THE NEW TREATMENT OF DIPHTHERIA.

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ADMINISTERING THE DIPHTHERIA ANTI-TOXINE.

There is good reason to believe that with a fuller knowledge of the best methods for its employment diphtheria may be brought almost absolutely under control.

### THE EXPERIMENTS THAT LED TO THE DISCOVERY.

A number of series of experimental observations regarding the nature and causation of diphtheria preceded the discovery of the new remedy. These began with the discovery of the diphtheria bacillus by Klebs in 1883. In the following year, 1884, the organisms described by

Klebs were more carefully studied by Loeffler, were cultivated outside the living body, and diphtheria, or a disease resembling it, was reproduced in animals by inoculating them with the cultures of this germ. Loeffler was unable, however, to reproduce the various forms of paralysis which frequently follow diphtheria, but Roux and Yersin, in Paris, in 1888, succeeded in reproducing artificially, by the inoculation of animals with cultures of the diphtheria bacillus, a perfectly characteristic diphtheritic paralysis, and they were also successful in separating from the cultures of this organism a poison (the

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diphtheria toxine) with which they also produced paralysis in animals. Then Behring and Kitasato, in Berlin, found that by the inoculation of animals with the poison obtained from cultures of the diphtheria bacillus they could be gradually rendered extraordinarily insusceptible to both the poison and the diphtheria bacilli themselves. They further showed that this insusceptibility or immunity was due to the formation and presence in the blood of some substance which it has not been possible to separate chemically, and which is known as the diphtheria anti-toxine, or, from its wonderful action, the curative serum. Then followed experiments by Behring, Ehrlich, and other observers in Germany, and Roux in Paris, experiments designed to make this discovery practically available for the prevention and treatment of diphtheria in the human being.

The first important results of these experiments were published in the early part of last year, and they showed a striking diminution in the mortality, in a series of cases of diphtheria subjected to the new treatment. The results obtained in these first cases have been more than confirmed by subsequent experiences in the treatment of this disease. In order to gain an intelligent conception of the nature of the new treatment, it is necessary to know something of certain facts regarding the infectious diseases which underlie it. It has been long known that in many infectious diseases one attack grants a more or less complete insusceptibility, or, as it is called, immunity, to future attacks. The same individual rarely has two attacks of small-pox or scarlet fever, because the first attack has given nearly or complete immunity to the disease.

It has been the endeavor in many bacteriological studies of different infectious diseases, to devise or to discover some means or method by which immunity to these diseases can be artificially induced in animals and in man. These investigations have met with considerable success. In vaccination for small-pox, immunity to small-pox is produced in human beings by inoculation, through vaccination, with the virus of cow-pox, which is a closely allied disease occurring in cattle. Pasteur some years ago succeeded in conferring immunity on cattle and sheep to anthrax, or splenic fever (a disease which sometimes occurs in human beings), by inoculating them with cultures of the anthrax germ, whose virulence had been partially attenuated by the application of heat. In

Pasteur's prophylactic treatment for hydrophobia, immunity is conferred by successive inoculations with a virus of constantly increasing strength, the first inoculations being made with a virus having little or no virulence. In this case the virus is obtained from the spinal cords of rabbits which have died from rabies after inoculation. The virulence of the virus in the cords is attenuated by drying for varying periods of time. A spinal cord which has been dried for fourteen days is by this process deprived of its virulence, and those which have been dried a shorter period have proportionately greater virulence.

In the production of the diphtheria anti-toxine, a high degree of immunity is first conferred on animals by successive inoculations with

DR. ROUX.

larger and larger amounts of the diphtheria toxine, the smaller doses giving tolerance to the succeeding larger doses; this tolerance being due to the formation in the blood of anti-toxine. In the prevention of diphtheria by the use of the anti-toxine, a certain proportion of the immunity which has been conferred upon animals, is transferred from the immunized animal to the individual. This is done by the injection under the skin of a given amount of blood serum, curative serum, which contains the anti-toxine, and which is derived from an immunized animal. The amount of insusceptibility conferred by these injections is proportionate to the amount of blood serum that is thus introduced, and the degree of insusceptibility to diphtheria which the animal from which it was obtained has acquired. In the treatment of diphtheria by anti-toxine, the same immunity is transferred, and is almost immediately produced in the individual, by the introduction of this curative serum; and as the individual by its introduction is rendered relatively or absolutely immune to the disease, the disease is at once partially or completely arrested.

The results which have been obtained from the treatment of diphtheria by the

["THE NEW TREATMENT OF DIPHTHERIA.", "363", "new remedy, are far better than have ever been obtained by any other method. Speaking generally for the children's hospitals in Europe and in this country, it has been found that, with other methods of treatment, from 40 to 55 per cent. of the cases of diphtheria occurring in children under five years of age die. With the new method of treatment, this mortality has been reduced first to 25 per cent., then to 15 per cent., to 13 per cent., 11 per cent., and it has been said that in the last series of cases treated by Roux the mortality was only 8 per cent. The striking influence upon the mortality from this disease brought about by the use of anti-toxine, is shown in the reduced death-rate in Paris during the last few months as compared with the corresponding months of previous years. Tables are appended which show the number of deaths from diphtheria for each week during 1894, and the mortality for each month during the last five years.* The influence of the use of this agent on the death-rate from diphtheria, as shown by these tables, constitutes, in my opinion, an exhibit of the saving of life by a new remedy so extraordinary as to be without a parallel in the history of medicine. No such results have ever before been obtained, and the cumulative results, as shown by these statistics, are no more remarkable than are the immediate", "effects frequently seen in individual cases produced by the administration of the curative serum. The results are so extraordinary as to seem almost incredible to those who have been familiar with the usual course of diphtheria and the effects of remedies on it.", "In the large majority of cases, when the anti-toxine is administered during the first twenty-four or forty-eight hours of the disease, and sometimes also during the third or fourth day, the effects are most striking. If the temperature has been elevated to perhaps one hundred and three or one hundred and four degrees, it falls to normal or nearly normal within a few hours, the extension of the membrane in the throat is arrested, and the swelling and soreness in part or entirely disappear. If the membrane is only on the surface, is of recent formation and is not very thick, and has not as yet involved the substance of the tissue, it will often entirely separate within the first twenty-four hours after the injection, and convalescence is at once established. In the most severe cases, and in those where the remedy is not administered until later in the course of the disease, the influence is usually less marked, and it becomes necessary to administer the remedy a second, a third, or even a fourth time, at intervals of twelve to twenty-four", "*DEATHS IN PARIS FROM DIPHTHERIA (INCLUDING CROUP) IN 1894:", "<table><thead><tr><th>Week ending</th><th>January</th><th>February</th><th>March</th><th>April</th><th>May</th><th>June</th><th>July</th><th>August</th><th>September</th><th>October</th></tr></thead><tbody><tr><td>\"</td><td>6</td><td>13</td><td>10</td><td>7</td><td>5</td><td>2</td><td>7</td><td>4</td><td>8</td><td>6</td></tr><tr><td>\"</td><td>\"</td><td>20</td><td>\"</td><td>14</td><td>12</td><td>16</td><td>14</td><td>21</td><td>28</td><td>11</td></tr><tr><td>\"</td><td>\"</td><td>27</td><td>\"</td><td>24</td><td>19</td><td>23</td><td>20</td><td>17</td><td>15</td><td>12</td></tr><tr><td>\"</td><td>\"</td><td>3</td><td>\"</td><td>10</td><td>19</td><td>30</td><td>19</td><td>4</td><td>12</td><td>10</td></tr><tr><td>\"</td><td>\"</td><td>\"</td><td>\"</td><td>\"</td><td>\"</td><td>\"</td><td>\"</td><td>\"</td><td>\"</td><td>\"</td></tr><tr><td>\"</td><td>\"</td><td>\"</td><td>\"

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hours. There are, however, a few cases of diphtheria, especially those complicated with septic infection, which die, even if the remedy is used early in the course of the disease. The complications which are common during the course of diphtheria and following it, with other methods of treatment, are far less frequent and less

fessors Behring and Ehrlich, and that produced under the supervision of Dr. Aronson. The former has been produced either at the Institute for Infectious Diseases in Berlin (the amount there being only limited in quantity, and intended for experimental purposes, and for use in the hospitals connected with the institution), or by a manufacturing firm at Hoechst-am-Main. The latter, that produced under the supervision of Dr. Aronson, comes from the pharmaceutical house of Schering. Almost all that has reached this country within the last three months is the Behring product, and up to the 20th of January altogether amounted to perhaps one thousand two hundred vials. Larger consignments are now expected. In this country, measures were taken some months ago by the New York City Health Department, and more recently by the health departments of other cities, and by some private parties, for the home production of anti-toxine. That prepared in this country under the supervision of the New York City Health Department has, at the time of writing, been already employed in more than one hundred and fifty cases, and the mortality in cases thus treated has been about twelve per cent.

It does not seem, with such knowledge as we now have, as if too great enthusiasm regarding the importance of this discovery were possible. It apparently places at once within our control the means for the restriction of the most dreaded and most fatal disease of childhood—a disease which appeared only a few years ago, and which has been rapidly increasing in frequency and mortality all over the civilized world. In New York City alone, during 1894, there were over two thousand two hundred deaths reported as due to this malady. Aside from the direct practical advantage which is to be derived from the use of anti-toxine, the discovery of this new method for the treatment of an infectious disease opens a great field for study and investigation, where there is the brightest promise that other discoveries may be made which will place all infectious diseases as completely within our control as it seems probable now will be the case with diphtheria.

PROFESSOR EHRLICH.

severe, and in the cases which are treated early they are almost entirely obviated.

The production of anti-toxine requires considerable time, a high grade of technical skill, and is attended with very considerable expense. The cost of the remedy in this country up to the present time has been excessive. Where it could be obtained at all, the price has been from three to twelve dollars a dose, depending upon the strength of the serum. The prices have now been very much reduced, and probably there will be a still further reduction, as the supply is more nearly equal to the demand; but under all conditions it must be a comparatively expensive remedy. In France, the production of it has already been placed under the control of the government. It is produced only at the Pasteur Institute in Paris, under the supervision of Dr. Roux, and it is furnished from this institution to the whole of France, under certain restrictions and regulations, without charge. It cannot be bought or exported. In Germany, up to the present time,

the largest supplies come from two sources; that produced under the supervision of Pro-

SYRINGE USED IN ADMINISTERING THE ANTI-TOXINE, SHOWN AT ABOUT HALF ITS REAL SIZE,