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Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 VIROLOGY RESEARCH PROGRESS

PARVOVIRUS B19
AND HEMATOLOGICAL
DISORDERS IN CHILDREN

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Parvovirus B19 and Hematological Disorders in Children

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Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 VIROLOGY RESEARCH PROGRESS

PARVOVIRUS B19
AND HEMATOLOGICAL
DISORDERS IN CHILDREN
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

MAYSAA EL SAYED ZAKI

Nova Science Publishers, Inc.

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Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 Copyright © 2010 by Nova Science Publishers, Inc.

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LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA

El Sayed Zaki, Maysaa.
Parvovirus B19 and hematological disorders in children / Maysaa El Sayed Zaki.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-61668-405-1 (eBook)
1. Parvovirus infections. 2. Hemolytic anemia--Complications. 3. Anemia in children--
Complications. I. Title.
[DNLM: 1. Parvoviridae Infections--complications. 2. Parvovirus B19, Human--pathogenicity. 3.
Child. 4. Hematologic Diseases--complications. WC 500 E49p 2010]
QR201.P33E4 2010
618.92'152--dc22
2010001752

Published by Nova Science Publishers, Inc. New York

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 CONTENTS

Preface vii
Chapter 1 Parvovirus B19 (PB19) 1
Chapter 2 Clinical Aspects of PB19 Infection
in Immunocompetent Patients 21
Chapter 3 PB19 Infection in Immunodeficiency Disorders 43
Chapter 4 Hematological Consequences of PB19 Infection 61
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Chapter 5 PB19 and Blood Transfusion 93

Chapter 6 Occupational Infection by PB19 109
Chapter 7 PB19 Genetic Study, Relation to Pathogenesis 119
Chapter 8 Laboratory Diagnosis of PB19 143
Index 170

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 PREFACE

Parvovirus B19 is a childhood infectious disease of global proportions. It

is the leading cause of erythema infectiousum, affecting mainly young age
children. This book outlines the recent advances in understanding Parvovirus
infection in children particularly associated hematological consequences.
Also, it describes the associated complications by in utero infection such as
hydropes fetalis and acute leukemia. It is emerged as occupational viral
infection both to health care workers and school workers. It carries the danger
of serious affection of recipients of blood and blood products transfusion. This
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

book provides some glimpses into the current situation of this virus.
Parvovirus B19 PB19 is a very small (22 nm) non enveloped virus with a
negative single-stranded DNA genome. It is the only member of the family
parvoviridae known to be pathogenic in humans. The only natural host cell of
PB19 is the human erythroid progenitors. In healthy individuals, the major
presentation of PB19 infection is erythema infectiosum. However, in patients
with underlying hemolytic disorders, infection is the primary cause of transient
aplastic crisis. In immunosuppressed patients, persistent infection may develop
that presents as pure red cell aplasia and chronic anemia. Inutero infection may
result in hydrops fetalis or congenital anemia. Moreover, PB19 infection has
been implicated in the development of childhood leukemia.
The virus can be transmitted by respiratory secretion, vertical transmission
from mother to fetus and even by blood and blood products transfusion.. Some
acute or chronic anemia may occur following the lysis of its target cell, the
erythroid progenitors. Other clinical manifestations can be observed especially
in immunocompromized patients.
Major advances in diagnosis of PB19 infection have taken place,
including standardization of serological and DNA-based detection method-

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 viii Maysaa El Sayed Zaki

ologies. As there is no reliable immunological method for antigen detection,

hybridization or polymerase chain reaction (PCR) are needed for detecting
viremia. Combined use of PCR and ELISA are optimal for diagnosis of PB19
infection.
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 Chapter 1

PARVOVIRUS B19 (PB19)

ABSTRACT

Parvovirus B19 (PB19) virion is DNA virus. It has a simple structure

composed of only 2 proteins and a linear, single stranded DNA molecule.
The non enveloped viral particles are 22 to 24 nm in diameter with
icosahedral symmetry, and both empty and full capsids are visible by
negative staining and electron microscopy. PB19 is an autonomous virus;
its replication is dependant on cellular factors expressed transiently in the
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

cell during the late S or early G2 phases of mitosis. The pathogenesis of

PB19 is associated with erythroid tropism. The life cycle of PB19 like
those of other non-enveloped DNA viruses. PB19 DNA has been found in
the respiratory secretions at the time of viremia; transmission of infection
via the respiratory route seems to be the most common route of spread of
infection. Vertical transmission (from mother to fetus) occurs in one-third
of cases involving serologically confirmed primary maternal infections.
Furthermore, PB19 infection can be transmitted via blood derived
products administrated parentally as the virus presents in high titers in the
serum and is resistant to conventional heat treatments. Viremia is
accompanied by constitutional symptoms of fever and malaise, and by
erythroid progenitor cell depletion in the BM

Keywords: PB19 virology, epidemiology, pathogenesis.

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 2 Maysaa El Sayed Zaki

INTRODUCTION

PB19 was first reported in 1974 while evaluating tests for hepatitis B virus
surface antigen in sera of asymptomatic patients. The virus was designated as
B19 after the code number of the serum sample (19) in panel B which
contained the unexpected virus [1]. The human parvovirus B19 is now divided
into three genotypes: type 1 (prototype), type 2 (A6- and LaLi-like), and type 3
(V9-like).
PB19 is a very small (22 nm) non enveloped virus with a negative single-
stranded DNA genome without virion polymerase. The capsid has icosahedral
symmetry (figure 1) and there is one serotype only. Since replication occurs
only in erythrocyte precursors, PB19 is now classified as a member of the
erythrocyte genus. It is the only one of parvovirus family which prove to infect
man; it causes erythema infectiosum, aplastic anaemia and fetal infections
including hydrops fetalis [2].
The development of PB19 specific serologic tests had led to the first
report of symptomatic infection in humans. A report had described two
soldiers who had a brief febrile illness with unknown origin. Subsequently, the
simultaneous reports of PB19 as the etiologic agent for transient aplastic crisis
(TAC) among patients with sickle cell disease and for erythema infectiosum
among school children have established the association between parvovirus
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

infection and these two disorders [4].

Figure 1. Parvoviruses are symmetrical icosahedral particles. They form small capsids
and contain a DNA genome. The viral genome encodes only three proteins with known
function, the nonstructural protein NS-1 and two capsid proteins VP1 and VP2.

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 Parvovirus B19 (PB19) 3

PARVOVIRUS FAMILY (PARVOVIRIDAE)

Parvoviruses have been isolated from a wide range of hosts, from

arthropods to humans. The family parvoviridae is divided into two
subfamilies: Parvovirinae & Densivirinae. Densivirinae subfamily infects only
invertebrates and is subdivided into 3 genera: Densovirus, Iteravirus and
Contravirus. On the other hand, Parvovirinae infects both arthropods &
humans. Parvovirinae similarly is subdivided into3 genera: Parvovirus,
Dependovirus and Erythrovirus (table 1), [5].

Table 1. Taxonomic organization of Parvoviridae

Minute virus of mice

Mice Sub clinical
(MVM)
Feline parvovirus Enteritis, leucopenia,
Cat
(FPV) cerebellar ataxia
Canine parvovirus
Dog Enteritis, myocarditis
(CPV)
Parvovirus
Porcine parvovirus
Pigs Reproductive failure
(PPV)
Aleutian disease virus
Mink Pneumonitis
(ADV)
Mink entritis virus
Mink Enteritis
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

(MEV)
Adeno-associated Humans &
Dependovirus Unknown
viruses (AAV) others
Respiratory tract
illness, aplastic crisis,
B19 Man erythema
Erythrovirus
infectiosum/5thdisease
& hydrops fetalis
Simian parvovirus Monkey Anemia

PARVOVIRUS GENETIC STRUCTURE

The PB19 virion has a simple structure composed of only two proteins and
a linear, single-stranded DNA molecule. The non-enveloped viral particles are
22 to 24 nm in diameter and show icosahedral symmetry, and often both empty
and full capsids are visible by negative staining and Electron Microscope (EM)
[6]. Mature infectious viral particles have a molecular weight of 5.6 x 106
Dalton [7]. The virion is composed of 60 copies of capsomers, and both
negative and positive strands of DNA are packaged. X-ray crystallography has

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 4 Maysaa El Sayed Zaki

shown that the surface of PB19 is significantly different from those of other
parvoviruses by lacking prominent spikes on the threefold icosahedral axes
involved in host recognition and antigenicity. The limited DNA content and
the absence of a lipid envelope make PB19 extremely resistant to physical
inactivation. The virus is stable at 56°C for 60 minutes, and lipid solvents have
no effect [7]. Inactivation of virus may be achieved by formalin, ß-
propiolactone, and gamma irradiation [8].
PB19 virus is one of the stable viruses. The genetic diversity among PB19
virus isolates has been reported to be very low, with less than 1 to 2%
nucleotide divergence in the whole genome, although full-length sequences are
available only for a limited number of isolates [9-12]. Partial sequence data
from different coding regions of the viral genome have confirmed this high
degree of similarity with a larger number of isolates [13-17]. For example,
sequence variation of the VP1/VP2 gene has been reported to be very low
among PB19 virus isolates obtained from a single community-wide outbreak
(0 to 0.6% base substitutions) and only slightly greater among PB19 virus
isolates obtained from distinct epidemiological settings and geographical area,
ranging between 0.5 and 4.8% for the most distant isolates [13]. PB19 virus
genomes recovered from synovial tissue during persistent infection have also
been reported to be very similar to those recovered from the same tissue during
acute infection and to those recovered from blood or bone marrow [16].
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

However, some isolates obtained from patients with persistent B19 virus
infection have been reported to exhibit a higher degree of variability in some
parts of the genome, with the VP1 unique region being the most variable at
both the DNA and protein levels with up to 4 and 8% divergence, respectively
[15]. Although different genome types have been described based on
restriction analysis of the PB19 virus genome [19, 20] sequence analysis has
not allowed the identification of phylogenetic clusters with well-resolved
nodes within the B19 viruses [11,17] .
Replication of a parvovirus entails double-stranded intermediate forms,
which can be detected in tissue culture and clinical specimens by simple
methods of DNA hybridization [11]. The transcription map of PB19 and the
other erythroviruses differs markedly from that of other Parvoviridae,
particularly in the use of a single promoter.
The viral genome encodes only three proteins of known function. The
nonstructural protein (NS1) plays an important role in replication by providing
endonuclease and helicase functions and initiating the complex transcription
process. Moreover, it is cytotoxic to host cells inhibiting cellular division [5].

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 Parvovirus B19 (PB19) 5

The two structural proteins, viral protein 1 (VP1) and viral protein 2
(VP2), arise from alternative splicing, so that VP1 is the same as VP2 except
for an additional 226 amino acids at its amino terminal[25]. NS1 is encoded by
genes on the left side of the genome and the two capsid proteins (VP1 and
VP2) by genes on the right side[21]. The viral capsid formed of 60 capsomeres
contains mainly VP2; while VP1 accounts for only about 5 percent of the
capsid protein. Folding of the proteins creates α-helical loops that appear on
the surface of the assembled capsids, where the host's immune system can
recognize them as antigenic determinants. The region unique to VP1 is
external to the capsid itself and contains many linear epitopes recognized by
neutralizing antibodies [21].
In the last decade, new variants in the genus Erythrovirus have been
described. Characterization of these isolates has shown a divergence of 10% or
more between thevariants. Based on their sequences divergence, the genus has
been divided into three genotypes: 1 (B19), 2 (A6 and LaLi), and 3 (V9) [22].
Few clinical and molecular data on genotype-3 strains were available until
West Africa was identified as an endemic region for genotype-3 infection [23].
Parsyan et al. 2007 [24], in a study with genotype-3 samples from Ghana,
observed two different clusters and proposed to recognize two subtypes of
genotype 3, called 3a (B19/3a) and 3b (B19/3b).
PB19 is an autonomous virus; not requiring the presence of a helper virus,
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

its replication is dependant on cellular factors expressed transiently in the cell

during the late S or early G2 phases of mitosis. The necessary factors may
only be produced at specific stages of cellular differentiation, thus PB19
requires dividing cells for replication, but not all dividing cells are
susceptible[5].
Parvovirus B19 is dependent on mitotically active erythroid progenitor
cells for replication. In human clonal progenitor studies there is marked
inhibition of erythroid colony formation by CFU-E and BFU-E, with virtually
no e€ect on colony formation from CFU-GM [25]. Susceptibility to parvovirus
B19 increases with differentiation, and the pluripotent stem cell appears to be
spared. In erythroid progenitors the virus is directly cytotoxic, with infected
cells showing the ultrastructural [26] and biochemical [27, 28] features typical
of apoptosis [26]. In addition, it has been shown in vitro that non-structural
protein expression induces expression of the inflammatory cytokine,
interleukin 6, which may contribute to disease pathology[27].
PB19 infected bone marrow cultures are characterized by the presence of
giant pronormoblasts or `lantern cells': early erythroid cells with cytoplasmic
vacuolization, immature chromatin and large eosinophilic nuclear inclusion

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 6 Maysaa El Sayed Zaki

bodies. The light microscopic findings are also seen in the bone marrow of
infected patients, with occasional giant pronormoblasts even seen in the
peripheral circulation.
In vitro, autonomous PB19V replication is limited to human erythroid
progenitor cells and in a small number of erythropoietin-dependent human
megakaryoblastoid and erythroid leukemic cell lines. It was reported report
that the failure of B19V DNA replication in nonpermissive [29] cells can be
overcome by adenovirus infection. More specifically, the replication of B19V
DNA in the [29] cells and the production of infectious progeny virus were
made possible by the presence of the adenovirus E2a, E4orf6, and VA RNA
genes that emerged during the transfection of the pHelper plasmid. Using this
replication system, the terminal resolution site was identified and the
nonstructural protein 1 (NS1) binding site on the right terminal palindrome of
the viral genome, which is composed of a minimal origin of replication
spanning 67 nucleotides. Plasmids or DNA fragments containing an NS1
expression cassette and this minimal origin were able to replicate in both
pHelper-transfected [29] cells and B19V-semipermissive UT7/Epo-S1 cells.
These results have important implications for understanding of native B19V
infection [30].
The pathogenesis of PB19 is associated with erythroid tropism for P blood
group. The erythroid tropism of PB19 is due to the tissue-specific expression
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

of the cellular receptor for parvovirus PB19 [31]. Virus host cell binding is
mediated through globoside, a neutral glycosphingolipid found predominantly
on erythroid cells or their progenitors, where it is known as the blood group P
antigen. Only red cells containing blood group P antigen can be
haemagglutinated, and bone marrow from patients that do not have P on their
erythrocytes cannot be infected with parvovirus B19 in vitro [32].
The P blood group was discovered in 1927 by Landsteiner and Levine as
part of studies to identify new human blood group antigens by immunizing
rabbits with human erythrocytes. It is now known that the P blood group
system contains two common antigens, P1 and P, and the rarer antigen, Pk.
Red cells of individuals with blood group P1 phenotype have P1 and P
antigens; individuals with P1 k phenotype have P1 and Pk antigens;
individuals with P2 phenotype have P antigen alone; and individuals with the
rare p phenotype (previously known as Tjaÿ) lack all three antigens. The P1
and P2 phenotypes are both very common and account for virtually 100% of
individuals in all ethnic groups studied. The Pk and p phenotypes are very
rare,with estimates of the prevalence of the p phenotype in the general
population being 1:200 000, but more frequent in Japan, Sweden, and among

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 Parvovirus B19 (PB19) 7

the Amish in the USA. In seroprevalence studies among the Amish in Ohio,
USA, it was shown that although B19 is prevalent in the Parvovirus B19
infection [33]community, individuals with p phenotype had no evidence of
previous infection with parvovirus B19 [34], confirming the importance of
globoside in B19 infection.
P antigen is found on erythroid progenitors, erythroblasts, and
megakaryoblasts and megakaryocytes. It is also present on endothelial cells,
which may be targets of viral infection involved in the pathogenesis of
transplacental transmission, possibly vasculitis and the rash of fifth disease,
and on fetal myocardial cells. Later on, it was found that mature human red
blood cells (RBCs), which express high levels of P antigen, but not α5β1
integrins, bind parvovirus B19 but do not allow viral entry. In contrast,
primary human erythroid progenitor cells express high levels of both P antigen
and α5β1 integrins and allow β1 integrin-mediated entry of parvovirus B19.
Thus, in a natural course of infection, RBCs are likely exploited for a highly
efficient systemic dissemination of parvovirus B19 [35].
The life cycle of PB19, like those of other non-enveloped DNA viruses,
includes binding of the virus to host cell receptors, internalization,
translocation of the genome to the host nucleus, DNA replication, RNA
transcription, assembly of capsids and packaging of the genome, and finally
cell lyses with release of the mature virions [2].
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

EPIDEMIOLOGY OF PB19

PB19 is a global and common infectious pathogen in humans. The

prevalence of IgG antibodies directed against PB19 ranges from 2 to 15% in
children 1 to 5 years old, 15 to 60% in children 6 to 19 years old, 30 to 60% in
adults, and more than 85% in the geriatric population [36]. Women of
childbearing age show an annual seroconversion rate of 1.5%[2]. Although
antibody is prevalent in the general population, viremia or presence of viral
DNA is rare. PB19 virus infection is endemic throughout the year in temperate
climates, but there is a seasonal increase in frequency in late winter, spring &
early summer months. Rates of infection may rise to an epidemic level every
4-5 years manifested by outbreaks of erythema infectiosum or PB19 induced
aplastic crisis [5].

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 8 Maysaa El Sayed Zaki

TRANSMISSION OF PB19

PB19 DNA has been found in the respiratory secretions at the time of
viremia; transmission of infection via the respiratory route seems to be the
most common route of spread of infection.
Vertical transmission (from mother to fetus) occurs in one-third of cases
involving serologically confirmed primary maternal infections[37-41]. Foetal
capillary endothelium in placental villi can be an additional target of
productive B19 virus infection. Infection of placental endothelial cells may
lead to a structural and functional damage critical both for altering maternal-
foetal blood exchanges and for spreading the infection to the foetus, possibly
concurring to the development of foetal hydrops and intrauterine foetal death
[39]. Nosocomial transmission has been described infrequently and
transmission has also been reported among staff in laboratories handling native
virus [40].
Furthermore, PB19 infection can be transmitted via blood derived
products administrated parentrally as the virus presents in high titers in the
serum and is resistant to conventional heat treatments. The risk of infection
using single-donor blood products is reportedly varied but is probably low
[38].
Several reports have proven that PB19 can be transmitted through blood
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

transfusions and plasma-derived products[41,42]. Screening of blood donations

for the presence of B19 DNA is not routine[43], despite the fact that this virus
is highly resilient and, like the hepatitis A virus, can withstand denaturation,
even at high temperatures[44].
Normally, in the general population, a continuous increase in PB19
seroreactivity is observed with age, with a seroprevalence for adults over 60
that reaches about 72 %. Interestingly, the haemophilic population that was
treated pre-1984 with non-inactivated clotting factor concentrates had an
increased seroprevalence of 98 % [45, 46].

PATHOGENESIS OF PB19 INFECTION

Human PB19 infects predominantly erythroid precursor cells, leading to

inhibition of erythropoiesis, thus it is called erythrogenic virus. This erythroid
cell damage is mediated by the viral NS1 through an apoptotic
mechanism[47]..

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 Parvovirus B19 (PB19) 9

The deficiencies of appropriate immune responses to B19 impair viral

elimination in vivo, which results in enlargement of B19-infected erythroid-
lineage cells. The B19-associated damage of erythroid lineage cells is due to
cytotoxicity mediated by viral proteins. B19-infected erythroid-lineage cells
show apoptotic features, which are thought to be induced by the non-structural
protein, NS1, of B19. In addition, B19 infection induces cell cycle arrests at
the G (1) and G(2) phases. The G(1) arrest is induced by NS1 expression prior
to apoptosis induction in B19-infected cells, while the G(2) arrest is induced
not only by infectious B19 but also by UV-inactivated B19, which lacks the
ability to express NS1[48].
The presence of a specific cellular receptor is thought to be necessary for
susceptibility to viral infection. The erythrocyte P antigen is suggested to be
the cellular receptor for PB19. PB19 &PB19 VP2 both bind directly to P
antigen, and in tissue culture either excess P antigen or anti-P monoclonal
antibody can protect erythroid progenitors from infection with PB19, thus
demonstrating that P antigen is the PB19 receptor. In addition, individuals who
are genetically lacking P antigen are naturally resistant to PB19 infection and
can't be infected even in the presence of high concentrations of the virus (38,
49). In spite of presence of P antigen on megakaryocytes, endothelial cells,
and fetal myocytes; none of these cell types have been shown to be permissive
for PB19 replication [2].
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Recent studies show that low oxygen pressure in the BM and fetal tissues
leads to higher yields of infectious PB19 progeny and to a higher level of viral
transcription than observed under normoxia [50, 51].
Viremia occurs during the first week of infection, accompanied by
constitutional symptoms of fever and malaise, and by erythroid progenitor cell
depletion in the BM. At the height of the viremia, a precipitous drop in the
reticulocytic count occurs followed by anemia, which is rarely clinically
apparent in healthy patients but can cause serious anemia if the red blood cell
count is already low. The reduction in the reticulocytic count is occasionally
accompanied by leucopenia and thrombocytopenia[4].

IMMUNE RESPONSE TO PB19

The unique region of the capsid protein VP1 (VP1u) of human PB19
elicits a dominant immune response and has a phospholipase A (2) activity,
which is necessary for the infection. When using a monoclonal antibody
against the N-terminal portion of VP1u, authors revealed that this region rich

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 10 Maysaa El Sayed Zaki

in neutralizing epitopes that is not accessible in native capsids. The anti-VP1u

antibody, although unable to bind free virus or to block virus attachment to the
cell, has neutralizing action for virus. This finding is revealing that the
exposure of the epitope and the subsequent virus neutralization occur only
after receptor attachment [52]. The majority of patients who develop
immunoglobulin (Ig) G antibodies against the capsid proteins VP1 and VP2
have life-long protection against reinfection. Most virus neutralizing
antibodies that offer protection are directed against VP1u. Immunoglobulin M
antibodies are mainly directed against VP2-specific epitopes. These antibodies
can be present for only a rather short period of 2 to 10 weeks after acute
infection [53].
The appearance of PB19 specific IgM antibodies in the serum in the
second week after inoculation corresponds with clearance of the viremia. In
the third week after inoculation, specific IgG antibodies appear in the serum,
and the rash of erythema infectiosum and arthropathy develop. The appearance
of the rash corresponds with the development of IgG antibodies and occurs
after the viremia has cleared. That‘s to say that the rash of erythema
infectiosum signifies that the virus can no longer be transmitted [4]
Figure (2) describes both T- and B- lymphocytes cell response to
parvovirus B19 infection. Upon PB19 infection, B cells divide to produce
plasma cells and memory cells. Plasma cells secrete IgM antibodies that are
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

specific for both conformational (N) and linear (D) epitopes of PB19, which
are usually detectable around 7 days post-infection. PB19-specific IgG is
detectable about 15 days post-infection and is directed initially against both
linear and conformational epitopes of the capsid proteins (VP1 and VP2) and,
to a lesser extent, against NS1, but declines against linear epitopes of the
proteins in a time-dependent manner. Infection by PB19 most likely confers
lifelong protection on the host, due to the development of memory B cells that
are specific for the conserved regions of the PB19 capsid and also linear
regions of the VP1 protein [54]. Antigen-presenting cells (APC) process the
virus and displayP B19 peptides on their surface combined with MHC I to Th
cells. These Th cells then secrete cytokines that play a role in mediating anti-
virus immunity and may also be associated with pathogenesis of B19 infection
(e.g. IL6 is associated with RA).

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 Parvovirus B19 (PB19) 11

Figure 2. Schematic depiction of T- and B-cell response to parvovirus B19 infection.

Cell-mediated immunity to B19 has not been studied extensively; this is

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

due primarily to the fact that the humoral response was thought to be most
important in combatting B19 infection. Indeed, initial attempts to demonstrate
specific T-cell proliferative responses to B19 were unsuccessful [55] and, for
some time, this work supported the prevailing theory that neutralizing antibody
production was the major mechanism of immunity in B19. In 1996, ex vivo
B19-specific CD4+ T-cell responses were first detected against E. coli-
expressed VP1, VP2 and NS1 antigens [56]. T-cell responses of 16 individuals
were analysed (ten seropositive and six seronegative blood donors), none of
whom had any evidence of acute infection. The majority (90 %) of
seropositive donors who were stimulated ex vivo by VP2 displayed specific T-
cell responses, with 80 % displaying VP1-specific responses. There was no
significant difference in T-cell proliferation for NS1 between seropositive and
seronegative individuals. Upon inclusion of mAbs that were specific for class I
and class II HLA, it was found that HLA class II-specific antibodies inhibited
T-cell proliferation, thus indicating that the effector T-cell population of B19
are CD4+ cells. Subsequent peripheral blood mononuclear cell (PBMC)
depletion of either CD4+ or CD8+ T cells and stimulation of the remaining
population confirmed this observation.

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
 12 Maysaa El Sayed Zaki

More recently, significant ex vivo T-cell reactivity was observed in

PBMCs of recently and remotely infected individuals by using a B19 candidate
vaccine [57] and also the B19 recombinant proteins, VP1 and VP2[62]. T cells
from recently infected individuals responded strongly to the B19 capsids,
giving a mean T-cell stimulation index (SI) of 36 [58]. Blood donors with past
infections gave comparable rates of T-cell stimulation. Seronegative
individuals had SI values of about 3.3 and this study also showed that the
responding population of T cells were CD4+. Although There is no difference
in T-cell responses to NS1 in seronegative and seropositive individuals,
significant responses to this antigen have been reported in recently infected
individuals and patients who developed chronic arthropathy following B19
infection [60, 61]. T-cell responses to NS1 were not seen in healthy individuals
with past B19 infection, except for two individuals who were also NS1 IgG-
seropositive.
Cellular immune response to an epitope of NS1 that is specifically
recognized by CD8+ T cells was investigated by using major histocompatibility
complex tetrameric complex binding [61]. The response of 21 individuals to
this epitope was examined in healthy volunteers and human immunodeficiency
virus (HIV)-1 infected adults and children. Sixteen of the volunteers were
HLA-matched (HLA B35) and six were mismatched. Sixty-three per cent of
matched individuals displayed specific CD8+ T-cell responses. Seventy-two
Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

per cent of matched individuals in the same cohort exhibited specific T-cell
responses by using an interferon (IFN- ) ELISpot assay [59]. The level of
B19-specific CD8+ T cells was similar among healthy and HIV-infected
individuals. The results presented in this report showed the important cellular
role of cytotoxic T cells in combating PB19 infection [60]. PB19-specific T-
cell responses may now represent a novel method for confirming past B19
infection [62].
Recent evidence shows the importance of evaluating T-cell responses in
understanding the nature of B19 infection. There has been identified an AIDS
patient with persistent B19 infection who showed an initial remission of B19
infection [63]. This remission was evident despite the lack of a specific
antibody response, thus indicating a role for cellular immunity in combatting
B19 infection. NS1-reactive lymphocytes have been detected in two B19-
seronegative individuals who were exposed to the virus, indicating a possible
subclinical B19 infection or perhaps a loss of antibodies against capsid
proteins [62]. The importance of cellular immunity in B19 was further
emphasized. The presence of PB19-specific CD8+ T-cell responses identified
two healthy adults and two HIV-1-infected patients who were seronegative for

Zaki, Maysaa El Sayed. Parvovirus B19 and Hematological Disorders in Children, Nova Science Publishers, Incorporated,
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