Peggy S. Weintrub

A Multicenter Trial of Oral Zidovudine in Children with Advanced Human Immunodeficiency Virus Disease

BACKGROUND AND METHODS Zidovudine has been shown to be an effective antiretroviral treatment in adults with human immunodeficiency virus (HIV) infection. We examined the safety of zidovudine and the tolerance of and therapeutic response to the drug in 88 children with advanced HIV disease. During a 24-week outpatient trial, zidovudine (180 mg per square meter of body-surface area per dose) was given by mouth every six hours and serial measurements were made of clinical, immunologic, and virologic indexes. Children who completed 24 weeks of treatment were permitted to continue receiving zidovudine. RESULTS Of the 88 children (mean age, 3.9 years; range, 4 months to 11 years), 61 completed the initial 24-week trial, and 49 continued to receive zidovudine for up to 90 weeks (median follow-up, 56 weeks). The patients generally tolerated zidovudine well. One or more episodes of hematologic toxicity occurred in 54 children (61 percent)--anemia (hemoglobin level, less than 75 g per liter) in 23 children (26 percent) and neutropenia (neutrophil count, less than 0.75 x 10(9) per liter) in 42 (48 percent). Many of these abnormalities resolved spontaneously, but 30 children required transfusions or a modification of the dose of zidovudine. Only three children had to stop receiving the drug because of hematologic toxicity. Kaplan-Meier analysis demonstrated that the probability of survival was 0.89 after 24 weeks and 0.79 after 52 weeks. There was marked improvement in weight gain, cognitive function (mainly in children less than 3 years old), serum and cerebrospinal fluid concentrations of p24 antigen, and the proportion of cerebrospinal fluid cultures negative for HIV. CD4+ lymphocyte counts (mean at base line, 0.263 x 10(9) per liter) improved during the first 12 weeks, although the improvement was not sustained through the 24th week. CONCLUSIONS Zidovudine in a dose of 180 mg per square meter every six hours can be safely administered to children with advanced HIV disease. The resultant clinical, immunologic, and virologic improvements in children are similar to those reported with zidovudine in adults.

Utility of DNA Microarrays for Detection of Viruses in Acute Respiratory Tract Infections in Children

Objective To assess the utility of a panviral DNA microarray platform (Virochip) in the detection of viruses associated with pediatric respiratory tract infections (RTIs). Study design The Virochip was compared with conventional direct fluorescent antibody (DFA)- and polymerase chain reaction (PCR)-based testing for the detection of respiratory viruses in 278 consecutive nasopharyngeal aspirate samples from 222 children. Results The Virochip was superior in performance to DFA, showing a 19% increase in the detection of 7 respiratory viruses included in standard DFA panels, and was similar to virus-specific PCR (sensitivity, 85% to 90%; specificity, ≥99%; positive predictive value, 94% to 96%; negative predictive value, 97% to 98%) in the detection of respiratory syncytial virus, influenza A, and rhinoviruses/enteroviruses. The Virochip also detected viruses not routinely tested for or missed by DFA and PCR, as well as double infections and infections in critically ill patients that DFA failed to detect. Conclusions Given its favorable sensitivity and specificity profile and expanded spectrum for detection, microarray-based viral testing holds promise for clinical diagnosis of pediatric RTIs.

Hepatitis C virus infection in infants whose mothers took street drugs intravenously

To assess the risk of transmission of hepatitis C virus from mother to infant during pregnancy or at delivery, we measured the antibody to hepatitis C virus (anti-HCV) by an enzyme-linked immunosorbent assay (ELISA) and a recombinant immunoblot assay (RIBA) in serum from 43 infants whose mothers took illicit drugs intravenously. Passively transmitted maternal anti-HCV was detected in 17 (40%) of the 43 infants tested with the ELISA during the first 4 postnatal months. Ten of these initially seropositive infants were followed to 15 months of age or beyond; anti-HCV cleared from nine infants and persisted in one. Among 24 initially seronegative infants, three (12.5%) showed persistent anti-HCV at 6, 11, and 18 months of age, respectively. The remaining two infants were initially tested with ELISA at 6 and 15 months of age; both were transiently seropositive, but anti-HCV disappeared by 12 and 24 months of age, respectively. Among the 17 infants with maternal antibody, nine with ELISA reactions greater than 2.5 optical density units were reactive by RIBA: the eight with weaker reactivity by ELISA were nonreactive by RIBA. When serum samples from the four infants who showed persistent reactivity by ELISA were tested with RIBA, one reacted to both antigens displayed by RIBA (C-100 and 5-1-1), one reacted to the 5-1-1 antigen only, and two were nonreactive. Serum transaminase values were elevated in three of these four infants; all four were also infected with human immunodeficiency virus. The results indicate that vertically transmitted hepatitis C virus may be a cause of hepatitis in infants, especially those coinfected with human immunodeficiency virus. Neonates at risk of hepatitis C virus infection should be monitored beyond 12 months of age. The interpretation of tests for anti-HCV antibody during infancy requires further investigation.

CD8 Cell Noncytotoxic Antiviral Activity in Human Immunodeficiency Virus-Infected and -Uninfected Children

CD8 cells from human immunodeficiency virus (HIV)-infected adults and children can show cytotoxic as well as noncytotoxic activity against viral replication. The noncytotoxic anti-HIV response, measured by suppression of acute viral infection of CD4 cells, has also been observed in uninfected adults who have a history of exposure to HIV. This CD8 cell antiviral activity was found to be detectable as well in approximately 50% of uninfected children born of infected mothers. The findings could reflect a protective response of the children to HIV after being exposed to the virus.

Polymerase chain reaction compared with concurrent viral cultures for rapid identification of human immunodeficiency virus infection among high-risk infants and children.

To determine the usefulness of DNA amplification by polymerase chain reaction for the early identification of human immunodeficiency virus type 1 (HIV-1) infection in infants and children, we compared the polymerase chain reaction and concurrent viral cultures of peripheral blood mononuclear cells from 25 high-risk subjects aged 5 weeks to 8 years. In two separate primer pairs, HIV-1 proviral DNA gag sequences were successfully identified in cell lysates from seven patients, including two infants with previously indeterminate HIV-1 status on the basis of serologic and culture results. In the remaining 18 patients the polymerase chain reaction was negative for HIV-1. Simultaneously grown HIV-1 cultures concurred with polymerase chain reaction results for all patients. In an 18-month-old infant who had had a single HIV-1 positive culture at 1 month of age with four subsequent negative cultures, both polymerase chain reaction and HIV-1 culture were negative. Our data demonstrate the clinical applicability of polymerase chain reaction on crude cell lysates for the rapid, early, definitive detection of HIV-1 infection in high-risk infants and children.

Detection of infection with human immunodeficiency virus (HIV) type 1 in infants by an anti-HIV immunoglobulin A assay using recombinant proteins

To diagnose infection with the human immunodeficiency virus (HIV) soon after birth in infants born to HIV type 1-infected women, we developed antiviral IgA Western blot and dot blot assays with recombinant HIV-1 proteins. Thirty-three infants born to HIV-1-seropositive mothers and nine infants born to HIV-1-seronegative intravenous drug-abusing mothers were followed prospectively. Infection was documented by positive virus culture. Results with the polymerase chain reaction were used for comparison. Twelve infants were found infected with HIV-1; the earliest age at which cultures became positive ranged from birth to 31 weeks of age. Of the 12 culture-positive infants, 10 had anti-HIV IgA antibodies detectable initially between birth (cord blood) and 27 weeks of age. Anti-HIV IgA was not present in the uninfected infants or in the control subjects, either by Western blot or dot blot assays. Testing for anti-HIV IgA antibodies with recombinant HIV-1 proteins is an effective method for detecting viral infection in newborn and young infants.

Haploidentical Bone Marrow Transplantation for Severe Combined Immunodeficiency Disease Using Soybean Agglutinin-Negative, T-Depleted Marrow Cells

The major limitation of mismatched bone marrow transplantation is fatal graft versus host disease (GVHD). We processed haplotype-identical parental marrow with soybean agglutinin (SBA), sheep erythrocytes (SRBC), and neur-aminidase-treated SRBC (N-SRBC) to enrich for marrow stem cells and remove mature T cells. Nine patients with severe combined immunodeficiency disease (SCID) who lacked histocompatible donors received these SBA-negative, SRBC-negative, N-SRBC-negative marrow transplants (0.5–5.0 × 108 cells/kg). Seven of the nine patients (78%) had documented T-lymphocyte engraftment based on HLA typing and/or chromosomal analysis. Six patients showed evidence of B-cell immunity on the basis of increased immunoglobulin levels, isohemagglutinins, and/or HLA-DR typing of non-T cells. Three patients received marrow ablative chemotherapy pretransplant for maternal-fetal GVHD; neutrophil engraftment occurred between 9 and 17 days posttransplantation, erythrocytes engrafted within 3–4 weeks of transplantation, and platelet recovery was seen between day 17 and day 49 following the transplants. No immunosuppression was given prophylactically posttransplant. Three patients had no GVHD, two had transient rash and/or fever, and two developed mild focal (stage I) chronic cutaneous GVHD. Of the seven who engrafted, five (71%) are alive and clinically well without GVHD 18–35 months posttransplant. These data demon-strate that SBA- and SRBC/N-SRBC-treated haploidentical marrow transplantation results in functional lymphocyte engraftment in SCID without significant GVHD, and can be used for some patients who otherwise would have no hope for survival.

Long-term follow-up and booster immunization with polyvalent pneumococcal polysaccharide in patients with sickle cell anemia

TRIALS WITH PNEUMOCOCCAL POLYSACCHARIDE vaccine have shown that patients with sickle cell disease who are immunized at or after 2 years of age have a good antibody response and fewer pneumoeoccal infections than unimmunized controls? However, the duration of the increased antibody levels has not been studied. The effect of booster immunization has been evaluated at 1 to 1 89 years after the original dose in a population of normal adults. Adverse local reactions were frequent, but no significant increase in antibody titers occurred, 2 We undertook this study in patients with sickle cell disease to determine (1) the duration of the antibody response 8 to 9 years after primary immunization, (2) the incidence of systemi c and severe local reactions with booster immunizations, and (3) the serologic response to booster immunization.

Risk factors and risk adjustment for surgical site infections in pediatric cardiothoracic surgery patients

BACKGROUND The complexity of congenital cardiac defects and the aggressive medical management required to support patients through their recovery place children at high risk for surgical site infection (SSI). METHODS We conducted a retrospective review of children undergoing cardiothoracic surgery at a tertiary care referral center between January 1, 2000, and June 30, 2001. Preoperative, intraoperative, and postoperative data were assessed by multivariate analysis. RESULTS Of 726 surgical procedures performed in 626 patients, SSIs occurred after 46 procedures performed in 46 patients (6.3%). Infections were superficial (n = 22; 47.8%), deep tissue (n = 7; 15.2%), or organ space (n = 17; 37.0%), including 5 episodes of mediastinitis. Median time to SSI was 10 days; 36% of the infections were identified after discharge. On multivariate analysis, children with SSIs were more likely to have been <30 days old (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.2-70), to have a perioperative medical device, and to use parenteral nutrition (OR, 3.3; 95% CI, 1.4-7.9). Multiple severity of illness scores, the Risk Adjustment for Congenital Heart Surgery (RACHS-1) category, and longer duration of postoperative antimicrobials were not associated with SSI. CONCLUSION The use of perioperative medical interventions increases the risk of SSI in young children after cardiac surgery. Prolonged postoperative courses of antimicrobials should be avoided in the absence of documented infection.

Immunologic abnormalities in patients with hemophilia A.

To assess the immunologic status of healthy persons with hemophilia A, we performed studies of T cell immunity in 21 patients, 10 given only cryoprecipitate and 11 given factor VIII concentrate. Patients in the factor VIII group had significantly decreased helper/suppressor T cell ratios. Both groups had diminished mononuclear cell response to phytohemagglutinin and normal mixed lymphocyte culture, compared with controls. Abnormalities in T cell number or function did not correlate with the presence of antibody to cytomegalovirus, Epstein-Barr virus, or hepatitis B. Physicians caring for patients with hemophilia A should realize that asymptomatic individuals may have early evidence of immunodeficiency.