Recent Advances in the Therapy Against Invasive Aspergillosis

  • Corina E. Gonzalez
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 549)


The members of the genus Aspergillus are opportunistic fungi that cause disease almost exclusively in patients with chronic lung pathology or depressed immune defenses. Aspergillus disease has a variety of clinical manifestations, ranging from allergic responses occurring in the absence of fungal growth or airway colonization to invasion and destruction of lung parenchyma with or without dissemination to other organs (Denning and Stevens, 1990; Greenberger, 2002; Marr et al., 2002; Muller et al., 2002). Over the past decades, the incidence of invasive aspergillosis has increased dramatically as a result of an expansion of the population of immunocompromised patients. At particular risk for invasive aspergillosis are those patients with persistent and profound neutropenia as a result of aggressive anticancer chemotherapy, hematopoietic stem cell transplant, or aplastic anemia (Gerson et al., 1984; Weinberger et al., 1992; Walsh et al., 1994; Perea and Patterson, 2002). In addition, congenital or acquired qualitative defects of the phagocytic cells have also been associated with the development of invasive aspergillosis: examples are patients with chronic granulomatous disease, Job syndrome, or those receiving prolonged courses of immunosuppressive agents such as corticosteroids. Aspergillosis is uncommon in patients with AIDS but when present it is associated with short survival after diagnosis (Shetty et al., 1997; Holding et al., 2000).


Hematopoietic Stem Cell Transplant Invasive Aspergillosis Chronic Granulomatous Disease Invasive Fungal Infection Liposomal Amphotericin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aliff, T.B., Maslak, P.G., Juric, J.G., Heaney, M.L., Cathcart, K.N., Sepkowitz, K.A. et al. (2003). Refractory aspergillus pneumonia in patients with acute leukemia. Successful therapy with combination caspofungin and liposomal amphotericin B. Cancer 97, 1025–1032.PubMedCrossRefGoogle Scholar
  2. Ascioglu, S., Rex, J.H., de Pauw, B., Bennett, J.E., Bille, J., Crokaert, F. et al., 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 (2002). Defining opportunistic invasive fungal infections in immunocompromised subjects with cancer and hematopoietic stem cell transplants: An international consensus. Clin. Infect. Dis. 34, 7–14.Google Scholar
  3. Bhatia, S., McCullough, J., Perry, E.H., Clay, M., Ramsay, N.K.C., and Neglia, J.P. (1994). Granulocyte transfusions: Efficacy in treating fungal infections in neutropenic patients following bone marrow transplantation. Transfusion 34, 226–232.PubMedCrossRefGoogle Scholar
  4. Bodey, G.P., Anaissie, E., Gutterman, J., and Vadhan-Raj, S. (1993). Role of granulocyte-macrophage colony-stimulating factor as adjuvant therapy for fungal infection in patients with cancer. Clin. Infect. Dis. 17(4), 705–707.PubMedCrossRefGoogle Scholar
  5. Brummer, E. and Stevens, D.A. (1987). Activation of pulmonary macrophages for fungicidal activity by inter-feron γ or lymphokines. Clin. Exp. Immunol. 70, 520–528.PubMedGoogle Scholar
  6. Caillot, D., Bassaris, H., McGeer, A., Arthur, C., Prentice, H.G., Seifert, W. et al. (2001). Intravenous itraconazole followed by oral itraconazole in the treatment of invasive pulmonary aspergillosis in patients with hematologic malignancies, chronic granulomatous disease, or AIDS. Clin. Infect. Dis. 33, 83–90.CrossRefGoogle Scholar
  7. Chanock, S.J. and Gorlin, J.B. (1996). Granulocyte transfusions. Time for a second look. Infect. Dis. Clin. North. Am. 10, 327–343.PubMedCrossRefGoogle Scholar
  8. Elanjikal, Z., Sorensen, J., Schmidt, H., Dupuis, W., Tintelnot, K., Jautzke, G. et al. (2003). Combination therapy with caspofungin and liposomal amphotericin B for invasive aspergillosis. Pediatr. Infect. Dis. J. 22, 653–656.PubMedGoogle Scholar
  9. Denning, D.W. and Stevens, D.A. (1990). Antifungal and surgical treatment of invasive aspergillosis: Review of 2,121 published cases. Rev. Infect. Dis. 12, 1147–1201.PubMedCrossRefGoogle Scholar
  10. Denning, D.W., Ribaud, P., Milpied, N., Caillot, D., Herbrecht, R., Thiel, E. et al. (2002). Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin. Infect. Dis. 34, 563–571.PubMedCrossRefGoogle Scholar
  11. Denning, D.W., Van Wye, J.E., Lewiston, N.J., and Stevens, D. (1991). Adjunctive therapy of allergic bron-chopulmonary aspergillosis with itraconazole. Chest 100, 813–819.PubMedCrossRefGoogle Scholar
  12. Deresinski, S.C. and Stevens, D.A. (2003). Caspofungin. Clin. Infect. Dis. 36, 1445–1457.PubMedCrossRefGoogle Scholar
  13. Gallin, J.I., Ailing, D.W., Malech, H.L., Wesley, R., Koziol, D., Marciano, B. et al. (2003). Itraconazole to prevent fungal infections in chronic granulomatous disease. N. Engl. J. Med. 348, 2416–2422.PubMedCrossRefGoogle Scholar
  14. Gerson, S.L., Talbot, G.H., Hurwitz, S., Strom, B.L., Lusk, E.J., and Cassileth, P.A. (1984). Prolonged granulo-cytopenia: The major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann. Intern. Med. 100,345–351.PubMedGoogle Scholar
  15. Ghannoum, M.A. and Kuhn, D.M. (2002). Voriconazole, better chances for patients with invasive mycoses. Eur. J. Med. Res. 7, 242–256.PubMedGoogle Scholar
  16. Greenberger, P.A. (2002). Allergic bronchopulmonary aspergillosis. J. Allergy Clin. Immunol. 110, 685–692.PubMedCrossRefGoogle Scholar
  17. Harbarth, S., Pestotnik, S.L., Stanley, L., Lloyd, J.F., Burke, J.P., and Samore, M.H. (2001). The epidemiology of nephrotoxicity associated with conventional amphotericin B therapy. Am. J. Med. 111, 528–534.PubMedCrossRefGoogle Scholar
  18. Herbrecht, R. (2002). Improving the outcome of invasive aspergillosis: New diagnostic tools and new therapeutic strategies. Ann. Hematol. 81(Suppl. 2), S52–S53.PubMedGoogle Scholar
  19. Herbrecht, R., Denning, D.W., Patterson, T.F., Bennett, J.E., Greene, R.E., Oestmann, J.W. et al., Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group. (2002). Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N. Engl. J. Med. 347, 408–415.PubMedCrossRefGoogle Scholar
  20. Holding, K.J., Dworkin, M.S., Wan, P.T., Hanson, D.L., Klevens, R.M., Jones, J.L. et al. (2000). Aspergillosis among people infected with human immunodeficiency virus: Incidence and survival. Clin. Infect. Dis. 31, 1253–1257.PubMedCrossRefGoogle Scholar
  21. Johnson, L.B. and Kauffman, C.A. (2003). Voriconazole: A new triazole antifungal agent. Clin. Infect. Dis. 36, 630–637.PubMedCrossRefGoogle Scholar
  22. Kauffman, H.F. and Tomee, J.F. (2002). Defense mechanisms of the airways against Aspergillus fumigatus: Role in invasive aspergillosis. Chem. Immunol. 81, 94–113.PubMedCrossRefGoogle Scholar
  23. Kawamura, S., Maesaki, S., Noda, T., Hirakata, Y., Tomono, K., Tashiro, T. et al. (1999). Comparison between PCR and detection of antigen in sera for diagnosis of pulmonary aspergillosis. J. Clin. Microbiol. 37, 218–220.PubMedGoogle Scholar
  24. Keating, G.M. and Jarvis, B. (2001). Caspofungin. Drugs 61, 1121–1129.PubMedCrossRefGoogle Scholar
  25. Kirkpatrick, W.R., Perea, S., Coco, B.J., and Patterson, T.F. (2002). Efficacy of caspofungin alone and in combination with voriconazole in a Guinea pig model of invasive aspergillosis. Antimicrob. Agents Chemother. 46, 2564–2568.PubMedCrossRefGoogle Scholar
  26. Kontoyiannis, D.P., Hachem, R., Lewis, R.E., Rivero, G.A., Torres, H.A., Thornby, J. et al. (2003). Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies. Cancer 98, 292–299.PubMedCrossRefGoogle Scholar
  27. Letscher-Bru, V. and Herbrecht, R. (2003). Caspofungin: The first representative of a new antifungal class. J. Antimicrob. Chemother. 51, 513–521.PubMedCrossRefGoogle Scholar
  28. Liles, W.C., Huang, J.E., van Burik, J.A., Bowden, R.A., and Dale, D.C. (1997). Granulocyte colony-stimulating factor administered in vivo augments neutrophil-mediated activity against opportunistic fungal pathogens. J. Infect. Dis. 175(4), 1012–1015.PubMedCrossRefGoogle Scholar
  29. Maertens, J., Verhaegen, J., Lagrou, K., Van Eldere, J., and Boogaerts, M. (2001). Screening for circulating galactomannan as a non-invasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: A prospective validation. Blood 97, 1604–1610.PubMedCrossRefGoogle Scholar
  30. Marr, K.A., Carter, R.A., Crippa, F., Wald, A., and Corey, L. (2002). Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin. Infect. Dis. 34, 909–917.PubMedCrossRefGoogle Scholar
  31. Marr, K.A., Patterson, T., and Denning, D. (2002). Aspergillosis. Pathogenesis, clinical manifestations, and therapy. Infect. Dis. Clin. North Am. 16, 875–894.PubMedCrossRefGoogle Scholar
  32. Morrison, V.A. (2002). The role of caspofungin and the echinocandins in the antifungal armamentarium. Curr. Opin. Investig. Drugs 3, 1432–1436.PubMedGoogle Scholar
  33. Muller, F.M., Trusen, A., and Weig, M. (2002). Clinical manifestations and diagnosis of invasive aspergillosis in immunocompromised children. Eur. J. Pediatr. 161, 563–574.PubMedCrossRefGoogle Scholar
  34. Nemunaitis, J., Meyers, J.D., Buckner, C.D., Shannon-Dorcy, K., Mori, M., Shulman, H. et al. (1991). Phase I trial of recombinant human macrophage colony-stimulating factor in patients with invasive fungal infections. Blood 78(4), 907–913.PubMedGoogle Scholar
  35. Perea, S., Gonzalez, G., Fothergill, A.W., Kirkpatrick, W.R., Rinaldi, M.G., and Patterson, T.F. (2002). In vitro interaction of caspofungin acetate with voriconazole against clinical isolates of Aspergillus spp. Antimicrob. Agents Chemother. 46, 3039–3041.PubMedCrossRefGoogle Scholar
  36. Perea, S. and Patterson, T.F. (2002). Invasive Aspergillus infections in hematologic malignancy patients. Semin. Respir. Infect. 17, 99–105.PubMedCrossRefGoogle Scholar
  37. Petraitis, V., Petraitiene, R., Sarafandi, A.A., Kelaher, A.M., Lyman, C.A., Casler, H.E. et al. (2003). Combination therapy in treatment of experimental pulmonary aspergillosis: Synergistic interaction between an antifungal triazole and an echinocandin. J. Infect. Dis. 187, 1834–1843.PubMedCrossRefGoogle Scholar
  38. Pfaller, M.A., Messer, S.A., Hollis, R.J., and Jones, R.N., SENTRY Participants Group. (2000). Antimicrob Antifungal activities of posaconazole, ravuconazole, and voriconazole compared to those of itraconazole and amphotericin B against 239 clinical isolates of Aspergillus spp. and other filamentous fungi: Report from SENTRY Antimicrobial Surveillance Program, 2000. Antimicrob. Agents Chemother. 46, 1032–1037.CrossRefGoogle Scholar
  39. Potoski, B.A. and Brown, J. (2002). The safety of voriconazole. Clin. Infect. Dis. 35, 1273–1275.PubMedCrossRefGoogle Scholar
  40. Roilides, E., Lamaignere, C.G., and Farmaki, E. (2002). Cytokines in immunodeficient patients with invasive fungal infections: An emerging therapy. Int. J. Infect. Dis. 6, 154–163.PubMedCrossRefGoogle Scholar
  41. Rubin, M.A., Carroll, K.C., and Cahill, B.C. (2002). Caspofungin in combination with itraconazole for the treatment of invasive aspergillosis in humans. Clin. Infect. Dis. 34, 1160–1161.PubMedCrossRefGoogle Scholar
  42. Sable, C.A., Nguyen, B.Y., Chodakewitz, J.A., and DiNubile, M.J. (2002). Safety and tolerability of caspofungin acetate in the treatment of fungal infections. Transpl. Infect. Dis. 4, 25–30.PubMedCrossRefGoogle Scholar
  43. Schaffner, A., Douglas, H., and Braude, A. (1982). Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus. J. Clin. Invest. 69, 617–631PubMedCrossRefGoogle Scholar
  44. Shetty, D., Giri, N., Gonzalez, C.E., Pizzo, P.A., and Walsh, T.J. (1997). Invasive aspergillosis in human immunodeficiency virus-infected children. Pediatr. Infect. Dis. J. 16, 216–221.PubMedCrossRefGoogle Scholar
  45. Stevens, D.A., Schwartz, H.J., Lee, J.Y., Moskovitz, B.L., Jerome, D.C., Catanzaro, A. et al. (2000). A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N. Engl. J. Med. 342, 756–762.PubMedCrossRefGoogle Scholar
  46. Walsh, T.J., Hiemenz, J., and Pizzo, P.A. (1994). Evolving risk factors for invasive fungal infections—all neutropenic subjects are not the same. Clin. Infect. Dis. 18, 793–798.PubMedCrossRefGoogle Scholar
  47. Walsh, T.J., Lutsar, I., Driscoll, T., Dupont, B., Roden, M., Ghahramani, P. et al. (2002a). Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children. Pediatr. Infect. Dis. J. 21, 240–248.PubMedCrossRefGoogle Scholar
  48. Walsh, T.J., Pappas, P., Winston, D.J., Lazarus, H.M., Petersen, F., Raffalli, J. et al. (2002b). Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N. Engl. J. Med. 346, 225–234.PubMedCrossRefGoogle Scholar
  49. Weinberger, M., Elattar, I., Marshall, D., Steinberg, S.M., Redner, R.L., Young, N.S. et al. (1992). Patterns of infection in patients with aplastic anemia and the emergence of Aspergillus as a major cause of death. Medicine 71, 24–43.PubMedGoogle Scholar
  50. Wingard, J.R., Kubilis, P., Lee, L., Yee, G., White, M., Walsh, T.J. et al. (1999). Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis. Clin. Infect. Dis. 29, 1402–1407.PubMedCrossRefGoogle Scholar

Copyright information

© Science+Business Media New York 2004

Authors and Affiliations

  • Corina E. Gonzalez

There are no affiliations available

Personalised recommendations