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An editorial focuses on two studies regarding the diagnosis of invasive aspergillosis (IA) using polymerase chain reaction (PCR) on plasma and bronchoalveolar lavage (BAL) fluid. It discusses the findings of these studies, emphasizing the improved accuracy of PCR in plasma compared to traditional tests like galactomannan. It also explores the challenges and questions raised by the studies, particularly in the context of the current definitions and classification criteria for IA.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article offers the author's insight on his tasks as editor-in-chief of the journal, providing information on the developments and accomplishments of the "Journal of Antimicrobial Chemotherapy" (JAC) in 2015. Topics include the rate of article submissions, the rejection rate of submissions, and the changes in the editorial team and structure of the journal.

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. [ABSTRACT FROM AUTHOR]

Abstract: 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 &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Goals of work Empirical antibiotic therapy usually started in patients who are neutropenic following treatment with cytostatic chemotherapy for a haematological malignancy as soon as fever develops to forestall fulminant sepsis. Hence, accurate and timely detection of fever is crucial to the successful management of infectious complications in these patients. We report an investigation of the feasibility and validity of continuous non-invasive body temperature measurement. Patients and methods The feasibility of non-invasive continuous measurement of the skin temperature was investigated using the Propaq® device in a cohort of 33 patients receiving an allogeneic HSCT who were all at risk of developing a febrile episode. Non-invasive continuous measurement of the skin temperature (CST) was compared with a standard episodic axillary temperature measurement (EAT) five times daily using a Terumo® device. The study period entailed monitoring during the 10 or 12 days that profound neutropenia was expected to be present. Main results Measuring the skin temperature continuously and accurately by using the Propaq® was feasible. The CST correlated well with the EAT measurements (Pearson r=0.782). Compared to EAT, the start of empirical therapy could be started 2.5 h earlier when relying on continuous measurements than was possible with EAT. Conclusion Continuous skin temperature measurements are feasible and valid compared to the conventional temperature measurement and may improve the management of infections by earlier detection of fever in neutropenic patients. [ABSTRACT FROM AUTHOR]

The availability of the Platelia Aspergillus, a sandwich ELISA kit that detects circulating galactomannan, has been a major advance for managing patients at risk for invasive aspergillosis because of the early detection of the antigen. The assay is now widely used throughout the world, including the USA. Although initial studies that assessed the performance characteristics of this assay reported high sensitivity and specificity, more recent studies show significant variation in performance. The causes of this variability are multifactorial and, in large part, cannot be explained because there is insufficient understanding of the kinetics of galactomannan in vivo. We explored some of the factors that affect the release of the aspergillus antigen that bears the epitope that reacts with the monoclonal antibody used in the ELISA, its leakage from the site of infection into the blood, and its binding to substances present in the blood. Factors that affect the detection of antigen in blood are also discussed, most notably the pretreatment procedure aimed at liberating the antigen from immune complexes. Understanding the biology of galactomannan release by aspergillus will greatly enhance our understanding of the kinetics of this and other surrogate markers and allow their optimum use in the management of invasive aspergillosis. [Copyright &y& Elsevier]

Oral mucositis represents a significant source of morbidity after chemotherapy and radiation therapy. Since infection may have an important role in the pathophysiology of oral mucositis, several antimicrobial agents have been investigated for their efficacy in preventing and treating this disease. We sought to establish the weight of evidence for antimicrobial treatment and identified 31 prospectively designed clinical trials of which 13 reported some benefit and 15 did not. No clear pattern was identified regarding patient type, cancer treatment, or type of antimicrobial agent used, and inconsistent assessment of oral mucositis made comparison of outcomes difficult. Newer drugs, such as the topical antimicrobial peptide iseganan HCl initially showed promise in reducing mucositis and the related oral pain but the results of a phase 3 trial were disappointing and the line of enquiry was abandoned altogether. Hence, there is a need to better understand the role of the microflora in the cause of oral mucositis if an antimicrobial agent for prevention and treatment of this disease is to be developed. [Copyright &y& Elsevier]

Discusses the relationship between mucosal barrier injury and candida colonization of the gut in neutropenic patients receiving cytotoxic treatment. Effect of cytotoxic therapy on invasive candidiasis; Phases of intestinal mucosal barrier injury; Ways of managing invasive candidiasis.

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. [ABSTRACT FROM AUTHOR]

The article focuses on the strategies for the treatment of invasive fungal diseases. It is stated that the need for empirical therapy was distilled into a definition of a fever that continued for three or more days despite broad-spectrum antibiotics. Several studies were conducted that compared the potential of several new antifungal drugs for empirical treatment and they found no major difference between them. It is stated that for the detection of pulmonary fungal disease, high-resolution Computerized Tomography (CT) of the chest is known to be superior to the traditional chest radiograph. It has also been shown that systematic use of this technique allows earlier diagnosis and treatment and thus better rates of survival.

The article presents the author's comment on the paper "The Evolution and Evaluation of a Whole Blood Polymerase Chain Reaction Assay for the Detection of Invasive Aspergillosis in Hematology Patients in a Routine Clinical Setting," that appear in the February 15, 2006 issue of the journal "Clinical Infectious Diseases." The primary aim of the researchers was to assess the performance of polymerase chain reaction (PCR) in terms of diagnosing invasive aspergillosis. They succeeded in supporting the value of a negative PCR result for ruling out invasive aspergillosis, thereby helping to limit empirical therapy to those patients who are most likely to have the disease.

The article discusses the 40th anniversary of the "Journal of Antimicrobial Chemotherapy," which will be celebrated with a series of articles, the Garrold Lecture and a special Supplement.

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. [ABSTRACT FROM AUTHOR]

Mucormycosis can be devastating and, as yet, there are no ideal therapies available. Observations that iron chelation may be a useful adjunct to antifungal treatment encouraged Spellberg et al. (J Antimicrob Chemother 2012; 715–22) to undertake a trial of deferasirox combined with liposomal amphotericin B (AmBisome®) as short-term therapy for mucormycosis. The results were disappointing as patients treated with deferasirox had a higher mortality rate at 90 days, leading the authors to conclude that the data did not support a role for initial, adjunctive deferasirox therapy for mucormycosis. We review the issues arising from this study to help decide whether the evidence that now exists supports further studies or represents the end of this line of enquiry. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented in response to the article about bronchoalveolar lavage (BAL) galactomannan enzyme immunoassay (EIA) for invasive aspergillosis diagnosis of patients suffering from hematologic diseases.

An introduction is presented in which the editor discusses various reports within the issue on topics including the high prevalence of azole resistance, cases of invasive aspergillosis defined by the detection of galactomannan, aspect of antimicrobial chemotherapy.

A response by Rocus R. Klont, J. Peter Donnelly, and Paul E. Verweij to a letter to the editor about their article published in a previous issue of the journal is presented.

The article focuses on invasive fungal disease (IFD). It relates the growing incidence of IFD in patients undergoing intensive chemotherapy for haematological malignancies. It outlines the various approaches to manage IFD in patients undergoing chemotherapy or conditioning therapy for haematological stem cell transplant (HSCT). An overview of a meeting that explored IFD diagnosis and treatment is presented.

A preface for the "Journal of Antimicrobial Chemotherapy" is presented.

An introduction to the journal is presented wherein the authors discuss the increasing number of patients undergoing treatment of haematological malignancies and haemotopoietic stem cell transplantation (HSCT), the development of an integrated care pathway in Cardiff, Wales, and a meeting of experts convened in Amsterdam, Netherlands on June 11-12, 2010.

This author comments on the drug posaconazole and its treatment of fungal infections. The drug is active against a wide range of yeasts and molds and appears to have an acceptable adverse-event profile and is well tolerated. The author concludes that posaconazole appears to be the drug of choice for prophylaxis whereas voriconazole remains the preferred treatment for aspergillosis.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article offers information on invasive fungal infections in much of the developed world are associated with medical progress. Topics include the millions of individuals worldwide living with human immunodeficiency virus who constitute a significant host group, and the infections are also common among other immunocompromised individuals as a reflection of technologic and therapeutic advances that have led to an enlarging susceptible host population.

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. [ABSTRACT FROM AUTHOR]

Antifungal prophylaxis during treatment for haematological malignancies has been studied for 50 years, yet it has not been wholly effective even when using antifungal drugs that exhibit potent activity in vitro against a broad range of fungal pathogens. Trials have demonstrated that it can reduce the incidence of invasive fungal diseases (IFD) and fungal deaths, but only two studies have had an impact on overall mortality. Furthermore, it has not significantly reduced the need for empirical antifungal therapy. Posaconazole was effective in preventing invasive aspergillosis in two studies of high-risk patients, and consensus guidelines grade it as a suitable choice for antifungal prophylaxis of invasive mould disease; however, its bioavailability was compromised by vomiting or diarrhoea so that an alternative parenteral antifungal drug was required. A recent trial of voriconazole prophylaxis after allogeneic stem cell transplantation failed to show superiority over fluconazole. With more accurate definitions of IFD, that utilize fungal biomarkers, such as galactomannan, together with computerized tomographic imaging, there is growing interest in a diagnostic-driven strategy, which could prove to be a more efficacious approach. [ABSTRACT FROM AUTHOR]

Presents several articles on internal medicine. Empiric therapy for febrile neutropenia; Calcium channel antagonists and gingival hyperplasia; Discussion on how to enhance professionalism of physicians.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Pneumocystis jirovecii can cause life-threatening pneumonia following treatment for haematological malignancies or after HSCT. The mortality rate of P. jirovecii pneumonia (PCP) in these patients is 30%-60%, especially after HSCT. The clinical presentation of PCP in haematology differs from that associated with HIV infection, with the disease being acute and more often severe, having a lower fungal burden and being more frequently linked to treatment with corticosteroids. Most cases occur in patients not receiving adequate prophylaxis. The development of new therapies, including targeted treatments and monoclonal antibodies in various haematological diseases, justifies constant vigilance in order to identify new at-risk populations and give prophylaxis accordingly. The fifth and sixth European Conferences on Infections in Leukaemia (ECIL-5 and ECIL-6) aimed to review risk factors for PCP in haematology patients and to establish evidence-based recommendations for PCP diagnosis, prophylaxis and treatment. This article focuses on the magnitude of the problem, the main differences in clinical presentation between haematology patients and other immunocompromised populations, especially HIV-infected patients, and the main risk factors. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article presents a view on the article--Prospective clinical evaluation of a LightCycler-mediated polymerase chain reaction assay, a nested-PCR assay and a galactomannan enzyme-linked immunosorbent assay for detection of invasive aspergillosis in neutropenic cancer patients and haematological stem cell transplant recipients--by D. Buchheidt along with others, published in "British Journal of Haematology." The article asserts that the specificity of the assay mentioned by D. Buchheidt was only 63.5% due to positive PCR (polymerase chain reaction) reactivity in blood samples in 38 of 104 patients classified as having no invasive aspergillosis.

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. [ABSTRACT FROM AUTHOR]

Episodes of invasive aspergillosis (IA) recruited to the voriconazole trial were reclassified according to the revised EORTC/MSG definitions. The efficacy of voriconazole was confirmed for possible, probable, and proven IA and was still better than found for the comparator arm.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. [ABSTRACT FROM PUBLISHER]

A correction is presented to the article "Epidemiology and Outcome of Fungemia in a Cancer Cohort of the Infectious Diseases Group (IDG) of the European Organization for Research and Treatment of Cancer.

More than two-thirds of patients with Epstein-Barr virus–related posttransplant lymphoproliferative disorder after hematopoietic stem cell transplant can be cured with rituximab-based treatment. Reduction of immunosuppression is associated with improved outcome; older age, extranodal disease, and acute graft-vs-host disease predict poor outcome.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. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM PUBLISHER]

Abstract: 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 &y& Elsevier]