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PubMed2005

PCR based identification and discrimination of agents of mucormycosis and aspergillosis in paraffin wax embedded tissue.

BACKGROUND: Invasive fungal infections are often diagnosed by histopathology without identification of the causative fungi, which show significantly different antifungal susceptibilities. AIMS: To establish and evaluate a system of two seminested polymerase chain reaction (PCR) assays to identify and discriminate between agents of aspergillosis and mucormycosis in paraffin wax embedded tissue samples. METHODS: DNA of 52 blinded samples from five different centres was extracted and used as a template in two PCR assays targeting the mitochondrial aspergillosis DNA and the 18S ribosomal DNA of zygomycetes. RESULTS: Specific fungal DNA was identified in 27 of 44 samples in accordance with a histopathological diagnosis of zygomycosis or aspergillosis, respectively. Aspergillus fumigatus DNA was amplified from one specimen of zygomycosis (diagnosed by histopathology). In four of 16 PCR negative samples no human DNA was amplified, possibly as a result of the destruction of DNA before paraffin wax embedding. In addition, eight samples from clinically suspected fungal infections (without histopathological proof) were examined. The two PCR assays detected a concomitant infection with Absidia corymbifera and A fumigatus in one, and infections with Rhizopus arrhizus and A fumigatus in another two cases. CONCLUSIONS: The two seminested PCR assays described here can support a histopathological diagnosis of mucormycosis or aspergillosis, and can identify the infective agent, thereby optimising antifungal treatment.

Aspergillosis↗

PubMed1985

Immunoblot analysis of serological responses in invasive aspergillosis.

The serological response to Aspergillus fumigatus was investigated in patients with pulmonary aspergillosis using the immunoblot technique. Antibody was detected against nine components of the fungus, ranging in molecular weight from 88 000 to 33 000 daltons. Antibody to a 40 000 dalton component was present in most patients (13 of 16). In surviving patients it was high (two with aspergilloma) or low but persistent (two with invasive aspergillosis). It was absent or fell in the 12 patients who died of invasive aspergillosis. Antibody to this 40 000 dalton antigen was not present in 10 sera from healthy controls. This antigen may form the basis of a more sensitive and specific serodiagnostic test for systemic aspergillosis.

Antibodies, Fungal↗

PubMed2006

Assessment of a commercial sandwich ELISA in the diagnosis of aspergillosis in falcons.

A commercial sandwich elisa (Platelia Aspergillus EIA; Bio-Rad) developed for the detection of galactomannan, a major cell wall constituent of Aspergillus species, was tested for its efficacy in the diagnosis of aspergillosis in falcons. Ninety serum samples from 50 aspergillosis-positive falcons and 182 samples from 142 aspergillosis-negative falcons were tested. The sensitivity of the test was only 12 per cent and its specificity was 95 percent. The test was therefore unsatisfactory for detecting galactomannan in the serum samples and cannot be used as a screening test for aspergillosis in falcons.

Animals↗

PubMed1982

Combination therapy of experimental candidiasis, cryptococcosis and aspergillosis in mice.

Combination pairs of the major systematic antimycotic drugs, amphotericin B (AmphB), 5-fluorocytosine (5-FC) and ketoconazole (Ktz) were administered to mice with experimental candidiasis, cryptococcosis and aspergillosis at a variety of combination ratios. The 3 mycoses were produced with 3 strains each of Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus, respectively, which were preselected to represent 3 different degrees of 5-FC sensitivity ('normally sensitive', 'moderately resistant', and 'definitely resistant'). The life-prolonging effect of the combinations was compared with the effect of each partner administered alone at the same and at the double dosage. Using the U test of Mann and Whitney and setting limits which on the whole were more rigorous than those of the isobole methods commonly applied to the study of drug interactions, the effects of the concentrations were classified as 'synergistic', 'additive', 'indifferent' or 'antagonistic'. The combination AmphB plus 5-FC was definitely synergistic or definitely additive in all 3 candidiasis models, the most pronounced synergism occurring in the infection with the 'definitely 5-FC-resistant' C. albicans strain; in cryptococcosis produced by any of the 3 C. neoformans strains the effect was definitely additive, but only slightly additive or indifferent in the 3 aspergillosis models. The combination AmphB plus Ktz was slightly synergistic in candidiasis produced by one C. albicans strain, but definitely antagonistic in this mycosis produced by the remaining 2 strains of the same species; the combination was definitely additive or, even, slightly synergistic in the 3 cryptococcus models, but, again, antagonistic in aspergillosis produced by all 3 strains of A. fumigatus. 5-FC plus Ktz was additive or indifferent in the 3 candidiasis models, but throughout indifferent in cryptococcosis and aspergillosis.

Amphotericin B↗

PubMed1987

Combination therapy of experimental candidiasis, cryptococcosis, aspergillosis and wangiellosis in mice.

Combination pairs of 5-fluorocytosine (5-FC) + itraconazole (Itra), 5-FC + fluconazole (Fluc), and amphotericin B (Amph B) + Itra were administered to mice with experimental candidiasis, cryptococcosis, aspergillosis and wangiellosis with a variety of combination ratios. The life-prolonging effect of the combinations was compared with the effect of each partner administered alone and with a double dosage. Using the U test of Mann and Whitney, the effects of the concentration were classified as synergistic, additive, indifferent or antagonistic; the degree of the interaction was compared with the known effect of Amph B and 5-FC combinations. The combination 5-FC + Itra was definitely synergistic or additive in candidiasis and aspergillosis. The most pronounced synergism occurred in the infection with a 5-FC-resistant strain of Candida albicans. The degree of synergism was the same as with 5-FC + Amph B. In cryptococcosis this combination was indifferent. The combination of 5-FC + Itra merits clinical investigation, especially in candidiasis and aspergillosis. Amph B + Itra was mostly indifferent and weakly antagonistic; the degree of antagonism was significantly weaker than the one observed with Amph B + ketoconazole (Keto). In candidiasis, 5-FC + Fluc was synergistic, but indifferent in cryptococcosis and aspergillosis.

Amphotericin B↗

PubMed1975

The general and specific humoral immune response to pulmonary aspergillosis.

The genus Aspergillus may cause one of several clinical entities in affected patients. Serum specimens from 79 patients, including 41 with aspergilloma, 28 with allergic bronchopulmonary aspergillosis, 3 with both aspergilloma and the allergic variant, and 7 with invasive or disseminated aspergillosis, were studied for antibodies to aspergillus. The ammonium sulfate test was used with a mycelial component labeled with iodine-125 derived from Aspergillus fumigatus. Complement fixation and immunodiffusion tests using a culture filtrate antigen (aspergillin) from the same species were also performed. Immunoglobulins G, A, and M and complement component C-3 were determined by radial immunodiffusion. Total serum IgE was measured by radioimmunoassay. Serum specimens from patients with aspergilloma manifested increased binding to the radio-labeled mycelial component, multiple precipitin bands, and/or increased complement fixation titers to aspergillin. Serum concentrations of IgG and IgA were increased. Patients with allergic bronchopulmonary aspergillosis were characterized by moderately increased binding to the radio-labeled mycelial component, a paucity of precipitating and complement-fixing antibody to aspergillin, and increased total serum IgE. Serum from patients with locally invasive or disseminated aspergillosis had increased concentrations of C-3 and variable binding to the radiolabeled mycelial component, depending on the duration of the disease process. Use of a battery of tests with both mycelial and culture filtrate antigens enhanced detection of circulating aspergillus antibody.

Ammonium Sulfate↗

PubMed1981

Immunodiagnosis of invasive pulmonary aspergillosis in rabbits. Fungal antigen detected by radioimmunoassay in bronchoalveolar lavage fluid.

To improve antemortem diagnosis of invasive pulmonary aspergillosis, we used a radioimmunoassay to detect an Aspergillus fumigatus antigen in bronchoalveolar lavage fluid (BALF) and evaluated this technique in a model of disseminated aspergillosis. Antigen was detected in 91% of BALF samples obtained from 11 rabbits with major pulmonary aspergillosis. In an additional 10 rabbits with only minor pulmonary involvement, antigen was detected in 40% of concentrated lavage samples. In contrast, antigenlike activity was found in only 1 of 17 BALF samples from control animals with systemic candidiasis, in none of 9 control animals with staphylococcal pneumonia and in none of 10 normal control animals. Although antigen was present in the serum of 76% of animals infected with Aspergillus, 27% of those with major pulmonary involvement had antigen detected in BALF alone. We found that an extracellular microbial antigen can be detected in BALF and that this technique in the disseminated aspergillosis model is both sensitive and specific for invasive pulmonary disease.

Animals↗

PubMed1985

Oxalic acid level in bronchoalveolar lavage fluid from patients with invasive pulmonary aspergillosis.

Oxalic acid is a fermentation product of Aspergillus. We have measured the oxalic acid level in bronchoalveolar lavage fluids recovered from immunocompromised patients with and without invasive pulmonary aspergillosis. These levels were significantly higher in patients with invasive aspergillosis than in patients with pneumonitis of other causes. Thus, the determination of oxalic acid in bronchoalveolar lavage could be a presumptive argument for invasive aspergillosis until positive fungal cultures or histologic diagnosis; its potential value in monitoring the course of invasive pulmonary aspergillosis, particularly under treatment, has to be confirmed in more patients.

Adolescent↗

PubMed2002

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.

Animals↗

PubMed2003

Chemokine-mediated recruitment of NK cells is a critical host defense mechanism in invasive aspergillosis.

Invasive aspergillosis is a severe pneumonia that is usually fatal despite currently available therapy. The disease disproportionately afflicts immunocompromised patients, indicating the critical importance of the immune status of the host in this infection, but the defense mechanisms against this pathogen remain incompletely understood. In the current study, we hypothesized that the chemokine ligand monocyte chemotactic protein-1, also designated CC chemokine ligand-2 (MCP-1/CCL2) is necessary for effective host defense against invasive aspergillosis in immunocompromised hosts. We found a rapid and marked induction of MCP-1/CCL2 in the lungs of neutropenic mice with invasive aspergillosis. Neutralizing MCP-1/CCL2 resulted in twofold greater mortality and greater than threefold increase in pathogen burden in the lungs. Neutralization of MCP-1/CCL2 also resulted in reduced recruitment of NK cells to the lungs at early time points, but did not affect the number of other leukocyte effector cells in the lungs. Ab-mediated depletion of NK cells similarly resulted in impaired defenses against the infection, resulting in a greater than twofold increase in mortality and impaired clearance of the pathogen from the lungs. These data establish MCP-1/CCL2-mediated recruitment of NK cells to the lungs as a critical early host defense mechanism in invasive aspergillosis and demonstrate NK cells to be an important and previously unrecognized effector cell in this infection.

Animals↗

PubMed1991

Sinus aspergillosis and allergic fungal sinusitis.

Aspergillosis of the sinonasal tract has four basic clinicopathologic presentations depending on the mucosal or extramucosal involvement by the fungus. Two are saprophytic (aspergilloma and allergic Aspergillus sinusitis) and two are infectious (chronic indolent and invasive fulminant sinusitis). Tissue-invasive and angioinvasive aspergillosis can be a rapidly lethal disease, particularly in the immune-compromised host. The allergic form of paranasal sinus aspergillosis is presumed to be initiated by hyperreactivity to fungal antigens. Not all allergic fungal sinusitis is associated with Aspergillus species, and culture confirmation is necessary to distinguish the fungal agent. Surgical removal of the offending fungus is the mainstay of therapy in all forms of sinonasal aspergillosis and other fungal sinusitis. Antifungal agents and steroids complement surgical removal, depending on the form of the sinusitis.

Antigens, Fungal↗

PubMed1996

Development of murine monoclonal antibodies for the immunohistochemical diagnosis of systemic bovine aspergillosis.

Murine monoclonal antibodies (MAbs) against water-soluble somatic antigens (WSSA) and the wall fraction (WF) from Aspergillus fumigatus were produced by fusion of splenocytes from immunized BALB/c mice with mouse myeloma X63-Ag 8.653 cells. The supernatants of in vitro cultured hybridomas were initially screened for reactivity with the WSSA and the WF from A. fumigatus and WSSA of other fungi in an enzyme-linked immunosorbent assay (ELISA). Supernatants reacting only with A. fumigatus antigens were subsequently screened for homologous and heterologous reactivity with immunohistochemical techniques using formalin-fixed, paraffin-embedded tissues from experimentally infected mice. Because of a high immunohistochemical reactivity with homologous fungi, 4 MAbs raised against A. fumigatus WSSA and WF were selected for a further evaluation of cross-reactivity (diagnostic specificity) in immunohistochemical and immunoblotting assays. In immunohistochemical assays, all MAbs raised against WSSA cross-reacted heavily with a number of other fungal species. All 4 MAbs (MAb-WF-AF-1-4) raised against the WF reacted strongly with hyphae of Aspergillus spp.; hyphae of Scedosporium apiospermum were also strongly labeled by MAb-WF-AF-3 and -4. The 2 specifically reacting MAbs (MAb-WF-AF-1 and -2) were of the IgM biotype and were precipitating, and in immunoblotting experiments both bound to a 106-kD antigen of the WF, whereas they did not bind to WSSA of A. fumigatus. One of the 2 aspergillosis-specific MAbs (MAb-WF-AF-1) was used to screen 145 mycotic lesions of cattle. The diagnoses on bovine lesions obtained by MAb-WF-AF-1 were compared with results based on reactivity with heterologously absorbed polyclonal antibodies and, for some lesions, to culture results. In the vast majority of lesions (n = 133), the MAb-WF-AF-1 and the polyclonal anti-Aspergillus antibodies reacted in a similar pattern, i.e., positively in 41 aspergillosis lesions and negatively in 92 zygomycotic lesions. Hyphae in 3 of 12 lesions that were not stained by the polyclonal antibodies reacted with the specific MAb-WF-AF-1; i.e., aspergillosis was diagnosed. The characteristics of the 2 MAbs (MAb-WF-AF-1 and -2) raised against the WF of A. fumigatus in ELISA and immunoblotting and immunohistochemical assays justify their application for the in situ diagnosis of systemic aspergillosis of cattle.

Animals↗

PubMed2003

Disseminated aspergillosis in intensive care unit patients: an autopsy study.

Disseminated aspergillosis is an uncommon but frequently fatal disease in critically ill populations. With studies suggesting that the incidence of this disease is increasing, and with relatively few epidemiological data available in this population, we evaluated cases of disseminated aspergillosis identified at autopsy over a one-year period on a 31-bed mixed medico-surgical intensive care unit (ICU) of an academic university hospital. In 1999, there were 489 deaths out of 2984 ICU admissions, and 222 autopsies were performed. Post-mortem examination demonstrated disseminated aspergillosis involving non-contiguous organs in 6 (2.7%) autopsies and, of these, five patients (2.3% of total) had had chronic obstructive pulmonary disease (COPD) and had been treated with corticosteroids and mechanical ventilation for pulmonary infection. One patient also had granulocytopenia. In each patient, sputum and bronchoalveolar lavage (BAL) cultures had been positive for Aspergillus fumigatus after ICU admission but this was considered as colonization and the patients were given fluconazole for suspected candidal infection. In conclusion, COPD patients treated with corticosteroids and presenting with pulmonary infection should be considered at risk for disseminated aspergillosis. The rapidly fatal outcome after ICU admission suggests that colonization with Aspergillus can occur before ICU admission.

Adrenal Cortex Hormones↗

PubMed1994

Central bronchiectasis in allergic bronchopulmonary aspergillosis: comparative evaluation of computed tomography of the thorax with bronchography.

Demonstration of central bronchiectasis (CB) with normal peripheral bronchi is an essential requirement for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA). Although the results of bronchography remain the gold standard for demonstration of central bronchiectasis they are not always diagnostic. Moreover, it is an unpleasant invasive procedure which may be difficult to perform in a patient of allergic bronchopulmonary aspergillosis with acute severe asthma. In an attempt to find a safe and effective alternative to demonstrate central bronchiectasis computed tomography (CT) of the thorax was evaluated against bronchography. Twenty one patients with allergic bronchopulmonary aspergillosis underwent computed tomography of the thorax followed by bronchography. Of the 378 bronchopulmonary segments available for analysis, 42 had to be excluded because of consolidation or non-filling of the contrast dye, leaving 336 segments for evaluation. CB was identified on CT in all 21 patients. Detailed analysis of the visualized segments revealed that computed tomography (using 8 mm contiguous scans) identified 146 of the 212 segments showing central bronchiectasis on bronchography (sensitivity 70%) and 114 of the 124, read as normal on bronchography (specificity 92%). Supplemental 4 mm scans, used in 8 out of 21 patients improved the overall sensitivity of computed tomography to 83%, whilst the specificity remained unchanged at 92%. Thus, computed tomography of the thorax, being more acceptable to the patient, has the potential of being the investigation of choice for the demonstration of central bronchiectasis in patients with allergic bronchopulmonary aspergillosis.

Adolescent↗

PubMed2005

Economic evaluation of voriconazole in the treatment of invasive aspergillosis in the Netherlands.

OBJECTIVE: To asses the cost-effectiveness of voriconazole in comparison to conventional amphotericin B and itraconazole for the treatment of invasive aspergillosis in the Netherlands. METHODS: The cost-effectiveness of voriconazole in comparison to conventional amphotericin B or itraconazole was evaluated with a decision tree model followed by a life-time Markov model, focusing on long-term survival of patients treated for invasive aspergillosis. Efficacy after 12 weeks of treatment from clinical trials was used to estimate long-term effectiveness by extrapolating these short-term results over time. Information on medical resource consumption, treatment pathways and switch proportions were obtained from both the literature and Experts. Probabilistic analysis was used to compare the cost-effectiveness among the regimens. RESULTS: With voriconazole, the mean cost for treating invasive aspergillosis per patient was E32 651 (2.5th percentile and 97.5th of uncertainty distribution: E30 037; E36 859), compared to E33 616 (E30 920; E39 633) for conventional amphotericin B and E29 115 (E23 537; E61 414) for itraconazole. The mean survival of patients treated with voriconazole was 174.0 life weeks (160.1; 188.8), compared to 116.1 life weeks (104.8; 128.0) for conventional amphotericin B and 150.4 life weeks (109.1; 194.4) for itraconazole. The beneficial effects of voriconazole on both cost and effectiveness compared with conventional amphotericin B resulted in a probability of 69.8% that voriconazole was a dominant treatment (i.e. less costs and longer survival). The incremental cost-effectiveness ratio of voriconazole versus itraconazole was E150 per life week (i.e. 7800 euros per life-year gained). Depending on the willingness to pay (WTP) the probability of being cost-effective vs. itraconazole increased to a maximum probability of 70%. CONCLUSION: In the treatment of invasive aspergillosis, voriconazole is dominant over amphotericin B and cost-effective in comparison to itraconazole.

Amphotericin B↗

PubMed1985

Invasive pulmonary aspergillosis in adult acute leukemia: clinical clues to its diagnosis.

Invasive pulmonary aspergillosis, a leading cause of morbidity and mortality in patients with acute leukemia, is difficult to diagnose antemortem because its signs and symptoms are ill-defined. To refine the clinical description of this infection, we reviewed our experience with 15 pathologically documented cases of invasive pulmonary aspergillosis in a population of 60 patients treated for acute leukemia. Findings occurring significantly more often (P less than or equal to .001) among cases than controls included pleuritic chest pain; acute sinus tenderness, and nasal discharge, epistaxis and eschar; rales; development of multilobar infiltrates after the 14th hospital day; and presence of nodular or cavitary infiltrates. In addition, patients with invasive pulmonary aspergillosis had a significantly prolonged duration of granulocytopenia, more febrile days and febrile episodes without a fever diagnosis and more febrile days on antibiotics (P less than or equal to .001 in all). This complex of findings should improve the clinician's ability to diagnose invasive pulmonary aspergillosis in patients with acute leukemia.

Acute Disease↗

PubMed1982

Aspergillosis of the nervous system.

Cerebral aspergillosis currently occurs most frequently with disseminated aspergillosis in immunocompromised hosts. Twelve patients with cerebral aspergillosis in this setting were seen over 10 years. Underlying illnesses were renal transplantation in six cases and one case each of subacute hepatic necrosis, head trauma, glioblastoma, microglioma, and esthesioneuroblastoma. All patients were receiving high dose steroid therapy except one who had ectopic ACTH syndrome. Eleven patients were receiving broad spectrum antibiotics. All patients were febrile and developed progressive pulmonary infiltrates preceding or coincident with neurologic symptoms. Sudden onset of neurologic deficits or seizures occurred in nine of 11 clinically analyzable cases. Brainstem or cerebellar signs and symptoms were a presenting feature in three cases and were eventually seen in five cases. Cranial computerized tomography in four cases showed low absorption areas with minimal enhancement and little mass effect. Neurologic deterioration was rapid with nine of 11 patients dying within 6 days of onset. Neuropathologic examination showed multiple abscess formation in 11 cases and prominent blood vessel invasion in all cases. The sudden onset of stroke-like deficits and brainstem findings in a febrile immunocompromised host with pulmonary infiltrates suggests the diagnosis of cerebral aspergillosis. Two cases of aspergillus meningitis were also seen, one postoperatively.

Adult↗

PubMed2002

Primary aspergillosis of the larynx associated with CD4+ T lymphocytopenia.

The purpose of this study was to report the first case (to our knowlege) of primary laryngeal aspergillosis in a patient with underlying CD4(+) T lymphocytopenia. Laryngeal involvement of Aspergillus is more commonly seen as a part of a wider infection involving the respiratory system in an immunocompromised host. However, primary infection of the larynx is extremely rare. Although there were 12 cases of primary laryngeal aspergillosis previously reported in healthy subjects, there is no known study describing immunological findings in detail. We report a case of primary laryngeal aspergillosis in a healthy 79-year-old male. The examination of his immunity subsequently revealed that there was a marked decline in the number of CD4(+) T lymphocytes and a decrease in the ratio of CD4(+) to CD8(+). It is suggested that it is essential to examine the defence mechanisms, specifically cell-mediated immunity in a patient showing primary laryngeal aspergillosis.

Aged↗