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      Treatment of Aspergillosis

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          Abstract

          Infections caused by Aspergillus spp. remain associated with high morbidity and mortality. While mold-active antifungal prophylaxis has led to a decrease of occurrence of invasive aspergillosis (IA) in those patients most at risk for infection, breakthrough IA does occur and remains difficult to diagnose due to low sensitivities of mycological tests for IA. IA is also increasingly observed in other non-neutropenic patient groups, where clinical presentation is atypical and diagnosis remains challenging. Early and targeted systemic antifungal treatment remains the most important predictive factor for a successful outcome in immunocompromised individuals. Recent guidelines recommend voriconazole and/or isavuconazole for the primary treatment of IA, with liposomal amphotericin B being the first alternative, and posaconazole, as well as echinocandins, primarily recommended for salvage treatment. Few studies have evaluated treatment options for chronic pulmonary aspergillosis (CPA), where long-term oral itraconazole or voriconazole remain the treatment of choice.

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          Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).

          Peter Pappas, Barbara D. Alexander, David Andes … (2010)
          Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among organ transplant recipients. Multicenter prospective surveillance data to determine disease burden and secular trends are lacking. The Transplant-Associated Infection Surveillance Network (TRANSNET) is a consortium of 23 US transplant centers, including 15 that contributed to the organ transplant recipient dataset. We prospectively identified IFIs among organ transplant recipients from March, 2001 through March, 2006 at these sites. To explore trends, we calculated the 12-month cumulative incidence among 9 sequential cohorts. During the surveillance period, 1208 IFIs were identified among 1063 organ transplant recipients. The most common IFIs were invasive candidiasis (53%), invasive aspergillosis (19%), cryptococcosis (8%), non-Aspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). Median time to onset of candidiasis, aspergillosis, and cryptococcosis was 103, 184, and 575 days, respectively. Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006, a total of 729 IFIs were reported among 633 persons. One-year cumulative incidences of the first IFI were 11.6%, 8.6%, 4.7%, 4.0%, 3.4%, and 1.3% for small bowel, lung, liver, heart, pancreas, and kidney transplant recipients, respectively. One-year incidence was highest for invasive candidiasis (1.95%) and aspergillosis (0.65%). Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005. We detected a slight increase in IFIs during the surveillance period. These data provide important insights into the timing and incidence of IFIs among organ transplant recipients, which can help to focus effective prevention and treatment strategies.
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            Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database.

            Dimitrios P Kontoyiannis, Kieren A Marr, Benjamin J Park … (2010)
            The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from single-institution retrospective studies. The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versus-host disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelve-month cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matched-related allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.
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              Combination antifungal therapy for invasive aspergillosis: a randomized trial.

              Oliver Cornely, J Maertens, Monica Slavin … (2015)
              Invasive aspergillosis (IA) is associated with poor outcomes in patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT). Small studies suggest a role for combination antifungal therapy. To assess the safety and efficacy of voriconazole and anidulafungin compared with voriconazole monotherapy for treatment of IA. Randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov: NCT00531479). 93 international sites. 454 patients with HM or HCT and suspected or documented IA were randomly assigned to treatment with voriconazole and anidulafungin or placebo. Primary analysis was done in the modified intention-to-treat population of 277 patients in whom IA was confirmed. The primary outcome was 6-week mortality; secondary outcomes included 12-week mortality, mortality in major subgroups, and safety measures. Mortality rates at 6 weeks were 19.3% (26 of 135) for combination therapy and 27.5% (39 of 142) for monotherapy (difference, -8.2 percentage points [95% CI, -19.0 to 1.5]; P  = 0.087). Secondary mortality outcomes favored combination therapy. Multivariable regression analysis suggested that maximum galactomannan value, Karnofsky score, and baseline platelet count had prognostic significance. Most patients (218 of 277 [78.7%]) had IA diagnosis established by radiographic findings and maximum galactomannan positivity. In a post hoc analysis of this dominant subgroup, 6-week mortality was lower in combination therapy than monotherapy (15.7% [17 of 108] vs. 27.3% [30 of 110]; difference, -11.5 percentage points [CI, -22.7 to -0.4]; P = 0.037). Safety measures, including hepatotoxicity, were not different. Mortality at 6 weeks was higher than expected, and the difference in mortality was lower than expected, which reduced power to detect a treatment effect. Enrollment was restricted to patients with HM or HCT, which limited generalizability. Compared with voriconazole monotherapy, combination therapy with anidulafungin led to higher survival in subgroups of patients with IA. Limitations in power preclude definitive conclusions about superiority. Pfizer.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Fungi (Basel)
                Journal ID (iso-abbrev): J Fungi (Basel)
                Journal ID (publisher-id): jof
                Title: Journal of Fungi
                Publisher: MDPI
                ISSN (Electronic): 2309-608X
                Publication date (Electronic): 19 August 2018
                Publication date Collection: September 2018
                Volume: 4
                Issue: 3
                Electronic Location Identifier: 98
                Affiliations
                [1 ]Department of Medicine, University of California–San Diego, San Diego, CA 92103, USA; jjenks@ 123456ucsd.edu
                [2 ]Division of Infectious Diseases, Department of Medicine, University of California–San Diego, San Diego, CA 92103, USA
                [3 ]Section of Infectious Diseases and Tropical Medicine and Division of Pulmonology, Medical University of Graz, Graz 8036, Austria
                Author notes
                [* ]Correspondence: mhoenigl@ 123456ucsd.edu ; Tel.: +1-619-543-5605
                Article
                Publisher ID: jof-04-00098
                DOI: 10.3390/jof4030098
                PMC ID: 6162797
                PubMed ID: 30126229
                SO-VID: e19e40b8-9768-455e-bbdf-abadbb96cdfd
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 24 July 2018
                Date accepted : 15 August 2018
                Categories
                Subject: Review

                Keywords: aspergillus,posaconazole,amphotericin,isavuconazole,voriconazole,itraconzole,invasive aspergillosis,chronic pulmonary aspergillosis,diagnosis,interleukin 8
                Data availability:
                Keywords: aspergillus, posaconazole, amphotericin, isavuconazole, voriconazole, itraconzole, invasive aspergillosis, chronic pulmonary aspergillosis, diagnosis, interleukin 8

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