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The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient's risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information. [ABSTRACT FROM AUTHOR]

Although various guidelines on antifungal prophylaxis and treatment have been published, the practical approach in the individual clinical setting might considerably differ because of special local circumstances. In addition, there are major differences between paediatric and adult patients regarding antifungal strategies and the use of antifungal compounds. We here present the antifungal approach in the Departments of Hematology and Oncology of the University Hospital of Frankfurt, where per year approximately 350 children and adults are diagnosed with cancer and an additional 100 patients undergo haematopoietic stem cell transplantation. The differences in the approach between the paediatric and adult setting are highlighted. [ABSTRACT FROM AUTHOR]

Background. With the advent of new antifungal agents, the identification of a causative pathogen is crucial to guide the antifungal treatment of invasive mold infection. However, tissue cultures often fail to grow a fungal pathogen in cases of suspected mold infection. Methods. In a prospective multicenter study, we compared the results of histopathological analysis, culture, and 2 seminested polymerase chain reaction assays identifying Aspergillus species and Zygomycetes as causative agents of invasive mold infections using respiratory tract biopsy samples obtained from 56 immuno-compromised patients who had suspected mold infection. Results. Mold hyphae were detected histopathologically in 27 (48%) of the tissue specimens. Hyphae corresponded to either aspergillosis (n = 18) or zygomycosis (n = 6) or could not be further specified (n = 3). A mold was cultured from 14 of 18 samples with aspergillus hyphae, 2 of 6 samples with Zygomycetes hyphae, and 1 of 3 samples with unspecified hyphae. Polymerase chain reaction was superior to culture in detecting the infecting mold (26 of 27 samples vs. 17 of 27 samples, respectively; P = .006) from histopathologically positive samples. Genus or species identification by sequencing of the polymerase chain reaction products were in accordance with culture results in 16 of 18 culture-positive samples. Both polymerase chain reaction assays failed to detect fungal DNA in 1 sample that had unspecified hyphae and negative culture results. Conclusion. The PCR assays offer a reliable etiologic diagnosis that is superior to culture in patients with proven invasive mold infection. This may improve patient management through tailored antifungal therapy when cultures fail to grow a pathogen. [ABSTRACT FROM AUTHOR]

Patients with haematological malignancies and prolonged periods of neutropenia after chemotherapy are at high risk for severe bacterial and fungal infections. Those infections have long time been considered as a contraindication for subsequent haematopoietic stem cell transplantation (HCT). We conducted a prospective, non-randomized study of granulocyte transfusions (GTX) to control acute life-threatening infections (44 episodes) and to prevent recurrence of severe fungal infections during HCT or intensive chemotherapy (23 episodes). GTX achieved control in 82% (36/44) of acute life-threatening infections. No single reactivation of a previous infection occurred under prophylactic GTX (0/23). Median survival was 170 days in the interventional group and 185 days in the prophylactic group; death in both patient groups was mainly due to underlying progressive malignant disease. We conclude that under GTX, the infection-related mortality even in high-risk patients is low. Due to a secondary prophylaxis with GTX, haematopoietic allografts can be safely given to patients with previous fungal infections. [ABSTRACT FROM AUTHOR]

Objectives: To describe changes in costs of managing hospitalised patients with acute myeloid leukaemia (AML) after chemotherapy in Germany over 3 yr, with a special focus on prophylaxis and treatment patterns as well as resource use related to invasive fungal infections (IFI). Methods: The study was conducted as a retrospective, single-centre chart review in patients with AML hospitalised for chemotherapy, neutropenia and infections after myelosuppressive chemotherapy from January 2004 to December 2006 in Germany. The following resource utilisation data were collected: inpatient stay, mechanical ventilation, parenteral feeding, diagnostics, systemic antifungal medication and cost-intensive concomitant medication. Direct medical costs were calculated from hospital provider perspective. Results: A total of 471 episodes in 212 patients were included in the analysis. Occurrence of IFI decreased from 5.9% in 2004 to 1.9% in 2006. Mean (±standard deviation) hospital stay decreased from 28.7 ± 17.9 d in 2004 to 22.4 ± 11.8 d in 2006. From 2004 to 2006, the use of a single antifungal drug increased from 30.4% to 46.9%, whereas the use of multiple antifungal drugs decreased from 24.4% to 13.1%. The use of liposomal amphotericin B declined between 2004 and 2006 (21.4% vs. 3.8%) and caspofungin between 2005 and 2006 (19.3% vs. 8.1%). Total costs per episode declined from €19 051 ± 19 024 in 2004 to €13 531 ± 9260 in 2006; major reductions were observed in the use of antimycotics and blood products as well as length of hospital stay. Conclusion: Analysis of real-life data from one single centre in Germany demonstrated a change in antifungal management of patients with AML between 2004/2005 and 2006, accompanied by a decline in total costs. [ABSTRACT FROM AUTHOR]

Seroconversion rates following influenza vaccination in patients with hematologic malignancies after hematopoietic stem cell transplantation (HSCT) are known to be lower compared to healthy adults. The aim of our diagnostic study was to determine the rate of seroconversion after 1 or 2 doses of a novel split virion, inactivated, AS03-adjuvanted pandemic H1N1 influenza vaccine (A/California/7/2009) in HSCT recipients (ClinicalTrials.gov Identifier: NCT01017172). Blood samples were taken before and 21 days after a first dose and 21 days after a second dose of the vaccine. Antibody (AB) titers were determined by hemagglutination inhibition assay. Seroconversion was defined by either an AB titer of ≤1:10 before and ≥1:40 after or ≥1:10 before and ≥4-fold increase in AB titer 21 days after vaccination. Seventeen patients (14 allogeneic, 3 autologous HSCT) received 1 dose and 11 of these patients 2 doses of the vaccine. The rate of seroconversion was 41.2% (95% confidence interval [CI] 18.4-67.1) after the first and 81.8% (95% CI 48.2-97.7) after the second dose. Patients who failed to seroconvert after 1 dose of the vaccine were more likely to receive any immunosuppressive agent (P = .003), but time elapsed after or type of HSCT, age, sex, or chronic graft-versus-host disease was not different when compared to patients with seroconversion. In patients with hematologic malignancies after HSCT the rate of seroconversion after a first dose of an adjuvanted H1N1 influenza A vaccine was poor, but increased after a second dose. [Copyright &y& Elsevier]

The article offers information on a medical research in which long term outcome of patients with steroid-refractory acute intestinal graft versus host disease after treatment with pentostatin was seen. It is stated that acute graft-versus-host disease (aGvHD) of the gastrointestinal tract is a major complication after allogeneic stem cell transplantation. It was concluded that the outcome of patients who fail firstline therapy with steroids is poor and no standard therapy has been developed.

Infectious complications after allogeneic haematopoietic stem cell transplantation (allo-HCT) remain a clinical challenge. This is a guideline provided by the AGIHO (Infectious Diseases Working Group) of the DGHO (German Society for Hematology and Medical Oncology). A core group of experts prepared a preliminary guideline, which was discussed, reviewed, and approved by the entire working group. The guideline provides clinical recommendations for the preventive management including prophylactic treatment of viral, bacterial, parasitic, and fungal diseases. The guideline focuses on antimicrobial agents but includes recommendations on the use of vaccinations. This is the updated version of the AGHIO guideline in the field of allogeneic haematopoietic stem cell transplantation utilizing methods according to evidence-based medicine criteria. [ABSTRACT FROM AUTHOR]

Abstract: To assess current clinical practice in diagnosis and treatment of acute graft-versus-host disease (aGVHD), we performed a survey among German, Austrian, and Swiss allogeneic hematopoietic stem cell transplantation (allo-HSCT) centers. Thirty-four of 72 contacted centers (47%) completed both the diagnostic and therapeutic sections of the survey, representing 65% of allo-HSCT activity within the participating countries in 2011. Three pediatric centers answered as requested only the diagnostic part of the survey. In the presence of diarrhea and decreased oral intake after engraftment, only 4 centers (12%) do not perform any endoscopy before the start of immunosuppressive treatment. In case of a skin rash with the differential diagnosis of drug reaction, only 12 centers (35%) perform a skin biopsy up front, whereas 19 do so after failure of systemic steroids. In the presence of rapidly increasing cholestasis occurring without any other signs of aGVHD, 11 centers (32%) perform a liver biopsy up front and 14 only after failure of steroid treatment, whereas 9 centers do not perform a liver biopsy at all. Twenty centers (59%) use a percutaneous approach, 12 a transvenous approach, and 1 mini-laparoscopy for liver biopsies. First-line treatment of cutaneous aGVHD stage 1 consists of topical treatment alone in 17 of 31 responding centers (61%), whereas isolated cutaneous aGVHD stage III is treated with systemic steroids (prednisolone below 0.5 mg/kg/day n = 2, 0.5 to 1.0 mg/kg/day n = 10, above 1.0 to 2.5 mg/kg/day n = 19) without or with topical agents (steroids n = 10; calcineurin inhibitors n = 3). In gastrointestinal manifestations of aGVHD, 9 centers (29%) add topical to systemic steroids, and 3 consider topical steroids as the only treatment for mild gastrointestinal and cutaneous aGVHD. The choice of agent for second-line treatment as well as the sequence of administration are extremely heterogeneous, most likely due to a lack of convincing data published. Most frequently used are mycophenolate mofetil (n = 14) and extracorporeal photopheresis (n = 10). Our survey also demonstrates that clinicians chose salvage therapies for steroid-refractory aGVHD based on their centers'' own clinical experience. [Copyright &y& Elsevier]

Antifungal prophylaxis during first remission induction chemotherapy for acute myelogenous leukaemia requires broad spectrum azoles. In a clinical trial, therapeutic drug monitoring (TDM) of antifungal prophylaxis with voriconazole 200 mg bid was evaluated in a population of six patients. High pressure liquid chromatography was applied. Trough levels were obtained 24 h after the last voriconazole dose. Median time of voriconazole exposure prior to sample acquisition was 16 days (range 9-21). The mean voriconazole concentration was 486 μg l and ranged from 136 μg l to 1257 μg l. Among possible or probable treatment-related adverse events, elevated liver function tests were the most frequent. Five of six patients developed fever during neutropenia, but none of them developed pulmonary infiltrates or other signs of invasive fungal infection while on voriconazole prophylaxis. Future investigations might aim at identifying drug level thresholds that allow for minimum toxicity and optimum efficacy of antifungal prophylaxis. [ABSTRACT FROM AUTHOR]

Catheter-related infections (CRI) cause considerable morbidity in hospitalized patients. The incidence does not seem to be higher in neutropenic patients than in nonneutropenic patients. Gram-positive bacteria (coagulase-negative staphylococci, Staphylococcus aureus) are the pathogens most frequently cultured, followed by Candida species. Positive blood cultures are the cornerstone in the diagnosis of CRIs, while local signs of infection are not necessarily present. Blood cultures should be taken from peripheral blood and from the venous catheter. A shorter time to positivity of catheter blood cultures as compared with peripheral blood cultures supports the diagnosis of a CRI. In many cases, a definite diagnosis requires catheter removal and microbiological analysis. The role plate method with semiquantitative cultures has been established as standard in most laboratories. Antimicrobial treatment of CRI should be directed by the in vitro susceptibility of the isolated pathogen. Primary removal of the catheter is mandatory in S. aureus and Candida infections, as well as in case of tunnel or pocket infections. Future studies will elucidate whether the rate of CRI in neutropenic patients may be reduced by catheters impregnated with antimicrobial agents. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

In a pilot study high-dose melphalan (HD-Mel, 200 mg/m2) and autologous stem cell transplantation (ASCT) were administered to 14 patients (median age 52, range 29–60 years) with acute myeloid leukaemia (AML) in first relapse after a previous ASCT in first complete remission ( n=11) or chemotherapy ( n=3). A first cohort of five patients received HD-Mel as salvage therapy after a previous cycle of mitoxantrone, topotecan and cytarabine (MTC) had failed in four out of five patients, while a second cohort of nine patients received HD-Mel in untreated relapse. Thirteen (93%) of 14 patients achieved a second complete remission (CR2), including all four patients who had been refractory to MTC. No treatment-related mortality was observed after HD-Mel. Thirteen (93%) patients were able to proceed to a dose-reduced allogeneic stem cell transplantation (allo-SCT) from human-leucocyte-antigens-compatible unrelated ( n=12) or sibling donors ( n=1) in CR2 ( n=11) or poor recovery/relapse ( n=2) after a median of 2 (1.7–4.5) months following HD-Mel. Three MTC-refractory patients, but none of the upfront HD-Mel patients, died due to an allograft-related non-relapse cause. Nine patients are alive in CR2 after a median of 6 (2–49) months after HD-Mel and a median of 4 (0.6–47) months after a sequential allo-SCT. Although median follow-up is still short, the proportion of patients achieving a CR2, as well as of those proceeding to a subsequent reduced-intensity-conditioning-allo-SCT, is superior to those previously reported. Our results highly encourage to further investigate HD-Mel and ASCT as a promising salvage regimen for relapsed AML patients for whom autologous peripheral blood stem cells are available. [ABSTRACT FROM AUTHOR]