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An aid in the diagnosis of invasive aspergillosis and assessing response to therapy
Invasive aspergillosis (IA) is a severe infection that occurs in patients with prolonged neutropenia, following transplantation or in conjunction with aggressive immunosuppressive regimens (eg, prolonged corticosteroid usage, chemotherapy). The incidence of IA is reported to vary from 5% to 20% depending on the patient population. IA has an extremely high mortality rate of 50% to 80% due in part to the rapid progression of the infection (ie, 1-2 weeks from onset to death). Approximately 30% of cases remain undiagnosed and untreated at death.
Definitive diagnosis of IA requires histopathological evidence of deep-tissue invasion or a positive culture. However, this evidence is often difficult to obtain due to the critically ill nature of the patient and the fact that severe thrombocytopenia often precludes the use of invasive procedures to obtain a quality specimen. The sensitivity of culture in this setting also is low, reportedly ranging from 30% to 60% for bronchoalveolar lavage fluid. Accordingly, the diagnosis is often based on nonspecific clinical symptoms (unexplained fever, cough, chest pain, dyspnea) in conjunction with radiologic evidence (computed tomography [CT] scan); and definitive diagnosis is often not established before fungal proliferation becomes overwhelming and refractory to therapy.
Recently, a serologic assay was approved by the Food and Drug Administration for the detection of galactomannan, a molecule found in the cell wall of Aspergillus species. Serum galactomannan can often be detected a mean of 7 to 14 days before other diagnostic clues become apparent, and monitoring of galactomannan can potentially allow initiation of preemptive antifungal therapy before life-threatening infection occurs.
A positive result supports a diagnosis of invasive aspergillosis (IA). Positive results should be considered in conjunction with other diagnostic procedures, such as microbiologic culture, histological examination of biopsy specimens, and radiographic evidence. See Cautions.
A negative result does not rule out the diagnosis of IA. Repeat testing is recommended if the result is negative but IA is suspected. Patients at risk of IA should have a baseline serum tested and should be monitored twice a week for increasing galactomannan antigen levels.
Galactomannan antigen levels may be useful in the assessment of therapeutic response. Antigen levels decline in response to antimicrobial therapy.
False-positive results are reported to occur at rates of 8% to 14% with this assay. For all positive patients, it is recommended that a new aliquot of the same specimen be repeated, as well as collection of a new specimen from the patient for follow-up testing. Two or more consecutive positive results should be obtained from separately drawn specimens before the patient is considered to have a positive Aspergillus antigen test.
Numerous foods (pasta, rice, etc.) contain galactomannan. It is thought that damage to the gut wall by cytotoxic therapy, irradiation, or graft-versus-host disease enables translocation of the galactomannan from the gut lumen into the blood and may be partially responsible for the high false-positive rate of this assay.
Other genera of fungi such as Penicillium and Paecilomyces have shown reactivity with the rat EBA-2 monoclonal antibody used in the assay. These species are rarely implicated in invasive fungal disease. Cross reactivity with Alternaria species also has been reported.
Semisynthetic antibiotics such as piperacillin, amoxicillin, and augmentin, which are based on natural compounds derived from the genus Penicillium, have been demonstrated to cross-react with the rat EBA-2 monoclonal antibody used in the assay.
The specificity of the assay for Aspergillus species cannot exclude the involvement of other fungal pathogens with similar clinical presentations such as Fusarium, Alternaria, and Mucorales.
The performance of the assay has not been evaluated with neonate serum specimens or for use with plasma or other specimen types such as urine or cerebrospinal fluid.
The assay may exhibit reduced detection of galactomannan in patients with chronic granulomatous disease and Job's syndrome.
The concomitant use of antifungal therapy in some patients with invasive aspergillosis may result in reduced sensitivity of the assay.
False-positive galactomannan results are possible in patients receiving PLASMA-LYTE for intravenous hydration or if PLASMA-LYTE is used for bronchoalveolar lavage.
Specimens containing Histoplasma antigen may cross-react in the Aspergillus galactomannan assay.
In clinical studies submitted for the Food and Drug Administration (FDA)-approval process, the sensitivity of the test was reported to be 81% for proven/provable invasive aspergillosis (N=31 patients), and the specificity was 89% (N=148 patients). The positive and negative predictive values were reported as 68% and 96% respectively, based on an average prevalence of 14% in the study population. In a low-prevalence population (5%), the positive predictive value decreases to 31%; the negative predictive value remains at 96%.(Package insert: Platelia Aspergillus EIA, Bio-Rad, Redmond, WA, 6/2003)
1. Maertens J, Verhaegen J, Lagrou K, et al: Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: a prospective evaluation. Blood 2001 March 15;97(6):1604-1610
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