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PubMed2004

Small-bowel infarction from disseminated aspergillosis.

INTRODUCTION: Despite the use of new, effective drugs, the disseminated invasive aspergillosis often remains lethal in neutropenic patients. Diagnosis is difficult because early symptoms are nonspecific. New tools could help in diagnosis and lead to early surgery when needed. METHODS: A neutropenic patient developed an acute abdomen. CT findings were a diffuse, small-bowel distention with a thickened, distal, ileum wall. Emergency surgery was performed with resection and immediate anastomosis of the distal ileum. Pathology of the small bowel showed a wall necrosis and invasion by Aspergillus fumigatus. RESULTS: The postoperative course was uneventful except for persisting diarrhea secondary to a coexistent infection with Clostridium difficile. Aspergillus antigene in serum was positive, whereas neither pulmonary nor central nervous system aspergillosis was observed on CT scan. CONCLUSIONS: This diagnosis should be considered when neutropenic patients show abdominal pain and distention with fever. Repetition of Aspergillus antigenemia, search for others aspergillosis localizations, CT scan, and colonoscopy with biopsies should be performed until diagnosis allows the administration of early antifungal therapy.

Abdominal Pain↗

PubMed2005

The contribution of galactomannan detection in the diagnosis of invasive aspergillosis in bone marrow transplant recipients.

Until recently, accurate microbiological diagnosis of invasive aspergillosis (IA) was seldom established in HSCT recipients. Blood samples are rarely positive for Aspergillus species, the reliability of the cultures depends of the specimen (if taken from a normally sterile site or not) and biopsy samples require invasive procedures, rarely recommended in patients with severe thrombocytopenia. Implementing the international consensus defining the microbiological criteria for the diagnosis of Aspergillus infection, we retrospectively evaluated the role of serum galactomannan (GM) detection by EIA to diagnose IA among HSCT patients with proven invasive fungal infection (IFI) and the impact of serum storage in GM concentrations. The EIA assay allowed categorizing as "probable" 5 of the 10 cases of "possible" aspergillosis (50%). Considering a lower cut-off level for the reaction (1.0), 80% of the cases could be categorized as "probable" aspergillosis. Positive or undetermined results were detected one to 4 months before the diagnosis of IA in eight of the 11 patients (72.7%) with proven IFI. Retesting the stored samples after a second storage for four years, we could observe lower reactivity in 20% of the samples. The detection of galactomannan by the EIA test represents a major advance in the diagnosis of IA in HSCT recipients at high risk of IA. A better understanding of the kinetics of the GM in different clinical situations is necessary to maximize the benefit of the test in Aspergillus surveillance.

Adolescent↗

PubMed2005

Antifungal drugs and rational use of antifungals in treating invasive aspergillosis: the role of the hospital pharmacist.

AIM: This review discusses the most common used antifungal agents in the treatment of invasive fungal infections. In addition, guidelines for the treatment of invasive aspergillosis, as used in the Ghent University Hospital, are described. Moreover, the importance of determining the effectiveness of antifungal therapy as well as the potential role of the hospital pharmacist in the management of this infection is highlighted. METHODS: A review of the English-language literature was conducted using the MEDLINE database and scientific websites. Search terms including antimycotics, antifungal therapy and invasive aspergillosis were used to refine the search, and preference was given to studies published after 1992. This was completed with recent treatment guidelines. RESULTS: An overview of the most recent advances in antifungal therapy is described. In addition, a flowchart for treatment of invasive aspergillosis (proven, probable or possible) has been developed. CONCLUSION: Invasive fungal infections will remain a frequent and important complication of modern medicine. Considering the clinical and financial outcome of invasive fungal infections, the role of the hospital pharmacist can be a paramount to the treatment.

Antifungal Agents↗

PubMed1981

Invasive aspergillosis. Progress in early diagnosis and treatment.

Ninety-one patients with documented invasive infections due to an Aspergillus species were identified at Memorial Sloan-Kettering Cancer Center from July 1, 1971, through December 31, 1976. Of the 29 patients in whom the diagnosis was made during life, 10 had successful treatment and survived the Aspergillus infection by two to 17 months. An immunodiffusion test was useful in the early diagnosis of invasive aspergillosis, and in 11 patients in whom the diagnosis was supported by seroconversion and who underwent treatment, the survival rate was 64 percent. Cultures of respiratory secretions were not reliable because they often reflected only colonization. In one year, only 9 percent of he patients with Aspergillus species isolated from the sputum had an invasive infection. The lung was the commonest site of involvement, 91 percent of the patients having pulmonary lesions. The most frequently affected extrapulmonary organ was the brain (18.3 percent). Eight patients had nonpulmonary aspergillosis as the only manifestation of this infection. Most of the 91 patients had hematologic neoplasms as the underlying disease, and neutropenia and antibacterial therapy preceded the diagnosis of aspergillosis in the majority of cases.

Adolescent↗

PubMed1985

Orofacial aspergillosis in acute leukemia.

The clinicopathologic characteristics of orofacial aspergillosis in thirteen hospitalized patients who developed the infection while receiving chemotherapy for acute leukemia are described. Clinically, the primary sites of infection, in decreasing order of frequency, were the paranasal sinuses, nasal cavity, mouth, and facial skin; the corresponding order for the secondary sites was orbit, nasal cavity, facial skin, and mouth. Pathologically, the fungal lesions in the nasal, oral and sinusoidal cavities were black, ulcerated, and escharotic due as a direct result of tissue destruction by the organism and an indirect result of thrombotic vascular infarction. The orbital lesions were deep red, granulomatous, and productive of proptosis and ectropion. Seven of the thirteen patients had concomitant pulmonary aspergillosis. The orofacial infections were not responsive to antifungal therapy in the absence of remission of the leukemia and restoration of depressed host defenses. In two patients who did achieve remission, the aspergillosis was controlled by the intravenous administration of amphotericin B.

Acute Disease↗

PubMed1996

Aspergillosis of the sphenoid sinus: presentation as a pituitary mass and postoperative gallium-67 imaging.

Invasive aspergillosis of the paranasal sinuses is an uncommon, but well-recognized, form of fungal infection. We describe an elderly female patient with invasive aspergillosis of the sphenoid sinus and associated osteomyelitis of the skull base, with clinical presentation as a pituitary mass. Postoperative gallium scan showed intense uptake in the sphenoid sinus, which resolved after treatment with amphotericin-B. This case demonstrates some of the pathologic and clinical features of invasive aspergillosis and suggests a potential role for gallium-67 imagining in monitoring clinical response to therapy.

Aged↗

PubMed1991

Ultrastructural demonstration of specific IgG and IgE antibodies binding to Aspergillus fumigatus from patients with aspergillosis.

Aspergillus-induced diseases usually demonstrate elevated circulating antibodies belonging to different isotypes. The antigens currently used to detect antibodies are crude culture filtrate and mycelial extracts of A. fumigatus (Af). Most Af-associated diseases result from the inhalation of the spores of the organisms present in the environment. However, it is not known whether specific circulating antibodies directed only against spore or mycelia of Af exist in the sera of patients with Af-induced diseases. With colloidal gold we have investigated thin sections of spores and hyphae of Af for their reactivity with Af-specific IgG and IgE antibodies. The results indicate that both spores and hyphae reacted identically with IgG and IgE antibodies from patients. None of the sera from normal control subjects reacted in this system, although low levels of antibodies were detected in the sera by ELISA. Sera from both patients with allergic bronchopulmonary aspergillosis or aspergilloma reacted with cell envelope antigens, whereas sera from patients with invasive aspergillosis also bound to cell sap. This method therefore demonstrates localization of antigens binding to different isotypes in the sera from different clinical forms of aspergillosis and may be useful in purifying specific antigens for immunodiagnosis.

Antibodies, Anti-Idiotypic↗

PubMed1992

Control of invasive pulmonary aspergillosis with oral itraconazole in a bone marrow transplant patient.

Pulmonary aspergillosis following bone marrow transplantation carries a mortality of 94%, irrespective of current treatment. We treated a patient who had acquired aspergillosis some 80 days after allogeneic bone marrow transplantation, with oral itraconazole, 600 mg daily. After initial deterioration, clinical and radiographic resolution occurred during 3 months of therapy despite severe graft-vs.-host and cytomegalovirus disease. Itraconazole should be considered for therapy of pulmonary aspergillosis in this and other immunocompromised settings.

Administration, Oral↗

PubMed2006

Recombinant antigens as diagnostic markers for aspergillosis.

Eight recombinant proteins and purified galactomannan of Aspergillus fumigatus were tested by enzyme-linked immunosorbent assay to quantify the anti-Aspergillus antibodies in sera of patients with aspergilloma, allergic bronchopulmonary aspergillosis (ABPA), and invasive aspergillosis (IA). In spite of the variability observed in the immune responses of individual patients, quantification of the antibody titers against the 18-kDa ribonuclease (RNU), the 360-kDa catalase (CAT), and the 88-kDa dipeptidylpeptidase V (DPPV) was useful for the diagnosis of aspergilloma and ABPA. Differential diagnosis of ABPA was even possible among cystic fibrosis as well as noncystic fibrosis patients. In the group of immunocompromised patients with IA, no antibody response was mounted in response to the Aspergillus infection in any of the patients. Interestingly, about half of the patients with proven IA came to the hospital with high titers of anti-Aspergillus antibodies, suggesting that they were infected upon entry to the hospital. These results suggest that recombinant RNU, CAT, and DPPV have a great potential in the serodiagnosis of all forms of aspergillosis in the immunocompromised and immunocompetent patient.

Antigens, Bacterial↗

PubMed2006

Detection of fungal DNA by real-time polymerase chain reaction: evaluation of 2 methodologies in experimental pulmonary aspergillosis.

The capabilities of 2 quantitative polymerase chain reaction (PCR) assays for detecting pulmonary aspergillosis were analyzed. Both methodologies were real-time (RT) based and were compared with quantitative cultures and galactomannan (GM) antigen detection in a rabbit model of invasive aspergillosis. A total of 106 samples including blood, serum, lung, and brain from 3 controls and 9 infected New Zealand rabbits were analyzed. The RT-PCR methodologies were an Aspergillus fumigatus-specific assay using fluorescent resonance energy transfer technology targeting a highly conserved region of the fungal 18S rRNA gene and a panfungal assay to amplify the internal transcribed spacer regions 1 and 2 from fungal rRNA gene complex, employing SYBRGreen fluorescent dye as a detector. The specificity for both PCR base assays, culture, and GM determination was 100%. The sensitivity of the specific PCR assay was 88.9% in lung samples, 66.6% in serum, 55.5% in blood, and 33.3 in brain specimens. The panfungal assay had a sensitivity of 33.3% in lung and serum samples, being brain and blood specimens invariably negative. Otherwise, 100% of the lungs resulted positive for culture, and all serum samples showed a GM index above 1.0 after 2 days of infection. The specific RT-PCR assay is a reliable technique to detect A. fumigatus DNA in vivo comparable to cultures and GM determination. The panfungal RT-PCR assay exhibited low sensitivity to diagnose invasive aspergillosis in rabbits advising against its clinical introduction.

Animals↗

PubMed2006

Caspofungin: an advanced treatment approach for suspected or confirmed invasive aspergillosis.

Invasive aspergillosis occurs in a wide range of immunocompromised patients and is typically associated with an extremely poor prognosis. Caspofungin represents an additional therapeutic alternative to standard antifungal therapies in patients with suspected or confirmed invasive aspergillosis, as evidenced by a growing body of experience confirming its utility in treating this patient population. Caspofungin has demonstrated clinical efficacy when administered as salvage therapy in patients refractory to or intolerant of standard antifungal therapies, as first-line empirical therapy in patients with persistent febrile neutropenia and as combination therapy in difficult-to-treat patients refractory to or intolerant of standard therapies. Further studies are warranted to establish the effectiveness of caspofungin either alone or in combination as primary therapy for invasive aspergillosis.

Antifungal Agents↗

PubMed2006

Nosocomial aspergillosis in outbreak settings.

Nosocomial aspergillosis represents a serious threat for severely immunocompromised patients and numerous outbreaks of invasive aspergillosis have been described. This systematic review summarizes characteristics and mortality rates of infected patients, distribution of Aspergillus spp. in clinical specimens, concentrations of aspergillus spores in volumetric air samples, and outbreak sources. A web-based register of nosocomial epidemics (outbreak database), PubMed and reference lists of relevant articles were searched systematically for descriptions of aspergillus outbreaks in hospital settings. Fifty-three studies with a total of 458 patients were included. In 356 patients, the lower respiratory tract was the primary site of aspergillus infection. Species identified most often were Aspergillus fumigatus (154 patients) and Aspergillus flavus (101 patients). Haematological malignancies were the predominant underlying diseases (299 individuals). The overall fatality rate in these 299 patients (57.6%) was significantly greater than that in patients without severe immunodeficiency (39.4% of 38 individuals). Construction or demolition work was often (49.1%) considered to be the probable or possible source of the outbreak. Even concentrations of Aspergillus spp. below 1 colony-forming unit/m(3) were sufficient to cause infection in high-risk patients. Virtually all outbreaks of nosocomial aspergillosis are attributed to airborne sources, usually construction. Even small concentrations of spores have been associated with outbreaks, mainly due to A. fumigatus or A. flavus. Patients at risk should not be exposed to aspergilli.

Air Pollutants↗

PubMed2005

Antifungal activity of the local complement system in cerebral aspergillosis.

Dissemination of aspergillosis into the central nervous system is associated with nearly 100% mortality. To study the reasons for the antifungal immune failure we analyzed the efficacy of cerebral complement to combat the fungus Aspergillus. Incubation of Aspergillus in non-inflammatory cerebrospinal fluid (CSF) revealed that complement levels were sufficient to obtain a deposition on the surface, but opsonization was much weaker than in serum. Consequently complement deposition from normal CSF on fungal surface stimulated a very low phagocytic activity of microglia, granulocytes, monocytes and macrophages compared to stimulation by conidia opsonized in serum. Similarly, opsonization of Aspergillus by CSF was not sufficient to induce an oxidative burst in infiltrating granulocytes, whereas conidia opsonized in serum induced a clear respiratory signal. Thus, granulocytes were capable of considerably reducing the viability of serum-opsonized Aspergillus conidia, but not of conidia opsonized in CSF. The limited efficacy of antifungal attack by cerebral complement can be partly compensated by enhanced synthesis, leading to elevated complement concentrations in CSF derived from a patient with cerebral aspergillosis. This inflammatory CSF was able to induce (i) a higher complement deposition on the Aspergillus surface than non-inflammatory CSF, (ii) an accumulation of complement activation products and (iii) an increase in phagocytic and killing activity of infiltrating granulocytes. However, levels and efficacy of the serum-derived complement were not reached. These data indicate that low local complement synthesis and activation may represent a central reason for the insufficient antifungal defense in the brain and the high mortality rate of cerebral aspergillosis.

Antibodies, Fungal↗

PubMed2005

Aspects of oxalosis associated with aspergillosis in pathology specimens.

Oxalosis (calcium oxalate deposition) is associated with various conditions, including aspergillosis. Some Aspergillus species produce oxalic acid, which reacts with blood or tissue calcium to precipitate calcium oxalate. Calcium oxalate crystals exhibit various shapes and are strongly birefringent. These occur in cytological specimens, as well as in tissues of patients with Aspergillus infection. Aspergillus species are hyaline septate moulds, and they can be accurately recognized in pathology specimens only if conidial heads (fruiting heads) are present. When these structures are not observed, detection of associated oxalosis in a mould infection supports the pathological diagnosis of aspergillosis. The presence of oxalosis is helpful when microbiological identification or immunohistological techniques for fungi are not available. Calcium oxalate crystals can induce cellular injury by several mechanisms, and there is increasing evidence that oxalosis-induced tissue damage may occasionally lead to a poor clinical outcome. This review discusses the diagnostic value and the potential clinical significance of oxalosis associated with aspergillosis.

Aspergillosis↗

PubMed2004

Evaluation of molecular and immunological techniques for the diagnosis of mammary aspergillosis in ewes.

Three techniques for the diagnosis of mammary aspergillosis in ewes were compared: indirect ELISA to detect the level of anti-Aspergillus IgG in serum, determination of galactomannan (Platelia procedure), and detection of DNA of Aspergillus in serum by a nested PCR. Twenty sera from proven cases of aspergillosis in ewes were positive using ELISA (100%), 80% were positive using PCR, but only 55% were positive using Platelia. All 20 control sera were negative using ELISA and PCR, whereas using Platelia methodology one was positive and the other doubtful. The detection of antibody by ELISA in sera is therefore a reliable criterion for the diagnosis of mammary aspergillosis in ewes. Platelia showed the same deficiencies reported in humans, with the appearance of false positives and negatives. The use of PCR was promising and might have valuable application in human medicine.

Animals↗

PubMed2006

Quantification of mRNA encoding cytokines and chemokines in nasal biopsies from dogs with sino-nasal aspergillosis.

Canine sino-nasal aspergillosis is usually caused by Aspergillus fumigatus and is similar to human chronic erosive non-invasive fungal sinusitis. The pathogenesis of the disease is poorly understood. We investigated the nature of the local immune response mounted in canine sino-nasal aspergillosis. Quantitative RT-PCR was carried out on RNA isolated from nasal biopsies from diseased and control dogs, using specific assays designed to amplify mRNA encoding a panel of cytokines and chemokines. Canine sino-nasal aspergillosis was associated with significantly increased expression of mRNA encoding MCP-1, -2, -3 and -4, IL-8, IL-10, IL-18 and TNF-alpha relative to controls (P<0.01) but there was no difference between groups with respect to IL-4, IL-5, IL-6, IL-12, TGF-beta, and eotaxin-2 and -3. The up-regulation of proinflammatory cytokines and chemokines related to the influx of phagocytic cells might account for the localisation of this infection to the upper respiratory tract. The up-regulation of the expression of the immunomodulatory cytokine IL-10 in nasal tissue from affected dogs might be important in limiting the extent of local tissue destruction, but might also account for the fact that infected dogs are generally unable to clear this infection spontaneously.

Animals↗

PubMed1987

Invasive aspergillosis in children.

Aspergillosis may complicate the course of the child in an immunocompromised state. When sinus or pulmonary infections present in immunocompromised children, one third of these patients are diagnosed accurately premortem as resulting from aspergillosis and two thirds remain undiagnosed. Mortality remains quite high, despite prompt treatment. Four children in our hospital during the last 4 years have had invasive aspergillosis presenting other than sinus or pulmonary infections. Each presented with extensive soft tissue infection. Three presented after traumatic devascularizing injuries to the leg in which massive soil and fecal contamination occurred. One child presented with absolute neutropenia secondary to treatment of acute lymphocytic leukemia. The child had a chest wall lesion develop at the site of an EKG electrode. All patients had a punctate black skin lesion with a halo of intense erythema surrounded by a zone of blanching. These lesions rapidly expanded. Initial extensive debridement of the lesions, combined with systemic chemotherapy with amphotericin B failed to halt the progression of the disease. Histology showed vascular invasion with hyphal forms. Each patient then responded well to radical debridement (three hemipelvectomies and one chest well resection). The child in an immunocompromised state who develops a red papule, then a black eschar with surrounding erythema, should have immediate biopsy that can easily demonstrate the characteristic hyphal forms. Early radical surgical debridement and antifungal therapy can be lifesaving. The initial debridement should include tissues well beyond any apparent involvement.

Amphotericin B↗

PubMed1979

Allergic bronchopulmonary aspergillosis in pediatric practice.

Twelve cases of allergic bronchopulmonary aspergillosis in the pediatric age group are reported. The average age of diagnosis was 14.5 years with a range from 6 to 18 years. All patients had a history of pulmonary infiltrations or atelectasis or both documented by chest radiographs. Eight patients had bronchograms or tomograms, and seven of them showed proximal bronchiectasis. Total serum IgE concentrations were elevated in all patients. Preciptitating antibodies against Aspergillus fumigatus were positive in all patients at the time of diagnosis, and became negative in some after therapy. The specific IgE or IgG antibody activity agaist Af was elevated in all 12 patients. After prednisone was started the total serum IgE sharply declined to a plateau and remained at this level until a flare of allergic aspergillosis occurred. A flare of allergic aspergillosis is characterized by an increasing total serum IgE concentration followed by pulmonary infiltration. Clinical and roentgenologic improvements were observed after steroid therapy. The importance and methods of early diagnosis in the pediatric population are discussed.

Adolescent↗