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Clinical manifestations and diagnosis of parvovirus B19 infection

Clinical manifestations and diagnosis of parvovirus B19 infection
Literature review current through: Jan 2024.
This topic last updated: Oct 23, 2023.

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 "Virology, 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 parvovirus 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 in children (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, miscarriage, or cardiomyopathy (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 parvovirus 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 infected with parvovirus B19 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. In contrast, 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 "Virology, 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 that last approximately three days. 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 parvovirus B19 infection (figure 1). Other hematologic abnormalities, including reduced hemoglobin concentration and hematocrit, leukopenia, and/or thrombocytopenia can also be observed.

In individuals with a normal immune response, 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 (table 1). (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 nucleic acid amplification tests (NAAT) like polymerase chain reaction (PCR) assays and is not believed to be clinically significant [16].

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 [17]. 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 2). 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) (picture 1). This facial rash is often followed several days later by a reticulated or lacelike rash on the trunk and extremities (picture 2A-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 [17]. 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 [18,19]. 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 [20]. 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 [21]. 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 3) [22]. (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) [23]. They occur most commonly in adults, particularly women, as discussed 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 [10,24].

Joint symptoms with parvovirus B19 are usually acute and symmetric, and most frequently involve the small joints of the hands, wrists, knees, and feet [25,26]. 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 [27] (see 'Erythema infectiosum' above). Joint symptoms usually resolve in three weeks, although a minority of patients may develop persistent or recurring arthropathy [28]. The arthritis associated with acute parvovirus B19 infection does not cause joint destruction [29]. (See "Viral arthritis: Causes and approach to evaluation and management".)

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 (table 1). 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 (37 percent) patients, of whom 91 (80 percent) developed TAC [30]. 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 [31]. 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 [30]. 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 [32]. TAC usually only occurs once in immunocompetent individual’s lifetime, presumably because of the development of protective immunity [33].

Laboratory analysis often demonstrates an undetectable peripheral reticulocyte count and a drop in hemoglobin concentration of >30 percent secondary to complete arrest of erythropoiesis [31,34]. 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 [33]. 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 4).

Neurologic manifestations — Neurologic complications have been reported in children and adults with parvovirus B19 infection [35,36]. One systematic review identified reports of 129 patients with neurologic manifestations of parvovirus B19 infection between 1970 and 2012 [35]. Seventy-nine patients (61 percent) had central nervous system complications; 50 of the 79 (63 percent) had encephalitis. Most of these cases were attributed to parvovirus B19 because of viral DNA detection in the cerebrospinal fluid or a positive IgM serology suggestive of acute infection in the setting of other findings consistent with parvovirus B19 (ie, erythema infectiosum rash or anemia). Among the 15 patients who had a rash and encephalitis, the timing of the rash with the onset of encephalitis was variable. Encephalitis was reported in both immunocompetent and immunocompromised individuals.

Peripheral nervous system manifestations post-parvovirus B19 infection include neuralgic amyotrophy (inflammatory brachial plexopathy), paresthesias, carpal tunnel syndrome, and Guillain-Barre syndrome [35].

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 [37]. (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 [38-42]. Chronic infection and anemia have been described in patients with certain leukemias or cancers, recipients of organ transplants, patients with congenital immunodeficiencies, and patients with advanced HIV [43-51].

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 4) [52]. 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 adults", section on 'Clinical features'.)

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 [53]. Anemia, leukopenia, and thrombocytopenia occurred in 99, 38, and 21 percent of patients, respectively. Hepatitis, myocarditis and pneumonitis were also reported. Neurologic complications, including encephalitis, have also been reported in immunocompromised patients [35]. (See 'Neurologic manifestations' above.)

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 NAAT 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 or EBV reactivation, respectively [54]. 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), hemophagocytic syndrome, fulminant liver disease, generalized edema, as well as many other conditions (table 3) [55-62]. 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 NAAT for extended periods after infection without evidence of disease in some individuals.

Because parvovirus B19 infections are associated with high-titer viremia, 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 [63-68].

In a study of 172 consecutive patients with myocarditis, endomyocardial biopsies demonstrated the presence of enterovirus, adenovirus, parvovirus, or human herpesvirus type 6 by PCR in 33, 8, 37, and 11 percent of samples, respectively [63]. 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 virus detected [67]. 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 [67].

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 parvovirus B19 DNA in heart tissue could represent persistent infection with no or limited associated inflammation [69,70]. 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 [69]. 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 [70]. 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 [71].

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 parvovirus 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 [72]. In another study in which 21 children with myocarditis were evaluated for known cardiotropic viruses, two children (9.5 percent) tested positive for parvovirus B19 DNA by PCR from blood samples [73].

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 [74]. In a study using a mouse model, expression of parvovirus B19 NS1 protein induced double-stranded DNA auto-antibodies, inflammation, apoptosis, and end-organ damage [75].

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. Parvovirus 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 [26]. The association of parvovirus DNA and chronic arthropathy in children is unclear.

DIAGNOSIS

Diagnostic approach — The possibility of parvovirus B19 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 B19 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 2A and picture 1), 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) periods 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 [76]. 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 using 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. An exception is checking parvovirus B19 PCR on cerebrospinal fluid in patients with encephalitis of uncertain etiology, among whom a positive result, in addition to serology suggestive of acute infection, would suggest the diagnosis. (See 'Neurologic manifestations' above.)

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 or hematocrit. 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). 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 parvovirus 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 parvovirus 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) [77-79].

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 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) [80].

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 [79,81]. 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 [78,82,83]. 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 parvovirus B19 antigens have improved performance over kits containing only linear antigens [77].

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 [77,84].

The choice of antigen(s) is critical when selecting a diagnostic serology assay [85,86]. 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) [87,88]. 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 lab-developed or unlicensed commercial real-time PCR assays is now routinely performed in many clinical laboratories and has been shown to be much more sensitive than antigen-based detection systems [89-91].

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, and if the primer and probe sequences used are located in a non-homologous gene set [4,5,92]. 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 [4,5,92,93]. Some PCR assays can quantitate parvovirus B19 DNA for all three genotypes [94]. To ensure that the parvovirus B19-specific NAAT being used in the lab can detect all three genotypes, the World Health Organization (WHO) International Reference Panel can be included as part of the testing [95,96].

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 amplification control (eg, an endogenous human gene target) 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 [26,52,97]. 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 or after the analysis, which eliminates post amplification handling of the amplicons.

Another strength of the real-time PCR assay is its ability to be quantitative. Determining viral load has both prognostic and diagnostic value [98,99]. Viral load levels tend to correlate with clinical manifestation(s) [100]. 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) [101-105]. 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 [106].

With the introduction of a World Health Organization International Standard for parvovirus B19 DNA (NIBSC 99/800), quantitative PCR assay standardization is possible [107].

Antigen detection — Immunohistochemical (IHC) techniques can be used to detect parvovirus B19 antigens in a variety of tissues, especially fetal and placental tissues [108-110]. 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 [111].

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 [112-114].

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 and diagnosis' 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 "Viral arthritis: Causes and approach to evaluation and management".)

The differential diagnosis and workup of pure red cell aplasia is discussed in detail elsewhere. (See "Acquired pure red cell aplasia in adults", section on 'Pathogenesis' and "Overview of causes of anemia in children due to decreased red blood cell production" and "Acquired pure red cell aplasia in adults", section on 'Diagnosis'.)

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

SUMMARY AND RECOMMENDATIONS

Spectrum of clinical features – The clinical presentations associated with parvovirus 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.)

Incubation and infectious periods – 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.)

Specific clinical syndromes

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 2A-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 or individuals with HIV, 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.)

Parvovirus 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".)

Diagnostic approach – The possibility of parvovirus B19 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 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.)

Differential diagnosis – 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 39.0

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