Abstract
Understanding fungal pathogenesis and host-pathogen immune interaction at various stages of infection is critical to examine strategies for bolstering antifungal immune defenses. Recombinant myeloid growth factors, especially granulocyte-macrophage colony-stimulating factor and the protagonist T helper (Th) 1 cytokine, interferon-γ, are most frequently used in patients with refractory invasive aspergillosis. These cytokines are given alone or in combination and have also been used together in neutropenic patients receiving donor granulocyte transfusions. Recently, a number of investigators have presented provoking data regarding auxiliary effect of conventional antifungal drugs on hosts’ immune response and pathogen’s susceptibility for antifungal immune defenses. Antifungal immunotherapy and its ameliorative role in treatment for Aspergillus disease will need clinical trials that 1) consider well-characterized fungal disease; 2) illustrate underlying immune defect(s) (such as Th1 vs Th2, vs Th17 and functional status of natural killer and effector scavenger cells); 3) include a more specific patient population; 4) include standardized antifungal drug therapy; and importantly 5) consider its impact on hosts’ immune response and changes in pathogen’s susceptibility and virulence. At present, immunotherapy is reserved for patients with life-threatening invasive fungal disease in whom conventional antifungal drug therapy has failed, or for patients with advanced fungal disease and with factors associated with high probability of failure of conventional therapy alone.
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Papers of particular interest, published recently, have been highlighted as follows: • Of importance
Neofytos D, Horn D, Anaissie E, et al.: Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis 2009, 48:265–273.
Chamilos G, Luna M, Lewis RE, et al.: Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period (1989–2003). Haematologica 2006, 91:986–989.
Roden MM, Zaoutis TE, Buchanan WL, et al.: Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005, 41:634–653.
Leventakos K, Lewis RE, Kontoyiannis DP: Fungal infections in leukemia patients: how do we prevent and treat them? Clin Infect Dis 2010, 50:405–415.
Gerson SL, Talbot GH, Hurwitz S, et al.: Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann Intern Med 1984, 100:345–351.
Yuen KY, Woo PC, Ip MS, et al.: Stage-specific manifestation of mold infections in bone marrow transplant recipients: risk factors and clinical significance of positive concentrated smears. Clin Infect Dis 1997, 25:37–42.
Marr KA, Carter RA, Boeckh M, et al.: Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 2002, 100:4358–4366.
Paczesny S, Hanauer D, Sun Y, Reddy P: New perspectives on the biology of acute GVHD. Bone Marrow Transplant 2010, 45:1–11.
Safdar A, Rodriguez GH, De Lima MJ, et al.: Infections in 100 cord blood transplantations: spectrum of early and late posttransplant infections in adult and pediatric patients 1996–2005. Medicine (Baltimore) 2007, 86:324–333.
Safdar A, Rodriguez GH, Mihu CN, et al.: Infections in non-myeloablative hematopoietic stem cell transplantation patients with lymphoid malignancies: spectrum of infections, predictors of outcome and proposed guidelines for fungal infection prevention. Bone Marrow Transplant 2009 Jun 29 (Epub ahead of print).
Safdar A: Strategies to enhance immune function in hematopoietic transplantation recipients who have fungal infections. Bone Marrow Transplant 2006, 38:327–337.
Brown GD, Gordon S: Immune recognition of fungal beta-glucans. Cell Microbiol 2005, 7:471–479.
• Wheeler RT, Fink GR: A drug-sensitive genetic network masks fungi from the immune system. PloS Pathol 2006, 2:e35. In this article, Wheeler and Fink have shown the impact of immunologically active fungal antigen exposure following fungal cell wall-active drugs and the ancillary immune modulatory role of fungicidal drugs.
Mircescu MM, Lipuma L, van Rooijen N, et al.: Essential role for neutrophils but not alveolar macrophages at early time points following Aspergillus fumigatus infection. J Infect Dis 2009, 200:647–656.
Park SJ, Hughes MA, Burdick M, et al.: Early NK cell-derived IFN-{gamma} is essential to host defense in neutropenic invasive aspergillosis. J Immunol 2009, 182:4306–4312.
Gafa V, Lande R, Gagliardi MC, et al.: Human dendritic cells following Aspergillus fumigatus infection express the CCR7 receptor and a differential pattern of interleukin-12 (IL-12), IL-23, and IL-27 cytokines, which lead to a Th1 response. Infect Immun 2006, 74:1480–1489.
Zelante T, De Luca A, Bonifazi P, et al.: IL-23 and the Th17 pathway promote inflammation and impair antifungal immune resistance. Eur J Immunol 2007, 37:2695–2706.
Zelante T, De Luca A, D’Angelo C, et al.: IL-17/Th17 in anti-fungal immunity: what’s new? Eur J Immunol 2009, 39:645–648.
Armstrong-James DP, Turnbull SA, Teo I, et al.: Impaired interferon-gamma responses, increased interleukin-17 expression, and a tumor necrosis factor-alpha transcriptional program in invasive aspergillosis. J Infect Dis 2009, 200:1341–1351.
Bergmann A, Hartmann T, Cairns T, et al.: A regulator of Aspergillus fumigatus extracellular proteolytic activity is dispensable for virulence. Infect Immun 2009, 77:4041–4050.
Alp S, Arikan S: Investigation of extracellular elastase, acid proteinase and phospholipase activities as putative virulence factors in clinical isolates of Aspergillus species. J Basic Microbiol 2008, 48:331–337.
Ben-Ami R, Lewis RE, Leventakos K, et al.: Aspergillus fumigatus inhibits angiogenesis through the production of gliotoxin and other secondary metabolites. Blood 2009, 114:5393–5399.
Herbrecht R, Denning DW, Patterson TF, et al.: Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002, 347:408–415.
Rowe JM: Concurrent use of growth factors and chemotherapy in acute leukemia. Curr Opin Hematol 2000, 7:197–202.
Smith TJ, Khatcheressian J, Lyman GH, et al.: 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006, 24:3187–3205.
Godwin JE, Kopecky KJ, Head DR, et al.: A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest oncology group study (9031). Blood 1998, 91:3607–3615.
Heil G, Hoelzer D, Sanz MA, et al.: A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. The International Acute Myeloid Leukemia Study Group. Blood 1997, 90:4710–4718.
Smith TJ, Khatcheressian J, Lyman GH, et al.: 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006, 24:3187–3205.
Lyman GH, Kleiner JM: Summary and comparison of myeloid growth factor guidelines in patients receiving cancer chemotherapy. J Natl Compr Canc Netw 2007, 5:217–228.
Roilides E, Uhlig K, Venzon D, et al.: Enhancement of oxidative response and damage caused by human neutrophils to Aspergillus fumigatus hyphae by granulocyte colony-stimulating factor and gamma interferon. Infect Immun 1993, 61:1185–1193.
Polak-Wyss A: Protective effect of human granulocyte colony-stimulating factor (hG-CSF) on Cryptococcus and Aspergillus infections in normal and immunosuppressed mice. Mycoses 1991, 34:205–215.
Roilides E, Uhlig K, Venzon D, et al.: Prevention of corticosteroid-induced suppression of human polymorphonuclear leukocyte-induced damage of Aspergillus fumigatus hyphae by granulocyte colony-stimulating factor and gamma interferon. Infect Immun 1993, 61:4870–4877.
Sionov E, Mendlovic S, Segal E: Experimental systemic murine aspergillosis: treatment with polyene and caspofungin combination and G-CSF. J Antimicrob Chemother 2005, 56:594–597.
Graybill JR, Bocanegra R, Najvar LK, et al.: Granulocyte colony-stimulating factor and azole antifungal therapy in murine aspergillosis: role of immune suppression. Antimicrob Agents Chemother 1998, 42:2467–2473.
Patera AC, Menzel F, Jackson C, et al.: Effect of granulocyte colony-stimulating factor combination therapy on efficacy of posaconazole (SCH56592) in an inhalation model of murine pulmonary aspergillosis. Antimicrob Agents Chemother 2004, 48:3154–3158.
Dornbusch HJ, Urban CE, Pinter H, et al.: Treatment of invasive pulmonary aspergillosis in severely neutropenic children with malignant disorders using liposomal amphotericin B (AmBisome), granulocyte colony-stimulating factor, and surgery: report of five cases. Pediatr Hematol Oncol 1995, 12:577–586.
Brummer E, Kamberi M, Stevens DA: Regulation by granulocyte-macrophage colony-stimulating factor and/or steroids given in vivo of proinflammatory cytokine and chemokine production by bronchoalveolar macrophages in response to Aspergillus conidia. J Infect Dis 2003, 187:705–709.
Choi JH, Brummer E, Kang YJ, et al.: IkB and NFkB in GM-CSF antagonism of dexamethasone suppression of macrophage response to Aspergillus fumigatus conidia. J Infect Dis 2006, 193:1023–1028.
Roilides E, Blake C, Holmes A, et al.: Granulocyte-macrophage colony-stimulating factor and interferon-gamma prevent dexamethasone-induced immunosuppression of antifungal monocyte activity against Aspergillus fumigatus hyphae. J Med Vet Mycol 1996, 34:63–69.
Roilides E, Holmes A, Blake C, et al.: Antifungal activity of elutriated human monocytes against Aspergillus fumigatus hyphae: enhancement by granulocyte-macrophage colony-stimulating factor and interferon-gamma. J Infect Dis 1994, 170:894–899.
Bandera A, Trabattoni D, Ferrario G, et al.: Interferon-gamma and granulocyte-macrophage colony stimulating factor therapy in three patients with pulmonary aspergillosis. Infection 2008, 36:368–373.
Safdar A, Rodriguez G, Rolston KV, et al.: High-dose caspofungin combination antifungal therapy in patients with hematologic malignancies and hematopoietic stem cell transplantation. Bone Marrow Transplant 2007, 39:157–164.
Bodey GP, Anaissie E, Gutterman J, et al.: Role of granulocyte-macrophage colony-stimulating factor as adjuvant therapy for fungal infection in patients with cancer. Clin Infect Dis 1993, 17:705–707.
Emminger W, Emminger-Schmidmeier W, Peters C, et al.: Capillary leak syndrome during low dose granulocyte-macrophage colony-stimulating factor (rh GM-CSF) treatment of a patient in a continuous febrile state. Blut 1990, 61:219–221.
Rodriguez G, Georgescu G, Islam S, Safdar A: Safety of granulocyte macrophage-colony stimulating factor (GM-CSF) in 66 cancer patients with invasive fungal infections [abstract #3520]. Paper presented at the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America 46th Annual Meeting. Washington, DC; October 25–28, 2008.
Safdar A, Georgescu G, Rodriguez G, Champlin R: Granulocyte macrophage colony stimulating factor (GM-CSF) in stem cell transplant recipients: response to immune enhancement in early versus late serious post-transplant infections [abstract #2203]. The 2008 Annual Meeting of the American Society of Hematology. Blood (ASH Annual Meeting Abstracts) 2008, 112:4373.
Stevens DA: Th1/Th2 in aspergillosis. Med Mycol 2006, 44:S229–S235.
Stevens DA, Brummer E, Clemons KV: Interferon-gamma as an antifungal. J Infect Dis 2006, 194:S33–S37.
Clemons KV, Kamberi P, Chiller TM, et al.: Effects of interferon-gamma gene therapy in the murine central nervous system and concentrations in cerebrospinal fluid after intrathecal or intracerebral administration. Biotechnology 2005, 4:11–18.
Nagai H, Guo J, Choi H, Kurup V: Interferon-gamma and tumor necrosis factor-alpha protect mice from invasive aspergillosis. J Infect Dis 1995, 172:1554–1560.
A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic Granulomatous Disease Cooperative Study Group. N Engl J Med 1991, 324:509–516.
Dignani MC, Rex JH, Chan KW, et al.: Immunomodulation with interferon-gamma and colony-stimulating factors for refractory fungal infections in patients with leukemia. Cancer 2005, 104:199–204.
• Safdar A, Rodriguez G, Ohmagari N, et al.: The safety of interferon-gamma-1b therapy for invasive fungal infections after hematopoietic stem cell transplantation. Cancer 2005, 103:731–739. IFN-γ was considered to play a role in GVHD following allogeneic transplantation. This was the first report showing safety of recombinant IFN-γ therapy in allogeneic HSCT recipients; in fact, a number of patients with severe GVHD had improvement in GVHD despite partial withdrawal of anti-GVHD therapy during and immediately after IFN-γ therapy.
Steele C, Rapaka RR, Metz A, et al.: The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus. PLoS Pathog 2005, 1:e42.
Bellocchio S, Gaziano R, Bozza S, et al.: Liposomal amphotericin B activates antifungal resistance with reduced toxicity by diverting Toll-like receptor signalling from TLR-2 to TLR-4. J Antimicrob Chemother 2005, 55:214–222.
Lewis RE, Chamilos G, Prince RA, et al.: Pretreatment with empty liposomes attenuates the immunopathology of invasive pulmonary aspergillosis in corticosteroid-immunosuppressed mice. Antimicrob Agents Chemother 2007, 51:1078–1081.
Wheeler RT, Fink GR: A drug-sensitive genetic network masks fungi from the immune system. PLoS Pathog 2006, 2:e35.
Lamaris GA, Lewis RE, Chamilos G, et al.: Caspofungin-mediated beta-glucan unmasking and enhancement of human polymorphonuclear neutrophil activity against Aspergillus and non-Aspergillus hyphae. J Infect Dis 2008, 198:186–192.
Hohl TM, Feldmesser M, Perlin DS, et al.: Caspofungin modulates inflammatory responses to Aspergillus fumigatus through stage-specific effects on fungal beta-glucan exposure. J Infect Dis 2008, 198:176–185.
Safdar A: Fungal cytoskeleton dysfunction or immune activation triggered by beta-glucan synthase inhibitors: potential mechanisms for the prolonged antifungal activity of echinocandins. Cancer 2009, 115:2812–2815.
Safdar A, Rodriguez GH, Lichtiger B, et al.: Recombinant interferon gamma1b immune enhancement in 20 patients with hematologic malignancies and systemic opportunistic infections treated with donor granulocyte transfusions. Cancer 2006, 106:2664–2671.
Seidel MG, Peters C, Wacker A, et al.: Randomized phase III study of granulocyte transfusions in neutropenic patients. Bone Marrow Transplant 2008, 42:679–684.
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Dr. Safdar has received a research grant from Bayer.
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Safdar, A. Immunomodulation Therapy for Invasive Aspergillosis: Discussion on Myeloid Growth Factors, Recombinant Cytokines, and Antifungal Drug Immune Modulation. Curr Fungal Infect Rep 4, 1–7 (2010). https://doi.org/10.1007/s12281-010-0006-x
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DOI: https://doi.org/10.1007/s12281-010-0006-x