eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Parvovirus B19 Infection

Author: David J Cennimo, MD, FAAP, AAHIVS, Fellow in Infectious Diseases, Department of Pediatrics, University of Medicine and Dentistry of New Jersey-New Jersey Medical School
Coauthor(s): Arry Dieudonne, MD, Associate Professor of Pediatrics, Division of Pulmonology, Allergy, Immunology and Infectious Diseases, University of Medicine and Dentistry of New Jersey-New Jersey Medical School; Clinical Director, Francois-Xavier Bagnold Center for Children, University Hospital
Contributor Information and Disclosures

Updated: Aug 4, 2009

Introduction

Background

Parvovirus B19 (B19V) is a single-stranded DNA virus of the family Parvoviridae and genus Erythrovirus. Although parvoviruses commonly cause disease in animals, it was only in 1975 that the first human pathogen of this family was discovered by Cossart and colleagues while screening normal blood bank donors' sera for the hepatitis antigen (one of the donors' serum samples was coded B19).^1,2

The presence of immunoglobulin antibodies to this virus in the serum of half of the adult population was established by epidemiological surveys, suggesting acquisition of immunity during childhood. Evidence of recent infection (viral antigen, immunoglobulin M [IgM]-specific antibodies to the virus) was first found in the blood of Jamaican children living in London, England, all of whom presented with transient aplastic crisis (TAC) of sickle cell disease.³

Later, Serjeant et al confirmed the close association of parvovirus and aplastic crisis in a large retrospective study of sera from sickle cell disease patients with this complication.⁴ Later, human parvovirus B19 was shown to be the etiologic agent of erythema infectiosum in hematologically normal persons.^5,6  Erythema infectiosum was originally named Fifth disease because it was the fifth of 6 classic exanthematous diseases of childhood to be described. Later, cases of nonimmune hydrops fetalis were reported when infection in a woman occurred during pregnancy⁷ . Parvovirus B19 has also been associated with multiple other conditions.^8,2,5,9

Pathophysiology

The incubation period from infection to initial, nonspecific symptoms ranges from 4-14 days.  Cases have been reported as long as 21 days after exposure. The rash and joint symptoms usually occur 2-3 weeks after initial infection. Patients are most contagious in the few days preceding rash. Patients with aplastic anemia are considered contagious before the onset of symptoms and for at least 1 week.^5,9,8,10

Parvovirus B19 has a unique tropism for human erythroid progenitor cells. The virus requires the P blood antigen receptor (also known as globoside) to enter the cell. Rare individuals who lack the P antigen are immune to parvovirus B19 infection. Once inside the host cell, viral DNA enters the nucleus. The 3' end of the DNA strand folds back on itself, forming a hairpinlike bend that functions as a self-primer for viral DNA replication. The virus is cytotoxic to host cells.^2,11 This, coupled with the tropism for rapidly dividing erythrocyte precursors (particularly pronormoblasts and normoblasts, wherein they replicate to high titers), leads to the suppression of erythrogenesis seen during infection. No reticulocytes (immature erythrocytes) are available to replace aging or damaged erythrocytes as they are cleared by the reticuloendothelial system.^5,2  

Although decreases in hemoglobin levels of greater than 1 g/dL are rare in healthy children infected with parvovirus B19, decreases of 2-6 g/dL may be observed in patients with hemoglobinopathies or hemolytic anemias. Occasionally, the virus infects leukocytes (especially neutrophils).¹² Parvovirus B19 does not infect megakaryocytes; however, in vitro, parvovirus B19 proteins have a cytotoxic effect on megakaryocytes. Although B19V infection may manifest with pancytopenia, it is not believed to contribute significantly to true aplastic anemia.^9,10

Fetal myocardial cells are known to express P antigen and may become infected with parvovirus B19. This may explain some of the direct myocardial effects seen in fetal infection.^2,13

Frequency

United States

Parvovirus B19 infection is extremely common. Seropositivity rates are 5-10% among young children (aged 2-5 years), increasing to 50% by age 15 years and 60% by age 30 years. A small percentage of adults acquire infection every year, resulting in an incidence of approximately 90% in adults older than 60 years.^8,6 The annual seroconversion rate among pregnant women without parvovirus B19 is 1.5%.⁹

Clinical cases of parvovirus B19 infection (erythema infectiosum) may be sporadic or may occur in outbreaks in the late winter through early spring. Attack rates during school outbreaks may be as high as 60%,⁸ and secondary spread through nonimmune household contacts is common. Infection can be an occupational hazard in child care workers, with a rate of 20% reported in some studies.⁹  A cyclic increase in the number of infections is also observed, peaking every 3-4 years.⁸

International

Parvovirus B19 infection is common worldwide. The age distribution is similar to that observed in the United States. A small number of groups, living in remote geographical locations, have not been exposed to human parvovirus.²

Mortality/Morbidity

Parvovirus B19 infection in otherwise healthy children and adults has an extremely low mortality rate.^5,2,10

Morbidity is as follows:

• Erythema infectiosum (Fifth disease) is described in clinical manifestations below.
• Polyarthropathy syndrome is mostly seen in adult women with acute infection. Patients develop acute symmetric arthritis affecting the small joints of the hands and feet, typically lasting for 1-3 weeks. In a small number, the arthritis may be prolonged, lasting for months. These symptoms can be confused with rheumatoid arthritis and further complicated by transient rheumatoid factor production during parvovirus B19 infection.¹⁴  For this reason, parvovirus B19 infection should be considered in the differential diagnosis of rheumatoid arthritis. Studies have not shown a causal link between parvovirus B19 infection and rheumatoid arthritis, and parvovirus B19 does not cause degenerative joint changes.⁸
• In patients with hemoglobinopathies or hemolytic anemias, in whom the duration of erythrocyte survival is decreased, a decrease in the reticulocyte count to less than 1% (usually to 0%) may precipitate a TAC. Such a crisis is characterized by profound anemia caused by a temporary halt in new erythrocyte production.⁴ Because the reticuloendothelial system removes abnormal erythrocytes from circulating blood, abnormal erythrocytes have a significantly shortened half-life. Any interruption in new erythrocyte production may trigger a crisis. The bone marrow during TAC reveals an absence of erythroid precursors and the presence of striking giant pronormoblasts; rarely, necrosis may occur.¹⁵  Parvovirus B19 is the only infectious cause of TAC known and has been shown to be the cause of aplastic crisis in over 80% of patients with sickle cell disease.^2,8 .
• Patients who are immunocompromised (eg, receiving chemotherapy or immunosuppressive drugs or have immune defects [congenital and acquired]) may develop chronic parvovirus B19 infection that results in chronic anemia. Pure red cell aplasia (PRAC) persists until the virus is cleared and should be distinguished from the transient anemia described above.^8,5,6 Chronic parvovirus B19 infection in transplant recipients has been linked to anemia, other hematologic abnormalities, myocarditis, and pneumonitis.¹⁶ Pediatric patients with hematologic malignancies and parvovirus B19 infection have suffered prolonged anemia that interferes with chemotherapy timing¹⁷ .
• Parvovirus B19 has been linked to other hematologic abnormalities. Thrombocytopenia, leukopenia, or both may be seen in acute infection, even in immunologically normal hosts. Cases of immune thrombocytopenic purpura, Henoch-Schönlein purpura, and the hemophagocytic syndrome have been attributed to parvovirus B19. However, transient erythroblastopenia of childhood and true aplastic anemia are not associated with infection.^8,18,10
• Hydrops fetalis, perhaps the most serious complication of parvovirus B19 infection, may occur when a nonimmune woman is infected, usually in the first 20 weeks of pregnancy. 
  • Parvovirus B19 infection is the most common cause of nonimmune hydrops fetalis and can result in fetal death in 2-6% of cases.⁹  
  • As many as 50% of women of childbearing age may not be immune to parvovirus B19 and are susceptible to infection.⁵ The seroconversion rate in the same group is 1.5% per year.⁹ The vertical infection rate is estimated at 25-50%. The rate of fetal loss is estimated to be 1.6-9%.^5,19,20  Of fetuses infected in the first half of pregnancy, 85% develop hydrops develops within 10 weeks (mean 6-7 wk).
  • The most critical gestational age appears to be 13-16 weeks' gestation, when the fetus has the highest rates of hepatic hematopoiesis. 
  • Historically, hydrops had a 30% mortality rate; however, newer data demonstrate a resolution of 94% of cases within 6-12 weeks and a mortality rate of less than 10% if the fetus can be supported by transfusion.²¹
  • Intrauterine growth retardation, myocarditis, and pleural and pericardial effusions, may also occur but parvovirus B19 is not associated with a congenital malformation.^9,8,13,20  
  • Infection in the pregnant patient is further covered below.

Race

No racial predilection is known.

Sex

In general, parvovirus B19 infection affects males and females in equal numbers. Adult females are more likely to develop postinfectious arthritis.

Age

Parvovirus B19 infection is common in school-aged and younger children who attend daycare facilities. In general, children transmit the virus to parents and siblings. In young children, the antibody seroprevalence ranges from 5-10%. This increases to 50% in adolescents and approaches 90% in the elderly.^9,2

Clinical

History

• Common symptoms of parvovirus B19 (B19V) infection include a mild nonspecific prodromal illness that may consist of fever (15-30% of patients), malaise, headache, myalgia, nausea, and rhinorrhea; typically beginning 5-7 days after initial infection.^8,22 These symptoms correspond to the initial viremia and dissipate in 2-3 days.⁵ Approximately 1 week later, a bright red macular exanthem appears on the cheeks and is often associated with circumoral pallor.^9,5 A diffuse maculopapular rash can appear 1-4 days later and fades to a lacy erythematous rash, which may be pruritic and may spread gradually toward the distal extremities. Most seropositive patients have no history of this classic biphasic illness. The clinical symptoms widely vary, and the classic "slapped cheek" rash is much more common in young children.⁸
• The cause of parvovirus B19 rash is believed to be immunologically mediated, and the rash corresponds to the appearance of immunoglobulin M (IgM) in the serum. This signals the clearance of viremia. Recurrence of the rash (lasting for weeks or more) may be provoked by sunlight, stress, or exercise and does not indicate relapsed infection.^2,5
• Alternatively, parvovirus B19 infection may manifest with purpuric rash, erythema multiforme, or pruritus of the soles of the feet. Parvovirus B19 may cause a papular-purpuric "gloves-and-socks" syndrome (PPGSS), which manifests as an erythematous exanthem of the hands and feet with a distinct margin at the wrist and ankle joints. It is mainly seen in young adults and initially presents with painful erythema and induration of the hands and feet. Less commonly, the penis, vulva, thighs, cheeks, and elbows may be involved. This syndrome occurs exclusively with parvovirus B19 infection and is an uncommon manifestation. The skin changes may progress to petechia, purpura, and bulla with skin sloughing. PPGSS usually resolves in 1-3 weeks without scaring.^5,6,23,24
• Transient small joint arthropathy may be the main clinical presentation of parvovirus B19 in adults. Most have some joint pain, but few progress to frank arthritis. In general, the timing of joint symptoms coincide with the expected onset of rash in children. Arthritis usually improves in 1-3 weeks but may persist for months. Parvovirus B19 infection is not associated with chronic degenerative arthritis.^8,2,6 Less then 10% of children experience arthropathy; however, in these cases, the knees are most commonly involved.⁹
• Patients with severe anemia due to transient aplastic crisis (TAC) may present with pallor, fatigue, or signs of an aplastic crisis. Underlying hemoglobinopathies should be sought in these patients. Patients with thrombocytopenia may exhibit bruising.^8,10,2,12
• Rarely, parvovirus B19 infection manifests as myocarditis, vasculitis, glomerulonephritis, or encephalitis. B19V infection has been reported in association with idiopathic thrombocytopenia purpura, Henoch-Schönlein purpura, and pseudoappendicitis. It has also been reported to precipitate hemophagocytic syndrome.^5,8,2,10 In rare cases, parvovirus B19 has been implicated in fatal myocarditis in transplant patients,¹⁶ and has been implicated as a cause of endothelial dysfunction in patients with diastolic dysfunction.²⁵
• Parvovirus B19 infection in pregnant women may result in hydrops fetalis, particularly when infection occurs before 20 weeks' gestation. In the United States, the most common etiology of hydrops fetalis is parvovirus B19 infection.^21,9,8,20
• Neurologic manifestations associated with parvovirus B19 infection widely vary.⁵ Peripheral nervous system involvement such as neuropathy may be seen more frequently in older immunocompetent individuals. CNS involvement, including meningitis, encephalitis, and seizure, has been demonstrated in younger children and immunocompromised patients.²⁶
• Many individuals may experience asymptomatic or unrecognized infection.⁵

Physical

• Parvovirus B19 infection may be indistinguishable from other viral illnesses in the absence of the classic exanthem.
• Children are often febrile, but their appearance is nontoxic and the prodrome is nonspecific.
• Patients with aplastic crisis have pallor and tachycardia secondary to anemia. Children with aplastic crisis usually do not have a rash.⁹ The absence of rash may result from prolonged viremia and lack of anti–parvovirus B19 IgM. Another hypothesis is that patients in aplastic crisis often receive blood transfusions, and any rash may be attributed to a transfusion reaction.
• A friction rub may be audible if pericarditis is present. Benign flow murmurs are common in anemic children with tachycardia. Patients with myocarditis or severe anemia may present with physical findings of heart failure.
• The small joints of the hands, feet, elbows, and knees may exhibit signs of arthritis.
• Painful pruritic papules and purpura may be present on the hands and feet as part of PPGSS.

Causes

• Classic fifth disease, aplastic crisis, and PPGSS are caused almost exclusively by parvovirus B19. This virus, distributed worldwide, infects only humans. Transmission occurs via vertical transmission (birth), large droplet respiratory secretions, transfusion of blood products, and percutaneous exposure to blood.^9,22
• Parvovirus B19 has been spread by blood products, such as intravenous immunoglobulin (IVIG), packed RBCs, platelets, and nonrecombinant clotting factors. Because the virus lacks an outer lipid envelope and the genome is very stable, it is extremely resistant to heat, cold, and solvents. Since 2002, makers of plasma-derived products have screened for parvovirus B19.²

• Search for CME/CE on This Topic »

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• Pediatrics, Fifth Disease or Erythema Infectiosum (Emergency Medicine)
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• Fifth Disease Treatment
• Fifth Disease Causes
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