ii.

  Gram-Positive Bacilli

Corynebacterium diphtheriae
206  (Diphtheria)
Rob Roy MacGregor

SHORT VIEW SUMMARY

Definition
• Corynebacterium diphtheriae, a gram-positive
bacillus, classically produces epidemic upper
respiratory tract infections with high mortality
rates in unimmunized subjects.
Epidemiology
• Humans are the only known reservoir, and the
disease spreads via air and direct contact.
Asymptomatic carriage is important in
transmission. Diphtheria is now rare in the West
and endemic in the Third World, especially
Southeast Asia. Fewer than 5000 annual cases
have been reported worldwide since 2000.
Microbiology
• The bacillus is nonsporulating,
unencapsulated, and nonmotile. It produces
brown colonies and halos on tellurite medium
and requires lysogenic β-phage to produce
toxin responsible for the disease. Four biovars
and 86 ribotypes have been identified for
tracking. Nontoxigenic strains occasionally
cause disease, as do toxin-producing
Corynebacterium ulcerans strains.
Clinical Manifestations
• Subacute faucial infection causes low-grade
fever, hoarseness, pain, and a necrotic
pseudomembrane that can extend to larynx
and cause stridor and fatal obstruction.
Circulating toxin causes potentially fatal
carditis and motor neuropathy. Cutaneous
infection causes indolent ulcers.
Diagnosis
• Diagnosis is presumptive, based on tonsillitis/
pharyngitis with necrotic membrane,
hoarseness, palatal paralysis, low-grade fever,
and recent travel to an endemic area.
Confirmation is made by observing brown
colonies on tellurite medium, a distinctive
Gram stain, and biochemical tests. Polymerase
chain reaction shows a toxin gene, which is
the key to alert the laboratory for culture.
Therapy
• Diphtheria antitoxin (DAT), produced in horses
and obtained from the Centers for Disease
Control and Prevention, must be given
intravenously without waiting for diagnosis
confirmation. The dose depends on the
duration and extent of disease. Test patients
first for horse protein hypersensitivity.
Consider tracheostomy to protect airway.
Cardiographic monitoring is wise because of
toxin cardiotoxicity. Antibiotics are given orally
or parenterally for 14 days to stop toxin
production and eradicate throat carriage.
Adults can be given procaine penicillin
600,000 units IM every 12 hours until oral
medication is tolerated, followed by penicillin
V 250 mg or erythromycin 500 mg every 6
hours.
Prevention
• Toxoid immunization consists of TDaP 5 times
up to 7 years of age. Td boosters should be
given at 10-year intervals. See text for use of
Tdap in adolecents and adults, and during
pregnancy. Penicillin or erythromycin should
be given for 14 days to carriers to prevent
clinical infection or spread. Close contacts of
cases should be cultured, given antimicrobial
prophylaxis, and, if not fully immunized,
vaccinated.

The name diphtheria was coined in 1821 by Bretonneau, from the
Greek root for “leather,” describing the tough pharyngeal membrane
that is the hallmark of the disease. The definition of diphtheria as a
unique syndrome, the explanation of its pathogenesis, and its subse-
quent control parallel the development of the fields of pathology, bac-
teriology, and immunology. Through the first half of the 20th century,
it was a major worldwide health problem and then yielded to vigorous
public health control measures. However, the epidemic that occurred
in the 1990s in the former Soviet Union and adjacent areas because
of relaxed immunization practices and social disorganization is a
reminder of the need for sustained vigilance.
HISTORY
Although clinical descriptions of sore throat, membrane production,
and death by suffocation appear in Hippocratic writings, epidemics of
“throat distemper” are not described until the 16th century.1 A major
epidemic occurred in New England in the early 1700s, killing an
estimated 2.5% of the total population and up to one third of all chil-
dren. Thereafter, similar epidemics were reported at about 25-year
intervals throughout the 18th and 19th centuries. Diphtheria was not
clearly differentiated from other upper respiratory illnesses, viewed
collectively as “croup” or “distemper,” until an epidemic in southern
France in 1821 when the clinician-pathologist Pierre Bretonneau first
described its unique clinical characteristics. However, arguments about
the differentiation among diphtheria, croup, and other throat distem-
pers continued through most of the 1800s.2
2366
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The first major advance occurred in 1883 when Klebs described
chaining cocci and bacilli in microscopic sections of diphtheritic mem-
branes. The following year, working in Koch’s laboratory in Berlin,
Loeffler first isolated the diphtheria bacillus in pure culture, aided by a
culture medium of his own design that is still used today. He then dem-
onstrated that the organism could reproduce the disease in guinea pigs,
thus fulfilling his mentor’s postulates for proof that it was the etiologic
agent for diphtheria.3 He demonstrated that healthy individuals could
carry the organism asymptomatically in their throats, thus establishing
the carrier state as an important phenomenon in the maintenance and
spread of the disease. He also noted that the organisms remained in the
membrane without invading the tissues of the throat or more distant
sites and theorized that the neurologic and cardiologic manifestations
of the disease were caused by a toxic substance elaborated by the organ-
ism. In 1888 Roux and Yersin, working at the Pasteur Institute, proved
Loeffler correct by demonstrating that bacteria-free filtrates of cultures
of diphtheria bacilli were able to kill guinea pigs. Two years later, von
Behring, also working in Koch’s laboratory, demonstrated that antise-
rum against the toxin was capable of protecting infected animals from
death following infection. Then in 1894, Roux reported that adminis-
tration of antiserum produced in horses reduced mortality from diph-
theria among abandoned children in Paris from 51% to 24%.
In 1913 Schick reported that an individual’s local reaction to injec-
tion of toxin into the skin could be used to predict susceptibility to
infection (a negative reaction indicated presence of protective anti-
toxin antibodies). At the same time, Theobald Smith and von Behring
 2366.e1
KEYWORDS
antitoxin therapy; bullneck appearance; diphtheritic membrane;
epidemic risk; myocarditis; toxin effects; toxoid immunization

Chapter 206  Corynebacterium diphtheriae (Diphtheria)

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successfully immunized children with a toxin-antitoxin mixture. In
1923 Ramon, at the Pasteur Institute, found that exposure of toxin to
formalin and heat rendered it nontoxic to recipients while retaining its
ability to induce an antibody response. The following year, clinical
trials showed that injection of this “toxoid” induced a high level of
protection among recipients. Problems of antigenic standardization,
optimal dosage, need for boosting, and so forth delayed widespread
immunization with toxoid, but between 1930 and 1945, most Western
countries established intensive programs of childhood immunization.
The result was a dramatic decrease in the incidence of diphtheria, from
about 200,000 cases in the United States in 1921 to 0 to 2 cases yearly
since 2000. During the 1950s, toxin production by Corynebacterium
diphtheriae was shown to depend on the presence of a lysogenic β-
phage, and during the following decade, the mechanism by which
toxin inhibited protein synthesis was elucidated.4-6 By the 1980s, diph-
theria had become a rare occurrence in most countries that had effec-
tive immunization programs, but in 1990, a large epidemic of diphtheria
began in the former Soviet Union and extended to Eastern Europe and
parts of Asia. The reestablishment of vigorous immunization policies
and other public health measures after the peak of the epidemic in
1994 again controlled this ancient scourge.7
PATHOGEN
C. diphtheriae is a nonsporulating, unencapsulated, nonmotile, pleo-
morphic, gram-positive bacillus. Its name is derived from the Greek
korynee, or “club,” referring to its clubbed ends, and diphthera, meaning
“leather hide,” for the characteristic leathery pharyngeal membrane
that it provokes. When inoculated on the nutritionally inadequate
medium devised by Loeffler, it initially outgrows other throat flora, so
plates should be inspected for growth after 12 to 18 hours. The char-
acteristic metachromatic granules (best seen with methylene blue
staining) and “Chinese character” palisading morphology that differ-
entiate it from other corynebacteria are displayed more prominently
on smears taken from colonies grown on this medium than with direct
smears from clinical specimens. The current selective potassium tel-
lurite media, such as modified Tinsdale, inhibit many of the normal
throat flora and identify any C. diphtheriae (and Corynebacterium
ulcerans) present as brown/black colonies with brown halos containing
reduced tellurite. Tinsdale medium has a short shelf life, and most
laboratories do not stock this medium. C. diphtheriae will grow on
routine blood agar but will not be identified unless the laboratory is
alerted to the possible diagnosis.
The species is subdivided into four biovars—gravis, intermedius,
mitis, and belfanti—based on differing colonial morphology on tellu-
rite agar, fermentation reactions, and hemolytic potential. Modern
molecular techniques have proved to be more sensitive in recent out-
breaks for tracking different strains: Ribotyping (the use of restriction
endonucleases to detect polymorphisms of recombinant RNA genes),
pulsed-field gel electrophoresis (PFGE) analysis of genomic DNA, and
multilocus enzyme electrophoresis of organism sonicates have shown
that an epidemic clone of C. diphtheriae emerged in Russia in 1990 and
became increasingly common as the epidemic progressed.8,9 An inter-
national C. diphtheriae ribotype database, established at the Pasteur
Institute and now maintained at the Health Protection Agency in
London, contains more than 86 distinct BstEII ribotypes of toxigenic
and nontoxigenic C. diphtheriae submitted from throughout the
world.10 Ribotyping is considered the “gold standard” for discriminat-
ing among strain types, although multilocus sequence typing (MLST)
holds promise for fast and cheap alternatives.11 Up-to-date surveillance
information is available for Europe through the 25-nation Diphtheria
Surveillance Network (DIPNET).12
Exotoxin production by C. diphtheriae depends on the presence of
a lysogenic β-phage, which carries the gene encoding for toxin (tox+).4,6
In its lysogenic phase, the phage’s circular DNA integrates into the host
bacteria’s genetic material as a prophage, with the result that the host
cell now can express the gene necessary for synthesis of the polypeptide
toxin. When induced by stimuli such as ultraviolet light, the phage
enters a lytic cycle, destroying the host cell and releasing new β-phage.
Strains of C. diphtheriae lacking lysogenic phage do not produce toxin,
but they can be converted to toxigenicity in the laboratory by infection
with the lysogenic tox+ phage (“lysogenization”). Evidence has been
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2367
13
found that such conversion also occurs in nature. (As noted later,
strains of C. ulcerans and Corynebacterium pseudotuberculosis can also
carry the phage and produce a diphtheria-like illness.) In addition to
the tox+ gene, significant toxin production requires that bacterial
Chapter 206  Corynebacterium diphtheriae (Diphtheria)
growth be slowed by exhaustion of iron in the environment.
EPIDEMIOLOGY
Humans are the only known reservoir for C. diphtheriae. The primary
modes of spread are by airborne respiratory droplets and direct contact
with either respiratory secretions or exudate from infected skin lesions.
Fomites can play a role in transmission, and epidemics have been
caused by contaminated milk. In temperate climates, most respiratory
tract disease occurs in the colder months, associated with crowded
indoor living conditions and hot, dry air. Asymptomatic respiratory
carriage is important in perpetuating both endemic and epidemic
diphtheria, and immunization reduces an individual’s likelihood of
being a carrier. Current reservoirs for disease are obscure. In endemic
conditions, 3% to 5% of healthy individuals may harbor the organism
in their throats,14 but in the West, where the disease has become
uncommon, isolation of the organism from healthy individuals has
become extremely rare. Skin infection, once thought to be primarily a
problem in tropical environments, has caused several recent epidemics
in Europe and North America among alcoholics and other disadvan-
taged groups.15,16 Thus, skin carriage of C. diphtheriae can act as a silent
reservoir for the organism, and it has been found that person-to-per-
son spread from infected skin sites is more efficient than from the
respiratory tract.17,18
The incidence and pattern of diphtheria in the Western world
changed dramatically during the 20th century, to the point at which it
has become rare (Fig. 206-1). For example, 147,991 cases were reported
in the United States in 1920 (151 cases/100,000 population) but only
0 to 2 since 1998 (<0.001/100,000).19,20 From the 1960s to 1990, similar
decreases occurred in Europe20-22 and, less dramatically, worldwide,
although the disease has remained endemic in many parts of the Third
World (e.g., Haiti, Eastern Mediterranean region, the Indian subcon-
tinent, Indonesia, the Philippines).20,23 Moreover, pockets of skin and
pharyngeal colonization and disease continue to be identified among
Native American groups, destitute inner-city dwellers, substance
abusers, and homosexual men, giving rise to concern that outbreaks
could occur, particularly among adults in the West, where the propor-
tion of adults with protective antibody levels is as low as 50%.24
Beginning in 1990, epidemic diphtheria began in Russia and swiftly
spread to all countries of the Russian Federation and Baltic states.7,25
In 1995 a peak of 50,425 cases were reported there, for a yearly rate of
17.3/100,000.25 The World Health Organization (WHO) and United
Nations Children’s Fund (UNICEF) formulated a strategic plan to
control the epidemic, including (1) mass immunization with at least
one dose of toxoid to the whole population, (2) early detection and
proper management of cases, and (3) early identification and proper
management of close contacts. In response, new cases in the Russian
250,000 6
5
Number of cases
200,000 4
Number of cases
3
150,000
2
100,000 1
0
50,000 80 83 86 89 92 95 98
Year
0
1920 1930 1940 1950 1960 1970 1980 1990
Year
FIGURE 206-1  Annual incidence of diphtheria in the United
States, 1920 to 1998. (From Golaz A, Hardy IR, Strebel P, et al. Epidemic
diphtheria in the Newly Independent States of the former Soviet Union:
implications for diphtheria control in the United States. J Infect Dis 2000;
181[suppl 1]:S237-S243.)
 2368
Federation fell to 1377 in 2001 and to fewer than 100 in 2007.20,26 The
2011 WHO summary of vaccine-preventable diseases20 reported a total
of fewer than 5000 cases of diphtheria worldwide, roughly stable since
2000. Ninety percent of cases were from the Southeast Asia region,
Part III  Infectious Diseases and Their Etiologic Agents
with 79% of those from India. Localized outbreaks are also reported
broadly across the region, with a major focus in East Java. Elsewhere,
an outbreak of more than 10,000 cases was reported in the Darfur
region of the Sudan, and endemic cases continue in Haiti and the
Dominican Republic. Unfortunately, most of these reports are faulted
by a paucity of laboratory confirmation. Travelers to any of these areas
should be sure that their immunization is current and consider diph-
theria if they develop suggestive symptoms.
A defining characteristic of the Russian epidemic was that half or
more of cases occurred among those 15 years of age or older, suggest-
ing that the young remained relatively well protected by the high rates
of infant immunization operative in the 1980s. Older people were
vulnerable because they had either not been vaccinated as children or
their protective antibody levels had faded in the absence of subsequent
boosting by vaccine or colonization.7,24,27,28
When it was common in the West, diphtheria primarily affected
children younger than 15 years, but recent outbreaks have also involved
unimmunized or poorly immunized adults, particularly the urban and
rural poor. Minority racial groups have had attack rates 5 to 20 times
higher than whites. For example, in 1996, a focus of toxigenic diphthe-
ria was discovered among Native Americans in South Dakota, which
by molecular subtyping methods was found to have been endemic in
the area since the 1970s. Enhanced surveillance of patients in this
community with upper respiratory symptoms showed that almost 4%
of them were carrying toxigenic C. diphtheriae.29,30
Since 1995, there has been growing awareness of two phenomena:
disease caused by nontoxigenic strains of C. diphtheriae and disease
caused by toxin-producing C. ulcerans. Nontoxigenic C. diphtheriae
has produced typical respiratory tract diphtheria, milder pharyngitis
and asymptomatic pharyngeal carriage, bacteremia, endocarditis, and
bone and joint infections.15,31-39,40 Toxigenic C. ulcerans can also cause
classic respiratory diphtheria and skin lesions.41,42 Of more recent
concern, among the isolates recovered from nontoxigenic invasive
disease strains, are strains that bear the tox gene but do not express the
toxin.42a These strains carry the potential to serve as a reservoir for
diphtheria, given their potential to revert to toxin producers.
Although immunized individuals can still develop clinical diphthe-
ria, prior immunization reduces the frequency and severity of disease:
Between 1959 and 1970 in the United States, two thirds of reported
cases had received no immunization, 13% more had had one to two
doses of toxoid, and only 19% reported receiving three or more doses
and could be considered fully immunized.43 Among cases reported
since 1980, no cases were fully immunized.19 Disease was considered
severe in 25% of unimmunized patients compared with 6.3% of those
fully immunized; even partial immunization reduced morbidity and
mortality rates by more than 50%. The benefit of prior immunization
was also demonstrated in the recent Russian epidemic.44,45
The full explanation for the dramatic decrease in diphtheria’s inci-
dence in immunized populations is not evident. Immunization with
toxoid is generally thought to attenuate only the local and systemic
effects of toxin without preventing local colonization with the organ-
ism. If so, carriage would be expected to remain high in the population,
and diphtheria should be an ongoing occurrence among the sizable
proportion believed to be inadequately immunized. However, disease
has become rare and surveys show an extremely low incidence of
carrier state. Nonetheless, results from the Third National Health and
Nutrition Examination Survey (1988 to 1994) showed what are con-
sidered subprotective levels of serum antitoxin in 40% of the overall
population.46 The percentage with protective antibody decreased with
increasing age, and only 30% of men aged 60 to 69 years were thought
to have protective levels. In 1985 the U.S. preschool immunization rate
was only 64.9% for diphtheria-pertussis-tetanus (DPT)47; fortunately,
the 2011 National Immunization Survey showed that since 2007 at least
95% of children 19 to 35 months of age had received at least three doses
of DPT vaccine.48 Several factors may contribute to the current low
incidence of disease. First, although unproved, historical evidence
suggests that diphtheria has occurred in cycles that include gaps of
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100 years or more.1 Second, organisms isolated from immunized indi-
viduals are less likely to be toxigenic than are those from unimmunized
carriers (64% vs. 94%).46 If toxin production confers no advantage to
the organism in an immunized host, its metabolic cost would put
toxigenic organisms at a selective disadvantage, and so loss of this
attribute might be predicted.5 Third, some experts believe that the local
elaboration of toxin, in the absence of antibody, enhances an organ-
ism’s ability to colonize. Immunization with toxoid could counteract
this selective advantage of toxigenic strains. Fourth, virulence factors
other than toxin production may exist. For example, in an outbreak in
Sweden, investigators used genetic probes to demonstrate that all clini-
cal cases were caused by a single strain, although several different
toxigenic strains were present in the population.49 Finally, protection
may correlate with lower serum concentrations of antitoxin antibody,
or other immune mechanisms that are not measured may be protec-
tive. To explain the absence of diphtheria in the West and the occur-
rence of the recent epidemic in the Russian Federation, the following
model has been proposed24,25,27,45: Absence of an effective immuniza-
tion program allows for high carriage rates of toxigenic strains, which
leads to high rates of infant disease, and survivors in such populations
are continually immunized by adult colonization with toxigenic strains,
which explains low adult disease rates. Pediatric immunization pro-
grams reduce carriage rates of toxigenic strains because toxin produc-
tion does not provide an advantage to the organism, and even
nontoxigenic strain carriage falls. As a result, adults lose the opportu-
nity for natural antibody boosting from asymptomatic carriage, so
protective antibody levels wane in the adult population immunized
only in childhood. Fortunately, good pediatric immunization pro-
grams appear to be sufficient to keep toxigenic strains from circulating
and causing adult disease. Ultimately, if pediatric programs lapse, the
population then contains both vulnerable children and adults, a situa-
tion that promotes epidemics. Thus, the public health strategy must be
to maintain pediatric programs with more than 90% immunization
rates and to strongly promote periodic adult boosters.
PATHOGENESIS
C. diphtheriae is not a very invasive organism, ordinarily remaining in
the superficial layers of the respiratory mucosa and skin lesions, where
it can induce a mild inflammatory reaction in the local tissue. The
major virulence of C. diphtheriae results from the action of its potent
exotoxin, which inhibits protein synthesis in mammalian cells but not
in bacteria. The 62,000-Da polypeptide toxin is composed of two seg-
ments: B, which binds to specific receptors on susceptible cells, and A,
the active segment. After proteolytic cleavage of the bound molecule,
segment A enters the cytosol, where it catalyzes inactivation of the
transfer RNA (tRNA) translocase, “elongation factor 2,” present in
eukaryotic cells but not in bacteria. Loss of this enzyme prevents the
interaction of messenger RNA and transfer RNA, stopping further
addition of amino acids to developing polypeptide chains.50 The toxin
affects all cells in the body, but the most prominent effects are on the
heart (myocarditis), nerves (demyelination), and kidneys (tubular
necrosis). Diphtheria toxin is extremely potent: A single molecule can
stop protein synthesis in a cell within several hours, and 0.1 µg/kg will
kill susceptible animals.
Within the first few days of respiratory tract infection, toxin elabo-
rated locally induces a dense necrotic coagulum composed of fibrin,
leukocytes, erythrocytes, dead respiratory epithelial cells, and organ-
isms (Fig. 206-2). Removal of this adherent gray-brown “pseudomem-
brane” reveals a bleeding edematous submucosa. The membrane can
be local (tonsillar, pharyngeal, nasal) or extend widely, forming a cast
of the pharynx and tracheobronchial tree. The underlying soft tissue
edema and cervical adenitis can be intense, and, particularly in the
proportionally smaller airways of children, can cause respiratory
embarrassment and a bullneck appearance. In both adults and chil-
dren, a common cause of death is suffocation after aspiration of the
membrane.
CLINICAL MANIFESTATIONS
Symptoms of infection with C. diphtheriae occur locally in the respira-
tory tract and skin secondary to noninvasive infection of these two
organs, as well as at distant sites secondary to absorption and

FIGURE 206-2  Diphtheria involving a pharyngeal tonsil. The
membrane-tissue junction is clearly marked by intense cellular infiltration.
(From Moore RA. A Textbook of Pathology. Philadelphia: Saunders; 1944.)
dissemination of diphtheria toxin. Occasionally, C. diphtheriae dis-
seminates from the skin or respiratory tract and causes systemic infec-
tions, including bacteremia, endocarditis, and arthritis.
Respiratory Tract Diphtheria
Asymptomatic upper respiratory tract carriage of the organism occurs
commonly in areas where diphtheria is endemic and is an important
reservoir for maintenance and spread of the organism in a population.
However, in the industrial Western world, throat colonization has
become exceedingly rare, except in individuals associated with pockets
of infection, such as the inner-city poor and rural poverty areas.
Following an incubation period averaging 2 to 4 days, local signs
and symptoms of inflammation can develop at various sites within the
respiratory tract.
Anterior Nasal
Infection limited to the anterior nares presents with a serosanguineous
or seropurulent nasal discharge often associated with a subtle whitish
mucosal membrane, particularly on the septum. The discharge can
excite an erosive reaction on the external nares and upper lip, but
symptoms generally are mild and signs indicating toxin effects are rare.
Faucial
Including the posterior structures of the mouth and the proximal
pharynx, this area is the most common site for clinical diphtheria.
Onset is usually subacute over several days, with low-grade fever
(rarely >102.5° F), malaise, sore throat, mild pharyngeal injection, and
development of a membrane typically on one or both tonsils, with
extension variously to involve the tonsillar pillars, uvula, soft palate,
oropharynx, and nasopharynx (Fig. 206-3). The membrane initially
appears white and glossy but evolves into a dirty gray color, with
patches of green or black necrosis. The severity of symptoms correlates
with the extent of the membrane: Localized tonsillar disease is often
mild, but involvement of the posterior pharynx, soft palate, and peri-
glottal areas is associated with profound malaise, weakness, prostra-
tion, cervical adenopathy, and swelling. The latter can distort the
normal contour of the submental and cervical area, creating a bullneck
appearance and causing respiratory stridor.
Laryngeal and Tracheobronchial
Pharyngeal infection may spread downward into the larynx, or occa-
sionally the disease may begin there. Symptoms then include hoarse-
ness, dyspnea, respiratory stridor, and a brassy cough. Edema and
membrane involving the trachea and bronchi can embarrass respira-
tion further, such that patients appear anxious and cyanotic, use acces-
sory muscles of respiration, and demonstrate inspiratory retractions of
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2369
Chapter 206  Corynebacterium diphtheriae (Diphtheria)
FIGURE 206-3  Pharynx of a 39-year-old woman with bacteriologi-
cally confirmed diphtheria. Photograph taken 4 days after the onset of
fever, malaise, and sore throat. Hemorrhage due to removal of the mem-
brane by swabbing appears as dark area on the left.
intercostal, supraclavicular, and substernal tissues. If this state is not
relieved promptly by intubation and mechanical removal of mem-
brane, patients become exhausted and die.
Systemic complications are due to diphtheria toxin, which, although
toxic to all tissues, has its most striking effects on the heart and nervous
system.
Cardiac Toxicity
Subtle evidence of myocarditis can be detected in up to two thirds of
patients, but 10% to 25% develop clinical cardiac dysfunction, with the
risk to an individual patient correlating directly with the extent and
severity of local disease.51,52 Cardiac toxicity can be acute, with conges-
tive failure and circulatory collapse, or more insidious, after 1 to 2
weeks of illness with progressive dyspnea, weakness, diminished heart
sounds, cardiac dilation, and gallop rhythm. Changes in electrocardio-
graph (ECG) pattern, particularly ST-T wave changes and first-degree
heart block, can progress to more severe forms of block, atrioventricu-
lar (AV) dissociation, and other arrhythmias. Because patients without
clinical evidence of myocarditis may have significant electrical changes,
it is important to monitor their cardiograms routinely. Elevations of
serum aspartate transaminase (AST) concentration closely parallel the
intensity of myocarditis and so may be used to monitor its course.
From a prognostic standpoint, patients with electrocardiographic
changes of myocarditis have a mortality rate three to four times higher
than those with normal tracings. In particular, AV and left bundle-
branch blocks carry a mortality rate of 60% to 90%, and survivors may
be left with permanent conduction defects.53 Patients with prolonged
P-R intervals and minor T-wave changes generally do well, and these
abnormalities ordinarily resolve with time.
Neurologic Toxicity
This complication is also proportional to the severity of the primary
infection. Mild disease only occasionally produces neurotoxicity, but
up to three fourths of patients with severe disease can develop neu-
ropathy. Within the first few days of disease, local paralysis of the soft
palate and posterior pharyngeal wall occurs commonly, manifested
by regurgitation of swallowed fluids through the nose. Thereafter,
cranial neuropathies causing oculomotor and ciliary paralysis are also
common, and dysfunction of facial, pharyngeal, or laryngeal nerves,
although rare, can contribute to the risk for aspiration. Peripheral
neuritis develops later, from 10 days to 3 months after the onset of
disease in the throat.54 Principally a motor defect, it begins with proxi-
mal muscle groups in the extremities and extends distally, particularly
affecting the dorsiflexors of the feet. Dysfunction varies from mild
weakness with diminished tendon reflexes to total paralysis. Occasion-
ally motor nerves of the trunk, neck, and upper extremity are involved,
as are sensory nerves, resulting in a glove-and-stocking neuropathy.
 2370
Microscopic examination of affected nerves shows degeneration of
myelin sheaths and axon cylinders. Although slow, total resolution of
all diphtheritic nerve damage is the rule.
Part III  Infectious Diseases and Their Etiologic Agents
Other Complications
Renal failure from direct toxin action or hypotension and pneumonia
are common in severe cases. Rarely, encephalitis and cerebral infarc-
tion have been described.
Several excellent clinical descriptions of endemic and epidemic
diphtheria in the United States indicate that roughly half of all reported
cases were categorized as mild, often without a membrane, and that
both the frequency of various symptoms and severity of disease are
inversely proportional to the patient’s immunization history.54-58 Mor-
tality rates vary from 3.5% to 12% and have not changed in the past 50
years. Rates are highest in the very young and very old. Most deaths
occur in the first 3 to 4 days from asphyxia or myocarditis; fatal
outcome is rare in a fully immunized individual. Sore throat (85% to
90%), fever (50% to 85%), and dysphagia (26% to 40%) are the most
common symptoms, and membranes and cervical adenopathy are seen
in about half of cases. The recent experience in Russia has been
similar.44 The frequency of complications such as myocarditis and neu-
ritis is directly related to the time between onset of symptoms and
administration of antitoxin and to the extent of membrane formation.
Cutaneous Diphtheria
It has long been recognized that, particularly in the tropics, C. diph­
theriae can cause clinical skin infections characterized by chronic non-
healing ulcers with a dirty gray membrane and often associated with
Staphylococcus aureus and group A streptococci. More recently, the
significance of this infection in the United States has been emphasized
by several outbreaks among alcoholic homeless men and impoverished
groups such as Native Americans.15-18 Thirty-three cases of chronic skin
ulcers were reported in homeless persons from Vancouver, British
Columbia. All strains were nontoxigenic and occurred along with
other potential skin pathogens.76 The presentation is indolent and non-
progressive and is only rarely associated with signs of intoxication.
Nonetheless, these infections can induce high antitoxin levels and thus
appear to act as natural immunizing events.58,59 They also serve as a
reservoir for the organism under conditions of both endemic and
epidemic respiratory tract diphtheria: Cutaneous sites of C. diphtheriae
have been shown to contaminate the inanimate environment and
induce throat infections more efficiently than does pharyngeal coloni-
zation, and bacterial shedding from cutaneous infections continues
longer than from the respiratory tract.17,28,60 Despite these facts, the
clinical significance of isolating the organism from an individual skin
lesion is often unclear. Most lesions from which C. diphtheriae is iso-
lated are indistinguishable from other chronic dermatologic conditions
(e.g., eczema, psoriasis), and only about 15% fit the classic description
of diphtheritic ulcers given previously.61 Moreover, because C. diphthe­
riae is usually isolated in association with other known skin pathogens
and ulcers do not respond to antitoxin therapy, there is debate about
whether the isolates are actually causing clinical disease. By 1975, cuta-
neous diphtheria accounted for 56% of total C. diphtheriae isolates
reported in the United States, and in 1980, the Centers for Disease
Control and Prevention (CDC), in an effort to focus attention on
respiratory tract diphtheria, removed nontoxigenic skin isolates from
its list of reportable diseases. Of note, C. ulcerans is named for its ability
to cause chronic skin ulcers, but like C. diphtheriae, toxin-induced
disease is uncommon with C. ulcerans skin lesions.62
Invasive Disease
Endocarditis, mycotic aneurysms, osteomyelitis, and septic arthritis
have been described recently in clusters of drug addicts, alcoholics,
Australian Aboriginals, and young adults15,31-33,34-36—all caused by non-
toxigenic C. diphtheriae. Ribotyping has indicated that these outbreaks
have been caused by unique epidemic strains, and both skin and throat
colonization have been implicated as portals of entry. These illnesses
have been characterized by aggressive course, a high proportion of
bacteremia, endocarditis, arterial embolization, metastatic sites of
infection (joints, spleen, central nervous system), and high mortality.
Why these nontoxigenic strains are so virulent remains a mystery.
Coincident with these outbreaks of invasive disease, examples of
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non–toxin-producing strains causing clinical pharyngitis37-39 and even
fatal respiratory tract diphtheria40 have been published since 1990.
Other Sites
On rare occasions, clinical infection with C. diphtheriae can be seen in
other sites such as the ear, conjunctivae, or vagina.
DIAGNOSIS
The clinical outcome in diphtheria is improved most by the prompt
initiation of treatment. Therefore, physicians must act on a presump-
tive diagnosis on the basis of several clinical clues: (1) mildly painful
tonsillitis or pharyngitis with associated membrane, especially if the
membrane extends to the uvula and soft palate; (2) adenopathy and
cervical swelling, especially if associated with membranous pharyngi-
tis and signs of systemic toxicity; (3) hoarseness and stridor; (4)
palatal paralysis; (5) serosanguineous nasal discharge with associated
mucosal membrane; (6) temperature elevation rarely in excess of
102.5° F; and (7) history of recent travel to a country where diphtheria
is endemic. Moderate elevation of white blood cell count and tran-
sient proteinuria are common but nonspecific. In former times when
the disease was common, skilled practitioners could often make the
diagnosis on examination of methylene blue–stained smears of the
membrane or of throat swabs. Definitive identification of C. diphthe­
riae is made on the basis of colonial morphology, microscopic appear-
ance, and fermentation reactions of isolates from bits of membrane or
submembrane swabs cultured on tellurite-selective media such as Tin-
sdale agar. Although Tinsdale medium requires inoculation within 24
hours of its preparation, it has an advantage in that a brown-black
colony with a surrounding gray-brown halo is suggestive of the diag-
nosis. The combination of “Chinese characters” as seen on Gram
stain, distinctive colonies with halos on Tinsdale medium, and the
presence of metachromatic granules with methylene blue stain allows
a presumptive identification of C. diphtheriae. Final identification
requires biochemical tests. Toxin production is normally demon-
strated by an in vitro test available at the CDC, which detects an
immunoprecipitin band where antitoxin-impregnated filter paper is
laid over an agar culture of the organism in question (Elek test).
Recently, polymerase chain reaction probing of suspect organisms for
DNA sequences coding for the toxin’s A subunit has proved to be
sensitive and accurate in rapid identification of tox+ strains.63-65 None-
theless, because a strain can be tox+ but not be toxigenic, a confirma-
tory Elek test is necessary to demonstrate the presence of toxin.
Because routine methods of throat culture do not promote the isola-
tion and identification of C. diphtheriae, the laboratory must be
alerted to use selective media when the disease is suspected.
The differential diagnosis includes faucial mononucleosis, strepto-
coccal or viral pharyngitis and tonsillitis, Vincent’s angina, and acute
epiglottitis. The membrane of mononucleosis characteristically remains
on the tonsils, rarely loses its creamy-white appearance, and does not
cause bleeding when removed. Streptococcal infection usually pro-
duces a more intense local pharyngitis, higher fever, and more pro-
nounced dysphagia. Vincent’s angina often involves the gums, and
Gram stain of the exudate from the necrotic ulcerative pharyngeal
lesions shows characteristic fusobacteria and spirochetes. Bacterial epi-
glottitis secondary to Haemophilus influenzae often develops more
acutely, and indirect laryngoscopy shows a bright-red epiglottis without
associated membrane. Finally, toxin-producing C. ulcerans can cause
typical respiratory diphtheria, requiring the same treatment.41,42
THERAPY
Diphtheria antitoxin (DAT), hyperimmune antiserum produced in
horses, has been the cornerstone of therapy for diphtheria since it was
first shown to reduce mortality from 7% to 2.5% in a controlled trial
published in 1898. The antibodies only neutralize toxin before its entry
into cells, so it is critical that DAT be administered as soon as a pre-
sumptive clinical diagnosis has been made, before laboratory confir-
mation. The degree of protection is inversely related to the duration of
clinical illness preceding its administration.55 Although the minimal
therapeutic dose has never been determined, traditional (empirical)
dosage recommendations assume that the duration of disease and
extent of membrane formation roughly indicate the patient’s toxin
burden. The Committee on Infectious Diseases of the American

Academy of Pediatrics recommends 20,000 to 40,000 units of antitoxin
for pharyngeal or laryngeal disease of 48 hours’ duration or less; 40,000
to 60,000 units for nasopharyngeal lesions; and 80,000 to 120,000 units
for extensive disease of 3 or more days’ duration and for anyone with
brawny swelling of the neck.66 The antitoxin should be diluted in 250
to 500 mL of normal saline and infused intravenously over 60 to 120
minutes to inactivate toxin as rapidly as possible; some experts suggest
intramuscular injection of antitoxin for moderate disease and com-
bined intramuscular and intravenous administration for severe disease.
Repeated injections are of no additional benefit. Because 5% to 20% of
individuals may show some hypersensitivity to horse protein, even
very sick patients must be questioned first concerning known allergy
and evaluated first with a scratch test (a drop of 1 : 1000 dilution of
serum applied to a superficial scratch on the forearm), followed in 15
minutes if no wheal develops with 0.02 mL of a 1 : 1000 dilution
injected intracutaneously, with epinephrine available for immediate
administration.66 If an immediate reaction occurs, the patient should
be desensitized with progressively higher doses of antiserum. The inci-
dence of serum sickness after treatment of about 10% is acceptable in
light of the pronounced reduction in mortality resulting from antitoxin
administration. Diphtheria antitoxin is no longer licensed in the
United States, but a foreign-licensed product is available from the CDC
Emergency Operations Center by calling 770-488-7100.
Antibiotic therapy, by killing the organism, has three benefits: (1)
termination of toxin production; (2) amelioration of the local infec-
tion; and (3) prevention of spread of the organism to uninfected con-
tacts. Although several antibiotics, including penicillin, erythromycin,
clindamycin, rifampin, and tetracycline, are effective, only penicillin
and erythromycin are generally recommended. Intramuscular admin-
istration of procaine penicillin G (300,000 units for patients weighing
<20 lb; 600,000 units for those weighing >20 lb) at 12-hour intervals
is recommended until the patient can swallow comfortably, when oral
penicillin V (125 to 250 mg four times daily) or erythromycin estolate
or succinate (125 to 500 mg four times daily) may be substituted for a
recommended total treatment period of 14 days. Both drugs are equally
effective in resolving fever and local symptoms, as well as in the time
to disappearance of membrane. Because erythromycin is marginally
superior to penicillin in eradicating the carrier state, some authorities
prefer it for initial treatment despite a significant incidence of throm-
bophlebitis when it is given intravenously and of gastrointestinal irrita-
tion when given orally. Patients should be maintained in strict isolation
throughout therapy and, after therapy, should have two consecutive
negative cultures at 24-hour intervals to document eradication of the
organism.66 The carrier state has a slow rate of spontaneous resolution
(12% after 1 month in one study),67 so it should be treated to prevent
spread of infection.68 A single intramuscular dose of benzathine peni-
cillin G (600,000 to 1,200,000 units) is prudent when compliance with
oral therapy is uncertain.66
Supportive care is also important. Bed rest is recommended during
the acute illness, but proof of its benefit when the patient feels able to
ambulate is lacking. Early in the disease, respiratory and cardiac com-
plications are the biggest threats. Airway obstruction can result from
aspiration of dislodged pharyngeal membrane, its direct extension into
the larynx, or from external compression by enlarged nodes and
edema. For this reason, many experts recommend tracheostomy or
intubation as an early measure when the larynx is involved, to provide
access for mechanical removal of tracheobronchial membranes and to
avoid the risk for sudden asphyxia. Vigilance must be maintained to
detect the development of primary or secondary bacterial pneumonia.
Cardiac complications can be minimized by close electrocardiographic
monitoring and prompt initiation of electrical pacing for conduction
disturbances, drugs for arrhythmias, or digitalis for heart failure. Phys-
ical therapy can preserve range of motion in paretic extremities while
awaiting return of neurologic function. A recent study has shown that
treatment of acute diphtheria with prednisone did not reduce the inci-
dence of carditis or neuritis.69
Treatment of systemic infection such as endocarditis and arthritis
has not been studied systematically, but most reports describe admin-
istration of IV penicillin or ampicillin, usually with an aminoglyco-
side, for 4 to 6 weeks.36 Mortality rates of 30% to 40% occur with
bacteremic disease, and valve replacement is often necessary in cases
of endocarditis.33,34
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2371
PREVENTION
The major manifestations of diphtheria can be prevented in individual
patients by immunization with formalin-inactivated toxin (“toxoid”).
Therefore, documentation of inadequate levels of antitoxin in a large
Chapter 206  Corynebacterium diphtheriae (Diphtheria)
proportion of the adult population in North America and western
Europe has caused great concern that a toxigenic strain introduced into
these populations could cause an outbreak of disease similar to that
in the former Soviet Union. Historically, the presence of immunity
against diphtheria toxin was determined by the response to intrader-
mal injection of small amounts of toxin (the Schick test). Currently,
serum antitoxin levels can be measured by toxin neutralization tests
in rabbit or guinea pig skin or by protection against cytopathic effect
in Vero cell culture, with roughly equivalent results. Hemagglutination
and enzyme-linked immunosorbent assays are less sensitive at the
lower levels of antitoxin. Concentrations of 0.01 to 0.1 IU generally
are thought to confer protection. For example, data from a recent
outbreak showed that 90% of clinical cases had antitoxin levels
below 0.01 IU/mL, whereas 92% of asymptomatic carriers had titers
above 0.1 IU/mL.70 After immunization, antitoxin levels decline
slowly over time so that up to 50% of individuals older than 60
years have serum titers below 0.01 IU/mL.22,67,68 For this reason,
booster doses of tetanus and diphtheria toxoids [Td]) should be
administered at 10-year intervals to maintain antitoxin levels in the
protective range.
The current recommendations from the Advisory Committee on
Immunization Practices include71-73:
For children from 6 weeks to 7 years old: Three 0.5-mL intramuscular
injections of diphtheria and tetanus toxoids and acellular pertussis
(DTaP) vaccine should be given at 4- to 8-week intervals, beginning
at 6 to 8 weeks of age, followed by a fourth dose 6 to 12 months
after the third. A fifth dose is given at age 4 to 6 years.
For children 7 to 10 years old: 0.5-mL Td (toxoid-adult) is given twice
at a 4- to 8-week interval, with a third dose 6 to 12 months later.
One of the three should be given as Tdap. Because subjects older
than 7 years have a higher incidence of local and systemic reactions
to the concentration of diphtheria toxoid in pediatric DTaP vaccine
(7 to 25 limit flocculation [Lf] units) and because a lower dose of
toxoid has been shown to induce protective levels of antitoxin,74 the
Td formulation of vaccine contains a maximal concentration of 2 Lf
units of diphtheria toxoid. If the recommended sequence of primary
immunizations is interrupted, normal levels of immunity can be
achieved simply by administering the remaining doses without need
to restart the series.
For persons 10 or more years old: A single 0.5-mL Tdap is followed 4
to 8 weeks later by 0.5 mL Td, with a second dose of Td 6 to 12
months after the first.
Booster immunizations: Persons 10 years old and older should receive
one dose of Tdap and then receive the standard Td booster at
10-year intervals to reduce carriage, clinical illness, and transmis-
sion of pertussis.72,73 As a help to memory, this should be done
at decade or mid-decade intervals (e.g., ages 15, 25, 35, etc., or
20, 30, 40). Careful attention to this adult booster strategy is
important to ensure population protection in areas with excel-
lent childhood immunization programs. Travelers to areas where
diphtheria is still endemic should be particularly careful to ensure
their immunization is current. Although the recommended booster
dose of 1.5 to 2.0 Lf units will increase antitoxin levels to above
0.01 IU in 90% to 100% of previously immunized individuals,75
some authorities have recommended using 5 Lf units because
antitoxin levels remain above 0.01 IU/mL for a longer period than
with 2 Lf units.75 Because of the risk of neonatal pertussis, the
CDC recommends that all women receive a Tdap booster at each
pregnancy.
Patients should receive toxoid immunization in the convalescent
stage of their disease because clinical infection does not always induce
adequate levels of antitoxin. Close contacts whose immunization status
is incomplete or unclear should promptly receive a dose of toxoid
appropriate for their age and complete the proper series of immuniza-
tions. In addition, they should receive prophylactic treatment with
erythromycin or penicillin, pending the results of pretreatment
cultures. Given these preventive measures, the prophylactic use of
antitoxin is considered unwarranted.
 2372
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For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.

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