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Published ahead of print on December 30, 2005, doi:10.1164/rccm.200505-727SO
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American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 707-717, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200505-727SO

State of the Art

Current Approaches to Diagnosis and Treatment of Invasive Aspergillosis

Brahm H. Segal and Thomas J. Walsh

Department of Medicine, SUNY at Buffalo, Division of Infectious Diseases, Roswell Park Cancer Institute, Buffalo, New York; and Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Correspondence and requests for reprints should be addressed to Brahm H. Segal, M.D., Assistant Professor of Medicine, Department of Medicine, SUNY at Buffalo, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263. E-mail: brahm.segal{at}roswellpark.org


   ABSTRACT
TOP
 ABSTRACT
CONTENTS
 PATIENTS AT RISK FOR...
 DIAGNOSIS OF INVASIVE...
 THERAPY FOR INVASIVE...
 IMMUNE AUGMENTATION STRATEGIES
 GENOMICS
 REFERENCES
 
Filamentous fungi (moulds) are ubiquitous soil inhabitants whose conidia are inhaled into the respiratory tract, where they may cause life-threatening infections. Among these infections is invasive aspergillosis, which is a major cause of morbidity and mortality in the severely immunocompromised. Risk factors for invasive aspergillosis include prolonged and severe neutropenia, hematopoietic stem cell and solid organ transplantation, advanced AIDS, and chronic granulomatous disease. Invasive aspergillosis most commonly involves the sinopulmonary tract reflecting inhalation as the principal portal of entry. Chest computed tomography scans and new non-culture–based assays such as antigen detection and polymerase chain reaction may facilitate the early diagnosis of invasive aspergillosis, but have limitations. Reflecting an important unmet need, there has been a significant expansion in the antifungal armamentarium. The second-generation triazole, voriconazole, was superior to conventional amphotericin B as primary therapy for invasive aspergillosis, and is the new standard of care for this infection. There is significant interest in combination antifungal therapy pairing an echinocandin with either an azole or amphotericin B formulation as therapy for invasive aspergillosis. In addition, there has been an increased understanding of the immunology of Aspergillus infection, paving the way to novel immune augmentation strategies in animal models that merit evaluation in phase I clinic trials.

Key Words: Aspergillus • immunocompromised • neutropenia • transplant


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 ABSTRACT
 CONTENTS
PATIENTS AT RISK FOR...
 DIAGNOSIS OF INVASIVE...
 THERAPY FOR INVASIVE...
 IMMUNE AUGMENTATION STRATEGIES
 GENOMICS
 REFERENCES
 

Patients at Risk for Invasive Aspergillosis
Neutropenia
Hematopoietic Stem Cell Transplantation
Solid Organ Transplantation
AIDS
Chronic Granulomatous Disease

Diagnosis of Invasive Aspergillosis
Chest Computed Tomography Scans
Laboratory Markers

Therapy for Invasive Aspergillosis
Immune Augmentation Strategies
Augmentation of Neutrophil Number
Interferon-{gamma}
Innate Pathogen Recognition Pathways
Vaccines
Genomics

Aspergillus species are ubiquitous soil inhabitants. Alveolar macrophages constitute the first line of host defense against aerosolized conidia. Neutrophils are the dominant host defense against the invasive hyphal stage. Aspergillus infection causes a spectrum of illnesses reflecting the immune status of the host (Figure 1). Our review focuses on acute invasive aspergillosis, a major cause of mortality in highly immunocompromised patients.


Figure 1
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  		Figure 1. Spectrum of diseases caused by Aspergillus infection. Invasive aspergillosis occurs in the highly immunocompromised and is frequently fatal. Note that invasive aspergillosis in chronic granulomatous disease (CGD) is distinct from other immunocompromised host conditions in that a robust pyogranulomatous response occurs, but neutrophil-mediated hyphal killing is defective. Also, hyphal angioinvasion and coagulative necrosis are not features of invasive aspergillosis in CGD. Chronic necrotizing aspergillosis occurs principally in patients with structural lung disease and general debilitation and may require years of antifungal therapy. Aspergillomas result from colonization of preexisting lung cavities; erosion thorough blood vessels may lead to severe hemoptysis. Allergic bronchopulmonary aspergillosis (ABPA) and allergic sinusitis result from allergic responses to hyphal elements colonizing the sinopulmonary tract. HSCT = hematopoietic stem cell transplant; SOT = solid organ transplant.

 
Mortality from invasive aspergillosis increased several-fold in the 1980s and 1990s (1, 2), a reflection of more patients undergoing treatment for hematologic malignancies and allogeneic hematopoietic stem cell transplantation (HSCT). Deficits in host defense that render susceptibility to invasive aspergillosis are complex, but can be broadly divided into these categories: (1) neutropenia, (2) qualitative deficits in phagocyte function, and (3) deficits in cell-mediated immunity (Table 1). We will review the epidemiology, diagnosis, and management of invasive aspergillosis, and strategies for immune augmentation.


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  		TABLE 1. PATIENT POPULATIONS AT RISK FOR INVASIVE ASPERGILLOSIS

 

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Neutropenia
The risk of invasive aspergillosis is strongly related to the duration and degree of neutropenia. Most cases of neutropenia-associated aspergillosis occur in patients receiving potent cytotoxic regimens for hematologic malignancies and myeloablative HSCT (3–5). Invasive aspergillosis is also a major cause of mortality in patients with aplastic anemia and prolonged neutropenia (6). Multiple cycles of prolonged neutropenia, such as in refractory leukemia, further predispose patients to invasive filamentous fungal infection. Small foci of invasive fungal disease may be clinically and radiographically inapparent during the initial cycle of neutropenia, but manifest clinically during a subsequent cycle. Concomitant therapy with systemic corticosteroids and other immunosuppressive agents increase the risk of invasive aspergillosis. Therefore, knowledge about current and prior cycles of chemotherapy is key in risk stratification.

Hematopoietic Stem Cell Transplantation
Allogeneic HSCT recipients have a higher risk of invasive aspergillosis than do autologous HSCT recipients because of the greater intensity of immunosuppression. The spectrum of pathogens to which allogeneic HSCT recipients are most susceptible follows a timeline corresponding to the predominant immune defects at different periods (Table 1). In the early stage, neutropenia after the conditioning regimen is the principal host defense defect. Most cases of invasive aspergillosis in allogeneic HSCT occur after neutrophil recovery in the setting of potent immunosuppressive therapy for graft-versus-host disease (GVHD) (5, 7–14). There are three likely reasons: (1) shortening of the duration of neutropenia period from infusion of larger numbers of myeloid progenitors and treatment with colony stimulating factors; (2) increased proportion of unrelated donors and HLA-mismatched transplants, which predispose to GVHD; and (3) increased proportion of patients surviving beyond the early transplant period.

Factors associated with an increased risk of invasive aspergillosis in allogeneic HSCT recipients after engraftment include receipt of T-cell–depleted or CD34-selected stem cell products, receipt of corticosteroids, neutropenia, lymphopenia, GVHD, and cytomegalovirus disease (12). Corticosteroids have profound effects on the distribution and function of neutrophils, monocytes, and lymphocytes. Corticosteroids directly stimulate the growth of Aspergillus fumigatus in vitro (15) possibly via sterol binding proteins in the fungus. Tumor necrosis factor-{alpha} is a principal mediator of acute inflammation, and stimulates the activation and recruitment of neutrophils and monocytes. Tumor necrosis factor-{alpha} antagonists used to control GVHD are associated with an increased risk of invasive aspergillosis (16).

Solid Organ Transplantation
The period of highest risk for invasive mould infections is generally within the first year of transplant. Intensification of immunosuppressive therapy to treat allograft rejection increases the risk of opportunistic infections. Among solid organ transplant recipients, lung transplant recipients are at the highest risk of invasive pulmonary aspergillosis (17). Anastomotic infections occur in approximately 5% of lung transplant recipients, and are principally caused by Candida and Aspergillus species (18). Infection typically responds to appropriate systemic antifungal therapy, and anastomotic dehiscence is uncommon (18). Colonization of the native lung with Aspergillus spp., which occurs commonly in end-stage lung disease, is an important source of posttransplant aspergillosis in single lung transplants (19, 20). Although most cases of posttransplant isolation of an Aspergillus sp. represent transient infection, Cahill and colleagues (21) reported that only Aspergillus colonization within the first 6 mo of transplant was predictive of subsequent invasive disease.

AIDS
Invasive aspergillosis is a relatively uncommon but devastating infection in patients with advanced AIDS (22–27). Mortality from opportunistic fungal infections has been reduced with the availability of highly active antiretroviral therapy (1). A low CD4 count, generally less than 100/ul, was present in almost all cases of AIDS-associated aspergillosis. Coexistent neutropenia or use of corticosteroids occurred in about 50% of patients; the remaining cases appear to have no other risk factors other than advanced AIDS. Isolation of an Aspergillus species from respiratory secretions has poor predictive value for invasive disease in patients with AIDS, and histopathology may be required to establish the diagnosis (28).

Chronic Granulomatous Disease
Chronic granulomatous disease (CGD) is an inherited disorder of the NADP reduced oxidase complex characterized by recurrent bacterial and fungal infections. Invasive aspergillosis is the most important cause of mortality in CGD (29–32). Despite the routine use of IFN-{gamma} prophylaxis, fungal infections are a persistent problem with an incidence of 0.1 fungal infections per patient year (33). A randomized, study showed that itraconazole prophylaxis was safe and effective in preventing fungal infections in CGD (34).


   DIAGNOSIS OF INVASIVE ASPERGILLOSIS
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Aspergillosis can involve virtually any organ in the immunocompromised host, but sinopulmonary disease is the most common. Angioinvasion of hyphae leading to vascular thrombosis and tissue infarction and coagulative necrosis is characteristic of invasive aspergillosis in neutropenia, but is also observed in non-neutropenic allogeneic HSCT recipients with GVHD (14) (Figure 2). Early diagnosis of aspergillosis in highly immunocompromised patients remains difficult. Bronchoalveolar (BAL) cultures have approximately 50% sensitivity in focal pulmonary lesions (35), and definitive diagnosis often requires an invasive procedure (e.g., thoracoscopic biopsy). Isolation of an Aspergillus species from sputum or BAL is highly predictive of invasive disease in neutropenic patients (36). A diagnostic algorithm for invasive aspergillosis is summarized in Figure 3.


Figure 2
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  		Figure 2. Invasive pulmonary aspergillosis in an allogeneic hematopoietic stem cell transplant recipient at autopsy. (A) Lower power view shows arterial thrombosis (hematoxylin and eosin, 40x). Solid arrow, vessel wall; dashed arrows, intramural thrombus. (B) Higher power magnification shows hyphae invading the arterial wall (200x) and (C) invasive hyphae (arrows) within the thrombus (400x).

 

Figure 3
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  		Figure 3. Diagnostic algorithm for suspected invasive aspergillosis. BAL = bronchoalveolar lavage; GMA = galactomannan assay; IA = invasive aspergillosis; IPA = invasive pulmonary aspergillosis.

 
Chest Computed Tomography Scans
One or more nodules is the most common finding on chest computed tomography (CT) in early invasive pulmonary aspergillosis in neutropenic patients and HSCT recipients, and may be inapparent on chest radiographs (37) (Figure 4). The "halo sign," a haziness surrounding a nodule or infiltrate, is a characteristic chest CT feature of angioinvasive organisms, and is highly suggestive of invasive aspergillosis in patients with prolonged neutropenia (38). In one study, chest CT scanning in patients with persistent neutropenic fever led to earlier diagnosis of invasive aspergillosis and initiation of therapy, which may have improved outcome (39).


Figure 4
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  		Figure 4. Value of chest computed tomography scan for early detection of invasive aspergillosis. (A) Chest radiograph and (B) chest computed tomography scan obtained on the same day in a patient with refractory leukemia and prolonged neutropenic fever. Bronchoalveolar lavage culture was positive for A. fumigatus. Adapted from Figure 111.2 from Segal BH, and Walsh TJ. Opportunistic fungal infections. In: Cohen J, Powderly WG, editors. Infectious diseases, 2nd ed. New York: Elsevier; 2004.

 
Sequential chest CT scans on neutropenic patients with invasive aspergillosis demonstrated that halo signs were common at diagnosis but decreased during the first week of infection as the frequency of the air crescent sign increased (40). Despite a positive clinical response in most patients, the median volume of lesions increased during the first week of therapy and remained stable during the second week. An increase in size of pulmonary lesions within the first week did not predict a negative response to therapy. This study has implications in interpreting the results of salvage therapy studies in which patients with invasive aspergillosis could be enrolled after only 7 d of standard antifungal therapy if the size of pulmonary lesions were unchanged or increased.

Aspergillus sinusitis may present as pressure, nasal congestion, or pain. Endoscopy may show sentinel eschars along the nasal turbinates. Brushings and biopsies of these lesions may show hyphae on direct smear and may grow Aspergillus species. Involvement of the ethmoid sinus carries a particularly high risk of extension to the cavernous sinus. Early signs of ophthalmoplegia may precede radiologic evidence of cavernous sinus thrombosis.

Laboratory Markers
Laboratory markers that detect Aspergillus infection can be used in three possible modes: (1) a diagnostic adjunct, (2) surveillance tool in high-risk patients (e.g., allogeneic HSCT recipients) to detect early aspergillosis before clinically overt disease, and (3) monitoring response to antifungal therapy. A double sandwich ELISA for detection of the fungal cell wall constituent, galactomannan, was recently Food and Drug Administration approved (41). The combination of host factors predisposing to invasive aspergillosis (e.g., prolonged neutropenia), compatible clinical and radiologic findings (e.g., pulmonary nodule), and two consecutive positive serum galactomannan assays can be equated with "probable invasive aspergillosis" (42) and obviate the need for an invasive procedure (Figure 3). Host factors and medications can affect the sensitivity and specificity of the assay (43, 44). Most notably, the sensitivity of the assay is reduced by concomitant use of antifungal agents with activity against moulds (45). Piperacillin/tazobactam causes false-positive galactomannan results (46).

The value of surveillance serum galactomannan monitoring is unclear. In the best scenario, prospective serial monitoring of galactomannan antigenemia in allogeneic HSCT recipients yielded positive and negative predictive values of 94.4 and 98.8%, respectively, and antigenemia preceded radiographic findings by more than a week in 80% of cases of invasive aspergillosis (47). In another study, the sensitivity was only 64.5% in cases of definite invasive aspergillosis (48). The positive predictive value was poor when used as a surveillance tool in patients with persistent neutropenic fever (positive predictive value = 7.1%) and in HSCT (mostly autologous) recipients (positive predictive value = 10%). In a study of 170 patients at high risk for invasive mould infection from North American cancer centers, the galactomannan assay identified 25 of 31 patients with invasive aspergillosis (81% sensitivity), and had a specificity of 89% (http://www.fda.gov/bbs/topics/NEWS/2003/NEW00907.html). The lack of consistent results likely relate to different cutoff values for a positive result, differences in patient populations, and possibly practices involving use of mould-active prophylaxis. Further studies will be required to demonstrate whether surveillance galactomannan testing in targeted high-risk patients will translate into improved outcomes.

Detection of serum B-glucan, a fungal cell wall constituent, has recently received Food and Drug Administration approval. In patients with acute myeloid leukemia and myelodysplastic syndrome, the assay was highly sensitive and specific in detecting early invasive fungal infections, including candidiasis, fusariosis, trichosporonosis, and aspergillosis (49). The B-glucan assay has shown promise as a diagnostic adjunct for a variety of fungal infections in other patient populations (50). However, more research is required to define the utility of this assay in nonneutropenic patients at high risk for invasive mould infections, most notably, in allogeneic HSCT recipients with GVHD.

Polymerase chain reaction–based detection of aspergillosis applied to blood (51–53) and BAL (54–56) is another promising tool for early diagnosis. Specific primers and conditions vary in published series, and will require standardization and validation in reference laboratories before they can be widely applied. Prospective studies are required to define which diagnostic methods—or combination of methods—confer optimal sensitivity and specificity in detecting early Aspergillus infection.


   THERAPY FOR INVASIVE ASPERGILLOSIS
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There have been important new developments in antifungal agents (Table 2). Voriconazole was more effective than amphotericin B as initial therapy for invasive aspergillosis and was associated with significantly improved survival (71 vs. 58%, respectively) (57). The rate of successful outcomes was superior in voriconazole compared with amphotericin B recipients (53 vs. 32%, respectively). The poorest prognosis occurred in extrapulmonary aspergillosis and in allogeneic HSCT recipients. Voriconazole led to a successful outcome in 34% of patients with central nervous system aspergillosis (58), an infection previously associated with almost universal mortality (25). Voriconazole appears to have comparable safety and efficacy in children with invasive mould infections compared with adults (59). Aspergillus terreus has been observed with increased frequency at several cancer centers, and is notable for being resistant to amphotericin B, but sensitive to voriconazole (60, 61). We advise voriconazole as first-line therapy for invasive aspergillosis.


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  		TABLE 2. ANTIFUNGAL AGENTS USED AS PROPHYLAXIS AND THERAPY FOR INVASIVE ASPERGILLOSIS

 
Echinocandins have not been evaluated as initial monotherapy for invasive aspergillosis in clinical trials. Caspofungin as salvage therapy in patients with invasive aspergillosis led to a favorable response in 37 (45%) of 83 patients. There has been significant interest in combination therapy pairing an echinocandin with either an amphotericin B preparation or a mould-active azole. The rationale is that echinocandins target a site (the B-glucan constituent of the fungal cell wall) distinct from the polyenes and azoles that target the fungal cell membrane. The combination of an echinocandin with an azole or amphotericin B has neutral to synergistic activity in vitro. Enhanced efficacy of combination regimens pairing an echinocandin with either an azole or an amphotericin B formulation occurred in some animal models of aspergillosis (62–64), but not in others (65–67).

The combination of caspofungin and liposomal amphotericin B as salvage therapy led to a favorable outcome in approximately 40 to 60% of patients with invasive aspergillosis, though these series included cases of "possible" aspergillosis (68, 69). Marr and colleagues (70) reported a survival advantage of voriconazole plus caspofungin compared with voriconazole alone in a retrospective analysis of salvage therapy for invasive aspergillosis. This database involved small numbers of patients, and the two groups were noncontemporaneous; therefore, other host and infection-related factors may have influenced the outcome. A randomized, prospective study is required to definitively assess the benefit of combination antifungal therapy in invasive aspergillosis.

Posaconazole, an investigational azole, has been effective as salvage therapy against a broad spectrum of invasive fungal infections (71). Forty-two percent of patients with invasive aspergillosis that was refractory or who had intolerance to standard antifungal therapy had a complete or partial response to posaconazole (71). In a pilot study of CGD patients with invasive mould infections refractory to voriconazole, posaconazole was safe and effective (72).

Patients who recover from an episode of invasive aspergillosis are at risk for recurrence during subsequent immunosuppression (73, 74). In patients with invasive aspergillosis before HSCT, antifungal therapy for more than a month and resolution of radiologic abnormalities correlate with a lower likelihood of post-transplant recurrence of infection (74). Secondary prophylaxis with a mould active agent is advised for the entire period of immunosuppression.

Debridement of locally invasive disease, such as sinusitis or primary cutaneous aspergillosis, should be performed when feasible. Resection of localized pulmonary aspergillosis before undergoing subsequent allogeneic HSCT has been advised based on small numbers of patients (10). With more effective and safer antifungal agents that enable administration of prolonged therapy, the value of "preemptive" resection in cases of pulmonary aspergillosis responding to antifungal therapy is unclear.


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Augmentation of Neutrophil Number
Colony-stimulating factors.
Colony-stimulating factors (CSFs) are used to accelerate myelopoiesis in neutropenic patients. Prophylaxis with a CSF can reduce the incidence of neutropenic fever by as much as 50%, which in some studies translated into a reduction in hospitalization and use of antibiotics (75). In one randomized study in patients receiving chemotherapy for acute myelogenous leukemia, prophylaxis with granulocyte-macrophage colony–stimulating factor (GM-CSF) led to a lower frequency of fatal fungal infections compared with placebo (1.9 vs. 19%, respectively) and reduced overall early mortality (76, 77). However, CSFs have not produced a survival advantage in the remainder of studies.

CSFs also augment phagocyte function. Granulocyte colony-stimulating factor (G-CSF), GM-CSF, and macrophage colony–stimulating factor increase the fungicidal activity of phagocytes in vitro against Candida and Aspergillus species (78–81). G-CSF influences survival, proliferation, and differentiation of all cells in the neutrophil lineage and augments the function of mature neutrophils. Macrophage colony–stimulating factor increases phagocytosis, chemotaxis, and secondary cytokine production in monocytes and macrophages (82). GM-CSF stimulates various neutrophil effector functions and prolongs neutrophil survival in vitro, accelerates the proliferation of the monocyte–macrophage system, and is a potent activator of monocytes and macrophages (82). Thus GM-CSF may have a theoretical advantage against pathogens such as Aspergillus species, for which host defense is dependent on both neutrophil and macrophage function.

The clinical database on CSFs as adjunctive therapy for fungal infections is inadequate to assess efficacy. The American Society of Clinical Oncology appropriately advises that a CSF should be considered in serious infections, such as invasive fungal infections (75).

Granulocyte transfusions.
The rationale for granulocyte transfusions is to provide supportive therapy for neutropenic patients with a life-threatening infection by augmenting the number of circulating neutrophils until neutrophil recovery occurs. Today, the impetus to reevaluate granulocyte transfusions stems largely from improvements made in donor mobilization using G-CSF and corticosteroids (83). The use of community donors for granulocytapheresis was safe in a phase I/II study, thus increasing the pool of potential donors (84).

We reserve granulocyte transfusions for patients with prolonged neutropenia and life-threatening infections refractory to conventional therapy. In allogeneic transplants in which the donor and recipient are CMV seronegative, using CMV-seronegative granulocyte donors is advised (85). The Transfusion Medicine and Hemostasis network of the National Heart Lung and Blood Institute is planning a randomized study of adjunctive granulocyte transfusions in neutropenic patients with severe bacterial and fungal infections.

Interferon-{gamma}
Several cytokines (e.g., interleukin 12 [IL-12], IL-15, IL-18, chemokines) (86–89) hold promise as adjunctive therapeutics for invasive fungal infections. We will focus on recombinant interferon (rIFN) {gamma} because the database is the most developed (90). IFN-{gamma} augments innate and Th1-dependent immunity, both of which contribute to host defense against Aspergillus infection. IFN-{gamma} augmented human neutrophil oxidative response and killing of Aspergillus hyphae in vitro, and acted additively with G-CSF (78). It prevented corticosteroid-mediated suppression of neutrophil killing of hyphae (91) and enhanced killing of Aspergillus hyphae by human monocytes (79). Administration of rIFN-{gamma} to CGD patients augmented ex vivo neutrophil-mediated damage of Aspergillus hyphae, presumably through non-NADP reduced oxidase–dependent pathways (92). In animal models, augmentation of the Th1/Th2 cytokine balance either through administration or depletion of cytokines conferred protection in experimental aspergillosis (93–97).

rIFN-{gamma} is licensed as a prophylactic agent in patients with CGD based on a randomized trial in which IFN-{gamma} reduced the number and severity of infections (mostly bacterial) in CGD by about 70% (98). Data on rIFN-{gamma} as adjunctive therapy for invasive aspergillosis are limited to case reports and small series (99, 100), and no recommendation about its use in this setting can be made. It was disappointing that a randomized trial evaluating rIFN-{gamma} as adjunctive therapy for invasive aspergillosis was prematurely terminated before any patient was enrolled. One concern about rIFN-{gamma} in allogeneic HSCT recipients is the potential for worsening GVHD. Though preliminary results suggest that rIFN-g is safe in allogeneic HSCT recipients (99, 100), the safety of rIFN-{gamma} cannot be predicted based on this limited database, and therefore merits evaluation in a clinical trial with safety as the primary endpoint.

Innate Pathogen Recognition Pathways
Toll-like receptors.
Toll-like receptors (TLRs) recognize common pattern motifs on microbes, and initiate T-cell and dendritic cell (DC) maturation. Aspergillus conidia, but not hyphae, stimulate macrophages to produce the proinflammatory cytokines tumor necrosis factor-{alpha} and IL-1 in a TLR4-dependent fashion (101). In contrast, Aspergillus hyphae, but not conidia, stimulated production of the anti-inflammatory cytokine IL-10 through TLR2-dependent mechanisms. This switch from a proinflammatory to antiinflammatory signals during germination may help Aspergillus evade host defense. Others found that both TLR2 and TLR4 recognize Aspergillus hyphae, stimulate proinflammatory cytokines in effector cells, and stimulate neutrophil recruitment (102, 103).

Local delivery of CpG oligodeoxynucleotides (which signal through TLR9) and the Aspf16 Aspergillus allergen resulted in activation of airway DCs capable of inducing Th1 priming and resistance to the fungus in mice (104). Thymosin {alpha}1, a naturally occurring thymic peptide, induced maturation and IL-12 production in DCs pulsed with Aspergillus, an effect mediated by distinct TLRs (105). Thymosin {alpha}1 augmented Th1 immunity against Aspergillus, accelerated myeloid recovery in neutropenic mice, and was protective against Aspergillus challenge in murine HSCT recipients.

Recognition of Aspergillus motifs and activation of neutrophils is coordinated by distinct members of the TLR family, each likely activating specialized antifungal effector functions and inflammatory responses (106). Indeed, liposomal amphotericin B, in addition to its intrinsic antifungal activity, may activate antifungal resistance by activating TLR-4 in neutrophils (107). These studies provide a rationale to stimulate or inhibit specific classes of TLRs to enhance innate and antigen-specific immunity to fungi (Table 3).


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  		TABLE 3. AIMS AND STRATEGIES FOR IMMUNE AUGMENTATION AGAINST ASPERGILLUS INFECTION

 
Pentraxins.
Pentraxin-3 is an innate pathogen recognition protein that binds to specific motifs on A. fumigatus and other pathogens. Pentraxin-3–deficient mice had defective recognition of conidia by alveolar macrophages and DCs, inappropriate induction of type 2 cytokine responses, and were highly susceptible to Aspergillus infection (108). Administration of Pentraxin 3 protected against Aspergillus challenge in murine HSCT recipients (108) and potentiated the protective effect of subtherapeutic amphotericin B (109).

Vaccines
Vaccine development is a priority for several fungal pathogens and requires knowledge about host-pathogen interactions (110, 111). The importance of cell-mediated immunity against Aspergillus infection has become well established in mice (93–96). Immunization of immunocompetent mice with an Aspergillus crude filtrate resulted in memory responses mediated by antigen-specific, Th-1–committed CD4+ T cells (112). Adoptive transfer of these cells conferred protection to neutropenic mice—establishing a "proof of principle" regarding the cellular immunity as a target for immune augmentation in invasive aspergillosis (112). A vaccine conjugate of diphtheria toxoid and laminarin, a poorly immunogenic B-glucan preparation from the brown alga Laminaria digitata (B-glucan is also a major fungal cell wall constituent), conferred protection against Candida albicans and A. fumigatus challenge in mice through mechanisms that may include generation of anti–B-glucan antibodies (113).

Cellular adoptive immunotherapy may also include active vaccination with DCs. DCs pulsed with Candida albicans or A. fumigatus activated CD4+ Th1 cell responses on adoptive transfer into immunocompetent mice. The infusion of fungus-pulsed DCs accelerated the recovery of antifungal Th1 responses in mouse allogeneic HSCT recipients and conferred protection against aspergillosis (114). DCs are also key in containing and dampening inflammatory responses by tolerization through the induction of regulatory T cells (115). These studies in mice demonstrate the functional plasticity of DCs in response to fungi that can be exploited in vaccine development (115–117).


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Fungal genomics offers an opportunity to develop novel antifungal agents that are complementary to traditional drug-screening methods focused on existing targets. DNA microarray chips for A. fumigatus are now being made available to investigators through The Institute for Genomic Research.

Genomics will be an important tool in understanding the molecular biology of Aspergillus and will facilitate the identification of novel virulence genes. Emerging experimental analysis tools, such as chemogenomics, fitness profiling, transcript profiling, and proteomics will further enhance the analysis of genomewide functional studies (118). This knowledge may be exploited to identify novel targets for drug discovery. Moreover, characterizing gene profiles of host cells (e.g., phagocytes, endothelial cells) to Aspergillus will shed new light on the broad range of host responses to this pathogen, and potentially pave the way to new immune augmentation strategies.


   FOOTNOTES
 
Originally Published in Press as DOI: 10.1164/rccm.200505-727SO on December 30, 2005

Conflict of Interest Statement: B.H.S. has been reimbursed by Schering-Plough for serving on Data Review Committees, has received speaking honoraria from Merck and Pfizer, and laboratory support from Fujisawa Healthcare (now Astellas.) and Enzon. T.J.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form May 9, 2005; accepted in final form December 22, 2005


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 REFERENCES
 

  1. McNeil MM, Nash SL, Hajjeh RA, Phelan MA, Conn LA, Plikaytis BD, Warnock DW. Trends in mortality due to invasive mycotic diseases in the United States, 1980–1997. Clin Infect Dis 2001;33:641–647.[CrossRef][Medline]
  2. Denning DW. Introduction: the Aspergillus fumigatus genome database. Vol. 2003: The Institute for Genomic Research (TIGR). Available from: www.tigr.org/tdb/e2k1/afu1/intro.shtml (accessed 2003).
  3. Gerson SL, Talbot GH, Hurwitz S, Strom BL, Lusk EJ, Cassileth PA. Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann Intern Med 1984;100:345–351.[CrossRef][Medline]
  4. Denning DW, Marinus A, Cohen J, Spence D, Herbrecht R, Pagano L, Kibbler C, Kcrmery V, Offner F, Cordonnier C, et al. An EORTC multicentre prospective survey of invasive aspergillosis in haematological patients: diagnosis and therapeutic outcome. EORTC Invasive Fungal Infections Cooperative Group. J Infect 1998;37:173–180.[CrossRef][Medline]
  5. Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997;175:1459–1466.[Medline]
  6. Weinberger M, Elattar I, Marshall D, Steinberg SM, Redner RL, Young NS, Pizzo PA. Patterns of infection in patients with aplastic anemia and the emergence of Aspergillus as a major cause of death. Medicine (Balt) 1992;71:24–43.
  7. Baddley JW, Stroud TP, Salzman D, Pappas PG. Invasive mold infections in allogeneic bone marrow transplant recipients. Clin Infect Dis 2001;32:1319–1324.[CrossRef][Medline]
  8. Grow WB, Moreb JS, Roque D, Manion K, Leather H, Reddy V, Khan SA, Finiewicz KJ, Nguyen H, Clancy CJ, et al. Late onset of invasive aspergillus infection in bone marrow transplant patients at a university hospital. Bone Marrow Transplant 2002;29:15–19.[CrossRef][Medline]
  9. Jantunen E, Ruutu P, Niskanen L, Volin L, Parkkali T, Koukila-Kahkola P, Ruutu T. Incidence and risk factors for invasive fungal infections in allogeneic BMT recipients. Bone Marrow Transplant 1997;19:801–808.[CrossRef][Medline]
  10. McWhinney PH, Kibbler CC, Hamon MD, Smith OP, Gandhi L, Berger LA, Walesby RK, Hoffbrand AV, Prentice HG. Progress in the diagnosis and management of aspergillosis in bone marrow transplantation: 13 years' experience. Clin Infect Dis 1993;17:397–404.[Medline]
  11. Yuen KY, Woo PC, Ip MS, Liang RH, Chiu EK, Siau H, Ho PL, Chen FF, Chan TK. 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.[Medline]
  12. Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 2002;100:4358–4366.[Abstract/Free Full Text]
  13. Martino R, Subira M, Rovira M, Solano C, Vazquez L, Sanz GF, Urbano-Ispizua A, Brunet S, De la Camara R. Invasive fungal infections after allogeneic peripheral blood stem cell transplantation: incidence and risk factors in 395 patients. Br J Haematol 2002;116:475–482.[CrossRef][Medline]
  14. Shaukat A, Bakri F, Young P, Hahn T, Ball D, Baer MR, Wetzler M, Slack JL, Loud P, Czuczman M, et al. Invasive filamentous fungal infections in allogeneic hematopoietic stem cell transplant recipients after recovery from neutropenia: clinical, radiologic, and pathologic characteristics. Mycopathologia 2005;159:181–188.[CrossRef][Medline]
  15. Ng TT, Robson GD, Denning DW. Hydrocortisone-enhanced growth of Aspergillus spp.: implications for pathogenesis. Microbiol 1994;140:2475–2479.[Abstract/Free Full Text]
  16. Marty FM, Lee SJ, Fahey MM, Alyea EP, Soiffer RJ, Antin JH, Baden LR. Infliximab use in patients with severe graft-versus-host disease and other emerging risk factors for non-Candida invasive fungal infections in allogeneic hematopoietic transplant recipients: a cohort study. Blood 2003;102:2768–2776.[Abstract/Free Full Text]
  17. Patterson JE, Peters J, Calhoon JH, Levine S, Anzueto A, Al-Abdely H, Sanchez R, Patterson TF, Rech M, Jorgensen JH, et al. Investigation and control of aspergillosis and other filamentous fungal infections in solid organ transplant recipients. Transpl Infect Dis 2000;2:22–28.[CrossRef][Medline]
  18. Hadjiliadis D, Howell DN, Davis RD, Lawrence CM, Rea JB, Tapson VF, Perfect JR, Palmer SM. Anastomotic infections in lung transplant recipients. Ann Transplant 2000;5:13–19.[Medline]
  19. Westney GE, Kesten S, De Hoyos A, Chapparro C, Winton T, Maurer JR. Aspergillus infection in single and double lung transplant recipients. Transplantation 1996;61:915–919.[CrossRef][Medline]
  20. Hadjiliadis D, Sporn TA, Perfect JR, Tapson VF, Davis RD, Palmer SM. Outcome of lung transplantation in patients with mycetomas. Chest 2002;121:128–134.[Abstract/Free Full Text]
  21. Cahill BC, Hibbs JR, Savik K, Juni BA, Dosland BM, Edin-Stibbe C, Hertz MI. Aspergillus airway colonization and invasive disease after lung transplantation. Chest 1997;112:1160–1164.[Abstract/Free Full Text]
  22. Denning DW, Follansbee SE, Scolaro M, Norris S, Edelstein H, Stevens DA. Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med 1991;324:654–662.[Abstract]
  23. Denning DW, Lee JY, Hostetler JS, Pappas P, Kauffman CA, Dewsnup DH, Galgiani JN, Graybill JR, Sugar AM, Catanzaro A, et al. NIAID Mycoses Study Group Multicenter Trial of Oral Itraconazole Therapy for Invasive Aspergillosis. Am J Med 1994;97:135–144. [Published erratum appears in Am J Med 1994;97:497.][CrossRef][Medline]
  24. Denning DW. Therapeutic outcome in invasive aspergillosis. Clin Infect Dis 1996;23:608–615.[Medline]
  25. Holding KJ, Dworkin MS, Wan PC, Hanson DL, Klevens RM, Jones JL, Sullivan PS. Aspergillosis among people infected with human immunodeficiency virus: incidence and survival. Adult and adolescent spectrum of HIV Disease Project. Clin Infect Dis 2000;31:1253–1257.[CrossRef][Medline]
  26. Mylonakis E, Rich J, Skolnik PR, De Orchis DF, Flanigan T. Invasive Aspergillus sinusitis in patients with human immunodeficiency virus infection: report of 2 cases and review. Medicine (Baltimore) 1997;76:249–255.[CrossRef][Medline]
  27. Mylonakis E, Barlam TF, Flanigan T, Rich JD. Pulmonary aspergillosis and invasive disease in AIDS: review of 342 cases. Chest 1998;114:251–262.[Abstract/Free Full Text]
  28. Pursell KJ, Telzak EE, Armstrong D. Aspergillus species colonization and invasive disease in patients with AIDS. Clin Infect Dis 1992;14:141–148.[Medline]
  29. Mouy R, Veber F, Blanche S, Donadieu J, Brauner R, Levron JC, Griscelli C, Fischer A. Long-term itraconazole prophylaxis against Aspergillus infections in thirty-two patients with chronic granulomatous disease. J Pediatr 1994;125:998–1003.[CrossRef][Medline]
  30. Cohen MS, Isturiz RE, Malech HL, Root RK, Wilfert CM, Gutman L, Buckley RH. Fungal infection in chronic granulomatous disease: the importance of the phagocyte in defense against fungi. Am J Med 1981;71:59–66.[CrossRef][Medline]
  31. Segal BH, Holland SM. Invasive aspergillosis in chronic granulomatous disease. Available from: http://www.aspergillus.man.ac.uk (accessed 2003).
  32. Almyroudis NG, Holland SM, Segal BH. Invasive aspergillosis in primary immunodeficiencies. Med Mycol Suppl 2005;43:S247–S259.[CrossRef]
  33. Winkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI, Malech HL, Holland SM, Ochs H, Quie P, et al. Chronic granulomatous disease: report on a national registry of 368 patients. Medicine (Baltimore) 79:155–169.
  34. Gallin JI, Alling DW, Malech HL, Wesley R, Koziol D, Marciano B, Eisenstein EM, Turner ML, DeCarlo ES, Starling JM, et al. Itraconazole prophylaxis for fungal infections in chronic granulomatous disease of childhood. N Engl J Med 2003;348:2416–2422.[Abstract/Free Full Text]
  35. Levine SJ. An approach to the diagnosis of pulmonary infections in immunosuppressed patients. Semin Respir Infect 1992;7:81–95.[Medline]
  36. Yu VL, Muder RR, Poorsattar A. Significance of isolation of Aspergillus from the respiratory tract in diagnosis of invasive pulmonary aspergillosis: results from a three-year prospective study. Am J Med 1986;81:249–254.[CrossRef][Medline]
  37. Greene R. The radiologic spectrum of pulmonary aspergillosis. Presented at Advances against Aspergillosis conference; September 9–11, 2004; San Francisco, CA.
  38. Kuhlman JE, Fishman EK, Burch PA, Karp JE, Zerhouni EA, Siegelman SS. Invasive pulmonary aspergillosis in acute leukemia: the contribution of CT to early diagnosis and aggressive management. Chest 1987;92:95–99.[Abstract/Free Full Text]
  39. Caillot D, Casasnovas O, Bernard A, Couaillier JF, Durand C, Cuisenier B, Solary E, Piard F, Petrella T, Bonnin A, et al. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol 1997;15:139–147.[Abstract/Free Full Text]
  40. Caillot D, Couaillier JF, Bernard A, Casasnovas O, Denning DW, Mannone L, Lopez J, Couillault G, Piard F, Vagner O, et al. Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol 2001;19:253–259.[Abstract/Free Full Text]
  41. Bretagne S, Costa JM, Bart-Delabesse E, Dhedin N, Rieux C, Cordonnier C. Comparison of serum galactomannan antigen detection and competitive polymerase chain reaction for diagnosing invasive aspergillosis. Clin Infect Dis 1998;26:1407–1412.[Medline]
  42. Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE, Erjavec Z, et al. 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.[CrossRef][Medline]
  43. Wheat LJ. Rapid diagnosis of invasive aspergillosis by antigen detection. Transpl Infect Dis 2003;5:158–166.[CrossRef][Medline]
  44. Mennink-Kersten MA, Donnelly JP, Verweij PE. Detection of circulating galactomannan for the diagnosis and management of invasive asperillosis. Lancet Infect Dis 2004;4:349–357.[CrossRef][Medline]
  45. Marr KA, Laverdiere M, Gugel A, Leisenring W. Antifungal therapy decreases sensitivity of the Aspergillus galactomannan enzyme immunoassay. Clin Infect Dis 2005;40:1762–1769.[CrossRef][Medline]
  46. Sulahian A, Touratier S, Ribaud P. False positive test for Aspergillus antigenemia related to concomitant administration of piperacillin and tazobactam. N Engl J Med 2003;349:2366–2367.[Free Full Text]
  47. Maertens J, Van Eldere J, Verhaegen J, Verbeken E, Verschakelen J, Boogaerts M. Use of circulating galactomannan screening for early diagnosis of invasive aspergillosis in allogeneic stem cell transplant recipients. J Infect Dis 2002;186:1297–1306.[CrossRef][Medline]
  48. Herbrecht R, Letscher-Bru V, Oprea C, Lioure B, Waller J, Campos F, Villard O, Liu KL, Natarajan-Ame S, Lutz P, et al. Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients. J Clin Oncol 2002;20:1898–1906.[Abstract/Free Full Text]
  49. Odabasi Z, Mattiuzzi G, Estey E, Kantarjian H, Saeki F, Ridge RJ, Ketchum PA, Finkelman MA, Rex JH, Ostrosky-Zeichner L. Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis 2004;39:199–205.[CrossRef][Medline]
  50. Ostrosky-Zeichner L, Alexander BD, Kett DH, Vazquez J, Pappas PG, Saeki F, Ketchum PA, Wingard J, Schiff R, Tamura H, et al. Multicenter clinical evaluation of the (1 -> 3) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans. Clin Infect Dis 2005;41:654–659.[CrossRef][Medline]
  51. Pham AS, Tarrand JJ, May GS, Lee MS, Kontoyiannis DP, Han XY. Diagnosis of invasive mold infection by real-time quantitative PCR. Am J Clin Pathol 2003;119:38–44.[CrossRef][Medline]
  52. Ferns RB, Fletcher H, Bradley S, Mackinnon S, Hunt C, Tedder RS. The prospective evaluation of a nested polymerase chain reaction assay for the early detection of Aspergillus infection in patients with leukaemia or undergoing allograft treatment. Br J Haematol 2002;119:720–725.[CrossRef][Medline]
  53. Hebart H, Loffler J, Reitze H, Engel A, Schumacher U, Klingebiel T, Bader P, Bohme A, Martin H, Bunjes D, et al. Prospective screening by a panfungal polymerase chain reaction assay in patients at risk for fungal infections: implications for the management of febrile neutropenia. Br J Haematol 2000;111:635–640.[CrossRef][Medline]
  54. Buchheidt D, Baust C, Skladny H, Ritter J, Suedhoff T, Baldus M, Seifarth W, Leib-Moesch C, Hehlmann R. Detection of Aspergillus species in blood and bronchoalveolar lavage samples from immunocompromised patients by means of 2-step polymerase chain reaction: clinical results. Clin Infect Dis 2001;33:428–435.[CrossRef][Medline]
  55. Raad I, Hanna H, Huaringa A, Sumoza D, Hachem R, Albitar M. Diagnosis of invasive pulmonary aspergillosis using polymerase chain reaction-based detection of aspergillus in BAL. Chest 2002;121:1171–1176.[Abstract/Free Full Text]
  56. Kawazu M, Kanda Y, Goyama S, Takeshita M, Nannya Y, Niino M, Komeno Y, Nakamoto T, Kurokawa M, Tsujino S, et al. Rapid diagnosis of invasive pulmonary aspergillosis by quantitative polymerase chain reaction using bronchial lavage fluid. Am J Hematol 2003;72:27–30.[CrossRef][Medline]
  57. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, Kern WV, Marr KA, Ribaud P, Lortholary O, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408–415.[Abstract/Free Full Text]
  58. Troke PF, Schwartz S, Ruhnke M, Ribaud P, Corey L, Driscoll T, Fatkenheuer G, Schuler U, Thiel E, Dodell B, et al. Voriconazole (VCR) therapy (Rx) in 86 patients (pts) with CNS aspergillosis (CNSA): a retrospective analysis. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2003.
  59. Walsh TJ, Lutsar I, Driscoll T, Dupont B, Roden M, Ghahramani P, Hodges M, Groll AH, Perfect JR. Voriconazole in the treatment of aspergillosis, scedosporiosis, and other invasive fungal infections in children. Pediatr Infect Dis J 2002;21:240–248.[CrossRef][Medline]
  60. Walsh TJ, Petraitis V, Petraitiene R, Field-Ridley A, Sutton D, Ghannoum M, Sein T, Schaufele R, Peter J, Bacher J, et al. Experimental pulmonary aspergillosis due to Aspergillus terreus: pathogenesis and treatment of an emerging fungal pathogen resistant to amphotericin B. J Infect Dis 2003;188:305–319.[CrossRef][Medline]
  61. Steinbach WJ, Benjamin DK, Jr., Kontoyiannis DP, Perfect JR, Lutsar I, Marr KA, Lionakis MS, Torres HA, Jafri H, Walsh TJ. Infections due to Aspergillus terreus: a multicenter retrospective analysis of 83 cases. Clin Infect Dis 2004;39:192–198.[CrossRef][Medline]
  62. Kirkpatrick WR, Perea S, Coco BJ, Patterson TF. Efficacy of caspofungin alone and in combination with voriconazole in a Guinea pig model of invasive aspergillosis. Antimicrob Agents Chemother 2002;46:2564–2568.[Abstract/Free Full Text]
  63. Petraitis V, Petraitiene R, Sarafandi AA, Kelaher AM, Lyman CA, Casler HE, Sein T, Groll AH, Bacher J, Avila NA, et al. Combination therapy in treatment of experimental pulmonary aspergillosis: synergistic interaction between an antifungal triazole and an echinocandin. J Infect Dis 2003;187:1834–1843.[CrossRef][Medline]
  64. Luque JC, Clemons KV, Stevens DA. Efficacy of micafungin alone or in combination against systemic murine aspergillosis. Antimicrob Agents Chemother 2003;47:1452–1455.[Abstract/Free Full Text]
  65. Chandrasekar PH, Cutright JL, Manavathu EK. Efficacy of voriconazole plus amphotericin B or micafungin in a guinea-pig model of invasive aspergillosis. Clin Microbiol Infect 2004;10:925–928.[CrossRef][Medline]
  66. Sivak O, Bartlett K, Risovic V, Choo E, Marra F, Batty DS, Wasan KM. Assessing the antifungal activity and toxicity profile of amphotericin B lipid complex (ABLC; Abelcet) in combination with caspofungin in experimental systemic aspergillosis. J Pharm Sci 2004;93:1382–1389.[CrossRef][Medline]
  67. Graybill JR, Bocanegra R, Gonzalez GM, Najvar LK. Combination antifungal therapy of murine aspergillosis: liposomal amphotericin B and micafungin. J Antimicrob Chemother 2003;52:656–662.[Abstract/Free Full Text]
  68. Aliff TB, Maslak PG, Jurcic JG, Heaney ML, Cathcart KN, Sepkowitz KA, Weiss MA. Refractory Aspergillus pneumonia in patients with acute leukemia: successful therapy with combination caspofungin and liposomal amphotericin. Cancer 2003;97:1025–1032.[CrossRef][Medline]
  69. Kontoyiannis DP, Hachem R, Lewis RE, Rivero GA, Torres HA, Thornby J, Champlin R, Kantarjian H, Bodey GP, Raad II. 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 2003;98:292–299.[CrossRef][Medline]
  70. Marr KA, Boeckh M, Carter RA, Kim HW, Corey L. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis 2004;39:797–802.[CrossRef][Medline]
  71. Raad I, Chapman S, Bradsher R, Morrison V, Goldman M, Graybill J, Perfect JR, Patterson T, Walsh T, Corcoran G, et al. Posaconazole (POS) salvage therapy for invasive fungal infections. Forty-fourth Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC (M-669), 2004.
  72. Segal BH, Barnhart LA, Anderson VL, Walsh TJ, Malech HL, Holland SM. Posaconazole as salvage therapy in patients with chronic granulomatous disease with invasive filamentous fungal infection. Clin Infect Dis 2005;40:1684–1688.[CrossRef][Medline]
  73. Offner F, Cordonnier C, Ljungman P, Prentice HG, Engelhard D, De Bacquer D, Meunier F, De Pauw B. Impact of previous aspergillosis on the outcome of bone marrow transplantation. Clin Infect Dis 1998;26:1098–1103.[Medline]
  74. Fukuda T, Boeckh M, Guthrie KA, Mattson DK, Owens S, Wald A, Sandmaier BM, Corey L, Storb RF, Marr KA. Invasive aspergillosis before allogeneic hematopoietic stem cell transplantation: 10-year experience at a single transplant center. Biol Blood Marrow Transplant 2004;10:494–503.[CrossRef][Medline]
  75. Ozer H, Armitage JO, Bennett CL, Crawford J, Demetri GD, Pizzo PA, Schiffer CA, Smith TJ, Somlo G, Wade JC, et al. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 2000;18:3558–3585.[Free Full Text]
  76. Giles FJ. Monocyte-macrophages, granulocyte-macrophage colony-stimulating factor, and prolonged survival among patients with acute myeloid leukemia and stem cell transplants. Clin Infect Dis 1998;26:1282–1289.[Medline]
  77. 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.[Abstract/Free Full Text]
  78. Roilides E, Uhlig K, Venzon D, Pizzo PA, Walsh TJ. 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.[Abstract/Free Full Text]
  79. 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.[Medline]
  80. Roilides E, Sein T, Holmes A, Chanock S, Blake C, Pizzo PA, Walsh TJ. Effects of macrophage colony-stimulating factor on antifungal activity of mononuclear phagocytes against Aspergillus fumigatus. J Infect Dis 1995;172:1028–1034.[Medline]
  81. Roilides E, Holmes A, Blake C, Pizzo PA, Walsh TJ. Effects of granulocyte colony-stimulating factor and interferon-gamma on antifungal activity of human polymorphonuclear neutrophils against pseudohyphae of different medically important Candida species. J Leukoc Biol 1995;57:651–656.[Abstract]
  82. Nemunaitis J. Use of macrophage colony-stimulating factor in the treatment of fungal infections. Clin Infect Dis 1998;26:1279–1281.[Medline]
  83. Bensinger WI, Price TH, Dale DC, Appelbaum FR, Clift R, Lilleby K, Williams B, Storb R, Thomas ED, Buckner CD. The effects of daily recombinant human granulocyte colony-stimulating factor administration on normal granulocyte donors undergoing leukapheresis. Blood 1993;81:1883–1888.[Abstract/Free Full Text]
  84. Price TH, Bowden RA, Boeckh M, Bux J, Nelson K, Liles WC, Dale DC. Phase I/II trial of neutrophil transfusions from donors stimulated with G-CSF and dexamethasone for treatment of patients with infections in hematopoeitic stem cell transplantation. Blood 2000;95:3302–3309.[Abstract/Free Full Text]
  85. Nichols WG, Price T, Boeckh M. Cytomegalovirus infections in cancer patients receiving granulocyte transfusions. Blood 2002;99:3483–3484.[Free Full Text]
  86. Winn RM, Gil-Lamaignere C, Roilides E, Simitsopoulou M, Lyman CA, Maloukou A, Walsh TJ. Selective effects of interleukin (IL)-15 on antifungal activity and IL-8 release by polymorphonuclear leukocytes in response to hyphae of Aspergillus species. J Infect Dis 2003;188:585–590.[CrossRef][Medline]
  87. Vazquez N, Walsh TJ, Friedman D, Chanock SJ, Lyman CA. Interleukin-15 augments superoxide production and microbicidal activity of human monocytes against Candida albicans. Infect Immun 1998;66:145–150.[Abstract/Free Full Text]
  88. Mehrad B, Strieter RM, Moore TA, Tsai WC, Lira SA, Standiford TJ. CXC chemokine receptor-2 ligands are necessary components of neutrophil-mediated host defense in invasive pulmonary aspergillosis. J Immunol 1999;163:6086–6094.[Abstract/Free Full Text]
  89. Stevens DA. Combination immunotherapy and antifungal chemotherapy. Clin Infect Dis 1998;26:1266–1269.[Medline]
  90. Segal BH, Holland SM. Interferon-gamma in infectious diseases. In: Kawakami K, Stevens DA, editors. Immunomodulators as promising therapeutic agents against infectious diseases. Kerala, India: Research Signpost; 2004. pp. 23–54.
  91. Roilides E, Uhlig K, Venzon D, Pizzo PA, Walsh TJ. 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.[Abstract/Free Full Text]
  92. Rex JH, Bennett JE, Gallin JI, Malech HL, DeCarlo ES, Melnick DA. In vivo interferon-gamma therapy augments the in vitro ability of chronic granulomatous disease neutrophils to damage Aspergillus hyphae. J Infect Dis 1991;163:849–852.[Medline]
  93. Del Sero G, Mencacci A, Cenci E, d'Ostiani CF, Montagnoli C, Bacci A, Mosci P, Kopf M, Romani L. Antifungal type 1 responses are upregulated in IL-10-deficient mice. Microbes Infect 1999;1:1169–1180.[CrossRef][Medline]
  94. Cenci E, Mencacci A, Del Sero G, Bacci A, Montagnoli C, d'Ostiani CF, Mosci P, Bachmann M, Bistoni F, Kopf M, et al. Interleukin-4 causes susceptibility to invasive pulmonary aspergillosis through suppression of protective type I responses. J Infect Dis 1999;180:1957–1968.[CrossRef][Medline]
  95. Cenci E, Mencacci A, Fe d'Ostiani C, Del Sero G, Mosci P, Montagnoli C, Bacci A, Romani L. Cytokine- and T helper-dependent lung mucosal immunity in mice with invasive pulmonary aspergillosis. J Infect Dis 1998;178:1750–1760.[CrossRef][Medline]
  96. Cenci E, Perito S, Enssle KH, Mosci P, Latge JP, Romani L, Bistoni F. Th1 and Th2 cytokines in mice with invasive aspergillosis. Infect Immun 1997;65:564–570.[Abstract]
  97. 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.[Medline]
  98. International Chronic Granulomatous Disease Cooperative Study Group. 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.[Abstract]
  99. Fleming RV, Anaissie EJ, Kantarjian HM, Savary C, Rex JH. Safety of interferon-gamma plus G-CSF in cancer patients with refractory fungal infections: a pilot study. Thirty-seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 1997.
  100. Safdar A, Rodriguez G, Ohmagari N, Kontoyiannis DP, Rolston KV, Raad II, Champlin RE. The safety of interferon-gamma-1b for invasive fungal infections after hematopoietic stem cell transplantation. Cancer 2005;103:731–739.[CrossRef][Medline]
  101. Netea MG, Warris A, Van der Meer JW, Fenton MJ, Verver-Janssen TJ, Jacobs LE, Andresen T, Verweij PE, Kullberg BJ. Aspergillus fumigatus evades immune recognition during germination through loss of toll-like receptor-4-mediated signal transduction. J Infect Dis 2003;188:320–326.[CrossRef][Medline]
  102. Meier A, Kirschning CJ, Nikolaus T, Wagner H, Heesemann J, Ebel F. Toll-like receptor (TLR) 2 and TLR4 are essential for Aspergillus-induced activation of murine macrophages. Cell Microbiol 2003;5:561–570.[CrossRef][Medline]
  103. Mambula SS, Sau K, Henneke P, Golenbock DT, Levitz SM. Toll-like receptor (TLR) signaling in response to Aspergillus fumigatus. J Biol Chem 2002;277:39320–39326.[Abstract/Free Full Text]
  104. Bozza S, Gaziano R, Lipford GB, Montagnoli C, Bacci A, Di Francesco P, Kurup VP, Wagner H, Romani L. Vaccination of mice against invasive aspergillosis with recombinant Aspergillus proteins and CpG oligodeoxynucleotides as adjuvants. Microbes Infect 2002;4:1281–1290.[CrossRef][Medline]
  105. Romani L, Bistoni F, Gaziano R, Bozza S, Montagnoli C, Perruccio K, Pitzurra L, Bellocchio S, Velardi A, Rasi G, et al. Thymosin alpha 1 activates dendritic cells for antifungal Th1 resistance through toll-like receptor signaling. Blood 2004;103:4232–4329.[Abstract/Free Full Text]
  106. Bellocchio S, Moretti S, Perruccio K, et al. TLRs govern neutrophil activity in aspergillosis. J Immunol 2004;173:7406–7415.[Abstract/Free Full Text]
  107. Bellocchio S, Gaziano R, Bozza S, Rossi G, Montagnoli C, Perruccio K, Calvitti M, Pitzurra L, Romani L. 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.[Abstract/Free Full Text]
  108. Garlanda C, Hirsch E, Bozza S, Salustri A, De Acetis M, Nota R, Maccagno A, Riva F, Bottazzi B, Peri G, et al. Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response. Nature 2002;420:182–186.[CrossRef][Medline]
  109. Gaziano R, Bozza S, Bellocchio S, Perruccio K, Montagnoli C, Pitzurra L, Salvatori G, De Santis R, Carminati P, Mantovani A, et al. Anti-Aspergillus fumigatus efficacy of pentraxin 3 alone and in combination with antifungals. Antimicrob Agents Chemother 2004;48:4414–4421.[Abstract/Free Full Text]
  110. Romani L. Immunity to fungal infections. Nat Rev Immunol 2004;4:1–23.[CrossRef][Medline]
  111. Stevens DA. Vaccinate against aspergillosis! A call to arms of the immune system. Clin Infect Dis 2004;38:1131–1136.[CrossRef][Medline]
  112. Cenci E, Mencacci A, Bacci A, Bistoni F, Kurup VP, Romani L. T cell vaccination in mice with invasive pulmonary aspergillosis. J Immunol 2000;165:381–388.[Abstract/Free Full Text]
  113. Torosantucci A, Bromuro C, Chiani P, De Bernardis F, Berti F, Galli C, Norelli F, Bellucci C, Polonelli L, Costantino P, et al. A novel glyco-conjugate vaccine against fungal pathogens. J Exp Med 2005;202:597–606.[Abstract/Free Full Text]
  114. Bozza S, Perruccio K, Montagnoli C, Gaziano R, Bellocchio S, Burchielli E, Nkwanyuo G, Pitzurra L, Velardi A, Romani L. A dendritic cell vaccine against invasive aspergillosis in allogeneic hematopoietic transplantation. Blood 2003;5:5.
  115. Perruccio K, Bozza S, Montagnoli C, Bellocchio S, Aversa F, Martelli M, Bistoni F, Velardi A, Romani L. Prospects for dendritic cell vaccination against fungal infections in hematopoietic transplantation. Blood Cells Mol Dis 2004;33:248–255.[CrossRef][Medline]
  116. Bozza S, Montagnoli C, Gaziano R, Rossi G, Nkwanyuo G, Bellocchio S, Romani L. Dendritic cell-based vaccination against opportunistic fungi. Vaccine 2004;22:857–864.[CrossRef][Medline]
  117. Romani L, Montagnoli C, Bozza S, Perruccio K, Spreca A, Allavena P, Verbeek S, Calderone RA, Bistoni F, Puccetti P. The exploitation of distinct recognition receptors in dendritic cells determines the full range of host immune relationships with Candida albicans. Int Immunol 2004;16:149–161.[Abstract/Free Full Text]
  118. Jiang B, Bussey H, Roemer T. Novel strategies in antifungal lead discovery. Curr Opin Microbiol 2002;5:466–471.[CrossRef][Medline]



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