EIA Test for Aspergillus galactomannan Officially Here — But How Good Is It?
Abstracts & Commentary
Synopsis: The Platelia Aspergillus EIA for detecting Aspergillus galactomannan in blood has been recently approved by the Food and Drug Administration for use in the United States.
Sources: http://www.fda.gov/bbs/topics/NEWS/2003/NEW00907.html; Pinel C, et al. Detection of circulating Aspergillus fumigatus galactomannan: Value and limits of the platelia test for diagnosing invasive aspergillosis. J Clin Microbiol. 2003;41(5):2184-2186.In May, the Food and Drug Administration (FDA) cleared the Platelia Aspergillus EIA test manufactured by Bio-Rad Laboratories, of Redmond, Wash, for detecting Aspergillus galactomannan in blood. This antigen is a good indicator of invasive infection, with the results being available in a matter of hours rather than days. The product was granted clearance based on clinical studies of the test’s performance at 3 cancer centers that tested 1890 blood samples collected from 170 patients. Thirty-one patients had proven or probable invasive aspergillosis. The EIA correctly identified 25 of the 31 people who had proven or probable invasive aspergillosis (81% sensitivity) and correctly identified 132 of the 148 without the disease (89% specificity).
Comment by J. Peter Donnelly, PhD
The combined number of invasive Aspergillus cases in Europe and North America is estimated to be a few thousand per year, but the mortality exceeds 50%. The disease also affects individuals who have undergone extensive and, therefore, expensive treatment for cancer or who have had haematopoietic stem cell or solid organ transplants. Prevention is untenable, and effective prophylaxis remains a distant prospect, hence, early diagnosis with effective treatment is the main goal. The EIA will be most useful when it forms part of the definition of probable aspergillosis together with host factors and radiological evidence.
Although new to the United States, the Aspergillus EIA test has been available in Europe since 1995 and has been tested in a variety of settings. Initially, the reports were enthusiastic about both the sensitivity and specificity of the test (see Figure) but the sensitivity has apparently diminished latterly.
| Figure |
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| Source: Adapted from an original of P.E. Verweij. 2003. |
The article of Pinel and associates is a case in point. In their selection of patients, antigen was not detected at all in almost half the cases they considered probable aspergillosis (see Table). Moreover, antigen was detected in only 9 of the 23 cases with lesions typical of pulmonary aspergillosis (ie, cavitations, halo signs, and pulmonary nodules). By contrast, antigen was detected in 7 of the 8 cases of ill-defined lesions not typical of pulmonary aspergillosis. This suggests that antigen release may be related to the site and nature of the lesion. Clearly, a much larger prospective study is required to confirm these findings and also to identify the factors that lead to high antigen concentration when there is no disease. Pinel et al found 3 such patients from whom antigen was repeatedly and clearly detected and suggested it might be related to the use of drugs of fungal origin. An alternative explanation might be that Pinel et al did not apply the criteria for defining aspergillosis strictly. For instance, patients with pulmonary abnormalities other than a halo sign, air-crescent sign, or cavitation might be considered by some as being possible rather than probable cases of aspergillosis. However, even if this were true, antigen was still only detected in 4 of the 11 cases that would remain probable and in 12 of the 20 cases that might be downgraded to possible disease. This would make the EIA results look even less favorable.
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Table |
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Performance of Antigen Test in Probable Aspergillosis |
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Pulmonary appearance |
No with antigen/ No of cases |
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| Typical | 9/23 | |
| Cavitation | 1/4 | |
| Halo sign | 6/12 | |
| Nodules | 2/7 | |
| Ill-defined | 7/8 | |
| Infiltrate | 6/7 | |
| Necrosis | 1/1 | |
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Source: Pinel C, et al. J Clin Microbiol. 2003;41(5):2184-2186. |
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The explanation for the French results and the drop in sensitivity reported by others might be simply due to differences in the patient populations tested, for instance, children rather than adults or patients with graft-vs-host disease rather than those with severe mucosal barrier injury to the gut following intense chemotherapy. There are also differences in the intensity of screening. For instance, once weekly rather than twice or even 3 times weekly. The observed fall in sensitivity might even be a reflection of true state of play in the field since early investigations of new tests tend to rely on selected patient populations rather than prospective cohorts of all patients at risk.
As with any indirect test, the performance of the Aspergillus EIA will depend crucially on the constitution of the test population. When prevalence is low and the disease is infrequent, the post-test performance will be adversely affected. Moreover, aiming at high specificity will only be achieved at the expense of high sensitivity. We might like to have our cake and eat it, but this is never so in reality. The expectations of the consumer also play a role in so far as a test can be used to exclude or include cases. To exclude patients and make sure that cases are not going to be missed, false-positive results are tolerated. To aim at including patients, the reverse is true and false negatives are tolerated since a mistaken diagnosis is considered unacceptable. Many physicians think they are getting the best of both worlds, but this is seldom the case. For instance, the original threshold for determining a positive EIA result was a ratio of 1.5. This has been altered to 1.0 in practice, whereas the FDA has set the threshold to 0.5. This will increase the number of false-positive results. Moreover, it makes comparison of studies done in the United States difficult to compare with those done previously in Europe.
The EIA will be used under circumstances where the pretest probability has artificially increased by testing only those patients at high risk (eg, HSCT recipients or those treated with high-dose corticosteroids or with prolonged neutropenia). The performance of the test will, therefore, be different when used for different at-risk groups such as liver transplant recipients. The success of the EIA test will also depend upon the location and nature of the lesion, exposure to other substances that might contain galactomannan (eg, foodstuffs, drugs, the prevalence of the disease in different patient populations, as well as the quality of the laboratory performing the test). Only time will tell whether the EIA lives up to its promise in helping to recognize aspergillosis early enough to target effective treatment. Equally, it will be interesting indeed to see whether or not use of the test leads to less empirical treatment and to more preemptive approach to managing invasive aspergillosis. This would certainly be welcome, especially if the benefits outweighed the costs.
Suggested Reading
1. Verweij PE, et al. Sandwich enzyme-linked immunosorbent assay compared with Pastorex latex agglutination test for diagnosing invasive aspergillosis in immunocompromised patients. J Clin Microbiol. 1995;33(7):1912-1914.
2. Machetti M, et al. Comparison of an enzyme immunoassay and a latex agglutination system for the diagnosis of invasive aspergillosis in bone marrow transplant recipients. Bone Marrow Transplant. 1998;21(9):917-921.
3. Maertens J, et al. Autopsy-controlled prospective evaluation of serial screening for circulating galactomannan by a sandwich enzyme-linked immunosorbent assay for hematological patients at risk for invasive aspergillosis. J Clin Microbiol. 1999;37(10): 3223-3228.
4. Ulusakarya A, et al. Surveillance of Aspergillus galactomannan antigenemia for invasive aspergillosis by enzyme-linked immunosorbent assay in neutropenic patients treated for hematological malignancies. Hematol J. 2000;1(2):111-116.
5. Sulahian A, et al. Value of antigen detection using an enzyme immunoassay in the diagnosis and prediction of invasive aspergillosis in two adult and pediatric hematology units during a 4-year prospective study. Cancer. 2001;91(2):311-318.
6. Herbrecht R, et al. Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients. J Clin Oncol. 2002;20(7):1898-1906.
7. Becker MJ, et al. Galactomannan detection in computerized tomography-based broncho-alveolar lavage fluid and serum in haematological patients at risk for invasive pulmonary aspergillosis. Br J Haematol. 2003; 121(3):448-457.
Dr. Donnelly is Clinical Microbiologist University Hospital Nijmegen, The Netherlands Section Editor, Microbiology.
The Platelia Aspergillus EIA for detecting Aspergillus galactomannan in blood has been recently approved by the Food and Drug Administration for use in the United States.Subscribe Now for Access
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