![]() ![]() The antitoxin in turn required standardisation. At the end of this time the horse plasma contained possibly 1,000 antitoxin units per cc and the animal could continue to provide antitoxin for 2-4 years. Gradually increasing subcutaneous doses of toxin were administered over a period of 2-3 months. The antiserum was usually produced in horses. The lethal volume was required to be below 0.1cc for the toxin to be of adequate strength (4). ![]() This was the measurement of the volume of filtrate that would kill a guinea pig of 250g body weight within 5 days. The toxin could only be standardised by a biological assay. Typically, a virulent strain of bacillus was grown on a shallow layer of medium and, after 6-8 days, the formed toxin was obtained by filtration. To produce an effective antitoxin, a potent toxin was required. According to most accounts the first clinical use of the antitoxin was in Berlin on Christmas Eve 1891, when von Behring administered it to a seriously ill girl who subsequently recovered (Fig. The subsequent observation that this plasma, when actually administered to animals, could protect them from fatal doses of diphtheria toxin paved the way for the use of âdiphtheria antitoxin â to treat diphtheric patients. Consequently in 1890, von Behring and Kitasato were able to show that administration of very small amounts of diphtheria toxin to animals resulted in the presence in their plasma of a factor which, when mixed with the toxin, rendered it innocuous to animals (3). This observation was very important, since studies on hog cholera in 1885 had demonstrated that administration to an animal of very small concentrations of a bacterial product could eventually produce immunity to that infection. Thus the systemic symptoms of the disease were due to the absorption of a toxin exuded during the growth of the bacilli on the mucous membrane. The filtered broth was also shown to be toxic for rabbits, dogs, cats and horses (2). The anomaly was resolved in 1888 by the observation by two of Pasteurâs colleagues, Roux and Yersin, that the broth used to grow the cultures of bacillus diphtheriae remained toxic for guinea pigs after the bacteria had been removed by filtration. In both animals and man infected with the supposed causative organism there are severe systemic disturbances and even organ degeneration, but the bacillus could be found only in the local lesion. Nevertheless, Loefflerâs report was somewhat reserved, since he was unable to explain the systemic symptoms of diphtheria. When the cultures were inoculated onto injured mucous membranes of various animals, pseudomembranes developed, resembling those in patients. A year later Loeffler isolated and cultured the bacillus from 13 undisputed cases of diphtheria. The straight or slightly curved rods described by Klebs we know today were indeed Corynebacterium diphtheriae, although Klebsâ study was purely morphological. Klebs in 1883 described a bacillus obtained from the pseudomembranes of diphtheria patients. The emergence of the germ theory triggered the start of the scientific investigation of the aetiology of diphtheria. Should the lesion occur in the laryngeal region, the airway may become occluded and intubation would therefore be necessary. It is a thick, leathery, bluish-white pseudomembrane composed of bacteria, dead cells and fibrin. The primary lesion of the disease occurs in the upper respiratory tract. The epidemics tended to be cyclical âoften lasting for many years, and followed by intervals of quiescenceâ (1). Add to this the demoralisation and sense of impotence caused by the lack of effective treatment, then one can appreciate how dispiriting the practice of medicine could be at that time.ĭiphtheria was formally described by Bretonneau in 1826, although epidemics among children of âmalignant sore throat destroying life by suffocation and sometimes leaving paralytic sequelaeâ had been described since earliest times. The melancholic effect of having to watch a succession of children die either from suffocation or, as the disease progressed, from paralysis and heart failure, was wretched enough. These treatments stemmed from basic research into causative agents and mechanisms of toxicity.Ī prime example is diphtheria. An inability, or unwillingness, to undertake this exercise largely explains the misrepresentation by some of the value of early treatments of infections. Yet this is the only way to appreciate the progress made in the treatment and prevention of infective disease. In the sanitary 1990s it is hard to envisage the experiences of physicians working in the fever hospitals a century ago. Diphtheria levies a toll of clinical incidence of 10% of all born with a mortality of 5 to immunisation reduces this to an incidence of 1% and zero mortality.
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