erythrovirus b19 (formerly known as parvovirus b19)
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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
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infectionusingsalivary antibodyassays.Epidemiol Infect1996;116:331e3.
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Gynaecol 1998; 105: 174e8.
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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.
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