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Faisst S, Rommelaere J (eds): Parvoviruses. From Molecular Biology to Pathology and
Therapeutic Uses. Contrib Microbiol. Basel, Karger, 2000, vol 4, pp 107±122
Epidemiology and Pathology of
K.E. Brown, N.S. Young
Hematology Branch NHLBI, Bethesda, Md., USA
Erythroviruses are named for their tropsim for red blood cell progenitor cells. For parvovirus B19, the only member of the Parvoviridae family
known to be pathogenic in humans, tissue specificity is mediated by the cellular receptor, the neutral glycolipid globoside (blood group P antigen) [1].
Hematological disease due to parvovirus B19 is the result of direct viral cytotoxic effect on erythroid progenitor cells in bone marrow with interruption
of erythrocyte production. The physiology of host hematopoiesis and the
competence of the immune antiviral response both determine clinical manifestations of infection (table 1).
Cynomolgus monkeys are infected by a simian parvovirus [2] which is
remarkably similar to human B19 parvovirus in its predilection for host
bone marrow in vitro and ability to cause serious anemia in some infected
animals. More recently we have identified two further simian parvoviruses,
a pig-tailed macaque parvovirus (PTPV) and a rhesus monkey virus
(RhPV); at the molecular level all three viruses are as different from each
other as they are from the human virus, but all are associated with profound
anemia in immunosuppressed animals.
Erythroviruses appear to be common pathogens of primates. In humans,
by age 15 approximately 50% of children have detectable parvovirus B19
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Prevalence of Erythrovirus Infection
Table 1. Disease manifestations and persistence of parvovirus B19 infection in different host populations
Fifth disease
Polyarthropathy syndrome
Transient aplastic crisis
Persistent anemia
Hydrops fetalis/
congenital anemia
Normal children
Normal adults
Patients with increased
immunocompromised patients
Fetus (< 20 weeks)
IgG, and infection occurs throughout adult life, so that more than 90% of
the elderly are seropositive [3]. Women of childbearing age show an annual
seroconversion rate of 1.5% [4]. Studies in different countries (USA [5],
France [6], Germany [7], Japan [8]) show similar patterns, with a slightly
higher prevalence in children from countries such as Brazil [9] and the African continent [10] compared to Europe and the United States. Some isolated tribal populations in Brazil and Africa have a much lower rate of infection: a general seroprevalence of 2% on Rodriguez Island, Africa [10]
and 4±10% among the Amazonian tribesmen around BeleÂm, Brazil [11]. No
antigenic strain variation has been detected, even between isolates from different countries.
Less is known about the non-human primate erythroviruses. An estimation of the seroprevalence of antibody has been obtained using the expressed SPV VP2 protein in a Western blot assay. Preliminary results indicate that approximately 50% of captive cynomolgus monkeys have evidence
of previous infection with SPV. About 35% of captive rhesus macaques have
antibody that binds to SPV proteins, presumably indicating prior infection
with the cross-reactive RhPV. Seroprevalence studies have yet to be performed in wild monkey populations.
Although antibody is prevalent in the general population, viremia is
rare. One study in human blood donors indicated that approximately
1:20,000±1:40,000 units of blood during epidemic seasons will contain high
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Incidence of Erythrovirus Infection
titers of B19 [12]. In a separate study, screening of pooled samples from
blood donors showed that 1:3,000 units contained detectable B19 DNA by
the more sensitive PCR technique [13].
Epidemic Behavior and Contagiousness
B19 infections in temperate climates are more common in late winter,
spring, and early summer months [14]. Rates of infection may also increase
every three to four years, reflected in corresponding increases in the major
clinical manifestations of B19 infection, transient aplastic crises (TAC) and
erythema infectiosum (EI) [15].
Parvovirus B19 can be readily transmitted by close contact. The secondary attack (seroconversion) rate from symptomatic TAC or EI patients to
susceptible (IgG negative) household contacts was approximately 50% in a
Centers of Disease Control study of a Cleveland outbreak [16]. In schools,
10±60% of students may develop a rash disease consistent with B19 infection [17±19]. In some outbreaks, the seroconversion rate was 20±30% for
personnel in close contact with affected children (daycare providers and
school personnel) [17]. Nosocomial transmission in hospital situations has
been described [20, 21] but is probably infrequent [22]. Nevertheless, patients with TAC or persistent infection should be considered infectious. (The
rash or arthropathy stage of fifth disease is not concurrent with viremia, and
therefore clinically apparent fifth disease is not infectious.)
For the simian erythroviruses, at least two outbreaks of SPV infection
in cynomolgus monkey colonies have been identified. In the original outbreak at Bowman Gray CMCRC [2], all symptomatic monkeys with severe
anemia had active concurrent infection with type D simian retrovirus
(SRV), a virus known to be immunosuppressive. In the second outbreak in a
commercial laboratory performing preclinical drug trials of an experimental
antidiabetic drug [23] the role of SRV or of high dose of experimental drug
predisposing to severe anemia was less clear. In the single outbreaks of
PTPV and RhPV the presence of parvovirus were associated with infection
studies of SHIV-2.
B19 DNA has been found in the nasopharyngeal secretions of patients
at the time of viremia [16, 24], suggesting that infection is generally transmitted by the respiratory route. However, in contrast to other respiratory
Epidemiology and Pathology of Erythroviruses
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Mechanism and Routes of Transmission
viruses, no site of replication for B19 has been found in the nasopharynx.
There is little evidence of virus excretion in feces or urine [25].
The virus can be found in serum, and infection also can be transmitted
by blood and blood products. Due to the lack of lipid membrane, erythroviruses are very temperature resistant, and B19 at high concentration can
withstand heat treatment (80 °C for 72 h) conventionally used to destroy microbial infectivity. In addition, solvent/detergent methods for inactivation of
lipid enveloped viruses are ineffective. B19 infection has been transmitted
by steam or dry heat-treated factor VIII and IX [26, 27] and by solvent/detergent-treated factor VIII [28]. However, in one study, hemophiliacs who
received heat-treated factor VIII alone had lower prevalence of B19 antibody and lower rates of seroconversion compared to those receiving nonheat-treated factor [29]. Transmission of B19 infection has not been associated with transfusion of albumin, and in a recent study of protein batches
from two different manufacturers, B19 DNA was not detectable even by
PCR techniques [30].
Little is known about routes of transmission of the simian viruses,
although transmission of natural simian parvovirus infection is almost certainly through the respiratory route or by fomites. In the second SPV outbreak, infected animals were housed in single cages, physically separated
but sharing the same ventilation system. Possibly virus could have been
aerosolized during the regular cleaning of the cages or even transmitted by
animal handlers.
Following the discovery of parvovirus B19 in 1974 [31], many unsuccessful attempts were made to grow parvovirus B19 in a wide range of primary
and permanent cell lines. The discovery that B19 infection in sickle cell patients was associated with an arrest of erythropoiesis and that B19-containing sera inhibited colony formation by bone marrow erythroid progenitor
cells [32] led to the use of bone marrow as a tissue culture system [33]. B19
was shown to replicate in erythroid progenitor cells, initially human bone
marrow [33, 34] and later fetal liver [35, 36], blasts from a patient with erythroleukemia [37], and normal peripheral blood [38]. In all types of culture,
viral infection is dependent on the presence of the hormone erythropoietin,
required to maintain mitotically active erythroid cells; parvovirus B19, like
all the autonomous parvoviruses, requires dividing cells for its own replication. In bone marrow, the susceptibility of erythroid progenitors to parvovirus B19 increases with their stage of differentiation. The pluripotent pro-
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In vitro Infection ± Tissue Culture and Propagation
genitor cell appears to be spared and the main target cells are the more mature erythroid progenitor cells (CFUE) and erythroblasts [39]; primitive erythroid cells (BFU-E) can also be less efficiently infected.
Primary culture explants are not suitable for long-term viral propagation. B19 has been propagated in two megakaryocytoblastoid cell lines,
UT7/Epo [40] and MB02 [41], and an erythroleukemic cell line, JK-1 [42].
However, in all cell lines the level of B19 expression is low compared with
bone marrow culture, and none is suitable as a practical source of virus.
Studies with SPV in erythroid colony inhibition assays indicate that
SPV is also highly erythrotropic: there was marked inhibition of erythroid
colony formation without inhibition of myeloid colonies. A method for detecting replicative forms of SPV has not been developed, but evidence of
SPV includes increased SPV DNA after 48 h propagation, in situ hybridization, and immunofluorescence. B19 and SPV DNA and capsid proteins
showed similar localization within infected cells. Simian retrovirus was not
required as a cofactor for SPV replication [Gallinella G, Young NS, Brown
KE, unpublished observations].
Cells infected with erythrovirus have the typical appearance of cells
undergoing apoptosis, with marginated chromatin, cytoplasmic vacuolization, and nuclear blebbing. At the ultrastructural level typical affected
cells show the presence of viral arrays in both nucleus and cytoplasm [2,
43]. Immuno-gold electron microscopy studies have detected B19 nonstructural protein in association with both nuclear and cytoplasmic arrays
of capsids [44].
The cytotoxicity of parvovirus B19 is a direct function of expression of
the large non-structural protein [45]. Infection with a recombinant parvovirus B19 containing the B19 genome within the terminal repeats of AAV
(an AAVB19 hybrid) and encapsidated in AAV capsids [46] inhibited megakaryocytic colony formation, but when a frame shift mutation was induced
in the nonstructural protein region this inhibition was abolished [47]. More
specifically, transfection of plasmids expressing the nonstructural protein are
directly toxic to HeLa cells [45] and K562 cells [48], and the cytotoxicity can
be abolished by single amino acid mutations in the NTP-binding domain of
the protein [48, 49]. Cytotoxicity is due to the induction of apoptosis, and
can be blocked by inhibition of caspase 3 and/or increased expression of
bcl-2 [48].
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Erythrovirus Cytotoxicity
Parvovirus B19 Cellular Receptor
Parvovirus B19, like most autonomous parvoviruses, agglutinates red
cells of a variety of species including human erythrocytes [50]. Because of
the known tropism of parvovirus B19 for erythroid progenitor cells, hemagglutination was initially used as a surrogate assay to identify globoside, or
blood group P antigen as the B19 receptor [1]. P antigen expression on red
blood cells is not invariant in human populations and erythrocytes lacking P
antigen (p phenotype) cannot be agglutinated with parvovirus B19 [1]. Confirmation that P antigen is the receptor for B19 was obtained in a study of
Amish individuals who genetically lacked P antigen (p phenotype), which
showed that they appeared to be insusceptible to B19 infection; none
showed serological evidence of previous infection with B19, and their bone
marrow could not be infected in vitro even with large amounts of parvovirus
B19 [51].
P antigen is expressed not only on erythrocytes and erythroid progenitors but also on megakaryocytes and hematopietic cells of the fetal liver [52,
53]. P antigen does not appear to be present on other hematopoietic lineages
or on more immature erythroid cells [52], compatible with the known permissivity of B19 for marrow cell types. P antigen is also found in endothelium, kidney cortex, and placenta, and in the fetus on the myocardium [52,
53]. However, none of these cell types have been shown to be permissive for
B19 replication. Following fetal infection, B19 DNA is readily detected in
many tissues, which could be evidence of tissue infection or simply contamination by circulating virus of visceral organs. However, B19 has been demonstrated in the myocardial cells of infected fetuses [54, 55], and studies are in
progress to see if fetal myocardial cells can be infected with B19 in vitro.
In vivo Infection
Two studies of experimentally infected volunteers have elucidated the
kinetics of infection [25, 56]. Volunteers were infected by intranasal inoculation of a saline solution containing approximately 108 virus particles. Viremia was first detected from day 6 and reached a peak at days 8±9 of about
1011 particles/ml, a level comparable to that seen in natural infections in
blood donors and in patients with aplastic crisis [57]. B19 DNA was detected
in throat swabs and gargles only at the time of viremia, and virus was not
found in urine or feces. On days 6±8, the volunteers showed the typical
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Experimental B19 Infection
symptoms of viremia, with headache, myalgia, and chills, associated with
pyrexia (fig. 1). (These features are generally thought to be due to the production of inflammatory cytokines, but a-interferon was not detected in the
serum by immunoassay.)
At the height of the viremia there was a precipitous drop in the reticulocyte count of the volunteers, indicating cessation of red cell production in
the marrow. The viremia resolved as the volunteers developed a detectable
antibody response (fig. 1), and 2 days later the reticulocyte count returned.
Even in these individuals with normal erythroid turnover there was a measurable fall in the hemoglobin concentration over the following week. Modest neutropenia, lymphopenia and thrombocytopenia also were observed.
In a second study, bone marrow morphology was examined at intervals
[56]. On day 6 post inoculation, the marrrow was normal, but by day 10
Epidemiology and Pathology of Erythroviruses
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Fig. 1. Virological, immunological and clinical course after acute B19 infection in a
normal individual. (Adapted from references 25 and 73; originally published in reference
there was an almost total loss of erythroid precursors at all stages of development, with the appearance in the marrow of `large cells with uniform nuclei' or giant pronormoblasts. BFUE from bone marrow and peripheral
blood were reduced but the myeloid compartment of the bone marrow appeared normal (although CFU-GM were also reduced).
A second phase of the illness began at day 15±17 [25] as the virus-specific IgM response peaked and IgG became detectable. Such symptoms are typical of the childhood exanthema, erythema infectiosum, with pruritis of the
limbs and trunk, followed by the development of a fine maculopapular cutaneous eruption. Arthralgia and in some cases mild arthritis also developed
at this time. The cutaneous eruption was present for 2±4 days and the joint
symptoms for 4±6 days. In the second volunteer study none of the patients
developed the second phase symptoms (these volunteers were male and
joint symptoms in natural B19 infection appear to be much less frequent in
male patients).
Cynomolgus monkeys were experimentally inoculated with SPV to investigate their potential usefulness as an animal model of human B19 parvovirus [58]. Six adult female cynomolgus monkeys received purified SPV by intravenous or intranasal routes and were monitored for evidence of clinical
abnormalities and hematological changes, and viremia and simian parvovirus-specific antibody by dot-blot hybridization and Western blot, respectively.
Bone marrow was examined at necropsy 6, 10, or 15 days post infection.
All monkeys developed a smoldering, low-grade viremia that peaked
approximately 10±12 days after inoculation. Peak viremia coincided with the
appearance of specific antibody and was followed by abrupt clearance of
virus and complete although transient disappearance of reticulocytes from
the peripheral blood. Clinical signs were mild; some animals became anorexic and lost weight. (In contrast to human volunteers experimentally infected with B19 [25] who developed cutaneous eruptions and arthropathy.)
SPV infection was associated with mildly decreased hemoglobin, hematocrit,
and red cell number, with bone marrows showing marked destruction of erythroid cells coincident with peak viremia. Monkeys with evidence of previous infection by SPV, as detected by the presence of SPV antibody, could
not be reinfected with the virus. These findings indicate that infection of
healthy monkeys by simian parvovirus is probably self-limited and mild,
with transient cessation of erythropoiesis, very similar to the course of parvovirus B19 infection in normal people.
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Experimental SPV Infection
Natural Infection
Parvovirus B19 has a wide range of disease manifestations, depending
on the infected host (table 1). The majority of infections are probably
asymptomatic, but acute infection can cause fifth disease in children, polyarthropathy syndrome in adults, transient aplastic crisis in patients with underlying chronic hemolytic anemia, and chronic anemia due to persistent infection in immunocompromised patients [59]. Infection in pregnancy can lead
to hydrops fetalis with possible fetal loss or congenital infection [60]. Hemophagocytosis has also been described associated with B19 infection [61]. The
clinical details of these disease manifestations have been described at length
elsewhere [62], and this chapter will concentrate on the pathophysiological
mechanisms responsible for the different manifestations.
Erythema Infectiosum
The pathogenesis of the rash in erythema infectiosum and polyarthropathy is almost certainly immune complex-mediated (fig. 2). In normal volunteers, the rash and joint symptoms appeared when viremia was no longer detectable and concurrent with development of a measurable specific antiviral
immune response. Similar clinical findings have been reported in chronically
infected individuals treated with immunoglobulin therapy [63]. The detection of parvovirus B19 DNA and capsid proteins in the epidermis of a child
with the classical rash of erythema infectiosum may represent immune complex deposition or evidence of direct infection of epidermal cells [64].
Volunteer studies showed that B19 infection led to an acute but selflimited cessation of red cell production and a corresponding decline in hemoglobin level even in normal individuals. However, with normal erythroid
turnover (i. e. red blood cell lifespan of 120 days), a short cessation of red
cell production will not lead to anemia. In persons with high red cell turnover, as for example due to hemolysis or hemorrhage, even a brief interruption of erythropoiesis can precipitate an aplastic crisis, with severe and possibly life-threatening anemia. The crisis resolves as virus is neutralized and
removed from the circulation by the immune response, and the erythroid
progenitor pool is regenerated from earlier hematopoietic cells. In patients
who are immuno-compromised and do not mount an adequate immune re-
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Transient Aplastic Crisis
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Fig. 2. Pathogenesis of B19 disease in adults and children and the fetus. TAC, transient aplastic crisis; PRCA, pure red cell aplasia. (Originally published in reference 75.)
sponse (see next section), infection may persist and produce chronic pure
red cell aplasia and transfusion-dependent anemia.
Immunosuppressed/Immunocompromised Patients
Persistent B19 parvovirus infection is the result of failure to produce effective neutralizing antibodies by an immunocompromised host. In normal
individuals the early antibody response is to the major capsid protein VP2,
but as the immune response matures, reactivity to the minor capsid protein
VP1 dominates, at least as determined by immunoblot. However, in patients
with persistent B19 infection specific antibodies to parvovirus B19, as determined by immunoassays, immunoblot, or neutralization assays, are not present, although some patients with congenital immunodeficiency may have
an antibody response suggestive of early infection (IgM antibody and/or
IgG antibody directed to VP2 alone) [65]. The importance of the antibody
response to VP1 may be reflected in the response of persistently infected
patients to treatment with antibody; administration of commercial immunoglobulin leads to a marked reduction of B19 viremia, reticulocytosis, and resolution of B19-induced anemia within 1±2 weeks of treatment.
The role of the cellular immune response in controlling persistent B19
infection is less clear. Patients with persistent infection often have defective
T-cell function as recognized by suceptibility to other infections (in HIV
antibody positive patients) or by immunological assays (in congenital immunodeficiency [66, 67]). However, some patients with pure red cell aplasia
due to persistent B19 infection do not have clinically obvious immune deficiency, with apparently normal immune response to other infections [68],
and an attempt to measure a lymphocyte proliferative response to parvovirus B19 in healthy donors was unsuccessful [65]. Perhaps because of the
limited numbers of epitopes presented to the immune system by B19 parvovirus, the defect in cellular immunity associated with persistent B19 infections may be subtle, with susceptibility largely restricted to B19.
If the mother is infected with B19 during pregnancy the fetus may suffer severe effects because of the combination of the high fetal red blood cell
turnover and the immaturity of the immune response. The huge increase in
the fetal red cell mass during the second trimester may partly explain the
great risk to the fetus during this period. Some evidence suggests that the fe-
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Infections during Pregnancy
tus may also develop myocarditis [69, 70] compounding the severe anemia
and adding primary to secondary cardiac failure. By the third trimester, a
more effective fetal immune response to the virus could decrease the risk of
fetal loss.
The pathogenesis of congenital anemia due to parvovirus B19 [60] is
unknown. In contrast to the chronic anemia of persistent B19 infection in
immunocompromised/suppressed patients, immunoglobulin treatment is ineffective. The lack of improvement despite clearance of B19 DNA from the
bone marrow suggests a `hit and run' mechanism rather than the direct cytotoxic effect of virus seen in acute and persistent infections. Infection during
a critical stage of fetal development, other host characteristics, or treatment
with intrauterine blood transfusion, may have allowed induction of tolerance to B19 and/or the development of an autoimmune response to erythroid precursors; an anti-idiotypic response to B19 directed to the viral attachment epitopes would have globoside or blood group P antigen
specificity and might therefore be directed against erythroid precursors
(which have P antigen on their cell surface).
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Although thrombocytopenia, myocarditis and vasculitis are unusual presentations, there have been a number of case reports documenting an association with B19 infection [71]. The cellular receptor, P antigen, is present
on the plasma membranes of megakaryocytes, endothelial cells, and fetal
myocardium [52, 53], and B19 may bind to these cells; however none have
been shown to be permissive for B19 replication. Transfection studies of permissive and non-permissive cells with plasmids containing the B19 genome
suggest that in cells non-permissive for B19 there may be a block in fulllength transcript production, overproduction of the non-structural gene transcripts, with corresponding production of the cytotoxic non-structural protein [72]. Alternatively, binding of virus to the cell membrane may produce
a local inflammatory response and an associated localized vasculitis. B19
may by these mechanisms cause cell death and organ destruction without
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Kevin E. Brown, Bldg 10/Room 7C218, National Institutes of Health, 9000 Rockville Pike,
Bethesda, MD 20892 (USA)
Tel. +1 301 496 2479, Fax +1 301 496 8396, E-Mail
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combined immunodeficiency associated with chronic pure red cell aplasia. Eur J Pediatr
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