Vaccine-Preventable Diseases

Diphtheria

Diphtheria is an acute communicable disease primarily affecting the upper respiratory tract. It is characterized by the formation of a greyish membrane in the respiratory tract with surrounding inflammation which may lead to respiratory obstruction. Toxigenic strains of Corynebacterium diphtheriae cause the disease. The organism (both toxigenic and non-toxigenic strains) may be harboured in the nasopharynx, skin, and other sites of asymptomatic carriers. Diphtheria has a case-fatality rate of 5% to 10% with the highest death rates occurring among the very young and the elderly.

The highest ever-recorded annual number of diphtheria cases in Canada was 9,000 in 1924. The diphtheria toxoid was licensed for use in Canada in 1926 and introduced into routine immunization programs for infants and children in 1930. In the immediate post-immunization period, an average of 2,000 cases were reported annually. Routine immunization had led to a remarkable decline in both the morbidity and mortality of diphtheria by the mid-1950s. Diphtheria incidence has remained at a very low level since the early 1980s; only two to five cases were reported annually from 1986 to 1995. The majority of reported cases in the last 10 years have been in persons aged >= 20 years without adequate protection. Classic diphtheria is rare in Canada; no deaths have been reported since 1983.

National reporting of diphtheria is based on a case definition of clinical symptoms involving the upper respiratory tract (pharyngitis and/or laryngitis) with or without a membrane, and/or toxic symptoms (cardiac or neurologic involvement), and laboratory confirmation of a toxigenic strain. However, toxigenic strains of diphtheria continue to be isolated each year in carriers, mainly in northern and western Canada among Aboriginal populations; these are sometimes associated with mild clinical symptoms. Because such mild cases are not reported, the level of circulation of toxigenic strains is not entirely known. However, based on the minimal incidence of reportable cases, circulation is believed to be low. The apparent increase of diphtheria which was observed in the 1970s is due to the inclusion of non-classic diphtheria cases (carriers) in the western provinces; it does not correspond to a real increase in disease incidence.

In 1996, the Division of Immunization conducted a serosurvey of a sample of healthy adult blood donors in five centres across Canada; 13% to 32% had levels of diphtheria antitoxin below the minimum considered to protect them against the disease. Overall levels of immunity also varied by age group; the proportion of susceptibility ranged from 10% in those 30 to 39 years of age to 36% in those >= 60 years of age. Potential susceptibility to diphtheria differed among adults in different parts of the country; however, overall conclusions about the potential for diphtheria to resurface with large epidemics are troubling. The results are even more significant given that the sample represented a relatively healthy population. The actual levels of immunity in the general adult population are likely to be lower. It is possible that a certain proportion of seronegative individuals would be protected because they may have kept their immunologic memory, although their antibody levels have fallen.

The possibility of diphtheria resurfacing in Canada is highlighted by two factors: the low levels of immunity among Canadian adults and the resurgence of diphtheria in parts of Europe during this decade. Starting from 1990, major diphtheria epidemics have been reported in the Newly Independent States (NIS) of Eastern Europe with subsequent importation to other European countries. In the Russian Federation alone, where most of the cases occurred, the number of reported cases went from about 200 to 300 annually in the mid-1970s to almost 2,000 in 1990 to 1991, and to over 15,000 by 1993. Major reasons are low immunization coverage rates among infants and children, poor quality of some vaccines, waning immunity among adults, and large movements of the population during recent years. From 1990 to 1995, approximately 125,000 cases and 4,000 deaths had been reported in the NIS; this represents approximately 90% of cases reported worldwide. Despite the level of serosusceptibility observed in Canada, it is reassuring to note that the epidemic in the NIS started mostly in younger age groups before spreading to older ones, and that Canadian children are very well protected against diphtheria. Despite a high volume of travel reported between Canada and affected European countries, to date no cases in Canada have been linked to the resurgence of diphtheria in Europe.

Nonetheless, travellers to those regions need to be fully informed of the current recommendations for booster immunization. Routine immunization against diphtheria is recommended in Canada for all persons. Recommendations are for primary immunization of children consisting of four doses between the ages of 2 and 18 months, and booster doses at 4 to 6 years of age and every 10 years thereafter. Although mild clinical diphtheria occasionally occurs in fully immunized persons, the antitoxin stimulated by immunization is believed to persist at protective levels for 10 years or more.

1998 Update:  One probable diphtheria case was reported in the Yukon in 1997. The case was a 64-year-old male who developed swelling and redness in the left tonsillar region, with a greyish-white membrane on the left lateral tonsil that extended up onto the soft palate. The patient received diphtheria antitoxin and eventually recovered. He had received a diphtheria and tetanus toxoid (Td adult type) vaccination approximately four years earlier.

Diphtheria Toxoid

Diphtheria toxoid is a cell-free preparation of diphtheria toxin detoxified with formaldehyde. It is highly immunogenic, but two to three primary doses are necessary to ensure reliable seroconversion and sufficiently high concentrations of protective antibody. Titres decline slowly with time but can be boosted by additional doses. In terms of protection against diphtheria, the significance of loss of antitoxin in adequately immunized people is not clear. The immunity conferred is antitoxic, not antibacterial, and thus protects against the potentially lethal systemic effects of diphtheria toxin but not directly against local infection. However, carriage of C. diphtheriae has been observed to be lower in immunized populations.

Diphtheria toxoid is available as a preparation adsorbed with aluminum phosphate and combined with other toxoids or vaccines (e.g., tetanus, poliomyelitis or pertussis, see Appendix III of the Guide ). The amount of toxoid present is measured in flocculating units (Lf). It should be noted that the amount of diphtheria toxoid in combined preparations of diphtheria and tetanus toxoids varies widely with the specific product and manufacturer. Preparations containing only 2 Lf of diphtheria toxoid (commonly designated Td) are intended for use in people >= 7 years of age.

Recommended Usage

Routine immunization against diphtheria is recommended for everyone, regardless of age at which immunization is begun. Adsorbed vaccines must be injected intramuscularly.

Primary immunization of children < 7 years of age

The recommended time interval between the initial three doses is normally 8 weeks. Longer intervals do not compromise the final level of antibody achieved, but the interval between doses should not be < 4 weeks. The fourth dose should be given 6 to 12 months after the third. A further booster dose is recommended 30 to 54 months after the fourth dose, most commonly at 4 to 6 years (school entry). This booster dose is not necessary if the fourth dose in the primary series was given on or after the fourth birthday. Although diphtheria toxoid is not essential for the fifth dose, a fifth dose of pertussis vaccine is strongly recommended and is most easily given combined with diphtheria and tetanus toxoids. An additional booster dose of adult-type preparation (Td) should be given at 14-16 years of age (school leaving booster) and at least once again during adult life (see below).

Primary immunization of persons >= 7 years of age

The recommended agent is a combined adsorbed tetanus and diphtheria preparation (Td, adult-type) containing less diphtheria toxoid than preparations given to younger children. This reduced amount is less likely to cause reactions in older people. Two doses are given 4 to 8 weeks apart, with a further dose 6 to 12 months later to complete the course.

Booster Doses

Ensuring that children receive the recommended series of doses, including the school leaving dose at 14 to 16 years of age, and that adults have completed primary immunization should be the first priority.

The acceptable options for adult booster doses are

• to continue to offer boosters of Td at 10-year intervals, or

• as a minimum, to review immunization status at least once during adult life, e.g., at 50 years of age, and offer a single dose of Td to everyone who has not received one within the previous 10 years.

In addition,

• People who are travelling to areas where they are likely to be exposed to diphtheria may be offered a booster dose of Td if > 10 years have elapsed since their most recent booster.

• If a case of diphtheria occurs, close contacts (household, classroom or similar) should be given a dose of a toxoid preparation appropriate for their age unless they are known to have been fully immunized and the last dose was given in the previous 10 years. The remaining doses required to provide full immunization should be given to any contacts who were previously unimmunized or incompletely immunized. Patients convalescent from diphtheria should be given a complete primary course of toxoid, unless serologic testing indicates protective levels of antitoxin, since diphtheria infection does not always confer immunity. People requiring a booster dose of tetanus toxoid for wound management should receive Td as a convenient means of reinforcing their diphtheria protection.

Adverse Reactions

Contraindications and Precautions

When a combined diphtheria-tetanus preparation is being considered, care should be taken to avoid administration of tetanus toxoid more frequently than is recommended (see section on Tetanus Toxoid), or adverse reactions may result. It is important to ensure that adsorbed products are given intramuscularly, since subcutaneous injection of adsorbed products produces a much higher rate of local reactions.

Combined Vaccines Against Diphtheria, Pertussis, Tetanus and Poliomyelitis

It is recommended that diphtheria and tetanus toxoids, and acellular pertussis and poliomyelitis vaccines always be administered in a combined formulation appropriate for age.

Local and systemic reactions associated in the past with the primary series of DPT or DPT-Polio containing whole cell pertussis vaccine appear to have been due primarily to the pertussis component. Reaction rates of the combined vaccines were similar to those of pertussis vaccine alone. Vaccines containing acellular pertussis vaccine have much lower rates of adverse reaction, but local reactions have been observed with the fourth and fifth doses of vaccine.

Combined adsorbed preparations of diphtheria and tetanus toxoid formulated for adults (Td or dTap) are the preferred immunizing agents for people >= 7 years of age. They are recommended as follows:

1. primary immunization of older children and adults against diphtheria and tetanus;

2. regular booster doses for children at 14 to 16 years of age, and for adults; and

3. management of wounds when tetanus toxoid is indicated.

A combined adsorbed preparation containing diphtheria and tetanus toxoids, and inactivated poliomyelitis vaccine (Td-Polio) is available for immunization of older children >= 7 years and selected adults. For details of usage and precautions to be taken, see relevant sections of the Guide.

Diphtheria Selected References

Galazka AM, Robertson SE. Immunization against diphtheria with special emphasis on immunization of adults. Vaccine 1996;14:845-57.

Galazka AM, Robertson SE, Oblapenko GP. Resurgence of diphtheria. Eur J Epidemiol 1995;11:95-105.

Gupta RK, Griffin Jr. P, Xu J et al. Diphtheria antitoxin levels in US blood and plasma donors. J Infect Dis 1996;173:1493-7.

Larsen K, Ullberg-Olsson K, Ekwall E et al. The immunization of adults against diphtheria in Sweden. J Biol Stand 1987;15:109-16.

Maple PA, Efstratiou A, George RC et al. Diphtheria immunity in UK blood donors. Lancet 1995;345:963-5.

Plotkin SA, Orenstein WA. Vaccines. 3rd edition. Philadelphia: W.B Saunders Company, 1999.

Simonsen O, Kjeldsen K, Vendborg H-A et al. Revaccination of adults against diphtheria. 1: Responses and reactions to different doses of diphtheria toxoid in 30-70-years-old persons with low serum antitoxin levels. Acta Pathol Microbiol Immunol Scand [C] 1986;94:213-18.

Yuan L, Lau W, Thipphawong J et al. Diphtheria and tetanus immunity among blood donors in Toronto. Can Med Assoc J 1997;156:985-90.