Maria Marluce dos Santos Vilela

Impaired Humoral Response to Vaccines among HIV-Exposed Uninfected Infants

ABSTRACT Little is known about the vaccine protective response for infants born from HIV-infected mothers. We evaluated the antibody response to hepatitis B, tetanus, and diphtheria vaccine in vertically HIV-exposed uninfected infants and compared them to those of control infants not exposed to the virus. The quantitative determination of specific neutralizing antibodies against hepatitis B, diphtheria, and tetanus were performed blindly on serum samples. The results showed that 6.7% of the HIV-exposed uninfected individuals were nonresponders to hepatitis B vaccine (anti-HBs titer, <10 mIU/ml), and 64.4% were very good responders (anti-HBs titer, ≥1,000 mIU/ml), whereas only 3.6% of the nonexposed infants were nonresponders (χ2=10.93; 1 df). The HIV-exposed uninfected infants showed protective titers for diphtheria and tetanus but lower geometric mean anti-tetanus titers compared to those of the HIV-unexposed infants. Our data point to the necessity of evaluating vaccine immune responses in these children and reinforced that alterations in lymphocyte numbers and functions reported for newborns from HIV-infected mothers interfere with the vaccine response.

Impaired Bacillus Calmette-Guérin cellular immune response in HIV-exposed, uninfected infants.

Objective:To evaluate cell-mediated immune response to Bacillus Calmette–Guérin (BCG) vaccination in uninfected, HIV-1-exposed infants, comparing it with unexposed children. Design:It is designed as a cross-sectional study. Methods:BCG-specific lymphoproliferation and T-cell subsets (CD4+, CD8+ and TCR &ggr;&dgr;+) by flow cytometry and interleukin-10, interferon-&ggr; (IFN-&ggr;) and tumor necrosis factor-&agr; (TNF-&agr;) concentration by ELISA were analyzed in HIV-exposed and unexposed infants. Whole blood lymphocyte immunophenotyping and blood counts were performed in exposed children. Nonparametric tests were used (P < 0.05). Results:Given the ontogeny of the immune system, exposed infants were separated into three groups according to age: exposed 1 (E1, aged 6.1–8.8 months), E2 (aged 9.1–17.1 months) and E3 (aged 18.1–26.3 months). Unexposed infants (UE group) and E1 were matched for age. Cell proliferation was not different among the three exposed groups, neither for BCG nor for phytohemagglutinin (PHA)-stimulated cultures. Furthermore, BCG-stimulated lymphoproliferation was reduced in the E1 group in comparison with the UE group. T-lymphocyte subpopulations also showed differences, with the youngest HIV-exposed groups (E1 and E2) showing a predominant proliferation of CD4+ T cells in cultures with BCG, whereas E3 and UE groups had a robust &ggr;&dgr;+ T-cell expansion. There was lower IFN-&ggr; concentration in the samples from E1 group in comparison with all of the other groups. The unexposed infants showed higher TNF-&agr; concentration in cultures with BCG and PHA in comparison with E1 group. Conclusion:BCG-specific T-cell proliferation was reduced in HIV-exposed uninfected infants and IFN-&ggr; concentration was lower in younger exposed infants, showing a delay in immune system maturation of HIV-exposed infants.

First Report of the Hyper-IgM Syndrome Registry of the Latin American Society for Immunodeficiencies: Novel Mutations, Unique Infections, and Outcomes

Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.

The impact of maternal HIV infection on cord blood lymphocyte subsets and cytokine profile in exposed non-infected newborns

BackgroundChildren born to HIV+ mothers are exposed intra-utero to several drugs and cytokines that can modify the developing immune system, and influence the newborns immune response to infections and vaccines. We analyzed the relation between the distribution of cord blood lymphocyte subsets and cytokine profile in term newborns of HIV+ mothers using HAART during pregnancy and compared them to normal newborns.MethodsIn a prospective, controlled study, 36 mother-child pairs from HIV+ mothers and 15 HIV-uninfected mothers were studied. Hematological features and cytokine profiles of mothers at 35 weeks of pregnancy were examined. Maternal and cord lymphocyte subsets as well as B-cell maturation in cord blood were analyzed by flow cytometry. The non-stimulated, as well as BCG- and PHA-stimulated production of IL2, IL4, IL7, IL10, IL12, IFN-γ and TNF-alpha in mononuclear cell cultures from mothers and infants were quantified using ELISA.ResultsAfter one year follow-up none of the exposed infants became seropositive for HIV. An increase in B lymphocytes, especially the CD19/CD5+ ones, was observed in cord blood of HIV-exposed newborns. Children of HIV+ hard drug using mothers had also an increase of immature B-cells. Cord blood mononuclear cells of HIV-exposed newborns produced less IL-4 and IL-7 and more IL-10 and IFN-γ in culture than those of uninfected mothers. Cytokine values in supernatants were similar in infants and their mothers except for IFN-γ and TNF-alpha that were higher in HIV+ mothers, especially in drug abusing ones. Cord blood CD19/CD5+ lymphocytes showed a positive correlation with cord IL-7 and IL-10. A higher maternal age and smoking was associated with a decrease of cord blood CD4+ cells.Conclusionsin uninfected infants born to HIV+ women, several immunological abnormalities were found, related to the residual maternal immune changes induced by the HIV infection and those associated with antiretroviral treatment. Maternal smoking was associated to changes in cord CD3/CD4 lymphocytes and maternal hard drug abuse was associated with more pronounced changes in the cord B cell line.

Immunogenicity of a Whole-Cell Pertussis Vaccine with Low Lipopolysaccharide Content in Infants

ABSTRACT The lack of a clear correlation between the levels of antibody to pertussis antigens and protection against disease lends credence to the possibility that cell-mediated immunity provides primary protection against disease. This phase I comparative trial had the aim of comparing the in vitro cellular immune response and anti-pertussis toxin (anti-PT) immunoglobulin G (IgG) titers induced by a cellular pertussis vaccine with low lipopolysaccharide (LPS) content (wPlow vaccine) with those induced by the conventional whole-cell pertussis (wP) vaccine. A total of 234 infants were vaccinated at 2, 4, and 6 months with the conventional wP vaccine or the wPlow vaccine. Proliferation of CD3+ T cells was evaluated by flow cytometry after 6 days of peripheral blood mononuclear cell culture with stimulation with heat-killed Bordetella pertussis or phytohemagglutinin (PHA). CD3+, CD4+, CD8+, and T-cell receptor γδ-positive (γδ+) cells were identified in the gate of blast lymphocytes. Gamma interferon, tumor necrosis factor alpha, interleukin-4 (IL-4), and IL-10 levels in supernatants and serum anti-PT IgG levels were determined using enzyme-linked immunosorbent assay (ELISA). The net percentage of CD3+ blasts in cultures with B. pertussis in the group vaccinated with wP was higher than that in the group vaccinated with the wPlow vaccine (medians of 6.2% for the wP vaccine and 3.9% for the wPlow vaccine; P = 0.029). The frequencies of proliferating CD4+, CD8+, and γδ+ cells, cytokine concentrations in supernatants, and the geometric mean titers of anti-PT IgG were similar for the two vaccination groups. There was a significant difference between the T-cell subpopulations for B. pertussis and PHA cultures, with a higher percentage of γδ+ cells in the B. pertussis cultures (P < 0.001). The overall data did suggest that wP vaccination resulted in modestly better specific CD3+ cell proliferation, and γδ+ cell expansions were similar with the two vaccines.

Usefulness of pharmacy dispensing records in the evaluation of adherence to antiretroviral therapy in Brazilian children and adolescents.

INTRODUCTION Adherence, which is crucial to the success of antiretroviral therapy (HAART), is currently a major challenge in the care of children and adolescents living with HIV/AIDS. OBJECTIVE To evaluate the prevalence of nonadherence to HAART using complementary instruments in a cohort of children and adolescents with HIV/AIDS followed in a reference service in Campinas, Brazil. METHODS The level of adherence of 108 patients and caregivers was evaluated by an adapted standardized questionnaire and pharmacy dispensing records (PDR). Non-adherence was defined as a drug intake lower than 95% (on 24-hour or seven-day questionnaires), or as an interval of 38 days or more for pharmacy refills. The association between adherence and clinical, immunological, virological, and psychosocial characteristics was assessed by multivariate analysis. RESULTS Non-adherence prevalence varied from 11.1% (non-adherent in three instruments), 15.8% (24-hour self-report), 27.8% (seven-day self-report), 45.4% (PDR), and 56.3% (at least one of the outcomes). 24-hour and seven-day self-reports, when compared to PDR, showed low sensitivity (29% and 43%, respectively) but high specificity (95% and 85%, respectively). In multivariate analysis, medication intolerance, difficulty of administration by caregiver, HAART intake by the patient, lower socioeconomical class, lack of virological control, missed appointments in the past six months, and lack of religious practice by caregiver were significantly associated with non-adherence. CONCLUSION A high prevalence of HAART non-adherence was observed in the study population, and PDR was the most sensitive of the tested instruments. The instruments employed were complementary in the identification of non-adherence.

Autoimmune lymphoproliferative syndrome presenting with glomerulonephritis

Abstract.Autoimmune lymphoproliferative syndrome (ALPS) is characterized clinically by chronic non-malignant lymphoproliferation and autoimmunity and is caused by a genetic defect in programmed cell death (apoptosis). Most patients with ALPS have heterozygous mutations in the Fas gene. We describe an 11-year-old Brazilian boy with hepatosplenomegaly, lymphadenopathy, hemolytic anemia, and hypergammaglobulinemia since early infancy. T cell lines from the patient were defective in Fas-mediated apoptosis. He was diagnosed as having ALPS and found to have a novel Fas gene mutation (IVS4+1G>A). In addition, he presented with glomerulonephritis in infancy. An aunt and uncle who had the same Fas mutations also had histories of glomerulonephritis. Although glomerulonephritis is common in Fas-deficient mice, it is infrequent in human ALPS. Corticosteroid therapy ameliorated the glomerulonephritis in our patient, as well as his lymphoproliferation, anemia, and hypergammaglobulinemia. This study suggests that glomerulonephritis is one of the characteristic features of ALPS.

Implementação oportuna de intervenções para reduzir a transmissão vertical do HIV: uma experiência brasileira bem-sucedida

OBJETIVO: Descrever o impacto da implementacao oportuna de novas condutas recomendadas por consensos clinicos nacionais dirigidos a prevencao da transmissao vertical de HIV na maternidade de um hospital universitario publico no Brasil. METODO: Realizou-se um estudo retrospectivo de coorte dos partos de mulheres infectadas pelo HIV atendidos na instituicao de 1990 a 2000. As condutas adotadas nesse periodo foram: 1) ate 1994, amamentacao contra-indicada, sem uso de drogas anti-retrovirais; 2) de 1995 a 1996, uso de zidovudina (AZT) pela gestante e pelo recem-nascido; 3) de 1997 a 1998, uso de AZT conforme protocolo ACTG 076; e 4) de 1999 a 2000, terapia anti-retroviral multipla e cesarea eletiva. Em todos os periodos, a distribuicao das drogas foi gratuita. Foram calculadas as taxas de transmissao nas quatro fases e as razoes de risco de transmissao congenita para as fases e para cada intervencao profilatica (amamentacao, tipo de terapia anti-retroviral, tipo de parto). RESULTADOS: Foram estudadas 197 gestacoes. Houve reducao na transmissao vertical da primeira para a quarta fase, de 32,3 para 25,7, 2,2 e 2,9%. A maior queda, observada na terceira fase, ocorreu apos a introducao do esquema completo do ACTG 076. O uso de terapia anti-retroviral combinada aumentou de 0% na primeira fase para 46,4% na quarta fase. Nao houve nenhum caso de transmissao vertical nas gestantes tratadas com multiplas drogas. O risco de transmissao vertical foi 5 vezes maior com amamentacao do que sem amamentacao (razao de risco = 5,06), 5 vezes maior sem terapia anti-retroviral contra uso do esquema ACTG completo (razao de risco = 5,29) e 4 vezes maior para parto com forcipe contra cesarea eletiva (razao de risco = 4,13). CONCLUSAO: A adocao oportuna de intervencoes atualizadas, recomendadas por consenso nacional de especialistas, com provisao gratuita de drogas, mostrou-se eficiente para reduzir a transmissao congenita do HIV.

Antenatal maternal corticosteroid administration and markers of oxidative stress and inflammation in umbilical cord blood from very low birth weight preterm newborn infants

OBJECTIVE To investigate the association between antenatal maternal corticosteroid administration and blood levels of reactive oxygen intermediates (ROI), reduced glutathione (GR) and interleukin-6 (IL-6) in preterm, very low birth weight infants. METHODS This was a cohort study in which cord blood samples were used for the following tests: baseline and stimulated granulocyte ROI were measured by flow cytometry; GR was assayed by spectrophotometry; and IL-6 by enzyme-linked immunosorbent assay. Two different comparative analyses of antenatal corticosteroid (betamethasone) were conducted: the first compared administration against no administration and the second compared mothers who received the complete cycle with those given only a partial antenatal corticosteroid cycle. Maternal and neonatal variables were analyzed in order to compare groups. Categorical variables were compared using the chi-square or Fischer tests, and blood marker test results were compared using the Mann-Whitney test. RESULTS The different corticoid therapy groups were similar in terms of all of the maternal and neonatal variables with the exception of vaginal delivery, which was significantly associated with not receiving antenatal corticosteroid. The results for ROI, GR and IL-6 did not differ when the comparison was based on simple presence or absence of administration of the steroid. However, when the complete cycle was compared against incomplete administration, median ROI and IL-6 were lower among those given the complete cycle. CONCLUSION Administration of the complete cycle of betamethasone to the mother had a suppressive effect on baseline ROI and IL-6 production in very low birth weight preterm newborn infants.

Evolution of nutritional status of infants infected with the human immunodeficiency virus

CONTEXT There are today only a limited number of studies defining growth parameters and nutritional status for HIV children. OBJECTIVE To study the nutritional status of infants infected with the human immunodeficiency virus. TYPE OF STUDY Longitudinal study. SETTING Department of Pediatrics, Faculty of Medical Sciences, UNICAMP, Campinas, Brazil. PARTICIPANTS One hundred and twenty-four children born to HIV infected mothers were evaluated from birth until the age of two years. They were subdivided into two groups: 71 infected children and 53 non-infected children. MAIN MEASUREMENTS Growth was evaluated in both groups by comparing Z-scores for weight/age (w/a), length/age (H/a) and weight/length (w/H) (using the NCHS curves as reference). RESULTS The Z-score analyses showed that there was a significant difference between the two groups for all the variables studied, except for the H/a value at 3 months of age and the W/H value at 21 months of age, which showed P > 0.05. CONCLUSIONS The growth of infected infants was observed to be severely affected in comparison with that of seroreversed infants in the same age groups. Although clinical manifestations may take time to appear, the onset of growth changes begin soon after birth.