[Show abstract][Hide abstract] ABSTRACT: Invasive fungal disease (IFD), predominantly aspergillosis, is associated with significant morbidity and mortality in immunocompromised patients, especially those with haematological malignancies and recipients of allogeneic haematopoietic stem cell transplantation. There has been a great deal of scientific debate as to the effectiveness of antifungal prophylaxis in preventing infection in different patient groups and in which patients it is an appropriate management option. Deciding on an appropriate prophylaxis regimen for IFD is challenging as the incidence varies among different patient groups, due to the varied nature of their underlying haematological disease, and in different regions and centres. Attempts have been made to define risk factors and include them in treatment protocols. Impaired immune status of the patient, especially neutropenia, is a key risk factor for IFD and can sometimes be related to specific polymorphisms of genes controlling innate immunity. Risk factors also vary according to the type of fungal pathogen. Consequently, prophylaxis needs to be tailored to individual patient groups. Furthermore, the choice of antifungal agent for prophylaxis depends on the potential for drug-drug interactions with the patients' concomitant medications. Additional challenges are optimal timing of antifungal prophylaxis, when to change from prophylaxis to antifungal treatment and how to prevent recurrence of IFD. This article considers the use of antifungal prophylaxis for patients at risk of IFD in daily clinical practice, with clinical profiles that may be distinct from those covered by guidelines, and aims to provide practical advice for treatment of these patient groups.
[Show abstract][Hide abstract] ABSTRACT: Abstract The objective of this retrospective, multicenter study was to evaluate the efficacy and safety of micafungin as empirical antifungal therapy during febrile neutropenia (FN) in 73 hematological patients from 6 centers in two countries. All patients received 100 mg of micafungin/day. The overall favorable response rate (RR) was 64.8% when the resolution of fever during neutropenia was included in the response criteria and 84.5% when excluded. A significantly lower favorable RR in patients with persistent fever and non-specific pulmonary infiltrates compared to patients with persistent fever only (82.8 vs. 52.4%, respectively; p = 0.011) was not found when resolution of fever was not included in the composite endpoint criteria (93.1 vs. 78.6%, respectively; p = 0.180). Breakthrough fungal disease developed in 2.7% patients. Treatment was discontinued in 16.4% of cases. Only one patient (1.4%) discontinued therapy due to an adverse event. Posaconazole prophylaxis improved favorable RR when defervescence was included as composite endpoint criteria (p = 0.047), but not when it was excluded (p = 0.485). However, neutrophil recovery did not influence favorable RR (p = 0.803 and p = 0.112, respectively). These data suggest that micafungin is safe and effective as an empirical therapy in patients with FN.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: To evaluate risk factors, diagnostic procedures, and treatment outcomes of invasive aspergillosis (IA) in patients with hematological malignancies. METHODS: A retrospective analysis of data from proven/probable IA cases that occurred from 2005 to 2009 at 10 hematology centers was performed. RESULTS: We identified 176 IA cases that mainly occurred in patients with acute leukemias (58.5%), mostly those on induction/re-induction treatments (39.8%). Prolonged neutropenia was the most frequent risk factor for IA (61.4%). The lungs were the most frequently affected site (93.8%) and computed tomography detected abnormalities in all episodes; however, only 53.7% of patients had findings suggestive of IA. Galactomannan (GM) detection in serum or bronchoalveolar lavage fluid (positive in 79.1% and 78.8% of episodes, respectively) played a crucial role in IA diagnosis. Neutrophil count and antifungal prophylaxis did not influence the GM positivity rate, but empirical therapy decreased this rate (in serum). Of the IA cases, 53.2% responded to initial antifungal therapy. The combination of voriconazole and echinocandin, even as initial or salvage therapy, did not perform better than voriconazole monotherapy (p=0.924 for initial therapy and p=0.205 for salvage therapy). Neutrophil recovery had a significant role in the response to initial (but not salvage) antifungal therapy. CONCLUSIONS: Our retrospective analysis identified key diagnostic and treatment characteristics, and this understanding could improve the management of hematological malignancy patients with IA.
International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 10/2012; · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this retrospective study was to evaluate results from voriconazole therapeutic drug monitoring (TDM) in haematological patients in routine clinical practice. Between 2005 and 2010, 1228 blood samples were obtained from 264 haematological patients (median 3 samples/patient; range 1-27) receiving voriconazole for targeted/preemptive treatment of invasive aspergillosis (IA) (46.3% of samples), empirical therapy (12.9%) or prophylaxis (40.8%). A high-pressure liquid chromatography assay was used to analyse voriconazole concentrations. Clinical and laboratory data were analysed retrospectively. The median of the detected voriconazole plasma concentration was 1.00 μg ml(-1) (range <0.20-13.47 μg ml(-1) ). Significant inter- and intra-patients variability of measured concentrations (81.9% and 50.5%) were identified. With the exception of omeprazole administration, there was no relevant relationship between measured voriconazole concentrations and drug dose, route administration, age, gender, CYP2C19*2 genotype, gastrointestinal tract abnormality, administration via nasogastric tube, serum creatinine, and liver enzymes. However, per patient analysis identified significant role of individual voriconazole dose and drug form change on measured plasma concentration. Measured voriconazole concentrations did not correlate with the treatment outcome of patients with IA. We only identified a limited number of adverse events related to voriconazole therapy; however, the median plasma concentration was not different from concentrations measured in samples without reported toxicity. Our retrospective study has suggested that routine monitoring of voriconazole plasma concentrations has probably only a limited role in daily haematological practice.
[Show abstract][Hide abstract] ABSTRACT: We investigated the impact of ABO and Rhesus (Rh) blood group matching on the outcome of hematopoietic stem cell transplantation (HSCT) of 154 patients matched at 10/10 HLA loci with unrelated donors. ABO and Rh, as potential risk factors, were modeled with the clinical outcome--acute and chronic graft-versus-host disease (aGVHD, cGVHD), relapse, treatment-related mortality (TRM), and overall survival (OS)--by simple, multiple, and competing risk analyses. We found that minor ABO-mismatches represent a significant risk factor for aGVHD (II-IV) with an estimated risk increase of almost 3-fold (hazard ratio [HR]=2.92, 95% confidence interval [CI]: 1.43-5.95, P=.003), and even 4-fold for aGVHD (III-IV) (HR=4.24, 95% CI: 1.70-10.56, P=.002), but not for other transplant endpoints. No significant association of the Rh matching status with any of the HSCT endpoints was seen. These results suggest that ABO minor mismatches may play a role in aGvHD pathophysiology, possibly by providing the setting for T cell activation and antibody mediated damage. To decrease the risk of aGVHD, ABO matching should be considered in HSCT.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2009; 15(11):1400-6. · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: C/EBPalpha (CCAAT/enhancer binding protein alpha) belongs to the family of leucine zipper transcription factors and is necessary for transcriptional control of granulocyte, adipocyte and hepatocyte differentiation, glucose metabolism and lung development. C/EBPalpha is encoded by an intronless gene. CEBPA mutations cause a myeloid differentiation block and were detected in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), multiple myeloma and non-Hodgkin's lymphoma (NHL) patients. In this study we identified in 41 individuals from 824 screened individuals (290 AML patients, 382 MDS patients, 56 NHL patients and 96 healthy individuals) a single class of 23 deletions in CEBPA gene which involved a direct repeat of at least 2 bp. These mutations are characterised by the loss of one of two same repeats at the ends of deleted sequence. Three most frequent repeats included in these deletions in CEBPA gene are CGCGAG (493-498_865-870), GCCAAGCAGC (508-517_907-916) and GG (486-487_885-886), all according to GenBank accession no. NM_004364.2. A mechanism for deletion formation between two repetitive sequences can be recombination events in the repair process. Double-stranded cut in DNA can initiate these recombination events of adjacent DNA sequences.
[Show abstract][Hide abstract] ABSTRACT: Interactions of polymorphic killer Ig-like receptor (KIR) receptors with KIR ligands have been shown to modify the outcome of hematopoietic SCT (HSCT). The association of these genetic factors with different transplantation endpoints, however, varies substantially, depending on clinical and study setup variables. We aimed to assess whether KIR ligands, KIR genes and KIR haplotypes are associated with HSCT outcome of 124 patients with various hematological malignancies, transplanted with 12/12 HLA matched grafts from unrelated donors. For this purpose, patient and donor KIR gene and KIR ligand polymorphisms were determined and correlated with clinical data in simple and multiple models. We found that a missing HLA-C2 ligand for donor inhibitory KIR2DL1 was significantly associated with an increased risk of acute GVHD (aGVHD) (II-IV) (hazard ratio (HR)=2.23, 95% confidence interval (95% CI): 1.21-4.10, P=0.010), as were the AA KIR haplotypes in patients and donors in HLA-C1CX (HR=2.37, 95% CI: 1.16-4.84, P=0.018) and in HLA-Bw4(-) (HR=3.20, 95% CI: 1.35-7.60, P=0.008) patients. On the contrary, transplantation of HLA-C1C2 patients with KIR2DS2 positive grafts were associated with a decreased risk of aGVHD (II-IV) (HR=0.24, 95% CI: 0.07-0.85, P=0.027). Thus, our single center study provides evidence for the modification of aGVHD risk by KIRs and their ligands.
Bone marrow transplantation 02/2009; 44(2):97-103. · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: National working group representing clinicians (hematologists, oncologists, infection diseases and ICU specialists), microbiologists, and different special medical societies and working groups prepared evidence-based guidelines for the treatment established fungal infection--invasive candidiasis in the adult hematology and ICU patients. These guidelines updated those published in the Czech Republic in 2003-2004. Evidence criteria of the Infectious Diseases Society of America (IDSA) were used for assessing the quality of clinical trials, and EORTC/MSG Consensus Group for definitions of invasive fungal disease.
[Show abstract][Hide abstract] ABSTRACT: An increasing incidence of invasive aspergillosis is observed in most immunocompromised patients, and especially patients with acute leukemia and after hematopoietic stem cell transplantation. In order to decrease the mortality due to this infection, the clinicians need to optimise their treatment choice. The objective of these guidelines is to summarize the current evidence for treatment of invasive aspergillosis. The recommendations have been developed by an expert panel following an evidence-based search of literature with regard to current recommendation of European Conference in Infections in Leukemia and Infectious Diseases Society of America.
[Show abstract][Hide abstract] ABSTRACT: The interpretation of the role of HLA-DPB1 in unrelated haematopoietic stem cell transplantation (HSCT) is subject to discussion. We have investigated the role of HLA-DPB1 allele matching in HSCT outcomes in 161 recipients who were HLA-A, -B, -C, -DRB1 and -DQB1-matched with their unrelated donors at the allelic level (10/10). In addition, we analysed the association of polymorphic amino acid mismatches of DPB1 molecule with HSCT end-points, and a previously published permissiveness concept. HLA-DPB1 allele mismatches were significantly associated with an increased incidence of acute graft-versus-host disease (aGvHD) and worse overall survival (OS). The mismatch at amino acid position 69 significantly increased the risk for transplant-related mortality (TRM). Risk factors for aGvHD also included mismatches at positions 8, 9, 35, 76 and 84. This is to our knowledge, the first report of an in vivo effect of single amino acid mismatches on HSCT outcomes. In this study, grouping of allelic mismatches into permissive and non-permissive categories and their association with transplantation end-points was relevant for TRM but not for other clinical end-points.
British Journal of Haematology 07/2008; 142(3):436-43. · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT) and a leading cause of non-relapse mortality (NRM). Currently, biology-based markers are lacking both for diagnosis and for monitoring the activity of cGVHD. Seventy patients who received HSCT were enrolled in a pilot study, including 21 without cGVHD and 49 with active or resolved cGVHD. Evaluations were comprised of clinical parameters including cGVHD severity and infections. Peripheral blood cells were analyzed by multi-parameter flow cytometry. The CD19+ B cell compartment was further subdivided by staining for surface IgD, CD21 and CD27. No significant differences in absolute B, T, and natural killer (NK) cell numbers were observed between the groups with and without cGVHD. However, elevated numbers (>15% of B lymphocytes) of immature/transitional CD19+/CD21(-) B cells were associated with the occurrence of severe infections (P = .003). Most significantly, all patients with active cGVHD and elevated numbers of CD19+/CD21(-) B lymphocytes experienced severe infections (P = .00016). The numbers of both non-class-switched and class-switched memory B cells were significantly lower in patients with active cGVHD when compared to patients who never experienced cGVHD (P = .002 and P = .001). Perturbation of circulating B lymphocyte compartments may serve as a novel biomarker for monitoring cGVHD activity and its impact on the immune system. A prospective study on unselected patients assessed serially for B cell reconstitution after HSCT is warranted.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2008; 14(2):208-19. · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report a fifty-year-old woman presenting with severe aplastic anaemia (SAA) and prolonged high Human Herpesvirus 6 (HHV6) variant A DNAeamia detected by quantitative PCR. Multiple antiviral treatments failed to affect the HHV6 DNAemia and subsequent immunosuppressive treatment reached only partial improvement as judged by bone marrow examinations. The patient remained dependent on thrombocyte transfusions and G-CSF treatment. After one year of steady high HHV6 DNA load in blood, viral chromosomal integration was proved by demonstrating the viral DNA in hair follicles. This condition appeared to be unconnected with, and to have no effect, on the original SAA.
[Show abstract][Hide abstract] ABSTRACT: Purpose: Introduction: Bone Marrow Transplantation because of Leukemia is followed by changes of the immunological system. Patients suffer from complaints of the disease and its consequences, like Graft versus host reactions. In ophthalmologic observations we often can asses chronic inflammations with dry eyes. Those are induced by stress reaction, any kind of inflammation and any kind of irritations.Now we wanted to know, if there is a correlation of the ophthalmological changes, especially the dryness and the mental state, according to the bone marrow transplantation.Methods: 26 patients were observed, 11 of them in a follow up after 100 days. For ocular evaluations slit lamp obeservation were done. Severeness of Dryness was defined by a Sicca-Score, a mean of results of Schirmer‘s test, break up time, lipid layer thickness, and estimation of the tear meniscus. All results were equated. 0 for normal and 1 for worst possible result.Psychiatric symptoms were assesed by the symptom check list 90R (Derogatis) at baseline and follow up. We compared the results before and 100 days after the transplantation. For statistical analysis students-T-test and the Pearson correlation by SPSS was used.Results: There was a significant aggravation of the dryness in one eye; and there was a correlation in parts of the records between the dryness and the mental state.Conclusions: Bone marrow transplantation is an event, which influences the immunological system, the tearing system and the mental state of health.
[Show abstract][Hide abstract] ABSTRACT: Incidence of Gram-positive infections caused by bacteria resistant to commonly used antibiotics has increased in the last decades. Resistant strains appeared later in the Czech Republic, however their number has been increasing and new antibiotics have to be used. The greatest increase of frequency can be seen in infections caused by methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci. Vancomycin-resistant enterococci are usually found in hematooncology patients. Curative use of vancomycin is limited due to a narrow spectrum of activity, nephrotoxicity, and limited penetration into tissues (lung) and cerebrospinal fluid. Linezolid is a good option mainly in infections of skin and soft tissues, and it has an evincible advantage over vancomycin in the treatment of nosocomial pneumonia and surgical-site infections. Oral formulations are favourable allowing switch therapy and earlier discharge from hospital.
Klinicka mikrobiologie a infekcni lekarstvi 03/2006; 12(1):4-9.