Detection of platelet-binding anti-measles and anti-rubella virus IgG antibodies in infants with vaccine-induced thrombocytopenic purpura

Article (PDF Available)inVaccine 29(31):4878-80 · May 2011with36 Reads
DOI: 10.1016/j.vaccine.2011.04.036 · Source: PubMed
Abstract
A 15-month-old infant presented with thrombocytopenic purpura after sequential administration of measles-rubella combined vaccine, varicella vaccine and mumps vaccine every 4 weeks. Her thrombocytopenia persisted for more than 12 months. Both anti-measles and anti-rubella virus IgG antibodies were detected in the patient's-isolated platelets on day 154 of illness, which were not detected when there was a reduction of the serum IgG antibody titers on days 298 and 373 of illness, respectively.We also detected the isolated platelet-binding anti-measles and anti-rubella virus IgG antibodies in two other pediatric patients. This is the first report demonstrating direct evidence of vaccine-induced thrombocytopenic purpura.

Figures

Vaccine
29 (2011) 4878–
4880
Contents
lists
available
at
ScienceDirect
Vaccine
j
ourna
l
ho
me
pag
e:
www.elsevier.com/locate/vaccine
Short
communication
Detection
of
platelet-binding
anti-measles
and
anti-rubella
virus
IgG
antibodies
in
infants
with
vaccine-induced
thrombocytopenic
purpura
Naho
Okazaki
,
Masahiro
Takeguchi,
Kohji
Sonoda,
Yohsuke
Handa,
Tatsuo
Kakiuchi,
Hiroaki
Miyahara,
Kensuke
Akiyoshi, Seigo
Korematsu,
Soichi
Suenobu,
Tatsuro
Izumi
Department
of
Pediatrics
and
Child
Neurology,
Oita
University
Faculty
of
Medicine,
Hasama,
Yufu,
Oita
879-5593,
Japan
a
r
t
i
c
l
e
i
n
f
o
Article
history:
Received
30
December
2010
Received
in
revised
form
1
April
2011
Accepted
12
April
2011
Available online 1 May 2011
Keywords:
ITP
MR
vaccination
Platelet-binding
anti-MR
viruses
IgG
antibodies
Detection
from
isolated
platelets
a
b
s
t
r
a
c
t
A
15-month-old
infant
presented
with
thrombocytopenic
purpura
after
sequential
administration
of
measles-rubella
combined
vaccine,
varicella
vaccine
and
mumps
vaccine
every
4
weeks.
Her
thrombocy-
topenia
persisted
for
more
than
12
months.
Both
anti-measles
and
anti-rubella
virus
IgG
antibodies
were
detected
in
the
patient’s-isolated
platelets
on
day
154
of
illness,
which
were
not
detected
when
there
was
a
reduction
of
the
serum
IgG
antibody
titers
on
days
298
and
373
of
illness,
respectively.We
also
detected
the
isolated
platelet-binding
anti-measles
and
anti-rubella
virus
IgG
antibodies
in
two
other
pediatric
patients.
This
is
the
first
report
demonstrating
direct
evidence
of
vaccine-induced
thrombocytopenic
purpura.
© 2011 Elsevier Ltd. All rights reserved.
1.
Introduction
Idiopathic
thrombocytopenic
purpura
(ITP)
in
usually
preceded
by
a
viral
infection
or
vaccination
[1,2],
but
it’s
direct
identification
of
the
causal
virus
and/or
virus
antibodies
has
not
been
demon-
strated.
We
herein
detected
anti-measles-rubella
(MR)
combined
vaccine
virus
antibodies
on
the
isolated
platelets
of
a
patient
who
presented
with
chronic
ITP
after
sequential
administration
of
the
MR
combined
vaccine,
varicella
vaccine
and
mumps
vaccine
every
4
weeks.
2.
Case
report
A
female
infant,
who
was
the
second
offspring
of
unrelated
healthy
Japanese
parents,
had
experienced
normal
and
unevent-
ful
psychomotor
development.
She
was
sequentially
administered
the
MR
vaccine,
varicella
vaccine
and
mumps
vaccine
every
4
weeks
from
12
months
of
age.
Twelve
days
after
the
last
vacci-
nation
for
mumps,
she
presented
a
fever
and
petechiae
on
the
abdomen
and
in
the
oral
cavity.
No
other
symptoms,
such
as
cough,
rhinorrhea,
parotid
gland
swelling
and
tenderness,
or
diar-
rhea
were
not
observed.
Her
laboratory
examinations
revealed
that
Abbreviations:
ITP,
idiopathic
thrombocytopenic
purpura;
MR,
measles-rubella;
MMR,
measles-mumps-rubella;
PAIgG,
platelet-associated
IgG
antibody.
Corresponding
author.
Tel.:
+81
97
586
5833;
fax:
+81
97
586
5839.
E-mail
address:
naho-chi@oita-u.ac.jp
(N.
Okazaki).
thrombocytopenia
of
less
than
5000/l,
RBC
of
505
×
10
4
/l,
Hb
of
11.6
g/dl,
Ht
of
35.1%,
MCV
of
70.6%,
MCH
of
22.8
pg
and
MCHC
of
32.3%.
The
platelet-associated
IgG
antibody
(PAIgG)
increased
to
39.0
ng/10
7
cells
(<25.0)
on
day
65
of
illness.
As
shown
in
Fig.
1,
on
day
67
of
illness,
her
serum
anti-virus
IgM/IgG
antibodies
for
measles,
rubella,
varicella,
and
mumps
were
0.53/37.4,
0.28/3.8,
0.24/3.8
and
6.8/<2.0
EIA,
respectively
(normal
range;
anti-virus
IgM
antibody
<0.8,
anti-virus
IgG
antibody
<2.0).
A
bone
marrow
examination
showed
normal
numbers
of
megakaryocytes
and
few
platelets
on
the
surface
of
megakaryocytes.
After
the
administra-
tion
of
oral
prednisolone
(4
mg/kg/day),
her
platelet
counts
were
transiently
elevated.
Her
thrombocytopenia,
however,
persisted
for
more
than
12
months,
8000–65,000/l,
which
was
exacerbated
by
fever
due
to
non-specific
infections.
The
clinical
and
laboratory
findings,
such
as
markers
associated
with
systemic
lupus
erythe-
matosus
or
other
autoimmune
diseases,
were
within
the
normal
ranges,
and
the
anti-nuclear
antibody
titer
was
<40
times,
and
the
patient
was
negative
for
rheumatoid
factor.
3.
Isolation
of
the
platelet-binding
anti-virus
IgG
antibodies
Platelet-binding
anti-virus
IgG
antibodies
were
examined
three
times,
on
days
154,
298
and
373
of
her
illness,
using
the
previ-
ously
described
methods
[3].
Briefly,
with
the
informed
consent
from
her
parents,
10
ml
of
whole
blood
was
drawn
in
a
conical
tube
containing
30
mol
EDTA,
and
platelet-rich
plasma
was
obtained
by
centrifugation
(200
×
g,
Kubota
KS-20,000S,
Japan)
for
10
min
at
0264-410X/$
see
front
matter ©
2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2011.04.036
N.
Okazaki
et
al.
/
Vaccine
29 (2011) 4878–
4880 4879
Fig.
1.
The
clinical
course
of
the
female
infant
with
vaccine-induced
ITP.
A
female
infant
was
sequentially
administered
the
MR
combined
vaccine,
varicella
vaccine
and
mumps
vaccine
every
4
weeks
from
12
months
of
age.
Twelve
days
after
the
last
vaccination
for
mumps,
she
developed
a
fever
and
petechiae
on
the
abdomen
and
in
the
oral
cavity.
On
day
154
of
illness,
platelet-binding
anti-measles
and
anti-rubella
IgG
were
detected
at
7.3
and
2.1
EIA/10
2
platelets,
respectively,
while
the
anti-measles
and
anti-rubella
IgG
were
both
below
the
limits
of
detection
on
days
298
and
373
of
illness.
4
C.
Next,
the
platelet-rich
plasma
was
centrifuged
(2250
× g)
for
15
min
at
4
C,
and
then
the
supernatant
was
removed.
To
remove
residual
red
blood
cells,
the
concentrated
cells
were
treated
via
hypotonic
lysis
by
resuspending
each
pellet
in
3
ml
of
distilled
water
for
90
s.
At
the
end
of
this
period,
isotonicity
was
restored
by
adding
1
ml
of
3.6%
NaCl.
Then,
the
red
cell
membranes
were
removed
by
centrifugation
(100
×
g)
for
10
min
at
4
C,
followed
by
another
centrifugation
(2250
×
g)
for
15
min
at
4
C
to
purify
the
components.
The
purification
rate
of
isolated
platelets
was
almost
100%
based
on
a
microscopic
examination.
Finally,
a
puri-
fied
platelet
pellet
was
suspended
in
1.5
ml
of
0.05%
Tween-PBS
to
separate
the
platelet-binding
IgG
antibodies.
Thereafter,
anti-virus
IgG
antibodies
titers
for
the
measles,
rubella,
mumps
and
varicella,
were
calculated
using
the
ELISA
method
(SRL,
Inc.,
Japan).
These
procedures
were
carried
out
with
duplicate
samples,
and
then
the
data
were
presented
as
the
mean
values.
The
detection
limit
was
0.4
EIA/10
2
platelets.
4.
Results
On
day
154
of
her
illness,
platelet-binding
anti-measles
and
anti-rubella
viruses
IgG
antibodies
were
detected
to
be
2.4
and
0.7
EIA/10
2
platelets
(<0.1),
respectively.
Both
the
anti-varicella
virus
and
anti-mumps
virus
IgG
antibodies
were
lower
than
the
limits
of
detection.
On
days
298
and
373
of
illness,
the
anti-measles
and
anti-rubella
virus
IgG
antibody
levels
were
reduced
to
below
the
limit
of
detection.
During
the
preparation
of
this
paper,
we
also
detected
isolated
platelet-binding
anti-measles
and
anti-rubella
virus
IgG
antibodies
in
two
other
patients.
The
first
was
a
4-year-old
female
with
chronic
ITP,
whose
onset
was
2
months
after
administration
of
the
MR
vac-
cine
at
17-months
of
age.
The
patient
showed
a
platelet-binding
anti-measles
virus
IgG
antibody
level
of
32.7
EIA/10
2
platelets
and
an
anti-rubella
virus
IgG
antibody
level
of
37.4
EIA/10
2
platelets
on
day
247
of
her
illness.
The
other
patient,
a
9-year-old
male
patient
with
acute
ITP
showed
a
platelet-binding
anti-measles
virus
IgG
antibody
level
of
5.8
EIA/10
2
platelets
on
day
23
of
his
ITP
illness.
He
was
infected
naturally
with
measles
about
2
years
ago.
5.
Discussion
A
15-month-old
female
presented
with
ITP
after
the
sequen-
tial
administration
of
MR
combined
vaccine,
varicella
vaccine
and
mumps
vaccine
every
4
weeks.
Her
thrombocytopenia
persisted
for
more
than
12
months.
Anti-measles
and
anti-rubella
virus
IgG
antibodies
were
detected
on
her
isolated
platelets
on
day
154
of
illness,
although
there
were
no
adherent
anti-varicella
virus
or
anti-mumps
virus
IgG
antibodies.
She
was
diagnosed
with
MR
vaccine-induced
thrombocytopenic
purpura.
4880 N.
Okazaki
et
al.
/
Vaccine
29 (2011) 4878–
4880
The
adherence
of
an
autoantibody
on
the
platelet
surface
occurs
in
a
small
number
of
infants
and
children
1–4
weeks
after
exposure
to
common
infections
and
some
vaccinations.
The
exact
antigenic
target
for
most
such
antibodies
in
most
cases
of
acute
ITP,
however,
remains
undetermined.
After
binding
of
the
IgG
antibody
to
platelet
surface,
the
circulating
IgG
antibody
binding
platelets
are
then
rec-
ognized
by
the
Fc
receptor
on
the
spleen
macrophages,
ingested,
and
finally
destroyed.
A
preceding
history
of
viral
illness
and/or
vaccination
is
recognized
in
50–65%
of
pediatric
patients
with
ITP,
and
vaccination
can
be
easily
confirmed
as
the
direct
and
distinct
causal
origin[4].
Thrombocytopenia
is
common
in
many
infectious
pro-
cesses,
especially
in
association
with
infectious
mononucleosis,
cytomegalovirus
infection,
rubella,
measles,
Gram-negative
bacte-
ria,
and
rickettsial
diseases.
The
combined
live
vaccines
such
as
the
measles-mumps-rubella
(MMR)
and
MR
vaccines
[5,6]
may
have
an
increased
risk
for
inducing
ITP,
especially
in
early
infancy
[7].
Rajantie
et
al.
[1]
described
that
35
patients
(7%)
had
been
vacci-
nated
within
1
month
before
diagnosis,
and
24
patients
had
been
given
the
first
dose
of
the
MMR
vaccine.
Jonville-Bera
et
al.
[8]
described
that
the
relative
risk
of
the
onset
of
ITP
increased
for
a
multivalent
vaccine,
compared
with
a
monovalent
rubella
vac-
cine,
having
an
incidence
of
0.17–0.23/100,000
doses,
MR
vaccine
of
0.87/100,000
doses
and
the
MMR
vaccine
of
0.95/100,000
doses.
The
combined
vaccine,
short
interval
vaccinations
and
subsequent
non-specific
infection
may
cause
and
exacerbate
ITP.
This
is
the
first
report
to
demonstrate
direct
evidence
of
distinct
vaccine-induced
thrombocytopenic
purpura,
which
may
help
to
elucidate
the
basic
mechanisms
of
infection/vaccination-
associated
thrombocytopenia.
Acknowledgements
This
study
was
supported
by
Research
on
Regulatory
Science
of
Pharmaceuticals
and
Medical
Devices
Grants,
The
Research
on
Accumulation
of
Evidence
for
Effective
Vaccine
Use
and
Vaccine
Policy,
Japanese
Ministry
of
Health
and
Welfare.
Conflict
of
interest
statement:
The
authors
confirm
that
they
have
read
the
Journal’s
position
on
issues
involved
in
ethical
publication
and
affirm
that
this
report
is
consistent
with
those
guidelines.
References
[1] Rajantie
J,
Zeller
B,
Treutiger
I,
Rosthoj
S.
Vaccination
associated
thrombocy-
topenic
purpura
in
children.
Vaccine
2007;25:1838–40.
[2] Cines
DB,
Kiebman
H,
Stasi
R.
Pathobiology
of
secondary
immune
thrombocy-
topenia.
Semin
Hematol
2009;46:S2–14.
[3]
Nishioka
T,
Yamane
T,
Takubo
T,
Ohta
K,
Park
K,
Hino
M.
Detection
of
various
platelet-associated
immumoglobulins
by
flow
cytometry
in
idiopathic
throm-
bocytopenic
purpura.
Cytom
B
Clin
Cytom
2005;68B:37–42.
[4]
Scott
JP,
Montgomery
RR.
Nelson
textbook
of
pediatrics.
18th
ed.Philadelphia:
Elsevier
Saunders:
2007
[Reference
to
a
chapter
in
an
edited
book].
[5] Miller
E,
Waight
P,
Farrington
CP,
Andrews
N,
Stowe
J,
Taylor
B.
Idio-
pathic
thrombocytopenic
purpura
and
MMR
vaccine.
Arch
Dis
Child
2001;84:
227–9.
[6]
Mantadakis
E,
Farmaki
E,
Buchanan
GR.
Thrombocytopenic
purpura
after
measles-mumps-rubella
vaccination:
a
systemic
review
of
the
literature
and
guidance
for
management.
J
Pediatr
2010;156:623–8.
[7]
France
EK,
Glanz
J,
Xu
S,
Hambidge
S,
Yamasaki
K,
Black
SB,
et
al.
Risk
of
immune
thrombocytopenic
purpura
after
measles-mumps-rubella
immunization
in
chil-
dren.
Pediatrics
2008;121:e687–92.
[8]
Jonville-Bera
AP,
Autret
E,
Galy-Eyraud
C,
Hessel
L.
Thrombocytopenic
purpura
after
measles,
mumps
and
rubella
vaccination:
a
retrospective
survey
by
the
French
regional
pharmacovigilance
centres
and
Pasteur-merieux
serums
et
vac-
cins.
Pediatr
Infect
Dis
J
1996;15:44–8.
  • [Show abstract] [Hide abstract] ABSTRACT: The most important reasons cited by the opponents of vaccines are concerns about vaccine safety. Unlike issues such as autism for which no indisputable documentation of direct relationship with vaccine use is available, immune thrombocytopenic purpura (ITP) is an adverse event that can really follow vaccine administration, and may limit vaccine use because little is known about which vaccines it may follow, its real incidence and severity, the risk of chronic disease, or the possibility of recurrences after new doses of the same vaccine. The main aim of this review is to clarify the real importance of thrombocytopenia as an adverse event and discuss how it may interfere with recommended vaccination schedules. The available data clearly indicate that ITP is very rare and the only vaccine for which there is a demonstrated cause-effect relationship is the measles, mumps and rubella (MMR) vaccine that can occur in 1 to 3 children every 100,000 vaccine doses. However, also in this case, the incidence of ITP is significantly lower than that observed during the natural diseases that the vaccine prevents. Consequently, ITP cannot be considered a problem limiting vaccine use except in the case of children suffering from chronic ITP who have to receive MMR vaccine. In these subjects, the risk-benefit ratio of the vaccine should be weighed against the risk of measles in the community.
    Full-text · Article · Jan 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Immune thrombocytopenic purpura (ITP) is an autoimmune condition characterized by low platelet count with mucocutaneous and other bleedings. Clinical manifestations may range from spontaneous formation of purpura and petechiae, especially on the extremities, to epistaxis, bleeding at the gums or menorrhagia, any of which occur usually if the platelet count is below 20,000 per μl. A very low count may result in the spontaneous formation of hematomas in the mouth or on other mucous membranes. Fatal complications, including subarachnoid or intracerebral, lower gastrointestinal or other internal bleeding can arise due to an extremely low count. Vaccines may induce ITP by several mechanisms. Vaccine-associated autoimmunity may stem not only from the antigen-mediated responses but also from other constituents of the vaccine, such as yeast proteins, adjuvants, and preservatives diluents. The most likely is through virally induced molecular mimicry. The binding of pathogenic autoantibodies to platelet and megakaryocytes may cause thrombocytopenia by different mechanisms, such as opsonization, direct activation of complement, or apoptotic pathways. The autoantibodies hypothesis is not sufficient to explain all ITP cases: In the anti-platelet antibody-negative cases, a complementary mechanism based on T cell immune-mediated mechanism has been suggested. In particular, T cell subsets seem dysregulated with an increased production of pro-inflammatory cytokines, as IFN-γ and TNF, and chemokines, as CXCL10. Vaccines are one of the most striking discoveries in human history that changed dramatically life expectancy. Nonetheless, the occurrence of adverse events and autoimmune phenomena has been described following vaccination, and ITP may represent one of this.
    Article · Nov 2014