Vincent R. Bonagura

Virologic and Immunologic Outcomes after 24 Weeks in HIV Type 1-Infected Adolescents Receiving Highly Active Antiretroviral Therapy

BACKGROUND Adolescents represent the fastest growing demographic group of new human immunodeficiency virus (HIV) infections in the United States. At present, there is little information available about their response to therapy. METHODS We studied 120 adolescents infected via high-risk behaviors who began receiving highly active antiretroviral therapy (HAART), to determine their virologic and immunologic response to therapy. RESULTS Subjects were enrolled at 28 sites of the Pediatric Acquired Immunodeficiency Syndrome Clinical Trials Group. After 16-24 weeks of HAART, 59% of subjects had reproducible undetectable virus loads, according to repeat measurements (virologic success). As enumerated by flow-cytometric analysis, increases in levels of CD4 helper cells (both naive and memory) and decreases in levels of CD8 suppressor cells were observed. Partial restoration of some immunologic parameters for patients who did not achieve virologic success was also observed, but to a more limited extent than for adolescents with virologic success. Adherence to HAART was the only predictor of achieving undetectable virus loads. CONCLUSIONS Adolescents have the capacity to improve their immunologic status with HAART. Lower than expected success in virologic control is related to lack of adherence, and efforts to improve treatment outcome must stress measures to assure adherence to medication.

Immunodeficiency in long-term survivors of acute lymphoblastic leukemia treated with Berlin-Frankfurt-Münster therapy☆☆☆★

OBJECTIVE To determine whether the immune systems of long-term survivors of acute lymphoblastic leukemia (ALL) have persistent immune defects after Berlin-Frankfurt-Münster (BFM) treatment. STUDY DESIGN We evaluated the cellular and humoral immune responses of 13 children with ALL in complete remission and off modified protocol treatment for 2 or more years. All patients had received complete immunizations for measles, mumps, rubella, and poliovirus before ALL developed. They were challenged with Haemophilus influenzae type B (Hib) and Pneumococcus vaccines after baseline serum samples were obtained. We also determined in vivo humoral immune responses to bacteria and viruses that cause common pediatric diseases. RESULTS Compared with age-matched control subjects, the long-term survivors of ALL had a significant difference in the presence of protective antibodies to measles (p < 0.0001) and polioviruses (p < 0.0001) in their baseline sera; more than half had no protective antibodies to one or more previously administered vaccines or related infections. Most produced protective concentrations of specific antibody after reimmunization, but some were repeatedly unable to make protective antibodies, or mount a normal antibody response, despite natural disease and/or revaccination. Four children had significant infections. CONCLUSIONS Long-term survivors of ALL who had BFM treatment may have persistent immune defects with respect to common childhood bacterial and viral diseases they previously had, or vaccines they received.

Common variable hypogammaglobulinemia, recurrent Pneumocystis carinii pneumonia on intravenous γ-globulin therapy, and natural killer deficiency

A toddler with common variable hypoimmunoglobulinemia (CVH), inflammatory bowel disease, and recurrent Pneumocystis carinii pneumonia (PCP) on intravenous gammaglobulin (IVIG) replacement was evaluated for a combined cellular immunodeficiency. He had a normal number of circulating T-cells, natural killer (NK) cells, T-cell subset percentages, and his peripheral blood mononuclear (PBM)-derived B-cell number was low. PBM mitogen blastogenesis and mixed lymphocyte reaction (MLR) were normal. MLR activated T-cells expressed class I and II MHC antigens, interleukin 2 (IL-2), and B-cell growth factor (IL-5)-related receptors. The patients T-cells induced control B-cell maturation with pokeweed mitogen (PWM-PC), and did not suppress PWM-PC production by allogeneic PBM. Bone marrow (BM) CD19+ B-cell number varied between 10 and 44% of all PBM, and the BM B-cell-enriched fraction failed to differentiate to PWM-PC with autologous or allogeneic T-cell help. The NK activity assayed using K562 target cells was deficient, 9.2 x 7.7% (6.9-9.2%) pt, control 35.9 x 35.8% (16.3-67.2% +/- 12.8). In the presence of interferon-alpha, 800 U/ml, the patients NK activity increased to 17.2 x 14.9% (12.6-17.2%), control 35.9 x 51.0% (36.5-72.3% +/- 12.0). The patients cell-mediated lympholysis of HLA nonidentical, allogeneic stimulators was normal. Maintaining trough serum IgG levels above 500 mg/dl was required to suppress recurrent PCP. This functional NK deficiency may be relevant to the development of recurrent PCP in IVIG-treated CVH patients.

Dysfunction of natural killer cells in human immunodeficiency virus-infected children with or without Pneumocystis carinii pneumonia*

The development of Pneumocystis carinii pneumonia (PCP) in human immunodeficiency virus (HIV)-infected children with normal T-cell numbers is contrary to previous experience with HIV-infected adults, in whom low CD4+ T-cell numbers predict susceptibility to PCP. To determine whether PCP in HIV-infected children reflects a qualitative T-cell or other immune defect, we studied four HIV-infected children who also had PCP and 10 others without PCP for T-cell and natural killer (NK) cell function. Most of the HIV-infected children had normal T-cell numbers for age, and all had CD4+ T-cell numbers greater than those predictive of PCP in HIV-infected adults. All HIV-infected children had normal T-cell function in vitro. The HIV-infected children as a whole had deficient NK cell cytolysis. We obtained a significant interactive effect of age by health status for NK cell function between patients and age-matched control subjects. All HIV-infected children with defective NK cell function failed to enhance their NK cell cytolysis when their mononuclear cells were stimulated with recombinant interferon alfa (r-IFN-alpha). This NK cell defect in HIV-infected children may facilitate the development of secondary infection.

Toxicity and efficacy of daily vs. weekly dapsone for prevention of Pneumocystis carinii pneumonia in children infected with human immunodeficiency virus

BACKGROUND Dapsone is an alternative drug for Pneumocystis carinii pneumonia (PCP) prophylaxis in individuals intolerant to trimethoprim-sulfamethoxazole (T/S). There are, however, few data on the pharmacokinetics, toxicity or efficacy of dapsone in children. Design. Randomized, multicenter trial comparing daily (1 or 2 mg/kg) with weekly (4 mg/kg) dapsone regimens in 94 HIV-infected children intolerant to T/S. METHODS Hematologic and hepatic toxicity was monitored, as well as the occurrence of skin rash, PCP or death. RESULTS Initial pharmacokinetic data indicated that adequate serum dapsone concentrations were not achieved with the daily 1-mg/kg regimen; the daily dose was then increased to 2 mg/kg. Both short and long term hematologic toxicities were marginally greater in children receiving the daily 2 mg/kg compared with the weekly regimen. Allergic skin rashes were similar in children receiving the daily and weekly regimens (17% in both) and were not associated with prior history of rash with T/S. PCP occurred most frequently with the daily 1-mg/kg regimen (22.0 cases/100 patient years), least frequently with the daily 2-mg/kg regimen (0 case/100 patient years) and at intermediate frequency with the weekly regimen (9.5 cases/100 patient years). More deaths were observed in patients receiving the daily than the weekly regimen (8 vs. 2, respectively), although the deaths were not directly attributable to dapsone treatment. CONCLUSION Although a weekly dapsone regimen of 4 mg/kg produced less hematologic toxicity than a daily regimen of 2 mg/kg, this advantage was offset by a trend toward higher breakthrough rates of PCP.

Population pharmacokinetics of dapsone in children with human immunodeficiency virus infection

Previous studies of dapsone pharmacokinetics in children have been too small to allow assessment of the relationships between dapsone pharmacokinetic parameters and patient characteristics or markers of efficacy and toxicity.

A newborn with complete heart block and structural cardiac defects

HISTORY OF PRESENT ILLNESS A 3,200-g girl was born to a 37-year-old human immunodeficiency virus–negative woman at 36 weeks’ gestation. The pregnancy was complicated by maternal type 2 diabetes mellitus (requiring insulin therapy during pregnancy) and by hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome.1 The baby was delivered by emergency cesarean section for maternal preeclampsia. Apgar scores were 8 at 1 minute of life and 9 at 5 minutes of life. Complex congenital heart disease had been diagnosed in utero by fetal ultrasound. The infant was promptly administered prostaglandin E2 shortly after birth and then was transferred to the neonatal intensive care unit. A chest radiograph (Fig 1) revealed a boot-shaped heart secondary to right ventricular hypertrophy and an abnormal main pulmonary artery segment. Also notable is the absence of a thymic shadow. Echocardiography revealed complete atrioventricular heart block, pulmonary atresia, and an unbalanced atrioventricular canal. Laboratory evaluation revealed a white blood cell count of 15,700/ L (reference range, 5,000–20,000/ L), a hemoglobin level of 17.3 g/dL (reference range, 13.5–20.5 g/dL), a platelet count of 151,000/ L (reference range, 140,000– 440,000/ L), an absolute lymphocyte count of 1,300/ L (reference range, 2,000–17,000/ L), and an absolute neutrophil count of 12,500/ L (reference range, 1,000–9,500/ L). Serum electrolyte values were normal except for a total calcium level of 7.5 mg/dL (reference range, 8.8–10.0 mg/ dL) and an ionized calcium level of 0.83 mmol/ L (reference range, 1.03–1.23 mmol/ L). The infant began peripheral hyperalimentation and underwent a Blalock-Taussig shunt and placement of an epicardial pacing system. Unifocalization of the pulmonary artery, a surgical technique to connect all pulmonary segments to convergent central pulmonary arteries, was performed on day 4 of life. It was confirmed at surgery that the thymus was absent. The infant began to have increasing calcium requirements, and at 1 week of age she was diagnosed as having hypoparathyroidism, with a parathyroid hormone level of 1 pg/mL (reference range,12–72 pg/mL).