Abstract
The re-emergence of diphtheria in the Newly Independent States of the former Soviet Union in the 1990s raised global awareness of the potential for resurgent disease in countries with long-standing immunization programs. In the United States, the large population of susceptible adults and the possibility of a reintroduction of toxigenic strains of diphtheria create a setting in which diphtheria could spread. In addition, at least one focus of continued circulation of endemic toxigenic Corynebacterium diphtheriae has been identified. Few physicians now have expertise in the diagnosis and treatment of persons with diphtheria, and laboratory capacity is lacking throughout the country. These concerns highlight the importance of maintaining high levels of age-appropriate diphtheria toxoid vaccination, surveillance, accessible and reliable laboratory testing, and training of health care providers. Although the risk of resurgence of diphtheria in the United States is low, public health authorities must ensure that the capacity to recognize, diagnose, and control diphtheria is maintained.
After 30 years of control, epidemic diphtheria, caused by toxigenic strains of Corynebacterium diphtheriae, re-emerged in the early 1990s in the Newly Independent States (NIS) of the former Soviet Union. The epidemic peaked in 1994–1995 and was on the decline by 1996. This article reviews the diphtheria epidemic in the NIS, the epidemiology of diphtheria in the United States, and the implications of the NIS diphtheria epidemic for prevention of diphtheria in the United States.
The Diphtheria Epidemic in the NIS
In the late 1950s, universal childhood immunization with diphtheria toxoid was begun throughout the former Soviet Union, and the immunization program successfully controlled diphtheria for almost 30 years. In 1976, reported cases in the Soviet Union fell to <200 (incidence rate, 0.08/100,000 population) [1], compared with 1955, when >100,000 cases were reported in Russia alone. During the 1970s, most of the reported cases were from the Central Asian Republics. In the mid-1980s, there was a small resurgence of almost 2000 cases per year, mostly in Russia, which was then followed by a decrease to 839 cases in 1989.
The diphtheria epidemic began in 1990 in the Russian Federation, spread to Ukraine in 1991, and spread to 12 of the 13 remaining NIS during 1993–1994 [1, 2]. In 1994–1995, the peak of the epidemic,>98,000 cases and 3400 deaths were reported in the NIS. By 1996, the incidence of diphtheria had begun to decline in most affected countries [2].
Serologic studies in the Soviet Union during the 1980s documented high rates of diphtheria susceptibility among adults. Passive hemagglutination and more sensitive toxin neutralization assays showed susceptibility rates of 19%–66% among adults ⩾20 years old [3–5].
Between 1985 and 1990, a large proportion of children in some of the NIS were given adult-formulation tetanus-diphtheria toxoids (Td), which contained only 5 limit of flocculation (Lf) units of diphtheria toxoid per dose, compared with 15–30 Lf in pediatric formulations [2]. The diphtheria toxoid Lf content in the adult formulation is insufficient for primary vaccination but is sufficient to induce anamnestic responses in previously immunized persons and minimizes reactivity in such persons. In 1986, the number of booster doses in later childhood was reduced, and the increased interval between doses was later found to increase the risk of diphtheria [6].
In 1991, after the breakup of the Soviet Union, vaccine supplies were interrupted to countries in Central Asia, the Caucuses, and the Baltics, which led to disruption of routine childhood vaccination programs. Routine adult booster immunization against diphtheria was not recommended in the former Soviet Union after the age of 14–16 years, when the last booster dose with diphtheria toxoid-containing vaccine was administered [2]. However, in 1986, because of the increase in diphtheria cases in the mid-1980s, adult vaccination was begun on a small scale for members of certain occupational groups believed to be at higher risks of exposure to diphtheria [2].
The primary underlying causes of the epidemic are thought to include (1) low levels of immunity in the population due to lack of receipt of a complete childhood vaccination series of five doses of diphtheria toxoid-containing vaccine and a lack of routine administration of booster doses to adults; (2) resurgence of toxigenic C. diphtheriae strains; and (3) socioeconomic instability, deterioration of the health infrastructure, and increased movement of the population following the dissolution of the Soviet Union [1, 2].
Diphtheria in the United States
In the first half of the 20th century in industrialized countries, diphtheria was a major killer of children. In the United States in 1921, the highest number of reported cases was 206,939 (incidence rate, 191/100,000 population) (figure 1). Diphtheria toxoid vaccine was introduced in the mid-1920s, and its use became universal by the late 1940s [7]. The number of cases of diphtheria reported annually declined from 18,675 in 1945 to 3 in 1980. Diphtheria remained endemic in some states through the 1970s, with reported incidence rates of >1.0 per million population in six states (Alaska, Arizona, Montana, New Mexico, South Dakota, and Washington) [8].
Reported diphtheria cases—United States, 1920–1998
Reported diphtheria cases—United States, 1920–1998
The last large outbreak of diphtheria in the United States occurred in the 1970s among alcoholic adults in Seattle [9]. The outbreak was associated with poor hygiene, crowding, and underlying skin disease. From 1980 through 1994, 41 cases of diphtheria were reported in the United States, including 4 fatal cases (10%) among unvaccinated children [10]. None of the patients were up to date with diphtheria toxoid vaccination. No adult cases were known to have received full primary vaccination and a diphtheria toxoid booster within the 10 years before illness onset. None of the 41 cases were the source of secondary cases. Five of the 6 culture-positive patients who were diagnosed after 1988 were thought to be associated with importation of the organism from other countries. Two cases of respiratory diphtheria were reported in 1996 (including a case caused by toxigenic Corynebacterium ulcerans infection [11]), 4 cases were reported in 1997, and 1 was reported in 1998 (Centers for Disease Control and Prevention [CDC], unpublished data, 1998).
National surveillance data suggest that strains of toxigenic C. diphtheriae are not widely circulating in the US population, despite seroprevalence studies that documented adult susceptibility [12–15]. However, in 1996, both toxigenic and nontoxigenic C. diphtheriae strains were isolated in a Northern Plains American Indian community from patients with acute pharyngitis: The strains were shown by molecular methods to be similar to strains isolated from the same area in the 1970s [16, 17]. These data strongly suggest that there is at least one focus of transmission of endemic toxigenic C. diphtheriae in the United States. The lack of reported respiratory diphtheria cases from this region, despite continued circulation of endemic toxigenic C. diphtheriae, could be due to inadequate case ascertainment or high levels of population immunity resulting from vaccination or natural infection. A similar situation of long-standing circulation of endemic toxigenic strains exists in native populations in Canada [18]. In Oregon in 1997, enhanced surveillance for diphtheria was undertaken in an American Indian community and only nontoxigenic strains of C. diphtheriae were found (CDC; unpublished data, 1997).
It is surprising that the United States has had little or no diphtheria, given its susceptible adult population, extensive travel to and from countries with endemic C. diphtheriae, and at least one domestic focus of endemic C. diphtheriae infection. Reasons for the rare occurrence of diphtheria are unclear. In the area known to have endemic C. diphtheriae, levels of immunity in the population are probably high enough to prevent clinical cases of diphtheria. In most other regions or in different population groups, where levels of adult immunity are low, the risk of exposure to toxigenic strains of C. diphtheriae is probably very low. In addition, one of the critical factors in the resurgence of diphtheria in the NIS was the low immunization coverage among children and lack of a booster dose at school entry [19, 6]; in contrast, immunization coverage of children in the United States is at an all-time high. It may also be possible that persons in the United States who received diphtheria toxoid in the past and now have waning antibody levels still possess immunologic memory sufficient to protect them against diphtheria.
Current Diphtheria Control Issues in the United States
The epidemic of diphtheria in the NIS has implications for the United States, including the need to (1) maintain high population immunity, especially high coverage (including a pre-school vaccine booster) among children; (2) recognize the risk of spread of diphtheria from an imported case or from a domestic endemic focus; (3) protect US travelers to countries where the disease is endemic; (4) maintain adequate supplies of both diphtheria antitoxin and toxoid vaccine; (5) maintain clinical expertise, laboratory capability, and surveillance for diphtheria; and (6) conduct additional research addressing key issues for control of diphtheria in the United States (table 1).
Implications of the diphtheria epidemic in the Newly Independent States (NIS) of the former Soviet Union for diphtheria control in the United States.
| Implications for the United States | ||
| Lesson learned in NIS epidemic | Current status | Activities |
| Need for high immunity across all age groups | 94% coverage with 5th dose of DTP at 4–6 years of age; 19%–77% of adults susceptible | Maintain high 5th dose coverage at school entry and implement strategies to increase Td coverage in adults |
| Need to document presence of organism | One identified focus | Maintain high coverage across all ages and provide surveillance |
| Need to recognize risk of importation | Low risk of importation | Provide surveillance |
| Need to protect travelers abroad | Low risk for travelers | Ensure age-appropriate vaccination before departure |
| Need for adequate supplies of antitoxin and Td | Current supplies adequate | Ensure adequate supplies |
| Need for early clinical and laboratory diagnosis | Low clinical awareness and limited laboratory capacity | Raise clinical awareness and develop laboratory capacity at state level |
| Value of case-based surveillance and contact management | Low public health awareness | Develop public health surveillance and response at county and state levels and at CDC |
| Need for microbiologic, clinical, and epidemiologic research | Few ongoing projects | Support applied laboratory and epidemiologic research |
| Implications for the United States | ||
| Lesson learned in NIS epidemic | Current status | Activities |
| Need for high immunity across all age groups | 94% coverage with 5th dose of DTP at 4–6 years of age; 19%–77% of adults susceptible | Maintain high 5th dose coverage at school entry and implement strategies to increase Td coverage in adults |
| Need to document presence of organism | One identified focus | Maintain high coverage across all ages and provide surveillance |
| Need to recognize risk of importation | Low risk of importation | Provide surveillance |
| Need to protect travelers abroad | Low risk for travelers | Ensure age-appropriate vaccination before departure |
| Need for adequate supplies of antitoxin and Td | Current supplies adequate | Ensure adequate supplies |
| Need for early clinical and laboratory diagnosis | Low clinical awareness and limited laboratory capacity | Raise clinical awareness and develop laboratory capacity at state level |
| Value of case-based surveillance and contact management | Low public health awareness | Develop public health surveillance and response at county and state levels and at CDC |
| Need for microbiologic, clinical, and epidemiologic research | Few ongoing projects | Support applied laboratory and epidemiologic research |
Implications of the diphtheria epidemic in the Newly Independent States (NIS) of the former Soviet Union for diphtheria control in the United States.
| Implications for the United States | ||
| Lesson learned in NIS epidemic | Current status | Activities |
| Need for high immunity across all age groups | 94% coverage with 5th dose of DTP at 4–6 years of age; 19%–77% of adults susceptible | Maintain high 5th dose coverage at school entry and implement strategies to increase Td coverage in adults |
| Need to document presence of organism | One identified focus | Maintain high coverage across all ages and provide surveillance |
| Need to recognize risk of importation | Low risk of importation | Provide surveillance |
| Need to protect travelers abroad | Low risk for travelers | Ensure age-appropriate vaccination before departure |
| Need for adequate supplies of antitoxin and Td | Current supplies adequate | Ensure adequate supplies |
| Need for early clinical and laboratory diagnosis | Low clinical awareness and limited laboratory capacity | Raise clinical awareness and develop laboratory capacity at state level |
| Value of case-based surveillance and contact management | Low public health awareness | Develop public health surveillance and response at county and state levels and at CDC |
| Need for microbiologic, clinical, and epidemiologic research | Few ongoing projects | Support applied laboratory and epidemiologic research |
| Implications for the United States | ||
| Lesson learned in NIS epidemic | Current status | Activities |
| Need for high immunity across all age groups | 94% coverage with 5th dose of DTP at 4–6 years of age; 19%–77% of adults susceptible | Maintain high 5th dose coverage at school entry and implement strategies to increase Td coverage in adults |
| Need to document presence of organism | One identified focus | Maintain high coverage across all ages and provide surveillance |
| Need to recognize risk of importation | Low risk of importation | Provide surveillance |
| Need to protect travelers abroad | Low risk for travelers | Ensure age-appropriate vaccination before departure |
| Need for adequate supplies of antitoxin and Td | Current supplies adequate | Ensure adequate supplies |
| Need for early clinical and laboratory diagnosis | Low clinical awareness and limited laboratory capacity | Raise clinical awareness and develop laboratory capacity at state level |
| Value of case-based surveillance and contact management | Low public health awareness | Develop public health surveillance and response at county and state levels and at CDC |
| Need for microbiologic, clinical, and epidemiologic research | Few ongoing projects | Support applied laboratory and epidemiologic research |
Maintenance of a High Population Immunity
Several small serologic studies in the United States found that 19%–77% of adults ⩾20 years old were susceptible to diphtheria [12–15]. These figures may underestimate the actual level of susceptibility since an antitoxin level cut-point of ⩾0.01 IU/mL was assumed to be protective; other studies suggest that circulating antitoxin levels of ⩾0.1 IU/mL are needed for protection [20]. Unpublished data on diphtheria immunity in non-institutionalized US civilian adults were available from the first National Health and Nutrition Examination Survey conducted from 1971 to 1975 (CDC; unpublished data). Diphtheria antitoxin levels were measured by passive hemagglutination in a subsample of 2405 men and 2788 women who were 25–74 years old. Among men, susceptibility rates (i.e., antitoxin levels ⩽0.1 IU/mL) increased with age, from 26% among men 25–34 years old to 46%–49% in older age groups. Women had higher susceptibility rates, which increased from 40% among women 25–34 years old to 50%–64% in older age groups. These differences between the sexes have been attributed to greater vaccination rates in men because of military service and possibly from higher rates of injury and, thus, a higher rate of receiving Td vaccine. These data contrast with experience from the pre-vaccine era, when almost all adults were immune to diphtheria because of infection in childhood [21].
The current recommended immunization schedule in the United States is a primary immunization series of three doses of diphtheria toxoid-containing vaccine in the first year of life and booster doses at 15–18 months of age, 4–6 years of age, and thereafter, every 10 years. Childhood diphtheria toxoid coverage is high: In 1997, 95% of children 19–35 months old had received three or more doses of diphtheria-tetanus toxoids-pertussis or diphtheria-tetanus toxoids (or both) vaccine, and 81% had received four or more doses [22].
Data on adult compliance with the recommendation for decennial Td boosters are limited. From 1980 to 1993, the CDC Biologics Surveillance System showed that the number of doses of tetanus toxoid-containing vaccines (i.e., TT [tetanus toxoid] and Td) for adults did not increase, although the proportion of Td doses distributed increased from 47% in 1980 to 82% in 1993 (CDC; unpublished data, 1994). The US population ⩾15 years old numbers ∼200 million. Therefore, assuming 25% vaccine wastage, at least 25 million doses of Td would be required to ensure compliance with the decennial booster recommendation, whereas, in 1997, ∼15.2 million Td doses were distributed (CDC; unpublished data, 1998). Data from the 1995 National Health Interview Survey (NHIS) show that coverage varied by age group, with 65%, 54%, and 40% of adults 18–49, 50–64, and ⩾65 years old, respectively, recalling having had a tetanus immunization within the last 10 years (CDC; unpublished data, 1995 NHIS); the doses-distributed data suggest that ∼80% of these doses were Td.
Strategies are needed to maintain high coverage for children and increase vaccine coverage among adults, especially among persons ⩾45 years old. Providers should use each encounter with patients to review immunization history and vaccinate if indicated. The Task Force on Adult Immunization of the American College of Physicians and the Advisory Committee on Immunization Practices (ACIP) recommend a preventive health visit at age 50; this visit should be promoted as an opportunity to administer Td and other vaccines [23].
The ACIP also recommends the use of Td in preference to TT for wound management and for routine decennial booster doses [23]; however, despite the ACIP recommendation, ∼20% of adults currently receive TT. Physicians may still be using TT for wound management in emergency rooms because of habit, concerns for adverse events after multiple doses of Td, and the perception of a low risk of diphtheria. The private-sector price for TT is only marginally different from the price per dose for Td. To increase the use of Td, as recommended by the ACIP, all major medical societies should be made aware that Td, not TT, should be used for immunization, and effective ways of educating providers and promoting increased Td coverage should be developed [24]. Additional strategies to raise coverage among adults could include evaluation of Td coverage along with other adult vaccinations as part of quality assessment of managed-care organizations and screening for Td vaccination status among influenza vaccine recipients.
Recognition of the Risk of Spread of Diphtheria
During the diphtheria epidemic in the NIS, >20 imported diphtheria cases were reported in European countries, including Bulgaria, Finland, Germany, Norway, and Poland. In both Finland and Poland, large numbers of adults were vaccinated against diphtheria as part of the response to the imported cases. In view of the imported cases in Europe, it appeared likely that imported cases related to the epidemic were also likely to occur in the United States; however, no cases of diphtheria related to the epidemic in the NIS are known to have been imported into the United States. The possibility remains, however, of importation of C. diphtheriae from countries where it is endemic, including non-NIS countries. In the event of such importation, secondary cases may occur, and an outbreak or resumption of indigenous transmission could result. In the mid-1980s in Sweden, after 24 years without reported indigenous disease, 33 diphtheria cases (almost all among adults) occurred over a 2-year period [25]. It is believed that the diphtheria strain responsible for this outbreak was imported, although the source is unknown.
The risk of a large diphtheria outbreak in the United States due to importation of diphtheria from other countries or from a domestic focus of endemic infection appears to be low, although the relatively high proportion of susceptible adults in the United States could facilitate transmission. If multiple simultaneous importations occurred (for example, several C. diphtheriae-infected carriers among a large group of athletes), allowing some spread of C. diphtheriae before the importation was recognized, it is possible that a moderately sized outbreak (20–200 cases) could occur. If such an outbreak was sufficiently spread throughout a large city, vaccination of hundreds of thousands of persons might be required to ensure high levels of immunity in the population.
There are no vaccination requirements for travelers. More specific measures to prevent importation of diphtheria from countries where it is endemic would be difficult to enforce, especially in time of lower risk. Surveillance for communicable diseases, including diphtheria, needs to be increased when circumstances conducive for an outbreak (e.g., international sporting events) exist.
In the event of an outbreak of diphtheria, health care providers would be a group at risk of contracting the disease. However because the current risk is low, there is no special vaccination requirement related to diphtheria for health care workers. Health care providers need to be appropriately immunized according to age, as recommended by the ACIP for all adults. If diphtheria is suspected in a patient, it is recommended that he or she receive a booster dose of Td if >5 years have elapsed since the last dose [26].
Protection of US Travelers to Countries with Endemic C. diphtheriae
During the NIS diphtheria epidemic, the US Department of Health and Human Services released advisory memoranda that recommended that travelers to areas where diphtheria was occurring should be appropriately immunized, and the recommendations were widely distributed to travel agencies [27, 28]. In late 1994, 2 cases of diphtheria were reported among US citizens working in or visiting countries of the former Soviet Union [29].
Currently, travelers may still be at risk for exposure to strains of C. diphtheriae in countries where it is endemic, especially with prolonged travel, extensive contact with children, or exposure to poor hygiene, and they should be appropriately immunized (according to age) against diphtheria (i.e., completion of a primary series and receipt of a diphtheria toxoid booster within the previous 10 years).
In 1999, one lot of a licensed diphtheria-tetanus toxoids-acellular pertussis (DTaP) vaccine was found to have subpotent diphtheria toxoid by the manufacturer and consequently was recalled from use. Children who were vaccinated with this lot and who were traveling to a country where the risk of diphtheria was high before their scheduled fourth dose of DTaP were recommended to get an additional dose of vaccine on an accelerated schedule [30].
Availability of Antitoxin and Vaccine
Until 1996, antitoxin was manufactured in the United States; however, because of low demand for equine diphtheria antitoxin, domestic pharmaceutical manufacturers no longer produce and distribute it in the United States. Since 1997, a French product manufactured by Pasteur Mérieux Connaught has been made available to suspected diphtheria cases in the United States through an investigational new drug protocol administered by the CDC [31]. Although there are few reported diphtheria cases in the United States, there are ∼20–30 suspected cases per year for which antitoxin is released; only a minority of the cases are actually treated with antitoxin. An adequate supply of diphtheria antitoxin and diphtheria toxoid–containing vaccines should be assured.
Surveillance
Despite the fact that diphtheria is now rare in the United States, it is essential to maintain clinician awareness. It is unlikely that an outbreak of diphtheria would go unrecognized because the disease has a distinctive clinical presentation. However, most practicing US clinicians have never seen a case of respiratory diphtheria, and the diagnosis may not be considered until disease is advanced, and sporadic or mild cases may not be diagnosed or reported to public health officials. Membranous pharyngitis can be associated with infections by other organisms, and the likelihood that a patient with membranous pharyngitis has respiratory diphtheria is low in the United States. Therefore, the clinical management of a patient with membranous pharyngitis could represent a dilemma for the practitioner who suspects diphtheria. The benefits and risks of diphtheria antitoxin treatment need to be weighed on a case-by-case basis [32]. The CDC epidemiologist on call for diphtheria antitoxin can provide information to the practitioner that may be useful in the clinical management of a case [26, 32]. The experience of CDC epidemiologists is obtained from combining the limited domestic exposure to suspected diphtheria cases with assistance given in other countries with diphtheria surveillance and control (e.g., countries in the NIS).
In 1994, a survey of public health laboratories in the 50 states, Puerto Rico, and Washington, DC, found that it is standard procedure in only 4% of 45 laboratories to culture throat specimens for C. diphtheriae; however, all laboratories will test specimens if specifically requested (CDC; unpublished data, 1994). After isolation of the organism, only 31% of the 45 state laboratories perform the Elek test for detection of diphtheria toxin, three state laboratories (7%) perform in vivo testing for the detection of diphtheria toxin, and two state laboratories perform polymerase chain reaction (PCR) for detection of diphtheria toxin genes. None of the state laboratories perform molecular subtyping of C. diphtheriae. Despite the low volume of cultures currently performed for C. diphtheriae, it appears that state public health laboratories would have the capability to increase the number of diphtheria cultures in the event of a suspected diphtheria outbreak. In a separate National Laboratory Training Network Survey, 15% of 54 state public health laboratories indicated that they required additional training in diphtheria microbiologic methods (CDC; unpublished data, 1994). For a disease like diphtheria, it would probably not be cost-effective for private laboratories to maintain the capacity to isolate and identify C. diphtheriae.
The expertise of the CDC Diphtheria Laboratory needs to be maintained so that it can continue to serve as the national reference laboratory. The laboratory needs to provide rapid response in diphtheria case and contact investigations and epidemiologic activities, and it needs to monitor possible changes in the organism at the molecular level. The CDC Diphtheria Laboratory provides reference facilities for diphtheria diagnosis, including confirmation of cultures and toxigenicity and PCR for detection of the diphtheria toxin gene in clinical specimens. In addition, every state public health laboratory should have ready access to diphtheria microbiology expertise to identify C. diphtheriae. The Manual for the Surveillance of Vaccine-Preventable Diseases produced by the CDC was widely distributed in the United States and provides information about clinical and laboratory diagnosis of diphtheria and contact management [33].
Research Needs
Although the demand for diphtheria antitoxin is low, use of the currently available equine antitoxin is associated with a risk of serum sickness. Development of human diphtheria immunoglobulin would represent a major improvement. Additional research projects could include the assessment of whether toxigenic or nontoxigenic strains are circulating in areas of previous endemicity, in low socioeconomic populations, or in regions where immigrant populations from areas where C. diphtheriae is endemic live and how the circulation of nontoxigenic strains potentially impacts diphtheria control. Cutaneous diphtheria and its role in transmission of toxigenic C. diphtheriae in the focus of circulating endemic toxigenic strains needs to be investigated. In addition, there are microbiologic issues of clinical and public health importance to consider. For example, the role of nontoxigenic, tox gene-bearing strains as a potential reservoir of the tox gene, and identification of other potential virulence factors in the strains endemic in the United States. Studies to determine the immunologic basis of protection and the optimal adult vaccine booster schedule should also be part of the research agenda.
Conclusions
The recent epidemic in the NIS demonstrates that diphtheria can re-emerge after years of decline and near elimination. Although the risk of resurgence of diphtheria in the United States is low, the capacity to control diphtheria should be maintained. Diphtheria control and prevention is part of the renewed public health goals for strengthening infectious disease surveillance and response in the United States, improving tools for identifying and understanding emerging and re-emerging infectious diseases, determining risk factors for infectious diseases, enhancing epidemiologic and laboratory capacity, and conducting research to develop and evaluate prevention and control strategies [34].
References
Author notes
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