Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Doenças Pulmonares Intersticiais/etiologia , Transplante de Células-Tronco de Sangue Periférico , Doadores não Relacionados , Injúria Renal Aguda/induzido quimicamente , Lesão Pulmonar Aguda/etiologia , Adulto , Bronquite/complicações , Enterococcus faecium , Feminino , Infecções por Bactérias Gram-Positivas/complicações , Infecções por Bactérias Gram-Positivas/microbiologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Vírus da Influenza B/isolamento & purificação , Influenza Humana/complicações , Influenza Humana/virologia , Lenograstim , Doenças Pulmonares Intersticiais/tratamento farmacológico , Masculino , Otite Média/complicações , Otite Média/microbiologia , Derrame Pleural/etiologia , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Prednisona/uso terapêutico , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacologia , Adulto JovemRESUMO
Primary infection and reactivation of human cytomegalovirus (CMV) remain a major problem in immunocompromised patients, frequently resulting in a life threatening CMV disease. Intravenous polyvalent (hyper)-immunoglobulins (IVIG) can be administered for therapy and prophylaxis of CMV infections. However, only limited data about the efficacy and mechanism of action of IVIG products against viral infections in vitro are available so far. In this study, the effect of IVIG on CMV infection in vitro was investigated using isolates from CMV-infected patients as well as the laboratory strains AD169 and TB40. A qualitative and quantitative comparison of five different commercially available IVIG products in different human cell lines was performed concerning their ability (1) to neutralize cell-free virus, (2) to inhibit cell-to-cell spread and cell-associated transmission and (3) to influence CMV mRNA levels. All IVIG tested exhibited a high neutralization activity in epithelial and endothelial cell cultures (50% inhibition dose <0.1 mg/ml). However, qualitative differences between the products could be demonstrated in neutralization tests using human embryonal lung fibroblasts (HELF). The IVIG products also significantly differed in their ability to inhibit cell-to-cell spread within an CMV-infected HELF monolayer displaying inhibition rates that varied between 61 and 100%. No correlation between the ability to neutralize cell-free virus and to inhibit cell-to-cell spread could be observed. The incubation with IVIG influenced the amount of CMV immediate early and late mRNA, as indicated by a significant reduction in CMV mRNA in infected epithelial cells after incubation with IVIG in a dose-dependent manner. This study suggests different antiviral functions of polyvalent IVIG and confirms their potential to inhibit a CMV infection in vitro, with profound differences between the hereby used IVIG products.
Assuntos
Antivirais/farmacologia , Citomegalovirus/efeitos dos fármacos , Células Endoteliais/virologia , Células Epiteliais/virologia , Imunoglobulinas Intravenosas/farmacologia , Antivirais/imunologia , Linhagem Celular , Citomegalovirus/genética , Citomegalovirus/isolamento & purificação , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/virologia , Fibroblastos/virologia , Humanos , Hospedeiro Imunocomprometido , Imunoglobulinas Intravenosas/imunologia , Leucócitos/virologia , Testes de Neutralização , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
We analyzed cytomegalovirus (CMV) infection risk factors and immune reconstitution kinetics in 89 patients after allogeneic stem cell transplantation (allo-SCT). The use of alemtuzumab for in vivo T cell depletion (TCD) had, besides the donor/recipient CMV serostatus, the strongest influence on the CMV infection risk in univariate and multivariate analyses. In comparison to without use of in vivo TCD, the CMV infection risk [hazard ratio (HR)] was 4.82-fold after TCD with alemtuzumab, but only 1.40-fold after TCD with antithymocyte globulin (ATG). Alemtuzumab strongly depressed CD4(+) and CD8(+) T cell reconstitution, whereas ATG only delayed CD4(+) T cell reconstitution. Considering the reconstitution kinetics of CD4(+) and CD8(+) T cells, CMV-specific CD8(+) T cells, NK cells and the IgG concentration, only a low day +60 NK cell count (< or =161 versus >161/microl) was significantly associated with CMV infection development (HR 2.92, p = 0.034). CMV-specific CD8(+) T cells were detected in 57% of patients with a CMV-seropositive donor, but in none of the patients with a CMV-seronegative donor on day +30 (p = 0.01). Our data indicate that the type of in vivo TCD (alemtuzumab or ATG) differentially influences both the CMV infection risk and CD4(+)/CD8(+) T cell reconstitution kinetics in patients after allo-SCT.
Assuntos
Infecções por Citomegalovirus/etiologia , Depleção Linfocítica , Transplante de Células-Tronco/efeitos adversos , Adolescente , Adulto , Idoso , Alemtuzumab , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/efeitos adversos , Anticorpos Antineoplásicos/uso terapêutico , Soro Antilinfocitário/efeitos adversos , Soro Antilinfocitário/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Transplante Homólogo , Adulto JovemRESUMO
We developed a novel algorithm to define the need for high-dose prophylactic i.v. Igs (IVIG) in periods of high risk for CMV to patients after allo-SCT. IVIG were administered only if at least one of the following, monthly-assessed, criteria was fulfilled: (1) IgG concentration <4 g/l, (2) NK (natural killer) cell count <100/microl, (3) CD4(+) cell count <100/microl, (4) acute or chronic GVHD. The primary endpoint was to determine the cumulative incidence of CMV infection in patients who received prophylactic IVIG according to the algorithm (intervention group) and compare it with that of a sequentially assessed control group, to which prophylactic IVIG were not administered. The study included 79 patients (44 in the intervention and 35 in the control group). The estimated cumulative incidence of CMV infection in the intervention and control group did not differ significantly (44 and 36%; P=0.31). Additionally, prophylactic IVIG did not reduce the frequency of CMV infection episodes. CMV disease was rare in both cohorts (5 and 9%; P=0.65). We conclude that prophylactic IVIG should not be administered after allo-SCT, even if administered selectively in a high dose to patients with delayed immune reconstitution or GVHD.
Assuntos
Infecções por Citomegalovirus/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoglobulinas Intravenosas/administração & dosagem , Adolescente , Adulto , Idoso , Algoritmos , Infecções por Citomegalovirus/imunologia , Feminino , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Adulto JovemRESUMO
Although thymoglobulin and alemtuzumab are frequently used in hematopoietic stem cell transplantation (HSCT), little is known of their effects on NK cells, which mediate important functions in post-transplantation immunology. In the present study, we determined NK cell death in vitro using propidium iodide and Annexin V. The NK cell activity in 34 patients at day +30 after allogeneic HSCT was assessed using the CD107a assay. Alemtuzumab and thymoglobulin were similarly very potent in inducing NK cell death in vitro. Even in low concentrations (<1 microg/ml) the antibodies induced apoptosis and necrosis in a relevant percentage of NK cells (>30%). However, the number of tumor reactive (CD107a+) NK cells was 13.16 per mul and 1.15 per microl (mean) in patients receiving T-cell depletion with 6 mg/kg thymoglobulin and in patients receiving 100 mg alemtuzumab, respectively (P=0.02). Although thymoglobulin and alemtuzumab are equally NK cell toxic in vitro, the recovery of NK cell frequency and anti-tumor reactivity is reduced in recipients of alemtuzumab. Our findings can be explained by a longer half-life of alemtuzumab as compared to active thymoglobulin under therapeutic conditions. Prolonged immunosuppression with increased risk of infections and tumor relapse are a potential threat to patients undergoing HCST and receiving alemtuzumab as T-cell depletion.
Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Antineoplásicos/farmacologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Depleção Linfocítica/efeitos adversos , Adolescente , Adulto , Idoso , Alemtuzumab , Anticorpos Monoclonais Humanizados , Soro Antilinfocitário , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Pessoa de Meia-Idade , Transplante HomólogoRESUMO
Human cytomegalovirus (CMV) is a major cause of death after transplantation. The frequency of pp65-specific T cells was examined in 38 HLA-A2+ stem cell recipients during the first year after transplantation. Patients were divided into four groups based on donor/recipient serostatus: d+/r+ (n=17), d+/r- (n=7), d-/r+ (n=9) and d-/r- (n=5). Peripheral blood mononuclear cells were stimulated with the CMVpp65 peptide NLVPMVATV, and the specific T-cell frequency was assessed by interferon gamma (IFN-gamma) ELISPOT assay. Responding T cells were characterized by flow cytometry revealing a terminal differentiated effector phenotype. Surveillance of CMV infection was carried out by real-time polymerase chain reaction (n=26) or immunofluorescence (n=12). Infection was present in 7/9 d-/r+ high-risk patients, and CMV disease occurred exclusively in this group with delayed or absent virus-specific T-cell recovery. In contrast, 16/24 intermediate-risk patients showed CMV-specific T cells. Our data suggest that CMV infection and disease rates are elevated in high-risk patients with delayed CMV-specific T-cell immune reconstitution and lower in those with early recovery of T-cell immunity. We recommend preferring CMV seropositive donors for CMV seropositive recipients, as this should lead to durable CMV-specific T-cell responses soon after transplantation with consecutive protection from CMV disease.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Recuperação de Função Fisiológica/imunologia , Transplante de Células-Tronco , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Antígeno HLA-A2/imunologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Humanos , Interferon gama/imunologia , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Peptídeos/imunologia , Fosfoproteínas/imunologia , Fatores de Risco , Transplante Homólogo , Proteínas da Matriz Viral/imunologiaRESUMO
A case of corrosive burns to the face and upper airway from administration of chloral hydrate is presented. Events leading to the accident and dispensing of the drug are discussed.