Central venous catheter infection by Aspergillus fumigatus in a patient with B-type non-Hodgkin lymphoma

Invasive Aspergillus infection is still a major problem in immunocompromised patients. A central venous catheter infection by Aspergillus fumigatus, however, has not yet been reported. We describe the case of a 10-year-old female patient with B-type non-Hodgkin lymphoma treated according to the German chemotherapy protocol NHL-BFM 90. Isolation of Aspergillus fumigatus from the blood was the first hint of invasive aspergillosis. A central venous catheter-associated infection was suggested, since Aspergillus was also isolated from the thrombotic tip of the removed catheter. Secondary pulmonary aspergillosis was documented radiologically. The patient was treated successfully by Ampho-thericin B and Itraconazol and explantation of the central venous catheter under conditions of complete hematopoietic regeneration of the bone marrow with omission of the final chemotherapeutic cycle.     

The alkaline protease of Aspergillus fumigatus is not a virulence determinant in two murine models of invasive pulmonary aspergillosis

Little is known of the pathophysiology of invasive pulmonary aspergillosis (IPA), an opportunistic fungal infection usually caused by Aspergillus fumigatus. It has been suggested that the ability of the fungus to degrade elastin may aid its invasion and growth in lung tissue. We have described previously the construction of a strain of A. fumigatus in which the gene encoding an alkaline protease, AFAlp, had been disrupted (C.M. Tang, J. Cohen, and D.W. Holden, Mol. Microbiol. 6:1663-1671, 1992); this mutant is deficient in extracellular proteolytic and elastinolytic activity over a broad pH range. In this study, we compared the pathogenicity of this and another AFAlp disruptant with their isogenic, elastase-producing parental strains in two murine models of IPA. In both models, animals were inoculated via the respiratory tract. In the first model, the inoculum was delivered as airborne conidia and animals developed signs of respiratory distress within 2 to 4 days. In the second model, conidia were administered intranasally as a suspension and the disease developed over a 2-week period. No difference was observed between the wild-type and AFAlp disruptants in terms of mortality, and elastin breakdown was detected in lung tissue from animals inoculated with all four strains. We conclude that AFAlp is not a virulence determinant in these models of IPA.     

Aspergillus laryngotracheobronchitis presenting as stridor in a patient with peripheral T cell lymphoma

Invasive aspergillosis is a serious opportunistic infection in immunocompromised patients. The case history is described of a 44 year old patient with peripheral T cell lymphoma who developed hoarseness and stridor after chemotherapy. Aspergillus fumigatus was isolated repeatedly from the sputum. Bronchoscopic examination showed symmetrical creamy-white exophytic lesions involving both vocal cords and the supraglottic area. There was diffuse tracheobronchitis with multiple raised cream-coloured plaques in the trachea which histologically consisted of numerous septate branching hyphae consistent with Aspergillus species. The lesions responded to systemic treatment with amphotericin B.     

Cytokine- and T helper-dependent lung mucosal immunity in mice with invasive pulmonary aspergillosis

The role of cytokine- and T helper (Th)-dependent lung mucosal antifungal immunity in murine invasive pulmonary aspergillosis (IPA) was investigated. Intact or leukopenic DBA/2 mice were resistant or highly susceptible, respectively, to infection caused by multiple intranasal injections of viable Aspergillus fumigatus conidia. Resistance was associated with unimpaired innate antifungal activity of pulmonary phagocytic cells, concomitant with high-level production of tumor necrosis factor (TNF)-alpha and interleukin (IL)-12 and the presence of interstitial lymphocytes producing interferon-gamma and IL-2. Conversely, production of TNF-alpha and IL-12 was down-regulated in highly susceptible mice, which also had defective innate antifungal immunity and high-level production of IL-4 and IL-10 by lung lymphocytes. Resistance was increased in susceptible mice upon local IL-4 or IL-10 neutralization or IL-12 administration. These results indicate that, similar to observations in mice with disseminated aspergillosis, innate and Th1-dependent immunity play an essential role in host defense against IPA.     

A fatal case of ovarian hyperstimulation syndrome with cerebral infarction

BACKGROUND: A 76-year-old man developed allergic bronchopulmonary aspergillosis initially presenting with cough variant asthma. Symptoms worsened after exposure to ground mulch which was an identifiable source of Aspergillus fumigatus. Symptoms improved after corticosteroids and avoidance measures were instituted. OBJECTIVE: To report a case of allergic bronchopulmonary aspergillosis presenting as cough variant asthma with identifiable source of Aspergillus fumigatus. METHODS: Single case report. Serum precipitating antibodies against Aspergillus fumigatus were tested using gel diffusion techniques. Total IgE, specific IgE, and IgG indices were measured by ELISA. Cutaneous reactivity to Aspergillus fumigatus was also tested. RESULTS: Skin test and serum precipitating antibodies to Aspergillus fumigatus were positive. Precipitins were also detected between Aspergillus fumigatus and the mulch. Total serum IgE was 538 IU/mL (1290 ng/mL) which declined to 228 IU/mL (544 ng/mL) after corticosteroid therapy. IgE index = 1.10 and IgG index = 2.86. CONCLUSION: Allergic bronchopulmonary aspergillosis can present as cough variant asthma. Identification of exacerbating factors such as sources of Aspergillus fumigatus are important in management.     

Late lateralizing and localizing EEG features of scalp-recorded temporal lobe seizures

The fungicidal properties of the synthetic peptide D4E1 were studied with nongerminated and germinating conidia of Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Fusarium moniliforme, and Fusarium oxysporum. The minimal lethal concentrations (MLC) needed to kill 100% of germinating conidia of A. fumigatus, A. flavus, and A. niger were 12.5, 12.5, and 25 microM, respectively. The MLC value for nongerminated and germinating conidia of both Fusarium spp. was 3.0 microM. Except for A. fumigatus, D4E1 was inactive against the nongerminated conidia of the Aspergillus spp. Physicochemical studies showed D4E1 complexed with ergosterol, a sterol present in conidial walls. Cholesterol, present in nongerminated conidia of F. moniliforme, had a greater affinity for D4E1 than did ergosterol. D4E1 was more resistant to fungal and plant protease degradation than the natural peptide, cecropin A. These in vitro results suggest D4E1 is a candidate for transgenic expression in plants to enhance host resistance to fungal infection.     

Combination of three typing methods for the molecular epidemiology of Aspergillus fumigatus infections. European Research Group on Biotype and Genotype of Aspergillus

This study investigated the source of infection and strain relatedness of Aspergillus fumigatus isolates from bronchial colonisation and invasive aspergillosis (IA) in four transplant patients. Environmental isolates from the patient's home and from the hospital and infecting isolates were obtained for patient A who developed IA. Clinic environmental and colonising isolates were obtained for patient B. Sequential isolates were obtained from various organs from patient C who developed IA and also from patient D who had a bronchitic aspergillosis that developed into IA. Ninety-one A. fumigatus isolates were analysed by three typing methods: multi-locus enzyme electrophoresis (MLEE), random amplified polymorphic DNA (RAPD) and sequence-specific DNA primers (SSDP). The three combined typing methods demonstrated a greater differentiation of isolates than the typing methods used separately or in pairs. This demonstrated the genotypic variability of A. fumigatus and facilitated better epidemiological analysis. Large polymorphisms were demonstrated for each patient isolate between and colonies within various samples. The relatedness of the isolates suggested nosocomially acquired aspergillosis for patient B, but the source of infection for patient A remained unclear. The results suggested at least three multiple infections among the four patients. This study enabled the identification of the source of infection and strain relatedness, which in turn facilitates the development of preventive measures for patient management in the future.     

Invasive pulmonary aspergillosis due to Aspergillus terreus: 12-year experience and review of the literature

A 12-year retrospective analysis was done to identify and evaluate in detail cases of invasive pulmonary aspergillosis (IPA) caused by Aspergillus terreus. We identified 13 A. terreus infections among 133 total cases of confirmed invasive aspergillosis; 11 were IPA and 2 were primary peritoneal infections. Of the 11 patients with IPA, 7 developed neutropenia during hospitalization, and the remaining four were receiving immunosuppressive agents. Ten patients with IPA died; one liver transplantation patient without neutropenia survived after treatment with amphotericin B, itraconazole, and a pulmonary lobectomy. Six patients developed disseminated disease, with the heart the most common extrapulmonary site identified (four patients). These cases demonstrate that IPA caused by A. terreus rapidly progresses in immunocompromised patients receiving amphotericin B and illustrate the need for sensitive diagnostic tests and more effective antifungal agents.     

Invasive pulmonary aspergillosis: a study of 33 cases

Invasive pulmonary aspergillosis (IPA) is an infectious complication appearing mainly in immunosuppressed patients, whose diagnosis is often difficult and lately made, and that usually bears a dismal prognosis. Patients diagnosed as having IPA from 1989 to 1994 were retrospectively analyzed. Probable IPA was diagnosed on the basis of a positive culture for Aspergillus together with a consistent radiological image. Confirmed IPA was diagnosed if there was, in addition to the former, a pathological examination showing Aspergillus hifae invading pulmonary parenchyma and/or pulmonary vessels. There were 25 men and 8 women with a mean age of 53.7 +/- 16.9 years (range: 22-86 years). IPA was confirmed in 11 cases and probable in 22. Sixty three percent of the patients had hematologic malignancy or solid cancer, whereas 30.3% did not have prior granulocytopenia or immunosuppressive therapy. The mean (SD) interval between admission and diagnosis was 40.2 (37.1) days (range: 1-180 days), and the diagnosis was made while the patient was still alive in 75% of the cases. Fifteen percent of the patients had extrapulmonary aspergillosis. The most frequent finding both on X-ray film of the chest and pulmonary computed tomography were bilateral multiple pulmonary nodules. Thirteen patients were treated with itraconazole, 6 with amphotericin B, 5 received both drugs, and 2 received fluconazole. Nineteen patients (57.6%) died and the case-fatality rate among treated patients was 46.1%. IPA presents mainly in immunosuppressed patients, but there was a not negligible proportion of patients lacking the classical risk factors. IPA is often a lately made diagnosis and in a quarter of the patients it is not made when the patient is alive. The most frequent radiological presentation are multiple bilateral nodules. The case-fatality rate of IPA is exceedingly high, even when if the patient has been adequately treated.     

Hospital construction-associated outbreak of ocular aspergillosis after cataract surgery

OBJECTIVE: This study aimed to report an outbreak of Aspergillus endophthalmitis after cataract extraction during hospital construction. DESIGN: The study design is a case series of an outbreak of Aspergillus endophthalmitis. PARTICIPANTS: Five patients in whom Aspergillus endophthalmitis developed during a period of hospital construction in Jeddah, Saudi Arabia, participated. Severe postoperative uveitis occurred in all five patients and failed to subside with topical steroid therapy. The patients were referred to the King Khaled Eye Specialist Hospital for treatment. The causative organism was identified as Aspergillus fumigatus in each case. INTERVENTION: All five patients were subjected to aqueous or vitreous tap. Three patients had vitrectomy. Patients were given systemic, periocular, and intravitreous antifungal agents. MAIN OUTCOME: The final outcome in each patient was evisceration or enucleation, despite an intensive course of antifungal therapy. RESULTS: There were five patients, three females and two males, ranging in age from 51 to 65 years. Postoperative signs of infection developed in the patients 4 to 15 days after surgery. In all five cases, cultures of aqueous or vitreous grew A. fumigatus. CONCLUSION: Aspergillus endophthalmitis is a serious and devastating complication of ocular surgery. The outbreak, herewith, may have been related to hospital construction. The infection can be prevented, notably, by proper maintenance of old, "sick" buildings and by following certain procedures during hospital construction.     

Molecular typing of environmental and patient isolates of Aspergillus fumigatus from various hospital settings

Fingerprinting of more than 700 clinical and environmental isolates of Aspergillus fumigatus from four differential hospital settings was undertaken with a dispersed repeated DNA sequence. The analysis of the environmental isolates showed that the airborne A. fumigatus population is extremely diverse, with 85% of the strains being represented as a single genotype isolated once. The remaining 15% of the strains were isolated several times and were able to persist for several months in the same hospital environment. No strains were found to be associated with a specific location inside the hospital, and identical strains were isolated from different buildings of the hospital and outdoors. Isolation of the same strain both from patients and from the environment of the same hospital is highly suggestive of a nosocomial infection. The characteristics of the environmental fungal population explains the two main results obtained from the typing of the clinical isolates: (i) the absence of a common strain responsible for an invasive aspergillosis outbreak results from the extreme diversity of the environmental population of A. fumigatus in contact with the patients, and (ii) patients hospitalized in different wards of the same hospital can be infected with the same strain since every patient might inhale the same spore population.     

Organism-dependent fungicidal activities of azoles

We investigated the antifungal activities of itraconazole and voriconazole on Aspergillus species by time kill studies, and the results were compared with those obtained for Candida species. Exposure of Aspergillus fumigatus conidia to varying concentrations (1.25 to 10 microg/ml) of itraconazole and voriconazole resulted in cellular death; the cytocidal effect was time and concentration dependent. In contrast, no killing of Candida albicans occurred in the presence of itraconazole and voriconazole at concentrations as high as 10 microg/ml, although candidal growth was inhibited compared to the drug-free control. Amphotericin B (1.25 to 10 microg/ml), on the other hand, killed both A. fumigatus and C. albicans. Similar results were obtained for non-A. fumigatus aspergilli and non-C. albicans Candida species. These observations indicate that both itraconazole and voriconazole are cytocidal agents for Aspergillus species but not for Candida species, suggesting that azoles possess organism-dependent fungicidal activities.     

Invasive pulmonary aspergillosis in an apparently nonimmunocompromised host

Invasive aspergillosis generally occurs in patients with hematologic malignancies, neutropenia or other severe derangements of host defense. An adult patient without such a predisposition, and without a previous history of susceptibility to infections, had rapidly progressive respiratory failure associated with repeated growth of Aspergillus fumigatus on culture of sputum and bronchoscopy specimens. At autopsy he proved to have invasive pulmonary aspergillosis.     

The major late promoter and bipartite leader sequence of fowl adenovirus

Invasive pulmonary aspergillosis in immunocompromised patients (ICP) is the second most frequent opportunistic fungal infection. The causative organism includes 16 species of Aspergillus, of which A. fumigatus dominates the ubiquitous incidence of invasive or allergic broncho-pulmonary aspergillosis (ABPA). The definitive diagnosis of invasive aspergillosis is difficult. We have analyzed 24 strains of A. fumigatus recovered from ICP using the RAPD technique. The profiles generated with the 20 primers tested were mostly unique. These results may have a profound impact on the management of aspergillosis, especially in the ICP.     

Effect of exercise-induced activation of sympathetic nerve activity on clearance of 123I-MIBG from the myocardium

BACKGROUND: Chronic necrotizing pulmonary aspergillosis (CNPA) is a chronic pulmonary infection caused by the genus Aspergillus, which usually involves moderately immunosuppressed patients. METHOD: We describe 3 patients with a toxic syndrome that had lasted several weeks or months, with lung infiltrates in the chest X-ray and the CT scan. Mycobacterium tuberculosis could not be isolated from different respiratory smears (sputum, bronchoaspiration, Barlett catheter and pulmonary punction in the third case). Moreover, there was no response to anaerobic treatment. RESULTS: All 3 patients were moderately immunosuppressed (2 men were COPD and the woman was an asthmatic patient). One of the men was being treated for a nocardiosis. In all three cases, A. fumigatus was isolated from de different respiratory smears. CONCLUSIONS: To diagnose a CPNA, a high degree of clinical suspicion is needed. The differential diagnose should be done with pulmonary tuberculosis and anaerobic infections. The presence of a member of the genus Aspergillus in the tracheobronchial secretions of a patient should not be systematically considered a saprofit, specially when other microorganisms can not be isolated.     

Characterization of Aspergillus isolates by pyrolysis mass spectrometry

Pyrolysis mass spectrometry (PYMS) is a useful typing method for many bacterial and Candida species. We attempted to type Aspergillus spp. by PYMS. Four distinct A. fumigatus isolates could not be distinguished from each other, whereas one A. niger and one A. terreus could. Poor reproducibility was shown using multiple identical cultures of a single A. fumigatus isolate and several isolates of the same DNA type. PYMS is obviously an unsuitable typing method for Aspergillus spp.     

Granulocyte colony-stimulating factor and azole antifungal therapy in murine aspergillosis: role of immune suppression

Outbred ICR mice were immune suppressed either with hydrocortisone or with 5-fluorouracil and were infected intranasally with Aspergillus fumigatus. Beginning 3 days before infection some groups of mice were given recombinant human granulocyte colony-stimulating factor (G-CSF), SCH56592 (an antifungal triazole), or both. Corticosteroid-pretreated mice responded to SCH56592 and had reduced counts in lung tissue and prolonged survival. In these mice, G-CSF strongly antagonized the antifungal activity of SCH56592. Animals treated with both agents developed large lung abscesses with polymorphonuclear leukocytes and large amounts of Aspergillus. In contrast, mice made neutropenic with 5-fluorouracil and then infected with A. fumigatus conidia benefited from either G-CSF or triazoles, and the effect of the combination was additive rather than antagonistic. Host predisposing factors contribute in different ways to the outcome of growth factor therapy in aspergillosis.     

Allergic bronchopulmonary aspergillosis effectively treated with itraconazole

A 23-year-old man with bronchial asthma presented with fever, cough, and sputum. A chest X-ray examination showed pulmonary infiltrations in the left upper and lower lung fields with central bronchiectasis. Although his temperature came down with antibiotics, pulmonary infiltrations persisted with cough and sputum. Following bronchoscopy and an allergological examination, the patient was given a diagnosis of allergic bronchopulmonary aspergillosis (ABPA) based on Rosenberg's criteria, including peripheral blood eosinophilia, a high serum IgE level, immediate skin reaction to Aspergillus antigen, positive precipitating antibodies, and Aspergillus fumigatus in sputum. The patient was treated with itraconazole instead of corticosteroids. His respiratory symptoms, eosinophilia, and pulmonary infiltration then disappeared, and his IgE serum level gradually decreased. An antifungal agent alone was effective in treating this ABPA patient.     

Genetic diversity among clinical and environmental isolates of Aspergillus fumigatus

To determine if cases of invasive aspergillosis (IA) were caused by strains of Aspergillus fumigatus with unique characteristics, strains from immunosuppressed patients with IA were compared to strains obtained from sputa of patients with cystic fibrosis and to strains from the environment. An extremely high genomic diversity was observed among the 879 strains typed by Southern blotting with a retrotransposon-like element from A. fumigatus (C. Neuvéglise, J. Sarfati, J. P. Latgé, and S. Paris, Nucleic Acids Res. 24:1428-1434, 1996). Analysis of Southern blot hybridization patterns showed the absence of clustering between environmental isolates and clinical isolates from patients with IA or cystic fibrosis. In addition, strains could not be clustered depending on their geographical location. This study implies that practically any strain of A. fumigatus is potentially pathogenic and can provoke a case of IA when it encounters a favorable environment in an immunosuppressed host.     

Analysis of HIV seropositive thalassemic children for antibodies specific to Aspergillus fumigatus by luminescent immunoassay

The applicability of luminescent immunoassay (LIA) in serodiagnosis of fungal infections in multitransfused (MT) thalassemic children seropositive for human immunodeficiency virus (HIV) was investigated. Thirty-one sera samples from HIV infected pediatric patients with thalassemia receiving repeated blood transfusions were analysed for the presence of antibodies specific to Aspergillus fumigatus by LIA. The LIA was standardized using well defined antigens of A. fumigatus. Ten out of 31 (32.2%) of the MT-HIV positive patients were found to have anti-Aspergillus antibodies in their sera by LIA. The ELISA could detect A. fumigatus specific antibodies in 25.8% (8 out of 31) of the patients. Thus, 20% more number of patients turned to be positive for aspergillosis by LIA as compared to ELISA. The difference was found to be statistically significant (p < 0.005). Of the MT-HIV negative patients only 1 out of 33 (3%) showed A. fumigatus specific antibodies by LIA and ELISA both. In age and sex matched control group (n = 25) none of the patients was found to be positive for antibodies to A. fumigatus. LIA was found to have better discriminatory value indicating, thereby, its utility in diagnosis of aspergillosis in compromised patients.