ANAPHYLAXIS 361 



This generalization of Richet's observations had really been 

 foreshadowed by the observations of Magendie and by the experi- 

 ments of Flexner quoted above, but this work had been lost sight 

 of and the attention of investigators was again focused upon the 

 problem mainly by the publication of Arthus 6 in 1903 on the re- 

 peated injection of horse serum into rabbits, and some observations 

 made upon guinea pigs by Theobald Smith and communicated by 

 him in 1904 to Ehrlich. 



Arthus 7 found that horse serum injected into rabbits by any of 

 the usual paths of entrance is entirely innocuous. It is possible to 

 inject 10, 20, or even 40 c. c. without harm. If, however, one re- 

 peatedly injects small amounts, 5 c. c. or less, subcutaneously, at 

 intervals of several days, eventually the later injections will give 

 rise to infiltrations, edema, sterile abscesses, and even gangrene at 

 the points of injection. He recognized that this was not due to 

 cumulative action, and that it was not necessary to inject several 

 times in the same place to produce the characteristic response. For 

 instance, the early injections might be made into the peritoneum, 

 the subsequent ones into the skin, and the local reactions to the later 

 injections might nevertheless ensue. In other words, he recognized 

 the systemic nature of the phenomenon and regarded it as analogous 

 to the observations of Richet in that he spoke of the hypersensitive 

 rabbits as "anaphylactises" by a series of preparatory injections. 



The "phenomenon of Theobald Smith" is closely related to that 

 of Arthus, and was made in the course of the standardization of 

 diphtheria antitoxin in guinea pigs. It was noticed that guinea 

 pigs which had been used for this purpose and had survived had 

 acquired great susceptibility to subsequent injections of normal horse 

 serum made several days or weeks later. 



With these observations as points of departure, together with the 

 studies of v. Pirquet and Schick 8 upon the clinical manifestations 

 of antitoxin injections into human beings, a number of investigators 

 took up the problem, chief among them Rosenau and Anderson, of 

 the United States Hygienic Laboratory, and R, Otto, of the Frank- 

 furt Institute of Experimental Therapy. 



Although the paper of Otto 9 appeared in print a little earlier 

 than did the first one of the American workers, the investigations 

 were independent and almost synchronous. Their results, moreover, 

 confirm each other in all essentials. Otto showed that the Theobald 

 Smith phenomenon was entirely independent of the toxin or anti- 



6 Arthus. C. E. de la Soc. Biol., Vol. 55, p. 817, Reunion biol., Marseille, 

 June, 1903. 



7 Arthus et Breton. C. E. de la Soc. Biol., 55, p. 1478. 



8 Von Pirquet u. Schick. "Die Serumkrankheit," Deuticke, Wien, 1906. 



9 Otto. "Das Theobald Smithsche Phaenomen, etc., v. Leuthold Gedenk- 

 schrift," Vol. 1. 1905 ; also Otto in Erganzungsband 2, "Kolle u. Wassermann 

 Handbuch," etc. 



