Abstract
Evidence from several in vitro and animal model studies suggests a modulatory role of haemopoietic, TH1 and TH2 cytokines in host defence against fungi, and highlights their potential utility as adjunctive therapy for management of systemic mycoses (SM). However, there are limited clinical data to support the use of cytokines in prevention and treatment of SM. Thus, at present no adjunctive treatment is justified for routine use in all patients. Potential application of these immunomodulatory agents include the use of granulocyte-macrophage colony-stimulating factor or macrophage colony-stimulating factor in the management of mycoses in neutropenic patients with myelogenous leukaemia or bone marrow transplantation. Interferon-γ may have a useful role against aspergillosis in patients with chronic granulomatous disease. Granulocyte colony-stimulating factor-elicited white blood cell transfusions may be life saving to patients with refractory SM. Better understanding of synergy between cytokines and specific antifungals may provide powerful tools for managing these serious infections.
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Gaviria JM, van Burik JA, Dale DC, et al. Comparison of interferon-gamma, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor for priming leukocyte-mediated hyphal damage of opportunistic fungal pathogens. J Infect Dis 1999; 179: 1038–41
Vecchiarelli A, Monari C, Baldelli F, et al. Beneficial effect of recombinant human granulocyte colony-stimulating factor on fungicidal activity of polymorphonuclear leukocytes from patients with AIDS. J Infect Dis 1995; 171: 1448–54
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 interferon-γ. Infect Immun 1993; 61: 4870–7
Roilides E, Blake C, Holmes A, et al. Granulocyte-macrophage colony-stimulating factor and interferon-γ prevent dexamethasone-induced immunosuppression of antifungal monocyte activity against Aspergillus fumigatus hyphae. J Med Vet Mycol 1996; 34: 63–9
Lieschke G, Burgess A. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. N Engl J Med 1992; 327: 28–35
Morrissey PJ, Grabstein KH, Reed SG, et al. Granulocyte-macrophage colony-stimulating factor: a potent activation signal for mature macrophages and monocytes. Int Arch Allergy Immunol 1989; 88: 40–5
Rex JH, Bhalla SC, Cohen DM, et al. Protection of human polymorphonuclear leukocyte function from the deleterious effects of isolation, irradiation and storage by gamma-interferon and granulocyte colony-stimulating factor. Transfusion 1995; 35: 605–11
Roilides E, Pizzo PA. Modulation of host defenses by cytokines: evolving adjuncts in prevention and treatment of serious infections in immunocompromised hosts. Clin Infect Dis 1992; 15: 508–24
Roilides E, Sein T, Holmes A, et al. Effects of macrophage colony-stimulating factor on antifungal activity of mononuclear phagocytes against Aspergillus fumigatus. J Infect Dis 1995; 172: 1028–34
Roilides E, Holmes A, Blake C, et al. Effects of granulocyte colony-stimulating factor and interferon-γ on antifungal activity of human polymorphonuclear neutrophils against pseudohyphae of different medically important Candida species. J Leukoc Biol 1995; 57: 651–6
Roilides E, Kadiltsoglou I, Dimitriadou A, et al. Interleukin-4 suppresses antifungal activity of human mononuclear phagocytes against Candida albicans in association with decreased uptake of blastoconidia. FEMS Immunol Med Microbiol 1997; 19: 169–80
Roilides E, Katsifa H, Tsaparidou S, et al. Interleukin-10 suppresses phagocytic and antihyphal activities of human neutrophils. Cytokine 2000; 12: 379–87
Romani L, Mencacci A, Tonnetti L, et al. Interleukin-12 but not interferon-gamma production correlates with induction of T helper type-1 phenotype in murine candidiasis. Eur J Immunol. 1994; 24: 909–15
Vazquez N, Lyman CA, Chanock SJ, et al. Interleukin-15 augments superoxide production and microbicidal activity of human monocytes against Candida albicans. Infect Immun 1998; 66: 145–50
Polak-Wyss A. Protective effect of human granulocyte colony-stimulating factor on Cryptococcus and Aspergillus infections in normal and immunosuppressed mice. Mycoses 1991; 34: 205–15
Muranaka H, Suga M, Nakagawa K, et al. Effects of granulocyte and granulocyte-macrophage colony-stimulating factors in a neutropenic murine model of trichosporonosis. Infect Immun 1997; 65: 3422–9
Kullberg BJ, van der Meer JW, Meis JF, et al. Recombinant murine granulocyte colony-stimulating factor protects against acute disseminated Candida albicans infection in nonneutropenic mice. J Infect Dis 1998; 177: 175–81
Mayer P, Schutze C, Lam C, et al. Recombinant murine granulocyte-macrophage colony-stimulating factor augments neutrophil recovery and enhances resistance to infections in myelosuppressed mice. J Infect Dis 1991; 163: 584–90
Cenci E, Bartocci A, Puccetti P, et al. Macrophage colony-stimulating factor in murine candidiasis: serum and tissue levels during infection and protective effect of exogenous administration. Infect Immun 1991; 59: 868–72
Walsh T, Gonzalez C, Lyman C, et al. Human recombinant macrophage colony stimulating factor (M-CSF) augments pulmonary host defense against Aspergillus fumigaius [abstract no. F-27]. Abstracts of the Annual Meeting of the American Society of Microbiology; 1994 May; Las Vegas
Kullberg BJ, Van’t Wout JW, Hoogstraten C, et al. Recombinant interferon-γ enhances resistance to acute disseminated Candida albicans infection in mice. J Infect Dis 1993; 168: 436–43
Garner RE, Kuruganti U, Czarniecki CW, et al. In vivo immune responses to Candida albicans modified by treatment with recombinant murine gamma interferon. Infect Immun 1989; 57: 1800–8
Cenci E, Mencacci A, Del Sero G, et al. Interleukin-4 causes susceptibility to invasive aspergillosis through suppression of protective type 1 responses. J Infect Dis 1999; 180: 1957–68
Del Sero G, Mencacci A, Cenci E, et al. Antifungal type 1 responses are upregulated in IL-10-deficient mice. Microbes Infect 1999; 1: 1169–80
Mehrad B, Strieter RM, Standiford TJ. Role of TNF-alpha in pulmonary host defense in murine invasive aspergillosis. J Immunol 1999; 162: 1633–40
American Society of Clinical Oncology. Recommendations for use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol 1994; 12: 2471–508
Trillet-LenoirV, Green J, Manegold C, et al. Recombinant granulocyte colony-stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 1993; 29A: 319–24
Gerhartz HH, Engelhard M, Meusers P, et al. Randomized, double-blind, placebo-controlled phase III study of recombinant human granulocyte-macrophage colony-stimulating factor, as adjunct to induction treatment of high-grade malignant non-Hodgkin’s lymphomas. Blood 1993; 15: 2329–39
Rowe JM, Anderson JW, Mazza JJ, et al. Arandomized placebocontrolled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (>55 to 70 years) with acute myelogenous leukemia: a study by the Eastern Cooperative Oncology Group (E1490). Blood 1995; 86: 457–62
Rowe JM. Treatment of acute myeloid leukemia with cytokines: effect on duration of neutropenia and response to infections. Clin Infect Dis 1998; 26: 1290–4
Heil G, Hoelzer D, Sanng MA, et al. A randomized, doubleblind, placebo-controlled, phase III study of Filgrastin in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. Blood 1997; 90: 4710–8
Nemunaitis J, Shannon-Dorcy K, Appelbaum FR, et al. Longterm follow-up of patients with invasive fungal disease who received adjunctive therapy with recombinant human macrophage colony-stimulating factor. Blood 1993; 82: 1422–7
Aviles A, Guzman R, Garcia EL, et al. Results of a randomized trial of granulocyte colony-stimulating factor in patients with infection and severe granulocytopenia. Anti-Cancer Agents 1996; 7: 392–3
Ohno R, Miyawaki S, Hatake K, et al. Human urinary macrophage colony-stimulating factor reduces the incidence and duration of febrile neutropenia and shortens the period required to finish three courses of intensive consolidation therapy in acute myeloid leukemia: a double-blind controlled study. J Clin Oncol 1997; 15: 2954–65
Nemunaitis J, Buckner CD, Dorsey KS, et al. Retrospective analysis of infectious disease in patients who receive recombinant human granulocyte-macrophage colony-stimulating factor versus patients not receiving a cytokine who underwent autologous bone marrow transplantation for treatment of lymphoid cancer. Am J Clin Oncol 1998; 21: 341–6
Grauer ME, Bokemeyer C, Bautsch W, et al. Successful treatment of a Trichosporon beigelii septicemia in a granulocytopenic patient with amphotericin B and granulocyte colony-stimulating factor. Infection 1994; 22: 283–6
Gonzalez CE, Couriel DR, Walsh TJ. Successful treatment of disseminated zygomycosis in a neutropenic patient with amphotericin B lipid complex and granulocyte colony-stimulating factor. Clin Infect Dis 1997; 24: 192–6
Hennequin C, Benkerrou M, Gaillard JL, et al. Role of granulocyte colony-stimulating factor in the management of infection with Fusarium. oxysporum. in a neutropenic child. Clin Infect Dis 1994; 18: 490–1
Bodey GP, Anaissie E, Gutterman J, et al. Role of granulocytemacrophage colony-stimulating factor as adjuvant therapy for fungal infection in patients with cancer. Clin Infect Dis 1993; 17: 705–7
Kullberg BJ, van de Woude K, Aoun M, et al. A double-blind, randomized, placebo-controlled phase II study of Filgrastim (recombinant granulocyte colony-stimulating factor) in combination with fluconazole for treatment of invasive candidiasis and candidemia in nonneutropenic patients [abstract no. J-100]. Program and Abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, 1998
Peters BG, Adkins DR, Harrison BR, et al. Antifungal effects of yeast-derived rhu-GM-CSF in patients receiving high-dose chemotherapy given with or without autologous stem cell transplantation: a retrospective analysis. Bone Marrow Transplant 1996; 18: 93–102
Nemunaitis J, Cox J, Meyer W, et al. Comparison of neutrophil and monocyte function by microbicidal cell-kill assay in patients with cancer receiving granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or no cytokine after cytotoxic chemotherapy. Am J Clin Oncol 1998; 21: 308–12
Flynn TN, Kelsey SM, Hazel DL, et al. Cost effectiveness of amphotericin B plus G-CSF compared with amphotericin B monotherapy. Treatment of presumed deep-seated fungal infection in neutropenic patients in the UK. Pharmacoeconomics 1999; 16: 543–50
Ezekowitz RAB, Dinauer MC, Jaffe HS, et al. Partial correction of the phagocyte defect in patients with X-linked chronic granulomatous disease by subcutaneous interferon gamma. N Engl J Med 1988; 319: 146–51
Rex JH, Bennett JE, Gallin JI, et al. In vivo interferon-Á therapy augments the in vitro ability of chronic granulomatous disease neutrophils to damage Aspergillus hyphae. J Infect Dis 1991; 163: 849–52
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: 509–16
Ozsahin H, von Planta M, Muller I, et al. Successful treatment of invasive aspergillosis in chronic granulomatous disease by bone marrow transplantation, granulocyte colony-stimulating factor-mobilized granulocytes, and liposomal amphotericin-B. Blood 1998; 92: 2719–24
Roilides E, Sigler L, Bibashi E, et al. Disseminated infection due to Chrysosporium zonatum in a patient with chronic granulomatous disease and review of non-Aspergillus infections in these patients. J Clin Microbiol 1999; 37: 18–25
Touza Rey F, Martinez Vazquez C, Alonso J, et al. The clinical response to interferon-gamma in a patient with chronic granulomatous disease and brain abscesses due to Aspergillus fumigatus. Ann Med Int 2000; 17: 86–7
Sreenan C, Osiovich H. Myeloid colony-stimulating factors. Use in the newborn. Arch Pediatr Adolesc Med 1999; 153: 984–8
Kuritzkes DR, Parenti D, Ward DJ, et al. Filgrastim prevents severe neutropenia and reduces infective morbidity in patients with advanced HIV infection: results of a randomized, multicenter, controlled trial. AIDS 1998; 12: 65–74
Bensinger WI, Price TH, Dale DC, et al. The effects of daily recombinant human granulocyte colony-stimulating factor administration on normal granulocyte donors undergoing leukapheresis. Blood 1993; 81: 1883–8
Gaviria JM, van Burik JA, Dale CD, et al. Modulation of neutrophil-mediated activity against the pseudohyphal form of C. albicans by granulocyte colony-stimulating factor administered in vivo. J Infect Dis 1999; 179: 1301–4
Dignani MC, Anaissie EJ, Hester JP, et al. Treatment of neutropenia-related fungal infections with granulocyte colonystimulating factor-elicited white blood cell transfusions: a pilot study. Leukemia 1997; 11: 1621–30
Peters C, Minkov M, Matthes-Martin S, et al. Leucocyte transfusions from rhG-CSF or prednisolone stimulated donors for treatment of severe infections in immunocompromised neutropenic patients. Br J Haematol 1999; 106: 689–96
Vora S, Purimetla N, Brummer E, et al. Activity of voriconazole, a new triazole, combined with neutrophils or monocytes against Candida albicans: effect of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. Antimicrob Agents Chemother 1998; 42: 907–10
Vora S, Chauhan S, Brummer E, et al. Activity of voriconazole combined with neutrophils or monocytes against Aspergillus fumigatus: effects of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. Antimicrob Agents Chemother 1998; 42: 2299–303
Roilides E, Lyman CA, Sein T, et al. Amphotericin μ lipid complex synergizes with pulmonary alveolar macrophages to destroy conidia of A. fumigatus [abstract no. 700]. Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco: American Society for Microbiology, 1999
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: 2467–73
Kuhara T, Uchida K, Yamaguchi H. Therapeutic efficacy of human macrophage colony-stimulating factor, used alone and in combination with antifungal agents, in mice with systemic Candida albicans infection. Antimicrob Agents Chemother 2000; 44: 19–23
Roilides E, Uhlig C, 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: 1185–93
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-γ. J Infect Dis 1994; 170: 894–9
Poynton CH, Barnes RA, Rees J. Interferon gamma and granulocyte-macrophage colony-stimulating factor for the treatment of hepatosplenic candidosis in patients with acute leukemia. Clin Infect Dis 1998; 26: 239–40
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Farmaki, E., Roilides, E. Immunotherapy in Patients with Systemic Mycoses. BioDrugs 15, 207–214 (2001). https://doi.org/10.2165/00063030-200115040-00001
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DOI: https://doi.org/10.2165/00063030-200115040-00001