Diphtheria is an acute, toxin-mediated disease caused by
Corynebacterium diphtheriae. The name of the disease is derived
from the Greek diphthera, meaning leather hide. The disease was
described in the 5th Century B.C. by Hippocrates, and epidemics
were described in the 6th Century A.D. by Aetius. The bacterium
was first observed in diphtheritic membranes by Klebs in 1883 and
cultivated by Löffler in 1884. Antitoxin was invented in late 19th
century, and toxoid was developed in the 1920s.
C. diphtheriae is an aerobic gram-positive bacillus.Toxin production
(toxigenicity) occurs only when the bacillus is itself infected (lysogenized)
by a specific virus (bacteriophage) carrying the genetic
information for the toxin (tox gene). Only toxigenic strains can
cause severe disease.
Culture of the organism requires selective media containing tellurite.
If isolated, the organism must be distinguished in the laboratory
from other Corynebacterium species that normally inhabit the
nasopharynx and skin (e.g., diphtheroids).
There are three biotypes — gravis, intermedius, and mitis. The
most severe disease is associated with the gravis biotype, but any
strain may produce toxin. All isolates of C. diphtheriae should be
tested by the laboratory for toxigenicity.
Susceptible persons may acquire toxigenic diphtheria bacilli in the
nasopharynx. The organism produces a toxin that inhibits cellular
protein synthesis and is responsible for local tissue destruction and
membrane formation. The toxin produced at the site of the membrane
is absorbed into the bloodstream and then distributed to the
tissues of the body. The toxin is responsible for the major complications
of myocarditis and neuritis and can also cause low platelet
counts (thrombocytopenia) and protein in the urine (proteinuria).
Clinical disease associated with non-toxin-producing strains is generally
milder. While rare severe cases have been reported, these may
actually have been caused by toxigenic strains which were not
detected due to inadequate culture sampling.
The incubation period of diphtheria is 2-5 days (range, 1-10 days).
Disease can involve almost any mucous membrane. For clinical
purposes, it is convenient to classify diphtheria into a number of
manifestations, depending on the site of disease.
ANTERIOR NASAL DIPHTHERIA
The onset is indistinguishable from that of the common cold and is
usually characterized by a mucopurulent nasal discharge (containing
both mucus and pus) which may become blood-tinged. A
white membrane usually forms on the nasal septum. The disease is
usually fairly mild because of apparent poor systemic absorption of
toxin in this location, and can be terminated rapidly by antitoxin
and antibiotic therapy.
PHARYNGEAL AND TONSILLAR DIPHTHERIA
The most common sites of infection are the tonsils and the pharynx.
Infection at these sites is usually associated with substantial
systemic absorption of toxin. The onset of pharyngitis is insidious.
Early symptoms include malaise, sore throat, anorexia, and lowgrade
fever. Within 2-3 days, a bluish-white membrane forms and
extends, varying in size from covering a small patch on the tonsils
to covering most of the soft palate. Often by the time a physician
is contacted, the membrane is greyish-green in color, or black if
there has been bleeding. There is a minimal amount of mucosal
erythema surrounding the membrane. The membrane is adherent
to the tissue, and forcible attempts to remove it cause bleeding.
Extensive membrane formation may result in respiratory obstruction.
The patient may recover at this point; or if enough toxin is
absorbed, develop severe prostration, striking pallor, rapid pulse,
stupor, coma, and may even die within 6 to 10 days. Fever is usually
not high, even though the patient may appear quite toxic.
Patients with severe disease may develop marked edema of the submandibular
areas and the anterior neck along with lymphadenopathy,
giving a characteristic "bullneck" appearance.
Laryngeal diphtheria can be either an extension of the pharyngeal
form or the only site involved. Symptoms include fever, hoarseness,
and a barking cough. The membrane can lead to airway
obstruction, coma, and death.
CUTANEOUS (SKIN) DIPHTHERIA
In the United States, cutaneous diphtheria has been most often
associated with homeless persons. Skin infections are quite common
in the tropics and are probably responsible for the high levels
of natural immunity found in these populations. Skin infections
may be manifested by a scaling rash or by ulcers with clearly
demarcated edges and membrane, but any chronic skin lesion may
harbor C. diphtheriae, along with other organisms. Generally, the
organisms isolated from recent cases in the United States were
non-toxigenic. In general, the severity of the skin disease with toxigenic
strains appears to be less than in other forms of infection
with toxigenic strains. Skin diseases associated with nontoxigenic
strains are no longer reported to the National Notifiable Diseases
Surveillance System in the United States.
Other sites of involvement include the mucous membranes of the
conjunctiva and vulvo-vaginal area, as well as the external auditory
Most complications of diphtheria, including death, are attributable
to effects of the toxin. The severity of the disease and complications
are generally related to the extent of local disease. The toxin,
when absorbed, affects organs and tissues distant from the site of
invasion. The most frequent complications of diphtheria are
myocarditis and neuritis:
Myocarditis may present as abnormal cardiac rhythms and can
occur early in the course of the illness or weeks later, and can lead
to heart failure. If myocarditis occurs early, it is often fatal.
Neuritis most often affects motor nerves and usually resolves completely.
Paralysis of the soft palate is most frequent during the
third week of illness. Eye muscles, limbs, and diaphragm paralysis
can occur after the fifth week. Secondary pneumonia and respiratory
failure may result from diaphragmatic paralysis.
Other complications include otitis media and respiratory insufficiency
due to airway obstruction, especially in infants.
The overall case-fatality rate for diphtheria is 5%-10%, with higher
death rates (up to 20%) in persons <5 and >40 years of age. The
case-fatality rate for diphtheria has changed very little during the
last 50 years.
Diagnosis is usually made based on the clinical presentation since
it is imperative to begin presumptive therapy quickly.
Culture of the lesion is done to confirm the diagnosis. It is critical
to take a swab of the pharyngeal area, especially any discolored
areas, ulcerations, and tonsillar crypts. Culture medium containing
tellurite is preferred because it provides a selective advantage for
the growth of this organism. A blood agar plate is also inoculated
for the detection of hemolytic streptococcus. If diphtheria bacilli
are isolated, they must be tested for toxin production.
Gram stain and Kenyon stain of material from the membrane
itself can be helpful when trying to confirm the clinical diagnosis.
The Gram stain may show multiple club-shaped forms which look
like Chinese characters. Other Corynebacterium species ("diphtheroids")
that can normally inhabit the throat may confuse the
interpretation of direct stain. However, treatment should be started
if clinical diphtheria is suggested, even in the absence of a diagnostic
In the event that prior antibiotic therapy may have impeded a positive
culture in a suspect diphtheria case, two sources of evidence
may aid in presumptive diagnosis: (1) isolation of the C. diphtheriae
from culturing of close contacts, and/or (2) a low non-protective
diphtheria antibody titer in sera obtained prior to antitoxin administration
(<0.1 I.U.) This is done by commercial laboratories and
requires several days. To isolate C. diphtheriae from carriers, it is
best to inoculate a Löffler’s or Pai’s slant with the throat swab.
After an incubation period of 18-24 hours, growth from the slant is
used to inoculate a medium containing tellurite.
Diphtheria antitoxin, produced in horses, was first used in the
United States in 1891. It is no longer indicated for prophylaxis of
contacts of diphtheria cases, only for the treatment of diphtheria.
Since 1997, diphtheria antitoxin has been available only from
CDC, and only under an Investigational New Drug (IND) protocol.
Antitoxin will not neutralize toxin that is already fixed to tissues,
but will neutralize circulating (unbound) toxin and will prevent
progression of disease. The patient must be tested for sensitivity
before antitoxin is given. Consultation on the use of diphtheria
antitoxin is available at all times through the CDC operator at
(404) 639-2889 or 2888. During office hours, 8:00 am - 4:30 pm
EST, contact staff at the National Immunization Program, (404)
Persons with suspected diphtheria should be given antibiotics and
antitoxin in adequate dosage and placed in isolation after the provisional
clinical diagnosis is made and appropriate cultures are
obtained. Respiratory support and airway maintenance should also
be administered as needed.
Treatment with erythromycin orally or by injection (40 mg/kg/day;
maximum, 2 gm/day) for 14 days, or procaine penicillin G daily,
intramuscularly (300,000 U/day for those weighing 10 kg or less
and 600,000 U/day for those weighing more than 10 kg) for 14
days. The disease is usually not contagious 48 hours after antibiotics
are instituted. Elimination of the organism should be documented
by two consecutive negative cultures after therapy is completed.
For close contacts, especially household contacts, a diphtheria
booster, appropriate for age, should be given. Contacts should also
receive antibiotics—benzathine penicillin G (600,000 units for per-
sons less than 6 years old and l,200,000 units for those 6 years old
and older) or a 7- to 10-day course of oral erythromycin,
(40 mg/kg/day for children and 1 g/day for adults). For compliance
reasons, if surveillance of contacts cannot be maintained, they
should receive benzathine penicillin G. Identified carriers in the
community should also receive antibiotics. Maintain close surveillance
and begin antitoxin at the first signs of illness.
Contacts of cutaneous diphtheria should be handled as above;
however, if the strain is shown to be nontoxigenic, investigation of
contacts can be discontinued.
Diphtheria occurs worldwide, but clinical cases are more prevalent
in temperate zones. In the United States during the pretoxoid era,
the highest incidence was in the Southeast during the winter.
More recently, highest incidence rates have been in states with significant
populations of Native Americans. No geographic concentration
of cases is currently observed in the United States.
Human carriers are the reservoir for C. diphtheriae, and are usually
asymptomatic. In outbreaks, high percentages of children are
found to be transient carriers.
Transmission is most often person-to-person spread from the respiratory
tract. Rarely, transmission may occur from skin lesions or
articles soiled with discharges from lesions of infected persons
In temperate areas, diphtheria most frequently occurs during winter
Transmission may occur as long as virulent bacilli are present in
discharges and lesions. The time is variable, but organisms usually
persist 2 weeks or less, and seldom more than 4 weeks, without
antibiotics. Chronic carriers may shed organisms for 6 months or
more. Effective antibiotic therapy promptly terminates shedding.
SECULAR TRENDS IN THE UNITED STATES
Diphtheria was once a major cause of morbidity and mortality among
children. In England and Wales during the 1930s, diphtheria was
among the top three causes of death for children <15 years of age.
In the 1920s in the United States, 100,000-200,000 cases if diphtheria
(140-150 cases per 100,000 population) and 13,000-15,000
deaths were reported each year. In 1921, a total of 206,000 cases
and 15,520 deaths were reported. The number of cases gradually
fell to about 19,000 cases in 1945 (15 per 100,000 population). A
more rapid decrease began with the widespread use of toxoid in
the late 1940s.
From 1970 to 1979, an average of 196 cases per year were reported.
This included a high proportion of cutaneous cases from an
outbreak in Washington state. Beginning in 1980, all cases with
non-toxigenic cutaneous isolates were excluded from reporting.
Diphtheria was seen most frequently in Native Americans and persons
in lower socioeconomic strata.
From 1980 through 2000, 51 cases of diphtheria were reported in
the United States, an average of 2-3 per year (range, 0-5 cases per
year). No cases were reported in 1993 and 1995. Only one case
was reported each year in 1998, 1999, and 2000.
Of 49 reported cases with known age
since 1980, twenty-seven
(55%) cases were in persons >20 years of age; 43% of cases were
among persons >40 years of age. Most cases have occurred in
unimmunized or inadequately immunized persons. The current
age distribution of cases corroborates the finding of inadequate levels
of circulating antitoxin in many adults (up to 60% with less
than protective levels).
Although diphtheria disease is rare in the United States, it appears
that Corynebacterium diphtheriae continues to circulate in areas of
the country with previously endemic diphtheria. In 1996, 10 isolates
of C. diphtheria were obtained from persons in an American
Indian community in South Dakota. Eight of these isolates were
toxigenic. None of the infected persons had classic diphtheria disease,
although 5 had either pharyngitis or tonsillitis. The presence
of toxigenic C. diphtheria in this community is a good reminder for
providers not to let down their guard against this organism.
Diphtheria continues to occur in other parts of the world. A major
epidemic of diphtheria occurred in countries of the former Soviet
Union beginning in 1990. By 1994, the epidemic had affected all
15 Newly Independent States (NIS). More than 157,000 cases
and more than 5000 deaths were reported. In the six years from
1990 through 1995, the NIS accounted for over 90 percent of all
diphtheria cases reported to the World Health Organization from
the entire world. In some NIS countries, up to 80% of the epidemic
diphtheria cases have been among adults. The outbreak,
and the age distribution of cases, is believed to be due to several
factors, including a lack of routine immunization of adults in these
Beginning in the early 1900s, prophylaxis was attempted with
toxin-antitoxin mixtures. Toxoid was developed around 1921, but
was not widely used until the early 1930s. It was incorporated with
tetanus toxoid and pertussis vaccine and became routinely used in
Diphtheria toxoid is produced by growing toxigenic C. diphtheriae
in liquid medium. The filtrate is incubated with formaldehyde to
convert toxin to toxoid. It is adsorbed onto an aluminum salt and
preserved with thimerosal.
Diphtheria toxoid is produced by growing toxigenic C. diphtheriae
in liquid medium. The filtrate is incubated with formaldehyde to
convert toxin to toxoid. It is adsorbed onto an aluminum salt and
preserved with thimerosal.
Single antigen diphtheria toxoid is not available. Diphtheria toxoid
is available combined with tetanus as pediatric DT or adult Td,
and with both tetanus toxoid and acellular pertussis vaccine as
DTaP. Pediatric formulations (DT and DTaP) contain a similar
amount of tetanus toxoid as adult Td, but contain 3-4 times as
much diphtheria toxoid. Children younger than 7 years of age
should receive either DTaP or pediatric DT. Persons 7 years of age
or older should receive the adult formulation (adult Td), even if
they have not completed a series of DTaP or pediatric DT.
IMMUNOGENICITY AND VACCINE EFFICACY
After a primary series of three properly spaced diphtheria toxoid
doses in adults or four doses in infants, a protective level of antitoxin
(defined as >0.1 international units of antitoxin/ml) is
reached in over 95%. Diphtheria toxoid has been estimated to have
a clinical efficacy of 97%.
VACCINATION SCHEDULE AND USE
DTaP (diphtheria and tetanus toxoids and acellular pertussis vaccine)
is the vaccine of choice for children 6 weeks through 6 years
of age. The usual schedule is a primary series of 4 doses at 2,4,6,
and 15-18 months of age. The first, second, and third doses of
DTaP should be separated by a minimum of 4 weeks. The fourth
dose should follow the third dose by no less than 6 months.
If a child has a valid contraindication to pertussis vaccine, pediatric
DT should be used to complete the vaccination series. If the child
is less than 12 months old when the first dose of DT is administered
(as DTP, DTaP, or DT), the child should receive a total of
four primary DT doses. If the child is 12 months of age or older at
the time that the first dose of DT is administered, a third dose 6-
12 months after the second completes the primary DT series.
If the fourth dose of DT, DTP or DTaP is administered before the
fourth birthday, a booster (fifth) dose is recommended at 4-6 years
of age. The fifth dose is not required if the fourth dose was given
on or after the fourth birthday.
Because of waning antitoxin titers, most individuals have antitoxin
levels below optimal levels 10 years after the last dose. Tetanus
toxoid should be given with diphtheria toxoid as Td every 10 years.
The first booster dose may be given at 11-12 years of age, if at
least 5 years have elapsed since the last dose of DTP, DTaP, or
DT. If a dose is given sooner as part of wound management, the
next booster is not needed for 10 years thereafter. More frequent
boosters are not indicated and have been reported to result in an
increased incidence and severity of local adverse reactions.
Td is the vaccine of choice for children 7 years old and older, and
for adults. A primary series is three doses. The first two doses
should be separated by at least 4 weeks, and the third dose given 6-
12 months after the second. A booster dose of Td should be given
every 10 years.
Interrupting the recommended schedule or delaying subsequent
doses does not reduce the ultimate immunity. There is no need to
restart a series regardless of the time elapsed between doses.
Diphtheria disease may not confer immunity. Individuals recovering
from diphtheria should begin or complete active immunization
with diphtheria toxoid during convalescence.
ADVERSE REACTIONS FOLLOWING VACCINATION
Local reactions, generally erythema and induration with or without
tenderness, are common after the administration of vaccines
containing diphtheria antigen. They are usually self-limited and
require no therapy. A nodule may be palpable at the injection site
for several weeks. Abscess at the site of injection has been reported.
Fever and other systemic symptoms are uncommon.
Exaggerated local (Arthus-like) reactions are occasionally
reported following receipt of a tetanus-containing vaccine. These
unusual reactions present as extensive painful swelling, often from
shoulder to elbow. They generally begin from 2 to 8 hours after
injections, and are reported most often in adults, particularly those
who have received frequent doses of tetanus toxoid. Persons experiencing
these severe reactions usually have very high serum tetanus
antitoxin levels; they should not be given further routine or emergency
booster doses of Td more frequently than every 10 years.
Less severe hypersensitivity local reactions may occur in persons
who have multiple prior boosters.
Rarely, severe systemic reactions such as generalized urticaria,
anaphylaxis, or neurologic complications have been reported by
those receiving diphtheria toxoid.
CONTRAINDICATIONS AND PRECAUTIONS TO
Persons with a history of neurologic or severe allergic reaction
following a previous dose should not receive additional doses of
diphtheria toxoid. Diphtheria toxoid should be deferred for those
individuals who have moderate to severe acute illness, but persons
with mild illness may be vaccinated. Immunosuppression and
pregnancy are not contraindications to diphtheria toxoid.
VACCINE STORAGE AND HANDLING
The vaccine may be shipped without refrigeration if deliverable in
4 days. Refrigerant may be used. It should be refrigerated immediately
upon arrival and stored at a temperature of 2o-8oC (35o-
46oF). It should not be frozen — this reduces potency, and it
should not be stored in direct contact with refrigerant.
SUSPECT CASE INVESTIGATION AND CONTROL
Immediate action on all highly suspect cases (including cutaneous)
is warranted until shown not to be toxigenic C. diphtheriae. The
following action should also be taken for any toxigenic C. diphtheriae
carriers who are detected.
1. Contact state health department or CDC.
2. Obtain appropriate cultures and preliminary clinical and epidemiological
information (including vaccine history).
3. Begin early presumptive treatment with antibiotics and
antitoxin. Start antibiotics and antitoxin. Impose strict isolation
until at least two cultures are negative 24 hours after antibiotics
4. Identify close contacts, especially household members and other
persons directly exposed to oral secretions of the patient. Culture
all close contacts, regardless of their immunization status. Ideally,
culture should be from both throat and nasal swabs. After culture,
all contacts should receive antibiotic prophylaxis. Inadequately
immunized contacts should receive DTaP/DT/Td boosters. If
fewer than three doses of diphtheria toxoid have been given, or vaccination
history is unknown, an immediate dose of diphtheria toxoid
should be given and the primary series completed according to
the current schedule. If >5 years have elapsed since administration
of diphtheria toxoid-containing vaccine, a booster dose should be
given. If the most recent dose was within 5 years, no booster is
required (see the ACIP's 1991 Diphtheria,Tetanus, and Pertussis:
Recommendations for Vaccine Use and Other Preventive Measures for
schedule for children <7 years of age.)
Unimmunized contacts should start a course of DTaP/DT/Td vaccine
and be monitored closely for symptoms of diphtheria for 7
5. Treat any confirmed carrier with adequate course of antibiotic,
and repeat cultures at a minimum of 2 weeks to assure eradication
of the organism. Persons who continue to harbor the organism
after treatment with either penicillin or erythromycin should
receive an additional 10-day course of erythromycin and should
submit samples for follow-up cultures.
6. Treat any contact with antitoxin at the first sign of illness.
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