OVERVIEW: What every practitioner needs to know
Are you sure your patient has a parvovirus infection? What are the typical findings for this disease?
Parvoviruses are single-stranded DNA viruses that commonly infect a variety of animals, including humans. The four types of parvoviruses known to infect humans include adeno-associated viruses, parvovirus B19, Parv4 and 5 viruses, and human bocavirus. Of these four, only parvovirus B19 has been demonstrated to cause disease. Bocavirus has been found in association with respiratory tract and gastrointestinal illness in children, but a causal connection has not been demonstrated.
The most frequent manifestation of parvovirus B19 in children is erythema infectiosum (EI), otherwise known as fifth disease. Clinical manifestations of EI include mild fever (≤30%) followed by a “slapped cheek” rash, often with circumoral pallor. This initial rash is followed by a maculo-papular, lace-like rash that spreads to the trunk, arms, buttocks and thighs and may be somewhat pruritic. In this phase the rash may be exacerbated by temperature fluctuations brought on by exercise, hot baths, or sunlight, and the rash may persist, fluctuating in intensity, for weeks or months.
Symmetrical poly-arthritis or arthralgia commonly accompany parvovirus B19 infection in adults, especially women, who may have no accompanying rash. Joint involvement is less common in children, affecting only about 10%.
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Less common clinical conditions:
Papulopurpuric gloves-and-socks syndrome (PPGSS):
Rarely, children who have no history of immune defects, develop painful and pruritic papules, petechiae, and even purpura of the hands and feet associated with fever and arthropathy when infected with parvovirus B19 infection.
Transient aplastic crisis:
In patients with hemolytic disorders or hemoglobinopathies, such as sickle cell disease, thalassemia, or hereditary spherocytosis, parvovirus B19 may cause transient reticulocytopenia leading to an aplastic crisis. The transient aplasia may be preceded by a mild prodromal illness with fever, malaise and myalgia, but rash usually is absent.
Chronic bone marrow failure:
Patients with congenital immunodeficiency or whose immune system is suppressed by medication or infection (e.g., HIV) may suffer persistent parvovirus B19 infection with resulting reticulocytopenia and anemia.
Fetal infection and hydrops:
Maternal infection during the first half of gestation can lead fetal hydrops, intrauterine growth retardation, pleural, and pericardial effusions. Fetal loss occurs in less than 10% of affected pregnancies. Parvovirus B19 has not been shown to be a cause of congenital anomalies.
Myocarditis:
Parvovirus B19 has been found to be a cause of viral myocarditis in children and adults. Limited studies suggest that outcomes for patients with parvovirus myocarditis may be more severe (greater likelihood of death and requirement for cardiac transplantation) than seen in other viral causes of myocarditis.
What other disease/condition shares some of these symptoms?
The mild generalized symptoms and rash of EI can be mistaken for rubella or roseola (due to human herpesvirus 6).
Depending on the specific clinical manifestations that predominate, PPGSS can suggest meningococcemia or Rocky Mountain spotted fever.
Despite vigorous search for other causative agents, transient aplasia seen in children with red blood cell defects has been seen only in association with parvovirus B19; however, parvovirus has not been associated with transient erythroblastic anemia of childhood (TEC).
Fetal hydrops can be caused by a variety of infectious agents, by Rh isoimmunization, by congenital heart disease, and by genetic metabolic diseases.
Viral myocarditis can be caused by a variety of agents, including enteroviruses, adenovirus, Epstein Barr virus, and cytomegalovirus.
What caused this disease to develop at this time?
Parvovirus B19 infection is seen worldwide and is a common infection in both children and adults. Humans are the only known hosts. The virus is transmitted most commonly by respiratory tract secretions, but exposure to infected blood or blood products can also transmit infection, and transplacental infection from mother to fetus can occur. Outbreaks typically occur during late winter and spring, but sporadic infection also occurs.
Approximately 5-10% of young children have antibody against parvovirus B19, and by age 15 approximately 50% are seropositive. Acquisition of infection continues to occur among seronegative individuals throughout adulthood, presumably due to continued contact with children who may be infected.
The period from exposure to development of symptoms (incubation period) is variable. It can be as short as 4 days and as long as 21 days. Individuals with EI are most infectious during the prodromal period, before the rash is apparent. As a result secondary spread occurs commonly in schools while infected children are asymptomatic or have only mild symptoms. Approximately 20% of susceptible school contacts develop infection. Studies have demonstrated transmission of infection to 50% of exposed household contacts.
Patients with aplastic crisis due to parvovirus B19 are contagious during their reticulocytopenia and anemia; appropriate precautions should be taken if these children are hospitalized for any reason during their aplastic crisis and for at least one week after onset.
Approximately 50% of pregnant women in the United States are susceptible to (seronegative for) parvovirus B19. Depending upon the nature of exposure (community versus household), seronegative women have a 30% to 50% chance, respectively, of developing infection if they come into contact with an infected individual. Studies have demonstrated that less than 10% of fetuses of women infected during the first half of pregnancy will develop hydrops. Overall, it is estimated that approximately 10% to 20% of cases of non-immune hydrops are caused by fetal parvovirus B19 infection.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Diagnosis of parvovirus B19 infection is usually made based on clinical presentation of EI, PPGSS, or aplastic crisis in a patient with red blood cell defect. CBC will detect a decline in hemoglobin in patients with shortened red cell life span and aplastic crisis.Serology can confirm the diagnosis, and detection of parvovirus B19-specific IgM is the preferred test. Radioimmunoassay or enzyme immunoassay will detect virus-specific IgM in 90% of patients by the time symptoms of EI are evident and for approximately 4 months following infection. IgG antibody rises quickly and is present usually within the first week of illness, but since IgG persists for life, a positive test does not confirm that the acute illness is caused by parvovirus.
Parvovirus B19 can be detected in serum by nucleic acid hybridization or polymerase chain reaction (PCR). This is the preferred method for detecting infection in immunocompromised patients with suspected chronic parvovirus infection, since such patients may not produce an antibody response. Virus can also be found in the serum of patients with aplastic crisis before an antibody response is detectable. Quantitation of virus detected by PCR is important, because, though levels of virus fall quickly after acute infection, some virus can persist in serum for many months. Greater than 105genome copies per milliliter of serum suggest acute infection in patients with aplastic anemia due to parvovirus B19.
PCR can also be used to detect parvovirus B19 in amniotic fluid and placental tissue if fetal infection is suspected and in endomyocardial biopsy in patients with myocarditis.
Parvovirus B19 cannot be detected in standard tissue culture systems.
Would imaging studies be helpful? If so, which ones?
Imaging is not useful in diagnosing or managing parvovirus infection in patients with EI or PPGSS. When fetal hydrops is suspected, ultrasound examination of the fetus will demonstrate generalized edema and fluid collection in the chest and abdominal cavity. Echocardiography is used to assess patients with suspected myocarditis.
If you are able to confirm that the patient has a parvovirus infection, what treatment should be initiated?
There is no known anti-viral agent effective for treatment of parvovirus B19 infection.
EI is a self-limited condition with minimal systemic symptoms. Anti-pyretics may be used for fever, and anti-inflammatory agents such as ibuprofen may be used for the minority of patients who have joint inflammation.
Patients with red cell defects and aplastic crisis due to parvovirus infection sometimes require red blood cell transfusion.
Intravenous immune globulin (IVIG) is effective in treating immunocompromised patients with chronic infection due to parvovirus. The recommended dose is 400 mg/kg/day for 5-10 days.
Intrauterine blood transfusions have been used to treat the anemia that leads to fetal hydrops.
What are the adverse effects associated with each treatment option?
Transmission of viral or bacterial infection in blood transfusion is rare in the United States today because of careful screening of donors and of donated blood, but transmission still occurs rarely. IVIG has been reported to cause fever, headache, chills, aseptic meningitis, and anaphylaxis, particularly in individuals with IgA deficiency. Intrauterine blood transfusion can precipitate uterine contraction.
What are the possible outcomes of parvovirus infection?
Parvovirus B19 infection is usually self-limited with no sequelae. Chronic infection associated with immune compromise can result in bone marrow failure, and fetal infection can lead to severe anemia, hydrops, and even death. In rare instances patients who develop polyarthropathy during parvovirus infection will have persistence or recurrences that may continue for years. The outcome for patients with parvovirus B19 myocarditis varies from complete recovery with normal cardiac function to persistent ventricular dysfunction, requirement for cardiac transplantation, and even death.
What causes this disease and how frequent is it?
Parvovirus B19 has a worldwide distribution in humans. By age 15 years, approximately 50% of the population has been infected, and approximately 90% of elderly individuals are seropositive, indicating past infection. There is no known relationship between genes and manifestation of parvovirus infection, except that individuals who lack the red blood cell P antigen are naturally resistant to parvovirus B19 infection (see below). There is ongoing exploration of the possibility that clinical manifestations of infection are related to specific genes.
How do these pathogens/genes/exposures cause the disease?
Parvovirus B19 replicates in red blood cell precursors in the bone marrow leading to reticulocytopenia and arrest of red blood cell production. Tropism for the red blood cell precursor is related to the parvovirus B19 receptor, the blood group P antigen, also known as globoside. This antigen is found on erythrocyte precursors, but it is also found on endothelial cells, megakaryocytes, placenta, and fetal myocardium and liver cells. Viremia follows infection and is often associated with a non-specific febrile illness. In immunocompetent individuals IgM is produced in response to infection, and IgG production follows quickly, leading to resolution of viremia. The rash that is characteristic of EI and the arthropathy that sometimes occurs are mediated by this immune response. Failure to mount an immune response can lead to chronic infection and chronic anemia.
Rare individuals lack the blood group P antigen and are naturally resistant to parvovirus B19 infection.
What complications might you expect from the disease or treatment of the disease?
See above
Are additional laboratory studies available; even some that are not widely available?
Though parvovirus B19 replication takes place in red blood cell precursors, clinical anemia is not apparent in immunocompetent infected individuals. Intentional infection of adult volunteers led to reduced red cell production and a small decline in hemoglobin concentration, but the effects of this relative decline are not clinically apparent, and measurement of hemoglobin may demonstrate an acceptably normal level.
How can parvovirus infection be prevented?
There is no antiviral therapy and no vaccine available to prevent parvovirus B19 infection. Spread of infection can be prevented by routine hygienic practices, including hand washing and proper disposal of used tissues. There is no reason to preclude children with EI from school attendance, because they are no longer contagious by the time the cutaneous manifestations of the infection are apparent.
Women who are anticipating pregnancy or who are pregnant and concerned about the possibility of acquiring parvovirus infection may undergo serologic testing for IgG antibody against the virus.
Since 2002 donated plasma derivatives have been screened for parvovirus B19 DNA to reduce the likelihood of transmission of infection via blood products.
What is the evidence?
Anderson, MJ, Higgins, PG, Davis, LR. “Experimental parvoviral infection in humans”. J Infect Dis. vol. 152. 1985. pp. 257-65.. (Description of clinical, laboratory, and viral consequences of experimental infection of adult human volunteers.)
Fretzayas, A, Douros, K, Moustaki, M, Nicolaidou, P. “Papular-purpuric gloves and socks syndrome in children and adolescents”. Pediatr Infect Dis J. vol. 28. 2009. pp. 250-2. (This article describes a 12-year old patient with this syndrome and reviews the condition.)
Koch, WC, Massey, GV. “Aplastic crisis”. Pediatr Rev. vol. 12. 1990. pp. 142-8.. (Includes a description of aplastic crisis due to parvovirus B19.)
Gratacos, E, Torres, PJ, Vidal, J. “The incidence of human parvovirus B19 infection during pregnancy and its impact on perinatal outcome”. J Infect Dis. vol. 171. 1995. pp. 1360-3.
Lassen, J, Bager, P, Wohlfahrt, J. “Parvovirus B19 in pregnancy and subsequent morbidity and mortality in offspring”. Int J Epidemiol. vol. 42. 2013. pp. 1070-6. (This is a Danish study that assessed the outcome of 1095 children born to women who were infected with parvovirus B19 during pregnancy.)
Molina, KM, Garcia, X, Denfield, SW. “Parvovirus B19 myocarditis causes significant morbidity and mortality in children”. Pediatr Cardiol. vol. 34. 2013. pp. 390-7. (Describes the clinical course of 19 children with myocarditis due to parvovirus B19.)
Pickering, LK, Baker, CJ, Kimberlin, DW, Long, SS. “American Academy of Pediatrics. Parvovirus B19”. 2012. pp. 539-41. (General information about infection with this virus from experts in pediatric infectious diseases.)
Ongoing controversies regarding etiology, diagnosis, treatment
Outbreaks of EI (fifth disease) in day care or schools sometimes causes alarm among female teachers who are or may become pregnant. Recognizing that approximately 50% of adults are seropositive and therefore not susceptible to infection, that transmission of infection in the school setting affects only about 20% to 30% of susceptible contacts, and that less than 10% of the fetuses of infected pregnant women develop hydrops, all suggest that the risk of fetal loss in this situation is very small. However, it is reasonable to attempt reassurance by testing such women for parvovirus B19 IgG and, if they are seronegative, offering to repeat testing if exposure occurs.
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