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PubMed1999

Diagnostic yield of bronchoscopy in histologically proven invasive pulmonary aspergillosis.

Invasive pulmonary aspergillosis (IPA) is a life-threatening infectious complication in neutropenic patients after high-dose chemotherapy or hematopoietic stem cell transplantation. Its diagnosis is mainly based on clinical symptoms, and radiological signs on thoracic CT scan. The value of bronchoscopy is controversial. We analyzed the diagnostic yield of bronchoscopy in 23 consecutive patients with histologically proven invasive pulmonary aspergillosis. In seven patients (30%) bronchoscopically obtained specimens were diagnostic for pulmonary fungal infection. Typical hyphae were detected by cytology in six patients and fungal cultures were positive in four cases. Patients with a positive bronchoscopic result presented more often with multiple changes on thoracic CT scan (71%; 5/7), but had received a lower median cumulative dose of amphotericine B (300 mg; 168-3010 mg) compared to patients with non-diagnostic bronchoscopy (25% multiple lesions (4/16); amphotericine dose 1100 mg, 260-2860 mg). The diagnostic yield of bronchoscopy was not associated with clinical symptoms or duration of neutropenia. Bronchoscopy allows the diagnosis of IPA in about one third of patients. Fungal cultures and cytological examination of intrabronchial specimens obtained during bronchoscopy have a high specificity, but its sensitivity is low. It is advisable to perform diagnostic bronchoscopy before starting antifungal therapy. Better diagnostic tools are urgently needed.

Adolescent↗
PubMed2000

Successful treatment of invasive aspergillosis in chronic granulomatous disease by granulocyte transfusions followed by peripheral blood stem cell transplantation.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by impaired microbial killing and susceptibility to bacterial and fungal infections. Cure of the disease can be achieved by stem cell transplantation when performed early in its course, and before severe infections have developed. Invasive aspergillosis constitutes a very high risk for transplantation. We report a 4-year-old boy with X-linked CGD who underwent successful HLA-identical peripheral blood stem cell (PBSC) transplantation during invasive pulmonary aspergillosis and osteomyelitis of the left fourth rib, which was unresponsive to antifungal treatment. During the 2 months prior to the transplant he received G-CSF-mobilized granulocyte transfusions (GTX) from unrelated donors three times a week in addition to the antifungal treatment. This resulted in clinical improvement in his respiratory status. He also received GTX during the aplastic period after the conditioning regimen, until he had engrafted. Post-transplant superoxide generation test revealed that neutrophil function was within normal range. One year post transplant the CT scan showed almost complete clearance of the pulmonary infiltrates and a marked improvement in the osteomyelitic process. Based on other reports and our own experience, GTX can serve as important treatment in patients with CGD who have failed conventional anti-fungal treatment and for whom stem cell transplantation is the only chance for cure.

Amphotericin B↗
PubMed2001

A novel type of metastatically spreading subcutaneous aspergillosis without epidermal lesions following allogeneic stem cell transplantation.

Systemic mycosis is among the most feared opportunistic infections in the immunocompromised host. Difficulty and delay in diagnosis and treatment often result in poor outcomes. In this communication a metastatically spreading form of subcutaneous aspergillosis developed in a patient with a history of allogeneic stem cell transplantation for relapsed Hodgkin's lymphoma. Strikingly, necrotizing cutaneous papules or ulcerating lesions were absent. Diagnosis was accomplished after excision of a clinically non-suggestive subcutaneous nodule. Despite prompt initiation of antimycotic therapy the outcome was fatal; dosage of conventional and liposomal amphotericin B was limited due to treatment-related toxicities. This case report describes a novel form of aspergillosis and underlines the need for an aggressive diagnostic approach in severely immunocompromised patients.

Adult↗
PubMed2004

Frequent severe liver iron overload after stem cell transplantation and its possible association with invasive aspergillosis.

Iron overload is associated with free radical generation and tissue damage. Our main objective was to ascertain the frequency and severity of iron overload in a group of 59 patients who died after conventional-intensity autologous (n=24) or allogeneic (n=35) haematopoietic stem cell transplantation (HSCT). A second objective was to investigate associations between liver-iron concentration and causes of transplant-related mortality. The median age was 41 years (range, 19-66), 41 were males and 18 females. In total, 26 patients had acute leukaemia or MDS, 10 CML, 17 lymphoma, four myeloma and two aplastic anaemia. The median hepatic iron concentration (HIC) was 138 micromol/g dry weight (7.7 mg/g; range 31-631 micromol/g). In total, 4/32 (12%) patients with HIC <150 micromol/g and 10/27 (37%) with hepatic iron > or =150 micromol/g showed invasive aspergillosis at autopsy (P=0.035). This was significant in multivariate analysis (RR 9.0; 95% CI 1.6-50.3, P=0.012). In conclusion, severe iron overload is frequent in patients who die following HSCT and is associated with invasive aspergillosis.

Adult↗
PubMed2005

Effectiveness of amphotericin B lipid complex (ABLC) treatment in allogeneic hematopoietic cell transplant (HCT) recipients with invasive aspergillosis (IA).

A total of 85 allogeneic hematopoietic cell transplant (HCT) recipients with invasive aspergillosis treated with amphotericin B lipid complex (ABLC) were identified from the Collaborative Exchange of Antifungal Research (CLEAR) database. Of these patients, 78% (66/85) presented with pulmonary aspergillosis. Graft-versus-host disease (GVHD) was present in 24 of 85 patients. The response rate to ABLC was 31% (26/85) overall and 21% (5/24) in patients with GVHD. The overall response rate to first-line ABLC treatment was 41% (11/27). Four of nine (44%) patients with GVHD responded to first-line treatment with ABLC, while only one of 13 (8%) responded to ABLC as second-line therapy. Five of 18 (28%) and four of 14 (29%) patients, respectively, responded to sequential or concurrent treatment with ABLC and itraconazole. None of seven patients responded who continued receiving itraconazole after the start of ABLC therapy. At the end of ABLC therapy, serum creatinine had doubled in 12% of patients (10/85), and 2% (2/85) had developed a requirement for dialysis. These data suggest that ABLC, especially when administered as first-line therapy, can result in clinical response even in the most immunocompromised patients, that is, HCT recipients with GVHD, with minimal effects on renal function.

Adolescent↗
PubMed2005

Dendritic cells transduced with an adenovirus vector encoding interleukin-12 are a potent vaccine for invasive pulmonary aspergillosis.

Invasive pulmonary aspergillosis (IPA) is a common and devastating pneumonia. We developed a novel antiinfective vaccine that couples the potent Ag-presenting capacity of dendritic cells (DCs) with paracrine delivery of interleukin-12 (IL-12) to local immune response sites. Our results showed that DCs engulfed Aspergillus conidia through coiling phagocytosis. Transfection of DCs with adenovirus encoding the cDNA of IL-12 did not affect their morphology and capacity to engulf conidia. The transduced DCs secreted IL-12, which was biologically active, to induce the production of gamma interferon (IFN-gamma) from spleen cells. Adoptive transfer of DCs pulsed with heat-inactivated Aspergillus fumigatus (HAF) to naive mice induced the Ag-specific production of IFN-gamma; the transduced HAF-pulsed DCs augmented this immune response further. Animals receiving HAF-pulsed DCs had lower fungal burdens, a more than three-fold higher survival rate at day 3. This protection was associated with a pronounced enhancement in the Aspergillus-specific IFN-gamma response. IL-12-engineered DCs augmented this protection strikingly as judged by a higher survival, and almost no Aspergillus could be detected in the lung of mice that had received IL-12-transduced HAF-pulsed DCs. These results suggest that antigen-pulsed DCs and IL-12 gene therapy could be used as adjunct therapy for aspergillosis.

Adenoviridae↗
PubMed1998

Cutaneous aspergillosis: a report of six cases.

Skin invasion by Aspergillus is infrequent. We here describe six immunocompromised patients with skin manifestations caused by Aspergillus. A heart transplant recipient developed a primary cutaneous aspergillosis; two patients (one with chronic granulomatous disease and another treated with a high dose of corticosteroids) presented with nodular lesions secondary to haematogenous dissemination; and three patients with acute myelogenous leukaemia had skin dissemination by contiguity from orbit and sinus invasion. A. flavus was isolated in the three cases of leukaemia; the infection was due to A. fumigatus in the transplant recipient; A. fumigatus and A. versicolor were isolated in the patients with the secondary aspergillosis. In most cases, amphotericin B was useful, with clinical and mycological remission in four patients. A patient with leukaemia died without undergoing treatment, and a child carrier of chronic granulomatous disease died after only 12 days of treatment.

Aged↗
PubMed2000

Diagnosis of invasive aspergillosis in bone marrow transplant recipients by polymerase chain reaction.

A nested polymerase chain reaction (PCR) test targeting Aspergillus spp. large ribosomal subunit genes was evaluated retrospectively on 175 serum samples from 37 bone marrow transplant recipients, 70% of whom received grafts from unrelated donors. Six patients had proven infection, seven had probable infection, and three had possible infection, using the revised EORTC case definitions. These 16 patients were all PCR positive (57 out of 93 samples tested). Two additional patients who did not fulfil current diagnostic criteria, but in whom invasive aspergillosis (IA) was thought clinically probable, were also PCR positive (five out of nine samples). Invasive aspergillosis was unlikely in the remaining 19 patients, four of whom were PCR positive on a single occasion (four out of 70 samples). Three samples were inhibitory to PCR. Sensitivity of PCR in diagnosing patients with IA was 100%, specificity was 79% and positive predictive value was 80%, using the criterion of a single positive result. If two positive results were required, these values were 81%, 100% and 100% respectively. The median duration of infection documented by PCR was 36 days (range 3-248 days) in 17 out of 18 patients (94%) who did not survive. Positive PCR results predated the institution of antifungal therapy in two-thirds of patients. Four patients became PCR positive during pretransplant conditioning therapy.

Adolescent↗
PubMed2004

IgE antibody to Aspergillus fumigatus recombinant allergens in cystic fibrosis patients with allergic bronchopulmonary aspergillosis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) is characterized by a heightened Th2 CD4+ T-cell response to Aspergillus fumigatus (Af) allergens and a hyper-immunoglobulin E (IgE) state compared with cystic fibrosis patients without ABPA. The IgE serologic differentiation of ABPA from atopic CF patients can be difficult. We propose as the reactivity with purified antigens varies qualitatively and quantitatively and that the antibody response is more specific than with crude Af antigen extract, the IgE responses to purified recombinant Af allergens may differentiate ABPA from atopic CF patients. METHODS: Serum IgE reactivity to seven recombinant purified allergens and to a crude extract of Af was measured in 15 ABPA, in 23 Af skin test positive (ST+), and in 19 Af skin test negative (ST-) CF patients. Four of the ABPA CF patients were studied before and after developing ABPA. Nine ABPA patients were studied during flares and remissions of ABPA. RESULTS: Allergic bronchopulmonary aspergillosis patients had significantly increased IgE reactivity to Asp f2, f3, f4, f6, and f16 compared with the Af ST+ and ST- non-ABPA CF patients. In the ABPA patients studied before and after developing ABPA, IgE reactivity also increased to Asp f2, f3, f4, and f6, and to the crude extract. In ABPA CF patients, IgE reactivity to Asp f1, f2, f3, and f6 significantly increased during periods of ABPA flares compared with periods of remission. Analysis of the receiver operating curve demonstrated that IgE reactivity to Asp f3 and f4 gave the best sensitivity and specificity and were better than IgE reactivity to a crude extract of Aspergillus. Furthermore, in ABPA patients studied during periods of remission the IgE reactivity to Asp f3 and f4 remained significantly elevated compared with Af ST+ non-ABPA patients. The IgE responses when considered either to be positive or negative to Asp f3 and f4 significantly differentiated ABPA from Af ST+ and ST- non-ABPA CF patients. In contrast, IgE reactivity was considered positive to the crude extract in 89% of ABPA, 61% of Af ST+, and 0% of Af ST- non-ABPA CF patients. CONCLUSIONS: Immunoglobulin E reactivity to a panel of purified Af allergens, especially to Asp f3 and f4, differentiates ABPA from atopic Af ST+ non-ABPA CF patients. Serial determinations of IgE reactivity to individual purified Aspergillus antigens, especially Asp f3, demonstrates that increases in IgE reactivity may provide improved distinction between stages of flares and remission compared with changes in IgE reactivity to a crude Aspergillus extract.

Allergens↗
PubMed1999

Early investigation and initiation of therapy for invasive pulmonary aspergillosis in leukaemic and bone marrow transplant patients.

Invasive fungal infections are an increasingly common problem in cancer patients and in other vulnerable groups. Invasive pulmonary aspergillosis (IPA) in the neutropenic host presents particular challenges in terms of diagnosis and therapy. Against the background of a recognized problem of invasive aspergillosis in haematology/oncology patients treated at the Christie Hospital, we undertook a prospective study in patients at risk for IPA. The aim of the study was to improve outcome by using the linked strategies of first, early diagnosis, and secondly, early aggressive therapy with a lipid-associated formulation of amphotericin B, amphotericin B colloidal dispersion ('Amphocil'). Early investigation comprised the use of high-resolution computerized tomography scanning of the thorax and fibreoptic bronchoscopy to obtain bronchoalveolar lavage specimens, processed using conventional detection and culture methods. Using this approach, the incidence of proven or probable IPA in patients with acute leukaemia was 9%. Prompt initiation of amphotericin B colloidal dispersion therapy led to a successful outcome in 11 of 13 patients, compared with a mortality of 100% in historical controls.

Adolescent↗
PubMed2003

Disseminated aspergillosis due to Aspergillus flavus in an experimental model: efficacy of azole therapy.

The aim of this investigation was to create a reproducible experimental model of disseminated Aspergillus flavus aspergillosis, and to compare the relative therapeutic efficacies of itraconazole and fluconazole in this model. Temporarily immunosuppressed male Wistar rats received intravenous challenge by A. flavus conidia. Treatment was initiated 24 h later with oral itraconazole (1 mg kg-1 BW day-1), oral fluconazole (1 mg kg-1 BW day-1) or excipient only (infected-untreated rats); this was continued for 10 days. At this time, although 100% mortality had occurred among all infected-untreated rats, no mortality was noted among the control-uninfected, infected-itraconazole-treated or infected-fluconazole-treated rats. After killing, essential organs were processed for microbiological and histopathological studies. Aspergillus flavus was recovered in high colony counts from the organs of infected-untreated rats (lungs > liver > brain > kidneys), but in significantly lower colony counts, or not at all, from the organs of itraconazole-treated and fluconazole-treated rats. Histopathological alterations were pronounced in tissues of infected-untreated rats, but less so in treated rats. These data suggest that administration of itraconazole or fluconazole sufficiently early may prevent, or retard, progression of lesions in disseminated aspergillosis.

Administration, Oral↗
PubMed2003

Increase in aspergillosis and severe mycotic infection in patients with leukemia and MDS: comparison of the data from the Annual of the Pathological Autopsy Cases in Japan in 1989, 1993 and 1997.

To study the relationship between the changes in visceral mycoses rates and recently advanced medical care in hematological settings, data on visceral mycosis cases with leukemia and myelodysplastic syndrome (MDS) that had been reported in the Annual of the Pathological Autopsy Cases in Japan in 1989, 1993 and 1997 were analyzed. The frequency rate of visceral mycoses with leukemia and MDS was 27.9% (435/1557) in 1989, 23.0% (319/1388) in 1993 and 22.3% (246/1105) in 1997. In comparing the rate of mycoses in recipients of organ or bone marrow transplantation with that of non-recipients, that of recipients was approximately 10% higher. The predominant causative agents were Candida and Aspergillus, at approximately the same rate as in 1989. The rate of candidosis decreased to one-half that of aspergillosis by 1993. Furthermore, severe mycotic infections clearly increased from 58.9% in 1989 to 75.6% in 1997. Among a total of 1000 cases with mycotic infection in those 3 years, acute lymphatic leukemia and acute myeloid leukemia were the major diseases (40.6% and 34.8%, respectively), followed by MDS (26.1%). The reasons for increased rates of aspergillosis and of severe mycotic infection can be surmised to be: (i) candidosis had become controllable by prophylaxis and by empiric therapy for mycoses with effective antifungal drugs; (ii) the marketed antifungal drugs were not sufficiently effective against severe infections or Aspergillus infections; and (iii) the number of patients surviving in an immunocompromised state had increased due to developments in chemotherapy and progress in medical care.

Adolescent↗
PubMed1999

Unusual radiological presentation and rapid fatal progression of invasive pulmonary aspergillosis in an immunocompetent young patient.

Invasive aspergillosis occurs very rarely in immunocompetent hosts. We describe a 21-year-old female with no obvious immunosuppression or underlying lung disease, who presented with minimal symptoms and bilateral hilar prominence on chest X-ray. Invasive aspergillosis was diagnosed on an open lung biopsy. She deteriorated in the ensuing 2 weeks and died of a sudden massive haemoptysis. This initial radiological abnormality and the rapid clinical course of the disease in young immunocompetent patients have not been previously reported.

Adult↗
PubMed2001

Allergic bronchopulmonary aspergillosis: a rare cause of pleural effusion.

Aspergillus fumigatus is one of the most ubiquitous of the airborne saprophytic fungi. Allergic bronchopulmonary aspergillosis (ABPA) is a syndrome seen in patients with asthma and cystic fibrosis, and is characterized by hypersensitivity to chronic colonization of the airways with A. fumigatus. We report the case of a patient with ABPA presenting with pleural effusion. A 27-year-old male was referred with recurrent right pleural effusion. Past medical history was remarkable for asthma, allergic sinusitis, and recurrent pleurisy. Investigations revealed peripheral eosinophilia with elevated serum immunoglobulin E and bilateral pleural effusions with bilateral upper lobe proximal bronchiectasis. Precipitating serum antibodies to A. fumigatus were positive and the A. fumigatus immediate skin test yielded a positive reaction. A diagnosis of ABPA associated with bilateral pleural effusions was made and the patient was commenced on prednisolone. At review, the patient's symptoms had considerably improved and his pleural effusions had resolved. ABPA may present with diverse atypical syndromes, including paratracheal and hilar adenopathy, obstructive lung collapse, pneumothorax and bronchopleural fistula, and allergic sinusitis. Allergic bronchopulmonary aspergillosis is a rare cause of pleural effusion and must be considered in the differential diagnosis of patients presenting with a pleural effusion, in particular those with a history of asthma.

Adult↗
PubMedDate not supplied

Neonatal primary cutaneous aspergillosis: case report and review of the literature.

Neonatal primary cutaneous aspergillosis usually presents as an erythematous plaque with pustules that evolve into an eschar. Immunocompromised patients and premature neonates are at risk of developing this disease. Early diagnosis and treatment are critical in preventing progression to a systemic illness. We report a preterm neonate with primary cutaneous aspergillosis and discuss the etiologies, presentations, and treatments for this illness.

Aspergillosis↗
PubMed2001

Relationship between environmental fungal contamination and the incidence of invasive aspergillosis in haematology patients.

Invasive aspergillosis (IA) is a major opportunistic infection in haematology patients. Spore inhalation is the usual route of Aspergillus infection, suggesting a determining role of environmental contamination by spores in the epidemiology of IA. We prospectively examined the relationship between environmental contamination by Aspergillus and other fungal species and the incidence of invasive nosocomial aspergillosis (INA) in a bone marrow transplantation unit and two haematology wards. During a four-year period, levels of air and surface fungal contamination were determined bi-monthly in patients' rooms (some equipped with HEPA filters and LAF systems), and various common sites in each ward (corridors, nursing stations, etc.). Results were compared to the incidence of INA. A total of 3100 air and 9800 surface samples were collected, and 79 cases of IA were diagnosed, of which 64 were probably or possibly INA. Patterns of fungal contamination were comparable in the three wards, with a gradient ranging from high levels in common sites to a virtual absence in rooms equipped with HEPA filters and LAF systems. Using a regression model, a significant relationship was found between the incidence of INA and the degree of fungal contamination of air and surfaces in conventional patient rooms (not equipped with HEPA) and common sites. This study shows that in a non-epidemic setting, there is a significant relationship between environmental fungal contamination in haematology wards and the incidence of INA. Our findings underline the importance of environmental surveillance and strict application of preventive measures.

Aspergillosis↗
PubMed2001

Pelvic aspergillosis with tubo-ovarian abscess in a renal transplant recipient.

Common clinical manifestations of aspergillosis in renal transplant recipients are fever and pulmonary infiltrates, but involvement of the reproductive system is rare. We report a case of pelvic aspergillosis with tubo-ovarian abscess in a renal transplant patient. The patient received a cadaveric renal transplantation, and two episodes of acute rejection were treated with methylprednisolone pulse therapy. Surgical biopsy specimens of pelvic abscess detected by ultrasonogram and CT revealed Aspergillus. With amphotericin B treatment, the patient is well with normalization of erythrocyte sedimentation rate and C-reactive protein.

Abdominal Abscess↗