William C. Koch

Manifestations and treatment of human parvovirus B19 infection in immunocompromised patients.

We diagnosed infections from human parvovirus B19 in three patients by using dot-blot hybridization and a polymerase chain reaction to detect B19 DNA and using an enzyme immunoassay to detect IgG and IgM to B19. For 5 months a 5-year-old boy with acute lymphoblastic leukemia in remission had anemia without reticulocytes or bone marrow erythrocyte precursors. His serum lacked IgG and IgM to B19 but contained B19 DNA. He received gamma globulin intravenously (0.4 gm/kg/day for 5 days); his viremia promptly cleared and reticulocytosis developed. A 14-year-old boy with acute lymphoblastic leukemia in remission had fever, rash, neutropenia (less than 300 leukocytes/mm3), and a hemophagocytic syndrome lasting 3 weeks. His serum contained IgM to B19 and B19 DNA. Without therapy, IgG to B19 developed; although low levels of B19 DNA persisted, the leukocyte count returned to normal. In a 19-year-old patient with systemic lupus erythematosus and hemolytic anemia, an aplastic crisis lasted 2 weeks. Her serum lacked IgG and IgM to B19 but contained B19 DNA. Without therapy, IgG and IgM to B19 appeared, viremia diminished, and reticulocytosis occurred. These patients illustrate the varied manifestations of chronic B19 infections, the importance of DNA detection for diagnosis, and the possible efficacy of gamma globulin therapy.

Human Parvovirus B19 Infection in Infancy Associated with Acute and Chronic Lymphocytic Myocarditis and High Cytokine Levels: Report of 3 Cases and Review

Human parvovirus B19 infection is occasionally associated with acute lymphocytic myocarditis (ALM). Three infants with B19 virus-associated ALM were followed up clinically, histologically, and immunovirologically. Each infant had B19 virus DNA in the blood or B19 virus-specific IgM antibodies. Two infants with postnatal infection recovered after immunosuppressive therapy. The third infant with possible prenatal infection developed chronic persistent myocarditis associated with persistent B19 virus DNA in the blood. All 3 infants had increased levels of interferon-gamma, tumor necrosis factor-alpha, and interleukins -6 and -8. Four newborns with congenital B19 virus infection and 4 infants and children who had postnatally acquired B19 virus infection without myocarditis all had normal levels of these cytokines. These observations suggest that B19 virus infection in infancy causes ALM in some infants and children.

Serologic and virologic evidence for frequent intrauterine transmission of human parvovirus B19 with a primary maternal infection during pregnancy.

OBJECTIVE To define the intrauterine viral transmission rate during primary maternal parvovirus B19 infection and identify factors that may influence this rate. METHODS Forty-three pregnant women at two medical centers were identified with a primary B19 infection and followed to delivery. At delivery maternal and infant (umbilical cord) blood was obtained for B19 serologic and virologic PCR testing. RESULTS All of the women delivered healthy infants at term and none was hydropic. Overall 22 (51%) of the 43 infants had some evidence of a congenital B19 infection. B19-specific IgM was detected in 11 infants at delivery, B19 IgA was detected in 10 and B19 DNA was detectable by PCR in 11 infants. One infant was negative at birth but became positive for IgM, IgA and PCR at 6 weeks of age. No association was found between the likelihood of intrauterine infection and: maternal age; symptomatic maternal infection; method of delivery; maternal IgG titer at delivery; maternal IgG avidity at delivery; or maternal viremia at delivery. Intrauterine infection was associated with maternal IgM positivity at delivery; this association may have been a result of maternal infection occurring later in gestation. CONCLUSION Although the incidence of intrauterine hydrops and fetal demise after maternal infection is low, there is a high rate of intrauterine viral infection that occurs throughout gestation and yields newborns who, although infected in utero, are asymptomatic at birth.

Antivirals for cytomegalovirus infection in neonates and infants: focus on pharmacokinetics, formulations, dosing, and adverse events.

Cytomegalovirus (CMV) infection is very common throughout the world, and has become more of a pediatric clinical concern given the high incidence of congenital CMV infections as well as the increasing numbers of immunocompromised patients. Because of this, the need for antiviral therapies in infants and neonates is growing.Currently, there are four antivirals available that are active against CMV: ganciclovir, valganciclovir, foscarnet, and cidofovir. At this time, none have approved indications for use in children. Although there are limited data regarding the dose, pharmacokinetics (PK), safety, and adverse events for some of these antivirals, ganciclovir, and its oral prodrug valganciclovir, have been the best studied in the infant and neonate populations. In general, pharmaceutical PK studies in young children are limited by the constraints of sampling difficulties and blood volume requirements; fewer sampling times and studies may be available for drug evaluation. Given this caveat, ganciclovir and valganciclovir PK in children thus far appears to follow a monocompartmental model, contrary to what has been described in adults. However, when normalized for weight, the volume of distribution, clearance, and half-life of ganciclovir are similar to those found in adults. Given the findings that ganciclovir (and thus valganciclovir) clearance is directly proportionate to renal function, care must be taken when administering the drug to patients with impaired renal function. Recent studies evaluating valganciclovir PK in infants (at a dose of 16 mg/kg every 12 hours) have shown similar areas under the plasma concentration-time curve (AUCs) to intravenous ganciclovir (at a dose of 6 mg/kg every 12 hours), and that these AUCs remain quite stable over a number of weeks. As seen in adults, oral ganciclovir has a low bioavailability (4.8% in a pediatric analysis) and is therefore a poor alternative for treating serious CMV infections.Neutropenia is the most frequent toxicity associated with ganciclovir and valganciclovir therapy, whereas significant (and possibly irreversible) renal toxicity can be seen with cidofovir. Foscarnet administration can also result in renal toxicity as well as significant electrolyte imbalances. Several of these drugs have potential toxicities that are of concern, including carcinogenesis, teratogenesis, and azospermia (ganciclovir, valganciclovir, and cidofovir) and deposition into bone or dentition (foscarnet) that may have significant implications when treating an infant. Given these potential ill effects, careful consideration of the indications for the clinical use of these antivirals is necessary before using them for CMV infection in neonates and infants.

Intrauterine parvovirus B19 infection may cause an asymptomatic or recurrent postnatal infection

Although infection with parvovirus B19 (B19) during pregnancy may cause fetal demise, the true incidence of intrauterine infection is unknown. For 19 women with serologically confirmed B19 infections between 4 and 38 weeks of gestation, we performed follow-up examinations of their infants. Serial sonograms of the 19 fetuses showed that none developed hydrops. All 19 women delivered healthy term infants. Cord sera of four infants were tested for IgM to B19 and three were positive. Between 3 and 21 months of age, all 19 infants had normal physical examinations, developmental evaluations and hematocrits; and 16 lacked IgG to B19. One infant who was IgM-positive to B19 at birth was IgM-positive at age 7 months when he also had an IgG titer to B19 of 1:500,000 (mothers concurrent titer, 1:10,000), and had B19 DNA in serum detected by polymerase chain reaction. The other two infants who were IgM-positive at birth were IgM- and IgG-negative by 11 and 16 months of age. These results suggest that intrauterine B19 infection may be frequent and occasionally cause an asymptomatic postnatal infection.

A synthetic parvovirus B19 capsid protein can replace viral antigen in antibody-capture enzyme immunoassays

To establish a renewable source of parvovirus B19 antigens for diagnostic tests, gene sequences for the viral capsid proteins, VP1 and VP2, were cloned into baculovirus expression vectors and the recombinant viruses used to infect Sf9 insect cells. Cell lysates examined by immunoblotting demonstrated reactive proteins corresponding to the expected sizes of native VP1 (83 kDa) and VP2 (58 kDa). The VP2 protein was produced efficiently in quantity and self-assembled into empty capsids as shown by density equilibration in a CsCl step gradient. The VP2 protein was purified and used as an antigen in antibody-capture enzyme immunoassays for the detection of B19 IgG and IgM antibodies. Compared to a standard antibody-capture EIA based on whole viral antigen, the VP2-EIA gave a sensitivity of 100% and specificity of 97% in detection of B19 IgM in 138 patients suspected of B19 infection. No IgM-positive specimens were missed. IgG detection yielded a sensitivity of 100% and specificity of 96% in the same population. Recombinant VP2 capsid proteins expressed in baculovirus-infected insect cells can substitute for serum-derived B19 virus in standard antibody-capture EIA for the detection of B19 IgG and IgM with comparable results.

Chapter 27 – Human Parvovirus Infections

The parvoviruses are a family of small, single-stranded DNA viruses that have a wide cellular tropism and broad host range, causing infection in invertebrate and vertebrate species from insects to mammals. Although many are important veterinary pathogens, there is only one proven human pathogen in the family, the human parvovirus B19. The virus is most commonly referred to as parvovirus B19, or simply B19. A new genus and name have been proposed for this virus: erythrovirus B19, 1 based on its cellular tropism for erythroid lineage cells and to distinguish it from the other mammalian parvoviruses.

NATURAL HISTORY OF CONGENITAL PARVOVIRUS B19 INFECTION: FACTORS AFFECTING INTRAUTERINE TRANSMISSION • 729

NATURAL HISTORY OF CONGENITAL PARVOVIRUS B19 INFECTION: FACTORS AFFECTING INTRAUTERINE TRANSMISSION • 729

Human Parvovirus (HPV)-B19-Associated Anemia in Pediatric HIV Infection: The Importance of High-Dose Intravenous Immune Globulin(IVIG) 770

Human Parvovirus (HPV)-B19-Associated Anemia in Pediatric HIV Infection: The Importance of High-Dose Intravenous Immune Globulin(IVIG) 770