophylaxis is the other strategy for prevention. This includes use of potentially antibacterial, antiviral and antifungal agents. Antibacterial prophylaxis against pneumococcal infections is recommended, but its efficacy is limited by the rate of antibiotic resistance in the community.51 Prophylaxis against P. jirovecii pneumonia is generally recommended in patients with GVHD and seems to have been effective in our cohort, since the only P. jirovecii pneumonia-related fatality developed in a patient who had discontinued the prophylaxis. Two patients died from disseminated varicella zoster infection. Boeckh et al.54 recently showed that 800 mg acyclovir given b.i.d. for 12 months effectively prevented zoster reactivation. This is in contrast to the results of previous studies involving shorter prophylaxis,62 Bone Marrow Transplantation

and acyclovir prophylaxis should therefore be considered, at least in high-risk patients. The promising results with posaconazole in the prophylaxis of aspergillus infections,63 in particular, support the use of antifungal prophylaxis in high-risk patients such as those with severe chronic GVHD. The results of this study might be used to identify a subgroup of patients that might benefit from more intensive prophylactic measures, although additional studies are needed in particular including patients after RIC and those having received cord blood grafts.

Acknowledgements This study was supported by grants from The Stockholm Cancer Fund and from The Cancer and Traffic Injury Fund, Sweden.

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