Lamivudine in children with human immunodeficiency virus infection: a phase I/II study. The National Cancer Institute Pediatric Branch-Human Immunodeficiency Virus Working Group.

The safety, tolerability, pharmacokinetic profile, and preliminary activity of lamivudine (2'-deoxy-3'-thiacytidine), a novel cytidine nucleoside analogue with antiretroviral activity, in human immunodeficiency virus (HIV)-infected children beyond the neonatal period were studied. Ninety children received dosages of 1-20 mg/kg/day. Pharmacokinetic evaluation demonstrated serum and cerebrospinal fluid concentrations that increased proportionally to dose. As of January 1994, 11 children had been withdrawn from study for disease progression and 10 because of possible lamivudine-related toxicity, and 6 had died. CD4 and CD8 cell counts remained stable over 24 weeks in therapy-naive children and decrease slightly in previously treated children. Quantitative immune complex-dissociated p24 antigen and HIV RNA were decreased significantly at 12 and 24 weeks. In vitro resistance to lamivudine was documented in sequential virus isolates from some patients by 12 weeks. Lamivudine was well-tolerated and exhibited virologic activity in children, although future use in children is likely to be in combination antiretroviral regimens.

Effect of zidovudine and didanosine treatment on heart function in children infected with human immunodeficiency virus.

OBJECTIVES: Human immunodeficiency virus (HIV) infection in children can be complicated by the development of cardiac disease. Decreased left ventricular function has been temporally associated with the use of zidovudine (azidothymidine; AZT) in adults with HIV and has been associated with changes in cardiac muscle mitochondria in animal models. This study was done in an attempt to determine whether the cardiac disease is related to the antiretroviral therapy or to progressive HIV infection. METHODS: We retrospectively reviewed echocardiograms, clinical records, and laboratory data from 137 HIV-infected children who were being treated by the Pediatric Branch, National Cancer Institute, and who were receiving AZT or didanosine, both drugs, or no antiretroviral therapy. RESULTS: Despite correction of the echocardiographic results for HIV disease severity with markers such as CD4+ lymphocyte count, time since infection, mode of acquisition of HIV, and age, children who were treated with AZT had a lower average fractional shortening than those who were not treated with AZT (p < 0.00001). There was a nonlinear relation between days of AZT use and this There was a nonlinear relation between days of AZT use and this decrease in fractional shortening. The odds that a cardiomyopathy would develop was 8.4 times greater in children who had previously used AZT than in those who had never taken AZT (95% confidence interval, 1.7 to 42.0). Didanosine was not associated with the development of a cardiomyopathy. CONCLUSIONS: Treatment of HIV-infected children with AZT may be associated with the development of a cardiomyopathy; didanosine does not appear to increase the risk of cardiomyopathy. The continued use of AZT in a child in whom a cardiomyopathy develops should be carefully assessed, and all children receiving AZT should be followed by serial cardiac examination and echocardiograms.

Pulmonary malignant lymphoma of mucosa-associated lymphoid tissue (MALT) arising in a pediatric HIV-positive patient.

A malignant lymphoma arising in the lung of a pediatric HIV-positive patient exhibited histologic and clinical features of low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). Clinically, the neoplasm consisted of a 4-cm mass in the left-upper lobe of the lung of a 7-year-old girl. The lung mass was surgically resected. Monoclonal immunoglobulin heavy and light chain gene rearrangements were shown by Southern blot. Monoclonality of light chain expression was demonstrated by immunohistochemistry. Coexpression of Leu-22 (CD43) by the tumor cells supported the diagnosis of lymphoma. The remainder of the pulmonary parenchyma distal to the mass was associated with pulmonary lymphoid hyperplasia/lymphocytic interstitial pneumonitis, which may have been a predisposing factor. Gastric MALT lymphomas have recently been described in adult HIV-antibody-positive patients. Ours represents the first reported case of a pulmonary MALT lymphoma in a pediatric HIV-positive patient. In addition, at age 7, this is the youngest patient reported with a MALT lymphoma.

Comparative virulence of Staphylococcus epidermidis isolates in a murine catheter model.

Among coagulase-negative staphylococci, Staphylococcus epidermidis is the species most commonly implicated in catheter-related infections. Whether some staphylococcal organisms are inherently more virulent than others, or whether their ability to infect relates more to the sheer numbers of organisms at the catheter site, remains unclear. We therefore compared eight S. epidermidis isolates and two other coagulase-negative staphylococci using a murine model that allowed us to quantify catheter colonization and abscess formation in the same animal. The organisms were isolated from different clinically relevant settings and were classified according to their slime phenotype. The ability to evoke abscesses or colonize catheters in half of the animals (ID50) was assessed. ID50 inoculum titers (log10 data +/- SD) ranged widely, from 8.5 +/- 0.3 to 10.2 +/- 0.2 for abscess formation (p < 0.005) and from 7.5 +/- 0.5 to 10.3 +/- 1.0 for catheter colonization (p < 0.005). ID50 values by statistical criteria suggested variability among organisms in the ability to induce abscess formation. High slime production correlated with both parameters, but not with the clinical source of the isolate. Our findings demonstrate impressive heterogeneity in the ability of a representative group of S. epidermidis isolates to colonize catheters and to evoke abscess formation and implicate slime productivity as a major virulence factor. The murine model used permitted simultaneous analysis of multiple factors involved in pathogenesis and should be useful in establishing the basis of S. epidermidis pathogenicity.

Typhlitis in children with cancer: a 30-year experience.

We identified 24 children treated for malignancies between 1962 and 1992 who had antemortem diagnoses of typhlitis that were confirmed on review. The study criteria specified the presence of fever, abdominal pain, and tenderness, with radiological evidence of right-sided colonic inflammation. Typhlitis was most frequent in patients treated for acute leukemias. Computed tomography and ultrasonography were more sensitive than plain radiography (false-negative rates, 15%, 23%, and 48%, respectively). The wider availability of these sensitive procedures and the increased intensity of chemotherapeutic regimens may account for a marked increase in the incidence of typhlitis over the past 5 years. Most patients responded to aggressive medical management, and typhlitis was fatal in only two cases (1 of 21 cases managed medically and 1 of 3 taken to surgery). Seven patients are alive > 1 year following the diagnosis. These findings contrast with prior descriptions of typhlitis as a preterminal event. Computed tomography and/or ultrasonography should be performed in all neutropenic patients with right-lower-quadrant signs to permit prompt diagnosis and treatment.

A transformation-incompetent, nuclear antigen 2-deleted Epstein-Barr virus associated with replicative infection.

Epstein-Barr virus (EBV) obtained directly from the oropharynx was used to detect viral DNA deleted for the EBV nuclear antigen 2 (EBNA2)-encoding gene that is essential for lymphocyte transformation. By polymerase chain reaction analysis, the deletion was found in virus from 5 of 33 healthy adult donors and 11 of 12 patients with concurrent human immunodeficiency virus infection. Lymphoblastoid cell lines that produce standard transforming EBV also harbored EBNA2-deleted virus in cells permissive of EBV replication. In vitro infectivity studies indicated that the DNA is packaged and transmissible, with biologic properties similar to those of a laboratory mutant, P3HR-1, which also lacks the EBNA2 gene. These findings, obtained from productively infected cell systems, provide evidence for the existence in nature of a transformation-incompetent EBV variant that may facilitate EBV persistence and the emergence of reactivation diseases.