ARTICLE
Auteur(s) : F
Lachenal1, C Sebban1, M
Duruisseaux1, P Biron1, J-Y Blay2,
H Ghesquières1
1Centre Léon-Bérard, department of haematology,
28, rue Laennec, 69008 Lyon, France
2Centre Léon-Bérard, department of medical
oncology, 28, rue Laennec, 69008 Lyon, France
Article reçu le 8 Decembre 2009, accepté le 4 Mars 2010
Introduction
Patients with haematologic malignancies are at special risk of
influenza infection because of constitutive immunodeficiency,
intensified by immunotherapy and chemotherapy, and usually old age.
Mortality of influenza is increased as well: death from
influenza-related infections can occur in 8.9% of patients with
haematologic cancer hospitalized for such, which is 10 times
more than in the general population [5].
Vaccination against influenza in patients with haematologic
malignancies has long been a matter of clinical uncertainty.
Because of impaired humoral and cellular immunity, the
immunological response to influenza vaccination was expected to be
significantly less effective than in healthy people. Nevertheless,
most of recent studies demonstrated the immunogenicity and the
tolerance of the vaccine in this population and did not reveal any
exacerbation of the haematologic disease after vaccination [1, 4,
6, 12, 13]. However practices are still heterogeneous and there are
no established routines in France regarding the influenza
vaccination of these patients, despite recommandations of the
national health insurance agency. The main goal of this study was
to analyse vaccinal practices in a single centre. We carried out a
prospective monocentric study to evaluate influenza vaccine rate,
factors influencing vaccination and its clinical efficiency in
patients with haematologic malignancies.
Patients and methods
All patients attending the outpatient clinic or hospitalized in our
department for haematologic malignancies between 1st and
31 January 2008 were considered for the study.
A standardized questionnaire was proposed in order to collect
informations concerning influenza vaccination. To estimate clinical
efficiency of influenza vaccination, patients were then observed
prospectively during the epidemic season to May, 2008; episodes of
severe respiratory infection, flu and flu-like syndroms were
collected. Correlation between vaccinal policy and occurence of
infections was searched.
Two-hundred patients were finally included (table 1). The median age was 58.3 (range 18-87);
40% of patients were older than 65 y and could benefit as
patients with underlying chronic disease from a free influenza
vaccine after information by French national health insurance
agency. Most patients (96%) suffered from lymphoid malignancies.
The treatment was ongoing in 48.5% of cases, using aplasia-inducing
chemotherapy regimens (expected to induce neutropenia of < 0.5 x
109/l) in 27.5%, rituximab in 27.5% and/or steroids in
33.5%. One quarter of patients disclosed one or several
comorbidities and 14.5% had a a past medical history of autologous
stem cell transplantation. Lymphopenia was present in 29.7% of
cases and hypogammaglobulinemia in 21.7%.
Written informed consent was obtained for each patient.
Table 1 Patients characteristics.
|
No of patients
|
(%)
|
|
Mean age (range): 58.3 (18-87)
|
|
|
|
Patients ≥ 65 years
|
80
|
(40)
|
|
Sex ratio: 1.00
|
|
|
|
Male
|
100
|
(50)
|
|
Female
|
100
|
(50)
|
|
Diagnosis
|
|
|
|
Diffuse large B-cell lymphoma
|
51
|
(25.5)
|
|
Low grade lymphoma
|
|
|
|
Follicular lymphoma
|
43
|
(21.5)
|
|
Marginal lymphoma
|
13
|
(6.5)
|
|
Mantle cell lymphoma
|
6
|
(3)
|
|
Lymphoplasmocytic lymphoma
|
3
|
(1.5)
|
|
Lymphocytic lymphoma
|
3
|
(1.5)
|
|
Multiple myeloma
|
27
|
(13.5)
|
|
Hodgkin lymphoma
|
26
|
(13)
|
|
Chronic lymphocytic leukemia
|
10
|
(5)
|
|
T-cell lymphoma
|
7
|
(3.5)
|
|
Myeloproliferative disorder
|
5
|
(2.5)
|
|
Burkitt lymphoma
|
3
|
(1.5)
|
|
Others
|
3
|
(1.5)
|
|
Comorbidities
|
48
|
(24)
|
|
Diabetes mellitus
|
12
|
(6)
|
|
Chronic cardiac failure
|
12
|
(6)
|
|
Other cancer
|
12
|
(6)
|
|
HIV infection
|
5
|
(2.5)
|
|
Chronic respiratory failure
|
4
|
(2)
|
|
Neurologic disease
|
4
|
(2)
|
|
Chronic renal insufficiency
|
3
|
(1.5)
|
|
Type of chemotherapy
|
|
|
|
Ongoing therapy
|
|
|
|
Aplasia-inducing chemotherapy regimens
|
55
|
(27.5)
|
|
Low intensity
|
42
|
(21)
|
|
Discontinued chemotherapy
|
103
|
(51.5)
|
|
Rituximab ongoing therapy
|
55
|
(27.5)
|
|
Ongoing steroids
|
77
|
(33.5)
|
|
Biological features
|
|
|
|
Hypogammaglobulinemia (<6g/l)
|
33/152
|
(21.7)
|
|
Lymphopenia (<1G/l)
|
58/195
|
(29.7)
|
Results
The vaccination against influenza was proposed to 53% of patients
(via a voucher from the French national health insurance agency for
64.2% of them, by general practitioners for 31.1% and by
occupationnal doctors for 4.7%) The rate of shot proposition raised
to 88.7% in patients older than 65 y. The vaccination was
asked to the physicians by the patients themselves in 6% of cases
and was not proposed to the 41% lasting patients.
Global vaccinal rate was 25.5%; it was 16.6% among patients
younger than 65 y and 38.75% among those older than 65 y
(p= .0008). Vaccination rate was also signifiantly higher in
patients with comorbidities (39.5% versus 21%, p= .017). Only 13.4
% of patients with no other indication for vaccination than
haematologic malignancy received influenza shots.
The most frequent reasons for not being vaccinated were: the
vaccination was not suggested to the patients (53.7%), vaccination
was contraindicated by doctors (24.2%), the patient refused the
vaccine (21.5%). The main reasons for physicians for
contraindicating the vaccine were: haematologic malignancy could be
worsened by vaccination (33.3%), vaccination could generate illness
or asthenia (27.8%), vaccination would not be efficient (16.7%),
unknown (22.2%). Half of patients who refused the vaccine were
afraid of having fever; 21.8% prefered homeopathy to prevent
influenza; 15.5% refused because they thought that the vaccine was
uselessness.
Thirteen patients (6.7%) suffered with a flu-like illness during
follow-up and 38 (19.5%) presented a significant pulmonary
infection. We did not establish a significant link between the
vaccination and a protection against influenza nor between
vaccination and prevention of lower respiratory tract infections.
Analysis were performed on subgroups of patients, classified
according to malignancy, treatment, underlying chronic diseases,
age or biological features. Occurence of flu-like episodes was not
significantly different between them. Whatever the subgroup
analyzed, we failed to establish a significant link between the
vaccination and a protection against influenza or respiratory
infections.
Discussion
Our study revealed a poor uptake of influenza vaccination in
patients with haematologic malignancies, with a vaccinal rate of
only 25.5%. The vaccinal coverage was particularly low in patients
younger than 65 y with no comorbidities (13.4%).
Except for elderly patients who received a voucher from the
health insurance agency, the rate of shot proposition was low. This
absence of vaccinal exhortation was the main explanation for the
low vaccinal rate. For our patients the vaccination was never
suggested by the attending haematologists themselves, despite the
high frequency of hospital consultations or incoming; moreover
haematologist contraindicated vaccination in half of patients to
whom influenza shot was suggested by general practitionners, health
agency or occupationnal doctors. We tried to analyse their
reluctance about influenza vaccination. The three main reasons for
physicians to contraindicate vaccination were the fear for
worsening the haematologic malignancies, especially low grade
lymphomas, the fear of generating illness or asthenia and the
belief that the vaccination would not be efficient.
Analysis of the literature did not reveal any evidence of
aggravation of haematologic malignancies following flu vaccination.
Moreover a negative association between influenza immunization and
lymphoid neoplasms has been previously reported for several
subtypes of non-hodgkin’s lymphomas especially diffuse large B-cell
lymphoma, chronic lymphoid leukemia (CLL) and multiple myeloma [7,
10].
This analysis revaled that influenza vaccine is well tolerated
in patients suffering from haematologic malignancies and that
systemic or local side-effects are not more severe than in normal
hosts [1, 6, 9, 13, 14].
The question of the immunogenicity of influenza vaccination in
patients with haematologic malignancies has long been a matter of
uncertainty. Most of recent studies have demonstrated
immunogenicity of standard influenza vaccination in patients with
non Hodgkin lymphoma [4, 12], irrespective of previous chemotherapy
[4], Hodgkin lymphoma [12] and CLL [1, 3, 4, 6, 12]. Nethertheless,
humoral immune response to vaccination was sometimes found inferior
to those seen in healthy control [2, 4, 12], especially among CLL
patients with hypogammaglobulinemia or in advanced stages of the
disease [3, 6]. Data are more heterogeneous concerning patients
with multiple myeloma with one study showing poor antibody
responses to influenza vaccination [14] and one demonstrating
immunogenicity of vaccination [12].
If the immunogenicity of influenza vaccination seems established
in most studies, the question of whether immune response to
vaccination actually protect against influenza infection or not
remains. Humoral response, considered in clinical studies as the
main criteria of vaccine immunogenicity, constitutes only one part
of the protective immune response. Chemotherapy-induced disruption
of mucosal barriers and impaired cellular immunity due to
malignancies and treatments may facilitate infection despite high
antibody titers [13]. No population-based study comparing
nonvaccinated and vaccinated people with haematologic malignancies
are available. Additionally, as the immunogenicity may be
negatively influenced by the simultaneous administration of
anticancer drugs, the timing of vaccination with respect to
chemotherapy is to determinate.
Questions about immunogenicity and efficiency of vaccination
remain in two populations of patients. Existing data are limited
for patients who have undergone autologous stem cell
transplantation [8]. Additionnal studies are also required in
numerous patients treated by rituximab: one study demonstrated
immunogenicity of influenza vaccine in patients with rheumatoid
arthritis [11] but results are discordant in other ones led in
autoimmune diseases; only one very small negative study is
available in patients with haematologic malignancies [9].
In conclusion our study revealed that the vaccination coverage
could be improved in patients with haematologic malignancies. We
believe that a better knowledge by physicians of studies
demonstrating its tolerance and immunogenicity could enhance the
rate of vaccination. An improved use of the vaccination in this
highly susceptible population could perhaps lead to reduce use of
antibiotics, hospitalizations, treatment delays and deaths.
Prospective studies seem warranted to assess practical benefit of
the vaccination and to established vaccinal guidelines for
physicians. Waiting for these studies, other preventive strategies
such as immunization of hospital staff and family members should be
associated to patients’ vaccination.
Conflict of interest
None.
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