Parvovirus B19 and Pregnant Women: A Bibliographic Review

Bouraddane M; Warda K; Zouhair S

Review Article

J Fam Med. 2021; 8(9): 1277.

Parvovirus B19 and Pregnant Women: A Bibliographic Review

Bouraddane M1*, Warda K1 and Zouhair S1,2

¹Laboratory of Bacteriology-Virology of the Faculty of Medicine and Pharmacy of Marrakech (FMPM), Morocco

²Bacteriology-Virology Laboratory of the Avicenne Military Hospital in Marrakech (HMA), Morocco

*Corresponding author: Bouraddane Majda, Laboratory of Bacteriology-Virology of the Faculty of Medicine and Pharmacy of Marrakech (FMPM), Morocco

Received: September 29, 2021; Accepted: November 01, 2021; Published: November 08, 2021

Introduction

Parvovirus B19 (PVB19) is one of the smallest viruses that are known to infect humans [1]. The clinical manifestations of B19V infection vary greatly and depend on age, hematologic and immunologic status. In immunocompetent individuals, the infection can be completely asymptomatic or can cause mild and self-limiting clinical manifestations such as erythema infectiosum or fifth disease during childhood, arthralgias and arthritis in adults, particularly in women [2,3], chronic hemolytic anemia, and fetal death in utero or non-immune hydrops fetalis in pregnant women [4]. Due to the efficient replication of B19V in the erythroid progenitor cells [5].

In temperate climates, the infection may occur throughout the year, Infection is most common in late winter or early spring [6]. During pregnancy, the virus is transmitted through exposure to infected respiratory droplets or blood products and vertically from mother to fetus [7,8]. The vertical transmission of B19 occurs in about one-third of women infected [9].The proportion of pregnant women susceptible to B19 infection ranges from 34% to 65% in various parts of the world. The incidence of seroconversion during pregnancy is estimated at between 1% and 1, 5% in the endemic period, increasing to 13% in the epidemic period [10]. Non-immune women are most likely to be infected by young children [11].

Parvovirus infection of mothers is diagnosed using serologic or an immune assay enzyme B19 IgM and B19 IgG [12]. Viral DNA can be detected by Polymerase Chain Reaction (PCR) and is considered to be the best indicator of infection in maternal, fetal blood, and amniotic fluid [13].

In these conditions, it seemed necessary to us to study this virus in this article and to answer the various practical questions raised by the occurrence of contagion and/or infection with Parvovirus B19 during pregnancy.

Parvovirus B19: A Few Words of History

Parvovirus B19 particles were first described in 1975 by Cossart, an Australian virologist working in London [1]. While checking normal blood donor’s serum in an assay for hepatitis B she noticed an anomalous reaction in position 19 plate B [14]. This virus was successively called SPLV (Serum Parvovirus like Virus), Aurilac antigen (in France), Nakatani antigen (in Japan), then B19, number of the blood bag where it was isolated for the first time. This explains the name of the virus when there is no parvovirus B1 to B18.The pathogenic role of the virus was first identified in 1981 during erythroblastopenia attacks in patients with sickle cell disease. In 1983, it was recognized as the cause of erythema infectiosum or the 5th pediatric disease [15]. Subsequently, PVB19 infections have been linked to fetoplacental hydrops, Fetal Deaths in Utero (MFIU) secondary to fetal anemia or myocardial involvement [16].

Virology and Pathophysiology of B19V Infection

B19 virus: Virology

Taxonomy: Parvoviruses are common animal and insect pathogens. The Parvoviridae family is divided into two sub-groups:the Parvovirinae infecting vertebrate cells, and the Densoviridaeinfecting invertebrate cells (Table 1) [17]. The Parvovirinae are further subdivided into three groups:

Table 1: Excerpt of the current classification of the subfamily Parvoviridae, including proposed members of the genus Erythrovirus placed tentatively [17].




  
    Genus
    Virus
    Natural hosts(s)
    Clinical spectrum
  
  
    Parvovirus
    Aleutian    mink disease virus
    Mink, ferret, skunk,raccoon
    Immune complex disease and fetal death
  
  
    Canine    parvovirus
    Dog
    Enteritis, myocarditis
  
  
    Mice    minute virus
    Mouse, rat
    No known disease
  
  
    Porcine    parvovirus
    Pig
    Abortion, fetal death
  
  
    Dependovirus
    Adeno-associated    virus 1 to 6
    Human
    No known disease
  
  
    Avian    adeno-associated virus
    Birds
    No known disease
  
  
    Canine    adeno-associated virus
    Dog
    No known disease
  
  
    Bovine    adeno-associated virus
    Cow
    No known disease
  
  
    Erythrovirus
    Parvovirus    B19
    Human
    Erythema infectiosum, aplastic crisis, arthritis,    hydrops fetalis, etc.
  
  
    Parvovirus    V9a
    Human
    Aplastic crisis?
  
  
    Chipmunk    parvovirusa
    Chipmunk
    No known disease
  
  
    Simian    Parvovirusa
    Cynomolgus monkeys
    Anemia
  
  
    Pig-tailed    macaque Parvovirusa
    Pig-tailed macaques
    Anemia and immunosuppression
  
  
    Rhesus    Parvovirusa
    Rhesus monkeys
    Anemia
  
  
    a Proposed member of genus.



Table 1: Excerpt of the current classification of the subfamily Parvoviridae, including proposed members of the genus Erythrovirus placed tentatively [17].

• Genus Parvovirus that replicate autonomously.

• Genus Dependovirus that needs helper viruses to replicate.

• Genus Erythrovirus that need erythroid cells to replicate.

Parvovirus B19 belongs to the genus Erythrovirus.

Morphology: Parvovirus B19 is a small single-stranded DNA virus [18]. Parvovirus B19 is a non-enveloped, 22 to 26 nm icosahedral virus (Figure 1), containing a single strand of DNA of approximately 5,500 nucleotides. As with other parvoviruses, B19 employs overlapping reading frames to encode on-structural proteins and two capsid proteins. The B19 virion is an icosahedron consisting of 60 copies of the capsid proteins.

Figure 1: Transmission Electron Micrographs Showing Native Parvovirus B19 in Serum and Cells and Recombinant Capsid [14]. Panel A shows symmetric, icosahedral particles, about 25 nm in diameter, and empty capsids (arrowheads) in serum from an infected. Panel B shows human erythroid progenitor cells infected in vitro with the virus; vacuoles and cytoplasmic pseudopods are present (×10,000). In Panel C which shows part of Panel B at higher magnification, marginated chromatin contains assembled capsids (×100,000). Panel D shows empty recombinant parvovirus capsids produced in a baculovirus system (×154,000).

    
    
    Figure 1: Transmission Electron Micrographs Showing Native Parvovirus B19 in Serum and Cells and Recombinant Capsid [14].
Panel A shows symmetric, icosahedral particles, about 25 nm in diameter, and empty capsids (arrowheads) in serum from an infected. Panel B shows human
erythroid progenitor cells infected in vitro with the virus; vacuoles and cytoplasmic pseudopods are present (×10,000). In Panel C which shows part of Panel B
at higher magnification, marginated chromatin contains assembled capsids (×100,000). Panel D shows empty recombinant parvovirus capsids produced in a
baculovirus system (×154,000).

Most of the capsid consists of VP2, the major structural protein (molecular weight 58 kDa), with 5% or less of the larger VP1 protein, the minor protein (83kDa). Using genetic engineering techniques, the capsid proteins have been expressed in a variety of both mammalian and insect cell lines, where they self-assemble in the absence of DNA and form recombinant empty capsids [19]. VP1 is not required for capsid formation. The limited DNA content and the absence of a lipid envelope makes this virus resistant to heat (56oC for 60 min) and lipid solvents [20].

Genomic structure and organization: As in most animal Parvoviruses, the B19 genome has two large open reading frames, with the single Nonstructural Protein (NS1) encoded by genes on the left side of the genome and the two capsid proteins (VP1 and VP2) by genes on the right side. The non-structural protein, from NS1, sub serves multiple replicative functions and is cytotoxic to host cells [21]. The two structural proteins, Viral Protein1 (VP1) and Viral Protein 2 (VP2), arise from alternative splicing so that VP1 is the same as VP2 except for an additional 226 amino acids at its amino-terminal (Figure 2) [22-24].

Figure 2: Schematic Representation of B19V Genome Organization and Functional Mapping [22-24]. (A) Transcription map of B19V genes. The 9 main transcripts are represented. (B) Expression of viral mRNAs in primary erythroid cells. The viral mRNAs were detected by Northern blotting, using a radiolabeled probe in non-infected and infected primary erythroid cells as described previously.

    
    
    Figure 2: Schematic Representation of B19V Genome Organization and Functional Mapping [22-24].
(A) Transcription map of B19V genes. The 9 main transcripts are represented. (B) Expression of viral mRNAs in primary erythroid cells. The viral mRNAs were
detected by Northern blotting, using a radiolabeled probe in non-infected and infected primary erythroid cells as described previously.

NS1 is a 671 amino acid long protein that has an MW of ~75 kDa. NS1 contains two nuclear localization signals. NS1 contains a DNA binding and endonuclease domain at the N-terminus

In short, NS1 is a multifunctional protein and plays various roles during B19V infection [25]. VP2 is the predominant protein, comprising 95% of the virus capsid. VP1 is the same as VP2 except for an additional 226 amino acids at its amino-terminal [26]. VP1makes up only 5% of the capsid, has its unique region external to the viral capsid itself, and is thought to be the main target of neutralizing antibodies. Sequence analysis reveals that NS1 is highly conserved, while VP1and VP2 show greater variation [27]. Despite variations in VP1 and VP2, the antigens are commonly and successfully used in serologic tests.

B19V as a species is subdivided into three genotypes, the prototype genotype 1, and two variant genotypes 2 and 3. At the nucleotide level, the diversity between genotype clusters is about 10%, while the diversity within each genotype cluster is normally lower than 2% for genotype 1 and in the range 3-10% for genotypes 2 and 3 [28]. All genotypes co-circulate, but with different frequencies and geographical distributions [29].

Pathogenesis and Infection

Viral life cycle

The only known natural host cell of parvovirus B19 is the human erythroid progenitor. Like other non-enveloped DNA viruses the Parvovirus B19 life cycle includes the following stages: binding to host cell receptor, internalization, translocation of the genome to the host nucleus, DNA replication, RNA transcription, assembly of capsid, packing the genome, and cell lines is with release of the mature virion [3] (Figure 3). The P antigen on the red blood cell is a cellular receptor of the Parvovirus B19.However, all P antigen expressing cells are not permissive to B19V. Various other co-receptors like integrina5β1, and antibody-mediated B19V entry routes are presumed to be involved in B19V entry [30].

Figure 3: Proposed model of B19V life cycle [31].

    
    
    Figure 3: Proposed model of B19V life cycle [31].

Pathogenesis and Immune Response

After primary infection, mild symptoms of fever and general illness usually start after 6-10 days when viremia is highest. These symptoms will recede within a week [32,33]. During the second week after infection, the viremia titer decreases, and IgM antibodies are detected. In the third week, the well-known slapped cheeks and rash and the possible arthralgia occur, which coincides with an IgG antibody response [34]. These IgG antibodies can persist for years, while the IgM antibodies disappear after 6-10 weeks (Figure 4).

Figure 4: Virologic, immunologic, and clinical course following B19 infection [37].

    
    
    Figure 4: Virologic, immunologic, and clinical course following B19 infection [37].

Recovery involves production of IgM antibody 10 to 12 days post infection, coinciding with a peak in virus level. IgM usually persists in serum samples for approximately 3 months but may be found for several months [35]. IgG antibody is detectable in volunteers about 2 weeks after inoculation and presumably persists for life and protects against secondary infections. IgA may also be detected and probably plays a role in protection against infection by the natural nasopharyngeal route [36].

Parvovirus B19 and Autoimmunity

Apart from Rheumatoid Arthritis (RA), B19 infection has been associated with the onset of numerous autoimmune disorders including Systemic Lupus Erythematosus (SLE) [38], other connective tissue diseases, and systemic vasculitides. Although a few cases of erosive RA and SLE have been associated with B19 infection, the virus is probably an extremely rare cause of these diseases. Systemic vasculitides including, for example, Henoch-Schönlein purpura, periarteritis nodosa, and giant cell arteritis can occur after acute B19 infection [39]. The role of B19 in these disorders is not clear and in some cases, the infection may be a pure coincidence and in other cases, it can be a triggering or even a rare aetiological factor [40].

Parvovirus B19 Infection in Pregnancy

Acute parvovirus B19 infection is a risk for pregnant women. Since B19 infection occurs mainly during childhood, children represent a main source for virus transmission.

Human parvovirus B19 infection is widespread. Approximately 30-50% of pregnant women are nonimmune, and vertical transmission is common following maternal infection in pregnancy. The magnitude of B19 has been studied in many developed countries [41] whereby the prevalence of specific B19 antibodies among pregnant women has been found to range from 1 to 5% with a transmission rate to the fetus of about 17-33% [42].

Approximately 50% to 75% of women of reproductive age have developed immunity to parvovirus B19 [43,44]. Without known exposure, about 1% to 3% of susceptible pregnant women will develop serologic evidence of infection in pregnancy [45]. Rising to over 10% in epidemic periods [46]. Where there is extensive opportunity for exposure to parvovirus B19, such as in a daycare center or school, it is estimated that 20% to 30% of susceptible women will develop an infection, while 50% of susceptible women exposed through household contacts will become infected [47].The risk of infection in pregnant women with one child is (are)3 times more than nulliparous women, but this risk for women with three or more children is (are) 7,5 times more. The other risk factors are working in the school, care centers, and other full stress jobs [48,49].

Fetal Effects of Parvovirus B19 Infection

Primary PVB19 infection during pregnancy is potentially fatal to the fetus. Transplacental passage would occur at the time of the maximum peak of viremia following maternal contamination approximately one week. It is made possible by the expression of the P antigen on the surface of placental cells. The actual incidence of a fatal outcome for the fetus after parvovirus B19 infection remains difficult to establish. Vertical transmission of B19 has been shown to occur throughout pregnancy from 7-8 weeks of amenorrhea [50].

A relevant property of B19V is its ability to cross the placental barrier and infect the fetus [51]. When in the fetal circulation, the virus can infect erythroid progenitor cells, in liver and/or bone marrow depending on the gestational age, and can be detected in erythroid cells circulating in the vessels of several tissues, in endothelial placental cells as well as in the amniotic fluid.

Parvovirus B19 infection during pregnancy can cause severe anemia, Nonimmune Hydrops Fetalis (NIHF), miscarriage, or even fetal death in utero [52] (Figure 5 and Table 2). Intrauterine growth retardation, myocarditis, pleural effusion, pericardial effusion, pericardial effusion and brain involvement of the fetus may occur following infection with the virus. Although, Parvovirus B19 is not related to congenital malformations [53].

Figure 5: B19-associated hydrops fetalis [55]. Panel A shows a bone marrow aspirate with no mature erythroid precursors and with characteristic giant pronormoblasts. In Panel B, hydrops fetalis is evident in an infant who was infected in utero in midtrimester.

    
    
    Figure 5: B19-associated hydrops fetalis [55].
Panel A shows a bone marrow aspirate with no mature erythroid precursors and with characteristic giant pronormoblasts. In Panel B, hydrops fetalis is evident in
an infant who was infected in utero in midtrimester.

Table 2: General characteristics of studies reporting on outcome of fetuses with parvovirus B19 (PB19) infection included in systematic review.




  
    Authors (years)
    Period of study
    Country
    Number of serum samples tested
    Clinical Symptoms
    Fetal Effects
  
  
    [56]
    1999-2004
    Sendai, Japan
    478

       
      

      100 pregnant women had been exposed to B19 (21%)

 49 51

         
      

      Symptomatic Asymptomatic
    Facial Rasch (51%) (25/49)

      Most common Infection

       
      

      Children living at home
    Hydrops fetalis et fetal death

      7% (7/100)

      >20 weeks
  
  
    [57]
    2005-2010
    Bologna, Italy
    72

       
      

      68 pregnant women had been exposed to B19 (94.1%)

        29 39

         
      

      Symptomatic Asymptomatic
    Rash, fever and polyarthralgia

      (79.3%) 23/29
    -10,2% fetal deaths

      -11,9 % Hydrops fetalis
  
  
    [58]
    2004
    Stuttgart, Germany
    1018
    -
    - 6.3% fetal deaths (64/1018)

      -3.9 % Hydrops fetalis (40/1018)
  
  
    [59]
    1985-1988 and 1992-1995
    London
    420 pregnant women with B19 infection
    -
    Fetal loss averaged 9%
  
  
    [60]
    2010
    Germany
    236 pregnant women with B19 infection
    -
    -18.8% fetal loss(8/236)

      - 23.6 % Hydrops fetalis (10/236)
  
  
    [61]
    2014
    Paris, France
    -
    -
    20 cases of congenital parvovirus B19 Infection (1/20 (neonatal death)



Table 2: General characteristics of studies reporting on outcome of fetuses with parvovirus B19 (PB19) infection included in systematic review.

The vertical transmission of B19V occurs in about one third of women infected during pregnancy. Consequently, in the first trimester, the risk of fetal loss is 5-10%, while in the second trimester is about 11-12, 5%. It is considered that up to 20% nonimmune hydrops fetalis may be caused by B19V [54].

Epidemiological Studies

Infection with B19 is very common and cases of infection have been reported all over the world in all seasons. Parvovirus B19 is active worldwide with neither ethnical nor geographical boundaries, albeit with some regional differences [18].

Generally, seropositivity is lowest among young children, rises to around 50% at puberty [41]. And in-creases further at lower rates throughout adulthood. Seropositivity is correlated with age, a history of transfusion, and urban residency.

Worldwide, the prevalence of PVB19 in pregnant women is variable, generally between 60% and 80%, with lower prevalence in Asian regions [62].

Data on the seroprevalence of women susceptible to B19 infection in early pregnancy report a value of 26% to 43.5% in European countries and Japan [43,49,63].

In developing countries, the percentages are very similar, although the incidence and extent of infection have been studied in smaller population samples (Table 3).

Reference number	Year	Country	Total number of serum samples tested	Number of serum samples infected by B19	Percentage B19 positive
[64]	2016	Ardabil, Iran	350	242	69.10%
[65]	2014	Azerbaijan, Iran	86	65	75.60%
[66]	2014-2015	Mwanza, Tanzania	258	142	55%
[67]	2013	Ogbomoso, Nigeria	231	55	24%
[68]	2012	Sudan	147	73	49.70%
[69]	2011	Tunisie	404	307	76.20%
[70]	2007	Cordoba, Spain	42	27.7	66%
[71]	2007-2008	Tripoly, Libya	150	100	66%
[72]	2007-2008	Bialystok, Poland	55	24	43%
[73]	2008-2009	Khartoum state, Sudan	500	287	57.40%
[74]	2003-2010	Milan, Italy	37	29	78.30%
[75]	1999	Kuwait	1047	560	53.30%
[56]	1999-2004	Sendai, Japan	478	100	21%
[76]	1999-2008	Oslo, Norway	1349	832	61.70%
[77]	1998-2000	Nijmegen, The Netherlands	2567	1788	70%

Manufacture	Methodc	Antigen and Source	FDA approved
Botrin International (Dublin Ireland)	Indirect IgG EIA and class-capture IgM EIA	Baculovirus-expressed VP2a	Yes
Diasorin (Saluggia, Italy)	Indirect IgG EIA and class-capture IgM CLIA-Liaison platform	Baculovirus-expressed VP2a	No
Denka Seiken (Tokyo, Japan)	Indirect IgG and IgM EIA	Baculovirus-expressed VP2a and VP2	No
Medac Diagnostika (Wedel, Germany)	Indirect IgG EIA and class-capture IgM EIA	Baculovirus-expressed VP2a and VP2	No
Euroimmun(LÜbeck, Germany)	Indirect IgG EIA and class-capture IgM EIA	yeast-expressed VP2	No
IBL(Hamburg, Germany)	Indirect IgG and IgM EIA	E.coli-expressed VP1	No
Focus Parvovirus Dxselect (Cyprus, CA)	Indirect IgG and IgM EIA	Recombinant VP1	No
Mikrogen (Martinsried, Germany)	Indirect IgG and IgM and Strip immunoassay	E.coli-expressed VP1 baculovirus-expressed VP2	No
Botrin International (Dublin Ireland)	Indirect IgG and IgM immunofluorescebce (IFA)b	Baculovirus-expressed VP1	No
aVP2 comprises >95% of capsid antigen and appears to be conserved among genotypes. bPretreatment with adsorbent reagent is needed to prevent interference from rheumatoid factors. cEIA: Enzyme Immunoassay; CLIA: Chemiluminescence Immunoassay.

Sample	Technique
Maternal serum	IgG/IgM, ELISA, Western blot, immunofluorescence
Maternal serum	In situ hybridization
Maternal serum	AFP (elevated prior to detection of hydrops)
Maternal serum	AFP (elevated )
Maternal serum	PCR
Maternal serum	IgG antibodies against viral non-structural protein NSI
Amniotic fluid	PCR
Amniotic fluid	PCR, Southern blot, chemiluminescence
Amniotic fluid	Enzymatic amplification of parvovirus B19 (segment)
Fetal blood	PCR, dot-blot hybridization, in situ hybridization
Fetal blood	Enzymatic amplification of parvovirus B19 (segment)
Fetal serum	PCR
Fetal heart tissue	Microscopy: VP1 and VP2 viral particles
Fetal tissue	Microscopy: histology was found to be as sensitive as PCR
Ig: Immunoglobulin; ELISA: Enzyme-Linked Immunosorbent Assay; AFP: Alpha-Fetoprotein; PCR: Polymerase Chain Reaction (DNA test).

Parvovirus B19 and Pregnant Women: A Bibliographic Review

Introduction

Parvovirus B19: A Few Words of History

Virology and Pathophysiology of B19V Infection

B19 virus: Virology

Pathogenesis and Infection

Viral life cycle

Pathogenesis and Immune Response

Parvovirus B19 and Autoimmunity

Parvovirus B19 Infection in Pregnancy

Fetal Effects of Parvovirus B19 Infection

Epidemiological Studies

Laboratory Testing Options, Applications and Interpretation

Cell culture

Serology

Viral DNA detection (PCR)

Anatomopathological analysis

Ultrasound examination of the fetus

Antenatal biological diagnosis

Management of Infection to B19

Prognosis, Prevention and Therapeutic Approaches

Prognosis

Prevention

Therapeutic approaches

B19 vaccine

References