Diphtheria 

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.

PATHOGENESIS

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.

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.

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.

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

canal.

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

Gram stain.

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)

639-8255.

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

(fomites).

In temperate areas, diphtheria most frequently occurs during winter

and spring.

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.

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

countries.

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

the 1940s.

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.

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%.

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.

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.

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.

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.

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

were stopped.

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

days.

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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