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Invasive aspergillosis in liver transplant recipients: association with candidemia and consumption coagulopathy and failure of prophylaxis with low-dose amphotericin B.

Invasive aspergillosis developed in three (5%) of 55 adult liver transplant recipients at our institution. All three of our patients had concomitant candidemia and consumption coagulopathy, and invasive aspergillosis developed while they were receiving therapy with intravenous amphotericin B (0.5 mg/[kg.d]). The simultaneous occurrence of candidemia and invasive aspergillosis in liver transplant recipients may reflect a common defect in the host-defense mechanism against Candida and Aspergillus organisms (i.e., impaired phagocytic and mononuclear macrophage function) and liver disease per se. These three cases suggest that such low-dose intravenous amphotericin B will likely be ineffective if used as antifungal prophylaxis for invasive aspergillosis.

Adult↗

Therapeutic outcome in invasive aspergillosis.

A review of series of > or = 4 cases of invasive aspergillosis (total, 1,223 cases) was undertaken to establish the crude mortality and rate of response to therapy with amphotericin B in the major at-risk host groups. In association with pulmonary, sinus, and cerebral aspergillosis in immunocompromised patients, the crude mortality rates were 86%, 66%, and 99%, respectively. No untreated patient survived. Among 84 patients treated for 1-13 days, only one survived. Among those with invasive pulmonary aspergillosis treated for > or = 14 days, the response rates to amphotericin B deoxycholate were 83% (in cases of heart and renal transplantation), 54% (leukemia), 33% (bone marrow transplantation) and 20% (liver transplantation). Patients with AIDS mostly received both amphotericin B and itraconazole, and 37% of those treated for > or = 14 days responded to therapy. Substantial variation in outcome from series to series was related to underlying disease status, site of disease, and management. Invasive aspergillosis remains a devastating opportunistic infection despite current treatment.

Amphotericin B↗

Localization of aspergillosis to the central nervous system among patients with acute leukemia: report of 14 cases. Gruppo Italiano Malattie Ematologiche dell'Adulto Infection Program.

We retrospectively studied a consecutive series of 100 patients with acute leukemia and aspergillosis to evaluate the clinical findings and risk factors for colonization of the central nervous system (CNS) by Aspergillus species. The diagnosis of CNS aspergillosis was made in 14 patients on the basis of the following criteria: neurological signs of CNS involvement (13 of 14 patients); cerebral CT scan findings (9 of 12); microbiological findings (6 of 12); and histological findings at autopsy (11 of 11). The majority of patients had severe neurological complications (i.e., hemiparesis or seizures), due mainly to brain abscesses or mycetomas. Autopsies were performed on 11 of 14 patients and provided evidence that CNS localization was secondary to invasive aspergillosis; in each case, the most likely primary focus of infection was the lung. Although all patients had received oral antimycotic prophylaxis and had received timely empirical antifungal treatment, they all died within a median time of 5 days from the onset of neurological symptoms. Analysis of the characteristics of patients with invasive aspergillosis did not reveal any difference between those with CNS localization and those without CNS localization.

Acute Disease↗

Invasive pulmonary aspergillosis in nonimmunocompromised, nonneutropenic hosts.

Invasive pulmonary aspergillosis occurs predominantly in individuals who are neutropenic or who have severe defects in cell-mediated immunity. The isolation of Aspergillus from respiratory secretions of normal hosts usually signifies tracheobronchial colonization, not disease. Recent experience with three nonimmunocompromised patients who had invasive pulmonary aspergillosis, each of whom had Aspergillus isolated from respiratory secretions early in his illness, led to a reassessment of the significance of the isolation of Aspergillus from tracheobronchial secretions. Two of 10 nonimmunocompromised, nonleukopenic individuals who had pulmonary infiltrates and whose sputum yielded Aspergillus had invasive pulmonary aspergillosis, whereas two of five individuals who had pulmonary infiltrates and whose bronchial washings grew Aspergillus had invasive disease. These findings indicate that invasive pulmonary aspergillosis should be considered when Aspergillus is isolated from the respiratory secretions of anyone who has pneumonia, regardless of host defense status.

Aged↗

Effect of elimination of phagocytic cells by liposomal dichloromethylene diphosphonate on aspergillosis virulence and toxicity of liposomal amphotericin B in mice.

The role of macrophages in the toxicity and efficacy of liposomal amphotericin B (L-Amp B) was studied in a murine aspergillosis model infection. Macrophages and polymorphonuclear phagocytes (PMN cells) were depleted in the liver and spleen of mice by the administration of liposome encapsulated dichloromethylene diphosphonate. Macrophage depletion had no effect on the lethality of Fungizone, a commercial deoxycholate preparation of Amp B, but significantly increased the lethality of L-Amp B (P < 0.01). Macrophage depletion led to an increase in the fungal loads in the lung, liver and kidney (P < 0.05) and to an increase in the virulence of aspergillosis (P < 0.05). Tissue distribution analysis of L-Amp B revealed that in macrophage/PMN-depleted mice there was a decrease in the concentration of Amp B in the liver, with concomitant increases in the circulation, spleen and lung, both in the uninfected and in the infected conditions. The results clearly demonstrate that depletion of macrophage/PMN cells increases the virulence of aspergillosis, as well as the toxicity of L-Amp B. Moreover, L-Amp B treatment does not improve the survival rate of macrophage/PMN-depleted mice subjected to aspergillosis challenge.

Amphotericin B↗

Experimental systemic murine aspergillosis: treatment with polyene and caspofungin combination and G-CSF.

OBJECTIVES: In view of the poor therapy outcomes of invasive aspergillosis, the objective of this study was to evaluate the efficacy of combination treatment consisting of the polyene amphotericin-B-intralipid, the echinocandin caspofungin and granulocyte-colony stimulating factor (G-CSF) in experimental murine systemic aspergillosis. With inhibition of synthesis of 1,3-beta-d-glucan in the fungal cell wall by caspofungin and an effect on the cell membrane by amphotericin-B-intralipid, this treatment may result in a synergic effect against Aspergillus fumigatus. Addition of G-CSF may further contribute to therapy of aspergillosis. METHODS: ICR mice were immunosuppressed by intraperitoneal administration of cyclophosphamide. Three days later, the mice were inoculated intravenously (iv) with A. fumigatus conidia. Infection and treatment were evaluated during an observation period of 30 days in terms of mortality (survival rate and mean survival time) and morbidity (quantitative determination of fungal burden, histopathology, and detection of serum galactomannan). RESULTS: Combination of caspofungin + G-CSF or addition of G-CSF to the combination of caspofungin + amphotericin-B-intralipid increased the survival rate of infected mice up to 78.9% and prolonged their mean survival time to 25 days. These combinations also resulted in a reduction in fungal burden in organs, and a decrease in serum galactomannan. CONCLUSIONS: The successful results obtained in the experimental model may possibly open the way to more effective management of aspergillosis in humans.

Amphotericin B↗

Case report: invasive pulmonary aspergillosis in a nonimmunosuppressed patient.

A patient with no known underlying immunosuppressive disorder who developed invasive pulmonary aspergillosis is described. A review of the English literature revealed ten other presumably nonimmunosuppressed patients with invasive aspergillosis. All had evidence of necrotizing pneumonitis with frequent cavity formation. Nine of the 11 patients died without the diagnosis of aspergillosis having been entertained. Invasive pulmonary aspergillosis does occur in the nonimmunosuppressed host and should be considered when an etiologic agent is not readily identified in a patient with rapidly progressive diffuse necrotizing pneumonitis.

Adult↗

Aspergillosis in 25 renal transplant patients. Epidemiology, clinical presentation, diagnosis, and management.

In immunocompromised renal transplant patients, aspergillosis can be a life-threatening opportunistic infection. During an 8-year period, 25 renal transplant recipients at the University of Minnesota Hospitals developed unequivocal invasive aspergillosis that occurred in epidemic-like patterns in immunocompromised patients throughout the hospital. The premortem diagnosis was made in only 14 of the 25 patients. Seventeen patients died, and three of the eight survivors lost their allografts. The prognosis was dependent upon the clinical pattern of illness: three clinical patterns emerged: (1) cavitary lung disease, (2) diffuse pulmonary disease, and (3) central nervous system disease. All patients in the latter two categories died. The best results were with those patients treated with both amphotericin B and excision of cavitary lung lesions. All three patients treated in this manner survived with functioning grafts. Traditionally, sputum cultures have been thought to be unreliable because Aspergillus is a common colonizer of the upper respiratory tract and a contaminant in laboratories. In this study, false positive sputum cultures were common. A positive sputum culture can be helpful, however, all patients with two positive sputum cultures proved to have invasive aspergillosis. In addition, 86% of patients with positive sputum cultures who were clinically ill proved to have invasive infection. Bronchoscopy is a useful technique to follow up a positive sputum culture or investigate negative sputum cultures with typical clinical patterns. Routine bronchoscopy, unfortunately, also yields a high incidence of false positive cultures. Since the use of covered brush bronchoscopy technique, however, no false positive transbronchial cultures have been found. Transbronchial biopsy is a useful adjunct and is proof of the presence of invasive disease when the results are positive. However, false negative results are also found. Overall, the highest diagnostic yield is obtained both with transbronchial lung biopsy and covered brush bronchoscopy culture. All eight patients with both these procedures were correctly identified as having invasive pulmonary aspergillosis.

Adult↗

Invasive aspergillosis. Clinical features of 35 proven cases at a single institution.

Thirty-five patients with clinical features and histologically or microbiologically proven infection met predetermined stringent criteria for invasive aspergillosis over a 5-year period at our institution. Underlying conditions included hematologic malignancy, solid tumor, bone marrow and solid organ transplantation, and immunosuppressive therapy. The majority of patients (94%) presented with respiratory symptoms and abnormal pulmonary chest radiography; only 40% had neutropenia at time of infection. Invasive aspergillosis was suspected in only 21 cases (60%). Concomitant infections were present in 83% of patients. Half of patients had pathogenic or potentially pathogenic microorganisms other than Aspergillus spp. isolated from pulmonary specimens at time of aspergillosis. Aspergillus spp. were recovered from sputum in 75% of patients and from bronchoalveolar lavage in only 52%. Invasive aspergillosis is an unexpectedly unrecognized disease with poor outcome; overall mortality was 94% in our series. The lack of sensitivity of diagnostic procedures, together with the high frequency of concomitant infections, delays the time of diagnosis. Early diagnostic tests are needed, and presumptive antifungal therapy among high-risk patients is mandatory.

Adult↗

Fatal myocardial aspergillosis in an immunosuppressed child.

A girl with resistant acute myeloid leukemia (AML) had a stem cell transplantation. Preceding transplantation, she had recurrent pneumonitis. No causative agent was identified. Despite several antibiotics including high-dose liposomal amphotericin-B, pulmonary infection progressed. Aspergillosis, always considered, could not be documented. She died from cardiac arrest on the second day after transplantation, with no forewarning of previous heart disease. Pericardial and myocardial aspergillosis was an autopsy finding. Pericardial and myocardial aspergillosis, rare manifestations of systemic aspergillosis, should be considered in any immunocompromised patient with long-lasting pulmonary infection, even in the absence of specific cardiac findings.

Amphotericin B↗

Pediatric aspergillosis: disease and treatment differences in children.

Invasive aspergillosis is an increasing problem, yet there are few specific data on pediatric aspergillosis. The underlying patient diseases and treatments differ in children and adults, and there is a heterogeneity of invasive aspergillosis that extends to children. Although new diagnostic tools hold great promise for adult patients, it appears that they have limited usefulness in children without the appropriate testing. Antifungal management of pediatric aspergillosis also requires unique dosing schemes that are not used in adult patients.

Adolescent↗

Primary intestinal aspergillosis after high-dose chemotherapy and autologous stem cell rescue.

Primary invasive aspergillosis of the gut is a rare event and is associated with high mortality. We report for the first time on a patient who had isolated aspergillosis of the small bowel after autologous stem cell transplantation. Diagnosis of invasive aspergillosis of the gut was based on abdominal pain, galactomannan antigenemia and isolation of Aspergillus fumigatus from the stool and was later confirmed by pathohistologic examination. No other site of invasive aspergillosis was evident. The patient was successfully treated with early surgery and combination antifungal therapy.

Antineoplastic Agents↗

Refractory pulmonary aspergillosis: compassionate trial with terbinafine.

The frequency of bronchopulmonary aspergillosis is increasing due to the growing number of patients requiring steroids or other immunosuppressive therapies. Conventional treatments are ineffective in some patients and side-effects are an important issue. The aim of this work was to evaluate the effectiveness and safety of terbinafine, a new allylamine antimycotic drug, in three immunocompetent patients affected by lower respiratory tract aspergillosis [one chronic empyema due to Aspergillus fumigatus (AF) and two chronic necrotising aspergillosis] not responsive to the usual antimycotic therapies. In in vitro and animal model systems, terbinafine is as active as amphotericin B and itraconazole. Patients received terbinafine at doses ranging from 5 to 15 mg/kg per day, according to clinical status, for 3-5 months, depending on the clinical course of the disease and compliance. In patient 1 a negative anti-AF precipitin was obtained together with eradication of AF from the pleural cavity, which allowed a successful intrathoracic myo-omento-mammoplasty. In patients 2 and 3, AF was eradicated, anti-AF immunoprecipitins decreased, and clinical and radiological findings significantly improved. On the basis of the effectiveness of terbinafine demonstrated in this preliminary work, large studies to evaluate the use of terbinafine in bronchopulmonary aspergillosis are warranted. Moreover, the drug is not associated with resistance or significant side-effects.

Adult↗

Environmental factors in allergic bronchopulmonary aspergillosis.

Many workers have suggested that exposure to an environment rich in Aspergillus spores is aetiologically significant in allergic bronchopulmonary aspergillosis. This hypothesis has been investigated by means of an environmental survey in which eight urban dwelling patients with this disease and five atopic control patients took part. Enquiries were made about contact with known sources of Aspergillus fumigatus and air spora studies were conducted in the home. Findings were similar for both groups. No high spore concentrations were recorded in the homes of either group. Patients with allergic bronchopulmonary aspergillosis had not been more exposed to potentially rich sources of A. fumigatus than the atopic control patients. The view is expressed that specific host susceptibility is more important in the pathogenesis of allergic bronchopulmonary aspergillosis than environmental factors. Ince a patient is sensitized however minor increases in spore concentration can cause symptomatic disease producing the recognized winter exacerbations of allergic bronchopulmonary aspergillosis. Possible mechanisms allowing the development of the disease in the presence of low spore concentrations are discussed.

Adolescent↗

Obstructive bronchial aspergillosis after heart transplantation.

Obstructive bronchial aspergillosis is a rarely observed consequence of Aspergillus infection. It occurs not only in patients with the acquired immunodeficiency syndrome (AIDS), but also after heart transplantation (HTx) if T cells are reduced markedly by the application of antithymocyte globulin (ATG) in addition to immunosuppression with corticosteroids. In contrast to invasive aspergillosis or Aspergillus tracheobronchitis, the course of this form of Aspergillus infection may not be accompanied by symptoms, because bronchial inflammation with pseudomembranes, ulcers or destruction of mucosa and intrapulmonary infiltrates are absent. To prevent invasive aspergillosis following HTx, intensive antifungal therapy is necessary in cases of bronchial obstructive aspergillosis, because this form of Aspergillus infection seems to represent a stage before recognizable invasive disease, as in other immunocompromised patients.

Aspergillosis↗

Primary frontal sinus aspergillosis: an uncommon occurrence.

Primary frontal sinus aspergillosis is extremely uncommon with only few cases reported in the English literature. Isolated frontal sinus aspergillosis is usually asymptomatic and produces symptoms due to orbital or intracranial involvement. We report two cases of primary frontal sinus aspergillosis, presenting as frontoethmoidal mucocele and mimicking a 'Pott's puffy tumor,' respectively. Forehead swelling produced by frontal sinus aspergillosis will be the first to be reported in the English literature.

Adult↗

Invasive pulmonary aspergillosis in chronic obstructive pulmonary disease: an emerging fungal pathogen.

Acute invasive pulmonary aspergillosis occurs predominantly in immunocompromised hosts, with increasing numbers of cases of invasive aspergillosis among patients with chronic obstructive pulmonary disease (COPD) being reported. Among 13 cases of invasive aspergillosis diagnosed in COPD patients admitted to the intensive care unit with acute respiratory distress, the only risk factor for invasive fungal infection was corticosteroid treatment. Invasive aspergillosis should be suspected in COPD patients receiving steroid treatment who have extensive pulmonary infiltrates. Survival depends on rapid diagnosis and early appropriate treatment. A decrease or interruption of steroid treatment should be considered as part of the overall therapeutic strategy.

Aspergillosis↗

Post-operative aspergillosis.

While invasive aspergillosis occurs typically in severely immunocompromised patients, cases of surgical site infection have been reported in immunocompetent individuals. The Medline, LILACS and EMBASE databases were searched for descriptions of cases of post-operative aspergillosis, and references from relevant articles and conference abstracts were reviewed. More than 500 cases of post-operative aspergillosis were found. Cardiac surgery (n = 188), ophthalmological surgery (n > 90) and dental surgery (n > 100) were associated with the majority of cases. Other cases involved wound infections (n = 22), bronchial infections (n = 30), mediastinitis (n = 11), pleural aspergillosis (n = 1), infections following orthopaedic surgery (n = 42), vascular prosthetic surgery (n = 22), breast surgery (n = 5), abdominal surgery (n = 10) and neurosurgery (n = 25). In most patients, the source was presumed to be airborne infection during the surgical procedure. Prevention of these infections requires special care of the ventilation system in the operating room. Successful treatment requires rapid diagnosis, surgical debridement and antifungal therapy, often with voriconazole. In order to improve the outcome, better diagnostic methods are needed, particularly for cases of endocarditis and aortitis.

Air Microbiology↗