Serum tetanus antitoxin levels were determined in 104 World War II veterans immunized 15 or more years ago while in active military service. The majority had significant antibody. A standard booster raised the antibody level significantly after seven days. It is felt that except for grossly contaminated wounds, such a booster provides ample protection even though the initial immunization was done 15 years earlier. ANTIBODY RESPONSE TO TETANUS TOXOID 15 AFTER INITIAL IMMUNIZATION YEARS James R. McCarroll, M.D., F.A.P.H.A.; Irving Abrahams, Ph.D.; and Paul A. Skudder, M.D. NO PREVENTIVE measure the physician can offer his patient promises surer protection than active immunization with tetanus toxoid. Nevertheless, the failure of our preventive programs to reach many groups of our citizens forces the daily use of large amounts of tetanus antitoxin in the treatment of traumatic injuries. The considerable morbidity associated with this use of antiserum1 results in the paradox of more illness due to the prevention of a disease than would result from the disease itself. At the present time only two large groups may be presumed with any degree of accuracy to have been immunized against tetanus. These are veterans of service in the American armed forces since 194, and most American children under the age of 18. Even for this latter group the presumption cannot be made with any degree of certainty since the almost universal use of diphtheria-pertussis-tetanus immunization in childhood is only now becoming a reality. Immunization of armed forces personnel, however, has been a univ-ersal requirement of military service since 194, so that it has become routine in most hospital emergency units to accept a history of military service as evidence of previous active immunization against tetanus. This is of considerable practical importance since most of the million veterans are members of the active working population running the risk of repeated injuries for which prophylaxis against tetanus must be offered. Until recently, therefore, it has been customary to rely on a single booster dose of tetanus toxoid as prophylaxis against tetanus in treating these injuries. This procedure has offered the multiple advantages of certain protection against the disease, elimination of the considerable hazards and morbidity associated with antitoxin, and of bolstering the immune status of the individual. As the length of time since World War II and discharge from active military service increases for most veterans, the question of duration of protection remaining from the initial immunization becomes more important. Persistence of solid immunity in most persons together with a rapid anamnestic response to a booster dose of toxoid for the remainder OCTOBER, 1996 1 669
has been well demonstrated for sizable groups of persons up to ten years after initial immunization. A few studies have included scattered cases of persons followed for longer periods,3'4 but no sizable group has been carefully studied for more than ten years from the time of initial immunization. To determine the present immunity status of World War II veterans now 15 or more years after their initial tetanus immunization, and to determine whether a booster dose of tetanus toxoid provides sufficiently rapid antibody response to provide protection at this time, the present study was carried out. Materials and Methods Population Studied The study population was composed entirely of veterans of World War II admitted as patients to the medical and surgical services of the New York Veterans Administration Hospital. Every World War II veteran admitted to these services during a three-month period was carefully interviewed to determine his suitability for inclusion in this study. Only two criteria were used to determine this suitability. First, active service in any one of the branches of the armed forces during World War II was considered evidence of active immunization against tetanus. Initially it was planned to use the records of the Armed Forces Records Bureau to determine the exact dates of basic tetanus immunizations and subsequent booster doses for each individual. These records, however, were not sufficiently complete for this purpose. However, all veterans included in this study spent some period of time on active duty between 194 and 1946, during which time active immunization against tetanus with one form or another of tetanus toxoid was a universal requirement of all components of the American armed forces. 1670 The second criterion for inclusion in the study was absence of any evidence of either active or passive tetanus immunization since discharge from military service. A careful medical history was taken from each patient and all persons were eliminated who gave any history of parenteral injection unless the agent administered was definitely known. Furthermore, all patients were eliminated who gave a history of any type of injury, burn, or bite for which medical treatment was given which might have included either active or passive tetanus immunization. To aid in the recollection of injuries and illnesses which might have occurred up to 15 years previously, a second identical interview was conducted after three or four days. Through this double screening process a study group was derived which in our judgment included only individuals who had received a full immunizing course of tetanus toxoid at least 15 years previously and had not received any booster injections after discharge from service. Approximately 300 patients were interviewed to obtain the study sample of 104 persons. No other criteria were used for their selection. Patients with all the diagnoses commonly encountered on general medical and surgical services were included. The resulting group approximates the general composition of the World War II veteran population of New York City. Their ages varied from 3 to 64 years, with an average age of 46.1 years. Four of the group were females, 17 were Negroes, and were Orientals. Veterans of service in all branches of the armed forces were included and no distinction among the various components was made, although basic immunizing schedules and agents varied somewhat among them. If the patient was deemed suitable for inclusion in the study, a base line serum was drawn and a standard booster dose of 0.5-ml fluid tetanus toxoid was administered VOL. 5. NO. 10. A.J.P.H.
ANTIBODY RESPONSE TO TETANUS TOXOID intramuscularly. Repeat bleedings were obtained at 4, 7, and 14 days. Laboratory Determinations Titrations for serum antitoxin levels were made in 0-gram Swiss Webster male mice from the Camm Research Institute. Tetanus toxin and standard NIH antitoxin were prepared and generously supplied to us by Lt. Colonel A. S. Benenson of the Walter Reed Army Institute of Research. The test methods were modified slightly from those used in Benenson's laboratory. Tests for antitoxin levels were made from 0.005 units per ml to 30 units per ml at twofold or half-log intervals. Two levels of toxin test doses were used: 5L+/,ooo doses per ml or 5L+/ioo doses per ml. Titrations of standard NIH antitoxin were made with each test as a control on the toxin dilution preparation and on other factors of the test. The mixtures of serum and toxin were kept at room temperature for one hour, and 0.6-ml amounts were injected subcutaneously at the base of the tail. The end point was taken as that mixture of serum and toxin which resulted in survival with symptoms of tetanus at the end of five days after injection. If no end point reactions were observed, the titer was estimated between the highest dilution of serum permitting survival and the lowest dilution resulting in death. Results Base Line Antibody Levels Of 104 persons from whom base line serum was obtained, only 8 showed complete absence of tetanus antitoxin at the lowest dilution tested, 0.005 units per ml (Figure 1). Forty-five (43.3 per cent) had antibody levels of 0.1 units or greater, or well within the commonly accepted protective level. The remaining 46 patients had antitoxin titers between 0.01 units and 0.055 units per ml. If 0.01 units per ml can be accepted as offering significant protection against tetanus, then 88 per cent of this group still had significant protection remaining from immunizations received during World War II. There was no apparent correlation between clinical diagnosis and the base line antibody titer. Antibody Response Four Days after Booster Injection Four days after receiving a standard booster dose of 0.5-ml fluid tetanus toxoid intramuscularly there was no es- Units of Antitoxin/ml. Serum (0.005 0.005 0.005 0.01 0.017 0.03 0.055 0.1 0.17 0.3 0.55 1.0 >I Number of Subjects 8 3 8 16 4 18 3 3 13 1 3 l 13 (1.5%) l V -IIl I 46 (44.%) V 91 (87.5%) 45 (43.3%) Figure 1-Serum Tetanus Antitoxin Titers of 104 World War IT Veterans 15 or More Years after Initial Immunization I OCTOBER, 196 1671
T o t a S ub je cts 3 3 0 5 10 6 4 Pre - Booster Serum Antitoxin Titer units/nm I. < 0.0 1 0.01 0.03 0. 0.3 1.0+ SERUM TETANUS ANTITOXIN TITERS 4 DAYS AFTER BOOSTER DOSE OF TETANUS TOXOID (0.01 0.01 0.03 0.1, 0.3, 10aover - L * T o t a ISu bj ec t s 8 6 4 8 1 Pre - Booster Serum Antitoxin Titer u n t s/mi. < 0 0 1 0 0 1 0. 03 0. 0. 3.0+ SERUM TETANUS ANTITOXIN TITERS 7 DAYS AFTER BOOSTER DOSE OF TETANUS TOXOID <0 01 0.01 0.03 0 1 00.3 0, 5.0 10.0 aover ~~V~~~i17irn 4 3 9 F13 iu 9 6 4 4 T o t a Subj ects 9 3 3 10 5 9 Pre-Booster S e r u m Antitoxin Titer units/ml. (0.01 0.01 0.03 0.1 0.3 1.0+ SERUM TETANUS ANTITOXIN TITERS 14 DAYS AFTER BOOSTER DOSE OF TETANUS TOXOID <0.01 0.01 0.03I 31,03I 5-0, 30083over 100 = SUB-OPTIMA- PPCTEIVE TIT PS = NC THADsNE FROM PRE-SCESTER T TER Figure sential antill(odv chaingye in most subjects testedl (Figure ).* Only 9 of the 101 perso,is tested at 4 days showed any detectable rise in antibodv titer. ancd 7 ulljects, hiadl ani actual drop in titer. The * For clarity the nulmlber of diluitionis listed in Figure hlas been reduiced, each b)ox inclidin, both serunm5s whose enid poinit titer O(C111 redl at that diluition, aind those with end point titers at the next higher unlisted diliitioii, e._., 0.03 includes both 0.03 anid 0.055. Ibiș,combining occasionally miiasks in the taille a few of the more mll inlol changes cited if] the text. 1 67 c(han-es in antibody titer at 4 davs, wn-hether rise or fall. wvere all of lowv dea-ree. None of the indlividuals showingr a fall at 4 days had an eind point titer moire thain 1 (ilutioi less thani his base line level. The rises at 4 days w-ere also of slirht de-ree wvith oinly subjects showin- a rise of dilutions (a 3-fold rise). There wvas no apparent relationiship between the base line antibody titer and a rise or fall at 4 days. Among persons shown'ing- anv change in either VOL. 5, NO. 10, A.J.P.H.
ANTIBODY RESPONSE TO TETANUS TOXOID direction at 4 days were subjects with all levels of base line antibody titer, from extremely low to very high. Antibody Response Seven Days after Booster Injection After 7 days, 87 per cent (70 of 81) of the subjects tested showed a significant rise in antibody titer. Only 3 persons showed a fall of one dilution in antibody titer at this point. Again there was no correlation between the initial antibody level and the response at 7 days. Of the 8 subjects showing no antibody response at this time, 4 had no detectable antibody whatever, and the remaining 4 had base line levels of 0.1 units or greater. The majority of patients (85 per cent), however, had serum antitoxin titers of 0.1 units per ml, or greater, by 7 days, placing them definitely in the "protected range." Antibody Response 14 Days after Booster Injection Fourteen-day bleedings could be obtained from only 59 of the original group, but all of these had antibody titers of 0.1 units or greater regardless of the base line antibody level. All of these, furthermore, represented a marked increase in antibody titer with a single exception. This one patient had a high antibody titer (0.55 units per ml) at the time of his initial bleeding; this titer persisted unchanged on subsequent determinations, although his hospital chart records the booster dose as given. The Correlation of Clinical Diagnosis with Antibody Response There was no correlation whatever between either rapidity or degree of antibody response and the clinical diagnosis recorded for these study patients. The most frequent clinical diagnosis was cirrhosis, often associated with chronic alcoholism and malnutrition, but these patients showed as rapid and high an antibody response as the total group. Many types of malignant disease were also present in the study group, including malignancies of the lymphopoietic system, but all such patients showed antibody responses equal in degree and rapidity of rise to the total group. There was also no discernible correlation between the clinical diagnosis and an initial fall in antibody titer at either 4 or 7 days. Sex, race, and age also bore no relation to antibody response. Discussion The nearly perfect record of tetanus toxoid in protecting immunized individuals against active disease is one of the most remarkable in preventive medicine. In degree of protection afforded and duration of immunity provided, it is far superior to any other nonliving immunizing agent. Although fewer than 500 cases of tetanus are reported each year in the United States, the occurrence of even one case of a completely preventable disease is excessive. Since tetanus, furthermore, may develop after the most minor and inconspicuous of injuries, a physician treating a patient for any type of trauma must always consider the possibility of the disease and offer some type of prophylaxis against it. Although adequate wound care, including careful debridement, is the most effective measure in preventing tetanus, some patients will still require passive protection with tetanus antitoxin. Since up to half of all persons tested may show sensitivity to the equine and bovine preparations,1 and since human antitoxin is expensive and not readily available, the paradox arises of a preventive measure producing more morbidity than is due to the disease it prevents. There is obviously OCTOBER. 196 1 673
no substitute for active immunization against tetanus and every opportunity to accomplish this should be taken. Immunization with tetanus toxoid should always be started on unimmunized individuals at the time injuries are treated, regardless of whether or not passive immunization with antitoxin is also used to protect the individual at that time. The persistence of significant amounts of antibody in these World War II veterans at least 15 years after their initial immunization series confirms the impression that artificially produced active immunity against tetanus persists for long periods of time. The prompt rise in antibody titer in response to a booster dose of toxoid indicates reliance for protection may.be placed on a booster dose of tetanus toxoid in the case of persons actively immunized up to 15 years previously. In occasional cases in which massive contamination of wounds exist, and in which adequate debridement may be delayed or impossible, it may be deemed advisable to add the protection of antitoxin as well as tetanus toxoid. The excellent antibody response of even the most debilitated and cachectic patients, and those with chronic and terminal illnesses, indicates these conditions do not interfere with adequate antibody response. The practical importance of this information is obvious. Since more than million veterans of military service and a considerable portion of the 66 million children under the age of 0 have received a basic course in tetanus immunization, the hazards of tetanus antitoxin administration can usually be avoided for most members of these groups. It is apparent that a single booster dose of tetanus toxoid provides sufficient antibody response to protect against clinical tetanus (excepting, perhaps, in grossly contaminated wounds) in all individuals immunized up to 15 years previously and probably for longer periods. 1674 Summary Serum tetanus antitoxin levels were determined by a standard mouse protection test on 104 World War II veterans who had been immunized 15 or more years previously during active military service. Careful histories were obtained to eliminate all subjects from the study group who might have received tetanus toxoid since discharge from military service. A standard booster dose of fluid tetanus toxoid was administered and serum drawn at 4, 7, and 14 days for tetanus antibody determinations. Only 8 of the 104 subjects tested had no detectable antibody 15 or more years after immunization; 45 had at least 0.1 units of antitoxin per ml. Eighty-four per cent of the patients tested 4 days after toxoid injection showed no change in titer; the remainder showed slight increases or decreases. Seven days after booster injection 70 of 81 patients (86 per cent) showed a significant rise in antibody level, and all but one of these had titers of 0.1 units per ml or greater. Fourteen days after booster injection 58 of 59 patients tested showed marked increase in titer over base line levels. The one patient showing no increase in antibody titer had a high base line level and it is questioned whether he actually received his booster injection. There was no correlation of either rapidity or degree of antibody response with any of the various clinical diagnoses recorded on these patients. Patients with advanced liver disease and malignancies of the hematopoietic system showed equally good and rapid responses as all other groups of patients. It is considered that except for grossly contaminated wounds, a single booster dose of tetanus toxoid provides ample protection against clinical tetanus for all persons immunized at any time up to 15 years previously, and probably for considerably longer periods. VOL. 5, NO. 10. A.J.P.H.
ANTIBODY RESPONSE TO TETANUS TOXOID ACKNOWLEDGMEN I[S - The authors gratefully acknowledge the generous cooperation of Dr. J. James Smith, chief of the medical service, New York Veterans Administration Hospital, and of all the staff of the medical and surgical services who assisted in this project. Blaine A. Braniff, Robert Bruce McFadden, and Richard M. Sallick of the Cornell University Medical College conscientiously recorded the time-consuming medical histories and obtained all necessary serum specimens. The technical assistance of Mr. Thomas Gilleran in the laboratory is also acknowledged with gratitude. REFERENCES 1. Skudder, P.; McCarroll, J.; Ecker, R.; and Cahow, E. The Incidence of Reactions Following the Administration of Tetanus Antitoxin. J. Trauma 1:41, 1961.. Turner, T.; Stafford, E.; and Goldman, L. Studies on the Duration of Protection Afforded by Active Immunization Against Tetanus. Bull. Johns Hopkins Hosp. 94:04, 1954. 3. Loonery, J.; Edsall, G.; Ipsen, J.; and Chasen, W. Persistence of Antitoxin Levels after Tetanus Toxoid Inoculation in Adults, and Effect of a Booster Dose after Various Intervals. New England J. Med. 54:6 (Jan. 5), 1956. 4. Ruegsegger, J. Further Observations on the Permanence of Tetanus Antitoxin. A.M.A. Arch. Int. Med. 106:410 (Sept.), 1960. Dr. McCarroll is director, Division of Epidemiologic Research, and assistant professor of public health; Dr. Abrahams is assistant professor of microbiology and immunology; and Dr. Skudder is surgeon to the Emergency Unit of New York Hospital-Cornell Medical Center and clinical assistant professor of surgery; Cornell University Medical College, New York, N. Y. This paper was presented before the Epidemiology Section of the American Public Health Association at the Eighty-Ninth Annual Meeting in Detroit, Mich., November 14, 1961. This investigation was supported (in part) by a Public Health Service research grant (E3369) from the National Institute of Allergy and Infectious Disease. Guides Caseworker in Indigent Care "Casework Services in Public Assistance Medical Care" by Sarah A. Butts (chief medical assistance specialist, Division of Medical Care Standards, Bureau of Family Services, Social Security Administration) delineates the crucial area of casework responsibility concerned with enabling public assistance recipients needing medical attention to take full advantage of what is available to them in the way of medical care opportunities in the community. The caseworker's collaboration with physicians, nurses, and agencies is discussed; other topics in this 110-page booklet include under- and overuse of medical care provisions and special patient needs related to such common illnesses as cancer, tuberculosis, heart disease, and arthritis. Should be useful in promoting community efforts to provide continuity of care. Government Printing Office, Washington 5, D. C.; 50 cents. OCTOBER, 196 1675