VIRAL INFECTIONS

Erythrovirus B19 (formerlyknown as parvovirus B19)Philip Rice

AbstractHuman erythrovirus B19, previously called parvovirus B19, discovered

more than 30 years ago by astute experimental observations, is the

cause of the common yet mild childhood illness, slapped cheek

syndrome. Winterespring outbreaks are seen every few years which

may involve the general population as well as schools and hospitals.

However, the virus is not always so benign and is a prominent cause of

foetal loss in the first two trimesters of pregnancy, severe and sudden

life-threatening anaemia in patients with inherited or acquired disorders

of erythrocytes and chronic anaemia in the immunocompromised. Labo-

ratory diagnosis can be complicated by the short duration of the IgM

response and by the long-term persistence of viraemia even in healthy

individuals. Specific antivirals are not available as treatment is by trans-

fusion or intravenous immunoglobulin. Vaccination is theoretically

possible with virus-like particles but the economic and disease burden

case has yet to be made.

Keywords erythrovirus B19; fifth disease; hydrops foetalis; parvovirus

B19; slapped cheek syndrome

The virus and its discovery

The only erythrovirus capable of infecting humans was discov-

ered in 1975 as a result of scientific curiosity; when a blood

sample labelled ‘panel B, serum number 19’ consistently gave

a false-positive reaction for hepatitis B surface antigen, revealed

non-enveloped viral particles of approximately 25 nm diameter

on electron microscopy.1 Since then, human erythrovirus B19

has been shown to cause the common childhood infection

‘slapped cheek syndrome’ or fifth disease. The genome

comprises a single-stranded DNA of 5600 bases and sequencing

has demonstrated that there are three genotypes differing by as

much as 10% across the genome, but they comprise one sero-

type as there is cross-protective immunity. There are several

animal parvoviruses (cat, dog, pig and mink) but none can

infect man.

Epidemiology

Infection occurs globally in epidemic waves lasting two years,

broadly in a 4-yearly cycle; 2002e2003 were the last epidemic

years in the UK. Similar to respiratory virus infections, epidemics

occur in winter and spring with sporadic cases occurring all year

round. The peak incidence is in children aged 5e15 years such

that by adulthood 60e70% of individuals are immune. One

Philip Rice BSc MBBS FRCPath is a Consultant Virologist at St George’s

Hospital, London, UK.

MEDICINE 37:12 673

attack confers life-long immunity. Parvovirus B19 is not as

infectious as varicella as it requires close household contact and/

or sharing of cups or utensils. However, school and hospital

outbreaks can occur, with attack rates as high as 50% in

susceptible individuals.2 Rarely, infection has been transmitted

by solvent-detergent treated clotting factor concentrates as the

virus does not have a lipid envelope; it is also relatively heat

resistant. As a result, testing of blood donations for B19 DNA is

now commonplace.

Clinical features

Most childhood infections and approximately 20e30% of those

occurring in adults are symptomless. If symptoms do occur, they

typically comprise a mild feverish illness with coryza, during

which intense viraemia (1011e1013 viruses/ml plasma) is asso-

ciated with pharyngeal virus excretion supporting spread by

respiratory droplet. These initial symptoms are often unrecog-

nized and patients present to their doctor only when a lacy,

reticular rash or slapped cheeks appearance, and widespread

arthralgia develop 7e10 days later (Figure 1). Arthralgia, and

inflammatory arthritis, often in isolation, is the most common

presenting symptom in adults, particularly women. Any joint can

be involved; those most often affected are, in order of incidence,

the small joints of the hands, knees, ankles, wrists, elbows and

shoulders. Arthralgia generally persists for a few weeks, but in

10% of individuals can last for a few months. Erythrovirus B19 is

unlike all other viral exanthems because the rash and arthralgia

are believed to arise as a result of antigeneantibody complexes,

indicating that neutralization of virus occurs. At this stage,

therefore, the individual is non-infectious. However, because the

incubation period from infection to development of symptoms is

usually 2e3 weeks and an individual is infectious 7e10 days

Figure 1 Erythrovirus B19 rash. Photograph courtesy of Dr Yvonne Young.

� 2009 Published by Elsevier Ltd.

Figure 2 Hydrops foetalis.

VIRAL INFECTIONS

before their onset, secondary cases will already be infectious

when the joint/rash symptoms are identified. This can make

infection control difficult in institutions such as schools and

hospitals.

Excretion of

throat virus

Viral detection assays in parvovirus B19 infection

0

Inoculation/

exposure

7 days 14 days

Time since exp

Tit

re o

f vi

rus

an

d a

nti

bo

dy

Serum electron

microscopy positive

Serum DNA

hybridization p

Polyme

Infectious

period

Titre of virus

S

Figure 3

MEDICINE 37:12 674

Special syndromes

The major interest in human erythrovirus B19 stems from the

ability of the virus to replicate in erythroid progenitor cells in the

bone marrow. The virus uses a common blood group antigen

(P globoside) to facilitate cellular entry.3 Virus replication in such

cells underlies three important clinical syndromes e aplastic

crises, chronic transfusion-dependent anaemia and miscarriage.

Aplastic crises

Aplastic crises in patients with reduced red blood cell survival

(e.g. sickle cell disease, thalassaemia, hereditary spherocytosis),

a catastrophic decrease in haemoglobin (often to as low as 2e3

g/dl) occurs during acute infection. Infection should therefore be

suspected in any patient with a rapidly declining haemoglobin

concentration, particularly children.4 All such patients should be

admitted initially to a side-room, particularly during an epidemic

year, because they tend to present earlier, while they are still

infectious. A further clue to this syndrome may be the low or

normal reticulocyte count, indicating that the bone marrow is

unable to respond to the decline in haemoglobin.

Transfusion-dependent anaemia

Chronic transfusion-dependent anaemia is seen in immuno-

compromised patients (e.g. bone marrow and solid organ

transplantation, HIV infection).5,6 These patients require treat-

ment with intravenous immunoglobulin, often over several

weeks, because they are unable to mount a neutralizing antibody

reaction to clear virus from the bone marrow. In HIV-infected

patients, recovery has also been reported with antiretroviral

therapy demonstrating the immune restorative effect of such

treatment.

21 days 2 months 3 months

osure to virus

ositive

rase chain reaction analysis positive

ymptoms

Virus-specific IgG

Virus-specific IgM

� 2009 Published by Elsevier Ltd.

VIRAL INFECTIONS

Pregnancy

Practice points

C Animal parvoviruses do not infect humans

C Erythrovirus B19 infection is responsible for a 10% excess

foetal loss rate when maternal infection occurs in the first 20

weeks of gestation

C Hospital and school outbreaks may be difficult to control

because secondary cases are already infectious at the time of

notification of the index case

C Intrauterine blood transfusion should be used to treat eryth-

rovirus B19-induced hydrops foetalis

The largest study of erythrovirus B19 infection in pregnancy has

shown that infection leads to miscarriage in 10% of cases, and there

is an additional 3% risk of foetal hydrops (Figure 2), though only

when maternal infection occurs in the first 20 weeks of gestation.7

After this time, though more than 50% of foetuses become infected

in utero there is no risk of foetal loss. Infection does not result in

congenital damage. This risk of miscarriage should not be under-

estimated e in a recently completed prospective study of suscep-

tible pregnant women, the incidence of adult infection was about

1% in non-epidemic years, but 13% during an epidemic.8

As the interval between maternal infection and the develop-

ment of foetal hydrops is 2e17 weeks, the woman may have lost

virus-specific IgM by the time hydrops is diagnosed. Therefore,

all women in contact with the virus up to the 20th week of

gestation should be offered testing for evidence of prior or

current infection. Those shown to be susceptible should be re-

tested four weeks later and, if seroconversion is demonstrated,

offered ultrasonography at fortnightly intervals. Whilst sponta-

neous recovery can occur in up to 25% of infected foetuses,

a single intrauterine blood transfusion is often curative.

Responding to outbreaks in schools where a member of staff

is pregnant can be difficult. In such cases, serological testing is

recommended, and susceptible pregnant women may choose to

remain absent from work until the outbreak is over. The time

required is uncertain; 4e6 weeks is likely.

Other associations: other diseases that have tentatively been

linked with B19 infection include myocarditis, vasculitis,

nephritis, peripheral neuropathy, hepatitis, encephalitis, Kawa-

saki disease and chronic fatigue syndrome. Absolute proof of

a causal link requires further epidemiological studies.

Diagnosis

Erythrovirus B19 cannot be grown in routine cell culture, so

laboratory diagnosis relies on serology and virus detection using

molecular methods. Various virus-specific IgG and IgM tests

(Figure 3) are widely available; virus-specific IgM is detectable

from the onset of rash/arthralgia, but persists for only 2e3

months. In foetal hydrops and transfusion-dependent anaemia,

detection of virus by quantitative real-time polymerase chain

reaction (PCR) analysis in amniotic fluid is the test of choice and

in patients in whom the immune response is poor or non-exis-

tent. Use of PCR to detect viraemia is very sensitive, the inter-

pretation of a low viral load (c.103e105/ml) can be problematic

because viral DNA can persist for more than a year at such levels

after infection, even in healthy adults.

Prevention of infection

It is possible that, within 10 years, B19 infection may be prevent-

able. Candidate recombinant vaccines, based on virus-like parti-

cles akin to the human papillomavirus vaccine, have generated

MEDICINE 37:12 675

excellent neutralizing antibody responses in primate models.

Studies of families in which an index case presents with acute

parvovirus infection indicate that the presence of specific IgG

directed against parvovirus antigens correlates with protection.A

REFERENCES

1 Cossart YE, Field AM, Cant B, Widdows D. Parvovirus-like particles in

human sera. Lancet 1975; ii: 72e3.

2 Rice PS, Cohen B. Investigation of a school outbreak of parvovirus B19

infectionusingsalivary antibodyassays.Epidemiol Infect1996;116:331e3.

3 Brown KE, Anderson SM, Young NS. Erythrocyte P antigen: cellular

receptor for B19 parvovirus. Science 1993; 262: 114e17.

4 Pattison JR, Jones SE, Hodgson J, et al. Parvovirus infections and

hypoplastic crisis in sickle-cell anaemia. Lancet 1981; i: 664e5.

5 Kerr JR, Kane D, Crowley B, et al. Parvovirus B19 infection in AIDS

patients. Int J STD AIDS 1997; 8: 184e6.

6 Moudgil A, Shidban H, Nast CC, et al. Parvovirus B19 infection-related

complications in renal transplant recipients: treatment with intrave-

nous immunoglobulin. Transplantation 1997; 64: 1847e50.

7 Miller E, Fairley CK, Cohen BJ, Seng C. Immediate and long-term

outcome of human Parvovirus B19 Infection in Pregnancy. Br J Obstet

Gynaecol 1998; 105: 174e8.

8 Jensen IP, Thorsen P, Jeune B, Moller BR, Vestergaard BF. An epidemic

of parvovirus B19 in a population of 3596 pregnant women: a study of

sociodemographic and medical risk factors. Br J Obstet Gynaecol

2000; 107: 637e43.

FURTHER READING

Anderson LJ, Young NS, eds. Human parvovirus B19. Monogr Virol 1997: 20.

Brown KE, Young NS. Parvovirus B19 in human disease. Ann Rev Med

1997; 48: 59e67.

Cohen BJ. Parvovirus B19: an expanding spectrum of disease. BMJ 1995;

311: 1549e52.

Young NS, Brown KE. Parvovirus B19. N Engl J Med 2004; 350: 586e97.

� 2009 Published by Elsevier Ltd.