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PubMed2005

Laboratory diagnosis of invasive aspergillosis.

Invasive aspergillosis occurs in a wide range of clinical scenarios, is protean in its manifestations, and is still associated with an unacceptably high mortality rate. Early diagnosis is critical to a favourable outcome, but is difficult to achieve with current methods. Deep tissue diagnostic specimens are often difficult to obtain from critically ill patients. Newer antifungal agents exhibit differential mould activity, thus increasing the importance of establishing a specific diagnosis of invasive aspergillosis. For these reasons, a range of alternate diagnostic strategies have been investigated. Most investigative efforts have focused on molecular and serological diagnostic techniques. The detection of metabolites produced by Aspergillus spp and a range of aspergillus-specific antibodies represent additional, but relatively underused, diagnostic avenues. The detection of galactomannan has been incorporated into diagnostic criteria for invasive aspergillosis, reflecting an increased understanding of the performance, utility, and limitations of this technique. Measurement of (1,3)-beta-D glucan in blood may be useful as a preliminary screening tool for invasive aspergillosis, despite the fact that this antigen can be detected in a number of other fungi. There have been extensive efforts directed toward the detection of Aspergillus spp DNA, but a lack of technical standardisation and relatively poor understanding of DNA release and kinetics continues to hamper the broad applicability of this technique. This review considers the application, utility, and limitations of the currently available and investigational diagnostic modalities for invasive aspergillosis.

Antibodies, Fungal↗
PubMed1992

Rhinocerebral aspergillosis.

Aspergillosis is increasingly being recognised as a common fungal infection of the paranasal sinuses. Although the disease is almost endemic in neighbouring Sudan, there are few reported cases from the Kingdom of Saudi Arabia. We report four cases of sinus aspergillosis with involvement of the skull bases and/or intracranial spread; a condition we have termed rhinocerebral aspergillosis. Invasive aspergillosis in our subgroup of patients occurs in otherwise healthy patients with normal immune status, quite unlike most reported cases in the western literature. The causative agent in all our patients was identified as aspergillus flavus, similar to patients reported from Sudan. This is again at variance with the case reports from other geographical locations, where aspergillus fumigatus is the commonest causative agent. Saudi Arabia would appear to represent a distinct geographical enclave, together with Sudan, where rhinocerebral aspergillosis of the sinuses and skull base may be more common than has previously been realised.

Adult↗
PubMed2002

Voriconazole in the management of invasive aspergillosis in two patients with acute myeloid leukemia undergoing stem cell transplantation.

The management of invasive aspergillosis in patients with hematological malignancies remains controversial. A major problem is how to manage patients who had invasive aspergillosis during remission induction and consolidation therapy and then undergo SCT. Indeed in these patients the mortality rate related to invasive aspergillosis recurrence remains unacceptably high. We report two cases of patients who underwent remission induction for AML, developed invasive aspergillosis during antifungal prophylaxis with itraconazole, failed amphotericin B deoxycholate and liposomal amphotericin B treatment, were successfully treated with voriconazole and eventually underwent SCT with voriconazole prophylaxis without reactivation of invasive aspergillosis.

Adult↗
PubMed2006

Severe primary cutaneous aspergillosis refractory to amphotericin B and the successful treatment with systemic voriconazole in two premature infants with extremely low birth weight.

Primary cutaneous aspergillosis is a rare, life-threatening, infectious complication in premature infants that may result in fulminant sepsis and subsequent multi-organ failure. In the past decade, the incidence of primary aspergillosis has increased significantly, whereas the high morbidity and mortality of invasive aspergillosis remains unaltered. In vitro studies reveal that more and more Aspergillus species seem to be refractory to the classical treatment with fluconazole or amphotericin B. This case report presents two extremely low birth weight infants (ELBW) with primary cutaneous aspergillosis, which was refractory to amphotericin B. Both patients were successfully treated with systemic voriconazole, an extended-spectrum triazole antifungal, supported by topical care. This paper provides the clinical manifestation, diagnostics and pharmacotherapy of primary cutaneous aspergillosis, as well as pharmacokinetic aspects of voriconazole in ELBW infants.

Amphotericin B↗
PubMed2002

Clinical significance of extra-pulmonary involvement of invasive aspergillosis: a retrospective autopsy-based study of 107 patients.

Disseminated aspergillus infection has a poor prognosis, but few reports have been published on extra-pulmonary involvement in aspergillosis. We reviewed 107 autopsy records of patients with invasive aspergillosis. Fifty-five patients had extra-pulmonary aspergillosis. Organs involved included heart, kidney, central nervous system, gastrointestinal tract, spleen, liver, thyroid gland and pancreas. Extra-pulmonary aspergillosis produces different manifestations according to involved organs. Risk factors associated with dissemination included cytotoxic chemotherapy within a month of death (P=0.0087). Lack of response to empiric or preemptive treatment of amphotericin B predicted IA dissemination (P=0.0328). To improve prognosis of IA, it is important to recognize clinical features of extra-pulmonary aspergillosis and to institute the aggressive anti-fungal treatment.

Adult↗
PubMed2001

Galactomannan and polymerase chain reaction for the diagnosis of primary digestive aspergillosis in a patient with acute myeloid leukaemia.

Primary intestinal invasive aspergillosis is rarely reported in leukaemic patients. We describe a case of jejunal invasive aspergillosis in the setting of aplasia following chemotherapy for acute myeloid leukaemia. The diagnosis was confirmed by biopsy obtained during surgery and our polymerase chain reaction (PCR) test confirmed Aspergillus flavus as the fungus responsible. This patient had high levels of circulating galactomannan, an antigen secreted by Aspergillus sp., in serum. The ELISA test for galactomannan has been developed to improve the diagnosis of invasive aspergillosis but presents a 5-15% false positive rate. We suggest that some false positive results might be due to non-respiratory invasive aspergillosis, the usual localization of invasive aspergillosis. Our PCR test was also positive in serum. In case of positive results in serum with antigen and/or PCR tests without respiratory symptoms, the intestinal localizations should be investigated.

Aspergillosis↗
PubMedDate not supplied

Route of infections in bovine aspergillosis.

Repeated DNA sequences were used to fingerprint strains of Aspergillus fumigatus isolated from a cow with disseminated systemic aspergillosis, cows with single aspergillosis lesions, calves aborted due to bovine aspergillosis, mothers of those calves, and cattle without aspergillosis. The analysis of the Southern blot hybridization patterns obtained suggested that: (i) the portal of entry of aspergillosis in cattle is the gastrointestinal tract, and (ii) infection of aborted calves is due to maternally derived strains. Cattle from the same farm slaughtered on the same day harbour the same strain, suggesting a contamination from feed material.

Animals↗
PubMed2002

Fatal airway obstruction caused by invasive aspergillosis of the thyroid gland.

Invasive aspergillosis is a common form of fungal infection in patients with hematological malignancies. Because Aspergillus species have angioinvasive properties, they frequently disseminate from the lung to a variety of organs via hematogenous spread. Extra-pulmonary involvement occurs at an advanced stage of invasive aspergillosis, and represents an ominous sign. However, few reports have been published on extra-pulmonary involvement in cases of aspergillosis. Its clinical features have not been fully clarified. We experienced a patient who developed thyrotoxicosis and fatal airway obstruction caused by invasive aspergillosis of the thyroid. A 26-year-old man was admitted to our hospital for the treatment of non-Hodgkin's lymphoma. During myelosuppression following the chemotherapy, he developed cervical swelling and hyperthyroidism. We suspected lymphoma infiltration to the thyroid, and irradiated it with a total of 26 Gy. However, the cervical lesion enlarged rapidly, and he complained of wheezing and dyspnea. We underwent immediate tracheostomy to secure the airway, but he died. Autopsy findings were striking. Extensive necrosis with diffuse infiltration of Aspergillus hyphae was observed in the thyroid gland. Necrotic tissues of the thyroid protruded into the tracheal lumen, causing airway obstruction. This case demonstrated that invasive aspergillosis of the thyroid can lead to medical emergency.

Adult↗
PubMed2005

Invasive aspergillosis in the hematologic and immunologic patient: new findings and key questions in leukemia.

Patients suffering from acute leukemia are at high risk for invasive aspergillosis and a large review and a recent clinical trial have shown that they represent the largest group of patients developing the disease. New host groups such as patients with multiple myeloma or low-grade lymphoproliferative disorders have contributed to an increase in the incidence of invasive aspergillosis over recent years. There are substantial differences in the diagnostic strategy and therapeutic outcome of disease between patients with a hematological malignancy and other host groups such as allogeneic hematopoietic stem cell transplant patients. Galactomannan detection ELISA test is more specific in adult patients with hematological malignancies than in hematopoietic stem cell transplantation recipients. As a result of possible improvement of the underlying immune deficiency upon recovery from neutropenia, survival is higher in leukemic patients with invasive aspergillosis than in other host groups. However, there is currently no evidence of an effective antifungal prophylaxis strategy against aspergillosis in leukemic patients. As these patients account for a majority of the aspergillosis cases, clinical trials on prophylaxis should not only be focused on allogeneic stem transplant recipients but also be designed for the patient with leukemia.

Aspergillosis↗
PubMed2005

The contribution of animal models of aspergillosis to understanding pathogenesis, therapy and virulence.

Animal models of aspergillosis have been used extensively to study various aspects of pathogenesis, innate and acquired host-response, disease transmission and therapy. Several different animal models of aspergillosis have been developed. Because aspergillosis is an important pulmonary disease in birds, avian models have been used successfully to study preventative vaccines. Studies done to emulate human disease have relied on models using common laboratory animal species. Guinea pig models have primarily been used in therapy studies of invasive pulmonary aspergillosis (IPA). Rabbits have been used to study IPA and systemic disease, as well as fungal keratitis. Rodent, particularly mouse, models of aspergillosis predominate as the choice for most investigators. The availability of genetically defined strains of mice, immunological reagents, cost and ease of handling are factors. Both normal and immunosuppressed animals are used routinely. These models have been used to determine efficacy of experimental therapeutics, comparative virulence of different isolates of Aspergillus, genes involved in virulence, and susceptibility to infection with Aspergillus. Mice with genetic immunological deficiency and cytokine gene-specific knockout mice facilitate studies of the roles cells, and cytokines and chemokines, play in host-resistance to Aspergillus. Overall, these models have been critical to the advancement of therapy, and our current understanding of pathogenesis and host-resistance.

Animals↗
PubMed2006

Clinical issues regarding relapsing aspergillosis and the efficacy of secondary antifungal prophylaxis in patients with hematological malignancies.

Advancements in early diagnosis and the introduction of effective agents have improved the rates of response of aspergillosis to primary antifungal therapy. These changes allow the subsequent continuation of cytotoxic chemotherapy and/or performance of hematopoietic stem cell transplantation in an increasing number of patients with hematological malignancies. These developments have increased interest in secondary prophylaxis of aspergillosis, because the resumption of myelotoxic chemotherapy in these patients is associated with high rates of relapse of this opportunistic mycosis in the absence of prophylaxis. However, the risk factors for relapsing invasive aspergillosis and the strategies for reducing risk are not well defined. Furthermore, differentiating aspergillosis relapse from reinfection with a new Aspergillus isolate is problematic when using the available laboratory tools. We summarize the existing knowledge regarding the pathogenesis of, risk factors for, and natural history of relapsing invasive aspergillosis and review the limited data regarding the role of secondary antifungal prophylaxis.

Antifungal Agents↗
PubMed1989

Incidence of nosocomial aspergillosis in patients with leukemia over a twenty-year period.

The incidence of invasive nosocomial aspergillosis was studied in leukemia patients at an oncology center from 1964 to 1983. A total of 97 cases of aspergillosis occurred in 1,866 patients, yielding an overall case rate of 5.2 cases per 100 patients and an incidence rate of 9.1 per 10,000 patient days. The highest incidence rate was in patients with chronic myelogenous leukemia (13.7 cases per 10,000 patient days), followed by patients with acute myelogeneous leukemia (10.6 cases per 10,000 patient days). Subdividing patients after 1978 into those receiving bone marrow transplantation and those who did not demonstrated the predisposition of transplant recipients to aspergillosis. The rates of aspergillosis among those patients who did not receive a bone marrow transplant were highest for patients with acute myelogeneous leukemia. Increases in the annual rates of aspergillosis over time coincided with the level of internal renovation activity and major construction projects upwind of patient care facilities.

Aspergillosis↗
PubMed1993

Nosocomial invasive aspergillosis in lymphoma patients treated with bone marrow or peripheral stem cell transplants.

OBJECTIVES: To determine the prevalence of aspergillosis in lymphoma patients housed in a protective environment while undergoing a bone marrow transplant or peripheral stem cell transplant and its relation to lymphoma type, type of transplant, period of neutropenia, method of diagnosis, species of Aspergillus, and the use of empiric amphotericin B. DESIGN: Clinical, autopsy, and microbiology records were reviewed retrospectively to determine the presence or absence of invasive aspergillosis. All positive specimens underwent further review to determine parameters outlined above. SETTING: The review took place at the University of Nebraska Medical Center with lymphoma patients housed in the oncology/hematology special care unit, which consists of 30 single-patient rooms under positive pressure with high-efficiency particulate air filtration. PATIENTS: 417 lymphoma patients admitted to the oncology/hematology special care unit who underwent 427 courses of high-dose chemotherapy with or without total body irradiation followed by a stem cell rescue. RESULTS: Twenty-two cases (5.2%) of nosocomial invasive aspergillosis (14 caused by Aspergillus flavus, 2 by Aspergillus terreus, 2 by Aspergillus fumigatus, and 4 by characteristic histology) were diagnosed. The prevalence of disease according to transplant was 8.7% for allogeneic bone marrow transplant (2/23 treatments), 5.6% for autologous peripheral stem cell transplant (9/161), and 4.5% for autologous bone marrow transplant (11/243). Fifteen patients were presumptively diagnosed prior to death (68.2%) most commonly by histologic examination of skin biopsies. All 22 patients received amphotericin B therapy, 17 prior to aspergillosis diagnosis, and 7 (31.8%) survived. No patient with disseminated disease survived. CONCLUSIONS: Even when housing lymphoma patients undergoing myeloablative therapy in a protective environment containing high-efficiency particulate air filtration, there was a risk of developing aspergillosis. These data also showed that antemortem diagnosis with aggressive amphotericin B therapy was most effective in the management of infected lymphoma patients when engraftment occurred and the disease did not become disseminated.

Amphotericin B↗
PubMed1986

The role of bronchoalveolar lavage in the diagnosis of invasive pulmonary aspergillosis.

Cultures and histochemical stains for fungi were performed on concentrated, cytocentrifuged bronchoalveolar lavage (BAL) samples from 82 immunocompromised patients undergoing bronchoscopic evaluation of new pulmonary infiltrates. Aspergillus hyphae were identified in 9 of 17 BAL samples from patients with invasive pulmonary aspergillosis and from 3 of the remaining 65 study patients without this diagnosis. Thus, the presence of Aspergillus hyphae in BAL samples had a 53% sensitivity, 97% specificity, and 75% positive predictive value for the diagnosis of invasive pulmonary aspergillosis. BAL fungal cultures were positive in only 4 of 17 cases (23% sensitivity). A combination of fungal stains and cultures yielded a diagnostic sensitivity of 58% and a specificity of 92%. Results of routine fiberoptic bronchoscopy procedures in the 17 patients with aspergillosis who had BAL and in a retrospectively identified group of 10 patients with invasive aspergillosis who had only routine bronchoscopy were tabulated. Routine bronchoscopy procedures yielded a diagnosis in 5 of 27 cases (22% overall yield), with washings diagnostic in 4 of 27 cases (15%), and transbronchial biopsies positive histologically in 2 of 11 cases (18%). BAL is a valuable first procedure for diagnosing invasive pulmonary aspergillosis in the compromised host.

Adult↗
PubMed1997

Chronic invasive aspergillosis in apparently immunocompetent hosts.

Seventeen cases of invasive aspergillosis occurring since 1987 in apparently immunologically normal hosts have been reviewed: 9 of invasive sinus aspergillosis, 2 of isolated brain abscesses, 3 of pneumonia (1 in a patient who developed mediastinitis), 2 of lymph node aspergillosis, and 1 of osteomyelitis of the foot. Two of the 9 patients with sinus aspergillosis died; the rest were stable up to March 1993. They responded initially to combined surgical and medical therapy. Both patients with brain abscesses survived following surgery, but one had neurological sequelae. Both patients with pneumonia were well following therapy with amphotericin B; one also received itraconazole. The patient with mediastinitis died, but this disease was diagnosed late. The patients with lymph node involvement were lost to follow-up, as was the patient with osteomyelitis. Invasive aspergillosis may be common in Pakistan. Greater awareness would allow earlier diagnosis and therapy, thereby improving the outcome.

Adolescent↗
PubMed1980

Diagnosis of invasive aspergillosis by passive hemagglutination assay of antibody.

Sheep red cells treated with concanavalin A and sensitized with a partially purified aspergillus antigen were used to detect antibody to Aspergillus by passive hemagglutination (PHA). Sera from eight patients with aspergillomas or allergic aspergillosis had PHA titers of greater than or equal to 1:800 and antibody detectable by immunodiffusion (ID). Of 122 hospitalized cancer patients without invasive aspergillosis, 118 had titers of less than or equal to 1:80, 86 of < 1:10, two of 1:160, and two of 1:320. None had antibody by ID. Antibody was detectable by PHA in sera from 12 of 14 healthy microbiology laboratory workers. Of 55 cancer patients who had sera available for testing within two weeks before diagnosis of invasive aspergillosis, 18 patients seroconverted: 13 by both PHA and ID, two by PHA alone, and three by ID alone. PHA titers rose from < 1:10 to between 1:40 and 1:1,280. In immunosuppressed patients who were at risk of developing invasive aspergillosis, the appearance of antibody correlated with the diagnosis of invasive aspergillosis.

Antibodies, Fungal↗
PubMed1987

Serodiagnosis of invasive aspergillosis in patients with hematologic malignancy: validation of the Aspergillus fumigatus antigen radioimmunoassay.

Six hundred sixteen sera from 79 hematology patients admitted on 152 occasions were analyzed for validation of the Aspergillus fumigatus antigen radioimmunoassay (RIA). Invasive aspergillosis developed on 24 admissions of 22 patients. Maximal antigenic activity was significantly higher in patients with invasive aspergillosis than in controls (P less than .0005). At the level of antigenic activity selected as the cutoff value, the sensitivity of the RIA was 74%, the specificity 90%, the positive predictive value 82%, and the negative predictive value 85%. Antigen was detected before invasive aspergillosis was suspected during 30% of admissions and before pathological or even preliminary microbiological evidence for disease in 46%. In 17 (77%) of the 22 episodes of pulmonary aspergillosis, the RIA would have been the first positive diagnostic test for aspergillosis or would have confirmed a diagnosis established by other means. Overall, the test would have been of clinical usefulness in diagnosis, management, and prognosis in 80% of 16 fatal cases.

Agranulocytosis↗
PubMed2001

Aspergillosis of the maxillary sinus as a complication of overfilling root canal material into the sinus: report of two cases.

Aspergillosis of the maxillary sinus is a relatively rare disease in nonimmunocompromised patients. In recent years a number of cases of aspergillosis of the maxillary sinus have been reported in association with overextension of root canals fillings with certain root canal cements. It has been suggested that zinc oxide-based root canal cements might promote the infection with the Aspergillus species. In particular Aspergillus fumigatus has been found to be associated with the maxillary sinus infection. Radiographically the unique appearance of a dense opacity foreign body reaction in the maxillary sinus was considered a characteristic finding in maxillary sinus aspergillosis. Because this association of overfilling of root canal cements and aspergillosis of the maxillary sinus is not too well known we report two cases of young healthy female patients with the characteristic findings, both radiographically and clinically. In both patients the first maxillary molar was involved. Patients were symptomless and the diagnosis was made accidently. However at surgical inspection both patients revealed aspergillomas, including the overextended root canal cement. The surgical procedure is described as are the microscopic findings in both cases showing the characteristic branching hyphae and conidophores typical of Aspergillus. Overextension into the maxillary sinus with root canal cements has to be avoided; material has to be removed from the sinus because otherwise aspergillosis infection may ensue.

Adult↗