November i, 1894J 



AVi TURE 



17 



almost incredible degree, and that the therapeutic value 

 of this serum increased up to a certain extent with the 

 amount of diphtheria-toxine which had been introduced 

 into the system ; whilst, on the other hand, the same 

 toxine injected in too large quantities might cause the 

 serum to lose its " anti-toxic" property. 



Behring afterwards immunised large animils, such as 

 sheep, horses, &:c., against diphtheria by the repeated 

 injection of diphtheria-toxine, and he observed that their 

 serum was of great value when injected into human beings 

 suffering from this disease. Before proceeding, however, 

 it may be convenient to discuss these statements at some- 

 what greater length, and illustrate them by an account of 

 a few experiments. 



Let us draw some blood from a horse which has been 

 thoroughly immunised against diphtlieria, and decant 

 the serum after its separation. We now take a filtered 

 diphtheria culture, a given quantity of which we know to 

 prove fatal to a guinea-pig of a certain weight in a certain 

 number of hours. Let us divide, for instance, 5 c.c. of 

 this filtered culture into five doses, and inject i c.c. mto 

 a guinea-pig (A) weighing 500 grammes without the 

 addition of any serum. Four other guinea-pigs of the 

 same weight as the first receive the same amount of 

 toxine and 'l c.c, 'oi c.c, 001 c.c, '0001 c.c. of the horse's 

 serum respectively. The first guinea-pig (A) will die in 

 less than twenty-four hours, but of the others, the three 

 first will recover without any symptom of illness ; whilst 

 the last, which has received "oooi c.c. only, will probably 

 die after some delay. We know, then, that the dose of 

 serum which will protect a guinea-pig of a given weight 

 against a known amount of toxine injected at the same 

 time as the serum, lies somewhere between 'ooi c.c. and 

 "OOOI c.c, and, by further experiments, the exact dose 

 may be accurately determined. In this way we may form 

 an idea of the strength of the serum, but we must always 

 remember that the data thus obtained are but approxi- 

 mate ones. 



The curative serum may be introduced into the animal 

 the day before the toxine is injected, but, in that case, a 

 much larger quantity of serum will be necessary to pro- 

 tect the animal. If the serum be inoculated at the same 

 time as the toxine, and in a different part of the body, 

 the quantity of serum must also be increased if the 

 curative effects are to be apparent. If, some time is 

 allowed to elapse between the injection of the toxine and 

 that of the curative serum, the quantity of serum — in order 

 to be effective — must be proportionately greater ; but I 

 have seen animals recover when the injection of the 

 curative serum had been delayed eleven hours after the 

 introduction of the toxine, which proved fatal to the 

 control animals in 28-4S hours. In this latter case the 

 dose necessary to cure was 5000 times that sufficient to 

 immunise when the serum was injected with the toxine. 



Can any opinion be formed as to the mechanism 

 in which this serum exerts its action.' The first ex- 

 planation which suggests itself is that when the curative 

 serum and the toxine are mixed together in the syringe 

 or in the animal's body, the toxine is either destroyed or 

 simply neutralised, just as the acid in a given solution 

 may be neutralised by an alkali. 



Yet there are several facts which negative this opinion, 

 or rather which tend to prove that this destruction and 

 neutralisation of the toxine, if destruction or neutralisa- 

 tion there be, is eftected through the agency of the cells 

 of the body. In the first place, if the whole were simply 

 a chemicaL process, we should expect it to take place 

 with mathematical precision. Thus, if -001 c.c. of horse's 

 serum did destroy or neutralise i c.c. of toxine, this 

 neutralisation should be apparent whether the mixture 

 be injected into a guinea pig, a rabbit, or a sparrow. 

 But it is not so ; on the contrary, it has been found that in 

 certain animals a very small amount of curative serum is 

 sufficient to render harmless a certain amount of toxine 



NO. 



VOL. 



51] 



when the same amount of serum utterly fails to do so in 

 animals of another species. Even if the same species of 

 animals be used the curative effect will differ in intensity, 

 according to whether the mixture be injected directly into 

 the blood, or into the subcutaneous tissue. .Moreover, 

 if a number of guinea-pigs be injected each with the same 

 amount of toxine and varying doses of curative serum, it 

 is of frequent occurrence that some animals will resist 

 when they have received but a very small quantity of 

 serum ; while others, which have received equal or even 

 larger quantities of serum, speedily perish. Had we to 

 deal with a simple chemical neutralisation or destruction 

 of poison, identical results should occur in all animals. 

 The action of the curative serum may also be inhibited 

 by weakening the cells of the animal body by the action 

 of bacterial or other protoplasmic poisons. Hence I 

 consider that the term "anti-toxic," which has been used 

 up to the present to denote this property of the serum, is 

 only approximately correct ; and I would prefer to sub- 

 stitute the word "curative," until such time as the mode 

 of action of the serum has been accurately determined. 



Before speaking of the application of this method to 

 the cure of diphtheria in the human subject, and to the 

 results which have been obtained in the hands of such 

 experimenters as Behring, Koux, Khriich, Kossel, 

 Wassermann, Heubner and others, it must be pointed 

 out how the disease in man differs from and resembles 

 that produced experimentally in animals by the subcu- 

 taneous inoculation of the bacillus diphtheria', or of its 

 poisons. In both man and animals the symptoms are, 

 to some extent, produced (Roux, Behring, Sidney Martin) 

 by the absorption of the poisons secreted by this specific 

 bacillus. But in man the production of these poisons is 

 facilitated by the fact that the bacillus lives on the 

 surface of the membrane, where it is exposed continually 

 to the action of the air entering and leaving the lungs. 

 Now, it has been shown experimentally that the easiest 

 way of obtaining a large amount of diphtheria toxine 

 from the diphtheria-bacillus growing in an artificial 

 medium, is to expose the surface of this medium 

 to a current of air. In the respiratory passages of 

 man these conditions are exactly fulfilled, and the 

 bacillus is able to produce large quantities of toxine. 

 In the second place, the upper respiratory passages are 

 crowded with all sorts of non pathogenic and some 

 pathogenic micro-organisms, the chief among the latter 

 being the staphylococcus albus and aureus, and the 

 various kinds of streptococci. These multiply on the 

 soil prepared by the bacillus diphtheria-, and secrete 

 their toxine, which being absorbed, add their poisoning 

 action to the deleterious action of the specific bacillus. 

 In the preceding paragraph, I have drawn attention 

 to the fact that the toxines of another micro-organisn\ 

 will inhibit the action of the curative serum ; and 

 there can be little doubt that the toxines secreted by 

 these micro-organisms in man will have the same effects. 

 The formation of the membrane also, and the mechanical 

 obstruction so produced, may in themselves be the cause 

 of death. It must be added, also, that diphtheria is 

 chielly a disease of the poor, and that in many cases the 

 diagnosis is delayed, and the treatment is not begun 

 until the patient is almost moribund. It is plain, there- 

 fore, that in the diphtheria of man we have al". the con- 

 ditions which are favourable to the production of the 

 poison, and the inhibition of the action of the therapeutic 

 serum. Hence we cannot be astonished that the ileath- 

 rate at the Hupital Trousseau in Paris amounted during 

 the last six months to 62 per cent, of all cases admiiteci 

 for this disease, and not treated with curative serum. 



An examination of the statistics lately published by 

 Dr. Koux, the eminent director of the Instilut Pasteur, 

 will allow us to form some idea of the value of the cura- 

 tive serum when applied to man. The reason for 

 choosing these statistics is that they contain all the 



