Systemic Epstein-Barr virus infection associated with membranous nephropathy in children.

Epstein-Barr virus (EBV) infection can cause diverse renal manifestations ranging from microscopic hematuria to acute renal failure. Membranous nephropathy (MN) is an uncommon and usually secondary cause of nephrotic syndrome in children, and has been reported after chronic infections and antigenemia. We report two pediatric cases of secondary MN associated with acute and chronic systemic EBV infection. Patient 1 had a liver transplant for cirrhosis due to biliary atresia and developed chronic EB viremia. Membranous nephropathy occurred 3 years later and with aggressive therapy has partially subsided, in temporal association with a drop in blood EBV PCR levels. The other patient had a primary immunodeficiency and developed a lymphoproliferative disorder attributed to EBV. Nephrotic syndrome developed at initial presentation and was associated with MN on biopsy. The patient cleared the virus from blood, which was associated with eventual resolution of the MN. We postulate that EB viremia in patients lacking a fully competent immune system, but without a renal allograft, may create a susceptible environment for chronic systemic EB antigenemia that can then lead to immune-complex MN in the kidney. The association of EBV with renal histological changes consistent with MN has been suggested but not directly described before.

Pharmacokinetics and tolerability of a new intravenous immunoglobulin preparation, IGIV-C, 10% (Gamunex, 10%).

BACKGROUND AND OBJECTIVES: A new intravenous immunoglobulin (IGIV) process has been developed that integrates efficient inactivation of enveloped virus, using caprylate, with immunoglobulin G (IgG) purification and caprylate removal by column chromatography. Two clinical studies were conducted to compare the pharmacokinetics of the new product, IGIV-C, 10% (Gamunex, 10%), formulated with glycine, with the licensed solvent-detergent (SD)-treated intravenous immunoglobulin IGIV-SD, 10% (Gamimune N, 10%), formulated with glycine, and IGIV-C, 5%, formulated with 10% maltose. MATERIALS AND METHODS: Both studies were randomized, multicentre crossover trials of 18 and 20 (respectively) adult patients with primary humoral immune deficiency in which patients received one IGIV product for three consecutive periods (3-4 weeks) before crossing over to the other product. Pharmacokinetic parameters were determined after the third infusion of each product. RESULTS: IGIV-C, 10% was bioequivalent to IGIV-SD, 10%, with half-lives (t1/2) of 35 and 34 days, respectively. IGIV-C, 5%, was bioequivalent to IGIV-C, 10%, with t1/2 of 35 and 36 days, respectively. The products had comparable safety profiles. CONCLUSIONS: The pharmacokinetic profiles observed in these trials indicate that IGIV-C, 10% may replace, and be administered in a manner similar to, IGIV-SD, 10%.

Treatment of post-transplant lymphoproliferative disease with induction chemotherapy followed by haploidentical peripheral blood stem cell transplantation and Rituximab.

Management of monoclonal lymphoproliferative disease following stem cell transplantation is difficult and previous attempts to eradicate tumor using chemotherapy or radiation therapy alone have not been successful. We report successful early eradication of an EBV negative, B cell non-Hodgkin's lymphoma in a child who received a T cell-depleted, maternal haploidentical bone marrow transplant for severe combined immunodeficiency disease. Our treatment strategy involved combining conventional induction chemotherapy with re-transplantation using the paternal donor as a source of peripheral blood stem cells, followed by treatment with anti-CD 20 monoclonal antibody (Rituximab). This strategy exploits the potential graft-versus-tumor activity of the mature T cells in the graft, while providing a source of stem cells to confer long-term immune function. The administration of Rituximab in the early post-transplant course may provide additional anti-tumor activity without affecting the new stem cell compartment.

Distinct T cell developmental consequences in humans and mice expressing identical mutations in the DLAARN motif of ZAP-70.

The protein tyrosine kinase, ZAP-70, is pivotally involved in transduction of Ag-binding signals from the TCR required for T cell activation and development. Defects in ZAP-70 result in SCID in humans and mice. We describe an infant with SCID due to a novel ZAP-70 mutation, comparable with that which arose spontaneously in an inbred mouse colony. The patient inherited a homozygous missense mutation within the highly conserved DLAARN motif in the ZAP-70 kinase domain. Although the mutation only modestly affected protein stability, catalytic function was absent. Despite identical changes in the amino acid sequence of ZAP-70, the peripheral T cell phenotypes of our patient and affected mice are distinct. ZAP-70 deficiency in this patient, as in other humans, is characterized by abundant nonfunctional CD4(+) T cells and absent CD8(+) T cells. In contrast, ZAP-70-deficient mice lack both major T cell subsets. Although levels of the ZAP-70-related protein tyrosine kinase, Syk, may be sufficiently increased in human thymocytes to rescue CD4 development, survival of ZAP-70-deficient T cells in the periphery does not appear to be dependent on persistent up-regulation of Syk expression.

Thalidomide in children undergoing bone marrow transplantation: series at a single institution and review of the literature.

Thalidomide has one of the most notorious drug histories because of its teratogenicity. Its widespread use in the 1960s led to a worldwide epidemic of phocomelia in inborns; this in turn led to its complete ban in most of the world. However, it has now been licensed for selected indications including graft-versus-host-disease (GVHD) after bone marrow transplantation, wasting associated with tuberculosis and human immunodeficiency virus infection, and leprosy. Little is known, however, about its use in children in these settings. Therefore, we report our experience and review the literature on thalidomide in children for GVHD after bone marrow transplantation. We studied 6 patients, 2 with chronic GVHD, 2 with acute GVHD, and 2 with acute GVHD progressing into chronic disease. One patient with chronic GVHD had a complete response, whereas the other had a partial response. Side effects consisted primarily of sedation and constipation, which are reported previously and well known side effects. None had neuropathy. One patient had rash, eosinophilia, and early pancreatitis that began shortly after initiation of thalidomide, persisted, and resolved only after discontinuation of thalidomide. Eosinophilia and pancreatitis are both previously unreported side effects or associated findings of thalidomide treatment. Review of the literature reveals three major studies of thalidomide in GVHD; of these two included children and adults together, and one in which age range of patients was not mentioned. In addition, four series of children receiving only thalidomide are reported. These series contained 1 to 14 patients each. Results show efficacy in at least 50% of children with chronic GVHD and little or no efficacy in children with exclusively acute GVHD. Side effects are similar to those reported in adults and consisted mostly of sedation and constipation, both of which subsided over time and resolved after discontinuing the drug. We speculate on the reasons for which thalidomide is more effective in chronic, compared with acute, GVHD in children, and make recommendations for future study.

Alpha 1-antitrypsin deficiency in a child with X-linked lymphoproliferative disease.

An 18-month-old white male infant with X-linked lymphoproliferative disease was evaluated for persistent hepatic dysfunction following primary Epstein-Barr virus infection. A liver biopsy revealed cirrhosis with a dense mononuclear cell infiltrate. These findings were confounding because cirrhosis is not a typical finding in either normal or immunodeficient individuals following infection with Epstein-Barr virus. An alpha 1-antitrypsin level obtained shortly after biopsy was spuriously within the lower limits of the physiologic range. Further investigation demonstrated a homozygous Z phenotype, the classic protease inhibitor variant described in alpha 1-antitrypsin deficiency. A repeat liver biopsy confirmed the presence of a second hereditary disease. This is a unique concurrence of two uncommon genetic disorders.

CD4+ memory T cells are the predominant population of HIV-1-infected lymphocytes in neonates and children.

BACKGROUND: CD4+ memory T cells express CD45RO and are the principal viral reservoir in HIV-infected adults. In infants and children, CD45RO T cells comprise the minority of the CD4+ T-cell population. The majority of blood CD4+ T cells are naive, expressing CD45RA. OBJECTIVE: To determine the developmental stage at which pediatric CD4+ T cells become susceptible to HIV-1 infection in vivo by determining which T-cell population harbors HIV-1 proviral DNA. DESIGN: A prospective, cross-sectional analysis of peripheral blood CD8+ T cells, CD45RA, or CD45RO CD4+ T cells obtained from 10 HIV-infected neonates and children were analysed for provirus. METHODS: Semi-quantitative polymerase chain reaction methods were used to detect HIV-1 proviral DNA within purified lymphocyte populations selected using immunoaffinity magnetic microspheres. RESULTS: CD8+ T cells harbored no detectable HIV-1, indicating that infection of common thymocytes does not contribute to the population of infected blood T cells. In five children and two of the five neonates, the CD4+ CD45RO memory T lymphocytes contained 10-100-fold greater numbers of infected cells than the CD4+ CD45RA naive T-cell population. Three neonates, who exhibited rapid disease progression, demonstrated high proviral levels in their CD4+ CD45RA T cells. The normal age-related predominance of CD4+ CD45RA T cells was preserved independent of CD4+ T-cell attrition. CONCLUSIONS: The majority of HIV-1-infected blood CD4+ T cells in infants and children are restricted to the small population of terminally differentiated CD4+ CD45RO memory T cells. Neonates with rapid CD4+ T-cell attrition display high levels of provirus in their CD4+ CD45RA T-cell population.