Outcome Of Invasive Aspergillosis Research Articles

Invasive aspergillosis in patients with liver disease

Invasive aspergillosis (IA) has been traditionally considered an infection occurring in patients with well established risk factors, such as neutropenia, hematologic malignancies, organ transplantation, or HIV. However there is increasing evidence that apparently immunocompetent patients, such as those with severe liver disease, are also at high risk for Aspergillus infections. Here we report two cases of proven invasive aspergillosis and review 72 others of aspergillosis reported since 1973 in patients with liver disease. Most patients had end-stage cirrhosis or acute hepatic failure. Overall mortality rate was 72.2% and the majority of patients who died had CNS involvement, disseminated infections, and received antifungal agents on a less common basis. A trend toward higher survival for cases reported during the period 2000-2009 was observed. Literature data suggest that invasive aspergillosis is a potential fatal complication of severe liver disease. The high mortality rate observed in these patients appears to be related not only to the severity of their underlying conditions, but also to a lack in clinical diagnosis. New diagnostic tools, e.g., galactomannan (GM) antigen test, in association with increased clinical suspicion may allow an early diagnosis and improve the outcome of IA in this particular category of patients.

Major Improvement of Invasive Aspergillosis Outcome Is Not Enough to Improve Overall Survival In Allogeneic Hematopoietic Stem Cell Transplant Recipients: Results From a Single-Center Retrospective Analysis

AbstractAbstract 1244 Background.Voriconazole (V) treatment has been shown to improve the 12 week (W) survival rate of hematological patients (pts) with invasive aspergillosis (IA), including recipients of allogeneic hematopoietic stem cell transplants (HSCT). We investigated whether this early survival advantage could translate into a significant increase in overall survival. Methods.We retrospectively reviewed all consecutive pts who received a transplant between Sept. 1997 and Dec. 2008 at Saint-Louis Hospital and were diagnosed as having IA. The temporal origin of the study was the date of IA diagnosis for each patient. Factors associated with survival were analyzed using Cox proportional hazard models. Separate models were estimated for survival up to 12 W and for survival between 12 W and 24 months (M) in pts surviving longer than 12 W. The deaths of pts with and without IA were analyzed with a competing risk framework. Cumulative incidence curves were compared using Gray's tests. Results.Our study examined 89 IA pts. The median follow-up was 70 M (range, 11–130 M). Two pts did not receive any antifungal treatment and were excluded from subsequent analyses. Of the 87 pts, 42 received first-line V and 45 primarily received a lipid formulation of amphotericin B (n=25), amphotericin B deoxycholate (n=10), caspofungin (n=8) or itraconazole (n=2). The primary characteristics of pts with IA and their causes of death, separated by V as first-line treatment, are shown in the table below.No voriconazole (n=45)Voriconazole (n=42)Median age4033Good risk transplant (%)21 (48)18 (43)Stem cell source (%)Bone marrow29 (64)21 (50)Peripheral blood stem cells10 (22)15 (36)Cord blood6 (13)6 (14)Donor type: identical sibling (%)23 (51)9 (21)Recipient CMV positive (%)25 (60)25 (61)Myeloablative conditioning (%)35 (81)25 (60)Progressive GVHD at IA diagnosis (%)25 (56)18 (43)ANC/mm3, median (range)1000 (0 to 12000)1805 (100 to 7000)Corticosteroid dose (mg/kg)At diagnosis, median (range)1 (0 to 7)1 (0 to 4)Cumulated dose over the last 7 days, median (range)7 (0 to 48)8 (0 to 32)Years of IA diagnosisUp to 200232 (71)5 (12)From 200313 (29)37 (88)Type of IA diagnosis (EORTC/MSG 2008) (%)Proven8 (18)5 (12)Probable32 (71)33 (79)Possible5 (11)4 (10)IA onset within 30 days from transplant (%)9 (20)6 (14)Bilateral pulmonary lesions (%)27 (71)16 (46)Number of deaths (%)36 (80)35 (83)Main cause of death (%)IA21 (58)8 (23)GVHD4 (11)6 (17)Relapse2 (6)5 (14)Infection (not IA)4 (11)7 (17)Acute respiratory distress syndrome4 (11)3 (9)Other1 (3)6 (17)The median survival was 2.6 M, and the overall survival at 24 M was 19% (95% CI 12–30 M) (see figure). [Display omitted] Overall, the survival rates of the two groups were significantly different (P= 0.010). However, the differences in survival were quite dramatic prior to 10 M, whereas both survival curves became very close after one year. At 18 M, the numbers of surviving pts were almost identical in the two groups [19% (95% CI: 11–34%) in pts who did not receive V as first-line treatment vs. 21% (95% CI 11–38%) in pts who did]. Pts who did not receive V as a first-line treatment displayed a higher probability of dying from IA than those who did (P=0.004), whereas opposite results were found for mortality in pts without IA (P=0.006). The 24-M cumulative incidence of death from IA was 47% (95% CI 31–61%) in the no V group and 19% (95% CI 9–33%) in the group treated with V. The 24-M cumulative incidence of death in pts without IA was 4% (95% CI 7–14%) in the no V group and 27% (95% CI 14–42%) in pts treated with V. The probability of death from another cause, with IA, was similar in both groups (29% vs. 36% at 24 M; P=0.46). After adjusting for donor type, conditioning regimen, progressive GVHD at diagnosis of IA and cumulated steroid dose (mg/kg) in the W preceding IA diagnosis, administration of V as first-line treatment was found to decrease the risk of death during the first 12 W by approximately 70% [HR=0.31 (95% CI 0.16–0.60); P=0.0005]. Conversely, analysis of mortality between 12 W and 24 M failed to identify any significant predictor of risk of death; however, only 24 pts died during this period. Conclusions.The finding that first-line treatment with V, which is associated with a tremendous improvement in IA outcome, does not translate into an increase in overall survival (even in the context of early diagnosis) is striking. Diagnosis of IA following HSCT, whatever the outcome, appears to be a strong marker for poor long-term prognosis. Disclosures:Bergeron:Pfizer: Speakers Bureau, none; Merck: Speakers Bureau, none; Schering: Speakers Bureau, none. Sulahian:Pfizer: Research Funding, non; Merck: Research Funding, none. Ribaud:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, none; Schering: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, none; Gilead: Speakers Bureau, none.

Early Proinflammatory Cytokines and C‐Reactive Protein Trends as Predictors of Outcome in Invasive Aspergillosis

Monitoring treatment response in invasive aspergillosis is challenging, because an immunocompromised host may not exhibit reliable symptoms and clinical signs. Cytokines play a pivotal role in mediating host immune response to infection; therefore, the profiling of biomarkers may be an appropriate surrogate for disease status. We studied, in a cohort of 119 patients with invasive aspergillosis who were recruited in a multicenter clinical trial, serum interleukin (IL)-6, IL‐8, IL‐10, interferon‐γ, and C‐reactive protein (CRP) trends over the first 4 weeks of therapy and correlated these trends to clinical outcome parameters. Circulating IL‐6 and CRP levels were high at initiation of therapy and generally showed a downward trend with antifungal treatment. However, subjects with adverse outcomes exhibited a distinct lack of decline in IL‐6 and CRP levels at week 1, compared with responders (P = .02, for both IL‐6 and CRP). Nonresponders also had significantly elevated IL‐8 levels (P = .001). High initial IL‐8 and persistently elevated IL‐6, IL‐8, and CRP levels after initiation of treatment may be early predictors of adverse outcome in invasive aspergillosis. Cytokine and CRP profiles could be used for early identification of patients with a poor response to antifungal treatment who may benefit from more‐aggressive antimicrobial regimens.

Invasive aspergillosis in patients with acute myeloid leukemia: a SEIFEM-2008 registry study

The aim of this study was to evaluate prognostic factors, treatments and outcome of invasive aspergillosis in patients with acute myeloid leukemia based on data collected in a registry. The registry, which was activated in 2004 and closed in 2007, collected data on patients with acute myeloid leukemia, admitted to 21 hematologic divisions in tertiary care centers or university hospitals in Italy, who developed proven or probable invasive aspergillosis. One hundred and forty cases of invasive aspergillosis were collected, with most cases occurring during the period of post-induction aplasia, the highest risk phase in acute myeloid leukemia. The mortality rate attributable to invasive aspergillosis was 27%, confirming previous reports of a downward trend in this rate. Univariate and multivariate analyses revealed that the stage of acute myeloid leukemia and the duration of, and recovery from, neutropenia were independent prognostic factors. We analyzed outcomes after treatment with the three most frequently used drugs (liposomal amphotericin B, caspofungin, voriconazole). No differences emerged in survival at day 120 or in the overall response rate which was 71%, ranging from 61% with caspofungin to 84% with voriconazole. Our series confirms the downward trend in mortality rates reported in previous series, with all new drugs providing similar survival and response rates. Recovery from neutropenia and disease stage are crucial prognostic factors. Efficacious antifungal drugs bridge the period of maximum risk due to poor hematologic and immunological reconstitution.

Risk factors for invasive aspergillosis and related mortality in recipients of allogeneic SCT from alternative donors: an analysis of 306 patients

Invasive aspergillosis (IA) is a serious complication in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT), particularly from donors other than HLA-identical sibling. All 306 patients who underwent alternative donor HSCT between 01 January 1999 and 31 December 2006 were studied. Late IA was defined as occurring >or=40 days after HSCT. The median follow-up was 284 days (range, 1-2709). Donors were matched unrelated (n=185), mismatched related (n=69), mismatched unrelated (n=35) and unrelated cord blood (n=17). According to European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria, 2 patients already had IA at HSCT, 23 had early IA and 20 had late IA (IA incidence 15%). Eight patients had proven and 37 probable IA. Multivariate analyses showed that significant predictors of IA were delayed neutrophil engraftment, extensive chronic GVHD (cGVHD), secondary neutropenia and relapse after transplant. Early IA was associated with active malignancy at HSCT, CMV reactivation and delayed lymphocyte engraftment. Late IA was predicted by cGVHD, steroid therapy, secondary neutropenia and relapse after HSCT. IA-related mortality among IA patients was 67% and was influenced by use of anti-thymocyte globulin, steroids, higher levels of creatinine, and lower levels of IgA and platelets. The outcome of IA depends on the severity of immunodeficiency and the status of the underlying disease.

Galactomannan serves as a surrogate endpoint for outcome of pulmonary invasive aspergillosis in neutropenic hematology patients

A noninvasive, objective, reproducible, and quantitative Aspergillus-specific surrogate marker is needed for a more accurate assessment of the outcome of invasive aspergillosis (IA) in patients with a hematologic disorder. The quantitative serum galactomannan index (GMI) assay seems to fulfill the requirements of surrogacy for outcome evaluation. Kappa statistics were used to determine the strength of correlation between GMI outcome and clinical outcome (survival or death), autopsy data, and response outcome of IA in 70 adults with prolonged neutropenia. All patients underwent serial GMI monitoring until discharge or death. The overall correlation between GMI and clinical outcome was good at 6 weeks (kappa=0.5882; 95% confidence interval [95% CI], 0.4023-0.7741) and was excellent at 12 weeks (kappa=0.8857; 95% CI, 0.7766-0.9948). Concordance with autopsy findings was perfect (kappa=1). At 6 weeks, the correlation between GMI and response outcome (favorable or unfavorable) was excellent (kappa=0.7523; 95% CI, 0.5803-0.9243). Survival was significantly better in patients who became GMI-negative (P<.0001). In neutropenic patients with seropositive IA, serum galactomannan index outcome strongly correlates with survival, autopsy findings, and response outcome. This finding may have implications for patient management and for clinical trial design.

Risk stratification for invasive aspergillosis: early assessment of host susceptibility

Outcomes of invasive aspergillosis are substantially improved with early initiation of therapy. Unfortunately, the diagnosis remains difficult to establish so that early suspicion of infection is imperative. Identification of high risk patients and use of non-culture-based diagnostics and radiographic studies can facilitate earlier recognition of infection. It is important to realize that the timing and spectrum of risk for invasive aspergillosis have expanded. While patients with hematological malignancies and hematopoietic stem cell transplants make up the highest risk groups, patients such as those receiving steroids and other immunosuppressive therapies are also at risk. Non-culture-based methods (including galactomannan, 1,3-beta-D-glucan, and PCR-based methods) are actively being pursued to improve early diagnosis. Thus, identifying patients at high risk for infection and utilizing non-culture-based methods and radiologic studies to assist in establishing a likely diagnosis of invasive aspergillosis will further enhance the role of new agents in the early, effective treatment and prophylaxis of invasive aspergillosis.

Therapeutic Outcome and Prognostic Factors of Invasive Aspergillosis in an Infectious Disease Department: A Review of 34 Cases

Invasive aspergillosis (IA) is one of the most frequent, feared and life-threatening opportunistic infection in immunocompromised patients. We wished to assess the therapeutic outcome and identify prognostic factors of IA. We reviewed retrospectively all patients managed in our department for a proven or probable IA over the last 10 years. A total of 34 patients were identified: 20 hematopoietic stem cell recipients, 7 infected with the human immunodeficiency virus, 6 hematological malignancies, and only 1 diabetes mellitus. IA involved the lower respiratory tract in all but one case with sinonasal infection. Among patients with pulmonary IA, sinuses were involved in four cases and the brain in five cases. First line antifungal therapy included amphotericin B deoxycholate (56%) or its lipid formulations (18%), itraconazole (15%) and voriconazole (12%). Eight patients also underwent surgery. Median survival was only 64 days and 73% of patients died during follow-up. A favorable outcome of IA was documented in only 48% of patients. Multivariate analysis identified neutropenia as the only factor associated with unsuccessful outcome (p = 0.003). IA remains therefore associated with a highmortality rate, especially in patients with neutropenia.

Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America

Thomas J. Walsh, Elias J. Anaissie, David W. Denning, Raoul Herbrecht, Dimitrios P. Kontoyiannis, Kieren A. Marr, Vicki A. Morrison, Brahm H Segal, William J. Steinbach, David A. Stevens, Jo-Anne van Burik, John R. Wingard, and Thomas F. Patterson Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland; University of Arkansas for Medical Sciences, Little Rock; The University of Texas M. D. Anderson Cancer Center, Houston, and The University of Texas Health Science Center at San Antonio, San Antonio; Oregon Health and Sciences University, Portland; Veterans Affairs Medical Center and University of Minnesota, Minneapolis, Minnesota; Roswell Park Cancer Institute, Buffalo, New York; Duke University Medical Center, Durham, North Carolina; Santa Clara Valley Medical Center, San Jose, and Stanford University, Palo Alto, California; University of Florida, College of Medicine, Gainesville, Florida; University of Manchester, Manchester, United Kingdom; and University Hospital of Strasbourg, Strasbourg, France

Invasive aspergillosis in a paediatric haematology department: a 15‐year review

Invasive aspergillosis (IA) is an increasingly common and often fatal fungal infection in children with haematological disorders. To describe the epidemiology, diagnosis, treatment and outcome of IA in children, retrospective review of the medical records of proven and probable IA between January 1986 and December 2000 was used. Twenty-four patients with IA were identified (10 proven and 14 probable) with a median age of 8.5 years. The incidence of IA was particularly high in acute myeloblastic leukaemia (5.35%) and leukaemia relapse (4%). Twenty-two patients presented with lung involvement. Broncho-alveolar lavage led to a diagnosis in 11 cases, but diagnosis was difficult and repeated invasive explorations were required. Antifungal therapy mainly consisted of amphotericin B. Eight patients underwent open-thorax surgery without any complication. Nine patients (37.5%) were cured of IA and three are still alive. The mortality was 87.5%. Three patients died of massive haemoptysis, including two before neutropenia recovery. Four patients presented with IA recurrence and three were cured again. Despite significant progress having been made in the treatment and diagnosis of IA, it is still a devastating complication in children with haematological disorders. New antifungal therapies and strategies are promising, but objective data are still lacking.

Outcome of Invasive Aspergillosis (IA) in 30 Patients with Hematological Cancer (Hem-Ca): Immunity Is (Almost) Everything.

Background: Among IA pts receiving antifungal therapy, a strong relationship exists between outcome of IA and resolution of immunosuppression. Determining the respective contributions of immune reconstitution and antifungal therapy to response has not been attempted. Yet, treatment strategies for IA have focused almost exclusively on antifungal agents to the detriment of immune therapies. Galactomannan (GM) is an Aspergillus-specific polysaccharide released during aspergillosis and detected by the serum GM test. This FDA-approved test is an accepted diagnostic marker for aspergillosis and preliminary data suggest a correlation between GM index (GMI) and outcome.Purpose: using GMI, to describe the contribution of immune recovery to outcome of IA in pts with hematological cancer (Hem-Ca).Patients and Methods: From 11/03–2/06, pts at risk for IA underwent GMI screening during periods at risk. The clinical and radiological findings of pts with ≥ 2 positive (+) GMI (optical density ≥ 0.5) were reviewed.Results: 30 pts had GMI (+) aspergillosis of the respiratory tract [myeloma 92%; median age: 59 years (27–75); 15 males]. Aspergillosis developed following stem cell transplant (SCT) [autologous (11), allogeneic (1)], or conventional chemotherapy (18). 25 pts were neutropenic (<1000/ml). The critical role of immune reconstitution was evident in 15/30 pts (50%). 7 of 25 (28%) neutropenic pts developed transient clinical and radiological worsening coinciding with immune recovery and rapid decline in GMI. All 7 responded without treatment modifications, suggesting an immune reconstitution inflammatory syndrome (IRIS). 6 pts had spontaneous clinical response with GMI normalization before commencing antifungal therapy (4 after neutrophil recovery, and 2 non-neutropenic pts after tapering immunosuppressants). 2 pts with IA refractory to prolonged and maximal antifungal therapy rapidly responded to interferon γ (1) and leukocyte transfusions (1) with GMI normalization within 48 h and subsequent clinical response.Overall, all 3 pts who remained neutropenic died compared to 2 of 22 pts whose myelosuppression resolved and 1/5 non-neutropenic pts (p=0.005).Conclusion: In addition to the strong association between neutrophil recovery and IA response, the critical role of immunity in IA is supported by common development of IRIS, spontaneous resolution of IA and response to immunomodulatory therapies. Daily GMI testing should be performed to accurately assess aspergillosis response. Declining GMI index obviates the need for invasive procedures and / or therapy modification. Immune therapies should be explored in IA.

Immune Reconstruction Inflammatory Syndrome (IRIS) with Invasive Aspergillosis (IA) in Patients (pts) with Hematological Cancer (Hem-Ca): Clinical and Research Implications.

Background: Assessing IA outcome with conventional criteria is difficult particularly when clinical and radiological worsening coincides with neutrophil recovery. This worsening is assumed to be related to immune reconstitution (IRIS). Because it is not possible to distinguish between pts whose worsening is transient from those who have progressive IA, clinical and radiological deterioration usually prompts invasive diagnostic procedures and therapeutic modifications including investigational agents, surgery, others. Galactomannan (GM) is an Aspergillus-specific polysaccharide released during aspergillosis and detected by the serum GM test. This FDA-approved test is an accepted diagnostic marker for aspergillosis and preliminary data suggest a correlation between GM index (GMI) and outcome.Purpose: using GMI, to distinguish response from progressive IA among patients with IRIS.Patients and Methods: patients at risk for IA (11/03–2/06) underwent GMI screening during periods at risk. The clinical and laboratory findings of pts with ≥ 2 (+) GMI (optical density ≥ 0.5) were reviewed.Results: 30 pts had GMI (+) aspergillosis of the respiratory tract [myeloma 92%; median age: 59 years (27–75); 15 males]. Invasive aspergillosis developed following stem cell transplantation [autologous (11), allogeneic (1)], or conventional chemotherapy (18). 12 of 25 (48%) neutropenic pts (<1000/ml) developed transient clinical and radiological worsening coinciding with neutrophil recovery, suggesting an IRIS. This deterioration coincided with rapidly declining GMI in 7 pts, all of whom survived with complete resolution of IA and without therapeutic modifications while the remaining 5 pts had persistently elevated GMI and rapidly died of IA.Conclusion: These data establish the presence of IRIS among Hem-Ca pts with IA who suffer clinical and radiologic deterioration coinciding with neutrophil recovery. IRIS is common and occurs among both responders and non-responders. Declining GMI values implies IRIS with response and obviates the need for invasive procedures and / or therapy modification while persistent GMI elevation is indicative of IRIS with progressive infection. Serial GMI testing should be performed to guide management and evaluate pts prior to therapy with investigational antifungal agents.

Clinical antifungal efficacy trials in invasive aspergillosis: Consensus standards for trial design and room for improvement.

Despite recent improvements in outcome of invasive aspergillosis there are still high failure and fatality rates. The trial comparing voriconazole to amphotericin B deoxycholate has become a reference for clinical trials in invasive aspergillosis due to the large number of patients included, the use of definition criteria close to the international consensus criteria, the inclusion of the halo sign on chest computed tomography for the definition of probable cases, the extensive review of the data by a panel of experts including radiologists, and most important, the successful efficacy results. Similar strict methodology for eligibility and assessment of outcome has been applied in the recently completed liposomal amphotericin B trial. This study compared a standard daily dose of liposomal amphotericin B (3 mg/kg) versus a high loading dose (10 mg/kg/d). The option to include possible cases in this trial and to give the investigators a few days to upgrade the diagnosis to a probable or definite level proved to be an effective strategy, saving four months in the duration of the recruitment period. Additional progress can be expected in future trials with the use of a standardized cutoff for the galactomannan detection test and a stratification at randomization on the most critical prognostic factor such as progressive underlying malignancy or allogeneic stem cell transplantation.

Th1/Th2 in aspergillosis.

The outcome of the Th1/Th2 balance is a critical determinant of the outcome in invasive aspergillosis. The innate immune system encounters the pathogen first. Dendritic cells (DC) appear to be the critical fulcrum at the intersection of the innate immune system, and which receptors are engaged, particularly which Toll-like receptors are triggered by the pathogen, likely determines which co-stimulatory molecules are expressed during the DC maturation process, and thus which cytokine pathway will eventually dominate. Some proinflammatory cytokines initially produced by naïve phagocytes may also direct dendritic cell direction. Thus DC are the main connections of the innate and adaptive immune systems. The cytokine pathway may be affected by the antigen load, whether and what type of immunosuppressive drug or immunosuppressive co-morbidity is present, the pathogen's success in converting from conidia to hyphae, the pathogen's production of toxins, and later whether appropriate antimicrobial chemotherapy is given. Chemokines triggered by cellular interaction with the pathogen call different host cell populations to the site of infection, collectins affect the phagocyte-fungus interaction, and the cytokines produced by the adaptive immune system then regulate the antifungal power of mononuclear phagocytes and polymorphonuclear neutrophils. In these ways the innate and adaptive immune systems work together in host defense. The key cytokines associated with a successful outcome of Aspergillus infection are upregulation of Th1 and proinflammatory cytokines IFNγ, TNFα, IL-12, GM-CSF, IL-1, IL-6 and IL-18, and down-regulation of IL-4 and IL-10. The converse is associated with progressive disease. The most data about favorable cytokine effects on phagocytes vs. Aspergillus concerns IFNγ, GM-CSF and G-CSF, and for unfavorable effects, IL-10 and IL-4. GM-CSF and IFNγ have also been shown to possess the ability to reverse the down-regulating effects of immunosuppressants on anti-Aspergillus phagocyte function. Neutralization of several Th1 cytokines in vivo has been shown directly to result in a bad outcome of infection, whereas administering Th1 or proinflammatory cytokines or neutralizing Th2 cytokines has been shown to produce a favorable outcome. Antifungal chemotherapy is associated with a switch to a Th1 profile, and antifungal chemotherapy combined with Th1 cytokine immunotherapy acts synergistically. Thus improved definition of the Th1/Th2 balance is essential for future prospects for immunotherapy, antimicrobial chemotherapy, and vaccination.

Itraconazole added to a lipid formulation of amphotericin B does not improve outcome of primary treatment of invasive aspergillosis

Invasive aspergillosis (IA) is associated with poor outcome in patients with hematologic malignancy treated with amphotericin B (AMB)-based therapy. Itraconazole (ITC), a triazole with activity against Aspergillus, has been used in combination with AMB or lipid formulations of AMB (LipoAMB) in the treatment of IA, although the efficacy of this strategy is uncertain. To determine whether the addition of ITC to LipoAMB improves outcome of IA, the authors retrospectively studied 179 consecutive patients with hematologic malignancies and definite or probable IA who received primary antifungal therapy with either LipoAMB (n = 146), or lipoAMB plus ITC (n = 33) between June 1993 and June 2003. In view of the erratic absorption of ITC tablets, only patients who received either intravenous or liquid ITC were analyzed. Patients who received < 1 week of treatment were excluded. Evaluable patients in both groups (LipoAMB: n =101; ITC and LipoAMB: n = 11) had comparable distribution of risk factors of poor outcome such as neutropenia at onset of IA, persistent neutropenia, systemic steroids, previous antifungal prophylaxis, admission to the intensive care unit, disseminated IA, previous bone marrow transplant, and IA due to infection by a non-fumigatus Aspergillus species. Response to primary antifungal therapy was equally poor in both groups (LipoAMB group: 10%; ITC and LipoAMB group: 0%; P = not significant). In the authors' 10-year study of patients with hematologic malignancy and IA, the response rate to LipoAMB given as primary therapy was very poor. In a comparable group of patients, the addition of ITC did not result in a therapeutic benefit.

Amphotericin B lipid complex for the treatment of invasive fungal infections

Amphotericin B lipid complex (ABLC; Abelcet®, Enzon Pharmaceuticals) has become the dominant marketed lipid amphotericin B compound to emerge since the approval of these agents from the mid-1990s onwards. This agent is a 1:1 combination of amphotericin B and a lipid moiety consisting of dimyristoyl phosphatidylcholine and dimyrisoyl phosphatidylcholine, which exists in a ribbon-like molecular structure. ABLC undergoes rapid reticuloendothelial uptake from the circulation and achieves significantly higher tissue concentrations in the liver, spleen and lung compared to comparably dosed conventional amphotericin B. ABLC is approved by the FDA for all mycoses in amphotericin B-intolerant or -refractory infection. Randomised, controlled trials of amphotericin B have shown comparable efficacy in candidiasis and an improved outcome in invasive aspergillosis versus historical controls. ABLC has demonstrated a reduced incidence of nephrotoxicity and infusion reactions versus amphotericin B. Comparative studies against other lipid formulations are quite limited and have shown variable differences in infusion toxicity, nephrotoxicity, hepatotoxicity and clinical efficacy. Postapproval experience has shown substantial efficacy for less common mycotic pathogens including zygomycosis. The precise position of ABLC versus both other lipid formulations and expanding formulary of new antifungal agents is in flux. Future studies which examine its clinical efficacy, role in combination therapy, toxicity and cost-effectiveness in these complex patients are needed.

Aspergillosis caused by non- fumigatus Aspergillus species: risk factors and in vitro susceptibility compared with Aspergillus fumigatus

Invasive aspergillosis (IA) caused by inherently more antifungal-resistant non- fumigatus Aspergillus species has become an important life-threatening complication in severely immunocompromised patients with cancer. The purpose of this study was to compare the relative incidence of, risk factors for, and in vitro correlation of amphotericin B and itraconazole with the clinical outcome of IA caused by Aspergillus fumigatus with those of IA caused by non- fumigatus Aspergillus spp. in patients with cancer. A retrospective search of our tertiary care cancer center’s microbiology laboratory reports from 1998–2001 revealed 40 patients with cancer and IA. A non- fumigatus Aspergillus species caused IA in 28 (70%) of those patients. A. fumigatus was the predominant cause of late-onset IA after bone marrow transplantation ( p = 0.05), whereas IA due to non- fumigatus Aspergillus spp. was more common in patients with neutropenia ( p = 0.01). The minimum inhibitory concentration (50/90) and minimum fungicidal concentration (50/90) for amphotericin B were higher in the non- fumigatus Aspergillus spp. group than in the A. fumigatus one. The Aspergillus species distribution in IA cases in our institution shows a predominance of the more antifungal-resistant or -tolerant non- fumigatus Aspergillus spp.

Trends in risk profiles for and mortality associated with invasive aspergillosis among liver transplant recipients.

To discern whether the characteristics and outcome of invasive aspergillosis in liver transplant recipients have evolved during the past decade, 26 patients who underwent transplantation during 1990-1995 (known as "the earlier cohort") were compared with 20 patients who underwent transplantation during 1998-2001 (known as "the later cohort"). Twenty-three percent of the Aspergillus infections in the earlier cohort occurred > or =90 days after transplantation, compared with 55% of such infections in the later cohort (P=.026). The earlier cohort was significantly more likely to have disseminated infection (P=.034) and central nervous system (CNS) involvement (P=.0004) than was the later cohort. The mortality rate was significantly higher for the earlier cohort (92%) than for the later cohort (60%; P=.012). Only disseminated infection (not the year of transplantation) approached statistical significance as an independent predictor of outcome. In the current era, invasive aspergillosis occurs later in the posttransplantation period, is less likely to be associated with CNS infection, and is associated with a lower mortality rate, compared with invasive aspergillosis in the early 1990s.

Invasive Aspergillosis in Italian AIDS patients.

We studied the prevalence, epidemiological features, symptoms, diagnosis, treatment and outcome of invasive aspergillosis in AIDS patients in Italy. All patients affected by both aspergillosis and AIDS hospitalized between January 1986 and April 1997 (before highly-active antiretroviral therapy, HAART) in four Italian Department of Infectious Disease. Patients were included in the study only if culture, cytology or histology showed firm evidence of Aspergillus infection. Invasive aspergillosis was defined as the presence of characteristic, closely septate hyphae with repeated acute angle branching in either biopsy materials or percutaneous aspirates from tissues other than the lung. Hyphae were identified using hematoxylin-eosin and methenamine silver stain. During the study, 54 out of 2,614 patients admitted with AIDS showed aspergillosis (2.1%). The disease usually occurred in patients with < 50 CD4 cells/mm(3). Aspergillosis was associated with neutropenia and steroid treatment. Nonspecific symptoms were frequently encountered. Fever and cough were both present in > 70% of the cases of pulmonary aspergillosis. Biopsy specimens were analyzed for definitive diagnosis. Invasive aspergillosis is usually treated with amphotericin B, but in 90% of the cases this did not prevent death. In AIDS patients with neutropenia and long-term steroid therapy, it is important to consider invasive aspergillosis in the differential diagnosis of opportunistic infections.

Transient lung-specific expression of the chemokine KC improves outcome in invasive aspergillosis.

Invasive aspergillosis is a common and devastating pneumonia in immunocompromised hosts. Neutrophils are critical for defense against this infection, and ELR+ CXC chemokines are potent neutrophil chemoattractants. We hypothesized that transient lung-specific overexpression of one such ligand, KC, in mice with invasive aspergillosis improves the outcome of disease. We generated mice in which transgenic expression of KC was limited to the lungs and occurred only upon exposure to tetracycline analogues, and we exposed them to doxycycline after the onset of invasive aspergillosis. Transgenic mice had a threefold greater survival, a 74% lower lung fungal burden, a greater magnitude of lung KC induction, and an earlier and higher peak of lung neutrophil influx compared with wild-type mice. In addition to a higher number of neutrophils, we found a 1.8-fold higher number of monocytes-macrophages in the lungs of transgenic mice as compared with wild-type mice. Furthermore, transgenic mice had greater lung expression of interferon-gamma and interleukin-12 in response to infection, suggesting that transgenic expression of KC indirectly regulated the expression of other cytokines associated with improved host defense against this pathogen. Taken together, these data suggest that overexpression of KC in the lung in the setting of established invasive aspergillosis results in improved host defense and outcome of disease.