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Bone Marrow Transplantation (2007) 40, 1055–1062
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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 Université 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
1056
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
Risk factors for fatal infections after HSCT
A Bjorklund et al
1057
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
Risk factors for fatal infections after HSCT
A Bjorklund et al
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.
Risk factors for fatal infections after HSCT
A Bjorklund et al
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
Risk factors for fatal infections after HSCT
A Bjorklund et al
1060
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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