Serum interleukin-6 concentrations are elevated and associated with elevated tumor necrosis factor-alpha and immunoglobulin G and A concentrations in children with HIV infection.

Hypergammaglobulinemia is one of the most consistent, and usually the first observable abnormality in infants vertically infected with HIV. We have analyzed serum interleukin (IL)-4, IL-6, tumor necrosis factor (TNF)-alpha, and immunoglobulin (Ig) concentrations in 23 HIV-infected and 21 uninfected children. IL-6 and TNF-alpha concentrations in HIV-infected children were significantly higher than those in uninfected children, and mutually correlated. No differences in serum IL-4 levels between infected and uninfected children were observed. There was a correlation between serum IL-6 and IgG and between IL-6 and IgA concentrations. Furthermore, during follow-up changes in IL-6 levels were usually accompanied by corresponding changes in IgG levels. Our data indicate an association between HIV, IL-6, TNF-alpha and hypergammaglobulinemia. Regardless of the source and initial stimulus, continued production of IL-6 and TNF-alpha may result in augmentation in an auto-feedback manner, accompanied by increases in Ig synthesis and, more importantly, HIV replication. Thus, elucidation of the mechanisms responsible for overproduction of these two cytokines in HIV-infected patients is not only interesting from a biologic point of view, but is likely to have important clinical implications as well.

Maternally transmitted HIV infection in children.

We evaluated 16 children at high risk for AIDS because of mothers infected with HIV. Two children were persistently seropositive and had laboratory and clinical evidence of HIV infection but had no detectable infectious HIV in their peripheral blood mononuclear cells (PBMC). Seven children, all of whom had clinical and laboratory evidence of HIV infection, were seropositive and virus culture-positive. One child who died at 10 months of age of candida septicemia was HIV antibody-negative but HIV was grown from cultures of his PBMC. Six children had no serologic or virologic evidence of HIV infection; of these, four who were asymptomatic with normal laboratory studies were HIV antibody-positive up to 12 months of age but became antibody-negative by 15 months of age. These observations indicate that: (1) as many as 60% of infants of infected mothers may be infected with HIV; (2) maternal antibody can result in a false-positive or false-negative diagnosis of HIV infection in infants exposed in utero or perinatally, and (3) the use of viral cultures for HIV is valuable for the early diagnosis of maternally transmitted HIV infection.

Serum levels of soluble CD8, neopterin, beta 2-microglobulin and p24 antigen as indicators of disease progression in children with AIDS on zidovudine therapy.

OBJECTIVE: To test the hypothesis that serum levels of soluble markers in children change after initiation of zidovudine therapy and that the extent and pattern of these longitudinal changes correlates with clinical outcome. PATIENTS AND METHODS: We measured serum levels of soluble CD8, neopterin, beta 2-microglobulin (beta 2M), and p24 antigen, and CD4 cell counts, before the initiation of zidovudine therapy and at 12, 24 and 48 weeks of treatment in 24 HIV-1-infected children (Centers for Disease Control classification P2) and 15 controls. RESULTS: Soluble CD8 levels were elevated before therapy in 70% of the infected children; subsequent decreases were associated with lower risk of disease progression. The mean serum neopterin level before treatment was elevated in infected children; decreases in neopterin levels marginally reflected improved or stable clinical status. Serum beta 2M levels and CD4+ cell counts were not associated with clinical outcome. Only 10 out of the 24 patients had detectable levels of serum p24 antigen before treatment; again, the amount of decline after initiation of therapy did not predict clinical outcome. CONCLUSION: Decreasing levels of soluble CD8 and neopterin in HIV-1-infected children receiving zidovudine therapy might reflect a good response to treatment and a slowing of disease progression.

Immune regulation: what immunodeficiency disease has taught us.

"Immune regulation: what immunodeficiency disease has taught us" is reviewed by discussing three immuno-deficiency disorders. Hypogammaglobulinemia, the first documented primary immunodeficiency disorder, has a well defined and uniform clinical presentation which reflects a variety of underlying abnormalities involving the B cell, T cell, and monocyte. X-linked hypogammaglobulinemia, transient hypogammaglobulinemia of infancy common variable immunodeficiency, and their pathogenesis are discussed. Combined immunodeficiency with adenosine deaminase (ADA) deficiency first led to the now accepted concept that a biochemical abnormality may result in immunodeficiency. The clinical presentation, possible biochemical abnormalities resulting in the observed immunodeficiency, relative selectivity of the defect for the immune system, and potential applications of knowledge gained from the study of ADA deficiency are presented. Acquired immunodeficiency (AIDS) has resulted in the concept that a virus is cytopathic for a specific population of T cells and that this, at least in part, results in the immunodeficiency seen in AIDS.

Effect of thymosin on cellular immunity in old age.

Cell-mediated immunity (CMI) in a population of 28 well-nourished, disease-free old-age individuals (65--103 years) was compared to that of healthy young adult controls (22--41 years) and the effects in vitro of thymosin fraction 5 (TF5) evaluated. The number of T cells (T cell rosettes, TCR) in the peripheral blood was the same as controls. However, there was a significant depression in lymphocyte response to phytohemagglutinin (PHA) (p Less Than 0.005). Limiting dilution of the PHA response revealed an inherent defect in the function of those cells that are capable of responding to PHA. The formation of TCR from old-age subjects was similar to controls when incubated with TF5, i.e. there was no enhancement. When TF5 was incubated with old-age and normal control lymphocytes in the mixed lymphocyte reaction (MLR), there were significant increases in the responses in both (71 +/- 39% and 64 +/- 52%, respectively; p Greater Than 0.2). There was also a mitogenic effect of TF5 on resting lymphocytes which was significantly greater in the control than in the old-age population (p Less Than 0.002). Our results suggest that in old age: (1) there is no loss in absolute numbers of T lymphocytes; (2) there is a defect in the ability of individual lymphocytes to function; and (3) the response of lymphocytes in vitro to TF5 in forming TCR and in the MLR is statistically similar to young adult controls, and suggests that the decline in CMI with age is not due to a loss of thymosin-responsive cells.

Quantitation of B cells in peripheral blood by polyacrylamide beads coated with anti-human chain antibody.

A method for quantitating peripheral blood B cells is described which utilizes anti-heavy chain specific antibody attached to polyacrylamide beads. The method has the advantages of ease of performance, of utilizing reagents which are commercially available and routine phase microscopy. In addition, the reagents are stable for prolonged periods of time and only small amounts are required. Utilizing this assay, the following percentages of B cells have been found in normals: IgG 6.3 +/- 0.6; IgM 4.3 +/- 0.5; IgA 4.0 +/- 0.5. The polyacrylamide beads may be phatocytized allowed recognition of certain phagocytic mononuclear cells.

Comparison of high-dose and low-dose intravenous immunoglobulin therapy in patients with primary immunodeficiency diseases.

To assess safety and efficacy of high-dose intravenous immunoglobulin therapy in patients with primary immunodeficiency syndromes we treated a group of 19 patients with a monthly dose of 400 mg/kg of reduced and alkylated, maltose-containing immunoglobulin (Gamimune, Cutter Biological, Berkeley, California) and compared their responses with a group of 16 patients receiving 100 mg/kg per month intravenously. Side effects observed were mild to moderately severe and similar in both groups. In one adult patient receiving the high dose a severe enough reaction developed during the first infusion to exclude her from the study. Serum IgG levels of patients receiving high-dose immunoglobulin showed a stepwise increase in both trough and peak values until a new plateau was reached after four to six infusions. None of the patients receiving the low dose showed such a stepwise increase. On average, serum IgG levels rose by approximately 250 mg/dl for each 100 mg/kg immunoglobulin infused. The mean catabolic rate of the infused IgG was estimated to be 26 days in patients receiving high-dose immunoglobulin infusions. We demonstrated that 400 mg/kg immunoglobulin given intravenously every four weeks to patients with immunodeficiency results in a substantial increase in serum IgG during the postinfusion period, suggesting persistence of specific antibody throughout the interval between infusions.

Toxicities of total-body irradiation for pediatric bone marrow transplantation.

PURPOSE: To determine the acute and late effects, including cognitive function, of total body irradiation (TBI) and chemotherapy for bone transplant (BMT) in children with immunodeficiency or hematologic disorders. METHODS AND MATERIALS: At UCSF, 15 children with immunodeficiency disorders and 58 children with leukemia received chemoradiotherapy between July 1982 and November 1993 and were evaluated for toxicity. Patients with severe combined immunodeficiency disorder (SCID) received 7 Gy TBI while leukemia patients received 12 Gy TBI. RESULTS: Eight immunodeficient patients (53%) are alive at 4 months to 11 years posttransplant. Acute toxicity was limited and treatment well tolerated. Most patients developed mild nausea and vomiting, skin rash, or erythema. Transient fever/chills, oral mucositis, and alopecia were noted in approximately 50% of patients. Seventy-three percent of all patients demonstrated acute liver dysfunction, but only four (27%) developed veno-occlusive disease. All children had decreased growth velocity but normal growth hormone levels. Other endocrinologic evaluations including adrenocorticotropic hormone (ACTH), cortisol, and thyroid hormones were normal. Only one evaluable girl had delayed puberty with late onset of secondary sexual characteristics. Neuropsychological testing demonstrated an intelligence quotient (IQ) reduction between the baseline and 1 year post-BMT, with some recovery at 3 years. Only one patient developed a clinically significant cataract. Thirteen percent of patients had chronic interstitial lung disease. Four children developed exostosis. Only 1 of the 15 children developed a second malignancy (acute myelogenous leukemia) at age 5, 51 months posttransplant for SCID. For patients with leukemia, similar toxicities were observed. Twenty-nine percent disease-free survival was noted with a mean follow-up of 4.7 years. Twenty-two percent had chronic interstitial lung disease and two patients were diagnosed with cataracts. Graft-vs.-host-disease (GVHD), pubertal development arrest, and delayed puberty were seen. One child developed papillary thyroid carcinoma, 49 months post-BMT. Similar neuropsychological testing decrements were also observed. CONCLUSION: Our experience suggests that intensive chemoradiotherapy, even at a young age, does not cause severe, acute, or late toxicities but does result in a small IQ decrement and the risk of secondary malignancy in children with long-term follow-up.

Thymus transplantation in patients with thymic hypoplasia and abnormal immunoglobulin synthesis.

Fetal thymus transplantation was performed in three patients with thymic hypoplasia with abnormal immunoglobulin synthesis, one patient with ataxia telangiectasia, and one patient with immunodeficiency with eczema and thrombocytopenia. All patients received transfer factor before transplantation of a fetal thymus i.p. Reconstitution of cell-mediated immunity occurred in three of five patients. Two of the three patients with reconstitution of cell-mediated immunity also had evidence of improved antibody-mediated immunity. Reconstitution of cell-mediated immunity was characterized as occurring rapidly and being of varying duration, and was unassociated with HL-A chimerism. Successful reconstitution of immunity in these patients may have been related to several factors, including the use of fetal thymus less than 6 hr after abortion, i.p. transplantation, and a synergistic effect of transfer factor.

Maternal transmission of acquired immune deficiency syndrome.

Acquired immune deficiency syndrome (AIDS) has been reported in previously healthy homosexual or bisexual males, intravenous drug users, heterosexual men with hemophilia, and Haitians. The finding of heterosexual hemophiliacs with AIDS has raised the possibility of a transmittable blood-borne agent as a cause of this disease. We have found three female half-siblings who had clinical and laboratory evidence for AIDS. All three had evidence of abnormal in vitro cellular immunity; two had chronic active Epstein-Barr virus infection and lymphadenopathy; all three had chronic cutaneous Candida sp infection; and two had Pneumocystis carinii pneumonia. Their mother is a prostitute/drug addict with abnormal T-cell immunity including clinical and laboratory findings of mucocutaneous candidiasis. Histocompatibility typing is consistent with the history of different fathers for each child. Immunologic studies in one child evaluated prospectively from birth were abnormal by 2 months of age. These findings and the clinical histories indicate AIDS and strongly suggest vertical transmission of an agent(s) during the perinatal period.

Life events, cardiovascular reactivity, and risk behavior in adolescent boys.

BACKGROUND: Risk behavior contributes to injuries, one of the most important sources of morbidity and mortality in adolescents. Although research has shown that environmental stress makes adolescents more likely to engage in risk behavior and to sustain injuries, the magnitude of these associations has been small. Little is known about the role of individual differences in psychobiologic reactivity to stress in moderating the impact of stressful events. In this study, we examined associations among environmental stressors, cardiovascular reactivity to stress, and the level of risk behavior in adolescent boys. METHODS: Twenty-four 14- to 16-year-old boys underwent a laboratory protocol designed to measure responses to psychologically and physically stressful tasks. Changes in heart rate and mean arterial blood pressure were measured serially at standard points in the protocol, and levels of positive and negative life events and recent risk behavior were measured using self-report questionnaires. RESULTS: Neither life events nor cardiovascular reactivity were independently associated with risk behavior. Positive life events and mean arterial blood pressure reactivity significantly interacted, however, in predicting risk behavior (R2 increment = .25). Boys with high reactivity who reported numerous positive life events engaged in markedly less risk behavior than their peers. CONCLUSION: We conclude that adolescents with exaggerated cardiovascular responses to laboratory stressors are associated with less risk behavior in a setting of positive life circumstances. This result suggests that reactivity may exert protective, rather than harmful, influences in some environments.

Pneumococcal polysaccharide immunization in infants and children.

By using indirect hemagglutination, the antibody responses of normal infants and children to an octavalent pneumococcal vaccine that contained pneumococcal polysaccharide types 1, 3, 6, 7, 14, 18, 19, and 23 were evaluated. By 2 years of age, there was a significant rise in hemagglutination titers to all the polysaccharide types, except type 19. By 6 to 8 months of age, five of the eight types of pneumococcal polysaccharides tested resulted in up to 60% responders and, by 2 years, a significant number responded to all pneumococcal polysaccharide types in the vaccine. Pneumococcal polysaccharide type 3 resulted in a significant antibody response as early as 3 months of age, whereas type 19 never resulted in a significant antibody response. Except for type 3, it seemed that when the other pneumococcal polysaccharides tested produced an antibody response, the degree of resonse did not subsequently change significantly with increasing age. The relationship of antibody response to age for pneumococcal polysaccharides is similar to that found for other polysaccharide vaccines. Based on the results of our study, we would recommend immunization with pneumococcal vaccine at 6 months of age with repeat immunization at 2 years of age, especially in high-risk children.

Low number of antibody producing cells in patients with sickle cell anemia.

B cell function is impaired in patients with sickle cell anemia. Although the number of surface IgM positive cells was similar in sickle cell patients and controls, in vitro spontaneous IgM, and PWM stimulated IgA, IgM, and IgG synthesis was significantly lower in the patients than in controls. The number of PWM induced and antigen specific immunoglobulin producing cells after immunization with Pneumovax, containing 21 serotypes of Streptococcus pneumoniae, was about 100-fold lower in the patients as compared with controls. Finally, the ability of the patients' peripheral blood mononuclear cells to proliferate in response to mitogens (PWM, SAC, PHA) was diminished. Because of the observed impairments in both nonspecific and antigen specific immunoglobulin synthesis and cell proliferation assays in the patients, we determined serum concentrations of IL-4 and IL-6, two cytokines associated with antibody production. IL-4 concentrations appeared low in sickle cell patients, and correlated with that of serum IgM. We hypothesize that B cell maturation in sickle cell patients is arrested at an IL-4 dependent stage.

HIV type 1 Tat protein induces immunoglobulin and interleukin 6 synthesis by uninfected peripheral blood mononuclear cells.

Tat is a potent trans-activating protein encoded by the HIV genome. It is essential for viral replication, but has pleiotropic effects on host cells as well. We demonstrated that exogenous recombinant Tat increases immunoglobulin (Ig) and interleukin 6 (IL-6) production in vitro by normal uninfected peripheral blood mononuclear cells by 100-500%. The optimal Tat concentration was 100 ng/ml, but even a low concentration of 1 ng/ml induced a response in most subjects. The observed induction was inhibited by monoclonal anti-Tat antibodies and 2,3-dimercapto-1-propanol. Both anti-IL-6 antibodies and IL-6 antisense oligonucleotides inhibited Tat-induced IgG and IgA synthesis to some degree, whereas induction of IgM appeared to be independent of IL-6. We conclude that Tat can function in vitro in the absence of any other viral structures and induce Ig and IL-6 production; the clinical significance of these findings remains as yet undetermined.

Total body irradiation and bone marrow transplantation for immunodeficiency disorders in young children.

Congenital immunodeficiency disorders such as severe combined immunodeficiency disease (SCID), Wiskott-Aldrich syndrome, and Chediak-Hegashi syndrome are almost uniformly fatal with most children dying before age one. Allogeneic bone marrow transplant (BMT) is the treatment of choice. Few of these children have matched donors. We use bone marrow processing techniques that allow us to utilize marrow from the parents. Children who lack HLA-identical donors are offered haploidentical, T-cell depleted parental BMTs. Some of these children do not have an immune deficiency severe enough to allow durable engraftment of processed mismatched bone marrow. Successful engraftment may necessitate the use of immunosuppression. Total body irradiation (TBI) is part of our intensive conditioning regimen for children with Wiskott-Aldrich and Chediak-Hegashi syndrome and most children with SCID who have undergone an unsuccessful prior mismatched, T-cell depleted BMT, or who have a high likelihood of donor marrow rejection based on pre-transplant immune function testing. TBI is considered extremely toxic therapy in infancy, with little information available on the acute and chronic effects. The 10 children presented in this report are among the youngest to have received TBI. Five patients were 2 to 6 months of age when they received TBI. The conditioning regimen for all patients was; antithymocyte globulin (25 mg/kg/day, x 3 days), cyclophosphamide (60 mg/kg/day, x 2 days), and TBI. 7.0 Gy TBI was given as a single dose AP-PA at approximately 15 cGy/min. Half value blocks shielded the brain, eyes and lungs. Six of 10 children were alive from 7 to 72 months post transplant.(ABSTRACT TRUNCATED AT 250 WORDS)

Prenatal diagnosis of chronic granulomatous disease.

A luminol enhanced chemiluminescence micromethod has been adapted for use in prenatal diagnosis of chronic granulomatous disease (CGD). After validation of the assay in normal adults, newborns, fetuses, CGD carriers, and CGD patients, the fetuses of two pregnant CGD carriers were tested after fetoscopic aspiration of fetal blood. Normal neutrophil chemiluminescence and nitroblue tetrazolium slide tests were followed by delivery of two healthy infants whose normality was confirmed. Amniocytes proved useless for the prenatal diagnosis of CGD. They were found to have negligible nitroblue tetrazolium reduction, oxygen metabolism, and oxygen dependence.

Clinical and laboratory characteristics of a large cohort of symptomatic, human immunodeficiency virus-infected infants and children. AIDS Clinical Trials Group Protocol 152 Study Team.

BACKGROUND: A large cohort of antiretroviral therapy-naive, symptomatic, HIV-infected children were enrolled into a controlled therapeutic trial (AIDS Clinical Trials Group Protocol 152), providing an opportunity to describe their clinical and laboratory characteristics and determine age-related distinctions. METHODS: Study entry evaluations for 838 of 839 enrolled children were analyzed. Weight, head circumference (if < 30 months of age), neuroradiologic imaging of the head, developmental or cognitive status and neurologic examination were assessed. Laboratory studies included hemoglobin, absolute neutrophil count, CD4 cell count, serum amylase, alanine aminotransaminase, p24 antigen and HIV blood culture. Data were categorized by age (3 to < 12 months, 12 to < 30 months, 30 months to 6 years and > or = 6 years). RESULTS: Younger children had significantly higher rates of abnormalities before antiretroviral therapy, especially factors relating to growth and neurologic or cognitive function. Lower CD4+ cell counts and percentages as well as a positive serum p24 antigen correlated with lower weight-for-age Z scores and developmental indices. CONCLUSIONS: These data provide a description of the clinical characteristics of HIV-infected US children at the time antiretroviral therapy is initiated for HIV-related symptoms. The high rate of abnormalities of growth, development and cognitive ability that were observed in children < 30 months of age demonstrates that treatment strategies should be developed for earlier intervention.

Pediatric acquired immunodeficiency syndrome.

Approximately 40 to 50 infants and children with similar epidemiologic, clinical, and laboratory features of AIDS have been described. The occurrence of significant numbers of patients with PAIDS in geographic areas that are associated with similar risk factors and clinical features of AIDS suggests a common cause. Immunologic evaluation reveals hypergammaglobulinemia, decreased or absent antibody responses after immunization, normal to decreased T-cell numbers, decreased helper/suppressor cell ratios, and abnormal results of functional studies of T-cells. None of the patients described has the clinical or laboratory features of well-established congenital immunodeficiency disorders. No consistent viral agent has been documented except for antibody to ARV and HTLV III. The frequent finding of T-cell abnormalities in the mothers of infants with PAIDS is in contrast to the absence of such abnormalities in the mothers of infants with congenital immunodeficiency disorders. Future studies in PAIDS should be directed toward uncovering the etiology and risk factors as well as determining the response to treatment with various methods of immunologic reconstitution.

Ensuring the success of women faculty at AMCs: lessons learned from the National Centers of Excellence in Women's Health.

Since the early 1970s, the numbers of women entering medical school and, subsequently, academic medicine have increased substantially. However, women faculty have not advanced at the expected rate to senior academic ranks or positions of leadership. In 1996, to counter this trend, the U.S. Department of Health and Human Services (DHHS) Office on Women's Health included women's leadership as a required component of the nationally funded Centers of Excellence in Women's Health to identify effective strategies and initiate model programs to advance women faculty in academic medicine. The authors describe the experience of Centers at seven U.S. medical schools in initiating and sustaining leadership programs for women. The processes used for program formation, the current programmatic content, and program evaluation approaches are explained. Areas of success (e.g., obtaining support from the institution's leaders) and difficulties faced in maintaining an established program (such as institutional fiscal constraints and the diminishing time available to women to participate in mentoring and leadership activities) are reviewed. Strategies to overcome these and other difficulties (e.g., prioritize and tightly focus the program with the help of an advisory group) are proposed. The authors conclude by reviewing issues that programs for women in academic medicine will increasingly need to focus on (e.g., development of new kinds of skills; issues of recruitment and retention of faculty; and increasing faculty diversity).