INTRODUCTION — The Parvoviridae family contains two subfamilies: parvoviruses (Parvovirinae), which infect mammals and birds, and densoviruses (Densovirinae), which infect arthropods. The Parvovirinae subfamily has been subdivided into eight genera, of which five include human pathogens: Erythroparvovirus (B19), Dependoparvovirus (adeno-associated viruses), Protoparvovirus (human bufavirus), Bocaparvovirus (Human bocaviruses), and Tetraparvovirus (Human parvovirus 4) along with Aveparvovirus, Copiparvovirus, and Amdoparvovirus [1]. The focus here will be limited to Erythroparvovirus genera in the family Parvoviridae, and mainly to human parvovirus B19 (B19 prototype strain); only brief coverage will be given to the less common genotype 2 (prototype strain: LaLi) and genotype 3 (prototype strain: V9) genera within this subfamily [2].
Unless otherwise specified, parvovirus B19 will be the strain referred to when describing epidemiology and transmission, which are discussed in this topic. The spectrum of disease manifestations, diagnosis, treatment, and prevention of parvovirus B19 are discussed elsewhere. (See "Clinical manifestations and diagnosis of parvovirus B19 infection" and "Treatment and prevention of parvovirus B19 infection".)
VIROLOGY
Classification — There are three genotypes within the Erythroparvovirus genus. Parvovirus B19 is the predominant parvovirus pathogen in humans and the prototype genotype 1 strain. Genotype 2 is comprised of A6 and LaLi, while genotype 3 includes V9 and V9-related isolates [3-6]. Genotypes 1 and 2 are typically found in western countries (eg, United States and Europe), while genotype 3 circulates primarily in Africa and South America [6,7] but has been encountered in Europe and Asia. Compared with genotype 1, much less has been published on the transmission and epidemiology of genotype 2 and genotype 3. The nucleotide sequence differs among the three genotypes by 13 to 14 percent [5,8]. Not surprisingly, the divergence at the amino acid level among the three genotypes is significantly less than that seen at the nucleotide level.
Viral structure — Parvovirus B19 is a small (26 nm), nonenveloped, single-stranded DNA (5.6-kb) virus. It is among the smallest of the DNA animal viruses. The linear genome encodes the following proteins:
●Two viral capsid proteins: a minor structural protein VP1 (781 amino acids [aa], 84 kDa) and a major structural protein VP2 (554 aa, 58 kDa). These are encoded by overlapping reading frames and are expressed during productive infection. The smaller VP2 protein constitutes 95 percent of the capsid while the larger VP1 protein makes up only 5 percent.
●Three nonstructural proteins: a large nonstructural protein, NS1 (671 aa, 78 kDa), and two smaller nonstructural proteins (7.5 kDa and 11 kDa) [9,10]. The major nonstructural protein NS1 is a DNA-binding protein with helicase, nicking, and ATPase activity and is essential for viral DNA replication. NS1 is cytotoxic and induces cellular apoptosis in both permissive and nonpermissive cell types [11,12]. The inflammatory response associated with B19 infection is the result of NS1 transactivation of such pro-inflammatory cytokines as tumor necrosis factor (TNF)-alpha, IL-6, and p21 [13-15]. The NS1 protein is also responsible for inducing cell cycle arrest in erythroid progenitor cells at the G2 phase [10]. Like NS1, the 11 kDa nonstructural protein induces apoptosis as a result of parvovirus B19 infection [16] and enhances viral replication [17].
Cellular tropism — One of the hallmarks of Erythroparvoviruses is their extremely limited host range. The only known host for parvovirus B19 is humans [18]. Productive infections occur only in CD36 human erythroid progenitor cells. To date, erythroid precursor cells of the colony and burst forming units (E-CFU and E-BFU) are the only cells known to support a fully productive infection with parvovirus B19 [19].
The observed tropism of parvovirus is most likely due to the distribution of its cellular receptor, P blood group antigen, also known as globoside, which is found in high concentrations on red blood cells and their precursors [20]. Rare individuals who lack P antigen are resistant to infection with parvovirus [21]. In a well-defined lipid bilayer model, parvovirus B19 viral-like capsids interacted with globoside, suggesting a potential role of globoside as a receptor for B19 [22].
P antigen is also found to a lesser extent on other cell types, including endothelial cells, cardiomyocytes, megakaryocytes, and placental trophoblast cells [23,24]. The globoside-containing, nonerythroid cell types that become infected with parvovirus B19 produce little, if any, infectious virus. However, these nonproductive infections may contribute to disease through the expression of nonstructural (NS1) protein, which can induce cellular apoptosis in both permissive and nonpermissive cells [9,11,12,19].
Although P antigen may be necessary for infection, it is not sufficient. Some cell lines that are positive for P antigen fail to bind, whereas other cell lines have an ability to bind parvovirus B19 despite lack of P antigen [25]. Two coreceptors have been proposed for virus entry into target cells. These include integrin alpha 5 beta 1 [26] and Ku80, an autoantigen [27]. After the initial B19 VP2-associated binding to the globoside receptor, structural changes occur within the viral capsid, exposing VP1u protein onto the surface of the capsid. This higher affinity binding to an as yet unknown receptor results in internalization of the viral particle into the cytoplasm of the cell [28].
Viral life cycle — Following cell entry, viral DNA replication, RNA transcription, protein translation, and virus capsid assembly all occur in the cell's nucleus. In high concentrations, virus particles can be visualized in the nucleus by electron microscopy (EM). Upon viral maturation, parvovirus B19 causes cell lysis. The cytopathic effect induced during B19 infection can be seen in the form of giant pronormoblasts located in the patient's bone marrow [29]. These cells contain large eosinophilic nuclear inclusions, cytoplasmic vacuolization, and marginated chromatin.
Active or reactivated infection may be distinguished from latent infection by differential microRNA (miRNA) expression profiles. This was illustrated in a study of 60 patients with serologic evidence of parvovirus B19 infection who underwent endomyocardial biopsy for nonacute cardiomyopathy [30]. There were 29 miRNAs that were differentially regulated in cardiac tissue between the 15 patients with and the 45 patients without transcriptionally active parvovirus B19 infection (as manifest by detectable parvovirus B19 mRNA in biopsy specimens). These miRNAs coded for differentially expressed mRNAs from the cardiomyopathy and inflammatory response related pathways, including TNFα, RORC, and Cox1.
EPIDEMIOLOGY
Geographic and temporal distribution — Parvovirus B19 infection occurs worldwide. Cases can be sporadic or can occur in clustered outbreaks. Where reportable, communities have documented not only a seasonality to parvovirus B19 infections, but also cycles of local epidemics with case numbers that can peak every 4 to 10 years [31-33]. In the United States, parvovirus B19 infection occurs more frequently between late winter and early summer.
Parvovirus B19 genotype 1 is the predominant genotype circulating worldwide, while genotypes 2 and 3 are found much less frequently. Genotype 2 is primarily detected in Europe and Africa, while genotype 3 is detected mainly in Africa, South America, and to some extent in Asia [6]. Genotypes 2 and 3 are also identified among patients with underlying immune deficiencies.
Prevalence — Parvovirus B19 infection is common throughout the world. The percentage of people with measurable levels of parvovirus B19-specific IgG increases with increasing age, with most individuals becoming infected during their school years. During school outbreaks, 25 to 50 percent of students and 20 percent or more of susceptible staff may become infected. Between 50 to 80 percent of adults have measurable parvovirus B19-specific IgG antibodies [34,35]. Seroprevalence depends on the assay type used to measure B19-specific IgG antibodies [36-38].
When considering women as a separate group, approximately half of women of child-bearing age and approximately 30 to 40 percent of pregnant women lack measurable IgG to parvovirus B19 and are therefore presumed to be susceptible to B19 infection, which then places their fetus at risk. (See "Parvovirus B19 infection during pregnancy".)
Transmission and risk factors for infection — There are three documented modes of transmitting parvovirus B19:
●Respiratory transmission – Parvovirus B19 is easily transmitted from person to person via the respiratory route, which is the most common way an individual acquires this virus. Although parvovirus B19 infection is not primarily associated with respiratory symptoms, parvovirus B19 has consistently been found in respiratory secretions during the viremic phase of infection [39-41]. It can thus be transmitted through close person-to-person contact, fomites, and respiratory secretions and/or saliva [41]. Due to their nonenveloped virion capsid, parvoviruses, including B19, are stable in the environment, making fomites a likely and important source for transmission.
Young children are the main source of respiratory-acquired parvovirus B19. Individuals at highest risk for acquiring the virus include household contacts of infected individuals, daycare workers, and those in a crowded environment. Household transmission appears to be especially efficient, with about 50 percent of susceptible subjects becoming infected after household exposure to an individual with erythema infectiosum or transient aplastic crisis [39,40]. Among daycare workers working with children, rates of parvovirus B19 seroconversion are also higher than in the general population [42].
Many infections occur with no clearly defined exposure, especially during community outbreaks. During one outbreak, the risk of infection without a clearly defined exposure was 6 percent [43]. Other studies found that 0.5 to 1.5 percent of women without a specific exposure or defined community outbreak became infected during one year or during their pregnancy [36,44].
Nosocomial transmission of parvovirus B19 can occur from patient-to-patient, patient-to-staff, staff-to-patient, and staff-to-staff. In one study, for example, transmission from two patients with transient aplastic crisis was noted in 36 and 42 percent of susceptible contacts [45]. In several other reports, no source for infection was identified, but transmission apparently occurred between staff and patients [46,47]. However, other series did not find nosocomial transmission [48,49]; in these studies, the rate of infection in exposed or at-risk staff was similar to unexposed staff and/or community controls. It is therefore likely that many cases of presumed nosocomial transmission may actually represent infection acquired in the community during outbreaks of B19.
●Vertical transmission – A susceptible woman who becomes infected with parvovirus B19 during her pregnancy can transmit the virus to the fetus [50]. The risk of a poor outcome for the fetus is greatest when the congenital infection occurs within the first 20 weeks of gestation. (See "Parvovirus B19 infection during pregnancy".)
●Hematogenous transmission – Parvovirus B19 can be transmitted through blood or blood products that contain the virus [51-56]. Infected blood donors may be asymptomatic yet have very high circulating viral levels, up to 1012 viral particles/mL blood [57,58]. Individuals requiring regular infusions of blood product(s) that are made from large plasma pools are at greatest risk for acquiring the virus compared to those individuals receiving single units [53,54]. Both its small size and its lack of a lipid envelope make parvovirus B19 extremely difficult to inactivate or remove from blood products. In one study, 87 percent of 38 blood product and plasma pools were positive for parvovirus B19 DNA by a PCR assay despite a variety of purification and inactivation procedures [54]. Several nanofiltration methods have been developed to help remove virus particles during the manufacture of plasma derivatives or hemoglobin solution to prevent transmission of viruses. In one study, using a 20 nm Viresolve nanofilter (Millipore, USA), up to 6.43 10E5 units/mL of parvovirus B19 was successfully removed from human plasma, and the viral DNA was undetectable using a real-time PCR assay [59]. Other studies have shown that nanofiltration can decrease parvovirus B19 viral load by more than 6 log10 [60-62].
In 2009, the United States Food and Drug Administration (FDA) published guidance governing parvovirus B19 contamination of pooled plasma or blood products. B19 DNA levels within pooled plasma used for manufacturing blood products must not exceed 104 international units/mL [63]. This regulation was based on the observations in healthy volunteers that suggest that acute parvovirus B19 infection can be acquired from administration of blood components that contain greater than 107 genome equivalents/mL of viral DNA [64-66]. In contrast, patients receiving less than 106 genome equivalents/mL have not shown evidence of virus transmission. The presence of neutralizing activity in all these pools may help to explain the lack of infectivity with exposure to lower viral loads [51,64,67]. Additionally, because nucleic acid amplification testing (NAAT) can detect both intact parvovirus B19 genomes and fragments of degraded DNA, it is important to be cautious in interpreting NAAT data from filtered blood products [68,69].
In contrast to parvovirus B19 infections, infections with the emerging human parvovirus 4 (PARV4) are most frequently detected in people who inject drugs. PARV4 was first discovered in an injection drug user who was co-infected with hepatitis B virus [70]. Infection with PARV4 is strongly associated with bloodborne viruses like HBV, HIV, and HCV [71,72]. PARV4 has furthermore been found as a contaminant of plasma pools used in the manufacturing of blood products [70,73], which helps to explain the higher rates of seropositivity to PARV4 in hemophiliacs compared with their nonhemophiliac siblings and supports the predominant parenteral transmission route of this virus [74].
Parvovirus B19 has also been detected in urine, but urine has not yet been shown to be involved in transmission of the virus [75].
PATHOGENESIS — Parvovirus B19 is directly cytotoxic to colony-forming units (CFU-E) and burst-forming units (BFU-E) of the erythroid series [39,76]. The virus replicates in erythroid progenitor cells (late erythroid cell precursors and burst-forming erythroid progenitors) of the bone marrow and blood leading to their destruction and inhibition of erythropoiesis. During an acute infection, this results in a significant drop in hematocrit. In healthy individuals, red blood cell (RBC) production returns in 10 to 14 days with little anemia. However, in individuals with an increased RBC turnover, even a limited cessation of RBC production can lead to a clinically significant drop in hemoglobin and transient aplastic crisis (TAC). (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Infection in immunocompetent hosts'.)
Parvovirus B19-specific IgM antibodies to both VP1 and VP2 proteins develop soon after infection, can be detected at days 10 through 12, and can persist for up to five months; specific IgG antibodies to the viral capsid proteins are detectable about 15 days 15 days postinfection and persist long term. The role of the humoral immune system in control of parvovirus B19 appears dominant; development of a robust antibody response corresponds to virus clearance and subsequent protection from disease. Importantly, neutralizing antibodies to the unique 227 amino acids at the N-terminus of VP1 (VP1u) are required for an effective immune response [77,78]. Detectable anti-NS1 IgG has been suggested to be associated with persistent infection [79]. In patients unable to control parvovirus B19 infection because of immunosuppression or immunodeficiency, continued lysis of RBC precursors leads to prolonged cessation of RBC production and the development of a severe, chronic pure red cell aplasia and anemia. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Chronic infection in immunosuppressed hosts'.)
Although the pathogenesis of rash and arthropathy associated with parvovirus B19 infection is not clear, both symptoms generally coincide with measurable serum antibody production and are thus presumed to be at least partially immune mediated. The role of serum antibodies in rash development is also suggested by the appearance of rash after IVIG administration to immunodeficient patients with chronic infection [80]. Antigen-antibody immune complexes have been detected during acute infection and are proposed to participate in the pathogenesis of the disease [41].
Direct viral effects may also be involved in the pathogenesis of these symptoms. Parvovirus B19 DNA and antigen have been detected in a skin biopsy specimen from a patient with erythema infectiosum, suggesting that direct infection of epidermal cells may also contribute to rash development [81]. Studies of individuals presenting with acute parvovirus B19 arthritis have documented parvovirus B19 DNA in joint fluid specimens, but not within specific cells [82]. Thus, it is not yet clear whether viral DNA represents direct infection of the synovial tissue or systemic viremia with seeding of the joint space. It is possible that virus remains in lymphocytes, macrophages, and follicular dendritic cells for longer periods, as has recently been suggested to occur in patients with rheumatoid arthritis [83]. Viral presence in these cells may contribute to the pathogenesis of the disease process. After infection, the B19 DNA genome can persist in solid tissues for life. It is not yet known which cell type(s) harbor parvovirus B19 or what the mechanism is for persistent infection [84-86]. Congenital immunodeficiencies and immunosuppressive therapies increase one's risk of developing a persistent infection due to the person's inability to produce sufficient neutralizing antibodies to B19. For example, rituximab therapy given to lymphoma patients, which inhibits the production of B cells, is associated with B19 persistence, since production of neutralizing antibodies are necessary to clear this infection [62]. This can make it difficult when interpreting positive B19 DNA nucleic acid amplification test (NAAT) results from solid tissues.
Parvovirus B19 infection also elicits a Th-1 type cytokine response. This inflammatory cell-mediated immune response includes the production of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-2, and/or IL-6 [87-90]. A strong CD8 cell response has also been described [91]. A striking CD8 cell response was maintained and eventually increased over several months after the resolution of illness. The importance of cellular immunity is also suggested by clinical reports of remission of parvovirus B19-induced anemia after initiation of antiretroviral therapy in patients with advanced HIV disease.
SUMMARY AND RECOMMENDATIONS
●Virology – Parvovirus B19 is a small, single-stranded DNA virus that infects and replicates in erythroid progenitor cells of the bone marrow and blood, leading to inhibition of erythropoiesis. The observed tropism of parvovirus is most likely due to the distribution of its cellular receptor, P blood group antigen, globoside, which is found in high concentrations on red blood cells and their precursors. In addition, coreceptors have been shown to participate in viral binding and entry into cells. (See 'Virology' above.)
●Epidemiology – Parvovirus B19 infection occurs worldwide as sporadic cases or within clustered outbreaks and is highly prevalent. Between 50 and 80 percent of adults have evidence of parvovirus B19-specific IgG antibodies, suggesting prior infection. (See 'Epidemiology' above.)
●Transmission and risk factors for infection – Parvovirus B19 is most commonly transmitted via the respiratory route. Close contact and sharing of personal items expose susceptible individuals to the respiratory secretions and saliva of infected individuals. Parvovirus B19 is also transmitted vertically, from mother to child, and hematogenously. This latter route includes receipt of blood products, as it is difficult to inactivate or remove this small, nonenveloped virus from blood products. (See 'Transmission and risk factors for infection' above.)
●Pathogenesis – The direct cytotoxic effect of parvovirus B19 on colony- and burst-forming units of the erythroid series mediates the drop in hemoglobin and anemia that occurs during infection. Development of a robust antibody response corresponds to virus clearance and subsequent protection from disease. Antibody development also coincides with the development of rash and joint symptoms, which are thus thought to be at least partially immune mediated. (See 'Pathogenesis' above.)
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