Ben E. De Pauw

Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign.

BACKGROUND Computed tomography (CT) of the chest may be used to identify the halo sign, a macronodule surrounded by a perimeter of ground-glass opacity, which is an early sign of invasive pulmonary aspergillosis (IPA). This study analyzed chest CT findings at presentation from a large series of patients with IPA, to assess the prevalence of these imaging findings and to evaluate the clinical utility of the halo sign for early identification of this potentially life-threatening infection. METHODS Baseline chest CT imaging findings from 235 patients with IPA who participated in a previously published study were systematically analyzed. To evaluate the clinical utility of the halo sign for the early identification and treatment of IPA, we compared response to treatment and survival after 12 weeks of treatment in 143 patients who presented with a halo sign and in 79 patients with other imaging findings. RESULTS At presentation, most patients (94%) had > or =1 macronodules, and many (61%) also had halo signs. Other imaging findings at presentation, including consolidations (30%), infarct-shaped nodules (27%), cavitary lesions (20%), and air-crescent signs (10%), were less common. Patients presenting with a halo sign had significantly better responses to treatment (52% vs. 29%; P<.001) and greater survival to 84 days (71% vs. 53%; P<.01) than did patients who presented with other imaging findings. CONCLUSIONS Most patients presented with a halo sign and/or a macronodule in this large imaging study of IPA. Initiation of antifungal treatment on the basis of the identification of a halo sign by chest CT is associated with a significantly better response to treatment and improved survival.

International Conference for the Development of a Consensus on the Management and Prevention of Severe Candidal Infections

Because of the rapidly increasing incidence of serious candidal infections, a consensus conference of 22 investigators from the United States, Europe, and Japan was held to discuss strategies for the prevention and treatment of deep-organ infections caused by Candida species. Commonly asked questions concerning the management of candidal infections were selected for discussion by the participating investigators. Possible answers to the questions were developed by the investigators, who then voted anonymously for their preferences. In certain instances, unanimity or a strong consensus was the result. In all cases, the full spectrum of responses was recorded and is presented in this report. The forms of candidal infection addressed included candidemia, candiduria, hepatosplenic candidiasis (chronic systemic candidiasis), candidal endophthalmitis, and candidal peritonitis. Prevention and treatment strategies were considered for patients who have undergone surgery, for neutropenic and nonneutropenic patients, and for patients who have undergone bone marrow and solid organ transplantation. The therapeutic roles of amphotericin B (standard and lipid formulations) and the azoles were considered.

Defining responses to therapy and study outcomes in clinical trials of invasive fungal diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer consensus criteria.

Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge.

Monitoring myeloablative therapy-induced small bowel toxicity by serum citrulline concentration: a comparison with sugar permeability tests.

Intestinal mucositis is an important cause of cancer treatment‐related morbidity and mortality, carrying a serious economic burden. Currently, objective parameters are lacking that would enable the monitoring of gut damage in routine clinical practice, thus hindering the development of clinical studies designed to investigate potential new strategies aimed at reducing or preventing this side effect. The authors investigated the characteristics of serum citrulline concentration compared with sugar permeability tests with respect to its use as a marker for cancer treatment‐induced small bowel injury.

Efficacy of Itraconazole in the Prevention of Fungal Infections Among Neutropenic Patients with Hematologic Malignancies and Intensive Chemotherapy. A Double Blind, Placebo Controlled Study

We studied the efficacy and safety of itraconazole for the prevention of fungal infection in neutropenic patients given cytotoxic chemotherapy for hematologic malignancies. Patients were randomly allocated to receive either itraconazole (200 mg bd) or placebo in addition to oral amphotericin B until the patient either developed fungal infection or had completed antileukemic treatment. Forty six patients (83 neutropenic episodes) treated with itraconazole and 46 placebo treated patients (84 neutropenic episodes) were evaluable. No specific toxicity was noted. Nine fungal infections developed in the itraconazole group, of which four were histologically or microbiologically proven and 15 in the patients given placebo (eight proven) (p < 0.12). All these patients received IV amphotericin B. The incidence of Candida albicans infections tended to be lower in the itraconazole group, but overall, there was no measurable improvement in the prevention of fungal infections and mortality by itraconazole.

Comparison of Two Highly Discriminatory Molecular Fingerprinting Assays for Analysis of Multiple Aspergillus fumigatus Isolates from Patients with Invasive Aspergillosis

ABSTRACT Two highly discriminatory fingerprinting assays, short tandem repeat typing and amplified fragment length polymorphism (AFLP), were compared to determine the genetic relatedness between 55 isolates of Aspergillus fumigatus obtained from 15 different patients suffering from proven invasive aspergillosis. Both techniques showed that interpatient isolates belonged to different genotypes and that intrapatient isolates from deep sites were all of the same genotype. By contrast, multiple genotypes were found among isolates originating from respiratory samples. Both techniques have specific advantages and disadvantages. AFLP is more universally applicable, but short tandem repeat analysis offers better discriminatory power and should be the preferred method for standardizing typing of clinical isolates of Aspergillus fumigatus.

Forum Report: Issues in Clinical Trials of Empirical Antifungal Therapy in Treating Febrile Neutropenic Patients

There is inferential evidence that some patients with prolonged neutropenia and fever not responding to antibacterial agents are at sufficient risk of deep mycoses to warrant empirical therapy, although superiority of an antifungal agent over placebo has not been conclusively demonstrated. Amphotericin B deoxycholate, liposomal amphotericin B, and intravenous itraconazole followed by oral itraconazole solution are licensed in the United States for this indication. Fluconazole and voriconazole have given favorable results in clinical trials of patients with low and high risk of deep mold infections, respectively. Design features that can profoundly influence outcome of empirical trials are (1) inclusion of low-risk patients, (2) failure to blind the study, (3) obscuration of antifungal effects by changing antibacterial antibiotics, (4) failure to balance both arms of the study in terms of patients with prior antifungal prophylaxis or with severe comorbidities, (5) the merging of end points evaluating safety with those of efficacy, and (6) choice of different criteria for resolution of fever.

Two strategies for managing invasive aspergillosis: a decision analysis

We devised a diagnostic approach based on screening plasma for an Aspergillus antigen with use of a sandwich enzyme-linked immunosorbent assay (ELISA), thoracic computed tomographic scanning, and radionuclide imaging for managing patients at risk for invasive aspergillosis. We used a decision analytic model to compare this alternative strategy with the conventional strategy, which relies only on the presence of clinical symptoms, persistent fever, and chest roentgenographic findings. Use of the alternative strategy reduced the number of patients who would receive antifungal treatment empirically, but this strategy was more expensive. The specificity of the sandwich ELISA had a significant impact on cost, but the sensitivity did not. A 13% prevalence of infection resulted in equal costs for both strategies. As much as 43.3% of the patients treated empirically could be given liposomal amphotericin B (L-AmB) before the conventional strategy became the most expensive. The costs of the alternative strategy were less than those of the conventional strategy when >5.3% of all patients, irrespective of strategy, were treated with L-AmB.

Between Over- and Undertreatment of Invasive Fungal Disease

Received 7 July 2005; accepted 8 July 2005; electronically published 29 September 2005. Reprints or correspondence: Dr. Ben E. de Pauw, 603 Dept. of Blood Transfusion and Transplant Immunology, University Medical Center St. Radboud, Radboud University Nijmegen, Geert Grooteplein zuid 6, 6525 GA Nijmegen, The Netherlands (b.depauw@abti.umcn.nl). Clinical Infectious Diseases 2005; 41:1251–3 2005 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2005/4109-0006

Need for Alternative Trial Designs and Evaluation Strategies for Therapeutic Studies of Invasive Mycoses

15.00 BACKGROUND OF EMPIRICAL ANTIFUNGAL THERAPY