RESUMO
To determine the safety and pharmacokinetics of recombinant soluble CD4 (sCD4) administered by continuous intravenous infusion to children with symptomatic human immunodeficiency virus type 1 infection, we conducted a phase I study at the National Cancer Institute. Three dose levels of sCD4 were evaluated: 100, 300, and 1000 micrograms/kg per day. After an initial 12 weeks of treatment with sCD4 alone, dideoxyinosine at a dose of 90 mg/m2 every 8 hours was added and subjects were observed for an additional 12 weeks. Combination therapy was continued in patients in whom it was well tolerated. In addition to toxicity and pharmacokinetic monitoring, surrogate markers of antiviral activity were evaluated. Eleven children were enrolled in the study. During the 12 weeks of treatment with sCD4 alone, and during subsequent sCD4 plus dideoxyinosine combination therapy, no significant toxic reaction attributable to sCD4 or dideoxyinosine was encountered. Low-level anti-CD4 antibodies developed in two patients. Steady-state sCD4 levels increased proportionately at higher doses. The CD4 cell counts and serum p24 antigen levels did not provide evidence of antiviral activity. We conclude that sCD4 was well tolerated at doses up to 1000 micrograms/kg per day when administered by continuous intravenous infusion; however, evidence of in vivo antiviral activity was not observed in this study.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Antígenos CD4/uso terapêutico , Didanosina/uso terapêutico , Síndrome da Imunodeficiência Adquirida/imunologia , Adolescente , Antígenos Virais/sangue , Antígenos CD4/administração & dosagem , Linfócitos T CD4-Positivos , Criança , Pré-Escolar , Didanosina/administração & dosagem , Didanosina/farmacocinética , Avaliação de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Lactente , Infusões Intravenosas , Contagem de Leucócitos , Masculino , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Resultado do TratamentoRESUMO
To evaluate the possible effects of maternal intravenous drug use on infant immunity, we measured the in vitro peripheral blood mononuclear cell proliferative responses to phytohemagglutinin (PHA) and pokeweed mitogen, T cell subset numbers, immunoglobulin levels, and titers of antibodies to cytomegalovirus (CMV) and human immunodeficiency virus (HIV) in a group of drug-abusing mothers and their infants. Infants of drug abusers had a lower proliferative response to mitogen, associated with altered kinetics of the maximum response to PHA. The OKT4/OKT8 ratio decreased with age in the drug-exposed infants compared with control infants (P less than 0.005). There was no evidence of CMV infection in either group. One mother and her infant had antibody to HIV. Our data demonstrate that infants of intravenous drug-using mothers have distinct immunologic differences at birth compared with non-drug-exposed infants and that these persist throughout the first year of life. The cause appears unrelated to intrauterine viral infection, suggesting a direct toxic effect of the drugs on fetal immunologic development.
Assuntos
Linfócitos/imunologia , Efeitos Tardios da Exposição Pré-Natal , Transtornos Relacionados ao Uso de Substâncias/complicações , Anticorpos Antivirais/análise , Citomegalovirus/imunologia , Feminino , HIV/imunologia , Humanos , Lactente , Recém-Nascido , Contagem de Leucócitos , Ativação Linfocitária/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Fenótipo , Fito-Hemaglutininas/farmacologia , Mitógenos de Phytolacca americana/farmacologia , Gravidez , Transtornos Relacionados ao Uso de Substâncias/imunologia , Linfócitos T/classificação , Fatores de TempoRESUMO
Behcet syndrome, a multisystem disorder characterized by ocular, mucocutaneous, articular, vascular, gastrointestinal, and neurologic abnormalities, is described in six pediatric patients. The patients ranged in age from 2 months to 11 years at time of onset. Several years were usually required before additional manifestations of the disease occurred. Aphthous ulceration was present in all six patients, arthritis in three, erythema nodosum in four, sterile cellulitis in three, gastrointestinal manifestations in five, neurologic manifestations in two, and genital or perianal ulcerations in three; ocular involvement was present in only one. There were no diagnostic laboratory studies, and, as in the adult population, no cause for Behçet syndrome was found. Patients had a variable response to corticosteroid therapy. Two patients who had significant morbidity and who responded poorly to corticosteroid therapy also received chlorambucil therapy, which appeared to provide improved control of signs and symptoms. Based on the prolonged interval between onset and the appearance of complete manifestations, Behcet syndrome may be more common in children than previously reported.
Assuntos
Síndrome de Behçet/patologia , Artrite/patologia , Síndrome de Behçet/tratamento farmacológico , Criança , Pré-Escolar , Conjuntivite/patologia , Feminino , Gastroenteropatias/patologia , Humanos , Lactente , Masculino , Períneo , Úlcera Cutânea/patologia , Estomatite Aftosa/patologiaRESUMO
The acquired immunodeficiency syndrome has been observed with increasing frequency in children with associated hemophilia, high-risk environmental backgrounds, and blood transfusions. AIDS should be considered in the differential diagnosis of childhood immunodeficiency, and it must be distinguished from congenital disorders. We emphasize the importance of epidemiologic, clinical, and laboratory data in diagnosis and aggressive management of infectious complications. The relationship between human retrovirus infection and AIDS remains to be precisely defined, especially with regard to cofactors that may play a role in the development of severe immunodeficiency following exposure to the agent.
PIP: To date, the acquired immunodeficiency syndrome (AIDS) has been identified in over 50 children in the US, including those with associated hemophilia, high-risk environmental factors (Haitian background, parental intravenous drug abuse, or prostitution), and blood transfusions. The evaluation of an infant or young child in whom AIDS is suspected requires exclusion of congenital disorders of immune function. A specific test is not currently available, but inclusion criteria for childhood AIDS have been developed. The diseases accepted as indicative of underlying cellular immunodeficiency children are the same as those used in defining AIDS in adults, with the exclusion of congenital infections such as toxoplasmosis or herpes simplex virus infection in the 1st month of life or cytomegalovirus infection in the 1st 6 months of life. Specific conditions that must be excluded in children are primary immunodeficiency diseases (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome, ataxia-telangiectasia, neutrophil function abnormality) and secondary immuno-deficiency associated with immunosuppressive therapy, lymphoreticular malignancy, or starvation. Almost all young children with AIDS have hepatosplenomegaly, interstitial pneumonitis, and poor growth. The average age of 36 US child AIDS victims studied in detail was 5 months at presentation with findings suggestive of severe immunodeficiency. Mucocutaneous candidiasis was present in 75% of these 36 children, and Pneumocystis carinii and cytomegalovirus were each isolated from 30% of cases. Normal T4:T8 ratios occur in about 15% of pediatric AIDS cases. Laboratory evidence of polyclonal hypergammaglobulinemia generally supports the AIDS diagnosis. Recurrent infection and malnutrition are major problems in the clinical management of child AIDS patients.
Assuntos
Síndrome da Imunodeficiência Adquirida , Síndrome da Imunodeficiência Adquirida/diagnóstico , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/fisiopatologia , Síndrome da Imunodeficiência Adquirida/terapia , Síndrome da Imunodeficiência Adquirida/transmissão , Formação de Anticorpos , Linfócitos B/imunologia , Criança , Deltaretrovirus/imunologia , Hemofilia A/imunologia , Humanos , Imunidade Celular , Monócitos/imunologia , Fenômenos Fisiológicos da Nutrição , Recidiva , Infecções por Retroviridae/imunologia , Risco , Linfócitos T/imunologia , Reação TransfusionalAssuntos
Anemia Falciforme/complicações , Vacinas Bacterianas/administração & dosagem , Imunização Secundária , Infecções Pneumocócicas/prevenção & controle , Polissacarídeos Bacterianos/administração & dosagem , Streptococcus pneumoniae , Adolescente , Anticorpos Antibacterianos/análise , Criança , Pré-Escolar , Seguimentos , Humanos , Estudos Longitudinais , Infecções Pneumocócicas/imunologia , Talassemia/complicaçõesRESUMO
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.
Assuntos
Hemofilia A/imunologia , Síndrome da Imunodeficiência Adquirida/imunologia , Adolescente , Anticorpos Antivirais/análise , Criança , Pré-Escolar , Crioglobulinas/uso terapêutico , Fator VIII/uso terapêutico , Feminino , Humanos , Imunidade Celular , Lactente , Contagem de Leucócitos , Ativação Linfocitária , Masculino , Linfócitos T/imunologiaRESUMO
A girl with a history of autoimmune disease developed life-threatening agranulocytosis. A bone marrow biopsy demonstrated selective granulocytic hypoplasia. No antineutrophil antibodies were found. In vitro bone marrow culture of granulocytic progenitor cells suggested T cell-mediated inhibition of colony formation, which was reduced by in vitro treatment of marrow cells with either hydrocortisone or an antibody directed against T-lymphocytes and complement. The patient responded to treatment with antithymocyte globulin after administration of corticosteroids and other immunosuppressants failed to increase her neutrophil count significantly. Attempts to stop ATG treatment resulted in precipitous drops in her neutrophil counts, which reversed with readministration of ATG. She then received weekly ATG infusions for over 24 months until she was able to maintain a normal neutrophil count. A trial of ATG therapy may be indicated in severe neutropenia when in vitro culture results indicate a possible autoimmune basis.
Assuntos
Agranulocitose/terapia , Soro Antilinfocitário/uso terapêutico , Agranulocitose/complicações , Agranulocitose/imunologia , Anemia Hemolítica Autoimune/complicações , Criança , Ensaio de Unidades Formadoras de Colônias , Feminino , HumanosRESUMO
Seven children and adolescents are described with mixed connective tissue disease. The patients had varying clinical features, commonly characterized by Raynaud phenomenon, arthritis, abnormal pulmonary function, and esophageal dysmotility. All patients had speckled antinuclear antibodies and high titers (greater than 1:100,000) of antibodies to ribonuclease-sensitive extractable nuclear antigen. We prepared extractable nuclear material from radioactively labeled HeLa cells, analogous to classic extractable nuclear antigen. Sera from all seven patients precipitated ribonucleoprotein containing the small nuclear ribonucleic acid species U1 from the HeLa cell extract. Antibody to U1 ribonucleoprotein was not found in sera from 51 of 53 children and adults having a variety of autoimmune and other diseases, nor in sera from nine normal individuals. The U1 ribonucleoprotein appears to be the component of extractable nuclear antigen characteristically reacting with sera from patients with mixed connective tissue disease. The finding of a distinct molecular marker in all children studied with mixed connective tissue disease indicates that this is a distinct disease entity and not a heterogeneous population of immune disorders.
Assuntos
Doença Mista do Tecido Conjuntivo/imunologia , Nucleoproteínas/imunologia , RNA/imunologia , Ribonucleoproteínas/imunologia , Adolescente , Anticorpos/análise , Antígenos Nucleares , Criança , Feminino , Humanos , Masculino , RNA Nuclear PequenoRESUMO
Opsonic defects have been reported in unimmunized patients with sickle cell disease. We found significant increases (P less than 0.001) in serum opsonic activity, measured by a radiolabeled bacterial uptake assay, and in type 7 pneumococcal polysaccharide antibody concentration in 17 such patients 2 years of age or older after pneumococcal polysaccharide immunization. All 17 patients and six healthy controls achieved a type 7 antibody concentration of more than 300 ng antibody nitrogen per milliliter, believed to be the protective level of antibody in vivo. Six patients with sickle cell disease less than 2 years of age did not have a significant increase in type 7 antibody concentration after immunization. Only three of these six patients achieved a postimmunization type 7 antibody concentration exceeding 300 ng Ab N/ml. Overall, 16 of 23 patients with sickle cell disease (70%) had a twofold or greater increase in type 7 antibody concentration, and 13 of these (81%) had a corresponding increase in opsonic activity (P less than 0.001). Thus most patients who responded to pneumococcal polysaccharide immunization had a concurrent increase in opsonic activity in vitro.
Assuntos
Anemia Falciforme/imunologia , Anticorpos Antibacterianos/imunologia , Vacinas Bacterianas/administração & dosagem , Proteínas Opsonizantes/imunologia , Adolescente , Fatores Etários , Anemia Falciforme/complicações , Criança , Pré-Escolar , Feminino , Humanos , Imunização , Lactente , Masculino , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas , Streptococcus pneumoniae/imunologiaRESUMO
Sjögren syndrome, consisting of keratoconjunctivitis sicca and xerostomia with or without another autoimmune disease, is uncommon in children. We describe our retrospective experience with eight pediatric patients with SS. All had recurrent parotid enlargement and abnormal salivary gland biopsies, six had keratoconjunctivitis sicca, and five had other autoimmune manifestations, although only two of these had other clearly defined autoimmune disorders (mixed connective tissue disease and hypergammaglobulinemic purpura). Our patients had a higher incidence of primary SS, parotid enlargement, and hematologic abnormalities than did children previously reported with SS. Children with SS demonstrate a clinical heterogeneity comparable to that seen in adults.
Assuntos
Síndrome de Sjogren/diagnóstico , Adolescente , Doenças Autoimunes/diagnóstico , Criança , Pré-Escolar , Feminino , Humanos , Ceratoconjuntivite/diagnóstico , Masculino , Doenças Parotídeas/diagnóstico , Estudos Retrospectivos , Doenças das Glândulas Salivares/diagnósticoRESUMO
Reconstruction of the T-cell immune defect in patients with the DiGeorge syndrome has been accomplished in the past by fetal thymus transplantation. Because of the risk of fatal graft-versus-host reaction with fetal thymus transplantation in patients with abnormal T-cell immunity, we have examined the effects of a thymus tissue extract, thymosin fraction 5, on the in vitro and in vivo immune function in children with the DiGeorge syndrome. T-cell numbers were increased with thymosin F5 in vitro in three of five patients. T-cell number and function was improved in three of four patients treated with thymosin F5 in vivo. Spontaneous improvement in the immune function of these patients cannot be excluded. These results suggest, however, that further trials with thymosin F5 therapy may be indicated in patients with the DiGeorge syndrome.
Assuntos
Síndrome de DiGeorge/tratamento farmacológico , Síndromes de Imunodeficiência/tratamento farmacológico , Timosina/uso terapêutico , Hormônios do Timo/uso terapêutico , Humanos , Lactente , Recém-NascidoAssuntos
Aspergillus/imunologia , Doença Granulomatosa Crônica/imunologia , Imunidade , Disfunção de Fagócito Bactericida/imunologia , Adolescente , Adulto , Anticorpos Antifúngicos/análise , Aspergilose/imunologia , Aspergilose/terapia , Criança , Pré-Escolar , Humanos , Hipersensibilidade/imunologia , Hipersensibilidade Tardia/imunologia , Imunidade Celular , Técnicas Imunológicas , Lactente , Ativação Linfocitária , Testes Cutâneos , Linfócitos T/imunologia , Fator de Transferência/uso terapêuticoAssuntos
Anticorpos Antinucleares , Doenças do Colágeno/imunologia , Complemento C1/deficiência , Proteínas do Sistema Complemento/deficiência , Lúpus Eritematoso Sistêmico/diagnóstico , Doenças Linfáticas , Anticorpos Antinucleares/análise , Pré-Escolar , Doenças do Colágeno/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Doenças Linfáticas/patologiaRESUMO
Four infants with skin rash, hepatosplenomegaly, lymphocytosis, eosinophilis, and histiocytic infiltration of the lymph nodes and skin are described; in each of these infants an initial diagnosis of the Letterer-Siwe syndrome was made. Postmortem findings of thymic dysplasia and poorly differentiated, lymphopenic peripheral lympoid tissue in each of the four infants, as well as antimortem clinical findings in one, established a diagnosis of severe combined immunodeficiency. From these and similar cases in the literature, we postulate that the Letterer-Siwe syndrome may not be an unusual presentation of combined immunodeficiency. Appropriate immunologic studies will help to differentiate the two disorders.