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Volume: 24S3 - July 1998 Guidelines for the Control of Diphtheria in Canada BACKGROUNDClinical and bacteriologic information Diphtheria is caused by toxigenic strains of the bacteria Corynebacterium diphtheriae of gravis, mitis or intermedius biotypes. It is transmitted through personal contact and has an average incubation period of 2 to 5 days (range: l to 10 days). The disease affects primarily the upper respiratory tract (tonsils, pharynx, larynx, and nose) and occasionally other mucous membranes and skin; cutaneous diphtheria is more common in developing countries, particularly in tropical regions. The characteristic diphtheria lesion is a patch of an adherent greyish membrane with inflammation of surrounding tissue, associated in respiratory diphtheria with cervical lymphadenopathy. In severe cases of respiratory diphtheria there is marked swelling of the neck, the classical "bull-neck" appearance. The various clinical forms of diphtheria have been described in extensive detail(2-4). They are caused by an exotoxin produced by toxigenic strains of the bacteria; all toxigenic strains produce an identical toxin. Toxin production occurs following infection of a C. diphtheriae strain by a corynebacteriophage containing the tox gene. Non-toxigenic strains can also produce a mild, localized disease resembling that caused by toxigenic strains. Late effects of the diphtheria toxin are exerted on distant tissues and organs after 2 to 6 weeks causing especially cranial and peripheral motor and sensory palsies, and myocarditis in particular. Late effects are often severe. A case-fatality rate of 5% to 10% is reported for non-cutaneous diphtheria, with the highest rates among the very young and the elderly. Although infectivity does not appear to be related to the biotype, biotype gravis is reportedly the one most frequently found in association with fatal illness(3). Infections that are not apparent tend to outnumber clinical cases, and both toxigenic and non-toxigenic strains of C. diphtheriae may be harboured in the nasopharynx, skin, and other sites of asymptomatic carriers. Two mechanisms of infection have been described: direct transmission of toxigenic strains, or indirect transmission by transfer of the bacteriophage from a person infected with a toxigenic strain to a non-toxigenic strain in a carrier(2,5). The relative importance of these mechanisms in causing infection remains unclear(2). However, it has been suggested that direct transmission probably occurs among highly susceptible populations, whereas conversion of non-toxigenic strains to toxigenic ones would be the mode of transmission most likely to occur in an immunized population. The latter would likely result in limited spread unless there were appreciable numbers of susceptible individuals(5). Thus, the introduction of a toxigenic strain of C. diphtheriae into a community can initiate an outbreak by transfer of the bacteriophage to circulating non-toxigenic strains in the community. Immunity against diphtheria is antibody-mediated. Immunity is primarily against the toxin rather than the bacteria; therefore, immune persons can still harbour the organism. Diphtheria antitoxin production (primarily of IgG type) can be induced by the natural toxin during clinical infection or in the carrier state, or by immunization with diphtheria toxoid. The antibodies formed following natural infection or active immunization are identical and cannot be distinguished. A brief description of the laboratory measurement of diphtheria antitoxin is provided below, with particular reference to applying different methods and interpreting their results. The Schick test, used in the past as the standard procedure for determining an individual's susceptibility to diphtheria toxin, has been mostly replaced by more current serologic techniques. Despite being inexpensive and correlating well with serum antitoxin levels, the Schick test had a number of disadvantages compared with more recent tests: lack of a quantifiable result, both greater discomfort to the person being tested and technical difficulty (because of the need for a control injection to assess sensitivity to extraneous proteins in the test materials), and the possibility of false negative results (particularly in persons with skin anergy), which could lead to an inaccurate assumption of immunity(6). Among the common serologic techniques currently used, the in vivo neutralization test is considered the "gold standard"; it is recommended for use in calibrating the in vitro tests used more routinely in the laboratory(6). The in vivo neutralization test is based on injecting serial dilutions of serum mixed with fixed amounts of toxin into the depilated skin of rabbits or guinea pigs, and estimating the antitoxin concentration from the inflammatory reaction. It is laborious, time-consuming, and expensive. The in vitro tests are generally cheaper and less time-consuming. They include an in vitro neutralization test in cultured mammalian cells, a passive hemagglutination test, and an enzyme-linked immunosorbent assay (ELISA). The in vitro neutralization test shows good correlation with the in vivo neutralization test. However, the hemagglutination test and the ELISA correlate poorly with the in vivo and in vitro neutralization tests at low antitoxin levels: the hemagglutination test tends to underestimate low antitoxin concentrations, and the ELISA overestimates the levels (10 to 100 times higher with the direct ELISA, although better correlation has been reported with modified versions of the test)(6). The main advantage of the ELISA tests is the ability to measure IgG-specific diphtheria antibody. A circulating diphtheria antitoxin level of 0.01 IU/mL, as determined by in vivo or in vitro toxin neutralization tests, is widely accepted as indicative of clinical immunity against disease(2,6). There is no sharply defined level of antitoxin demonstrated to provide complete protection; levels between 0.01 IU/mL and 0.09 IU/mL are regarded as providing basic immunity, while levels > 0.1 IU/mL may be needed for full protection(6). Additional factors may influence an individual's susceptibility to infection, including the dose and virulence of the bacteria, and the individual's general immune status. It is generally believed that immunization of at least 70% of the population will result in a form of herd immunity against clinical diphtheria(2). In most industrialized countries primary immunization against diphtheria is given routinely in childhood (consisting of three to four doses) with a full-strength toxoid ranging in potency from 7 to 25 flocculating units (Lf) per immunizing dose. A notable exception is the use in Denmark of a 50 Lf toxoid for a three-dose series or 30 Lf for a four-dose series(7,8). Lower potency diphtheria toxoid (1 Lf to 7.5 Lf per dose) is used for adults, in both primary and booster immunizations. Following primary immunization with three doses of diphtheria toxoid, 94% to 100% of children in various studies have been shown to have antitoxin levels higher than 0.01 IU/mL, with mean levels ranging between 0.1 IU/mL and 1.0 IU/mL(8). There are, however, varying opinions about the persistence of immunity following primary immunization and the need for booster doses after childhood. In a review of the pertinent literature, declines in mean antitoxin levels were found to range from 3- to 50-fold 1 year after immunization with three doses of toxoid(6,8). For example, in one study in the United States, children who had received primary diphtheria toxoid combined with pertussis vaccine and tetanus toxoid (DPT) immunization were reported to have diphtheria antitoxin levels below the protective threshold (i.e. < 0.01 IU/mL) at 16 to 20 months of age. Other studies have suggested a longer duration of immunity: 96% to 100% of children studied in England and Italy still had protective antitoxin levels 4 to 8 years after receiving three doses of DPT or diptheria tetanus toxid (DT) in infancy. About 80% of the population in a Danish study were reported to have antibody levels above the protective threshold 25 to 30 years after the primary series with 50 Lf toxoid, suggesting that persistence of immunity after primary immunization is related to the strength of the toxoid used(7). The fourth dose of DT and subsequent boosters have been reported to stimulate progressively higher antitoxin levels (mean levels: > 1.0 IU/mL) associated with slower rates of decline(8). The antibody response to booster immunization in adults depends on the prior immune status (in turn related to natural immunity or to the schedule and potency of toxoids used in a primary series and the time since the last dose) as well as the dose of toxoid used for the booster. Prior immune status is more important in that, although a small amount of toxoid may be sufficient for a strong response in previously primed individuals, a large "booster" dose may not elicit a sufficient response in an individual without prior immunity(8). Mild clinical diphtheria occasionally occurs in fully immunized persons; however, the antitoxin stimulated by immunization is believed to persist at protective levels for 10 years or more. In countries with recommendations for adult diphtheria booster immunization, a booster dose is generally recommended at 10 year intervals; however, it has been noted that this interval is based on studies conducted during periods of repeated exposure to circulating C. diphtheriae (natural boosting). There are no contemporary studies addressing the appropriate interval for adult boosters under conditions of near elimination of diphtheria or a virtual lack of natural boosting, such as occur in Canada. Comparative studies in Denmark and the United States indicate a more rapid decline of diphtheria antitoxin levels in children following primary immunization in the 1980s as compared with the 1940s to 1960s, when there were more frequent opportunities for acquiring natural immunity from exposure to diphtheria organisms(6). Passive immunization with equine diphtheria antitoxin (prepared by hyperimmunizing horses with diphtheria toxoid and toxin) is used for the treatment of clinical diphtheria. Global trends in diphtheria incidence Historical evidence indicates the occurrence of major diphtheria epidemics in different parts of the world up to the mid-20th century. Routine immunization after this time in the industrialized countries of Europe and North America resulted in declines in both clinical disease and carriage rates(1). In addition, increasing proportions of cases were reported in older children and adults in countries with long-established routine immunization. The recent abrupt increase in diphtheria incidence in the Newly Independent States (NIS) of the former Soviet Union began after 1976 (when the lowest ever incidence was recorded at 0.08 per 100,000 population). An initial peak was reached in 1983 to 1985 (mean rate: 0.55 per 100,000); it was followed by a brief and marginal decline in incidence(1). Since 1990, diphtheria epidemics have been reported in all 15 Newly Independent States. In the Russian Federation alone (where most of the cases occurred), the number of reported cases increased from about 200 to 300 annually in the mid-1970s to almost 2,000 in 1990 to 1991 and 15,000 (10.2 per 100,000) by 1993. From 1990 to 1995, approximately 125,000 cases and 4,000 deaths were reported in the NIS; approximately 90% of cases reported worldwide were reported from the NIS(9). Major reasons for the diphtheria epidemic in the NIS have been described as follows: low immunization coverage rates among children (related to irregular supply of vaccines, decreased vaccine utilization by health workers due to an excessive list of contraindications to immunization, and a decreased acceptance of immunization by the public and the medical community resulting from anti-immunization propaganda); waning immunity among adults; and large movements of the population following the breakup of the former Soviet Union(1). The epidemic in the NIS resulted in a number of importations of diphtheria to other European countries, among them Finland, where four cases were reported in 1993 following 30 years of zero reporting. Two cases of diphtheria acquired in Eastern Europe have been reported in US citizens(10). To date, no cases have been reported in Canada with epidemiologic links to Eastern Europe. Another example of the potential risks associated with importation occurred in Sweden in 1984; 17 cases of clinical diphtheria (seven with involvement of the neurologic system and three fatalities) followed an importation from Denmark(11). The outbreak occurred after more than 2 decades of no indigenous cases being reported in Sweden (from 1960 to 1983), when the disease was regarded as eliminated. Notably, all 17 cases in Sweden were in or connected to subpopulations with histories of drug and alcohol abuse. Immunization rates among children were reportedly as high as 95% to 99% at the time of the outbreak, but low levels of immunity were documented even in healthy populations: 19% of a blood donor population < 20 years of age had mean antitoxin levels < 0.01 IU/mL. Among adults, up to 81% of women and 56% of men lacked immunity(12). Similar epidemiologic characteristics were also reported in Denmark, where the outbreak started. A changing epidemiology has also been recognized in non-industrialized countries, where diphtheria has mostly been of the cutaneous form. Since the 1980s, outbreaks of respiratory diphtheria with high case fatality rates and high rates of complications have reportedly occurred in several parts of Africa, Asia, the eastern Mediterranean, and Latin America(13). Epidemiology of diphtheria in Canada National notification of diphtheria in Canada began in 1924; the highest ever annual number of diphtheria cases (9,000) was recorded in the same year(14). The diphtheria toxoid was introduced for use in Canada in 1926 and more widely used from 1930. An average of 2,000 cases were reported annually in the immediate post-immunization period but, by the mid-1950s, remarkable declines had been achieved in both the morbidity and mortality associated with diphtheria. The downward trend continued until 1964, when only 23 cases (0.1 per 100,000) were reported. Active laboratory surveillance, with the inclusion of carriers, contributed to an increased annual incidence of 174 cases (0.8 per 100,000) in 1974. Since the late 1970s, diphtheria incidence has remained at a low rate ranging from 0.1 to 0.5 per 100,000 population. However, the steep decline in incidence starting from 1980 has been attributed, in part, to a change in case definition in 1980 to exclude carriers from reported cases in all provinces and territories(15). No deaths due to diphtheria have been reported since 1983. Data from the Notifiable Disease Reporting System, Laboratory Centre for Disease Control (LCDC), indicate that two to five cases were reported annually between 1986 and 1995 inclusively. No cases were reported in 1996 and a single case was reported in 1997 - a total of 33 cases for the 12-year period. Cases were reported from British Columbia (11), Alberta (10), Ontario (7), Manitoba (2), Saskatchewan (1), Northwest Territories (1) and the Yukon Territory (1). The age distribution of 30 cases for whom age information is available shows 50% occurred among persons aged > 30 years, 23% among those aged 5 to 9 years, and 13% each in the 10- to 19-year-old and 20- to 29-year-old age groups. It should be noted that current epidemiologic data are based upon the case definition for national notification of diphtheria in Canada developed in 1991, which was as follows:
This definition was used up to the time of publication of these guidelines. Revised surveillance case definitions are presented on pages 8 and 9. As part of the strategies for diptheria control, a carrier was defined as follows:
Asymptomatic persons and persons with upper respiratory tract symptoms harbouring non-toxigenic C. diphtheriae were not considered carriers or cases(16). Carriers were not and are still not nationally reportable, although reporting may be required in some jurisdictions. On the basis of the reported incidence of clinical diphtheria, circulation of toxigenic C. diphtheriae in Canada is believed to be very limited; however, the actual level of circulation is not known. Toxigenic strains of diphtheria continue to be isolated each year in carriers mainly in northern and western Canada, sometimes in association with mild clinical symptoms not fitting the reporting criteria. Diphtheria immunization status of Canadian population The National Advisory Committee on Immunization (NACI) recommends routine immunization against diphtheria for all persons in Canada(17). Diphtheria toxoid is available as a preparation adsorbed with aluminum phosphate and combined with other toxoids or vaccines (e.g. tetanus, poliomyelitis, or pertussis). For primary immunization of children < 7 years of age, it is preferable to use products in which diphtheria toxoid is combined with pertussis vaccine and tetanus toxoid (DPT) or tetanus toxoid and acellular pertussis vaccine (DTaP), with or without inactivated poliomyelitis vaccine (DPT-Polio or DTaP-Polio) and Haemophilus influenzae type b conjugate vaccine. The primary immunizing course of diphtheria toxoid alone or in combination consists of four doses and should ideally begin at 2 months of age. The recommended time interval between the initial three doses is normally 8 weeks (but should not be < 4 weeks); the fourth dose should be given 6 to 12 months after the third dose. A booster dose is recommended 30 to 54 months after the fourth dose, most commonly at 4 to 6 years of age (school entry). This booster dose is not necessary if the fourth dose in the primary series was given on or after the fourth birthday. An additional booster dose of adult-type preparation (Td) should be given at 14 to 16 years of age (school leaving booster) and at least once again during adult life (see below). For 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 is less likely to cause reactions in older persons. Two doses are given 4 to 8 weeks apart, with a further dose 6 to 12 months later to complete the course. NACI further recommends as a priority that children receive the recommended series of doses, including the school leaving dose at 14 to 16 years of age, and that adults complete primary immunization. The acceptable options for adult booster doses are
Persons requiring a booster dose of tetanus toxoid for wound management should receive Td as a convenient means of reinforcing their diphtheria protection. National estimates of immunization coverage against diphtheria in 1997 indicate that 98% of children have received at least three doses of a diphtheria-containing vaccine by the second birthday while 84% have received the recommended primary series of four doses(18). Despite these national estimates, survey data suggest that there are geographic areas with lower rates of coverage. Estimates of booster immunization among adolescents and adults have been less readily available and indicate very low immunization rates. In a 1991 national survey of vaccine coverage in the Canadian adult population aged > 18 years (with the exception of the Yukon and Northwest Territories), 6% of the survey respondents reported that they had been immunized against tetanus and diphtheria. The proportion decreased with age from 9% of those 18 to 24 years to 3% of those > 65 years(19). Furthermore, only 60% of the adults surveyed indicated an intent to comply with the NACI recommendations for 10-year diphtheria (and tetanus) boosters. In a 1996 survey of non-institutionalized adults aged > 18 years in Quebec, only 2.3% reported immunization against diphtheria compared with 32.5% who reported immunization against tetanus(20). These data suggest that diphtheria immunization coverage among adults is probably no higher than 60% and probably much lower. The large discrepancy between reported immunization with diphtheria and tetanus toxoids in the above survey is puzzling given that a high proportion (approximately 98%) of tetanus vaccination in Canadian adults is given as the combined Td vaccine. The available vaccine distribution data show a significant decrease in the use of monovalent tetanus toxoid from 23% in 1990 to 2% in 1995 as a proportion of tetanus vaccines used in adults. Serologic evidence of immunity to diphtheria in Canada In 1996, LCDC and the Canadian Red Cross conducted a serosurvey of a sample of healthy adult blood donors, aged 20 to 80 years, in five Canadian centres. Diphtheria antitoxin levels were measured by an in vitro neutralization test. Overall 20.3% (95% CI: 18.4% to 22.4%) of the study population had diphtheria antitoxin levels below the accepted protective threshold of 0.01 IU/mL, raising the possibility of clinical susceptibility. The proportion varied by age group, ranging from 9.5% (6.8% to 13.0%) among those in the 30- to 39-year-old age group to 36.3% (29.7% to 43.3%) in those aged > 60 years. As well, the proportion of susceptible persons differed by study centre, ranging from 13.4% (10.0% to 17.7%) to 32.2% (26.8% to 38.2%). In all age groups except the 40-49 year group, a higher proportion of males lacked protective antitoxin levels; overall 20.8% (18.5% to 23.2%) of males and 19.0% (15.4% to 23.3%) of females had antitoxin levels < 0.01 IU/mL. Similar low levels of diphtheria immunity were reported in another study of Canadian Red Cross adult donors in Toronto: the frequency of susceptibility ranged from 12.5% and 17.9% of male and female donors < 40 years of age to 42.6% and 40% of male and female donors aged > 60 years(21). These recent serosurveys indicate a lack of evidence of immunity to diphtheria among Canadian adults, leading to concerns about the potential for diphtheria to resurface in Canada. The results are particularly important given that these studies were based on relatively healthy populations and therefore the actual levels of immunity in the general adult population are likely to be even lower. Further, even in these healthy populations there appear to be subgroups at higher risk than others. However, the seroimmunity data obtained in Canada compare favourably with data reported from other industrialized countries. The recent resurgence of diphtheria in parts of Europe means that the possibility for the resurgence of diphtheria in Canada must be considered. No cases in Canada have yet been linked to the diphtheria epidemics in Europe despite a high volume of travel reported between Canada and the European countries affected by the epidemics. A reported rise in respiratory diphtheria in non-industrialized countries further increases the opportunities for importation of toxigenic strains.
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