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Journal of Clinical Microbiology, January 2004, p. 435-438, Vol. 42, No. 1
0095-1137/04/$08.00+0     DOI: 10.1128/JCM.42.1.435-438.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Efficacy of Galactomannan Antigen in the Platelia Aspergillus Enzyme Immunoassay for Diagnosis of Invasive Aspergillosis in Liver Transplant Recipients

Eun Jeong Kwak,¹ Shahid Husain,¹ Asia Obman,² Lisa Meinke,² Janet Stout,² Shimon Kusne,¹ Marilyn M. Wagener,² and Nina Singh^1,2*

Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center,¹ Veterans Affairs Medical Center, Pittsburgh, Pennsylvania 15240²

Received 28 July 2003/ Returned for modification 29 September 2003/ Accepted 2 October 2003

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The utility of galactomannan antigen for diagnosing invasive aspergillosis was evaluated in 154 liver transplant recipients. Sample agreement was 98.5%, and patient specificity was 87%. Galactomannan positivity correlated with mortality, even when controlled for the number of tests performed. Whether galactomannan positivity identifies a subgroup at risk for poor outcome warrants further evaluation.

Top Abstract Introduction References

 
The utility of the Platelia Aspergillus enzyme immunoassay (EIA) for the diagnosis of invasive aspergillosis (IA) was prospectively evaluated in liver transplant recipients. The study population comprised 154 patients undergoing liver transplantation between September 2001 and October 2002. Institutional review board approval was obtained, and all patients provided written informed consent. Tacrolimus (with or without mycophenolate mofetil) and low-dose prednisone were employed for immunosuppression. Induction with thymoglobulin followed by tacrolimus was employed in 65 patients (7). Routine antifungal prophylaxis was not used.

IA was diagnosed as per the EORTC/MSG (European Organization for Research and Treatment of Cancer/Mycoses Study Group) criteria (1) by investigators who were blinded to test results. Blood samples were collected twice weekly during the posttransplant and subsequent hospitalizations. Galactomannan was detected by one-stage immunoenzymatic sandwich microplate assay (Platelia Aspergillus EIA; Bio-Rad Laboratories, Marnes, France) as per the manufacturer's instructions. Samples with an index of 0.5 or greater were retested and considered positive only if the repeat test was also positive. Sensitivity and specificity were calculated in reference to the diagnosis of IA by using the total number of patients in the study.

The clinical characteristics of the patients are outlined in Table 1. IA developed in 1 of 154 (0.6%) of the patients and comprised a patient with probable pulmonary aspergillosis due to Aspergillus fumigatus 21 days posttransplantation. A total of 1,594 sera were analyzed, including 31 sera from the patient with probable IA and 1,563 sera from 153 patients without IA. The patient with probable IA had a positive result in three samples on initial, but not on repeat testing. Sample agreement was 98.5% (1,540 of 1,563 samples) in the patients without IA.

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TABLE 1. Demographic and clinical characteristics of the patients in this study

Twenty patients without IA had 23 false-positive tests that occurred in a median of 16 days posttransplantation (1 to 174 days). Patients undergoing transplantation for autoimmune liver disease were more likely to have false-positive tests than all others (Table 2). Patients with false-positive tests were more likely to have required dialysis than those with true-negative tests (P = 0.0015). Patients with positive tests had longer intensive care unit (ICU) stay; however, the duration of hospitalization and the number of tests performed per patient did not differ significantly for patients with positive tests versus those with negative tests (Table 2). Of 20 patients with false-positive tests, 7 (35%) were receiving piperacillin-tazobactam.

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TABLE 2. Clinical variables in patients with positive and negative galactomannan test

Mortality was 14.9% (23 of 154 patients). Of 23 patients who died, 4 had autopsies performed (none had IA). When controlled for the number of tests performed (positive tests/100 tests performed), the number of positive tests was higher in the patients who died than in those who lived (2.91 versus 1.05; P = 0.032).

Dialysis, cytomegalovirus (CMV) disease, intubation, longer length of ICU stay, mold-active antifungal agent use, and false-positive tests were significantly associated with death (Table 3). In a logistic regression model, however, only dialysis (odds ratio [OR], 12.5; 95% confidence interval [CI], 3.70 to 42.52; P = 0.0001) and the length of stay (OR, 1.03; 95% CI, 1.004 to 1.05; P = 0.023), but not test positivity (OR, 2.41; 95% CI, 0.060 to 9.70; P = 0.215) or antifungal agent use (OR, 1.75; 95% CI, 0.46 to 6.58; P = 0.408) were significantly associated with mortality. Of 20 patients with false-positive tests, 8 died (none had an autopsy performed). The latter had a longer ICU stay (51.9 versus 11.3 days; P = 0.0005) and were more likely to have required dialysis (6 of 8 versus 2 of 12; P = 0.019) than those who lived.

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TABLE 3. Factors associated with mortality in the study patients

In all, 26 of 154 patients received a mold-active antifungal agent (Table 4). In patients who received a mold-active antifungal agent, the false-positive test was documented in 40% (4 of 10) in those who died and in 5.9% (1 of 16) of the patients who lived (P = 0.055). The false-positive test preceded death by a median of 3 weeks. Among 128 patients who did not receive a mold-active antifungal agent, galactomannan positivity was observed in 30.8% (4 of 13) of the patients who died compared to 9.6% (11 of 115) of those who lived (P = 0.047).

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TABLE 4. Mold-active antifungal agent use in patients with false-positive and true-negative galactomannan test

The galactomannan test demonstrated a patient specificity of 87%. However, a low incidence of IA precluded meaningful assessment of the sensitivity of the test. Several observations concerning the galactomannan test in liver transplant recipients are nevertheless important. Patients with autoimmune liver disease were more likely to have false-positive tests. These patients comprise a unique group of transplant recipients who are deemed to be at higher risk for immune-mediated complications: e.g., chronic rejection (4). A false-positive test, due likely to autoreactive antibodies or paraproteins, has been reported in other conditions associated with autoimmune phenomenon: e.g., chronic graft-versus-host disease (3).

Patients requiring dialysis were more likely to have a false-positive test than all others. Rapid renal excretion and uptake by the macrophage mannose receptors are the major pathways by which the galactomannan is cleared from the bloodstream (2). In an animal model, excretion into the urine accounted for 35% of the dose by 24 h (2). Whether renal failure or dialysis affects the clearance of galactomannan is not known.

The patients who died had a higher number of positive tests, even when controlled for the number of tests performed. A false-positive test, however, was not an independently significant predictor of poor outcome. Nevertheless, the possibility that the test was in fact truly positive in these patients cannot be totally discounted. Liver transplant recipients with risk factors that confer a higher risk for aspergillosis (e.g., dialysis) (5, 6) were the very patients who had false-positive tests. Thus, IA may have been present but never documented due to the receipt of a mold-active antifungal agent as empirical therapy or treatment in many of these patients.

In summary, although the sensitivity of the Platelia Aspergillus EIA for the detection of IA could not be meaningfully assessed due to the fact that there was only a single case of IA, the test exhibited an excellent sample agreement of 98.5%. Correlation of galactomannan positivity with mortality in this patient population warrants validation in further studies.Whether a false-positive galactomannan test is a surrogate for greater severity of illness or an overall debilitated state of the patient or represents true infection that defied clinical detection remains to be determined.

 
Bio-Rad Laboratories, Redmond, Wash., provided kits and financial support for this study.

 
* Corresponding author. Mailing address: Infectious Disease Section, VA Medical Center, University Dr. C, Pittsburgh, PA 15240. Phone: (412) 688-6179. Fax: (412) 688-6950. E-mail: nis5\|[plus ]\|{at}pitt.edu.

Top Abstract Introduction References

 

1
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2. Bennett, J. E., M. M. Friedman, and B. Dupont. 1987. Receptor-mediated clearance of Aspergillus galactomannan. J. Infect. Dis. 155:1005-1010.[Medline]
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3. Hamaki, T., M. Kami, Y. Kanda, S. Miyakoshi, J. Ueyama, S. Morinaga, and Y. Mutou. 2001. False-positive results of Aspergillus enzyme-linked immunosorbent assay in a patient with chronic graft-versus-host disease after allogeneic bone marrow transplantation. Bone Marrow Transplant. 28:633-643.[CrossRef][Medline]
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4. Milkiewicz, P., B. Gunson, S. Saksena, M. Hathaway, S. Hubscher, and E. Elias. 2000. Increased incidence of chronic rejection in adult patients transplanted for autoimmune hepatitis: assessment of risk factors. Transplantation 70:477-480.[Medline]
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5. Paterson, D. L., and N. Singh. 1999. Invasive aspergillosis in transplant recipients. Medicine 78:123-138.[CrossRef][Medline]
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6. Singh, N., P. M. Arnow, A. Bonham, E. Dominguez, D. L. Paterson, G. A. Pankey, M. M. Wagener, and V. L. Yu. 1997. Invasive aspergillosis in liver transplant recipients in the 1990s. Transplantation 64:716-720.[Medline]
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7. Starzl, T. E., N. Murase, K. Abi-Elmagd, E. A. Gray, R. Shapiro, B. Eghtesad, R. J. Corry, M. L. Jordan, P. Fontes, T. Gayowski, G. Bond, V. P. Scantlebury, S. Patdor, P. Randhawa, T. Wu, A. Zeevi, M. A. Nalesniki, J. Woodward, A. Marcos, M. Trucco, A. J. Demetris, and J. J. Fong. 2003. Tolerogenic immunosuppression for organ transplantation. Lancet 361:1502-1510.[CrossRef][Medline]

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Journal of Clinical Microbiology, January 2004, p. 435-438, Vol. 42, No. 1
0095-1137/04/$08.00+0     DOI: 10.1128/JCM.42.1.435-438.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kwak, E. J. Articles by Singh, N. Search for Related Content PubMed PubMed Citation Articles by Kwak, E. J. Articles by Singh, N.