Pneumococcal vaccination for splenectomized patients with thalassemia
major in Indonesia
Teny Tjitra Sari a,⇑, Arwin
Ali P. Akib a, Djajadiman
Gatot a, Alida
Roswita Harahap b,
Saptawati Bardosono c, Sri
Rezeki S. Hadinegoro a
a Department
of Child Health, Faculty of Medicine, Universitas Indonesia/Dr. Cipto
Mangunkusumo Hospital, Jakarta, Indonesia
b Department of Clinical Pathology, Faculty of Medicine, Universitas
Indonesia/Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia
c Department of Clinical Nutrition, Faculty of Medicine, Universitas
Indonesia/Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia
a r t i c l e i n f o
Article
history:
Received
31 March 2017
Received in revised form 25 June 2017 Accepted 3 July 2017 Available
online 13 July 2017
Keywords:
Thalassemia
Pneumococcal
vaccination
a b s t r a c t
Introduction: Streptococcus pneumoniae is a capsulated bacterium that
can cause severe infection in patients with thalassemia major, particularly
those who have undergone splenectomy. The absence of the spleen as well as zinc
deficiency in splenectomized patients with thalassemia major increases the
possibility of developing invasive pneumococcal infection. The aims of this
study are to evaluate pneu-mococcal IgG levels following PCV and PPV
immunizations and the effect of zinc supplementation on qualitative specific
immune responses in splenectomized patients with thalassemia.
Methods: Splenectomized patients with thalassemia major were
administered a PCV pneumococcal vac-cine (Prevenar 13 ) at the start of the
trial, after which they were randomly assigned to 2 groups (zinc and placebo
group). After 8 weeks, the patients received a PPV pneumococcal vaccine
(Pneumovax ). Zinc syrup was provided to the zinc group at a dose of 1.5
mg/kg/day (maximum of 50 mg/day). Pneumococcal IgG examinations were conducted
at the start of the trial and after 12 weeks.
Results: In the group without PPV, the median initial pneumococcal IgG
value was 315 (ranging from 65 to 1419) mU/mL for the zinc group and 338.5
(ranging from 82 to 1648) mU/mL for the placebo group. The median final
pneumococcal IgG value was 1812.5 (ranging from 834 to 2444) mU/mL for the zinc
group and 2857.5 (ranging from 834 to 2624) for the placebo group. The increase
in the pneumococcal IgG value between the two groups was comparable (p =
0.642).
In the group with previous PPV, the median initial pneumococcal IgG
value was 1333 (ranging from 793 to 2031) mU/mL for the zinc group and 880
(ranging from 74 to 1686) mU/mL for the placebo group. The median final
pneumococcal IgG value was 1487 (ranging from 635 to 1757) mU/mL for the zinc
group and 1012 (ranging from 292 to 1732) mU/mL for the placebo group. The
increase in the pneumococcal IgG value between the two groups was comparable (p
= 0.528).
Conclusion: There is no difference in the increase in pneumococcal IgG
level in splenectomized patients with thalassemia major prior to and after
receiving PPV. There were no differences observed in the devel-opment of
pneumococcal IgG following zinc supplementation.
2017
Elsevier Ltd. All rights reserved.
1. Introduction
Thalassemia is a hereditary
anemia that occurs due to a mono-genic disorder causing a defect in globin
production [1]. The
increased vulnerability of thalassemia patients to infection is attributed to
their immune response, which is different from that of normal individuals [2–5].
Streptococcus pneumoniae is a
capsulated bacterium that can cause severe infection in patients with
thalassemia, particularly
⇑
Corresponding author.
those who have undergone splenectomy, and it may lead to a high
mortality rate. The absence of the spleen as well as zinc deficiency in
splenectomized patients with thalassemia major increases the possibility of
developing invasive pneumococcal infection [6–8]. In splenectomized patients, the absence of the spleen leads to an
inability to activate T cell-independent immune responses in the event of
infections or immunization with a capsulated polysaccha-ride antigen such as S.
pneumoniae [9]. The Thalassemia
Interna-tional Federation (TIF) and various countries recommend providing
immunization against S. pneumoniae, H. influenza, and meningococcus at least 2
weeks prior to surgery, followed by
4584 T.T. Sari
et al. / Vaccine 35 (2017) 4583–4586
administration of prophylactic antibiotics to prevent infections
fol-lowing splenectomy [10–13]. In Indonesia, a majority of patients with thalassemia scheduled for
splenectomy are not provided with immunization or prophylactic antibiotics
because of financial lim-itations. Therefore, an effort to increase the immune
response of patients with thalassemia is required, particularly following
splenectomy.
Several studies show that in when zinc deficiency
is present, the process of antibody formation may be disturbed following
admin-istration of several vaccines [6,14,15]. Animal studies have attempted to show these disturbances in antibody
production fol-lowing administration of pneumococcal vaccines under zinc
defi-ciency condition [6].
This study aims to evaluate pneumococcal IgG levels
following PCV and PPV immunizations and the effect of zinc supplementa-tion on
qualitative specific immune responses in splenectomized patients with
thalassemia.
2. Methods
All splenectomized patients with thalassemia major
were administered a PCV pneumococcal vaccine (Prevenar 13 ) at the start of the
trial. The patients were then randomly assigned into one of two groups (the
zinc group and the placebo group). Zinc was provided in syrup form at a dose of
1.5 mg/kg/day, with a maximum of 50 mg/day. The placebo was also provided in
syrup form, with similar shape and flavor. Both zinc and placebo syrup were
prepared for 4 weeks of consumption. At the end of week 4, all subjects
underwent complete physical and hematology examinations.
In week 8, subjects who had not received a PPV
vaccine were administered a PPV pneumococcal vaccine (Pneumovax ). Subjects
were then discharged home with a 4-week supply of either placebo or zinc syrup,
based upon their original group placement.
At the end of Week 12, all the thalassemia subjects
under-went a complete history taking, a physical examination, and sup-porting
examinations including a peripheral blood examination; peripheral blood smear;
and testing for levels of ferritin, trans-ferrin saturation, serum zinc, and
pneumococcal IgG. Following data collection, data analysis and interpretation
were conducted. Analysis was conducted using the Statistical Package for the
Social Sciences (SPSS) version 20.0. Changes in numerical immunologic
parameters were analyzed using the independent samples t-test when the data
followed normal distribution; the Mann-Whitney test was used if the data did
not follow normal distribution.
Pneumococcal IgG levels were measured using the
Pneumococ-cus IgG Immunopotency level/E-DG-MZ-001/04-04 kit (ZenTech, Belgium)
in the PRODIA Laboratory, Jakarta, with results expressed in milliunit per
millilitres (mU/mL). In agreement with the instruc-tions, serum was diluted to
1:510. Titers of anti-PCP IgG antibodies expressed as mU/mL were determined in
accordance to the stan-dard serum provided with the kit. Sensitivity of the kit
was reported at 6.9 mU/mL. The results (based on the manufacturer) are interpreted
as follows: hyporesponsive if <250 mU/mL, and good response or immune to
pneumococcal infections if 250 mU/mL. This assay was already validated and used
in studies conducted by Jahromi et al. [22] Evaluations of zinc levels were conducted using the Inductive Couple
Plasma Mass Spectrometry (ICP/MS) method. Frequency of blood transfusions was
classified using the Fucharoen classification [16].
This study was conducted following ethical approval
by the Ethics Committee of the Faculty of Medicine, Universitas Indonesia, with
ethical approval number 260/H2.F1/ETIK/2013.
3. Results
This study included 56 samples with a median age of
21 years (range 12–38 years) and 56.8% female participants. Characteristic of
samples used in this study are shown in Table 1. Most of the samples used had high ferritin levels (median range of
6950.31), with deferiprone as the most frequently used iron chelator. The
presence of hepatitis infection in the patient can also be an impor-tant
indicator of immune response. In this particular study, 12 patients were
identified as having hepatitis B and 22 patients as having hepatitis C;
information regarding the presence of cirrhosis was not gathered from the samples.
In this study, 50 patients had not received pneumococcal immunization; hence
they were given PCV and PPV immunizations. Six patients (4 from the zinc group
and 2 from the placebo group) had previously received PPV immu-nization, and
they were given only PCV immunization. The pneu-mococcal immunization provided
by the hospital to the 6 patients who underwent splenectomy between 2009 and
2013 was the PPV vaccine; this was due to financial limitations of these
patients, as PPV is less expensive than PCV.
Majority of the study population (80.4%) possessed
low zinc levels, with an average zinc level of 46.46 (±8.86). The effects of
zinc supplementation on changes in pneumococcal IgG levels in patients who did
not receive previous PPV immunization are pre-sented in Table 2.
Table 2 shows that at the start of the trial, immunity from pneu-mococcal
IgG had already been attained (>250 mU/mL) in the group which did not
receive PPV. Following immunization, pneu-mococcal IgG levels increased in both
groups. Comparison between the zinc and placebo groups showed no significant
differences in the increase in pneumococcal IgG following immunization.
The median initial pneumococcal IgG level for the
group who had previously received PPV immunization (6 patients) was 1333 (range
793 to 2031) mU/mL for the zinc group (n = 4) and 880 (range 74–1686) mU/mL for
the placebo group. The median final pneumococcal IgG level was 1487 (range 635–1757)
mU/mL for the zinc group and 1012 (range 292–1732) mU/mL for the placebo group.
There was a comparable increase in pneumococcal IgG in the two groups (p =
0.528).
All patients who had previously received a PPV
immunization attained protective levels of pneumococcal IgG (>250 mU/mL);
however, this generally decreased with an increase in the duration of
pneumococcal antibody protection (Table 3).
Table 1
Characteristics of the study
population.
Parameters
|
Number
of Subjects (n = 56)
|
|
|
Type of
thalassemia
|
|
Beta
|
28
|
Beta-HbE
|
28
|
Nutritional
status
|
|
Good
|
26
|
Undernourished
|
19
|
Severely
undernourished
|
11
|
Frequency
of blood transfusions
|
|
Seldom
(<1 time per year)
|
3
|
Sometimes
(2–3 times per year)
|
2
|
Often
( 4 times per year)
|
51
|
Type of
blood transfusions
|
|
PRC
|
4
|
Leukodepleted
PRC
|
21
|
Washed
PRC
|
31
|
Ferritin
(ng/mL)
|
6950.31
(645–21,835)
|
Transferrin
saturation (%)
|
94.84
(26–118)
|
Positive
hepatitis markers
|
|
Hepatitis
B
|
12
|
Hepatitis
C
|
22
|
|
|
T.T.
Sari et al. / Vaccine 35 (2017) 4583–4586
|
4585
|
Table 2
Effects
of zinc supplementation on pneumococcal IgG levels in patients who did not
receive previous PPV immunization.
|
Pneumococcal
IgG Levels
|
|
|
|
|
|
|
Zinc
Group
|
Placebo
Group
|
p-value
|
|
(n =
24)
|
(n =
26)
|
|
|
|
|
|
|
Median
(Range)
|
Median
(Range)
|
|
Initial
(mU/mL)
|
315
|
338.5
|
|
|
(65–1419)
|
(82–1648)
|
|
Final
(mU/mL)
|
1,812.5
|
1857.50
|
|
|
(834–2444)
|
(652–2624)
|
|
|
<0.001
|
<0.001
|
|
Change
(mU/mL)
|
Mean
(SD)
|
Mean
(SD)
|
|
|
1420.83
(377.32)
|
1,353.0
(626.09)
|
|
Percentage
change
|
Median
(Range)
|
Median
(Range)
|
|
|
413.50
|
406.58
|
|
|
(72.23–1935.51)
|
( 4.79 to 2261.86)
|
|
* Independent
samples t-test.
1
Mann-Whitney test.
2
Wilcoxon signed-rank test.
Table 3
Pneumococcal IgG levels in the splenectomized subjects who had
previously received PPV immunization.
Patient
|
Age at
PPV
|
Duration
of pneumococcal
|
Pneumococcal
IgG
|
number
|
immunization
|
antibody
protection
|
level
(mU/mL)
|
|
|
|
|
1
|
18
years
|
4
months
|
793
|
2
|
13
years
|
6
months
|
1686
|
3
|
14
years
|
9
months
|
2031
|
4
|
19
years
|
12
months
|
1859
|
5
|
21
years
|
16
months
|
807
|
6
|
25
years
|
45
months
|
74
|
|
|
|
|
The duration since splenectomy for the group that
had not pre-viously received PPV (50 patients) was 127.5 (53–243) months,
whereas that value for the group that had previously received PPV (6 patients)
was 17 (11–52) months (p < 0.001). There was no significant correlation
between duration since splenectomy and changes in pneumococcal IgG levels (r =
0.222, p = 0.101).
4. Discussion
In this study, patients who did not previously
receive PPV immunization were provided with PCV immunization followed by PPV
immunization after an interval of 6–8 weeks. On the other hand, patients who
had previously received PPV immunization were provided only with PCV
immunization, as it had been less than 5 years since their last PPV
immunization, in accordance with the guidelines of the Indonesian Society of
Pediatricians/Ikatan Dokter Anak Indonesia (IDAI) [17] and the Advisory Committee on Immunization Practices (ACIP) [18]. There
were no significant differences in the increase in pneumococcal IgG levels
between the patients who did not receive PPV and those who did as well as
between the zinc and placebo groups. This study shows that there is no effect
on the production of pneumococcal IgG following zinc supplementation,
accounting for the fact that a majority of the subjects in this study
population also had zinc deficiency. In agree-ment with previous studies
[19,20] patients with thalassemia do not experience disturbances in their
humoral immunity.
The increase in pneumococcal IgG is higher in
subjects who have not previously received PPV, as PCV plays a role in the
devel-opment of memory B cells [21]. This can manifest as a high increase in the pneumococcal IgG level
(>4-fold) following the administration of PPV. Subjects who have previously
received PPV showed a relatively small increase in pneumococcal IgG levels, as
pneumococcal IgG levels tend to decrease after the duration of
protection reaches 4 years; this indicates that the
PPV vaccine pro-duces only a small amount of memory due to short-term immunity
and lack of booster response [19,22]. The administration of PCV will repair the production of memory B cells
to maintain immunity against pneumococcus [19].
Only a small percentage of
patients (6 out of 56) received PPV immunization prior to splenectomy, and a
large majority of the patients had not previously received PPV immunization.
Regard-less of this, subjects who have not previously been immunized showed
protective levels of pneumococcal IgG (>250 mU/mL), demonstrating possible
previous exposure to pneumococcus anti-gen prior to the study. Because of the
endemicity of pneumococcus in Indonesia, prior exposure to its antigen can be
quite common, thus explaining why some of the samples had protective IgG levels
without history of immunization. A 4-fold increase following pneumococcus
immunization is considered an adequate antibody formation response, even
without a spleen [23].
A study by Orthopoulos et al. [19] shows that the administra-tion of
PCV and PPV vaccines to splenectomized patients with tha-lassemia results in an
immunological memory similar to that which results from the administration of 2
PCV vaccines with an interval of 1 month. This agrees with a study by Breukels
et al.
[24]
which stated that the spleen does
not greatly affect the anamnestic response process.
In contrast to a previous study [20], this
study did not find a cor-relation between duration since splenectomy and
changes in pneu-mococcal IgG levels from baseline. A study by Jahromi et al. [20] measured
pneumococcal IgG levels following PPV immunization prior to splenectomy, and
found a strong negative correlation between protective pneumococcal IgG levels,
and duration since splenectomy (r = 0.863, p = 0.0001).
The study was unable to examine
all the factors that may alter the final immune response; presence of hepatitis
in some patients may be concomitant with presence of cirrhosis, which in turn
may hinder immune response. Because of the limited availability of samples, the
study was unable to examine immune response in relationship to gender or age.
Age may play an important role, as older patients may have more mature immune
systems. Studies with larger samples need to be conducted in the future to find
sig-nificant results.
In conclusion, splenectomized
patients with administered with PCV 13 would have similar immunological
responses compared to non-splenectomized patients, but further studies with
healthy control groups are required to confirm the result. Zinc
supplemen-tation does not affect the production of pneumococcal IgG.
Conflict of interest
This
author declares no conflict of interest.
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