Tejpratap S.P. Tiwari

Infectious Agent

• Diphtheria is caused by toxigenic strains of Corynebacterium diphtheriae biotype mitis, gravis, intermedius, or belfanti.
• The bacteria produce an exotoxin which, if absorbed in the bloodstream, may damage organs such as the heart, kidneys, and nerves.

Mode of Transmission

• Humans are the only known reservoir of C. diphtheriae.
• Person-to-person transmission occurs through oral or respiratory droplets, close physical contact, and rarely by fomites.
• Cutaneous diphtheria is common in tropical countries, and contact with discharge from skin lesions may play an important role in transmission of infection in these environments.

Occurrence

• Diphtheria is found worldwide. Countries with endemic diphtheria are shown in Table 2-20.
• Diphtheria causes significant morbidity and mortality in developing countries where vaccination coverage is low.
• During the 1990s, large epidemics occurred in the newly independent states of the former Soviet Union. More recently in the Americas, diphtheria outbreaks occurred in Paraguay, the Dominican Republic, and Haiti.
• Diphtheria is uncommon in industrialized countries because of long-standing routine use of DTP (diphtheria and tetanus toxoids and pertussis vaccine). Diphtheria is uncommon in the United States; and the last case occurred in an elderly traveler returning from Haiti in 2003.

Risk for Travelers

• Symptomatic infection is extremely rare in adequately immunized persons, although active immunization with diphtheria toxoid does not prevent colonization or transient carriage of C. diphtheriae.
• Exposure and higher risk of acquiring disease and potentially life-threatening complications are possible in inadequately immunized or unimmunized travelers to countries with endemic diphtheria.

Clinical Presentation

• The incubation period is 2–5 days (range 1–10 days).
• Nasal diphtheria can be asymptomatic or mild, with a blood-tinged discharge.
• Affected anatomic sites include the mucous membrane of the upper respiratory tract (nose, pharynx, tonsils, larynx, and trachea [respiratory diphtheria]), skin (cutaneous diphtheria), or rarely, mucous membranes at other sites (eye, ear, vulva).
• Respiratory diphtheria has a gradual onset and is characterized by a mild fever (rarely >101° F or >38.3° C), sore throat, difficulty in swallowing, malaise, loss of appetite, and if the larynx is involved, hoarseness may occur.
• The hallmark of respiratory diphtheria is the presence of a membrane that appears within 2–3 days of illness over the mucous membrane of the tonsils, pharynx, larynx, or nares, and which can extend into the trachea. The membrane is firm, fleshy, grey, and adherent, and bleeds following attempts to remove or dislodge it.
• Local complications such as life-threatening or fatal airway obstruction can result from extension of the membrane or dislodgement of a piece of the membrane into the larynx or trachea.
• In severe respiratory diphtheria, cervical lymphadenopathy and soft-tissue swelling in the neck give rise to a “bull-neck” appearance.
• The case–fatality rate of respiratory diphtheria is 5%–10%.
• Systemic complications, including myocarditis, and polyneuropathies, can result from absorption of diphtheria toxin from the infection site. However, cutaneous and nasal diphtheria are localized and rarely associated with systemic toxicity.

Diagnosis

• A presumptive diagnosis is usually based on clinical features.
• A confirmed diagnosis is made by isolation of C. diphtheriae from culture of nasal or throat swabs, or membrane tissue.
• Toxin production is confirmed by performing a modified Elek test.
• Polymerase chain reaction assays can also be performed on isolates, swabs, or membrane specimens to rapidly confirm the presence of tox gene responsible for production of diphtheria toxin, but the test is available only in research or reference laboratories.

Treatment

• Patients with respiratory diphtheria require hospitalization to monitor response to treatment and manage complications.
• Equine diphtheria antitoxin (DAT) is the mainstay of treatment and is administered after sensitivity testing, without waiting for laboratory confirmation. In the United States, DAT is available to physicians under an FDA-approved Investigational New Drug protocol by contacting CDC at 770-488-7100.
• An appropriate antibiotic (erythromycin or penicillin) to eliminate the causative organisms, stop exotoxin production, and reduce communicability.
• Supportive care (airway, cardiac monitoring) is required.
• Antimicrobial prophylaxis (erythromycin or penicillin) is recommended for close contacts of patients.

Preventive Measures for Travelers

Vaccine

• For protection against diphtheria, all travelers should be up-to-date with diphtheria toxoid vaccine before departure. Diphtheria toxoid is not manufactured as a monovalent vaccine but is available in pediatric (D) and adult formulations (d) that are combined with other vaccines such as tetanus toxoid (DT, Td), or tetanus toxoid and acellular or whole-cell pertussis antigens (DTaP, DTwP, Tdap), or as a DTwP/DTaP combination with other antigens (e.g., hepatitis B, inactivated poliovirus vaccines, or Hib vaccine).
• In the United States, infants and children <7 years of age are vaccinated with diphtheria toxoid in combination with tetanus toxoid and acellular pertussis vaccine (DTaP) according to a routine childhood immunization schedule as recommended by the ACIP (see the Vaccine Recommendations for Infants and Children section in Chapter 7).
• Immunization for infants and children <7 years of age consists of five doses of DTaP vaccine. The first three doses are usually given at ages 2, 4, and 6 months, followed by booster doses at ages 12–18 months and 4–6 years (see Table 7-2).
• Adolescents 11–18 years of age should receive a dose of Tdap instead of Td for booster immunization against tetanus, diphtheria, and pertussis if they have completed the recommended childhood DTwP/DTaP vaccination series (see Table 7-3).
• Adults 19–64 years of age should receive a single dose of age-appropriate Tdap to replace a single dose of Td for active booster immunization against tetanus, diphtheria and pertussis. Thereafter, routine booster doses with Td should be given every 10 years to maintain seroprotection against diphtheria as well as tetanus. This booster is particularly important for travelers who will live or work with local populations in countries where diphtheria is endemic.
• Adults >65 years of age should receive Td; Tdap is not licensed for this age group.
• Persons >7 years of age and with uncertain vaccination history or who have never been vaccinated against tetanus, diphtheria, or pertussis should receive three doses of an age-appropriate tetanus and diphtheria toxoid-containing vaccine. If a person is 10–65 years old, a single dose of Tdap may be substituted for one Td dose for added protection against pertussis.

References

1. American Academy of Pediatrics. Diphtheria. In: Pickering LK, Baker CJ, Long SS, McMillan JA, editors. Red book: 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006:p.277–81.
2. World Health Organization. WHO vaccine-preventable diseases monitoring system: 2005 global summary. Geneva, Switzerland: World Health Organization; 2005 Dec. 333 p. Report No.: WHO/IVB/2005.
3. Galazka A. The changing epidemiology of diphtheria in the vaccine era. J Infect Dis. 2000 Feb;181 Suppl 1:S2–9.
4. CDC. Fatal respiratory diphtheria in a U.S. traveler to Haiti—Pennsylvania, 2003. MMWR Morbid Mortal Wkly Rep. 2004;52(53):1285–6.
5. Wharton M, Vitek CR. Diphtheria toxoid. In: Plotkin SA, Orenstein WA, editors. Vaccines. 4th ed. Philadelphia: W.B. Saunders; 2004:211–28.
6. Bisgard KM, Hardy IRB, Popovic T, et al. Respiratory diphtheria in the United States, 1980 through 1995. Am J Public Health. 1998;88(5):787–91.
7. CDC. Diphtheria acquired by U.S. citizens in the Russian Federation and Ukraine—1994. MMWR Morbid Mortal Wkly Rep. 1995;44(12):237, 243–4.
8. Farizo KM, Strebel PM, Chen RT, et al. Fatal respiratory disease due to Corynebacterium diphtheriae: case report and review of guidelines for management, investigation, and control. Clin Infect Dis. 1993;16(1):59–68.
9. CDC. Availability of diphtheria antitoxin through an Investigational New Drug protocol. MMWR Morb Mortal Wkly Rep. 2004;53(19);413.
10. Kretsinger K, Broder KR, Cortese MM, et al. Preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP) and recommendation of ACIP, supported by the Healthcare Infection Control Practices Advisory Committee (HICPAC) for use of Tdap among health-care personnel. MMWR Recomm. Rep. 2006;55(RR-17):1–37.