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We report on four cases of aspergillosis which developed during therapy with fluconazole in patients who were immunosuppressed or granulocytopenic. Fluconazole may obscure the onset of aspergillosis. We feel that it should neither be given prophylactically nor for fever of unknown origin in patients who are at high risk of contracting aspergillosis.
Aspergillosis is one of the most common invasive fungal infections in patients with leukemia. In this patient group, this form of Aspergillus infection is a life-threatening condition with a mortality of 50-100%. The lungs are most often affected, but the esophagus can also be involved.The authors report the case of a child with leukemia who developed invasive esophageal aspergillosis. The condition was diagnosed by microscopic examination of endoscopic biopsy specimens. The patient was already receiving empirical liposomal amphotericin B when the diagnosis was made, so a second antifungal (caspofungin) was added to the regimen. This combination was successful. This case to demonstrates a case of successful treatment of invasive esophageal aspergillosis using combination therapy of liposomal amphotericin B and caspofungin.
The diagnosis of invasive aspergillosis remains very difficult, coupled with limited treatment options. Animal models have been utilized to evaluate both the diagnosis and treatment of infection and to assess the pathogenicity and virulence of the organism. However, animal models have not been standardized and have been used in only a limited fashion for genomic evaluation in this disease. Extensive efforts are underway to expand significantly the Aspergillus genomic information. Thus, the standardization of animal models of invasive aspergillosis is critical to create a unified platform to enhance evaluation of newer genomic information and allow assessment of pathogenicity and virulence factors. Proposed models, supported by a recently awarded National Institutes of Health/National Institute of Allergy and Infectious Diseases contract, will be developed in close interaction with the extended Aspergillus community (including academia and industry) to answer key questions in this disease. The goal of this work is to provide the framework to evaluate genomic targets in animal models in order to improve the diagnosis and treatment of invasive aspergillosis that will ultimately result in improved outcomes of patients with this frequently fatal infection.
Chronic necrotizing pulmonary aspergillosis is not common and usually involves mildly immunosuppressed patients. We present a case of a 58-year-old man with a history of mining-related pneumoconiosis and corticosteroid therapy who developed bilateral pulmonary infiltrates and subsequent cavitation. The patient was treated at first as having community-acquired pneumonia and was only belatedly diagnosed as suffering from aspergillosis after Aspergillus fumigatus precipitins appeared in blood and the same fungus grew from bronchoalveolar lavage fluid. A transthoracic needle biopsy revealed fungal filaments present in material extracted from a pulmonary lesion that was visible on scans. Treatment with amphotericin B, begun at the time that aspergillosis was diagnosed, proved to be ineffective, as was a later change to amphotericin B lipid complex. The diagnosis was confirmed at necropsy.
Changing transplantation practices, novel immunosuppressive protocols, and evolving recipient characteristics have led to notable changes in the epidemiology of invasive aspergillosis in transplant recipients. The frequency of disseminated infection and of central nervous system involvement has declined significantly in organ transplant recipients in the recent years. Amongst variables that may have contributed to these trends is an overall lesser severity of illness of transplant recipients in the current era. Calcineurin-inhibitor immunosuppressive agents may also have had a role in altering the disease course and the risk of dissemination. A new paradigm in the management of post-transplant immunosuppression is the use of calcineurin-inhibitor and corticosteroid sparing regimens by pretreatment of the recipient with T-cell depleting agents (Campath 1-H or thymoglobulin) and utilization of minimal post-transplant immunosuppression. The impact of these potent lymphoablative regimens on opportunistic mycoses in organ transplant recipients remains to be fully discerned. Although still unacceptably high, the mortality rate in organ transplant recipients with invasive aspergillosis in the current era appears to have declined. A focus of a great interest and controversy is the use of combination therapy for invasive aspergillosis in transplant recipients.
Mortality from invasive pulmonary aspergillosis approaches 80% with few useful therapeutic options available. In these studies, we examined the efficacy of micafungin (MICA) alone or in combination with other antifungals in a model of pulmonary aspergillosis in immunosuppressed DBA/2 mice infected intranasally with conidia of Aspergillus fumigatus 10AF. In the initial study, groups of mice were given saline, or 1, 3 or 10 mg kg(-1) of MICA b.i.d., s.c. All saline controls, and 90% of untreated mice succumbed to infection. The efficacy of MICA was difficult to assess because of an apparent toxicity at 10 mg kg(-1). MICA given at 1 mg/kg significantly prolonged survival over the saline controls (P = 0.008). MICA at 3 or 10 mg kg(-1) versus the saline controls approached significance. No treatment regimen differed in efficacy. The efficacy of combination therapy was assessed, with mice given either no treatment, MICA at 1 mg/kg/dose, 0.8 mg kg(-1) of intravenous amphotericin B (AMB), 100 mg kg(-1) of oral itraconazole (ICZ), or 100 mg/kg/dose of twice-daily subcutaneous nikkomycin Z (NIK). AMB alone and MICA + AMB or MICA +NIK significantly prolonged survival (P < 0.05 - 0.02) over that of the controls. ICZ alone, ICZ+MICA and NIK alone did not significantly prolong survival. MICA alone at 1 mg/kg approached significance in prolonging survival. The combination of MICA and ICZ appeared to be potentially antagonistic. Although AMB+MICA was efficacious, no synergistic activity was noted for any of the regimens. Overall, these results indicate that MICA has moderate activity against pulmonary aspergillosis and might be useful in combination with conventional AMB.
We have reported earlier that Aspergillus fumigatus is inhibited in vitro by Candida albicans which also interferes in its isolation from sputum experimentally seeded with predetermined graded inocula of the two fungi. It was further shown that this interference was neutralized by employing peptone glucose agar with incorporation of fluconazole which is more inhibitory to C. albicans than to A. fumigatus. This communication embodies the results of evaluation of peptone glucose fluconazole agar (PGFA) as a selective culture medium for rapid and enhanced isolation of A. fumigatus from sputum of patients clinically suspected of aspergillosis with C. albicans colonization in the respiratory tract. Of the 23 sputum specimens and one broncho-alveolar lavage collected from 15 suspected aspergillosis patients, A. fumigatus was isolated from all (100%) on PGFA as against only 19 specimens (79%) that proved to be positive on the control PGA medium (P<0.05). The greater efficacy of PGFA than that of PGA was further evident from the 2-fold higher A. fumigatus mean colony count (8.2+/-1.87) on the former medium than on the latter (3.7+/-1.00), and this difference was found to be statistically significant (P<0.05). Besides, A. fumigatus colonies were macroscopically recognizable within 2-3 days on PGFA at 28 degrees C in strong contrast to 5-7 days required on PGA. Based upon these observations, PGFA is recommended for wider application as a selective medium for rapid and enhanced recovery of A. fumigatus from sputum of patients clinically suspected of aspergillosis with C. albicans colonization in their respiratory tract.
We assessed predictive factors and characteristics of patients with late-onset invasive aspergillosis in the current era of novel immunosuppressive agents. Forty transplant recipients with invasive aspergillosis were included in this prospective, observational study initiated in 2003 at our institutions. In 50% (20/40) of these patients, the infections were late-occurring. Receipt of sirolimus in conjunction with tacrolimus for refractory rejection or cardiac allograft vasculopathy (P=0.047) was significantly associated with late-onset infection. The use of depleting or non-depleting T or B-cell antibodies, either as induction or as antirejection therapy did not correlate with time to onset of invasive aspergillosis. Mortality at 90 days was 20% (4/20) for the patients with early-onset infection and 45% (9/20) for those with late-onset infection (P=0.17). Thus, nearly one-half of the Aspergillus infections in transplant recipients in the current era are late-occurring. These data have implications relevant for prophylactic strategies and guiding clinical management of transplant recipients presenting with pulmonary infiltrates.
To update the case-fatality rate (CFR) associated with invasive aspergillosis according to underlying conditions, site of infection, and antifungal therapy, data were systematically reviewed and pooled from clinical trials, cohort or case-control studies, and case series of >/=10 patients with definite or probable aspergillosis. Subjects were 1941 patients described in studies published after 1995 that provided sufficient outcome data; cases included were identified by MEDLINE and EMBASE searches. The main outcome measure was the CFR. Fifty of 222 studies met the inclusion criteria. The overall CFR was 58%, and the CFR was highest for bone marrow transplant recipients (86.7%) and for patients with central nervous system or disseminated aspergillosis (88.1%). Amphotericin B deoxycholate and lipid formulations of amphotericin B failed to prevent death in one-half to two-thirds of patients. Mortality is high despite improvements in diagnosis and despite the advent of newer formulations of amphotericin B. Underlying patient conditions and the site of infection remain important prognostic factors.
Nosocomial invasive aspergillosis can cause life-threatening infections among immunosuppressed patients and is thought to be primarily airborne. Despite the use of appropriate hospital air filtration systems, however, the incidence of this infection continues to increase. In this article, we present our hypothesis, which is that nosocomial aspergillosis can be airborne from a water source in the hospital. If confirmed by ongoing studies, this hypothesis would imply a change in the current infection control practices aimed at preventing nosocomial aspergillosis.
Invasive pulmonary aspergillosis is an emerging devastating infection in the immunocompromised host that is treated with corticosteroids for neoplastic disease or for organ transplantation. By use of a model of invasive pulmonary aspergillosis in corticosteroid-treated CF-1 mice, prior infection and 2 Aspergillus fumigatus vaccine preparations (sonicate and filtrate) administered intranasally and subcutaneously were tested for efficacy in protecting against subsequent lethal A. fumigatus infection. The mortality rates were as follows: control subjects, 100%; prior infection, 12.5%; sonicate administered intranasally, 29%; sonicate given subcutaneously, 0%; filtrate given intranasally, 75%; and filtrate given subcutaneously, 50%. Prior infection and A. fumigatus sonicate vaccine administered by 2 routes protected corticosteroid-treated animals against subsequent lethal invasive pulmonary aspergillosis. The sonicate vaccine was more protective, but the subcutaneous route was more effective.
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.
A recent trial of drugs for invasive aspergillosis was used as a background for discussing critical features in the design of antifungal trials. The study under discussion allowed stopping either drug without classifying the patient as having treatment failure, so the trial should be understood as a comparison of 2 treatment strategies, not just 2 drugs. Although the study was a noninferiority trial, the outcome permitted a claim of superiority. Use of the category of "probable" in addition to "proven" aspergillosis permitted inclusion of patients for whom the diagnosis was less certain but who were still early enough in the disease progression to respond to therapy. Different opinions still exist about some of the criteria for the diagnosis of "probable" aspergillosis. A blinded data review committee was helpful in evaluating efficacy in this unblinded trial but had limited value in assessing toxicity. An understanding of these features of design of antifungal drug trials is important in applying the results to clinical practice.
Invasive pulmonary aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Simultaneous inhibition of fungal cell-wall and cell-membrane biosynthesis may result in synergistic interaction against Aspergillus fumigatus. We studied the antifungal activity of micafungin, a new echinocandin, in combination with ravuconazole, a second-generation triazole, against experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits. This combination led to significant reductions in mortality (P</=.001), residual fungal burden (P</=.05), and serum galactomannan antigenemia (P</=.01), compared with either agent alone. Combination therapy also resulted in reduction (P</=.05) of organism-mediated pulmonary injury and of pulmonary infiltrates detected by thoracic computed tomography (P</=.001). No toxicity was observed with the echinocandin-triazole combination. An MTT hyphal damage assay demonstrated significant in vitro synergistic interaction between the antifungal triazole and the echinocandin. The combination of an antifungal triazole and echinocandin may represent a new strategy for treatment of invasive pulmonary aspergillosis.
Invasive aspergillosis is a devastating and increasingly common disease, seen almost exclusively in immunosuppressed patients. Immunizing an immunocompromised host would seem to be a formidable task; however, virulence factors and immunogens of the pathogen have now been identified and could be targeted, mapping of the genome sequence of the pathogen will soon be completed, and the protective host immune responses and cytokine networking are better understood. These facts, together with recent advances in vaccine science, make consideration of such an approach now possible. Some populations that are at risk for aspergillosis might be likely candidates for receiving the first vaccinations against aspergillosis, or vaccination of a stem cell donor might be considered in some circumstances. Successful immunizations have been demonstrated in turkeys and mice.
BACKGROUND: In a previous randomized trial of voriconazole versus amphotericin B deoxycholate for primary therapy of invasive aspergillosis, voriconazole demonstrated superior efficacy and better survival. In that trial, treatment with voriconazole or amphotericin B deoxycholate could be followed with other licensed antifungal therapies (OLAT). Here, we report the impact of OLAT on the outcome of patients with invasive aspergillosis. METHODS: Data on dose, duration, and the reason for switching to the first OLAT were analyzed, and outcome at week 12 was assessed. RESULTS: Fewer patients in the voriconazole group (52 [36%] of 144) switched to OLAT, compared with patients in the amphotericin B deoxycholate group (107 [80%] of 133). Lipid formulations of amphotericin B were the most common OLAT (38% of patients). Switches were made because of intolerance or insufficient response in 70% for patients in the amphotericin B deoxycholate group, compared with 24% of patients in the voriconazole group. Favorable responses to OLAT in the amphotericin B deoxycholate group occurred in only 19% of patients with initial insufficient response and 38% of patients with intolerance. Salvage therapy with a lipid formulation of amphotericin B after initial treatment with amphotericin B deoxycholate was successful for only 30% of patients (14 of 47). Treatment success among patients randomized to receive amphotericin B, including those whose treatment was switched to OLAT, was 32%, compared with 55% among patients who received voriconazole alone (P<.001). CONCLUSIONS: This study highlights the limited efficacy of salvage antifungal therapy, including therapy with lipid formulations of amphotericin B, and demonstrates the importance of effective initial therapy in invasive aspergillosis.
OBJECTIVE: To characterize the epidemiology of invasive pulmonary aspergillosis (IPA). DESIGN: A retrospective case series. SETTING: An 850-bed, academic, tertiary-care medical center. PARTICIPANTS: Adult inpatients, between January 1, 1990, and December 31, 1998, with either a histopathology report consistent with IPA or a discharge diagnosis of aspergillosis. METHODS: We reviewed medical records and categorized case-patients as definitive or probable and acquisition of IPA as nosocomial, indeterminate, or community using standard definitions. To determine the rate of aspergillus respiratory colonization, we identified all inpatients who had a respiratory culture positive for Aspergillus species without a histopathology report consistent with IPA or a discharge diagnosis of aspergillosis. Three study intervals were defined: interval 1, 1990 to 1992; interval 2, 1993 to 1995; and interval 3, 1996 to 1998. Carpeting in rooms for patients following heart-lung and liver transplant was removed and ceiling tiles were replaced during interval 1; a major earthquake occurred during interval 2. RESULTS: 72 case-patients and 433 patients with respiratory colonization were identified. Acquisition was nosocomial for 18 (25.0%), indeterminate for 9 (12.5%), and community-acquired for 45 (62.5%) case-patients. Seventeen (23.6%) of the 72 case-patients had prior transplants, including 15 solid organ and 2 bone marrow. The IPA rate per 100 solid organ transplants (SOTs) decreased from 2.45 during interval 1 to 0.93 during interval 2 and to 0.52 during interval 3 (chi-square for trend, 5.44; P<.05). The hospitalwide IPA rate remained stable at 0.03 per 1,000 patient days. CONCLUSIONS: The SOT IPA rate decreased after intervals 1 and 2, although the hospitalwide IPA rate remained stable during the study period. Post-earthquake hospital demolition and construction occurring after interval 2 was not associated with an increase in the rate of IPA at our institution.
To prevent nosocomial pulmonary aspergillosis during hospital construction, neutropenic patients with hematologic malignancy were required to wear high-efficiency masks when leaving their rooms. The rate of nosocomial aspergillosis decreased from 0.73 per 1,000 hospital patient-days during fiscal years 1993 to 1996 to 0.24 per 1,000 hospital patient-days during fiscal years 1996 to 1999 (P < .001). High-efficiency masks reduced nosocomial aspergillosis during hospital construction.