ORIGINAL CONTRIBUTION tetanus, immunization
Tetanus Immunization Status and Immunologic Response to a Booster in an Emergency D e p a r t m e n t Geriatric Population Study objectives: Although effective procedures for the prevention of tetanus have long been available, serosurveys done since •977 demonstrate that 49% to 66% of the elderly population lacks a protective antitoxin level (more than 0.01 IU/mL). This study was undertaken to assess the tetanus immunization status of patients presenting to an emergency department and to evaluate their immunologic response to a tetanus booster. Setting: The study was conducted in a tertiary care ED. Type of participants: The patients enrolled were 65 or more years old and had breaks in their skin barriers. Design: A t each patient's initial presentation, pertinent demographic data and tetanus immunization history were recorded. The patient was then followed for 21 days. Interventions: Each patient's antitoxin titer was determined on a serum sample by ELISA, and, if required by the Advisory Committee on Immunization Practices criteria, a booster was administered at the first visit. Measurements and main results: Serum antitoxin assays were repeated on days 7, 14, and 21 after the initial visit until seroconversion (titer more than 0.01 IU/mL). Forty-four patients (55%)had protective levels at initial presentation, and in 36 (45%) the levels were not protective. Age and sex were not predictive of protection. Past military service and a definite history of three or more previous immunizations were good predictors of protection. Of 34 patients who were followed serially for inadequate initial titers, only 19 (56%) seroconverted by day 14. Patients who did not seroconvert were more likely to be older (P < .05). Conclusions: This study demonstrated that a significant number of elderly patients lacked an initial protective level of tetanus antitoxin. Of these, 44% failed to seroconvert within 14 days and carried a potential risk of developing tetanus. [Gareau AB, Eby R J, McLellan BA, Williams DR: Tetanus immunization status and immunologic response to a booster in an emergency department geriatric population. Ann Emerg Med December 1990;19:1377-1382.]
Annie B Gareau, MD, FRCPC RJ Eby, MD, FRCPC BA McLellan, MD, FRCPC DR Williams, MD, FRCPC Toronto, Ontario, Canada From the Department of Emergency Medicine, Sunnybrook Health Science Centre, University of Toronto, Toronto, Ontario, Canada. Received for publication April 20, 1990. Accepted for publication June 27, 1990. Presented at the Society for Academic Emergency Medicine Annual Meeting in San Diego, May 1989. Address for reprints: BA McLellan, MD, Department of Emergency Medicine, Suite 15, B-Ground, Sunnybrook Health Science Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
INTRODUCTION Although effective procedures for the prevention of tetanus have long been available, this disease remains a significant health problem. The average annual incidence rate of tetanus had been steadily declining between 1947 and 1976; however, during the past decade, the rate has not changed substantiallyJ One hundred forty-seven cases of tetanus were reported in the United States between 1985 and 1986; 60% of these cases occurred in elderly patients (60 years old or older), with a case fatality rate of 52% .2,3 In Canada, 17 patients are hospitalized each year with the diagnosis of tetanus, and two thirds of these patients are more than 45 years old. 4 Serosurveys done since 1977 indicate that 49% to 66% of the elderly population lacks a protective level of circulating tetanus antitoxin. 5-7 Active i m m u n i z a t i o n is highly effective, with a failure rate in fully immunized patients of less than four per 100 million. 8 For this reason, tetanus has been referred to as an "inexcusable" disease. 9 11 This descriptive prospective study was undertaken to assess the tetanus i m m u n i z a t i o n status of a geriatric population presenting to an emergency
19:12 December 1990
Annals of Emergency Medicine
1377/41
TETANUS IMMUNIZATION Gareau et al
Inclusion Criteria Eligible Population
Age of 65 or more years Any break in the skin barrier, including laceration or abrasion, burn, frostbite, animal or human bite, and corneal abrasion Availability for follow-up Agreeable to signing a consent
i
History of Adequate Immunization
I History of Inadequate Immunization
Antitoxin Titer Drawn
Exclusion Criteria Allergy to tetanus toxoid Immunosuppression due to chemotherapy, chronic steroid use, or known malignancy Unavailability for follow-up
=[
FIGURE 1. Patient population inclu-
sion and exclusion criteria. da
da'
Tetanus Booster ]
[
Discharged from study
21 14
y
I
I
I
FIGURE 2. Study algorithm.
I
I I day 7 I A n t i t o x i n Titer .o,,ow0p
I
]
d e p a r t m e n t w i t h a break in the skin barrier and to e v a l u a t e this population's i m m u n o l o g i c response to a tetanus booster given in the ED.
0-q
METHODS S u n n y b r o o k H e a l t h Science Centre is a t e r t i a r y - c a r e t e a c h i n g h o s p i t a l t h a t is l o c a t e d n o r t h of t h e d o w n t o w n Toronto core and serves a large community-based population. The ED has a p p r o x i m a t e l y 37,000 patient visits per year. Patients were enrolled in the study from February through September 1988 in a n o n c o n s e c u t i v e manner, following the inclusion and exclusion criteria o u t l i n e d (Figure 1). O n each p a t i e n t ' s initial presentation, i m m u n i z a t i o n history, previous m i l i t a r y service, and country of origin were recorded. A d e s c r i p t i o n of the w o u n d in t e r m s of depth, length, m e c h a n i s m of injury, and evidence of c o n t a m i n a t i o n was also documented. T e t a n u s a n t i t o x i n titers were drawn on a l l p a t i e n t s c o n s e n t i n g to t h e s t u d y and a n a l y z e d by the e n z y m e l i n k e d i m m u n o s o r b e n t assay (ELISA) method. T h e s e r u m s a m p l e t a k e n from 10 mL of venous blood was incubated in wells coated w i t h tetanus toxoid after dilution. Enzyme-labeled protein conjugate was added, and the excess was w a s h e d a w a y after i n c u b a t i o n . T h e a m o u n t of e n z y m e r e m a i n i n g was detected by the color change brought about by the degradation of
42/1378
day 28
Family Doctor
[
Follow-Up
2 an added s u b s t r a t e . T h e a b s o r b e n c e of the final color, proportional to the a m o u n t of a n t i b o d y in t h e s e r u m , was analyzed by a m u l t i s c a n reader and c o m p a r e d w i t h a positive reference serum. Protection was defined as a s e r u m level of m o r e t h a n 0.01 IU/mL. This corresponds to 1/100 of the internat i o n a l (World H e a l t h O r g a n i z a t i o n ) s t a n d a r d s e r u m and is g e n e r a l l y accepted as the m i n i m a l protective ant i t o x i n c o n c e n t r a t i o n . 12 T h e classic m e t h o d of reference is the in vitro n e u t r a l i z a t i o n t e s t , in w h i c h t h e t o x i n n e u t r a l i z a t i o n p r o p e r t y of ser u m is m e a s u r e d directly by protection or s u s c e p t i b i l i t y of an a n i m a l (eg, mouse) a g a i n s t t h e l e t h a l effect of tetanus toxin. However, the ELISA m e t h o d is an accepted, reliable, less expensive, and less t i m e - c o n s u m i n g m e t h o d that correlates well w i t h the t o x i n - n e u t r a l i z a t i o n test. 9,t3 Patient i m m u n i z a t i o n history was d e f i n e d as " a d e q u a t e " or " i n a d e -
Annals of Emergency Medicine
quate" in accordance w i t h the m o s t r e c e n t g u i d e l i n e s of t h e A d v i s o r y C o m m i t t e e on I m m u n i z a t i o n Practices (ACIP) 2 (Table 1). A known complete primary immun i z a t i o n h i s t o r y as well as a booster received w i t h i n the past five or ten y e a r s , d e p e n d i n g on t h e t y p e of wound, were considered adequate. A h i s t o r y of n o v a c c i n a t i o n , an u n k n o w n h i s t o r y , or less t h a n t h r e e doses p r e v i o u s l y received were considered i n a d e q u a t e . P a t i e n t s w i t h a last booster received more than five or ten years earlier, depending on the s t a t u s of t h e w o u n d (clean, m i n o r w o u n d s versus others) were considered i n a d e q u a t e l y i m m u n i z e d . P a t i e n t s w i t h an i n a d e q u a t e i m munization status by history were given 0.5 mL of t e t a n u s vaccine cont a i n i n g 5 L i m e s F l o c c u l a t i o n (Lf) u n i t s of t e t a n u s t o x o i d adsorbed to 1.5 m g of a l u m i n u m phosphate. Patients with adequate immunization s t a t u s by h i s t o r y were n o t i n i t i a l l y
19:12 December 1990
SEROSURVEY
FIGURE 3. Study outcome synopsis
SEROCONVERSION
w i t h seroconversion defined as a titer of more than 0.01 I U / m L at 14 days.
SEROCONVF:RTED 19/34 (56%)
0 DID NOT SEROCONVER 15/3q (44%)
3
TABLE 1. S u m m a r y guide to tetanus prophylaxis in routine wouzld 171 a n a g e m
en t
Wounds History of Adsorbed Tetanus Toxoid
Clean, Minor Td TIG
All Others* Td TIG
U n k n o w n or less than three d o s e s
Yes
No
Yes
Yes
More than or e q u a l to three d o s e s
Not
No
Nee
No
Td, tetanus and diphtheria toxoid adsorbed (for adult use); TIG, tetanus immune globulin. For children less than seven years old, DTP (DT, if pertussis vaccine is contraindicated) is preferred to tetanus toxoid alone. For persons 7 years old or older, Td is preferred to tetanus toxoid alone. If only three doses of fluid toxoid have been received, then a fourth dose of toxoid, preferably an adsorbed toxoid, should be given. *Including but not limited to wounds contaminated with dirt, feces, soil, saliva, and so on; puncture wounds; avulsions; and wounds resulting from missiles, crushing, burns and frostbite. rYes, if more than ten years since last dose. eYes, if more than five years since last dose. More frequent boosters are not needed and can accentuate side effects. Source is ACIP: Diphtheria, tetanus and pertussis guidelines for vaccine prophylaxis and other preventive measures. MMWR 1985;405-414,419-426.
boosted but were later contacted and immunized if the initial titer was unprotective (titer, equal to or less than 0.01 IU/mL). Seven days after initial presentation to the ED, another antitoxin titer was drawn on the patients boosted and not protected on initial presentation (Figure 2). If still not protected, the same patients were followed and had antibody titers drawn at days 14 and 21 if seroconversion did not occur. The patient with a titer of more than 0.01 IU/mL at any time during this period was discharged from the study and returned to the family physician for w o u n d care and completion of im19:12 December 1990
munization if needed. This study was reviewed and approved by the Ethics Committee on H u m a n R e s e a r c h of S u n n y b r o o k H e a l t h S c i e n c e C e n t r e . Statistical analysis was performed by the Dep a r t m e n t of R e s e a r c h D e s i g n and Biostatistics at the same institution. D i c h o t o m o u s variables were compared by X2 analysis and considered statistically significant at P < .05. The analysis of variable for continuous variables was analyzed by the Wilcoxon two-sample test with continuity correction of .5 and considered statistically significant at P < .05. Annals of Emergency Medicine
RESULTS Eighty patients were entered into the study. There were 42 w o m e n and 38 m e n (age range, 65 to 98 years; mean, 79 years). Their initial immun o l o g i c s t a t u s and s u b s e q u e n t response to a booster are depicted (Figure 3). Thirty-six of 80 patients (45%) had inadequate titers at initial presentation. This population was then followed (two patients were lost to follow-up and were excluded f r o m the analysis). Fourteen days after the booster, 15 of the remaining 34 patients (44%) failed to demonstrate an antibody rise. The results of the serosurvey are outlined (Table 2). Mean age of the unprotected group was 80 years, not significantly older than the protected population. Patients who had been in the military were more likely to be initially protected (P = .03). All patients who gave a definite history of a d e q u a t e i m m u n i z a t i o n w e r e protected; it is n o t e w o r t h y that only five of 80 patients could provide such a history. Patients w i t h an inadequate i m m u n i z a t i o n status by history had an equal chance of being either protected (52%) or unprotected 148%). Results of the seroconversion part of the study are outlined (Table 3). P a t i e n t s w h o did n o t s e r o c o n v e r t were significantly older than those w h o did (P = .02). All five patients who gave a positive history of military service seroconverted (P = .03). Again, there was no significant difference between the number of m e n and w o m e n who seroconverted and those who failed to do so. In addition to the variables listed, each patient's country of origin and h o m e situation (ie, nursing h o m e or independent living) were docum e n t e d and analyzed. Forty-two patients (53%) were born in either Canada or the U n i t e d States. T w e n t y patients ( 2 5 % ) w e r e originally from the U n i t e d K i n g d o m , w h e r e a s 18 (22%) were born in other countries. The country of origin was not a predictor of seroprotection (P = .4) or seroconversion (P = .6). Sixty-nine patients (86%) were living at home, and the remaining 11 1379/43
TETANUS IMMUNIZATION Gareau et al
(14%) were living in i n s t i t u t i o h s for the aged (ie, nursing h o m e s or senior citizens' facilities). Again, n e i t h e r seroprotection nor seroconversion (P = .9 and .8, respectively) could be pred i c t e d by t h e h o m e s i t u a t i o n . N o s y s t e m i c or s e v e r e l o c a l r e a c t i o n s from the tetanus toxoid booster were encountered. DISCUSSION Forty-five p e r c e n t of our geriatric study population had tetanus antit o x i n t i t e r s of less t h a n p r o t e c t i v e l e v e l s on p r e s e n t a t i o n to t h e ED. This percentage is s i m i l a r to those of other studies done among elderly populations, a l t h o u g h they were n o t done in EDs.S,7, TM R u b e n et al rand o m l y tested 69 residents of a h o m e for t h e a g e d to a s s e s s i m m u n i t y a g a i n s t d i p h t h e r i a a n d t e t a n u s and r e p o r t e d p r o t e c t i v e a n t i t o x i n levels a g a i n s t t e t a n u s in 51% of t h e resid e n t s , s A s e r o l o g i c a l s u r v e y conducted in Los Angeles e s t i m a t e d that 46% of subjects a t t e n d i n g senior citizen centers had levels of t e t a n u s ant i t o x i n equal to or less than 0.01 IU/ mL. 7 Scher et al identified a populat i o n of i n d i v i d u a l s m o r e t h a n 50 years old and living in rural areas to be at high risk of being inadequately i m m u n i z e d against tetanus. 14 Immunization history was not h e l p f u l in p r e d i c t i n g i n i t i a l serop r o t e c t i o n in our elderly p o p u l a t i o n unless receipt of three or m o r e doses of t e t a n u s t o x o i d b o o s t e r c o u l d be d o c u m e n t e d . A p o o r r e c o l l e c t i o n of past i m m u n i z a t i o n was evidenced by 12 p a t i e n t s (15%) w h o e m p h a t i c a l l y r e l a t e d no p r e v i o u s i m m u n i z a t i o n a g a i n s t t e t a n u s b u t h a d s e r u m tetanus a n t i t o x i n levels of m o r e t h a n 0.01 I U / m L on i n i t i a l p r e s e n t a t i o n to the ED. Because n a t u r a l l y a c q u i r e d t e t a n u s a n t i b o d i e s do n o t occur in N o r t h America, we can a s s u m e that t h e s e p a t i e n t s r e c e i v e d p r i m a r y imm u n i z a t i o n or a b o o s t e r at s o m e time. Stair et al also reported the inadequacy of i m m u n i z a t i o n h i s t o r y as a predictor in assessing the need for a booster in the ED. is A history of m i l i t a r y service as a predictor of initial p r o t e c t i o n in our s t u d y can be explained by the instit u t i o n of r o u t i n e t e t a n u s toxoid imm u n i z a t i o n during World War II. Mili t a r y r e c r u i t s r e c e i v e d at ]east one dose of t o x o i d before e n r o l l m e n t . ~6 R o u t i n e p r i m a r y i m m u n i z a t i o n in C a n a d i a n school c h i l d r e n s t a r t e d in 44/1380
TABLE 2. Tetanus i m m u n i z a t i o n status at initial presentation
Mate Female Mean age (yr) Military service Yes No Immunization adequate by history
Protected (N = 44)
Unprotected (N = 36)
P
22 (58%) 22 (52%) 78
16 (42%) 20 (48%) 80
NS NS NS
17 (74%) 27 (47%)
6 (26%) 30 (53%)
.03
5 (100%)
0 (0%) .04
Immunization inadequate by history
39 (52%)
36 (48%)
TABLE 3. Tetanus toxoid booster response at day 14
Male Female Mean age (yr) Military service Yes No
Seroconverted (N = 19)
Did Not Seroconvert (N = 15)
P
9 (64%) 10 (5o%) 78
5 (35%) 10 (50%) 84
NS NS .02
5 (100%) 14 (48%)
0 (0%) 15 (52%)
.03
1948; 17 it is therefore c o m m o n for elderly individuals w h o have n o t been in t h e m i l i t a r y to be i n a d e q u a t e l y p r o t e c t e d a g a i n s t t e t a n u s e i t h e r because they never received a full course of i m m u n i z a t i o n as a child or because they had not received booster injections throughout their lives. 14 S e r u m a n t i t o x i n l e v e l s of m o r e t h a n 0.01 I U / m L h a v e been conside r e d p r o t e c t i v e a g a i n s t t e t a n u s , alt h o u g h the a c t u a l e s t a b l i s h m e n t of a protective level has been s o m e w h a t arbitrary and based on a n i m a l studies done in 1937.18,19 In 1972, G o u l o n et al reported ten of 64 cases of tetanus o c c u r r i n g in i n d i v i d u a l s w i t h docum e n t e d a n t i t o x i n levels of m o r e than 0.01 IU/mL. 2° A case of tetanus has also been described in a p a t i e n t w i t h a s e r u m level of 0.16 IU/mL. 21 The 0.01 l i m i t , b a s e d on t h e s e case reports, has been criticized by s o m e authors. 12 T h e r e is p r o b a b l y no absoAnnals of Emergency Medicine
l u t e or u n i v e r s a l p r o t e c t i v e level of a n t i t o x i n a n t i b o d i e s , 22 a n d p r o t e c tion m a y result w h e n there is suffic i e n t t o x i n - n e u t r a l i z i n g a n t i b o d y in relation to the t o x i n load. ~1 Based on the general c o n s e n s u s and t h e curr e n t l y a c c e p t e d l e v e l in t h e l i t e r a ture, 0.01 I U / m L was c o n s i d e r e d to be t h e m i n i m u m p r o t e c t i v e v a l u e against t e t a n u s in our study. T h e i n c u b a t i o n period for tet~inus is u s u a l l y 7 to 14 days, but m a y be as short as 24 hours and as long as 21 days.8, a3 We did levels at 21 days to assess h o w m a n y and w h i c h patients could p o t e n t i a l l y be at risk of developing t e t a n u s despite i m m u n i z a t i o n c o n s i d e r i n g t h a t t h e i n c u b a t i o n period for tetanus could be as long as 21 days. T h e s e r o c o n v e r s i o n in p r e v i o u s l y i m m u n i z e d i n d i v i d u a l s v a r i e s bet w e e n 24 hours and 11 days according to t h e l i t e r a t u r e : R o t h s t e i n a n d Baker 24 r e p o r t e d t h a t if the p a t i e n t 19:12 December 1990
had received a single toxoid injection m a n y years earlier, the second imm u n i z a t i o n w o u l d p r o d u c e protective levels w i t h i n n i n e to 11 days. Brown 25 stated that safe antibody titers will develop in a previously imm u n i z e d person in a day or less after a booster dose of toxoid. Robles and Walske z6 h a v e s h o w n t h a t b o o s t e r doses of t e t a n u s t o x o i d w i l l adequately recall antibody titers w i t h i n seven days for as long as 25 years after previous i m m u n i z a t i o n .26 With such discrepancy in the literature, we defined seroconversion as 14 days. It is conceivable that if we had t a k e n a n o t h e r level at 30 days some of our patients might have converted. U n f o r t u n a t e l y , their i m m u n i z a t i o n h i s t o r y was so u n r e l i a b l e that we could not have stated whether this late rise was due to no previous primary i m m u n i z a t i o n or to an i n a b i l i t y to m o u n t a n a d e q u a t e a n t i b o d y r e s p o n s e despite p r e v i o u s tetanus boosters. Fourteen days after a d m i n i s t r a t i o n of the t e t a n u s toxoid booster in the ED, 44% of p a t i e n t s w i t h i n i t i a l levels equal to or less t h a n 0.01 IU/ mL failed to d e m o n s t r a t e an a n t i t o x i n a n t i b o d y i n c r e a s e above the recommended protective level. Booster a d m i n i s t r a t i o n is usually followed by a cellular response of a variety of l y m p h o c y t e s u b p o p u l a t i o n s (T cell-dependent as well as T celli n d e p e n d e n t ) and by the p r o d u c t i o n of n e u t r a l i z i n g IgG antibodies. These a n t i b o d i e s i n c r e a s e to a d e q u a t e a m o u n t s of p r o t e c t i o n w i t h i n three to five days if m e m o r y lymphocytes are primed by a previous tetanus toxoid injection. 27 Ruben et al reported the failure at 21 days of one dose of t e t a n u s and diphtheria toxoid to increase sera to protective levels in 69 n u r s i n g h o m e residents (mean age, 80 years old). s S i m o n s e n et al s t u d i e d t h e i m m u nologic response to a tetanus toxoid booster i n a r a n d o m group of 25- to 30-year-old Danes. T h o s e w h o had not received tetanus vaccination w i t h i n the past ten years were revaccinated w i t h one subcutaneous dose of 12 Lf of adsorbed tetanus toxoid, and the i m m u n o l o g i c a l response was assessed at four weeks. Postbooster concentrations were found to be dep e n d e n t o n the i n t e r v a l s i n c e primary i m m u n i z a t i o n and suggest that there m a y be a point beyond w h i c h one reinforcing dose will n o t produce 19:12 December 1990
a s a t i s f a c t o r y a n t i b o d y response. ~8 This could explain why, in our study, older patients had less chance of seroconverting, a s s u m i n g the i n t e r v a l since t h e i r last t e t a n u s booster, if ever received, would have been longer t h a n i n younger patients. In another study, 24 D a n i s h military recruits w i t h d o c u m e n t e d primary i m m u n i z a t i o n and no revaccin a t i o n were boosted s u b c u t a n e o u s l y with 6 Lf of adsorbed tetanus toxoid. The i m m u n o l o g i c response was assessed at four, 11, and 24 days, and 8% of the r e c r u i t s , w h o had f i r s t been vaccinated ten to 19 years earlier, were f o u n d to have n o n p r o t e c tive levels at day 4. Again, the res p o n s e was slower w i t h i n c r e a s i n g intervals from primary vaccination. 27 A n o t h e r factor that could explain the delayed response to the tetanus booster in our elderly population was the vaccine potency variation among different countries and the use of the adsorbed preparation versus plain fluid toxoid. In Canada, the use of adsorbed toxoid, as r e c o m m e n d e d by the Canadian National Advisory C o m m i t t e e on I m m u n i z a t i o n , began in 1981 and replaced the p r e v i o u s l y used fluid toxoid. Adsorbed vaccines produce a higher and longer-lasting i m m u n i t y to disease than do comparable fluid preparations. 29-31 White et al also r e p o r t e d l o w e r s e r u m a n t i toxin levels after i m m u n i z a t i o n w i t h the fluid preparation of tetanus toxoid. 31 It is k n o w n that the i n c u b a t i o n period of t e t a n u s varies from three to 21 days depending on the proximity of the injury to the central nervous system, extent of devitalized tissues, degree of w o u n d c o n t a m i n a t i o n , and i m m u n i z a t i o n status of the individual. 23 T h e i n a d e q u a t e i m m u n o l o g i c response at 14 days observed in 44% of our study population after receiving a t e t a n u s toxoid booster m a y be considered insufficient protection against the disease after a break i n the skin barrier. CONCLUSION Our hypotheses in conducting this study were that elderly people are inadequately protected against tetanus a n d t h a t t h e i r i m m u n o l o g i c a l res p o n s e s after o n e dose of t e t a n u s booster are delayed. That 45% of our study population (36 of 80 patients) was inadequately protected on i n i t i a l p r e s e n t a t i o n to Annals of Emergency Medicine
the ED and that 44% of these did not seroconvert at 14 days tend to support our hypotheses. It m a y be postul a t e d t h a t those w h o failed to seroconvert carry a risk of developing t e t a n u s despite the prophylaxis adm i n i s t e r e d according to the c u r r e n t ACIP standards. Careful history-taking w i t h specific a t t e n t i o n to older age and the absence of previous military service helps to i d e n t i f y this subgroup. M a i n t e n a n c e of c o m p l e t e v a c c i n a t i o n r e c o r d s i n a d u l t life could overcome the difficulties encountered as a result of u n k n o w n or i n a c c u r a t e details of i m m u n i z a t i o n history. A more liberal approach to the use of t e t a n u s i m m u n o g l o b u l i n m i g h t be considered when elderly patients with u n k n o w n i m m u n i z a t i o n histories and no military service present to the ED w i t h breaks in the s k i n barrier. However, additional research and data c o l l e c t i o n f r o m a larger, m u l t i c e n t e r e d p o p u l a t i o n is necessary before these predictors can be applied to r o u t i n e clinical practice. The authors thank Connaught Laboratories for tetanus antitoxin assays, Dr J Szalai and Mr M Katic for statistical analysis, and Martha Flavelle for manuscript preparation.
REFERENCES
1. Tetalrus-United States, 1985 1986.MMWR 1987;36:477-481. 2. Diphtheria, tetanus and pertussis: Guidelines for vaccine prophylaxis and other preventive measures. MMWR 1985;34:419-426. 3. Tetanus-United States, 1982-1986. MMWR 1985;34:602-611. 4. National AdvisoryCommittee on Immunization: A case of tetanus-Quebec.CDWR 1987;13: 227-230. 5. Ruben FL, Nagel J, Firman P: Antitoxin responses in elderly to tetanus-diphtheria(T2)immunization. Ann J Epidemiol 1978;108:145-149. 6. Crossley K, Irvine P~ Warren JB, et al: Tetanus and diphtheria immunity in urban Minnesota adults. JAMA 1979;242:2298-2300. 7. WeissBP, StrassburgMA, FeelayJC: Tetanus and diphtheria immunity in an elderly population in Los AngelesCounty.Am J Public Health 1983;73:802-804. 8. Bleck TP: Pharmacology of tetanus. Clin Neuropharmacol 1986;9:103-120. 9. Furste W: The SeventhInternational Conference on Tetanus, Copanello (Catanzaro},Italy, 1984. J Trauma 1987;27:99-103. 10. Pai S, Romanic BM, Deforest A, et al: Tetanus immune status of adult patients in an urban family practice. J Faro Pract 1986;23: 582-583. 11. Goeffrey E: The inexcusabledisease. ]liMA 1381/45
TETANUS IMMUNIZATION Gareau et al
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]ergy 1937;8:230-245.
12. Lindsey D: Tetanus prophylaxis - Do our g u i d e l i n e s assure protection? ] Trauma 1984; 24:1063-t064.
19. Peebles TC, Levine L, Eldred MC, et ah Tetanus-toxoid emergency boosters, a reappraisal. N Engl J Med 1969;280:575~580.
13. Varela LR, B l a c k FL, M e n d i z a b a l - M o r r i s CA: Tetanus antitoxin titers in w o m e n of childbearing age from nine diverse populations. ] h~ fect Dis 1985;151:850-853.
20. Goulon M, Girard O, Grosbuis S, et al: Les anticorps antitetaniques: Titrage avant sero an atoxinotherapie chez 64 tetaniques. Nouv Presse Med 1972;1:3049-3050.
14. Scher KS, Baldera A, Wheeler WE, et al: Inadequate tetanus protection among the rural elderly. South Med ] 1985;78:153-156.
21. Passen EL, A n d e r s e n BR: Clinical tetanus despite a "protective" level of toxin-neutralizing antibody. JAMA 1986;255:1171-1173.
15. Stair TO, Lippe MA, Russell H, et al: Tetanus i m m u n i t y in e m e r g e n c y d e p a r t m e n t patients (abstract). Ann Emerg Med 1987;16:1100.
22. Berger SA, C h e r u b i n CE, N e l s o n S, et al:
16. D i x o n AM, Bibby JA: Tetanus i m m u n i z a tion in a general practice population. Br Med J 1988;297:598.
23. Martin RR: Clostridium tetani (tetanus), in MandelI GL, Doughlas RD Jr, Bennett JE (eds): Principles and Practice of Infectious Diseases, ed 2. N e w York, John Wiley & Sons, 1985, p 1864-1870.
17. Varughese P: Tetanus in Canada .... 1921 to 1978. CDWR 1980;6:113-118. 18. Gold H: Studies on tetanus toxoid: Active i m m u n i z a t i o n of allergic individuals w i t h tetanus toxoid, a l u m precipitated, refined. J A1
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Tetanus despite p r e e x i s t i n g a n t i t e t a n u s antibody. JAMA 1978;240:761-770.
24. Rothstein RJ, Baker FJ: Tetanus. Prevention and treatment. JAMA 1978;240:675-676. 25. Brown H: Tetanus. JAMA 1968;204:614-616.
Annals of Emergency Medicine
26. Robles NL, Walske BR: Current concepts of t e t a n u s p r o p h y l a x i s . A m / Surg 1969;118: 835-838. 27. S i m o n s e n O, Klaerke M, Jensen JE, et al: Revaccination against tetanus 17 to 20 years after primary vaccination: Kinetics of antibody response. / Trauma 1987;27:1358-1361. 28. S i m o n s e n O, Kjeldsen K, Heron I: h n l n u nity against tetanus and effect of revaccination 2 5 - 3 0 years after primary vaccination. Lancet 1984;2:1240-1242. 29. MacLeod DR, lng WK, Belcourt RJ, et ah A n t i b o d y s t a t u s to p o l i o m y e l i t i s , m e a s l e s , rubella, diphtheria and tetanus, Ontario 1969 1970: Deficiencies discovered and remedies required. Can Med Assoc J 1975;113:619-623. 30. Levine L, M c C o m b JA, Dwyer RC, et ah Active passive t e t a n u s i m m u n i z a t i o n . N Eng] ] Med 1966;274:186-190. 31. White WG, Crale D, Barnes GM, et ah Duration of i m m u n i t y after active i m m u n i z a t i o n against tetanus. Lancet 196;1:95-96.
19:12 December 1990
Tetanus Immunization Status and Immunologic Response to a Booster in an Emergency D e p a r t m e n t Geriatric Population Study objectives: Although effective procedures for the prevention of tetanus have long been available, serosurveys done since •977 demonstrate that 49% to 66% of the elderly population lacks a protective antitoxin level (more than 0.01 IU/mL). This study was undertaken to assess the tetanus immunization status of patients presenting to an emergency department and to evaluate their immunologic response to a tetanus booster. Setting: The study was conducted in a tertiary care ED. Type of participants: The patients enrolled were 65 or more years old and had breaks in their skin barriers. Design: A t each patient's initial presentation, pertinent demographic data and tetanus immunization history were recorded. The patient was then followed for 21 days. Interventions: Each patient's antitoxin titer was determined on a serum sample by ELISA, and, if required by the Advisory Committee on Immunization Practices criteria, a booster was administered at the first visit. Measurements and main results: Serum antitoxin assays were repeated on days 7, 14, and 21 after the initial visit until seroconversion (titer more than 0.01 IU/mL). Forty-four patients (55%)had protective levels at initial presentation, and in 36 (45%) the levels were not protective. Age and sex were not predictive of protection. Past military service and a definite history of three or more previous immunizations were good predictors of protection. Of 34 patients who were followed serially for inadequate initial titers, only 19 (56%) seroconverted by day 14. Patients who did not seroconvert were more likely to be older (P < .05). Conclusions: This study demonstrated that a significant number of elderly patients lacked an initial protective level of tetanus antitoxin. Of these, 44% failed to seroconvert within 14 days and carried a potential risk of developing tetanus. [Gareau AB, Eby R J, McLellan BA, Williams DR: Tetanus immunization status and immunologic response to a booster in an emergency department geriatric population. Ann Emerg Med December 1990;19:1377-1382.]
Annie B Gareau, MD, FRCPC RJ Eby, MD, FRCPC BA McLellan, MD, FRCPC DR Williams, MD, FRCPC Toronto, Ontario, Canada From the Department of Emergency Medicine, Sunnybrook Health Science Centre, University of Toronto, Toronto, Ontario, Canada. Received for publication April 20, 1990. Accepted for publication June 27, 1990. Presented at the Society for Academic Emergency Medicine Annual Meeting in San Diego, May 1989. Address for reprints: BA McLellan, MD, Department of Emergency Medicine, Suite 15, B-Ground, Sunnybrook Health Science Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
INTRODUCTION Although effective procedures for the prevention of tetanus have long been available, this disease remains a significant health problem. The average annual incidence rate of tetanus had been steadily declining between 1947 and 1976; however, during the past decade, the rate has not changed substantiallyJ One hundred forty-seven cases of tetanus were reported in the United States between 1985 and 1986; 60% of these cases occurred in elderly patients (60 years old or older), with a case fatality rate of 52% .2,3 In Canada, 17 patients are hospitalized each year with the diagnosis of tetanus, and two thirds of these patients are more than 45 years old. 4 Serosurveys done since 1977 indicate that 49% to 66% of the elderly population lacks a protective level of circulating tetanus antitoxin. 5-7 Active i m m u n i z a t i o n is highly effective, with a failure rate in fully immunized patients of less than four per 100 million. 8 For this reason, tetanus has been referred to as an "inexcusable" disease. 9 11 This descriptive prospective study was undertaken to assess the tetanus i m m u n i z a t i o n status of a geriatric population presenting to an emergency
19:12 December 1990
Annals of Emergency Medicine
1377/41
TETANUS IMMUNIZATION Gareau et al
Inclusion Criteria Eligible Population
Age of 65 or more years Any break in the skin barrier, including laceration or abrasion, burn, frostbite, animal or human bite, and corneal abrasion Availability for follow-up Agreeable to signing a consent
i
History of Adequate Immunization
I History of Inadequate Immunization
Antitoxin Titer Drawn
Exclusion Criteria Allergy to tetanus toxoid Immunosuppression due to chemotherapy, chronic steroid use, or known malignancy Unavailability for follow-up
=[
FIGURE 1. Patient population inclu-
sion and exclusion criteria. da
da'
Tetanus Booster ]
[
Discharged from study
21 14
y
I
I
I
FIGURE 2. Study algorithm.
I
I I day 7 I A n t i t o x i n Titer .o,,ow0p
I
]
d e p a r t m e n t w i t h a break in the skin barrier and to e v a l u a t e this population's i m m u n o l o g i c response to a tetanus booster given in the ED.
0-q
METHODS S u n n y b r o o k H e a l t h Science Centre is a t e r t i a r y - c a r e t e a c h i n g h o s p i t a l t h a t is l o c a t e d n o r t h of t h e d o w n t o w n Toronto core and serves a large community-based population. The ED has a p p r o x i m a t e l y 37,000 patient visits per year. Patients were enrolled in the study from February through September 1988 in a n o n c o n s e c u t i v e manner, following the inclusion and exclusion criteria o u t l i n e d (Figure 1). O n each p a t i e n t ' s initial presentation, i m m u n i z a t i o n history, previous m i l i t a r y service, and country of origin were recorded. A d e s c r i p t i o n of the w o u n d in t e r m s of depth, length, m e c h a n i s m of injury, and evidence of c o n t a m i n a t i o n was also documented. T e t a n u s a n t i t o x i n titers were drawn on a l l p a t i e n t s c o n s e n t i n g to t h e s t u d y and a n a l y z e d by the e n z y m e l i n k e d i m m u n o s o r b e n t assay (ELISA) method. T h e s e r u m s a m p l e t a k e n from 10 mL of venous blood was incubated in wells coated w i t h tetanus toxoid after dilution. Enzyme-labeled protein conjugate was added, and the excess was w a s h e d a w a y after i n c u b a t i o n . T h e a m o u n t of e n z y m e r e m a i n i n g was detected by the color change brought about by the degradation of
42/1378
day 28
Family Doctor
[
Follow-Up
2 an added s u b s t r a t e . T h e a b s o r b e n c e of the final color, proportional to the a m o u n t of a n t i b o d y in t h e s e r u m , was analyzed by a m u l t i s c a n reader and c o m p a r e d w i t h a positive reference serum. Protection was defined as a s e r u m level of m o r e t h a n 0.01 IU/mL. This corresponds to 1/100 of the internat i o n a l (World H e a l t h O r g a n i z a t i o n ) s t a n d a r d s e r u m and is g e n e r a l l y accepted as the m i n i m a l protective ant i t o x i n c o n c e n t r a t i o n . 12 T h e classic m e t h o d of reference is the in vitro n e u t r a l i z a t i o n t e s t , in w h i c h t h e t o x i n n e u t r a l i z a t i o n p r o p e r t y of ser u m is m e a s u r e d directly by protection or s u s c e p t i b i l i t y of an a n i m a l (eg, mouse) a g a i n s t t h e l e t h a l effect of tetanus toxin. However, the ELISA m e t h o d is an accepted, reliable, less expensive, and less t i m e - c o n s u m i n g m e t h o d that correlates well w i t h the t o x i n - n e u t r a l i z a t i o n test. 9,t3 Patient i m m u n i z a t i o n history was d e f i n e d as " a d e q u a t e " or " i n a d e -
Annals of Emergency Medicine
quate" in accordance w i t h the m o s t r e c e n t g u i d e l i n e s of t h e A d v i s o r y C o m m i t t e e on I m m u n i z a t i o n Practices (ACIP) 2 (Table 1). A known complete primary immun i z a t i o n h i s t o r y as well as a booster received w i t h i n the past five or ten y e a r s , d e p e n d i n g on t h e t y p e of wound, were considered adequate. A h i s t o r y of n o v a c c i n a t i o n , an u n k n o w n h i s t o r y , or less t h a n t h r e e doses p r e v i o u s l y received were considered i n a d e q u a t e . P a t i e n t s w i t h a last booster received more than five or ten years earlier, depending on the s t a t u s of t h e w o u n d (clean, m i n o r w o u n d s versus others) were considered i n a d e q u a t e l y i m m u n i z e d . P a t i e n t s w i t h an i n a d e q u a t e i m munization status by history were given 0.5 mL of t e t a n u s vaccine cont a i n i n g 5 L i m e s F l o c c u l a t i o n (Lf) u n i t s of t e t a n u s t o x o i d adsorbed to 1.5 m g of a l u m i n u m phosphate. Patients with adequate immunization s t a t u s by h i s t o r y were n o t i n i t i a l l y
19:12 December 1990
SEROSURVEY
FIGURE 3. Study outcome synopsis
SEROCONVERSION
w i t h seroconversion defined as a titer of more than 0.01 I U / m L at 14 days.
SEROCONVF:RTED 19/34 (56%)
0 DID NOT SEROCONVER 15/3q (44%)
3
TABLE 1. S u m m a r y guide to tetanus prophylaxis in routine wouzld 171 a n a g e m
en t
Wounds History of Adsorbed Tetanus Toxoid
Clean, Minor Td TIG
All Others* Td TIG
U n k n o w n or less than three d o s e s
Yes
No
Yes
Yes
More than or e q u a l to three d o s e s
Not
No
Nee
No
Td, tetanus and diphtheria toxoid adsorbed (for adult use); TIG, tetanus immune globulin. For children less than seven years old, DTP (DT, if pertussis vaccine is contraindicated) is preferred to tetanus toxoid alone. For persons 7 years old or older, Td is preferred to tetanus toxoid alone. If only three doses of fluid toxoid have been received, then a fourth dose of toxoid, preferably an adsorbed toxoid, should be given. *Including but not limited to wounds contaminated with dirt, feces, soil, saliva, and so on; puncture wounds; avulsions; and wounds resulting from missiles, crushing, burns and frostbite. rYes, if more than ten years since last dose. eYes, if more than five years since last dose. More frequent boosters are not needed and can accentuate side effects. Source is ACIP: Diphtheria, tetanus and pertussis guidelines for vaccine prophylaxis and other preventive measures. MMWR 1985;405-414,419-426.
boosted but were later contacted and immunized if the initial titer was unprotective (titer, equal to or less than 0.01 IU/mL). Seven days after initial presentation to the ED, another antitoxin titer was drawn on the patients boosted and not protected on initial presentation (Figure 2). If still not protected, the same patients were followed and had antibody titers drawn at days 14 and 21 if seroconversion did not occur. The patient with a titer of more than 0.01 IU/mL at any time during this period was discharged from the study and returned to the family physician for w o u n d care and completion of im19:12 December 1990
munization if needed. This study was reviewed and approved by the Ethics Committee on H u m a n R e s e a r c h of S u n n y b r o o k H e a l t h S c i e n c e C e n t r e . Statistical analysis was performed by the Dep a r t m e n t of R e s e a r c h D e s i g n and Biostatistics at the same institution. D i c h o t o m o u s variables were compared by X2 analysis and considered statistically significant at P < .05. The analysis of variable for continuous variables was analyzed by the Wilcoxon two-sample test with continuity correction of .5 and considered statistically significant at P < .05. Annals of Emergency Medicine
RESULTS Eighty patients were entered into the study. There were 42 w o m e n and 38 m e n (age range, 65 to 98 years; mean, 79 years). Their initial immun o l o g i c s t a t u s and s u b s e q u e n t response to a booster are depicted (Figure 3). Thirty-six of 80 patients (45%) had inadequate titers at initial presentation. This population was then followed (two patients were lost to follow-up and were excluded f r o m the analysis). Fourteen days after the booster, 15 of the remaining 34 patients (44%) failed to demonstrate an antibody rise. The results of the serosurvey are outlined (Table 2). Mean age of the unprotected group was 80 years, not significantly older than the protected population. Patients who had been in the military were more likely to be initially protected (P = .03). All patients who gave a definite history of a d e q u a t e i m m u n i z a t i o n w e r e protected; it is n o t e w o r t h y that only five of 80 patients could provide such a history. Patients w i t h an inadequate i m m u n i z a t i o n status by history had an equal chance of being either protected (52%) or unprotected 148%). Results of the seroconversion part of the study are outlined (Table 3). P a t i e n t s w h o did n o t s e r o c o n v e r t were significantly older than those w h o did (P = .02). All five patients who gave a positive history of military service seroconverted (P = .03). Again, there was no significant difference between the number of m e n and w o m e n who seroconverted and those who failed to do so. In addition to the variables listed, each patient's country of origin and h o m e situation (ie, nursing h o m e or independent living) were docum e n t e d and analyzed. Forty-two patients (53%) were born in either Canada or the U n i t e d States. T w e n t y patients ( 2 5 % ) w e r e originally from the U n i t e d K i n g d o m , w h e r e a s 18 (22%) were born in other countries. The country of origin was not a predictor of seroprotection (P = .4) or seroconversion (P = .6). Sixty-nine patients (86%) were living at home, and the remaining 11 1379/43
TETANUS IMMUNIZATION Gareau et al
(14%) were living in i n s t i t u t i o h s for the aged (ie, nursing h o m e s or senior citizens' facilities). Again, n e i t h e r seroprotection nor seroconversion (P = .9 and .8, respectively) could be pred i c t e d by t h e h o m e s i t u a t i o n . N o s y s t e m i c or s e v e r e l o c a l r e a c t i o n s from the tetanus toxoid booster were encountered. DISCUSSION Forty-five p e r c e n t of our geriatric study population had tetanus antit o x i n t i t e r s of less t h a n p r o t e c t i v e l e v e l s on p r e s e n t a t i o n to t h e ED. This percentage is s i m i l a r to those of other studies done among elderly populations, a l t h o u g h they were n o t done in EDs.S,7, TM R u b e n et al rand o m l y tested 69 residents of a h o m e for t h e a g e d to a s s e s s i m m u n i t y a g a i n s t d i p h t h e r i a a n d t e t a n u s and r e p o r t e d p r o t e c t i v e a n t i t o x i n levels a g a i n s t t e t a n u s in 51% of t h e resid e n t s , s A s e r o l o g i c a l s u r v e y conducted in Los Angeles e s t i m a t e d that 46% of subjects a t t e n d i n g senior citizen centers had levels of t e t a n u s ant i t o x i n equal to or less than 0.01 IU/ mL. 7 Scher et al identified a populat i o n of i n d i v i d u a l s m o r e t h a n 50 years old and living in rural areas to be at high risk of being inadequately i m m u n i z e d against tetanus. 14 Immunization history was not h e l p f u l in p r e d i c t i n g i n i t i a l serop r o t e c t i o n in our elderly p o p u l a t i o n unless receipt of three or m o r e doses of t e t a n u s t o x o i d b o o s t e r c o u l d be d o c u m e n t e d . A p o o r r e c o l l e c t i o n of past i m m u n i z a t i o n was evidenced by 12 p a t i e n t s (15%) w h o e m p h a t i c a l l y r e l a t e d no p r e v i o u s i m m u n i z a t i o n a g a i n s t t e t a n u s b u t h a d s e r u m tetanus a n t i t o x i n levels of m o r e t h a n 0.01 I U / m L on i n i t i a l p r e s e n t a t i o n to the ED. Because n a t u r a l l y a c q u i r e d t e t a n u s a n t i b o d i e s do n o t occur in N o r t h America, we can a s s u m e that t h e s e p a t i e n t s r e c e i v e d p r i m a r y imm u n i z a t i o n or a b o o s t e r at s o m e time. Stair et al also reported the inadequacy of i m m u n i z a t i o n h i s t o r y as a predictor in assessing the need for a booster in the ED. is A history of m i l i t a r y service as a predictor of initial p r o t e c t i o n in our s t u d y can be explained by the instit u t i o n of r o u t i n e t e t a n u s toxoid imm u n i z a t i o n during World War II. Mili t a r y r e c r u i t s r e c e i v e d at ]east one dose of t o x o i d before e n r o l l m e n t . ~6 R o u t i n e p r i m a r y i m m u n i z a t i o n in C a n a d i a n school c h i l d r e n s t a r t e d in 44/1380
TABLE 2. Tetanus i m m u n i z a t i o n status at initial presentation
Mate Female Mean age (yr) Military service Yes No Immunization adequate by history
Protected (N = 44)
Unprotected (N = 36)
P
22 (58%) 22 (52%) 78
16 (42%) 20 (48%) 80
NS NS NS
17 (74%) 27 (47%)
6 (26%) 30 (53%)
.03
5 (100%)
0 (0%) .04
Immunization inadequate by history
39 (52%)
36 (48%)
TABLE 3. Tetanus toxoid booster response at day 14
Male Female Mean age (yr) Military service Yes No
Seroconverted (N = 19)
Did Not Seroconvert (N = 15)
P
9 (64%) 10 (5o%) 78
5 (35%) 10 (50%) 84
NS NS .02
5 (100%) 14 (48%)
0 (0%) 15 (52%)
.03
1948; 17 it is therefore c o m m o n for elderly individuals w h o have n o t been in t h e m i l i t a r y to be i n a d e q u a t e l y p r o t e c t e d a g a i n s t t e t a n u s e i t h e r because they never received a full course of i m m u n i z a t i o n as a child or because they had not received booster injections throughout their lives. 14 S e r u m a n t i t o x i n l e v e l s of m o r e t h a n 0.01 I U / m L h a v e been conside r e d p r o t e c t i v e a g a i n s t t e t a n u s , alt h o u g h the a c t u a l e s t a b l i s h m e n t of a protective level has been s o m e w h a t arbitrary and based on a n i m a l studies done in 1937.18,19 In 1972, G o u l o n et al reported ten of 64 cases of tetanus o c c u r r i n g in i n d i v i d u a l s w i t h docum e n t e d a n t i t o x i n levels of m o r e than 0.01 IU/mL. 2° A case of tetanus has also been described in a p a t i e n t w i t h a s e r u m level of 0.16 IU/mL. 21 The 0.01 l i m i t , b a s e d on t h e s e case reports, has been criticized by s o m e authors. 12 T h e r e is p r o b a b l y no absoAnnals of Emergency Medicine
l u t e or u n i v e r s a l p r o t e c t i v e level of a n t i t o x i n a n t i b o d i e s , 22 a n d p r o t e c tion m a y result w h e n there is suffic i e n t t o x i n - n e u t r a l i z i n g a n t i b o d y in relation to the t o x i n load. ~1 Based on the general c o n s e n s u s and t h e curr e n t l y a c c e p t e d l e v e l in t h e l i t e r a ture, 0.01 I U / m L was c o n s i d e r e d to be t h e m i n i m u m p r o t e c t i v e v a l u e against t e t a n u s in our study. T h e i n c u b a t i o n period for tet~inus is u s u a l l y 7 to 14 days, but m a y be as short as 24 hours and as long as 21 days.8, a3 We did levels at 21 days to assess h o w m a n y and w h i c h patients could p o t e n t i a l l y be at risk of developing t e t a n u s despite i m m u n i z a t i o n c o n s i d e r i n g t h a t t h e i n c u b a t i o n period for tetanus could be as long as 21 days. T h e s e r o c o n v e r s i o n in p r e v i o u s l y i m m u n i z e d i n d i v i d u a l s v a r i e s bet w e e n 24 hours and 11 days according to t h e l i t e r a t u r e : R o t h s t e i n a n d Baker 24 r e p o r t e d t h a t if the p a t i e n t 19:12 December 1990
had received a single toxoid injection m a n y years earlier, the second imm u n i z a t i o n w o u l d p r o d u c e protective levels w i t h i n n i n e to 11 days. Brown 25 stated that safe antibody titers will develop in a previously imm u n i z e d person in a day or less after a booster dose of toxoid. Robles and Walske z6 h a v e s h o w n t h a t b o o s t e r doses of t e t a n u s t o x o i d w i l l adequately recall antibody titers w i t h i n seven days for as long as 25 years after previous i m m u n i z a t i o n .26 With such discrepancy in the literature, we defined seroconversion as 14 days. It is conceivable that if we had t a k e n a n o t h e r level at 30 days some of our patients might have converted. U n f o r t u n a t e l y , their i m m u n i z a t i o n h i s t o r y was so u n r e l i a b l e that we could not have stated whether this late rise was due to no previous primary i m m u n i z a t i o n or to an i n a b i l i t y to m o u n t a n a d e q u a t e a n t i b o d y r e s p o n s e despite p r e v i o u s tetanus boosters. Fourteen days after a d m i n i s t r a t i o n of the t e t a n u s toxoid booster in the ED, 44% of p a t i e n t s w i t h i n i t i a l levels equal to or less t h a n 0.01 IU/ mL failed to d e m o n s t r a t e an a n t i t o x i n a n t i b o d y i n c r e a s e above the recommended protective level. Booster a d m i n i s t r a t i o n is usually followed by a cellular response of a variety of l y m p h o c y t e s u b p o p u l a t i o n s (T cell-dependent as well as T celli n d e p e n d e n t ) and by the p r o d u c t i o n of n e u t r a l i z i n g IgG antibodies. These a n t i b o d i e s i n c r e a s e to a d e q u a t e a m o u n t s of p r o t e c t i o n w i t h i n three to five days if m e m o r y lymphocytes are primed by a previous tetanus toxoid injection. 27 Ruben et al reported the failure at 21 days of one dose of t e t a n u s and diphtheria toxoid to increase sera to protective levels in 69 n u r s i n g h o m e residents (mean age, 80 years old). s S i m o n s e n et al s t u d i e d t h e i m m u nologic response to a tetanus toxoid booster i n a r a n d o m group of 25- to 30-year-old Danes. T h o s e w h o had not received tetanus vaccination w i t h i n the past ten years were revaccinated w i t h one subcutaneous dose of 12 Lf of adsorbed tetanus toxoid, and the i m m u n o l o g i c a l response was assessed at four weeks. Postbooster concentrations were found to be dep e n d e n t o n the i n t e r v a l s i n c e primary i m m u n i z a t i o n and suggest that there m a y be a point beyond w h i c h one reinforcing dose will n o t produce 19:12 December 1990
a s a t i s f a c t o r y a n t i b o d y response. ~8 This could explain why, in our study, older patients had less chance of seroconverting, a s s u m i n g the i n t e r v a l since t h e i r last t e t a n u s booster, if ever received, would have been longer t h a n i n younger patients. In another study, 24 D a n i s h military recruits w i t h d o c u m e n t e d primary i m m u n i z a t i o n and no revaccin a t i o n were boosted s u b c u t a n e o u s l y with 6 Lf of adsorbed tetanus toxoid. The i m m u n o l o g i c response was assessed at four, 11, and 24 days, and 8% of the r e c r u i t s , w h o had f i r s t been vaccinated ten to 19 years earlier, were f o u n d to have n o n p r o t e c tive levels at day 4. Again, the res p o n s e was slower w i t h i n c r e a s i n g intervals from primary vaccination. 27 A n o t h e r factor that could explain the delayed response to the tetanus booster in our elderly population was the vaccine potency variation among different countries and the use of the adsorbed preparation versus plain fluid toxoid. In Canada, the use of adsorbed toxoid, as r e c o m m e n d e d by the Canadian National Advisory C o m m i t t e e on I m m u n i z a t i o n , began in 1981 and replaced the p r e v i o u s l y used fluid toxoid. Adsorbed vaccines produce a higher and longer-lasting i m m u n i t y to disease than do comparable fluid preparations. 29-31 White et al also r e p o r t e d l o w e r s e r u m a n t i toxin levels after i m m u n i z a t i o n w i t h the fluid preparation of tetanus toxoid. 31 It is k n o w n that the i n c u b a t i o n period of t e t a n u s varies from three to 21 days depending on the proximity of the injury to the central nervous system, extent of devitalized tissues, degree of w o u n d c o n t a m i n a t i o n , and i m m u n i z a t i o n status of the individual. 23 T h e i n a d e q u a t e i m m u n o l o g i c response at 14 days observed in 44% of our study population after receiving a t e t a n u s toxoid booster m a y be considered insufficient protection against the disease after a break i n the skin barrier. CONCLUSION Our hypotheses in conducting this study were that elderly people are inadequately protected against tetanus a n d t h a t t h e i r i m m u n o l o g i c a l res p o n s e s after o n e dose of t e t a n u s booster are delayed. That 45% of our study population (36 of 80 patients) was inadequately protected on i n i t i a l p r e s e n t a t i o n to Annals of Emergency Medicine
the ED and that 44% of these did not seroconvert at 14 days tend to support our hypotheses. It m a y be postul a t e d t h a t those w h o failed to seroconvert carry a risk of developing t e t a n u s despite the prophylaxis adm i n i s t e r e d according to the c u r r e n t ACIP standards. Careful history-taking w i t h specific a t t e n t i o n to older age and the absence of previous military service helps to i d e n t i f y this subgroup. M a i n t e n a n c e of c o m p l e t e v a c c i n a t i o n r e c o r d s i n a d u l t life could overcome the difficulties encountered as a result of u n k n o w n or i n a c c u r a t e details of i m m u n i z a t i o n history. A more liberal approach to the use of t e t a n u s i m m u n o g l o b u l i n m i g h t be considered when elderly patients with u n k n o w n i m m u n i z a t i o n histories and no military service present to the ED w i t h breaks in the s k i n barrier. However, additional research and data c o l l e c t i o n f r o m a larger, m u l t i c e n t e r e d p o p u l a t i o n is necessary before these predictors can be applied to r o u t i n e clinical practice. The authors thank Connaught Laboratories for tetanus antitoxin assays, Dr J Szalai and Mr M Katic for statistical analysis, and Martha Flavelle for manuscript preparation.
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