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Diphtheria (page 1)
This chapter has 4 pages
© Kenneth Todar, PhD
Corynebacteria are Gram-positive, aerobic, nonmotile, rod-shaped
bacteria classified as Actinobacteria.
Corynebacteria are related phylogenetically to mycobacteria and
actinomycetes. They do
not form spores or branch as do the
actinomycetes, but they have the characteristic of forming irregular,
club-shaped or V-shaped arrangements in normal growth. They undergo
movements just after cell division, which brings them into
characteristic forms resembling Chinese letters or palisades.
The genus Corynebacterium consists of a diverse group of
including animal and plant pathogens, as well as saprophytes. Some
are part of the normal flora of humans, finding a suitable niche in
every anatomic site, especially the skin and nares. The best known
and most widely studied species is
diphtheriae, the causal agent of the disease diphtheria.
Figure 1. Stained Corynebacterium
cells. The "barred" appearance is due to the presence of polyphosphate
inclusions called metachromatic granules. Note also the characteristic
"Chinese-letter" arrangement of cells.
Diphtheria is an upper
respiratory tract illness characterized by sore throat, low fever, and
an adherent membrane (called a pseudomembrane
on the tonsils, pharynx, and/or nasal cavity. Diphtheria toxin
produced by C. diphtheriae,
can cause myocarditis, polyneuritis, and other systemic toxic effects.
A milder form of diphtheria can be
restricted to the skin.
Diphtheria is a contagious disease spread by
direct physical contact or breathing aerosolized secretions of infected
individuals. Once quite common, diphtheria has largely been eradicated
in developed nations through wide-spread use of the DPT vaccine. For
example, in the U.S., between 1980 and 2004 there were 57 reported
of diphtheria. However, it remains somewhat of a problem worldwide
(3,978 reported cases to WHO in 2006) in the face of efforts
to achieve global vaccination coverage.
Diphtheria is a serious disease, with fatality rates between 5% and
10%. In children under 5 years and adults over 40 years, the fatality
rate may be as much as 20%. Outbreaks, although very rare, still occur
worldwide, even in developed nations. Following the breakup of the
former Soviet Union in the late 1980s, vaccination rates in the
countries fell so low that there was a surge in diphtheria cases. In
there were 2,000 cases of diphtheria in the USSR. By 1998, according to
Red Cross estimates, there were as many as 200,000 cases in the
Commonwealth of Independent States, with 5,000 deaths.
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
Consequently, highly effective methods of treatment and prevention of
have been developed.
The study of Corynebacterium diphtheriae traces closely the
of medical microbiology, immunology and molecular biology. Many
to these fields, as well as to our understanding of host-bacterial
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
Syria and Egypt.
In the 17th century, murderous epidemics of diphtheria swept Europe;
in Spain the disease became known as "El garatillo" (the strangler"),
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
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
and properly identified Corynebacterium diphtheriae as the
of the disease.
In 1884, Loeffler concluded that C. diphtheriae produced a
toxin, and thereby provided the first description of a bacterial
In 1888, Roux and Yersin demonstrated the presence of the toxin in
cell-free culture fluid of C. diphtheriae which, when injected
suitable lab animals, caused the systemic manifestation of diphtheria.
Two years later, von Behring and Kitasato succeeded in immunizing
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
cause severe local reactions in humans and could not be used as a
In 1909, Theobald Smith, in the U.S., demonstrated that diphtheria
that had been neutralized by antitoxin (forming a Toxin-Anti-Toxin
remained immunogenic and eliminated local reactions seen in the
toxin. For some years, beginning about 1910, TAT was used for active
against diphtheria. TAT had two undesirable characteristics as a
First, the toxin used was highly toxic, and the quantity injected could
result in a fatal toxemia unless the toxin was fully neutralized by
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
or immunity to diphtheria in humans. Diphtheria toxin will cause an
reaction when very small amounts are injected intracutaneously. The
Test involves injecting a very small dose of the toxin under the skin
the forearm and evaluating the injection site after 48 hours. A
test (inflammatory reaction) indicates susceptibility (nonimmunity). A
negative test (no reaction) indicates immunity (antibody neutralizes
In 1924, Ramon demonstrated the conversion of diphtheria toxin to
nontoxic, but antigenic, equivalent (toxoid) by treating with
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
strains of C. diphtheriae are
lysogenic, (i.e., are infected by a temperate
Beta phage), while non lysogenized strains are avirulent. Subsequently,
was shown that the gene for toxin production is located on the DNA of
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
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
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
Diphtheria in the United States
At the turn of the century, in the United States, diphtheria
occurring primarily in children and was one of the leading causes of
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
immunization became widespread in the late 1940's, a more rapid
in the number of cases and deaths occurred.
From 1970 to 1979, an average of 196 cases per year were
outbreaks of 15 or more cases occurred in the United States between
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
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
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.