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Modulating the immune system against fungal infections—where are we?
EDITORIAL
10.1111/j.1469-0691.2011.03747.x
Modulating the immune system against fungal infections—where are we?
E. Roilides and A. Katragkou 3rd Department of Paediatrics, Infectious Diseases Unit, Aristotle University School of Medicine, Thessaloniki, Greece E-mail: [email protected]
Article published online: 29 November 2011
It has become increasingly clear that we have made important progress in understanding the immune response to various pathogens, including fungi. This may soon be translated to the development of effective approaches for modulating the immune system against invasive fungal infections (IFIs). What do immunomodulation and immunotherapy mean for the future of effective IFI management? During the last several decades, a growing population of immunocompromised patients has emerged, including patients with haematological malignancies, solid organ transplant recipients, patients with AIDS, those hospitalized in intensive-care units who undergo aggressive instrumental interventions and prolonged treatment with broad-spectrum antibacterials, premature infants, and patients with underlying conditions, such as diabetes mellitus, ketoacidosis, and iron overload. Despite the advent of newer antifungal agents and advances in critical care and surgical management, IFIs constitute a leading cause of morbidity and mortality, especially in immunocompromised patients [1]. Among fungal pathogens, Candida, Aspergillus and Cryptococcus spp. are responsible for the bulk of IFIs, and other fungi that are less common but have a worldwide distribution, such as Rhizopus, Mucor, Lichtheimia (formerly Absidia), Fusarium and Scedosporium spp. significantly contribute to IFI morbidity and mortality [2,3]. Given the limitations of the current antifungal armamentarium, manipulations aimed at the host immune response appear to constitute a rational approach. The papers presented in this theme section review important aspects of work on the immunotherapy of IFI, including mucocutaneous and invasive candidiasis, invasive aspergillosis, cryptococcosis, and other infections caused by more rare filamentous fungi, such as mucormycosis, fusariosis, and scedosporiosis. Van de Veerdonk et al. [4] describe the role of recombinant cytokines in the treatment of disseminated candidiasis. They first present an updated overview of the mechanisms behind the pathogenesis of Candida infections, providing the rationale for the use of adjuvant immunotherapy, and then present up-to-date data of studies in animal models or humans with a focus on the use of recombinant cytokines as a strategy to improve antifungal host defence.
The review by Carvalho et al. [5] highlights the conceptual advances made in our knowledge of cellular and immunological mechanisms, and how this knowledge could be exploited for the successful design of immunotherapeutic interventions against aspergillosis. They underline the fact that the progress in understanding the pathogenesis of fungal infections through the integration of immunological and genetic data will pay dividends in clinical practice. Antachopoulos and Walsh [6] present an overview of immune responses against Cryptococcus, and discuss the effects of immunomodulatory agents, mainly cytokines and monoclonal antibodies, that have been extensively studied in vitro and in vivo. In view of the Th1–Th2 balance concept, the question that arises is: are all patients with cryptococcal disease likely to benefit from immunomodulatory treatment? The authors conclude that, despite the progress made, the currently published clinical data on the adjunctive use of immunotherapy in patients with cryptococcal infections are too limited to lead to firm recommendations. The fourth paper [7] reviews the immunotherapeutic options for treating infections with rare filamentous fungi, such as Zygomycetes, Scedosporium and Fusarium spp. Among the immunotherapeutic agents, cytokines, including interferon-c, granulocyte–macrophage colony-stimulating factor, and granulocyte colony-stimulating factor, and granulocyte transfusion therapy, have shown the most promising results in ex vivo experiments, animal studies, case reports, and small case series. All of the reviews recapitulate the usefulness of sufficiently powered studies on the role of new immunotherapeutic agents against IFI. Clinical trials are needed to clarify some controversial issues, such as dosing, timing of immunomodulatory intervention, and the patient groups that would receive the most benefit.
Transparency Declaration E. Roilides has received grant support from Pfizer, Gilead, and Merck. He has made contributions to advisory boards of
ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases
Editorial
CMI
Gilead, Astellas, and Pfizer. A. Katragkou is supported by the Amphiarion Foundation of Chemotherapeutic Studies, Athens, Greece.
References 1. Zaoutis TE, Argon J, Chu J, Berlin JA, Walsh TJ, Feudtner C. The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis 2005; 41: 1232–1239. 2. Park BJ, Pappas PG, Wannemuehler KA et al. Invasive non-aspergillus mold infections in transplant recipients, United States 2001–2006. Emerg Infect Dis 2011; 17: 1855–1864.
111
3. Walsh TJ, Groll A, Hiemenz J, Fleming R, Roilides E, Anaissie E. Infections due to emerging and uncommon medically important fungal pathogens. Clin Microbiol Infect 2004; 10 (suppl 1): 48–66. 4. van de Veerdonk FL, Kullberg BJ, Netea M. Adjunctive immunotherapy with recombinant cytokines for the treatment of disseminated candidiasis. Clin Microbiol Infect 2012; 18: 112–119. 5. Carvalho A, Cunha C, Bistoni F, Romani L. Immunotherapy of aspergillosis. Clin Microbiol Infect 2012; 18: 120–125. 6. Antachopoulos C, Walsh T. Immunotherapy of Cryptococcus infections. Clin Microbiol Infect 2012; 18: 126–133. 7. Katragkou A, Roilides E. Immunotherapy of infections caused by rare filamentous fungi. Clin Microbiol Infect 2012; 18: 134–139.
ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 110–111
10.1111/j.1469-0691.2011.03747.x
Modulating the immune system against fungal infections—where are we?
E. Roilides and A. Katragkou 3rd Department of Paediatrics, Infectious Diseases Unit, Aristotle University School of Medicine, Thessaloniki, Greece E-mail: [email protected]
Article published online: 29 November 2011
It has become increasingly clear that we have made important progress in understanding the immune response to various pathogens, including fungi. This may soon be translated to the development of effective approaches for modulating the immune system against invasive fungal infections (IFIs). What do immunomodulation and immunotherapy mean for the future of effective IFI management? During the last several decades, a growing population of immunocompromised patients has emerged, including patients with haematological malignancies, solid organ transplant recipients, patients with AIDS, those hospitalized in intensive-care units who undergo aggressive instrumental interventions and prolonged treatment with broad-spectrum antibacterials, premature infants, and patients with underlying conditions, such as diabetes mellitus, ketoacidosis, and iron overload. Despite the advent of newer antifungal agents and advances in critical care and surgical management, IFIs constitute a leading cause of morbidity and mortality, especially in immunocompromised patients [1]. Among fungal pathogens, Candida, Aspergillus and Cryptococcus spp. are responsible for the bulk of IFIs, and other fungi that are less common but have a worldwide distribution, such as Rhizopus, Mucor, Lichtheimia (formerly Absidia), Fusarium and Scedosporium spp. significantly contribute to IFI morbidity and mortality [2,3]. Given the limitations of the current antifungal armamentarium, manipulations aimed at the host immune response appear to constitute a rational approach. The papers presented in this theme section review important aspects of work on the immunotherapy of IFI, including mucocutaneous and invasive candidiasis, invasive aspergillosis, cryptococcosis, and other infections caused by more rare filamentous fungi, such as mucormycosis, fusariosis, and scedosporiosis. Van de Veerdonk et al. [4] describe the role of recombinant cytokines in the treatment of disseminated candidiasis. They first present an updated overview of the mechanisms behind the pathogenesis of Candida infections, providing the rationale for the use of adjuvant immunotherapy, and then present up-to-date data of studies in animal models or humans with a focus on the use of recombinant cytokines as a strategy to improve antifungal host defence.
The review by Carvalho et al. [5] highlights the conceptual advances made in our knowledge of cellular and immunological mechanisms, and how this knowledge could be exploited for the successful design of immunotherapeutic interventions against aspergillosis. They underline the fact that the progress in understanding the pathogenesis of fungal infections through the integration of immunological and genetic data will pay dividends in clinical practice. Antachopoulos and Walsh [6] present an overview of immune responses against Cryptococcus, and discuss the effects of immunomodulatory agents, mainly cytokines and monoclonal antibodies, that have been extensively studied in vitro and in vivo. In view of the Th1–Th2 balance concept, the question that arises is: are all patients with cryptococcal disease likely to benefit from immunomodulatory treatment? The authors conclude that, despite the progress made, the currently published clinical data on the adjunctive use of immunotherapy in patients with cryptococcal infections are too limited to lead to firm recommendations. The fourth paper [7] reviews the immunotherapeutic options for treating infections with rare filamentous fungi, such as Zygomycetes, Scedosporium and Fusarium spp. Among the immunotherapeutic agents, cytokines, including interferon-c, granulocyte–macrophage colony-stimulating factor, and granulocyte colony-stimulating factor, and granulocyte transfusion therapy, have shown the most promising results in ex vivo experiments, animal studies, case reports, and small case series. All of the reviews recapitulate the usefulness of sufficiently powered studies on the role of new immunotherapeutic agents against IFI. Clinical trials are needed to clarify some controversial issues, such as dosing, timing of immunomodulatory intervention, and the patient groups that would receive the most benefit.
Transparency Declaration E. Roilides has received grant support from Pfizer, Gilead, and Merck. He has made contributions to advisory boards of
ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases
Editorial
CMI
Gilead, Astellas, and Pfizer. A. Katragkou is supported by the Amphiarion Foundation of Chemotherapeutic Studies, Athens, Greece.
References 1. Zaoutis TE, Argon J, Chu J, Berlin JA, Walsh TJ, Feudtner C. The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis 2005; 41: 1232–1239. 2. Park BJ, Pappas PG, Wannemuehler KA et al. Invasive non-aspergillus mold infections in transplant recipients, United States 2001–2006. Emerg Infect Dis 2011; 17: 1855–1864.
111
3. Walsh TJ, Groll A, Hiemenz J, Fleming R, Roilides E, Anaissie E. Infections due to emerging and uncommon medically important fungal pathogens. Clin Microbiol Infect 2004; 10 (suppl 1): 48–66. 4. van de Veerdonk FL, Kullberg BJ, Netea M. Adjunctive immunotherapy with recombinant cytokines for the treatment of disseminated candidiasis. Clin Microbiol Infect 2012; 18: 112–119. 5. Carvalho A, Cunha C, Bistoni F, Romani L. Immunotherapy of aspergillosis. Clin Microbiol Infect 2012; 18: 120–125. 6. Antachopoulos C, Walsh T. Immunotherapy of Cryptococcus infections. Clin Microbiol Infect 2012; 18: 126–133. 7. Katragkou A, Roilides E. Immunotherapy of infections caused by rare filamentous fungi. Clin Microbiol Infect 2012; 18: 134–139.
ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 110–111