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Aspergillosis


Definition

Aspergillosis is a large spectrum of diseases caused by members of the genus Aspergillus(see Table below). The three principal entities are: allergic bronchopulmonary aspergillosis, pulmonary aspergilloma and invasive aspergillosis [2163]. Colonization of the respiratory tract is also common. The clinical manifestation and severity of the disease depends upon the immunologic state of the patient [218]. Lowered host resistance due to such factors as underlying debilitating disease, neutropenia chemotherapy, disruption of normal flora, and an inflammatory response due to the use of antimicrobial agents and steroids can predispose the patient to colonization, invasive disease, or both [458, 830, 1581]. Aspergillus spp. are frequently secondary opportunistic pathogens in patients with bronchiectasis, carcinoma, other mycoses, sarcoid, and tuberculosis [779, 2081, 2148].

Forms of the disease

Categories Sites Involved
Colonization Sinuses, lungs
Toxicoses  
Allergic bronchopulmonary aspergillosis Sinuses, lungs
Pulmonary aspergilloma Pre-existing lung cavity
Invasive aspergillosis - Pulmonary aspergillosis 1
- CNS aspergillosis
- Sinonasal aspergillosis
- Osteomyelitis
- Endophthalmitis
- Endocarditis
- Renal abscesses
- Cutaneous
Others - Cutaneous: burns, post surgical wounds, IV insertion sites, etc.
- Otomycosis
- Exogenous endophthalmitis
- Allergic fungal sinusitis
- Urinary tract fungus balls
1This is the most common site of primary invasive aspergillosis.



Prognosis and therapy

Special resources: You may also want to refer to the Infectious Disease Society of America-Mycoses Study Group (IDSA-MSG) Practice Guidelines for this disease. It is available at the IDSA website. In addition, The Aspergillus web site offers an in-depth look into all aspects of invasive aspergillosis.

Prognosis depends upon the type and severity of disease as well as the immunological status of the patient [2163]. Allergic aspergillosis is typically a chronic entity, but evolves from episodes of acute corticosteroid-responsive asthma to fibrotic end-stage lung disease [1734]. Allergic aspergillosis has been successfully treated with corticosteroids, and intraconazole [2164]. The prolonged use of steroids in cases of chronic aspergillosis should be approached with caution [2163].

Aspergillomas may be treated by surgical resection [575, 1163]. However, this approach may cause significant morbidity and mortality, therefore it should be reserved for patients at high risk to develop severe hemoptysis [852, 1462].

Invasive aspergillosis may be treated with voriconazole [1029], amphotericin B (deoxycholate and lipid preparations), and itraconazole [575, 2163]. The ability of voriconazole to effectively treat invasive aspergillosis and to reduce associated mortality was recently demonstrated by a large well-conducted randomized trial and is particulary noteworthy. A large number of new investigational drugs (posaconazole, ravuconazole, caspofungin, FK463, and anidulafungin (LY303366)) have activity against Aspergillus spp. and are being extensively evaluated. Caspofungin was also recently licensed in the United States for treatment of invasive aspergillosis in patients who are refractory to, or intolerant of other therapies (i.e., amphotericin B, lipid formulations of amphotericin B, and/or itraconazole) [1406]. However, despite these advances in therapy, the invasive forms of aspergillosis are often associated with significant morbidity and mortality [575].

Selection of therapy also needs to consider the certainty of the diagnosis. Voriconazole, itraconazole, the investigational azoles with anti-mould activity, and amphotericin B all possess a reasonably broad-spectrum of activity against Aspergillus and the related hyaline moulds. Their activity does, however, vary for the agents of zygomycosis, with posaconazole being the azole with the most reliable activity against this class of fungi. The echinocandin glucan synthesis inhibitors (caspofungin, FK463, and anidulafungin) possess a narrower spectrum of activity and should only be used if the infection is known to be due to Aspergillus spp.

Histopathology

The tissue reaction in aspergillosis is acute suppurative inflammation with areas of ischemic necrosis. The fungus proliferates as septate hyphae 2.5-4.5 µm in diameter . The hyphae can be characterized as branching dichotomously (approximately 45°C angle) with the overall appearance of an army on the march. The hyphae may branch irregularly and appear similar to hyphae found in zygomycosis. Blood vessel invasion, thrombosis, infarction, and dissemination are extremely common.

Laboratory

Direct examination
Clinical material, such as fluids, sputa, or tissue, is mounted in 10% KOH. Long, branching, hyaline, septate hyphae approximately 3.0 µm in diameter typify aspergillosis. The demonstration of hyphae in the clinical specimen and the repeated recovery of the same species of Aspergillus in culture is critical in supporting the diagnosis of aspergillosis. It must always be remembered that a number of other fungi can be morphologically identical to Aspergillus in tissue. On rare occasions, the hyphae of an Aspergillus sp. may have lateral conidia in tissue.
Isolation
Inoculate the clinical material onto Sabouraud glucose agar, Inhibitory Mould Agar (IMA) or other proper medium with antibiotics (gentamicin or chlorampenicol) and incubate at 30°C. The aspergilli are sensitive to cycloheximide, hence they will not grow on media containing this antimicrobial agent. Discard negative cultures after 4 weeks.
Mycology (principal fungi)
- Aspergillus flavus
- Aspergillus fumigatus
- Aspergillus glaucus group
- Aspergillus nidulans
- Aspergillus niger
- Aspergillus terreus group
Detection of galactomannan antigen in serum
The mortality rate of invasive aspergillosis is as high as 50-100% and definitive diagnosis by culture may take as long as 4 weeks. Thus, early diagnosis is of remarkable significance for earlier initiation of antifungal therapy and reduction of mortality rates. Detection of galactomannan antigen, an exoantigen of Aspergillus, has recently been shown to be a useful screening test for early diagnosis of invasive aspergillosis. Platelia Aspergillus EIA (Bio-Rad Laboratories) is a commercially available kit used to detect galactomannan antigen in body fluids. This method can detect as little as 1 ng/ml of galactomannan in the tested sample. Serum is the most frequently tested specimen and appears to provide highest sensitivity. Use of other samples such as bronchoalveolar lavage [2009] and cerebrospinal fluid [2315, 2333] also appears to provide promising results.

Galactomannan antigen positivity is among the microbiological diagnostic criteria proposed by European Organization for Research and Treatment of Cancer (EUORTC) and Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) for diagnosis of invasive aspergillosis [136]. This tool continues to gain acceptance: the US Food & Drug Administration approved the marketing of Platelia Aspergillus EIA kit in USA on 16 May 2003.

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) [2316]. The test should be used as a screening test for patients at high risk of developing invasive aspergillosis [1407, 1408]. Detection of positive results particularly in two consecutive serum samples provides strong support for the diagnosis of invasive aspergillosis. Platelia Aspergillus EIA can also be used for follow-up of clinical response to antifungal therapy. The titer of the antigen tends to decrease in case of clinical response [307], except for patients who are treated with an echinocandin compound [1766].

The overall sensitivity and specificity of the method were 80.7% and 89.2%, respectively, in the dataset submitted to the US FDA. False positive reactions have been observed in 1-18% of the tested samples and may be due to cross reactivity or false positive antigenemia. Cross reactivity may be due to the existence of other fungi, such as Penicillium chrysogenum, Penicillium digitatum, Rhodotorula rubra, and Paecilomyces variotii in the tested sample [2208]. The mechanism of false positive antigenemia, on the other hand, has not been fully clarified. It appears to be more frequent in children [1031, 1323] and may develop after translocation of galactomannan antigen found in various food stuff (bread, pasta, corn flakes, rice, cake, turkey, sausage, etc.) through the damaged intestinal mucosa [1323]. In addition to these, very recent data have shown that the serum samples of patients receiving piperacillin/tazobactam (Zosyn®), an injectable antibacterial combination product from Wyeth Pharmaceuticals, may also yield false positive galactomannan antigen test results. Detection of galactomannan antigen in certain batches of Zosyn® strengthened this finding. Thus, Bio-Rad, the manufacturer of the Platelia Aspergillus EIA kit, now states that positive galactomannan antigen test results in patients treated with Zosyn® should be interpreted cautiously. Since the existence of invasive aspergillosis cannot be ruled out in these patients, other methods should be used for confirmation of the diagnosis. You may refer to the practice caution document (released on November 20, 2003) concerning Zosyn® and the Platelia Aspergillus EIA test kit for more detailed information.

You may also want to review our subpage for more detailed information on the key data regarding the use of the galactomannan antigen test in the diagnosis of invasive aspergillosis.
Natural habitat

Aspergillus spp. are ubiquitous in the environment. They are especially common in the soil and decaying vegetation.

Susceptibility Testing

Susceptibility testing is not routinely used to guide therapy of aspergillosis. We offer both a general discussion of susceptibility testing and a searchable database from which you can retrieve specific results from a variety of published articles.

Related Sites and Therapy Information

  • The Aspergillus web site is an excellent and comprehensive resource on all aspects of diagnosis and management of invasive aspergillosis.
  • The Infectious Disease Society of America-Mycoses Study Group (IDSA-MSG) Practice Guideline for treating aspergillosis is available at the IDSA website.


Search for Aspergillosis articles

PubMed



Aspergillus flavus in sputum, PAS stain
PAS stained sputum of patient with Aspergillus flavus
Aspergillus fumigatus in GMS stained lung
GMS stained lung of patient with Aspergillus fumigatus

Gram stained cornea of patient showing Aspergillus flavus hyphae



References

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

218. Bennett, J. E. 1995. Aspergillus species, p. 2306-2310. In G. L. Mandell, J. E. Bennett, and R. Dolin (ed.), Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases, 4th edition ed. Churchill Livingstone, New York.

307. Boutboul, F., C. Alberti, T. Leblanc, A. Sulahian, E. Gluckman, F. Derouin, and P. Ribaud. 2002. Invasive aspergillosis in allogeneic stem cell transplant recipients: Increasing antigenemia is associated with progressive disease. Clin Infect Dis. 34:939-943.

458. Cohen, M. S., R. E. Isturiz, H. L. Malech, R. K. Root, C. M. Wilfert, L. Gutman, and R. H. Buckley. 1981. Fungal infection in chronic granulomatous disease. The importance of the phagocyte in defense against fungi. Am J Med. 71:59-66.

575. Denning, D. W., and D. A. Stevens. 1990. Antifungal and surgical treatment of invasive aspergillosis: Review of 2,121 published cases. Rev. Infect. Dis. 12:1147-1201.

779. Fujimura, M., Y. Ishiura, K. Kasahara, T. Amemiya, S. Myou, Y. Hayashi, Y. Watanabe, E. Takazakura, A. Nonomura, and T. Matsuda. 1998. Necrotizing bronchial aspergillosis as a cause of hemoptysis in sarcoidosis. Am J Med Sci. 315:56-8.

830. Gerson, S. L., G. H. Talbot, S. Hurwitz, B. L. Strom, E. J. Lusk, and P. A. Cassileth. 1984. Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann. Intern. Med. 100:345-351.

852. Glimp, R. A., and A. S. Bayer. 1983. Pulmonary aspergilloma. Diagnostic and therapeutic considerations. Arch Intern Med. 143:303-8.

1029. Herbrecht, R., D. W. Denning, T. F. Patterson, W. V. Kern, K. A. Marr, D. Caillot, E. Thiel, P. Ribaud, O. Lortholary, R. Greene, C. Durand, J. W. Oestmann, P. S. Stark, R. Sylvester, P. F. Troke, H. Schlamm, J. R. Wingard, R. H. Rubin, B. De Pauw, J. E. Bennett, and EORTC-IFIG. 2001. Open, randomised comparison of voriconazole and amphotericin B followed by other licensed antifungal therapy for primary therapy of invasive aspergillosis. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract No. J-680.

1031. Herbrecht, R., V. Letscher-Bru, C. Oprea, B. Lioure, J. Waller, F. Campos, O. Villard, K. L. Liu, S. Natarajan-Ame, P. Lutz, P. Dufour, J. P. Bergerat, and E. Candolfi. 2002. Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients. J Clin Oncol. 20:1898-1906.

1163. Kauffman, C. A. 1996. Quandary about treatment of aspergillomas persists [see comments]. Lancet. 347:1640.

1323. Letscher-Bru, V., A. Cavalier, E. Pernot-Marino, H. Koenig, D. Eyer, J. Waller, and E. Candolfi. 1998. Aspergillus galactomannan antigen detection with Platelia (R) Aspergillus: multiple positive antigenemia without Aspergillus infection. J Mycologie Medicale. 8:112-113.

1406. Maertens, J., I. Raad, C. A. Sable, A. Ngai, R. Berman, T. F. Patterson, D. Denning, and T. Walsh. 2000. Multicenter, noncomparative study to evaluate safety and efficacy of caspofungin in adults with aspergillosis refractory or intolerant to amphotericin B, amphotericin B lipid formulations, or azoles. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract No. 1103.

1407. Maertens, J., J. Van Eldere, J. Verhaegen, E. Verbeken, J. Verschakelen, and M. Boogaerts. 2002. Use of circulating galactomannan screening for early diagnosis of invasive aspergillosis in allogeneic stem cell transplant recipients. J Infec Dis. 186:1297-1306.

1408. Maertens, J., J. Verhaegen, K. Lagrou, J. Van Eldere, and M. Boogaerts. 2001. Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: a prospective validation. Blood. 97:1604-1610.

1462. Massard, G., N. Roeslin, J. M. Wihlm, P. Dumont, J. P. Witz, and G. Morand. 1992. Pleuropulmonary aspergilloma: clinical spectrum and results of surgical treatment [see comments]. Ann Thorac Surg. 54:1159-64.

1581. Morrison, V. A., R. J. Haake, and D. J. Weisdorf. 1993. The spectrum of non-Candida fungal infections following bone marrow transplantation. Medicine (Baltimore). 72:78-89.

1734. Patterson, R., P. A. Greenberger, R. C. Radin, and M. Roberts. 1982. Allergic bronchopulmonary aspergillosis: Staging as an aid to management. Ann. Intern. Med. 96:286-291.

1766. Petraitiene, R., V. Petraitis, A. H. Groll, T. Sein, R. L. Schaufele, A. Francesconi, J. Bacher, N. A. Avila, and T. J. Walsh. 2002. Antifungal efficacy of caspofungin (MK-0991) in experimental pulmonary aspergillosis in persistently neutropenic rabbits: Pharmacokinetics, drug disposition, and relationship to galactomannan antigenemia. Antimicrob. Agents Chemother. 46:12-23.

2009. Salonen, J., O. P. Lehtonen, M. R. Terasjarvi, and J. Nikoskelainen. 2000. Aspergillus antigen in serum, urine and bronchoalveolar lavage specimens of neutropenic patients in relation to clinical outcome. Scand J Infec Dis. 32:485-490.

2081. Severo, L. C., G. R. Geyer, and N. S. Porto. 1990. Pulmonary Aspergillus intracavitary colonization (PAIC). Mycopathologia. 112:93-104.

2148. Stanley, M. W., M. Deike, J. Knoedler, and C. Iber. 1992. Pulmonary mycetomas in immunocompetent patients: diagnosis by fine-needle aspiration. Diagn Cytopathol. 8:577-9.

2163. Stevens, D. A., V. L. Kan, M. A. Judson, V. A. Morrison, S. Dummer, D. W. Denning, J. E. Bennett, T. J. Walsh, T. F. Patterson, and G. A. Pankey. 2000. Practice guidelines for diseases caused by Aspergillus. Clin. Infect. Dis. 30:696-709.

2164. Stevens, D. A., H. J. Schwartz, J. Y. Lee, B. L. Moskovitz, D. C. Jerome, A. Catanzaro, D. M. Bamberger, A. J. Weinmann, C. U. Tuazon, M. A. Judson, T. A. E. Platts-Mills, A. C. DeGraff, Jr., J. Grossman, R. G. Slavin, and P. Reuman. 2000. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med. 342:756-762.

2208. Swanink, C. M. A., J. F. G. M. Meis, A. J. M. M. Rijs, J. P. Donnelly, and P. E. Verweij. 1997. Specificity of a sandwich enzyme-linked immunosorbent assay for detecting Aspergillus galactomannan. J. Clin. Microbiol. 35:257-260.

2315. Verweij, P. E., K. Brinkman, H. P. H. Kremer, B. J. Kullberg, and J. Meis. 1999. Aspergillus meningitis: Diagnosis by non-culture-based microbiological methods and management. J Clin Microbiol. 37:1186-1189.

2316. Verweij, P. E., J.-P. Latge, A. J. M. M. Rijs, W. J. G. Melchers, B. E. De Pauw, J. A. A. Hoogkamp-Korstanje, and J. F. G. M. Meis. 1995. Comparison of antigen detection and PCR assay using bronchoalveolar lavage fluid for diagnosing invasive pulmonary aspergillosis in patients receiving treatment for hematological malignancies. J. Clin. Microbiol. 33:3150-3153.

2333. Viscoli, C., M. Machetti, P. Gazzola, A. De Maria, D. Paola, M. T. Van Lint, F. Gualandi, and M. Truini. 2002. Aspergillus galactomannan antigen in the cerebrospinal fluid of bone marrow transplant recipients with probable cerebral aspergillosis. J Clin Microbiol. 40:1496-1499.



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