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Aspergillosis
Clinical
Microbiology Newsletter Vol. 4, N o . 2
January 154 1982
i
_t
Aspergillosis Norman L. Goodman, Ph.D. Professor and Director Clinical Microbiology Laboratories Department of Pathology University of Kentucky College of Medicine Lexington, Kentucky 40536 Aspergillosis is a complex ffroup of diseases caused by several species of Aspergillus. Aspergillus fumigatus is the most common etiologic agent of aspergillosis, with A. flavus, A. niger, A. clavatus, A. terreus and other species also causing infection. Types of Disease
Pulmonary aspergillosis is the most common form of disease. Basically, three forms of this disease are currently recognized: a) allergic aspergillosis, which may cause asthma-like symptoms or bronchitis with plugging of bronchi by mucds; b) aspergilloma, or "fungus ball," caused by growth of the fungus in pre-existing lung cavities, and c) invasive aspergillosis, in which the fungus invades tissue. The invasive form of the disease is usually found in patients with'impaired immunity, and the fungus may disseminate to any organ of the body, including the skin (13). Clinical symptoms of pulmonary aspergillosis usually include fever and cough, with bloodtinged sputum in aspergilloma. Aspergillosis is a common secondary disease of the compromised patient. It has been estimated that 5% of leukemia patients have
aspergillosis (10), which has been reported as a complication of a high percentage of organ transplants (13) as well as in many forms of cancer (9, 14). Ear infections (otomycosis) are usually caused by A. niger. These are benign conditions resulting from the growth of the fungus in the cerumen and debris in the external auditory canal. Sinus infections by aspergilli may result in a fungus ball lying free or attached to the sinus mucosa. Invasive sinusitis may occur in the maxillary sinuses, with erosion into adjoining structures and eventually into the meninges or brain. Trauma to the cornea by objects infested with Aspergilhts sp. may cause infection and subsequent invasion of the eye. Hematogenous spread of the fungus from other focal sites may result in endophthalmitis (5). The aspergilli are ubiquitous fungi found in soil, air, plant, and animal substrates (3). There is no apparent differential association of aspergillosis with age, sex, or race. The disease is noncommunicable and has a worldwide distribution. Infection occurs from inhaling spores of the fungus or by inoculation with material containing fungal elements (4, 12).
Collection of proper specimens from patients with suspected aspergillosis depends on the type of disease and the site of the lesion(s). As with all opportunistic organisms, contamination by aspergillus spores that are transient or colonizing must be avoided if possible. When possible, tissue from the infected site should be excised under aseptic conditions and submitted for histopathologic examination and culture. Specimens such as sputum and exudates should be collected as aseptically as possible and processed immediately for microscopic examination and culture. When attempting to obtain a diagnosis from sputum specimens, multiple specimens should be collected, preferably early in the morning, on consecutive days. The patient's mouth should be thoroughly cleaned before collecting sputum. Blood, spinal fluid, and urine specimens rarely yield aspergilli in infections.
Specimen Collection
Nitrate Reductase-Negative Mycobacterium Tuberculosis . . . . . 12
Since aspergilli are found universally in the environment and aspergillosis is an opportunistic disease, specimen collection and handling are critical steps in reaching a correct diagnosis (1, 6).
In This Issue Aspergillosis . . . . . . . . . . . . . . . . . . . .
9
Review o f the disease and diagnostic methods Politics and Microbiologists . . . . . . Should you be involved?
11
A biochemical variant causing disease in a patient with Hodgkin's disease Letters . . . . . . . . . . . . . . . . . . . . . . . .
14
Positions . . . . . . . . . . . . . . . . . . . . . .
16
Diagnostic Procedures Direct Microscopy Direct microscopic examination of a freshly collected specimen is often rewarding in making a diagnosis. Small portions of the specimen should be examined for the presence of hyphae or hyphal elements. Opaque, specimens should be clarified with 10% KOH. Clear specimens may be observed directly or stained by the lactophenol cotton blue method. Aspergilli grow in vivo in the hyphal form only; therefore, if the fungus is growing in the tissue from which the specimen came, it will appear in the specimen as branching, septate hyphae, 5-6 nm in diameter. The hyphae may appear pleomorphic and have enlarged, rounded segments. Often, the hyphae will fragment, and these septate fragments will be distributed throughout the specimen.
Histopathological examination A definitive diagnosis of invasive aspergillosis can only be made by demonstrating the fungus in tissue. A portion of all tissue should be submitted for histopathologic study. Tissue should be stained by the periodic acid-Schiff and methenamine silver methods. Aspergilli in tissue will appear as septate hyphae with acute angle branching. However, these morphological features are also characteristic of other members of the Ascomycetes, which also may cause opportunistic disease. Therefore, all tissue should be cultured in order to obtain a specific identification of the etiologic agent.
Culture methods The aspergilli grow well on all enriched laboratory media. The medium of choice for isolation and preliminary identification of these fungi from clinical specimens is Sabouraud agar. Plated media should be used when culturing specimens that are likely to contain mixed flora. Aspergillus species grow relatively rapidly on
Sabouraud agar, with colonies appearing in 3-4 days when incubated at 25-30 ° C. As indicated above, colonial morphology and pigmentation vary greatly depending on the species. All aspergilli produce septate hyphae and conidiophores enlarged at the tips to form vesicles; the latter are covered with sterigmata, which in turn bear chains of conidia. The criteria for identifying an isolate include: colony texture; color; rate of growth; conidiophore morphology, including the number of rows of sterigmata; conidial characters relative to size, shape, and arrangement on heads; and characteristics of any cleistothecia and ascospores. These characteristics, as exhibited on Czapek-Dox agar, are essential for speciation. The monograph by Raper and Fennell on The Genus Aspergilhts should be consulted for a detailed description of all the groups and species (11). Other references containing less detailed keys may also be useful (1, 4, 12).
Serologic Procedures Detection and quantitation of antibodies by serologic methods may assist the physician in diagnosing aspergillosis. However, it must be emphasized that positive serologic results alone are not diagnostic. Conversely, a negative serologic test does not rule out disease. Patients with allergic bronchopulmonary aspergillosis often have serum precipitins, detectable in the immunodiffusion (ID) test (7). Those with aspergilloma almost always produce large quantities of IgG, detectable by the ID method (7). Multiple bands are usually observed. The usefulness of serologic methods in invasive aspergillosis has not been established. Results of the complement fixation (CF) test usually agree with those of the ID test and may be obtainable earlier in the course of disease. Additionally, quantitation of antibody is provided by the CF test. Because of the availability of ID reagents and the simplicity of the
test, it is advisable to screen with the ID test and submit the serum to a reference laboratory for CF testing. The value of serologic tests for extrapulmonary aspergillosis has not been established. Because aspergillosis is primarily an opportunistic disease and the host may not be capable of mounting an immunologic response, work is being done to detect Aspergillus antigen in the host (8). These tests are still experimental and not available for general use. However, they do offer promise of better diagnostic methods in the future.
Treatment Amphotericin B is the drug of choice for forms of aspergillosis (primarily the invasive form) that allow the drug to reach the site of infection. Surgical excision is indicated for colonized sinuses, brain abscesses, cardiac valves, pulmonary aspergillomas, and other sites where removal of the organism would prevent possible spread by invasion (2). 5-Fluorocytosine has been used to treat various forms of aspergillosis; however, its efficacy has not been established. Miconazole and ketaconazole are drugs of the imidazole group with reported success for the treatment of aspergillosis. Their usefulness has not been well established. Testing the susceptibility of aspergilli to these drugs is not standardized; thus, results from such testing are subject to interpretation. Agar dilution methods appear to be the method of choice for susceptibility testing.
Evaluation of Laboratory Findings Since aspergilli can be isolated readily from the environment, and infection by these fungi is usually in a compromised host, the presence of these fungi in clinical specimens must be interpreted cautiously. Unless the aspergilli are observed growing in tissue, there is always some doubt as to the etiologic status of the fungus. When an infection is suspected, and the organism is isolated from
sputum or other specimens that may contain transient aspergilli, results o f serologic tests may be helpful. Demonstration of precipitins or complement-fixing antibodies to aspergilli indicates active disease and gives added weight to the importance of isolating the fungus from clinical specimens. Multiple isolations o f aspergilli, even without positive serology, should warrant a call to the patient's physician to determine the clinical and immunologic status of the patient. References 1. AustwJck, P. K. C., and J. L. Longsbottom. 1980. Medically important Aspergillus species, pp. 620-627. In E. H. Lennette, et al. (eds.), Manual of clinical microbiology, 3rd ed. American Society for Microbiology, Washington, D.C. 2. Bennett, J. E. 1979. Aspergillus species, pp. 2001-2008. In G_L. Mondell, et al. (eds.), Principles and
3.
4. 5.
6.
7.
8.
practice of infectious diseases. John Wiley and Sons, New York. Cooke, W. B. 1971. Our mouldy earth. U.S. Department of the Interior, Federal Water Pollution Control Administration, Cincinnati, Ohio. Emmons, C. W., et al. 1977. Medical mycology. 3rd ed. Lea and Febiger, Philadelphia. Francois, J., and M. Rysselaere. 1972. Oculomycoses. Charles C. Thomas, Springfield, Ill. Goodman, N. L. 1981. Opportunistic mycoses, pp 1071-1092. In A. Balows and W. J. Hausler, Jr. (eds.), Diagnostic procedures for bacterial, mycotic and parasitic infections, 6th ed. American Public Health Association, Washington, D.C. Kaufman, L. 1980. Serodiagnosis of fungal diseases, pp 628-646. In E. H. Lennette, et al. (eds.), Manual of clinical microbiology. American Society for Microbiology, Washington, D.C. Lehman, P. F., and E. Relss. 1978. Invasive aspergillosis: Anti-
9. 10. 11.
12.
13.
14.
serum for circulating antigen produced after immunization with serum from infected rabbits. Infect. Immun. 20:570. Meyer, R. I., et al. 1973. Aspergillosis complicating neoplastic disease. Am. J. Med. 54:6-15. Mirsky, H. S., and J. Cuttnor. 1972. Fungal infections in acute leukemia. Cancer 30:1348-1352. Raper, K. B., and D. I. Fennell. 1965. The genus Aspergillus. Williams and Wilkins Co., Baltimore, Md. Rippon, J. W. 1974. Medical mycology: The pathogenic fungi and the pathogenic actinomycetes. W. B. Saunders Co., Philadelphia. Williams, D. M., J. A. Krick, and J. S. Remington. 1976. Pulmonary infection in the compromised host. Am. Rev. Respir. Dis. 114:359-394. Young, R. C., et al. 1970. Aspergillosis: The spectrum of the disease in 98 patients. Medicine 49: 147-213.
Editorial
P o l i t i c s a n d the M i c r o b i o l o g i s t
Robert D. Watkins Director, Public Affairs American Society for Microbiology Washington, D.C. Our representative system o f government places a special responsibility on individual citizens and on the many special interest groups that make up the complex society of the United States. These individuals have not only the right but also the obligation to make themselves heard in Washington. Representation of viewpoints is an inseparable part of the American political system. It is a communication process involving the advancement o f a position, supported by solid facts and figures. As long as the representation is clear as to its intention and honest and complete in presentation, government will be aided in its efforts to reach responsible-decisions on issues that often encompass conflicting interests. For the scientific community, the process is more important now than
ever. The m o o d o f the American people is to cut the federal budget. Science is going to have a continual struggle to maintain stability and modest growth in the budget for research, improved clinical laboratory services, and other health and science-related areas. The fact is that the FY 1982 budget is still in difficulty, and the FY 1983 budget is now in worse shape with the political reality of the 1980 election year and increasing pressure on Congress to balance the budget. As a result, legislative and regulatory actions that affect the scientific community have increased greatly in complexity and impact. Our representatives in Washington and officials in federal departments a n d , agencies need information from knowledgeable persons on issues that will have an impact upon them. Observe, for example, the emergent philosophy of the present administration. There is a shifting away from a federally controlled health care delivery policy to a state-
controlled health care delivery policy. While this shift in authority is in process, less funds are being appropriated at the federal level to maintain existing programs at the original federal/state level of funding. This means that the states have hard funding decisions to make and need all the expert advice they can get. A further illustration o f this shift in authority is the Omnibus Budget Reconciliation Act o f 1981 (Pub-L. 97-35), which revises in several ways the current requirements regarding the right of Medicaid beneficiaries to choose among participating providers o f covered items or services. One change is that states will be able to enter into certain arrangements to purchase laboratory services or medical devices through competitive bids, the intention being to give states the flexibility necessary to achieve more cost-effective delivery o f health care services to Medicaid beneficiaries. It has been my observation that
Microbiology Newsletter Vol. 4, N o . 2
January 154 1982
i
_t
Aspergillosis Norman L. Goodman, Ph.D. Professor and Director Clinical Microbiology Laboratories Department of Pathology University of Kentucky College of Medicine Lexington, Kentucky 40536 Aspergillosis is a complex ffroup of diseases caused by several species of Aspergillus. Aspergillus fumigatus is the most common etiologic agent of aspergillosis, with A. flavus, A. niger, A. clavatus, A. terreus and other species also causing infection. Types of Disease
Pulmonary aspergillosis is the most common form of disease. Basically, three forms of this disease are currently recognized: a) allergic aspergillosis, which may cause asthma-like symptoms or bronchitis with plugging of bronchi by mucds; b) aspergilloma, or "fungus ball," caused by growth of the fungus in pre-existing lung cavities, and c) invasive aspergillosis, in which the fungus invades tissue. The invasive form of the disease is usually found in patients with'impaired immunity, and the fungus may disseminate to any organ of the body, including the skin (13). Clinical symptoms of pulmonary aspergillosis usually include fever and cough, with bloodtinged sputum in aspergilloma. Aspergillosis is a common secondary disease of the compromised patient. It has been estimated that 5% of leukemia patients have
aspergillosis (10), which has been reported as a complication of a high percentage of organ transplants (13) as well as in many forms of cancer (9, 14). Ear infections (otomycosis) are usually caused by A. niger. These are benign conditions resulting from the growth of the fungus in the cerumen and debris in the external auditory canal. Sinus infections by aspergilli may result in a fungus ball lying free or attached to the sinus mucosa. Invasive sinusitis may occur in the maxillary sinuses, with erosion into adjoining structures and eventually into the meninges or brain. Trauma to the cornea by objects infested with Aspergilhts sp. may cause infection and subsequent invasion of the eye. Hematogenous spread of the fungus from other focal sites may result in endophthalmitis (5). The aspergilli are ubiquitous fungi found in soil, air, plant, and animal substrates (3). There is no apparent differential association of aspergillosis with age, sex, or race. The disease is noncommunicable and has a worldwide distribution. Infection occurs from inhaling spores of the fungus or by inoculation with material containing fungal elements (4, 12).
Collection of proper specimens from patients with suspected aspergillosis depends on the type of disease and the site of the lesion(s). As with all opportunistic organisms, contamination by aspergillus spores that are transient or colonizing must be avoided if possible. When possible, tissue from the infected site should be excised under aseptic conditions and submitted for histopathologic examination and culture. Specimens such as sputum and exudates should be collected as aseptically as possible and processed immediately for microscopic examination and culture. When attempting to obtain a diagnosis from sputum specimens, multiple specimens should be collected, preferably early in the morning, on consecutive days. The patient's mouth should be thoroughly cleaned before collecting sputum. Blood, spinal fluid, and urine specimens rarely yield aspergilli in infections.
Specimen Collection
Nitrate Reductase-Negative Mycobacterium Tuberculosis . . . . . 12
Since aspergilli are found universally in the environment and aspergillosis is an opportunistic disease, specimen collection and handling are critical steps in reaching a correct diagnosis (1, 6).
In This Issue Aspergillosis . . . . . . . . . . . . . . . . . . . .
9
Review o f the disease and diagnostic methods Politics and Microbiologists . . . . . . Should you be involved?
11
A biochemical variant causing disease in a patient with Hodgkin's disease Letters . . . . . . . . . . . . . . . . . . . . . . . .
14
Positions . . . . . . . . . . . . . . . . . . . . . .
16
Diagnostic Procedures Direct Microscopy Direct microscopic examination of a freshly collected specimen is often rewarding in making a diagnosis. Small portions of the specimen should be examined for the presence of hyphae or hyphal elements. Opaque, specimens should be clarified with 10% KOH. Clear specimens may be observed directly or stained by the lactophenol cotton blue method. Aspergilli grow in vivo in the hyphal form only; therefore, if the fungus is growing in the tissue from which the specimen came, it will appear in the specimen as branching, septate hyphae, 5-6 nm in diameter. The hyphae may appear pleomorphic and have enlarged, rounded segments. Often, the hyphae will fragment, and these septate fragments will be distributed throughout the specimen.
Histopathological examination A definitive diagnosis of invasive aspergillosis can only be made by demonstrating the fungus in tissue. A portion of all tissue should be submitted for histopathologic study. Tissue should be stained by the periodic acid-Schiff and methenamine silver methods. Aspergilli in tissue will appear as septate hyphae with acute angle branching. However, these morphological features are also characteristic of other members of the Ascomycetes, which also may cause opportunistic disease. Therefore, all tissue should be cultured in order to obtain a specific identification of the etiologic agent.
Culture methods The aspergilli grow well on all enriched laboratory media. The medium of choice for isolation and preliminary identification of these fungi from clinical specimens is Sabouraud agar. Plated media should be used when culturing specimens that are likely to contain mixed flora. Aspergillus species grow relatively rapidly on
Sabouraud agar, with colonies appearing in 3-4 days when incubated at 25-30 ° C. As indicated above, colonial morphology and pigmentation vary greatly depending on the species. All aspergilli produce septate hyphae and conidiophores enlarged at the tips to form vesicles; the latter are covered with sterigmata, which in turn bear chains of conidia. The criteria for identifying an isolate include: colony texture; color; rate of growth; conidiophore morphology, including the number of rows of sterigmata; conidial characters relative to size, shape, and arrangement on heads; and characteristics of any cleistothecia and ascospores. These characteristics, as exhibited on Czapek-Dox agar, are essential for speciation. The monograph by Raper and Fennell on The Genus Aspergilhts should be consulted for a detailed description of all the groups and species (11). Other references containing less detailed keys may also be useful (1, 4, 12).
Serologic Procedures Detection and quantitation of antibodies by serologic methods may assist the physician in diagnosing aspergillosis. However, it must be emphasized that positive serologic results alone are not diagnostic. Conversely, a negative serologic test does not rule out disease. Patients with allergic bronchopulmonary aspergillosis often have serum precipitins, detectable in the immunodiffusion (ID) test (7). Those with aspergilloma almost always produce large quantities of IgG, detectable by the ID method (7). Multiple bands are usually observed. The usefulness of serologic methods in invasive aspergillosis has not been established. Results of the complement fixation (CF) test usually agree with those of the ID test and may be obtainable earlier in the course of disease. Additionally, quantitation of antibody is provided by the CF test. Because of the availability of ID reagents and the simplicity of the
test, it is advisable to screen with the ID test and submit the serum to a reference laboratory for CF testing. The value of serologic tests for extrapulmonary aspergillosis has not been established. Because aspergillosis is primarily an opportunistic disease and the host may not be capable of mounting an immunologic response, work is being done to detect Aspergillus antigen in the host (8). These tests are still experimental and not available for general use. However, they do offer promise of better diagnostic methods in the future.
Treatment Amphotericin B is the drug of choice for forms of aspergillosis (primarily the invasive form) that allow the drug to reach the site of infection. Surgical excision is indicated for colonized sinuses, brain abscesses, cardiac valves, pulmonary aspergillomas, and other sites where removal of the organism would prevent possible spread by invasion (2). 5-Fluorocytosine has been used to treat various forms of aspergillosis; however, its efficacy has not been established. Miconazole and ketaconazole are drugs of the imidazole group with reported success for the treatment of aspergillosis. Their usefulness has not been well established. Testing the susceptibility of aspergilli to these drugs is not standardized; thus, results from such testing are subject to interpretation. Agar dilution methods appear to be the method of choice for susceptibility testing.
Evaluation of Laboratory Findings Since aspergilli can be isolated readily from the environment, and infection by these fungi is usually in a compromised host, the presence of these fungi in clinical specimens must be interpreted cautiously. Unless the aspergilli are observed growing in tissue, there is always some doubt as to the etiologic status of the fungus. When an infection is suspected, and the organism is isolated from
sputum or other specimens that may contain transient aspergilli, results o f serologic tests may be helpful. Demonstration of precipitins or complement-fixing antibodies to aspergilli indicates active disease and gives added weight to the importance of isolating the fungus from clinical specimens. Multiple isolations o f aspergilli, even without positive serology, should warrant a call to the patient's physician to determine the clinical and immunologic status of the patient. References 1. AustwJck, P. K. C., and J. L. Longsbottom. 1980. Medically important Aspergillus species, pp. 620-627. In E. H. Lennette, et al. (eds.), Manual of clinical microbiology, 3rd ed. American Society for Microbiology, Washington, D.C. 2. Bennett, J. E. 1979. Aspergillus species, pp. 2001-2008. In G_L. Mondell, et al. (eds.), Principles and
3.
4. 5.
6.
7.
8.
practice of infectious diseases. John Wiley and Sons, New York. Cooke, W. B. 1971. Our mouldy earth. U.S. Department of the Interior, Federal Water Pollution Control Administration, Cincinnati, Ohio. Emmons, C. W., et al. 1977. Medical mycology. 3rd ed. Lea and Febiger, Philadelphia. Francois, J., and M. Rysselaere. 1972. Oculomycoses. Charles C. Thomas, Springfield, Ill. Goodman, N. L. 1981. Opportunistic mycoses, pp 1071-1092. In A. Balows and W. J. Hausler, Jr. (eds.), Diagnostic procedures for bacterial, mycotic and parasitic infections, 6th ed. American Public Health Association, Washington, D.C. Kaufman, L. 1980. Serodiagnosis of fungal diseases, pp 628-646. In E. H. Lennette, et al. (eds.), Manual of clinical microbiology. American Society for Microbiology, Washington, D.C. Lehman, P. F., and E. Relss. 1978. Invasive aspergillosis: Anti-
9. 10. 11.
12.
13.
14.
serum for circulating antigen produced after immunization with serum from infected rabbits. Infect. Immun. 20:570. Meyer, R. I., et al. 1973. Aspergillosis complicating neoplastic disease. Am. J. Med. 54:6-15. Mirsky, H. S., and J. Cuttnor. 1972. Fungal infections in acute leukemia. Cancer 30:1348-1352. Raper, K. B., and D. I. Fennell. 1965. The genus Aspergillus. Williams and Wilkins Co., Baltimore, Md. Rippon, J. W. 1974. Medical mycology: The pathogenic fungi and the pathogenic actinomycetes. W. B. Saunders Co., Philadelphia. Williams, D. M., J. A. Krick, and J. S. Remington. 1976. Pulmonary infection in the compromised host. Am. Rev. Respir. Dis. 114:359-394. Young, R. C., et al. 1970. Aspergillosis: The spectrum of the disease in 98 patients. Medicine 49: 147-213.
Editorial
P o l i t i c s a n d the M i c r o b i o l o g i s t
Robert D. Watkins Director, Public Affairs American Society for Microbiology Washington, D.C. Our representative system o f government places a special responsibility on individual citizens and on the many special interest groups that make up the complex society of the United States. These individuals have not only the right but also the obligation to make themselves heard in Washington. Representation of viewpoints is an inseparable part of the American political system. It is a communication process involving the advancement o f a position, supported by solid facts and figures. As long as the representation is clear as to its intention and honest and complete in presentation, government will be aided in its efforts to reach responsible-decisions on issues that often encompass conflicting interests. For the scientific community, the process is more important now than
ever. The m o o d o f the American people is to cut the federal budget. Science is going to have a continual struggle to maintain stability and modest growth in the budget for research, improved clinical laboratory services, and other health and science-related areas. The fact is that the FY 1982 budget is still in difficulty, and the FY 1983 budget is now in worse shape with the political reality of the 1980 election year and increasing pressure on Congress to balance the budget. As a result, legislative and regulatory actions that affect the scientific community have increased greatly in complexity and impact. Our representatives in Washington and officials in federal departments a n d , agencies need information from knowledgeable persons on issues that will have an impact upon them. Observe, for example, the emergent philosophy of the present administration. There is a shifting away from a federally controlled health care delivery policy to a state-
controlled health care delivery policy. While this shift in authority is in process, less funds are being appropriated at the federal level to maintain existing programs at the original federal/state level of funding. This means that the states have hard funding decisions to make and need all the expert advice they can get. A further illustration o f this shift in authority is the Omnibus Budget Reconciliation Act o f 1981 (Pub-L. 97-35), which revises in several ways the current requirements regarding the right of Medicaid beneficiaries to choose among participating providers o f covered items or services. One change is that states will be able to enter into certain arrangements to purchase laboratory services or medical devices through competitive bids, the intention being to give states the flexibility necessary to achieve more cost-effective delivery o f health care services to Medicaid beneficiaries. It has been my observation that