The Tragedy of Viral Diagnosis

Postgrad Med J: first published as 10.1136/pgmj.46.539.545 on 1 September 1970. Downloaded from Postgraduate Medical Journal (September 1970) 46, 545-550. The tragedy of viral diagnosis ERNEST C. HERRMANN, JR Ph.D. Mayo Clinic and Mayo Foundation, Department ofMicrobiology and Immunology Rochester, Minnesota Summary Retrospective diagnosis The shortcomings of the methods commonly recom- Perhaps one can obtain a clue to the problem in mended for the diagnosis of viral infections are what Lennette, a recognized leader in viral diagnosis, emphasized. says: 'Isolation and identification of an agent are Most of them are laborious and expensive, and are still, in most cases, relatively costly procedures and of very little practical value to the clinician. seldom give information which cannot be more Nine years' experience has confirmed that the simply, more rapidly, and less expensively (albeit use of a single swab, obtained during the acute stage retrospectively) obtained by serologic methods' of the illness, for bacterial culture and viral isolation (Lennette, 1964). Lennette is also the chief editor (looking for cytopathic effects or haemadsorption) of the latest version of another manual purporting copyright. provides the diagnosis quickly in the great majority to show how viral disease should be diagnosed, and of viral infections. he is consistent (Blair, Lennette & Truant, 1970). The serological approach is emphasized in virtually every presentation on the subject. As will be shown, Introduction this emphasis is wrong. The key words in Lennette's Most infectious disease suffered by humans remarks are, of course, 'albeit retrospectively'. affects the upper respiratory tract. If, as has been A retrospective diagnosis is largely an academic shown in a variety of studies (Dingle et al., 1953; exercise, not very useful in the practice of medicine. Hope-Simpson & Higgins, 1969), each person The emphasis on serologic methods seems unique http://pmj.bmj.com/ averages seven respiratory infections annually, then to virology, for in the Introduction to the Manual there are well over one billion such cases in the of Clinical Microbiology the editor states the manual United States each year. It has been estimated that is devoted to 'the isolation and identification of on the average this huge morbidity can be related to disease-producing organisms' (Blair et al., 1970, identifiable microorganisms at least 50% ofthe time, p. 3). Those constructing the virology portion seem and these organisms are mostly viruses (Hilleman, to have been unaware of these objectives. In 1961 a and his detailed 1963). The average virology textbook emphasizes respected virologist colleagues on September 29, 2021 by guest. Protected the more serious viral illness requiring hospitaliza- the case against the serologic approach (Henle tion, when in fact over 90% of viral disease affects et al., 1961). Their plea for an emphasis on virus the upper respiratory tract. This is the true nature isolation seemingly was ignored. of viral disease. Physicians in the United States How did the diagnostic virologists become probably see no more than 5% of this total disease isolated from the aspirations of microbiology (Hope-Simpson & Higgins, 1969), which could and from the needs of medical practice? Perhaps represent upwards of fifty million visitations per they feel themselves to be more serologists than year. Such a burden weighs heaviest on the pediatri- virologists; perhaps it is the early pride and com- cian and the general practitioner. Faced with this radeship of workers in the Public Health Labora- enormous case-load physicians find meaningful tories that were successful in making the Wassermann laboratory aid in diagnosing viral disease virtually test work that has led them to emphasize programs nonexistent. It is the purpose of the following of complement-fixation tests. After performing discussion to examine why this is true and whether thousands of such tests, I have become aware that it need be. consistent and useful results are an illusion. The Postgrad Med J: first published as 10.1136/pgmj.46.539.545 on 1 September 1970. Downloaded from 546 Ernest C. Herrmann sine qua non for diagnosis of infectious disease is isolate? As every microbiologist should know, there the isolation of the pathogen, which in virology are only a few pathogens that are not at times pre- today is by far the most rapid, least expensive, sent in healthy individuals. Perhaps this fact has most comprehensive, useful, and accurate method made virologists somewhat insecure, so they de- of diagnosis. mand additional evidence that an isolate is perti- The fact that virus isolation is readily done is nent. They would like to be sure the infection was now recognized by many. Unfortunately, some unquestionably related to the disease. Unfortunately, serologists still feel that isolation of a potential serology cannot produce such security. It is still pathogen is not enough; one must further 'prove' possible that the patient was infected with a virus, the significance of the virus isolation by showing, producing antibody rises and extensive virus excre- with acute and convalescent sera, a rise in some tion, yet it still had nothing to do with the disease. type of antibody specific for the isolate. The term This is the nature of medicine; rarely does one have 'proof' is in fact used, indicating a substantial faith absolute proof. in antibody rises (Sohier, Chardonnet & Prunieras, These traditions may well have started with two 1965). But a rise in antibody titre even over the historic episodes in clinical virology. First, there course of the disease does not prove what caused was the discovery that normal human adenoid the disease. All that has been done is to confirm tissue could harbour adenoviruses (Rowe et al., what would already be known by viral isolation, that 1953). These contaminating viruses, which were the individual was infected. 'Infection' cannot be at such low levels that they were almost undetectable, equated with 'disease'. It is relatively easy to prove may have led many to believe that such viruses are someone is infected, but there is no scientific method common in the throats of healthy individuals and to prove that the disease was in fact caused by the are readily isolated. Few have considered that there isolated pathogen. Other pathogens, known and is a significant difference between the quantity of unknown, could have also been present and over- virus found in adenoid tissue in these original looked. The best that virology can do, with or observations and the amount that must be trans- without confirmatory antibody rises, is to offer ported via a swab to the virus laboratory to be the physician a clue to the possible causal agent. detected in cell culture. The significance of the copyright. This is the working philosophy of the bacterial quantity of virus does not seem to have been diagnostic laboratory. How often is it found useful much considered as a further guide to the pertinence to 'prove' the significance of an isolated bacterial of a viral isolate. Despite the fact that over 30 pathogen by measuring antibody rises? serotypes of adenoviruses have been found in humans, types 1, 2, 3 and 5 represent 90%/ of the Virology or epidemiology? isolations, primarily from children with pharyngi- The first function of a diagnostic laboratory is tis and fever (Herrmann, 1968). This experience to aid in diagnosing disease, and therefore it must should suggest which serotypes are pathogenic. be related to medical practice. Most who claim to The ludicrousness of the situation is emphasized http://pmj.bmj.com/ practice diagnostic virology are in fact involved in when the virus laboratory requests 25 grams offaeces epidemiology. Epidemiology, on the other hand, as well as throat swabs and blood specimens in is a productive area of research that aims to produce order to make a viral diagnosis. That this is an data to clarify the significance of various micro- unnecessary practice in respiratory disease has not organisms isolated from disease situations. The been sufficiently emphasized. As might be expected, epidemiologist must use every tool available to aid after the extraction and culturing of such a faecal in the role of certain in specimen, one or more viruses are found-which establishing organisms on September 29, 2021 by guest. Protected disease; many have emphasized the measurement can only confound the diagnosis. Numerous of antibody levels, even in the absence of isolation adenoviruses, for example, can be found in the faeces, of the pathogen. This has led to significant errors. many serotypes in fact only in the faeces, which Antibody measurements are inadequate, for at best have no relationship to human disease (Vargosko they can indicate only that the patient was infected, et al., 1965). and at worst they indicate he was infected when he was not (Henle et al., 1961). For the epidemiologist Faecal specimens the alternative is to fulfill Koch's postulates, a The use of faecal specimens in diagnostic virology most demanding procedure, but one that was in can be traced to a second historic episode related to fact undertaken in establishing the pathogenic poliomyelitis research. Many attitudes and practices nature of Eaton's agent (Mycoplasma pneumoniae) today are based on that experience, which is not (Rifkind et al., 1962). related to the nature of most viral disease. Finding How did the emphasis on serologic confirmation a host of viruses in the faeces, often unrelated to any arise for establishing the significance of a viral disease, has further contributed to the insecurities Postgrad Med J: first published as 10.1136/pgmj.46.539.545 on 1 September 1970. Downloaded from The tragedy of viral diagnosis 547 of the clinical virologist, so he searches for addi- great importance in preparing a paper for publica- tional means to make such isolations pertinent. tion. Serotyping is usually unimportant to the The frequent recommendation that extracts offaeces practice of medicine, however.

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