VACCINE RECOMMENDATIONS: CHALLENGES AND CONTROVERSIES 0891-5520/01 $15.00 + .OO ISSUES RELATED TO THE DECENNIAL TETANUS- DIPHTHERIA TOXOID BOOSTER RECOMMENDATIONS IN ADULTS Pierce Gardner, MD In the United States, immunization with tetanus toxoid and diphthe- ria toxoid (Td) has be& a staple of immunization programs for more than 50 years. Over the past decade, tetanus cases have hovered between 35 and 50 cases per year,% and diphtheria cases between 1 and 5 cases per ~ear.2~ Despite this obvious success story, several important ques- tions about current and future immunization policy remain to be an- swered. SHOULD THE RECOMMENDATION FOR ROUTINE TETANUS-DIPHTHERIA TOXOID (TD) BOOSTERS EVERY 10 YEARS BE CHANGED? To question the current Advisory Committee on Immunization Prac- tices (ACIP) decennial Td booster recommendation’, a fundamental stan- dard of adult immunization policy for decades, may appear akin to assaulting apple pie and motherhood. Nevertheless, it behoves us to examine the epidemiology data to identify the essential ingredients of success and to change practices that are unnecessary, wasteful, or harmful. From the Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York INFECTIOUS DISEASE CLINICS OF NORTH AMERICA VOLUME 15 * NUMBER 1 * MARCH 2001 143
Transcript
VACCINE RECOMMENDATIONS: CHALLENGES AND CONTROVERSIES 0891-5520/01 $15.00 + .OO
ISSUES RELATED TO THE DECENNIAL TETANUS-
DIPHTHERIA TOXOID BOOSTER RECOMMENDATIONS IN ADULTS
Pierce Gardner, MD
In the United States, immunization with tetanus toxoid and diphthe- ria toxoid (Td) has be& a staple of immunization programs for more than 50 years. Over the past decade, tetanus cases have hovered between 35 and 50 cases per year,% and diphtheria cases between 1 and 5 cases per ~ e a r . 2 ~ Despite this obvious success story, several important ques- tions about current and future immunization policy remain to be an- swered.
SHOULD THE RECOMMENDATION FOR ROUTINE TETANUS-DIPHTHERIA TOXOID (TD) BOOSTERS EVERY 10 YEARS BE CHANGED?
To question the current Advisory Committee on Immunization Prac- tices (ACIP) decennial Td booster recommendation’, a fundamental stan- dard of adult immunization policy for decades, may appear akin to assaulting apple pie and motherhood. Nevertheless, it behoves us to examine the epidemiology data to identify the essential ingredients of success and to change practices that are unnecessary, wasteful, or harmful.
From the Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York
INFECTIOUS DISEASE CLINICS OF NORTH AMERICA
VOLUME 15 * NUMBER 1 * MARCH 2001 143
144 GARDNER
Epidemiology of Tetanus
Since 1975, reported cases of tetanus in the United States have been below 100 per year, and for the past 10 years have averaged less than 50 per year.= Thus, tetanus has become a rare disease, ranking in frequency behind botulism, brucellosis, leprosy, Rocky Mountain spotted fever, and typhoid fever. This happy situation can be attributed to several factors, including a decrease in environmental exposure to teta- nus bacilli, improved management of tetanus-prone wounds, and uni- versal immunization of children and the military. The relative contribu- tion of the decennial Td booster recommendation is small, however, as evidenced by the fact that the reduction in disease incidence occurred despite strong serologic evidence that most adults (and their physicians) have not adhered to the booster recommendation^.^' Because the primary tetanus toxoid series induces excellent immune memory, booster doses reliably result in a brisk anamnestic antibody response, even when intervals of 20 years or more have elapsed since the last Therefore, an antitoxin level below 0.01 IU/mL (the generally accepted minimum protective level) is strong, evidence that either (1) the individual never received a primary series of tetanus toxoid, or (2) has not received a booster dose in the previous decade.
A national population-based serologic survey conducted from 1988 to 1991 showed serologic evidence of immunity declining over from 80% among persons age 6 to 39 years to 28% among persons 70 years or 01der.l~ In national health interview surveys, only 27% to 36% of individ- uals age 65 or older reported receiving a tetanus vaccination during the previous 10 years.'O More than 90% of the small number of remaining cases in the United States occur in individuals who do not know their immunization status or report having received less than the full primary immunization series.'O
Thus, despite the serologic evidence that large numbers of adults are susceptible, tetanus is a rare disease among individuals who have at any previous time completed their full primary series (Table 1). This epidemiologic fact strongly suggests that the protective antitoxin stan- dard of 0.01 IU/mL is not nearly as reliable as a history of full primary tetanus toxoid immunization in predicting protection from disease. Ad- ditional evidence of the long-term protective effect of the primary immu- nization series is the lifelong amelioration of disease severity. In re- viewing more than 20 years of Centers for Disease Control and Prevention (CDC) data,7-10,19,27 the author can find no deaths from tetanus among individuals who have at any time completed the full primary series.
Universal diphtheria-tetanus-pertussis (DTP/DTaP) immunization of children has all but eliminated pediatric tetanus (except among immi- grant children and other pockets of subpar vaccine delivery), and tetanus has become primarily a disease of adults who have never been immu- nized fully. Special risk factors include injection drug use and chronic wounds, in addition to acute traumatic injuries. It should be emphasized
DECENNIAL Td BOOSTER RECOMENDATIONS IN ADULTS 145
Table 1. TETANUS TOXOID VACCINATION STATUS AND DEATHS AMONG PERSONS WITH REPORTED TETANUS, BY VACCINATION STATUS- UNITED STATES, 1995-1 997 &
that The recommendations for use of tetanus toxoid and tetanus immune globulin in the treatment of tetanus-prone wounds remain intactlo and would not be affected by a decrease in frequency of Td boosters.
To reduce further the incidence of tetanus in the United States, the focus of immunization efforts should be making sure all children receive the full immunization series (including the adolescent Td booster) and that every adult has received a primary series of at least three doses of tetanus toxoid. This is best accomplished by incorporating an immuniza- tion history as a routine in the care of adults (and adolescents) in all patient encounters (e.g., emergency rooms, hospitals, doctors' offices). Because age-based recommendations are more successful and easier to implement, the ACIP6 and the American College of Physicians (ACP)2 have sought to improve adult coverage by adopting a policy that the 50th birthday should be used as a special date to review overall immuni- zation status, and to give appropriate vaccines, including Td primary series or boosters if indicated. Because the age of starting universal influenza immunization now has been reduced to age 50 (and the pneumococcal vaccine age recommendations may follow), this becomes an opportune moment to improve the vaccine coverage levels for each of these vaccines.
Once individuals have completed the primary series of tetanus immunizations, the decennial booster policy offers marginal additional protection and is not supported by careful cost-benefit studies that indicate an excessive cost compared to other preventive measure^.^, 22
Therefore, the ACP2 and the American Academy of Family Practice have advocated, as a prudent alternative, a focus on assuring completion of the primary series (including the adolescent booster), followed by a single midlife Td booster at age 50 to 65 years. Some hoped-for advan- tages that might result from this policy are
1.
2.
Improved compliance with age-based recommendations and a simplified schedule, thereby increasing the levels of coverage. Better acceptance of recommendations that are based on epidemi- ologic data and cost-benefit analyses rather than tradition.
3. Reduction of adverse reactions due to overimmunization (see next section).
SHOULD ADVERSE EVENTS FOLLOWING BOOSTER IMMUNIZATIONS INFLUENCE POLICY, GIVEN THAT TETANUS AND DIPHTHERIA HAVE BECOME RARE IN THE UNITED STATES?
Td and tetanus toxoid (TT) are used almost exclusively in adults, and approximately 16 million doses are distributed annually in the United States.34 It is estimated that approximately half the total is deliv- ered as part of routine care (the decennial booster) and the other half is used in the management of tetanus-prone wounds. Approximately 36
DECENNIAL Td BOOSTER RECOMMENDATIONS IN ADULTS 147
million trauma visits to emergency rooms each year in the United States, suggests that a larger proportion of Td and TT may be delivered in trauma settings.
Factors associated with increased incidence and severity of reactions to Td toxoid boosters include the number of prior doses, a short interval since the previous dose, the toxoid antigen dose, the presence of adju- vant, subcutaneous rather than intramuscular administration (as per jet injector gun), and history of prior severe local or systemic reaction.13, 15, 20, ~ 3 , 24, Most Td recipients (50% to 85%) report pain or tenderness at the injection site, and 25% to 30% develop erythema and edema. Marked local reactions occur in less than 2%. True Arthus reactions with massive local pain and swelling occurring 2 to 8 hours after injection are uncom- mon and are associated with markedly elevated antitoxin levels in individuals who have received multiple booster doses.
In addition to local reactions, regional reactions (e.g., adenopathy) and systemic reactions (e.g., fever, headache, and malaise) can occur, but are rarely severe.
Rare, but more serious, adverse events include serious allergic reac- tions (anaphylaxis, with a frequency of approximately 1.6 per million doses) and peripheral neuropathy, especially brachial plexus neuropathy. The Vaccine Safety Committee of the Institute of Medicine33 concluded that the evidence supported a causal relationship between tetanus toxoid and brachial plexus neuropathy at a frequency of 0.5 to 1 case per 100,000 recipients. Cases were associated with frequent booster doses. In addition, Guillain-Barre syndrome has been well documented with recurring illness after repeated injections of tetanus toxoid, although the incidence is believed to be no more than 0.4 cases per million. However, if one multiplies the frequency of these rare but serious reactions by the approximately 16 million doses of Td and TT distributed annually in the United States, the total of severe events (25.6 severe allergic events, 80 to 160 cases of brachial plexus neuritis, 6.4 cases Guillain-Bar& syndrome per year) far exceeds the current level of tetanus cases (35 to 50 cases per year).
.
Policy Implications
Einstein once opined "everything should be made as simple as possible, but no simpler." Our goal in setting the Td booster policy should be to find the optimal balance between providing protection against disease and avoiding adverse reactions. Two truths have particu- lar pertinence in this deliberation. First, completion of a primary series of tetanus toxoid confers a high degree of protection from disease and provides lifelong benefit to the recipient by reducing incidence and severity of the disease. Second, adverse events following Td or TT boosters are correlated with the frequency of boosting and the presence of pre-existing antitoxin. Overimmunization provides a negligible incre- ment of protection at a cost of patient harm. Therefore, the optimal policy
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should focus on improving rates of complete primary immunization in adults and children and on reducing the number of booster doses. The booster policy that best fits these truths (and is the most cost effective) is to give a single midlife booster at age 50 to 65 years?, 22
WOULD A CHANGE FROM THE CURRENT DECENNIAL Td BOOSTER POLICY TO A SINGLE MIDLIFE BOOSTER INCREASE THE FUTURE RISK OF DIPHTHERIA?
Since 1980, the annual incidence of diphtheria reported in the United States has been five or fewer cases per year.= Even considering the possibility of significant underreporting, diphtheria is a rare disease in the United States. This success is attributable to current immunization policies, and therefore any change must be examined carefully (if it's working, why change it?). Unlike tetanus, diphtheria is a communicable disease and outbreaks in Eastern show the consequences of ineffective immunization programs due to inadequate delivery or poorly immunogenic vaccine. Even in well-immunized populations such as Sweden and Denmark, sporadic localized outbreaks have occurred.
The current pediatric immunization schedule in the United States calls for five doses of DTaP (2,4, 6 months, 15 months, and 4 to 6 years) and a Td booster at 14 to 16 ~ears .2~ The ACE' has set a standard of Td boosters at 10-year intervals. Absorbed, adjuvant containing Td with two Lf units of diphtheria toxoid is the only currently available product available for adolescents and adults in the United Statesz5 Seropreva- lence studies indicate that half or more adults in the United States lack what are considered protective antitoxin levels (0.1 IU/mL) against diphtheria.'l, *st 35 Despite the serologic evidence of susceptibility and the corollary that most adults have not complied with the decennial booster recommendation, diphtheria remains a disease of negligible inci- dence in the United States, rankiig behind plague, cholera, and tulare- mia.
Because diphtheria historically has been a pediatric disease, the focus of diphtheria immunization programs has been children. Before the Td combination was developed in the mid-1960s' there was no recommendation for diphtheria boosters for adults. The adult diphtheria toxoid recommendation came about because of the availability of a combined Td product, rather than an independent concern about diph- theria. Ironically, as the epidemiology of tetanus leads us to consider abandoning the decennial booster policy, concern about diphtheria sus- ceptibility is the major impediment to change (a classic case of the tail wagging the dog).
The efficacy of diphtheria toxoid in preventing disease has never been established in formal trials, although there is consensus that it is highly effective (approximately 90%). The protection against cutaneous
DECENNIAL Td BOOSTER RECOMMENDATION5 IN ADULTS 149
diphtheria appears to be less. As many as one third of diphtheria cases have occurred in individuals who have received partial or full imm~nization.2~ More adults lack protective antibody levels to diphthe- ria toxin than to tetanus toxin, suggesting that the duration of immunity following diphtheria toxoid immunization is not as long as that resulting from tetanus toxoid. Studies in Europe also have shown that most adults lack what are considered protective levels of diphtheria antitoxin?, 5, l6
Therefore, it is surprising that there has been so little diphtheria and that the sporadic outbreaks have been small and easily contained.
Of the 41 cases of diphtheria reported in the United States during a 13-year period from 1980 to 1992 (data supplied by Centers for Disease Control and Prevention), most had never received a primary immuniza- tion series. One case occurred in an individual considered fully immu- nized, and eleven (27%) in individuals with elapsed immunity (report- edly fully immunized during childhood but not subsequently boosted). Among those who had completed a primary series during childhood the disease was milder, indicating a degree of long-term protection. Of the 12 cases occurring among persons with full or lapsed immunity, none died and 10 (83%) had mild to moderate disease. Although 75% of the cases occurred in adults, children had more severe disease and accounted for 2 of the 3 deaths. These data corroborate Danish studies done over 50 years ago, in which severity of disease decreased with increasing number of vaccinations, and no deaths occurred in individu- als who had been immunized fully.18
Policy Implications
Achieving high levels of DPT or DtaP immunization among children is the cornerstone of diphtheria prevention in the United States. Among the handful of diphtheria cases (0 to 5 per year), most cases and all deaths have occurred among individuals who never received the pri- mary immunization series. Lapsed cases (childhood DPT immunization but no adult boosters) have averaged less than 1 per year since 1980, and among those individuals the disease has been milder with no deaths. These rare, lapsed cases are the individuals targeted by the decennial booster policy. Therefore, despite the poor record of adult immunization and the serologic evidence that most United States adults lack protective antibody levels, the current incidence and severity of diphtheria among individuals who have received a primary immuniza- tion series does not indicate a significant public health problem and programs to boost diphtheria immunity levels among adults should not be assigned a high priority. Finally, it is possible (perhaps likely) that a simplified schedule, that focuses on primary immunization followed by a single midlife Td booster, would result in increased compliance and better immunization against diphtheria.
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SHOULD ACELLULAR PERTUSSIS VACCINES BE COMBINED WITH TD FOR USE IN ADULTS?
The availability of acellular pertussis vaccines, that appear to be both safe and immunogenic in adults, will require that vaccine advisory groups make recommendations regarding their use. Pertussis in adults has negligible mortality, but could be responsible for as much as one quarter of cases of chronic cough syndrome in young adults.26, 29 Parents and other infant caregivers are important transmitters of pertussis to infants, the group with the highest morbidity and morta1ity.l Assuming that further studies confirm the immunogenicity and safety profile of acellular pertussis vaccines in adults, recommendations can be made for its use for universal immunization of adolescents, epidemic control, and strongly considered for adults who give care to infants. Safety studies in pregnant women, with an evaluation of maternal antibody protection of infants in the first months of life, deserve high priority. Additional studies are needed regarding age-specific morbidity data and vaccine efficacy studies with cost-benefit analyses; evaluation of the importance of adult immunization in crkating herd immunity; and evaluation of the role of certain subgroups (e.g., health care workers, daycare staff, and teachers) in the epidemiology of pertussis.
Several experts have advocated universal immunization of adults with acellular pertussis vaccine with the goals of reducing pertussis morbidity among adults and inducing herd immunity to reduce trans- mission of Bordeteh pertussis (especially to infants) and possibly some- day eradicate pertussis. Because the decennial Td booster recommenda- tion is in place, and because pertussis antigens have been combined with tetanus and diphtheria toxoids in the pediatrics schedule, it is initially attractive to consider combining the same antigens in an adult formulation. There are several drawbacks that would be difficult to reconcile, however. These include the following:
1. The duration of serologic immunity following immunization of acellular pertussis vaccine is short relative to the immunity in- duced by tetanus and diphtheria toxoids. Therefore, to immunize effectively against pertussis, boosters would be required more often than the 10-year interval for Td currently recommended by ACIP.
2. Toxicity issues related to overimmunization with tetanus- diphtheria toxoids (see previous section) provide a strong impe- tus to reduce the Td schedule rather than to increase it. Also, the low compliance with the current decennial booster recommenda- tion for Td and cost-benefit studies strongly favor a single midlife booster with Td as the preferable policy. If a single midlife booster becomes the standard (as recommended by some advi- sory groups), the need for frequent boosters of acellular pertussis vaccine will not be served by combining it with the tetanus and diphtheria toxoids.
DECENNIAL Td BOOSTER RECOMMENDATIONS IN ADULTS 151
3. In the management of tetanus-prone wounds that accounts for approximately half the use of Td vaccine in the United States, the addition of diphtheria toxoid to tetanus toxoid was made at a negligible cost increment. The subsequent addition of acellular pertussis vaccine to tetanus-diphtheria toxoids likely will result in a significant cost increase and could result in mild incremental toxicity. In a cost-conscious world, emergency room physicians could be reluctant to use the new TdaP vaccine and might even return to using tetanus toxoid alone as the most cost-effective way to prevent tetanus. This would have the negative impact of reducing levels of diphtheria immunity.
Policy Implications
Currently the level of awareness and concern about pertussis in adults is low, both in the medical profession and in the population. Acceptance of a more expknsive (and possibly more reactogenic) com- bined vaccine will require favorable cost-benefit studies, and a major educational effort to inform the public and the medical community about adult pertussis and its consequences. The most obvious role for the combined vaccine is in the universal immunization of adolescents, because Td already is recommended and pertussis immunization would have the added benefit of boosting immunity to individuals as they enter their reproductive years. A stand-alone acellular pertussis vaccine would appear to be preferable in most other situations, including epi- demic control, and in immunization of other targeted adults, such as those who give care to infants and health care workers. Universal immu- nization of all adults with acellular pertussis vaccine must await further cost-benefit studies. Young adults appear to bear the brunt of chronic cough syndrome, and it is unlikely that the elderly and the infirm who are the current focus of adult immunization programs (influenza and pneumococcal vaccine) will be important targets for adult pertussis immunization. To achieve universal immunization of adults with acellu- lar pertussis vaccine, major new delivery systems would need to be implemented. This is unlikely, because adult pertussis has negligible mortality and does not command a high priority among adult preventive medicine practices.
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Pierce Gardner, MD School of Medicine
State University of New York at Stony Brook Stony Brook, NY 11794-8432
