History

It is impossible to determine whether diphtheria was at any point a “new” disease in recorded human history, though it is so described during the early modern period. Diseases resembling diphtheria are also described in Greek medical literature of antiq­uity (English 1985) and during the sixteenth through eighteenth century.

A clinician of Tours trained during the French Revolution, Pierre Bretonneau was the first to de­scribe the specific clinical features of diphtheria and to give the disease its name. Witnessing relatively severe epidemics in the mid-1820s, Bretonneau care­fully noted the appearance of a pseudomembrane as a hallmark of the disease and used this particular infection to elaborate his concepts of disease specific­ity, based on uniform clinical and postmortem find­ings. Nevertheless, diphtheria was usually viewed as a disease of poverty, rather than as an exception­ally severe threat to human survival, as were epi­demics of cholera and yellow fever. Periodic peaks in diphtheria mortality received no attention among clinicians.

Immediately after Robert Koch articulated a germ theory of disease based on his 1882 work with tubercu­losis, Klebs and Loftier clearly demonstrated the pre­cise causal connection between diphtheritic organ­isms and membranous sore throat. Loftier especially provided an elegant summary of the isolation and culture of C. diphtheriae together with a description of Koch’s principles as “postulates” proving the germ theory (Lechevalier and Solotorovsky 1974). Lδffler^,s classic paper in 1884 also introduced some of the most basic and innovative research problems for germ theo­rists.

Filtering cultures of bacilli in Louis Pasteur’s labo­ratory, P. P Emile Roux and Alexandre Yersin demon­strated the probability of Loffler’s hypothesis that a toxin was involved in lethal cases of diphtheria. In 1888 they showed that bacteria-free filtrates repro­duced all features of the disease in experimental ani­mals except the formation of a membrane, and they tried unsuccessfully to apply Pasteur’s rabies method in habituating animals to the toxin. Soon afterward, in 1890, Emil Behring and Shibasaburo Kitasato, working in Koch’s laboratory, explored the use of serum from convalescing individuals to treat diphthe­ria patients (and experimental animals). Thus before the beginning of the twentieth century, diphtheria had provided the best single model for proving the germ theory of disease, and suggested the concept of the healthy carrier, the possibility of filterable (non- bacterial) disease agents, and the general usefulness of serology in diagnosis and treatment of infectious disease.

After a legendary, dramatic, Christmas eve rescue of a diphtheritic child with the Kitasato-Behring serum, Behring personally escalated his study and production of “antitoxin,” standardizing and popular­izing his procedures for harvesting immune serum from horses inoculated with filtered toxin. Diphthe­ria rapidly became a largely curable disease, and Behring was honored as the “children’s savior” and elevated to the hereditary nobility of Germany.

Finally, the study of diphtheria was involved in two further stages of twentieth-century research on the germ theory and its applications. First, the Schick test helped to identify individuals who had no immune response to small doses of toxin injected just under the skin. In the testing of immunity and the anaphylactic responses of individuals with “serum sickness” in response to foreign sera (a considerable problem with Behring’s method), clinicians used

Table VIII.36.1. Diphtheria mortality rate per

100,000 population

Levy, F.

Major, Ralph H. 1965. Classic descriptions of disease, 3d edition. Springfield, Ill.

Rice, Thurman B. 1927. The conquest of disease. New York.

Weinberg, Eugene D. 1978. Iron and infection. Microbio­logical Reviews 42: 45—66.

Williams, William C. 1984. The use of force. In The doctor stories, ed. Robert Coles. New York.

Ziporyn, Terra. 1988. Disease in the popular American press: The case Ofdiphtheria, typhoid fever, and syphi­lis, 1870-1920. Westport, Conn.

Source: Diphtheria mortality in large cities of the United States in 1947 (1948).

diphtheria throughout the early part of the century to delineate the research problems in human immu­nity (Levy 1975). (See Table VIII.36.1 for trends in large U.S. cities.) Second, in the early 1950s, identifi­cation and isolation of the phage virus that infected diphtheria bacilli greatly aided early research estab­lishing phage-bacterial chromosome relationships and, in the process, the fields of bacterial genetics and molecular biology (Berksdale 1971).

Ann G. Carmichael