1.       Alexander B.D. Diagnosis of fungal infection: New technologies for the mycology laboratory. Transplant Infectious Disease 4 (Supplement 3):32-37 (2002)

2.       Ascioglu S., Rex J. H., de Pauw B., Bennett J. E., Bille J., Crokaert F., Denning D. W., Donnelly J. P., Edwards J. E., Erjavec Z., Fiere D., Lortholary O., Maertens J., Meis J. F., Patterson T. F., Ritter J., Sellesag D., Shah P. M., Stevens D. A., and Walsh T. J. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: An international consensus. Clinical Infectious Diseases 34:7-14 (2002)

3.       Cheung N. V., Modak S., Vickers A., and Knuckles B. Orally administered b-glucans enhance anti-tumor effects of monoclonal antibodies. Cancer Immunology Immunotherapy 51:557-564 (2002)

4.       Chiba M., Mikami K., Iizuka M., Yukawa M., Watanabe S., Takazoe M., FukushimaT., Koganei K., and Kishibe T. Elevated plasma (1,3)-ß-D-glucan, a fungal cell wall constituent, in a subgroup of Crohns Disease. Scandinavian Journal of Gastroenterology 36(4):447-448 (2001)

5.       Hong F., Hansen R. D., Yan J., Allendorf D. J., Baran J. T., Ostroff G. R., and Ross G. D. b-glucan functions as an adjuvant for monoclonal antibody immunotherapy recruiting tumoricidal granulocytes as killer cells. Cancer Research 63:9023-9031 (2003)

6.       Hossain M. A., Miyazaki T., Mitsutake K., Kakeya H., Yamamoto Y., Yanagihara K., Kawamura S., Otsubo T, Hirakata Y., Tashiro T., and Kohno S. Comparison between Wako-WB003 and Fungitec G tests for the detection of (1,3)-ß-D-glucan in systemic mycosis. Journal of Clinical Laboratory Analysis 11:73-77 (1997)

7.       Ikemura K., Ikegami K., Shimazu T., Yoshioka T., and Sugimoto T. False positive result in limulus test caused by limulus amebocyte lysate reactive material in immunoglobulin products. Journal of Clinical Microbiology 27(9):1965-1968 (1989)

8.       Ishizuka Y., Tsukada H., Gejyo F. Interference of (1,3)-ß-D-glucan administration in the measurement of plasma (1,3)-ß-D-glucan. Internal Medicine. 43(42):97-101 (2004)

9.       Iwama A., Yoshida M., Miwa A., Obayashi T., Sakamoto S., and Miura Y. Improved survival from fungaemia in patients with haematological malignancies: Analysis of risk factors for death and usefulness of early antifungal therapy. European Journal of Haematology 51:156-160 (1993)

10.   Jones B., and McLintock L. Impact of diagnostic markets on early antifungal therapy. Current Opinion in Infectious Disease 16:521-526 (2003)

11.   Kami M., Tanaka Y., Kanda Y., Ogawa S., Masumoto T., Ohtomo K., Matsumura T., Saito T., Machida U., Kashima T., and Hirai H. Computed tomographic scan of the chest, latex agglutination test and plasma (1,3)-ß-D-glucan assay in early diagnosis on invasive pulmonary aspergillosis: A prospective study of 215 patients. Haematologica 85:745-752 (2000)

12.   Kato A., Takita T., Furuhashi M., Takahashi T., Maruyama Y., and Hishida A. Elevation of blood (1,3)-ß-D-glucan concentrations in hemodialysis patients. Nephron 89:15-19 (2001)

13.   Kawayama T., Fujiki R., Honda J., Rikimaru T., and Aizawa H. High concentration of (1,3)-ß-D-glucan in BAL fluid in patients with acute eosinophilic pneumonia. Chest Journal123:1302-1307 (2003)

14.   Kimura Y., Nakao A., Tamura H., Tanaka S., and Takagi H. Clinical and experimental studies of the limulus test after digestive surgery. Japan J. Surg. 25:790-794 (1995)

15.   Kondori N., Edebo L., and Mattsby-Baltzer I. Circulating (1,3)-ß-D-glucan and Immunoglobin G subclass antibodies to candia albicans cell wall antigens in patients with systemic candidiasis. Clinical and diagnostic Laboratory Immunology. 11(2):344-350 (2004)

16.   Kusanagi H., Shimura T., and Teramoto A. The usefulness of fluconazole administration and b-D-glucan measurement in neurosurgical patients with deep-seated mycosis. No Shinkei Geka 28(8):685-690 (2000)

17.   Matsumoto Y., Matsuda S., and Tegoshi T. Yeast glucan in the cyst wall of pneumocystis carinii. Journal of Protozool. 36(1):215-225 (1989)

18.   Mitsutake K., Miyazaki T., Tashiro T., Yamamoto Y., Kakeya H., Otsubo T., Kawamura S., Hossain M. A., Noda T., Hirakata Y., and Kohno S. Enolase antigen, mannan antigen, candtec antigen, and beta-glucan in patients with candidemia. Journal of Clinical Microbiology 34(8):1918-1921 (1996)

19.   Miyazaki T., Kohno S., Koga H., Kaku M., Mitsutake K., Maesaki S., Yasuoka A., Hara K., Tanaka S., and Tamura H. G test, a new direct method for diagnosis of candida infection: Comparison with assays for beta-glucan and mannan antigen in a rabbit model of systemic candidasis. Journal of Clinical Laboratory analysis 6:315-318 (1992)

20.   Miyazaki T., Kohno S., Mitsutake K., Maesaki S., Tanaka K., and Hara K. (1,3)-ß-D-glucan in culture fluid of fungi activates factor G, a limulus coagulation factor. Journal of Clinical Laboratory Analysis 9:334-339 (1995)

21.   Miyazaki T., Kohno S., Mitsutake K., Maesaki S., Tanaka K., Ishikawa N., and Hara K. Plasma (1,3)-ß-D-glucan and fungal antigenemia in Patients with candidemia, aspergillosis, and cryptococcosis. Journal of Clinical Microbiology December:3115-3118 (1995)

22.   Nakao A., Kato H., Kanbe T., Tanaka K., Tamura H., Tanaka S., and Takagi H. Quantitative assay of (1,3)-ß-D-glucan in culture media of candida albicans using the G-test. European Surgical Journal 26:194-200 (1994)

23.   Nakao A., Tamura H., Tanaka S., Kawagoe T., and Takagi H. (1,3)-ß-D-glucan determination in rat organs with limulus coagulation factor G. Research in Experimental Medicine 196:339-343 (1997)

24.   Nakao A., Yasui M., Kawagoe T., Tamura H., Tanaka S., and Takagi H. False-positive endotoxemia derives from gauze glucan after hepatectomy for hepatocellularcarcinoma with cirrhosis. Hepato-Gastroenterology 44:1413-1418 (1997)

25.   Nichterlein T., Buchheidt D., Hein A., Becker K. P., Mosbach K., and Kretschmar M. Comparison of glucan detection and galactomannan enzyme immunoassay in gastrointestinal ans systemic murine candidiasis. Diagnostic Microbiology and Infectious Disease. 46:103-108 (2003)

26.   Obayashi T., Yoshida M., Tamura H., Aketagawa J., Tanaka S., and Kawai T. Determination of plasma (1,3)-ß-D-glucan: A new diagnostic aid to deep mycosis. Journal of Medical and Veterinary Mycology 30:275-280 (1992)

27.   Obayashi T., Yoshida M., Mori T., Goto H., Yasuoka A., Iwasaki H., Teshima H., Kohno S., Horiuchi A., Ito A., Yamaguchi H., Shimada K., and Kawai T. Plasma (1,3)-ß-D-glucan measurement in diagnosis of invasive deep mycosis and fungal febrile episodes. The Lancet 345:17-20 (1995)

28.   Odabasi Z., Mattiuzzi G., Estey E., Kantarjian H., Saeki F., Ridge R., Ketchum P., Finkelman M., Rex J. and Ostrosky-Zeichner L. (2004) Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: Validation, cutoff development, and performance in patients with Acute Myelogenous Leukemia and Myelodysplastic Syndrome. Clinical Infectious Diseases. 39:199-205.

29.   Reiss E., Obayashi T., Orle K., Yoshida M., and Zancope-Oliveira R. M. Non-culture based diagnostic tests for mycotic infections. Medical Mycology 38(1):147-159 (2000)

30.   Tamura H., Arimoto Y., Tanaka S., Yoshida, Obayashi T., and Kawai T. Automated kinetic assay for endotoxin and (1,3)-ß-D-glucan in human blood. Clinica Chimica Acta 226:109-112 (1994)

31.   Tanaka S., Aketagawa J., Takahashi S., Shibata Y., Tsumuraya Y., and Hashimoto Y. Activation of limulus coagulation factor G by (1,3)-ß-D-glucans. Carbohydrate Research 218:167-174 (1991)

32.   Usami M., Ohata A., Horiuchi T., Nagasawa K., Wakabayashi T., and Tanaka S. Positive (1,3)-ß-D-glucan in blood components and release of (1,3)-ß-D-glucan from depth-type membrane filters for blood processing. Transfusion 42:1189-1195 (2002)

33.   Verweij, P.E., and Meis J.F.G.M. Microbiological diagnosis of invasive fungal infections in transplant recipients. Transplant Infectious Disease 2:80-87 (2000)

34.   Yasuoka A., Tachikawa N., Shimada K., Kimura S., and Oka S. (1,3)-ß-D-glucan as a quantitative serological marker for pneumocyitis carinni pneumonia. Clinical and Diagnostic Laboratory Immunology 3(2):197-199 (1996)

35.   Yoshida M., Roth R., Grunfeld C., Feingold K., and Levin J. Soluble (1,3)-ß-D-glucan purified from candida albicans: Biologic effects and distribution in blood and organs in rabbits. Journal of Laboratory Clinical Medicine 128 (1):103-114 (1996)

36.   Yoshida M., Roth R., Grunfeld C., Feingold K., and Levin J. Pharmacokinetics, biological effects and distribution of (1,3)-ß-D-glucan in blood and organs in rabbits. Mediators of Inflammation 6:279-283 (1997)

37.   Yoshida, M. Obayashi T., Iwama A., Ito M., Tsunoda S., Suzuki T., Muroi K., Ohta M., Sakamoto S., and Miura Y. Detection of plasma (1,3)-ß-D-glucan in patients with fusarium, trichosporon, saccharomyces and acremonium fungaemias. Journal of Medical & Veterinary Mycology 35:371-374 (1997)

38.   Yoshia M. Infections in patients with hematological diseases: Recent advances in serological diagnosis and empiric therapy. International Journal of Hematology 66:279-289 (1997)

39.   Yuasa K., and Goto H. (1,3)-ß-D-glucan in patients with pulmonary aspergilloma. Mediators of Inflammation Vol. 6:285-287 (1997)

40.   Pazos C., Ponto J., and Del Palacio A. Contribution of (1,3)-ß-D-glucan chromogenic assay to diagnosis and therapeutic monitoring of invasive aspergillosis in neutropenic adult patients: A comparison with serial screening for circulating galactomanna. Journal of Clinical Microbiology 43(1): 299-305 (2005)


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reference abstracts

The following articles are available by request.  To request a full text reprint of the article, click on the link and fill out the information request form.  Be certain to indicate which article you are requesting.  We must have a mailing address in order to send the article.  Article reprints are only available in printed form. 

1. Diagnosis of fungal infection: new technologies for the mycology laboratory.

Alexander BD.

Transplant Infectious Diseases Services, Clinical Mycology Laboratory, Duke University Medical Center, Durham, NC 27710, USA. alexa011@mc.duke.edu

Abstract: The dramatic increase in nosocomial invasive mycoses over the past two decades has led to increased interest in the area of antifungal development. Unfortunately, the infusion of new diagnostic technology into the clinical mycology laboratory has lagged behind. Although newer, automated, continuous-monitoring blood culture systems are as sensitive as the older, manual "gold standard" system, the recovery of fungi from blood, as well as other clinical specimens, remains an insensitive marker for invasive fungal infection. Antigen assays for the rapid diagnosis of invasive fungal infections are in development, and galactomannan and glucan are two such promising antigens. Glucan may be present in the blood of patients with infection secondary to a wide variety of fungal pathogens, including Candida, Aspergillus, Fusarium, Saccharomyces, Trichosporon and Acremonium species. Early data suggest galactomannan may be present in the blood in detectable levels very early in the course of invasive aspergillosis. The galactomannan assay currently undergoing evaluations may actually be positive prior to the clinical suspicion for infection and may be useful in monitoring therapeutic response as well; however, the etiology of false-positive results following cytotoxic chemotherapy still has to be elucidated. PCR assays are also being developed in the research laboratory, however, the PCR assays will require a significant amount of adaptation and validation before they are ready for clinical care. Well-planned studies to evaluate the performance characteristics as well as appropriate clinical and cost-effective application of these new tests are needed.
 

2. Plasma (1,3)-ß-D-glucan and fungal antigenemia in patients with candidemia, aspergillosis, and cryptococcosis.

T Miyazaki, S Kohno, K Mitsutake, S Maesaki, K Tanaka, N Ishikawa, and K Hara

Second Department of Internal Medicine, Nagasaki University School of Medicine, Japan.

(1,3)-ß-D-Glucan is one of the major structural components of fungi, and it seems that it can be detected by the fractionated (1,3)-ß-D-glucan-sensitive component from a Limulus lysate, factor G. We evaluated the concentration of (1,3)-ß-D-glucan by using factor G and other fungal antigens in 24 patients with clinical evidence of mycosis and 36 healthy subjects. The mean concentration of (1,3)-ß-D-glucan in the plasma of the healthy subjects was found to be 2.7 +/- 1.9 pg/mL (range, < 6.9 pg/mL), and it was found to be substantially higher in all 11 patients with candidemia (mean, 2,207.4 pg/mL; range, 325.4 to 8,449.0 pg/mL). Eight of those 11 patients with candidemia (73%) were positive for the Cand-Tec heat-labile candida antigen and only 3 patients (27%) were positive for mannan antigen. Three patients with invasive pulmonary aspergillosis were positive for galactomannan and had, in addition, high concentrations of (1,3)-ß-D-glucan (mean, 323.3 pg/mL; range, 27.0 to 894.0 pg/mL). All 10 patients with cryptococcosis (including 2 patients with probable cryptococcosis) were positive for cryptococcal antigen by the Eiken latex test; however, (1,3)-ß-D-glucan levels were not elevated in these patients (mean, 7.0 pg/mL; range, < 16.5 pg/mL). Our results indicated that (1,3)-ß-D-glucan levels are elevated in patients with candidiasis and aspergillosis but not in those with cryptococcosis.

3. Impact of diagnostic markers on early antifungal therapy.

Jones BL, McLintock LA.

Department of Medical Microbiology, North Glasgow Hospitals University NHS Trust, Royal Infirmary, University of Glasgow, Glasgow, UK. b.l.jones@clinmed.gla.ac.uk

Purpose of Review The early treatment of invasive fungal infection is critical but is hampered by the non-specific nature of clinical and radiological signs and the insensitivity of current laboratory diagnostic methods. If mortality due to invasive fungal infection is to be reduced, new, preemptive therapeutic strategies, targeting those patients at highest risk, are required and these will depend on the development of rapid, sensitive diagnostic methods. Such methods have become available in the form of high-resolution computed tomography scanning and serological and molecular techniques and in this review the authors describe recent studies assessing the utility of these methods and consider their role in management strategies.

Recent Findings: Sensitive assays for the detection of fungal DNA and antigens such as galactomannan and glucan have been prospectively evaluated in the clinical setting and enable identification of patients at an earlier stage of infection. However, the sensitivity and specificity of the assays vary considerably in different studies, depending on several factors including patient selection and clinical application of the test, and issues regarding the release and circulation of galactomannan and fungal DNA remain to be clarified.

Summary: Rapid serological and molecular diagnostic methods facilitate the early diagnosis of invasive fungal infection and would appear to be most useful when used prospectively to screen high-risk patients. However, in order to determine the optimal approach to treatment it is essential that these tests are incorporated into management strategies and their impact on incidence of invasive fungal infection and clinical outcome evaluated in further clinical trials. 

5. Plasma (1,3)-ß-D-glucan measurement in diagnosis of invasive deep mycosis and fungal febrile episodes.

Obayashi, T., Yoshida, M., Mori, T., Goto, H. Yasuoka, A., Iwasaki, H., Teshima, H., Kohno, S., Horichi, A., Ito, A., Yamaguchi, H., Shimada, K., and Kawai, T. (1995)

Summary

(1,3)-ß-D-glucan is a characteristic fungal cell-wall constituent. To assess the clinical usefulness of this glucan in screening for invasive fungal infection or fungal febrile episodes, we measured the plasma concentration at the time of routine blood culture in 202 febrile episodes by means of factor G , a horseshoe-crab coagulation enzyme that is extremely sensitive to this polysaccharide.

With a plasma cut-off value of 20 pg/mL, 37 of 41 episodes of definite fungal infections (confirmed at necropsy or by microbiology) had positive results (sensitivity 90%). All of 59 episodes of non-fungal infections, tumour fever, or collagen diseases had concentrations below the cut-off value (specificity 100%). Of 102 episodes of fever of unknown origin, 26 had plasma glucan concentrations of more than 20 pg/mL. With those 102 cases taken as non-fungal infections, the positive predictive value of the test was estimated as 59% (37/63), the negative predictive value as 97% (135/139), and the efficiency as 85% 9172/202). The positive predictive value should improve if there were a sensitive gold standard that could discriminate fungal from non-fungal infections. Causative fungi included candida, aspergillus, cryptococcus, and trichosporon.

Determination of plasma (1,3)-ß-D-glucan with factor G is a highly sensitive and specific test for invasive deep mycosis and fungal febrile episodes, and will substantially benefit immunocompromised patients.

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6. (1,3)-ß-D-glucan in patients with pulmonary aspergilloma.

Yuasa K., and Goto H. (1997)

Division of Hematology, Department of Medicine and Department of Clinical Pathology, Jichi Medical School, Minamikawachi-machi, Tochigi-ken, Japan, 329-04

Abstract: To elucidate the role of (1,3)-ß-D-glucan in pulmonary aspergilloma, serum concentrations of (1,3)-ß-D-glucan were measured repeatedly for as long as 10 months in eight patients. In four patients with inactive disease, concentrations of (1,3)-ß-D-glucan were in the normal range.The concentrations of (1,3)-ß-D-glucan increased in two patients, although the disease was inactive. This increase might show the earliest stage of the invasive process of the disease. In two other patients with active disease, (1,3)-ß-D-glucan increased. Other parameters, such as galactomannan, immunodiffusion and a radio-allergosorbent test, as well as inflammatory markers such as C-reactive protein and the leukocyte count, did not show any consistent tendency in regard to the activity of the disease. Thus, a (1,3)-ß-D-glucan assay may add valuable data for evaluating the disease activity and understanding the disease process of pulmonary aspergilloma.

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7. Detection of plasma (1,3)-beta-D-glucan in patients with Fusarium, Trichosporon, Saccharomyces and Acremonium fungaemias.

Yoshida M, Obayashi T, Iwama A, Ito M, Tsunoda S, Suzuki T, Muroi K, Ohta M, Sakamoto S, Miura Y. (1997)

Department of Medicine, Jichi Medical School, Tochigi-ken, Japan.

Abstract: (1,3)-ß-D-glucan, a characteristic fungal molecule, is known to increase in blood in invasive candidiasis, aspergillosis and cryptococcosis. This report shows that the plasma glucan concentration was also elevated in four patients infected with Fusarium, Trichosporon beigelii, Saccharomyces cerevisiae and Acremonium. In three of the patients, the elevation preceded positive blood cultures by 5-17 days, and in one of them it even preceded the onset of fever by 6 days. In a fourth patient, the glucan level decreased with clinical improvement. Plasma (1,3)-ß-D-glucan determination appears to be useful also for diagnosis and follow-up of these unusual deep mycoses.

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8. Contribution of (1,3)-beta-D-glucan chromogenic assay to diagnosis and therapeutic monitoring of invasive aspergillosis in neutropenic adult patients: A comparison with serial screening for circulating galactomannan.

Pazos C, Ponton J, Del Palacio A.

Unidad de Micologia, Departamento de Microbiologia, Hospital Universitario 12 de Octubre, Avenida de Cordoba s/n, 28041 Madrid, Spain. pazos.c@terra.es

Abstract: Two noninvasive diagnostic tests, (1,3)-ß-D-glucan (BG) (Glucatell) and galactomannan (GM) (Platelia Aspergillus), were used retrospectively in a twice-weekly screening for the diagnosis of invasive aspergillosis (IA) in 40 treatment episodes (one hospital visit per patient) in 40 neutropenic adult patients at high risk for IA. Five proven IA cases, three probable IA cases, and three possible IA cases were diagnosed. Diagnostic levels of both BG and GM were detected in 100% of patients with proven IA cases and in 66% of patients with probable IA cases. The kinetics of both markers in patients with IA were similar. The sensitivity, specificity, and positive and negative predictive values for GM and BG were identical, namely, 87.5, 89.6, 70, and 96.3%, respectively. False-positive reactions occurred at a rate of 10.3% in both tests, but the patients showing false-positive results were different in each test. Both tests anticipated the clinical diagnosis, computed tomography abnormalities, and the initiation of antifungal therapy in most patients, but BG tended to become positive earlier than GM. A combination of the two tests improved the specificity (to 100%) and positive predictive value (to 100%) of each individual test without affecting the sensitivity and negative predictive values. In conclusion, BG and GM detection are useful tests for the diagnosis of IA in high-risk hematological patients, but a combination of the two tests was very useful to identify false-positive reactions by each test.

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resource links

Dr. Fungus	www.doctorfungus.org
The Aspergillus Website	www.aspergillus.man.ac.uk
NIH - Medline Plus	http://www.nlm.nih.gov/medlineplus/ fungalinfections.html
PubMed	http://www.ncbi.nlm.nih.gov/entrez/query.fcgi

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