Clinical Information

Diphtheria is an acute, bacterial disease caused by toxin-producing strains of Corynebacterium diphtheriae. Infection can result in respiratory or non-respiratory disease, such as cutaneous infections. Two other Corynebacterium species (C. ulcerans and C. pseudotuberculosis) may produce diphtheria toxin; both species are zoonotic. Toxin-producing C. ulcerans may cause disease indistinguishable from that caused by toxin-producing C. diphtheriae, but person-to-person spread has not been documented. Toxin-producing C. pseudotuberculosis can cause lymphadenitis in humans.

Non-toxin-producing strains of C. diphtheriae can also cause disease. It is generally less severe, potentially causing a mild sore throat and, rarely, a membranous pharyngitis. Invasive disease, including bacteremia and endocarditis, has been reported for non-toxin-producing strains of C. diphtheriae.

Vaccination is highly protective against disease caused by toxin-producing strains, but does not prevent carriage of C. diphtheriae, regardless of toxin production status.

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).

Transmission

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).

Clinical features

A clinician palpates for lymphadenopathy.

The incubation period of diphtheria is usually 2–5 days (range: 1–10 days). Diphtheria can involve almost any mucous membrane. For clinical purposes, it is convenient to classify diphtheria into type of manifestation, depending on the site of disease. These sites mostly commonly include:

• Respiratory diphtheria
  • Nasal diphtheria
  • Pharyngeal and tonsillar diphtheria
  • Laryngeal diphtheria
• Cutaneous diphtheria

Respiratory diphtheria has a gradual onset and is characterized by:

• Mild fever
• Sore throat
• Difficulty swallowing
• Malaise
• Loss of appetite
• Hoarseness (if the larynx is involved)

The hallmark of respiratory diphtheria is a pseudomembrane that appears within 2–3 days of illness. It appears over the mucous lining of the tonsils, pharynx, larynx, or nares and can extend into the trachea. Fatal airway obstruction can result if the pseudomembrane extends into the larynx or trachea or if a piece of it becomes dislodged.

Cutaneous diphtheria may present as a scaling rash or ulcers with clearly demarcated edges and membrane, but any chronic skin lesion may harbor C. diphtheriae along with other organisms. The systemic complications from cutaneous diphtheria with toxigenic strains appear to be less than from other sites.

Diagnostic testing and differential diagnoses

Diagnosis of diphtheria is confirmed by isolating C. diphtheriae and testing the isolate for toxin production by the Elek test, an in vitro immunoprecipitation (immunodiffusion) assay. Other tests, such as polymerase chain reaction (PCR) and matrix assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF), may identify C. diphtheriae. However, when used alone, these tests do not confirm toxin production and are considered supplemental.

Specimens for culture should be obtained from the nares and oropharynx, or any mucosal or cutaneous lesion. If possible, material should be obtained from beneath the membrane (if present) or a portion of the membrane itself. Specimens are more likely to be culture-positive if obtained before the patient receives antibiotic treatment.

Respiratory diphtheria is uncommon in the United States. Infection with other pathogens could result in a similar clinical presentation as diphtheria; testing for other pathogens should be considered. Pathogens include group A beta-hemolytic Streptococcus, Staphylococcus aureus, Candida albicans, and viruses such as Epstein-Barr, cytomegalovirus, adenovirus, and herpes.

Medical management

Diagnosis of respiratory diphtheria is usually made on the basis of clinical presentation since it is imperative to begin presumptive therapy quickly. After making the provisional clinical diagnosis, obtain appropriate clinical specimens, and start antitoxin and antibiotic treatment. Respiratory support and airway maintenance may be needed.

Even though disease is usually not contagious 48 hours after antibiotic treatment begins, maintain droplet precautions until the diphtheria patient has completed the antibiotic course and is culture-negative. Document elimination of the organism by obtaining two consecutive negative cultures 24 hours apart, once antibiotic therapy is completed.

Treatment of cutaneous diphtheria with antibiotics is usually sufficient, and antitoxin is typically not needed. Contact precautions are recommended for cutaneous disease, until elimination of the organism is documented by obtaining two consecutive negative cultures 24 hours apart, once antibiotic therapy is completed

Diphtheria disease might not confer immunity. Persons recovering from diphtheria should begin or complete vaccination with diphtheria toxoid during convalescence if not up to date with vaccination.

Diphtheria antitoxin

In the United States, clinicians can obtain diphtheria antitoxin from CDC on request. Learn more about diphtheria antitoxin and how to request it.

Antibiotics

The recommended antibiotics for respiratory or cutaneous diphtheria are either erythromycin or penicillin.

Complications

Most complications of respiratory diphtheria, including death, are attributable to effects of the toxin. The most frequent complications of respiratory diphtheria are myocarditis and neuritis. 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%) among persons younger than 5 and older than 40 years of age.

Cutaneous diphtheria infection rarely results in severe disease.

Preventive measures

State or local health departments conduct a contact investigation for all suspected respiratory and non-respiratory diphtheria cases. This investigation should include:

• Obtaining nasal and throat cultures
• Collecting preliminary epidemiologic and clinical information
• Identifying close contacts

Close contacts of diphtheria patients include:

• All household members
• Persons with a history of habitual, close contact with the patient
• Persons directly exposed to secretions from the suspected infection site of the patient

Management of close contacts should include monitoring for possible respiratory or cutaneous diphtheria for 7 to 10 days from the time of the last exposure to the diphtheria patient and obtaining nasal and throat cultures for C. diphtheriae. Close contacts should also receive erythromycin or penicillin as prophylaxis. For compliance reasons, if the health department cannot maintain surveillance of close contacts, the close contacts should receive a dose of intramuscular benzathine penicillin. The health department should also direct close contacts to receive a diphtheria toxoid booster, appropriate for age, if they are not up to date with diphtheria vaccination.

Close contacts of persons with cutaneous diphtheria should be treated as described above; however, if the strain is shown to be nontoxigenic, the health department can discontinue investigation of contacts.

Surveillance

The National Notifiable Diseases Surveillance System conducts national surveillance for diphtheria. CDC also identifies cases by requests for diphtheria antitoxin (DAT); since 1997, DAT is available for U.S. healthcare professionals only through CDC.