TH Scarlet Fever' BY GEORGE F. DICK AND GLADYS H. DICK, Chicago, Illinois HE intelligent prevention and treatment of a disease must depend on a definite knowledge of its cause. Attempts to learn the etiology of scarlet fever have long been hampered by failure to obtain the disease experimentally. Symptoms that might represent scarlet fever in animals had been described by various authors; but these symptoms were indefinite and inconstant, and had followed inoculation with different materials and cultures. No organism had produced in animals a condition that could be accepted as experimental scarlet fever. After three or four years of work on the bacteriology of the throat, blood, urine, and organs of scarlet fever patients, we had been able to verify the results of previous investigators in regard to certain facts. First, that hemolytic streptococci are practically constantly associated with scarlet fever. Second, that, while a variety of bacteria may be found in blood cultures, no one organism is present constantly in the blood stream during the acute stage of the disease. We attempted to produce experimental scarlet fever in guinea-pigs, mice, rabbits, dogs, pigeons, and small white pigs. Monkeys were not used; because they had been so thoroughly tried by previous investigators that it seemed unnecessary to repeat their 1 Alpha Omega Alpha Address, University of Michigan, December 4, 1924. ANNALS OF CLINICAL MEDICINE, VOL. III, No. 8 work. The animals were inoculated with blood from early cases, and with pure cultures of many different bacteria obtained from scarlet fever, also with ground-up organs from postmortems, and with mucus freshly obtained from the throat early in the disease. In this long series of animal inoculations, an occasional rash was obtained, and, less frequently, desquamation. But no one organism produced these symptoms constantly in any species. So that the most essential evidence for the determination of the etiology of scarlet fever was still lacking. We decided that animals are comparatively insusceptible to the disease, and that it would be necessary to use human volunteers for the production of experimental scarlet fever. man. The successful inoculation of small pox as a preventive measure had led to the hope of a like success from inoculation of scarlet fever, and numerous attempts had been made to reproduce the disease experimentally in Erasmus Darwin, the grandfather of Charles Darwin, had urged the medical profession to undertake such inoculations in the hope of discovering a method of preventing scarlet fever. He had suggested that matter might be taken from the ulcers in the throat, or that some of the skin might be scraped off and inoculated. Attempts had been made to produce experimental scarlet fever in man by inoculation with material from erythematous areas; serum from miliary vesicles; skin scales, and blood from scarlet fever patients. Up to January, 1923, there was on record no case of undoubted experimental scarlet fever. The accidental inoculations of human beings had occurred under conditions that threw no light on the etiology of the disease. Even with human volunteers, we did not expect to obtain experimental scarlet fever readily; for it was known that less than half of the persons exposed to scarlet fever contract the disease. Healthy young adults who said that they had not had scarlet fever were chosen. In the first series of human inoculations, reported in 1921, volunteers were inoculated with fresh whole blood and fresh blood serum from acute cases of scarlet fever; also with filtered throat mucus from early cases. The results of these inoculations were negative. Then, since the hemolytic streptococcus is the organism most constantly associated with scarlet fever, and the one to which immune bodies are most constantly produced, the next volunteers were inoculated with pure cultures of hemolytic streptococci isolated from scarlet fever. In this series, we obtained an occasional sore throat and fever, but no rash. We thought that failure to obtain the rash might be due to a relative insusceptibility on the part of the volunteers, and decided to do some further inoculation experiments, using volunteers of an intelligent type, who could give their full personal and family history, and to choose them, so far as possible, from those who had never been exposed to scarlet fever. In this series, reported in 1923, we obtained a case of typical scarlet fever by inoculation with a pure culture of a hemolytic streptococcus. This streptococcus had been isolated from a lesion on the finger of a nurse who acquired the disease while caring for a convalescent scarlet fever patient. This was the first case of typical scarlet fever produced experimentally with a pure culture of any organism. A It was still necessary to learn whether the experimental scarlet fever had been produced by the hemolytic streptococcus or by a filterable virus associated with it in the culture. second group of volunteers were inoculated with a culture of the same organism after it had been passed through a Berkefeld “V” filter. These volunteers remained well. After two weeks had elapsed, and they were still well, they were inoculated with the unfiltered culture. Forty-eight hours later, one of them developed scarlet fever. This experiment furnished evidence that the experimental disease was not caused by a filterable virus but was due to the hemolytic streptococcus itself. There were still some difficulties. First, not all of the hemolytic streptococci associated with scarlet fever are of the same cultural type. Some ferment mannite, while others do not ferment mannite. And it was necessary to show that each type is capable of producing the disease. This was done by inoculating other volunteers with the second cultural type, and obtaining another case of experimental scarlet fever. The requirements of Koch's laws had now been fully met, and we were justified in concluding that scarlet fever is caused by the hemolytic streptococcus. Since the hemolytic streptococcus is found in the throat, and is only seldom present in the blood, it is evident that the rash of scarlet fever is not produced by the direct action of the streptococcus on the skin. It was still important to learn by what means the streptococcus, growing in the throat, causes the rash. We found that the scarlet fever streptococci produce a toxin. When this toxin is absorbed into the blood, it produces the rash. A The toxin is obtained by inoculating plain broth with the strains of streptococci that produced experimental scarlet fever in human beings. small amount of blood is usually added to the broth at the time of inoculation. After incubation, the broth cultures are passed through porcelain filters to remove the bacteria. The filtrate is cultured for sterility, and kept in a refrigerator. When suitable amounts of toxin are injected in susceptible persons, it may cause a reaction characterized by general malaise, nausea, vomiting, fever, and a generalized scarlatinal rash. In other words, the sterile toxin, alone, is capable of producing the characteristic symptoms of scarlet fever, including the rash. These symptoms appear within a few hours after injection of the toxin, and disappear within forty-eight hours. The toxin is resistant to heat at temperatures ordinarily employed to kill bacteria, but is destroyed by still higher temperatures. It is neutralized by convalescent scarlet fever serum due to the presence of an antitoxin in the blood of recovered patients. If persons susceptible to scarlet fever are immunized by injections of small doses of toxin, their blood serum acquires similar antitoxic properties. These facts indicate that we are dealing with a true soluble toxin, specific for scarlet fever. While minute quantities of the toxin will produce symptoms of scarlet fever in susceptible adults, laboratory animals are comparatively insusceptible to it, so that it is necessary to standardize the toxin on human beings. The discovery of this toxin offered a scientific basis for: 1. The recognition of scarlet fever streptococci. 2. The development of a skin test for susceptibility to scarlet fever. 3. Preventive immunization. The two strains of streptococci that caused experimental scarlet fever in man differed culturally, and were not agglutinated by the same immune serum, but they had in common the property of producing the specific toxin of scarlet fever. Up to the present time, there has been no satisfactory way of identifying scarlet fever streptococci. Since the recognition of the specificity of the agglutination test, and its application to the diagnosis of typhoid fever, many observations have been made on the agglutination of streptococci in relation to scarlet fever. The results of early investigators indicated that most, but not all, of the streptococci associated with scarlet fever are agglutinated by the same immune serum. But the agglutination test has not |