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