Background/Aims: Adding granulocyte macrophage colony-stimulating factor (GM-CSF) may improve the response to antifungal therapy in immunosuppressed patients with invasive fungal disease (IFD). Methods: We retrospectively assessed 66 patients in whom GM-CSF was given during antifungal therapy. Results: Severe neutropenia (77%) and refractory/relapsed cancer (65%) were common in the group. Prior to GM-CSF therapy, 15% of patients received high-dose corticosteroids for a median of 30 ± 16 days [median cumulative dose (c.d.) 1,184 ± 1,019 mg], and 9 received steroids during GM-CSF therapy for a median of 16 ± 12 days (median c.d. 230 ± 1,314 mg). Mild toxic effects were noted in 9% of patients; there were no cases of cardiopulmonary toxicity. All-cause deaths were observed in 68% of patients and 48% died of progressive IFD. High-dose corticosteroids prior to GM-CSF (OR 24; 95% CI 2.21–264.9; p ≤ 0.009), GM-CSF started in the intensive care unit (OR 10; 95% CI 1.66–63.8; p ≤ 0.01), concurrent granulocyte transfusions (OR 5; 95% CI 1.27–16.8; p ≤ 0.02) and proven/probable IFD (OR 4; 95% CI 1–16.2; p ≤ 0.05) predicted antifungal treatment failure. Conclusions: GM-CSF adjuvant therapy was tolerated without serous toxicity and antifungal treatment failure remained a challenge in patients treated with high-dose systemic corticosteroids.

1.
Safdar A: Difficulties with fungal infections in acute myelogenous leukemia patients: immune enhancement strategies. Oncologist 2007;12(suppl 2):2–6.
2.
Safdar A: Strategies to enhance immune function in hematopoietic transplantation recipients who have fungal infections. Bone Marrow Transplant 2006;38:327–337.
3.
Safdar A: Immunomodulation therapy for invasive aspergillosis: discussion on myeloid growth factors, recombinant cytokines and antifungal drug immune modulation. Curr Fungal Infect Rep 2010;4:1–7.
4.
Roilides E, Holmes A, Blake C, Venzon D, Pizzo PA, Walsh TJ: 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.
5.
Roilides E, Blake C, Holmes A, Pizzo PA, Walsh TJ: 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.
6.
Gil-Lamaignere C, Simitsopoulou M, Roilides E, Maloukou A, Winn RM, Walsh TJ: Interferon-gamma and granulocyte-macrophage colony-stimulating factor augment the activity of polymorphonuclear leukocytes against medically important zygomycetes. J Infect Dis 2005;191:1180–1187.
7.
Rodríguez MM, Calvo E, Mariné M, Pastor FJ, Fernandez-Ballart J, Guarro J: Efficacy of liposomal amphotericin B combined with gamma interferon or granulocyte-macrophage colony-stimulating factor for treatment of systemic zygomycosis in mice. Antimicrob Agents Chemother 2009;53:3569–3571.
8.
Lamaris GA, Chamilos G, Lewis RE, Safdar A, Raad II, Kontoyiannis DP: Scedosporium infection in a tertiary care cancer center: a review of 25 cases from 1989–2006. Clin Infect Dis 2006;43:1580–1584.
9.
Safdar A, Papadopoulos EB, Young JW: Breakthrough Scedosporium apiospermum (Pseudallescheria boydii) brain abscess during therapy for invasive pulmonary aspergillosis following high-risk allogeneic hematopoietic stem cell transplantation. Scedosporiasis and recent advances in antifungal therapy. Transpl Infect Dis 2002;4:212–217.
10.
Roilides E, Simitsopoulou M, Katragkou A, Walsh TJ: Host immune response against Scedosporium species. Med Mycol 2009;47:433–440.
11.
Lewis R, Hogan H, Howell A, Safdar A: Progressive fusariosis: unpredictable posaconazole bioavailability, and feasibility of recombinant interferon-gamma plus granulocyte macrophage-colony stimulating factor for refractory disseminated infection. Leuk Lymphoma 2008;49:163–165.
12.
Abzug MJ, Walsh TJ: Interferon-gamma and colony-stimulating factors as adjuvant therapy for refractory fungal infections in children. Pediatr Infect Dis J 2004;23:769–773.
13.
Bandera A, Trabattoni D, Ferrario G, Cesari M, Franzetti F, Clerici M, Gori A: Interferon-gamma and granulocyte-macrophage colony stimulating factor therapy in three patients with pulmonary aspergillosis. Infection 2008;36:368–373.
14.
Dignani MC, Rex JH, Chan KW, Dow G, de Magalhaes-Silverman M, Maddox A, Walsh T, Anaissie E: Immunomodulation with interferon-gamma and colony-stimulating factors for refractory fungal infections in patients with leukemia. Cancer 2005;104:199–204.
15.
Bodey GP, Anaissie E, Gutterman J, Vadhan-Raj S: Role of granulocyte-macrophage colony-stimulating factor as adjuvant therapy for fungal infection in patients with cancer. Clin Infect Dis 1993;17:705–707.
16.
Safdar A, Rodriguez GH, Lichtiger B, Dickey BF, Kontoyiannis DP, Freireich EJ, Shpall EJ, Raad II, Kantarjian HM, Champlin RE: Recombinant interferon γ1b immune enhancement in 20 patients with hematologic malignancies and systemic opportunistic infections treated with donor granulocyte transfusions. Cancer 2006;106:2664–2671.
17.
Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE, Erjavec Z, Fiere D, Lortholary O, Maertens J, Meis JF, Patterson TF, Ritter J, Selleslag D, Shah PM, Stevens DA, Walsh TJ, Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer, Mycoses Study Group of the National Institute of Allergy and Infectious Diseases: Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002;34:7–14.
18.
Safdar A, Singhal S, Mehta J: Clinical significance of non-Candida fungal blood isolation in patients undergoing high-risk allogeneic hematopoietic stem cell transplantation (1993–2001). Cancer 2004;100:2456-2461.
19.
Safdar A, Rodriguez GH, De Lima MJ, Petropoulos D, Chemaly RF, Worth LL, Shpall EJ, Rolston KV, Raad II, Chan KW, Champlin RE: Infections in 100 cord blood transplantations: spectrum of early and late posttransplant infections in adult and pediatric patients 1996–2005. Medicine 2007;86:324–333.
20.
Safdar A, Hanna HA, Boktour M, Kontoyiannis DP, Hachem R, Lichtiger B, Freireich EJ, Raad II: Impact of high-dose granulocyte transfusions in patients with cancer with candidemia: retrospective case-control analysis of 491 episodes of Candida species bloodstream infections. Cancer 2004;101:2859–2865.
21.
Chemaly RF, Torres HA, Hachem R, Kontoyiannis DP, Safdar A, Raad II: Human herpesvirus-6 DNAemia in immunosuppressed adult patients with leukemia at risk for mold infection. Haematologica 2008;93:157–158.
22.
Rowe JM, Andersen JW, Mazza JJ, Bennett JM, Paietta E, Hayes FA, Oette D, Cassileth PA, Stadtmauer EA, Wiernik PH: A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (>55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 1995;86:457–462.
23.
Verbeek W, Wörmann B, Koch P, Aul C, Hinrichs HF, Balleisen L, Rowe JM, Bennett J, Haase D, Fonatsch C, Heinecke A, Büchner T, Hiddemann W: Results of a randomized double-blind placebo-controlled trial evaluating sequential high-dose cytosine arabinoside/mitoxantrone chemotherapy with or without granulocyte/macrophage-colony-stimulating factor in high-risk myelodysplastic syndromes. J Cancer Res Clin Oncol 1999;125:369–374.
24.
Heaney ML, Toy EL, Vekeman F, Laliberté F, Dority BL, Perlman D, Barghout V, Duh MS: Comparison of hospitalization risk and associated costs among patients receiving sargramostim, filgrastim, and pegfilgrastim for chemotherapy-induced neutropenia. Cancer 2009;115:4839–4848.
25.
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.
26.
Choi JH, Brummer E, Kang YJ, Jones PP, Stevens DA: Inhibitor ĸB and nuclear factor ĸB in granulocyte-macrophage colony-stimulating factor antagonism of dexamethasone suppression of the macrophage response to Aspergillus fumigatus conidia. J Infect Dis 2006;193:1023–1028.
27.
Schmidt S, Tramsen L, Hanisch M, Latgé JP, Huenecke S, Koehl U, Lehrnbecher T: Human natural killer cells exhibit direct activity against Aspergillus fumigatus hyphae, but not against resting conidia. J Infect Dis 2011;203:430–435.
28.
Safdar A, Shelburne SA, Evans SE, Dickey BF: Inhaled therapeutics for prevention and treatment of pneumonia. Expert Opin Drug Saf 2009;8:435–449.
29.
Quezada G, Koshkina NV, Zweidler-McKay P, Zhou Z, Kontoyiannis DP, Kleinerman ES: Intranasal granulocyte-macrophage colony-stimulating factor reduces the Aspergillus burden in an immunosuppressed murine model of pulmonary aspergillosis. Antimicrob Agents Chemother 2008;52:716–718.
30.
Rao RD, Anderson PM, Arndt CA, Wettstein PJ, Markovic SN: Aerosolized granulocyte macrophage colony-stimulating factor (GM-CSF) therapy in metastatic cancer. Am J Clin Oncol 2003;26:493–498.
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