Diphtheria (Corynebacterium diphtheriae)

About Diptheria

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.

Corynebacterium Diphtheriae

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.

Clinical Features

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.

Complications

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.

Death

The overall case-fatality rate for diphtheria is 5%-10%, with higher death rates (up to 20%) in persons 40 years of age. The case-fatality rate for diphtheria has changed very little during the last 50 years.

Laboratory Diagnosis

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 (

Treatment

Antibiotics

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.

Preventive Measures

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.