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CDC Health Information for International Travel 2008

Chapter 4
Prevention of Specific Infectious Diseases



Diphtheria is an acute bacterial disease caused by toxigenic strains of Corynebacterium diphtheriae. There are four biotypes: gravis, mitis, intermedius and belfanti (1). Toxin-producing strains of C. ulcerans may also cause a diphtheria-like illness. The disease affects the mucous membranes of the respiratory tract (respiratory diphtheria), the skin (cutaneous diphtheria), and occasionally mucous membranes at other sites (eyes, ears, or vagina). Cutaneous diphtheria is common in tropical countries (2). Humans are the only known reservoir of C. diphtheriae. Diphtheria is transmitted to close contacts by respiratory droplets or by direct contact with discharge from skin lesions, and rarely from fomites. Raw milk or dairy products have been reported as vehicles for transmission (3).


Diphtheria is sporadically reported in the US and the last case occurred in an elderly traveler immediately after returning to the US from a country with endemic diphtheria (4). However, the disease can cause morbidity and mortality in developing countries where childhood vaccination coverage is low (5). Large outbreaks of diphtheria occurred in the 1990s throughout Russia and the newly independent states of the former Soviet Union (6). In the Americas, diphtheria was more recently reported from Paraguay, the Dominican Republic, and Haiti (5). Countries with endemic diphtheria (5) are shown in the Table 4-1.

Risk for Travelers

Travelers to countries with endemic diphtheria are at a higher risk of disease following exposure to toxigenic C. diphtheriae if they are inadequately immunized or not up-to-date with diphtheria booster immunizations. Although immunization does not prevent colonization or carriage of C. diphtheriae, symptomatic, or clinically evident infection is extremely rare in adequately immunized persons. Most cases occur in unvaccinated or inadequately immunized persons (7–9).

Clinical Presentation

The incubation period is 2-5 days (range 1-10 days), and the onset of symptoms is gradual. Early symptoms of respiratory diphtheria include malaise, sore throat, difficulty in swallowing, loss of appetite, and a mild fever (rarely >101° F). If the larynx is involved, the affected person may become hoarse. Within 2–3 days, an adherent, gray membrane forms over the mucous membrane of the tonsils, pharynx, or both. Attempts to remove the membrane cause bleeding. In severe cases of respiratory diphtheria, cervical lymphadenopathy and soft tissue swelling in the neck give rise to a “bull-neck” appearance (10). Extensive membrane formation may result in life-threatening or fatal airway obstruction. Diphtheria toxin can cause serious systemic complications, including myocarditis and neuropathies, if it is absorbed from the site of infection. Cutaneous and nasal diphtheria are localized infections that are rarely associated with systemic toxicity. The case-fatality rate of respiratory diphtheria is 5%-10%.



Routine Immunizations for Infants and Children <7 Years of Age

Immunization with diphtheria toxoid in combination with tetanus toxoid and acellular pertussis vaccine (DTaP) during infancy is recommended (see Tables 8-2, 8-3, and 8-4) (11). Combination vaccines contain diphtheria and tetanus toxoids and either whole-cell pertussis antigens (DTwP) or acellular pertussis antigens (DTaP). DTwP vaccine is no longer available in the United States but is used in other countries. Three brands of DTaP currently are approved for use and are available in the United States. Whenever possible, the same brand of DTaP vaccine should be used for all doses of the vaccination series; however, any licensed DTaP vaccine may be used to continue or complete the vaccination series if the type of vaccine previously administered is not known or the type of vaccine used for earlier doses is not available (11).

Immunization for infants and children up to the seventh birthday consists of five doses of DTaP vaccine. The first three doses are usually given at ages 2, 4 and 6 months, the fourth dose at ages 15-18 months, and the fifth dose at ages 4-6 years. The fifth dose is not necessary if the fourth dose was given after the child’s fourth birthday (11).

Travelers should be advised to complete as many doses as possible of the primary series before traveling. At least three doses of DTaP are necessary for protection against diphtheria. If an accelerated schedule is required to complete the series of DTaP vaccine, the schedule may be started as soon as the infant is 6 weeks of age, with the second and third doses given 4 weeks after each preceding dose (Table 8-4). The fourth dose should not be given before the child is 12 months of age and should be separated from the third dose by at least 6 months. The fifth dose should not be given before the child is age 4 years. Interruption of the recommended schedule or delay in doses does not lead to a reduction in the level of immunity reached on completion of the primary series. There is no need to restart a series regardless of the time that has elapsed between doses. For infants and children older than 7 years with a contraindication to the pertussis component of DTaP, diphtheria-tetanus (DT) can be used (11) (Tables 8-2, 8-3 and 8-4).

Primary Immunizations for Children ≥7 Years of Age, Adolescents, and Adults

There is no pertussis-containing vaccine licensed for children 7 to 9 years of age. In 2005, two tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines were licensed for use by the FDA. BOOSTRIX (GlaxoSmith-Kline Biologicals) has been licensed for use in people 10-18 years old and ADACEL (Sanofi Pasteur) has been licensed for use in people 11-64 years old (12).

Children 7–9 years of age who have not received a primary series against tetanus and diphtheria should receive three doses of Td because no pertussis-containing vaccine is licensed for use in this age group (11). If a child is 10 years old, a single dose of BOOSTRIX may be substituted for one of the Td doses.

Persons older than 11 years of age who have never been vaccinated against tetanus, diphtheria or pertussis (no dose of pediatric DTP/DTaP/DT/ or Td) should receive three doses of a tetanus and diphtheria toxoid-containing vaccine. For persons 11–64 years of age, the preferred schedule is a single Tdap dose, followed by a dose of Td given 4-8 weeks later. A second dose of Td is given at 6–12 months after the earlier Td dose. Two doses of a Td-containing vaccine can provide some protection against diphtheria, but a single dose is of little benefit. In the rare instance when vaccine administration following a 6–12-month interval cannot be ensured, an interval of 4-8 weeks may be used to complete the primary series (12,13).

Anyone whose history of primary tetanus and diphtheria vaccination is uncertain should be considered unvaccinated and should receive the three-dose series. Anyone who has received only one or two prior doses of tetanus and diphtheria toxoids should receive additional dose(s) to complete the three-dose series. A single dose of Tdap can be substituted for any of the Td doses (11,12).

Booster Immunizations for Children ≥7 Years of Age, Adolescents, and Adults

Adolescents 11–18 years of age should receive a single 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. Thereafter, routine booster doses of Td vaccine should be given at 10-year intervals (11,12). This is especially important for travelers who will be living or working with local populations in countries where diphtheria is endemic.

Adults 19–64 years of age should receive a single dose of Tdap (ADACEL) to replace a single dose of Td for active booster immunization against tetanus, diphtheria and pertussis, if they received their last dose of Td more than 10 years earlier and have not previously received a dose of Tdap. Replacing one dose of Td with Tdap should reduce the morbidity associated with pertussis in adults and may reduce the risk of transmitting pertussis to persons at increased risk for pertussis and its complications (13). Tdap is not licensed or recommended for adults 65 years of age and older, who should receive Td instead.

Adverse Reactions

Local reactions (erythema and induration with or without tenderness) are common after the administration of vaccines containing diphtheria, tetanus, and pertussis antigens (DTaP, TD, Td, Tdap) (11,12). Mild systemic reactions such as drowsiness, fretfulness, and low-grade fever can occur after vaccination with DTaP. These reactions are self-limited and can be managed with symptomatic treatment of acetaminophen or ibuprofen. Swelling involving the entire thigh or upper arm has occurred after the fourth and fifth doses of DTaP. These reactions are also self limited (11).

Anaphylactic and other serious adverse reactions are rare after receipt of preparations containing diphtheria, tetanus or pertussis components, or a combination of these. Arthus-type hypersensitivity reactions, characterized by severe local reactions, have been reported in adults who received frequent boosters of tetanus or diphtheria toxoids (11).

Precautions and Contraindications

An immediate anaphylactic reaction to a prior dose of vaccine or vaccine component is a contraindication to further vaccination with DTaP, DT, Tdap, or Td. Encephalopathy not due to another identifiable cause within 7 days of vaccination is a contraindication to further vaccination with a pertussis-containing vaccine. DT or Td may be substituted for DTaP or Tdap, respectively.

Moderate or severe acute illness is a precaution to vaccination. Mild illnesses, such as otitis media or upper respiratory infection, are not contraindications. Anyone for whom vaccination is deferred because of moderate or severe acute illness should be vaccinated when the condition improves.

Development of Guillain-Barré syndrome 6 weeks or less after a previous dose of a tetanus toxoid-containing vaccine is considered a precaution. Risks and benefits of immunization should be evaluated by the vaccine provider before administering Td or Tdap. Certain infrequent adverse events following pertussis vaccination are considered precautions (not contraindications) to additional doses of DTaP but not to Tdap: a seizure, with or without fever, occurring within 3 days of immunization; temperature higher than 40.5° C (105° F) not resulting from another identifiable cause within 48 hours of immunization; collapse or a shock-like state (hypotonic-hyporesponsive episode) within 48 hours of immunization, or persistent, inconsolable crying lasting longer than 3 hours and occurring within 48 hours of immunization. These events have not been demonstrated to cause permanent sequelae. In certain circumstances (e.g., during a communitywide outbreak of pertussis), the benefit of additional vaccination with DTaP in children or Tdap in adults may outweigh the risk of another reaction.

Progressive neurologic conditions characterized by changing developmental findings are considered contraindications to receipt of pertussis vaccine. Such disorders include infantile spasms and other epilepsies beginning in infancy (3). Infants and children with stable neurologic conditions such as cerebral palsy or controlled seizures should be vaccinated.


The diagnosis is usually presumptive, based on clinical features. A definitive diagnosis is based on a positive culture of C. diphtheriae from a throat swab, membrane. Toxin production is confirmed by performing a modified Elek test.

Patients with respiratory diphtheria require hospitalization, immediate treatment with diphtheria antitoxin (DAT), appro-priate antibiotics and supportive care, and monitoring of their close contacts (14,15).


  1. Funke F, von Graevenitz A, Clarridge JE 3rd, Bernard KA. Clinical microbiology of coryneform bacteria. Clin Microbiol Rev. 1997;10:125-59.
  2. Galazka AM. The immunologic basis for immunization: Diphtheria (WHO/EPI/GEN/13.13). Geneva, World Health Organization, 1993. Available at:
  3. American Academy of Pediatrics. Diphtheria. In: Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Red Book: 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006:277–81.
  4. CDC. Summary of notifiable diseases—United States, 2004. MMWR Morbid Mortal Wkly Rep. 2004;53:46.
  5. World Health Organization. WHO vaccine-preventable diseases monitoring system: 2005 global summary. Geneva, Switzerland: World Health Organization, 2006.
  6. Galazka A. The changing epidemiology of diphtheria in the vaccine era. J Infect Dis. 2000;181(suppl 1):S2-9.
  7. Bisgard KM, Hardy IRB, Popovic T, Strebel PM, Wharton M, Chen RT, et al. Respiratory diphtheria in the United States, 1980 through 1995. Am J Public Health. 1998;88:787–91.
  8. CDC. Fatal respiratory diphtheria in a U.S. traveler to Haiti—2003. MMWR Morbid Mortal Wkly Rep. 2003;52:1285–6.
  9. CDC. Diphtheria acquired by U.S. citizens in the Russian Federation and Ukraine—1994. MMWR Morbid Mortal Wkly Rep. 1995; 44:243–4.
  10. Wharton M, Vitek CR. Diphtheria toxoid. In: Plotkin SA, Orenstein WA, eds. Vaccines. 4th ed. Philadelphia: W.B. Saunders; 2004:211–28.
  11. CDC. General recommendations on immunizations: recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR Recomm Rep. 2002;51(RR-2):1–35.
  12. CDC. Preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recommm Rep. 2006;55(RR-3):1–50.
  13. CDC. ACIP Votes to Recommend Use of Combined Tetanus, Diphtheria and Pertussis (Tdap) Vaccine for Adults. Available at PDF (Accessed on August 11, 2006.
  14. Farizo KM, Strebel PM, Chen RT, Kimbler A, Cleary TJ, Cochi SL. Fatal respiratory disease due to Corynebacterium diphtheriae: case report and review of guidelines for management, investigation, and control. Clin Infect Dis. 1993;16:59-68.
  15. CDC. Notice to Readers: Availability of diphtheria antitoxin through an Investigational New Drug protocol. MMWR Morbid Mortal Wkly Rep. 2004;53:413.

TABLE 4-01. Countries with endemic diphtheria

AfricaAlgeria, Angola, Egypt, Niger, Nigeria, Sudan, and sub-
Saharan countries
Americas Bolivia, Brazil, Colombia, Dominican Republic, Ecuador,
Haiti, and Paraguay
Asia/South Pacific Afghanistan, Bangladesh, Bhutan, Burma (Myanmar), Cambodia,
China, India, Indonesia, Laos, Malaysia, Mongolia,
Nepal, Pakistan, Papua New Guinea, Philippines, Thailand,
and Vietnam
Middle East Iran, Iraq, Saudi Arabia, Syria, Turkey, and Yemen
Europe Albania, Russia, and countries of the former Soviet Union
  • Page last updated: January 07, 2009
  • Content source:
    Division of Global Migration and Quarantine
    National Center for Preparedness, Detection, and Control of Infectious Diseases
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