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Clinical manifestations and diagnosis 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: Jun 29, 2018.

INTRODUCTION

Human parvovirus B19 belongs to the Erythroparvovirus genus within the Parvoviridae family [1]. It
was first discovered in 1975 while screening units of blood for hepatitis B virus in asymptomatic
donors [2]. Sample 19 in panel B (hence the name parvovirus B19) was read as a false-positive result
on a counterimmunoelectrophoresis assay. B19 is the predominant parvovirus pathogen in humans,
first associated with clinical disease in 1981. The other less common and more recently described
erythroviruses infecting humans include genotype 2 (prototype strain, LaLi) and genotype 3
(prototype strain, V9) [3-5]. Genotypes 1 and 2 are typically found in western countries (eg, the United
States and Europe), while genotype 3 is found primarily in sub-Saharan Africa and South America
(especially in Brazil), but is spreading [6,7].

The clinical manifestations and diagnosis of parvovirus B19 infection will be discussed here. The
microbiology, epidemiology, transmission, pathogenesis, treatment, and prevention of this infection,
as well as issues of infection during pregnancy, are discussed elsewhere. (See "Microbiology,
epidemiology, and pathogenesis of parvovirus B19 infection" and "Parvovirus B19 infection during
pregnancy" and "Treatment and prevention of parvovirus B19 infection".)

CLINICAL FEATURES

The clinical presentations associated with B19 infection vary greatly, ranging from benign to life
threatening. The clinical presentation is influenced by the infected individual's age and hematologic
and immunologic status.

The five well-established syndromes associated with parvovirus B19 are:

● Fifth disease/erythema infectiosum (see 'Erythema infectiosum' below)


● Arthropathy (see 'Arthralgia and/or arthritis' below)
● Transient aplastic crisis in those with chronic hemolytic disorders (see 'Transient aplastic crisis'
below)
● Fetal infection leading to non-immune hydrops fetalis, intrauterine fetal death, or miscarriage
(see "Parvovirus B19 infection during pregnancy")
● Pure red blood cell aplasia in immunocompromised individuals (see 'Chronic infection in
immunosuppressed hosts' below)

A wide range of other syndromes and clinical manifestations have been reported to be associated
with B19 infections, but for many of them, a causal role for the virus has yet to be conclusively
established [8]. (See 'Unconfirmed disease associations' below.)

Incubation period and infectivity — Patients with parvovirus B19 infection are most contagious during
the phase of active viral replication and viral shedding. Viremia occurs approximately 5 to 10 days
after exposure and usually lasts approximately 5 days, with virus titers peaking on the first few days
of infection, which can reach or exceed 1012 viral particles/mL blood. During this phase, patients can
be asymptomatic or present with non-specific flu-like illness, and patients with underlying
hematologic abnormalities can suffer severe anemia.

Subsequently, in immunocompetent hosts, parvovirus B19-specific antibodies are produced and


antigen-antibody immune complex formation occurs. At this point, immunocompetent patients may
present with specific symptoms or signs (eg, arthralgia, arthritis, and/or an exanthem) of parvovirus
B19 infection. Individuals are no longer infectious when exhibiting these clinical characteristics.
Immunocompromised individuals who lack detectable immune response to parvovirus B19 can suffer
from extended bouts of infection with measurable levels of virus [9]. If a person has detectable
viremia without neutralizing antibody production, it is assumed that they would be infectious.
However, no studies to date have addressed this issue.

Routes of transmission of parvovirus B19 are discussed elsewhere. (See "Microbiology, epidemiology,
and pathogenesis of parvovirus B19 infection", section on 'Transmission and risk factors for
infection'.)

Infection in immunocompetent hosts — There is a wide spectrum of clinical findings in


immunocompetent patients with parvovirus B19 infection. Most individuals who have serologic
evidence of prior infection do not recall ever having any specific symptoms classically associated
with parvovirus B19 [10]. Approximately 25 percent of infected individuals will be completely
asymptomatic during their infection, while 50 percent will have only non-specific flu-like symptoms of
malaise, muscle pain, and fever. The remaining 25 percent of infected individuals present with the
rash of erythema infectiosum and/or arthralgias, two classic syndromes associated with parvovirus
B19 infection [10-13]. Children present mainly with erythema infectiosum, whereas joint symptoms
are the most common manifestations in adults (particularly women), although either can be seen in
both children and adults. (See 'Erythema infectiosum' below and 'Arthralgia and/or arthritis' below.)

Because parvovirus B19 destroys erythrocyte progenitor cells, a dramatic decrease or absence of
measurable reticulocytes is a hallmark laboratory finding in persons with B19 infection (figure 1).
Other hematologic abnormalities, including reduced hemoglobin concentration, leukopenia, and/or
thrombocytopenia can also be observed.

In normal individuals, the destruction of reticulocytes has minimal clinical effect, as erythrocytes have
long life spans. However, in certain settings, the transient decrease in erythropoiesis can have more
serious consequences. In individuals with a history of hematologic abnormalities, including increased
RBC destruction (eg, sickle cell disease, thalassemia, hereditary spherocytosis) or decreased RBC
production (eg, iron deficiency anemia), the decline in RBC production with parvovirus B19 infection
can result in a transient aplastic crisis (TAC) with severe anemia. (See 'Transient aplastic crisis'
below.)

In addition, in resource-limited settings where other co-morbidities that cause anemia, such as
malaria, iron deficiency, and hookworm infection, are common, acute parvovirus B19 infection has
also been associated with the development of severe anemia in children [14].

Some studies have suggested that a minority of immunocompetent patients with parvovirus B19 IgG
antibodies continue to have detectable parvovirus B19 DNA in the blood [15]. This likely represents
the high sensitivity of polymerase chain reaction (PCR) assays and is not believed to be clinically
significant.

Erythema infectiosum — Parvovirus B19 most classically causes erythema infectiosum (EI), a mild
febrile illness with rash. It often occurs in outbreaks among school-aged children, although it can
occur in adults as well [16]. EI is also referred to as "fifth disease" since it represents one of six
common childhood exanthems, each named in order of the dates they were first described.

The illness begins with nonspecific prodromal symptoms, such as fever, coryza, headache, nausea,
and diarrhea (table 1). These constitutional symptoms coincide with onset of viremia. Two to five
days later, the classic erythematous malar rash appears with relative circumoral pallor (the so-called
slapped cheek rash). This facial rash is often followed several days later by a reticulated or lacelike
rash on the trunk and extremities (picture 1A-B).
The estimated incubation period from exposure to the onset of rash is generally one and two weeks
but can be as long as three weeks [16]. The rash is thought to be immunologically mediated, and by
the time it appears, viremia has resolved and the patient usually feels well. In most patients,
symptoms resolve within a few weeks, but symptoms can last for months, or rarely even years, in
some patients [17,18]. A typical feature of EI is recrudescence of the rash after a variety of
nonspecific stimuli, such as change in temperature, exposure to sunlight, exercise, or emotional
stress.

These clinical features of parvovirus B19 infection in an otherwise normal, healthy individual were
illustrated in a study performed in human volunteers who were inoculated intranasally with parvovirus
B19 virus [19]. The incubation period for this viral infection was 4 to 14 days. The infected volunteers
had a typical biphasic illness (figure 1):

● In the first week after inoculation, intense viremia was accompanied by a non-specific flu-like
illness, with symptoms of fever, malaise, myalgia, coryza, headache, and pruritus. Hematologic
abnormalities, including reticulocytopenia, reduced hemoglobin concentration, leukopenia,
and/or thrombocytopenia were observed.

● In the following week, the more specific symptoms of rash and/or arthralgia occurred.

Skin eruptions other than the classic malar rash have also been described. In adults, the rash is less
characteristic than in children and may be confused with rubella. Parvovirus B19 infection has also
been associated with other types of rashes including morbilliform, confluent, and vesicular rashes. In
association with the Gianotti-Crosti syndrome, a papulovesicular acrodermatitis may be accompanied
by severe pruritus [20]. Parvovirus B19 DNA was also identified by polymerase chain reaction in a
cutaneous biopsy specimen of patients with papular-purpuric "gloves and socks" syndrome, an illness
characterized by pruritic painful acral erythema associated with fever and mucosal lesions (picture 2)
[21]. (See "Atypical exanthems in children", section on 'Papular-purpuric gloves and socks syndrome'.)

In children with EI, arthralgias occur in a minority of cases (approximately 10 percent) [22]. They
occur most commonly in adults, particularly women, as below.

Arthralgia and/or arthritis — Parvovirus B19 infection can present as an acute arthritis or


arthralgias in the absence or presence of a rash. Joint manifestations are more common in adults,
and particularly in women, than in children [10,23].

Joint symptoms with parvovirus B19 are usually acute and symmetric, and most frequently involve
the small joints of the hands, wrists, knees, and feet [24,25]. Joint stiffness is common.
Approximately 75 percent of patients will also develop a rash, although less than 20 percent will have
the appearance of the typical malar ("slapped cheeks") rash seen in EI [26] (see 'Erythema
infectiosum' above). Joint symptoms usually resolve in three weeks, although a minority of patients
may develop persistent or recurring arthropathy [27]. The arthritis associated with acute parvovirus
B19 infection does not cause joint destruction [28]. (See "Viruses that cause arthritis".)

Transient aplastic crisis — Parvovirus B19 can cause transient aplastic crisis (TAC), in which the
temporary suspension of erythropoiesis leads to severe anemia and related complications. This
occurs in individuals with hematologic abnormalities, including increased RBC destruction (eg, sickle
cell disease, hereditary spherocytosis) or decreased RBC production (eg, iron deficiency anemia).
Genotype 3 erythroviruses have also been associated with TAC [3]. (See "Overview of the clinical
manifestations of sickle cell disease", section on 'Aplastic crisis'.)

TAC from parvovirus B19 is a relatively common event for patients with sickle cell disease. In a study
of 308 patients with homozygous sickle cell disease, acute infection with parvovirus B19 was
documented in 114 patients, of whom 91 (80 percent) developed TAC [29]. The remaining 23 patients
with parvovirus B19 infection had slight or no hematologic changes. Parvovirus B19 accounted for all
of the cases of aplasia seen in that study. In a similar study, 280 patients with sickle cell disease were
followed from birth [30]. By the age of 20 years, 70 percent of patients showed evidence of
seroconversion to parvovirus B19, with 67 percent of those individuals experiencing aplastic crisis.

Patients with TAC usually present with pallor, weakness, and lethargy secondary to severe anemia.
Infection in such cases can rarely be fatal due to congestive heart failure, cerebrovascular accidents,
and acute splenic sequestration [29]. Most of these patients will not develop a rash, possibly because
patients with TAC are generally older and the rash is less common in adults than in children. TAC is
self-limited, as red cell production returns to baseline once viremia declines and the infection is
resolved, usually in one to two weeks [31]. TAC usually only occurs once in immunocompetent
individual’s lifetime, presumably because of the development of protective immunity [32].

Laboratory analysis often demonstrates an undetectable peripheral reticulocyte count and a drop in
hemoglobin concentration of >30 percent secondary to complete arrest of erythropoiesis [30,33]. The
anemia is often sufficiently severe to require transfusion until the patient's immune response
eliminates the infection and red cell production returns. Although TAC usually manifests as a pure red
cell aplasia, white cell and platelet counts may also decline [32]. A bone marrow biopsy is usually
remarkable for severe aplasia of the red cell line and often reveals characteristic giant
pronormoblasts with viral inclusions (picture 3).

Fetal infection — The fetus is especially susceptible to the effects of parvovirus B19-induced


anemia due to its shortened RBC half-life and the expanding RBC volume. The relatively immature
fetal immune system is also less able to effectively control virus infection. Parvovirus B19 infection
during pregnancy can thus result in fetal complications including miscarriage, intrauterine fetal death,
and/or non-immune hydrops fetalis. Because of this potential, it is critical to determine the serologic
status of the pregnant woman who has a history of significant exposure to the virus or who has any
of the classic symptoms of parvovirus B19 infection [34]. (See "Parvovirus B19 infection during
pregnancy".)

Immunity following infection — Immunocompetent individuals who develop detectable parvovirus


B19 IgG following infection generally have protective immunity against future infection. (See
'Documentation of previous infection' below.)

Chronic infection in immunosuppressed hosts — Because of the inability or decreased ability to


mount an immune response to clear viremia, chronic or reactivated parvovirus B19 infection can
occur in immunosuppressed individuals. This can lead to hypoplasia or aplasia of the erythroid cells
and precursors and a severe acute or chronic anemia, which can be life-threatening [35-39]. Chronic
infection and anemia have been described in patients with certain leukemias or cancers, recipients of
organ transplants, patients with congenital immunodeficiencies, and HIV-infected patients with
advanced immunodeficiency [40-48].

Since the anemia is due to a pure red cell aplasia, peripheral reticulocytes are significantly reduced.
Giant pronormoblasts are characteristically observed in the bone marrow (picture 3) [49]. These cells
contain large eosinophilic nuclear inclusions, cytoplasmic vacuolization, and marginated chromatin.
Other clinical findings of pure red cell aplasia in general are discussed elsewhere. (See "Acquired pure
red cell aplasia in the adult", section on 'Presentation'.)

In a retrospective review of 98 transplant recipients who developed post-transplant parvovirus B19


infection, the median time to onset of disease was seven weeks after transplantation [50]. Anemia,
leukopenia, and thrombocytopenia occurred in 99, 38, and 21 percent of patients, respectively.
Hepatitis, myocarditis and pneumonitis were also reported.

Immunocompromised patients with parvovirus B19 infection generally do not manifest the
characteristic immune-mediated symptoms, such as rash or joint symptoms, which may be due to the
inadequate immune response in this patient population.

The frequency of parvovirus B19 viremia among immunocompromised patients may be


underestimated; however, persistent viremia in this population is not always clinically significant. As
an example, in a study of 60 renal transplant patients who underwent nucleic acid testing for various
opportunistic viruses within the first year after renal transplant, 10 percent had parvovirus B19
viremia, compared with 13 and 12 percent with CMV and EBV reactivation [51]. The majority of the
cases were reactivation as opposed to primary infection, and anemia was not more frequent among
the patients with parvovirus B19 viremia.
Unconfirmed disease associations — Parvovirus B19 infection has been reported in association with
a wide range of diseases and clinical manifestations, including chronic arthritis, vasculitis,
myocarditis, nephritis, lymphadenitis, immune thrombocytopenia (ITP), meningitis and encephalitis,
hemophagocytic syndrome, fulminant liver disease, generalized edema, as well as many other
conditions (table 2) [52-60]. The strength of the association of these diseases with parvovirus is
frequently difficult to evaluate because the diagnosis of acute parvovirus B19 might be erroneously
made for the following reasons (see 'Accuracy of diagnostic techniques' below):

● Some parvovirus B19-specific serologic assays have the potential for false-positive IgM antibody,
false-negative IgG antibody results, or cross-reactivity with antibodies to other infectious agents
or rheumatoid factor.

● Parvovirus B19 DNA can remain detectable by nucleic acid amplification testing (NAAT) for
extended periods after infection without evidence of disease in some individuals.

● False-positive parvovirus B19 DNA NAAT results from laboratory contamination can occur,
especially when using a nested PCR testing approach, or a non-real-time PCR assay.

Myocarditis — Parvovirus B19 infection has been associated with myocarditis, dilated


cardiomyopathy, and isolated left ventricular diastolic dysfunction, although a causal link has not
been definitively established [61-66].

In a study of 172 consecutive patients with myocarditis, endomyocardial biopsies demonstrated the
presence of enterovirus, adenovirus, parvovirus, or human herpesvirus type 6 by polymerase chain
reaction in 33, 8, 37, and 11 percent of samples [61]. Follow-up analysis of subsequent biopsies
documented spontaneous clearance of viral genomes in 36 percent of all patients with single
infections, which was associated with improvement in left ventricular ejection fraction. Similarly, in a
separate study that analyzed endomyocardial biopsy samples from 100 adults with heart failure,
parvovirus B19 was detected by PCR in 12 percent and was the only one of five viruses detected.
However, the causative role of parvovirus B19 in these cases could not be established, as none of the
individuals had detectable IgM to parvovirus B19, which would suggest acute infection; they only had
IgG, which reflects prior infection [65].

Other studies have suggested that detecting parvovirus B19 DNA in myocardial tissue alone is not
sufficient to suggest a cause and effect and that detecting B19 DNA in heart tissue could represent
persistent infection with no or limited associated inflammation [67,68]. In one study of 69 autopsies
that underwent serologic and PCR testing, parvovirus B19 DNA was found in myocardial tissues from
46 of 48 (95.8 percent) of the seropositive cases, but in none of the 21 seronegative cases [67]. In
another autopsy study, 29 percent of 112 cases of myocarditis-related deaths and 44 percent of 84
control cases tested positive for parvovirus B19 DNA by PCR [68]. Nevertheless, another study
identified parvovirus B19 genomes more frequently and at higher viral loads in endomyocardial
biopsies of patients with myocarditis or dilated cardiomyopathy compared with noninflamed heart
tissue from autopsy controls; 500 genomic equivalents was suggested as the threshold for an
association with myocardial inflammation [69].

Furthermore, in a study of 17 children with myocarditis, parvovirus B19 DNA was detected in the
blood of 16, 2 of 11 tested positive for B19 IgM antibodies, and of the six who underwent
endomyocardial biopsy five had parvovirus B19 DNA detected by PCR and five had lymphocytic
infiltrates on histology [70].

Other in vitro data strongly suggest that parvovirus B19 infection can cause inflammatory
cardiomyopathy and endothelial cell dysfunction through downregulation of K+ channels by the
parvovirus capsid protein VP1 [71].

Chronic arthritis — The relationship between juvenile chronic arthropathy and parvovirus infection
was investigated in synovial tissue samples of children with juvenile idiopathic arthritis and from
healthy young adults. B19 DNA was detected in synovial tissue specimens from 28 percent of
children with chronic arthritis but also in 48 percent of those without chronic joint disease [25]. The
association of parvovirus DNA and chronic arthropathy in children is unclear.

DIAGNOSIS

Diagnostic approach — The possibility of parvovirus BV19 infection should be suspected in patients


who present with symptoms consistent with the associated clinical syndromes, including erythema
infectiosum, acute arthralgias, transient aplastic crises, and chronic reticulocytopenic anemia in the
setting of immunosuppression. The diagnostic approach depends on the host and the clinical
presentation.

Immunocompetent host without aplasia — The possibility of parvovirus BV19 infection should be


suspected in immunocompetent patients who present with febrile illnesses accompanied by rash
and/or arthropathy. In immunocompetent children who present with the classic malar rash of
erythema infectiosum (picture 1A), the presumptive diagnosis can be made on the clinical features
alone (see 'Erythema infectiosum' above). Confirmation of the viral etiology is generally not essential
to clinical care in such cases.

Diagnostic testing for parvovirus B19 may be warranted when knowledge of a specific etiology would
affect management decisions, as in atypical presentations of the infection or in patients with new-
onset arthropathy of unclear cause. In these cases, the diagnosis of acute parvovirus B19 can be
confirmed by serologic tests demonstrating a positive parvovirus B19-specific IgM antibody. Acute
infection can also be diagnosed retrospectively by checking serologies in the acute and convalescent
(approximately four to six weeks later) period and demonstrating a fourfold or greater rise in the
parvovirus B19-specific IgG titer.

Because the nonhematologic manifestations of parvovirus B19 infection are thought to be mediated
by the immune response, antibodies are typically detectable at the time these symptoms appear.
Detectable levels of parvovirus B19-specific IgM can be found within 7 to 10 days of virus exposure
and remain measurable for approximately two to three months before diminishing [72]. In some
patients, parvovirus B19-specific IgM antibodies can persist for six months or more. Therefore, the
presence of these IgM antibodies, especially at low titers, is suggestive, but not conclusive proof, of
recent infection. In addition, false-positive IgM can occur in the setting of rheumatoid factor and other
antibodies. (See 'Serologic testing' below.)

Serologic testing for parvovirus B19 in most laboratories includes concurrent analyses for both IgM
and IgG antibodies from a single blood sample. IgG antibodies usually appear and begin to rise
approximately two weeks following infection and then persist for life. The close timing that exists
between developing IgM and IgG antibodies means that it is rare to find an IgM-positive serum
sample that is not also IgG-positive.

Detection of parvovirus B19 DNA through polymerase chain reaction (PCR) is generally not useful for
the diagnosis of acute infection in immunocompetent hosts without aplasia. By the time symptoms
arise, viremia has generally resolved, so a negative PCR test does not rule out acute parvovirus B19
infection. Furthermore, low levels of parvovirus B19 DNA may be present in serum and other body
fluids or tissues for months to years following infection, even in healthy patients, so detectable DNA
by PCR does not necessarily indicate acute infection. Thus, serology remains the diagnostic method
of choice in such patients.

Patients with transient or chronic aplasia — The possibility of parvovirus B19 infection should be
suspected in an individual with severe anemia and a paradoxically low reticulocyte count. Clinically
significant aplasia occurs predominantly in patients with pre-existing hematologic disorders or
immunocompromising conditions (who typically present with transient and chronic aplasia,
respectively). In the setting of this aplasia, the diagnosis of parvovirus B19 infection can be made by
detection of parvovirus DNA through nucleic acid amplification testing (NAAT, usually PCR). At the
time that anemia develops, parvovirus B19 DNA levels are generally very high.

In immunocompetent patients with transient aplastic crisis, serology can also be useful to support
the diagnosis. IgM antibodies are detectable by the third day of a transient aplastic crisis in the
majority of patients. Thus, the presence of IgM antibodies can be diagnostic of acute parvovirus B19
infection in this setting, but the absence of IgM antibodies does not rule out the possibility.
In contrast, immunocompromised patients with chronic parvovirus infection typically do not generate
detectable antibody levels, and so parvovirus B19 serology is not useful in these hosts.

Documentation of previous infection — Documenting previous infection, which infers immunity, is


a common practice in obstetrics when the clinician is concerned about the immune status of a
pregnant woman who has a history of exposure to an individual infected with parvovirus B19.
Previous infection is best confirmed by serologic testing that detects B19-specific IgG antibodies. The
presence of IgG antibodies in the absence of IgM antibodies suggests that previous infection was at
least several months earlier.

Accuracy of diagnostic techniques

Serologic testing — A thorough serologic analysis of B19-specific antibody status includes testing
for both IgM and IgG antibodies recognizing viral capsid antigen(s) (VP1 and/or VP2).

Unlike NAAT, serology testing does not appear to suffer from recognition issues between genotypes
1, 2, and 3 as the level of divergence among the strains at the amino acid level is significantly less
than that seen at the nucleotide level.

● IgM antibody assays — Detecting parvovirus B19-specific IgM antibodies to viral capsid
antigen(s) is the cornerstone in determining whether immunocompetent individuals are actively
infected. Several parvovirus B19-specific IgM enzyme immunoassays (EIAs) are commercially
available. However, the performance of these assays can vary considerably both in sensitivity (70
to 100 percent) and specificity (76 to 100 percent) [73-75].

In a study that was designed to compare correlations between parvovirus B19 viral DNA loads
and antibody responses to viral antigens VP1 and VP2, the anti-VP2 EIA (Biotrin, Ltd, Dublin,
Ireland, recently acquired by Diasorin S.p.A., Saluggia, Italy) demonstrated significantly better
sensitivity compared to the anti-VP1 immunofluorescence assay (91 versus 66 percent); both
assays had good specificity (94 and 97 percent, respectively) [76].

Parvovirus B19-specific IgM assay performance and thus its accuracy is greatly enhanced when
the serologic method includes a step in its protocol to deplete or remove IgG antibodies from the
serum sample [75,77]. Because IgG antibodies are present in significantly higher concentrations
than IgM antibodies, assays lacking this design are subject to higher rates of false-negative
results due to antibody competition. The mu capture format helps minimize false-negative IgM
results resulting in excellent sensitivity and specificity [74,78,79]. The presence of rheumatoid
factor, anti-nuclear antibodies, and Epstein-Barr virus IgM in a specimen can generate false-
positive IgM results.
● IgG antibody assays — Several EIA kits are commercially available for parvovirus B19-specific
IgG analysis, many of which have excellent sensitivity and specificity. The different kits vary in
their antigen composition: some contain recombinant VP2 alone, while others consist of a
combination of VP1 and VP2 antigens. Kits containing conformational B19 antigens have
improved performance over kits containing only linear B19 antigens [73].

It is well established that for better accuracy, the parvovirus B19-specific IgG enzyme
immunoassay should incorporate a conformational capsid antigen. This is based on the fact that
circulating IgG antibodies directed against linear epitopes of the capsid antigens gradually
decline postinfection; however, parvovirus B19-specific IgG directed against conformational
epitopes of those capsid antigens are maintained long term [73,80].

The choice of antigen(s) is critical when selecting a diagnostic serology assay [81,82].
Commercial companies cannot rely on native virus as a source of antigen for their kits, since
parvovirus B19 isn't readily propagated in a tissue culture system. As a result, recombinant viral
antigens are used. These antigens have been produced both in a prokaryotic expression vector
(E. coli) and a eukaryotic expression system (Baculovirus) [83,84]. The viral antigens produced in
the baculovirus system can self-assemble into empty capsids as demonstrated by electron
microscopy studies, and as such are more similar to native virions than the linear antigens
produced in E. coli.

Nucleic acid detection — Detecting parvovirus B19 DNA using NAAT is now routinely performed in
many clinical laboratories and has been shown to be much more sensitive than antigen-based
detection systems [85-87].

Appropriate clinical specimens for NAAT analysis include serum, plasma, bone marrow, amniotic
fluid, and placental and fetal tissues. To ensure diagnostic testing accuracy, it is critical that the
laboratory has adequately assessed the analytical performance characteristics (eg, analytical
sensitivity, analytical specificity, reproducibility, and limit of detection) of the parvovirus B19 NAAT
prior to its clinical implementation on each sample type that will be analyzed. As with any diagnostic
test, NAAT can produce false-positive and/or false-negative results.

False-negative NAAT results can occur in the following situations:

● If the individual's infection is due to the less common genotypes 2 or 3 if the primer and probe
sequences used are located in a non-homologous gene set being used targets a divergent region
[4,5,88]. Numerous PCR-based primer and probe sets have been described for detecting
parvovirus B19-specific DNA target(s). Most of these oligonucleotides were designed to detect
genotype 1 DNA, but not genotypes 2 or 3, which can lead to failure in detecting non-genotype 1
erythrovirus infections [4,5,88,89]. Some PCR assays can quantitate B19 DNA for all three
genotypes [90]. To ensure that the B19-specific NAAT being used in the lab can detect all three
B19 genotypes, the World Health Organization (WHO) International Reference Panel can be
included as part of the testing [91,92].

● When specimens contain inhibitor(s). This is especially true when using a crude cell lysate rather
than purified nucleic acid in the NAAT assay. An internal control should be included in each run
when analyzing samples so that significant levels of inhibitors can be detected. This approach
allows one to be more confident that the negative result is due to lack of detectable target and
not to inhibitors in the specimen.

False-positive NAAT results can occur in the following situations:

● In some immunocompromised patients, among whom parvovirus B19-specific DNA has been
described to be found circulating for months or even years after the infection. This is especially
true when testing bone marrow or synovial fluid [25,49,93]. Thus, detection of parvovirus B19
DNA, especially at very low levels, does not necessarily indicate an acute or recent infection.

● Contamination of either carry-over of genomic DNA during processing of a specimen containing


a high viral load, or from high levels of the amplified target generated from a previous run. This is
especially true in laboratories using a nested PCR assay for parvovirus B19 DNA amplification
and those that do not incorporate pre-amplification contamination control steps. Risk of
contamination can be reduced significantly if real-time PCR testing is used. In this approach,
amplification and detection are performed in a closed, self-contained vessel that is not opened
during the analysis, which eliminates post amplification handling of the amplicons.

Another strength of the real-time PCR assay is its ability to be quantitative. However, at this time it
does not appear that determining viral load has a prognostic value outside of the blood banking
industry [94]. Several real-time PCR assays have been described for detecting parvovirus B19 DNA.
Although none have been cleared by the Food and Drug Administration, some NAAT kits comply with
European requirements for health and safety (ie, Roche Molecular Diagnostics, Abbott Molecular,
Altona Diagnostics) [95-99]. Several manufacturers now offer analyte specific reagents for detecting
parvovirus B19 DNA; some have been designed to detect and differentiate between all three
genotypes while others do not [100].

With the introduction of a World Health Organization International Standard for parvovirus B19 DNA
(NIBSC 99/800), quantitative PCR assay standardization is possible [101].

A new approach to detecting disseminated viral infections, including parvovirus B19 infection, is
PCR/electrospray ionization mass spectrometry (PCR/ESI-MS) [102]. This method combines target
specific PCR amplification with mass spectrometry. The limit of detection for B19 using mass
spectrometry, which provided sequence-derived base composition analysis, was 1.2 x 103 copies/mL.

Antigen detection — Immunohistochemical (IHC) techniques can be used to detect parvovirus B19


antigens in a variety of tissues, especially fetal and placental tissues [103-105]. There are
commercially available sources of monoclonal or polyclonal parvovirus B19 specific antibodies that
recognize parvovirus B19 capsid proteins VP1 and VP2. Antibodies recognizing NS1 protein have
been reported, but are not yet commercially available. Although IHC techniques allow for direct
visualization of virus within a tissue, it suffers from suboptimal sensitivity compared with NAAT and if
used alone for diagnosis will miss parvovirus B19-positive cases [106].

Virus isolation — Freshly harvested bone marrow or fetal cord blood, or several continuous cell
lines (eg, megakaryoblastoid cell lines or erythroid leukemia cell lines) can support low-level
parvovirus B19 replication in vitro. However, these in vitro systems have not been used for clinical
applications [107-109].

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of parvovirus B19 infection depends on the clinical presentation.

For erythema infectiosum, the main differential diagnosis includes other infectious exanthems,
including roseola, rubella, measles, enteroviral infections, and group A streptococcal infection. The
quality and distribution of the skin eruptions, as well as vaccination history and the presence of other
symptoms, can often be used to distinguish between these infections. In adults and adolescents,
other considerations of fever and rash include acute HIV infection and infectious mononucleosis.
These may be associated with other signs or symptoms, such as pharyngitis or lymphadenopathy,
that are not typical of parvovirus B19 infection. If acute HIV infection is a possibility, it should be ruled
out by laboratory testing. (See "Acute and early HIV infection: Clinical manifestations and diagnosis",
section on 'Diagnostic algorithm'.)

Other non-infectious etiologies, such as drug hypersensitivity, are also possible. The approach to
immunocompetent patients with fever and a rash is discussed elsewhere. (See "Fever and rash in the
immunocompetent patient".)

The acute polyarthritis syndrome associated with parvovirus B19 infection can be mistaken for acute
rheumatoid arthritis, but the symptoms of rheumatoid arthritis do not generally resolve after several
weeks. Follow-up for resolution of the symptoms can distinguish the two, with specific testing for
rheumatoid arthritis in patients with persistent symptoms (see "Diagnosis and differential diagnosis
of rheumatoid arthritis", section on 'Evaluation for suspected RA' and "Diagnosis and differential
diagnosis of rheumatoid arthritis", section on 'Differential diagnosis'). Otherwise, many other viral
infections, including hepatitis viruses, alphaviruses, and herpesviruses, are associated with transient
arthritides. These are discussed in detail elsewhere. (See "Viruses that cause arthritis".)

The differential diagnosis and workup of pure red cell aplasia (table 3) is discussed in detail
elsewhere. (See "Acquired pure red cell aplasia in the adult", section on 'Etiology and pathogenesis'
and "Acquired pure red cell aplasia in the adult", section on 'Diagnosis' and "Anemia in children due to
decreased red blood cell production".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Erythema infectiosum (fifth disease) (The Basics)")

SUMMARY AND RECOMMENDATIONS

● The clinical presentations associated with B19 infection vary greatly, ranging from benign to life
threatening, and are dependent on the infected individual's age and hematologic and
immunologic status. The five classic syndromes associated with parvovirus B19 infection are
erythema infectiosum, arthropathy, transient aplastic crisis, fetal infection, and pure red blood
cell aplasia in immunocompromised individuals. (See 'Clinical features' above.)

● Patients with parvovirus B19 infection are most contagious during the phase of active viral
replication and viral shedding, which occurs approximately 5 to 10 days after exposure and
usually lasts approximately 5 days. By the time symptoms of rash and/or arthropathy emerge,
infected individuals are no longer infectious. (See 'Incubation period and infectivity' above.)
● Erythema infectiosum is a mild febrile illness characterized by an erythematous malar rash with
relative circumoral pallor (slapped cheeks rash) followed by a lacy rash over the trunk and
extremities (picture 1A-B). It most commonly occurs in children; when it occurs in adults, the
rash is often less characteristic. (See 'Erythema infectiosum' above.)

● In adults, particularly women, parvovirus B19 infection can present as an acute arthritis with or
without a rash. Joint symptoms are usually symmetric and most frequently involve the small
joints of the hands, wrists, knees, and feet. (See 'Arthralgia and/or arthritis' above.)

● Parvovirus B19 infection can lead to transient aplastic crisis, in which the temporary suspension
of erythropoiesis results in severe anemia and related complications. It can occur in patients with
increased red blood cell destruction (eg, patients with sickle cell anemia) or decreased red blood
cell production (eg, iron deficiency anemia). There is often an undetectable peripheral
reticulocyte count and a drop in hemoglobin concentration of >30 percent. Transient aplastic
crisis usually occurs only once in a patient’s lifetime. (See 'Transient aplastic crisis' above.)

● Immunosuppressed patients, such as transplant recipients, can develop chronic or reactivated


parvovirus B19 infection with pure red cell aplasia and severe chronic anemia due to lack of
neutralizing antibody responses against the virus. The anemia is characterized by a significant
reduction in peripheral reticulocytes and giant pronormoblasts in the bone marrow. (See 'Chronic
infection in immunosuppressed hosts' above.)

● B19 infection during pregnancy can result in fetal complications including miscarriage,
intrauterine fetal death, and/or non-immune hydrops fetalis. (See "Parvovirus B19 infection
during pregnancy".)

● The possibility of parvovirus BV19 infection should be suspected in patients who present with
symptoms consistent with the associated clinical syndromes. The diagnostic approach depends
on the host and the clinical presentation (see 'Diagnostic approach' above):

• In immunocompetent children who present with the classic malar rash of erythema
infectiosum, the presumptive diagnosis can be made on the clinical features alone.
Confirmation of the viral etiology is generally not essential to clinical care in such cases.
(See 'Immunocompetent host without aplasia' above.)

• When a specific etiologic diagnosis is warranted in immunocompetent patients (ie, when


knowledge of a specific etiology would affect management decisions), the diagnosis of
acute parvovirus B19 is made with serologic tests that demonstrate a positive parvovirus
B19-specific IgM antibody. (See 'Immunocompetent host without aplasia' above.)
• In the setting of transient aplastic crisis or chronic pure red cell aplasia, the diagnosis of
parvovirus B19 is made by detection of high levels of parvovirus B19 DNA through nucleic
acid amplification testing (NAAT). Immunocompromised patients with chronic parvovirus
infection often do not generate detectable antibodies, so negative serology does not rule out
infection in such patients. (See 'Patients with transient or chronic aplasia' above.)

• Previous infection is best confirmed through serologic testing for B19-specific IgG
antibodies, the presence of which reflects immunity. (See 'Documentation of previous
infection' above.)

● Depending on the presentation, the differential diagnosis of parvovirus B19 infection includes
other viral exanthems, drug hypersensitivity, and acute rheumatoid arthritis. (See 'Differential
diagnosis' above.)

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Topic 8272 Version 23.0


GRAPHICS

Course of parvovirus B19 infection

Schematic representation of the clinical course and laboratory abnormalities in normal hosts with parvovirus B19
infection. As expected for a virus that infects red cell precursors, a transient reticulocytopenia and slight drop in
hemoglobin level develop during the viremic stage of infection; platelets and leukocytes (not shown) also fall during this
period. Once the host mounts an immune response beginning 10 to 14 days after the infection, the viremia resolves and
reticulocytes return. Note the biphasic timing of symptoms, during the peak viremia and again after the viremia has
cleared. Rash, arthritis, and other symptoms typically associated with B19 occur during the second period.

Graphic 75004 Version 2.0


Range of parvovirus B19 symptoms and signs in children

Symptom or sign Percent affected

Fever 14 to 53

Headache 12 to 53

Sore throat 12 to 60

Pruritus 0 to >50

Cough 5 to 40

Diarrhea 0 to 40

Nausea and/or vomiting 0 to 33

Coryza and/or conjunctivitis 4 to 27

Arthralgia and/or arthritis 0 to 9

Adapted from Anderson, LJ. Pediatr Infect Dis J 1987; 6:711.

Graphic 66085 Version 1.0


Slapped cheek rash of parvovirus B19

A child with the characteristic malar ("slapped cheek") rash associated with parvovirus B19
(erythema infectiosum, fifth disease).

Courtesy of Moise L Levy, MD.

Graphic 71737 Version 2.0


Erythema infectiosum

Reticulated blanching erythema on the extremities due to parvovirus B19. Rash is more
common in children. The presence of intense erythema (a slapped cheek appearance) on
the face is highly characteristic.

Courtesy of Lee T Nesbitt, Jr. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT
Jr (Eds), Williams & Wilkins, Baltimore, 1995.

http://www.lww.com
Graphic 75125 Version 7.0
Gloves and socks syndrome secondary to parvovirus B19 infection

Papular-purpuric rash on the hands and feet of a patient with acute parvovirus B19 infection.

Reproduced with permission from: Anderson DJ, Fangman W, Fowler VG, et al. A returning traveler
with fever and rash. Clin Infect Dis 2005; 41:1453. Copyright © 2005 University of Chicago Press.

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Conditions associated with parvovirus B19 infection

Cardiovascular Neurologic
Acute heart failure Brachial plexus abnormalities

Myocarditis Sensorineural abnormalities

Pericardial effusions Meningitis/encephalopathy

Pericarditis Seizures

Generalized edema  Ocular


Cutaneous Conjunctivitis

Gianotti-Crosti syndrome (papular acrodermatitis of childhood and papulovesicular Ophthalmoplegia


acrolated syndrome)
Renal
Papular-purpuric gloves and socks syndrome
Acute renal failure
Vascular purpura
Nephrotic syndrome
Acute renal failure
Respiratory
Erythema nodosum
Acute chest syndrome in sickle cell disease
Erythema multiforme
Pleural effusions
Livedo reticularis
Pneumonia
Hematologic
Rheumatic
Hemophagocytic syndrome
Autoimmunity and immune mediated
Aplastic anemia (not transient)
inflammation
Autoimmune hemolytic anemia
Juvenile idiopathic arthritis
Chronic neutropenia
Rheumatoid arthritis
Thrombocytopenia purpura
Systemic lupus erythematosus
Transient erythroblastopenia of childhood
Vasculitis
Juvenile idiopathic arthritis

Hepatobiliary
Elevated liver enzymes

Acute liver failure

Those for which B19 is more likely to have a causal link appear in bold.

Adapted from: Torok TJ. Unusual clinical manifestations reported in patients with parvovirus B19 infection. In: Monographys in Virology: Human
Parvovirus B19, Anderson LJ, Young NS (Eds), Karger 1997; p.61.

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Causes of acquired pure red cell aplasia

Idiopathic Lymphoid malignancies

Drugs Chronic lymphocytic leukemia

Phenytoin LGL leukemia

Trimethoprim-sulfamethoxazole Hodgkin lymphoma

Zidovudine Non-Hodgkin lymphoma

Chlorpropamide Myeloma

Recombinant human erythropoietins Myeloid malignancies


Mycophenolate mofetil Chronic myeloid leukemia

Infection Agnogenic myeloid metaplasia with myelofibrosis

B19 parvovirus Prodrome to myelodysplastic syndrome

HIV Other cancers


Viral hepatitis Thymoma (10 to 15 percent of cases)

Immune disorders Malignancies with chemotherapy-associated anemia treated with recombinant human
erythropoietin
Autoimmune hemolytic anemia
Pregnancy
Systemic lupus erythematosus

Rheumatoid arthritis

ABO-incompatible hematopoietic cell


transplantation

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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)].

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
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