Bone Marrow Transplantation (2005) 36, 897900

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The benet of inuenza vaccination after bone marrow transplantation

CM Machado1,2, MRA Cardoso3, IF da Rocha2, LSV Boas1,2, FL Dulley2 and CS Pannuti1
1

Virology Laboratory (LIM 52-HCFMUSP) of Instituto de Medicina Tropical de Sao Paulo, Sao Paulo, Brazil; 2BMT Program,
Discipline of Haematology, University of Sao Paulo Medical School, Sao Paulo, Brazil; and 3Department of Epidemiology, University
of Sao Paulo School of Public Health, Sao Paulo, Brazil

Summary:
Inuenza vaccine is recommended yearly for recipients
after the sixth month of BMT. Although a higher risk of
complications of inuenza is expected to occur in BMT
patients, no study has addressed the clinical efcacy of
inuenza vaccination in this setting. Focusing on the
clinical benets of inuenza vaccination, we evaluated
the risk factors for inuenza infection in a cohort of 177
BMT recipients followed up for 1 year. Inuenza was
diagnosed in 39 patients. Multivariate analyses showed
that seasonal exposure and more aggressive conditioning
regimens were independently associated with increased
risk for inuenza. Inuenza vaccination and steroid use
showed a protective role. Of the 43 patients who had
received BMT longer than 6 months, 19 were vaccinated
(compliance rate 44.2%) and vaccine efcacy was 80%.
We conclude that inuenza vaccination plays an important
role in protecting BMT recipients against inuenza and all
efforts should be made to ensure good compliance with
vaccination.
Bone Marrow Transplantation (2005) 36, 897900.
doi:10.1038/sj.bmt.1705159; published online 19 September
2005
Keywords: inuenza; risk factors; vaccination; compliance

Inuenza continues to cause annual worldwide epidemics

and a higher risk of complications, such as inuenza
pneumonia, are expected to occur in transplant patients.
Historically, the incidence of inuenza pneumonia in BMT
recipients has varied from 9.5 to 75% in different studies.14
Vaccination is one of the strategies currently available
for the control of inuenza and its complications in this
setting. The effectiveness of inuenza vaccine depends
primarily on the age and immunocompetence of the
vaccine recipient and the degree of similarity between
the viruses in the vaccine and those in circulation. When the

Correspondence: Dr CM Machado, Virology Laboratory (LIM 52HCFMUSP) of Instituto de Medicina Tropical de Sao Paulo, University
of Sao Paulo, Av. Dr. Eneas de Carvalho Aguiar, 470, Sao Paulo,
SP 05403-000, Brazil; E-mail: clarimm@usp.br
Received 26 October 2004; accepted 3 August 2005; published online 19
September 2005

vaccine and circulating viruses are antigenically similar,

inuenza vaccine is expected to prevent inuenza illness in
approximately 7090% of healthy persons aged less than
65 years.5
In HSCT recipients, inuenza vaccination studies have
focused on serological response end points and have
showed a poor response in patients vaccinated within 6
months of transplantation.6 Therefore, inactivated inuenza vaccine has been recommended annually for patients
after the sixth month of transplantation.68
The high rate of inuenza infections observed in our
BMT program9 raised concerns about the efcacy of
inuenza vaccine and also about patient compliance with
inuenza vaccination. Thus, we retrospectively reviewed
vaccination records to evaluate the risk factors for
acquiring inuenza, patient compliance with yearly
inuenza vaccination and the efcacy of inuenza vaccine
from the perspective of clinical response end points.

Patients and methods

Patients and RV diagnosis
A total of 177 BMT recipients, followed up at the BMT
Program of the University of Sao Paulo Medical School,
with respiratory symptoms and at least one nasal wash
(adult patients) or nasal aspirate (children) taken over a
1-year interval were evaluated. Samples were routinely
taken from symptomatic patients only. A total of 775
samples were taken, mean 4.3 (119) per patient. Inuenza
was diagnosed by direct immunouorescence assay
(Imagens DAKO, Cambridgeshire, UK) according to the
manufacturers instructions.
To access the risk factors for acquisition of inuenza, the
following variables were retrospectively reviewed from
patients charts: seasonal exposure, time after transplant,
inuenza vaccination status and steroid therapy at the time
of sample collection. Patient characteristics are shown
in Table 1.

Definitions
Seasonal exposure to inuenza viruses was categorized
as high or low according to the period when the nasal
wash sample was taken (FallWinter or SpringSummer,
respectively).

Clinical efficacy of influenza vaccine

CM Machado et al

898

Vaccination policy

Results

After the 6th month of BMT, inuenza vaccination is

offered annually to all patients during six consecutive
months starting in the beginning of Fall. Patients received
one dose of inuenza vaccine (A/New Caledonia/20/99
(H1N1), A/Moscow/10/99 (H3N2), B/Sichuan/379/99) and
were asked to report any side effect by phone call or
directly to the pharmacist or nurses assisting the BMT
program.

Statistical analysis
Vaccine efcacy (VE) was determined by the formula:
VE ((r0r1):r0); where r0 is the rate in unvaccinated and r1
the rate in vaccinated patients. Compliance with inuenza
vaccination was evaluated in 43 patients transplanted
longer than 6 months, where vaccination had been advised.
Risk factors for acquisition of inuenza infection were
evaluated by univariate and multivariate analysis. The
following variables were analyzed: gender, donor match,
underlying disease, conditioning regimen, seasonal risk
(high or low), time after transplant (o180 days or X180
days), graft-versus-host disease, steroid therapy, and
inuenza vaccination status. Variables showing a P-value
o0.20 on univariate analysis were included in the multivariate model. Pp0.05 was considered statistically signicant. Statistical software SPSS version 11.0 was used for
the analysis.
Table 1

Patient characteristics

Variable

118 (71.2)

Male sex

104 (58.7)

Seasonal risk
High

119 (67.2)

Time after BMT

o180 days
X180 days
Conditioning
Busulfan+Melphalan
Busulfan+Cyclophosphamide
TBI based
Other

No. with
influenza
83
22
32
40

(46,9)
(12.4)
(18.1)
(22.6)

Vaccinated
n = 19

Unvaccinated
n = 24

12

Inuenza vaccine statusa

Vaccinated

19 (44.2)

Steroid therapy at sample collection

With steroid

51 (28.8)

(27.7)
(25.4)
(12.4)
(12.4)
(11.9)
(10.2)

25

Figure 1 Study algorithm.

Table 2
model
49
45
22
22
21
18

Bone Marrow Transplantation

> 6m BMT
n = 43

< 6m BMT
n = 134

134
43

Underlying diseases
Chronic myelogenous leukemia
Acute leukemia
Severe aplastic anemia
Non-Hodgkins lymphoma
Multiple myeloma
Other

In 43 patients after the sixth month of BMT.

177 pts

Number of patients (%)

Type of BMT
Allogeneic

Inuenza A or B was diagnosed in 39 patients (nine

autologous, 30 allogeneic BMT recipients).
In all, 134 patients were within the rst 6 months after
BMT and were not eligible for inuenza vaccination. Of
these, 25 (18.6%) acquired inuenza. The remaining 43
patients had undergone BMT longer than 6 months
previously and were, therefore, eligible to receive inuenza
vaccine (Figure 1). In total, 19 patients were vaccinated and
two acquired inuenza (r1 0.10). Compliance with vaccination was 44.2%. Among the remaining 24 unvaccinated
patients (due to low compliance with the vaccination
program), inuenza was diagnosed in 12 (r0 0.50). VE
was 80% ((r0r1):r0).
On univariate analysis, patients with respiratory symptoms during the inuenza season and those within the rst
6 months of transplantation were more likely to acquire
inuenza infection (P 0.001 and 0.056, respectively).
Considering only the 43 patients after the sixth month of
BMT, inuenza vaccine signicantly reduced the occurrence of inuenza in this group (P 0.015).
On multivariate analysis, seasonal exposure and conditioning regimens including TBI and melphalan/busulfan
were independently associated with increased risk for
inuenza, whereas inuenza vaccine and steroid therapy
showed a protective role (Table 2). Gender, BMT type,
underlying disease and graft-versus-host disease were not
associated with risk of inuenza infection.

Risk factors for inuenza after BMT in a multivariate

Variables

OR

95% CI

Lower Upper
Seasonal exposure
Vaccination status

1.753 5.772 1.724 19.325 0.004

2.568 0.077 0.014 0.432 0.004

Conditioning
TBI based
1.827 6.218
Busulfan+Melphalan
2.121 8.337
Busulfan+Cyclophosphamide
1.725 5.610
Steroid therapy
0.969 0.379
Time after BMT
0.826 2.284

1.047 36.929 0.044

1.601 43.416 0.012
0.800 39.350 0.083
0.151 0.956 0.040
0.779 6.699 0.133

Clinical efficacy of influenza vaccine

CM Machado et al

899

Discussion
As expected, BMT recipients who enter respiratory virus
season each year are at great risk of acquiring inuenza
infection, as observed in this study by univariate and
multivariate analyses. Similar ndings were reported by
Nichols et al,10 who recently observed an increased risk of
inuenza in patients transplanted during the inuenza
season, in those with advanced disease and in females.
Patients conditioned with more aggressive regimens such as
busulfan and melphalan and those including TBI were also
more likely to acquire inuenza in the present series. This
observation may reect the degree of immunosuppression
and/or the impact of those regimens on the integrity of
respiratory mucosae and local immunity.
Of note on multivariate analyses, steroid use and
inuenza vaccination showed as independent factors preventing the acquisition of inuenza.
After adjusting for the time after transplant, the apparent
protective role of steroid use in the acquisition of inuenza
is a surprising result. However, other authors have recently
observed that the use of corticosteroids reduces the risk
of progression of inuenza from the upper to the lower
respiratory tract. In that series, the authors hypothesized
that steroids may promote a salutary immunomodulation
in some circumstances.10 Thus, in opposition to the
deleterious effects of aggressive conditioning regimens,
which promoted the risk for inuenza infection in the
present study, the use of corticosteroids could possibly
restore part of respiratory mucosa integrity and improve
local immunity. More studies are needed to conrm these
ndings.
The benecial effect of inuenza vaccination observed
in the present study encourages preventive policies in
this population. Inuenza vaccination studies in BMT
recipients have focused on serological end points and
showed poor serological responses, irrespective of the
source of stem cells (marrow or peripheral blood).6,7
A longer interval between BMT and inuenza vaccination
has been associated with a better serological response,
vaccination of BMT recipients before the sixth month
of transplantation being totally ineffective.6 Seroconversion
is also more likely to occur in autologous BMT or
PBSCT in comparison to allogeneic BMT or PBSCT
recipients.7
Although no previous study has addressed the clinical
efcacy of inuenza vaccine, yearly vaccination of
BMT recipients is recommended in most centers, before
respiratory virus season. In the present study, serological
response was not assessed. However, considering only
patients at higher seasonal risk and transplanted longer
than 6 months, we observed an 80% rate of clinical efcacy
of inuenza vaccine, similar to the rates observed in healthy
adults under 65 years old. Unfortunately, regardless of
having an active long-term follow-up program, we also
observed a surprisingly low compliance with inuenza
vaccination (44.2%) in our BMT recipients.
Since 2000, the number of inuenza vaccine doses per
1000 persons in Brazil has risen to levels similar to those in
many Western Europe countries.11 This increase may reect
the successful efforts of the Brazilian Health Ministry in the

vaccination campaign for the elderly, but not in other highrisk populations. Indeed, worldwide, health-care workers
(HCWs) compliance with inuenza vaccination has been
disappointing, varying from 2 to 36% in different series.12
Perhaps the greatest misconception about the vaccine
is that it may actually cause the recipient to acquire
inuenza.12 This belief may inuence the HCWs willingness to counsel patients about vaccination.
Information on the clinical efcacy of inuenza vaccine
provided by the present study should encourage BMT
centers to revise their policies on inuenza control and
exhort their HCW not only to accept the vaccine but also
to inform and guide patients and family caregivers to be
vaccinated.
It is important to highlight that a substantial number
of BMT recipients in the present study (n 76) were within
6 months of transplantation and around 28% of them
acquired inuenza. Since vaccine effectiveness is limited
(if any) during this period, other strategies such as
vaccination of contacts and pre-emptive or prophylactic
therapy should be considered especially during inuenza
A and/or B outbreaks, as recommended to other high-risk
patients.13 Pre-emptive oseltamivir seemed to play
some role in protecting patients from developing inuenza
pneumonia,9,10 but controlled studies are needed to conrm such data. Postponing BMT is an alternative to be
considered on an individual basis. Other strategies such as
donor vaccination deserve further investigation.
We concluded that inuenza vaccination plays an
important role in the control of inuenza in BMT recipients
and all efforts should be made to ensure compliance with
this policy.

Acknowledgements
We thank Drs AVA Mendes, MCA Macedo, RL Silva and RS
Saboya from the BMT Program for providing excellent patient
care, and Dr MH Lopes, from the Centro de Referencia para
Imunobiologicos Especiais (CRIE), University of Sao Paulo
Medical School.

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