RESUMO
Despite the availability of new antifungal compounds, invasive aspergillosis carries high morbidity and mortality in hematopoietic stem cell transplant recipients. In vitro studies and animal models suggest that the adoptive transfer of natural killer (NK) cells might be a promising immunotherapeutic option in this setting. As it is unclear whether the viability and function of human NK cells are affected by common antifungal agents, we analyzed the interaction of various concentrations of amphotericin B deoxycholate (AmB-D), liposomal amphotericin B, caspofungin, fluconazole, voriconazole, and posaconazole with human NK cells. When adding NK cells to therapeutic concentrations of antifungal agents, a significant increase in the antifungal effect was seen for caspofungin and voriconazole, whereas NK cells significantly decreased the hyphal damage of escalated doses of AmB-D. In contrast, therapeutic concentrations of all antifungal compounds tested did not have a negative effect on proliferation, viability, and the release of soluble immunomodulatory molecules of NK cells. These data indicate that therapeutic concentrations of the antifungal agents tested do not negatively affect the functional properties of human NK cells, which is a prerequisite for further studies evaluating NK cells as antifungal immunotherapy in immunocompromised patients suffering from invasive aspergillosis.
Assuntos
Antifúngicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Anfotericina B/farmacologia , Caspofungina/farmacologia , Ácido Desoxicólico/farmacologia , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacologia , Combinação de Medicamentos , Fluconazol/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Polietilenoglicóis/farmacologia , Triazóis/farmacologia , Voriconazol/farmacologiaRESUMO
Allogeneic hematopoietic stem cell transplant (HSCT) recipients are at high risk for invasive aspergillosis. Whereas adoptive immunotherapy transferring donor-derived anti-Aspergillus TH1 cells has been shown to be beneficial for HSCT recipients suffering from invasive aspergillosis, little is known about the impact of commonly used immunosuppressants on the functional properties of anti-Aspergillus TH1 cells. Anti-Aspergillus TH1 cells were coincubated with different concentrations of methylprednisolone, cyclosporine (CsA), mycophenolic acid (MPA), the active component of mycophenolate mofetil, and rapamycin. Immunosuppressants were tested in concentrations reflecting common target levels in serum and in significantly lower and higher concentrations. Apoptosis of anti-Aspergillus TH1 cells, as well as proliferation and production of gamma interferon (IFN-γ) and CD154 upon restimulation, was evaluated in the presence and absence of immunosuppressive compounds. All dosages of CsA, MPA, and methylprednisolone significantly decreased the number of viable anti-Aspergillus TH1 cells in the cell culture, which was due partly to an impaired proliferative capacity of the cells and partly to an increased rate of apoptosis. In addition, CsA significantly decreased the number of IFN-γ-producing cells and had the highest impact of all immunosuppressants on IFN-γ levels in the supernatant. CsA also significantly decreased the expression of CD154 by anti-Aspergillus TH1 cells. Variant dosages of immunosuppressants exhibit particular effects on essential functional properties of anti-Aspergillus TH1 cells. Our findings may have an important impact on the design of clinical trials evaluating the therapeutic benefit of anti-Aspergillus TH1 cells in allogeneic HSCT recipients suffering from invasive aspergillosis.
Assuntos
Aspergillus fumigatus/imunologia , Imunossupressores/farmacologia , Células Th1/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Aspergilose/imunologia , Aspergilose/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ciclosporina/farmacologia , Citocinas/metabolismo , Humanos , Interferon gama/metabolismo , Metilprednisolona/farmacologia , Ácido Micofenólico/farmacologia , Sirolimo/farmacologiaRESUMO
Mucormycoses remain a serious complication in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT). In these patients, mortality rates of mucormycosis reach up to 90%, which is due, at least in part, to the severe and prolonged immunosuppression after transplantation. Although prolonged neutropaenia is one of the most important risk factors for mucormycosis, other cell populations, such as CD4(+) T cells may also provide critical defence mechanisms against this infection. The management of mucormycosis includes antifungal therapy, surgery and, most importantly, the control of the underlying predisposing conditions, such as the correction of an impaired immune system. Here, we review the current data of granulocytes, antifungal T cells and natural killer cells regarding their activity against mucormycetes and regarding a potential immunotherapeutic approach. It is hoped that further animal studies and clinical trials assessing immunotherapeutic strategies will ultimately improve the poor prognosis of allogeneic HSCT recipients suffering from mucormycosis.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Mucormicose/tratamento farmacológico , Antifúngicos/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Granulócitos/imunologia , Humanos , Células Matadoras Naturais/imunologia , Mucormicose/prevenção & controle , Neutropenia/microbiologiaRESUMO
BACKGROUND AIMS: Invasive fungal infections, in particular, infections caused by Candida, Aspergillus and mucormycetes, are a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation. Adoptive transfer of donor-derived anti-fungal T cells shows promise to restore immunity and to offer a cure. Because T cells recognize only specific epitopes, the low rate of patients in which the causal fungal pathogen can be identified and the considerable number of patients with co-infection with several genera or species of fungi significantly limit the application of adoptive immunotherapy. METHODS: Using the interferon-γ secretion assay, we isolated multi-specific human anti-fungal T cells after simultaneous stimulation with cellular extracts of Aspergillus fumigatus, Candida albicans and Rhizopus oryzae. Cells were phenotypically and functionally characterized by flow cytometry. RESULTS: Of a total of 1.1 × 10(9) peripheral blood mononuclear cells, a median number of 5.2 × 10(7) CD3+ CD4+ T cells was generated within 12 days. This cell population consisted of activated memory TH1 cells and reproducibly responded to a multitude of Aspergillus spp., Candida spp. and mucormycetes with interferon-γ production. On re-stimulation, the generated T cells proliferated and enhanced anti-fungal activity of phagocytes and showed reduced alloreactivity compared with the original cell fraction. CONCLUSIONS: Our rapid and simple method of simultaneously generating functionally active multi-specific T cells that recognize a wide variety of medically relevant fungi may form the basis for future clinical trials investigating adoptive immunotherapy in allogeneic hematopoietic stem cell transplantation recipients with invasive fungal infection.
Assuntos
Aspergillus/isolamento & purificação , Candida/isolamento & purificação , Interferon gama/imunologia , Rhizopus/isolamento & purificação , Linfócitos T/imunologia , Adulto , Aspergillus/imunologia , Aspergillus/patogenicidade , Candida/imunologia , Candida/patogenicidade , Feminino , Citometria de Fluxo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Interferon gama/metabolismo , Testes de Liberação de Interferon-gama , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Rhizopus/imunologia , Rhizopus/patogenicidade , Linfócitos T/citologiaRESUMO
Infections due to mucormycetes have a poor outcome, in particular in allogeneic hematopoietic stem cell transplantation (HSCT). In order to evaluate the cellular host response against mucormycetes, we enriched and cultivated anti-Rhizopus oryzae T cells from healthy individuals. These cells were characterized as memory/effector T(H)1 cells, they proliferated upon restimulation, they exhibited cross-reactivity to some but not all Mucorales species tested, and they increased the activity of phagocytes. Compared with the original cell fraction, the generated cells exhibited significant lower alloreactivity. Our data may form the basis for further investigations, which may ultimately lead to adoptive immunotherapeutic strategies for allogeneic HSCT recipients suffering from mucormycosis.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunidade Celular/imunologia , Rhizopus/imunologia , Células Th1/imunologia , Antígenos de Fungos/imunologia , Processos de Crescimento Celular/imunologia , Citocinas/imunologia , Humanos , Ativação Linfocitária/imunologia , Mucormicose/imunologia , Fagócitos/imunologia , Transplante HomólogoRESUMO
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma (STS) in childhood. Whereas more than 90% of patients with localized low-risk RMS can be cured, metastatic RMS have a dismal outcome, with survival rates of less than 30%. The HD CWS-96 trial showed an improved outcome for patients receiving maintenance therapy after completing intensive chemotherapy. Consequently, the international clinical trials CWS-IV 2002 and CWS DOK IV 2004 on metastatic disease of STS of the Cooperative Weichteilsarkom Studiengruppe (CWS) were designed in addition to the CWS-2002P trial for localized RMS disease. All patients received a multimodal intensive treatment regimen. To maintain remission, three options were compared: long-term maintenance therapy (LTMT) versus allogeneic hematopoietic stem cell transplantation (alloHSCT) versus high-dose chemotherapy (HDCT). A total of 176 pediatric patients with a histologically confirmed diagnosis of metastatic RMS or RMS-like tumor were included. A total of 89 patients receiving LTML showed a significantly better outcome, with an event-free survival (EFS) of 41% and an overall survival (OS) of 53%, than alloHSCT (n = 21, EFS 19%, p = 0.02, OS 24%, p = 0.002). The outcome of LTML was slightly improved compared to HDCT (n = 13, EFS 35%, OS 34%). In conclusion, our data suggest that in patients suffering from metastatic RMS, long-term maintenance therapy is a superior strategy in terms of EFS and OS compared to alloHSCT. EFS and OS of HDCT are similar in these strategies; however, the therapeutic burden of LTMT is much lower.
RESUMO
Because natural killer (NK) cells kill tumor cells and combat infections, there is growing interest in adoptively transferring NK cells to hematopoietic stem cell recipients. Unfortunately, in humans, the activity of NK cells against Aspergillus species, the major cause of invasive fungal infection in stem cell recipients, are poorly characterized. Our results show that unstimulated and interleukin-2 prestimulated human NK cells kill Aspergillus fumigatus hyphae but do not affect resting conidia. Killing is also induced by the supernatant of prestimulated NK cells and human perforin. The high levels of interferon-γ and granulocyte macrophage colony-stimulating factor produced by prestimulated NK cells are significantly reduced by Aspergillus, indicating an immunosuppressive effect of the fungus. Whereas Aspergillus hyphae activate NK cells, resting, and germinating, conidia and conidia of ΔrodA mutants lacking the hydrophobic surface layer do not. Our results suggest that adoptively transferred human NK cells may be a potential antifungal tool in the transplantation context.
Assuntos
Aspergillus fumigatus/fisiologia , Hifas/fisiologia , Células Matadoras Naturais/fisiologia , Esporos Fúngicos/fisiologia , Aspergillus fumigatus/imunologia , Células Cultivadas , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Regulação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Hifas/imunologia , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Esporos Fúngicos/imunologiaRESUMO
The morbidity and mortality rates of invasive fungal infection in allogeneic stem cell recipients are still unacceptably high and have not been significantly improved by alternative antifungal strategies to date. Over the last few years, rapid methods for the clinical-scale generation of functionally active and well characterized antifungal T(H)1 cells have become available. In addition, current data on the use of donor-derived virus-specific T cells in allogeneic stem cell transplantation suggest that the risk of severe adverse events, in particular the risk of graft-versus-host disease, is negligible. Therefore, adoptive antifungal immunotherapeutic strategies should be evaluated in clinical trials. However, one has to recognize that these trials are only meaningful with sufficiently large and homogenous cohorts of patients and if the settings of adoptive antifungal immunotherapy are comparable. Ultimately, the strategy of adoptively transferring antifungal immune responses might improve the outcome in hematopoietic stem cell recipients suffering from invasive fungal infection.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunoterapia Adotiva/métodos , Micoses/terapia , Complicações Pós-Operatórias/terapia , Linfócitos T/imunologia , Animais , Fungos/patogenicidade , Humanos , Micoses/microbiologia , Complicações Pós-Operatórias/microbiologia , Transplante Homólogo/efeitos adversosRESUMO
Despite the availability of new antifungal compounds, morbidity and mortality of invasive fungal disease in allogeneic hematopoietic stem cell recipients are still unacceptably high. Over the past decade, one could witness an exciting improvement of the understanding of the molecular pathogenesis and of the complexity of host antifungal immune responses. This, in turn, provides critical information to augment host immunity against fungal pathogens. Strategies for enhancing the immune system include the administration of effector and regulatory cells (e.g., granulocytes, antigen-specific T cells, dendritic cells) as well as the administration of recombinant cytokines, interferons and growth factors (e.g., interferon-γ, keratinocyte growth factor, granulocyte- and granulocyte-macrophage colony stimulating factor). One has to recognize at the same time, however, that data of in vitro assays and animal models cannot necessarily be transferred into the clinical setting. In addition, meaningful clinical trials in allogeneic stem cell recipients suffering from invasive fungal disease require sufficiently large and homogenous cohorts of patients and can only be performed in international collaboration, but may ultimately improve the outcome of allogeneic transplant recipients with invasive fungal disease.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunoterapia/métodos , Micoses/imunologia , Micoses/terapia , Animais , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/imunologia , Camundongos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Invasive fungal infections remain a serious and life-threatening complication in patients undergoing hematopoietic stem cell transplantation. Since it became clear that lymphocytes, in particular lymphocytes from the T helper 1 (T(H)1) subset, play a critical secondary defense against fungal pathogens, the adoptive transfer of functionally active antifungal T(H)1 cells might be an attractive option to restore adaptive antifungal immune effector mechanisms. Major advances have been made in the generation and characterization of antifungal T cells, which are active against medical important fungi such as Aspergillus spp and Candida spp. However, given the paucity of large homogenous patient populations, major challenges remain in evaluating the clinical usefulness of adoptive antifungal immunotherapy, which should be performed in international collaborative trials.
RESUMO
Invasive aspergillosis remains a serious complication in patients undergoing allogeneic stem cell transplantation. Since it became clear that lymphocytes provide a critical secondary defense against fungi, adoptive transfer of functionally active anti-Aspergillus T cells might be an option to restore adaptive immune effector mechanisms. Using the interferon (IFN)-gamma secretion assay, we isolated human activated T cells upon stimulation with a cellular extract of Aspergillus fumigatus. After a culturing period for 14 days, we could characterize these cells as T(H)1 cells, which also proliferated upon restimulation. The generated cells responded upon stimulation with antigens of A. flavus, A. niger and Penicillium chrysogenum, but not upon activation with Alternaria alternata and Candida albicans. In addition, the cultivated T cells were able to induce damage to A. fumigatus hyphae and showed a reduced alloreactivity compared to unselected CD4+ T cells. We further established a clinical-scale generation of anti-Aspergillus T cells. However, before performing clinical trials, open questions such as which patient population will benefit from adoptive immunotherapy with anti-Aspergillus T cells have to be addressed.
Assuntos
Aspergillus/imunologia , Células Th1/imunologia , Transferência Adotiva , Aspergilose/terapia , Células Cultivadas , Humanos , Hospedeiro Imunocomprometido , Penicillium chrysogenumRESUMO
Changes of the immune system can be a consequence of an underlying malignancy or induced by antineoplastic treatment. Both influence the risk for infectious complications and relapse. Over the past decade, there have been a series of major developments in the laboratory assessment of immune dysfunction, particularly as it relates to the complex interactions of the distinct components of the immune system. In addition, several new therapeutic strategies that modulate the immune system have been introduced. We review new findings that can affect clinical decision making. Better insights into the impairment of host response could provide the rationale for the development of new therapeutic strategies, for both supportive care and anticancer treatment.
Assuntos
Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Dendritos , Imunoterapia/tendências , Células Matadoras Naturais , Neoplasias/imunologia , Fagócitos , Linfócitos T , Antineoplásicos/efeitos adversos , Antineoplásicos/imunologia , Citotoxinas/imunologia , Dendritos/efeitos dos fármacos , Dendritos/imunologia , Dendritos/fisiologia , Humanos , Imunoterapia/métodos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Neoplasias/terapia , Fagócitos/efeitos dos fármacos , Fagócitos/imunologia , Fagócitos/fisiologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/fisiologiaRESUMO
Invasive aspergillosis remains a life-threatening complication in patients undergoing allogeneic stem cell transplantation (SCT). Since CD4(+) T-cells provide a critical secondary defense against Aspergillus spp., the quantification of "functional" anti-Aspergillus T-cells might be important in the clinical care of allogeneic transplant patients. We present a rapid, simple and reproducible method to enumerate functionally active, cytokine-producing anti-Aspergillus T-cells in peripheral blood by means of flow cytometry, by which these cells were also phenotypically characterized as memory CD4(+) T-cells. When using 100,000 PBMCs and requiring a minimum of 50 events, at least one anti-Aspergillus T-cell among 1000 CD4(+) T-cells can be detected. Compared to healthy individuals, the number of anti-Aspergillus T-cells in patients up to one year after SCT was significantly lower. The presented method might help to define hematopoietic transplant recipients who will benefit from adoptive transfer of anti-Aspergillus T cells.
Assuntos
Aspergilose/imunologia , Aspergillus fumigatus/imunologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Citometria de Fluxo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunofenotipagem/métodos , Adolescente , Adulto , Antígenos de Fungos , Aspergilose/etiologia , Aspergilose/microbiologia , Linfócitos T CD4-Positivos/microbiologia , Estudos de Casos e Controles , Células Cultivadas , Criança , Feminino , Humanos , Memória Imunológica , Masculino , Fenótipo , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
BACKGROUND: Normal values of lymphocyte subpopulations for healthy children and adults have been published in defined age groups exclusively, which results in difficult data interpretation for patients close to the limit of contiguous age group ranges. In addition, normal values for a number of lymphocyte subpopulations have not been established to date. OBJECTIVE: The aim of this study was to develop a model which provides continuous age-dependent reference values. This model was applied for lymphocyte subpopulations such as naïve and memory T cells as well as their activation profile with diagnostic relevance in children and adults. STUDY DESIGN: A total of 100 blood samples, obtained from 80 healthy children and 20 adults were analysed by means of four colour-flow cytometry. Continuous age-dependent reference values were computed based on the residual values in an exponential regression model. RESULTS: We calculated a continuous age-related regression model for both, absolute cell counts and percentages of CD3(+)CD4(+) T helper (T(H)) cells, CD3(+)CD8(+) cytotoxic T cells, CD56(+)CD3(-) natural killer (NK) cells, CD56(+)CD3(+) T cells, CD3(+)CD4(+)CD45RA(+) naïve T(H) cells, CD3(+)CD4(+)CD45RO(+) memory T(H) cells, CD3(+)CD8(+)CD45RA(+)CD28(+) naïve cytotoxic T cells, CD3(+)CD8(+)CD45RO(+) memory cytotoxic T cells, CD3(+)CD8(+)CD69(+) early activated cytotoxic T cells and CD3(+)CD8(+)HLA-DR(+) late activated cytotoxic T cells, respectively, to obtain reference values. CONCLUSION: Based on an exponential regression model, the obtained reference values reflect the continuous maturation of lymphocyte subsets during childhood.
Assuntos
Subpopulações de Linfócitos , Valores de Referência , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Lactente , Masculino , Análise de Regressão , Adulto JovemRESUMO
Natural Killer (NK) cells are involved in the host immune response against infections due to viral, bacterial and fungal pathogens, all of which are a significant cause of morbidity and mortality in immunocompromised patients. Since the recovery of the immune system has a major impact on the outcome of an infectious complication, there is major interest in strengthening the host response in immunocompromised patients, either by using cytokines or growth factors or by adoptive cellular therapies transfusing immune cells such as granulocytes or pathogen-specific T-cells. To date, relatively little is known about the potential of adoptively transferring NK cells in immunocompromised patients with infectious complications, although the anti-cancer property of NK cells is already being investigated in the clinical setting. This review will focus on the antimicrobial properties of NK cells and the current standing and future perspectives of generating and using NK cells as immunotherapy in patients with infectious complications, an approach which is promising and might have an important clinical impact in the future.
RESUMO
Invasive fungal infections are still an important cause of morbidity and mortality in immunocompromised patients such as patients suffering from hematological malignancies or patients undergoing hematopoietic stem cell transplantion. In addition, other populations such as human immunodeficiency virus-patients are at higher risk for invasive fungal infection. Despite the availability of new antifungal compounds and better supportive care measures, the fatality rate of invasive fungal infection remained unacceptably high. It is therefore of major interest to improve our understanding of the host-pathogen interaction to develop new therapeutic approaches such as adoptive immunotherapy. As experimental methodologies have improved and we now better understand the complex network of the immune system, the insight in the interaction of the host with the fungus has significantly increased. It has become clear that host resistance to fungal infections is not only associated with strong innate immunity but that adaptive immunity (e.g., T cells) also plays an important role. The antifungal activity of natural killer (NK) cells has been underestimated for a long time. In vitro studies demonstrated that NK cells from murine and human origin are able to attack fungi of different genera and species. NK cells exhibit not only a direct antifungal activity via cytotoxic molecules but also an indirect antifungal activity via cytokines. However, it has been show that fungi exert immunosuppressive effects on NK cells. Whereas clinical data are scarce, animal models have clearly demonstrated that NK cells play an important role in the host response against invasive fungal infections. In this review, we summarize clinical data as well as results from in vitro and animal studies on the impact of NK cells on fungal pathogens.
RESUMO
Mesenchymal stromal cells (MSCs) are increasingly given as immunotherapy to hematopoietic stem cell transplant (HSCT) recipients with refractory graft-versus-host disease (GvHD). Whereas the immunosuppressive properties of MSCs seem to be beneficial in GvHD, there is, at the same time, major concern that MSCs increase the risk for infection. We therefore investigated the interplay of human MSCs with Aspergillus fumigatus and the impact of MSCs on different arms of the anti-Aspergillus host response in vitro. Although A. fumigatus hyphae increase mRNA levels of IL6 in MSCs, the extracellular availability of IL-6 and other pro-inflammatory cytokines remains unaffected. Human MSCs are able to phagocyte Aspergillus conidia, but phagocytosis of conidia is not associated with an alteration of the cytokine production by MSCs. In addition, human MSCs do not affect activation and function of A. fumigatus specific CD4+ T cells, and MSCs do not negatively impact the oxidative burst activity of phagocytes. Our in vitro data indicate that administration of human MSCs is not associated with a negative impact on the host response against A. fumigatus and that the fungus does not stimulate MSCs to increase the release of those cytokines which play a central role in the pathophysiology of GvHD.
RESUMO
PURPOSE: Although nonpharmacologic anti-infective measures are widely used in children treated for acute myeloid leukemia (AML), there is little evidence of their effectiveness. PATIENTS AND METHODS: We analyzed infectious complications in children during intensive treatment of AML according to the AML-BFM 2004 trial and surveyed sites on institutional standards regarding recommended restrictions of social contacts (six items), pets (five items), and food (eight items). A scoring system was developed with a restriction score for each item. Multivariable Poisson regression adjusted for sex, age, weight group, risk stratification, and prophylactic antibiotics was used to estimate the impact of the restrictions on the incidence ratios of fever of unknown origin, bacteremia, pneumonia, and gastroenteritis. RESULTS: Data on recommendations of nonpharmacologic anti-infective measures and infectious complications were available in 339 patients treated in 37 institutions. Analyses did not demonstrate a significant benefit of any of the restrictions regarding food, social contacts, and pets on the risk of fever, bacteremia, pneumonia, and gastroenteritis. In contrast, age, weight group, risk stratification, and nonabsorbable antibiotics had some influence on infections complications. CONCLUSION: The lack of effectiveness of dietary restrictions and restrictions regarding social contacts and pets should result in reconsideration of anti-infective policies.
Assuntos
Antibacterianos/uso terapêutico , Antibioticoprofilaxia , Dieta , Controle de Infecções/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Animais de Estimação , Participação Social , Adolescente , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bacteriemia/prevenção & controle , Criança , Pré-Escolar , Feminino , Febre de Causa Desconhecida/microbiologia , Febre de Causa Desconhecida/prevenção & controle , Gastroenterite/microbiologia , Gastroenterite/prevenção & controle , Humanos , Lactente , Recém-Nascido , Masculino , Neutropenia/induzido quimicamente , Neutropenia/dietoterapia , Pneumonia/microbiologia , Pneumonia/prevenção & controle , Distribuição de Poisson , Fatores de RiscoRESUMO
Despite the availability of new antifungal compounds, invasive fungal infection remains a significant cause of morbidity and mortality in children and adults undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Allogeneic HSCT recipients suffer from a long lasting defect of different arms of the immune system, which increases the risk for and deteriorates the prognosis of invasive fungal infections. In turn, advances in understanding these immune deficits have resulted in promising strategies to enhance or restore critical immune functions in allogeneic HSCT recipients. Potential approaches include the administration of granulocytes, since neutropenia is the single most important risk factor for invasive fungal infection, and preliminary clinical results suggest a benefit of adoptively transferred donor-derived antifungal T cells. In vitro data and animal studies demonstrate an antifungal effect of natural killer cells, but clinical data are lacking to date. This review summarizes and critically discusses the available data of immunotherapeutic strategies in allogeneic HSCT recipients suffering from invasive fungal infection.
RESUMO
Despite the availability of new antifungal compounds, morbidity and mortality of invasive aspergillosis are still unacceptably high, in particular in immunocompromised patients such as patients with hematological malignancies or allogeneic hematopoietic stem cell or solid organ transplant recipients. Over the last decades, our knowledge of the immunopathogenesis of invasive aspergillosis has greatly advanced. This, in turn, provided critical information to augment host immunity against fungal pathogens. Potential approaches for enhancing the host immune system in the combat against Aspergillus include the administration of effector and regulatory cells (e.g., granulocytes, antigen-specific T cells, natural killer cells, dendritic cells) as well as the administration of recombinant cytokines, interferons and growth factors (e.g., interferon-γ,granulocyte- and granulocyte-macrophage colony stimulating factor) and various vaccination strategies. Although promising results are reported on in vitro data and animal studies, current data are too limited to allow solid conclusions on the risk and the benefit of these strategies in the clinical setting. Therefore, the real challenge in the future is to perform appropriately designed and powered clinical trials. These require international, multi-center collaboration, but may ultimately improve the outcome in immunocompromised patients suffering from invasive aspergillosis.