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Microbiology, epidemiology, and pathogenesis of parvovirus

B19 infection
Author: Jeanne A Jordan, PhD
Section Editors: Martin S Hirsch, MD, Morven S Edwards, MD
Deputy Editor: Meg Sullivan, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2019. | This topic last updated: Feb 01, 2019.

INTRODUCTION

The Parvoviridae family contains two subfamilies: Parvovirinae, which infect mammals and birds, and
Densovirinae, which infect arthropods. The Parvovirinae subfamily has been subdivided into eight
genera, of which five include human pathogens: Erythroparvovirus (parvovirus B19),
Dependoparvovirus (adeno-associated virus), Protoparvovirus (bufavirus), Amdoparvovirus,
Bocaparvovirus (human bocavirus), Aveparvovirus, Copiparvovirus, and Tetraparvovirus (PARV4) [1].
The focus here will be limited to Erythroparvovirus genera in the family Parvoviridae, and mainly to
human parvovirus B19 (B19 prototype strain); only brief coverage will be given to the less common
genotype 2 (prototype strain: LaLi) and genotype 3 (prototype strain: V9) genera within this subfamily
[2].

Unless otherwise specified, parvovirus B19 will be the strain referred to when describing
epidemiology and transmission, which are discussed in this topic. The spectrum of disease
manifestations, diagnosis, treatment, and prevention of parvovirus B19 are discussed elsewhere. (See
"Clinical manifestations and diagnosis of parvovirus B19 infection" and "Treatment and prevention of
parvovirus B19 infection".)

VIROLOGY

Classification — There are three genotypes within the Erythroparvovirus genus. Parvovirus B19 is the
predominant parvovirus pathogen in humans and the prototype genotype 1 strain. Genotype 2
(prototype strain, LaLi) and genotype 3 (prototype strain, V9) are less common and more recently
described [3-5]. Genotypes 1 and 2 are typically found in western countries (eg, United States and
Europe), while genotype 3 circulates primarily in sub-Saharan Africa and South America [6], but has
been encountered in Europe and India. Compared with genotype 1, much less has been published on
the transmission and epidemiology of genotype 2 and genotype 3. The nucleotide sequence differs
among the three genotypes by 13 to 14 percent [5,7]. Not surprisingly, the divergence at the amino
acid level among the three genotypes is significantly less than that seen at the nucleotide level.

Viral structure — Parvovirus B19 is a small (26 nm), non-enveloped, single stranded DNA (5.6-kb)
virus. It is among the smallest of the DNA animal viruses. The linear genome encodes the following
proteins:

● Two viral capsid proteins: a minor structural protein VP1 (781 amino acids [aa], 84 kDa) and a
major structural protein VP2 (554 aa, 58 kDa). These are encoded by overlapping reading frames
and are expressed during productive infection. The smaller VP2 protein constitutes 95 percent of
the capsid while the larger VP1 protein makes up only 5 percent.

● Three nonstructural proteins: a large nonstructural protein, NS1 (671 aa, 78 kDa), and two smaller
nonstructural proteins (7.5 kDa and 11 kDa) [8,9]. The major nonstructural protein NS1 is a DNA
binding protein with helicase, nicking, and ATPase activity and is essential for viral DNA
replication. NS1 is cytotoxic and induces cellular apoptosis in both permissive and non-
permissive cell types [10,11]. The inflammatory response associated with B19 infection is the
result of NS1 transactivation of such pro-inflammatory cytokines as TNF-alpha, IL-6, and p21 [12-
14]. The NS1 protein is also responsible for inducing cell cycle arrest in erythroid progenitor cells
at the G2 phase [9].

Cellular tropism — One of the hallmarks of Erythroparvoviruses is their extremely limited host range.
The only known host for parvovirus B19 is humans [15]. Productive infections occur only in CD36
human erythroid progenitor cells. To date, erythroid precursor cells of the colony and burst forming
units (E-CFU and E-BFU) are the only cells known to support a fully productive infection with
parvovirus B19 [16].

The observed tropism of parvovirus is most likely due to the distribution of its cellular receptor, P
blood group antigen, also known as globoside, which is found in high concentrations on red blood
cells and their precursors [17]. Rare individuals who lack P antigen are resistant to infection with
parvovirus [18]. In a well-defined lipid bilayer model, parvovirus B19 viral-like capsids interacted with
globoside, suggesting a potential role of globoside as a receptor for B19 [19].

P antigen is also found to a lesser extent on other cell types, including endothelial cells,
cardiomyocytes, megakaryocytes, and placental trophoblast cells [20,21]. The globoside-containing,
non-erythroid cell types that become infected with parvovirus B19 produce little, if any, infectious
virus. However, these nonproductive infections may contribute to disease through the expression of
nonstructural (NS1) protein, which can induce cellular apoptosis in both permissive and non-
permissive cells [8,10,11,16].

Although P antigen may be necessary for infection, it is not sufficient. Some cell lines that are positive
for P antigen fail to bind, whereas other cell lines have an ability to bind parvovirus B19 despite lack
of P antigen [22]. Two coreceptors have been proposed for virus entry into target cells. These include
integrin alpha 5 beta 1 [23] and Ku80, an autoantigen [24]. After the initial B19 VP2-associated binding
to the globoside receptor, structural changes occur within the viral capsid, exposing VP1u protein
onto the surface of the capsid. This higher affinity binding to an as yet unknown receptor results in
internalization of the viral particle into the cytoplasm of the cell [25].

Viral life cycle — Following cell entry, viral DNA replication, RNA transcription, protein translation, and
virus capsid assembly all occur in the cell's nucleus. In high concentrations, virus particles can be
visualized in the nucleus by electron microscopy (EM). Upon viral maturation, parvovirus B19 causes
cell lysis. The cytopathic effect induced during B19 infection can be seen in the form of giant
pronormoblasts located in the patient's bone marrow [26]. These cells contain large eosinophilic
nuclear inclusions, cytoplasmic vacuolization, and marginated chromatin.

Active or reactivated infection may be distinguished from latent infection by differential microRNA
(miRNA) expression profiles. This was illustrated in a study of 60 patients with serologic evidence of
parvovirus B19 infection who underwent endomyocardial biopsy for non-acute cardiomyopathy [27].
There were 29 miRNAs that were differentially regulated in cardiac tissue between the 15 patients
with and the 45 patients without transcriptionally active parvovirus B19 infection (as manifest by
detectable parvovirus B19 mRNA in biopsy specimens). These miRNAs coded for differentially
expressed mRNAs from the cardiomyopathy and inflammatory response related pathways, including
TNFα, RORC, and Cox1.

EPIDEMIOLOGY

Geographic and temporal distribution — Parvovirus B19 infection occurs worldwide. Cases can be
sporadic or can occur in clustered outbreaks. Where reportable, communities have documented not
only a seasonality to parvovirus B19 infections, but also cycles of local epidemics with case numbers
that can peak every four to 10 years [28-30]. In the United States, parvovirus B19 infection occurs
more frequently between late winter and early summer.

Parvovirus B19 genotypes 2 and 3 are found much less commonly than genotype 1 in the US and
Europe [31]. Early on, genotypes 2 and 3 were primarily detected in Northern European countries but
are spreading (eg, Denmark, Finland, Sweden, France, and Germany) [3-5,32-34]. Genotype 3 is also
responsible for outbreaks in West African countries, Brazil, and India [6]. Genotypes 2 and 3 are also
identified among patients with underlying immune deficiencies.

Prevalence — Parvovirus B19 infection is common throughout the world. The percentage of people
with measurable levels of parvovirus B19-specific IgG increases with increasing age, with most
individuals becoming infected during their school years. During school outbreaks, 25 to 50 percent of
students and 20 percent or more of susceptible staff may become infected. Between 50 to 80 percent
of adults have measurable parvovirus B19-specific IgG antibodies [35,36]. Seroprevalence depends on
the assay type used to measure B19-specific IgG antibodies [37-39].

When considering women as a separate group, approximately half of women of child-bearing age and
approximately 30 to 40 percent of pregnant women lack measurable IgG to parvovirus B19 and are
therefore presumed to be susceptible to B19 infection, which then places their fetus at risk. (See
"Parvovirus B19 infection during pregnancy".)

Transmission and risk factors for infection — There are three documented modes of transmitting
parvovirus B19:

● Respiratory transmission – Parvovirus B19 is easily transmitted from person to person via the
respiratory route, which is the most common way an individual acquires this virus. Although
parvovirus B19 infection is not primarily associated with respiratory symptoms, parvovirus B19
has consistently been found in respiratory secretions during the viremic phase of infection [40-
42]. It can thus be transmitted through close person-to-person contact, fomites, and respiratory
secretions and/or saliva [42]. Due to their non-enveloped virion capsid, parvoviruses, including
B19, are stable in the environment, making fomites a likely and important source for
transmission.

Young children are the main source of respiratory-acquired parvovirus B19. Individuals at highest
risk for acquiring the virus include household contacts of infected individuals, daycare workers,
and those in a crowded environment. Household transmission appears to be especially efficient,
with about 50 percent of susceptible subjects becoming infected after household exposure to an
individual with erythema infectiosum or transient aplastic crisis [40,41]. In schools or child care
centers, transmission rates varied between 8 to 50 percent depending upon the intensity of the
exposure [43].

Many infections occur with no clearly defined exposure, especially during community outbreaks.
During one outbreak, the risk of infection without a clearly defined exposure was 6 percent [44].
Other studies found that 0.5 to 1.5 percent of women without a specific exposure or defined
community outbreak became infected during one year or during their pregnancy [37,45].
 Nosocomial transmission of parvovirus B19 can occur from patient-to-patient, patient-to-staff,
staff-to-patient, and staff-to-staff. In one study, for example, transmission from two patients with
transient aplastic crisis was noted in 36 and 42 percent of susceptible contacts [46]. In several
other reports, no source for infection was identified, but transmission apparently occurred
between staff and patients [47,48]. However, other series did not find nosocomial transmission
[49,50]; in these studies, the rate of infection in exposed or at-risk staff was similar to unexposed
staff and/or community controls. It is therefore likely that many cases of presumed nosocomial
transmission may actually represent infection acquired in the community during outbreaks of
B19.

● Vertical transmission – A susceptible woman who becomes infected with parvovirus B19 during
her pregnancy can transmit the virus to the fetus [51]. The risk of a poor outcome for the fetus is
greatest when the congenital infection occurs within the first 20 weeks of gestation. (See
"Parvovirus B19 infection during pregnancy".)

● Hematogenous transmission – Parvovirus B19 can be transmitted through blood or blood

products that contain the virus [52-57]. Infected blood donors may be asymptomatic yet have
very high circulating viral levels, up to 1012 viral particles/mL blood [58,59]. Individuals requiring
regular infusions of blood product(s) that are made from large plasma pools are at greatest risk
for acquiring the virus compared to those individuals receiving single units [54,55]. Both its small
size and its lack of a lipid envelope make parvovirus B19 extremely difficult to inactivate or
remove from blood products. In one study, 87 percent of 38 blood product and plasma pools
were positive for parvovirus B19 DNA by a PCR assay despite a variety of purification and
inactivation procedures [55]. Nanofiltration methods have been developed to help remove virus
particles during the manufacture of plasma derivatives or hemoglobin solution to prevent
transmission of viruses [60,61].

In 2004, the United States Food and Drug Administration (FDA) rolled out a new regulation
governing parvovirus B19 contamination of pooled plasma or blood products. B19 DNA levels
within pooled plasma used for manufacturing blood products must not exceed 104 international
units/mL [62]. This regulation was based on the observations in healthy volunteers that suggest
that acute parvovirus B19 infection can be acquired from administration of blood components
that contain greater than 107 genome equivalents/mL of viral DNA [63-65]. In contrast, patients
receiving less than 106 genome equivalents/mL have not shown evidence of virus transmission.
The presence of neutralizing activity in all these pools may help to explain the lack of infectivity
with exposure to lower viral loads [52,63,66]. Additionally, because nucleic acid amplification
testing (NAAT) can detect both intact parvovirus B19 genomes and fragments of degraded DNA,
it is important to be cautious in interpreting NAAT data from filtered blood products [67,68].
In contrast to parvovirus B19 infections, infections with the emerging human parvovirus 4 (PARV4)
are most frequently detected in people who inject drugs. PARV4 was first discovered in an injection
drug user who was co-infected with hepatitis B virus [69]. Co-infection of PARV4 is also seen with
other blood-borne virus like HIV and hepatitis C virus [70]. PARV4 has furthermore been found as a
contaminant of plasma pools used in the manufacturing of blood products [69,71], which helps to
explain the higher rates of seropositivity to PARV4 in hemophiliacs compared with their non-
hemophiliac siblings and supports the predominant parenteral transmission route of this virus [72].

Parvovirus B19 has also been detected in urine, but urine has not yet been shown to be involved in
transmission of the virus [73].

PATHOGENESIS

Parvovirus B19 is directly cytotoxic to colony-forming units (CFU-E) and burst-forming units (BFU-E)
of the erythroid series [40,74]. The virus replicates in erythroid progenitor cells (late erythroid cell
precursors and burst-forming erythroid progenitors) of the bone marrow and blood leading to their
destruction and inhibition of erythropoiesis. During an acute infection, this results in a significant drop
in hematocrit. In healthy individuals, red blood cell (RBC) production returns in 10 to 14 days with little
anemia. However, in individuals with an increased RBC turnover, even a limited cessation of RBC
production can lead to a clinically significant drop in hemoglobin and transient aplastic crisis (TAC).
(See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Infection in
immunocompetent hosts'.)

Parvovirus B19-specific IgM antibodies to both VP1 and VP2 proteins develop soon after infection,
can be detected at days 10 through 12, and can persist for up to five months; specific IgG antibodies
to the viral capsid proteins are detectable about 15 days post-infection and persist long term. The role
of the humoral immune system in control of parvovirus B19 appears dominant; development of a
robust antibody response corresponds to virus clearance and subsequent protection from disease.
Importantly, neutralizing antibodies to the unique 227 amino acids at the N-terminus of VP1 (VP1u)
are required for an effective immune response [75,76]. Detectable anti-NS1 IgG has been suggested
to be associated with persistent infection [77]. In patients unable to control parvovirus B19 infection
because of immunosuppression or immunodeficiency, continued lysis of RBC precursors leads to
prolonged cessation of RBC production and the development of a severe, chronic pure red cell aplasia
and anemia. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on
'Chronic infection in immunosuppressed hosts'.)

Although the pathogenesis of rash and arthropathy associated with parvovirus B19 infection is not
clear, both symptoms generally coincide with measureable serum antibody production and are thus
presumed to be at least partially immune mediated. The role of serum antibodies in rash
development is also suggested by the appearance of rash after IVIG administration to
immunodeficient patients with chronic infection [78]. Antigen-antibody immune complexes have been
detected during acute infection and are proposed to participate in the pathogenesis of the disease
[42].

Direct viral effects may also be involved in the pathogenesis of these symptoms. Parvovirus B19 DNA
and antigen have been detected in a skin biopsy specimen from a patient with erythema infectiosum,
suggesting that direct infection of epidermal cells may also contribute to rash development [79].
Studies of individuals presenting with acute parvovirus B19 arthritis have documented parvovirus B19
DNA in joint fluid specimens, but not within specific cells [80]. Thus, it is not yet clear whether viral
DNA represents direct infection of the synovial tissue or systemic viremia with seeding of the joint
space. It is possible that virus remains in lymphocytes, macrophages, and follicular dendritic cells for
longer periods, as has recently been suggested to occur in patients with rheumatoid arthritis [81].
Viral presence in these cells may contribute to the pathogenesis of the disease process. After
infection, the B19 DNA genome can persist in solid tissues for life [82,83]. This can make it difficult
when interpreting positive B19 DNA nucleic acid amplification test (NAAT) results from solid tissues.

Parvovirus B19 infection also elicits a Th-1 type cytokine response. This inflammatory cell-mediated
immune response includes the production of tumor necrosis factor (TNF)-alpha, interferon (IFN)-
gamma, interleukin (IL)-2, and/or IL-6 [84-87]. A strong CD8 cell response has also been described
[88]. A striking CD8 cell response was maintained and eventually increased over several months after
the resolution of illness. The importance of cellular immunity is also suggested by clinical reports of
remission of parvovirus B19-induced anemia after initiation of antiretroviral therapy in patients with
advanced HIV disease.

SUMMARY AND RECOMMENDATIONS

● Parvovirus B19 is a small, single stranded DNA virus that infects and replicates in erythroid
progenitor cells of the bone marrow and blood, leading to inhibition of erythropoiesis. The
observed tropism of parvovirus is most likely due to the distribution of its cellular receptor, P
blood group antigen, globoside, which is found in high concentrations on red blood cells and their
precursors. In addition, coreceptors have been shown to participate in viral binding and entry into
cells. (See 'Virology' above.)

● Parvovirus B19 infection occurs worldwide as sporadic cases or within clustered outbreaks and
is highly prevalent. Between 50 and 80 percent of adults have evidence of parvovirus B19-
specific IgG antibodies, suggesting prior infection. (See 'Epidemiology' above.)
 ● Parvovirus B19 is most commonly transmitted via the respiratory route. Close contact and
sharing of personal items expose susceptible individuals to the respiratory secretions and saliva
of infected individuals. Parvovirus B19 is also transmitted vertically, from mother to child, and
hematogenously. This latter route includes receipt of blood products, as it is difficult to inactivate
or remove this small, non-enveloped virus from blood products. (See 'Transmission and risk
factors for infection' above.)

● The direct cytotoxic effect of parvovirus B19 on colony- and burst-forming units of the erythroid
series mediates the drop in hemoglobin and anemia that occurs during infection. Development of
a robust antibody response corresponds to virus clearance and subsequent protection from
disease. Antibody development also coincides with the development of rash and joint symptoms,
which are thus thought to be at least partially immune mediated. (See 'Pathogenesis' above.)

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Topic 8274 Version 16.0

Contributor Disclosures
Jeanne A Jordan, PhD Nothing to disclose Martin S Hirsch, MD Nothing to disclose Morven S Edwards,
MD Grant/Research/Clinical Trial Support: Pfizer [Group B Streptococcus]. Meg Sullivan,
MD Grant/Research/Clinical Trial Support: Gilead Sciences [Pre-exposure prophylaxis for contraception
(Tenofovir)]. Consultant/Advisory Boards: Gilead Sciences [Pre-exposure prophylaxis for contraception
(Tenofovir)].

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