Clinical features and prognostic factors of Magnusiomyces (Saprochaete) infections in haematology. A multicentre study of SEIFEM/Fungiscope.

BACKGROUND: Our multicentre study aims to identify baseline factors and provide guidance for therapeutic decisions regarding Magnusiomyces-associated infections, an emerging threat in patients with haematological malignancies. METHODS: HM patients with proven (Magnusiomyces capitatus) M. capitatus or (Magnusiomyces clavatus) M. clavatus (formerly Saprochaete capitata and Saprochaete clavata) infection diagnosed between January 2010 and December 2020 were recorded from the SEIFEM (Sorveglianza Epidemiologica Infezioni nelle Emopatie) group and FungiScope (Global Emerging Fungal Infection Registry). Cases of Magnusiomyces fungemia were compared with candidemia. RESULTS: Among 90 Magnusiomyces cases (60 [66%] M. capitatus and 30 (34%) M. clavatus), median age was 50 years (range 2-78), 46 patients (51%) were female and 67 (74%) had acute leukaemia. Thirty-six (40%) of Magnusiomyces-associated infections occurred during antifungal prophylaxis, mainly with posaconazole (n = 13, 36%) and echinocandins (n = 12, 34%). Instead, the candidemia rarely occurred during prophylaxis (p < .0001). First-line antifungal therapy with azoles, alone or in combination, was associated with improved response compared to other antifungals (p = .001). Overall day-30 mortality rate was 43%. Factors associated with higher mortality rates were septic shock (HR 2.696, 95% CI 1.396-5.204, p = .003), corticosteroid treatment longer than 14 days (HR 2.245, 95% CI 1.151-4.376, p = .018) and lack of neutrophil recovery (HR 3.997, 95% CI 2.102-7.601, p < .001). The latter was independently associated with poor outcome (HR 2.495, 95% CI 1.192-5.222, p = .015). CONCLUSIONS: Magnusiomyces-associated infections are often breakthrough infections. Effective treatment regimens of these infections remain to be determined, but neutrophil recovery appears to play an important role in the favourable outcome.

The role of palliative care in acute care setting.

While terminal palliative care focuses primarily on the management of symptoms of immediate dying, early palliative care provides an opportunity for the patient and his loved ones to understand the trajectory of the illness, to receive support for coping with the diagnosis, increase the quality of decision-making to match the patients values and preferences. The emphasis is on realistic expectations of the outcome of treatment and timely anticipation of further disease course. The paper focuses on an overview of the evidence of palliative and supportive interventions, comparing the different trigger mechanisms for palliative intervention and presents the content of the intervention of the palliative team. The establishment and integration of the consultative palliative team in the tertiary hospital is described. An illustrative care report describes the goals of care conversation and its impact on advance care planning. Palliative care is widely accepted and recommended standard of high quality care for seriously ill patients. In the Czech Republic, it is necessary to extend its availability for patients hospitalized in acute care setting.

Proven Invasive Pulmonary Aspergillosis in Stem Cell Transplant Recipient Due to Aspergillus sublatus, a Cryptic Species of A. nidulans.

Invasive fungal disease represents one of the severe complications in haematopoietic stem cell transplant recipients. We describe a case of a patient treated for relapse of chronic lymphoblastic leukaemia 6 years after HSCT. The patient was treated for invasive pulmonary aspergillosis but died 3 months later from multiple organ failures consisting of haemorrhagic necrotizing fungal pneumonia, refractory chronic hepatic graft versus host disease and cytomegalovirus hepatitis. Autopsy samples revealed histopathological evidence of fungal hyphae and an unusual Aspergillus nidulans-like species was isolated in pure culture. More precise identification was achieved by using scanning electron microscopy of ascospores and sequencing of calmodulin gene, and the isolate was subsequently re-identified as A. sublatus (section Nidulantes) and showed good in vitro susceptibility against all classes of antifungals. Commonly used ITS rDNA region and ß-tubulin gene fail to discriminate A. sublatus from related pathogenic species, especially A. quadrilineatus and A. nidulans. Although this is the first case of proven IPA attributed to A. sublatus, we demonstrated that at least some previously reported infections due to A. quadrilineatus were probably caused by this cryptic species.

Preventing invasive fungal disease in patients with haematological malignancies and the recipients of haematopoietic stem cell transplantation: practical aspects.

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.

Monitoring trough voriconazole plasma concentrations in haematological patients: real life multicentre experience.

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.

Minor ABO-mismatches are risk factors for acute graft-versus-host disease in hematopoietic stem cell transplant patients.

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.

Nature of frequent deletions in CEBPA.

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.

Elevated numbers of immature/transitional CD21- B lymphocytes and deficiency of memory CD27+ B cells identify patients with active chronic graft-versus-host disease.

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.

Impact of HLA-DPB1 allelic and single amino acid mismatches on HSCT.

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.

Role of linezolid in the treatment of resistant gram-positive infections.

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.

Micafungin as empirical antifungal therapy in hematological patients: a retrospective, multicenter study in the Czech and Slovak Republics.

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 six 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% of 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 criterion (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.

Invasive aspergillosis in patients with hematological malignancies in the Czech and Slovak republics: Fungal InfectioN Database (FIND) analysis, 2005-2009.

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.