• The single known reservoir for C. diphtheriae is humans; disease is acquired by contact with either a carrier or a diseased person.
• Though the disease is distributed throughout the world, it is endemic, primarily in developing regions of Africa, Asia, and South America. In the Western world, the incidence of diphtheria has changed dramatically in the past 50 to 75 years, as a result of the widespread use of diphtheria toxoid after World War II. The incidence has declined steadily and is now a rare occurrence.
• Recent outbreaks have occurred, most notably in the new independent states of the former Soviet Union, and supply additional evidence that disease occurs among the socioeconomically disadvantaged living in crowded conditions.
• The majority of cases occur during the cooler autumn and winter months in individuals less than 15 years of age who are unimmunized.

• Respiratory tract diphtheria:
  • Nasal diphtheria starts with mild rhinorrhea that gradually becomes serosanguineous, then mucopurulent, and often malodorous. This form occurs most often in infants.
  • Tonsillar and pharyngeal diphtheria begins with anorexia, malaise, low-grade fever, and pharyngitis. A membrane appears within 1 to 2 days. Cervical lymphadenitis and edema of the cervical soft tissues may be severe. Disease course varies with extent of toxin elaboration and membrane production. Respiratory and cardiovascular collapse may occur.
  • Laryngeal diphtheria most often represents extension of a pharyngeal infection and clinically presents as typical croup. Acute airway obstruction may occur, and in severe cases, the membrane may invade the entire tracheobronchial tree.
  • Cutaneous diphtheria occurs in warmer tropical regions. It is characterized by chronic non-healing ulcers with gray membrane and may serve as a reservoir in endemic and epidemic areas of respiratory diphtheria.
• Other sites: rarely vulvovaginal, conjunctival, or aural forms occur.

• Cardiac toxicity: myocarditis may develop secondary to elaborated toxin anytime between the first and sixth week of illness. Though cardiac failure can occur, the majority of cases are transient.
• Neurological toxicity again occurs secondary to toxin elaboration and mainly reflects bilateral motor involvement.
• Paralysis of the soft palate is most common, but ocular paralysis, diaphragm paralysis, peripheral neuropathy of the extremities, and loss of deep tendon reflexes also occur.
• The frequency of all complications, including those listed above, increases with increasing time between symptom onset and antitoxin administration and also with extent of membrane formation.

• Most strongly dependent on the immunization status of the host. Those without prior adequate immunization have significantly higher morbidity and mortality.
• Delay to onset of treatment also increases mortality. When appropriate treatment has been administered on day 1 of illness, mortality may be as low as 1%. When treatment has been delayed until day 4, the mortality rate is up to 20-fold higher.
• Organism virulence: toxigenic strains are associated with more severe disease and a poorer prognosis.
• Location of membrane: laryngeal diphtheria has a higher mortality owing to airway obstruction.
• A megakaryocytic thrombocytopenia and WBC .25,000 are associated with poor outcome.

• Nasal diphtheria can present much like the common cold, nasal foreign body, sinusitis, adenoiditis, or snuffles (congenital syphilis).
• Tonsillar or pharyngeal diphtheria may be confused with streptococcal pharyngitis, infectious mononucleosis, primary herpetic tonsillitis, thrush, Vincent angina, post-tonsillectomy faucial membranes, or the oropharyngeal involvement caused by toxoplasmosis, cytomegalovirus, tularemia, and salmonellosis.
• Laryngeal diphtheria: differential diagnosis includes croup, acute epiglottitis, aspirated foreign body, peripharyngeal and retropharyngeal abscess, laryngeal papillomas, or other masses.

HISTORY

Question: Exposure?
Significance: Exposure to an individual with diphtheria is not necessarily elicited because contact with an asymptomatic carrier may be the only source of infection.

Question:
Significance: The incubation period is 1 to 6 days. Respiratory diphtheria, depending on the site of infection, may begin with nasal discharge alone or with pharyngitis accompanied by mild systemic symptoms. Progression of symptoms thereafter occurs as outlined under “Associated Illnesses.”

Finding: Nasal discharge, nasal or pharyngeal membrane, heart rate out of proportion to body temperature, respiratory distress, stridor, cough, hoarseness, palatal paralysis, neck swelling, and cervical lymphadenitis. Attempts to remove any membrane present will result in bleeding.
Significance: Classic findings.

Finding: Conjunctival diphtheria
Significance: Gives palpebral conjunctival involvement with a red, edematous, membranous appearance.

Finding: Aural diphtheria
Significance: Presents as otitis externa with a purulent, malodorous discharge.

Finding: Cutaneous diphtheria
Significance: See Associated Illnesses.

Test: Diagnosis should be on clinical grounds.
Significance: Delay in treatment increases morbidity and mortality.

Test: Culture of material from the membrane or beneath the membrane should be attempted.
Significance: If a strain of C. diphtheriae is isolated, additional testing for presence or absence of toxin production should be conducted by a laboratory prepared to conduct an animal neutralization test or, alternatively, neutralization (with antitoxin) in tissue culture.

Test: Examination of a methylene blue-stained lesion
Significance: Metachromatic granules can be helpful, if performed by an experienced technician.

Test: Fluorescent antibody testing and counter-immunoelectrophoresis
Significance: Previously performed in state laboratories, are no longer widely available.

• Pharyngeal or laryngeal disease of <48 hours; duration, 20,000 to 40,000 units IV
• Nasopharyngeal lesions, 40,000 to 60,000 units IV
• Extensive disease of 3 or more days duration or diffuse neck swelling, 80,000 to 100,000 units IV

• Antibiotic therapy should be used in addition to DAT, not in place of it, as follows:
• Respiratory diphtheria
  • Penicillin G
    • Aqueous crystalline, 100,000 to 150,000 U/kg/d in four divided doses ×14 days
    • Procaine, 25,000 to 50,000 U/kg/d in two divided doses ×14 days
      or
    • Erythromycin, 40 to 50 mg/kg/× (maximum 2 gm/d) PO or parenterally ×14 days
  • Cutaneous diphtheria: requires local care of the lesion with soap and water and administration of antimicrobials for 10 days.

• 2 months to 7 years: five doses of diphtheria vaccine, the first three given as DTP vaccine 0.5 mL IM at 2-month intervals beginning at 2 months of age. The fourth dose should be either DTaP or DTP at 15 to 18 months of age, and a fifth dose of DTaP or DTP at 4 to 6 years of age.
• 7 years: primary immunization of those >7 years should be conducted with adult-type diphtheria and tetanus toxoids, adsorbed (Td) with two doses given IM at least 4 weeks apart and a booster dose 1 year later.
• Booster doses of Td should be given at 10-year intervals to all immunized individuals. Isolation of patients with diphtheria is required until culture from the site of infection is negative on three consecutive specimens.

• In mild cases of diphtheria, after membrane sloughs off in 7 to 10 days, recovery is usually uneventful.
• In more severe cases, recovery may be slower and serious complications can occur.

Q: Are there currently places in the world where diphtheria is a problem?
A: Yes. A diphtheria epidemic began in 1990 in Russia, spread in 1991 to the Ukraine, and during 1993 and 1994 spread to the remaining New Independent States of the former Soviet Union. During 1994, provisional totals of 47,802 cases (39,907 in Russia) and 1746 deaths due to diphtheria were reported throughout the New Independent States.

Q: What is the incidence of diphtheria in the United States?
A: From 1980 to 1993, only 40 cases of diphtheria were reported in the United States, an average of three per year (all respiratory disease).

Q: What precautions should be taken by travelers to areas of the world with diphtheria outbreaks?
A: The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention recommends that travelers to such areas should be up-to-date for diphtheria immunization. Infants traveling to areas where diphtheria is endemic or epidemic should receive three doses of DTP or DT before travel.

Bisgard KM, Hardy IR, Popovic T, et al. Respiratory diphtheria in the United States, 1980 through 1995. Am J Public Health 1998;88(5):787–791.

Enhanced surveillance of non-toxigenic Corynebacterium diphtheriae infections. CDR Weekly 1996 Jan 26:6(4):29, 32.

Feigin RD, Stechenberg BW, Strandgaard BH. Diphtheria. In: Feigin RD, Cherry JD, eds. Textbook of pediatric infectious diseases, 3rd ed. Philadelphia: WB Saunders, 1992:1110–1115.

MacGregor RR. Corynebacterium diphtheriae. In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of infectious diseases, 3rd ed. New York: Churchill Livingstone, 1990:1574–1581.

Toxigenic Corynebacterium diphtheriae—Northern Plains Indian Community, August–October 1996. MMWR 1997;46(22):506–510.

Copyright © 2000 Lippincott Williams & Wilkins
M. William Schwartz, Louis M. Bell, Jr., Peter M. Bingham, Esther K. Chung, David F. Friedman and Andrew E. Mulberg, The 5 Minute Pediatric Consult