Epidemiology As A Liberal Art
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Cited References
Scientific Method
Central to the scientific method are the framing of a hypothesis based on a particular conception of causality in a given situation and the carrying out of an experiment to test that hypothesis. If the data turn out to be inconsistent with the hypothesis, the hypothesis is rejected, and alternatives are sought that can in turn be tested. If the data are consistent with the hypothesis, it is retained, and further ways are sought to test its validity. In laboratory science, that experiment is planned and executed prospectively. In epidemiology, the "experiment" is often carried out by the collection of information retrospectively, after events have already occurred. The information is analyzed in much the same way as that from prospective experiments, although -- because the investigator does not control the conduct of the "experiment" -- additional care must be taken to find convincing evidence that the hypothesized chain of causation, and not some confounding alternative, led to the observed pattern of events.
In April 1973, reports of eight instances of a severe grippe-like illness of uncertain cause in employees of Strong Memorial Hospital and the University of Rochester School of Medicine prompted an epidemiologic investigation (Ref. 4). One of the first steps in such an investigation is to define, at least tentatively, what constitutes a case of the illness. In the first few days of this investigation, before the infectious agent was discovered, a case was defined as occurring in an employee of or a visitor to the medical center who had an episode of fever and muscle aches after January 1, 1971. Once the agent was shown to be lymphocytic choriomeningitis virus, a virus that infects rodents and that may be excreted in their urine for years, another requirement was added: serum antibody to lymphocytic choriomeningitis virus had to be demonstrated by indirect immunofluorescence at a serum dilution of 1:12. That revised definition was used in reporting the results here, although the preliminary definition led to the same conclusions.
A total of 23 cases were found by interviewing employees and reviewing records. Four cases had occurred sporadically before October 1972, but cases had occurred every month thereafter, reaching a maximum of seven in April 1973. Eighteen cases were in people who worked in the radiation departments, and three were in people who worked in the vivarium, the medical center's animal-holding facility.
Testing of serum from various groups of employees confirmed that the radiation therapy department was the focus of infection. Thirty-one of 80 radiation workers (39 percent) had demonstrable antibody to lymphocytic choriomeningitis virus, as compared with 12 of 60 vivarium employees (20 percent) and 5 of 25 others (20 percent). The presence of antibody correlated particularly well with reports of grippe-like illness in the radiation departments, providing further evidence that the recent outbreak was centered there: in the radiation departments, 17 of 31 ill workers (55 percent) had demonstrable antibody, as compared with 14 of 49 workers who were well (29 percent); in other departments, 4 of 20 ill workers (20 percent) had antibody, as compared with 13 of 65 workers who were well (20 percent).
The fact that lymphocytic choriomeningitis virus causes persistent infections in some animals suggested that animal contact might account for the outbreak among the radiation workers. In fact, animals were kept in the radiation department for experiments on the effect of x-rays on implanted tumors. As predicted, the presence of serum antibody in the radiation employees was associated with direct contact with animals in the animal-holding room. Fourteen of 20 persons who had such direct contact (70 percent) were seropositive, as compared with 17 of 60 (28 percent) with no direct contact. However, more than half of the seropositive radiation workers (17 of 31) reported no such contact with animals, so the mechanism of their infections remained unexplained.
It happened, however, that limitations of space in the radiation department had led to creative combinations of functions in the available rooms. One of these involved placing the departmental Xerox machine on the back wall of the animal-holding room. To get to the machine, employees had to pass through a narrow passage flanked by rabbit and hamster cages.
This suggested the hypothesis that the risk of acquiring infection with lymphocytic choriomeningitis virus might be related to the frequency with which one used the Xerox machine. Among those with no direct animal contact, this was indeed the case. Eight of the 14 who entered the holding room daily had antibodies to lymphocytic choriomeningitis virus, whereas 6 of 14 with a weekly exposure of once to four times, 2 of 10 with an exposure of less than once a week, and 1 of 22 with no exposure were seropositive. As for the employees in the vivarium, the pattern of seropositivity confirmed the hypothesis that infection was particularly associated with direct contact with hamsters or rabbits. That left only the illnesses of two other people to explain. One was a plumber, who worked throughout the medical center and was likely to have had considerable contact with rodent urine. The other was the Xerox repairman, who had last serviced the machine in the animal-holding room on March 16 and who became ill on April 4.
This investigation demonstrated that lymphocytic choriomeningitis virus could spread not only by direct contact with infected animals but also indirectly -- probably through the inhalation of infected urine droplets or droplet nuclei. Subsequent testing of the animals and their implanted tumors showed that the hamsters, not the rabbits, were infected and that the source of the infection had been the tumors themselves, which were already infected when the medical center received them several years earlier. Destroying the infected tumor lines and killing the hamsters stopped the outbreak. Nine months later, a nationwide outbreak of lymphocytic choriomeningitis in persons with pet hamsters was traced to a part-time breeder whose regular job was with the firm that had propagated and distributed the tumor lines that the University of Rochester had received contaminated with lymphocytic choriomeningitis virus (Ref. 5). Although it was never proved, an attractive theory is that the breeder had started his colony with infected hamsters he had brought home from work.
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