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Erythrovirus B19 (formerly known as parvovirus B19)
VIRAL INFECTIONS
Erythrovirus B19 (formerly known as parvovirus B19)
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.
Philip Rice
Abstract Human 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. Laboratory 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 transfusion or intravenous immunoglobulin. Vaccination is theoretically possible with virus-like particles but the economic and disease burden case has yet to be made.
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 associated with pharyngeal virus excretion supporting spread by respiratory droplet. These initial symptoms are often unrecognized 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
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 discovered 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 serotype 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
Figure 1 Erythrovirus B19 rash. Photograph courtesy of Dr Yvonne Young.
673
Ó 2009 Published by Elsevier Ltd.
VIRAL INFECTIONS
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 immunocompromised patients (e.g. bone marrow and solid organ transplantation, HIV infection).5,6 These patients require treatment 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.
Figure 2 Hydrops foetalis.
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.
Viral detection assays in parvovirus B19 infection Serum electron microscopy positive
Serum DNA hybridization positive
Titre of virus and antibody
Polymerase chain reaction analysis positive
Infectious period
Symptoms
Titre of virus Virus-specific IgG Excretion of throat virus Virus-specific IgM
0
Inoculation/ exposure
7 days
14 days
21 days
2 months
3 months
Time since exposure to virus
Figure 3
MEDICINE 37:12
674
Ó 2009 Published by Elsevier Ltd.
VIRAL INFECTIONS
Pregnancy 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 underestimated e in a recently completed prospective study of susceptible 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 development 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 retested four weeks later and, if seroconversion is demonstrated, offered ultrasonography at fortnightly intervals. Whilst spontaneous 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, Kawasaki disease and chronic fatigue syndrome. Absolute proof of a causal link requires further epidemiological studies.
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 infection using salivary antibody assays. Epidemiol Infect 1996; 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 intravenous 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.
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-existent. Use of PCR to detect viraemia is very sensitive, the interpretation 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.
Practice points C C
C
Prevention of infection It is possible that, within 10 years, B19 infection may be preventable. Candidate recombinant vaccines, based on virus-like particles akin to the human papillomavirus vaccine, have generated
MEDICINE 37:12
C
675
Animal parvoviruses do not infect humans Erythrovirus B19 infection is responsible for a 10% excess foetal loss rate when maternal infection occurs in the first 20 weeks of gestation Hospital and school outbreaks may be difficult to control because secondary cases are already infectious at the time of notification of the index case Intrauterine blood transfusion should be used to treat erythrovirus B19-induced hydrops foetalis
Ó 2009 Published by Elsevier Ltd.
Erythrovirus B19 (formerly known as parvovirus B19)
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.
Philip Rice
Abstract Human 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. Laboratory 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 transfusion or intravenous immunoglobulin. Vaccination is theoretically possible with virus-like particles but the economic and disease burden case has yet to be made.
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 associated with pharyngeal virus excretion supporting spread by respiratory droplet. These initial symptoms are often unrecognized 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
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 discovered 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 serotype 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
Figure 1 Erythrovirus B19 rash. Photograph courtesy of Dr Yvonne Young.
673
Ó 2009 Published by Elsevier Ltd.
VIRAL INFECTIONS
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 immunocompromised patients (e.g. bone marrow and solid organ transplantation, HIV infection).5,6 These patients require treatment 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.
Figure 2 Hydrops foetalis.
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.
Viral detection assays in parvovirus B19 infection Serum electron microscopy positive
Serum DNA hybridization positive
Titre of virus and antibody
Polymerase chain reaction analysis positive
Infectious period
Symptoms
Titre of virus Virus-specific IgG Excretion of throat virus Virus-specific IgM
0
Inoculation/ exposure
7 days
14 days
21 days
2 months
3 months
Time since exposure to virus
Figure 3
MEDICINE 37:12
674
Ó 2009 Published by Elsevier Ltd.
VIRAL INFECTIONS
Pregnancy 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 underestimated e in a recently completed prospective study of susceptible 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 development 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 retested four weeks later and, if seroconversion is demonstrated, offered ultrasonography at fortnightly intervals. Whilst spontaneous 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, Kawasaki disease and chronic fatigue syndrome. Absolute proof of a causal link requires further epidemiological studies.
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 infection using salivary antibody assays. Epidemiol Infect 1996; 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 intravenous 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.
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-existent. Use of PCR to detect viraemia is very sensitive, the interpretation 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.
Practice points C C
C
Prevention of infection It is possible that, within 10 years, B19 infection may be preventable. Candidate recombinant vaccines, based on virus-like particles akin to the human papillomavirus vaccine, have generated
MEDICINE 37:12
C
675
Animal parvoviruses do not infect humans Erythrovirus B19 infection is responsible for a 10% excess foetal loss rate when maternal infection occurs in the first 20 weeks of gestation Hospital and school outbreaks may be difficult to control because secondary cases are already infectious at the time of notification of the index case Intrauterine blood transfusion should be used to treat erythrovirus B19-induced hydrops foetalis
Ó 2009 Published by Elsevier Ltd.