THE PROBLEM OF THE ETIOLOGY OF HERPES ZOSTER.
Attempts were made to produce lesions in. animals by the injection of material obtained from the vesicles and involved skin of nine cases of herpes zoster. All the cases, with the exception of one (Case II), were characteristic cases of idiopathic herpes zoster and the question of their being cases of so called zosteriform herpes or symptomatic herpes zoster can hardly be raised. As regards Case II, if this case occurred alone, there might be some doubt as to its nature on account of the mildness of the symptoms and the small area of skin involvement. Taken in connection with Cases III and IV, however, which occurred in the same ward and in patients who were quite closely in contact with Patient II, it seems fairly reasonable to assume that they were all of the same character. Cases of herpes zoster have been extremely rare in this hospital and the occurrence of three cases in the same ward within a very short period of time suggests very strongly a transference of infection from one case to the other. That Case II was not one of herpes simplex also seems fairly certain from the negative results obtained by inoculation of rabbits' eyes with vesicle material. In making the animal experiments we employed various methods which were suggested largely by the technique used by previous observers, especially by those who have reported results which were considered positive. In making inoculations into the corneas the technique recommended by Lipschütz was employed as far as possible. Young rabbits were used and the material was obtained from fresh vesicles early in the disease and inoculated with as little delay as possible. The material injected into rabbits' eyes was obtained from seven cases and twenty-four rabbits were used. In judging of the results obtained in this kind of experimentation great caution must be observed. Our experience convinces us that slight opacities occurring along the lines of scarification and mild conjunctivitis cannot be held to indicate the effect of a specific virus. As regards the interpretation of the microscopic changes found, we were quite familiar with the appearance of intranuclear inclusion bodies as seen in the lesions of experimental herpes simplex and the filterable virus (Virus III) indigenous to rabbits described by Rivers and Tillett (5). We also had no difficulty in imding intranuclear inclusions in the sections of skin removed from patients. It is not likely, therefore, that these structures were overlooked in our study of the sections. Briefly stated, although the material studied was satisfactory and in spite of the fact that a considerable number of animals were used for each case, we have been unable to confirm the observations of Lipschütz regarding the experimental production of specific lesions in the corneas of rabbits. We realize that this is only negative evidence and therefore not of conclusive importance in view of Lipschütz's observations. It indicates, however, that the production of specific lesions in rabbits' eyes with material from herpes zoster vesicles is extremely difficult and that successful results may be a matter of chance, depending, possibly, on peculiar susceptibility on the part of the rabbits. In view of the fact, however, that a careful analysis of the positive results reported by other observers shows that the conclusions were based on insufficient evidence, we believe that further work is necessary before the successful inoculation of the rabbits' corneas with herpes zoster virus can be accepted as fully demonstrated. To make the evidence convincing specific lesions should be obtained with a fair degree of regularity and the virus should be successfully transmitted through at least two generations. Apparently the latter was not attempted by Lipschütz. Intracerebral inoculations into three rabbits with material from two cases (Nos. I and IV) were made. Two rabbits were also inoculated intraspinally with material from one case (No. IV). None of these animals showed any reaction. In the case of one of the animals inoculated into the brain (Case I) although this rabbit showed no symptoms, we thought it conceivable that the susceptibility of the species for the virus might be so slight that no obvious lesion had been produced. Nevertheless it was thought that the virus might possibly remain alive at the seat of inoculation and by repeated transfers become adapted to the rabbit. This phenomenon has been observed by Noguchi with vaccine virus, and by Rivers and Tillett with the rabbit virus isolated by these workers. This possibility was tested by us by making serial corneal and brain inoculations. Corneal transfers were carried through fourteen animals in series, and brain transfers through ten. No specific lesions developed in any of the animals. The work of Teague and Goodpasture suggested that the skin might be rendered more susceptible to infection by previous treatment with tar. Material from two cases (Nos. I and VIII) was inoculated into the tarred skin of guinea pigs and rabbits. The material was injected intracutaneously and also rubbed into the scarified skin. No reaction was obtained in any of the animals. Finally, the transmission of herpes zoster to monkeys was attempted. Blanc and Caminopetros, and Bastai and Busacca, as discussed in the review of the literature, inoculated monkeys (Macacus) in various ways, without success. It was thought possible that although monkeys of the genus Macacus might be refractory, monkeys of another genus might prove susceptible. Consequently, besides the inoculation of two Macacus monkeys, attempts were made to infect five vervets. Moreover, in view of the fact that the virus of vaccinia and the rabbit virus of Rivers and Tillett could be successfully cultivated in the testicle, intratesticular inoculations were employed. The testicles were removed at varying periods following inoculation. Numerous sections of these testicles were made and examined, but in no instance were any lesions found which could be interpreted as specific. No cells containing intranuclear inclusion bodies were found. These experiments, therefore, have also led to purely negative results. This report of our work is made at the present time because a considerable amount of literature has been published which gives the impression that herpes zoster has been successfully transmitted to animals. Although the observations of Lipschütz are suggestive, it is important that they be confirmed by further investigations. Until herpes zoster can be regularly transmitted to animals and cross-immunity tests be carried out, the relation of the virus of herpes zoster to that of herpes simplex remains a matter of speculation. In view of the fact that herpes simplex can be easily and regularly transmitted to rabbits, whereas in the hands of a large number of investigators similar experiments with herpes zoster are completely negative, it does not seem likely that the etiological agent concerned in these two diseases can be absolutely identical. The question of the identity or non-identity of herpes zoster and varicella is even more difficult to answer, because at present neither of these infections is readily transmissible to animals. The work of Kundratitz is extremely interesting. His observations, aside from indicating a close immunological relationship between herpes zoster and varicella, are important in that they seem to show the presence of a transmissible virus in the vesicles of herpes zoster. The only question that arises is whether the cases of herpes zoster from which Kundratitz was able to make successful transfers were true cases of idiopathic herpes zoster.
Cole
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Hospital of The Rockefeller Institute for Medical Research.
Kuttner
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