dose of diphtheria toxine, and in a test-tube adds a definite and known quantity of the blood to be tested. This mixture is then injected into a guinea-pig, and if the antitoxic power of the blood has been gauged aright, the animal does not suffer in the slightest degree from what under ordinary circumstances would kill ten guinea-pigs. The addition of less or weaker serum, or of more toxine, would leave the mixture still toxic. In order to obtain a definite standard with which to compare the antitoxic power of any serum, and to determine the dose of such serum, Behring and Ehrlich have described what they term a normal antitoxic serum-that is, a serum of such a strength that of a c.c. added to ten times the lethal dose of diphtheria toxine is exactly sufficient to render it innocuous, 1 c.c. of such normal serum contains one "immunisation unit," and should be sufficient, when added to a hundred times the lethal dose and injected, to render it innocuous. In horses wholly immunised the serum may be fifty or even a hundred times as active as the normal serum above mentioned, and the dose to be given varies according to the number of immunisation units in any sample. It is not here necessary to go into the question of dose, but it may be stated that 500 of these immunisation units are usually necessary to produce the desired effects in cases of diphtheria, though in some cases still larger quantities have to be used. Behring now supplies four strengths of the serum, the weakest (marked with a yellow label) is sent out for injection of cases where the disease has not already been contracted. The next (marked with a green label) is of a strength of 600 antitoxine units, and is given to those cases in which the treatment is commenced at the very outset of the disease —that is, when the first symptoms of diphtheria manifest themselves. The next stronger antitoxic serum (white label) equals 1000 antitoxine units, and is used for cases somewhat more advanced in which the prognosis is at all grave; whilst in still graver cases, and where the symptoms have been developed for some considerable time, it is often necessary to give a serum of 1500 units; this is marked with a red label, and is, of course, highly concentrated in order that the size of the dose may not be unduly increased. In place of No. 1, healthy children and adults who are exposed to diphtheritic infection may receive a quarter of the dose of the green label flask, which Behring considers will protect against diphtheria with very great certainty. Although these general directions are laid down, it is strongly insisted upon by Behring, Kossel, Roux, and in fact by all those who have had experience of antitoxic serum, that the dose must vary according to the severity of the disease, so that much must be left to the discretion of the medical practitioner in charge of the patient. The great error into which those who first use this agent fall, is the administration of far too small a dose, especially in the case of children, for whom the dose is nearly as large as it is for adults. For this reason some of the statistics published in this country and abroad are far too unfavourable to the method. The great drawback of this method is that the dose necessary to be injected is so large; but in the loose tissue of the side of the chest, the back, or the buttock, immediately under the skin, the fluid soon disappears. It is hoped that before long, however, the active principle may be separated, and so obtained in smaller bulk. So far we have dealt principally with the antitoxic serum as prepared by Behring and Roux and by Roux's method, which is certainly attended with comparatively few difficulties; these, however, have the disadvantage that they take from three to six months to give the desired results. In order to do away with this disadvantage, Klein has carried out a series of experiments in which he has been able to obtain serum of considerable activity in as short a period as 23 days. Instead of introducing the poison only, he adopts the plan used by Behring and Roux in their earlier experiments, of injecting living bacilli which have lost a certain degree of their activity, using for this purpose old cultures. He afterwards introduces toxine along with more virulent bacilli, and thus obtains in the animal such a degree of immunity that it is enabled to withstand, or to react very slightly to more than, a fatal dose of diphtheria bacilli. By the third week the animal will bear the injection of large quantities of virulent bacilli, and by the end of 23 or 26 days the serum has acquired such antitoxic properties that 1 c.c. of it will protect 40 to 80 guinea-pigs against a lethal dose of living diphtheria bacilli. It is difficult to compare these results with those obtained by Roux and Behring, but Klein's serum has been used with marked success in certain cases of diphtheria. It appears to have a special power of causing the membrane to clear away, and so to remove the manufactory of the poison, as on this membrane the diphtheria bacilli accumulate. This method is mentioned as one that may be used especially where it is desired to obtain antitoxic serum quickly. Smyrnow has suggested quite a different method of preparing antitoxine. Under Nencki's advice he passed electric currents through the serum of animals, and was thus able to endow it with a certain immunising power. But he was still more successful in obtaining powerful antitoxine by electrolysing diphtheria bouillon cultures; curiously enough, the more virulent the culture the more powerful was the antitoxic substance he obtained. When this antitoxic substance was injected into a rabbit, which 24 hours before had received about c.c. of a two or three days old diphtheria bouillon culture, there was a rapid rise of temperature followed by marked improvement in the condition of the animal. This observer believes that antitoxine can be obtained by this method that will be much more suitable for the treatment of the human subject than that obtained by the ordinary methods. His experiments, however, are far too few to carry any great weight, though they open up a most interesting field for future investigation. Assuming now that the antitoxic serum is available, how is it to be used? It has been strongly recommended that it should be used not only as a curative or direct therapeutic agent, but also as a prophylactic that is, as a protective agent against possible infection, especially during epidemics of diphtheria. It is almost too soon to consider this prophylactic property of antitoxic serum, as for some time to come the energy of those engaged in the preparation and use of this serum must be directed towards obtaining a sufficient supply for the treatment of cases of developed diphtheria. It may be well to consider what have been the results obtained up to the present, and for this purpose the statistical method will probably carry most conviction, especially if it is possible to give full and accurate detail; and now that these statistics have been criticised not only by those who have used this treatment, but also by those who oppose it because it runs counter to their feelings and ideas, they are every day more and more trustworthy, much fuller, and more valuable. It is first necessary to determine the average case mortality in diphtheria for some considerable period before the antitoxic treatment was introduced; then to see what has been the lowest case mortality during an equal and similar period for which we have any statistics; and lastly, to compare these with the case mortality of the period during which the antitoxic serum has been used. In Table I. are given the mean annual death rates from diphtheria per million living in England and Wales and in London, in four periods of three years each. Dr. Sykes gives the following statistics:-During the year 1892 there were 1962 deaths from diphtheria in London, whilst in 1893 there were 3265, or nearly twice as many deaths. Now let us see what has been the case mortality. Statistics after correction give the following results. During 1893 there were 13,694 cases of diphtheria notified in London. The mortality amongst these cases was 3195 (Lancet statistics corrected), or 23.3 per cent. Table II. gives further information, and enables us to see what is the diphtheria case mortality in large well-found hospitals. In Table III. are given statistics dealing with the diphtheria case mortality where the serum treatment has been used. Wherever possible, the case mortality over a considerable period is given in the last column of the table, for purposes of comparison. It is objected, however, that general statistics of this kind are of comparatively little value unless the age of the patient treated TABLE II. METROPOLITAN ASYLUMS BOARD: ADMISSIONS AND CASE MORTALITY, Note.-Diphtheria cases have only been admitted into the hospitals since October 23, 1883. is given. In order to determine the foundation upon which this certainly very legitimate objection is based, I have taken four series. of cases as reported, and have placed them side by side. The percentages of deaths at certain ages in the London Asylums Board hospitals before the serum treatment are given in Table IV., the percentages of deaths of four observers who have used the serum, in Tables V. and VI. It is very important, however, that the period of the disease at which the treatment is commenced should be taken into account, for, as already indicated, experience has taught that the later the stages of the disease at which this serum is injected, the stronger must be the dose given. It is necessary, therefore, to separate the cases in which the treatment is commenced at an early period from those in which it is commenced only when the poison has had time to disorganise the tissues, and to render them incapable of reacting to the antitoxic serum. Table VII., p. 448, given by Kossel, brings out the great importance of this element in keeping down the case mortality. In the first column is given the day of the illness on which antitoxic serum was first injected. For statistical purposes, too, only those cases which have been bacteriologically examined and found to be due to the action of Loeffler's diphtheria bacillus should be accepted as being cases of true' diphtheria. As most of the cases in which the diphtheria bacilli are absent run a much milder course, and are much more amenable to general treatment, and as many of these have been included under diphtheria in the old statistics, such elimination will necessarily make the record tell rather against the antitoxic serum treatment than in its favour. From a somewhat extended experience (although condensed into a very short period of time) I am satisfied that this question of the Loeffler bacillus is most important, and that every case in which the serum is used should be bacteriologically examined. |