Journal of Internal Medicine 2006; 260: 285–304
REVIEW
Clinical aspects of parvovirus B19 infection
K. BROLIDEN, T. TOLFVENSTAM & O. NORBECK
From the Department of Medicine, Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska Institutet, Karolinska University
Hospital, Stockholm, Sweden
Abstract. Broliden K, Tolfvenstam T, Norbeck O
(Karolinska Institutet, Karolinska University Hospi-
tal, Stockholm, Sweden). Clinical aspects of parvo-
virus B19 infection (Review). J Intern Med 2006;
260: 285–304.
Parvovirus B19 is a significant human pathogen
that causes a wide spectrum of clinical complica-
tions ranging from mild, self-limiting erythema in-
fectiosum in immunocompetent children to lethal
cytopenias in immunocompromised patients and
intrauterine foetal death in primary infected preg-
nant women. The infection may also be persistent
Viral characteristics
Parvovirus B19 (‘B19’) is a member of the erythro-
viruses, named so because of a pronounced tropism
for erythroid precursor cells. It is a single-stranded
nonenveloped DNA virus and one of the smallest
viruses known to infect mammalian cells [1]. B19 is
genetically stable, and sequenced isolates have
shown low variability in the range of a few
percentage for the two capsid proteins VP1 and
VP2, and even lower for the nonstructural protein
NS1 [2–4] (Fig. 1). Differences in clinical manifes-
tations of B19 infection have not been explained by
B19 sequence variability [5–8]. Novel viral isolates
have now also been sequenced that are similar to
B19 only to about 88–90%, and are proposed to
compose two novel genotypes within the erythrovi-
rus genus. These variants are not readily detected
by available B19 serology and polymerase chain
 2006 Blackwell Publishing Ltd
doi:10.1111/j.1365-2796.2006.01697.
and can mimic or trigger autoimmune inflammatory
disorders. Another important clinical aspect to
consider is the risk of infection through B19-con-
taminated blood products. Recent advances in
diagnosis and pathogenesis, new insights in the
cellular immune response and newly discovered
genotypes of human parvoviruses form a platform
for the development of modern therapeutic and
prophylactic alternatives.
Keywords: B19, clinical management, diagnosis,
parvovirus, pathogenesis, pregnancy
reaction (PCR) assays [9–13]. Recently, another
human parvovirus provisionally named human
bocavirus was cloned by molecular screening of
respiratory tract samples from children with lower
respiratory tract infections [14]. Although these
novel genotypes are capable of human infection and
were initially detected in individuals with B19-
related disease, the potential pathology has yet to be
established [8, 12, 15].
Infection and tropism
B19 is thought to exclusively infect humans, and
shows a pronounced tropism for erythroid precur-
sors [16–18]. The virus is very stable and often
survives in blood products despite standard proce-
dures for viral elimination [19, 20]. B19 uses at least
three cellular receptors for cell attachment and
entry. The first to be identified was the glycolipid
285
286 K . B R O L I D E N et al.
Fig. 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 nonstruc-
tural protein NS-1 and two capsid proteins VP1 and VP2.
globoside, also known as the blood group P antigen
(P-ag) [21, 22]. P-ag is present on the haematopoi-
etic precursors, erythroblasts and megakaryocytes
that B19 shows tropism for and also on a variety of
other cells including endothelial cells, foetal myo-
cytes, and placental trophoblasts [23–27]. These
latter cells have been thought to represent nonper-
missive cells into which B19 can enter but not
produce complete virions. For a productive infection
to occur, a co-receptor has been defined, the a5b1-
integrin. This integrin is involved in cell adhesion
and is expressed on erythroid progenitors, which
might explain the tropism of B19 and the active
replication seen in these cells [28, 29]. Another
molecule, the Ku80 autoantigen, has also been
suggested as a co-receptor for B19 allowing entry
into cells [30].
Epidemiology
B19 is a common virus that is spread worldwide,
and the seroprevalence increases with age, so that
15% of preschool children, 50% of younger adults
and about 85% of the elderly show serologic
evidence of past infection [31–35]. In developing
countries the seroprevalence has been shown to be a
little higher, probably because of poor and crowded
living standards, whereas in isolated tribal com-
munities seroprevalence figures are below 10%
[36–38]. Infection appears to confer lifelong immu-
nity to immunocompetent hosts. Although the
 2006 Blackwell Publishing Ltd Journal of Internal Medicine 260: 285–304
seroprevalence is high, viraemia or presence of viral
DNA is rare in healthy individuals. The frequency
of B19 viraemia in voluntary blood donors has
been estimated at rates of 1 : 167 to 1 : 35 000 [35,
39–43]. The frequency varies greatly depending on
epidemic periods and sensitivity of the methodology
used. Although B19 viraemia in blood is rare,
presence of B19 DNA in bone marrow (BM) samples
can be found by PCR in 2% of healthy individuals
and in up to 10% of children with haematologic
malignancies without concomitant viraemia [31,
44, 45]. The persistency of B19 DNA may represent
both infectious virus and residual DNA from remote
infection.
The incidence of infection shows a seasonal
variation in temperate climates, being more com-
mon during winter and early spring [46]. Epidemics
are noted at intervals of about 3–4 years, with
outbreaks of erythema infectiosum (EI) and B19-
related disease. B19 is normally transmitted through
the respiratory route, but can also be transmitted
vertically from the mother to the foetus, through BM
and organ transplantations, and via transfused
blood products [42, 47–51]. As most infections
occur in children aged 5–15 years, adults at risk are
parents of children in that age group, or those
working at day care centres or schools [52–54]. The
secondary attack rate during epidemics of EI is about
50% in susceptible children and 25% in susceptible
teachers [53, 55]. Nosocomial transmission may
occur and although rare, is a potential risk in
paediatric wards for immunocompromised children
[56–58].
Blood product safety
The genomic stability and the absence of a lipid
envelope make B19 resistant to heat inactivation
and solvent detergents normally used to inactivate
viral concomitants in blood products. The risk of
transmission through blood transfusions and plas-
ma-derived products has been known for many
years [59–63] and many manufacturers of plasma
derivatives screen their products by quantitative
PCR [64]. Quantitative measurements of B19 DNA
should also be considered in blood transfusions
intended for immunosuppressed individuals and
other risk groups, which has been reviewed by
Corcoran and Doyle [65]. Indeed, recommendations
have been made in the Netherlands that blood
 REVIEW: PARVOVIRUS B19 INFECTION 287

donors with high anti-B19 immunoglobulin G (IgG) children with low-grade fever, malaise and a char-
titres should be used for donations to high-risk acteristic facial rash that has given rise to the name
recipients [66]. ‘Slapped cheek syndrome’. Arthralgia may occur in
We thus still need to learn more about risk some children with EI but is not as common as in
judgement in recipients of blood products. The adults. The slapped-cheek appearance is followed by
susceptibility depends not only on host factors but the spread of a maculopapular rash on the trunk,
also on the relation of viral load and anti-B19 IgG back and extremities (Fig. 2). The infection is
titres in the blood product [67, 68]. Life-threatening normally self-limiting within a week or two but
B19 infection has even been transmitted by intra- the rash can be recurrent for some months following
venous immunoglobulin (IVIG) [69]. exposure to sunlight, heat, emotion, or exercise [75].
The rash and the joint symptoms are most likely
caused by immune complex deposition.
Clinical manifestations
After the discovery in 1974, it was not until 1981 a
Arthropathy
distinct disease was associated with infection of B19
when it was detected in a sickle-cell anaemic patient On average, 50% of adult cases of EI have associated
with transient aplastic crisis (TAC) [70]. It was joint manifestations that may persist for weeks to
subsequently shown to be the cause of EI in 1983, a months, and in a few cases for years. The typical facial
disease first described in 1799 [71]. exanthema and fever of EI is only seen in a minority of
The features of B19 infection have been studied in
experimental infections of healthy individuals [72,
73]. After intranasal inoculation of B19, there was a
biphasic clinical course. The viraemia peaked after
8–9 days at 1011 virions per mL, with viral excre-
tion through the respiratory tract, but not via urine
or faeces, accompanied with mild symptoms of fever,
malaise, myalgia and pruritus. About three weeks
after infection, a second phase of symptoms devel-
oped, with typical maculopapular rash for the B19
infection and in some cases arthralgia. The BM was
normal after 6 days, but on day 10 there was an
almost complete loss of erythroid precursors, and a
subsequent marked drop in the reticulocyte counts
was noted in peripheral blood. The effects on the
haemoglobin level and other blood cell counts were
less pronounced.
Since the time of these experiments, the wide
clinical spectrum of B19-associated complications
has been dissected and the different outcomes
depend heavily on the immune status of the host.

Erythema infectiosum
Erythema infectiosum is the most common clinical
manifestation of B19 infection in immunocompetent
hosts although asymptomatic infection is seen in
25–50% of infected individuals [55, 74]. Another
name for EI is the ‘Fifth disease’, referring to a fifth
place in a listing of the common infections dur-
ing childhood. Classically, EI affects school-aged
Fig. 2 The pathogenesis of erythema infectiosum is probably a
result of antibody-antigen immune complex depositions in skin,
blood vessels and synovia. The rash typically appears on the
cheeks followed by a lace-like maculopapular rash on the upper
part of the body. Joint symptoms are more common in adults than
in children. In addition to deposition of immune complexes, the
inflammatory response in synovial tissue may be a result of the
secreted phospholipase A2 motif in the unique region of the B19
minor capsid protein [89].

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288 K . B R O L I D E N et al.
adult cases. The arthropathy is particularly common
in middle-aged women, and is characterized by a
polyarthritis typically involving the metacarpopha-
langeal joints, knees, wrists, or ankles [76–79]. Both
arthralgia and inflammatory arthritis may occur and
the arthropathy sometimes even mimics classical
rheumatoid arthritis (RA). The joint involvement is
however not erosive and is probably immune-medi-
ated as it appears simultaneously with circulating
antibodies. B19 DNA has indeed been detected in
synovial fluid and biopsies in both acute and remotely
infected individuals [80–83]. Although B19 infection
may mimic RA, and even trigger a positive test for
rheumatoid factor, its role in the aetiology of this
disease has not been proved [84, 85].
Kerr et al. [86] have described an association
between development of symptoms during B19
infection and carriage of the HLA-DRB1*01, *04,
and *07 alleles. B19-associated arthritis may thus at
least partly be genetically associated and has, in
earlier studies, been shown to be more common in
individuals with HLA DR4 or B27 [87, 88]. The
mechanism of the arthropathy is partly unknown.
In addition to immune-mediated inflammation, one
hypothesis include the activation of synoviocytes by
the secreted phospholipase A2 motif in the B19 VP1
unique region. This activity would thus accelerate
the inflammatory response in synovial tissue [89].
The B19 NS1 protein causes the secretion of
proinflammatory cytokines, which could contribute
to the arthritis and inflammatory and autoimmune
disorders associated with the infection [90, 91].
Furthermore, peptides derived from VP2 may be
pathogenic in B19 arthropathy as they can induce
cross-reactive autoantibodies against human kera-
tin, collagen, and cardiolipin [92].
Autoimmune disorders
Apart from RA, B19 infection has been associated
with the onset of numerous autoimmune disorders
including systemic lupus erythematosus (SLE) [93,
94], other connective tissue diseases and systemic
vasculitides. Although a few cases of erosive RA and
SLE have been associated with B19 infection, the
virus is probably an extremely rare cause of these
diseases. Systemic vasculitides including for example
Henoch-Schönlein pupura [95], periarteritis nodosa
[96], and giant cell arteritis [97] can occur after
acute B19 infection. The role of B19 in these
 2006 Blackwell Publishing Ltd Journal of Internal Medicine 260: 285–304
disorders is not clear and in some cases the infection
may be a pure coincidence and in other cases it can
be a triggering or even a rare aetiological factor. In
any case, the infection is an important differential
diagnosis for several autoimmune disorders both in
clinical presentation and in immunological tests. In
conclusion, in individuals with immunogenetic pre-
disposing factors B19 may indeed be capable of
causing at least arthropathy associated with severe,
long-lasting morbidity.
Many viral infections including B19 induce the
production of autoantibodies. Although these re-
sponses are normally of short duration they can
create diagnostic difficulties. As reviewed by Meyer
[98], B19 can, for example, induce antibodies to
double-stranded DNA, anti-nuclear soluble antigens,
cardiolipin and rheumatoid factor. The autoanti-
body production most likely results from both
polyclonal stimulation of immune responses and
production of polyspecific anti-B19 antibodies [92].
Patients with increased red cell turnover
In patients with either decreased production or
increased loss of erythrocytes, there is a potential
risk that B19 infection leads to TAC. When the red
cell turnover is increased, the suppression of the BM
caused by B19 leads to a severe drop in the
haemoglobin level that can be fatal. This was first
described in patients with haemolytic anaemia, but
can occur in patients with a wide range of disorders,
including thalassemia, hereditary spherocytosis,
sickle-cell anaemia, malaria and even iron deficiency
and haemorrhage [70, 99–104]. In addition to a
cessation of the erythroid production, other blood
cell lineages can be affected with clinically signifi-
cant thrombocytopenia, neutropenia or pancytope-
nia as the result (Fig. 3) [105–107].
Once the immune response clears the infection,
the red cell production resumes and eventually
normalizes followed by lifelong immunity in most
cases. However, the aplastic crisis can cause severe
and even fatal anaemia resulting in congestive heart
failure, cerebrovascular events, and acute splenic
sequestration [108].
Other B19 associated disorders
B19 has a cardiotropic potential as P-ag is
expressed by myocytes and B19 DNA has indeed
 REVIEW: PARVOVIRUS B19 INFECTION 289

Fig. 3 B19 binds to immature erythroblasts thereby arresting production of mature erythropoietic cells. Following acute infection, the
reticulocyte count in peripheral blood is zero and if the patients have an underlying disorder with pathologic red cell survival, the number of
erythocytes may fall dramatically in peripheral blood. The pathogenesis of thrombocytopenia is thought to be explained by the cytotoxicity
of the NS1 protein [238].

been detected in heart tissue [24, 43, 109]. Cases
of sometimes fatal myocarditis and heart failure in
both children and adults have been reported [110–
115].
Other B19-associated disorders include hepatitis
[116–118], transient erythroblastopenia of child-
hood [119], neutropenia [120], trombocytopenia
[121], Kawasaki disease [122], Gloves-and-sock
syndrome [123], neurological disease including
meningitis and encephalitis [124, 125], fibromyal-
gia and chronic fatigue syndrome [126, 127].
Several other manifestations of B19 infection have
been reported and have been reviewed in detail by
Heegaard and Brown [128], but the evidence for a
clear causality, as stated above, is sometimes scarce.
It must be pointed out that apart from BM which is
the primary site of viral replication, B19 DNA is
found in tissues like synovia [83, 129], liver [130]
and in skin [131] in both B19-associated clinical
disorders and in healthy controls. This emphasize
that caution should be taken in drawing conclusions
 2006 Blackwell Publishing Ltd Journal of Internal Medicine 260: 285–304
about the aetiology of B19 in rheumatic and other
disorders.
B19 infection in immunocompromised individuals
The clinical picture of acute and persistent B19
infection in the immunocompromised host differs
significantly from immunocompetent subjects. In
the absence of an efficient humoral and/or cellular
immune response, the infection can cause persistent
BM suppression manifested by chronic anaemia but
not supposedly immune-mediated symptoms such as
rash and arthralgia [132]. Predisposing conditions
include congenital immunodeficiencies, leukaemia,
lymphoma, myelodysplastic syndrome, BM and solid
organ transplantation, chemotherapy, and infection
with human immunodeficiency virus [50, 51, 132–
142].
About 5% of adult patients and 10% of children
undergoing chemotherapy for haematological
malignancies are persistently infected with the virus
290 K . B R O L I D E N et al.

resulting in severe and even lethal cytopenias
whereas about 1–2% of organ and stem cell trans-
planted patients have life-threatening complications
caused by parvovirus infection [45, 50]. Cases of
parvovirus-associated pancytopenias or isolated
‘penias’ of different haematological cell lineages
can be misinterpreted as relapse of the underlying
malignant disorder or of other microbial infections,
graft failure or drug toxicity. In Fig. 4, a case of B19
infection in a child suffering from acute lymphatic
leukaemia is shown. In a group of children with
acute leukaemia, the number of days of unwanted
treatment interruptions was significantly higher in
parvovirus infected than in uninfected individuals
which is associated with poor prognosis (K. Broliden,
unpublished observation). Early diagnosis of parvo-
virus infection is therefore of extreme importance
and the infection can be treated with either blood
transfusion or intravenous immunoglobulin.
Many immunodeficiencies affect the production of
neutralizing antibodies against the virus resulting in
persistent infections associated with chronic anae-
mia [141, 143]. However, conditions or chemother-
apies leading to deficient cellular immune responses
may also result in persistent infections. The contri-
bution of the cellular immune response for elimin-
ation of B19 may thus explain why IVIG therapy
does not always clear infection in some cases and

Fig. 4 The clinical and laboratory outcome of a 10-year-old girl with acute lymphocytic leukaemia and B19 infection, adapted from
Broliden et al. [45]. The infection was not diagnosed until the end of December and thus the B19 diagnostic parameters were performed in
retrospect. During maintenance chemotherapy the patient developed a rash on her cheeks in April. The rash reappeared two times during
the observation time. During the ongoing B19 viraemia she had several periods of severe cytopenias that required blood transfusions. A
relapse of the leukaemia was suspected and a new bone marrow aspirate was performed in December. At this time the B19 diagnosis was
finally suspected and upon additional blood transfusions and three weekly periods of interruptions of the chemotherapy (November–
December) the infection spontaneously resolved. It can be speculated that early diagnosis already at time of the first rash and cytopenic
period in April followed by IVIG treatment could have led to immediate elimination of the B19 infection and avoidance of the critical course
of infection. It should also be noted that serology is unreliable in immunodeficient patients as she did not develop IgG and IgM until the end
of the infection when the immune system recovered following treatment interruption.

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 REVIEW: PARVOVIRUS B19 INFECTION 291

why chronic infection is seen in the presence of
neutralizing antibodies without viral clearance. Yet
another case demonstrating that neutralizing anti-
bodies may be complemented by a cellular immune
response was an AIDS patient with persistent B19
infection who showed an initial remission of B19
infection in the absence of a specific antibody
response [144].
B19 persistence in immunocompetent patients
In immunocompromised individuals, B19 is known
to cause persistent infection with potentially severe
and chronic anaemia as the result. In addition, B19
seems to be capable of persisting in a subset of
apparently immunocompetent individuals. B19 is
thus reported to be present in about 2% of BM
samples from healthy individuals [31]. The persist-
ence in these individuals is, however, not only
seemingly perpetual but also associated with various
long-lasting symptoms such as fatigue, fever, arth-
ralgia, and myalgia [145]. The symptom complex is
sometimes similar to the chronic fatigue syndrome,
and B19 has been proposed to play a role in this
disease [127, 146, 147]. Whereas no specific
sequence variations in the viral genome [3] or
abnormal humoral B19 epitope specificities [148] or
lack of functional neutralizing antibodies [145]
could explain the persistence, a selective defect
in the cellular immune response was seen in
immunocompetent subjects together with an altered
cytokine profile (K. Broliden, unpublished data)
[149]. However, the role of this aberrant cellular
immune response in relation to clinical symptoms or
establishment of the persistent infection has not
been proved.
B19 and pregnancy: vertical transmission and foetal
hydrops
The association between foetal B19 infection and the
development of non-immune foetal hydrops was first
proposed by Brown et al., and it is estimated that
about 15–20% of cases of non-immune hydrops
fetalis are caused by B19 [150–152]. About 50% of
pregnant women are susceptible to B19 infection,
and maternal infection is reported to occur in a few
percentage of pregnancies [153, 154]. There is
approximately a 30% risk of vertical transmission to
the foetus, and the over-all risk of an abnormal
outcome after maternal infection is estimated to 5–
10% [49, 151, 155–158]. Transmission over the
placenta is reportedly most likely to occur in the first
or second trimester, as placental P-ag, which may be
necessary for transmission, becomes less frequent
with increasing gestational age [23]. The infection
causes anaemia, hypoalbuminaemia, inflammation
of the liver and possible myocarditis, leading to
cardiac failure and the development of foetal hy-
drops (Fig. 5) [159]. The condition may resolve but

Fig. 5 Vertical transmission of B19 from a primary infected mother may cause foetal infection. Pathogenic mechanisms include devel-
opment of acute anaemia upon infection of foetal haematopoietic cells. In early pregnancy haematopoiesis is seen in the liver and in later
pregnancy this shifts to the bone marrow. The anaemia may resolve spontaneously or proceed by causing cardiac failure and development
of hydrops fetalis and in rare cases foetal death. The virus may also cause myocarditis and heart arrest by direct infection of myocardial
tissue. Modified from Anderson and Young [239].

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292 K . B R O L I D E N et al.
can also result in foetal death, with a mean time
span between maternal infection and foetal symp-
toms of six weeks, but it may be several months in
rare cases [151, 160–162].
Foetal B19 infection may also be asymptomatic,
and there are several observations of infants born
healthy despite evidence of intrauterine infection
diagnosed by the presence of IgM in umbilical cord
blood [163]. Malformations as a consequence of
intrauterine B19 infection have been reported in a
few isolated cases [164–166], but has not been
concluded to be a common feature of this infection
[49, 167].
B19 and pregnancy: intrauterine foetal death (IUFD)
There has been a prevailing apprehension that foetal
demise caused by B19 infection in the third trimester
is extremely rare or even nonexistent, but B19 is a
common cause of IUFD also in late gestation, but
without foetal hydrops in a majority of cases [168–
170]. By investigating cases of IUFD during a 6-year
period we found B19 DNA by PCR in 14%
representing both second and third trimester cases.
Table 1 summarizes the different pictures of B19-
associated IUFD that have emerged from our own
studies. In the first trimester B19 DNA was found in
3% of cases of spontaneous abortion and an
etiological link could not be proved [171]. In the
second trimester, a serologically evident recent
infection could be demonstrated in maternal sera.
The foetuses were normally hydropic and B19 DNA
was detected by PCR in foetal tissues and placenta
and histopathological investigation often confirmed
the diagnosis [168, 169]. This picture of second
trimester IUFD cases is often reported in studies
Table 1 Clinical complications associated with B19 infection during pregnancy
Trimester
First
Clinical foetal complication Spontaneous abortion
Frequency of B19-DNA positivity 3%
in placenta and/or foetal tissue
Maternal symptoms None
Maternal B19-IgM reactivity Negative
The table summarizes a generalized picture of more than 150 cases of spontaneous abortions and IUFDs representing different time-points
(trimesters) during pregnancy. The studies were performed by a nested B19 PCR technique for detection of qualitative PCR in placental and/
or foetal tissue [168–171].
 2006 Blackwell Publishing Ltd Journal of Internal Medicine 260: 285–304
selecting for hydrops or serologically evident infec-
tion [172]. On the other hand, a partly revised
clinical picture was proposed by our studies on B19
infection in late gestation [170]. The foetuses in
third trimester IUFD associated with B19 infection
were rarely hydropic and recent maternal infection
was not commonly evident by the detection of B19-
specific IgM. Maternal IgG may be present, or
seroconversion may occur months later following
IUFD [168]. The diagnosis was not readily estab-
lished by histopathological methods but viral DNA
was detected in foetal tissues and placenta.
It is interesting to speculate in the mechanisms
underlying these different pictures at various time of
gestation. The proposed pathogenic mechanism in
foetal infection is summarized in Fig. 5 as mentioned
above. In the second trimester, P-ag is present on
the trophoblast layer in the placenta to allow the
vertical transmission of B19 to the foetus from the
infected mother [23]. The haematopoiesis is at this
time located in the liver and is extremely active to
increase the erythrocyte cell mass 34-fold to match
the raised demand from the growing foetus. At the
same time, the lifespan of the red blood cells is
decreased to 45–70 days, making the foetus very
vulnerable to any pause in the haematopoietic
production [43]. The destruction of late erythroid
precursors, caused by the B19 infection, leads to
severe anaemia that in combination with the
hepatic inflammation and possibly myocarditis due
to B19 infection of cardiac myocytes, results in heart
failure and the development of hydrops fetalis. In
contrast, in the third trimester, the haematopoiesis
migrates to the BM, the need for a quickly increasing
red blood cell mass is relieved, and the lifespan of
the erythrocytes is normalized. The cellular receptor
Second Third
Hydrops fetalis and/ Foetal death
or foetal death
12% 7%
None or erythema infectiosum None
Positive Negative
 REVIEW: PARVOVIRUS B19 INFECTION
P-ag is virtually nonpresent in the third trimester
[23]. These factors act in concert to make the
development of anaemia and subsequent heart
failure and hydrops less likely. A low-grade persist-
ent foetal and/or maternal infection may also cause
IUFD at a later time-point, and in the case of
placental dysfunction even without foetal infection.
Degenerative lesions have been shown in the
placenta due to the inflammatory response to B19
infection [109, 159, 173, 174]. In the foetus,
myocarditis may be the cause of death caused by
dysrhythmia or cardiac arrest without the develop-
ment of anaemia or hydrops [159, 175]. Indeed,
investigation of endomyocardial biopsy specimens
revealed B19-associated inflammatory changes in
15% of cases of peripartum cardiomyopathy [176].
Immune responses in B19 infection
B19 is regarded to show a ‘hit-and-run’ mode of
infection, which in the normal host is believed to
quickly resolve with successful eradication of the
virus. Prolonged detection of B19 DNA peripherally,
in BM and in other compartments is now reported
by several investigators, indicating that it may take
longer to eradicate the virus than previously
thought [80, 177–180]. Viral and host properties
have thus been explored to explain this failure to
eventually clear the virus.
Immune responses to acute infection
The humoral immune response is thought to be the
most important in infections with short replication
cycles, characterized by quick lysis of the infected
cells and release of free virions readily exposed to
antibodies that can bind to them and facilitate their
destruction [181]. On the other hand, nonlytic and
persistent viruses such as human hepatitis B virus
(HBV), are less exposed to the humoral immune
system and the host is therefore more dependent on
the cellular immune response to localize and kill
infected cells [182, 183].
The humoral immune response has been the focus
of most studies on B19 and immunity, whereas the
cellular response and the CD8+ T cell response in
particular, has been detected and investigated only
recently [184]. Being a virus that shares character-
istics both with classically lytic resolving viruses and
nonlytic and persistent viruses, it is not surprising
 2006 Blackwell Publishing Ltd Journal of Internal Medicine 260: 285–304
293
that both the humoral and the cellular immune
systems are mounted to battle B19.
It was first reported that no cellular immune
responses were mounted in B19 infection, but
CD4+ T cell proliferative responses directed to VP1
and VP2 have now been shown in seropositive
individuals [185–189]. Analogous to the humoral
response, CD4+ T cell responses to NS1 may be
associated with acute and persistent arthropathy
[190]. In contrast, our studies of the CD8+ T-cell
response have revealed a predominance of NS1-
directed responses in acute and remote infection
whereas a skewing of the response towards VP2
was seen in persistent infection [184].
In 2001, Tolfvenstam et al. [184] defined the first
B19-specific CD8+ T-cell epitope in an individual
with remote infection, providing the first evidence of
an existent cytotoxic cellular response to this infec-
tion. In another report [191], this finding was
explored by following individuals with documented
primary B19 infection during the acute phase and a
thorough phenotypic analysis was later performed
on the CD8+ T cells [192]. The CD8+ T-cell
responses were mounted against three to five
epitopes per individual with no sign of changing
specificities over time, as for example seen in
infection with the latent cytomegalovirus virus
(CMV) [193]. The finding of predominantly NS1
specificities in acutely infected patients contrasts
what is known about the humoral response to B19,
where the neutralizing epitopes have been shown to
be located mainly in the structural proteins [194–
196]. The most unexpected finding was the lack of
rapid contraction of the expanded CD8+ T-cell clones
thought to be the hallmark of resolving infections of
the ‘hit-and-run’ type [197, 198]. Sustained re-
sponses were shown that in most cases peaked after
1 year and were still detectable after 2 years
(Fig. 6). Maintenance of the responses seems un-
likely in the absence of antigenic drive, which means
that B19, although not a classically persistent virus,
manage to persist in the body for an extended period
of time; and B19 may thus be more of a ‘hit-and-
hang’ type of infecting virus. Indeed, we detected
peripheral B19 DNA by PCR for over 1 year in some
of the patients, one of whom was still DNA positive
in the last sample collected after a little more than
2 years. It is plausible that B19 persists even longer
in the BM, although undetectable in peripheral
blood [145].
294 K . B R O L I D E N et al.

Fig. 6 B19-specific CD8+ T-cell responses in relation to B19 viraemia in a healthy immunocompetent individual who acquired acute B19
infection with the onset of symptoms (rash, arthritis and fever) at time-point zero. B19 IgG and B19 IgM were present at onset of symptoms
and the B19 IgM response disappeared after a few months. The B19-specific CD8+ response was measured in an ELISpot assay (gamma-
interferon secretion) by using overlapping B19-specific peptides covering the whole B19 genome, adapted from Norbeck et al. [191]. Thus,
this patient showed sustained levels of cells with three different specificities against the NS-1 protein (as represented by the blue, green and
red line, respectively). No response was seen against the capsid proteins VP1 or VP2. The CD8+ T-cell response was subsequently confirmed
by tetramer staining and the phenotypic markers were followed over time by multicolour staining using flow cytometry [192]. The
corresponding viral titres are also shown (black line) [180]. The Y-axis indicates number of spot-forming cells per 106 PBMC.

the infection with high viral load as a result

Immune responses in persistently infected individuals
Recent data thus suggested that there is a skewing
of the CD8+ T-cell responses in persistently infec-
ted individuals to the structural proteins when
compared with acutely infected and healthy indi-
viduals [149]. This is the first time a discrepancy
in the immune response was shown between
healthy and persistently B19-infected individuals,
and the lack of an efficient NS1 response may
allow the virus to establish persistence. However,
the other way around should be considered,
namely that the persistence and the continuous
antigenic stimulation results in exhaustion of the
NS1 response, a phenomenon reported to occur in
persistent infection [199]. The failed NS1 response
may in turn favour the expansion of VP-specific
CD8+ T-cell clones. It has been reported that
clones of CD8+ T cells with high antigenic
sensitivity are activated first, but succumb due to
exhaustion if they for some reason fail to control
 2006 Blackwell Publishing Ltd Journal of Internal Medicine 260: 285–304
[200]. In this situation clones with lower sensi-
tivity, possibly represented by the VP-specific CD8+
T cells in our study, have a better chance to avoid
exhaustion but may not achieve viral clearance.
In persistent HBV infection, low T-cell numbers is
reported and is possibly the result of immunologic
exhaustion [201]. The situation in persistent B19
infection may thus resemble that of HBV infection,
and the increased T-cell activity seen after inter-
feron treatment of HBV infection, suggests that a
similar approach might prove beneficial also in
B19-persistent infection [202]. Recently, Corcoran
et al. [203] showed persistent infection in a child
with acute lymphatic leukaemia despite the treat-
ment with intravenous immunoglobulin. Interest-
ingly, resolution of the infection was associated
with the simultaneous strengthening of antigen-
specific B-cell memory against B19 VP2 and
diminution in the memory response against B19
NS1.
 REVIEW: PARVOVIRUS B19 INFECTION
Diagnosis
Modern diagnostics of B19 infection usually include
measurement of B19 IgG and IgM antibodies in
blood and B19 DNA in blood or tissue samples by
PCR. Morphologically, BM aspirates show no mature
erythroid precursors and with characteristic giant
pronormoblasts at time of acute infection. Immu-
nohistochemistry may also be very specific and a
complement to the more sensitive PCR assay in
cases of placental or foetal infection.
Serology
Specific IgM antibodies directed to VP2 are present
after 10–12 days after infection and usually disap-
pear within 3–4 months, even though they may
occasionally remain detectable longer [204]. The
maturation and shift to IgG occurs shortly after the
advent of IgM, and these high-avidity antibodies
are believed to mediate lifelong immunity, with
slowly decreasing titres boosted by subsequent
encounters with B19. IgA antibodies are also
detectable for a short period and may play a
protective role in the respiratory tract [205]. In
addition, long-term B19-specific IgE antibodies
have been shown, but with unclear biological
function [206]. The IgG is directed to both VP1
and VP2 with the majority of linear epitopes
located in the VP1ur and the junction between
VP1 and VP2, and these specificities are reported to
represent the most effective immune response
[194]. However, others have shown that IgG
directed to VP2 is maintained even when IgG
directed to linear epitopes within VP1 is lost,
indicating immunodominance for VP2 [187, 195,
196]. Either way, the humoral responses seem to
be directed to the structural proteins in normal
infection, with persistence of IgG antibodies direc-
ted to conformational epitopes. Antibodies directed
to NS1 have been described to be a feature only of
acute and persistent infection [207–209], but this
has not been confirmed in other studies [210–212].
Caution should be made when interpreting serol-
ogy in immunodeficient individuals and in pregnant
women. Due to their immune status they are not
always able to mount an antibody response to
pathogens at all. Furthermore, blood products
or treatment with immunoglobulins may yield
false-positive B19 IgG responses. Supplementary
 2006 Blackwell Publishing Ltd Journal of Internal Medicine 260: 285–304
295
serological assays are sometimes needed for an accu-
rate diagnosis and timing of maternal infection dur-
ing pregnancy, which has recently been reviewed by
de Jong et al. [213] and Enders et al. [214].
Polymerase chain reaction
Serology must in many cases be complemented by
PCR analysis of B19 DNA. In immunocompromised
patients a positive PCR test in blood indicates
ongoing acute or persistent infection whereas a
positive PCR test in BM may indicate either acute or
remote infection as about 2% of healthy individuals
with remote infection are PCR positive [31]. In cases
of intrauterine foetal complications it can be very
useful to analyse amniotic fluid or cord blood for
viral DNA or RNA by PCR for differential diagnostic
purposes including B19 [215–218]. To learn more
about the clinical significance of viral load in foetal
infection is of high priority as therapeutic interven-
tion can be necessary in severe cases.
Detection of B19 DNA can thus be detected by
PCR in serum, BM and other tissues for diagnostic
purposes. Whilst B19 DNA may be positive also in
tissues of healthy individuals as previously men-
tioned, the development of a quantitative PCR has
been helpful in determining the viral load and
should be used routinely. This also allow differenti-
ation of human parvovirus variants [219, 220]. In
healthy individuals with acute B19 infection, viral
titres as high as 1012 geq mL)1 are detectable in
blood [61]. However, a marked drop is seen at time
of immunoglobulin production and onset of symp-
toms and titres remain at about 103 to 105 for
months and even a few years following acute
infection [180, 221]. Future studies will hopefully
determine the concentrations of viral load in differ-
ent tissues and clinical settings to guide the
clinicians in therapeutic choices.
Treatment and prophylaxis
There is no specific antiviral drug against B19
infection but a number of alternative options to
eliminate the virus can be recommended. The choice
of treatment of B19 infection must however take
host factors into account as the virus yields different
pathogenesis in different risk groups of patients
depending on underlying diseases and immunodefi-
ciency status (Table 2).
296 K . B R O L I D E N et al.

Table 2 Parvovirus B19-infection pathogenesis in different risk groups

Proposed Clinical and

Risk group pathogenesis laboratory signs Treatment

Immunocompetent Immune complex Erythema infectiosum, Antiinflammatory

individuals deposition arthropathy drugs
Patients with Reduced erythropoeisis Transient aplastic crisis Blood transfusion
increased
turnover of
red blood cells
Immunodeficient Deficient humoral and/or Chronic anemia IVIG
patients cellular immune response or cytopenia
Fetuses Deficient humoral and/or Hydrops fetalis, IUFD, anemia, Blood transfusion,
cellular immune response cardiac failure IVIG
Reduced erythropoiesis

The clinical and laboratory signs of B19 infection and corresponding therapeutic strategies is dependent on host factors and underlying
clinical disorders. For example, the pathogenesis in the B19-infected foetus is a result of the physiologically higher red blood cell turnover
and the relative immunodeficiency of the foetus. It must be pointed out that the infection resolves spontaneously in many cases in all risk
groups and treatment is therefore only given to severe cases.

antibodies does not respond well to IVIG treatment,

Immunocompetent hosts
There is no specific antiviral drug against B19 and
the infection does not normally need treatment in
the immunocompetent host. Nonsteroidal anti-
inflammatory drugs are sometimes useful for pro-
nounced symptoms such as arthralgia.
Transient aplastic crisis
Transient aplastic crisis usually requires hospitaliza-
tion and erythrocyte transfusions, but has good
prognosis if treated correctly with restored haema-
topoiesis within 1–10 days [103]. In a study inclu-
ding 62 patients with sickle-cell anaemia and B19-
induced TAC, 87% required transfusion therapy and
63% were hospitalized; one patient died before the
initiation of transfusion therapy [222].
Immunosuppressed patients
In immunosuppressed patients lacking neutralizing
antibodies, IVIG has proved to be useful for treatment
of persistent B19 infection. Administration of 0.4 g
kg)1 · 5 days or 1 g kg)1 · 3 days induces an in-
crease in reticulocytecount with an accompanied raise
in the haemoglobulin level, and is often curative in that
B19 is cleared from the body [58, 137, 142, 223].
Persistent infection in immunocompetent individuals
Persistent B19 infection in apparently immunocom-
petent individuals who already possess neutralizing
 2006 Blackwell Publishing Ltd Journal of Internal Medicine 260: 285–304
but it may induce a transient remission [145]. In
patients subject to chemotherapy or otherwise
iatrogenically immunosuppressed, a persistent B19
infection usually resolves upon cessation of the
therapy [224, 225].
Pregnancy
If B19 infection is confirmed in the pregnant
woman, monitoring of the foetus by weekly ultra-
sound examinations are usually recommended. It
must be emphasized though that foetal death may
occur several months postmaternal infection and
without foetal hydrops, or even in the absence of
laboratory or clinical signs of maternal infection
[160, 168, 226]. If hydrops and/or anaemia is
diagnosed by Doppler ultrasound and cordocentesis,
intrauterine erythrocyte transfusions have been
shown to reduce the mortality rate from about
50–18% [227–231]. Maternally administrated IVIG
or intrauterine therapy using B19 IgG-rich high titre
gamma-globulin has also been tried but needs
further evaluation [232, 233].
Vaccine development
A candidate vaccine has been tested consisting of
25% VP1 and 75% VP2, that with adjuvant elicits a
strong humoral response, and is well tolerated [234,
235]. The vaccine is optimized with a humoral
response in mind, which clearly has a well-docu-
mented role in B19 infection. However, in some
 REVIEW: PARVOVIRUS B19 INFECTION
situations the infection is not controlled despite the
presence of neutralizing antibodies, and evidence of
the importance of the cellular immune responses is
growing. Therefore, cellular immune responses
should be thought of when discussing responsiveness
to a future B19 vaccine. Our findings of a predom-
inant NS1-specific CD8+ T-cell response in normal
infection and the aberrant CD8+ T-cell response in
persistent infection may warrant the inclusion of
NS1 epitopes using T-cell vaccine techniques. Unfor-
tunately, commercial interest rather than lack of
efficacy and safety has limited the development of a
B19 vaccine [236]. The vaccine would primarily be
intended for certain risk groups of severe B19
infection. For example it could be used to prevent
TAC in patients with sickle-cell disease and pure red
cell anaemia (PRCA) in immunodeficient patients.
Whether seronegative women of childbearing age
should be included is a matter of controversy. The
risk of fatal outcome following maternal primary
infection may be too low to warrant a generalized
vaccination programme.
Conclusions and future perspectives
B19 infection causes a wide range of symptoms with
the most severe clinical outcome in foetuses and
immunosuppressed individuals. The infection can be
both acute as well as establish persistency. Although
BM is the major target organ for virus replication, the
persistent infections seen in some individuals for
years and even decades indicate that the virus may
reside in additional immunoprotected compart-
ments. The recently launched quantitative PCR
techniques for measurement of B19 DNA titres have
significantly improved the diagnostic repertoire as
serology and qualitative PCR is insufficient in some
cases. For example, increase in viral load could be
monitored prior to relapse of anaemia in an AIDS
patient with persistent B19 infection [237]. Likewise,
the possibility of monitoring transplanted patients for
B19 viral load with the aim of initiating preemptive
therapy may be a future strategy to combat viral
complications in this group of specific immunosup-
pressed patients. This strategy has been successful in
the case of CMV infections in BM-transplanted
patients. Furthermore, by performing quantitative
PCR in amniotic fluid, maternal sera and cord blood
we could correlate viral load to clinical outcome, in
which case the quantitative PCR could serve as a
 2006 Blackwell Publishing Ltd Journal of Internal Medicine 260: 285–304
297
diagnostic and prognostic tool, as well as be of
guidance for therapeutic intervention. However, we
still need to learn more about how to interpret
quantitative PCR results in blood and tissue samples
in relation to the immune status of the host.
B19 elicits a strong multi-specific CD8+ T-cell
response in the acute phase of the infection that is
sustained for up to 2 years. The specificity of the
response does not change during the course of
infection, and the response is probably antigen-
driven as B19 DNA is also durably detectable by PCR
in peripheral blood indicative of continued replica-
tion. This finding, unexpected in a virus typically
associated with ‘hit-and-run’ infection, reveals a
novel pattern of immune reactivity and mode of
infection for which the paraphrase ‘hit-and-hang’
may be more suitable. In contrast to the humoral
and CD4+ T-cell responses, the majority of the CD8+
T cell responses are directed to epitopes within NS1 in
normal infection. Based on the recent definition of
novel CD8+ T-cell epitopes, multimeric major histo-
compatibility complexes can be used for the detailed
study of B19-specific CD8+ T cells with regard to
frequency, phenotype and function. In this way, the
maturation of the CD8+ T-cell response in different
clinical manifestations of B19 infection can be
assessed. Such investigations could provide further
characterization of the concept of persistent versus
normal viral clearance patterns, and hopefully pro-
vide knowledge about the underlying mechanisms for
the unsuccessful clearance despite the presence of
neutralizing antibodies and specific CD8+ T cells.
Furthermore, the frequency, phenotype and function
of specific CD8+ T cells, peripherally and locally in the
placenta, will possibly reveal some new clues as to
what determines the outcome in foetal infection.
In summary, measurement of quantitative viral
titres and increased knowledge about the immune
response to the virus are new developments to study
B19 pathogenesis with the aim of improving the
medical care of infected patients.
Conflict of interest statement
The authors have no conflict of interest.
Acknowledgements
We hereby acknowledge the Swedish Children
Cancer Foundation, the Swedish Cancer Society,
298 K . B R O L I D E N et al.
the Swedish Medical Research Council and the
Tobias Foundation.
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Correspondence: Prof. Kristina Broliden, Department of Medicine,
Solna, Unit of Infectious Diseases, B2:00, Center for Molecular
Medicine, Karolinska Institutet, Karolinska University Hospital,
Solna, 171 76 Stockholm, Sweden.
(fax: +46 8 7178501; e-mail: kristina.broliden@karolinska.se).