Journal of Medical and Veterinary Mycology (1992), 30, Supplement 1,225-240
Immunomodulation and antifungal therapy of experimental invasive candidosis, histoplasmosis and aspergillosis: recent advances and concepts
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T. J. WALSH 1, J. VAN CUTSEM 2, A. M. POLAK 3 AND J. R. GRAYBILL 4
1National Cancer Institute, Bethesda, MD, USA; ZJanssen Research Foundation, Beerse, Belgium; 3Hoffmann-LaRoche, Basel, Switzerland; and 4University of Texas San Antonio and Audie L. Murphy VA Medical Center, San Antonio, TX, USA Disseminated candidosis and invasive pulmonary aspergillosis are the most common invasive fungal infections among granulocytopenic patients receiving cytotoxic chemotherapy for neoplastic diseases [1,43]. Disseminated histoplasmosis has emerged during the past decade as an important life-threatening" pathogen in HIVinfected patients [46]. The development of recombinant human cytokines and novel antifungal agents offers hope that these infections may be prevented or treated with more effective regimens. Recombinant human cytokines, for example, recombinant human granulocyte colony stimulating factor (G-CSF) and recombinant human macrophage colony stimulating factor have permitted early recovery from granulocytopenia in patients treated with intensive cytotoxic chemotherapy [23]. Several classes of antifungal compounds, including triazoles, lipopeptides and lipid formulations of amphotericin B are being developed for management of invasive candidosis [44]. The role of these compounds in the treatment and prevention of invasive candidosis, aspergillosis and histoplasmosis is not clearly defined or well understood. These issues were addressed at the Symposium on Animal Models in the Study of Immunomodulation and Antifungal Therapy of Experimental Mycoses of the XI Congress of the International Society for Human and Animal Mycology. This symposium reviewed selected topics of immunomodulation and antifungal therapy of experimental candidosis, aspergillosis and histoplasmosis. Where relevant, immunomodulation and antifungal therapy of other mycoses were also discussed. This paper recapitulates the symposium proceedings, reviews illustrative examples of important concepts of immunomodulation and antifungal therapy of experimental mycoses, and further identifies directions of future research in this vital field of investigation.
Concepts of pathogenesis Candidosis. Candida species are commensal organisms of the human mucocutaneous surfaces. Candida species may progress to become opportunistic pathogens in immunocompromised patients or may be transmitted by contact to other immunocompromised patients as a nosoeomial pathogen [43]. In order to establish an experimental basis for the rational use of potential antifungal chemotherapeutic and immunomodulatory agents in granulocytopenic hosts, we investigated their properties in persistently granulocytopenic rabbit models of disseminated candidosis. GranuloCorrespondenceaddress: Dr T. J. Walsh, Sectionof InfectiousDiseases, National CancerInstitute, Bldg. 10, Rm 13N-240, Bethesda, MD 20892, USA. 225
226
WALSH E T A L .
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cytopenia, broad-spectrum antibiotics, and central silastic venous catheters are well recognized as important factors contributing to the increased risk of invasive candidosis in granulocytopenic patients [1,43]. Thus, the following variables were controlled or examined in persistently granulocytopenic rabbits [39] in order to closely reflect the conditions encountered among granulocytopenic patients with invasive candidosis: (i) depth and duration of granulocytopenia; (ii) use of broad-spectrum antibiotics; (iii) central silastic venous catheters; (iv) patterns of disseminated candidosis; (v) timing of initiation of antifungal agents, (vi) the organ sites involved; and (vii) plasma pharmacokinetics, tissue penetration, and dose-response properties of the antifungal chemotherapeutic agents.
Histoplasmosis. Disseminated histoplasmosis in exposed patients probably occurs universally following pulmonary inhalation of the conidia, conversion to the yeast form within macrophages, and then hematogenous dissemination. Secondary loci within the spleen, lungs and lymph nodes may appear as radiographic calcification in patients who had asymptomatic primary infection. Dissemination occurs within the first weeks after infection and clinical resolution of the primary pulmonary infection (and secondary loci) occurs usually between 3 and 6 weeks after the infection [2]. In distinction to this 'natural' course of dissemination and resolution, clinical disseminated histoplasmosis occurs when cell-mediated immune processes are insufficient to control the organism [13]. The exact manner in which this occurs in humans is uncertain and may involve failure of one or several components of a complicated immunological process. Dissection of the orchestration of host defences in histoplasmosis has been minimal at the human level, but animal models, particularly the inbred mouse, have given us considerable insight into the normal course of development of resistance to histoplasmosis. The athymic mouse [48] has reproduced the process of general failure of cell-mediated immunity such as occurs with AIDS patients [47]. Finally, animal models have given us a good indication of which agents are likely to be successful in the treatment of histoplasmosis, and what might be expected in the immunologically intact as well as immunosuppressed host. The critical primary event in histoplasmosis is successful infection of, and replication within, host macrophages. In vitro studies in human macrophages have indicated that Histoplasma capsulatum is able to accomplish this by associating with macrophage receptors which mediate phagocytosis without triggering the respiratory burst [2]. The receptor involved is the CD18, and intact actin microfilaments in the macrophage cytoskeleton are required for the process of ingestion to occur [24]. How the organisms persist within macrophages without triggering this burst is unclear [9]. AsPergillosis. Various Aspergillus species can cause aspergillosis in animals and humans. The predominantly isolated species is Aspergillus fumigatus. Under natural conditions, large amounts of conidia are produced in dust, compost, soil and on decaying organic material. Large quantities of spores may be present in the air, but a strong air current is necessary to keep the Aspergillus conidia in suspension in an aerosol. The portal of entry is most often the respiratory tract, producing saprophytic colonization, pneumonia, pneumonitis, aspergilloma, allergic bronchopulmonary aspergillosis, invasive pulmonary or chronic necrotizing pulmonary aspergillosis.
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Other localizations are frequently affected, including dissemination or invasion of other organs; for example keratitis and otitis. Neutropenic and other immunodepressed patients are highly susceptible to progression of inhaled Aspergillus conidia to invasive hyphal pneumonia and possible disseminated aspergillosis. Numerous outbreaks of aspergillosis in gallinaceous birds have been described and young chickens especially are highly susceptible to acute and chronic disease. Aspergillosis, however, also causes serious problems in other animal species; for example, bovine abortion and canine sinusitis.
Med Mycol Downloaded from informahealthcare.com by V U L Periodicals Rec on 12/28/14 For personal use only.
Immunomodulation
Candidos&. The depth, duration and recovery from granulocytopenia were found to be significant factors affecting mortality and severity of disseminated candidosis in granulocytopenic rabbits (Kelly et al. Abstract F i l l , 89th Meeting of the American Society for Microbiology, New Orleans, LA, May 14-18, 1989). Among granulocytopenic rabbits (
Immunomodulation and antifungal therapy of experimental invasive candidosis, histoplasmosis and aspergillosis: recent advances and concepts
Med Mycol Downloaded from informahealthcare.com by V U L Periodicals Rec on 12/28/14 For personal use only.
T. J. WALSH 1, J. VAN CUTSEM 2, A. M. POLAK 3 AND J. R. GRAYBILL 4
1National Cancer Institute, Bethesda, MD, USA; ZJanssen Research Foundation, Beerse, Belgium; 3Hoffmann-LaRoche, Basel, Switzerland; and 4University of Texas San Antonio and Audie L. Murphy VA Medical Center, San Antonio, TX, USA Disseminated candidosis and invasive pulmonary aspergillosis are the most common invasive fungal infections among granulocytopenic patients receiving cytotoxic chemotherapy for neoplastic diseases [1,43]. Disseminated histoplasmosis has emerged during the past decade as an important life-threatening" pathogen in HIVinfected patients [46]. The development of recombinant human cytokines and novel antifungal agents offers hope that these infections may be prevented or treated with more effective regimens. Recombinant human cytokines, for example, recombinant human granulocyte colony stimulating factor (G-CSF) and recombinant human macrophage colony stimulating factor have permitted early recovery from granulocytopenia in patients treated with intensive cytotoxic chemotherapy [23]. Several classes of antifungal compounds, including triazoles, lipopeptides and lipid formulations of amphotericin B are being developed for management of invasive candidosis [44]. The role of these compounds in the treatment and prevention of invasive candidosis, aspergillosis and histoplasmosis is not clearly defined or well understood. These issues were addressed at the Symposium on Animal Models in the Study of Immunomodulation and Antifungal Therapy of Experimental Mycoses of the XI Congress of the International Society for Human and Animal Mycology. This symposium reviewed selected topics of immunomodulation and antifungal therapy of experimental candidosis, aspergillosis and histoplasmosis. Where relevant, immunomodulation and antifungal therapy of other mycoses were also discussed. This paper recapitulates the symposium proceedings, reviews illustrative examples of important concepts of immunomodulation and antifungal therapy of experimental mycoses, and further identifies directions of future research in this vital field of investigation.
Concepts of pathogenesis Candidosis. Candida species are commensal organisms of the human mucocutaneous surfaces. Candida species may progress to become opportunistic pathogens in immunocompromised patients or may be transmitted by contact to other immunocompromised patients as a nosoeomial pathogen [43]. In order to establish an experimental basis for the rational use of potential antifungal chemotherapeutic and immunomodulatory agents in granulocytopenic hosts, we investigated their properties in persistently granulocytopenic rabbit models of disseminated candidosis. GranuloCorrespondenceaddress: Dr T. J. Walsh, Sectionof InfectiousDiseases, National CancerInstitute, Bldg. 10, Rm 13N-240, Bethesda, MD 20892, USA. 225
226
WALSH E T A L .
Med Mycol Downloaded from informahealthcare.com by V U L Periodicals Rec on 12/28/14 For personal use only.
cytopenia, broad-spectrum antibiotics, and central silastic venous catheters are well recognized as important factors contributing to the increased risk of invasive candidosis in granulocytopenic patients [1,43]. Thus, the following variables were controlled or examined in persistently granulocytopenic rabbits [39] in order to closely reflect the conditions encountered among granulocytopenic patients with invasive candidosis: (i) depth and duration of granulocytopenia; (ii) use of broad-spectrum antibiotics; (iii) central silastic venous catheters; (iv) patterns of disseminated candidosis; (v) timing of initiation of antifungal agents, (vi) the organ sites involved; and (vii) plasma pharmacokinetics, tissue penetration, and dose-response properties of the antifungal chemotherapeutic agents.
Histoplasmosis. Disseminated histoplasmosis in exposed patients probably occurs universally following pulmonary inhalation of the conidia, conversion to the yeast form within macrophages, and then hematogenous dissemination. Secondary loci within the spleen, lungs and lymph nodes may appear as radiographic calcification in patients who had asymptomatic primary infection. Dissemination occurs within the first weeks after infection and clinical resolution of the primary pulmonary infection (and secondary loci) occurs usually between 3 and 6 weeks after the infection [2]. In distinction to this 'natural' course of dissemination and resolution, clinical disseminated histoplasmosis occurs when cell-mediated immune processes are insufficient to control the organism [13]. The exact manner in which this occurs in humans is uncertain and may involve failure of one or several components of a complicated immunological process. Dissection of the orchestration of host defences in histoplasmosis has been minimal at the human level, but animal models, particularly the inbred mouse, have given us considerable insight into the normal course of development of resistance to histoplasmosis. The athymic mouse [48] has reproduced the process of general failure of cell-mediated immunity such as occurs with AIDS patients [47]. Finally, animal models have given us a good indication of which agents are likely to be successful in the treatment of histoplasmosis, and what might be expected in the immunologically intact as well as immunosuppressed host. The critical primary event in histoplasmosis is successful infection of, and replication within, host macrophages. In vitro studies in human macrophages have indicated that Histoplasma capsulatum is able to accomplish this by associating with macrophage receptors which mediate phagocytosis without triggering the respiratory burst [2]. The receptor involved is the CD18, and intact actin microfilaments in the macrophage cytoskeleton are required for the process of ingestion to occur [24]. How the organisms persist within macrophages without triggering this burst is unclear [9]. AsPergillosis. Various Aspergillus species can cause aspergillosis in animals and humans. The predominantly isolated species is Aspergillus fumigatus. Under natural conditions, large amounts of conidia are produced in dust, compost, soil and on decaying organic material. Large quantities of spores may be present in the air, but a strong air current is necessary to keep the Aspergillus conidia in suspension in an aerosol. The portal of entry is most often the respiratory tract, producing saprophytic colonization, pneumonia, pneumonitis, aspergilloma, allergic bronchopulmonary aspergillosis, invasive pulmonary or chronic necrotizing pulmonary aspergillosis.
IMMUNOMODULATION AND ANTIFUNGAL THERAPY
227
Other localizations are frequently affected, including dissemination or invasion of other organs; for example keratitis and otitis. Neutropenic and other immunodepressed patients are highly susceptible to progression of inhaled Aspergillus conidia to invasive hyphal pneumonia and possible disseminated aspergillosis. Numerous outbreaks of aspergillosis in gallinaceous birds have been described and young chickens especially are highly susceptible to acute and chronic disease. Aspergillosis, however, also causes serious problems in other animal species; for example, bovine abortion and canine sinusitis.
Med Mycol Downloaded from informahealthcare.com by V U L Periodicals Rec on 12/28/14 For personal use only.
Immunomodulation
Candidos&. The depth, duration and recovery from granulocytopenia were found to be significant factors affecting mortality and severity of disseminated candidosis in granulocytopenic rabbits (Kelly et al. Abstract F i l l , 89th Meeting of the American Society for Microbiology, New Orleans, LA, May 14-18, 1989). Among granulocytopenic rabbits (
