Diphteria

Definition
Diphtheria is an acute toxic infection caused by Corynebacterium
species, typically Corynebacterium diphtheriae and rarely
toxigenic strains of Corynebacterium ulcerans. Diphtheria was the
1st infectious disease conquered by the principles of
microbiology, immunology, and public health
Etiology
Corynebacteria are aerobic, nonencapsulated, non-spore-forming,
mostly nonmotile, pleomorphic, gram-positive bacilli. C.
diphtheriae is by far the most commonly isolated agent of
diphtheria. C. ulcerans is more commonly isolated from cattle and
can cause similar disease.
As corynebacteria are not fastidious in growth requirements, their
isolation is enhanced by use of a selective medium (i.e., cystinetellurite blood agar) that inhibits growth of competing organisms
and, when reduced by C. diphtheriae, renders colonies gray-black.
Differentiation of C. diphtheriae from C. ulcerans is based on
urease activity, as C. ulcerans is urease-positive.
Four C. diphtheriae biotypes (mitis, intermedius, belfanti, gravis)
are capable of causing diphtheria and are differentiated by
colonial morphology, hemolysis, and fermentation reactions. The
ability to produce diphtheritic toxin results from acquisition of a
lysogenic Corynebacteriophage by either C. diphtheriae or C.
ulcerans, which encodes the diphtheritic toxin gene and confers
diphtheria-producing potential to these strains. Thus, indigenous
nontoxigenic C. diphtheriae can be rendered toxigenic and
disease-producing after importation of a toxigenic C. diphtheriae
and transmission of the bacteriophage. Demonstration of
diphtheritic toxin production or potential for toxin production by

an isolate is necessary to confirm disease. The former is

performed in vitro by the agar immunoprecipitin technique (Elek
test) or by the in vivo toxin neutralization test in guinea pigs, the
latter by polymerase chain reaction testing for carriage of the
toxin
gene.
Toxigenic
and
nontoxigenic
strains
are
indistinguishable by colony type, microscopy, or biochemical
tests.

Epidemiology
The only known reservoir for C. diphtheriae is the human.
Diphtheria spreads from person to person, either from acute
cases or from asymptomatic carriers. The principal modes of
spread are by respiratory droplets or direct contact with
secretions from the respiratory tract or exudate from infected
skin. Fomites and dust are not important vehicles of transmission,
but the organism can resist drying and may be isolated from floor
dust in a ward or a room in which an infected patient is being
nursed. Epidemics have been caused by milk contaminated by a
human carrier.
Some patients become carriers and continue to harbour C.
diphtheriae for weeks or months, or rarely, for a lifetime.
The incidence of diphtheria in the Western world has decreased in
the last 5075 years (152 cases per 100 000 population in 1920
to 0.002 per 100 000 in 1980 in the USA). In 2008, 47 cases were
reported across the EU. Of these, 62% were reported by Latvia.
Although diphtheria is a rare disease in the EU, the indigenous
transmission of the disease persists in certain countries and
suggests that epidemic diphtheria remains a potential threat to
the EU. Therefore, high vaccination coverage must be maintained,
adult booster coverage increased, and epidemiological
surveillance and laboratory capacity preserved despite the small
number of cases.
Although there has been a great decline in the disease in wealthy
countries (such that most physicians in these countries have

never seen a case of diphtheria), the disease is still a significant

problem in many developing countries.

easier. Diphtheria toxin can also be produced by C. ulcerans and

this has resulted in clinical diphtheria.

Pathogenesis

Diphtheria exotoxin is a 62 000 Da polypeptide, which includes

two segments: the active toxin moiety (A) and the binding (B)
segment, which binds to specific receptors on susceptible cells.
The binding B portion attaches to the cell membrane, allowing the
active A portion to enter the cells where it catalyses a reaction
that inactivates the transfer RNA (tRNA) translocase elongation
factor 2 (EF-2), in eukaryotic cells. This factor is essential for
reactions that transfer triplet codes from messenger RNA to
amino acid sequences via tRNA. Thus EF-2 inactivation stops
synthesis of the polypeptide chains. The diphtheria toxin affects
all human cells, but the most profound effects are on the
myocardium (myocarditis), peripheral nerves (demyelination) and
kidneys (acute tubular necrosis).

The potentially lethal effects of diphtheria in humans are caused

by an exotoxin. The toxigenicity of C. diphtheriae depends on the
presence of a tox+ phage ( lysogenic -phage) which induces
the organism to produce toxin. Harmless non-toxigenic strains of
C. diphtheriae, lacking the tox+ -phage, can be converted to
pathogenic toxigenic strains by infection with a lysogenic phage
(in vitro). This process may also occur in vivo.
Toxin production by corynebacteria is usually detected by Eleks
test8 or guinea pig inoculation, but recently enzyme
immunoassays have been developed which are cheaper and