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BackgroundInvasive 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.MethodsTo 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.ResultsThere 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.ConclusionsThese updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

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]

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 paradoxical increase in circulating Aspergillus antigen was observed during treatment with caspofungin in a patient with proven invasive aspergillosis. With the exception of treatment with the echinocandin, no other factors were found that might explain this clinical observation, which was supported by experiments done in vitro. [ABSTRACT FROM AUTHOR]

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.