US Food & Drug Administration (FDA) approves the marketing of Platelia Aspergillus EIA kit in USA

Invasive aspergillosis (IA) still remains difficult to diagnose and hard to treat in immunocompromised patients. The mortality rate due to this life-threatening opportunistic mycosis is as high as 50-100% and early diagnosis and prompt initiation of antifungal therapy remain as the crucial factors that may aid in reduction of the mortality rates. Definitive diagnosis of IA by cultivation of the infecting strain requires surgical biopsy of a sterile site for optimal results, may take as long as 4 weeks, and may be confounded by contamination. Although biopsy and culture will doubtless remain as gold standard tests, there is a remarkable demand for additional tests that may help in early diagnosis of this infection.

Among these, detection of galactomannan antigen in serum and body fluids has been intensively studied in recent years. Galactomannan is a component of the fungal cell wall and an exoantigen of Aspergillus
. The first test to detect this antigen used a latex agglutination (LA) method. Subsequently, an ELISA-based method was developed which provided higher sensitivity and specificity compared to LA [2125]. The ELISA-based kit is commercially available as "Platelia Aspergillus EIA" (Bio-Rad Laboratories). Galactomannan antigen positivity is among the microbiological diagnostic criteria proposed by European Organization for Research and Treatment of Cancer (EORTC) and Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) for diagnosis of IA. The kit has been available for some time in Europe and was cleared for diagnostic use in the United States by the FDA on 16 May 2003. The cut-off used in the European kit was an index of 1.0 for indeterminate and 1.5 for positive. The FDA cleared version of the test kit uses a cut-off of 0.5 index value and demonstrated good sensitivity and specificity claims in the clinical testing from three separate medical centers.

Here is a summary of the key data regarding use of the galactomannan antigen test in the diagnosis of IA:

  1. The test can detect as little as 0.5-1 ng/ml of galactomannan in the tested sample [2003].
  2. The most frequently tested sample and the one which provides highest sensitivity is serum [1840]. Other samples, such as bronchoalveolar lavage, urine [1840] and cerebrospinal fluid [2123, 2139] may also be beneficial in diagnosis of IA, but the kit is standardized and FDA cleared only for serum samples. The Platelia Aspergillus EIA has not been evaluated for use with plasma or other sample types such as urine, BAL or CSF in the US. In addition, the performance of the Platelia Aspergillus EIA has not been evaluated in neonate or pediatric serum samples in the US.
  3. The galactomannan antigen test is a screening test and should be employed as such. Collection of serum samples should be initiated right after hospitalization in patients at high risk of developing IA. Samples should be collected (at least) twice weekly from then on [1284]. The concomitant use of mould-active antifungal therapy in some patients with IA may result in reduced sensitivity with the Platelia Aspergillus EIA.
  4. Detection of positive results particularly in two consecutive serum samples provides strong support for the diagnosis of IA [1283, 1284]. The US package insert recommends that an initially positive sample be re-tested by performing a treatment of a new aliquot of the serum sample and also collecting another sample for testing. Samples should be reported as negative or positive for galactomannan. The index value for positive samples can prove to be useful. Negative samples should just be reported as negative. A negative test cannot rule out the diagnosis of IA. Repeat testing of additional samples should be considered where there is clinical suspicion of IA or a procedural error.
  5. Galactomannan detection can provide two types of information. First, early diagnosis is possible if the specimens are being tested upon collection. Galactomannan antigen positivity can be detected 5-8 days (average) before clinical signs develop (in 65.2% of patients), findings on chest X-ray are visible (in 71.5% of patients) and culture results become positive (in 100% of patients) [1283]. A second use is to provide negative data in patients with syndromes compatible with aspergillosis. In such settings, the absence of galactomannan positivity may provide support for more aggressive traditional diagnostic measures.
  6. The sensitivity and specificity of the test are favorable. In the dataset evaluated by FDA, the overall sensitivity and specificity of the method were 80.7% and 89.2%, respectively. For this evaluation, 1890 blood samples collected from 170 patients were tested. Among these, 31 patients had proven or probable IA. Galactomannan antigen was detected in 25 of these 31 patients with a resulting sensitivity of 80.7%. Of 148 patients who did not have IA, 132 were negative for galactomannan antigen, yielding a specificity of 89.2%. Of these 148 patients, a total of 1362 sera were obtained and tested. 1343 of these 1362 sera were initally negative, resulting in a sample agreement of 98.6% with a 95% CI of 97.9-99.3. On repeat testing, 1355 of the 1362 sera were negative.
  7. As with any serological test, false positive reactions may be observed. It has been detected in 1-18% of the tested samples [2264, 1284]. False positivity may originate from true antigenic cross reactivity with other fungi such as Penicillium chrysogenum, Penicillium digitatum, and Paecilomyces variotii [2024]. A pattern of false-positive antigenemia that is most common in children [1204] has been noted and may possibly develop after translocation of galactomannan antigen found in various foodstuffs (unsalted bread, macaroni, corn flakes, salted rice, dry cake, turkey slices, grilled sausage, fried potatoes, etc.) through the damaged intestinal mucosa [1204].
  8. As well as early diagnosis, the test may also be helpful in assessment of the prognosis and the clinical response to antifungal therapy [1583, 1788, 283]. In cases of a favorable clinical response, the titer of the antigen tends to either decline or does not change significantly compared to the baseline titer. In contrary, it increases significantly in case of treatment failure [1840, 2123, 283]. Of note, and possibly due to the distinctive mode of action of the drug, galactomannan antigenemia persisted despite clinical improvement in animals who were treated with caspofungin [1609]. This finding suggests that same may apply to patients who are treated with an echinocandin compound.