bone-cement interface in loosening of total hip replacement. Arch. Orthop. Trauma Surg. 109:83,

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of the Jarvik-7 artificial heart. JAMA 259:860-864.

36. Slusher, M.M. et al. 1987. Extended-wear lenses, biof'dm, and bacterial adhesion. Arch. Ophthalraol. 105:110--115.

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38. Birinyi, L.K. et al. 1987. Increased re sistanee to bacteremic graft infections after endothelial seeding. L Vasc. Surg. 5:193--197.

39. Stem, G.A., A. Lubniewski, and A. Clark. 1985. The interaction between Pseudomonas aeruginosa and the cor- neal epithelium. Arch. Ophthalmol. 103:1211-1255.

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Editorial

Limitations on Testing in the Clinical Virology Laboratory

Joseph L. Waner, Ph.D. Professor of Pediatrics University of Oklahoma Health Sciences

Center Director of Virology Laboratory University Hospitals Oklahoma City, OK 73190

A Perspective on Diagnostic Virology Laboratories

Newly recognized viruses, the accel- erating development of therapeutic agents, a greater understanding of the pathogenesis of viral diseases, and inno- vative technologies are challenging clinical virology laboratories to increase services. However, this is occurring in a time of diminishing resources and ad- ministrative edicts to be cost effective. Counter to the prevailing scientific in- centives, laboratories are being asked to identify tests that are essential to patient care and, implicitly, to identify tests that can be eliminated. Point-of-care testing, the disbursement of virology tests to other laboratories, and the con- so l id ,on of diverse clinical testing into technological centers are disturbing trends that are also being used to effect cost containment. The overall impact on the virology laboratory is a limitation on services and constraints on growth. To cope with these issues, the clinical virology laboratory must first be de- freed in terms that delineate the labora- tory's unique role in health care.

Diagnostic virology had its origins in

serology and cell culture methods. It was cell culture, however, that gave uniqueness to the discipline. The area that became the repository of cell cul- tures and possessed expertise in their cultivation frequently became the virol- ogy laboratory. Historically, the labora- tory was likely to he in the department of an individual who was using cell cul- ture for investigative purposes. Thus, the location of diagnostic virology labo- ratories was often outside the realm of traditional clinical laboratories and may have included missions that were not vi- rological in nature. As new uses for cell cultures evolved, new tasks originated for the laboratory: culturing for the diag- nosis of Chlamydia trachomatis is an example. Many institutions have com- monly assigned the diagnosis of any in- tracellular organism to the virology laboratory. These circumstances were often coupled with an attitude that a vi- ral diagnosis based on clinical findings was sufficient and, therefore, a labora- tory-derived diagnosis did not have an impact on patient care.

These early quandaries were over- come and clinical virology became a laboratory entity. Virology laboratories, however, retain unique characteristics. They are not standardized by a deline- ation of the services offered or by stand- ardization of the tests performed. The mission of the host institution---i.e., public health laboratory, hospital, small clinic, or private diagnostic laboratory-- often defines the virology laboratory. It is common to have virology tests per- formed in non-virology laboratories even though a virology laboratory is a

component of the local laboratory sys- tem. For example, hepatitis testing is often done in a chemistry laboratory, HIV testing in a blood bank; and tissue sections may be examined for viral anti- gens or nucleic acids in the cytology section of a pathology department, This evolutionary history worked to the detri- ment of clinical virology by obscuring a focused definition of the specialty and by enforcing the premise that the labora- tory was defined by the use of cell cul- tures.

In the current environment of limit- ing services and growth, the advent of rapid, non-culture technologies raises the specter of territorial disputes with other clinical laboratories and has been used to question the need for virology laboratories. Immunoassays, nucleic acid probes, and PCR are technologies not unique to virology and are routinely used in other diagnostic disciplines. Ad- ditionally, sophisticated, large-volume, automated instruments for the detection of diverse antigens and antibodies are becoming available, and their effect on the organizational interaction of virol- ogy, microbiology, and immunology laboratories is yet to be determined.

In considering limitations on virol- ogy services, it is important that the de- fining nature of the virology laboratory be the providing of services that impact on patient care. Clinical relevance can take different forms: initiation of antivi- ral therapy, patients cohorted to prevent nosocomial transmission, reduction or withdrawal of antibiotic therapy, and even doctor-patient literacy. Less appre- ciated is that a specific viral diagnosis

1 7 6 0196-4399/94/$0.00 + 07.00 © 1994 Elsevier Science Inc. Clinical Microbiology Newsletter 16:22,1994

may be cost effective by diminishing or eliminating further diagnostic testing, or shortening a hospital stay. Beyond the immediate impact on patient care, the diagnostic virology laboratory has a wider role in society through epidemiologic and academic missions. The detection of an outbreak of influ- enza and the isolation of new variants of the virus that will become the next vaccine can have global implications. Additionally, the evaluation of therapeu- tic agents and new technologies, and the training of clinical and scientific person- nel require comprehensive laboratories.

These missions are not accom- plished by a random application of tech- nology. Clinical virology, like other medical disciplines, is ultimately de- fined by the clinical virologists who ap- ply their collective knowledge and expertise to patient care and the associ- ated areas. It is time that professional certification that is unique for clinical virologists becomes available. Con- versely, certification of laboratories on the basis of services offered and demon- strated professional competence would be of considerable value to the con- sumer.

Limitations on Testing, or Redefining the Menu

The realities of limitations must be confronted. An initial approach may be not to concede readily that reductions in virology services should be considered along with other cutbacks. Few service laboratories have experienced growth like that of virology laboratories or have the same potential for future growth. In the past 15 years, human im- munodeficiency viruses, human T-cell leukemia viruses, hepatitis C virus, hepatitis E virus, human herpes viruses 6 and 7, hantavirus, and several viruses associated with gastrointestinal disease have been identified and have become amenable to diagnosis. Concurrently, methods have become available for the rapid detection of most common viral agents. Therapeutic agents have be- come available and new ones being de- veloped require clinical testing--to be followed, predictably, by the need to as- sess the development of resistant virus strains. The size and complexity of im- munocompromised patient populations

alone has greatly increased the need for virology services. Pragmatically, virol- ogy laboratories no longer have to be subsidized but can support themselves and even contribute revenue to the insti- tution. There are numerous examples of successful private laboratories and of in- stitution-based laboratories with out- reach programs that have greatly increased revenue.

Decisions that result in limitations on virology services should result only from discussions between laboratory and medical personnel that assess the ef- fect on patient care. A hospital's medi- cal care committee is often a good forum. The laboratory should bring to these discussions a thorough under- standing of the laboratory's pattern of service. The service pattern is usually not appreciated by the clinical staff, which represents diverse units. For ex- ample, the pattern of service for a labo- ratory dealing with a large transplant population will be different from that servicing a general pediatric population. Among the items in a pattern of service are the nature of the specimens re- ce ive t - - i.e., bloods, respiratory speci- mens, genital specimens; the percentage of specimens received from the differ- ent patient populations (or clinics) serv- iced; the number of specimens sent to the laboratory relative to the time of day; and knowledge of the epidemiol- ogy of viruses that occur seasonally, such as RSV, influenza, and rotavirus. The laboratory must be cognizant of the clinician's priorities, particularly when a timely diagnosis will immediately af- fect patient management. An acceptable definition of "timely" should he estab- lished, realizing that some specimens re- quire attention immediately or within hours, whereas a day or more may suf- fice for others. The medical staff's pri- orities should be integrated into the pattern of service. It is also within the pattern of service that issues such as un- necessary duplicate testing, specimen collection, and weekend service can he addressed.

The laboratory's test menu necessar- ily derives from the pattern of service. Implicit is the need to use the relevant but not necessarily the newest technol- ogy that is applicable. New technolo- gies are not obligatory improvements

over established methods for diagnosis. For example, the sensitivity of PCR is unquestioned. Using PC'R, however, is currently difficult to justify for diagno- sis of most common acute viral infec- tions for which other less expensive tests are available when those tests have acceptable sensitivity and specificity and are timely. PCR is most appreciated where other methods of detection are not available or where the application of PCR provides important diagnostic information that has an impact on pa- tient care.

A salient point is to define what is acceptable sensitivity and specificity. In fact, considerable information about various antigen and nucleic acid detec- tion methods with clinical relevance is available. Unfortunately, these are usu- ally reports from individual laborato- ries. Only multiple publications on the same method or an intimate knowledge of the laboratory that is reporting per- mits a useful interpretation. Inevitably, a laboratory evaluates each new test in- house before deciding whether or not to implement it. It may not be possible, however, to do an adequate evaluation if a sufficient number of positive speci- mens is not available. There must be progress in defining working groups that can evaluate test procedures with standardized protocols and reagents and that will publish their results jointly.

Diagnostic virology laboratories have several test options and protocols available for consideration when con- structing or altering test menus. A rea- sonable place to begin is with the conventional approaches. For example, some serologic tests may have an im- pact on patient care, whereas others may establish immune competence. The latter may be sent to referral laborato- ries to conserve resources for the for- mer. Serology that utilizes a single serum taken in any phase of disease, such as that for the hepatitis viruses or EBV, can impact on patient care. Assay- ing for specific IgM antibodies, particu- larly when good and timely virus detection methods are available, should be considered carefully.

Commercially available reagents and test kits can provide acceptable sensitiv- ity and specificity for screening and, in some cases, definitive rapid testing.

Clinical Microbiology Newsletter i 6:22,1994 ~ 1994 Elsevier Science Inc. 0196-4399/94/$0.00 ÷ 07.00 17"]

Many of the discordant experiences with these kits result from not follow- ing the manufacturer's protocol, which includes obtaining a correct and ade- quate specimen. Confirmation of all rapid tests by isolation in cell culture is no longer practical and in many cases may not be necessary. It is difficult to support doing a confh'mation test for a strongly positive EIA test (commercial) for respiratory syncytial virus (RSV) in the middle of the RSV season when greater than 50% of the pediatric speci- mens are positive for RSV. Weak posi- tive results, positive results that are obtained when RSV is an infrequent iso- late, or when RSV is identified in an un- likely patient should be confirmed. The negative predictive values of commer- cial EIA tests are often overlooked. Over the course of a year, the majority of tests will he negative. The need to confirm every negative result can counter the value of the test. Our labora- tory's experience is that direct im- munofluorescence (DI) is the most reliable rapid test that is commonly available and that DI can also function as the confirmatory test for many vi- ruses, eliminating the need for confu'ma- tion by isolation.

An understandable effect of cost con- tainment is to use techniques that target one virus, particularly when identifica-

tion of the targeted virus can immedi- ately affect patient management; RSV, influenza A virus, and herpes simplex virus are examples. The dilemma is the possibility of missing a different virus if the targeted virus is not identified. Cogent arguments are made that only timely tests for treatable virus infec- tions are worth the laboratory's effort. This approach should he recognized as an expedient that does not aid in a differ- ential diagnosis and prevents the realiza- tion of any value from identifw, ation of a different virus even if therapeutic treat- ment for that virus is not available.

The use of multiple cell cultures, or employing DI with a diverse panel of antibodies, is the best available alterna- tive to targeting a single virus, but it involves additional commitment of resources. The application of shell vial technology that utilizes multiple cell lines can provide a rapid diagnosis but is labor intensive. Selective use of cell cultures, however, appropriate to the pa- tient population and season can im- prove efficiency. Clearly, the use of cell cultures, like any test procedure, should be evaluated in each laboratory with ref- erence to the clinical relevance pro- vided for the patient population or for the individual patient in question. For example, pneumonitis in a bone mar- row recipient requires a rapid test for

CMV while congenital CMV in a new- born can be confirmed by the standard isolation technique. Cell cultures are no longer the defining characteristic of the diagnostic virology laboratory but re- main an important component of the available technology.

Virology laboratories will have to re- main technologically and organization- ally flexible. The use of common instrumentation can reduce capital ex- penditures. Cross-training of non-virol- ogy personnel in the use of rapid commercial test kits can provide mini- mum virology testing at times when the virology laboratory is not open; confir- mation of the tests performed can be ac- complished subsequently by the virology laboratory. The temptation to homogenize clinical laboratories, in- cluding virology laboratories, by purely administrative or technological defini- tions should be resisted. A more reason- able approach is an interconnected matrix of identifiable laboratories that can support and contribute to the unique mission of each member.

Acknowledgments The author acknowledges the thoughts

and in some instances the words of James Overall, Christine Robinson, Thomas Smith, and Gregory Storch.

Editors Mary Jane Ferraro Paul A. Granato Josephine A. Morello R.J. Zabransky

© 1994 Elsevier Science Inc.

ISSN 0196-4399 CMNEEJ 16(22) 171-178, 1994

Elsevier

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© 1994 Elsevier Science Inc. Clinical Microbiology Newsletter 16:22,1994