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. Historical interest in this particular disease has nevertheless been confined largely to the role diphtheria played in the emergence and confirmation of the germ theory of disease. As Terra Ziporyn (1988) points out, diphtheria was to a considerable extent "the darling of the bacteriological revolution."

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 Loffler clearly demonstrated the precise causal connection between diphtheritic organisms and membranous sore throat. Loffler 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). Loffler's classic paper in 1884 also introduced some of the most basic and innovative research problems for germ theorists. Speculating upon the reasons why diphtheria bacilli, unlike Mycobacterium tuberculosis, failed to invade areas of the body other than the nasopharynx, Loffler ventured that an "extraordinarily deleterious" poison was disseminated through the bloodstream. Moreover, his careful work illustrated that the organism could not always be cultured from the throats of clinically "typical" cases and that healthy individuals could carry diphtheria bacilli. The latter phenomenon led Loffler in 1887 to a description of nonvirulent strains of diphtheria.

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 (nonbacterial) 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. Simultaneously, however, diphtheria was depicted as a classic, feared contagious disease and, unlike so many diseases in this category, as a widespread, merciless killer of innocent children. Indiana physician Thur-man Rice, for example, vividly recalled that his father "drove two miles out of his way to avoid passing in front of a house where there was a case of diphtheria, and yet this house stood at least one hundred yards back from the road; he had children and was taking no chances" (Rice 1927). Diphtheria also frames the plot for one of the most famous physician stories in the English language, William Carlos Williams's "The Use of Force" (1933).

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

New

Pitts

Washing

York

Chicago

Boston

burgh

ton

1890-4

134.4

117.3

112.2

86.4

77.9

1895-9

85.8

69.7

83.9

32.9

50.9

1900-4

58.0

33.9

53.7

36.9

23.5

1905-9

40.0

27.0

26.2

20.4

11.2

1910-14

28.0

37.9

20.0

29.3

6.9

1915-19

21.8

31.2

26.3

22.3

11.9

1920-4

14.0

17.5

20.2

20.1

10.5

1925-9

10.7

11.7

8.3

11.5

7.1

1930-4

2.2

4.5

3.2

5.1

3.7

1935-9

0.6

2.2

0.7

1.3

2.8

1940-4

0.1

0.8

0.4

0.5

0.2

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

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