RESUMO
OBJECTIVE: To evaluate the outcome of children who received prolonged intravenous immunoglobulin (IVIg) replacement therapy early in life for X-linked agammaglobulinemia (XLA). STUDY DESIGN: We performed a retrospective study of the clinical features and outcome of patients with genetic and/or immunologic results consistent with XLA. Patients receiving IVIg replacement therapy within 3 months of the diagnosis and for at least 4 years between 1982 and 1997 were included. RESULTS: Thirty-one patients began receiving IVIg replacement therapy at a median age of 24 months and were followed up for a median time of 123 months. IVIg was given at doses >0.25 g/kg every 3 weeks, and mean individual residual IgG levels ranged from 500 to 1140 mg/dL (median, 700 mg/dL). During IVIg replacement, the incidence of bacterial infections requiring hospitalization fell from 0.40 to 0.06 per patient per year (P <. 001). However, viral or unidentified infections still developed, including enteroviral meningoencephalitis (n = 3) causing death in one patient, exudative enteropathy (n = 3), and aseptic arthritis (n = 1). At last follow-up, 30 patients were alive at a median age of 144 months (range, 58 to 253 months). Among 23 patients who were evaluated by respiratory function tests and computed tomography, 3 had an obstructive syndrome, 6 had bronchiectasis, and 20 had chronic sinusitis. CONCLUSION: Early IVIg replacement therapy achieving residual IgG levels >500 mg/dL is effective in preventing severe acute bacterial infections and pulmonary insufficiency. More intensive therapy may be required to fully prevent the onset of bronchiectasis, chronic sinusitis, and nonbacterial infections, particularly enteroviral infections, in all cases.
Assuntos
Agamaglobulinemia/genética , Agamaglobulinemia/terapia , Imunoglobulinas Intravenosas/uso terapêutico , Agamaglobulinemia/complicações , Agamaglobulinemia/imunologia , Criança , Pré-Escolar , Seguimentos , Ligação Genética , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Imunofenotipagem , Lactente , Infecções/etiologia , Estudos Retrospectivos , Cromossomo XRESUMO
We retrospectively analyzed the outcome of bone marrow transplantation (BMT) performed in 26 patients with Wiskott-Aldrich syndrome (WAS) in one center. Twenty-eight transplantation procedures were performed. Ten unselected patients received unmanipulated marrow from a donor with genetically identical human leukocyte antigen (HLA). Eight patients were cured and survive 1.5 to 16.5 years after BMT. One patient successfully received a T-cell-depleted marrow from a matched unrelated donor. Sixteen patients were selected to receive a related HLA partially incompatible BMT because of the occurrence of life-threatening complications from the WAS (i.e., refractory thrombocytopenia, autoimmunity including vasculitis and sepsis). All but one received T-cell-depleted marrow after a conditioning regimen of busulfan and cyclophosphamide. One patient had two BMTs. Engraftment occurred in 12 of 17 attempts. The addition of monoclonal antibodies to lymphocyte function-associated antigen-1 and CD2 molecules appeared to improve engraftment. Six patients were long-term survivors, whereas others died of viral infections (n = 7), among which Epstein-Barr virus-induced B-lymphocyte proliferative disorder was predominant. Delay in development of full T- and B-cell functions accounted for severe infectious complications. These results confirm the excellent outcome of HLA genetically identical BMT in WAS, whereas BMT from HLA partially incompatible donors should be strictly restricted to patients with severe complications of WAS.
Assuntos
Transplante de Medula Óssea , Síndrome de Wiskott-Aldrich/terapia , Adolescente , Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/complicações , Linfócitos B/imunologia , Bussulfano/uso terapêutico , Antígenos CD2/uso terapêutico , Criança , Pré-Escolar , Ciclofosfamida/uso terapêutico , Sobrevivência de Enxerto , Antígenos HLA/genética , Infecções por Herpesviridae , Herpesvirus Humano 4 , Humanos , Imunossupressores/uso terapêutico , Lactente , Depleção Linfocítica , Antígeno-1 Associado à Função Linfocitária/uso terapêutico , Estudos Retrospectivos , Sepse/complicações , Taxa de Sobrevida , Linfócitos T/imunologia , Trombocitopenia/complicações , Resultado do Tratamento , Vasculite Leucocitoclástica Cutânea/complicaçõesRESUMO
We report the outcome of allogeneic bone marrow transplantation (BMT) in nine consecutive patients with Omenn syndrome treated between 1980 and 1989. Five patients received unmanipulated marrow from a related matched donor, and four received T cell-depleted marrow from a haploidentical donor. The patients were conditioned with cyclophosphamide (200 mg/kg) and, except in one case, busulfan (16 mg/kg). Antithymocyte globulin and etoposide were given to three patients each; three recipients of T cell-depleted haploidentical marrow also received intravenous injections of an anti-leukocyte function-associated antigen type 1 antibody as graft rejection prophylaxis. All the patients were fed parenterally for 1 to 5 months before BMT to improve nutritional status and received topical corticosteroids (n = 8), systemic steroids (n = 2), etoposide (n = 1), or cyclosporine (n = 1) to control T-cell activation. Engraftment occurred in four of five recipients of human leukocyte antigen (HLA)-identical marrow and three of four recipients of HLA-haploidentical marrow. One patient died with cytomegalovirus infection. The other six patients are alive 4 to 11 years after BMT, with full chimerism in all but one case. Chronic graft-versus-host disease persists in one patient; the other five survivors have fully restored immune function and have no manifestations of Omenn syndrome, including failure to thrive. We conclude that both HLA-identical and haploidentical BMT can cure Omenn syndrome, provided that parenteral nutrition and immunosuppressive therapy are given before transplantation.
Assuntos
Transplante de Medula Óssea , Imunodeficiência Combinada Severa/terapia , Bussulfano/administração & dosagem , Bussulfano/uso terapêutico , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Feminino , Rejeição de Enxerto/prevenção & controle , Doença Enxerto-Hospedeiro/tratamento farmacológico , Antígenos HLA/sangue , Haplótipos , Humanos , Imunoglobulinas/sangue , Masculino , Estado Nutricional , Estudos Retrospectivos , SíndromeRESUMO
Partial albinism with immunodeficiency is a rare and fatal immunologic disorder characterized by pigmentary dilution and variable cellular immunodeficiency. To define the phenotype, therapy, and outcome, we retrospectively analyzed seven consecutive patients. Primary abnormalities included a silvery-grayish sheen to the hair, large pigment agglomerations in hair shafts, and an abundance of mature melanosomes in melanocytes, with reduced pigmentation of adjacent keratinocytes. Clinical onset occurred between the ages of 4 months and 4 years and was characterized by accelerated phases (lymphohistiocytic infiltration of multiple organs, including the brain and the meninges), triggered by viral and bacterial infections. Characteristic laboratory features included pancytopenia, hypofibrinogenemia, hypertriglyceridemia, and hypoproteinemia. Consistent immunologic abnormalities were characterized by absent delayed-type cutaneous hypersensitivity and impaired natural killer cell function. Some patients had secondary hypogammaglobulinemia, impaired major histocompatibility complex-mediated cytotoxic effects, a decreased capacity of lymphocytes to trigger a mixed lymphocyte reaction, or various functional granulocytic abnormalities. The disease seems to be invariably lethal without bone marrow transplantation; the mean age at the time of death was 5 years. Bone marrow transplantation has been performed in three cases; two patients died in the immediate posttransplantation period of infectious complications, but one patient is cured after a follow-up of 5 years. We conclude that partial albinism with immunodeficiency (Griscelli syndrome) can be differentiated from Chédiak-Higashi syndrome by pathognomonic histologic features. One of the underlying immunologic defects may be a defective function of natural killer cells, predisposing the patient to virus-associated hemophagocytic syndrome or accelerated phases. The prognosis is very poor unless early bone marrow transplantation is carried out.
Assuntos
Albinismo/complicações , Síndromes de Imunodeficiência/complicações , Corticosteroides/uso terapêutico , Albinismo/diagnóstico , Albinismo/genética , Albinismo/imunologia , Albinismo/terapia , Transplante de Medula Óssea , Doenças do Sistema Nervoso Central/etiologia , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Hipersensibilidade Tardia/imunologia , Imunidade Celular , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Terapia de Imunossupressão , Lactente , Infecções/etiologia , Células Matadoras Naturais/imunologia , Masculino , Fenótipo , Recidiva , Estudos Retrospectivos , Resultado do TratamentoRESUMO
We report on eight children with severe diarrhea beginning in the first 6 months of life (< 1 month in six cases), who had a number of features in common. All were small for gestational age and had an abnormal phenotype, including facial dysmorphism, hypertelorism, and woolly, easily removable hair with trichorhexis nodosa. Two were products of consanguineous marriages. Severe secretory diarrhea persisted despite bowel rest (n = 7). Jejunal biopsy specimens showed total or subtotal villous atrophy with crypt necrosis, and inconstant T-cell activation in some cases (n = 3). Colon biopsy specimens showed moderate nonspecific colitis. All the patients had defective antibody responses despite normal serum immunoglobulin levels, and defective antigen-specific skin tests despite positive proliferative responses in vitro. Three had monoclonal hyper-immunoglobulinemia A. The course was marked by diffuse erythroderma in two cases and mental retardation in three. Treatment included bowel rest, intravenous administration of immune globulins, administration of corticosteroids (n = 6) and cyclosporine (n = 2), and bone marrow transplantation (n = 1). Five patients died between the ages of 2 and 5 years (of sepsis or cirrhosis), two are being fed enterally, and one continues to receive total parenteral nutrition. The cause of the combined low birth weight, dysmorphism, severe diarrhea, trichorrhexis, and immunodeficiency is unclear. These features may constitute a specific syndrome within the group of intractable diarrheas of infancy.
Assuntos
Diarreia , Face/anormalidades , Cabelo/anormalidades , Síndromes de Imunodeficiência , Doença Crônica , Dermatite Esfoliativa , Diarreia/imunologia , Diarreia/patologia , Evolução Fatal , Feminino , Cabelo/patologia , Humanos , Hipertelorismo , Lactente , Recém-Nascido , Intestinos/patologia , Masculino , Fenótipo , SíndromeRESUMO
We carried out a retrospective analysis of 117 patients with severe combined immunodeficiency who were examined in a single center between Jan. 1, 1970, and Jan. 1, 1992, for the purpose of evaluating disease onset, progression, and outcome. The frequency of case referral increased from 8 from 1970 to 1975 to 56 from 1986 to 1991. The most frequent phenotype was T-/B+ (absence of T lymphocytes and presence of B lymphocytes) (n = 51); there were 36 cases of alymphocytosis, 16 of adenosine deaminase deficiency, 13 of Omenn syndrome, and 1 of reticular dysgenesis. Protracted diarrhea and lung infections were the main infectious complications; infection with bacillus Calmette-Guérin occurred in 10 of 28 vaccinated patients, but none of the six recipients of oral polio vaccine subsequently had poliomyelitis. The presence of maternal T cells was suspected or proved in half the patients with alymphocytosis or T-B+ severe combined immunodeficiency but did not occur in the other forms of the disease. Of the 117 patients, 22 died before transplantation could be performed. Adenosine deaminase deficiency and Omenn syndrome were more frequently associated with death before hematopoietic stem cell transplantation was possible. Fetal liver transplantation was successful in 1 of 10 cases. The survival rate among the 30 recipients of bone marrow with identical human leukocyte antigens (HLA) was 80%, with a median follow-up of 129 months; 23 of 25 patients recovered full immune function. The survival rate among the 50 recipients of HLA-haploidentical T cell-depleted bone marrow was 56%, with a mean follow-up of 35 months. Of the latter patients, 10 (35%) still require immunoglobulin substitution. There has been a trend toward improvement in the survival rate of haploidentical bone marrow recipients, presumably because of more effective infection-control measures and better transplantation strategy.
Assuntos
Imunodeficiência Combinada Severa/epidemiologia , Transplante de Medula Óssea , Feminino , Transplante de Tecido Fetal , Humanos , Imunofenotipagem , Incidência , Lactente , Recém-Nascido , Transplante de Fígado , Masculino , Prevalência , Estudos Retrospectivos , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Análise de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
Graft rejection is the major cause of failure of HLA mismatched bone marrow transplantation because of residual host immunity. we have proposed to use a monoclonal murine antibody specific for the LFA-1 molecule (25-3) to prevent graft failure in HLA mismatched bone marrow transplantation (BMT). The rationale for this approach is three fold: LFA-1 deficient patients (3/3) do not reject HLA mismatched BMT; anti LFA-1 blocka in vitro the induction of T cell responses and T/ non T cytotoxic functions; LFA-1 is not expressed by other cells than leucocytes. We have accordingly treated twenty two patients with inherited diseases and 8 with leikemia. The bone marrow was T cells depled by E rosetting of Campath antibody. The antibody was given at days -3, -1, +1, +3, +5 at dose of .1 mg/kg/d for the first 9 and then .2mg/kg/d from day -3 to +6. Engraftment occured in 23/30 patients as shown by at least HLA typing. Hematological recovery was rapid, GVH was limited. Side effects of antibody infusion included fever and possibly an increased incidence of early bacteral infection (sepsis, 1 death). Immunological reconstitution occured slowly leading in six cases to EBV-induced B cell poliferation (1 death and in two others to transient auto immune hemolytic anemia. There has been only one secondary graft rejection. Sisteen patients are alive 3 to 26 months post transplant with functional grafts. Although the number of patients treated is still low the absence of late rejection so far, gives hope for long term maintenance of the graft using anti LFA-1. Since the antibody is an IgG 1 unable to bind human complement, and since it is known to inhibit phagocytosis, there is a good suggestion that 25-3 act through functional blocking of host T and non T luymphocytes at both induction and effector levels.
Assuntos
Humanos , Células da Medula Óssea/citologia , Anticorpos Monoclonais , Antígeno-1 Associado à Função Linfocitária , Afinidade de AnticorposRESUMO
We performed a longitudinal study (mean follow-up 19.5 months, range 3 to 42 months) in 18 consecutive children with clinical symptoms of LAV/HTLV III infection. Twelve patients were born to mothers infected with LAV/HTLV III, and six were infected by blood products administered during the first weeks of life. Immunologic studies included lymphocyte markers, in vitro responses to mitogens and antigens with corresponding skin tests, and antibody response with isoagglutinins, post-vaccination antibodies, and Candida. A serologic profile of antibody to GP110, P18, and P25 LAV/HTLV III antigens by radioimmunoprecipitation assay was also performed. The antigen-induced proliferative responses were normal in 10 patients who had a stable course, but were profoundly impaired in eight others who died or had poor condition with opportunistic infections. These in vitro measurements were well correlated with antigen skin tests. An abnormal antibody response to antigens, a low level of isoagglutinins, and a peculiar profile of LAV/HTLV III antibodies were also frequently observed in these eight patients. These measurements appear to be of prognostic value because they were noticed soon after onset of clinical symptoms.