Experimental cholera in humans.

Following on the isolation of the cholera vibrio by Koch in 1883, the aetiology of the disease was established in 1892 by the fulfilment of the third of Koch's postulates in the first recorded instance of intentional infection of human beings with cholera vibrios in the laboratory. In that historic experiment Pettenkofer and Emmerich both swallowed pure cultures of Vibrio cholerae. Pettenkofer manifested a mild diarrhoea, while Emmerich was reported to have developed severe cholera (Greig, 1929). Since that time, and until recently, studies on the patho genesis of the disease have been restricted to a variety of animals, which failed to reproduce, uniformly or in a typical manner, the cardinal manifestation of the disease, the voluminous outpouring of fluid. Dutta and Habbu (1955) reported that the infant rabbit responded uniformly with choleraic diarrhoea after the intro duction of living cholera vibrios into the intestinal tract at laparotomy. This was followed by the further demonstration that experimental cholera could be produced in infant rabbits by oral administration of multiple doses of sterile filtrates of lysates of heavy suspensions of cholera vibrios (Dutta et al., 1959 ; Oza and Dutta, 1963) and even, in some cases, by sterile filtrates of the stool of cholera patients (Panse and Dutta, 1961). Thus it became evident, at least by such experiment, that choleraic disease could be produced in the absence of viable cholera vibrios. These demonstrations tended to revive the concept proposed by Koch (Pollitzer, 1959), that the signs and course of the disease in man could be explained on the assumption that the cholera vibrio pro duced a specific poison. While the pros and cons of this hypothesis have been argued by many cholera workers (Pollitzer, 1959), specific affirmative experimental evidence had been lacking. Previous reports that products of cholera vibrios could cause death of experimental animals could not be construed as conclusive evidence for a role of toxin in the disease, since the characteristic symptomatology was not reproduced. Further support for the participation of a cholerigenous pro duct released by cholera vibrios was provided by the observation (Finkelstein et al., 1964 ; Finkelstein and Norris. 1964) that filtrates of broth cultures of cholera vibrios would produce experimental cholera in infant rabbits administered single doses of those products by the oral route. A highly potent antigenic cholerigenous product was produced in a simple, synthetic liquid medium supplemented with amino acids. This filtrate, called Syncase, caused no symptoms when administered parenterally to infant rabbits. The pathological findings in the experimental cholera produced with cell-free filtrates were remarkably similar to those in humans. Sur vival of the infant rabbits with choleraic diarrhoea could be prolonged by administration of fluids according to their measured weight losses (R. A. Finkelstein, personal com munication). It was most significant that the endotoxin of the cholera vibrio could not be implicated in the production of symptoms in the infant rabbit. Similarly, cholera endo