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Figure 2. This figure shows the reported global incidence of diphtheria between 1980 and 2006. Generally, as vaccine coverage with DPT has increased, the incidence of diphtheria has decreased. However, note the spike between 1993 and 1997, attributable to a drop in vaccine coverage in new Independent States of the former Soviet Union, as explained in the text above. WHO.

History and Background

No bacterial disease of humans has been as successfully studied as diphtheria. The etiology, mode of transmission, pathogenic mechanism and molecular basis of exotoxin structure, function, and action have been clearly established. Consequently, highly effective methods of treatment and prevention of diphtheria have been developed.

The study of Corynebacterium diphtheriae traces closely the development of medical microbiology, immunology and molecular biology. Many contributions to these fields, as well as to our understanding of host-bacterial interactions, have been made studying diphtheria and the diphtheria toxin. Some of the milestones along this path are given below.

Hippocrates provided the first clinical description of diphtheria in the 4th century B.C. There are also references to the disease in ancient Syria and Egypt.

In the 17th century, murderous epidemics of diphtheria swept Europe; in Spain the disease became known as "El garatillo" (the strangler"), in Italy and Sicily as "the gullet disease".
 
In the 18th century, the disease reached the American colonies where it reached epidemic proportions about 1735. Often, whole families died of the disease in a few weeks.

The bacterium that causes diphtheria was first described by Klebs in 1883, and was cultivated by Loeffler in 1884, who applied Koch's postulates and properly identified Corynebacterium diphtheriae as the agent of the disease.

In 1884, Loeffler concluded that C. diphtheriae produced a soluble toxin, and thereby provided the first description of a bacterial exotoxin.

In 1888, Roux and Yersin demonstrated the presence of the toxin in the cell-free culture fluid of C. diphtheriae which, when injected into suitable lab animals, caused the systemic manifestation of diphtheria.
Two years later, von Behring and Kitasato succeeded in immunizing guinea pigs with a heat-attenuated form of the toxin and demonstrated that the sera of immunized animals contained an antitoxin capable of protecting other susceptible animals against the disease. This modified toxin was suitable for immunizing animals to obtain antitoxin, but it was found to cause severe local reactions in humans and could not be used as a vaccine.

In 1909, Theobald Smith, in the U.S., demonstrated that diphtheria toxin that had been neutralized by antitoxin (forming a Toxin-Anti-Toxin complex, TAT) remained immunogenic and eliminated local reactions seen in the modified toxin. For some years, beginning about 1910, TAT was used for active immunization against diphtheria. TAT had two undesirable characteristics as a vaccine. First, the toxin used was highly toxic, and the quantity injected could result in a fatal toxemia unless the toxin was fully neutralized by antitoxin. Second, the antitoxin mixture was horse serum, the components of which tended to be allergenic and to sensitize individuals to the serum.

In 1913, Schick designed a skin test as a means of determining susceptibility or immunity to diphtheria in humans. Diphtheria toxin will cause an inflammatory reaction when very small amounts are injected intracutaneously. The Schick Test involves injecting a very small dose of the toxin under the skin of the forearm and evaluating the injection site after 48 hours. A positive test (inflammatory reaction) indicates susceptibility (nonimmunity). A negative test (no reaction) indicates immunity (antibody neutralizes toxin).

In 1924, Ramon demonstrated the conversion of diphtheria toxin to its nontoxic, but antigenic, equivalent (toxoid) by treating with formaldehyde. He provided humanity with one of the safest and surest vaccines of all time, the diphtheria toxoid.

In 1951, Freeman made the remarkable discovery that pathogenic (toxigenic) strains of C. diphtheriae are lysogenic, (i.e., are infected by a temperate Beta phage), while non lysogenized strains are avirulent. Subsequently, it was shown that the gene for toxin production is located on the DNA of the Beta phage.

In the early 1960s, Pappenheimer and his group at Harvard conducted experiments on the mechanism of a action of the diphtheria toxin. They studied the effects of the toxin in HeLa cell cultures and in cell-free systems, and concluded that the toxin inhibited protein synthesis by blocking the transfer of amino acids from tRNA to the growing polypeptide chain on the ribosome. They found that this action of the toxin could be neutralized by prior treatment with diphtheria antitoxin.

Subsequently, the exact mechanism of action of the toxin was shown, and the toxin has become a classic model of an ADP-ribosylating bacterial exotoxin.

Diphtheria in the United States
At the turn of the century, in the United States, diphtheria was common, occurring primarily in children and was one of the leading causes of death in infants and children. In the l920's, when data were first gathered, there were approximately 150,000 cases and 13,000 deaths reported annually. After diphtheria immunization was introduced, the number of cases gradually fell to about 19,000 in 1945. When diphtheria immunization became widespread in the late 1940's, a more rapid decrease in the number of cases and deaths occurred.

From 1970 to 1979, an average of 196 cases per year were reported. Seventeen outbreaks of 15 or more cases occurred in the United States between 1959 and 1980, but there have been none since 1980. During 1980-1995, a total of 41 respiratory diphtheria cases were reported; of these, four (10%) were fatal, and all occurred in unvaccinated children.

Since 1988 Five of the six culture-positive diphtheria cases reported in the United States have been associated with importation of Corynebacterium diphtheriae, an organism believed to have become rare or to have disappeared from the United States. However, a case of infection with toxigenic C. diphtheriae discovered in 1996 showed that the bacterium remains present in areas where the disease was once endemic, such as the Northern Plains Indian Community of South Dakota. On June 1, 1996, the discovery of a 62-year-old American Indian woman infected with diphtheria led to increased surveillance of the disease among the community. C. diphtheriae was isolated in 5% of 133 patients surveyed during August-October 1996. The findings underline the need for timely vaccination by people of all ages throughout the US.