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Background: This meta-analysis examines the comparative diagnostic performance of polymerase chain reaction (PCR) for the diagnosis of Pneumocystis pneumonia (PCP) on different respiratory tract samples, in both human immunodeficiency virus (HIV) and non-HIV populations., Methods: A total of 55 articles met inclusion criteria, including 11 434 PCR assays on respiratory specimens from 7835 patients at risk of PCP. QUADAS-2 tool indicated low risk of bias across all studies. Using a bivariate and random-effects meta-regression analysis, the diagnostic performance of PCR against the European Organisation for Research and Treatment of Cancer-Mycoses Study Group definition of proven PCP was examined., Results: Quantitative PCR (qPCR) on bronchoalveolar lavage fluid provided the highest pooled sensitivity of 98.7% (95% confidence interval [CI], 96.8%-99.5%), adequate specificity of 89.3% (95% CI, 84.4%-92.7%), negative likelihood ratio (LR-) of 0.014, and positive likelihood ratio (LR+) of 9.19. qPCR on induced sputum provided similarly high sensitivity of 99.0% (95% CI, 94.4%-99.3%) but a reduced specificity of 81.5% (95% CI, 72.1%-88.3%), LR- of 0.024, and LR+ of 5.30. qPCR on upper respiratory tract samples provided lower sensitivity of 89.2% (95% CI, 71.0%-96.5%), high specificity of 90.5% (95% CI, 80.9%-95.5%), LR- of 0.120, and LR+ of 9.34. There was no significant difference in sensitivity and specificity of PCR according to HIV status of patients., Conclusions: On deeper respiratory tract specimens, PCR negativity can be used to confidently exclude PCP, but PCR positivity will likely require clinical interpretation to distinguish between colonization and active infection, partially dependent on the strength of the PCR signal (indicative of fungal burden), the specimen type, and patient population tested., Competing Interests: Potential conflicts of interest. A. A. has received honoraria from Gilead Sciences. S. C.-A. A. has received united educational grants from F2G Ltd and consulted for MSD Australia. T. R. R. has received grants from Pfizer and the Irish Department of Agriculture, Food and the Marine and honoraria from Gilead and Menarini Pharma. P. L. W. has performed diagnostic evaluations and received meeting sponsorship from Associates of Cape Cod, Bruker, Dynamiker, and Launch Diagnostics; speaker fees, expert advice fees, and meeting sponsorship from Gilead; and speaker and expert advice fees from F2G. J. P. D. has received personal fees from F2G, Gilead Sciences, and Pfizer. W. J. H. has received lecture honoraria from AbbVie, Amgen, AstraZeneca, Celgene/BMS, Gilead Sciences, Janssen, MSD, and Pfizer; has received support to attend meetings and travel support from AbbVie, Alexion, Astellas, Janssen, Lilly, MSD, Novartis, and Pfizer; and has participated on advisory boards for AbbVie, Amgen, AstraZeneca, Basilea, Celgene/BMS, Gilead Sciences, Janssen, and Sanofi-Aventis. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

This overview of reviews (i.e., an umbrella review) is designed to reappraise the validity of systematic reviews (SRs) and meta-analyses related to the performance of Aspergillus PCR tests for the diagnosis of invasive aspergillosis in immunocompromised patients. The methodological quality of the SRs was assessed using the AMSTAR-2 checklist; the quality of the evidence (QOE) within each SR was appraised following the GRADE approach. Eight out of 12 SRs were evaluated for qualitative and quantitative assessment. Five SRs evaluated Aspergillus PCR on bronchoalveolar lavage fluid (BAL) and three on blood specimens. The eight SRs included 167 overlapping reports (59 evaluating PCR in blood specimens, and 108 in BAL), based on 107 individual primary studies (98 trials with a cohort design, and 19 with a case-control design). In BAL specimens, the mean sensitivity and specificity ranged from 0.57 to 0.91, and from 0.92 to 0.97, respectively (QOE: very low to low). In blood specimens (whole blood or serum), the mean sensitivity ranged from 0.57 to 0.84, and the mean specificity from 0.58 to 0.95 (QOE: low to moderate). Across studies, only a low proportion of AMSTAR-2 critical domains were unmet (1.8%), demonstrating a high quality of methodological assessment. Conclusions. Based on the overall methodological assessment of the reviews included, on average we can have high confidence in the quality of results generated by the SRs.

Background: Empiric antifungal therapy is considered the standard of care for high-risk neutropenic patients with persistent fever. The impact of a preemptive, diagnostic-driven approach based on galactomannan screening and chest computed tomography scan on demand on survival and on the risk of invasive fungal disease (IFD) during the first weeks of high-risk neutropenia is unknown., Methods: Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and allogeneic hematopoietic cell transplant recipients were randomly assigned to receive caspofungin empirically (arm A) or preemptively (arm B), while receiving fluconazole 400 mg daily prophylactically. The primary end point of this noninferiority study was overall survival (OS) 42 days after randomization., Results: Of 556 patients recruited, 549 were eligible: 275 in arm A and 274 in arm B. Eighty percent of the patients had AML or MDS requiring high-dose chemotherapy, and 93% of them were in the first induction phase. At day 42, the OS was not inferior in arm B (96.7%; 95% confidence interval [CI], 93.8%-98.3%) when compared with arm A (93.1%; 95% CI, 89.3%-95.5%). The rates of IFDs at day 84 were not significantly different, 7.7% (95% CI, 4.5%-10.8%) in arm B vs 6.6% (95% CI, 3.6%-9.5%) in arm A. The rate of patients who received caspofungin was significantly lower in arm B (27%) than in arm A (63%; P < .001)., Conclusions: The preemptive antifungal strategy was safe for high-risk neutropenic patients given fluconazole as prophylaxis, halving the number of patients receiving antifungals without excess mortality or IFDs. Clinical Trials Registration. NCT01288378; EudraCT 2010-020814-27., Competing Interests: Potential conflicts of interest. J. M. reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD, Gilead Sciences, and Pfizer, including participation on a data and safety monitoring board or advisory board (DSMB) for MSD, Gilead, and Pfizer. T. L. reports payment for participation on virtual European Society for Blood and Marrow Transplantation meeting. J. P. D. reports consulting fees from F2G and Gilead Sciences, including payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from F2G, Gilead Sciences, and Pfizer, and unpaid leadership or fiduciary role in other board, society, committee, or advocacy group for the European PCR Initiative Foundation. C. R. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead and Sandoz and support for attending meetings and/or travel for Gilead, MSD, Pfizer, and Sandoz. N. B. reports participation as the chair on a DSMB for the SHORT trial and roles as the president of the Dutch Society of Hematology (unpaid), Treasurer Board member for HOVON (unpaid), chair of the Horizonscan WP Hematology Dutch Healthcare Institute (vacancy fee), and member of the board of supervisors for Matchis (compensation according to Dutch law). D. S. reports grants or contracts from Pfizer, Novartis, BMS, AbbVie, MSD, and Takeda, including consulting fees from Pfizer, Novartis, AbbVie, BMS, Takeda, MSD, Janssen-Cilag, and Astellas; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Novartis, AbbVie, BMS, Takeda, MSD, and Janssen-Cilag; support for attending meetings and/or travel from Pfizer, Novartis, BMS, AbbVie, Takeda, MSD, and Janssen-Cilag; and a leadership or fiduciary role for other board, society, committee, or advocacy groups, paid or unpaid for Belgian College for Reimbursement of Orphan Drugs. F. B. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie and Sanofi; support for attending an international meeting from Novartis and Pfizer; and participation on a DSMB or advisory board for some academic studies (no fee) and Maatpharma (paid to institution). W. J. H. reports payment or honoraria for presentations from AbbVie, Amgen, AstraZeneca, Celgene/BMS, Gilead Sciences, and Janssen; support for attending meetings from IPSEN Pharma, Amgen, and Abbvie; and support for attending adboards for Amgen, Astrazeneca, Celgene/BMS, Gilead Sciences Janssen, MSD, and Sanofi-Aventis. B. V. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Sanofi, and Al Miral; support for attending meetings and/or travel for ViiV; and participation on a DSMB or advisory board for Pfizer. L. D. reports consulting fees from MSD, Pfizer, and Teva; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD, Pfizer, Teva, and Sandoz; support for attending meetings and/or travel from Sandoz; and participation on an advisory board for Pfizer. C. C. L. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead and Kite and support for attending meetings and/or travel for Gilead and Kite. C. S. P. reports book royalties from Elsevier and Thieme and honoraria for lectures from Canon Medical Systems. R. B. reports consulting fees from Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead; and support for attending meetings and/or travel for Gilead. P. E. V. reports research grants from ZonMw, Welcome Trust, Eurostars, EORTC, and RIVM; consulting fees from F2G, Gilead Sciences, and Pfizer; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead Sciences and Pfizer. F. L. reports research grants from Merck, Sharpe & Dohme, Gilead, Pfizer, and Novartis and consulting fees (advisory board) from Gilead and Pfizer. P. Y. B. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead Sciences Switzerland AG and Pfizer PFE Switzerland GmbH and support for Gilead Sciences Switzerland Sarl for TIMM, Trends in Medical Mycology. D. H. reports employment with Merck & Co. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Mycobacterial infections, both tuberculosis and nontuberculous, are more common in patients with haematological malignancies and haematopoietic stem cell transplant recipients than in the general population-although these infections remain rare. Mycobacterial infections pose both diagnostic and therapeutic challenges. The management of mycobacterial infections is particularly complicated for patients in haematology because of the many drug-drug interactions between antimycobacterial drugs and haematological and immunosuppressive treatments. The management of mycobacterial infections must also consider the effect of delaying haematological management. We surveyed the management practices for latent tuberculosis infection (LTBI) in haematology centres in Europe. We then conducted a meticulous review of the literature on the epidemiology, diagnosis, and management of LTBI, tuberculosis, and nontuberculous mycobacterial infections among patients in haematology, and we formulated clinical guidelines according to standardised European Conference on Infections in Leukaemia (ECIL) methods. In this Review, we summarise the available literature and the recommendations of ECIL 8 for managing mycobacterial infections in patients with haematological malignancies., Competing Interests: Declaration of interests CL reports funding from German Center of Infection Research (DZIF). DG reports consultancy and lectures for Amgen, Biogen, Biomerieux, Cellgene, Diasorin, Eli Lilly, Janssen, PBD Biotech, Qiagen, Quidel. DG reports funding from the Italian Ministry of Health (Ricerca Corrente Linea 4). All other authors declare no competing interests. The eighth ECIL meeting (Sept 19–21, 2019) was supported by unrestricted educational grants of Basilea Pharmaceuticals, Cidara Therapeutics, F2G, Gilead Sciences, Merck Sharp and Dohme, and Takeda. Basilea Pharmaceuticals, Cidara Therapeutics, F2G, Gilead Sciences, Merck Sharp and Dohme, and Takeda had no role in the selection of experts and the design of the guideline, in the collection, analysis, and interpretation of the data at any time including the consensus conference, or in the writing and editing of the guideline and in the decision to submit it for publication., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Fungal PCR has undergone considerable standardization and, together with the availability of commercial assays, external quality assessment schemes, and extensive performance validation data, is ready for widespread use for the screening and diagnosis of invasive fungal disease (IFD)., Areas Covered: Drawing on the experience and knowledge of the leads of the various working parties of the Fungal PCR initiative, this review will address general considerations concerning the use of molecular tests for the diagnosis of IFD, before focusing specifically on the technical and clinical aspects of molecular testing for the main causes of IFD and recent technological developments., Expert Opinion: For infections caused by Aspergillus, Candida , and Pneumocystis jirovecii , PCR testing is recommended, and combination with serological testing will likely enhance the diagnosis. For other IFD (e.g. mucormycosis), molecular diagnostics represent the only non-classical mycological approach toward diagnoses, and continued performance validation and standardization have improved confidence in such testing. The emergence of antifungal resistance can be diagnosed, in part, through molecular testing. Next-generation sequencing has the potential to significantly improve our understanding of fungal phylogeny, epidemiology, pathogenesis, mycobiome/microbiome, and interactions with the host, while identifying novel and existing mechanisms of antifungal resistance and novel diagnostic/therapeutic targets.

Invasive aspergillosis (IA) is an acute infection affecting patients who are immunocompromised, as a result of receiving chemotherapy for malignancy, or immunosuppressant agents for transplantation or autoimmune disease. Whilst criteria exist to define the probability of infection for clinical trials, there is little evidence in the literature or clinical guidelines on when to change antifungal treatment in patients who are receiving prophylaxis or treatment for IA. To try and address this significant gap, an advisory board of experts was convened to develop criteria for the management of IA for use in designing clinical trials, which could also be used in clinical practice. For primary treatment failure, a change in antifungal therapy should be made: (i) when mycological susceptibility testing identifies an organism from a confirmed site of infection, which is resistant to the antifungal given for primary therapy, or a resistance mutation is identified by molecular testing; (ii) at, or after, 8 days of primary antifungal treatment if there is increasing serum galactomannan, or galactomannan positivity in serum, or bronchoalveolar lavage fluid when the antigen was previously undetectable, or there is sudden clinical deterioration, or a new clearly distinct site of infection is detected; and (iii) at, or after, 15 days of primary antifungal treatment if the patient is clinically stable but with ≥2 serum galactomannan measurements persistently elevated compared with baseline or increasing, or if the original lesions on CT or other imaging, show progression by >25% in size in the context of no apparent change in immune status., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Background: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential., Methods: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved., Results: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses., Conclusions: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Quantitative real-time PCR (qPCR) is increasingly used to detect Pneumocystis jirovecii for the diagnosis of Pneumocystis pneumonia (PCP), but there are differences in the nucleic acids targeted, DNA only versus whole nucleic acid (WNA), and also the target genes for amplification. Through the Fungal PCR Initiative, a working group of the International Society for Human and Animal Mycology, a multicenter and monocenter evaluation of PCP qPCR assays was performed. For the multicenter study, 16 reference laboratories from eight different countries, performing 20 assays analyzed a panel consisting of two negative and three PCP positive samples. Aliquots were prepared by pooling residual material from 20 negative or positive- P. jirovecii bronchoalveolar lavage fluids (BALFs). The positive pool was diluted to obtain three concentrations (pure 1:1; 1:100; and 1:1000 to mimic high, medium, and low fungal loads, respectively). The monocenter study compared five in-house and five commercial qPCR assays testing 19 individual BALFs on the same amplification platform. Across both evaluations and for all fungal loads, targeting WNA and the mitochondrial small sub-unit (mtSSU) provided the earliest Cq values, compared to only targeting DNA and the mitochondrial large subunit, the major surface glycoprotein or the beta-tubulin genes. Thus, reverse transcriptase-qPCR targeting the mtSSU gene could serve as a basis for standardizing the P. jirovecii load, which is essential if qPCR is to be incorporated into clinical care pathways as the reference method, accepting that additional parameters such as amplification platforms still need evaluation., (© The Author(s) 2019. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Background: This is an update of the original review published in the Cochrane Database of Systematic Reviews Issue 10, 2015.Invasive aspergillosis (IA) is the most common life-threatening opportunistic invasive mould infection in immunocompromised people. Early diagnosis of IA and prompt administration of appropriate antifungal treatment are critical to the survival of people with IA. Antifungal drugs can be given as prophylaxis or empirical therapy, instigated on the basis of a diagnostic strategy (the pre-emptive approach) or for treating established disease. Consequently, there is an urgent need for research into both new diagnostic tools and drug treatment strategies. Increasingly, newer methods such as polymerase chain reaction (PCR) to detect fungal nucleic acids are being investigated., Objectives: To provide an overall summary of the diagnostic accuracy of PCR-based tests on blood specimens for the diagnosis of IA in immunocompromised people., Search Methods: We searched MEDLINE (1946 to June 2015) and Embase (1980 to June 2015). We also searched LILACS, DARE, Health Technology Assessment, Web of Science and Scopus to June 2015. We checked the reference lists of all the studies identified by the above methods and contacted relevant authors and researchers in the field. For this review update we updated electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 3) in the Cochrane Library; MEDLINE via Ovid (June 2015 to March week 2 2018); and Embase via Ovid (June 2015 to 2018 week 12)., Selection Criteria: We included studies that: i) compared the results of blood PCR tests with the reference standard published by the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG); ii) reported data on false-positive, true-positive, false-negative and true-negative results of the diagnostic tests under investigation separately; and iii) evaluated the test(s) prospectively in cohorts of people from a relevant clinical population, defined as a group of individuals at high risk for invasive aspergillosis. Case-control and retrospective studies were excluded from the analysis., Data Collection and Analysis: Authors independently assessed quality and extracted data. For PCR assays, we evaluated the requirement for either one or two consecutive samples to be positive for diagnostic accuracy. We investigated heterogeneity by subgroup analyses. We plotted estimates of sensitivity and specificity from each study in receiver operating characteristics (ROC) space and constructed forest plots for visual examination of variation in test accuracy. We performed meta-analyses using the bivariate model to produce summary estimates of sensitivity and specificity., Main Results: We included 29 primary studies (18 from the original review and 11 from this update), corresponding to 34 data sets, published between 2000 and 2018 in the meta-analyses, with a mean prevalence of proven or probable IA of 16.3 (median prevalence 11.1% , range 2.5% to 57.1%). Most patients had received chemotherapy for haematological malignancy or had undergone hematopoietic stem cell transplantation. Several PCR techniques were used among the included studies. The sensitivity and specificity of PCR for the diagnosis of IA varied according to the interpretative criteria used to define a test as positive. The summary estimates of sensitivity and specificity were 79.2% (95% confidence interval (CI) 71.0 to 85.5) and 79.6% (95% CI 69.9 to 86.6) for a single positive test result, and 59.6% (95% CI 40.7 to 76.0) and 95.1% (95% CI 87.0 to 98.2) for two consecutive positive test results., Authors' Conclusions: PCR shows moderate diagnostic accuracy when used as screening tests for IA in high-risk patient groups. Importantly the sensitivity of the test confers a high negative predictive value (NPV) such that a negative test allows the diagnosis to be excluded. Consecutive positives show good specificity in diagnosis of IA and could be used to trigger radiological and other investigations or for pre-emptive therapy in the absence of specific radiological signs when the clinical suspicion of infection is high. When a single PCR positive test is used as the diagnostic criterion for IA in a population of 100 people with a disease prevalence of 16.3% (overall mean prevalence), three people with IA would be missed (sensitivity 79.2%, 20.8% false negatives), and 17 people would be unnecessarily treated or referred for further tests (specificity of 79.6%, 21.4% false positives). If we use the two positive test requirement in a population with the same disease prevalence, it would mean that nine IA people would be missed (sensitivity 59.6%, 40.4% false negatives) and four people would be unnecessarily treated or referred for further tests (specificity of 95.1%, 4.9% false positives). Like galactomannan, PCR has good NPV for excluding disease, but the low prevalence of disease limits the ability to rule in a diagnosis. As these biomarkers detect different markers of disease, combining them is likely to prove more useful.

Non-culture-based diagnostics have been developed to help establish an early diagnosis of invasive fungal infection. Studies have shown that these tests can significantly impact the diagnosis of infection in high risk patients. Aspergillus galactomannan EIA testing is well-recognized as an important adjunct to the diagnosis of invasive aspergillosis and can be detected in serum, bronchoalveolar lavage and other fluids. Galactomannan testing used along with PCR testing has been shown to be effective when integrated into care paths for high risk patients for both diagnoses and as a surrogate marker for outcome when used in serial testing. Beta-d-glucan assays are non-specific for several fungal genera including Aspergillus and Candida and in high risk patients have been an important tool to augment the diagnosis. Lateral flow technology using monoclonal antibodies to Aspergillus are available that allow rapid testing of clinical samples. While standard PCR for Candida remains investigational, T2 magnetic resonance allows for the rapid diagnosis of Candida species from blood cultures. Aspergillus PCR has been extensively validated with standardized approaches established for these methods and will be included in the diagnostic criteria in the revised European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC-MSG) definitions. Finally, these non-culture-based tests can be used in combination to significantly increase the detection of invasive mycoses with the ultimate aim of establishing an early diagnosis of infection., Competing Interests: For activities outside of the submitted work, T.F.P. has been a consultant for or served on advisory boards to Astellas, Basilea, Gilead, Merck, Pfizer, Scynexis, and Toyama. J.P.D is a member of the European Aspergillus PCR initiative (EAPCRI).

International guidelines on protective environment for HSCT recipients proposed a set of 10 global recommendations in 2009 on protective environment (GRPE) concerning hospital room design and ventilation. The EBMT Infectious Diseases Working Party undertook a survey on the status on protective environment for HSCT recipients with the aim of surveying current practices and their agreement with GRPE recommendations. The questionnaire consisted of 37 questions divided into 5 sections about filtration, air changes, maintenance, and the protective environment in rooms and the surrounding unit. Overall, 177 centres (response rate 33%) from 36 countries responded, indicating that 99.4% of patient rooms were equipped with HEPA filters, but only 48.6% of the centre's staff were aware of, and could confirm, regular replacement of filters based on manufacturers' recommendations. Well-sealed rooms were used in terms of windows (70.6%), ceilings (35%), and plumbing pipes (51.4%). The sensor monitors in the patient room used to determine when the HEPA filters require changing were installed only in 18.1% of centres. Only 1 centre fulfilled all 10 GRPE recommendations, while 62 centres fulfilled the 3 level "A" recommendations. In conclusion, HEPA-filtered rooms are available in almost all centres, while fewer centres fulfilled other requirements. Knowledge on the details and maintenance of protective environments in the HSCT setting was inadequate, reflecting a lack of communication between the health personnel involved, hospital infection control and the hospital maintenance services.

Standardization of Aspergillus polymerase chain reaction (PCR) protocols has progressed, and analytical validity of blood-based assays has been formally established. It remains necessary to consider how the tests can be used in practice to maximize clinical utility. To determine the optimal diagnostic strategies and influence on patient management, several factors require consideration, including the patient population, incidence of invasive aspergillosis (and other fungal disease), and the local antifungal prescribing policy. Technical issues such as specimen type, ease of sampling, frequency of testing, access to testing centers, and time to reporting will also influence the use of PCR in clinical practice. Interpretation of all diagnostic tests is dependent on the clinical context and molecular assays are no exception, but with the proposal to incorporate Aspergillus PCR into the second revision of the consensus guidelines for defining invasive fungal disease the acceptance and understanding of molecular tests should improve.

Objectives: To prevent invasive fungal disease (IFD) in adult patients undergoing remission-induction chemotherapy for newly diagnosed acute lymphoblastic leukaemia (ALL)., Patients and Methods: In a double-blind multicentre Phase 3 study, patients received prophylactic liposomal amphotericin B (L-AMB) at 5 mg/kg intravenously or placebo twice weekly in a 2:1 random allocation during remission-induction treatment. The primary endpoint was the development of proven or probable IFD. Secondary endpoints included those focused on the safety and tolerability of prophylactic L-AMB., Results: Three hundred and fifty-five patients from 86 centres in Europe and South America received at least one dose of L-AMB ( n =  237) or placebo ( n =  118). Rates of proven and probable IFD assessed independently were 7.9% (18/228) in the L-AMB group and 11.7% (13/111) in the placebo group ( P  =   0.24). Rates of possible IFD were 4.8% (11/228) in the L-AMB and 5.4% (6/111) in the placebo group ( P  =   0.82). The remission-induction phase was a median of 22 days for both groups. Overall mortality was similar between the groups: 7.2% (17/237) for L-AMB and 6.8% (8/118) for placebo ( P  =   1.00). Hypokalaemia and creatinine increase were significantly more frequent with L-AMB., Conclusions: The IFD rate among adult patients undergoing remission-induction chemotherapy for newly diagnosed ALL was 11.7% in the placebo group, and was not significantly different in patients receiving L-AMB, suggesting that the L-AMB regimen studied is not effective as prophylaxis against IFD. The IFD rate appears higher than previously reported, warranting further investigation. Tolerability of L-AMB was what might be expected. Further studies are needed to determine the optimal antifungal strategy during remission-induction chemotherapy of ALL., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A wide array of PCR tests has been developed to aid the diagnosis of invasive aspergillosis (IA), providing technical diversity but limiting standardisation and acceptance. Methodological recommendations for testing blood samples using PCR exist, based on achieving optimal assay sensitivity to help exclude IA. Conversely, when testing more invasive samples (BAL, biopsy, CSF) emphasis is placed on confirming disease, so analytical specificity is paramount. This multicenter study examined the analytical specificity of PCR methods for detecting IA by blind testing a panel of DNA extracted from a various fungal species to explore the range of Aspergillus species that could be detected, but also potential cross reactivity with other fungal species. Positivity rates were calculated and regression analysis was performed to determine any associations between technical specifications and performance. The accuracy of Aspergillus genus specific assays was 71.8%, significantly greater (P < .0001) than assays specific for individual Aspergillus species (47.2%). For genus specific assays the most often missed species were A. lentulus (25.0%), A. versicolor (24.1%), A. terreus (16.1%), A. flavus (15.2%), A. niger (13.4%), and A. fumigatus (6.2%). There was a significant positive association between accuracy and using an Aspergillus genus PCR assay targeting the rRNA genes (P = .0011). Conversely, there was a significant association between rRNA PCR targets and false positivity (P = .0032). To conclude current Aspergillus PCR assays are better suited for detecting A. fumigatus, with inferior detection of most other Aspergillus species. The use of an Aspergillus genus specific PCR assay targeting the rRNA genes is preferential., (© The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Many countries have observed an increase in the incidence of invasive fungal infections (IFIs) over the past two decades with emergence of new risk factors and isolation of new fungal pathogens. Early diagnosis and appropriate antifungal treatment remain the cornerstones of successful outcomes. However, due to non-specific clinical presentations and limited availability of rapid diagnostic tests, in more than half of cases antifungal treatment is inappropriate. As a result, the emergence of antifungal resistance both in yeasts and mycelial fungi is becoming increasingly common. The Delhi Chapter of the Indian Association of Medical Microbiologists (IAMM-DC) organized a 1 day workshop in collaboration with BSAC on 10 December 2015 in New Delhi to design a road map towards the development of a robust antifungal stewardship programme in the context of conditions in India. The workshop aimed at developing a road map for optimizing better outcomes in patients with IFIs while minimizing unintended consequences of antifungal use, ultimately leading to reduced healthcare costs and prevention development of resistance to antifungals. The workshop was a conclave of all stakeholders, eminent experts from India and the UK, including clinical microbiologists, critical care specialists and infectious disease physicians. Various issues in managing IFIs were discussed, including epidemiology, diagnostic and therapeutic algorithms in different healthcare settings. At the end of the deliberations, a consensus opinion and key messages were formulated, outlining a step-by-step approach to tackling the growing incidence of IFIs and antifungal resistance, particularly in the Indian scenario., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The 5th European Conference on Infections in Leukaemia (ECIL-5) meeting aimed to establish evidence-based recommendations for the prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in non-HIV-infected patients with an underlying haematological condition, including allogeneic HSCT recipients. Recommendations were based on the grading system of the IDSA. Trimethoprim/sulfamethoxazole given 2-3 times weekly is the drug of choice for the primary prophylaxis of PCP in adults ( A-II: ) and children ( A-I: ) and should be given during the entire period at risk. Recent data indicate that children may benefit equally from a once-weekly regimen ( B-II: ). All other drugs, including pentamidine, atovaquone and dapsone, are considered second-line alternatives when trimethoprim/sulfamethoxazole is poorly tolerated or contraindicated. The main indications of PCP prophylaxis are ALL, allogeneic HSCT, treatment with alemtuzumab, fludarabine/cyclophosphamide/rituximab combinations, >4 weeks of treatment with corticosteroids and well-defined primary immune deficiencies in children. Additional indications are proposed depending on the treatment regimen., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The Fifth European Conference on Infections in Leukaemia (ECIL-5) convened a meeting to establish evidence-based recommendations for using tests to diagnose Pneumocystis jirovecii pneumonia (PCP) in adult patients with haematological malignancies. Immunofluorescence assays are recommended as the most sensitive microscopic method (recommendation A-II: ). Real-time PCR is recommended for the routine diagnosis of PCP ( A-II: ). Bronchoalveolar lavage (BAL) fluid is recommended as the best specimen as it yields good negative predictive value ( A-II: ). Non-invasive specimens can be suitable alternatives ( B-II: ), acknowledging that PCP cannot be ruled out in case of a negative PCR result ( A-II: ). Detecting β-d-glucan in serum can contribute to the diagnosis but not the follow-up of PCP ( A-II: ). A negative serum β-d-glucan result can exclude PCP in a patient at risk ( A-II: ), whereas a positive test result may indicate other fungal infections. Genotyping using multilocus sequence markers can be used to investigate suspected outbreaks ( A-II: ). The routine detection of dihydropteroate synthase mutations in cases of treatment failure is not recommended ( B-II: ) since these mutations do not affect response to high-dose co-trimoxazole. The clinical utility of these diagnostic tests for the early management of PCP should be further assessed in prospective, randomized interventional studies., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Pulmonary complications affect up to 40% of patients with severe neutropenia lasting for more than 10 d. As they are frequently associated with fever and elevation of C-reactive protein or other signs of inflammation, they are mostly handled as pneumonia. However, the differential diagnosis is broad, and a causative microbial agent remains undetected in the majority of cases. Pulmonary side effects from cytotoxic treatment or pulmonary involvement by the underlying malignancy must always be taken into account and may provide grounds for invasive diagnostic procedures in selected patients. Pneumocystis jirovecii (in patients not receiving co-trimoxazole as prophylaxis), multi-resistant gram-negative bacilli, mycobacteria or respiratory viruses may be involved. High-risk patients may be infected by filamentous fungi, such as Aspergillus spp., but these infections are seldom proven when treatment is initiated. Microorganisms isolated from cultures of blood, bronchoalveolar lavage or respiratory secretions need careful interpretation as they may be irrelevant for determining the aetiology of pulmonary infiltrates, particularly when cultures yield coagulase-negative staphylococci, enterococci or Candida species. Non-culture based diagnostics for detecting Aspergillus galactomannan, beta-D-glucan or DNA from blood, bronchoalveolar lavage or tissue samples can facilitate the diagnosis, but must always be interpreted in the context of clinical and imaging findings. Systemic antifungal treatment with mould-active agents, given in combination with broad-spectrum antibiotics, improves clinical outcome when given pre-emptively. Co-trimoxazole remains the first-line treatment for Pneumocystis pneumonia, while cytomegalovirus pneumonia will respond to ganciclovir or foscarnet in most cases. The clinical outcome of acute respiratory failure can also be successful with proper intensive care, when indicated., (© 2016 John Wiley & Sons Ltd.)

The EuropeanAspergillusPCR Initiative (EAPCRI) has provided recommendations for the PCR testing of whole blood (WB) and serum/plasma. It is important to test these recommended protocols on nonsimulated "in vivo" specimens before full clinical evaluation. The testing of an animal model of invasive aspergillosis (IA) overcomes the low incidence of disease and provides experimental design and control that is not possible in the clinical setting. Inadequate performance of the recommended protocols at this stage would require reassessment of methods before clinical trials are performed and utility assessed. The manuscript describes the performance of EAPCRI protocols in an animal model of invasive aspergillosis. Blood samples taken from a guinea pig model of IA were used for WB and serum PCR. Galactomannan and β-d-glucan detection were evaluated, with particular focus on the timing of positivity and on the interpretation of combination testing. The overall sensitivities for WB PCR, serum PCR, galactomannan, and β-d-glucan were 73%, 65%, 68%, and 46%, respectively. The corresponding specificities were 92%, 79%, 80%, and 100%, respectively. PCR provided the earliest indicator of IA, and increasing galactomannan and β-d-glucan values were indicators of disease progression. The combination of WB PCR with galactomannan and β-d-glucan proved optimal (area under the curve [AUC], 0.95), and IA was confidently diagnosed or excluded. The EAPRCI-recommended PCR protocols provide performance comparable to commercial antigen tests, and clinical trials are warranted. By combining multiple tests, IA can be excluded or confirmed, highlighting the need for a combined diagnostic strategy. However, this approach must be balanced against the practicality and cost of using multiple tests., (Copyright © 2016 White et al.)

Steroid-refractory acute graft-versus-host disease (aGVHD) remains an important cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). A protocol on the management of aGVHD was introduced in our center that incorporated a prospective study on combination therapy with inolimomab (anti-IL-2Rα) and etanercept (anti-tumor necrosis factor-α) for steroid-refractory aGVHD. We evaluated the efficacy and safety in 21 consecutively treated patients. The patients had developed refractory aGVHD after SCT (n = 16) or donor lymphocyte infusion (n = 5), and aGVHD was classified as severe in all patients, mostly due to gastrointestinal involvement stages 2 to 4. No drug-related side effects were observed apart from the infections expected to occur in these severely immunocompromised patients. Overall response at day 28 of second-line therapy was 48% (10/21), with 6 and 4 patients achieving a complete and partial response, respectively. Eventually, 19 patients died (90%), with early mortality (<6 months) predominantly resulting from refractory aGVHD and secondary infections and late mortality resulting from relapse of the underlying disease. With a median follow-up of 55 days, the estimated rates of 6-month and 2-year overall survival were dismal, 29% and 10%, respectively. In conclusion, the combination of inolimomab and etanercept for steroid-refractory aGVHD failed to improve the dismal prognosis of severe steroid-refractory aGVHD., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Aspergillus polymerase chain reaction (PCR) was excluded from the European Organisation for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) definitions of invasive fungal disease because of limited standardization and validation. The definitions are being revised., Methods: A systematic literature review was performed to identify analytical and clinical information available on inclusion of galactomannan enzyme immunoassay (GM-EIA) (2002) and β-d-glucan (2008), providing a minimal threshold when considering PCR. Categorical parameters and statistical performance were compared., Results: When incorporated, GM-EIA and β-d-glucan sensitivities and specificities for diagnosing invasive aspergillosis were 81.6% and 91.6%, and 76.9% and 89.4%, respectively. Aspergillus PCR has similar sensitivity and specificity (76.8%-88.0% and 75.0%-94.5%, respectively) and comparable utility. Methodological recommendations and commercial PCR assays assist standardization. Although all tests have limitations, currently, PCR is the only test with independent quality control., Conclusions: We propose that there is sufficient evidence that is at least equivalent to that used to include GM-EIA and β-d-glucan testing, and that PCR is now mature enough for inclusion in the EORTC/MSG definitions., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

The use of serum or plasma for Aspergillus PCR testing facilitates automated and standardized technology. Recommendations for serum testing are available, and while serum and plasma are regularly considered interchangeable for use in fungal diagnostics, differences in galactomannan enzyme immunoassay (GM-EIA) performance have been reported and are attributed to clot formation. Therefore, it is important to assess plasma PCR testing to determine if previous recommendations for serum are applicable and also to compare analytical performance with that of serum PCR. Molecular methods testing serum and plasma were compared through multicenter distribution of quality control panels, with additional studies to investigate the effect of clot formation and blood fractionation on DNA availability. Analytical sensitivity and time to positivity (TTP) were compared, and a regression analysis was performed to identify variables that enhanced plasma PCR performance. When testing plasma, sample volume, preextraction-to-postextraction volume ratio, PCR volume, duplicate testing, and the use of an internal control for PCR were positively associated with performance. When whole-blood samples were spiked and then fractionated, the analytical sensitivity and TTP were superior when testing plasma. Centrifugation had no effect on DNA availability, whereas the presence of clot material significantly lowered the concentration (P = 0.028). Technically, there are no major differences in the molecular processing of serum and plasma, but the formation of clot material potentially reduces available DNA in serum. During disease, Aspergillus DNA burdens in blood are often at the limits of PCR performance. Using plasma might improve performance while maintaining the methodological simplicity of serum testing., (Copyright © 2015 Loeffler et al.)

Aspergillus PCR testing of serum provides technical simplicity but with potentially reduced sensitivity compared to whole-blood testing. With diseases for which screening to exclude disease represents an optimal strategy, sensitivity is paramount. The associated analytical study confirmed that DNA concentrations were greater in plasma than those in serum. The aim of the current investigation was to confirm analytical findings by comparing the performance of Aspergillus PCR testing of plasma and serum in the clinical setting. Standardized Aspergillus PCR was performed on plasma and serum samples concurrently obtained from hematology patients in a multicenter retrospective anonymous case-control study, with cases diagnosed according to European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus definitions (19 proven/probable cases and 42 controls). Clinical performance and clinical utility (time to positivity) were calculated for both kinds of samples. The sensitivity and specificity for Aspergillus PCR when testing serum were 68.4% and 76.2%, respectively, and for plasma, they were 94.7% and 83.3%, respectively. Eighty-five percent of serum and plasma PCR results were concordant. On average, plasma PCR was positive 16.8 days before diagnosis and was the earliest indicator of infection in 13 cases, combined with other biomarkers in five cases. On average, serum PCR was positive 10.8 days before diagnosis and was the earliest indicator of infection in six cases, combined with other biomarkers in three cases. These results confirm the analytical finding that the sensitivity of Aspergillus PCR using plasma is superior to that using serum. PCR positivity occurs earlier when testing plasma and provides sufficient sensitivity for the screening of invasive aspergillosis while maintaining methodological simplicity., (Copyright © 2015 White et al.)

Background: Anti-cancer treatment and the cancer population have evolved since the last European Organisation for Research and Treatment of Cancer (EORTC) fungemia survey, and there are few recent large epidemiological studies., Methods: This was a prospective cohort study including 145 030 admissions of patients with cancer from 13 EORTC centers. Incidence, clinical characteristics, and outcome of fungemia were analyzed., Results: Fungemia occurred in 333 (0.23%; 95% confidence interval [CI], .21-.26) patients, ranging from 0.15% in patients with solid tumors to 1.55% in hematopoietic stem cell transplantation recipients. In 297 evaluable patients age ranged from 17 to 88 years (median 56 years), 144 (48%) patients were female, 165 (56%) had solid tumors, and 140 (47%) had hematological malignancies. Fungemia including polymicrobial infection was due to: Candida spp. in 267 (90%), C. albicans in 128 (48%), and other Candida spp. in 145 (54%) patients. Favorable overall response was achieved in 113 (46.5%) patients by week 2. After 4 weeks, the survival rate was 64% (95% CI, 59%-70%) and was not significantly different between Candida spp. Multivariable logistic regression identified baseline septic shock (odds ratio [OR] 3.04, 95% CI, 1.22-7.58) and tachypnoea as poor prognostic factors (OR 2.95, 95% CI, 1.66-5.24), while antifungal prophylaxis prior to fungemia (OR 0.20, 95% CI, .06-.62) and remission of underlying cancer (OR, 0.18; 95% CI, .06-.50) were protective., Conclusions: Fungemia, mostly due to Candida spp., was rare in cancer patients from EORTC centers but was associated with substantial mortality. Antifungal prophylaxis and remission of cancer predicted better survival., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

An international expert panel was convened to deliberate the management of azole-resistant aspergillosis. In culture-positive cases, in vitro susceptibility testing should always be performed if antifungal therapy is intended. Different patterns of resistance are seen, with multi-azole and pan-azole resistance more common than resistance to a single triazole. In confirmed invasive pulmonary aspergillosis due to an azole-resistant Aspergillus, the experts recommended a switch from voriconazole to liposomal amphotericin B (L-AmB; Ambisome(®)). In regions with environmental resistance rates of ≥10%, a voriconazole-echinocandin combination or L-AmB were favoured as initial therapy. All experts recommended L-AmB as core therapy for central nervous system aspergillosis suspected to be due to an azole-resistant Aspergillus, and considered the addition of a second agent with the majority favouring flucytosine. Intravenous therapy with either micafungin or L-AmB given as either intermittent or continuous therapy was recommended for chronic pulmonary aspergillosis due to a pan-azole-resistant Aspergillus. Local and national surveillance with identification of clinical and environmental resistance patterns, rapid diagnostics, better quality clinical outcome data, and a greater understanding of the factors driving or minimising environmental resistance are areas where research is urgently needed, as well as the development of new oral agents outside the azole drug class., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Strict definition of invasive aspergillosis (IA) cases is required to allow precise conclusions about the efficacy of antifungal therapy. The Global Comparative Aspergillus Study (GCAS) compared voriconazole to amphotericin B (AmB) deoxycholate for the primary therapy of IA. Because predefined definitions used for this trial were substantially different from the consensus definitions proposed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group in 2008, we recategorized the 379 episodes of the GCAS according to the later definitions., Methods: The objectives were to assess the impact of the current definitions on the classification of the episodes and to provide comparative efficacy for probable/proven and possible IA in patients treated with either voriconazole or AmB. In addition to original data, we integrated the results of baseline galactomannan serum levels obtained from 249 (65.7%) frozen samples. The original response assessment was accepted unchanged., Results: Recategorization allowed 59 proven, 178 probable, and 106 possible IA cases to be identified. A higher favorable 12-week response rate was obtained with voriconazole (54.7%) than with AmB (29.9%) (P < .0001). Survival was higher for voriconazole for mycologically documented (probable/proven) IA (70.2%) than with AmB (54.9%) (P = .010). Higher response rates were obtained in possible IA treated with voriconazole vs AmB with the same magnitude of difference (26.2%; 95% confidence interval [CI], 7.2%-45.3%) as in mycologically documented episodes (24.3%; 95% CI, 11.9%-36.7%), suggesting that possible cases are true IA., Conclusions: Recategorization resulted in a better identification of the episodes and confirmed the higher efficacy of voriconazole over AmB deoxycholate in mycologically documented IA., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: Long-term health-related quality of life (HRQoL) was determined for patients admitted to the haematology ward who needed intensive care treatment (H-IC+) and compared with those who did not (H-IC-) as well as with that for patients admitted to the general ICU (nH-IC+)., Methods: A cross-sectional study was carried out median 18 months after admission by employing the short form-36, checklist for individual strength, cognitive failure questionnaire and hospital anxiety and depression scale., Results: 27 (79%) of the 34 H-IC+ patients approached, and 93 (85%) of the 109 H-IC- patients approached replied. Data were adjusted for relevant covariates and matched with those of 149 patients in the general ICU. Apart from the lower role-physical functioning score for H-IC+ (P = 0.04) no other differences were found between H-IC+ and H-IC-. Groups H-IC+ and nH-IC+ evaluated their HRQoL on SF-36 similarly, except for the lower aggregated physical component summary (PCS) for H-IC+ (P<0.0001). After adjusting for PCS, no significant differences in CIS, CFQ and HADS were observed between the groups., Conclusions: Eighteen months after admission, patients treated for haematological malignancies reported similar HRQoL, whether or not they had received intensive care treatment, but reported a lower PCS than those of patients in the general ICU. Hence, there is no reason to assume that admission to the ICU has a negative impact on long-term HRQoL, so this should not affect the decision whether or not to transfer patients with haematological malignancies to the ICU.

Healthy individuals possess an immune system comprising physical barriers, innate and acquired immunity as well as the indigenous microflora that populate the body surfaces. The immune system maintains constant vigilance over the body at the cellular level as well as at the interface between the host integument and the resident microflora. However, neoplastic diseases and their treatment often lead to impaired immunity resulting in an increased risk of infections due to viruses, bacteria, fungi, and protozoa. This chapter explores the various aspects of host impairment focusing on the components of immunity and the interplay between them to explain why it is that these patients succumb to infections per se. In so doing, we hope that the reader will be better equipped to understand the risks patients face so as to anticipate potential infectious complications and implement appropriate measures to help attain successful remission of the neoplastic diseases and maintain the best quality of life for the patient.

Timing of treatment for invasive fungal disease (IFD) is critical for making appropriate clinical decisions. Historically, many centres have treated at-risk patients prior to disease detection to try to prevent fungal colonization or in response to antibiotic-resistant fever. Many studies have indicated that a diagnostic-driven approach, using radiological tests and biomarkers to guide treatment decisions, may be a more clinically relevant and cost-effective approach. The Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) defined host clinical and mycological criteria for proven, probable and possible classes of IFD, to aid diagnosis. However, some patients at risk of IFD do not meet EORTC/MSG criteria and have been termed Groups B (patients with persistent unexplained febrile neutropenia) and C (patients with non-definitive signs of IFD) in a study by Maertens et al. (Haematologica 2012; 97: 325-7). Consequently, we considered the most appropriate triggers (clinical or radiological signs or biomarkers) for treatment of all patient groups, especially the unclassified B and C groups, based on our clinical experience. For Group C patients, additional diagnostic testing is recommended before a decision to treat, including repeat galactomannan tests, radiological scans and analysis of bronchoalveolar lavage fluid. Triggers for stopping antifungal treatment were considered to include resolution of all clinical signs and symptoms. For Group B patients, it was concluded that better definition of risk factors predisposing patients to fungal infection and the use of more sensitive diagnostic tests are required to aid treatment decisions and improve clinical outcomes.

Background:  The objective of this analysis was to investigate prognostic factors that influence the outcome of Epstein-Barr virus (EBV)-related posttransplant lymphoproliferative disorder (PTLD) after a rituximab-based treatment in the allogeneic hematopoietic stem cell transplant (HSCT) setting., Methods:  A total of 4466 allogeneic HSCTs performed between 1999 and 2011 in 19 European Group for Blood and Marrow Transplantation centers were retrospectively analyzed for PTLD, either biopsy-proven or probable disease., Results:  One hundred forty-four cases of PTLD were identified, indicating an overall EBV-related PTLD frequency of 3.22%, ranging from 1.16% for matched-family donor, 2.86% for mismatched family donor, 3.97% in matched unrelated donors, and 11.24% in mismatched unrelated donor recipients. In total, 69.4% patients survived PTLD. Multivariable analysis showed that a poor response of PTLD to rituximab was associated with an age ≥30 years, involvement of extralymphoid tissue, acute GVHD, and a lack of reduction of immunosuppression upon PTLD diagnosis. In the prognostic model, the PTLD mortality increased with the increasing number of factors: 0-1, 2, or 3 factors being associated with mortality of 7%, 37%, and 72%, respectively (P < .0001). Immunosuppression tapering was associated with a lower PTLD mortality (16% vs 39%), and a decrease of EBV DNAemia in peripheral blood during therapy was predictive of better survival., Conclusions:  More than two-thirds of patients with EBV-related PTLD survived after rituximab-based treatment. Reduction of immunosuppression was associated with improved outcome, whereas older age, extranodal disease, and acute graft-vs-host disease predicted poor outcome.

Objectives: The underlying mechanism for amphotericin B-induced acute kidney injury (AKI) remains poorly understood and may be immunologically mediated. We assessed whether the development of nephrotoxicity is linked to a distinct cytokine profile in patients receiving amphotericin B deoxycholate (AmBD)., Patients and Methods: In 58 patients who received AmBD, circulating serum interleukin (IL)-6, IL-8 and IL-10 were measured at baseline, week 1 and week 2 of antifungal treatment and correlated to the development of renal impairment. The Cox proportional hazards model approach was adopted for analysis., Results: The P value was 0.026 for the overall effect of IL-6 on time to development of AKI. An increasing or non-receding IL-6 trend by week 1 of AmBD treatment (followed by a decreasing or non-receding IL-6 trend from week 1 to week 2) correlated with an increased likelihood of nephrotoxicity [hazard ratio (HR) 6.93, P value 0.005 and HR 3.46, P value 0.035, respectively]. Similarly, persistently increasing IL-8 levels were linked to a 3.84-fold increased likelihood of AKI., Conclusions: In patients receiving AmBD, persistence of an elevated pro-inflammatory cytokine milieu is associated with a predisposition to drug-related kidney injury.

Twelve laboratories evaluated candidate material for an Aspergillus DNA calibrator. The DNA material was quantified using limiting-dilution analysis; the mean concentration was determined to be 1.73 × 10(10) units/ml. The calibrator can be used to standardize aspergillosis diagnostic assays which detect and/or quantify nucleic acid.

In the last decade, there have been some favourable developments in the management of invasive fungal diseases, including definitions, diagnosis and drugs for treatment. This has led to a gradual awareness that caring for patients at risk need not solely rely on an empirical therapy approach but that a degree of individualisation is possible, provided certain prerequisites are met., (Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Aim: This study was aimed to investigate whether any association could be found between the presence of an inflamed and infected periodontium (e.g., gingivitis and periodontitis) and the development of bacteremia during neutropenia following allogeneic hematopoietic stem cell transplantation (HSCT)., Methods: Eighteen patients underwent a periodontal examination before HSCT. Patients were classified as periodontally healthy [all periodontal pocket depths (PPD) ≤ 4 mm and bleeding on probing (BOP) ≤ 10%) or as having gingivitis/periodontitis (PPD ≥ 4 mm and BOP > 10%]. Oral mucositis (OM) was scored using the daily mucositis score. Blood cultures were taken at least twice weekly., Results: Five patients were periodontally healthy, while 13 patients had gingivitis or periodontitis. Twelve patients (67%) developed bacteremia during neutropenia, of which 11 patients (61%) had one or more episodes of bacteremia due to coagulase-negative staphylococci (CONS, most often Staphylococcus epidermidis) or to oral viridans streptococci (OVS), or both. Patients with gingivitis/periodontitis more often had bacteremia than those with a healthy periodontium (p = 0.047), and BOP was associated with bacteremia (p = 0.049). All patients developed ulcerative OM, but its severity and duration were not associated with bacteremia. OM duration and the length of stay in the hospital were strongly correlated (R = 0.835, p ≤ 0.001)., Conclusion: This study indicates that periodontal infections may contribute to the risk of developing OVS and CONS bacteremia during neutropenia following HSCT. While our results point to the importance of periodontal evaluation and management before HSCT, further studies on periodontal contribution to systemic infectious complications are warranted.

The efficacy of voriconazole is potentially compromised by considerable pharmacokinetic variability. There are increasing insights into voriconazole concentrations that are safe and effective for treatment of invasive fungal infections. Therapeutic drug monitoring is increasingly advocated. Software to aid in the individualization of dosing would be an extremely useful clinical tool. We developed software to enable the individualization of voriconazole dosing to attain predefined serum concentration targets. The process of individualized voriconazole therapy was based on concepts of Bayesian stochastic adaptive control. Multiple-model dosage design with feedback control was used to calculate dosages that achieved desired concentration targets with maximum precision. The performance of the software program was assessed using the data from 10 recipients of an allogeneic hematopoietic stem cell transplant (HSCT) receiving intravenous (i.v.) voriconazole. The program was able to model the plasma concentrations with a high level of precision, despite the wide range of concentration trajectories and interindividual pharmacokinetic variability. The voriconazole concentrations predicted after the last dosages were largely concordant with those actually measured. Simulations provided an illustration of the way in which the software can be used to adjust dosages of patients falling outside desired concentration targets. This software appears to be an extremely useful tool to further optimize voriconazole therapy and aid in therapeutic drug monitoring. Further prospective studies are now required to define the utility of the controller in daily clinical practice.

A role for gut bacteria in the pathogenesis of graft-versus-host disease (GVHD) has been firmly established; however, the role of Candida spp, which form part of the mycobiome, remains unknown. In a homogenous group of patients who underwent allogeneic stem cell transplantation (SCT), we found a significant impact of Candida colonization on the occurrence of acute GVHD. Patients colonized with Candida spp developed significantly more grade II-IV acute GVHD compared with noncolonized patients (50% vs 32%; P = .03), as well as more gastrointestinal (GI)-GVHD (33% vs 19%; P = .05). Colonization with Candida spp was more frequent in patients bearing the loss-of-function polymorphism Y238X, which results in dectin-1 dysfunction, compared with patients with the wild-type allele (73% vs 31%; P = .002). There was no direct effect of dectin-1 dysfunction on acute GVHD, although it did influence the occurrence of GVHD indirectly through Candida colonization. The exact mechanism of GVHD induction by Candida spp colonization of the mucosa is unknown, but the link might prove to be the induction of Th 17/IL-23 responses through activation of pattern recognition receptors by fungal motifs, including β-d-glucan and mannans. These data indicate a role for the mycobiome in the pathogenesis of GVHD and suggest that altering the mycobiome by antifungal drugs can help ameliorate GI-GVHD. In addition, given that the genetic constitution of patients affects susceptibility to both Candida colonization and GVHD, whether identifying gene polymorphisms will facilitate personalized treatment of SCT recipients remains to be determined., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)